Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki-Heck annulation reaction from (+)-Vince lactam-derived cyclopentenyl-tethered 2-bromo-N-methylanilines for the formation of N-methylspiroindolines. A series of 14 N-methylspiroindolines were synthesized in 59-81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.
Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki-Heck annulation reaction from (+)-Vince lactam-derived cyclopentenyl-tethered 2-bromo-N-methylanilines for the formation of N-methylspiroindolines. A series of 14 N-methylspiroindolines were synthesized in 59-81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.
The spiroindoline scaffold is present
in several natural products[1] and has received
interest for use in medicinal
chemistry projects with targets related to cancer,[2−4] antithrombosis,[5] as well as in vivo imaging of
neurodegenerative processes/disorders (Supporting Information).[6] To further improve
the utility of these unique scaffolds as tools in biotechnology and
drug development projects new synthetic methods to access spiroindolines,
preferably with high stereoselectivity, are needed. Several ways of
producing spiroindolines exist in the literature, such as through
interrupted Fischer indolization,[7] isomerization/spirocyclization/transfer
hydrogenation,[8,9] photocatalytic [2,2]-addition,[10] silver[11,12] and gold[13] catalyzed cyclization, as well as palladium-catalyzed
dearomative ring-closing (Supporting Information).[14] The Mizoroki–Heck reaction
is one of the prominent methods for carbon–carbon bond formation,
which is well-suited for utilization in the synthesis of sterically
demanding spirocyclic structures, as demonstrated in the synthesis
of spirooxindoles,[15−17] spirobenzofurans,[18] and
spirolactones.[19] This is due to the tendency
of the intramolecular Mizoroki–Heck reaction to selectively
yield the exo cyclization product upon the intramolecular
reaction between an aryl halide and an alkene.[20] This regioselectivity is observed in the construction of
five- or six-membered rings even when the electronic properties of
the alkene would suggest a different outcome, as the exo route is less sterically demanding. Even though the Mizoroki–Heck
reaction has been applied for the synthesis of other spirocycles,
palladium-catalyzed spiroindoline synthesis is less-explored. In this
work, a 2,5-dimethylpyrrole-protected amine is used as a chiral auxiliary
to construct the quaternary all-carbon spirocenter in the intramolecular
Mizoroki–Heck synthesis of spiroindolines with high stereocontrol.
This ability to achieve facial selectivity of the Mizoroki–Heck
annulation through protection of the amine functionality with bulky
protecting groups has earlier been investigated[21] and used in our group for the preparation of spirooxindoles[16,17] and spirobenzofurans.[18] The essential
chiral starting structure utilized in our new methodology, the stereopure
(+)-Vince lactam (1), has previously
garnered attention for its utilization in the synthesis of chiral,
substituted cyclopentyl- and pentenyl rings in drug discovery projects.
Some prominent examples are the synthesis of abacavir and peramivir,
which are used for the treatment of viral diseases.[22] Rigidified unnatural amino acids are also of importance
to drug discovery programs, where they can function either as single
molecular entities or be incorporated into proteins or peptides[23,24] to impart improved pharmacokinetic characteristics, such as higher
bioavailability and improved metabolic stability,[25] of the medicinal compounds.Herein, we report the
synthesis of 14 novel spiroindolines in a
diastereo- and regioselective manner through an intramolecular Mizoroki–Heck
cyclization of a series of amino group functionalized cyclopentenyl-tethered N-methylbromoanilines. Diversification of substrates was
achieved through varying the substitution of the anilines used for
the spiroindoline synthesis. Through palladium(0)-catalyzed carbonylation
chemistry, one compound was converted to an ester-protected unnatural
amino acid which was orthogonally deprotected.
