A Strategy to Construct cis-Hydrocarbazole via Nickel/Lewis Acid Dual-Catalyzed Arylcyanation

Article abstract of DOI:10.1021/acs.joc.9b03243

A strategy for the synthesis of cis-hydrocarbazole with a C3 quaternary carbon center has been developed through nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-hydrocarbazoles was accessed with high diastereoselectivities and atom eco

Full text of DOI:10.1021/acs.joc.9b03243

pubs.acs.org/joc
Note
A Strategy to Construct cis-Hydrocarbazole via Nickel/Lewis Acid
Dual-Catalyzed Arylcyanation
Hao Zhang, Peiqi Chen, Hesi Yang, Shiqiang Ma, Zemin Wang, Xingang Xie, Xiaolei Wang, Huilin Li,
and Xuegong She*
Cite This: https://dx.doi.org/10.1021/acs.joc.9b03243
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A strategy for the synthesis of cis-hydrocarbazole
with a C3 quaternary carbon center has been developed through
nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-
hydrocarbazoles was accessed with high diastereoselectivities and
atom economies in a good yield. The rich chemistry of the installed
nitrile group was demonstrated in the preparation of tryptamine-
and tryptophol-derived cis-hydrocarbazoles.
he cis-hydrocarbazole unit bearing two vicinal chiral
carbon centers at the C2 and C3 positions with C3 as the
all-carbon quaternary center is a prevalent structural element of
many terpene-indole alkaloids (Figure 1) with various
situ generated arynes to provide an alternative approach to a
variety of cis-hydrocarbazoles10c (Scheme 1b). Efficient
strategies for the synthesis of cis-hydrocarbazoles, particularly
those containing the C3 quaternary carbon center, are still
highly desirable. Inspired by research works from Nakao,
Hiyama, Ogoshi et al.,7 and Jacobsen et al.8 on nickel-catalyzed
arylcyanation,9 affording indanes or indolines, and with our
continuing interests in synthesis of biologically active terpene-
indole alkaloids,10 herein we report a novel synthetic strategy
for constructing cis-hydrocarbazoles containing C3 quaternary
carbon, utilizing nickel and Lewis acid dual-catalyzed
arylcyanation (Scheme 1c).
T
Our study was initiated with easily accessible benzonitrile 8b
as the model substrate to examine the feasibility of our
proposed strategy (Table 1). All substrates 8b−19b were
achieved through a three-step sequence consisting of a
substitution reaction between α-bromoketone 6 and aniline
7, Wittig reaction, and alkylation of aniline 8a−19a (Scheme
2). Thus, benzonitrile 8b was treated with Ni(cod)2 (5 mol %),
AlMe2Cl (20 mol %), and DPPE (10 mol %) in toluene at 100
°C for 12 h. To our delight, the cis-hydrocarbazole product 8c
was obtained in 10% yield with high regioselectivity and
diastereoselectivity (entry 1). The relative configuration of 8c
was established by NOE experiments (see the Supporting
Information for details). After screening several ligands
(entries 1−5) and Lewis acids (entries 5−7), the best set of
conditions include the Ni(cod)2/PEt3/AlMe2Cl system with
toluene as a solvent at 100 °C. As shown in Table 1, Lewis
acids (AlMe2Cl) could significantly promote the arylcyanation
Figure 1. Selected members of hydrocarbazole alkaloids.
biological properties and high structural diversity.1 For
instance, aspidospermidine (2) and minfiensine (3) share the
tryptamine-derived scaffold I,2,10e while mattogrossine (4) and
aspidophylline A (5) share the tryptophol-derived scaffold II.3
In addition, analogues of tryptamine-derived hydrocarbazole
were recently reported to resensitize methicillin-resistant
Staphylococcus aureus to β-lactam antibiotics.4 Therefore,
methods for constructing cis-hydrocarbazole in a highly
diastereoselective manner would be of great significance.
Numerous synthetic strategies to cis-fused hydrocarbazole
have been reported.5 Among them, [4+2] cycloaddition6 is the
most common approach (Scheme 1a). In 2017, our group
developed a novel [3+2]-annulation of p-quinamines and in
Received: December 1, 2019
Published: January 29, 2020
https://dx.doi.org/10.1021/acs.joc.9b03243
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Scheme 1. Established Methods and Our Strategy for Constructing cis-Hydrocarbazole
a
importance of each reagent. In the absence of the Lewis acid
(entry 12) or nickel/PEt3 (entry 13), experiments failed to
generate cis-hydrocarbazole product 8c.
Table 1. Optimization of the Reaction Conditions
With the optimized conditions in hand, we set out to explore
the scope of this strategy. As outlined in Table 2, several cis-
hydrocarbazoles were accessed through intramolecular arylcya-
nation in moderate to high yields and with high diaster-
eoselectivity. Both electron-withdrawing (9c) and electron-
donating substituents (10c, 11c) on the aryl ring were well-
tolerated. Specifically, the electron-withdrawing group (F) and
weak electron-donating group (methyl) at either the meta- or
para-position yield cis-hydrocarbazoles in a comparable yield as
that of the nonsubstituted substrate. Accordingly, the strong
electron-donating group MeO (12c) shows a deleterious effect
on the yield. The reactivity of a series of N-protected substrates
was also examined. For instance, N-methyl (8c), -ethyl (13b),
and -benzyl (14b) benzonitrile proceeded smoothly. N−H and
N-propargyl substrates decomposed and failed to provide the
desired products. The Al (III) would bond to the nitrogen
atom of the secondary amine in the N−H substrate (8a),
which would promote the oxidative addition of an electron-
rich nickel catalyst to allylic aniline, resulting in the formation
of an inactive π-allyl-nickel complex. A large-scale version of
the reaction using substrate 14b was carried out, and the
desired hydrocarbazole 14c was obtained in 73% yield on a
0.44 g scale. To further illustrate the power of this synthetic
strategy, the influence of substituents on cyclohexene was also
investigated. gem-Dimethyl (15c) and ketal protection (16c,
17c) had no significant impact. It is worth noting that a ketal
group convertible to various organic groups survived the
present conditions.
b
temp
time
(h)
yield
entry
ligand
solvent
Lewis acid
(°C)
(%)
c
e
1
2
3
4
5
6
7
8
DPPE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
DMF
DMSO
toluene
toluene
toluene
AlMe2Cl
AlMe2Cl
AlMe2Cl
AlMe2Cl
AlMe2Cl
AlMe3
100
100
100
100
100
100
100
100
100
100
60
12
12
12
12
12
12
12
24
12
12
24
12
12
10
e
PPh3
TPFPP
PMe3
PEt3
PEt3
PEt3
PEt3
PEt3
PEt3
PEt3
PEt3
44
d
0
e
81
e
83
0
nr
AlEtCl2
e
AlMe2Cl
AlMe2Cl
AlMe2Cl
AlMe2Cl
59
e
9
74
10
11
12
13
nr
e
62
100
100
nr
nr
AlMe2Cl
a
Reaction conditions: Substrate 8b (0.2 mmol), Ni(cod)2 (5 mol %),
ligand (10 mol %), Lewis Acid (20 mol %), and degassed solvent (2
b
c
mL) under argon. Isolated yields. DPPE
= 1,2-bis-
d
(diphenylphosphino)ethane. TPFPP = Tris(pentafluorophenyl)-
e
phosphine. Diastereomeric ratio, dr > 20:1.
of 8b, presumably through coordination with the cyano group
to further polarize the C−CN bond and accelerate the
oxidative addition step. We then turned our attention to
investigate the solvent effects for the arylcyanation and found
that the use of polar solvents CH3CN, DMF, and DMSO gave
inferior results (entries 8−10). Blank experiments verified the
Encouraged by the success of the intramolecular arylcyana-
tion with substrates to deliver cis-hydrocarbazoles, we intended
to apply this strategy to the rapid synthesis of other types of
B
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Scheme 2. Synthesis of Substrates 8b−19b
Table 2. Substrate Scope for the Synthesis of cis-
Hydrocarbazole
Scheme 3. Substrate Scope for the Synthesis of Other
Polycyclic Systems
a
Compound 18c possesses a 6/5/5 tricyclic skeleton of indole
alkaloid spermacoceine.11 Cyclohexane-fused tetrahydroisoqui-
noline 19c is the privileged substructure of amaryllidaceae
alkaloids, such as crinine.12 The relative configuration of 18c
and 19c was established by NOE experiments (see the
Supporting Information for details).
The chemistry detailed above has demonstrated the
substrate scope of the synthetic strategy. Some conversions
were conducted using cis-hydrocarbazole 14c to further assess
that the hydrocarbazoles thus obtained could serve as versatile
synthetic intermediates (Scheme 4). Upon treatment of 14c
with LiAlH4, tryptamine-derived cis-hydrocarbazole 20 was
obtained in an 88% yield. The tryptophol-derived cis-
hydrocarbazol 21 was readily achieved from 14c via two-step
reduction. Aldehyde 22 could also be obtained via reduction of
14c in an 82% yield.
