Construction of Indoline/Indolenine Ring Systems by a Palladium-Catalyzed Intramolecular Dearomative Heck Reaction and the Subsequent Aza-semipinacol Rearrangement

Article abstract of DOI:10.1021/acs.joc.1c00209

The palladium-catalyzed intramolecular dearomative Heck reaction of 2,3-disubstituted indoles serves as an access to spiro-indoline products. Herein, we report an efficient construction of indoline/indolenine core stuctures via a dearomative Heck reaction

Full text of DOI:10.1021/acs.joc.1c00209

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Article
Construction of Indoline/Indolenine Ring Systems by a Palladium-
Catalyzed Intramolecular Dearomative Heck Reaction and the
Subsequent Aza-semipinacol Rearrangement
Dong Gao and Lei Jiao*
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ABSTRACT: The palladium-catalyzed intramolecular dearomative
Heck reaction of 2,3-disubstituted indoles serves as an access to
spiro-indoline products. Herein, we report an efficient construction of
indoline/indolenine core stuctures via a dearomative Heck reaction
of simple 2,3-disubstituted indoles with all-carbon tethers and the
subsequent aza-semipinacol rearrangement. The Heck reaction
features a high C2-selectivity, and the stereospecific aryl/alkyl
migration selectivity has been investigated by DFT calculations.
Using this method, we accomplished the formal total synthesis of
akuammiline alkaloids vincorine.
position first underwent an oxidative addition to a Pd(0)
catalyst to generate the corresponding aryl-Pd(II) complex. A
regioselective migratory insertion of the aryl-Pd(II) bond into
the C2−C3 double bond of the indole unit afforded a
dearomatized C3−Pd(II) intermediate. Finally, a spirocyclic
indoline product bearing an exo-cyclic double bond was
formed by β-hydride elimination. Inspired by these findings,
we envisaged that the spiroindoline product could undergo an
aza-semipinacol rearrangement under acidic conditions to
produce a 2,3-fused indolenine product,6 which may open an
avenue to a number of natural product skeletons. For this aim,
an all-carbon tether instead of a heteroatom-containing tether
and a haloalkene unit instead of a haloarene unit are required.
To date, all reported examples used amide5a or ester5b tethers
between indole and the haloarene unit, and the alkenylative
dearomative Heck reaction of 2,3-disubstituted indoles was still
unprecedented. The planned acid-promoted aza-semipinacol
rearrangement also remained elusive; in particular, the alkyl/
aryl(alkenyl) migration selectivity is of great concern.
INTRODUCTION
■
Indolines and indolenines exist widely in a number of natural
products with divergent biological activities (Figure 1).1
Efficient construction of their common unique polycyclic
structures has attracted significant attention from the synthetic
community.2
Dearomatization of indole derivatives serves as a straightfor-
ward access to spiro- or fused-indolines.2e,3 In the past five
years, a palladium-catalyzed intramolecular Heck reaction has
been recognized as an efficient method for the dearomatization
of 2,3-disubstituted indoles (Scheme 1a).4,5 In these reactions,
the indoles bearing a haloarene unit tethered to the C2-
Despite these potential challenges, we intended to explore
whether or not the efficient construction of a natural product
skeleton could be enabled by this strategy. Herein, we report
Received: January 27, 2021
Published: March 31, 2021
Figure 1. Representative indoline/indolenine alkaloids.
https://doi.org/10.1021/acs.joc.1c00209
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Scheme 1. Dearomative Heck Reactions of 2,3-
Disubstituted Indoles
Table 1. Optimization of the Reaction Conditions for the
Dearomative Heck Reaction/Aza-semipinacol
Rearrangement of 1a
a
b
c
yield (%)
3aa
ee (%)
entry
ligand
3ab
3aa
3ab
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L8
64
0
39
0
0
0
22
0
8
0
0
0
0
19
d
21
22
0
33
e
8
10
11
our effort on the development of a dearomative Heck reaction
of simple 2,3-disubstituted indoles with an all-carbon tether
and the subsequent rearrangement to approach complex
indoline/indolenine skeletons, which was applied to the formal
total synthesis of akuammiline alkaloid vincorine (Scheme
1b).7
RESULTS AND DISCUSSION
■
Reaction Optimization. We began our study by
attempting the reaction of model substrate 1a with an all-
carbon tether (Table 1). With [Pd(C3H5)Cl]2 (2.5 mol %) as
the palladium source and Cs2CO3 (1.5 equiv) as the base, a
series of commercially available phosphine and phosphor-
amidite ligands were initially tested in toluene at 100 °C. To
our delight, when Q-phos (L1)8 was utilized, the desired
intramolecular dearomative Heck product, spirocyclic indoline
2a, could be detected by NMR with full conversion. Treatment
of the crude 2a with TFA afforded rearranged products 3aa
and 3ab in 64% and 22% isolated yields, respectively (entry 1).
The result indicated that, in the proposed acid-catalyzed aza-
semipinacol rearrangement, aryl migration is preferred over
alkyl migration, and the iminium ion could be efficiently
trapped by the ethaneamine side chain. The enantioselective
variant of the reaction was then investigated. However, to our
disappointment, by applying a series of chiral phosphine and
phosphoramidite ligands, product 3aa and 3ab could be
obtained in only moderate yields and insufficient ee’s (entries
2−8). As a result, we had to focus on the reaction using the
nonchiral ligand L1.
a
Reaction conditions: for dearomative Heck reactions, 1a (1.0
equiv), [Pd(C3H5)Cl]2 (2.5 mol %), L (7.5 mol %), Cs2CO3 (1.5
equiv), toluene (0.1 M), 100 °C for 24 h; for aza-semipinacol
rearrangement, TFA/DCM = 1:10 (0.1 M). Isolated yield.
Determined by chiral high-performance liquid chromatography
(HPLC). At 120 °C, DCE as the solvent for 72 h. At 120 °C for
48 h.
b
c
d
e
Reaction Scope. Under the optimal reaction conditions,
we tested the substrate scope of the above dearomative Heck
reaction and the subsequent aza-semipinacol rearrangement
(Table 2). We found that the protecting group R3 on the
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a
Table 2. Substrate Scope for the Dearomative Heck Reaction/Aza-semipinacol Rearrangement
a
Reaction conditions: 1a (1.0 equiv), [Pd(C3H5)Cl]2 (2.5 mol %), L1 (7.5 mol %), Cs2CO3 (1.5 equiv), toluene (0.1 M), 100 °C, 24 h; then
b
c
removal of the solvent and treatment with TFA/DCM = 1:10 (0.1 M) at rt. Yields of isolated products were reported. 1.36 g (2.79 mmol)
reaction scale.
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ethaneamine side chain exhibited a significant impact on the
reaction. Substrates bearing an N-Boc group (1a) was better
than the Ac-protcted substrate (1b). Morever, Ts-protected
substrate 1c was not tolerated in the dearomatization step,
presumably due to the presence of an acidic sulfonamide
moiety. Next, various substituted aryl bromides were
examined. To our delight, the intramolecular dearomatization
and the subsequent rearrangement proceeded smoothly.
Interestingly, substrates with an electron-rich aryl ring (1d−
f) or an aryl ring with meta- or para-halogen substitution (1g−
h) favored the aryl-migrated product, while substrates with an
electron-deficient trifluoromethyl-substituted aryl ring (1i)
favored the alkyl-migrated product. Bromonaphthalene 1j
was tolerated to give alkyl-migrated product 3jb as the single
product. Aryl iodide 1k was also tested to deliver 3aa and 3ab
in decreased yields. The Boc-protected indole substrate 1l with
a Cbz-protected ethaneamine side chain was then employed to
afford product 3la in 77% yield. Morever, C5-methoxy-
substituted substrate 1m was also found compatible, furnishing
indoline 3ma and 3mb in 42% and 7% isolated yields,
respectively. To confirm the scalability of the method, a gram-
scale reaction of 1m was carried out, and products 3ma and
3mb were obtained in 40% and 6% yields, respectively.
Particularly, substrate 1n with a methyl group at C3 also
underwent the reaction smoothly, leading to the desired
indolenine product 3na and 3nb in 20% and 49% yields.
Reversal of the selectivity may arise from the instability of
imine 3na.9 Interestingly, pyrido-fused indole substrate 1o
could also undergo the dearomatization reaction to afford
bridged tetracyclic product 2o in 41% yield. However, the
dearomatized product could not undergo the following aza-
semipinacol rearrangement.
Scheme 2. Confirmation of the Structures of the Aza-
Semipinacol Rearrangement Products 3ha and 3hb
a
Displacement ellipsoids are drawn at the 50% probability level
Scheme 3. Stereospecificity of the Aza-Semipinacol
Rearrangement
The structures of the two rearrangement products were
confirmed by chemical derivatization. The N-tosylation
reaction was performed for 3ha and 3hb to afford 4ha and
4hb in 90% and 64% yields, respectively. Structures of the
tosylation products were unambiguously confirmed by X-ray
crystallographic analysis to support the structural assignments
(Scheme 2).
Stereospecificity of the Rearrangement Step. Then,
we focused on the cascade rearrangement step to probe
whether it is a stereospecific process. Although in the
optimization study the rearranged products 3aa and 3ab
were produced with same extent of enantiomeric excess that
suggested a potential stereospecific rearrangement (Table 1,
entries 3 and 8), the enantiomeric excess of the dearomative
Heck product 2a was not available due to its lability.
Therefore, we performed the cascade reaction of 1n with
chiral ligand L8 to isolate a relatively stable and enantioen-
riched spiro product 2n and then performed its rearrangement
reaction. We found that spiro indoline 2n was produced in
69% yield with 37% ee, and the rearrangement of 2n under the
optimized conditions afforded indolenine 3na and 3nb in 8%
and 39% isolated yields with exactly the same enantiomeric
excess. This result confirmed a stereospecific aryl/alkyl
migration step. Based on the experimental result, a plausible
mechanism for the generation of 3na and 3nb was proposed
(Scheme 3), which consists of deprotection of the Boc group
to form intermediate A, the protonation of the exocyclic
methylene group, and the 1,2-aryl or alkyl migration.
was selected as the model substrate, and the rearrangement
pathways of the protonated carbocation intermediate 2ri was
investigated. The potential energy profile (Figure 2a) was
drawn based on the calculated relative Gibbs free energies in
dichloromethane. The indolenine structures 2ra and 2rb were
formed via TS1a (aryl migration) and TS1b (alkyl migration),
respectively. The calculations confirmed that the rearrange-
Computational Study. In order to gain more insight into
the stereospecific aza-semipinacol rearrangement process, we
performed a DFT calculation. Dearomative Heck product 2r
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Figure 2. Energy profile of the aza-semipinacol rearrangement. The calculation was performed on the M06-2X/6-311++G(2df,2p)//B3LYP/6-
31+G(d,p) level of theory.10,11
ment process is concerted based on the intrinsic reaction
coordinate (IRC) analysis of TS1a and TS1b. The aryl
migration (via TS1a) is favored over alkyl migration (via
TS1b) by 0.5 kcal/mol in terms of Gibbs free energy, which
correlated well with the experimental result (Table 1). The
substituent effect was then studied on a series of aryl
substituents (Figure 2b). The calculated ΔΔG⧧ [ΔG⧧(TS1a)
− ΔG⧧(TS1b)] correlated well with the σ+ parameter of the
substituent on the aryl ring, and the Hammett plot (Figure 2c)
exhibited a negative slope.12 This indicated that the partial
positive charge developed at the benzyl position during aryl
migration, which was in agreement with the experimental
results that electron-rich aryl groups favored aryl shift and
electron-poor aryl groups favored alkyl shift.
Particularly, calculations indicated that, in carbocation 2y,
the alkyl shift was predominant (ΔΔG⧧ = +5.7 kcal/mol),
which fits well with the experimental results (substrate 1j).
This was possibly due to the steric effect of the naphthalene
ring that overwhelmingly determined the migration selectivity
(The C8−H to C3a distance is 2.45 Å and the distance for
C8−H to C7a is 2.37 Å in 2y-TS1a, which result in significant
repulsion between the naphthyl group and the indole moiety).
Given the satisfactory predictive power of this calculation, we
have also evaluated the preference for alkyl and alkenyl
migration in carbocation 2z. Gratifyingly, a ΔΔG⧧ value of
−2.0 kcal/mol was obtained, which indicated a good selectivity
for alkenyl migration and verified the potential for its
application in the synthesis of indoline alkaloid vincorine.
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Scheme 4. Formal Total Synthesis of Vincorine
Formal Total Synthesis of Vincorine. With the
successful cascade reaction in hand, we further carried out
the more challenging alkenylative dearomative Heck reactions
(Scheme 4). Our synthesis commenced with the preparation of
trisubstituted alkenyl iodide 7 in four steps from 4.7b After
Dess−Martin oxidation of 4, the resulted aldehyde 5 was
subjected to a modified Horner−Wadsworth−Emmons
reaction to give vinyl iodide 613 in 45% yield. Reduction of
the unsaturated ester with DIBAL-H and subsequent
protection of allylic alcohol afforded TBDPS ether 7, which
served as the substrate for the crucial dearomative Heck
reaction. Different from haloarene substrate, Q-phos (L1) was
proven incompetent for the reaction of the trisubstituted
haloalkene substrate. Using the Carreira ligand L8,14 the
alkenyl dearomative Heck reaction proceeded smoothly to
generate the spiro indoline 8 with full conversion. Treatment
of indoline 8 with trifluoroacetic acid resulted in cascade aza-
semipinacol rearrangement and subsequent cyclization, deliv-
ering the tetracyclic indoline 9 as the only regioisomer in 40%
yield over 2 steps. The observed regioselectivity perfectly
matched the DFT prediction.
Intermediate 9 was then subjected to a regioselective
tosylation, providing sulfonamide 10 in 58% yield. At this
stage, we were able to determine the ee of intermediate 10 and
found that the enantioselectivity of the alkenylative dear-
omative Heck reaction was poor (7% ee). Finally, allylic
alcohol 12 was formed by installation of a Boc group by
treatment of triphosgene/pyridine/t-BuONa (56% yield) and
deprotection of the TBDPS group by TBAF (93% yield).
According to Qin’s report, intermediate 12 could be further
transformed to natural product vincorine;7a therefore, this
result represented the formal synthesis of racemic vincorine by
the designed cascade reaction.
Scheme 5. Dearomative Heck Reaction of Alkenyl
Substrates
CONCLUSIONS
■
In summary, we have accomplished an efficient construction of
indoline/indolenine ring systems via palladium-catalyzed
intramolecular dearomative Heck reactions of all-carbon
tethered 2,3-disubstituted indoles and the following aza-
semipinacol rearrangement. DFT calculations revealed a
concerted migration for the stereospecific rearrangement, in
which the migration selectivity was mainly determined by
electronic nature of the migration group. The haloolefin
substrate was proved competent in the present reaction to
afford the tetralcyclic indoline core, which was applied to the
formal total synthesis of vincorine.
EXPERIMENTAL SECTION
■
General Experimental Information. Unless stated otherwise, all
air- and moisture-sensitive reactions were carried out in oven-dried
glassware sealed with rubber septa under a positive pressure of dry
argon. Air- and moisture-sensitive liquids and solutions were
transferred by syringe. Reactions were stirred using Teflon-coated
magnetic stir bars. Elevated temperatures were maintained using
thermostat-controlled silicone oil baths. Organic solutions were
concentrated using a rotary evaporator with a diaphragm vacuum
In addition to substrate 7, we further explored the scope of
the haloolefin-paticipating reaction (Scheme 5). The trisub-
stituted alkenyl iodide 1p and tetrasubstituted alkenyl bromide
1q were tested under the optimized reaction conditions to
afford the dearomative products 2p and 2q in 52% and 82%
yields, respectively. However, the subsequent aza-semipinacol
rearrangement failed to give the desired product.
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pump. Analytical TLC was performed on silica gel GF254 plates. The
TLC plates were visualized by ultraviolet light (λ = 254 nm).
Purification of products was accomplished by flash column
chromatography on silica gel (Innochem SilicaFlash P60, 230−400
mesh). NMR spectra were recorded on a Bruker AVANCE III HD
400 (1H at 400 MHz, 13C at 100 MHz, 13F at 386 MHz) or a JEOL
JNM-ECA 600 (1H at 600 MHz, 13C at 150 MHz) nuclear magnetic
resonance spectrometer. The 1H NMR spectra were calibrated against
the peak of tetramethylsilane (TMS, 0 ppm), and the 13C NMR
spectra were calibrated against the peak of CDCl3 (77.16 ppm). Data
for 1H NMR are recorded as follows: chemical shift (δ, ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or
unresolved, br = broad singlet, dd = doublet of doublets, dt = doublet
of triplets, ddd = doublet of doublet of doublets, coupling constant (s)
in Hz, integration). Data for 13C{1H} NMR and 19F{1H} NMR are
reported in terms of chemical shift (δ, ppm). IR spectra were
measured using a Bruker FT-IR Alpha instrument (ATR mode).