Results and Discussion
The study was initiated with
the synthesis of N-allylaniline cyclization precursor 6 using a literature
procedure for the first three synthetic steps (Scheme ).[21,18] This was achieved through
acid-promoted ring opening of (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one
(1, (+)-Vince lactam) to get the optically
pure ammonium chloride salt 2. The free amine was converted
to the corresponding 2,5-dimethylpyrrole, a protecting group strategy
chosen due to its proven ability to control the diastereoselectivity
of a related intermolecular Mizoroki–Heck alkenylation/arylation
of alkene 3.[21] The air-sensitive
intermediate 2 was without further purification subjected
to a DBU-mediated double-bond isomerization to yield acrylic ester 3. The methyl ester was then reduced using DIBAL-H, followed
by conversion of the allyl alcohol 4 to the corresponding
allyl chloride 5 via an Appel reaction with triphenylphosphine
and carbon tetrachloride. To yield the secondary amine cyclization
precursor 6, allyl chloride 5 was substituted
with 2-bromoaniline under microwave heating in a sealed reaction vial
and with excess amounts of sodium hydride.
Reaction conditions
for a: 1 (1 equiv), SOCl2 (1.1
equiv),
MeOH, 100%. b: 1. 2 (1 equiv), hexane-2,5-dione
(1 equiv), DIPEA (1 equiv), MeOH. 2. DBU (3 equiv), THF, 85%. c: 3 (1 equiv), DIBAL-H (3 equiv), THF, 84%. d: 4 (1 equiv), PPh3 (1.2 equiv),
CCl4, DCM, 81%. e: 5 (1 equiv),
NaH (3 equiv), 2-bromoaniline (2 equiv), THF, microwave heated at
80 °C, 63%.With substrate 6 in hand, screening of reaction conditions
for the Mizoroki–Heck cyclization was commenced. The results
are presented in Table . A Pd(OAc)2/dppf catalytic system with Et3N as the base and DMF as the solvent was chosen as the starting point,
as this has previously been successfully used for the synthesis of
spiroxindoles using a related ring-closing protocol.[16] Screening of the reaction temperature showed no improvement
in conversion when raising the temperature from 80 to 100 °C
or 120 °C (entries 1–4). Decreasing dppf loading from
10 to 5 mol % as well as using precatalyst Pd(dppf)Cl2 (5
mol %) resulted in a dramatic lowering of the conversion from 6 to 7 (entries 5–7). Our focus was then
turned to other palladium ligands, where bis(tri-tert-butylphosphine)palladium (Pd(t-Bu3P)2) at higher loading (10 mol %) furnished an improved outcome
with >99% conversion after 16 h at 80 °C and an isolated yield
of 64% (entry 11). Old-fashioned PPh3 did not perform as
well as a ligand in the reaction (entry 8), presumably because of
the aryl bromide bond being relatively electron-rich due to the electron
donating effect of the aniline nitrogen, making oxidative addition
sluggish with this ligand.[20] A couple of
control experiments were also conducted, in which omission of palladium
afforded <1% conversion (entry 12), and omission of base provided
3% conversion after 16 h (entry 13), thus verifying the necessity
of these reaction components. During the optimization attempts, it
was observed that both 6 and 7 were somewhat
unstable under the reaction conditions, giving rise to unidentified
byproducts and low yields, prompting us to investigate if functionalization
of the secondary aniline could remedy these issues. Initially, benzylation
and acetylation of the secondary aniline nitrogen were attempted,
however unsuccessfully. N-Methylation of N-allylaniline 6 provided a way to synthesize N-methylallylaniline 8a (Scheme ), which was evaluated with the best-performing
conditions from the earlier reaction condition screening. For N-methylallylaniline 8a Pd(t-Bu3P)2 proved effective in catalyzing the
reaction, providing >99% conversion after 16 h at 80 °C with
an isolated yield of 83% (entry 14). The higher isolated yield with
the N-methylated substrate (entry 14 compared to
entry 11) indicates that our N-methylation strategy
was successful in improving compound stability. Compared to entry
1, the Pd(OAc)2/dppf catalytic system performed relatively
poorly with the N-methylallylaniline substrate (entry
15).