A plausible mechanism for the synthesis of hydrocarbazole
8c from 8b via the nickel and Lewis acid dual-catalyzed
intramolecular arylcyanation was proposed in Scheme 5. The
arylcyanation is initiated by the coordination of a cyano group
to nickel in A with the aid of AlMe2Cl, followed by oxidation
addition into the Aryl-CN bond.7a,8 The Lewis acid (AlMe2Cl)
is suggested to coordinate with the cyano group to further
polarize the aryl-CN bond and promote the oxidative addition
step. Then, coordination and migratory insertion of intra-
molecular alkene into the resulting aryl-nickel bond B give
a
Reaction conditions: substrate 8b−17b (0.2 mmol), Ni(cod)2 (5
mol %), PEt3 (10 mol %), and AlMe2Cl (20 mol %) in degassed
toluene (2 mL) at 100 °C under argon for 12 h. All yields shown are
isolated yields. Diastereomeric ratio, dr > 20:1. Substrate 14b (2
mmol), Ni(cod)2 (5 mol %), PEt3 (10 mol %), and AlMe2Cl (20 mol
%) in degassed toluene (20 mL) at 100 °C under argon for 12 h.
b
c
d
polycyclic cores, such as cyclopentane-fused indoline 6/5/5
and cyclohexane-fused tetrahydroisoquinoline 6/6/6 (Scheme
3). When cyclopentene substrate 18b and o-nitrile benzyl-
amine substrate 19b were subjected to our optimized reaction
conditions, 18c and 19c were obtained in up to 95% yields.
C
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
synthetic applications of this synthetic strategy toward the total
synthesis of relevant natural products are in progress.
Scheme 4. Derivatization Studies of cis-Hydrocarbazole 14c
EXPERIMENTAL SECTION
■
General Information. All commercially available reagents were
used without further purification unless otherwise noted. Column
chromatography was generally performed on silica gel (200−300
mesh), and reactions were monitored by thin-layer chromatography
(TLC) using silica gel GF254 plates. NMR spectra were recorded on
a 400 MHz (1H, 400 MHz; 13C, 100 MHz) spectrometer at 298 K.
The chemical shifts (δ) are reported in ppm with a reference to the
internal residual solvent [1H NMR, CDCl3 (7.26); 13C NMR, CDCl3
(77.0)]. Coupling constants (J) are reported in hertz (Hz). High-
resolution mass spectra (HRMS) were recorded on a FT-ICR
spectrometer using electrospray ionization (ESI).
General Procedure A: Synthesis of α-Amino Ketone. Under
an argon atmosphere, potassium carbonate (15 mmol, 1.5 equiv),
aniline 7 (10 mmol, 1.0 equiv), and acetone (0.5 M) were preheated
at 70 °C and stirred for 1 h. Then the mixture was cooled down, and
the solution of α-bromoketone 6 (10 mmol, 1.0 equiv) in DCM−
acetone (1:3, v/v) was added to the above suspension slowly. Then
the mixture was heated in an oil bath at 70 °C and stirred for 20 h.
Then the mixture was cooled down and filtered. The filtrate was
concentrated under the reduced pressure. The residue was purified by
column chromatography (silica gel, PE/EA = 3:1) to give α-amino
ketone.
Scheme 5. Plausible Catalytic Cycle of the Formation of
Compound 8c
General Procedure B: Wittig Olefination of α-Amino Ketone
to Provide Allylic Anilines 8a−19a. To a suspension of
methyltriphenylphosphonium bromide (11 mmol, 2.2 equiv) in
dried THF (0.2 M) at 0 °C under Ar was added NaHMDS (2 M in
THF, 11 mmol, 2.2 equiv), and the reaction mixture was stirred at 25
°C for 1 h. The suspension was cooled to 0 °C, and a solution of α-
amino ketone (5.0 mmol, 1.0 equiv) in dried THF (10 mL) was
added dropwise. The reaction mixture was warmed to 25 °C and
stirred for 2 h. The reaction was quenched by the saturated aqueous
NH4Cl solution. The mixture was extracted with EA (3×). The
combined organic extracts were washed with brine and dried over
anhydrous Na2SO4. The solution was concentrated in vacuo. The
residue was purified by column chromatography (silica gel, PE/EA =
3:1) to give allylic anilines 8a−19a.
General Procedure C: Alkylation of Allylic Aniline 8a−19a
to Provide Precursors 8b−19b. To the solution of allylic anilines
8a−19a (2.0 mmol, 1.0 equiv) in dried DMF (0.2 M) was added
tBuOK (6.0 mmol, 3.0 equiv) at 0 °C under Ar. The reaction mixture
was stirred at 25 °C for 30 min. Then, the alkyl iodide or benzyl
bromide (10 mmol, 5.0 equiv) was added dropwise to the reaction.
After the resulting mixture was stirred at 25 °C for 10 h, the reaction
was quenched by the saturated aqueous NH4Cl solution. The mixture
was extracted with EA (3×). The combined organic extracts were
washed with brine and dried over anhydrous Na2SO4. The solution
was concentrated in vacuo. The residue was purified by column
chromatography (silica gel, PE/EA = 5:1) to give the precursors 8b−
19b.
General Procedure D: Nickel/Lewis Acid Catalyzed Intra-
molecular Arylcyanation of 8b−19b. To a dried sealable Schlenk
tube was added Ni(cod)2 (0.01 mmol, 0.05 equiv) under argon in a
glovebox. The tube was sealed and taken out of the glovebox. The
PEt3 (0.02 mmol, 0.1 equiv) was added into the solution of Ni(cod)2
in degassed toluene (0.1 M). The mixture was stirred at 25 °C for 10
min. Benzonitriles 8b−19b (0.2 mmol, 1.0 equiv) and AlMe2Cl (1 M
in hexane, 0.04 mmol, 0.2 equiv) were added sequentially into the
reaction mixture. The vial was heated in an oil bath at 100 °C for 12
h. Then the mixture was cooled down and filtered through a silica gel
pad. The filtrate was concentrated under the reduced pressure. The
residue was purified by column chromatography (silica gel, PE/EA =
3:1) to give hexahydrocarbazoles 8c−19c.
complex C. Finally, reductive elimination of intermediate C
will afford the desired hydrocarbazole 8c and regenerate the
catalyst.
In conclusion, we have developed the novel synthetic
strategy for efficient construction of cis-hydrocarbazoles
bearing a quaternary carbon center at the C3-position through
nickel and Lewis acid dual-catalyzed arylcyanation. A series of
synthetic conversions of the resulting cis-hydrocarbazoles have
also been described for the preparation of tryptamine- and
tryptophol-derived cis-hydrocarbazoles, the key core structures
of many terpene-indole alkaloids. Moreover, the synthetic
strategy could also be extended to enable access to complex 6/
5/5 and 6/6/6 polycyclic systems with a benzylic quaternary
carbon center, which are the common structures of indole
alkaloids and amaryllidaceae alkaloids, respectively. Further
2-((2-Methylenecyclohexyl)amino)benzonitrile (8a). Com-
pound 8a was prepared by following general procedures A and B
1
and was obtained as a colorless oil (1.29 g, 61%). H NMR (300
MHz, CDCl3): δ 7.38 (dd, J = 7.7, 1.6 Hz, 1H), 7.32 (t, J = 7.9 Hz,
D
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
1H), 6.64 (td, J = 7.7, 0.9 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 4.77 (d, J
= 1.3 Hz, 1H), 4.73 (d, J = 0.9 Hz, 1H), 4.61 (d, J = 6.4 Hz, 1H),
3.85−3.70 (m, 1H), 2.44 (dd, J = 13.4, 1.5 Hz, 1H), 2.10 (dd, J =
11.8, 3.6 Hz, 2H), 1.98−1.71 (m, 2H), 1.69−1.33 ppm (m, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ 149.6, 147.5, 134.0, 132.5, 118.0,
116.3, 111.7, 110.0, 106.8, 95.1, 56.1, 35.1, 34.2, 27.9, 25.2 ppm.
HRMS (m/z): [M + Na]+ calcd for C14H16N2Na+, 235.1206; found,
235.1208.
2-(Methyl(2-methylenecyclohexyl)amino)benzonitrile (8b).