Enantiomeric excess (ee) values were determined by analytical high-
performance liquid chromatography (HPLC) analysis on a Shimadzu
LC-20A instrument using Daicel chiral columns Chiralpak IA, AD,
and OD (4.6 mm × 250 mm). Optical rotations were measured on a
Jasco P-2000 Polarimeter. High-resolution mass spectral data were
performed on a Thermo Scientific QExactive or a Shimadzu LCMS-
IT-TOF (positive mode) mass spectrometer.
Computational Methods. All calculations were performed with
the Gaussian 09 program.15 Geometry optimizations of all minima
and transition structures were carried out using the hybrid B3LYP
functional, with the 6-31+G(d,p) basis set for all elements. The
keyword “5D” was used to specify that five d-type orbitals were used
for all elements in the calculations. Frequency calculations at the same
level were performed to confirm that each stationary point was either
a minimum or a transition structure and to evaluate its zero-point
energy and the thermal corrections at 298 K. Based on the gas-phase
optimized structures, single-point energy calculations were carried out
using the M06-2X functional with the 6-311++G(2df,2p) basis set for
all atoms, using the CPCM solvent model. The computed structures
were illustrated using CYLview.16
The mixture was diluted with H2O and extracted with ethyl acetate.
The combined extracts were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The resulting residue was filtered through
a pad of silica gel (eluted with petroleum ether/ethyl acetate 10:1) to
afford crude olefin S3 as a yellow oil (1.20 g, 91% crude yield), which
was directly used in the next step without further purification. In GP-
C, to the above olefin S3 (1.20 g, 2.72 mmol, 1.0 equiv) dissolved in
EtOH (27 mL) were added TsNHNH2 (5.12 g, 27.2 mmol, 10.0
equiv) and NaOAc (2.22 g, 27.2 mmol, 10.0 equiv). The mixture was
then refluxed in an oil bath for 24 h. TsNHNH2 (5.12 g, 27.2 mmol,
10.0 equiv) and NaOAc (2.22 g, 27.2 mmol, 10.0 equiv) were then
added and refluxed for another 24 h until completion of the reaction
1
(monitored by H NMR). The reaction mixture was concentrated in
vacuo and filtered through a pad of silica gel. The crude product was
purified by flash column chromatography on silica gel (eluted with
petroleum ether/ethyl acetate 20:1 to 5:1) to afford S4 as a yellow oil
(1.04 g, 86% yield). TLC: Rf = 0.24 (petroleum ether/ethyl acetate =
1
7:1). H NMR (400 MHz, CDCl3): δ (ppm) 7.75−7.85 (br s, 1H),
7.56 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.9 Hz,
1H), 7.04−7.23 (m, 5H), 4.40−4.65 (br s, 1H), 3.20−3.40 (m, 2H),
2.98−3.12 (m, 4H), 2.86 (t, J = 6.0 Hz, 2H), 1.41 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 156.0, 140.3, 135.6, 135.2, 133.1,
130.8, 128.5, 128.3, 127.8, 124.4, 121.5, 119.5, 118.5, 110.6, 109.2,
∼
79.2, 41.2, 37.0, 28.6, 26.7, 24.9. IR (ATR): v (cm−1) = 1688, 1506,
1461. HRMS (ESI) m/z: [M + Na]+ calcd for C23H27BrN2O2Na,
465.1154; found, 465.1166.
tert-Butyl (2-(2-(2-Bromophenethyl)-1-methyl-1H-indol-3-yl)-
ethyl)carbamate (1a, Scheme S1, Reaction 1). In GP-D, to a
solution of S4 (1.30 g, 2.94 mmol, 1.00 equiv) dissolved in 30 mL dry
THF was added NaH (60% mineral oil dispersion, 129 mg, 3.23
mmol, 1.1 equiv) at 0 °C under an argon atmosphere, and the mixture
was warmed to rt and stirred for 1 h. The mixture was then cooled to
0 °C and dimethylsulfate (0.3 mL, 3 mmol, 1.1 equiv) was added. The
resulting mixture was heated to 50 °C and stirred for 6 h. Upon
completion (TLC), saturated aqueous NH4Cl solution was added and
the solvent was evaporated. The mixture was extracted with DCM.
The combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The resulting residue was
purified by flash column chromatography on silica gel (eluted with
petroleum ether/ethyl acetate 20:1 to 10:1) to afford 1a as a yellow
oil (1.42 g, 100% yield). TLC: Rf = 0.39 (petroleum ether/ethyl
acetate = 7:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.51−7.59 (m,
2H), 7.24−7.29 (m, 1H), 7.11−7.22 (m, 3H), 7.05−7.11 (m, 2H),
4.40−4.65 (br s, 1H), 3.67 (s, 3H), 3.20−3.40 (m, 2H), 2.95−3.12
(m, 4H), 2.88 (t, J = 6.1 Hz, 2H), 1.41 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 156.0, 140.3, 137.0, 136.8, 133.0, 131.0,
128.3, 127.8, 127.8, 124.3, 121.2, 119.2, 11∼8.5, 109.0, 108.7, 79.2,
Experimental Procedures for the Preparation of Aryl
Substrates, See Scheme S1, Scheme S2, and Scheme S3.
tert-Butyl (2-(2-Formyl-1H-indol-3-yl)ethyl)carbamate (S2, Scheme
S1, Reaction 1). In GP-A, to a solution of S1 (7.72 g, 28.4 mmol, 1.0
equiv) in 130 mL of 1,4-dioxane and 7.0 mL of H2O was added SeO2
(4.71 g, 42.4 mmol, 1.5 equiv). The mixture was heated under reflux
in an oil bath (120 °C) for 3 h until completion of the reaction
(TLC). The mixture was filtered through a pad of Celite and washed
with ethyl acetate. The resulting mixture was concentrated, and the
residue was diluted with ethyl acetate and washed with brine. The
combined extracts were dried over Na2SO4 and concentrated in
vacuo. The resulting residue was purified by flash column
chromatography on silica gel (eluted with petroleum ether/EtOAc
10:1 to 5:1) to afford S2 as a yellow solid (5.16 g, 63% yield). TLC: Rf
41.4, 37.3, 29.8, 28.6, 25.3, 25.2. IR (ATR): v (cm−1) = 1600, 1492,
1376. HRMS (ESI) m/z: [M + Na]+ calcd for C24H29BrN2O2Na,
479.1310; found, 479.1321.
1
= 0.36 (petroleum ether/ethyl acetate = 3:1). Mp: 120−121 °C. H
N-(2-(2-(2-Bromophenethyl)-1-methyl-1H-indol-3-yl)ethyl)-
acetamide (1b, Scheme S1, Reaction 2). To a solution of 1a (795
mg, 1.79 mmol) dissolved in DCM (10 mL) was added TFA (0.9
mL). The mixture was stirred at rt for 12 h until completion of the
reaction (TLC). Saturated aqueous NaHCO3 solution was slowly
added. The mixture was extracted with DCM and the combined
extracts were washed with brine, dried over Na2SO4, and concentrated
in vacuo gave S5 as a yellow oil, which was directly used in the next
step without further purification. To the above crude product S5 (225
mg, 0.63 mmol) dissolved in 6 mL DCM was added Ac2O (77 mg,
0.76 mmol) and NEt3 (77 mg, 0.76 mmol). The mixture was stirred at
rt for 4 h until completion of the reaction (TLC). Saturated aqueous
NaHCO3 solution was slowly added. The mixture was extracted with
DCM and the combined extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (eluted with petroleum
ether/ethyl acetate 10:1 to 5:1) to afford 1b as a yellow oil (214 mg,
NMR (400 MHz, CDCl3): δ (ppm) 9.95 (s, 1H), 9.13−9.59 (br s,
1H), 7.73 (d, 8.1 Hz, 1H), 7.35−7.45 (m, 2H), 7.16 (td, J = 7.9, 1.2
Hz, 1H), 4.53−5.27 (br s, 1H), 3.41−3.52 (m, 3H), 3.31 (t, J = 6.2
Hz, 1H), 1.44 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
180.8, 156.0, 137.8, 133.1, 127.8∼, 127.6, 125.9, 121.5, 120.9, 112.6,
79.7, 41.9, 28.5, 24.4. IR (ATR): v (cm−1) = 3307, 2976, 2931, 2863,
1687, 1644, 1509, 1457, 1391, 1365. HRMS (ESI) m/z: [M + Na]+
calcd for C16H20N2O3Na, 311.1366; found, 311.1395.
tert-Butyl (2-(2-(2-Bromophenethyl)-1H-indol-3-yl)ethyl)-
carbamate (S4, Scheme S1, Reaction 1). In GP-B, to a solution of
the phosphonium salt (2.13 g, 3.92 mmol, 1.3 equiv) in dry THF (20
mL) at 0 °C was added t-BuOK (439 mg, 3.92 mmol, 1.3 equiv)
under an argon atmosphere. The mixture was stirred at 0 °C for 1 h.
Aldehyde S2 (693 mg, 3.01 mmol, 1.0 equiv) dissolved in 10 mL of
THF was added dropwise in 15 min. The resulting mixture was
allowed to warm to room temperature and stirred for about 20 h until
the completion of the reaction (TLC). The reaction mixture was
quenched with H2O, and THF was removed under reduced pressure.
1
85%). TLC: Rf = 0.44 (petroleum ether/ethyl acetate = 1:1). H
NMR (400 MHz, CDCl3): δ (ppm) 7.52−7.58 (m, 2H), 7.27 (d, J =
5733
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The Journal of Organic Chemistry
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Article
8.2 Hz, 1H), 7.15−7.24 (m, 2H), 7.04−7.17 (m, 3H), 5.85 (br s, 1H),
3.67 (s, 3H), 3.45 (q, J = 6.7 Hz, 2H), 2.94−3.09 (m, 4H), 2.89 (t, J =
6.9 Hz, 2H), 1.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 170.1, 140.1, 137.0, 136.7, 133.0, 130.9, 128.3, 127.9, 127.8,
118.5, 109.0, 108.6, 79.1, 41.4, 36.8, 29.8, 28.6, 25.3, 25.3, 20.8. IR
∼
(ATR): v (cm−1) = 1699, 1492, 1471, 1391. HRMS (ESI) m/z: [M +
Na]+ calcd for C25H31BrN2O2Na, 495.1441; found, 495.1431.
tert-Butyl (2-(2-(2-Bromo-5-fluorophenethyl)-1-methyl-1H-indol-
3-yl)ethyl)carbamate (1g, Scheme S1, Reaction 1). The compound
was synthesized according to GP-B, GP-C, and GP-D using S2 to
afford 1g as a yellow oil (301 mg, 61% yield over 3 steps). TLC: Rf =
124.3, 121.2, 119.3, 118.3, 109.1, 108.5, 40.5, 37.2, 29.8, 25.1, 24.6,
∼
23.5. IR (ATR): v (cm−1) = 1646, 1552, 1470, 1434, 1368. HRMS
(ESI) m/z: [M + H]+ calcd for C21H24BrN2O, 401.1048; found,
401.1042.
1
0.60 (petroleum ether/ethyl acetate = 5:1). H NMR (400 MHz,
CDCl3): δ (ppm) 7.46−7.57 (m, 2H), 7.26 (t, J = 8.1 Hz, 1H), 7.19
(dd, J = 7.8, 7.2 Hz, 1H), 7.09 (dd, J = 7.5, 7.3 Hz, 1H), 7.00 (d, J =
8.0 Hz, 1H), 6.83 (td, J = 8.5, 3.1 Hz, 1H), 4.50−4.78 (br s, 1H), 3.70
(s, 3H), 3.37−3.41 (m, 2H), 3.00−3.09 (m, 2H), 2.91−3.00 (m, 2H),
2.85−2.93 (t, J = 7.1 Hz, 2H), 1.41 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 163.3 (C−F, 1JC−F = 246.0 Hz), 160.9 (C−F,
1JC−F = 246.0 Hz), 156.0, 142.5 (C−F, 3JC−F = 7.0 Hz), 142.4 (C−F,
N-(2-(2-(2-Bromophenethyl)-1-methyl-1H-indol-3-yl)ethyl)-4-
methylbenzenesulfonamide (1c, Scheme S1, Reaction 3). To the
above crude product, were added S5 (194 mg, 0.544 mmol) dissolved
in 5.5 mL of DCM, TsCl (124 mg, 0.651 mmol), and NEt3 (66 mg,
0.65 mmol). The mixture was stirred at rt for 4 h until completion of
the reaction (TLC). Saturated aqueous NaHCO3 solution was slowly
added. The mixture was extracted with DCM, and the combined
extracts were washed with brine, dried over Na2SO4, and concentrated
in vacuo. The crude product was purified by flash column
chromatography on silica gel (eluted with petroleum ether/ethyl
acetate 5:1 to 1:1) to afford 1c as a white foam (218 mg, 79%). TLC:
Rf = 0.49 (petroleum ether/ethyl acetate = 5:1). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.61 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.8 Hz, 1H),
7.34 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.13−7.22 (m,
4H), 7.00−7.10 (m, 3H), 4.41 (t, J = 6.1 Hz, 1H), 3.65 (s, 3H), 3.15
(q, J = 6.9 Hz, 2H), 2.88−3.03 (m, 4H), 2.85 (t, J = 6.9 Hz, 2H), 2.36
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 143.2, 140.0,
137.0, 136.95, 136.91, 132.8, 130.8, 129.6, 128.2, 127.8, 127.2, 127.1,
3
3JC−F = 7.0 Hz), 137.0, 136.3, 134.1 (C−F, JC−F = 8.0 Hz), 134.0
(C−F, 3JC−F = 8.0 Hz), 127.6, 121.3, 119.2, 118.4, 118.3 (C−F, 4JC−F
4
2
= 3.0 Hz), 118.2 (C−F, JC−F = 3.0 Hz), 117.8 (C−F, JC−F = 23.0
2
2
Hz), 117.6 (C−F, JC−F = 23.0 Hz), 115.5 (C−F, JC−F = 23.0 Hz),
2
115.3 (C−F, JC−F = 23.0 Hz), 109.0, 108.8, 79.2, 41.5, 37.3, 29.8,
28.5, 25.3, 25.0. 19F{1H} NMR (386 MHz, CDCl3): δ (ppm) −114.5
∼
(m). IR (ATR): v (cm−1) = 1698, 1504, 1470, 1392. HRMS (ESI)
m/z: [M + Na]+ calcd for C24H28BrFN2O2Na, 499.1190; found,
499.1176.
tert-Butyl (2-(2-(2-Bromo-4-chlorophenethyl)-1-methyl-1H-
indol-3-yl)ethyl)carbamate (1h, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S2 to afford 1h as a yellow oil (184 mg, 38% yield over 3 steps).
TLC: Rf = 0.75 (petroleum ether/ethyl acetate = 5:1). 1H NMR (400
MHz, CDCl3): δ (ppm) 7.60 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.26 (d, J = 8.8 Hz, 1H), 7.16−7.23 (m, 2H), 7.06−7.13 (m,
2H), 4.45−4.68 (br s, 1H), 3.66 (s, 3H), 3.31−3.39 (m, 2H), 2.92−
3.07 (m, 4H), 2.86 (t, J = 7.0 Hz, 2H), 1.41 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 156.0, 138.9, 137.0, 136.4, 133.1, 132.5,
131.7, 128.0, 127.7, 124.5, 121.3, 119.3, 11∼8.5, 109.0, 108.8, 79.2,
124.2, 121.2, 119.2, 118.0, 109.0, 107.1, 43.5, 37.0, 29.7, 25.1, 25.0,
∼
21.5. IR (ATR): v (cm−1) = 3281, 1470, 1372. HRMS (ESI) m/z: [M
+ H]+ calcd for C26H28BrN2O2S, 513.1032; found, 513.1033.
tert-Butyl (2-(2-(2-Bromo-5-methoxyphenethyl)-1-methyl-1H-
indol-3-yl)ethyl)carbamate (1d, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S2 to afford 1d as a yellow oil (139 mg, 13% yield over 3 steps).