Table 1
Optimization of Reaction Conditions
for Intramolecular Mizoroki–Heck Spirocyclization of 6/8aa
entry
starting material
Pd (mol %)
ligand (mol %)
temp (°C)
time (h)
NMR ratio (6:7 or 8a:9a)b
isolated yield of 7/9ac
1
6
Pd(OAc)2 (5)
dppf (10)
80
48
11:89
2
6
Pd(OAc)2 (5)
dppf (10)
100
16
25:75
3
6
Pd(OAc)2 (5)
dppf (10)
120
5
19:81
4
6
Pd(OAc)2 (5)
dppf (10)
120
16
22:78
5
6
Pd(OAc)2 (5)
dppf (5)
80
5
83:17
6
6
Pd(OAc)2 (5)
dppf (5)
80
16
82:18
7
6
Pd(dppf)Cl2 (5)
80
16
90:10
8
6
Pd(OAc)2 (5)
PPh3 (10)
80
16
55:45
9
6
Pd(OAc)2 (5)
XPhos (10)
80
16
96:4
10
6
Pd(t-Bu3P)2 (5)
80
5
11:89
11
6
Pd(t-Bu3P)2 (10)
80
16
1:99
64%
12
6
t-Bu3P (10)
80
16
100:0
13d
6
Pd(t-Bu3P)2 (10)
80
16
97:3
14
8a
Pd(t-Bu3P)2 (10)
80
16
1:99
83%
15
8a
Pd(OAc)2 (5)
dppf (10)
80
16
47:53
Reaction conditions: cyclization
precursor 6 or 8a (0.1 mmol, 1 equiv), Et3N (2 equiv), DMF. Amounts of palladium precatalyst and ligands
listed in the table.
Ratio
between 6:7 or 8a:9a determined by 1H NMR of crude reaction mixture.
Isolated yields after column chromatography.
Experiment run without Et3N. In all screening reactions diastereoselectivity toward
the anti product was >98% according to 1H NMR of
the crude reaction mixture.
Scheme 2
Synthesis of Precursors 8a–8n for
Intramolecular Cyclization through Allyl Chloride Substitution Followed
by N-Methylation
Reaction conditions:
1. 5 (1 equiv), aniline (2 equiv), NaH (3 equiv), dry
THF, microwave
heated at 80 °C. 2. MeI (1.2 equiv), 1.0 M KHMDS in dry THF (1.3
equiv), dry DMF. Isolated yields reported are for two steps (>95%
purity as determined by 1H NMR).
Synthesis of Precursors 8a–8n for
Intramolecular Cyclization through Allyl Chloride Substitution Followed
by N-Methylation
Reaction conditions:
1. 5 (1 equiv), aniline (2 equiv), NaH (3 equiv), dry
THF, microwave
heated at 80 °C. 2. MeI (1.2 equiv), 1.0 M KHMDS in dry THF (1.3
equiv), dry DMF. Isolated yields reported are for two steps (>95%
purity as determined by 1H NMR).Reaction conditions: cyclization
precursor 6 or 8a (0.1 mmol, 1 equiv), Et3N (2 equiv), DMF. Amounts of palladium precatalyst and ligands
listed in the table.Ratio
between 6:7 or 8a:9a determined by 1H NMR of crude reaction mixture.Isolated yields after column chromatography.Experiment run without Et3N. In all screening reactions diastereoselectivity toward
the anti product was >98% according to 1H NMR of
the crude reaction mixture.Rewardingly, in all entries of Table , compound 7/9a was always observed
as the diastereomer resulting from a stereocontrolled anti migratory insertion. As the secondary N-allylaniline
starting materials were found to be unstable during preparation, the
focus of our inquiry was shifted to N-methylallylaniline
Mizoroki–Heck substrates. Cyclization precursors 8a–8n based on this concept were prepared in a
two-step sequence, where allylic chloride substitution followed by N-methylation with methyl iodide and potassium bis(trimethylsilyl)amide
(KHMDS) gave the desired 8a–8n in
isolated yields ranging between 5–89% over two steps (Scheme ). Unfortunately,
some electron-deficient anilines furnished only low reactivity under
the investigated conditions. Allylation of 4-amino-3-bromobenzoic
