Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.
Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.
Since their discovery by Victor Grignard
at the turn of the 20th
century, alkylmagnesium halides have become ubiquitous organometallic
reagents, typically serving as carbanion equivalents.[1,2] For example, Grignard reagents readily react with carbonyl moieties
to afford secondary and tertiary alcohols (Scheme a).[3] Grignard
reagents also participate in cross-coupling (XC) reactions, once again
serving as carbanion equivalents (Scheme b).[4,5] Based on the structure
of the Grignard reagent and the electronegativity difference of the
Mg–X bond, it is plausible that Grignard reagents could also
serve as halide nucleophiles. For example, subjecting epoxides to
Grignard reagents can result in the formation of chlorohydrins.[6,7] Recently, in the context of development of a cross-electrophile
coupling (XEC) reaction of mesylates, our laboratory has demonstrated
that, in addition to the anticipated role of reducing the nickel catalyst,
methylmagnesium iodide also serves as a nucleophilic iodide source
(Scheme c).[8]
Scheme 1
Grignard Reagents as Carbanion Equivalents
and Halide Nucleophiles
R1, R3 =
Ar, alkyl; R2 = Ar, alkyl, H.
Grignard Reagents as Carbanion Equivalents
and Halide Nucleophiles
R1, R3 =
Ar, alkyl; R2 = Ar, alkyl, H.Alkyl
halides are versatile reagents in synthetic chemistry, most
commonly employed in the alkylation of enolates and as starting materials
for XC and XEC reactions, as well as the synthesis of Wittig and alkylmetal
reagents.[9−13] Therefore, we sought to develop new halogenation reactions that
start from alkyl alcohols. Numerous methods have been established
to transform alcohols into alkyl halides, in general, by coupling
alcohol activation with a nucleophilic halide source.[14,15] For example, the Appel reaction, which converts alcohols to iodides
with PPh3 and I2, is a robust method employed
by synthetic organic chemists.[16] In this
manuscript, we report a halogenation reaction with methylmagnesium
iodide and bromide for the rapid synthesis of alkyl iodides and bromides
(Scheme d). These
reactions showcase an unusual reactivity mode of Grignard reagents
and are stereospecific and scalable.
Results and Discussion
We began by optimizing the iodination
reaction of alkyl mesylates
utilizing mesylate 1 as a model substrate (Table ). This secondary mesylate was
chosen due to the low volatility of the corresponding iodide, allowing
for the ease of isolation and analysis of conversion. By performing
the iodination reaction with MeMgI at room temperature for 1 h,[8] iodide 2 was observed in an 81%
yield (entry 1). Excitingly, this reaction demonstrates minimal amounts
of elimination products. In an effort to minimize the formation of
alkenes, we performed the reaction at 0 °C and observed decreased
yields of alkenes 3 with no effect on the yield of iodide 2 (entry 2). In an attempt to further reduce the formation
of the elimination products, the reaction temperature was lowered
to −78 °C. Although we observed a decreased formation
of the elimination products, the conversion of mesylate 1 also decreased (entry 3). However, the yield of iodide 2 was not affected, which would prove useful for substrates with functional
groups that are sensitive to Grignard reagents (vide infra). We hypothesized
that at 0 °C, shortening the reaction time to 5 min could potentially
minimize the formation of elimination products while maintaining the
high conversion of mesylate. We were pleased to see that this afforded
iodide 2 in a 94% yield with a minimal amount of the
elimination product 3 (entry 4). While freshly prepared
MeMgI provided the highest rates, employing commercially available
MeMgI also provided good results (entries 5 and 6).
Table 1
Optimization of Iodination Reactiona
entry
temp. (°C)
time
yield 2 (%)b
yield 3 (%)b
RSM 1 (%)b
1
25
1 h
81
13
<5
2
0
1 h
84
8
<5
3
–78
1 h
81
5
11
4
0
5 m
92 (94)c
5(5)c
<5
Using
Commercial MeMgI:
5
0
5 m
75
6
11
6
0
1 h
80 (78)c
7(7)c
5
Using MgI2Instead of MeMgI:
7
25
5 m
27
<5
69
8d
25
5 m
69
6
20
9d
0
5 m
6
<1
81
Using PhMgI
10e
0
5 m
54c
24c
<1
R = (p-MeO)C6H4.
Determined
by 1H NMR
based on comparison to PhTMS as an internal standard.
Isolated yield.
30 μL of Et2O added.
Ph-substituted product was isolated
in a 14% yield.
R = (p-MeO)C6H4.Determined
by 1H NMR
based on comparison to PhTMS as an internal standard.Isolated yield.30 μL of Et2O added.Ph-substituted product was isolated
in a 14% yield.We set out to distinguish whether the Grignard reagent
itself,
or MgI2, formed in situ via competitive Wurtz coupling
during Grignard formation and the Schlenk equilibrium, serves as the
iodide source for this reaction.[15,17,18] To investigate the source of iodide, we subjected
mesylate 1 to reactions with MgI2. We observed
a decrease in yield compared to the standard reaction conditions employing
the Grignard reagent (c.f. entries 4 and 7). Because the Grignard
reagent is prepared in Et2O, and the low solubility of
MgI2 in PhMe could account for the lower conversion of
mesylate 1 to iodide 2 in entry 7, we performed
the reaction with the addition of 30 μL of Et2O.[19] Addition of Et2O did indeed increase
the yield of iodide 2 (entry 8); however, the rate remained
significantly slower than when MeMeI was employed. At 0 °C, the
reaction with MgI2 and Et2O only afforded the
desired iodide 2 in a 6% yield, with 81% of mesylate 1 observed (entry 9); in comparison, at the same temperature
and reaction times, reactions employing the commercial and freshly
prepared Grignard reagent provided 75% and 92% yields, respectively
(entries 4 and 5). These results are consistent with a faster iodination
reaction when MeMgI is used.[20] We investigated
if other Grignard reagents could be employed in the reaction to afford
the alkyl iodide product from mesylate 1. Employing PhMgI
instead of MeMgI resulted in a decrease in yield, with increased elimination
and SN2 substitution (entry 10).With optimized reaction
conditions in hand, we evaluated the functional
group compatibility of the iodination reaction (Scheme a). Both secondary and primary alkyl mesylates
provided the corresponding alkyl iodides 4–6 in excellent yields. As one would predict from an SN2 mechanism, when a substrate bearing both an aryl mesylate
and alkyl mesylate was subjected to the standard reaction conditions,
iodination occurred at the alkyl mesylate to afford iodide 7. Next, we explored functional groups that are typically sensitive
to nucleophilic Grignard reagents. Both a dibenzylated amine and an
ester provided the desired iodides 8 and 9, respectively, when modified reaction conditions were utilized.
Finally, the terpenol (R)-nopol cleanly underwent
the iodination reaction to afford 10 in an 81% yield,
comparing favorably to literature methods for the preparation of this
compound.[21]
Scheme 2
Iodination Reaction
of Mesylates and One-Pot Reaction of Alcohols
to Form Alkyl Iodides
1 h iodination reaction. b30 min iodination reaction. cEmploying commercial
MeMgI for 1 h. d5.0 equiv MeMgI. e–78
°C iodination reaction for 3 h. f5 min mesylation. g1.0 equiv MsCl, 1.0 equiv Et3N, 1.0 equiv MeMgI. h3.0 equiv MeMgI. i1 mmol scale. j2.5
equiv MsCl, 2.5 equiv Et3N, 5 min mesylation, 2.5 equiv
MeMgI, reaction followed by 1.0 equiv MeMgCl at rt for 1 h. k30. mmol (4.6 g) scale. l6 h mesylation, 2.5 equiv MeMgI,
2 h iodination reaction. m4 h iodination reaction. n–78 °C iodination reaction. o0.4 mmol
scale.
Iodination Reaction
of Mesylates and One-Pot Reaction of Alcohols
to Form Alkyl Iodides
1 h iodination reaction. b30 min iodination reaction. cEmploying commercial
MeMgI for 1 h. d5.0 equiv MeMgI. e–78
°C iodination reaction for 3 h. f5 min mesylation. g1.0 equiv MsCl, 1.0 equiv Et3N, 1.0 equiv MeMgI. h3.0 equiv MeMgI. i1 mmol scale. j2.5
equiv MsCl, 2.5 equiv Et3N, 5 min mesylation, 2.5 equiv
MeMgI, reaction followed by 1.0 equiv MeMgCl at rt for 1 h. k30. mmol (4.6 g) scale. l6 h mesylation, 2.5 equiv MeMgI,
2 h iodination reaction. m4 h iodination reaction. n–78 °C iodination reaction. o0.4 mmol
scale.Next, we envisioned a one-pot protocol
where the alcohol could
be directly transformed into the iodide by in situ mesylation followed
by iodination with MeMgI (Scheme b).[22] A variety of secondary
and primary alcohols underwent the one-pot reaction to give corresponding
iodides in very good yields. We were pleased to observe that electron-donating
groups (6, 11–12, 14–16), an electron-withdrawing group (13), and heteroaryl
groups (17–18) were tolerated to provide the desired
alkyl iodides in great yields. Excitingly, we observed that common
protecting groups—silyl ether, benzyl ether, acetal, and carbamate
—were also tolerated in the one-pot reaction (14, 19–21). We observed that 2-(4-hydroxyphenyl)
ethanol provided the phenol-substituted alkyl iodide 15 in an 85% yield, via mesylation, iodination, and in situ deprotection
of the phenol.[23] Next, we investigated
a benzylic alcohol substrate and observed the desired iodide 22 in moderate yields with a small amount of benzylic chloride
as a byproduct. We anticipate that this benzylic chloride forms under
the mesylation reaction conditions.[24] Tertiary
alcohols proved difficult for this reaction, resulting in the formation
of high yields of elimination products; however, under the one-pot
reaction conditions, iodide 23 could be obtained from
1-adamantanol in a 59% yield with a minor amount of alkyl chloride.
Another terpenol, citronellol, was subjected to the one-pot iodination
reaction to yield iodide 24 in moderate yield. Additionally,
we evaluated a series of substrates bearing functional groups that
are known to be sensitive to Grignard reagents. For a substrate bearing
a phthalimide, under the standard conditions at 0 °C, the Grignard
reagent reacted with both phthalimide and alkyl mesylate functionalities
to afford 25. We were pleased to see that at −78
°C, selectivity slightly favored the reaction of the alkyl mesylate
to afford 26, which could be separated from undesired 25 and mesylate that were each observed in a <20% yield.
Even more encouraging, an ester-containing substrate underwent the
one-pot mesylation and iodination reaction at low temperature to provide 9 in a 73% yield. Finally, derivatives of lithocholic acid
containing a secondary silyl ether, a secondary chloride, and a pendant
ester all provided the desired product in good yields (27–29). In comparison to literature methods reported
for the synthesis of the 23 known iodides in Scheme , the majority (15) of these reactions provided
similar yields (within ∼10%) to those previously reported.
Therefore, this reaction provides a new set of conditions for the
formation of alkyl iodides, with the advantage that the reactions
are rapid at low temperatures.With the success of the iodination
reaction, we aimed to synthesize
alkyl bromides through similar two-step and one-pot procedures (Scheme ).[25] We were pleased to see that employing MeMgBr in place of
MeMgI afforded the desired alkyl bromides. Both secondary and primary
bromides with pendant aryl substituents (30–31, 33–34) were synthesized in great yields. Similar
to the iodination reaction, silyl ether and acetal protecting groups
were tolerated in the reaction (34–35). An alkyl bromide (32) derived from chiral terpenol
(R)-nopol was obtained in a 75% yield. A lithocholic
acid derivative with a secondary alkyl chloride was also well tolerated
to afford 37 in this one-pot reaction. Finally, an ester-containing
lithocholic acid derivative provided secondary bromide 38 in moderate yield.
Scheme 3
Bromination Reaction of Mesylates and One-Pot
Reaction of Alcohols
to Form Alkyl Bromides
0 °C bromination
reaction.
4.0 equiv MeMgBr.
30 min mesylation, 2.0 equiv
MeMgBr,
2 h bromination reaction at 0 °C.
Bromination Reaction of Mesylates and One-Pot
Reaction of Alcohols
to Form Alkyl Bromides
0 °C bromination
reaction.4.0 equiv MeMgBr.30 min mesylation, 2.0 equiv
MeMgBr,
2 h bromination reaction at 0 °C.Next,
we turned our attention to the stereochemical outcome of
the halogenation reaction. We hypothesized that a stereospecific SN2 reaction was operative and would proceed cleanly with inversion.
To confirm this hypothesis, we prepared enantioenriched alcohol 39 via a lipase-catalyzed kinetic resolution[26] and subjected it to the one-pot mesylation and iodination
reaction (Scheme a).
The reaction afforded enantioenriched alkyl iodide 5 in
greater than 99% ee. To determine the stereochemical course of the
reaction, we synthesized diastereomeric aryl-substituted 4-hydroxy
tetrahydropyrans and investigated the outcome of the halogenation
reaction. We subjected both cis- and trans-substituted tetrahydropyrans 40 to the bromination
reaction (Scheme b).
We observed that cis-40 afforded trans-41, and similarly trans-40 provided cis-41, both
in >20:1 dr. These results demonstrated that the halogenation reaction
proceeds with inversion. These results also corroborated that the
substitution occurs with high stereochemical fidelity. Finally, we
investigated the scalability of the reaction (Scheme c). When we performed the one-pot mesylation
and iodination reaction of (R)-nopol on a two-gram
scale, the desired alkyl iodide 10 was afforded in a
92% yield. Therefore, this reaction provides a reliable method for
the preparative-scale synthesis of alkyl iodides and bromides.