Compound 8b was prepared by following general procedure C from
intermediate 8a and was obtained as a colorless oil (246 mg, 77%). 1H
NMR (400 MHz, CDCl3): δ 7.47 (dd, J = 7.8, 1.7 Hz, 1H), 7.34 (td, J
= 7.9, 1.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.84−6.72 (m, 1H), 4.87
(d, J = 1.6 Hz, 1H), 4.69 (d, J = 1.5 Hz, 1H), 4.11−4.00 (m, 1H),
3.05 (s, 3H), 2.49 (d, J = 13.8 Hz, 1H), 2.24−2.07 (m, 1H), 1.89 (dt,
J = 6.7, 3.2 Hz, 2H), 1.81−1.66 (m, 2H), 1.53−1.30 ppm (m, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 154.7, 146.1, 135.0, 133.1,
5-Methyl-2-(methyl(2-methylenecyclohexyl)amino)-
benzonitrile (10b). Compound 10b was prepared by following
general procedure C from intermediate 10a and was obtained as a
colorless oil (252 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 7.27 (d,
J = 1.4 Hz, 1H), 7.17 (dd, J = 8.6, 1.9 Hz, 1H), 6.83 (d, J = 8.6 Hz,
1H), 4.86 (s, 1H), 4.72 (d, J = 1.0 Hz, 1H), 3.97 (dd, J = 9.4, 2.8 Hz,
1H), 2.97 (s, 3H), 2.56−2.40 (m, 1H), 2.24 (s, 3H), 2.14 (dd, J =
16.3, 8.3 Hz, 1H), 1.93−1.80 (m, 2H), 1.80−1.62 (m, 2H), 1.41 ppm
(dd, J = 19.2, 10.2 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
152.8, 146.6, 134.3, 134.0, 128.5, 119.5, 118.6, 107.8, 101.2, 65.0,
36.8, 34.1, 31.7, 27.4, 24.9, 19.9 ppm. HRMS (m/z): [M + Na]+ calcd
for C16H20N2Na+, 263.1519; found, 263.1522.
2-(6,9-Dimethyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)acetonitrile (10c). Compound 10c was prepared by following
general procedure D from 10b and was obtained as a colorless oil (36
mg, 74% yield). 1H NMR (300 MHz, CDCl3): δ 6.94−7.01 (m, 2H),
6.44 (d, J = 8.3 Hz, 1H), 3.21−3.10 (m, 1H), 2.75−2.51 (m, 5H),
2.29 (s, 3H), 1.97 (ddd, J = 11.0, 7.2, 3.4 Hz, 1H), 1.83−1.67 (m,
2H), 1.51 (ddd, J = 14.4, 13.0, 8.0 Hz, 3H), 1.35 ppm (dd, J = 13.2,
6.9 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 148.7, 133.4, 128.8,
127.5, 122.4, 118.3, 108.2, 69.9, 44.5, 32.7, 31.6, 26.6, 23.7, 21.6, 21.1,
20.9 ppm. HRMS (m/z): [M + Na]+ calcd for C16H20N2Na+,
263.1519; found, 263.1521.
119.8, 118.4, 117.9, 107.7, 100.1, 65.0, 36.3, 34.4, 32.0, 27.4, 25.4
ppm. HRMS (m/z): [M + Na]+ calcd for C15H18N2Na+, 249.1362;
found, 249.1366.
2-(9-Methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
acetonitrile (8c). Compound 8c was prepared by following general
procedure D from 8b and was obtained as a colorless oil (38 mg, 83%
yield). 1H NMR (400 MHz, CDCl3): δ 7.15 (td, J = 7.6, 1.2 Hz, 1H),
7.13 (d, J = 7.4 Hz, 1H), 6.74 (td, J = 7.4, 0.9 Hz, 1H), 6.51 (d, J =
7.8 Hz, 1H), 3.20 (dd, J = 6.8, 5.1 Hz, 1H), 2.73 (s, 3H), 2.65 (d, J =
16.7 Hz, 1H), 2.57 (d, J = 16.7 Hz, 1H), 2.06−1.94 (m, 1H), 1.82−
1.70 (m, 2H), 1.63−1.40 (m, 3H), 1.36−1.27 ppm (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 150.8, 133.0, 128.6, 121.7, 118.18,
118.15, 108.1, 69.8, 44.7, 32.3, 31.5, 27.0, 24.0, 21.6, 21.0 ppm.
HRMS (m/z): [M + Na]+ calcd for C15H18N2Na+, 249.1362; found,
249.1363.
4-Methyl-2-((2-methylenecyclohexyl)amino)benzonitrile
(11a). Compound 11a was prepared by following general procedures
1
A and B and was obtained as a colorless oil (1.43 g, 63%). H NMR
(400 MHz, CDCl3): δ 7.26 (d, J = 7.88 Hz, 1H), 6.46 (d, J = 7,.92
Hz, 1H), 6.36 (s, 1H), 4.77 (s, 1H), 4.74 (s, 1H), 4.53 (d, J = 6.3 Hz,
1H), 3.85−3.72 (m, 1H), 2.44 (dd, J = 13.4, 1.4 Hz, 1H), 2.28 (s,
3H), 2.08 (dd, J = 11.9, 3.6 Hz, 2H), 1.89 (dd, J = 8.7, 4.8 Hz, 1H),
1.80 (dd, J = 8.7, 4.0 Hz, 1H), 1.64−1.56 (m, 1H), 1.52−1.39 ppm
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 149.7, 147.8, 145.0,
132.4, 118.4, 117.7, 112.1, 106.9, 92.6, 56.1, 35.3, 34.3, 28.0, 25.2,
22.4 ppm. HRMS (m/z): [M + Na]+ calcd for C15H18N2Na+,
249.1362; found, 249.1361.
4-Methyl-2-(methyl(2-methylenecyclohexyl)amino)-
benzonitrile (11b). Compound 11b was prepared by following
general procedure C from intermediate 11a and was obtained as a
colorless oil (261 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 7.36 (d,
J = 7.9 Hz, 1H), 6.67 (s, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.87 (d, J =
1.3 Hz, 1H), 4.71 (d, J = 1.4 Hz, 1H), 4.14−3.98 (m, 1H), 3.02 (s,
3H), 2.55−2.44 (m, 1H), 2.32 (d, J = 6.6 Hz, 3H), 2.16 (td, J = 13.2,
4.3 Hz, 1H), 1.96−1.82 (m, 2H), 1.81−1.64 (m, 2H), 1.52−1.31 ppm
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 154.7, 146.3, 143.9,
134.8, 120.0, 119.8, 118.3, 107.7, 97.5, 65.0, 36.2, 34.4, 32.0, 27.4,
25.4, 22.1 ppm. HRMS (m/z): [M + Na]+ calcd for C16H20N2Na+,
263.1519; found, 263.1523.
2-(7,9-Dimethyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)acetonitrile (11c). Compound 11c was prepared by following
general procedure D from 11b and was obtained as a colorless oil (38
mg, 78% yield). 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J = 7.4 Hz,
1H), 6.59 (d, J = 7.4 Hz, 1H), 6.37 (s, 1H), 3.21 (dd, J = 6.8, 5.2 Hz,
1H), 2.74 (s, 3H), 2.65 (d, J = 16.7 Hz, 1H), 2.56 (d, J = 16.7 Hz,
1H), 2.33 (s, 3H), 2.08−1.95 (m, 1H), 1.77 (ddd, J = 13.9, 7.7, 3.9
Hz, 2H), 1.63−1.42 (m, 3H), 1.41−1.28 ppm (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 150.8, 138.5, 130.3, 121.4, 118.9, 118.2,
109.2, 69.9, 44.4, 32.2, 31.5, 27.1, 24.0, 21.7, 21.5, 21.0 ppm. HRMS
(m/z): [M + Na]+ calcd for C16H20N2Na+, 263.1519; found,
263.1520.
4-Fluoro-2-(methyl(2-methylenecyclohexyl)amino)-
benzonitrile (9b). Compound 9b was prepared by following general
procedures A, B, and C and was obtained as a colorless oil (184 mg,
1
58%). H NMR (300 MHz, CDCl3): δ 7.38−7.47 (m, 1H), 6.42−
6.52 (m, 2H), 4.87 (d, J = 1.4 Hz, 1H), 4.61 (d, J = 1.4 Hz, 1H), 4.06
(d, J = 8.3 Hz, 1H), 3.08 (s, 3H), 2.49 (d, J = 13.7 Hz, 1H), 2.23−
2.08 (m, 1H), 1.98−1.86 (m, 2H), 1.86−1.65 (m, 2H), 1.48 (dd, J =
9.3, 3.2 Hz, 1H), 1.32 ppm (d, J = 12.6 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3): δ 165.8 (d, JC−F = 252.1 Hz), 163.6 (d, JC−F = 18.5
Hz), 145.2, 137.2 (d, JC−F = 11.7 Hz), 119.4, 111.1, 107.6, 105.9 (d,
J
C−F = 23.4 Hz), 103.8 (d, JC−F = 25.7 Hz), 65.0, 36.0, 34.5, 32.2, 27.2,
25.7 ppm. HRMS (m/z): [M + Na]+ calcd for C15H17FN2Na+,
267.1268; found, 267.1270.