acid and 2-bromo-5-nitroanline led to trace amounts of product formation
as seen on LC-MS with allyl chloride 5 still remaining
in the reaction mixture. 1-(3-Amino-4-bromophenyl)ethan-1-one afforded
only low amounts of product with the partial conversion of allyl chloride 5 but also significant byproduct formation.Having established
the optimum reaction conditions, the scope of
the intramolecular Heck–Mizoroki spirocyclization was investigated
by varying the substitution of the aniline. The results are presented
in Scheme . Analogous
to what was observed during reaction optimization, only the diastereomer
from an anti insertion was detected by 1H NMR for compounds 9a–9n. All substrates
applied in the spirocyclization reaction performed satisfactorily
with isolated yields ranging between 59 and 81%. No immediate pattern
could be discerned concerning the outcome of electron-poor compared
to electron-rich anilines. The chemoselectivity of the reaction was
displayed in the synthesis of 9c, where the chloride
was left intact with no signs of dehalogenation, and the compound
could be isolated in 61% yield. Methyl-substituted aniline precursors 8e–8h were all well accommodated in the
spirocyclization reaction giving moderate to good isolated yields.
Interestingly, the 3-position of the aniline could be substituted
with a methyl group without the additional steric hindrance around
the reactive center negatively effecting the reactivity, with the
isolated yield of 9e comparable to what was achieved
for 4-, 5-, and 6-methylanilines 9f–9h. Dibromo substrates 8j and 8k afforded
the corresponding spirocyclic products in 67% and 65% yield, respectively.
However, debromination was detected in the spirocyclization reactions
where in both cases debromination was seen only for the bromide in
the 4-position (8j) and 5-position (8k).
The debrominated product was in both cases observed as product 9a, and it is unknown whether this debromination occurs before
or after ring closing. The hydride for this dehalogenation might originate
from either triethylamine or DMF.[26,27]1H NMR analysis of the crude reaction mixture of the cyclization reactions
of substrates 8j and 8k displayed 9% and
12% debromination, respectively. Aminopyridine 8m was
well-tolerated in the reaction, providing the spirocyclic 7-azaindoline 9m in a very good isolated yield (81%). Compound 9m was also subjected to X-ray crystallography studies (CCDC2144389),
confirming the R-configuration of the spirocarbon
in accordance with an anti insertion (Figure ). The enantiomer 9n was prepared with excellent stereoselectivity and isolated in a
yield similar to 9a. Thus, the results of Scheme could be extrapolated to synthesize
any of the enantiomers of compounds 9a–9m starting from (−)-Vince lactam.
Scheme 3
Spirocyclization of N-Methylallylanilines 8a–8n
Reaction conditions
for the synthesis
of spiroindolines 9a–9n: cyclization
precursor 8a–8n (1 equiv), Pd(t-Bu3P)2 (10 mol %), Et3N (2 equiv), DMF. Isolated yields determined after flash chromatography
(>95% purity as determined by 1H NMR).
Figure 1
PyMOL visual representation
of the X-ray crystallography structure
of compound 9m.
PyMOL visual representation
of the X-ray crystallography structure
of compound 9m.