Scheme 4
Stereospecificity and Scalability
Conclusions
In summary, we have developed a halogenation
reaction to transform
alkyl alcohols into alkyl iodides and bromides that employs Grignard
reagents as nucleophilic halide sources. The reaction is compatible
with substrates containing various functional groups, including some
that are typically sensitive to Grignard reagents. Through various
stereochemical experiments, we have demonstrated that the halogenation
reaction occurs through a stereospecific SN2 reaction,
proceeding with inversion. This reaction was also effective on the
gram scale, which supports its synthetic utility. Most importantly,
this work clearly establishes that methyl Grignard reagents can act
as halide nucleophiles as well as carbanion equivalents.
Experimental Section
General Procedures
All reactions were carried out under
an atmosphere of N2 when noted. All glassware was oven-
or flame-dried prior to use. Tetrahydrofuran (THF), diethyl ether
(Et2O), dichloromethane (DCM), dimethylformamide (DMF),
and toluene (PhMe) were degassed with Ar and then passed through two
4 × 36 inch columns of anhydrous neutral A-2 alumina (8 ×
14 mesh; LaRoche Chemicals; activated under a flow of argon at 350
°C for 12 h) to remove H2O.[27] All other solvents utilized were purchased “anhydrous”
commercially or purified as described. 1H NMR spectra were
recorded on Bruker DRX-400 (400 MHz 1H, 100 MHz 13C, 376.5 MHz 19F), CRYO-500 (500 MHz 1H, 125.8
MHz 13C), or AVANCE-600 (600 MHz 1H, 150 MHz 13C, 564.7 MHz 19F) spectrometers. Proton chemical
shifts are reported in ppm (δ) relative to internal tetramethylsilane
(TMS, δ 0.00). Data is reported as follows: chemical shift (multiplicity
[singlet (s), broad singlet (br s), doublet (d), doublet of doublets
(dd), doublet of doublet of doublets (ddd), doublet of doublet of
doublet of doublets (dddd), triplet of doublets (td), doublet of triplet
of doublets (dtd), quartet of doublets (qd), triplet (t), doublet
of triplets (dt), doublet of doublet of triplets (ddt), triplet of
triplets (tt), quartet (q), triplet of quartets (tq), quintet (quint),
sextet (sext), apparent singlet (as), apparent doublet (ad), apparent
triplet (at), apparent quartet (aq), apparent quintet (aquint), apparent
septet (asept), multiplet (m)], coupling constants [Hz], integration).
Carbon chemical shifts are reported in ppm (δ) relative to TMS
with the respective solvent resonance as the internal standard (CDCl3, δ 77.16 ppm). Fluorine chemical shifts are reported
in ppm (δ) relative to the absolute frequency of 0.00 ppm in
the proton spectrum. NMR data were collected at 25 °C. Structural
assignments were made with additional information from gCOSY experiments.
Infrared (IR) spectra were obtained on a Thermo Scientific Nicolet
iS5 spectrometer with an iD5 ATR tip (neat) and are reported in terms
of the frequency of absorption (cm–1). Analytical
thin-layer chromatography (TLC) was performed using Silica Gel 60
F254 precoated plates (0.25 mm thickness). Visualization was accomplished
by irradiation with a UV lamp and/or staining with cerium ammonium
molybdate (CAM), phosphomolybdic acid (PMA), or potassium permanganate
(KMnO4) solutions. Flash chromatography was performed using
a SiliaFlash P60 (40–63 μm, 60 Å) from SiliCycle.
Melting points (m.p.) were obtained using a MelTemp melting point
apparatus and are uncorrected. Optical rotations were measured on
a Rudolph Research Analytical Autopol III Automatic Polarimeter. SFC
determinations of enantiopurity were determined by chiral SFC analysis
and performed on Agilent Technologies HPLC (1260 series) system AD
Chiralpak columns (100 bar, 50 °C, 254 nm). High-resolution mass
spectrometry was performed by the University of California, Irvine
Mass Spectrometry Center.
Reagents
Methylmagnesium iodide was titrated with iodine
prior to use.[28] All other chemicals were
purchased commercially and used as received unless otherwise noted.
General Procedures for the Synthesis of Iodides and Bromides
Method A: Mesylation
A flame-dried round-bottom flask
equipped with a stir bar was charged with alcohol (1.0 equiv) and
DCM (0.20 M in alcohol) under N2. Et3N (1.5
equiv) and DMAP (0–0.2 equiv) were added, and the reaction
mixture was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was
added, and the reaction mixture was allowed to stir at rt for 1–16
h. Once complete by TLC, sat. NaHCO3 (5 mL) was added,
and the reaction mixture was extracted with DCM (3 × 10 mL).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo.
Preparation of MeMgI
Under a N2 atmosphere,
a three-neck round-bottom flask equipped with a stir bar, a reflux
condenser, and a Schlenk filtration apparatus was charged with magnesium
turnings (4.3 g, 180 mmol, 1.5 equiv). The flask and magnesium turnings
were placed under vacuum and flame-dried and then back-filled with
N2. A crystal of iodine (ca. 2 mg) was added to the flask,
followed by anhydrous Et2O (30 mL). Freshly distilled iodomethane
(7.5 mL, 120 mmol, 1.0 equiv) was added dropwise until the reaction
initiated, and then the reaction mixture was cooled to 0 °C and
the remaining iodomethane was added slowly over 30 min to maintain
a gentle reflux. The mixture was stirred for 2 h at rt and then filtered
through the fritted Schlenk filter into a pear-shaped flask under
a N2 atmosphere. The pear-shaped flask was capped with
a septum, sealed with parafilm, and stored either in the glovebox
under a N2 atmosphere for up to 8 weeks or in a −20
°C freezer for up to 4 weeks. The resulting methyl Grignard reagent
was typically between 2.9 and 3.1 M, as titrated by Knochel’s
method.[28]
Method B: Iodination Reaction of Mesylates
Under a
N2 atmosphere, a flame-dried round-bottom flask equipped
with a stir bar was charged with mesylate substrate (1.0 equiv) and
PhMe (0.10 M in mesylate). The reaction mixture was cooled to 0 °C,
and then MeMgI (1.0 equiv, 2.4–3.2 M in Et2O) was
added dropwise. The reaction mixture was allowed to stir for 5 min.
If commercial MeMgI was employed, then the reaction mixture was allowed
to stir for 1 h instead. The reaction mixture was warmed to rt for
5 min. MeOH was added dropwise to quench the reaction, and then the
mixture was filtered through a plug of silica gel eluting with Et2O and concentrated in vacuo. The reaction mixture was purified
by column chromatography. For the optimization reactions, phenyltrimethylsilane
(PhTMS; 8.6 μL, 50 μmol) was added before purification
and the yield was determined by 1H NMR based on comparison
to PhTMS as the internal standard.
Method C: One-Pot Reaction of Alcohols to Form Iodides
A flame-dried round-bottom flask equipped with a stir bar was charged
with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N2. Et3N (1.5 equiv) was added, and the reaction mixture
was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and
the reaction mixture was allowed to stir at rt for 1 h. PhMe (0.20
M in alcohol) was added, the reaction mixture was cooled to 0 °C,
and then MeMgI (2.0 equiv, 2.4–3.2 M in Et2O) was
added dropwise. The reaction mixture was allowed to stir at 0 °C
for 5 min. If commercial MeMgI was employed, the reaction mixture
was allowed to stir for 1 h. Then, the reaction mixture was warmed
to rt for 5 min. MeOH was added dropwise to quench the reaction, and
then the mixture was filtered through a plug of silica gel eluting
with Et2O and concentrated in vacuo. The reaction mixture
was purified by column chromatography. If the reaction scale was 0.40
mmol or greater, then an extraction workup was carried out, instead
of the silica gel plug, as follows. After warming up the reaction
for 5 min, sat. aqueous NH4Cl was added dropwise. The layers
were separated, and then the aqueous layer was extracted with DCM
(×3). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. For the optimization reactions,
phenyltrimethylsilane (PhTMS; 8.6 μL, 50. μmol) was added
before purification and the yield was determined by 1H
NMR based on comparison to PhTMS as the internal standard.
Method D: Bromination Reaction of Mesylates
Under a
N2 atmosphere, a flame-dried round-bottom flask equipped
with a stir bar was charged with mesylate substrate (1.0 equiv) and
PhMe (0.10 M in mesylate). Then, commercial MeMgBr (2.0 equiv, 2.7–3.0
M in Et2O) was added dropwise, and the reaction mixture
was allowed to stir at rt for 1 h. MeOH was added dropwise to quench
the reaction, and then the mixture was filtered through a plug of
silica gel eluting with Et2O and concentrated in vacuo.
The reaction mixture was purified by column chromatography. For the
optimization reactions, phenyltrimethylsilane (PhTMS; 8.6 μL,
50. μmol) was added before purification, and the yield was determined
by 1H NMR based on comparison to PhTMS as the internal
standard.
Method E: One-Pot Reaction of Alcohols to Form Bromides
A flame-dried round-bottom flask equipped with a stir bar was charged
with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N2. Et3N (1.5 equiv) was added, and the reaction mixture
was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and
the reaction mixture was allowed to stir at rt for 1 h. PhMe (0.20
M in alcohol) was added, and then commercial MeMgBr (3.0 equiv, 2.7–3.0
M in Et2O) was added dropwise. The reaction mixture was
allowed to stir for 1 h at rt. MeOH was added dropwise to quench the
reaction, and then the mixture was filtered through a plug of silica
gel eluting with Et2O and concentrated in vacuo. The reaction
mixture was purified by column chromatography.
Characterization Data for Alcohols, Mesylates, Iodides, and
Bromides
Alcohol 42 was prepared according to the
following
procedure. A flame-dried round-bottom flask with a stir bar was charged
with Grignard SI-3 (5.3 mL, 8.3 mmol, 1.1 equiv, 1.6
M in Et2O) and cooled to 0 °C. A solution of aldehyde SI-2 (1.2 g, 7.5 mmol, 1.0 equiv) in anhydrous THF (38 mL,
0.20 M in substrate) was added dropwise. The reaction mixture was
allowed to stir at rt for at least 2 h. The reaction was quenched
with sat. aqueous NH4Cl (10 mL), and the mixture was extracted
with Et2O (3 × 20 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography
(0–25% EtOAc/hexanes) to afford the title compound as a white
solid (1.5 g, 5.4 mmol, 72% yield). m.p. 77–78
°C; TLC R = 0.5 (25% EtOAc/hexanes,
CAM stain); H NMR (400 MHz,
CDCl3) δ 7.31–7.26 (m, 2H), 7.26–7.16
(m, 3H), 7.10 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H), 3.66 (m, 1H), 2.83–2.57
(m, 4H), 1.88–1.69 (m, 4H), 1.34 (d, J = 5.2
Hz, 1H). Analytical data is consistent with literature values.[29]Mesylate 1 was prepared according to
Method A. The following amounts of reagents were used: alcohol 42 (0.27 g, 1.0 mmol, 1.0 equiv), MsCl (0.12 mL, 1.5 mmol,
1.5 equiv), triethylamine (0.21 mL, 1.5 mmol, 1.5 equiv), and DCM
(5.0 mL, 0.20 M in substrate). The reaction mixture was allowed to
stir overnight. The residue was purified by column chromatography
(0–25% EtOAc/hexanes) to afford the title compound as a colorless
oil (0.32 g, 0.93 mmol, 93% yield). TLC R = 0.6 (25% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.4 Hz, 2H), 7.23–7.15 (m, 3H), 7.09 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H),
4.80 (quint, J = 6.0 Hz, 1H), 3.78 (s, 3H), 2.98
(s, 3H), 2.81–2.60 (m, 4H), 2.15–1.95 (m, 4H); C{H} NMR (125.8 MHz, CDCl3) δ 158.1, 140.9,
132.8, 129.4 (2C), 128.7 (2C), 128.4 (2C), 126.3, 114.0 (2C), 82.6,
33.4, 38.8, 36.5, 36.3, 31.3, 30.4; IR (neat) 2935, 1611,
1512, 1330, 1244, 1169, 1033, 897, 700 cm–1; HRMS (TOF MS ES+) m/z: [M
+ Na]+ calcd for C19H24O4SNa, 371.1293; found, 371.1276.
From Mesylate
Iodide 2 was prepared according
to Method B. The following amounts of reagents were used: mesylate 1 (33 mg, 94 μmol, 1.0 equiv), MeMgI (32 μL, 94
μmol, 1.0 equiv, 2.9 M in Et2O), and PhMe (0.94 mL,
0.10 M in substrate). The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a yellow
oil (33 mg, 88 μmol, 94% yield) containing alkenes 3 (1 mg, 5 μmol, 5% yield). Refer to iodide 2 below
for analytical data.