2-(7-Fluoro-9-methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-
4a-yl)acetonitrile (9c). Compound 9c was prepared by following
general procedure D from 9b and was obtained as a colorless oil (39
mg, 80% yield). 1H NMR (400 MHz, CDCl3): δ 7.02 (dd, J = 8.0, 5.5
Hz, 1H), 6.39 (ddd, J = 10.1, 8.1, 2.3 Hz, 1H), 6.19 (dd, J = 10.1, 2.2
Hz, 1H), 3.26 (dd, J = 7.1, 5.2 Hz, 1H), 2.73 (s, 3H), 2.67−2.46 (m,
2H), 2.00 (dd, J = 8.2, 5.5 Hz, 1H), 1.82−1.69 (m, 2H), 1.53 (ddd, J
= 11.5, 9.7, 6.4 Hz, 2H), 1.47−1.35 (m, 1H), 1.33−1.26 ppm (m,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.2 (d, JC−F = 242.4
Hz), 152.4 (d, JC−F = 11.5 Hz), 128.2, 122.4 (d, JC−F = 10.7 Hz),
118.0, 103.9 (d, JC−F = 22.9 Hz), 96.1 (d, JC−F = 26.9 Hz), 70.1, 44.4,
32.0, 31.4, 27.5, 24.3, 21.5, 21.0 ppm. HRMS (m/z): [M + Na]+ calcd
for C15H17FN2Na+, 267.1268; found, 267.1271.
5-Methyl-2-((2-methylenecyclohexyl)amino)benzonitrile
4-Methoxy-2-((2-methylenecyclohexyl)amino)benzonitrile
(10a). Compound 10a was prepared by following general procedures
(12a). Compound 12a was prepared by following general procedures
1
1
A and B and was obtained as a colorless oil (1.47 g, 65%). H NMR
A and B and was obtained as a colorless oil (1.65 g, 68%). H NMR
(300 MHz, CDCl3): δ 7.18 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.6, 2.0
Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 4.74 (d, J = 11.3 Hz, 2H), 4.47 (d,
J = 6.2 Hz, 1H), 3.75 (s, 1H), 2.43 (dd, J = 11.1, 3.8 Hz, 1H), 2.19 (d,
J = 5.3 Hz, 3H), 2.06 (dd, J = 16.3, 8.7 Hz, 2H), 1.95−1.73 (m, 2H),
1.67−1.37 ppm (m, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 147.8,
147.7, 135.0, 132.2, 125.5, 118.2, 111.9, 106.7, 95.0, 56.2, 35.2, 34.2,
28.0, 25.2, 19.9 ppm. HRMS (m/z): [M + Na]+ calcd for
C15H18N2Na+, 249.1362; found, 249.1365.
(400 MHz, CDCl3): δ 7.31 (d, J = 8.6 Hz, 1H), 6.22 (dd, J = 8.6, 2.3
Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 4.82−4.72 (m, 2H), 4.58 (d, J =
6.2 Hz, 1H), 3.77 (s, 4H), 2.47−2.35 (m, 1H), 2.12−2.01 (m, 2H),
1.93−1.84 (m, 1H), 1.81−1.74 (m, 1H), 1.61−1.56 (m, 1H), 1.55−
1.50 (m, 1H), 1.46−1.38 ppm (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 164.4, 151.3, 147.5, 134.1, 118.5, 107.1, 103.0, 97.1, 88.3,
56.3, 55.3, 35.1, 34.1, 28.0, 25.0 ppm. HRMS (m/z): [M + Na]+ calcd
for C15H18N2ONa+, 265.1311; found, 265.1315.
E
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
4-Methoxy-2-(methyl(2-methylenecyclohexyl)amino)-
benzonitrile (12b). Compound 12b was prepared by following
general procedure C from intermediate 12a and was obtained as a
colorless oil (203 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 7.40 (d,
J = 8.5 Hz, 1H), 6.36 (dd, J = 8.6, 2.1 Hz, 1H), 6.34 (s, 1H), 4.87 (s,
1H), 4.69 (s, 1H), 4.08 (d, J = 10.3 Hz, 1H), 3.79 (s, 3H), 3.04 (s,
3H), 2.49 (d, J = 13.7 Hz, 1H), 2.14 (td, J = 13.2, 4.4 Hz, 1H), 1.89
(dd, J = 11.6, 2.5 Hz, 2H), 1.74 (ddd, J = 14.0, 9.5, 3.7 Hz, 2H),
1.52−1.29 ppm (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
163.5, 156.4, 146.1, 136.6, 120.2, 107.7, 104.9, 103.0, 92.6, 65.1, 55.3,
36.1, 34.5, 32.0, 27.4, 25.5 ppm. HRMS (m/z): [M + Na]+ calcd for
C16H20N2ONa+, 279.1468; found, 279.1466.
2-(7-Methoxy-9-methyl-2,3,4,4a,9,9a-hexahydro-1H-carba-
zol-4a-yl)acetonitrile (12c). Compound 12c was prepared by
following general procedure D from 12b and was obtained as a
colorless oil (31 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 7.02
(d, J = 8.1 Hz, 1H), 6.26 (dd, J = 8.0, 2.1 Hz, 1H), 6.08 (d, J = 2.1 Hz,
1H), 3.78 (s, 3H), 3.21 (dd, J = 6.9, 5.4 Hz, 1H), 2.72 (s, 3H), 2.57
(q, J = 16.6 Hz, 2H), 2.08−1.95 (m, 1H), 1.74 (ddd, J = 14.0, 9.8, 3.9
Hz, 2H), 1.60−1.47 (m, 2H), 1.43−1.36 (m, 1H), 1.34−1.25 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.0, 152.2, 125.5, 122.2,
118.3, 101.9, 95.7, 70.1, 55.3, 44.3, 32.0, 31.5, 27.6, 24.3, 21.6, 21.2
ppm. HRMS (m/z): [M + Na]+ calcd for C16H20N2ONa+, 279.1468;
found, 279.1467.
NMR (101 MHz, CDCl3): δ 149.9, 138.2, 132.4, 128.52, 128.50,
127.3, 127.1, 122.0, 118.3, 118.0, 108.4, 67.8, 49.3, 44.9, 31.0, 27.7,
24.4, 21.5, 21.4 ppm. HRMS (m/z): [M + Na]+ calcd for
C21H22N2Na+, 325.1675; found, 325.1677.
2-((5,5-Dimethyl-2-methylenecyclohexyl)amino)-
benzonitrile (15a). Compound 15a was prepared by following
general procedures A and B and was obtained as a colorless oil (1.49
1
g, 62%). H NMR (300 MHz, CDCl3): δ 7.38 (dd, J = 7.8, 1.2 Hz,
1H), 7.33 (td, J = 8.0, 1.0 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.55 (d, J
= 8.6 Hz, 1H), 4.76 (s, 1H), 4.69 (s, 1H), 4.51 (d, J = 6.5 Hz, 1H),
3.99−3.76 (m, 1H), 2.42−2.14 (m, 2H), 1.89−1.75 (m, 1H), 1.54
(dd, J = 12.7, 2.6 Hz, 1H), 1.42−1.23 (m, 2H), 1.11 (s, 3H), 1.00
ppm (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 149.7, 147.7,
134.1, 132.6, 118.0, 116.3, 111.6, 106.3, 95.2, 52.8, 48.0, 40.5, 32.2,
32.1, 30.8, 24.9 ppm. HRMS (m/z): [M + Na]+ calcd for
C16H20N2Na+, 263.1519; found, 263.1521.
2-((5,5-Dimethyl-2-methylenecyclohexyl)(methyl)amino)-
benzonitrile (15b). Compound 15b was prepared by following
general procedure C from intermediate 15a and was obtained as a
1
colorless oil (254 mg, 80%). H NMR (400 MHz, CDCl3): δ 7.46
(dd, J = 7.7, 1.7 Hz, 1H), 7.33 (td, J = 7.9, 1.7 Hz, 1H), 6.84 (d, J =
8.6 Hz, 1H), 6.75 (td, J = 7.5, 0.8 Hz, 1H), 4.89 (s, 1H), 4.65 (s, 1H),
4.37−4.20 (m, 1H), 3.07 (s, 3H), 2.35 (dd, J = 7.8, 3.1 Hz, 2H), 1.60
(dd, J = 13.0, 6.4 Hz, 2H), 1.47 (d, J = 13.0 Hz, 1H), 1.36−1.23 (m,
1H), 1.04 (s, 3H), 0.99 ppm (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 154.8, 145.5, 135.2, 133.2, 120.0, 117.9, 117.2, 107.4, 98.9,
61.3, 44.3, 39.7, 35.4, 32.6, 32.1, 30.7, 24.2 ppm. HRMS (m/z): [M +
Na]+ calcd for C17H22N2Na+, 277.1675; found, 277.1677.