Spirocyclization of N-Methylallylanilines 8a–8n
Reaction conditions
for the synthesis
of spiroindolines 9a–9n: cyclization
precursor 8a–8n (1 equiv), Pd(t-Bu3P)2 (10 mol %), Et3N (2 equiv), DMF. Isolated yields determined after flash chromatography
(>95% purity as determined by 1H NMR).In order to access the benzyl-protected C-terminal end
of our desired
unnatural amino acid, aryl bromide 9k was subjected to
a palladium-catalyzed benzyloxycarbonylation with a PdOAc2:XantPhos catalytic system (Scheme ).[28] The reaction was run
in a two-chamber system, where one chamber is dedicated to the in situ production of carbon monoxide from Mo(CO)6, which can then diffuse to the other chamber where the carbon monoxide-consuming
benzyloxycarbonylation can occur.[29,30] Employing
these conditions, the C- and N-protected unnatural amino acid 10 was synthesized and isolated in 64% yield.
Scheme 4
Benzyloxycarbonylation
of 5-Bromospiro-indoline 9k
Reaction conditions
for 10: 9k (1 equiv), Pd(OAc)2 (2 mol
%), XantPhos (4 mol %), Mo(CO)6 (2 equiv), DBU (3 equiv),
Et3N (2 equiv), and benzyl alcohol used in both chambers,
64%.
Benzyloxycarbonylation
of 5-Bromospiro-indoline 9k
Reaction conditions
for 10: 9k (1 equiv), Pd(OAc)2 (2 mol
%), XantPhos (4 mol %), Mo(CO)6 (2 equiv), DBU (3 equiv),
Et3N (2 equiv), and benzyl alcohol used in both chambers,
64%.The 2,5-dimethylpyrrole protected amine 10 was converted
to primary amine 11 through a deprotection protocol employing
excess amounts of hydroxylamine hydrochloride in a mixture of ethanol
and water (Scheme ).[31]
Scheme 5
Removal of 2,5-Dimethylpyrrole Protecting
Group to Form Free Amine 11a
Removal of 2,5-Dimethylpyrrole Protecting
Group to Form Free Amine 11a
Reaction conditions
for 11: 10 (1 equiv), NH2OH·HCl
(10
equiv), EtOH: H2O (2:1), 54%.For
the orthogonal deprotection of the carboxylic acid, hydrolysis
of the benzyl ester with LiOH in a THF:water mixture was used to provide
the free carboxylic acid in a yield of 83% (Scheme ).
Scheme 6
Removal of Benzyl Protecting Group
to Form Free Carboxylic Acid 12
Removal of Benzyl Protecting Group
to Form Free Carboxylic Acid 12
Reaction conditions
for 12: 10 (1 equiv), LiOH (5 equiv), THF:H2O (3:1), 83%.To further examine the
mechanism leading to the diastereoselectivity
of the reaction, computational studies were conducted.Density
functional theory calculations were performed for the Mizoroki–Heck
annulation of 8a essentially as described previously
for similar systems.[16,21] The stereoconfiguration of the
spirocenter is determined during the migratory insertion transition
state (MI). Starting from the aryl-palladium complex, two diastereomeric
π-complexes can form. It was found that the syn π-complex was slightly more stable than the anti π-complex. Assuming a fast equilibrium between the diastereomeric
π-complexes, Curtin–Hammett conditions apply,[32] and the diastereoselectivity will be governed
by the energy difference between the two diastereomeric migratory
insertions. The energy barrier for the migratory insertion leading
to anti product 9a was found to be 2.9
kcal/mol lower than the insertion leading to the syn diastereomer (Figure , Supporting Information), in line with
the Experimental Results. The transition states
for the migratory insertion leading to the anti and syn products are shown in Figure .
Figure 2
Relative free energies for Mizoroki–Heck
reaction intermediates
and transition states leading to syn and anti product calculated by DFT using B3LYP-D3. Additional
ligands removed from palladium in the image for clarity. R = π complex intermediate, MI = migratory insertion
transition state, I = σ complex intermediate, BHE = β-hydride elimination transition state, P = product.