From Alcohol
Iodide 2 was prepared according
to Method C. The following amounts of reagents were used: alcohol 42 (30. mg, 0.11 mmol, 1.0 equiv), MsCl (13 μL, 0.17
mmol, 1.5 equiv), Et3N (23 μL, 0.17 mmol, 1.5 equiv),
DCM (0.55 mL, 0.20 M in substrate), MeMgI (76 μL, 0.22 mmol,
2.0 equiv, 2.9 M in Et2O), and PhMe (0.55 mL, 0.20 M in
substrate). The residue was purified by column chromatography (0–5%
EtOAc/hexanes) to afford the title compound as a yellow oil (38 mg,
0.10 mmol, 91% yield) containing alkene 3 (2 mg, 7 μmol,
6% yield). To remove the alkenes, a modified Sharpless asymmetric
dihydroxylation was performed.[30] To a flame-dried
20 mL vial was added AD-mix-β (0.15 g, 1.4 g/mmol). Then, t-BuOH
(1.0 mL) and H2O (1.0 mL) were added via a syringe and
the vial was capped. The vial was cooled to 0 °C, and then the
mixture of iodide 2 and alkenes 3 was added
dropwise as a solution in t-BuOH (1.0 mL) and H2O (1.0
mL) via a syringe. The mixture was allowed to stir at 0 °C for
24 h. To quench, Na2SO3 (30. mg) was added and
the mixture was allowed to warm to rt and stir for 30 min. Then, the
mixture was transferred to a separatory funnel, and the organic layer
was extracted with EtOAc (×3). The combined organic layers were
washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a yellow
oil (33 mg, 86 μmol, 78% yield over two steps). TLC R = 0.4 (5% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.4 Hz, 2H), 7.22–7.14
(m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.00 (asept, J = 4.5 Hz,
1H), 3.77 (s, 3H), 2.84 (dddd, J = 23.3, 14.0, 9.3,
4.5 Hz, 2H), 2.67 (dddd, J = 20.6, 14.0, 9.0, 7.0
Hz, 2H), 2.18 (dtd, J = 23.5, 9.1, 5.2 Hz, 2H), 2.05–1.90
(m, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 158.1,
140.9, 132.9, 129.5 (2C), 128.60 (2C), 128.57 (2C), 126.2, 114.0 (2C),
55.3, 42.6, 42.4, 38.3, 35.7, 34.7; IR (neat) 2922, 1611,
1511, 1453, 1245, 1177, 1036, 825, 747, 699 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C18H21IO, 380.0637;
found, 380.0627.Bromide 30 was prepared
according to Method D. The following amounts of reagents were used:
mesylate 1 (35 mg, 0.10 mmol, 1.0 equiv), MeMgBr (67
μL, 0.20 mmol, 2.0 equiv, 3.0 M in Et2O), and PhMe
(1.0 mL, 0.10 M in substrate). The residue was purified by column
chromatography (0–5% EtOAc/hexanes) to afford the title compound
as a pale-yellow oil (28 mg, 84 μmol, 84% yield) containing
alkenes 3 (2.3 mg, 9.1 μmol, 9.0% yield). To remove
the alkenes, a modified Sharpless asymmetric dihydroxylation was performed.[30] To a flame-dried 20 mL vial was added AD-mix-β
(0.14 g, 1.4 g/mmol). Then, t-BuOH (1.0 mL) and H2O (1.0 mL) were added via a syringe and the vial was capped.
The vial was cooled to 0 °C, and then the mixture of bromide 30 and alkenes 3 was added dropwise as a solution
in t-BuOH (1.0 mL) and H2O (1.0 mL) via
a syringe. The mixture was allowed to stir at 0 °C for 24 h.
To quench, Na2SO3 (30. mg) was added and the
mixture was allowed to warm to rt and stir for 30 min. Then, the mixture
was transferred to a separatory funnel, and the organic layer was
extracted with EtOAc (×3). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a yellow
oil (29 mg, 87 μmol, 87% yield over two steps). TLC R = 0.3 (5% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.5 Hz, 2H), 7.21–7.13
(m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.94 (asept, J = 4.4 Hz,
1H), 3.78 (s, 3H), 2.85 (dddd, J = 30.2, 14.0, 9.0,
5.1 Hz, 2H), 2.76–2.63 (m, 2H), 2.20–2.00 (m, 4H); C{H} NMR (125.8 MHz, CDCl3) δ 158.0, 141.1,
133.0, 129.5 (2C), 128.59 (2C), 128.56 (2C), 126.2, 114.0 (2C), 56.8,
55.3, 41.2, 41.0, 33.8, 32.9; IR (neat) 2927, 1611, 1512,
1454, 1246, 1177, 1036, 825, 748, 700 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C18H21BrO, 332.0776; found,
332.0767.Bromide 30 was prepared according
to Method E. The following amounts of reagents were used: alcohol 42 (27 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15
mmol, 1.5 equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv),
DCM (0.50 mL, 0.20 M in substrate), MeMgBr (0.11 mL, 0.30 mmol, 3.0
equiv, 2.7 M in Et2O), and PhMe (0.50 mL, 0.20 M in substrate).
The residue was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a pale-yellow oil (31 mg, 81 μmol,
81% yield) containing alkene 3 (2.8 mg, 11 μmol,
11% yield). Refer to bromide 30 above for analytical
data.Alcohol 43 was prepared according to
the following procedure. Open to air, a round-bottom flask with a
stir bar was charged with 4-phenyl-2-butanone (0.75 mL, 5.0 mmol,
1.0 equiv), NaBH4 (0.38 g, 10. mmol, 2.0 equiv), and MeOH
(25 mL, 0.20 M in substrate). The reaction mixture was stirred for
2 h. After completion, the reaction mixture was concentrated in vacuo
and then dissolved in DCM. H2O was added, and the aqueous
layer was extracted with DCM. The combined organic layers were dried
and concentrated in vacuo. The residue was purified by flash column
chromatography (20% EtOAc/hexanes) to afford the title compound as
a colorless oil (710 mg, 4.8 mmol, 95%). TLC R = 0.5 (25% EtOAc/hexanes, KMnO4 stain); H NMR (400 MHz, CDCl3) δ 7.30–7.27 (m, 2H), 7.21–7.17 (m, 3H), 3.85–3.81
(m, 1H), 2.80–2.64 (m, 2H), 1.81–1.74 (m, 2H), 1.32
(br s, 1H), 1.23 (d, J = 6.2 Hz, 3H). Analytical
data is consistent with literature values.[31]Mesylate 44 was prepared according to
Method A. The
following amounts of reagents were used: alcohol 43 (300
mg, 2.0 mmol, 1.0 equiv), MsCl (0.23 mL, 3.0 mmol, 1.5 equiv), Et3N (0.42 mL, 3.0 mmol, 1.5 equiv), DMAP (24 mg, 0.20 mmol,
0.10 equiv), and DCM (10. mL, 0.20 M in substrate). The reaction mixture
was allowed to stir overnight. The residue was purified by flash column
chromatography (0–20% EtOAc/hexanes) to afford the title compound
as a pale-yellow oil (420 mg, 1.8 mmol, 92%). TLC R = 0.4 (20% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ
7.27–7.23 (m, 2H), 7.17–7.14 (m, 3H), 4.76 (tq, J = 6.4, 6.1 Hz, 1H), 2.88 (s, 3H), 2.75–2.60 (m,
2H), 2.03–1.94 (m, 1H), 1.90–1.81 (m, 1H), 1.39 (d, J = 6.3 Hz, 3H); C{H} NMR (100 MHz, CDCl3) δ 140.6, 128.3 (2C), 128.1 (2C), 125.9, 79.3, 38.2, 37.9,
31.1, 20.9; HRMS (TOF MS ES+) m/z: [M + Na]+ calculated for C11H16O3SNa, 251.0718, found 251.0724. Analytical data
is consistent with literature values.[32]Iodide 4 was prepared according
to a modified Method B. The following amounts of reagents were used:
mesylate 44 (29 mg, 0.13 mmol, 1.0 equiv), MeMgI (44
μL, 0.13 mmol, 1.0 equiv, 2.9 M in Et2O), and PhMe
(1.3 mL, 0.10 M in substrate). The reaction mixture was allowed to
stir at 0 °C for 1 h. The residue was purified by flash column
chromatography (0–10% Et2O/hexanes, CAM stain) to
afford the title compound as a colorless oil (30. mg, 0.12 mmol, 90%). TLC R = 0.7 (5% EtOAc/hexanes, CAM
stain); H NMR (400 MHz, CDCl3) δ 7.30–7.24 (m, 2H), 7.21–7.18 (m, 3H),
4.15–4.07 (m, 1H), 2.88–2.81 (m, 1H), 2.73–2.65
(m, 1H), 2.19–2.10 (m, 1H), 1.94 (d, J = 6.8
Hz, 3H), 1.92–1.83 (m, 1H). Analytical data is consistent with
literature values.[33]Iodide 4 was prepared according
to a modified Method C. The following amounts of reagents were used:
alcohol 43 (18 mg, 0.12 mmol, 1.0 equiv), MsCl (14 μL,
0.18 mmol, 1.5 equiv), Et3N (26 μL, 0.18 mmol, 1.5
equiv), DCM (0.62 mL, 0.20 M in substrate), followed by MeMgI (84
μL, 0.25 mmol, 2.0 equiv, 2.9 M in Et2O) and PhMe
(0.62 mL, 0.20 M in substrate). Upon the addition of MeMgI, the reaction
mixture was allowed to stir at 0 °C for 1 h. The residue was
purified by flash column chromatography (0–10% Et2O/hexanes) to afford the title compound as a colorless oil (29 mg,
0.11 mmol, 91%). Refer to iodide 4 above for analytical
data.Alcohol 39 was prepared according to
the following procedure. A flame-dried round-bottom flask with a stir
bar was charged with aldehyde SI-4 (0.78 g, 4.4 mmol,
1.0 equiv) and anhydrous THF (25 mL, 0.20 M in substrate) and cooled
to 0 °C. Then, MeMgCl (2.2 mL, 6.6 mmol, 1.5 equiv) was added
dropwise. The reaction mixture was allowed to stir at rt overnight.
The reaction was quenched with sat. aqueous NH4Cl (10 mL),
and the mixture was extracted with Et2O (3 ×20 mL).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (0–30% EtOAc/hexanes)
to afford the title compound as a pale-yellow oil (0.81 g, 4.2 mmol,
95%). TLC R = 0.4 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H),
6.65 (d, J = 7.9 Hz, 1H), 5.91 (s, 2H), 3.81 (br
s, 1H), 2.71–2.56 (m, 2H), 1.75–1.69 (m, 2H), 1.32 (br
s, 1H), 1.22 (d, J = 6.2 Hz, 3H); SFC analysis (Chiralcel AD, 1% IPA, 2.0 mL/min, 230 nm) indicated 0% ee: tR (minor enantiomer) = 37.0 min, tR (major enantiomer)
= 39.5 min. Analytical data is consistent with literature values.[34]Mesylate 45 was prepared according to
Method A. The
following amounts of reagents were used: alcohol 39 (0.14
g, 0.70 mmol, 1.0 equiv), MsCl (80. μL, 1.1 mmol, 1.5 equiv),
Et3N (0.15 mL, 1.1 mmol, 1.5 equiv), and DCM (3.5 mL, 0.20
M in substrate). The reaction mixture was allowed to stir overnight.
The residue was purified by flash column chromatography (0–30%
EtOAc/hexanes) to afford the title compound as a pale-yellow oil (0.18
g, 0.67 mmol, 96%). TLC R =
0.4 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 6.71 (d, J =
7.8 Hz, 1H), 6.67 (s, 1H), 6.63 (d, J = 7.8 Hz, 1H),
5.89 (s, 2H), 4.83–4.77 (m, 1H), 2.98 (s, 3H), 2.69–2.56
(m, 2H), 2.02–1.94 (m, 1H), 1.90–1.83 (m, 1H), 1.43
(d, J = 6.2 Hz, 3H); C{H} NMR (100 MHz, CDCl3) δ 147.6, 145.8, 134.5, 121.0, 108.7, 108.2, 100.8,
79.3, 38.6, 38.5, 31.0, 21.1; HRMS (TOF MS ES+) m/z: [M + Na]+ calculated for
C12H16O5SNa 295.0616, found 295.0605.
Analytical data is consistent with literature values.[32]Iodide 5 was prepared according
to a modified Method B. The following amounts of reagents were used:
mesylate 45 (20. mg, 73 μmol, 1.0 equiv), MeMgI
(25 μL, 0.10 mmol, 1.0 equiv, 2.9 M in Et2O), and
PhMe (0.73 mL, 0.10 M in substrate). The reaction mixture was allowed
to stir at 0 °C for 30 min. The residue was purified by flash
column chromatography (0–10% Et2O/hexanes) to afford
the title compound as a pale-yellow oil (19 mg, 63 μmol, 87%). TLC R = 0.5 (10% EtOAc/hexanes); H NMR (600 MHz, CDCl3) δ 6.73 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H),
6.66 (d, J = 7.9 Hz, 1H), 5.92 (s, 2H), 4.12–4.06
(m, 1H), 2.78–2.73 (m, 1H), 2.64–2.59 (m, 1H), 2.13–2.07
(m, 1H), 1.94 (d, J = 6.8 Hz, 3H), 1.85–1.79
(m, 1H); SFC analysis (Chiralcel AD, 1% IPA, 2.0 mL/min,
230 nm) indicated 0% ee: tR (major enantiomer) = 8.5 min,
tR (minor enantiomer) = 9.4 min. Analytical data is consistent
with literature values.[35]Iodide 5 was prepared according
to a modified Method C. The following amounts of reagents were used:
alcohol 39 (22 mg, 0.11 mmol, 1.0 equiv), MsCl (13 μL,
0.17 mmol, 1.5 equiv), Et3N (23 μL, 0.17 mmol, 1.5
equiv), DCM (0.56 mL, 0.20 M in substrate), followed by MeMgI (75
μL, 0.22 mmol, 2.0 equiv, 2.9 M in Et2O) and PhMe
(0.56 mL, 0.20 M in substrate). Upon the addition of MeMgI, the reaction
mixture was allowed to stir at 0 °C for 30 min. The residue was
purified by flash column chromatography (0–10% Et2O/hexanes) to afford the title compound as a pale-yellow oil (30.