2-(Ethyl(2-methylenecyclohexyl)amino)benzonitrile (13b).
Compound 13b was prepared by following general procedure C
from intermediate 8a and was obtained as a colorless oil (204, 60%).
1H NMR (300 MHz, CDCl3): δ 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.43
2-(2,2,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)acetonitrile (15c). Compound 15c was prepared by following
general procedure D from 15b and was obtained as a colorless oil (44
mg, 87% yield). 1H NMR (400 MHz, CDCl3): δ 7.17 (td, J = 7.6, 0.8
Hz, 1H), 7.11(d, J = 7.1 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.46 (d, J =
7.8 Hz, 1H), 3.49 (dd, J = 9.4, 5.6 Hz, 1H), 2.74 (s, 3H), 2.59 (d, J =
16.5 Hz, 1H), 2.44 (d, J = 16.5 Hz, 1H), 2.24−2.12 (m, 1H), 2.02−
1.93 (m, 1H), 1.55 (ddd, J = 13.4, 5.5, 2.0 Hz, 1H), 1.37−1.27 (m,
1H), 1.23−1.13 (m, 1H), 1.06−0.99 (m, 1H), 0.97 (d, J = 5.1 Hz,
3H), 0.88 ppm (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 150.2,
131.7, 128.9, 122.0, 118.4, 117.8, 107.7, 68.2, 44.8, 36.6, 34.6, 31.6,
31.5, 29.5, 28.4, 26.8, 25.0 ppm. HRMS (m/z): [M + Na]+ calcd for
C17H22N2Na+, 277.1675; found, 277.1678.
2-((8-Methylene-1,4-dioxaspiro[4.5]decan-7-yl)amino)-
benzonitrile (16a). Compound 16a was prepared by following
general procedures A and B from 7-bromo-1,4-dioxaspiro[4.5]decan-
8-one, which was synthesized according to literature,13 and was
obtained as a colorless oil (1.40 g, 52%). 1H NMR (300 MHz,
CDCl3): δ 7.36 (dd, J = 8.0, 1.6 Hz, H), 7.32 (td, J = 7.1, 1.5 Hz, 1H),
6.73−6.53 (m, 2H), 5.69 (d, J = 7.7 Hz, 1H), 4.90 (s, 2H), 4.27−3.85
(m, 5H), 2.47 (dd, J = 14.0, 6.2 Hz, 1H), 2.32−2.15 (m, 1H), 2.09
(dd, J = 13.0, 4.6 Hz, 1H), 1.90 (dd, J = 13.1, 7.2 Hz, 1H), 1.78 ppm
(t, J = 6.5 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 149.4, 145.4,
133.8, 132.5, 117.8, 116.1, 111.5, 109.8, 108.3, 95.7, 64.6, 64.4, 53.9,
41.2, 36.2, 28.8 ppm. HRMS (m/z): [M + Na]+ calcd for
C16H18N2O2Na+, 293.1260; found, 293.1262.
(td, J = 7.9, 1.7 Hz 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.96 (td, J = 7.6, 1.0
Hz, 1H), 4.88 (d, J = 8.5 Hz, 2H), 4.08 (t, J = 6.3 Hz, 1H), 3.31 (dd, J
= 11.5, 7.1 Hz, 2H), 2.47 (d, J = 4.7 Hz, 1H), 2.16−2.06 (m, 1H),
1.88−1.79 (m, 1H), 1.72 (t, J = 5.7 Hz, 2H), 1.58 (s, 1H), 1.50 (d, J =
3.9 Hz, 1H), 1.37 (s, 1H), 1.03 ppm (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 153.1, 148.0, 134.5, 132.5, 122.2, 120.9,
118.8, 108.4, 106.7, 64.7, 43.0, 33.5, 31.0, 27.6, 23.7, 12.3 ppm.
HRMS (m/z): [M + Na]+ calcd for C16H20N2Na+, 263.1519; found,
263.1517.
2-(9-Ethyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
acetonitrile (13c). Compound 13c was prepared by following
general procedure D from 13b and was obtained as a colorless oil (41
mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.10−7.16 (m, 2H),
6.71 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 3.40 (dd, J = 7.2,
5.0 Hz, 1H), 3.27 (dt, J = 14.5, 7.2 Hz, 1H), 3.03 (dq, J = 14.0, 7.1
Hz, 1H), 2.62 (d, J = 16.6 Hz, 1H), 2.54 (d, J = 16.6 Hz, 1H), 2.14−
2.01 (m, 1H), 1.76 (ddd, J = 14.0, 10.1, 4.0 Hz, 2H), 1.63−1.48 (m,
2H), 1.41−1.23 (m, 3H), 1.24−1.14 ppm (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 149.7, 132.5, 128.5, 121.9, 118.2, 117.6, 107.7,
66.3, 44.7, 38.4, 31.0, 27.5, 24.2, 21.6, 21.3, 12.4 ppm. HRMS (m/z):
[M + Na]+ calcd for C16H20N2Na+, 263.1519; found, 263.1521.
2-(Benzyl(2-methylenecyclohexyl)amino)benzonitrile
(14b). Compound 14b was prepared by following general procedure
C from intermediate 8a and was obtained as a colorless oil (355 mg,
83%). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J = 7.7, 1.5 Hz, 1H),
7.30−7.11 (m, 6H), 6.90 (d, J = 8.5 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H),
4.99 (s, 1H), 4.92 (s, 1H), 4.52 (s, 2H), 4.38−4.27 (m, 1H), 2.59−
2.43 (m, 1H), 2.21 (dd, J = 11.2, 7.6 Hz, 1H), 1.87 (dd, J = 7.9, 3.9
Hz, 2H), 1.74−1.60 (m, 2H), 1.42 ppm (t, J = 8.4 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 152.9, 147.8, 138.0, 134.8, 132.7, 128.2,
127.4, 126.7, 121.5, 120.7, 119.0, 108.1, 105.0, 65.8, 51.7, 34.2, 31.3,
27.4, 24.6 ppm. HRMS (m/z): [M + Na]+ calcd for C21H22N2Na+,
325.1675; found, 325.1676.
2-(Methyl(8-methylene-1,4-dioxaspiro[4.5]decan-7-yl)-
amino)benzonitrile (16b). Compound 16b was prepared by
following general procedure C from intermediate 16a and was
obtained as a colorless oil (192 mg, 61%). 1H NMR (400 MHz,
CDCl3): δ 7.47 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (td, J = 7.9, 1.7 Hz,
1H), 6.85 (d, J = 8.6 Hz, 1H), 6.78 (td, J = 7.5, 0.7 Hz, 1H), 4.97 (s,
1H), 4.76 (s, 1H), 4.41−4.25 (m, 1H), 4.05−3.89 (m, 4H), 3.10 (s,
3H), 2.43 (dd, J = 7.3, 3.2 Hz, 2H), 1.98 (d, J = 11.3 Hz, 2H), 1.88−
1.78 (m, 1H), 1.71−1.56 ppm (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 154.7, 143.4, 135.0, 133.2, 119.8, 118.4, 117.6, 108.9,
108.7, 99.6, 64.6, 64.5, 61.9, 39.9, 35.6, 35.3, 30.2 ppm. HRMS (m/z):
[M + Na]+ calcd for C17H20N2O2Na+, 307.1417; found, 307.1415.
2-(9-Methyl-1,3,4,4a,9,9a-hexahydrospiro[carbazole-2,2′-
[1,3]dioxolan]-4a-yl)acetonitrile (16c). Compound 6c was
prepared by following general procedure D from 16b and was
2-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
acetonitrile (14c). Compound 14c was prepared by following
general procedure D from 14b and was obtained as a colorless oil (47
mg, 77% yield). 1H NMR (400 MHz, CDCl3): δ 7.42−7.31 (m, 4H),
7.23−7.29 (m, 1H), 7.15 (dd, J = 7.3, 0.6 Hz, 1H), 7.08 (td, J = 7.7,
1.2 Hz, 1H), 6.75 (td, J = 7.5, 0.7 Hz, 1H), 6.43 (d, J = 7.8 Hz, 1H),
4.39 (d, J = 15.3 Hz, 1H), 4.16−4.04 (m, 1H), 3.32 (dd, J = 7.7, 5.3
Hz, 1H), 2.61 (s, 2H), 2.24−2.09 (m, 1H), 1.73 (ddd, J = 17.7, 9.4,
4.2 Hz, 2H), 1.62−1.48 (m, 2H), 1.43−1.15 ppm (m, 3H). 13C{1H}
1
obtained as a colorless oil (36 mg, 64% yield). H NMR (400 MHz,
F
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
CDCl3): δ 7.14−7.20 (m, 2H), 6.76 (t, J = 7.4 Hz, 1H), 6.48 (d, J =
7.7 Hz, 1H), 4.03−3.82 (m, 4H), 3.50 (dd, J = 9.3, 5.8 Hz, 1H), 2.73
(s, 3H), 2.62 (d, J = 16.5 Hz, 1H), 2.51 (d, J = 16.5 Hz, 1H), 2.36 (dt,
J = 14.1, 4.2 Hz, 1H), 2.14−1.99 (m, 1H), 1.93 (ddd, J = 13.3, 5.8, 2.3
Hz, 1H), 1.66 (ddd, J = 13.2, 6.6, 4.2 Hz, 1H), 1.52 (td, J = 13.0, 4.3
Hz, 1H), 1.41 ppm (dd, J = 13.3, 9.4 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3): δ 150.1, 130.7, 129.0, 122.2, 118.1, 117.9, 108.1,
107.7, 69.6, 64.4, 64.2, 44.6, 33.0, 31.6, 30.4, 28.2, 27.5 ppm. HRMS
(m/z): [M + Na]+ calcd for C17H20N2O2Na+, 307.1417; found,
307.1417.