Figure 3
Diastereomeric transition states for migratory insertion
illustrating
how the 2,5-dimethylpyrrole substituent determines the ring conformation
of the cyclopentene. This in turn makes the two trans protons in the
top left structure antiperiplanar to the aryl palladium, resulting
in a hyperconjugative stabilization of this diastereomeric migratory
insertion. Note that the structure to the right is inverted to facilitate
the structural comparison. Hydrogen atoms not belonging to the cyclopentenyl
ring have been removed from the image for clarity.
Relative free energies for Mizoroki–Heck
reaction intermediates
and transition states leading to syn and anti product calculated by DFT using B3LYP-D3. Additional
ligands removed from palladium in the image for clarity. R = π complex intermediate, MI = migratory insertion
transition state, I = σ complex intermediate, BHE = β-hydride elimination transition state, P = product.Diastereomeric transition states for migratory insertion
illustrating
how the 2,5-dimethylpyrrole substituent determines the ring conformation
of the cyclopentene. This in turn makes the two trans protons in the
top left structure antiperiplanar to the aryl palladium, resulting
in a hyperconjugative stabilization of this diastereomeric migratory
insertion. Note that the structure to the right is inverted to facilitate
the structural comparison. Hydrogen atoms not belonging to the cyclopentenyl
ring have been removed from the image for clarity.
Conclusion
A palladium-catalyzed Mizoroki–Heck
method employing Pd(t-Bu3P)2 was developed for the diastereoselective
spirocyclization of a series of N-methylallylanilines
to form spiroindolines. This diastereoselectivity was confirmed by
X-ray crystallography as well as 2D NOESY. Through a palladium-catalyzed
carbonylation protocol, a bromo-substituted spiroindoline was converted
to a C- and N-protected unnatural amino acid, where both the amine
and carboxylic acid moieties were subsequently orthogonally deprotected.
Experimental Section
General Methods
1H-, 13C-, and 19F-NMR as well as 2D-NMR spectra were recorded on a Bruker
400 MHz instrument with chemical shifts reported in parts per million
(ppm) and using the residual solvent peak as internal reference. High-resolution
mass spectra (HRMS) was recorded using a mass spectrometer with electrospray
ionization (ESI) with a 7-T hybrid linear ion trap. Thin-layer chromatography
(TLC) with Supelco TLC plates with fluorescence indicator (254 nm)
as well as LC/MS on a Thermo Fischer Scientific UltiMate 3000 HPLC
system with an MSQ Plus mass spectrometer was used for monitoring
of reactions. Manual flash chromatography was run using silica gel
(230–400 mesh). Automated flash chromatography was conducted
on a Biotage Isolera One flash purification instrument with Biotage
Sfär cartridges. Automated reverse phase flash chromatography
was performed on a Buchi Reveleris X2 flash chromatography purification
system using a Claricep Flash Spherical C18 column. For conventional
heating of reactions, DrySyn plates were used as heating mantle. For
microwave reactions, the reactions were run in sealed microwave vials
using an Anton Paar MonoWave 400 or Biotage Initiator microwave reactor.
Optical rotation was recorded on a Rudolph Autopol II polarimeter.
Palladium-catalyzed carbonylation reactions were run in two fused
microwave vials (H-tubes).
In an oven-dried reaction vial, Pd(t-Bu3)2 (13.0 mg, 25.4 μmol)
and Et3N (50.8 mg, 70 μL, 0.502 mmol) were taken
together. The vial was evacuated and flashed with nitrogen three times.