mg, 99 μmol, 89%). Refer to iodide 5 above for
analytical data. SFC analysis (Chiralcel AD, 1% IPA,
2.0 mL/min, 230 nm) indicated 0% ee: tR (major enantiomer)
= 9.1 min, tR (minor enantiomer) = 10.1 min.Alcohol 46 was prepared according to
a procedure reported by Nagano.[36] A two-neck
round-bottom flask was equipped with a reflux condenser and a stir
bar. Aryl bromide 53 (0.43 g, 2.0 mmol, 1.0 equiv), Pd(PPh3)4 (69 mg, 60. μmol, 0.030 equiv, 3.0 mol
%), 3-methoxyphenyl boronic acid (0.36 g, 2.4 mmol, 1.2 equiv), K2CO3 (2.8 g, 20. mmol, 10. equiv), 1,4-dioxane (16
mL, 0.13 M in substrate), and H2O (4.0 mL, 0.50 M in substrate)
were added under N2. The reaction mixture was allowed to
stir at reflux in an oil bath overnight. Once complete, the flask
was cooled to rt and H2O (10 mL) was added. The reaction
mixture was then extracted with EtOAc (3 ×20 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography (0–30% EtOAc/hexanes) to afford the title compound
as a white solid (0.40 g, 1.7 mmol, 83% yield). m.p. 41–44
°C; TLC R = 0.3 (25% EtOAc/hexanes,
CAM stain); H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H),
7.34 (t, J = 7.9 Hz, 1H), 7.30–7.25 (m, 2H),
7.17 (ad, J = 7.7 Hz, 1H), 7.11 (at, J = 2.0 Hz, 1H), 6.91–6.85 (m, 1H), 3.86 (s, 3H), 3.72 (aq, J = 6.0 Hz, 2H), 2.76 (at, J = 7.7 Hz,
2H), 1.94 (aquint, J = 7.5 Hz, 2H), 1.27 (t, J = 5.2 Hz, 1H); C{H} NMR (125.8 MHz, CDCl3) δ 160.0, 142.6, 141.2, 138.8, 129.8, 128.9 (2C), 127.2
(2C), 119.6, 112.8, 112.5, 62.3, 55.3, 34.2, 31.8; IR (neat) 3356, 2938, 1600, 1584, 1564, 1481, 1450, 1435, 1403, 1314,
1295, 1219, 1170, 1052, 1032, 1015, 835, 778, 696 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C16H18O2, 242.1307; found, 242.1297. Analytical data is consistent with literature
values.[8]Mesylate 47 was prepared according to
Method A. The
following amounts of reagents were used: alcohol 46 (0.16
g, 0.65 mmol, 1.0 equiv), MsCl (76 μL, 0.98 mmol, 1.5 equiv),
Et3N (0.14 mL, 0.98 mmol, 1.5 equiv), and DCM (3.3 mL,
0.20 M in substrate). The reaction mixture was allowed to stir overnight.
The residue was purified by column chromatography (0–30% EtOAc/hexanes)
to afford the title compound as a white solid (0.19 g, 0.61 mmol,
93% yield). m.p. 60–62 °C; TLC R = 0.3 (25% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.28–7.23 (m, 2H), 7.16 (ad, J = 7.6 Hz, 1H), 7.11 (t, J = 2.0 Hz, 1H),
6.89 (dd, J = 8.5, 2.3 Hz, 1H), 4.26 (t, J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.01 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.12 (aquint, J = 6.9
Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 160.0,
142.4, 139.6, 139.2, 129.8, 128.9 (2C), 127.4 (2C), 119.6, 112.8,
112.6, 69.1, 55.4, 37.5, 31.8, 30.7; IR (neat) 2939,
1600, 1481, 1351, 1295, 1220, 1172, 1052, 1030, 972, 926, 833, 781,
697 cm–1; HRMS (TOF MS ES+) m/z: [M + Na]+ calcd for C17H20O4SNa, 343.0980; found, 343.0987.Iodide 6 was prepared according
to a modified Method B. The following amounts of reagents were used:
mesylate 47 (32 mg, 0.10 mmol, 1.0 equiv), MeMgI (41
μL, 0.10 mmol, 1.0 equiv, 2.4 M in Et2O), and PhMe
(1.0 mL, 0.10 M in substrate). Commercial MeMgI was used. The reaction
mixture was allowed to stir at 0 °C for 1 h. The residue was
purified by column chromatography (0–5% EtOAc/hexanes) to afford
the title compound as a yellow oil (31 mg, 87 μmol, 87% yield). TLC R = 0.5 (5% EtOAc/hexanes, CAM
stain); H NMR (400 MHz, CDCl3) δ 7.51 (ad, J = 8.1 Hz, 2H), 7.34
(t, J = 8.0 Hz, 1H), 7.25 (ad, J = 8.1 Hz, 2H), 7.16 (ad, J = 7.7 Hz, 1H), 7.11
(at, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.2, 2.5 Hz, 1H), 3.85 (s, 3H), 3.19 (t, J =
6.8 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.16 (quint, J = 7.1 Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 160.1, 142.6, 139.8, 139.2, 129.9, 129.1 (2C), 127.4
(2C), 119.7, 112.9, 112.7, 55.4, 36.0, 35.0, 6.4; IR (neat)
2936, 2832, 1599, 1583, 1563, 1518, 1480, 1402, 1295, 1213, 1168,
1052, 1031, 1015, 861, 822, 776, 695 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C16H17IO, 352.0324; found,
352.0340.
From Alcohol Using MeMgI Prepared from Freshly Distilled MeI
Iodide 6 was prepared according to a modified Method
C. The following amounts of reagents were used: alcohol 46 (24 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5
equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50
mL, 0.20 M in substrate), MeMgI (69 μL, 0.20 mmol, 2.0 equiv,
2.9 M in Et2O), and PhMe (0.50 mL, 0.20 M in substrate).
Upon the addition of MsCl, the reaction mixture was allowed to stir
at rt for 5 min. The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a yellow
oil (31 mg, 87 μmol, 87% yield). Refer to iodide 6 above for analytical data.
From Alcohol Using Commercially Available MeMgI
Iodide 6 was prepared according to a modified Method C. The following
amounts of reagents were used: alcohol 46 (24 mg, 0.10
mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL, 0.20
M in substrate), MeMgI (82 μL, 0.20 mmol, 2.0 equiv, 2.4 M in
Et2O), and PhMe (0.50 mL, 0.20 M in substrate). Commercial
MeMgI was used. Upon the addition of MeMgI, the reaction mixture was
allowed to stir at 0 °C for 1 h. The residue was purified by
column chromatography (0–5% EtOAc/hexanes) to afford the title
compound as a yellow oil (31 mg, 88 μmol, 88% yield). Refer
to iodide 6 above for analytical data.Bromide 31 was prepared
according to Method D. The following amounts of reagents were used:
mesylate 47 (32 mg, 0.10 mmol, 1.0 equiv), MeMgBr (67
μL, 0.20 mmol, 2.0 equiv, 3.0 M in Et2O), and PhMe
(1.0 mL, 0.10 M in substrate). The residue was purified by column
chromatography (0–5% EtOAc/hexanes) to afford the title compound
as a pale-yellow oil (25 mg, 82 μmol, 82% yield). TLC
R = 0.3 (5% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.52 (ad, J = 8.1 Hz, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.28–7.22 (m, 2H), 7.16 (ad, J = 7.9 Hz, 1H), 7.11 (at, J = 2.0 Hz,
1H), 6.88 (dd, J = 8.3, 2.5 Hz, 1H), 3.85 (s, 3H),
3.42 (t, J = 6.6 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.20 (aquint, J = 7.0 Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 160.0, 142.5,
139.9, 139.1, 129.8, 129.0 (2C), 127.3 (2C), 119.6, 112.8, 112.6,
55.4, 34.2, 33.7, 33.2; IR (neat) 2937, 1600, 1584, 1564,
1518, 1480, 1435, 1403, 1295, 1220, 1170, 1053, 1032, 1016, 866, 829,
777, 696 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C16H17BrO, 304.0463; found, 304.0478.Bromide 31 was prepared according
to Method E. The following amounts of reagents were used: alcohol 46 (24 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15
mmol, 1.5 equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv),
DCM (0.50 mL, 0.20 M in substrate), MeMgBr (0.11 mL, 0.30 mmol, 3.0
equiv, 2.7 M in Et2O), and PhMe (0.50 mL, 0.20 M in substrate).
The residue was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a pale-yellow oil (26 mg, 86 μmol,
86% yield). Refer to bromide 31 above for analytical
data.Mesylate 48 was prepared according to
a modified Method A. The following amounts of reagents were used:
2-(4-hydroxyphenyl) ethanol (0.14 g, 1.0 mmol, 1.0 equiv), MsCl (0.19
mL, 2.5 mmol, 2.5 equiv), Et3N (0.35 mL, 2.5 mmol, 2.5
equiv), and DCM (5.0 mL, 0.20 M in substrate). The reaction mixture
was allowed to stir overnight. The residue was purified by column
chromatography (0–50% EtOAc/hexanes) to afford the title compound
as a yellow oil (0.25 g, 0.86 mmol, 86% yield). TLC R = 0.3 (50% EtOAc/hexanes, KMnO4 stain); H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.6 Hz, 2H), 7.27–7.24
(m, 2H), 4.42 (t, J = 6.8 Hz, 2H), 3.15 (s, 3H),
3.08 (t, J = 6.8 Hz, 2H), 2.91 (s, 3H). Analytical
data is consistent with literature values.[37]Iodide 7 was prepared according to a
modified Method
B. The following amounts of reagents were used: mesylate 48 (30. mg, 0.10 mmol, 1.0 equiv), MeMgI (0.17 mL, 0.50 mmol, 5.0 equiv,
3.0 M in Et2O), and PhMe (1.0 mL, 0.10 M in substrate).
The residue was purified by column chromatography (0–25% EtOAc/hexanes)
to afford the title compound as a white solid (23 mg, 69 μmol,
69% yield). m.p. 74–76 °C; TLC R = 0.2 (20% EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 7.27–7.23 (m, 4H), 3.34 (t, J =
7.6 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H), 3.14 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 148.0, 140.0,
130.0 (2C), 122.3 (2C), 39.5, 37.4, 4.9; IR (neat) 2921,
2851, 1499, 1362, 1331, 1193, 1170, 1143, 1020, 976, 870, 844, 821,
780, 731, 701, 599, 564 cm–1; HRMS (TOF
MS ES+) m/z: [M + Na]+ calcd for C9H11IO3SNa, 348.9371;
found, 348.9382.Alcohol 49 was prepared following a
procedure reported
by Porzi.[38] To a flame-dried round-bottom
flask equipped with a stir bar were added 3-amino-1-propanol (0.23
mL, 3.0 mmol, 1.0 equiv), K2CO3 (870 mg, 6.3
mmol, 2.1 equiv), and acetone (6.0 mL, 0.50 M in substrate). The reaction
mixture was allowed to stir for 5 min at rt. Benzyl bromide (0.75
mL, 6.3 mmol, 2.1 equiv) was then added dropwise via a syringe, and
the reaction mixture was allowed to stir for 16 h at rt. The reaction
was filtered over a pad of celite while flushing with DCM and then
concentrated in vacuo. The residue was purified by flash column chromatography
(0–30% EtOAc/hexanes) to afford the title compound as a yellow
oil (0.60 g, 2.4 mmol, 79%). TLC R = 0.3 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.30–7.24
(m, 8H), 7.21–7.17 (m, 2H), 4.42 (br s, 1H), 3.58 (t, J = 5.5 Hz, 2H), 3.50 (s, 4H), 2.55 (t, J = 6.0 Hz, 2H), 1.68 (tt, J = 8.7, 5.8 Hz, 2H).
Analytical data is consistent with literature values.[38]Mesylate 50 was prepared according to
Method A. The
following amounts of reagents were used: alcohol 49 (0.26
g, 1.0 mmol, 1.0 equiv), MsCl (0.12 mL, 1.5 mmol, 1.5 equiv), Et3N (0.21 mL, 1.5 mmol, 1.5 equiv), and DCM (5.0 mL, 0.20 M
in substrate). The reaction mixture was allowed to stir overnight.
The residue was purified by flash column chromatography (0–30%
EtOAc/hexanes) to afford the title compound as a pale-yellow oil (0.19
g, 0.57 mmol, 57%). TLC R =
0.3 (30% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.33–7.27 (m, 8H), 7.23–7.20
(m, 2H), 4.19 (t, J = 6.4 Hz, 2H), 3.53 (s, 4H),
2.76 (s, 3H), 2.52 (t, J = 6.6 Hz, 2H), 1.85 (tt, J = 9.7, 6.5 Hz, 2H). Analytical data is consistent with
literature values.[39]Iodide 8 was prepared according to Method
B. The following
amounts of reagents were used: mesylate 50 (34 mg, 0.10
mmol, 1.0 equiv), MeMgI (34 μL, 0.10 mmol, 1.0 equiv, 3.0 M
in Et2O), and PhMe (1.0 mL, 0.10 M in substrate). The residue
was purified by flash column chromatography (0–10% Et2O/hexanes) to afford the title compound as a yellow oil (23 mg, 62
μmol, 60%). TLC R = 0.5
(10% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.34–7.29 (m, 8H), 7.24–7.21
(m, 2H), 3.55 (s, 4H), 3.15 (t, J = 7.0 Hz, 2H),
2.51 (t, J = 6.5 Hz, 2H), 2.02–1.96 (m, 2H).