TLC: Rf = 0.44 (petroleum ether/ethyl acetate = 5:1). 1H NMR (400
MHz, CDCl3): δ (ppm) 7.54 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.7 Hz,
1H), 7.26 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 7.2, 7.8 Hz, 1H), 7.08
(dd, J = 7.5, 7.3 Hz, 1H), 6.62−6.72 (m, 2H), 4.48−4.68 (br s, 1H),
3.68 (s, 3H), 3.65 (s, 3H), 3.27−3.41 (m, 2H), 3.00−3.09 (m, 2H),
2.83−2.99 (m, 4H), 1.41 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ (ppm) 159.2, 156.1, 141.2, 137.0, 136.7, 133.4, 127.7, 121.2, 119.2,
41.4, 36.7, 29.9, 28.6, 25.3, 25.0. IR (ATR): v (cm−1) = 1698, 1504,
1470, 1392. HRMS (ESI) m/z: [M
+
Na]+ calcd for
C24H28BrClN2O2Na, 515.0881; found, 515.0894.
tert-Butyl (2-(2-(2-Bromo-4-(trifluoromethyl)phenethyl)-1-meth-
yl-1H-indol-3-yl)ethyl)carbamate (1i, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S2 to afford 1i as a yellow oil (277 mg, 53% yield over 3 steps).
118.4, 116.3, 114.7, 114.1, 109.0, 108.6, 79.1, 55.5, 41.5, 37.5, 29.8,
∼
28.6, 25.3, 25.2. IR (ATR): v (cm−1) = 1698, 1504, 1471, 1391.
1
HRMS (ESI) m/z: [M + Na]+ calcd for C25H31BrN2O3Na, 509.1410;
found, 509.1405.
TLC: Rf = 0.43 (petroleum ether/ethyl acetate = 10:1). H NMR
(400 MHz, CDCl3): δ (ppm) 7.70 (d, J = 8.2 Hz, 1H), 7.56 (d, J =
7.8 Hz, 1H), 7.51 (s, 1H), 7.37 (dd, J = 8.3, 2.2 Hz, 1H), 7.31 (d, J =
8.1 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 4.53−
4.71 (br s, 1H), 3.75 (s, 3H), 3.28−3.41 (m, 2H), 3.01−3.12 (m,
4H), 2.90 (t, J = 7.1 Hz, 2H), 1.42 (s, 9H). 13C{1H} NMR (100
tert-Butyl (2-(2-(2-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethyl)-1-
methyl-1H-indol-3-yl)ethyl)carbamate (1e, Scheme S1, Reaction
1). The compound was synthesized according to GP-B, GP-C, and
GP-D using S2 to afford 1e as a yellow oil (413 mg, 56% yield over 3
MHz, CDCl3): 156.0, 141.5, 137.1, 136.0, 133.6, 130.9 (C−F, 2JC−F
=
1
steps). TLC: Rf = 0.24 (petroleum ether/ethyl acetate = 10:1). H
2
2
32.0 Hz), 130.6 (C−F, JC−F = 32.0 Hz),130.2 (C−F, JC−F = 32.0
NMR (400 MHz, CDCl3): δ (ppm) 7.56 (d, J = 7.7 Hz, 1H), 7.28 (d,
J = 8.2 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H),
7.03 (s, 1H), 6.72 (s, 1H), 5.95 (s, 2H), 4.50−4.70 (br s, 1H), 3.72 (s,
3H), 3.29−3.44 (m, 2H), 2.97−3.05 (m, 2H), 2.85−2.96 (m, 4H),
1.43 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): 156.1, 147.7, 147.2,
137.0, 136.7, 133.4, 127.7, 121.2, 119.2, 118.5, 114.2, 112.8, 110.4,
2
4
Hz), 129.9 (C−F, JC−F = 32.0 Hz), 128.20 (C−F, JC−F = 1.0 Hz),
128.19 (C−F, 4JC−F = 1.0 Hz), 128.18 (C−F, 4JC−F = 1.0 Hz), 128.17
(C−F, 4JC−F = 1.0 Hz), 127.9 (C−F, 1JC−F = 271.0 Hz), 127.6, 127.52
(C−F, 3JC−F = 2.0 Hz), 127.50 (C−F, 3JC−F = 2.0 Hz), 127.48 (C−F,
3
3JC−F = 2.0 Hz), 127.46 (C−F, JC−F = 2.0 Hz), 126.2, 125.2 (C−F,
1JC−F = 271.0 Hz), 124.97 (C−F, 3JC−F = 4.0 Hz), 124.94 (C−F, 3JC−F
109.0, 108.6, 101.8, 79.2, 41.5, 37.2, 29.9, 28.6, 25.4, 25.3. IR (ATR):
∼
3
3
v (cm−1) = 1698, 1502, 1472, 1390. HRMS (ESI) m/z: [M + Na]+
= 4.0 Hz), 124.90 (C−F, JC−F = 4.0 Hz), 124.86 (C−F, JC−F = 4.0
Hz), 122.5 (C−F, 1JC−F = 271.0 Hz), 119.9 (C−F, 1JC−F = 271.0 Hz),
calcd for C25H29BrN2O4Na, 525.1182; found, 525.1176.
121.4, 119.3, 118.5, 109.0, 79.2, 41.6, 37.2, 29.9, 28.5, 25.4, 25.0.
tert-Butyl (2-(2-(2-Bromo-4-methylphenethyl)-1-methyl-1H-
indol-3-yl)ethyl)carbamate (1f, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S2 to afford 1f as a yellow oil (318 mg, 64% yield over 3 steps).
∼
19F{1H} NMR (386 MHz, CDCl3): −62.6 (s). IR (ATR): v (cm−1) =
1699, 1504, 1471, 1366. HRMS (ESI) m/z: [M + Na]+ calcd for
C25H28BrF3N2O2Na, 549.1158; found, 549.1144.
1
TLC: Rf = 0.42 (petroleum ether/ethyl acetate = 10:1). H NMR
tert-Butyl (2-(2-(2-(1-Bromonaphthalen-2-yl)ethyl)-1-methyl-1H-
indol-3-yl)ethyl)carbamate (1j, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S2 to afford 1j as a yellow oil (247 mg, 41% yield over 3 steps).
(400 MHz, CDCl3): δ (ppm) 7.56 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H),
7.27 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.4 Hz,
1H), 6.98−7.07 (m, 2H), 4.42−4.73 (br s, 1H), 3.68 (s, 3H), 3.29−
3.44 (m, 2H), 2.93−3.09 (m, 4H), 2.90 (t, J = 7.0 Hz, 2H), 2.32 (s,
3H), 1.43 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): 156.0, 138.3,
137.1, 137.0, 136.9, 133.3, 130.6, 128.6, 127.8, 124.0, 121.1, 119.1,
1
TLC: Rf = 0.34 (petroleum ether/ethyl acetate = 10:1). H NMR
(400 MHz, CDCl3): δ (ppm) 8.35 (d, J = 8.5 Hz, 1H), 7.81 (d, J =
8.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.56
5734
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Article
(d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.26−7.32 (m, 2H), 7.21
(t, J = 7.2 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.48−4.63 (br s, 1H),
3.70 (s, 3H), 3.32−3.44 (m, 2H), 3.21−3.30 (m, 2H), 3.11−3.19 (m,
2H), 2.93 (t, J = 7.0 Hz, 2H), 1.41 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): 156.0, 138.5 137.0, 136.8, 133.5, 132.6, 128.3, 128.2,
tert-Butyl (2-(2-(2-Bromophenethyl)-5-methoxy-1-methyl-1H-
indol-3-yl)ethyl)carbamate (1m, Scheme S1, Reaction 1). The
compound was synthesized according to GP-B, GP-C, and GP-D
using S11 to afford 1m as a yellow oil (166 mg, 41% yield over 3
1
steps). TLC: Rf = 0.25 (petroleum ether/ethyl acetate = 9:1). H
NMR (400 MHz, CDCl3): δ (ppm) 7.57 (d, J = 8.0 Hz, 1H), 7.13−
7.24 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 7.02 (s, 1H), 6.86 (dd, J = 8.8,
2.4 Hz, 1H), 4.47−4.71 (br s, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 3.30−
3.42 (m, 2H), 2.94−3.09 (m, 4H), 2.87 (t, J = 6.9 Hz, 2H), 1.42 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 156.0, 154.0,
140.3, 137.5, 132.9, 132.3, 130.9, 128.3, 128.0, 127.8, 124.3, 110.9,
109.7, 108.3, 100.8, 79.1, 56.2, 41.3, 37.2, 29.9, 28.6, 25.3
128.0, 127.7, 127.6, 127.3, 126.2, 123.7, 121.1, 119.2, 118.5, 109.0,
∼
108.6, 79.1, 41.4, 38.5, 29.8, 28.5, 25.3, 25.1. IR (ATR): v (cm−1) =
2361, 2341, 1698, 1501, 1471, 1391. HRMS (ESI) m/z: [M + Na]+
calcd for C28H31BrN2O2Na, 531.1441; found, 531.1431.
tert-Butyl (2-(2-(2-Iodophenethyl)-1-methyl-1H-indol-3-yl)ethyl)-
carbamate (1k, Scheme S2, Reaction 5). The compound was
synthesized according to GP-B, GP-C, and GP-D using S2 to afford
1k as a yellow oil (247 mg, 41% yield over 3 steps). TLC: Rf = 0.37
(petroleum ether/ethyl acetate = 10:1). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.82 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H),
7.04−7.29 (m, 5H), 6.90 (dd, J = 7.7, 7.4 Hz, 1H), 4.45−4.67 (br s,
1H), 3.66 (s, 3H), 3.27−3.39 (m, 2H), 2.94−3.09 (m, 4H), 2.88 (t, J
= 6.1 Hz, 2H), 1.41 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 156.1, 143.7, 139.7, 137.0, 136.6, 130.1, 128.7, 128.4, 127.8,
(overlapping). Some 13C peaks were identified in 2D HSQC
∼
spectrum. IR (ATR): v (cm−1) = 2932, 1699, 1567, 1365. HRMS
(ESI) m/z: [M + Na]+ calcd for C25H31BrN2O3Na, 511.1390; found,
511.1376.
tert-Butyl 2-(2-Bromophenethyl)-3-methyl-1H-indole-1-carboxy-
late (1n, Scheme S3, Reaction 6). To an 250 mL oven-dried round-
bottomed flask equipped with a magnetic stirrer was added 2,3-
dimethylindole S12 (1.50 g, 10.3 mmol, 1.0 equiv) under argon;
afterward, freshly distilled anhydrous THF (50 mL) was added to the
flask. The reaction mixture was cooled to −78 °C. Then n-BuLi (7.0
mL, 1.6 M in hexanes, 11 mmol, 1.1 equiv) was added dropwise into
the reaction system by syringe. After 10 min, dry CO2 (excess) was
bubbled into the reaction solution via a needle. The flask was allowed
to warm to rt carefully, and the solvent was removed under a vacuum.
Anhydrous THF (100 mL) was added into the round-bottomed flask
under argon, and the reaction system was stirred and cooled to −78
°C. t-BuLi (1.3 M in pentane, 8.8 mL, 11 mmol, 1.1 equiv) was added
dropwise by syringe, and then the reaction mixture was warmed up to
−40 °C and stirred for 1 h. 2-Bromobenzyl bromide (2.84 g, 11.4
mmol, 1.1 equiv) dissolved in dry THF (15 mL) was added under
argon. The resulting mixture was stirred at −78 °C for further 5 h and
quenched with saturated aqueous NH4Cl solution (30 mL), and the
pH was adjusted to 7 by 1 M HCl. The organic phase was separated
and washed by brine. The aqueous phase was extracted with DCM.
The combined organic phase was dried over Na2SO4 and
concentrated, and the crude product was filtrate through a pad of
silica gel (eluted with petroleum ether/ethyl acetate = 20:1 to 10:1)
to afford S14 as a colorless oil (1.59 g, 49% crude yield), which was
directly used in the next step. Compound 1n was synthesized
according to GP-E using S14. The crude product was purified by flash
column chromatography on silica gel (eluted with petroleum ether/
ethyl acetate 5:1) to afford 1n as a yellow oil (1.73 g, 83% yield).
121.2, 119.2, 118.5, 109.0, 108.8, 100.3, 79.2, 41.7, 41.4, 30.0, 28.6,
∼
25.4, 25.3. IR (ATR): v (cm−1) = 1703, 1502, 1470, 1365. HRMS
(ESI) m/z: [M + Na]+ calcd for C24H29IN2O2Na, 527.1166; found,
527.1163.
tert-Butyl 3-(2-(((Benzyloxy)carbonyl)amino)ethyl)-2-(2-bromo-
phenethyl)-1H-indole-1-carboxylate (1l, Scheme S1, Reaction 4).
To a solution of S4 (699 mg, 1.51 mmol) dissolved in DCM (14 mL)
was added TFA (1.4 mL) at 0 °C. The mixture was then stirred at rt
for 2.5 h until completion of the reaction (TLC). Saturated aqueous
NaHCO3 solution (15 mL) was slowly added, and the reaction
mixture was cooled to 0 °C. CbzCl (240 μL, 1.66 mmol) was added,
and the mixture was stirred for 0.5 h at rt. The mixture was extracted
with DCM, and the combined extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel (eluted with
petroleum ether/ethyl acetate 10:1 to 5:1) to afford S8 as a yellow oil
(602 mg, 83% yield over 2 steps). In GP-E, solution of S8 (150 mg,
0.315 mmol, 1.0 equiv) dissolved in DCM was added to Boc2O (76.6
mg, 0.351 mmol, 1.1 equiv) and 4-DMAP (3.7 mg, 0.030 mmol, 0.1
equiv). The mixture was stirred at rt for 33 h. Upon completion, the
solvent was evaporated, and water was added. The mixture was
extracted with DCM. The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
resulting residue was filtered through a pad of silica gel (eluted with
petroleum ether/ethyl acetate 20:1 to 10:1) to afford 1l as a yellow oil
(141 mg, 79%). TLC: Rf = 0.18 (petroleum ether/ethyl acetate =
9:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 8.3 Hz, 1H),
7.50 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.11−7.38 (m,
9H), 7.03 (t, J = 7.8 Hz, 1H), 5.08 (s, 2H), 4.52−4.75 (br s, 1H), 3.32
(t, J = 7.1 Hz, 2H), 3.20 (q, J = 6.4 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H),
2.68 (t, J = 6.9 Hz, 2H), 1.72 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 156.4, 150.6, 140.7, 136.9, 136.0, 132.8, 131.0,
129.8, 128.6, 128.3, 128.2, 128.0, 127.6, 126.8, 124.6, 123.9, 122.7,
1
TLC: Rf = 0.26 (petroleum ether/ethyl acetate = 50:1). H NMR
(400 MHz, CDCl3): δ (ppm) 8.11 (d, J = 8.3 Hz, 1H), 7.53 (d, J =
7.9 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.19−7.31 (m, 2H), 7.08−7.19
(m, 2H), 7.06 (td, J = 7.8, 1.9 Hz, 1H), 3.38 (t, J = 7.4 Hz, 2H), 3.10
(t, J = 7.4 Hz, 2H), 1.92 (s, 3H), 1.75 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 150.8, 140.9, 135.9, 135.6, 132.7, 131.0,
130.7, 127.8, 127.4, 124.7, 123.∼6, 122.4, 118.2, 115.7, 115.6, 83.6,
36.2, 28.5, 27.0, 8.4. IR (ATR): v (cm−1) = 3051, 2976, 1722, 1471,
1392, 1368, 1354, 1321. HRMS (ESI) m/z: [M + Na]+ calcd for
C22H24BrNO2Na, 436.0883; found, 436.0879.