105.6, 75.9, 53.2, 39.6, 32.6, 31.8, 28.6, 24.9 ppm. HRMS (m/z): [M
+
+ H]+ calcd for C14H17N2 , 213.1386; found, 213.1383.
N-(2-Methylenecyclohexyl)aniline (19a). Compound 19a was
prepared by following general procedures A and B and was obtained
as a colorless oil (1.35 g, 72%). 1H NMR (300 MHz, CDCl3): δ 7.15
(td, J = 8.0, 1.2 Hz, 2H), 6.66 (tt, J = 7.3, 1.1 Hz, 1H), 6.62−6.50 (m,
2H), 4.81 (s, 1H), 4.75 (s, 1H), 3.70 (dd, J = 10.6, 4.1 Hz, 2H),
2.50−2.33 (m, 1H), 2.08 (dd, J = 21.5, 9.4 Hz, 2H), 1.81 (dd, J =
11.0, 8.4 Hz, 2H), 1.57 (d, J = 13.0 Hz, 1H), 1.46−1.31 ppm (m,
2H). 13C{1H} NMR (75 MHz, CDCl3): δ 149.3, 147.6, 129.1, 116.9,
113.0, 106.4, 56.5, 35.6, 34.4, 28.2, 25.4 ppm. HRMS (m/z): [M +
H]+ calcd for C13H18N+, 188.1434; found, 188.1434.
2-(((2-Methylenecyclohexyl)(phenyl)amino)methyl)-
benzonitrile (19b). Compound 19b was prepared by following
general procedure C from intermediate 19a and obtained as a
colorless oil (266 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d,
J = 7.6 Hz, 1H), 7.45−7.54 (m, 2H), 7.33 (td, J = 7.2, 1.1 Hz, 1H),
7.18 (d, J = 7.6 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz,
2H), 4.83 (d, J = 12.5 Hz, 2H), 4.66 (d, J = 18.8 Hz, 1H), 4.52 (s,
1H), 4.27 (d, J = 8.1 Hz, 1H), 2.52 (d, J = 13.6 Hz, 1H), 2.17 (dd, J =
13.2, 3.8 Hz, 1H), 1.93−1.73 (m, 3H), 1.57−1.39 (m, 2H), 1.32 ppm
(dd, J = 8.4, 4.6 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ
148.9, 144.8, 144.6, 132.84, 132.78, 129.0, 127.7, 127.0, 117.1, 112.7,
109.5, 107.6, 61.6, 50.0, 34.9, 32.9, 27.3, 26.3 ppm. HRMS (m/z): [M
+ Na]+ calcd for C21H22N2Na+, 325.1675; found, 325.1674.
2-(Benzyl(8-methylene-1,4-dioxaspiro[4.5]decan-7-yl)-
amino)benzonitrile (17b). Compound 17b was prepared by
following general procedure C from intermediate 16a and was
obtained as a colorless oil (296 mg, 74%). 1H NMR (400 MHz,
CDCl3): δ 7.40 (dd, J = 7.7, 1.6 Hz, 1H), 7.10−7.20 (m, 5H), 7.05 (t,
J = 7.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H),
5.04 (s, 1H), 4.89 (s, 1H), 4.61−4.46 (m, 2H), 4.37 (d, J = 16.7 Hz,
1H), 3.91−3.70 (m, 4H), 2.43−2.25 (m, 2H), 2.00−1.89 (m, 1H),
1.83 (t, J = 12.3 Hz, 1H), 1.75−1.62 (m, 1H), 1.59−1.43 ppm (m,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 153.1, 145.1, 138.2, 135.1,
132.8, 128.4, 127.0, 126.8, 120.6, 120.5, 118.7, 108.9, 108.5, 104.7,
64.5, 64.34, 64.29, 50.0, 38.8, 35.0, 30.5 ppm. HRMS (m/z): [M +
Na]+ calcd for C23H24N2O2Na+, 383.1730; found, 383.1733.
2-(9-Benzyl-1,3,4,4a,9,9a-hexahydrospiro[carbazole-2,2′-
[1,3]dioxolan]-4a-yl)acetonitrile (17c). Compound 17c was
prepared by following general procedure D from 17b and was
2-(5-Phenyl-1,2,3,4,4a,5,6,10b-octahydrophenanthridin-
10b-yl)acetonitrile (19c). Compound 19c was prepared by
following general procedure D from 19b and was obtained as a
1
obtained as a colorless oil (41 mg, 57% yield). H NMR (400 MHz,
CDCl3): δ 7.41−7.27 (m, 5H), 7.20 (d, J = 7.2 Hz, 1H), 7.12 (td, J =
7.7, 1.0 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H),
4.39 (d, J = 14.9 Hz, 1H), 4.06 (d, J = 14.9 Hz, 1H), 3.88 (dd, J = 5.6,
1.7 Hz, 4H), 3.52 (dd, J = 9.7, 5.9 Hz, 1H), 2.73 (d, J = 16.4 Hz, 1H),
2.51 (d, J = 16.4 Hz, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.01 (d, J = 4.3
Hz, 1H), 1.91 (ddd, J = 13.2, 5.9, 2.4 Hz, 1H), 1.74−1.62 (m, 1H),
1.60−1.41 ppm (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
149.4, 137.8, 130.6, 129.1, 128.7, 127.6, 127.4, 122.6, 118.6, 117.9,
108.7, 107.7, 67.6, 64.4, 64.2, 48.9, 44.6, 33.4, 30.4, 28.5, 27.4 ppm.
HRMS (m/z): [M + Na]+ calcd for C23H24N2O2Na+, 383.1730;
found, 383.1736.
1
colorless oil (51 mg, 84% yield). H NMR (400 MHz, CDCl3): δ
7.49−7.38 (m, 1H), 7.37−7.24 (m, 5H), 7.02 (d, J = 8.1 Hz, 2H),
6.84 (t, J = 7.3 Hz, 1H), 4.47 (d, J = 16.2 Hz, 1H), 4.33 (d, J = 16.2
Hz, 1H), 3.96 (dd, J = 11.5, 3.6 Hz, 1H), 2.83 (d, J = 16.7 Hz, 1H),
2.68 (dd, J = 14.1, 2.1 Hz, 1H), 2.62 (d, J = 16.7 Hz, 1H), 1.86−1.76
(m, 1H), 1.71−1.55 (m, 3H), 1.39−1.15 ppm (m, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 148.7, 135.5, 133.7, 129.4, 127.2, 127.1,
125.7, 118.5, 118.1, 114.4, 59.8, 46.6, 41.7, 33.6, 31.9, 25.2, 23.3, 21.5
+
ppm. HRMS (m/z): [M + H]+ calcd for C21H23N2 , 303.1856; found,
303.1856.
2-((2-Methylenecyclopentyl)amino)benzonitrile (18a). Com-
pound 18a was prepared by following general procedures A and B and
was obtained as a colorless oil (1.29 g, 65%). H NMR (400 MHz,
2-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
ethanamine (20). A solution of compound 14c (24 mg, 0.08 mmol)
in THF (1 mL) was added dropwise to a stirred suspension of LiAlH4
(12 mg, 0.32 mmol) in THF (3 mL). The solution was then stirred at
25 °C for 8 h. To the mixture was added slowly H2O and 10% NaOH
at 0 °C. The mixture was stirred at 25 °C for an additional 0.5 h. The
mixture was filtered through a pad of silica gel and washed with Et2O.