DMF (1 mL) was introduced in the reaction vial, and the solution was
allowed to stir at room temperature for 5 min. Afterward, 6 (86.7 mg, 0.251 mmol) in 1 mL of DMF was introduced in the reaction
mixture and stirred for 16 h at 80 °C. After completion of the
reaction, the reaction mixture was quenched with water (5 mL), and
the product was extracted with ethyl acetate (3 × 10 mL). The
combined organic layer was washed with a saturated solution of brine
and dried over anhydrous MgSO4, evaporated, and purified
by column chromatography (0–12% EtOAc in pentane) to yield
the product as an oil (42.5 mg, 0.160 mmol, 64%). [α]D= −16.76 (c= 0.99, THF). 1H NMR (400 MHz, DMSO-d6) δ 7.01–6.91 (m, 2H), 6.58 (td, J = 7.4, 1.0 Hz, 1H), 6.54–6.50 (m, 1H), 5.93 (dd, J = 5.5, 1.9 Hz, 1H), 5.88 (dd, J = 5.5,
2.5 Hz, 1H), 5.61–5.54 (m, 4H), 3.59 (dd, J = 9.3, 2.0 Hz, 1H), 3.41 (dd, J = 9.3, 2.1 Hz,
1H), 2.64 (dd, J = 13.4, 8.5 Hz, 1H), 2.19 (s, 6H),
1.99 (dd, J = 13.4, 8.1 Hz, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 151.1, 137.4,
134.7, 131.1, 127.6, 127.2, 122.4, 117.3, 108.9, 106.0, 60.1, 59.3,
57.4, 46.5, 13.8. HRMS: calcd. for C18H21N2 [M + H]+ 265. 1705; found: 265.1710.General
procedure 1 for the synthesis of N-methylallylanilines 8a–8n. To a suspension of sodium hydride
(3 equiv) in dry THF (1 mL) was added a dry THF solution (2 mL) of
aniline (2 equiv) slowly at 0 °C. After stirring for 30 min,
allyl chloride 5 (1 equiv, 0.7 mmol) was added, and the
mixture was microwave heated at 80 °C for 2 h. Water (2 mL) was
slowly added (pay attention to hydrogen gas evolution), and the product
was extracted with EtOAc. The organic solvent was dried with MgSO4 and evaporated. Automated flash chromatography was run to
remove residual aniline from the mixture. The product was dissolved
in 3 mL of dry DMF in a 20 mL closed vial with a septum. The vial
was purged with nitrogen, and the mixture was cooled to 0 °C
on ice. 1.0 M KHMDS in dry THF (1.3 equiv) was added dropwise to the
cooled mixture, which was kept for stirring for 30 min. MeI (1.2 equiv)
was added dropwise, and the mixture was stirred for 1 h. After completion
of the reaction EtOAc (12 mL) was added, and the organic phase was
washed with water (3 × 12 mL), followed by brine (12 mL). The
organic phase was dried with MgSO4, and the solvent was
evaporated. The product was isolated by automated flash chromatography.
Compound 8n was synthesized according to general procedure 1 on a larger scale
(allyl chloride 5, 680 mg, 3.24 mmol). After flash chromatography
(0–4% EtOAc in pentane), the product was isolated as a white
solid (1038 mg, 2.88 mmol, 89% over two steps). [α]D25 = 19.01 (c = 0.1, THF). 1H NMR (400 MHz, acetonitrile-d3) δ 7.56 (dd, J = 8.0,
1.5 Hz, 1H), 7.33–7.27 (m, 1H), 7.22 (dd, J = 8.1, 1.6 Hz, 1H), 6.97–6.91 (m, 1H), 5.66–5.62 (m,
1H), 5.61 (s, 2H), 5.05–4.95 (m, 1H), 3.75 (d, J = 14.0 Hz, 1H), 3.64 (d, J = 14.0 Hz, 1H), 2.92–2.80
(m, 2H), 2.70 (s, 3H), 2.58–2.48 (m, 2H), 2.09 (s, 6H). 13C NMR (101 MHz, Aacetonitrile-d3) δ 152.0, 141.1, 134.6, 129.3, 128.3, 126.8, 125.6, 123.5,
120.9, 107.1, 56.9, 53.5, 42.2, 41.3, 40.1, 13.6. HRMS: calcd. for
C19H24BrN2 [M + H]+ 359.1123;
found: 359.1130.General procedure 2 for synthesis of N-methylspiroindolines 9a–9n. To an oven-dried reaction vial, Pd(t-Bu3P)2 (0.1 equiv) and Et3N (2 equiv) were added.