118.4, 116.5, 115.8, 84.0, 66.8, 41.1, 36.4, 28.5, 27.0, 24.6. IR (ATR):
∼
tert-Butyl 2-(2-Bromobenzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-
b]indole-9-carboxylate (1o, Scheme S3, Reaction 7). To a solution
of S15 (2.15 g, 12.5 mmol, 1.0 equiv) in dry DCM (50 mL) were
added NEt3 (2.0 mL, 14 mmol, 1.1 equiv) and 2-bromobenzoyl
chloride (2.74 g, 12.5 mmol, 1.1 equiv). The resulting mixture was
allowed to warm to room temperature and stirred for 2 h until the
completion of the reaction (TLC), and the reaction mixture was
quenched with H2O and extracted with DCM. The combined extracts
was washed with brine, dried over Na2SO4, and concentrated in
vacuo. The resulting residue was filtered through a pad of silica gel
(eluted with petroleum ether/ethyl acetate 3:1 to 2:1) to afford crude
amide S16 as a white solid (2.86 g, 81% crude yield), which was
directly used in the next step without further purification. To the
above crude amide S16 (1.04 g, 2.92 mmol, 1.0 equiv) dissolved in
DCM (29 mL) were added DMAP (35 mg, 0.29 mmol, 0.1 equiv)
and Boc2O (702 mg, 3.22 mmol, 1.1 equiv). The mixture was stirred
v (cm−1) = 3341, 1720, 1512, 1455, 1369, 1357. HRMS (ESI) m/z:
[M + Na]+ calcd for C31H33BrN2O4Na, 601.1495; found, 601.1486.
tert-Butyl (2-(2-Formyl-5-methoxy-1H-indol-3-yl)ethyl)-
carbamate (S11, Scheme S1, Reaction 1). The compound was
synthesized according to GP-A using S10 to afford S11 as a yellow
solid (505 mg, 89% yield). Reaction time: 7 h. TLC: Rf = 0.12
1
(petroleum ether/ethyl acetate = 3:1). Mp: 124−125 °C. H NMR
(400 MHz, CDCl3): δ (ppm) 9.89 (s, 1H), 9.31−9.74 (br s, 1H),
7.32 (d, 9.6 Hz, 1H), 7.00−7.10 (m, 2H), 4.47−4.95 (br s, 1H), 3.85
(s, 3H), 3.47 (q, J = 6.5 Hz, 2H), 3.26 (t, J = 5.6 Hz, 2H), 1.43 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 180.7, 156.0,
154.8, 133.6, 133.4, 127.∼7, 125.2, 119.7, 113.7, 101.0, 79.6, 55.9, 41.7,
28.5, 24.4. IR (ATR): v (cm−1) = 3306, 2976, 2933, 2834, 1688,
1641, 1532, 1437, 1391, 1365. HRMS (ESI) m/z: [M + Na]+ calcd
for C17H22N2O4Na, 341.1472; found, 341.1474.
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at room temperature for 19 h until the completion of the reaction
(TLC), and the reaction mixture was quenched with H2O and
extracted with DCM. The combined extracts was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The crude product
was purified by flash column chromatography on silica gel (eluted
with petroleum ether/ethyl acetate 5:1) to afford 1o as a white solid
(858 mg, 61%). TLC: Rf = 0.12 (petroleum ether/ethyl acetate =
5:1). Mp: 160−161 °C. 1H NMR (400 MHz, CDCl3) (ca. 1:1
mixture of rotamers, both reported): δ (ppm) 8.19 (d, J = 8.2 Hz,
1H), 7.55−7.65 (m, 1H), 7.51−7.34 (m, 2H), 7.19−7.34 (m, 4H),
5.19 (d, J = 18.4 Hz, 0.5H), 5.11 (d, J = 18.4 Hz, 0.5H), 4.69 (d, J =
17.6 Hz, 0.5H), 4.55 (d, J = 17.6 Hz, 0.5H), 4.21−4.31 (m, 0.5H),
3.92−4.03 (m, 0.5H), 3.48−3.63 (m, 1H), 2.90 (s,1H), 2.78−2.88
(m, 0.5H), 2.62−2.70 (m, 0.5H), 1.72 (s, 4.5H), 1.40 (s, 4.5H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 168.6, 168.5, 150.1,
149.7, 138.5, 136.2, 136.0, 133.1, 132.9, 131.1, 130.5, 130.4, 130.0,
128.8, 128.7, 128.0, 127.9, 127.9, 127.8, 124.6, 124.3, 123.1, 122.9,
119.4, 119.2, 118.1, 117.8, 115.8, 115.70, 115.65, 114.4,∼84.5, 84.1,
MHz, CDCl3): δ (ppm) 7.62 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz,
1H), 7.17 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.3
Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.62 (t, J = 7.2 Hz, 1H), 6.62 (d, J =
7.2 Hz, 1H), 3.09 (ddd, J = 11.0, 7.0, 1.3 Hz, 1H), 2.75 (td, J = 11.5,
5.3 Hz, 1H), 2.54 (s, 3H), 2.53 (dt, J = 12.7, 5.3 Hz, 1H), 2.36−2.47
(m, 2H), 2.24 (ddd, J = 11.0, 5.8, 1.3 Hz, 1H), 1.92 (br s, 1H), 1.86
(td, J = 11.7, 6.7 Hz, 1H), 1.70 (td, J = 12.3, 5.2 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 152.3, 139.8, 137.7, 133.1, 128.3,
128.2, 127.1, 126.12, 126.11, 123.4, 116.5, 103.7, 90.8, 57.6, 45.7,
∼
45.6, 36.5, 28.8, 27.4. IR (ATR): v (cm−1) = 2922, 1603, 1493.
HRMS (ESI) m/z: [M + H]+ calcd for C19H21N2, 277.1705; found,
277.1708.
Compound 3ba. The compound was synthesized according to
GP-F and GP-G using 1b (42.7 mg, 0.107 mmol, 1.0 equiv) to afford
3ba (5.1 mg, 15% yield over 2 steps) as a yellow oil. The reaction time
for GP-F was 48 h; the reaction time for GP-G was 2 h. The reaction
temperature for GP-F was 120 °C.
1-(7-Methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)benzo[c]-
47.1, 44.2, 42.5, 39.3, 28.4, 28.1, 22.0, 21.1. IR (ATR): v (cm−1) =
1727, 1640, 1475. HRMS (ESI) m/z: [M + Na]+ calcd for
C23H23BrN2O3Na, 477.0784; found, 477.0781.
carbazol-14-yl)ethan-1-one (3ba). TLC: Rf = 0.51 (petroleum
1
ether/ethyl acetate = 3:1). H NMR (400 MHz, CDCl3): δ (ppm)
7.52 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.7 Hz,
1H), 7.03−7.13 (m, 3H), 6.63 (t, J = 7.4 Hz, 1H), 6.36 (d, J = 7.9 Hz,
1H), 3.57 (ddd, J = 8.9, 8.9, 2.4 Hz, 1H), 3.31−3.46 (m, 2H), 3.07 (s,
3H), 2.68−2.82 (m, 2H), 2.64 (dt, J = 16.3, 4.4 Hz, 1H), 2.34 (ddd, J
= 12.0, 8.0, 7.5 Hz, 1H), 2.10−2.18 (m, 1H), 2.02 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 170.5, 150.5, 140.3, 136.1, 132.0,
128.8, 128.5, 127.1, 126.9, 126.3, 122.8,∼117.4, 105.9, 91.9, 58.6, 48.9,
General Procedures for the Palladium-Catalyzed Intra-
molecular Dearomative Heck Reaction (GP-F). To an oven-
dried 10 mL sealed tube were added [Pd(C3H5)Cl]2 (2.5 mol %),
ligand (L1, L3, or L8) (7.5 mol %), Cs2CO3 (59.6 mg, 0.183 mmol,
1.5 equiv), and toluene (0.2 mL) in a glovebox. After 20 min, the
aryl/alkenyl halide (0.1 mmol, 1.0 equiv) dissolved in toluene (0.8
mL) was added. The resulting mixture was heated at 100−120 °C in
an oil bath for 24−40 h until completion of the reaction (TLC). The
reaction was filtered through a pad of silica gel (eluted with petroleum
ether/ethyl acetate 5:1) to afford the crude product as a yellow oil,
which was directly used in the next step or further purified by flash
column chromatography on silica gel.
General Procedure for the Aza-semipinacol Rearrangement
(GP-G). The above crude product was dissolved in 1.0 mL of DCM−
TFA (v/v = 10:1). The mixture was stirred at rt for 0.5−1 h until
completion of the reaction (TLC). Saturated aqueous NaHCO3
solution or 1 M NaOH (aq) was slowly added. The mixture was
extracted with DCM, and the combined extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by flash column chromatography on silica gel to
afford 3a and 3b as a yellow oil. In order to identify the structure of
isomers 3a and 3b, 1D NOESY experiments were performed for both
compounds.
Compounds 3aa and 3ab. The compounds were synthesized
according to GP-F and GP-G using 1a (54.2 mg, 0.122 mmol, 1.0
equiv) to afford 3aa (21.5 mg, 64% yield over 2 steps) as a yellow oil
and 3ab (7.3 mg, 22% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 39 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 120 °C.
The same group of products could also be synthesized according to
GP-F and GP-G using 1k (137 mg, 0.271 mmol, 1.0 equiv) to afford
3aa (20.9 mg, 25% yield over 2 steps) as a yellow oil and 3ab (4.2 mg,
6% yield over 2steps) as a yellow oil. The reaction time for GP-F was
39 h; the reaction time for GP-G was 1 h. The reaction temperature
for GP-F was 120 °C.
37.6, 30.7, 27.2, 26.6, 25.0. IR (ATR): v (cm−1) = 1738, 1491, 1400.
HRMS (ESI) m/z: [M + H]+ calcd for C21H23N2O, 319.1805; found,
319.1803.
Compound 3da. The compound was synthesized according 1d
(84.8 mg, 0.174 mmol, 1.0 equiv) to GP-F and GP-G to afford 3da
(39.0 mg, 73% yield over 2 steps) as a yellow oil. The reaction time
for GP-F was 24 h; the reaction time for GP-G was 1 h. The reaction
temperature for GP-F was 110 °C.
3-Methoxy-7-methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)-
1
benzo[c]carbazole (3da). TLC: Rf = 0.08 (ethyl acetate). H NMR
(400 MHz, CDCl3): δ (ppm) 7.48 (d, J = 8.5 Hz, 1H), 7.01 (d, J =
7.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.82 (dd, J = 8.5, 2.7 Hz, 1H),
6.61 (d, J = 2.7 Hz, 1H), 6.51 (dd, J = 7.4, 7.3 Hz, 1H), 6.29 (d, J =
7.7 Hz, 1H), 3.76 (s, 3H), 3.09 (dd, J = 11.5, 6.8 Hz, 1H), 2.83 (s,
3H), 2.58−2.76 (m, 3H), 2.40−2.55 (m, 2H), 2.23 (td, J = 11.4, 6.7
Hz, 1H), 1.79−1.89 (br s, 1H), 1.54 (td, J = 12.8, 3.2 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 157.5, 151.6, 139.1,
135.3, 134.1, 128.1, 127.9, 123.5, 116.6, 113.1, 1∼12.7, 104.3, 91.8,
58.6, 55.3, 46.0, 45.0, 32.0, 28.0, 27.7. IR (ATR): v (cm−1) = 2932,
1602, 1495, 1375. HRMS (ESI) m/z: [M + H]+ calcd for C20H23N2O,
307.1805; found, 307.1797.
Compounds 3ea and 3eb. The compounds were synthesized
according to GP-F and GP-G using 1e (180 mg, 0.355 mmol, 1.0
equiv) to afford 3ea (83.6 mg, 74% yield over 2 steps) as a yellow oil
and 3eb (4.0 mg, 4% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 24 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 110 °C.
7-Methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)[1,3]dioxolo-
[4′,5′:4,5]benzo[1,2-c]carbazole (3ea). TLC: Rf = 0.23 (ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ (ppm) 6.97−7.09 (m,
3H), 6.50−6.57 (m, 2H), 6.30 (d, J = 7.8 Hz, 1H), 5.92 (s, 1H), 5.88
(s, 1H), 3.10 (dd, J = 11.4, 6.6 Hz, 1H), 2.82 (s, 3H), 2.55−2.75 (m,
3H), 2.38−2.50 (m, 2H), 2.21 (td, J = 11.5, 6.7 Hz, 1H), 1.84−1.95
(br s, 1H), 1.53 (td, J = 13.9, 4.2 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 151.6, 146.5, 145.4, 135.9, 133.7, 131.0, 128.0,
123.4, 116.5, 108.1, 107.4, 104.4, 100.8, 91.5, 59.1, 45.9, 44.9, 32.1,
7-Methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)benzo[c]-
carbazole (3aa). TLC: Rf = 0.21 (ethyl acetate). 1H NMR (400
MHz, CDCl3): δ (ppm) 7.56 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 7.3 Hz,
1H), 6.94−7.12 (m, 4H), 6.50 (t, J = 7.5 Hz, 1H), 6.28 (d, J = 7.7 Hz,
1H), 3.10 (ddd, J = 11.0, 7.1, 1.0 Hz, 1H), 2.83 (s, 3H), 2.60−2.77
(m, 3H), 2.54 (dt, J = 15.3, 3.6 Hz, 1H), 2.46 (dt, J = 13.2, 3.7 Hz,
1H), 2.26 (td, J = 11.5, 6.4 Hz, 1H), 1.80 (br s, 1H), 1.54 (td, J =
12.9, 3.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
27.67, 27.65. Some 13C peaks were identified in DEPT 135 spectrum.
151.8, 142.9, 137.8, 133.7, 128.1, 128.0, 127.2, 127.0, 125.7, 123.8,
∼
∼
IR (ATR): v (cm−1) = 2930, 2875, 1601, 1481, 1367. HRMS (ESI)
116.5, 104.3, 91.8, 59.2, 46.0, 44.9, 32.0, 27.69, 27.67. IR (ATR): v
m/z: [M + H]+ calcd for C20H21N2O2, 321.1598; found, 321.1591.
11-Methyl-5,6-dihydro-11H-11a,6a (epiminoethano)[1,3]-
dioxolo[4′,5′:4,5]benzo[1,2-a]carbazole (3eb). TLC: Rf = 0.38
(ethyl acetate). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.17 (s,
(cm−1) = 2930, 1600, 1491. HRMS (ESI) m/z: [M + H]+ calcd for
C19H21N2, 277.1705; found, 277.1705.
11-Methyl-5,6-dihydro-11H-11a,6a-(epiminoethano)benzo[a]-
1
carbazole (3ab). TLC: Rf = 0.39 (ethyl acetate). H NMR (400
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1H), 7.00−7.07 (m, 2H), 6.57−6.66 (m, 2H), 6.19 (d, J = 7.6 Hz,
1H), 5.93 (s, 2H), 3.07 (dd, J = 11.5, 6.7 Hz, 1H), 2.74 (td, J = 11.4,
5.4 Hz, 1H), 2.66 (s, 3H), 2.50 (dt, J = 12.7, 3.3 Hz, 1H), 2.31−2.38
(m, 1H), 2.23 (dd, J = 12.3, 5.3 Hz, 1H), 1.80−1.99 (m, 3H), 1.61−
1.72 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 152.0,
1H), 2.35−2.48 (m, 2H), 2.24 (ddd, J = 12.0, 5.0, 1.7 Hz, 1H), 1.80−
1.92 (m, 2H), 1.62−1.76 (m, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 162.9 (C−F, 1JC−F = 246.0 Hz), 160.4 (C−F, 1JC−F
= 246.0 Hz), 152.1, 142.4 (C−F, 3JC−F = 8.0 Hz), 142.3 (C−F, 3JC−F
4
4
= 8.0 Hz), 133.65 (C−F, JC−F = 3.0 Hz), 133.62 (C−F, JC−F = 3.0
Hz), 132.8, 128.3, 127.84 (C−F, 3JC−F = 8.0 Hz), 127.76 (C−F, 3JC−F
= 8.0 Hz), 123.4, 116.6, 115.0 (C−F, 2JC−F = 21.0 Hz), 114.8 (C−F,
146.3, 145.8, 133.7, 133.0, 130.7, 128.2, 123.3, 116.5, 108.7, 107.1,
∼
103.7, 101.0, 91.0, 57.3, 45.8, 45.4, 36.6, 28.9, 27.7. IR (ATR): v
2JC−F = 21.0 Hz), 112.8 (C−F, 2JC−F = 21.0 Hz), 112.6 (C−F, 2JC−F
=
(cm−1) = 2924, 1603, 1497, 1483, 1365. HRMS (ESI) m/z: [M + H]+
calcd for C20H21N2O2, 321.1598; found, 321.1590.
21.0 Hz), 103.8, 90.5, 57.5, 45.7, 45.5, 36.3, 28.9, 27.3. 19F{1H} NMR
∼
(CDCl3, 386 MHz): δ (ppm) −115.9 (m). IR (ATR): v (cm−1) =
Compounds 3fa and 3fb. The compounds were synthesized
according to GP-F and GP-G using 1f (128 mg, 0.273 mmol, 1.0
equiv) to afford 3fa (47.3 mg, 60% yield over 2 steps) as a yellow oil
and 3fb (8.5 mg, 11% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 24 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 110 °C.
2,7-Dimethyl-5,6-dihydro-7H-6a,11b-(epiminoethano)benzo[c]-
carbazole (3fa). TLC: Rf = 0.37 (ethyl acetate). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.37 (s, 1H), 7.04 (d, J = 7.3 Hz, 1H), 7.00 (t, J =
7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.52
(t, J = 7.3 Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 3.10 (dd, J = 11.4, 6.7
Hz, 1H), 2.84 (s, 3H), 2.60−2.76 (m, 3H), 2.42−2.57 (m, 2H), 2.38
(s, 3H), 2.26 (td, J = 11.4, 6.7 Hz, 1H), 1.80−1.97 (br s, 1H), 1.53
(td, J = 12.7, 3.1 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 151.7, 142.7, 136.3, 134.7, 133.7, 128.0, 127.8, 127.7, 126.5,
2926, 1605, 1590, 1493, 1379. HRMS (ESI) m/z: [M + H]+ calcd for
C19H20FN2, 295.1605; found, 295.1596.