Analytical data is consistent with literature values.[38]Mesylate 51 was prepared according to
Method A. The
following amounts of reagents were used: 6-hydroxy-hexanoic acid ethyl
ester (0.33 mL, 2.0 mmol, 1.0 equiv), MsCl (0.23 mL, 3.0 mmol, 1.5
equiv), Et3N (0.42 mL, 3.0 mmol, 1.5 equiv), and DCM (10.
mL, 0.20 M in substrate). The reaction mixture was allowed to stir
overnight. The residue was purified by flash column chromatography
(0–25% EtOAc/hexanes) to afford the title compound as a pale-yellow
oil (0.46 g, 1.9 mmol, 96%). TLC R = 0.2 (25% EtOAc/hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 4.23 (t, J = 6.5 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H),
3.00 (s, 3H), 2.32 (t, J = 7.4 Hz, 2H), 1.81–1.74
(m, 2H), 1.71–1.64 (m, 2H), 1.49–1.44 (m, 2H), 1.26
(t, J = 7.1 Hz, 3H). Analytical data is consistent
with literature values.[40]Iodide 9 was prepared according
to a modified Method B. The following amounts of reagents were used:
mesylate 51 (25 mg, 0.10 mmol, 1.0 equiv), MeMgI (34
μL, 0.10 mmol, 1.0 equiv, 3.0 M in Et2O), and PhMe
(1.0 mL, 0.10 M in substrate). The reaction mixture was allowed to
stir at −78 °C for 3 h. The residue was purified by flash
column chromatography (0–10% EtOAc/hexanes) to afford the title
compound as a pale-yellow oil (18 mg, 68 μmol, 66%). TLC
R = 0.4 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 4.13 (q, J = 7.1 Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H),
1.85 (quint, J = 7.2 Hz, 2H), 1.65 (quint, J = 7.6 Hz, 2H), 1.48–1.42 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). Analytical data is consistent with literature
values.[41]Iodide 9 was prepared according
to a modified Method C. The following amounts of reagents were used:
ethyl 6-hydroxyhexanoate (20. μL, 0.12 mmol, 1.0 equiv), MsCl
(10. μL, 0.12 mmol, 1.0 equiv), Et3N (17 μL,
0.12 mmol, 1.0 equiv), DCM (0.62 mL, 0.20 M in substrate), followed
by MeMgI (40 μL, 0.12 mmol, 1.0 equiv, 3.0 M in Et2O), and PhMe (0.62 mL, 0.20 M in substrate). Upon addition of MeMgI,
the reaction mixture was allowed to stir at −78 °C for
3 h. The residue was purified by flash column chromatography (0–10%
Et2O/hexanes) to afford the title compound as a pale-yellow
oil (24 mg, 90. μmol, 73%). Refer to iodide 9 above
for analytical data.Mesylate 52 was prepared according to
Method A. The following amounts of reagents were used: (1R)-(−)-nopol (0.17 mL, 1.0 mmol, 1.0 equiv), MsCl (0.12 mL,
1.5 mmol, 1.5 equiv), Et3N (0.21 mL, 1.5 mmol, 1.5 equiv),
and DCM (5.0 mL, 0.20 M in substrate). The reaction mixture was allowed
to stir overnight. The residue was purified by flash column chromatography
(0–20% EtOAc/hexanes) to afford the title compound as a pale-yellow
oil (0.24 g, 0.98 mmol, 98%). TLC R = 0.4 (20% EtOAc/hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 5.36 (br s,
1H), 4.21 (at, J = 7.1 Hz, 2H), 2.99 (s, 3H), 2.43–2.36
(m, 3H), 2.30–2.18 (m, 2H), 2.10–2.04 (m, 2H), 1.29
(s, 3H), 1.16 (d, J = 8.6 Hz, 1H), 0.84 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ 142.6, 119.8, 68.0,
45.5, 40.6, 38.0, 37.4, 36.3, 31.5, 31.3, 26.2, 21.1. HRMS (TOF MS CI+) m/z: [M]+ calculated for C12H20O3S 244.1133,
found 244.1126.Iodide 10 was prepared according
to Method B. The following amounts of reagents were used: mesylate 52 (25 mg, 0.10 mmol, 1.0 equiv), MeMgI (32 μL, 0.10
mmol, 1.0 equiv, 3.2 M in Et2O), and PhMe (1.0 mL, 0.10
M in substrate). The residue was purified by flash column chromatography
(100% hexanes) to afford the title compound as a colorless oil (23
mg, 83 μmol, 81%). TLC R = 0.8 (100% hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 5.31 (br s, 1H),
3.17–3.10 (m, 2H), 2.56–2.53 (m, 2H), 2.37 (dt, J = 8.6, 5.6 Hz, 1H), 2.27–2.24 (m, 1H), 2.19–2.15
(m, 1H), 2.08 (br s, 1H), 2.00 (td, J = 5.6, 1.4
Hz, 1H), 1.27 (s, 3H), 1.18 (d, J = 8.6 Hz, 1H),
0.84 (s, 3H). Analytical data is consistent with literature values.[21]
From Alcohol, 0.10 mmol Scale
Iodide 10 was prepared according to a modified Method C. The following amounts
of reagents were used: (1R)-(−)-nopol (20.
μL, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5
equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50
mL, 0.20 M in substrate), followed by MeMgI (94 μL, 0.30 mmol,
3.0 equiv, 3.2 M in Et2O), and PhMe (0.50 mL, 0.20 M in
substrate). The residue was purified by flash column chromatography
(100% hexanes) to afford the title compound as a colorless oil (25
mg, 91 μmol, 91%). Refer to iodide 10 above for
analytical data.
From Alcohol, 12 mmol Scale
To a flame-dried round-bottom
flask equipped with a stir bar was added (1R)-(−)-nopol
(2.1 mL, 12 mmol, 1.0 equiv), anhydrous DCM (60. mL, 0.20 M in substrate),
then Et3N (2.5 mL, 18 mmol, 1.5 equiv). The reaction mixture
was allowed to stir at rt for 5 min before adding MsCl (1.4 mL, 18
mmol, 1.5 equiv). The reaction mixture was allowed to stir at rt for
1 h before adding PhMe (60. mL, 0.20 M in substrate) and cooling to
0 °C. After 5 min at 0 °C, commercial MeMgI (15 mL, 36 mmol,
2.4 M in Et2O) was added, and the reaction mixture was
allowed to stir at 0 °C for 5 min. To quench, sat. NH4Cl solution was added, and the biphasic mixture was extracted with
DCM (×3), washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (100% hexanes) to afford the title compound
as a colorless oil (3.1 g, 11 mmol, 92% yield). Refer to iodide 10 above for analytical data.Bromide 32 was prepared
according to Method D. The following amounts of reagents were used:
mesylate 52 (29 mg, 0.12 mmol, 1.0 equiv), MeMgBr (90.
μL, 0.23 mmol, 2.0 equiv, 2.7 M in Et2O), and PhMe
(1.2 mL, 0.10 M in substrate). The residue was purified by flash column
chromatography (100% hexanes) to afford the title compound as a colorless
oil (18 mg, 77 μmol, 60%). TLC R = 0.7 (100% hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 5.32 (br s,
1H), 3.38–3.34 (m, 2H), 2.52 (at, J = 7.8
Hz, 2H), 2.40–2.35 (m, 1H), 2.30–2.17 (m, 2H), 2.09
(br s, 1H), 2.02 (at, J = 5.5 Hz, 1H), 1.28 (s, 3H),
1.17 (d, J = 8.8 Hz, 1H), 0.84 (s, 3H). Analytical
data is consistent with literature values.[42]Bromide 32 was prepared according
to a modified Method E. The following amounts of reagents were used:
(1R)-(−)-nopol (20. μL, 0.10 mmol, 1.0
equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv), Et3N
(21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL, 0.20 M in substrate),
followed by MeMgBr (0.15 mL, 0.40 mmol, 4.0 equiv, 2.7 M in Et2O), and PhMe (0.50 mL, 0.20 M in substrate). The residue was
purified by flash column chromatography (100% hexanes) to afford the
title compound as a colorless oil (17 mg, 75 μmol, 75%). Refer
to bromide 32 above for analytical data.Alcohol 53 was prepared according to
a modified procedure reported by Cole.[43] Under a N2 atmosphere, a flame-dried round-bottom flask
equipped with a stir bar was charged with the 3-(4-bromophenyl)propionic
acid (1.1 g, 5.0 mmol, 1.0 equiv) and THF (10. mL, 0.50 M in substrate).
The reaction mixture was cooled to 0 °C and BH3·THF
(15 mL, 1.5 mmol, 3.0 equiv, 1.0 M in THF) was added dropwise. The
mixture was brought to rt and allowed to stir for 16 h. Then, glacial
acetic acid was added dropwise until quenched, followed by the addition
of sat. aqueous NaHCO3 until a pH of 7 was achieved. This
mixture was extracted with EtOAc (×3), and the organic layers
were combined, dried with Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography (0–20%
EtOAc/hexanes) to afford the title compound as a yellow oil (0.94
g, 4.4 mmol, 88% yield). TLC R = 0.3 (25% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.40 (d, J =
8.2 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 2.67 (at, J = 7.7 Hz,
2H), 1.86 (tt, J = 7.8, 6.4 Hz, 2H), 1.29 (br s,
1H). Analytical data is consistent with literature values.[44]Iodide 11 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 53 (0.22
g, 1.0 mmol, 1.0 equiv), MsCl (0.12 mL, 1.5 mmol, 1.5 equiv), Et3N (0.21 mL, 1.5 mmol, 1.5 equiv), DCM (5.0 mL, 0.20 M in substrate),
MeMgI (0.69 mL, 2.0 mmol, 2.0 equiv, 2.9 M in Et2O), PhMe
(5.0 mL, 0.20 M in substrate). The residue was purified by column
chromatography (0–5% EtOAc/hexanes) to afford the title compound
as a colorless oil (0.29 g, 0.88 mmol, 88% yield). TLC R = 0.7 (5% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 3.15 (t, J = 6.8 Hz, 2H),
2.69 (t, J = 7.4 Hz, 2H), 2.10 (aquint, J = 7.0 Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ
129.4, 131.6 (2C), 130.4 (2C), 120.0, 35.6, 34.6, 5.9; IR (neat) 2928, 2855, 1487, 1445, 1424, 1403, 1210, 1071, 1010, 860,
812, 780, 746, 709, 649, 632 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C9H10BrI, 323.9011; found, 323.9016.
Analytical data is consistent with literature values.[44]Bromide 33 was prepared according to
Method E. The
following amounts of reagents were used: alcohol 53 (22
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgBr (0.10 mL, 0.30 mmol, 3.0 equiv, 3.0 M
in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a pale-yellow oil (21 mg, 77 μmol,
77% yield). TLC R = 0.5 (5%
EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.41 (d, J =
8.4 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 3.37 (t, J = 6.5 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H),
2.13 (aquint, J = 6.9 Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 139.5, 131.6 (2C), 130.4 (2C),
120.0, 33.9, 33.4, 32.8; IR (neat) 2918, 2849, 1488,
1435, 1240, 1072, 1011, 865, 823, 795, 560 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C9H10Br2, 275.9149;
found, 275.9146. Analytical data is consistent with literature values.[45]Iodide 12 was prepared according to
Method C. The
following amounts of reagents were used: 3-(4-chlorophenyl)-1-propanol
(18 mg, 0.11 mmol, 1.0 equiv), MsCl (13 μL, 0.17 mmol, 1.5 equiv),
Et3N (23 μL, 0.17 mmol, 1.5 equiv), DCM (0.55 mL,
0.20 M in substrate), MeMgI (73 μL, 0.22 mmol, 2.0 equiv, 3.0
M in Et2O), PhMe (0.55 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a yellow oil (25 mg, 87 μmol,
82% yield). TLC R = 0.4 (100%
hexanes, CAM stain); H NMR (400
MHz, CDCl3) δ 7.29–7.21 (m, 2H), 7.12 (d, J = 8.5 Hz, 2H), 3.15 (t, J = 6.7 Hz, 2H),
2.70 (t, J = 7.3 Hz, 2H), 2.09 (quint, J = 7.1 Hz, 2H). Analytical data is consistent with literature values.[46]Alcohol 54 was prepared according to
the following
procedure. Open to air, a round-bottom flask with a stir bar was charged
with aldehyde SI-5 (0.11 g, 0.53 mmol, 1.0 equiv), NaBH4 (40. mg, 1.0 mmol, 2.0 equiv), and MeOH (2.7 mL, 0.20 M in
substrate). The reaction mixture was stirred for 1 h. After completion,
the reaction mixture was concentrated in vacuo, and then dissolved
in DCM. H2O was added and the aqueous layer was extracted
with DCM. The combined organic layers were dried and concentrated
in vacuo. The residue was purified by column chromatography (0–25%
EtOAc/hexanes) to afford the title compound as a colorless oil (75
mg, 0.37 mmol, 70% yield). TLC R = 0.2 (20% EtOAc/hexanes, KMnO4 stain); H NMR (400 MHz, CDCl3) δ 7.48–7.36
(m, 4H), 3.69 (t, J = 6.4 Hz, 2H), 2.78 (at, J = 7.8 Hz, 2H), 1.95–1.87 (m, 2H), 1.30 (br s, 1H); C{H} NMR (150.9 MHz, CDCl3) δ 142.8, 131.9
(q, J = 1.0 Hz), 130.7 (q, J = 32.1
Hz), 128.8, 125.2 (q, J = 3.8 Hz), 124.3 (q, J = 272.1 Hz), 122.8 (q, J = 3.9 Hz), 62.0,
34.0, 31.9; F NMR (376.5 MHz,
CDCl3) δ −62.6 (3F); IR (neat)
3328, 2939, 1450, 1331, 1200, 1162, 112, 1073, 800, 702, 661 cm–1; HRMS (TOF MS ES−) m/z: [M – H]− calcd for
C10H10F3O, 203.0684; found, 203.0680.