The solution was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, CH2Cl2/MeOH = 10:1) to give
1
CDCl3): δ 7.34−7.39 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 6.65 (t, J =
7.5 Hz, 1H), 5.11 (dd, J = 4.5, 2.2 Hz, 1H), 5.06 (dd, J = 4.1, 2.2 Hz,
1H), 4.60 (d, J = 6.3 Hz, 1H), 4.20 (d, J = 7.2 Hz, 1H), 2.45 (ddd, J =
9.8, 5.0, 2.9 Hz, 2H), 2.19 (td, J = 11.7, 6.6 Hz, 1H), 1.81 (ddd, J =
12.3, 8.8, 3.6 Hz, 1H), 1.74−1.60 (m, 1H), 1.53 ppm (ddd, J = 16.4,
12.2, 7.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 152.4, 149.9,
134.1, 132.7, 117.8, 116.2, 111.1, 107.8, 95.6, 56.9, 33.5, 31.0, 22.2
ppm. HRMS (m/z): [M + Na]+ calcd for C13H14N2Na+, 221.1049;
found, 221.1049.
2-(Methyl(2-methylenecyclopentyl)amino)benzonitrile
(18b). Compound 18b was prepared by following general procedure
C from intermediate 18a and was obtained as a colorless oil (263 mg,
82%). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J = 7.7, 1.6 Hz, 1H),
7.38 (td, J = 7.9, 1.6 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.82 (t, J = 7.5
Hz, 1H), 5.12 (d, J = 1.9 Hz, 1H), 4.96 (d, J = 2.2 Hz, 1H), 4.72−
4.59 (m, 1H), 2.84 (s, 3H), 2.51−2.29 (m, 2H), 2.08−1.98 (m, 1H),
1.89−1.71 (m, 2H), 1.64−1.52 ppm (m, 1H). 13C{1H} NMR (101
MHz, CDCl3): δ 155.5, 148.9, 134.9, 133.3, 119.4, 119.0, 118.1,
108.0, 101.5, 67.2, 33.6, 31.8, 29.0, 22.5 ppm. HRMS (m/z): [M +
Na]+ calcd for C14H16N2Na+, 235.1206; found, 235.1206.
2-(4-Methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-
8b-yl)acetonitrile (18c). Compound 18c was prepared by following
general procedure D from and was obtained as a colorless oil (40 mg,
95% yield). 1H NMR (400 MHz, CDCl3): δ 7.13 (t, J = 7.6 Hz, 1H),
7.10 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.37 (d, J = 7.8 Hz,
1H), 3.79 (d, J = 3.7 Hz, 1H), 2.83 (s, 3H), 2.74 (d, J = 16.7 Hz, 1H),
2.66 (d, J = 16.7 Hz, 1H), 2.15−2.02 (m, 1H), 2.02−1.87 (m, 2H),
1.81 (tt, J = 12.8, 4.8 Hz, 2H), 1.66−1.52 ppm (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ 151.6, 132.6, 128.7, 122.5, 118.0, 116.8,
1
pure compound 20 (22 mg, 88% yield) as a colorless oil. H NMR
(400 MHz, CDCl3): δ 7.27−7.40 (m, 5H), 7.03−7.09 (m, 2H), 6.73
(t, J = 7.3 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 15.7 Hz,
1H), 4.12 (dd, J = 15.0, 9.3 Hz, 1H), 3.72 (s, 2H), 3.51 (t, J = 5.5 Hz,
1H), 1.93−1.83 (m, 1H), 1.73 (ddd, J = 14.3, 8.9, 4.1 Hz, 1H), 1.63−
1.52 (m, 4H), 1.50−1.42 (m, 2H), 1.35 (ddd, J = 12.4, 7.9, 3.8 Hz,
1H), 1.28−1.23 (m, 2H), 0.91−0.80 ppm (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 151.6, 138.9, 133.1, 128.5, 128.0, 127.3, 126.9,
122.0, 117.8, 108.0, 67.4, 65.1, 50.0, 48.6, 34.5, 30.1, 24.3, 21.5, 21.2
+
ppm. HRMS (m/z): [M + H]+ calcd for C21H27N2 , 307.2169; found,
307.2170.
2-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
ethanol (21). A solution of compound 22 (41 mg, 0.134 mmol) in
THF (1 mL) was added dropwise to a stirred suspension of LiAlH4
(10 mg, 0.27 mmol) in THF (3 mL). The solution was then stirred at
25 °C for 2 h. To the mixture were added slowly H2O and 10%
NaOH at 0 °C. The mixture was stirred at 25 °C for an additional 0.5
h. The mixture was filtered through a pad of silica gel and washed with
Et2O. The solution was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, PE/EA = 2:1) to give
1
pure compound 21 (40 mg, 97% yield) as a colorless oil. H NMR
(400 MHz, CDCl3): δ 7.41−7.26 (m, 5H), 7.05 (td, J = 7.7, 1.2 Hz,
1H), 7.02 (d, J = 7.2 Hz,1 H), 6.73 (t, J = 7.3 Hz, 1H), 6.45 (d, J = 7.8
G
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Hz, 1H), 4.40 (d, J = 15.5 Hz, 1H), 4.10 (d, J = 15.5 Hz, 1H), 3.70−
3.60 (m, 1H), 3.58−3.47 (m, 1H), 3.32 (t, J = 5.3 Hz, 1H), 2.15 (dt, J
= 14.3, 7.2 Hz, 1H), 1.91−1.76 (m, 3H), 1.69 (dt, J = 14.4, 4.8 Hz,
1H), 1.59−1.44 (m, 4H), 1.36−1.23 ppm (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3): δ 151.1, 138.7, 135.6, 128.5, 127.53, 127.46,
127.0, 121.9, 118.1, 108.5, 67.9, 59.9, 50.2, 45.3, 40.7, 34.7, 24.2, 21.7,
21.3 ppm. HRMS (m/z): [M + Na]+ calcd for C21H25NONa+,
330.1828; found, 330.1825.
Xiaolei Wang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Huilin Li − State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03243
2-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
acetaldehyde (22). To a solution of 14c (50 mg, 0.16 mmol) in
toluene (5 mL) was added dropwise DIBAL-H (1 M in toluene, 0.33
mL, 0.33 mmol) at −78 °C under Ar. The solution was then stirred at
−78 °C for 4 h. The reaction was quenched with saturated sodium
potassium tartrate. The mixture was stirred at 25 °C for 1 h. The
mixture was extracted with CH2Cl2. The combined organic extracts
were washed with brine and dried over anhydrous Na2SO4. The
solution was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, PE/EA = 10:1) to give 22 (41
mg, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.56 (dd,
J = 4.0, 2.4 Hz, 1H), 7.39−7.31 (m, 4H), 7.31−7.26 (m, 1H), 7.11 (d,
J = 7.2 Hz, 1H), 7.09 (td, J = 7.6, 1.2 Hz, 1H), 6.77 (td, J = 7.5, 0.8
Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 4.40 (d, J = 15.2 Hz, 1H), 4.09 (d,
J = 15.2 Hz, 1H), 3.28 (dd, J = 7.3, 5.1 Hz, 1H), 2.70 (dd, J = 14.8,
4.0 Hz, 1H), 2.52 (dd, J = 14.8, 2.4 Hz, 1H), 2.06 (ddd, J = 13.7, 7.2,
3.9 Hz, 1H), 1.79−1.66 (m, 1H), 1.64−1.38 (m, 4H), 1.38−1.14 ppm
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 202.8, 150.7, 138.3,
133.8, 128.5, 128.0, 127.7, 127.1, 122.0, 118.3, 108.5, 68.1, 52.0, 49.8,
45.4, 33.5, 24.2, 21.6, 21.5 ppm. HRMS (m/z): [M + Na]+ calcd for
C21H23NONa+, 328.1672; found, 328.1672.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
of China (21732001, 21871118, and 21572088) and PCSIRT
(IRT_15R28).
REFERENCES
■
(1) (a) Ramirez, A.; Garcia-Rubio, S. Current progress in the
chemistry and pharmacology of akuammiline alkaloids. Curr. Med.
Chem. 2003, 10, 1891. (b) Jordan, M. A.; Wilson, L. Microtubules as a
target for anticancer drugs. Nat. Rev. Cancer 2004, 4, 253.
(c) O’Connor, S. E.; Maresh, J. Chemistry and biology of
monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 2006, 23,
532.
(2) (a) Li, Z. Q.; Zhang, S. X.; Wu, S. T.; Shen, X. L.; Zou, L. W.;
Wang, F. Q.; Li, X.; Peng, F. Z.; Zhang, H. B.; Shao, Z. H.
Enantioselective palladium-catalyzed decarboxylative allylation of
carbazolones: total synthesis of (−)-aspidospermidine and (+)-kop-
sihainanine A. Angew. Chem., Int. Ed. 2013, 52, 4117. (b) Jones, S. B.;
Simmons, B.; MacMillan, D. W. C. Nine-step enantioselective total
synthesis of (+)-minfiensine. J. Am. Chem. Soc. 2009, 131, 13606.