Compound 3ha and 3hb. The compounds were synthesized
according to GP-F and GP-G using 1h (126 mg, 0.256 mmol, 1.0
equiv) to afford 3ha (33.6 mg, 42% yield over 2 steps) as a yellow oil
and 3hb (29.6 mg, 37% yield over 2 steps) as a yellow oil. The
reaction time for GP-F was 16 h; the reaction time for GP-G was 1 h.
The reaction temperature for GP-F was 110 °C.
2-Chloro-7-methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)-
1
benzo[c]carbazole (3ha). TLC: Rf = 0.1 (ethyl acetate). H NMR
(400 MHz, CDCl3): δ (ppm) 7.52 (d, J = 1.7 Hz, 1H), 6.95−7.09 (m,
4H), 6.54 (t, J = 7.4 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 3.11 (dd, J =
11.5, 6.7 Hz, 1H), 2.83 (s, 3H), 2.57−2.76 (m, 3H), 2.42−2.58 (m,
2H), 2.23 (td, J = 11.6, 6.7 Hz, 1H), 1.80−1.91 (br s, 1H), 1.50 (td, J
= 12.7, 3.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
123.7, 116.5, 104.2, 91.7, 59.1, 46.0, 44.9, 32.1, 27.7, 27.2, 21.5. IR
∼
(ATR): v (cm−1) = 2928, 2854, 1600, 1493, 1376. HRMS (ESI) m/z:
151.8, 144.8, 136.3, 132.8, 132.3, 129.3, 128.4, 127.1, 125.8, 123.8,
∼
[M + H]+ calcd for C20H23N2, 291.1856; found, 291.1849.
116.7, 104.5, 91.5, 59.3, 45.9, 44.7, 32.0, 27.7, 27.2. IR (ATR): v
(cm−1) = 2933, 1603, 1491, 1376. HRMS (ESI) m/z: [M + H]+ calcd
for C19H20ClN2, 311.1310; found, 311.1302.
2,11-Dimethyl-5,6-dihydro-11H-11a,6a-(epiminoethano)benzo-
1
[a]carbazole (3fb). TLC: Rf = 0.68 (ethyl acetate). H NMR (400
MHz, CDCl3): δ (ppm) 7.44 (s, 1H), 6.96−7.11 (m, 4H), 6.62 (t, J =
7.3 Hz, 1H), 6.18 (d, J = 7.8 Hz, 1H), 3.09 (ddd, J = 11.6, 6.6, 1.5 Hz,
1H), 2.74 (td, J = 11.5, 5.4 Hz, 1H), 2.65 (s, 3H), 2.53 (dt, J = 12.6,
3.3 Hz, 1H), 2.31−2.47 (m, 5H), 2.24 (dd, J = 11.9, 5.0 Hz, 1H),
1.80−1.99 (m, 2H), 1.68 (td, J = 12.4, 4.2 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 152.3, 137.5, 136.7, 135.5, 133.1, 128.2,
128.1, 127.8, 126.7, 123.3, ∼116.4, 103.6, 90.7, 57.6, 45.8, 45.5, 36.6,
2-Chloro-11-methyl-5,6-dihydro-11H-11a,6a-(epiminoethano)-
1
benzo[a]carbazole (3hb). TLC: Rf = 0.71 (ethyl acetate). H NMR
(400 MHz, CDCl3): δ (ppm) 7.61 (d, J = 1.9 Hz, 1H), 7.14 (dd, J =
8.1, 2.0 Hz, 1H), 7.00−7.09 (m, 3H), 6.64 (dd, J = 7.4, 7.3 Hz, 1H),
6.20 (d, J = 7.7 Hz, 1H), 3.07 (ddd, J = 11.6, 6.6, 1.3 Hz, 1H), 2.75
(td, J = 11.3, 5.4 Hz, 1H), 2.64 (s, 3H), 2.52 (dt, J = 12.8, 3.3 Hz,
1H), 2.45 (dt, J = 15.2, 3.2 Hz, 1H), 2.36 (td, J = 13.4, 2.7 Hz, 1H),
2.23 (ddd, J = 12.0, 5.3, 1.2 Hz, 1H), 1.76−1.97 (m, 2H), 1.64 (td, J =
12.9, 3.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
28.4, 27.4, 21.5. IR (ATR): v (cm−1) = 2923, 1604, 1495, 1378, 1308.
HRMS (ESI) m/z: [M + H]+ calcd for C20H23N2, 291.1856; found,
291.1849.
152.0, 139.6, 138.3, 132.8, 131.7, 129.5, 128.3, 127.0, 126.3, 123.4,
∼
116.8, 103.9, 90.3, 57.5, 45.5, 45.4, 36.4, 28.2, 27.4. IR (ATR): v
Compounds 3ga and 3gb. The compounds were synthesized
according to GP-F and GP-G using 1g (152 mg, 0.319 mmol, 1.0
equiv) to afford 3ga (50.0 mg, 53% yield over 2 steps) as a yellow oil
and 3gb (16.9 mg, 18% yield over 2 steps) as a yellow oil. The
reaction time for GP-F was 16 h; the reaction time for GP-G was 1 h.
The reaction temperature for GP-F was 110 °C.
(cm−1) = 2927, 1604, 1492, 1377. HRMS (ESI) m/z: [M + H]+ calcd
for C19H20ClN2, 311.1310; found, 311.1302.
Compounds 3ia and 3ib. The compounds were synthesized
according to GP-F and GP-G using 1i (104 mg, 0.198 mmol, 1.0
equiv) to afford 3ia (24.0 mg, 35% yield over 2 steps) as a yellow oil
and 3ib (26.5 mg, 39% yield over 2 steps) as a yellow oil. The
reaction time for GP-F was 24 h; the reaction time for GP-G was 1 h.
The reaction temperature for GP-F was 110 °C.
7-Methyl-3-(trifluoromethyl)-5,6-dihydro-7H-6a,11b-
(epiminoethano)benzo[c]carbazole (3ia). TLC: Rf = 0.20 (ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.66 (d, J = 8.1 Hz,
1H), 7.51 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.02 (t, J = 7.7 Hz, 1H),
6.99 (d, J = 7.1 Hz, 1H), 6.52 (t, J = 7.4 Hz, 1H), 6.31 (d, J = 7.8 Hz,
1H), 3.13 (dd, J = 11.5, 6.9 Hz, 1H), 2.84 (s, 3H), 2.57−2.82 (m,
4H), 2.51 (dt, J = 13.2, 3.5 Hz, 1H), 2.25 (td, J = 11.3, 6.4 Hz, 1H),
1.75−1.83 (br s, 1H), 1.53 (td, J = 13.1, 3.3 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 151.8, 146.8, 138.6, 132.6, 128.50
3-Fluoro-7-methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)-
1
benzo[c]carbazole (3ga). TLC: Rf = 0.1 (ethyl acetate). H NMR
(400 MHz, CDCl3): δ (ppm) 7.51 (dd, J = 8.7, 5.7 Hz, 1H), 6.90−
7.05 (m, 3H), 6.76 (dd, J = 9.4, 2.7 Hz, 1H), 6.52 (t, J = 7.4 Hz, 1H),
6.30 (d, J = 7.8 Hz, 1H), 3.10 (dd, J = 11.5, 6.7 Hz, 1H), 2.83 (s, 3H),
2.58−2.77 (m, 3H), 2.41−2.57 (m, 2H), 2.22 (td, J = 11.5, 6.8 Hz,
1H), 1.76−1.85 (br s, 1H), 1.53 (td, J = 12.8, 3.4 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 162.0 (C−F, 1JC−F = 243.0 Hz),
159.6 (C−F, 1JC−F = 243.0 Hz), 151.7, 140.05 (C−F, 3JC−F = 7.0 Hz),
139.98 (C−F, 3JC−F = 7.0 Hz), 138.72 (C−F, 4JC−F = 3.0 Hz), 138.69
4
3
(C−F, JC−F = 3.0 Hz), 133.5, 128.6 (C−F, JC−F = 8.0 Hz), 128.5
(C−F, 3JC−F = 8.0 Hz), 128.2, 123.6, 116.6, 114.5 (C−F, 2JC−F = 20.0
(overlapping), 128.46 (C−F, 1JC−F = 270.0 Hz), 128.4 (C−F, 2JC−F
=
2
2
Hz), 114.3 (C−F, JC−F = 20.0 Hz), 113.8 (C−F, JC−F = 21.0 Hz),
113.6 (C−F, 2JC−F = 21.0 Hz), 104.5, 91.6, 58.8, 45.9, 44.9, 31.8, 27.8,
2
2
32.0 Hz), 128.1 (C−F, JC−F = 32.0 Hz), 127.8 (C−F, JC−F = 32.0
Hz), 127.4 (C−F, 2JC−F = 32.0 Hz), 127.5, 124.89 (C−F, 3JC−F = 4.0
27.7. 19F{1H} NMR (CDCl3, 386 MHz): δ (ppm) −118.0 (m). IR
3
3
∼
Hz), 124.85 (C−F, JC−F = 4.0 Hz), 124.82 (C−F, JC−F = 4.0 Hz),
(ATR): v (cm−1) = 2934, 1602, 1492, 1375. HRMS (ESI) m/z: [M +
3
1
124.78 (C−F, JC−F = 4.0 Hz), 125.8 (C−F, JC−F = 270.0 Hz),
+
H]+ calcd for C19H20FN2 , 295.1605; found, 295.1597.
123.84 (C−F, 3JC−F = 4.0 Hz), 123.80 (C−F, 3JC−F = 4.0 Hz), 123.76
3-Fluoro-11-methyl-5,6-dihydro-11H-11a,6a-(epiminoethano)-
3
3
1
(C−F, JC−F = 4.0 Hz), 123.71 (C−F, JC−F = 4.0 Hz), 123.71
benzo[a]carbazole (3gb). TLC: Rf = 0.36 (ethyl acetate). H NMR
1
1
(overlapping), 123.1 (C−F, JC−F = 270.0 Hz), 120.4 (C−F, JC−F
=
(400 MHz, CDCl3): δ (ppm) 7.58 (dd, J = 8.5, 5.7 Hz, 1H), 7.06 (d, J
= 6.5 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.92 (ddd, J = 8.5, 8.5, 2.8 Hz,
1H), 6.82 (dd, J = 9.3, 2.7 Hz, 1H), 6.63 (dd, J = 7.4, 7.3 Hz, 1H),
6.19 (d, J = 7.8 Hz, 1H), 3.07 (ddd, J = 11.8, 6.7, 1.6 Hz, 1H), 2.75
(td, J = 11.5, 5.5 Hz, 1H), 2.62 (s, 3H), 2.53 (dt, J = 12.8, 3.4 Hz,
270.0 Hz), 116.8, 104.6, 91.6, 59.4, 45.9, 44.6, 31.8, 27.71, 27.69.
∼
19F{1H} NMR (386 MHz, CDCl3): −62.3 (s). IR (ATR): v (cm−1) =
2933, 1602, 1493, 1375, 1321. HRMS (ESI) m/z: [M + H]+ calcd for
C20H20F3N2, 345.1573; found, 345.1566.
5737
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J. Org. Chem. 2021, 86, 5727−5743

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
11-Methyl-3-(trifluoromethyl)-5,6-dihydro-11H-11a,6a-
(epiminoethano)benzo[a]carbazole (3ib). TLC: Rf = 0.69 (ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.74 (d, J = 8.1 Hz,
1H), 7.52 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H),
7.06 (t, J = 7.7 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.22 (d, J = 7.8 Hz,
1H), 3.09 (dd, J = 11.4, 6.6 Hz, 1H), 2.78 (td, J = 11.3, 5.4 Hz, 1H),
2.63 (s, 3H), 2.42−2.61 (m, 3H), 2.27 (dd, J = 12.1, 5.2 Hz, 1H),
1.97−2.12 (br s, 1H), 1.89 (td, J = 11.5, 6.8 Hz, 1H), 1.69 (td, J =
12.4, 3.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
152.1, 141.5, 140.7, 132.7, 131.1 (C−F, 1JC−F = 270.0 Hz), 129.6 (C−
F, 2JC−F = 32.0 Hz), 129.3 (C−F, 2JC−F = 32.0 Hz), 129.0 (C−F, 2JC−F
A gram-scale synthesis was conducted according to GP-F and GP-
G using 1m (1.36 g, 2.79 mmol, 1.0 equiv) to afford 3ma (338 mg,
40% yield over 2 steps) as a yellow oil and 3mb (48.5 mg, 6% yield
over 2steps) as a yellow oil. The eaction time for GP-F was 20 h; the
reaction time for GP-G was 1 h. The reaction temperature for GP-F
was 110 °C.
10-Methoxy-7-methyl-5,6-dihydro-7H-6a,11b-(epiminoethano)-
1
benzo[c]carbazole (3ma). TLC: Rf = 0.1 (ethyl acetate). H NMR
(400 MHz, CDCl3): δ (ppm) 7.55 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.2
Hz, 1H), 7.04−7.14 (m, 2H), 6.74 (d, J = 2.5 Hz, 1H), 6.58 (dd, J =
8.4, 2.5 Hz, 1H), 6.21 (d, J = 8.4 Hz, 1H), 3.69 (s, 3H), 3.10 (dd, J =
11.4, 6.7 Hz, 1H), 2.80 (s, 3H), 2.62−2.79 (m, 3H), 2.56 (dt, J =
15.4, 3.8 Hz, 1H), 2.43 (dt, J = 13.1, 3.8 Hz, 1H), 2.26 (td, J = 11.4,
6.7 Hz, 1H), 1.80−1.97 (br s, 1H), 1.55 (td, J = 12.9, 3.5 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 152.0, 146.4, 142.5,
137.7, 135.2, 128.0, 127.3, 127.0, 125.8, 112.1, 1∼12.0, 104.4, 91.9,
2
= 32.0 Hz), 128.6 (C−F, JC−F = 32.0 Hz), 128.37 (overlapping),
1
1
128.36 (C−F, JC−F = 270.0 Hz), 126.5, 125.7 (C−F, JC−F = 270.0
3
3
Hz), 125.10 (C−F, JC−F = 3.8 Hz), 125.06 (C−F, JC−F = 3.8 Hz),
125.03 (C−F, 3JC−F = 3.8 Hz), 124.99 (C−F, 3JC−F = 3.8 Hz), 123.4,
123.06 (C−F, 3JC−F = 3.8 Hz), 123.03 (C−F, 3JC−F = 3.8 Hz), 122.99
3
3
59.3, 56.2, 46.1, 44.6, 32.0, 28.3, 27.8. IR (ATR): v (cm−1) = 2932,
1663, 1595, 1495, 1375. HRMS (ESI) m/z: [M + H]+ calcd for
C20H23N2O, 307.1805; found, 307.1796.
(C−F, JC−F = 3.8 Hz), 122.95 (C−F, JC−F = 3.8 Hz), 122.9 (C−F,
1JC−F = 270.0 Hz) (overlapping), 117.0, 104.0, 90.2, 57.7, 45.5, 45.4,
36.3, 28.8, 27.3. 19F{1H} NMR (386 MHz, CDCl3): −62.4 (s). IR
∼
(ATR): v (cm−1) = 2930, 1604, 1493, 1378, 1339. HRMS (ESI) m/z:
8 - M e t h o x y - 1 1 - m e t h y l - 5 , 6 - d i h y d r o - 1 1 H - 1 1 a , 6 a -
(epiminoethano)benzo[a]carbazole (3mb). TLC: Rf = 0.21 (ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.64 (d, J = 7.6 Hz,
1H), 7.24 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.3
Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.4, 2.5 Hz, 1H), 6.10
(d, J = 8.4 Hz, 1H), 3.75 (s, 3H), 3.13 (dd, J = 11.6, 6.7 Hz, 1H),
2.85−3.50 (br s, 1H), 2.79 (td, J = 11.3, 5.5 Hz, 1H), 2.60 (s, 3H),
2.35−2.55 (m, 3H), 2.24 (dd, J = 12.2, 5.4 Hz, 1H), 1.91 (td, J = 11.7,
6.8 Hz, 1H), 1.69 (td, J = 12.1, 4.1 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 152.3, 146.8, 139.6, 137.0, 134.4, 128.3,
127.3, 126.3, 126.2, 112.3, ∼111.3, 104.0, 91.3, 57.8, 56.3, 45.3, 44.8,
[M + H]+ calcd for C20H20F3N2, 345.1573; found, 345.1567.