Analytical data is consistent with literature values.[47]Iodide 13 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 54 (20
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgI (69 μL, 0.20 mmol, 2.0 equiv, 2.9
M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexane) to
afford the title compound as a yellow oil (27 mg, 85 μmol, 85%
yield). TLC R = 0.7 (5% EtOAc/hexanes,
CAM stain); H NMR (400 MHz,
CDCl3) δ 7.50–7.36 (m, 4H), 3.17 (t, J = 6.8 Hz, 2H), 2.80 (at, J = 7.4 Hz,
2H), 2.15 (aquint, J = 7.1 Hz, 2H); C{H} NMR (150.9 MHz, CDCl3) δ 141.4, 132.0, 130.9 (q, J = 32.0 Hz), 129.0, 125.3 (q, J = 3.7
Hz), 124.2 (q, J = 272.5 Hz), 123.2 (q, J = 3.9 Hz), 36.1, 34.6, 5.7; F NMR (376.5 MHz, CDCl3) δ −62.6 (3F); IR (neat) 2923, 2851, 1450, 1328, 1213, 1199, 1164, 1125, 1073, 797,
702, 661 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C10H10F3I, 313.9779; found, 313.9778. Analytical
data is consistent with literature values.[48]Alcohol 55 was prepared according to
the following
procedure. In a glovebox, a flame-dried round-bottom flask with a
stir bar was charged with LiAlH4 (88 mg, 2.3 mmol, 2.2
equiv), capped, and brought out of the glovebox. A N2 inlet
and THF (5.3 mL, 0.20 M in substrate) was added. The mixture was cooled
to 0 °C, and carboxylic acid SI-6 (0.29 g, 1.1 mmol,
1.0 equiv) was added as a solution in THF (1.0 M in substrate). The
reaction mixture was warmed to rt and allowed to stir overnight. Then,
sat. aqueous NH4Cl was added, and the crude mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography
(0–25% EtOAc/hexanes) to afford the title compound as a colorless
oil (0.14 g, 0.51 mmol, 49% yield). TLC R = 0.5 (33% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.04 (ad, J = 8.4 Hz, 2H), 6.75 (ad, J = 8.5 Hz,
2H), 3.66 (t, J = 6.4 Hz, 2H), 2.64 (at, J = 7.6 Hz, 2H), 1.86 (tt, J = 7.6, 6.5
Hz, 2H), 1.23 (br s, 1H), 0.98 (s, 9H), 0.18 (s, 6H). Analytical data
is consistent with literature values.[49]Iodide 14 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 55 (27
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgI (68 μL, 0.20 mmol, 2.0 equiv, 3.0
M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a pale-yellow oil (36 mg, 95 μmol,
95% yield). TLC R = 0.8 (5%
EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 7.03 (d, J =
8.2 Hz, 2H), 6.75 (d, J = 8.1 Hz, 2H); 3.15 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H),
2.09 (quint, J = 7.1 Hz, 2H), 0.98 (s, 9H), 0.18
(s, 6H); C{H} NMR (125.4 MHz, CDCl3) δ 154.0,
133.1, 129.5 (2C), 120.1 (2C), 35.4, 35.1, 25.8 (3C), 18.2, 6.5, −4.4
(2C); IR (neat) 2955, 2928, 2856, 1609, 1508, 1471, 1252,
1212, 1168, 912, 837, 808, 779, 747, 687 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C15H25IOSi, 376.0720; found,
376.0704. Analytical data is consistent with literature values.[50]Bromide 34 was prepared according to
Method E. The
following amounts of reagents were used: alcohol 55 (27
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgBr (0.10 mL, 0.30 mmol, 3.0 equiv, 3.0 M
in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as a yellow oil (26 mg, 80. μmol,
80% yield). TLC R = 0.6 (5%
EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.04 (ad, J = 8.4 Hz, 2H), 6.76 (ad, J = 8.4 Hz, 2H), 3.37
(t, J = 6.7 Hz, 2H), 2.70 (t, J =
7.3 Hz, 2H), 2.12 (quint, J = 7.1 Hz, 2H), 0.98 (s,
9H), 0.18 (s, 6H); C{H} NMR (125.8 MHz, CDCl3) δ
154.0, 133.2, 129.5 (2C), 120.1 (2C), 34.4, 33.24, 33.19, 25.8 (3C),
18.3, −4.4 (2C); IR (neat) 2956, 2929, 2857, 1609,
1509, 1472, 1252, 1169, 913, 838, 810, 780, 687 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C15H25BrOSi, 328.0858;
found, 328.0868. Analytical data is consistent with literature values.[51]Iodide 15 was prepared according to
a modified Method
C. The following amounts of reagents were used: 2-(4-hydroxyphenyl)
ethanol (14 mg, 0.10 mmol, 1.0 equiv), MsCl (19 μL, 0.25 mmol,
2.5 equiv), Et3N (35 μL, 0.25 mmol, 2.5 equiv), DCM
(0.50 mL, 0.20 M in substrate), MeMgI (83 μL, 0.25 mmol, 2.5
equiv, 3.0 M in Et2O), PhMe (0.50 mL, 0.20 M in substrate).
Mesylation was allowed to stir for 5 min. Upon addition of MeMgI,
the reaction mixture was stirred at 0 °C for 5 mins, then the
flask was warmed up to rt and MeMgCl (33 μL, 0.10 mmol, 1.0
equiv) was added dropwise. In the development of this reaction, we
observed that subjecting an alkyl mesylate to MeMgCl resulted in conversion
back to the alcohol instead of to the alkyl chloride, so to obtain
the phenol as the exclusive product, we carried out this subsequent
step. The reaction mixture was stirred for 1 h at rt, quenched with
MeOH, filtered through a pad of silica gel eluting with 100% Et2O, and concentrated in vacuo. The residue was purified by
column chromatography (0–20% EtOAc/hexanes) to afford the title
compound as a white solid (21 mg, 85 μmol, 85% yield). TLC R = 0.4 (20% EtOAc/hexanes, CAM
stain); H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 8.5 Hz, 2H), 6.78
(d, J = 8.4 Hz, 2H), 4.63 (s, 1H), 3.31 (t, J = 7.8 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H).
Analytical data is consistent with literature values.[52]Alcohol 56 was prepared according to
a modified procedure
reported by Cole.[43] Under a N2 atmosphere, a flame-dried round-bottom flask equipped with a stir
bar was charged with 2-(4-methoxyphenyl) acetic acid (2.5 g, 15 mmol,
1.0 equiv) and THF (30. mL, 0.50 M in substrate). The reaction mixture
was cooled to 0 °C and BH3·THF (45 mL, 45 mmol,
3.0 equiv, 1.0 M in THF) was added dropwise. The mixture was brought
to rt and allowed to stir for 16 h. Then, glacial acetic acid was
added dropwise until quenched, followed by the addition of sat. aqueous
NaHCO3 until a pH of 7 was achieved. This mixture was extracted
with EtOAc (×3), and the organic layers were combined, dried
with Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (0–50% EtOAc/hexanes)
to afford the title compound as a colorless oil (2.3 g, 15 mmol, >99%
yield). TLC R = 0.2 (20% EtOAc/hexanes,
KMnO4 stain); H NMR (400 MHz, CDCl3) δ 7.14 (ad, J = 8.4 Hz, 2H), 6.86 (ad, J = 8.6 Hz, 2H), 3.86–3.76
(m, 5H), 2.81 (t, J = 6.6 Hz, 2H), 1.41 (br s, 1H); C{H} NMR (150.9 MHz, CDCl3) δ 158.3, 130.4,
130.0 (2C), 114.1 (2C), 63.9, 55.3, 38.3; IR (neat) 3348,
2935, 1612, 1512, 1464, 1300, 1244, 1178, 1110, 1037, 821 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C9H12O2, 152.0837; found, 152.0831. Analytical data is consistent with literature
values.[53]Iodide 16 was prepared according to
a modified Method
C. The following amounts of reagents were used: alcohol 56 (4.6 g, 30. mmol, 1.0 equiv), MsCl (3.5 mL, 45 mmol, 1.5 equiv),
Et3N (6.3 mL, 45 mmol, 1.5 equiv), DCM (150 mL, 0.20 M
in substrate), MeMgI (25 mL, 60. mmol, 2.0 equiv, 2.4 M in Et2O), PhMe (150 mL, 0.20 M in substrate). Commercial MeMgI was
used. Upon addition of MeMgI, the reaction mixture was allowed to
stir at 0 °C for 1 h. The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a yellow
oil (6.5 g, 25 mmol, 82% yield). TLC R = 0.6 (5% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.11 (ad, J = 8.6 Hz, 2H), 6.85 (ad, J = 8.7 Hz,
2H), 3.79 (s, 3H), 3.31 (at, J = 7.7 Hz, 2H), 3.11
(t, J = 7.8 Hz, 2H); C{H} NMR (150.9 MHz,
CDCl3) δ 158.5, 132.9, 129.4 (2C), 114.1 (2C), 55.3,
39.6, 6.4; IR (neat) 2954, 2833, 1611, 1510, 1463, 1301,
1245, 1176, 1122, 1034, 818, 754 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C9H11IO, 261.9855; found, 261.9842.
Analytical data is consistent with literature values.[54]Iodide 17 was prepared according to
a modified Method
C. The following amounts of reagents were used: 2-pyridine-ethanol
(11 μL, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol,
1.5 equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM
(0.50 mL, 0.20 M in substrate), MeMgI (68 μL, 0.20 mmol, 2.0
equiv, 3.0 M in Et2O), PhMe (0.50 mL, 0.20 M in substrate).
Upon addition of MeMgI, the reaction mixture was allowed to stir at
0 °C for 1 h. The residue was purified by column chromatography
(0–25% EtOAc/hexanes) to afford the title compound as a yellow
oil (19 mg, 82 μmol, 82% yield) containing alkenes 57 (0.2 mg, 2 μmol, 2%). To remove the alkenes, a modified Sharpless
asymmetric dihydroxylation was performed.[30] To a flame-dried 20 mL vial was added AD-mix-β (0.14 g, 1.4
g/mmol). Then t-BuOH (1.0 mL) and H2O
(1.0 mL) were added via syringe and the vial was capped. The vial
was cooled to 0 °C and then the mixture of iodide 17 and alkenes 57 was added dropwise as a solution in t-BuOH (1.0 mL) and H2O (1.0 mL) via syringe.
The mixture was allowed to stir at 0 °C for 24 h. To quench,
Na2SO3 (30. mg) was added and the mixture was
allowed to warm to rt and stir for 30 min. Then the mixture was transferred
to a separatory funnel, and the organic layer was extracted with EtOAc
(×3). The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (0–25% EtOAc/hexanes)
to afford the title compound as a yellow oil (17 mg, 73 μmol,
73% yield over 2 steps). TLC R = 0.3 (25% EtOAc/hexanes, KMnO4 stain); H NMR (500 MHz, CDCl3) δ 8.58
(ad, J = 4.8 Hz, 1H), 7.68 (td, J = 7.7, 1.7 Hz, 1H), 7.25–7.19 (m, 2H), 3.56 (t, J = 7.2 Hz,
2H), 3.39 (t, J = 7.2 Hz, 2H); C{H} NMR (125.8 MHz, CDCl3) δ 159.7, 149.7, 136.5, 123.3,
121.9, 42.0, 4.1; IR (neat) 2921, 2850, 1591, 1569, 1473,
1436, 1241, 1167, 1149, 1050, 994, 767, 751 cm–1; HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C7H8INH, 233.9780;
found, 233.9785.Alcohol 58 was prepared according to
a modified procedure
reported by Cole.[43] Under a N2 atmosphere, a flame-dried round-bottom flask equipped with a stir
bar was charged with indomethacin (0.36 g, 1.0 mmol, 1.0 equiv) and
THF (2.0 mL, 0.50 M in substrate). The reaction mixture was cooled
to 0 °C and BH3·THF (3.0 mL, 3.0 mmol, 3.0 equiv)
was added dropwise. The mixture was brought to rt and allowed to stir
for 16 h. Then, glacial acetic acid was added dropwise until quenched,
followed by the addition of sat. aqueous NaHCO3 until a
pH of 7 was achieved. This mixture was extracted with EtOAc (×3),
and the organic layers were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (0–30% EtOAc/hexanes) to afford the title
compound as a brown oil (23 mg, 0.11 mmol, 11%). TLC R = 0.2 (50% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.70
(br s, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.97 (ad, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.7, 2.4
Hz, 1H), 3.85 (s, 3H), 3.85–3.82 (m, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.39 (s, 3H), 1.43 (br s, 1H); HRMS (TOF MS CI+) m/z: [M + H]+ calculated for C12H15NO2H 206.1181, found 206.1183. Analytical data is consistent with literature
values.[55]Iodide 18 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 58 (23
mg, 0.11 mmol, 1.0 equiv), MsCl (20. μL, 0.28 mmol, 2.5 equiv),
Et3N (40. μL, 0.28 mmol, 2.5 equiv), DCM (0.56 mL,
0.20 M in substrate), followed by MeMgI (0.10 mL, 0.28 mmol, 2.5 equiv,
2.9 M in Et2O), and PhMe (0.56 mL, 0.20 M in substrate).
The residue was purified by flash column chromatography (0–30%
EtOAc/hexanes) to afford the title compound as a bright yellow oil
(18 mg, 56 μmol, 50%). TLC R = 0.4 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.71 (br s, 1H),
7.16 (d, J = 8.7 Hz, 1H), 6.91 (br s, 1H), 6.78 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.36–3.23 (m, 4H),
2.37 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ
154.2, 132.8, 130.4, 128.5, 111.4, 111.2, 110.9, 100.3, 56.2, 29.6,
12.1, 6.4; HRMS (TOF MS ES+) m/z: [M + H]+ calculated for C12H14INOH 316.0198, found 316.0202.Alcohol 59 was prepared according to
the following
procedure. Open to air, a round-bottom flask with a stir bar was charged
with benzyloxyacetaldehyde (0.70 mL, 5.0 mmol, 1.0 equiv), NaBH4 (0.38 g, 10. mmol, 2.0 equiv), and MeOH (25 mL, 0.20 M in
substrate). The reaction mixture was stirred for 30 min. After completion,
the reaction mixture was concentrated in vacuo, and then dissolved
in DCM. H2O was added and the aqueous layer was extracted
with DCM. The combined organic layers were dried and concentrated
in vacuo. The residue was purified by flash column chromatography
(0–50% EtOAc/hexanes) to afford the title compound as a pale-yellow
oil (0.65 g, 4.2 mmol, 85%). TLC R = 0.3 (30% EtOAc/hexanes, KMnO4 stain); H NMR (400 MHz, CDCl3) δ
7.38–7.27 (m, 5H), 4.57 (s, 2H), 3.78–3.74 (m, 2H),
3.60 (at, J = 4.6 Hz, 2H), 2.02 (t, J = 6.2 Hz, 1H). Analytical data is consistent with literature values.[56]Iodide 19 was prepared according to
a modified Method
C. The following amounts of reagents were used: alcohol 59 (18 mg, 0.12 mmol, 1.0 equiv), MsCl (13 μL, 0.17 mmol, 1.5
equiv), Et3N (24 μL, 0.17 mmol, 1.5 equiv), DCM (0.58
mL, 0.20 M in substrate), followed by MeMgI (96 μL, 0.29 mmol,
2.5 equiv, 3.0 M in Et2O), and PhMe (0.58 mL, 0.20 M in
substrate). Mesylation was allowed to stir for 6 h. Upon addition
of MeMgI, the reaction mixture was allowed to stir at 0 °C for
2 h. The residue was purified by flash column chromatography (0–10%
Et2O/hexanes) to afford the title compound as a pale-yellow
oil (26 mg, 97 μmol, 84%). TLC R = 0.6 (10% EtOAc/hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 7.36–7.27
(m, 5H), 4.58 (s, 2H), 3.74 (t, J = 6.8 Hz, 2H),
3.28 (t, J = 6.8 Hz, 2H); C{H} NMR (100
MHz, CDCl3) δ 137.9, 128.6 (2C), 128.0, 127.9 (2C),
73.0, 70.9, 3.0; HRMS (TOF MS ES+) m/z: [M]+ calculated for C9H11IO 261.9855, found 261.9851. Analytical data is consistent
with literature values.[57]Alcohol 60 was prepared according to
a procedure reported
by Molander.[58] To a flame-dried round-bottom
flask equipped with a stir bar was added 3-hydroxypropyltriphenylphosphonium
bromide (0.48 g, 1.2 mmol, 1.2 equiv), then THF (5.0 mL, 0.20 M in
substrate). The reaction mixture was cooled to 0 °C before adding n-BuLi (1.3 mL, 3.2 mmol, 3.2 equiv, 2.5 M in hexanes).