(3) (a) Wang, T. M.; Duan, X. G.; Zhao, H.; Zhai, S. X.; Tao, C.;
Wang, H. F.; Li, Y.; Cheng, B.; Zhai, H. B. Asymmetric total synthesis
of (−)-aspidophylline A. Org. Lett. 2017, 19, 1650. (b) Jiang, S. Z.;
Zeng, X. Y.; Liang, X.; Lei, T.; Wei, K.; Yang, Y. R. Iridium-catalyzed
enantioselective indole cyclization: application to the total synthesis
and absolute stereochemical assignment of (−)-aspidophylline A.
Angew. Chem., Int. Ed. 2016, 55, 4044. (c) Zu, L. S.; Boal, B. W.; Garg,
N. K. Total synthesis of ( )-aspidophylline A. J. Am. Chem. Soc. 2011,
133, 8877.
(4) (a) Podoll, J. D.; Liu, Y. X.; Chang, L.; Walls, S.; Wang, W.;
Wang, X. Bio-inspired synthesis yields a tricyclic indoline that
selectively resensitizes methicillin-resistant Staphylococcus aureus
(MRSA) to β-lactam antibiotics. Proc. Natl. Acad. Sci. U. S. A.
2013, 110, 15573. (b) Chang, L.; Podoll, J. D.; Wang, W.; Walls, S.;
O’Rourke, C. P.; Wang, X. Structure−activity relationship studies of
the tricyclic indoline resistance-modifying agent. J. Med. Chem. 2014,
57, 3803.
(5) (a) Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. A
novel route to ( )-aspidospermidine: first application of ‘radical-polar
crossover’reactions to total synthesis. Tetrahedron Lett. 1999, 40, 161.
(b) Alpers, D.; Gallhof, M.; Witt, J.; Hoffmann, F.; Brasholz, M. A
Photoredox-induced stereoselective dearomative radical (4 + 2)-
cyclization/1,4-addition cascade for the synthesis of highly function-
alized hexahydro-1H-carbazoles. Angew. Chem., Int. Ed. 2017, 56,
1402. (c) Beemelmanns, C.; Reissig, H. U. A short formal total
synthesis of strychnine with a samarium diiodide induced cascade
reaction as the key step. Angew. Chem., Int. Ed. 2010, 49, 8021.
(d) Daniels, B. E.; Ni, J.; Reisman, S. E. Synthesis of enantioenriched
indolines by a conjugate addition/asymmetric protonation/aza-Prins
cascade reaction. Angew. Chem., Int. Ed. 2016, 55, 3398. (e) Hyde, A.
M.; Buchwald, S. L. Palladium-catalyzed γ-arylation of β, γ-
unsaturated ketones: application to a one-pot synthesis of tricyclic
indolines. Angew. Chem., Int. Ed. 2008, 47, 177. (f) Wang, Z. S.; Chen,
L. X.; Yao, Y.; Liu, Z. G.; Gao, J. M.; She, X. G.; Zheng, H. J.
Dearomatization of indole via intramolecular [3 + 2] cycloaddition:
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03243.
Full spectroscopic data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Xuegong She − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; orcid.org/
0000-0002-3002-2433; Phone: +86-931-8912582;
Email: shexg@lzu.edu.cn
Authors
Hao Zhang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Peiqi Chen − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Hesi Yang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Shiqiang Ma − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Zemin Wang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Xingang Xie − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
H
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
access to the pentacyclic skeleton of strychons alkaloids. Org. Lett.
2018, 20, 4439.
(6) (a) Feng, L. W.; Ren, H.; Xiong, H.; Wang, P.; Wang, L. J.;
Tang, Y. Reaction of donor-acceptor cyclobutanes with indoles:
ageneral protocol for the formal total synthesis of ( )-strychnine and
the total synthesis of ( )-akuammicine. Angew. Chem., Int. Ed. 2017,
56, 3055. (b) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.;
Hoshikawa, T.; Matsuo, J. I.; Ishibashi, H. Regioselective inter-and
intramolecular formal [4 + 2] cycloaddition of cyclobutanones with
indoles and total synthesis of ( )-aspidospermidine. Angew. Chem.,
Int. Ed. 2013, 52, 906. (c) Jones, S. B.; Simmons, B.; Mastracchio, A.;
MacMillan, D. W. C. Collective synthesis of natural products by
means of organocascade catalysis. Nature 2011, 475, 183.
(7) (a) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.;
Ogoshi, S. Intramolecular arylcyanation of alkenes catalyzed by
nickel/AlMe2Cl. J. Am. Chem. Soc. 2008, 130, 12874. (b) Hsieh, J. C.;
Ebata, S.; Nakao, Y.; Hiyama, T. Asymmetric synthesis of indolines
bearing a benzylic quaternary stereocenter through intramolecular
arylcyanation of alkenes. Synlett 2010, 11, 1709.
(8) Watson, M. P.; Jacobsen, E. N. Asymmetric intramolecular
arylcyanation of unactivated olefins via C- CN bond activation. J. Am.
Chem. Soc. 2008, 130, 12594.
(9) Yen, A.; Lautens, M. Nickel-catalyzed intramolecular arylcyana-
tion for the synthesis of 3, 3-disubstituted oxindoles. Org. Lett. 2018,
20, 4323.
(10) (a) Liu, Z. M.; Ju, X. L.; Ma, S. Q.; Du, C. L.; Zhang, W. W.; Li,
H. L.; Wang, X. L.; Xie, X. G.; She, X. G. Asymmetric total synthesis
of (+)-winchinine B. J. Org. Chem. 2019, 84, 14994. (b) Zhang, W.
W.; Lin, S. H.; Du, C. L.; Feng, S. B.; Liu, Z. M.; Zhang, J.; Xie, X. G.;
Wang, X. L.; Li, H. L.; She, X. G. Total synthesis of
aspidofractininealkaloid paucidirinine. J. Org. Chem. 2019, 84, 1111.
(c) Xu, D. Y.; Zhao, Y. L.; Song, D. P.; Zhong, Z. L.; Feng, S. B.; Xie,
X. G.; Wang, X. L.; She, X. G. (3 + 2)-annulation of p-quinamine and
aryne: astrategy to construct the multisubstitutedhydrocarbazoles.
Org. Lett. 2017, 19, 3600. (d) Zhao, G. Y.; Xie, X. G.; Sun, H. Y.;
Yuan, Z. Y.; Zhong, Z. L.; Tang, S. C.; She, X. G. Bioinspired
collective syntheses of iboga-type indole alkaloids. Org. Lett. 2016, 18,
2447. (e) Ma, H. C.; Xie, X. G.; Jing, P.; Zhang, W. W.; She, X. G.
Concise total synthesis of ( )-aspidospermidine. Org. Biomol. Chem.
2015, 13, 5255. (f) Yang, J.; Xie, X. G.; Wang, Z. S.; Mei, R. M.;
Zheng, H. J.; Wang, X. L.; Zhang, L.; Qi, J.; She, X. G.
Stereoselectivesynthesis of fused spiroindolines via tandem man-
nich/intramolecular aminalformation. J. Org. Chem. 2013, 78, 1230.
(g) Jing, P.; Yang, Z.; Zhao, C. G.; Zheng, H. J.; Fang, B. W.; Xie, X.
G.; She, X. G. Total synthesis of ( )-kopsihainanine A. Chem. - Eur. J.
2012, 18, 6729.
́
(11) Balde, A. M.; Pieters, L. A.; Gergely, A.; Wray, V.; Claeys, M.;
Vlietinck, A. J. Spermacoceine, a bis-indole alkaloid from Borreria
verticillata. Phytochemistry 1991, 30, 997.
(12) (a) Wei, M. X.; Wang, C. T.; Du, J. Y.; Qu, H.; Yin, P. R.; Bao,
X.; Ma, X. Y.; Zhao, X. H.; Zhang, G. B.; Fan, C. A. Enantioselective
synthesis of Amaryllidaceae alkaloids (+)-vittatine, (+)-epi-vittatine,
and (+)-buphanisine. Chem. - Asian J. 2013, 8, 1966. (b) Zuo, X. D.;
Guo, S. M.; Yang, R.; Xie, J. H.; Zhou, Q. L. Bioinspired
enantioselective synthesis of crinine-type alkaloids via iridium-
catalyzed asymmetric hydrogenation of enones. Chem. Sci. 2017, 8,
6202.
(13) Sunnemann, H. W.; Hofmeister, A.; Magull, J.; de Meijere, A.
̈
Stille−Heck coupling sequences applied in a versatile new access to
steroid skeletons. Chem. - Eur. J. 2007, 13, 3739.
I
https://dx.doi.org/10.1021/acs.joc.9b03243
J. Org. Chem. XXXX, XXX, XXX−XXX