Compound 3jb. The compound was synthesized according to
GP-F and GP-G using 1j (112 mg, 0.220 mmol, 1.0 equiv) to afford
3jb (27.9 mg, 39% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 24 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 110 °C.
13-Methyl-7,8-dihydro-13H-13a,8a-(epiminoethano)naphtho-
[1,2-a]carbazole (3jb). TLC: Rf = 0.33 (petroleum ether/ethyl
acetate = 5:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.57 (d, J = 8.9
Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.52 (t, J
= 7.3 Hz, 1H), 7.42 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.09
(d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H),
6.23 (d, J = 7.8 Hz, 1H), 3.20 (dd, J = 12.0, 6.7 Hz, 1H), 2.80 (td, J =
12.0, 5.3 Hz, 1H), 2.52−2.75 (m, 6H), 2.28 (dd, J = 11.8, 5.0 Hz,
1H), 1.91−2.21 (br s, 1H), 1.73−1.91 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 152.9, 139.6, 133.8, 133.3, 132.9, 132.5,
129.1, 128.6, 128.4, 128.2, 128.0, 125.6, 124.6, 12∼3.3, 116.5, 104.2,
36.2, 28.7, 28.3. IR (ATR): v (cm−1) = 2924, 1601, 1497, 1364, 1238.
HRMS (ESI) m/z: [M + H]+ calcd for C20H23N2O, 307.1805; found,
307.1793.
Compounds 2n, 3na, and 3nb. The compounds were
synthesized according to GP-F and GP-G using 1n (299 mg, 0.721
mmol, 1.0 equiv) to afford 2n (200 mg, 83% yield) as a yellow oil and
3na (22.0 mg, 24% yield over 2 steps) as a yellow oil and 3nb (54.7
mg, 59% yield over 2 steps) as a yellow oil. The reaction time for GP-
F was 58 h; the reaction time for GP-G was 2 h. The eaction
temperature for GP-F was 110 °C.
94.0, 60.5, 45.9, 44.9, 36.3, 30.9, 30.2. IR (ATR): v (cm−1) = 2925,
1604, 1496, 1378, 1310. HRMS (ESI) m/z: [M + H]+ calcd for
C23H23N2, 327.1856; found, 327.1850.
tert-Butyl (S)-3′-Methylene-2,3-dihydrospiro[indene-1,2′-indo-
line]-1′-carboxylate (2n). TLC: Rf = 0.26 (petroleum ether/ethyl
acetate = 50:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.03 (s, 1H),
7.44 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.20−7.29 (m, 2H),
7.15 (t, J = 7.1 Hz, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.97 (d, J = 7.6
Hz, 1H), 5.36 (s, 1H), 4.53 (s, 1H), 3.07−3.26 (m, 2H), 2.84−2.97
(m, 1H), 2.35−2.46 (m, 1H), 1.15 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 154.0, 151.5, 147.4, 144.8, 142.6, 130.3,
Compound 3la. The compound was synthesized according to
GP-F and GP-G using 1l (118 mg, 0.204 mmol, 1.0 equiv) to afford
3la (62.4 mg, 77% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 24 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 110 °C.
Benzyl 5,6-Dihydro-7H-6a,11b-(epiminoethano)benzo[c]-
carbazole-14-carboxylate (3la). TLC: Rf = 0.18 (petroleum ether/
ethyl acetate = 9:1). 1H NMR (400 MHz, CDCl3) (ca. 4:1 mixture of
rotamers, both reported): δ (ppm) 7.52 (d, J = 8.1 Hz, 1H), 7.27−
7.48 (m, 6H), 7.20 (t, J = 7.7 Hz, 1H), 6.97−7.15 (m, 3H), 6.76 (t, J
= 7.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 0.8H), 6.76 (t, J = 7.8 Hz, 0.2H),
5.56−5.66 (br s, 0.8H), 5.36 (d, J = 12.3 Hz, 0.2H), 5.23 (d, J = 12.3
Hz, 0.2H), 5.19 (d, J = 12.6 Hz, 0.8H), 5.07 (d, J = 12.6 Hz, 0.8H),
4.90−4.97 (br s, 0.2H), 3.68−3.82 (m, 1H), 2.94−3.36 (m, 3H),
2.59−2.86 (m, 2H), 2.25−2.39 (m, 1H), 1.88 (td, J = 13.3, 4.2 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 154.4, 149.4,
148.7, 140.7, 140.6, 136.7, 136.6, 135.7, 135.2, 132.9, 132.6, 129.0,
128.8, 128.6, 128.5, 128.3, 128.1, 127.8, 127.2, 126.9, 126.8, 126.2,
123.7, 119.5, 119.2, 110.1, 109.8, 87.7, 87.1, 67.2, 66.6, ∼59.0, 57.9,
127.7, 127.0, 126.8, 124.7, 122.8, 122.8, 120.4, 115.7, 101.8, 80.9,
∼
79.9, 40.3, 30.2, 28.0. IR (ATR): v (cm−1) = 1702, 1601, 1477, 1464,
1368, 1164. HRMS (ESI) m/z: [M + Na]+ calcd for C22H23NO2Na,
356.1621; found, 356.1617.
11b-Methyl-6,11b-dihydro-5H-benzo[c]carbazole (3na). TLC: Rf
1
= 0.15 (petroleum ether/ethyl acetate = 5:1). H NMR (400 MHz,
CDCl3): δ (ppm) 7.78 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H),
7.59 (d, J = 7.5 Hz, 1H), 7.36 (td, J = 7.5, 1.2 Hz, 1H), 7.29 (td, J =
7.5, 1.2 Hz, 1H), 7.23 (dd, J = 8.1, 4.8 Hz, 1H), 7.16−7.18 (m, 2H),
3.38−3.53 (m, 1H), 3.06−3.25 (m, 3H), 1.62 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 188.9, 154.8, 143.7, 140.2, 135.4, 128.9,
47.4, 46.6, 36.8, 36.2, 30.5, 29.4, 28.03, 28.01. IR (ATR): v (cm−1) =
3380, 3030, 2938, 1683, 1607, 1482, 1464, 1404, 1350. HRMS (ESI)
m/z: [M + Na]+ calcd for C26H24N2O2Na, 419.1730; found,
419.1722.
128.2, 127.0, 126.95, 126.94, 125.3, 123.6, 120.6, 57.6, 32.7, 27.5,
∼
26.6. IR (ATR): (cm−1) = 3062, 2965, 2925, 1716, 1590, 1484,
1446, 1371. HRMS (ESI) m/z: [M + H]+ calcd for C17H16N,
234.1277; found, 234.1271.
v
Compounds 3ma and 3mb. The compounds were synthesized
according to GP-F and GP-G using 1m (81.1 mg, 0.166 mmol, 1.0
equiv) to afford 3ma (21.8 mg, 42% yield over 2 steps) as a yellow oil
and 3mb (3.5 mg, 7% yield over 2 steps) as a yellow oil. The reaction
time for GP-F was 19 h; the reaction time for GP-G was 1 h. The
reaction temperature for GP-F was 110 °C.
6a-Methyl-6,6a-dihydro-5H-benzo[a]carbazole (3nb). TLC: Rf =
0.53 (petroleum ether/ethyl acetate = 5:1). H NMR (400 MHz,
CDCl3): δ (ppm) 8.15 (dd, J = 7.7, 1.1 Hz, 1H), 7.71 (d, J = 8.3 Hz,
1H), 7.32−7.45 (m, 4H), 7.29 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.4 Hz,
1H), 3.32 (ddd, J = 17.7, 12.6, 5.8 Hz, 1H), 3.01 (dd, J = 17.4, 5.6 Hz,
1H), 2.42 (ddd, J = 13.3, 5.7, 1.4 Hz, 1H), 1.77 (td, J = 13.0, 5.9 Hz,
1
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Article
1H), 1.31 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
Cs2CO3 (54.3 mg, 0.165 mmol, 1.5 equiv), and toluene (0.2 mL) in a
glovebox. After 20 min, 1n (45.5 mg, 0.110 mmol, 1.0 equiv)
dissolved in toluene (0.8 mL) was added. The resulting mixture was
heated at 120 °C in an oil bath for 44 h until completion of the
reaction (TLC). The reaction was filtered through a pad of silica gel
to afford crude product, which was purified by flash column
chromatography on silica gel (eluted with petroleum ether/ethyl
acetate 200:1) to afford 2n as a yellow oil (25.2 mg, 69%, 37% ee).
[α]2D0 = −1.72 (c 3.60, CHCl3). The above product was dissolved in
0.5 mL of DCM−TFA (v/v = 10:1). The mixture was stirred at rt
for1 h until completion of the reaction (TLC). Saturated aqueous
NaHCO3 solution was slowly added. The mixture was extracted with
DCM, and the combined extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel to afford 3na (3.7 mg,
33%, 37% ee) as a yellow oil and 3nb (6.5 mg, 58%, 37% ee) as a
184.1, 155.3, 145.7, 139.8, 131.1, 130.1, 129.1, 128.1, 1∼26.9, 126.3,
125.3, 121.6, 120.9, 51.9, 32.3, 26.2, 20.0. IR (ATR): v (cm−1) =
3055, 2925, 1605, 1574, 1452, 1375. HRMS (ESI) m/z: [M + H]+
calcd for C17H16N, 234.1277; found, 234.1271.
Compound 2o. This compound was synthesized according to
GP-F using 1o (45.5 mg, 0.0999 mmol, 1.0 equiv) to afford 2o (15.4
mg, 41% yield) as a yellow oil. The crude product was purified by
flash column chromatography on silica gel (eluted with petroleum
ether/ethyl acetate 10:1 to 5:1). The reaction temperature for GP-F
was 110 °C, and the reaction time for GP-F was 24 h.
tert-Butyl (13aS)-5-Oxo-5H-6,13a-methanobenzo[6,7]azocino-
[5,4-b]indole-13(7H)-carboxylate (2o). TLC: Rf = 0.31 (petroleum
1
ether/ethyl acetate = 5:1). H NMR (400 MHz, CDCl3) (ca. 7:1
mixture of rotamers, both reported): δ (ppm) 8.19 (d, J = 8.0 Hz,
0.74H), 7.97−8.05 (m, 1H), 7.72 (d, J = 5.7 Hz, 0.23H), 7.26−7.37
(m, 4H), 7.03 (t, J = 7.5 Hz, 1H), 6.93−6.99 (m, 1H), 5.80 (s, 1H),
5.01 (d, J = 10.7 Hz, 0.22H), 4.70 (d, J = 12.3 Hz, 0.79H), 4.48 (dd, J
= 18.7, 2.8 Hz, 1H), 3.95 (dd, J = 18.5, 2.1 Hz, 1H), 3.54 (d, J = 12.4
Hz, 1H), 1.60 (s, 2.8H), 1.28 (s, 7.7H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 176.2, 151.7, 146.9, 144.2, 139.9, 132.8, 130.2,
yellow oil. For 3na, [α]D20 = +5.60 (c 1.06, CHCl3). For 3nb, [α]2D0
=
−1.76 (c 0.75, CHCl3). For compound 2n, the ee of compound 2n
was determined by HPLC using an OD column (n-hexane/i-PrOH =
100:0.8, flow rate = 1.0 mL/min. tmajor = 5.7 min, tminor = 6.6 min).
For compound 3na, the ee of compound 3na was determined by
HPLC using an OD column (n-hexane/i-PrOH = 100:1.5, flow rate =
1.0 mL/min. tmajor = 14.9 min, tminor = 16.8 min). For compound 3nb,
the ee of compound 3nb was determined by HPLC using an AD
130.1, 129.4, 128.2, 126.5, 123.7, 122.8, 121.0, 117.9, 115.5, 82.1,
∼
65.5, 55.8, 50.3, 28.2. IR (ATR): v (cm−1) = 1702, 1680, 1461, 1361.
HRMS (ESI) m/z: [M + Na]+ calcd for C23H22N2O3Na, 397.1523;
found, 397.1520.
column (n-hexane/i-PrOH = 100:0.8, flow rate = 1.0 mL/min. tmajor
16.5 min, tminor = 13.0 min).
=
Tosylation of 3ha and 3hb. 2-Chloro-7-methyl-14-tosyl-5,6-
dihydro-7H-6a,11b-(epiminoethano)benzo[c]carbazole (4ha). To a
10 mL sealed tube equipped with a magnetic stirrer was added TsCl
(369 mg, 1.93 mmol, 19.0 equiv) and K2CO3 (267 mg, 1.93 mmol,
19.0 equiv) under argon, afterward 3ha (29.9 mg, 0.0963 mmol, 1.0
equiv) dissolved in anhydrous CH3CN (2.0 mL) was added to the
tube. The resulting mixture was allowed to heated at 80 °C in an oil
bath and stirred for 20 h. Then the reaction was cooled to rt and
filtered through a pad of Na2SO4. The filtrate was concentrated and
the crude product was purified flash column chromatography on silica
gel (eluted with petroleum ether/ethyl acetate = 20:1 to 10:1) to
afford 4ha as a white solid (40.0 mg, 90% yield). TLC: Rf = 0.52
Formal Total Synthesis of Vincorine. tert-Butyl (Z)-3-(2-((tert-
Butoxycarbonyl)amino)ethyl)-2-(5-ethoxy-4-iodo-5-oxopent-3-en-
1-yl)-5-methoxy-1H-indole-1-carboxylate (6). tert-Butyl 3-(2-((tert-
butoxycarbonyl)amino)ethyl)-2-(3-hydroxypropyl)-5-methoxy-1H-in-
dole-1-carboxylate (4) was prepared according to previously reported
literature.7b To a solution of 4 (3.89 g, 8.68 mmol, 1.0 equiv) in 43.0
mL of DCM were added DMP (4.42 g, 10.4 mmol, 1.2 equiv) and
NaHCO3 (876 mg, 10.4 mmol, 1.4 equiv) at 0 °C. The mixture was
stirred for 0.5 h until completion of the reaction (TLC). The resulting
mixture was filtered through a short column, washed with DCM, and
concentrated under reduced pressure. The resulting residue was
filtered through a pad of silica gel (eluted with petroleum ether/
EtOAc 10:1 to 5:1) to afford 5 as a yellow oil (2.73 g, 81% crude
yield), which was directly used in the next step without further
purification. Using GP-H, to a stirred solution of NaH (60% mineral
oil dispersion, 1.12 g, 28.1 mmol, 4.0 equiv) in 15 mL of dry THF at 0
°C was added triethyl phosphonoacetate (3.07 g, 14.1 mmol, 2.0
equiv) under an argon atmosphere, and the mixture was stirred at
room temperature for 50 min. The mixture was cooled to 0 °C, and I2
(3.57 g, 14.1 mmol, 2.0 equiv) was added. After being stirred under
dark at room temperature for 2 h, the mixture was again cooled to 0
°C, and a solution of the aldehyde 5 (3.14 g, 7.03 mmol, 1.0 equiv) in
THF (20 mL) was added. After being stirred under darkness at rt for
2 h, the reaction was quenched with H2O. The reaction mixture was
extracted with ethyl acetate, washed saturated Na2S2O3 and brine,
dried over Na2SO4, and concentrated in vacuo. The crude product
was purified by flash column chromatography on silica gel (eluted
with petroleum ether/ethyl acetate 30:1 to 20:1 to 10:1) to afford 6 as
a yellow oil (2.13 g, 45%). TLC: Rf = 0.43 (petroleum ether/ethyl
acetate = 5:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96 (d, J = 9.0
Hz, 1H), 7.24 (t, J = 7.0 Hz, 1H), 6.98 (s, 1H), 6.87 (dd, J = 9.0, 2.6
Hz, 1H), 4.64 (br s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H),
3.30−3.42 (m, 2H), 3.21 (t, J = 7.8 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H),
2.67 (dt, J = 7.7, 7.1 Hz, 2H), 1.69 (s, 9H), 1.43 (s, 9H), 1.31 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 162.9,
156.1, 156.0, 151.8, 150.4, 137.0, 130.7, 130.6, 116.7, 112.4, 101.5,
96.2, 84.0, 79.4, ∼62.8, 55.9, 40.72, 40.65, 37.8, 28.6, 28.5, 25.0, 24.8,
1
(petroleum ether/ethyl acetate = 5:1). Mp: 206−207 °C. H NMR
(400 MHz, CDCl3): δ (ppm) 7.64 (d, J = 8.3 Hz, 2H), 7.42 (d, J =
2.0 Hz, 1H), 7.17−7.24 (m, 3H), 7.09 (td, J = 7.8, 1.0 Hz, 1H), 7.04
(dd, J = 8.2, 2.1 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.67 (td, J = 7.4,
0.6 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 3.54 (dd, J = 10.0, 7.3 Hz, 1H),
3.39 (dt, J = 14.1, 3.7 Hz, 1H), 3.06−3.16 (m, 1H), 3.06 (s, 3H),
2.61−2.70 (m, 3H), 2.38 (s, 3H), 2.16 (td, J = 12.1, 7.3 Hz, 1H), 2.02
(dt, J = 14.2, 8.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 150.3, 143.2, 142.7, 138.1, 134.2, 132.4, 130.8, 129.7, 129.6,
129.1, 127.0, 126.6, 126.4, 122.9,∼118.1, 106.1, 94.4, 60.2, 48.5, 37.9,
29.5, 29.5, 27.1, 21.6. IR (ATR): v (cm−1) = 3023, 2922, 1604, 1596,
1491, 1430, 1374, 1331, 1303. HRMS (ESI) m/z: [M + Na]+ calcd
for C26H25ClN2O2SNa, 487.1217; found, 487.1217.