The reaction mixture was allowed to stir at 0 °C for 30 min.
Then, 2,3-isopropylidene-glyceraldehyde (260 mg, 1.0 mmol, 1.0 equiv,
50% w/w in DCM) was added dropwise via a syringe, and the reaction
mixture was allowed to stir at 0 °C rt for 16 h. To quench, sat.
NH4Cl solution was added. The reaction mixture was extracted
with EtOAc (3 ×10 mL), and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash column chromatography
(0–30% EtOAc/hexanes) to afford the title compound as a mixture
of diastereomers as a yellow oil (0.12 g, 0.71 mmol, 71%, 1.6:1 dr). TLC R = 0.2 (50% EtOAc/hexanes, KMnO4 stain) For clarity, the 1H NMR data of the major
and minor diastereomers have been tabulated separately. Analytical
data is consistent with literature values.[58]
H
NMR (400 MHz, CDCl3) δ 5.82–5.76 (m,
1H), 5.59–5.52 (m, 1H), 4.48 (aq, J = 7.1
Hz, 1H), 4.11–4.06 (m, 1H), 3.65–3.53 (m, 3H), 2.54
(br s, 1H), 2.43–2.31 (m, 2H), 1.42 (s, 3H), 1.38 (s, 3H).Iodide 20 was prepared according to
Method C. The following amounts of reagents were used: alcohol 60 (22 mg, 0.13 mmol, 1.0 equiv), MsCl (20. μL, 0.19
mmol, 1.5 equiv), Et3N (30. μL, 0.19 mmol, 1.5 equiv),
DCM (0.65 mL, 0.20 M in substrate), followed by MeMgI (90. μL,
0.26 mmol, 2.0 equiv, 3.0 M in Et2O), and PhMe (0.65 mL,
0.20 M in substrate). The residue was purified by flash column chromatography
(0–50% EtOAc/hexanes) to afford the title compound as a yellow
oil (21 mg, 73 μmol, 56%, 1.6:1 dr). TLC R = 0.6 (20% EtOAc/hexanes, CAM stain). For clarity,
the 1H NMR data of the major and minor diastereomers have
been tabulated separately. Analytical data is consistent with literature
values.[58]H
NMR (400 MHz, CDCl3) δ 5.59–5.53 (m,
2H), 4.79 (aq, J = 7.0 Hz, 1H), 4.10 (aq, J = 7.3 Hz, 1H), 3.61–3.55 (m, 1H), 3.23–3.08
(m, 2H), 2.78–2.59 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H).H
NMR (400 MHz, CDCl3) δ 5.77–5.70 (m,
1H), 5.59–5.53 (m, 1H), 4.49 (aq, J = 7.0
Hz, 1H), 4.10 (aq, J = 7.3 Hz, 1H), 3.61–3.55
(m, 1H), 3.23–3.08 (m, 2H), 2.78–2.59 (m, 2H), 1.43
(s, 3H), 1.39 (s, 3H).Bromide 35 was prepared according to
a modified Method E. The following amounts of reagents were used:
alcohol 60 (18 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL,
0.16 mmol, 1.5 equiv), Et3N (22 μL, 0.16 mmol, 1.5
equiv), DCM (0.52 mL, 0.20 M in substrate), followed by MeMgBr (0.12
mL, 0.31 mmol, 3.0 equiv, 2.7 M in Et2O), and PhMe (0.52
mL, 0.20 M in substrate). Upon addition of MeMgBr, the reaction mixture
was allowed to stir at 0 °C for 1 h. The residue was purified
by flash column chromatography (0–50% Et2O/hexanes)
to afford the title compound as a mixture of diastereomers as a pale-yellow
oil (13 mg, 54 μmol, 52%, 1.7:1 dr). TLC R = 0.5 (20% hexanes, PMA stain); HRMS (TOF MS ES+) m/z: [M + H]+ calculated for C9H15BrO2H 235.0334, found 235.0323. For clarity, the 1H NMR and 13C{1H} NMR data for the major and minor diastereomers
have been tabulated separately.H
NMR (400 MHz, CDCl3) δ 5.66–5.54 (m,
2H), 4.81 (aq, J = 7.1 Hz, 1H), 4.12–4.07
(m, 1H), 3.61–3.54 (m, 1H), 3.46–3.31 (m, 2H), 2.77–2.57
(m, 2H), 1.43 (s, 3H), 1.40 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ 130.9, 130.5, 69.6, 35.6, 32.0, 31.8, 31.2, 26.9,
26.1.H
NMR (400 MHz, CDCl3) δ 5.82–5.75 (m,
1H), 5.66–5.54 (m, 1H), 4.49 (aq, J = 7.1
Hz, 1H), 4.12–4.07 (m, 1H), 3.61–3.54 (m, 1H), 3.46–3.31
(m, 2H), 2.77–2.57 (m, 2H), 1.43 (s, 3H), 1.39 (s, 3H); C{H} NMR (100 MHz, CDCl3) δ 131.5, 130.8, 72.0,
35.6, 32.0, 31.8, 31.2, 26.8, 26.0.Alcohol 61 was prepared according to
the following procedure. Open to air, a round-bottom flask with a
stir bar was charged with N-Boc-piperidine-4-carboxaldehyde (0.21
g, 1.0 mmol, 1.0 equiv), NaBH4 (78 mg, 2.0 mmol, 2.0 equiv),
and MeOH (5.0 mL, 0.20 M in substrate). The reaction mixture was stirred
for 1.5 h. After completion, the reaction mixture was concentrated
in vacuo, and then dissolved in DCM. H2O was added and
the aqueous layer was extracted with DCM. The combined organic layers
were dried and concentrated in vacuo. The residue was purified by
column chromatography (0–50% EtOAc/hexanes) to afford the title
compound as a white solid (0.19 g, 0.87 mmol, 87% yield). TLC
R = 0.3 (50% EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 4.13 (as, 2H), 3.50 (t, J = 5.6 Hz, 2H),
2.70 (t, J = 12.7 Hz, 2H), 1.78–1.59 (m, 3H),
1.46 (s, 9H), 1.36 (t, J = 5.4 Hz, 1H), 1.15 (qd, J = 12.4, 4.4 Hz, 2H). Analytical data is consistent with
literature values.[59]Iodide 21 was prepared according to
a modified Method
C. The following amounts of reagents were used: alcohol 61 (22 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5
equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50
mL, 0.20 M in substrate), MeMgI (68 μL, 0.20 mmol, 2.0 equiv,
3.0 M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The
reaction mixture was allowed to stir for 4 h after the addition of
MeMgI. The residue was purified by column chromatography (0–20%
EtOAc/hexanes) to afford the title compound as a white solid (26 mg,
80. μmol, 80% yield). TLC R = 0.6 (20% EtOAc/hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 4.12 (as, 2H), 3.10
(d, J = 6.6 Hz, 2H), 2.69 (t, J =
12.5 Hz, 2H), 1.83 (ad, J = 13.5 Hz, 2H), 1.67–1.54
(m, 1H), 1.46 (s, 9H), 1.14 (qd, J = 12.5, 4.4 Hz,
2H). Analytical data is consistent with literature values.[60]Alcohol 62 was prepared according to
the following
procedure. A flame-dried round-bottom flask with a stir bar was charged
with 4-(trifluoromethyl)benzaldehyde (0.14 mL, 1.0 mmol, 1.0 equiv)
and anhydrous THF (5.0 mL, 0.20 M in substrate), and cooled to 0 °C.
Then, MeMgCl (0.50 mL, 1.5 mmol, 1.5 equiv, 3.0 M in Et2O) was added dropwise. The reaction mixture was allowed to stir at
rt overnight. The reaction was quenched with sat. aqueous NH4Cl (10 mL), and the mixture was extracted with Et2O (3
×20 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (0–20% EtOAc/hexanes)
to afford the title compound as a colorless oil (0.11 g, 0.59 mmol,
59% yield). TLC R = 0.3 (20%
EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.61 (d, J =
8.1 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.97 (q, J = 6.5 Hz, 1H), 1.87 (br s, 1H), 1.51 (d, J = 6.5 Hz, 3H); C{H} NMR (150.9 MHz, CDCl3) δ
149.7 (q, J = 1.1 Hz), 129.7 (q, J = 32.4 Hz), 125.7 (2C), 125.5 (q, J = 3.8 Hz, 2C),
124.2 (q, J = 272.5 Hz), 69.9, 25.5; F NMR (376.5 MHz, CDCl3) δ −62.5
(3F); IR (neat) 3337, 2977, 1622, 1417, 1326, 1164, 1121,
1090, 1068, 1016, 900, 842, 738 cm–1; HRMS (TOF MS ES−) m/z: [M –
H]− calcd for C9H8F3O, 189.0527; found, 189.0519. Compound 62 is commercially
available: CAS 1737-26-4.Iodide 22 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 62 (19
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgI (69 μL, 0.20 mmol, 2.0 equiv, 2.9
M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–5% EtOAc/hexanes)
to afford the title compound as an orange oil (22 mg, 73 μmol,
73% yield) containing chloride 63 (2 mg, 7 μmol,
7% yield). TLC R = 0.7 (5% EtOAc/hexanes,
CAM stain); H NMR (400 MHz,
CDCl3) δ 7.58–7.50 (m, 4H), 5.36 (q, J = 7.1 Hz, 1H), 2.21 (d, J = 7.1 Hz, 3H); F NMR (376.5 MHz, CDCl3) δ −62.7 (3F). Analytical data is consistent with literature
values.[61]Iodide 23 was prepared according to
a modified Method
C. The following amounts of reagents were used: 1-adamantanol (0.15
g, 1.0 mmol, 1.0 equiv), MsCl (0.12 mL, 1.5 mmol, 1.5 equiv), Et3N (0.21 mL, 1.5 mmol, 1.5 equiv), DCM (5.0 mL, 0.20 M in substrate),
MeMgI (0.69 mL, 2.0 mmol, 2.0 equiv, 2.9 M in Et2O), PhMe
(5.0 mL, 0.20 M in substrate). The extraction procedure described
in the method was carried out instead of a silica plug, using Et2O instead of DCM. The residue was purified by column chromatography
(0–5% EtOAc/hexanes) to afford the title compound as a white
waxy solid (0.15 g, 0.59 mmol, 59% yield) containing chloride 64 (29 mg, 0.17 mmol, 17% yield). TLC R = 0.8 (100% hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 2.65
(d, J = 2.8 Hz, 6H), 1.96 (s, 3H), 1.82 (m, 6H).