The vial was sealed and purged three times with nitrogen. DMF (1 mL)
was added to the vial, which was stirred at room temperature for 5
min. A solution of N-methylallylaniline (1 equiv)
in DMF (1 mL) was added, and the mixture heated at 80 °C for
16 h. Ethyl acetate (10 mL) was added, and the organic phase washed
with water (3 × 10 mL), followed by brine (10 mL). The organic
phase was dried with MgSO4 and evaporated. The product
was isolated by automated flash chromatography.
A reaction vial was loaded with 10 (68.3 mg, 0.166 mmol) and lithium hydroxide (20.0 mg, 0.835
mmol), and a THF:H2O mixture (3:1, 1 mL) was added. The
mixture was heated to 50 °C and stirred at that temperature for
20 h. The reaction mixture was diluted with 10 mL water and washed
with EtOAc (3 × 10 mL). The water phase was acidified with 2
M HCl and extracted with EtOAc (3 × 10 mL). The organic phase
was dried with MgSO4, filtered, and evaporated to yield
the product as a dark brown oil (44.4 mg, 0.138 mmol), 83%). The sample
was too dark to obtain value for optical rotation. 1H NMR
(400 MHz, chloroform-d) δ 7.57 (dd, J = 7.6, 1.4 Hz, 1H), 7.25 (d, J = 1.4
Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.07 (dd, J = 5.5, 2.0 Hz, 1H), 5.93 (dd, J = 5.5,
2.5 Hz, 1H), 5.78 (s, 2H), 5.62–5.54 (m, 1H), 3.60 (d, J = 9.1 Hz, 1H), 3.39 (d, J = 9.1 Hz, 1H),
2.87 (s, 3H), 2.78 (dd, J = 13.8, 8.5 Hz, 1H), 2.28
(s, 6H), 2.25 (dd, J = 13.8, 8.1 Hz, 1H). 13C NMR (101 MHz, chloroform-d) δ 172.1, 151.6,
142.4, 136.5, 132.8, 129.6, 128.2, 122.0, 121.8, 108.9, 106.4, 68.3,
60.6, 56.9, 46.1, 35.9, 14.1. HRMS: calcd. for C20H23N2O2 [M + H]+ 323.1760;
found: 323.1759.
Authors: Jean-Nicolas Desrosiers; Liana Hie; Soumik Biswas; Olga V Zatolochnaya; Sonia Rodriguez; Heewon Lee; Nelu Grinberg; Nizar Haddad; Nathan K Yee; Neil K Garg; Chris H Senanayake Journal: Angew Chem Int Ed Engl Date: 2016-09-07 Impact factor: 15.336
Authors: Jennifer X Qiao; Tammy C Wang; Réjean Ruel; Carl Thibeault; Alexandre L'Heureux; William A Schumacher; Steven A Spronk; Sheldon Hiebert; Gilles Bouthillier; John Lloyd; Zulan Pi; Dora M Schnur; Lynn M Abell; Ji Hua; Laura A Price; Eddie Liu; Qimin Wu; Thomas E Steinbacher; Jeffrey S Bostwick; Ming Chang; Joanna Zheng; Qi Gao; Baoqing Ma; Patricia A McDonnell; Christine S Huang; Robert Rehfuss; Ruth R Wexler; Patrick Y S Lam Journal: J Med Chem Date: 2013-11-12 Impact factor: 7.446
Authors: Amit Kumar; Dipak D Vachhani; Sachin G Modha; Sunil K Sharma; Virinder S Parmar; Erik V Van der Eycken Journal: Beilstein J Org Chem Date: 2013-10-14 Impact factor: 2.883
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