2-Chloro-11-methyl-12-tosyl-5,6-dihydro-11H-11a,6a-
(epiminoethano)benzo[a]carbazole (4hb). Following the procedure
for the tosylation of 3ha, 3hb (23.4 mg, 0.0754 mmol, 1.0 equiv) was
tosylated to afford 4hb (22.3 mg, 64% yield) as a white solid. TLC: Rf
1
= 0.83 (petroleum ether/ethyl acetate = 5:1). Mp: 239−240 °C. H
NMR (400 MHz, CDCl3): δ (ppm) 8.34 (d, J = 2.1 Hz, 1H), 7.46 (d,
J = 8.3 Hz, 2H), 7.25 (dd, J = 8.0, 2.2 Hz, 1H), 7.06 (d, J = 8.0 Hz,
1H), 7.00 (d, J = 8.1 Hz, 2H), 6.87−6.94 (m, 2H), 6.64 (td, J = 7.4,
0.7 Hz, 1H), 6.02 (d, J = 7.8 Hz, 1H), 3.46−3.56 (m, 2H), 2.47 (s,
3H), 2.31−2.41 (m, 2H), 2.28 (s, 3H), 1.96−2.10 (m, 2H), 1.91 (td,
J = 12.7, 7.8 Hz, 1H), 1.36−1.46 (m, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 150.7, 142.6, 138.9, 137.4, 136.8, 132.6, 132.0,
130.0, 129.0, 128.5, 128.3, 128.1, 127.0, 122.5, 1∼19.2, 107.5, 94.4,
14.3. IR (ATR): v (cm−1) = 1712, 1478, 1367. HRMS (ESI) m/z: [M
+ Na]+ calcd for C28H39IN2O7Na, 665.1694; found, 665.1693.
tert-Butyl (Z)-3-(2-((tert-Butoxycarbonyl)amino)ethyl)-2-(5-
((tert-butyldiphenylsilyl)oxy)-4-iodopent-3-en-1-yl)-5-methoxy-1H-
indole-1-carboxylate (7). In GP-I, a solution of ester 6 (841 mg, 1.30
mmol, 1.0 equiv) in DCM/THF (v/v = 1:1, 14.0 mL) was added to
DIBAL-H (14.7 mL, 6.50 mmol, 1 M in hexanes, 5.0 equiv) dropwise
61.2, 49.0, 38.6, 36.4, 32.1, 27.1, 21.5. IR (ATR): v (cm−1) = 3024,
2921, 2858, 2820, 1603, 1489, 1359, 1334, 1305. HRMS (ESI) m/z:
[M + Na]+ calcd for C26H25ClN2O2SNa, 487.1217; found, 487.1218.
Preparation of Enantioenriched 2n and Its Rearrangement.
To an oven-dried 10 mL sealed tube were added [Pd(C3H5)Cl]2 (2.0
mg, 0.0055 mmol, 0.05 equiv), L8 (8.4 mg, 0.017 mmol, 0.15 equiv),
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under an argon atmosphere at −78 °C (over 15 min). The mixture
was stirred at −78 °C for 0.5 h and moved to −40 °C for another 4 h.
MeOH (1.0 mL) was added, and the mixture was allowed to warm to
rt. A solution of saturated aqueous Seignette salt was added, and the
mixture was stirred overnight. Then, the reaction mixture was
concentrated under reduced pressure to remove THF and DCM. The
water phase was extracted with DCM, and the combined organic
extracts were dried over Na2SO4 and concentrated in vacuo. The
resulting residue was filtered through a pad of silica gel (eluted with
petroleum ether/ethyl acetate 5:1 to 4:1) to afford the crude alcohol
(506 mg, 68% crude yield) as a yellow oil, which was directly used in
the next step without further purification. To the above crude alcohol
(136 mg, 0.238 mmol, 1.0 equiv) dissolved in DCM (2.4 mL) were
added 1H-imidazole (25.0 mg, 0.378 mmol, 1.0 equiv), 4-DMAP (2.9
mg, 0.024 mmol, 0.1 equiv), and TBDPSCl (99.0 mg, 0.360 mmol,
1.5 equiv) at 0 °C. The mixture was stirred at rt for 10 h until
completion of the reaction (TLC). The reaction was quenched with
water and extracted with DCM. The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The crude product was purified by flash column chromatography on
silica gel (eluted with petroleum ether/ethyl acetate 20:1 to 10:1) to
afford 7 as a yellow oil (163.2 mg, 81%). TLC: Rf = 0.61 (petroleum
5-(((tert-Butyldiphenylsilyl)oxy)methyl)-3-methoxy-10-tosyl-7,8-
dihydro-9H-8a,4b-(epiminoethano)carbazole (10). To a 10 mL
sealed tube equipped with a magnetic stirrer were added TsCl (51.7
mg, 0.271 mmol, 3.0 equiv) and 4-DMAP (2.0 mg, 0.018 mmol, 0.2
equiv) under argon; afterward, 9 (46.4 mg, 0.0908 mmol, 1.0 equiv)
dissolved in anhydrous DCM (2.0 mL) was added to the tube at 0 °C.
Then, DIPEA (18 μL, 0.27 mmol, 3.0 equiv) was added dropwise into
the reaction system by syringe. After 10 min, the tube was allowed to
warm to 30 °C and stirred for 22 h. Saturated aqueous NaHCO3
solution was added to quench the reaction. The organic phase was
separated, and the aqueous phase was extracted with DCM. The
combined organic phase was dried over Na2SO4 and concentrated,
and the crude product was purified by flash column chromatography
on silica gel (eluted with petroleum ether/ethyl acetate = 20:1 to
10:1) to afford 10 as a yellow oil (35.0 mg, 58% yield). [α]1D3 = −7.8
(c 0.40, CHCl3). TLC: Rf = 0.65 (petroleum ether/ethyl acetate =
5:1). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.69 (dd, J = 7.8, 1.5 Hz,
2H), 7.63 (dd, J = 7.8, 1.5 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.31−
7.46 (m, 6H), 7.17 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 2.5 Hz, 1H), 6.56
(dd, J = 8.4, 2.5 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.71 (d, J = 5.1 Hz,
1H), 4.95−5.05 (br s, 1H), 4.26 (d, J = 13.0 Hz, 1H), 4.05 (d, J =
13.0 Hz, 1H), 3.61 (s, 3H), 3.44 (t, J = 8.5 Hz, 1H), 2.81−2.95 (m,
2H), 2.63 (dd, J = 13.0, 6.2 Hz, 1H), 2.27−2.43 (m, 4H), 2.04−2.17
(m, 2H), 1.86 (td, J = 13.1, 5.4 Hz, 1H), 1.06 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 153.5, 143.0, 142.4, 137.3, 136.6, 135.7,
135.7, 133.6, 133.34, 131.25, 129.9, 129.8, 129.6, 127.9, 127.8, 127.2,
123.7, 113.8, 110.9, 110.8, 9∼2.9, 65.4, 58.3, 56.1, 47.4, 34.2, 30.7, 27.0,
1
ether/ethyl acetate = 5:1). H NMR (400 MHz, CDCl3): δ (ppm)
8.01 (d, J = 9.0 Hz, 1H), 7.61−7.69 (m, 4H), 7.32−7.46 (m, 6H),
6.96 (s, 1H), 6.87 (dd, J = 9.0, 2.6 Hz, 1H), 6.00 (t, J = 6.8 Hz, 1H),
4.59 (br s, 1H), 4.25 (d, J = 0.9 Hz, 2H), 3.86 (s, 3H), 3.28−3.41 (m,
2H), 3.09 (t, J = 7.9 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 2.50 (dt, J =
7.5, 7.2 Hz, 2H), 1.69 (s, 9H), 1.43 (s, 9H), 1.05 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 156.0, 155.9, 150.4, 137.6, 135.7,
133.2, 132.8, 130.9, 130.7, 129.9, 127.9, 116.7, 116.3, 112.2, 107.6,
101.4, 83.7, 79.3∼, 71.8, 55.9, 40.7, 36.2, 28.6, 28.5, 26.9, 25.6, 25.0,
24.0, 21.6, 19.3. IR (ATR): v (cm−1) = 3392, 2930, 2857, 1599, 1489,
1429, 1390, 1361, 1219. HRMS (ESI) m/z: [M + Na]+ calcd for
C39H45N2O4SSi, 665.2864; found, 665.2863. The ee of compound 10
was determined by HPLC using an OD column (n-hexane/i-PrOH =
100:1.5, flow rate = 1.0 mL/min. tmajor = 25.8 min, tminor = 31.9 min).
tert-Butyl 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-3-methoxy-10-
tosyl-7,8-dihydro-9H-8a,4b-(epiminoethano)carbazole-9-carboxy-
late (11). To a solution of 10 (12.6 mg, 0.0189 mmol, 1.0 equiv) in
DCM (1.0 mL) was added pyridine (40 μL, 0.50 mmol, 30.0 equiv)
under argon. Then, a solution of triphosgene (11.5 mg, 0.0380 mmol,
2.0 equiv) dissolved in anhydrous DCM (1.0 mL) was added slowly at
−40 °C, after which a white precipitation formed. The reaction was
allowed to slowly warm to rt and stirred for 30 min. The reaction
mixture became an yellow solution. At −40 °C, the reaction mixture
was transferred to a 10 mL Schlenk tube containing t-BuONa (91.7
mg, 0.954 mmol, 50.0 equiv) and THF (4.0 mL) via syringe. The
reaction was slowly warmed to 30 °C in an oil bath and stirred for 5 h.
Saturated aqueous NH4Cl solution was slowly added to quench the
reaction. The organic phase was separated, and the aqueous phase was
extracted with DCM. The combined organic phase was dried over
Na2SO4 and concentrated, and the crude product was purified by flash
column chromatography on silica gel (eluted with petroleum ether/
ethyl acetate = 20:1 to 10:1) to afford 11 as a yellow oil (8.3 mg, 57%
yield, 68% yield brsm) and recovered 10 (2.0 mg, 16% recovered
19.4. IR (ATR): v (cm−1) = 1712, 1504, 1389. HRMS (ESI) m/z: [M
+ Na]+ calcd for C42H55IN2O6SiNa, 861.2766; found, 861.2765.
5-(((tert-Butyldiphenylsilyl)oxy)methyl)-3-methoxy-7,8-dihydro-
9H-8a,4b-(epiminoethano)carbazole (9). To an oven-dried 10 mL
sealed tube were added [Pd(C3H5)Cl]2 (3.8 mg, 0.010 mmol, 0.05
equiv), L8 (15.7 mg, 0.030 mmol, 0.15 equiv), Cs2CO3 (98.9 mg,
0.30 mmol, 1.5 equiv), and toluene (2 mL) in a glovebox. After 20
min, 7 (170 mg, 0.20 mmol, 1.0 equiv) dissolved in toluene (1.8 mL)
was added. The resulting mixture was heated at 110 °C in an oil bath
for 48 h. [Pd(C3H5)Cl]2 (3.8 mg, 0.010 mmol, 0.05 equiv), L8 (15.7
mg, 0.0303 mmol, 0.15 equiv), and Cs2CO3 (98.9 mg, 0.303 mmol,
1.5 equiv) were added and heated for another 48 h. The reaction was
filtered through a pad of silica gel to afford crude product, which was
purified by flash column chromatography on silica gel (eluted with
petroleum ether/ethyl acetate 10:1) to afford 8 as a yellow oil (77.9
mg, 54%). To the above crude product was added 8 (77.9 mg, 0.11
mmol) dissolved in 10.0 mL of DCM−TFA (v/v = 5:1). The mixture
was stirred at rt for 40 min until completion of the reaction (TLC); 1
M NaOH (aq) was slowly added. The mixture was extracted with
DCM, and the combined extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (eluted with DCM/
methanol 50:1 to 10:1) to afford 9 (41.6 mg, 74% yield) as a yellow
1
yield). TLC: Rf = 0.71 (petroleum ether/ethyl acetate = 5:1). H
NMR (400 MHz, CDCl3): δ (ppm) 7.67 (dd, J = 8.0, 1.5 Hz, 2H),
7.62 (dd, J = 8.0, 1.4 Hz, 2H), 7.31−7.50 (m, 8H), 7.09 (d, J = 8.1
Hz, 2H), 7.14−8.83 (m, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.46 (dd, J =
9.0, 2.6 Hz, 1H), 5.62 (s, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.94 (d, J =
12.8 Hz, 1H), 3.66−3.82 (m, 2H), 3.62 (s, 3H), 2.84−3.06 (m, 1H),
2.68 (dd, J = 13.0, 6.1 Hz, 1H), 2.36 (s, 3H), 2.09−2.23 (m, 3H),
1.83−2.03 (m, 1H), 1.61 (s, 9H), 1.07 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 156.0, 142.5, 137.7, 135.72, 135.66, 135.56,
134.9, 133.5, 133.2, 132.4, 129.93, 129.88, 129.2, 127.9, 127.8, 126.9,
124.3, 119.0, 113.3, 108.8, 91.6, 81.9, 65.6, 59.3, 55.7, 48.7, 33.1, 30.5,
28.4, 27.0, 23.9, 21.5, 19.3. Some 13C peaks w∼ere identified in the 2D
1
oil. TLC: Rf = 0.60 (dichloromethane/methanol = 10:1). H NMR
(400 MHz, CDCl3): δ (ppm) 7.71 (dd, J = 7.8, 1.5 Hz, 2H), 7.65 (dd,
J = 7.8, 1.5 Hz, 2H), 7.33−7.48 (m, 6H), 6.69 (d, J = 2.2 Hz, 1H),
6.65 (dd, J = 8.5, 2.4 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 5.79 (d, J =
4.7 Hz, 1H), 5.40−6.20 (br s, 2H), 4.35 (d, J = 13.1 Hz, 1H), 4.18 (d,
J = 13.1 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, J = 11.0, 7.2 Hz, 1H), 2.82
(td, J = 11.9, 5.7 Hz, 1H), 2.69 (dd, J = 13.3, 5.5 Hz, 1H), 2.41 (d, J =
12.0 Hz, 1H), 2.08−2.36 (m, 4H), 1.08 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 153.9, 142.3, 137.4, 135.71, 135.68, 133.5,
133.3, 131.8, 130.0, 129.9, 127.91, 127.85, 123.5, 114.3, 110.9
(overlapping), 65.2, 57.8, 56.0, 53.6, 44.9, 38.0, 30.8, 27.0, 22.9, 19.4.
HSQC and 2D HMBC spectrum. IR (ATR): v (cm−1) = 2930, 2857,
1717, 1696, 1489, 1429, 1370, 1162. HRMS (ESI) m/z: [M + Na]+
calcd for C44H52N2O6SSiNa, 787.3208; found, 787.3191.
Some 13C peaks were identified in the 2D HSQC spectrum. IR
tert-Butyl 5-(Hydroxymethyl)-3-methoxy-10-tosyl-7,8-dihydro-
9H-8a,4b-(epiminoethano)carbazole-9-carboxylate (12). To a
solution of 11 (40.0 mg, 0.0522 mmol, 1.0 equiv) in THF (2.0
mL) was added TBAF (0.10 mL, 1 M in THF, 0.10 mmol, 2.0 equiv)
∼
(ATR): v (cm−1) = 2926, 2954, 1736, 1491, 1429, 1379. HRMS
(ESI) m/z: [M + Na]+ calcd for C32H39N2O2SSi, 511.2775; found,
511.2775.
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at 0 °C. The reaction was slowly warmed to rt and stirred for 1.5 h.
Water was slowly added to quench the reaction. The organic phase
was separated, and the aqueous phase was extracted with ethyl acetate.