Compound 23 is commercially available: CAS 768-93-4.Iodide 24 was prepared according to
Method C. The
following amounts of reagents were used: citronellol (20. μL,
0.11 mmol, 1.0 equiv), MsCl (13 μL, 0.16 mmol, 1.5 equiv), Et3N (23 μL, 0.16 mmol, 1.5 equiv), DCM (0.55 mL, 0.20
M in substrate), followed by MeMgI (72 μL, 0.22 mmol, 2.0 equiv,
3.0 M in Et2O), and PhMe (0.55 mL, 0.20 M in substrate).
The residue was purified by flash column chromatography (0–25%
Et2O/hexanes) to afford the title compound as a colorless
oil (23 mg, 87 μmol, 79%). TLC R = 0.5 (100% hexanes, PMA stain); H NMR (400 MHz, CDCl3) δ 5.10 (at, J = 7.0 Hz, 1H), 3.74–3.63 (m, 2H), 2.03–1.92
(m, 3H), 1.68 (s, 3H), 1.71–1.53 (m, 2H), 1.60 (s, 3H), 1.41–1.31
(m, 1H), 1.23–1.14 (m, 1H), 0.91 (d, J = 6.5
Hz, 3H). Analytical data is consistent with literature values.[62]Iodide 25 was prepared according to
Method C. The
following amounts of reagents were used: N-(3-hydroxypropyl)phthalimide
(21 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgI (66 μL, 0.20 mmol, 2.0 equiv, 3.0
M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–50% EtOAc/hexanes)
to afford the title compound as a yellow oil (29 mg, 87 μmol,
87% yield). TLC R = 0.6 (50%
EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 7.58–7.52 (m, 3H), 7.45–7.40
(m, 1H), 3.87 (br s, 1H), 3.49 (ddd, J = 14.4, 9.2,
5.7 Hz, 1H), 3.21–3.11 (m, 3H), 2.29–2.19 (m, 1H), 2.15–2.03
(m, 1H), 1.69 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 167.4, 148.1, 132.5, 130.1, 129.6, 123.3, 121.7, 88.8,
39.5, 32.9, 24.4, 3.1; IR (neat) 3306, 2925, 1675, 1616,
1470, 1407, 1373, 1199, 1141, 1092, 948, 764, 698 cm–1; HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C12H14INO2H, 332.0148; found, 332.0156.Iodide 26 was prepared according to
a modified Method
C. The following amounts of reagents were used: N-(3-hydroxypropyl)phthalimide (21 mg, 0.10 mmol, 1.0 equiv), MsCl
(12 μL, 0.15 mmol, 1.5 equiv), Et3N (21 μL,
0.15 mmol, 1.5 equiv), DCM (0.50 mL, 0.20 M in substrate), MeMgI (66
μL, 0.20 mmol, 2.0 equiv, 3.0 M in Et2O), PhMe (0.50
mL, 0.20 M in substrate). Upon addition of MeMgI, the reaction mixture
was allowed to stir at −78 °C for 5 min. The residue was
purified by column chromatography (0–50% EtOAc/hexanes) to
afford the title compound as a white solid (13 mg, 41 μmol,
41% yield). TLC R = 0.5 (25%
EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.4, 3.1 Hz,
2H), 3.78 (t, J = 6.8 Hz, 2H), 3.17 (t, J = 7.1 Hz, 2H), 2.25 (quint, J = 7.0 Hz, 2H). Analytical
data is consistent with literature values.[63]Bromide 36 was prepared according to
Method E. The
following amounts of reagents were used: N-(3-hydroxypropyl)phthalimide
(21 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgBr (0.11 mL, 0.30 mmol, 3.0 equiv, 2.7 M
in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (0–50% EtOAc/hexanes)
to afford the title compound as a pale-yellow solid (24 mg, 83 μmol,
83% yield). m.p. 85–88 °C; TLC R = 0.4 (50% EtOAc/hexanes, KMnO4 stain); H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 1H), 7.61–7.55
(m, 2H), 7.50–7.46 (m, 1H), 3.69 (ddd, J =
14.3, 8.6, 5.8 Hz, 1H), 3.50–3.45 (m, 2H), 3.41 (ddd, J = 14.4, 8.5, 6.2 Hz, 1H), 2.76 (s, 1H), 2.42–2.32
(m, 1H), 2.22 (sext, J = 7.1 Hz, 1H), 1.74 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 167.2, 147.9,
132.6, 130.4, 129.8, 123.4, 121.6, 88.8, 37.6, 32.2, 31.3, 24.3; IR (neat) 3311, 2926, 1678, 1470, 1409, 1374, 1141, 1095,
949, 764, 698 cm–1; HRMS (TOF MS ES+) m/z: [M + Na]+ calcd for C12H14BrNO2Na, 306.0106; found, 306.0104.Alcohol 65 was prepared according to
a procedure reported
by Hu.[64] In a glovebox, a flame-dried round-bottom
flask equipped with a stir bar was added LiAlH4 (77 mg,
2.0 mmol, 2.6 equiv). The flask with sealed with a septum and removed
from the glovebox. Under N2, THF (3.9 mL, 0.20 M in substrate)
was added, and the reaction mixture was cooled to 0 °C. After
5 min, SI-7 (390 mg, 0.78 mmol, 1.0 equiv) was added
dropwise. The reaction mixture was allowed to stir at 0 °C for
3 h. To quench, 1 M HCl was added dropwise at 0 °C. The reaction
mixture was extracted with EtOAc (3 ×20 mL), and the combined
organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (0–20% EtOAc/hexanes) to afford the title
compound as a white solid (310 mg, 0.65 mmol, 84%). TLC R = 0.4 (20% EtOAc/hexanes, CAM stain); H NMR (400 MHz, CDCl3) δ 3.63–3.54 (m, 3H), 1.97–0.89 (m, 44H), 0.64
(s, 3H), 0.06 (s, 6H). Analytical data is consistent with literature
values.[64]Iodide 27 was prepared according to
a modified Method
C. The following amounts of reagents were used: alcohol 65 (46 mg, 97 μmol, 1.0 equiv), MsCl (11 μL, 0.15 mmol,
1.5 equiv), Et3N (20. μL, 0.15 mmol, 1.5 equiv),
DCM (0.48 mL, 0.20 M in substrate), followed by MeMgI (96 μL,
0.29 mmol, 3.0 equiv, 3.0 M in Et2O), and PhMe (0.48 mL,
0.20 M in substrate). The residue was purified by flash column chromatography
(0–10% Et2O/hexanes) to afford the title compound
as a white solid (48 mg, 81 μmol, 84%, 8.2% DCM by NMR). TLC R = 0.3 (100% hexanes); H NMR (400 MHz, CDCl3) δ 3.62–3.55 (m, 1H), 3.21–3.10 (m, 2H), 1.95–1.73
(m, 7H), 1.56–0.89 (m, 36H), 0.63 (s, 3H), 0.06 (s, 6H). Analytical
data is consistent with literature values.[64]Alcohol 66 was prepared according to
the following
procedure. In a glovebox, a flame-dried round-bottom flask with a
stir bar was charged with LiAlH4 (59 mg, 1.6 mmol, 2.6
equiv), capped, and brought out of the glovebox. A N2 inlet
and THF (3.0 mL, 0.20 M in substrate) were added. The mixture was
cooled to 0 °C, and ester 68 (0.25 g, 0.60 mmol,
1.0 equiv) was added as a solution in THF (1.0 M in substrate). The
reaction mixture was warmed to rt and allowed to stir for 2 h. Then,
sat. aqueous NH4Cl was added, and the crude mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography
(0–20% EtOAc/hexanes) to afford the title compound as a sticky
white solid (0.19 g, 0.50 mmol, 83% yield). m.p. 39–46
°C; TLC R = 0.3 (20% EtOAc/hexanes,
CAM stain); H NMR (500 MHz,
CDCl3) δ 4.58 (as, 1H), 3.61 (m, 2H), 2.27–2.18
(m, 1H), 1.98 (ad, J = 12.8 Hz, 1H), 1.95–1.75
(m, 4H), 1.74–1.50 (m, 7H), 1.50–1.33 (m, 6H), 1.33–1.01
(m, 10H), 1.01–0.96 (m, 3H), 0.92 (d, J =
6.3 Hz, 3H), 0.65 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 63.7, 61.7, 56.7, 56.3, 42.8, 40.5, 40.3, 36.6,
35.7, 35.6, 35.2, 34.6, 31.9, 30.0, 29.4, 29.0, 28.3, 26.6, 26.4,
24.2, 23.8, 21.0, 18.9, 12.1; IR (neat) 3331, 2926, 2863,
1444, 1376, 1278, 1056, 1014, 983, 952, 890, 712, 615, 577 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C24H41ClO, 380.2846; found, 380.2831.Iodide 28 was prepared according to
Method C. The
following amounts of reagents were used: alcohol 66 (38
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgI (66 μL, 0.20 mmol, 2.0 equiv, 3.0
M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (100% hexanes) to afford the
title compound as a yellow oil (42 mg, 86 μmol, 86% yield). TLC R = 0.4 (100% hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 4.58 (br s, 1H), 3.19 (dt, J = 9.2, 6.9
Hz, 1H), 3.12 (dt, J = 9.0, 7.5 Hz, 1H), 2.26–2.18
(m, 1H), 2.00–1.65 (m, 8H), 1.62–1.51 (m, 4H), 1.51–1.33
(m, 5H), 1.32–0.95 (m, 13H), 0.91 (d, J =
6.6 Hz, 3H), 0.65 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 61.7, 56.7, 56.1, 42.8, 40.5, 40.2, 36.9, 36.6,
35.7, 35.2, 35.1, 34.6, 30.4, 30.0, 29.0, 28.4, 26.6, 26.4, 24.2,
23.8, 21.0, 18.8, 12.1, 7.8; IR (neat) 2926, 2861, 1444,
1376, 1278, 1251, 1236, 1171, 984, 906, 733, 711, 616 cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C24H40ClI, 490.1863;
found, 490.1877.Bromide 37 was prepared according to
Method E. The
following amounts of reagents were used: alcohol 66 (38
mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5 equiv),
Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50 mL,
0.20 M in substrate), MeMgBr (0.11 mL, 0.20 mmol, 2.0 equiv, 2.7 M
in Et2O), PhMe (0.50 mL, 0.20 M in substrate). The residue
was purified by column chromatography (100% hexanes) to afford the
title compound as a white solid (34 mg, 77 μmol, 77% yield). m.p. 59–63 °C; TLC R = 0.4 (100% hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 4.58 (as,
1H), 3.44–3.32 (m, 2H), 2.27–2.18 (m, 1H), 2.00–1.66
(m, 8H), 1.61–1.47 (m, 5H), 1.47–1.33 (m, 4H), 1.32–0.95
(m, 13H), 0.92 (d, J = 6.6 Hz, 3H), 0.65 (s, 3H); C{H} NMR (125.8 MHz, CDCl3) δ 61.7, 56.7, 56.1,
42.8, 40.4, 40.2, 36.6, 35.7, 35.26, 35.25, 34.64, 34.55, 34.5, 30.0,
29.6, 28.7, 28.3, 26.6, 26.4, 24.2, 23.8, 21.0, 18.7, 12.1; IR (neat) 2928, 2863, 1444, 1377, 1278, 1253, 984, 712, 615
cm–1; HRMS (TOF MS CI+) m/z: [M]+ calcd for C24H40ClBr, 442.2002; found, 442.2011.Alcohol 67 was prepared according to
a modified procedure
reported by Huo.[65] Under a N2 atmosphere, a round-bottom flask with a stir bar was charged with
lithocholic acid (1.9 g, 5.0 mmol, 1.0 equiv) and MeOH (17 mL, 0.30
M in substrate). H2SO4 (0.82 mL, 15 mmol, 3.0
equiv) was quickly added, and then the flask was equipped with a reflux
condenser and heated to reflux in an oil bath. The reaction mixture
was allowed to stir for 3 h before cooling and quenching dropwise
with sat. aqueous NaHCO3 until the bubbling stopped. The
reaction mixture was extracted with DCM (×3), dried with Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (0–30% EtOAc/hexanes) to
afford the title compound as a white solid (1.7 g, 4.5 mmol, 89% yield). TLC R = 0.4 (30% EtOAc/hexanes, KMnO4 stain); H NMR (400
MHz, CDCl3) δ 3.66 (s, 3H), 3.66–3.57 (m,
1H), 2.35 (ddd, J = 15.4, 10.3, 5.2 Hz, 1H), 2.27–2.17
(m, 1H), 1.95 (ad, J = 11.9 Hz, 1H), 1.91–1.70
(m, 5H), 1.66 (ad, J = 12.9 Hz, 1H), 1.61–1.47
(m, 2H), 1.46–0.85 (m, 24H), 0.64 (s, 3H). Analytical data
is consistent with literature values.[66]Iodide 29 was prepared according to
a modified Method
C. The following amounts of reagents were used: alcohol 67 (0.16 g, 0.40 mmol, 1.0 equiv), MsCl (47 μL, 0.60 mmol, 1.5
equiv), Et3N (84 μL, 0.60 mmol, 1.5 equiv), DCM (2.0
mL, 0.20 M in substrate), MeMgI (0.27 mL, 0.80 mmol, 2.0 equiv, 3.0
M in Et2O), PhMe (2.0 mL, 0.20 M in substrate). Upon addition
of MeMgI, the reaction mixture was allowed to stir at 0 °C for
1 h. The residue was purified by column chromatography (0–10%
EtOAc/hexanes) to afford the title compound as a white solid (0.17
g, 0.33 mmol, 83% yield). TLC R = 0.4 (10% EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 5.00 (as, 1H), 3.66
(s, 3H), 2.35 (ddd, J = 15.5, 10.3, 5.3 Hz, 1H),
2.21 (ddd, J = 16.2, 9.9, 6.5 Hz, 1H), 2.04–1.71 (m, 7H), 1.70–1.46
(m, 9H), 1.46–1.17 (m, 6H), 1.16–0.86 (m, 10H), 0.65
(s, 3H). Analytical data is consistent with literature values.[67]Bromide 38 was prepared according to
a modified Method
E. The following amounts of reagents were used: alcohol 67 (39 mg, 0.10 mmol, 1.0 equiv), MsCl (12 μL, 0.15 mmol, 1.5
equiv), Et3N (21 μL, 0.15 mmol, 1.5 equiv), DCM (0.50
mL, 0.20 M in substrate), MeMgBr (73 μL, 0.20 mmol, 2.0 equiv,
2.7 M in Et2O), PhMe (0.50 mL, 0.20 M in substrate). Mesylation
was allowed to stir for 30 min. Upon addition of MeMgBr, the reaction
mixture was allowed to stir at 0 °C for 2 h. The residue was
purified by column chromatography (0–10% EtOAc/hexanes) to
afford the title compound as a white solid (29 mg, 63 μmol,
63% yield) containing chloride 68 (2.3 mg, 6.0 μmol,
6% yield). TLC R = 0.5 (10%
EtOAc/hexanes, CAM stain); H NMR (500 MHz, CDCl3) δ 4.80 (aquint, J = 2.8 Hz, 1H), 3.66 (s, 3H), 2.35 (ddd, J = 15.5,
10.5, 5.2 Hz, 1H), 2.29–2.16 (m, 2H), 2.00–1.74 (m,
7H), 1.67–1.51 (m, 4H), 1.49–1.22 (m, 8H), 1.22–0.85
(m, 12H), 0.65 (s, 3H). Analytical data is consistent with literature
values.[68]
Authors: Geraldo Duran-Camacho; Devin M Ferguson; Jeff W Kampf; Douglas C Bland; Melanie S Sanford Journal: Org Lett Date: 2021-06-17 Impact factor: 6.005
Scheme 1
Scheme 2
Scheme 3
Scheme 4