The combined organic phase was dried over Na2SO4 and
concentrated, and the crude product was purified by flash column
chromatography on silica gel (eluted with petroleum ether/ethyl
acetate = 5:1 to 1:1) to afford 12 as a colorless oil (25.1 mg, 93%
was added, and the mixture was allowed to warm to rt. A solution of
saturated aqueous Seignette salt was added, and the mixture was
stirred overnight. The organic phase was separated, and the aqueous
phase was extracted with DCM. The combined organic phase was
dried over Na2SO4 and concentrated in vacuo. The resulting residue
was filtered through a pad of silica gel (eluted with petroleum ether/
ethyl acetate 30:1 to 20:1 to 10:1) to afford S21 as a colorless oil
(2.81 g, 86% crude yield), which was directly used in the next step
without further purification. Compound S22 was synthesized
according to GP-H using S21. The crude product was purified by
flash column chromatography on silica gel (eluted with petroleum
ether/ethyl acetate 100:1 to 50:1) to afford S22 as a yellow oil (1.85
1
yield). TLC: Rf = 0.53 (petroleum ether/ethyl acetate = 1:1). H
NMR (600 MHz, CDCl3): δ (ppm) 7.44 (d, J = 7.8 Hz, 2H), 6.87−
7.20 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 2.4 Hz, 1H), 6.48
(dd, J = 8.8, 2.6 Hz, 1H), 5.72 (t, J = 3.8 Hz, 1H), 4.15 (d, J = 12.9
Hz, 1H), 3.96 (d, J = 12.9 Hz, 1H), 3.70−3.78 (m, 2H), 3.73 (s, 3H),
2.87−3.04 (m, 1H), 2.67 (dd, J = 13.1, 6.1 Hz, 1H), 2.35 (s, 3H),
2.11−2.21 (m, 3H), 1.82−1.98 (m, 1H), 1.60 (s, 9H). 13C{1H} NMR
(151 MHz, CDCl3): δ (ppm) 156.0, 142.6, 137.5, 135.9, 135.5, 132.4,
1
g, 45%). TLC: Rf = 0.78 (petroleum ether/ethyl acetate = 4:1). H
NMR (400 MHz, CDCl3): δ (ppm) 8.09 (d, J = 7.7 Hz, 1H), 7.49 (d,
J = 7.1 Hz, 1H), 7.19−7.31 (m, 3H), 4.26 (q, J = 7.2 Hz, 2H), 3.79 (t,
J = 7.4 Hz, 2H), 3.26 (t, J = 7.9 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H),
2.66 (dt, J = 7.9, 7.2 Hz, 2H), 1.70 (s, 9H), 1.32 (t, J = 7.2 Hz, 3H),
0.88 (s, 9H), 0.01 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 162.9, 151.9, 150.6, 136.3, 136.1, 130.1, 123.9, 122.7, 118.5,
129.2, 126.8, 125.3, 119.0, 112.7, 109.4, 91.5, 82.0, 64.6, 59.2, 55.9,
∼
48.7, 33.0, 31.0, 28.3, 23.9, 21.5. IR (ATR): v (cm−1) = 3513, 1696,
1489, 1370, 1161, 808. HRMS (ESI) m/z: [M + Na]+ calcd for
C28H34N2O6SNa, 549.2030; found, 549.2027. The spectroscopic data
of synthesized 12 were identical to those reported in literature.7a
Preparation of the Alkenyl Substrates: See Scheme S4. tert-
Butyl 2-(3-Butoxy-3-oxopropyl)-3-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)-1H-indole-1-carboxylate (S20, Scheme S4, Reaction 8). To
a solution of TBS-protected tryptphol S17 (4.54 g, 14.7 mmol, 1.0
equiv) and Pd(OAc)2 (165 mg, 0.735 mmol, 0.05 equiv) in 22.5 mL
of 1,4-dioxane and 7.5 mL of AcOH were added n-butyl acrylate (7.54
g, 58.8 mmol, 4.0 equiv) and t-BuO2Bz (3.71 g, 19.1 mmol, 1.3 equiv)
under an argon atmosphere. The mixture was heated to 70 °C in an
oil bath for 34 h until completion of the reaction (TLC). Saturated
aqueous Na2CO3 solution was slowly added until pH = 8. The
mixture was extracted with ethyl acetate, and the combined extracts
were dried over Na2SO4 and concentrated in vacuo. The resulting
residue was filtered through a pad of silica gel (eluted with petroleum
ether/EtOAc 100:1 to 50:1 to 20:1) to afford S18 as a yellow oil
(4.20 g, 75% crude yield), which was directly used in the next step
without further purification. To the above crude product was added
S18 (2.65 g, 6.60 mmol, 1.0 equiv) dissolved in CH3CN, Boc2O (1.59
g, 7.27 mmol, 1.1 equiv), and 4-DMAP (81 mg, 0.66 mmol, 0.1
equiv). The mixture was stirred overnight at rt. Upon completion, the
solvent was evaporated, and water was added. The mixture was
extracted with DCM. The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
resulting residue was filtered through a pad of silica gel (eluted with
petroleum ether/ethyl acetate 100:1 to 20:1 to 10:1) to afford S19 as
a yellow oil (2.57 g, 75% crude yield), which was directly used in the
next step without further purification. To the above crude product
were added S19 (4.08 g, 8.13 mmol, 1.0 equiv) dissolved in 70 mL of
MeOH and 8 mL of THF in Pd/C (244 mg, 10 wt %, 0.1 equiv) and
HCO2NH4 (3.08 g, 48.8 mmol, 6.0 equiv). The mixture was stirred
for 48 h at rt. Upon completion, the solvent was evaporated, and the
crude product was purified by flash column chromatography on silica
gel (eluted with petroleum ether/ethyl acetate 10:1) to afford S20 as
116.5, 115.9, 96.0, 84.0, 63.1, 62.8, 38.0, 28.5, 28.2, 26.1, 24.9, 18.5,
∼
14.3, −5.1. IR (ATR): v (cm−1) = 1722, 1612. HRMS (ESI) m/z: [M
+ Na]+ calcd for C28H42INO5SiNa, 650.1775; found, 650.1787.
tert-Butyl (Z)-2-(5-((tert-Butyldimethylsilyl)oxy)-4-iodopent-3-
en-1-yl)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-1-car-
boxylate (1p, Scheme S4, Reaction 8). Compound S23 was
synthesized according to GP-I as a colorless oil, which was directly
used in the next step without further purification. To the above crude
was adde S23 dissolved in DCM (28 mL) 1H-imidazole (280 mg,
4.23 mmol) and TBSCl (638 mg, 4.23 mmol). The mixture was
stirred at rt for 13 h until completion of the reaction (TLC). The
reaction was quenched with water and extracted with DCM. The
combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (eluted with petroleum
ether/ethyl acetate 100:1 to 50:1) to afford 1p as a colorless oil (1.89
1
g, 92%). TLC: Rf = 0.85 (petroleum ether/ethyl acetate = 5:1). H
NMR (400 MHz, CDCl3): δ (ppm) 8.11 (dd, J = 7.3, 1.5 Hz, 1H),
7.47 (dd, J = 6.5, 1.7 Hz, 1H), 7.17−7.28 (m, 2H), 5.98 (t, J = 6.7 Hz,
1H), 4.23 (d, J = 1.3 Hz, 2H), 3.77 (t, J = 7.5 Hz, 2H), 3.14 (t, J = 7.7
Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.50 (dt, J = 7.7, 7.2 Hz, 2H), 1.69
(s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.08 (s, 6H), 0.02 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 150.6, 136.9, 136.2,
132.6, 130.1, 123.7, 122.5, 118.3, 116.1, 115.8, 108.2, 83.8, 71.6, 63.3,
36.4, 28.5, 28.2, 26.1, 26.0, 25.7, 18.53, 18.51, −5.1∼. Some 13C peaks
were identified in 2D HSQC spectrum. IR (ATR): v (cm−1) = 1729,
1458, 1360, 1323, 1253. HRMS (ESI) m/z: [M + Na]+ calcd for
C32H54INO4Si2Na, 722.2534; found, 722.2532.
Dimethyl 2-((2-Bromocyclohex-1-en-1-yl)methyl)-2-((1-((4-
bromophenyl)sulfonyl)-3-methyl-1H-indol-2-yl)methyl)malonate
(1q, Scheme S4, Reaction 9). To a stirred solution of NaH (60%
mineral oil dispersion, 355 mg, 8.87 mmol, 1.9 equiv) in 30 mL of dry
THF at 0 °C was added dimethyl malonate (1.23 g, 9.34 mmol, 2.0
equiv) under an argon atmosphere, and the mixture was stirred at
room temperature for 15 min. The mixture was then cooled to 0 °C,
and S24 (2.07 g, 4.67 mmol, 1.0 equiv) dissolved in THF (20 mL)
was added by a syringe. The resulting mixture was stirred at rt for 16 h
until completion of the reaction (TLC). H2O was added, and the
solvent was evaporated. The mixture was extracted with ethyl acetate.
The combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The resulting residue was filtered
through a pad of silica gel (eluted with petroleum ether/ethyl acetate
10:1) to afford S25 as a white foam (2.69 g, 79% crude yield), which
was directly used in the next step without further purification. To a
stirred solution of NaH (60% mineral oil dispersion, 346 mg, 8.65
mmol, 1.75 equiv) in 47 mL of dry THF at 0 °C was added diester
S25 (1.23 g, 9.34 mmol, 1.0 equiv) under an argon atmosphere, and
the mixture was stirred at room temperature for 30 min. The mixture
was then cooled to 0 °C, and the bromide was added by a syringe.
The resulting mixture was stirred at rt for 20 min until completion of
the reaction (TLC). H2O was added, and the solvent was evaporated.
1
a yellow oil (3.54 g, 86%). H NMR (400 MHz, CDCl3): δ (ppm)
8.10 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.16−7.28 (m,
2H), 4.08 (t, J = 6.7 Hz, 2H), 3.78 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 7.9
Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.9 Hz, 2H), 1.68 (s,
9H), 1.56−1.61 (m, 2H), 1.30−1.41 (m, 2H), 0.88−0.94 (t, J = 7.2
Hz, 3H), 0.87 (s, 9H), 0.01 (s, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 172.9, 150.5, 136.3, 136.1, 130.0, 123.8, 122.6,
118.4, 116.3, 115.8, 83.9, 64.5, 63.2,∼34.9, 30.8, 28.3, 28.1, 26.1, 22.6,
19.3, 18.5, 13.8, −5.2. IR (ATR): v (cm−1) = 1728, 1607. HRMS
(ESI) m/z: [M + Na]+ calcd for C28H45NO5SiNa, 526.2965; found,
526.2974.
tert-Butyl (Z)-3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-(5-
ethoxy-4-iodo-5-oxopent-3-en-1-yl)-1H-indole-1-carboxylate (S22,
Scheme S4, Reaction 8). To a solution of ester S20 (3.85 g, 7.60
mmol, 1.0 equiv) in dry DCM (75 mL) was added DIBAL-H (11.4
mL, 11.4 mmol, 1 M in hexane, 1.5 equiv) dropwise under an argon
atmosphere at −78 °C (over 20 min). The mixture was stirred at −78
°C for 2 h until completion of the reaction (TLC). MeOH (3 mL)
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J. Org. Chem. 2021, 86, 5727−5743

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Article
The mixture was extracted with DCM, and the combined organic
extracts were washed with brine, dried over Na2SO4, and concentrated
in vacuo. The crude product was purified by flash column
chromatography on silica gel (eluted with petroleum ether/ethyl
acetate 10:1 to 5:1) to afford 1q as a white solid (2.65 g, 85%). TLC:
Rf = 0.66 (petroleum ether/ethyl acetate = 10:1). Mp: 130−131 °C.
1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (d, J = 8.2 Hz, 1H), 7.53
(d, J = 7.5 Hz, 2H), 7.40 (dd, J = 7.5, 7.5 Hz, 1H), 7.17−7.34 (m,
5H), 3.92 (s, 2H), 3.71 (s, 6H), 3.03 (s, 2H), 2.51 (t, J = 6.0 Hz, 2H),
2.22 (s, 3H), 2.06 (t, J = 6.0 Hz, 2H), 1.54−1.70 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 171.3, 137.6, 137.3, 133.4, 133.2,
132.3, 132.2, 128.8, 126.5, 125.0, 124.1, 123.46, 123.45, 119∼.0, 116.4,
high-performance liquid chromatography (HPLC)
traces, and additional computational information
(PDF)
Accession Codes
CCDC 2052643−2052644 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
58.3, 52.7, 42.2, 37.6, 31.6, 31.4, 24.8, 22.9, 10.5. IR (ATR): v (cm−1)
= 1731, 1370. HRMS (ESI) m/z: [M + Na]+ calcd for
C28H30BrNO6SNa, 610.0875; found, 610.0859.
AUTHOR INFORMATION
Corresponding Author
■
Lei Jiao − Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University, Beijing
100084, China; orcid.org/0000-0002-8465-1358;
Email: Leijiao@mail.tsinghua.edu.cn
Dearomative Heck Reaction of the Alkenyl Substrate. tert-
Butyl 3′-(2-((tert-Butyldimethylsilyl)oxy)ethylidene)-2-(((tert-
butyldimethylsilyl)oxy)methyl)spiro[cyclopentane-1,2′-indolin]-2-
ene-1′-carboxylate (2p). To an oven-dried 10 mL sealed tube were
added [Pd(C3H5)Cl]2 (1.3 mg, 0.0036 mmol, 0.05 equiv), L9 (5.2
mg, 0.0108 mmol, 0.15 equiv), Cs2CO3 (37.0 mg, 0.108 mmol, 1.5
equiv), and toluene (0.1 mL) in a glovebox. After 20 min, the aryl/
alkenyl halide 1p (50.2 mg, 0.0717 mmol) dissolved in toluene (0.6
mL) was added. The resulting mixture was heated at 100 °C in an oil
bath for 62 h until completion of the reaction (TLC). The reaction
was filtered through a pad of silica gel and concentrated to afford the
crude product, which was further purified by flash column
chromatography on silica gel (eluted with petroleum ether/ethyl
acetate 200:1) to afford 2p as a yellow oil (27.5 mg, 67%, E/Z = 8:1).
TLC: Rf = 0.85 (petroleum ether/ethyl acetate = 5:1). 1H NMR (400
MHz, CDCl3) (ca. a 9:1 mixture of E/Z isomers, both reported): δ
(ppm) 7.78−8.18 (m, 1H), 7.15−7.31 (m, 2H), 6.09−7.06 (m, 1H),
5.99 (t, J = 6.0 Hz, 0.1H), 5.89 (s, 1H), 5.46 (t, J = 5.4 Hz, 0.9H),
4.55−4.67 (m, 1.8H), 4.39 (dd, J = 14.6, 6.0 Hz, 0.1H), 4.28 (dd, J =
14.6, 6.0 Hz, 0.1H), 3.88−4.05 (m, 2H), 2.38−2.67 (m, 3H), 2.10−
2.21 (m, 1H), 1.52 (s, 9H), 0.81−0.93 (m, 18H), 0.06−0.12 (m, 6H),
−0.05 (s, 2.7H), −0.07 (s, 2.7H), −0.08 (s, 0.3H), −0.10 (s, 0.3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 151.7, 146.3, 141.2,
Author
Dong Gao − Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University, Beijing
100084, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00209
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Natural Science Foundation of China
(21822304) is acknowledged for financial support. The
technology platform of CBMS is acknowledged for providing
instrumentation.
129.4, 126.7, 126.4, 124.7, 122.6, 122.5, 115.6, 81.7, 81.4, 61.1, 59.9,
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2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46−7.54 (m, 2H), 7.35−7.42 (m,
2H), 7.20 (t, J = 8.4 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 5.37 (s, 1H),
4.70 (s, 1H), 3.68 (s, 3H), 3.59 (s, 3H), 3.26 (d, J = 14.0 Hz, 1H),
2.80 (d, J = 16.6 Hz, 1H), 2.64 (dd, J = 14.2, 2.1 Hz, 1H), 2.39 (d, J =
16.6 Hz, 1H), 2.23 (dt, J = 17.8, 7.7 Hz, 2H), 1.74−1.96 (m, 2H),
1.51−1.72 (m, 3H), 1.35−1.48 (m, 1H). 13C{1H} NMR (100 MHz,
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130.1, 129.2, 128.1, 127.09, 127.08, 122.8, 121.2, 113.9, 104.3, 78.4,
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53.1, 52.4, 52.1, 37.2, 34.5, 31.1, 25.2, 22.9, 22.8. IR (ATR): v (cm−1)
= 1732. HRMS (ESI) m/z: [M + Na]+ calcd for C28H29NO6SNa,
530.1613; found, 530.1619.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00209.
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