Metal-Free Blue-Light-Mediated Cyclopropanation of Indoles by Aryl(diazo)acetates

Article abstract of DOI:10.1055/s-0037-1610668

Blue-light-mediated cyclopropanation of indoles with aryl(diazo)acetates has been developed. The salient features of this strategy are that it is metal-free, operationally simple and atom-efficient, and that it uses an environmentally friendly energy sour

Full text of DOI:10.1055/s-0037-1610668

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
de
X. Zhang et al.
Paper
Synthesis
Metal-Free Blue-Light-Mediated Cyclopropanation of Indoles by
Aryl(diazo)acetates
Xing Zhang
Cong Du
R2
He Zhang
H
Xiao-Cai Li
N2
only blue light
COOMe
R1
R1
Yun-Long Wang
Jun-Long Niu*
H
N
COOMe
DCM, r.t., 6 h
N
R2
0
0
0
0-
0
0
0
1-8
0
1
2-4
6
7
6
O
O
Mao-Ping Song*
R1, R2 = H, Me, OMe, NO2, COOMe, CN, X
31 examples
up to 98% yield, dr > 20:1
College of Chemistry and Molecular Engineering, Zhengzhou
University, Kexue avenue 100, Zhengzhou, P. R. of China
niujunlong@zzu.edu.cn
• metal-free • eco-friendly energy • operational simplicity • high diastereoselectivity
mpsong@zzu.edu.cn
Received: 12.09.2018
Accepted after revision: 10.10.2018
Published online: 20.11.2018
O
MeO
MeO
N
N
DOI: 10.1055/s-0037-1610668; Art ID: ss-2018-h0615-op
N
N
Abstract Blue-light-mediated cyclopropanation of indoles with
aryl(diazo)acetates has been developed. The salient features of this
strategy are that it is metal-free, operationally simple and atom-effi-
cient, and that it uses an environmentally friendly energy source. In this
protocol, blue light was employed as the sole energy source for the
transformation. A variety of cyclopropane-fused indoline compounds
was obtained in moderate to excellent yields and high diastereoselectiv-
ities under mild conditions.
COOMe
COOMe
lundurine A
lundurine B
MeO
N
N
COOMe
Key words metal-free, blue light, cyclopropanation, indoles, diazo
compounds, aryl(diazo)acetate
lundurine C
Figure 1 Selected indole-containing alkaloids
Cyclopropane-fused indolines represent an important
and versatile structure commonly existing in many medici-
nal agents1 and natural products.2 These structural units
have substantial utilities in the synthesis of indole-contain-
ing polycyclic compounds and indole alkaloids, such as lun-
durine A–C (Figure 1).3 Typically, strategies for the con-
struction of indolines containing a cyclopropane moiety
strongly rely on transition-metal-catalyzed [2+1] cycload-
ditions of indoles with diazo compounds1e,4 or tosylhydra-
zones.5 Cyclopropanation of indoles with metal carbenes to
construct these structural units have been reported recent-
ly by Zhou,6 Pirovano,7 and other groups4,5,8 (Scheme 1).
Noteworthy is that transition-metal catalysts were essen-
tial in the above strategies, while metal-free approaches
were reported only rarely; this makes the available proto-
cols relatively unattractive from a sustainable perspective.
In sharp contrast, photochemistry has been widely de-
veloped in green organic synthesis due to its characteristics
of operational simplicity, lower energy consumption, and
higher atom economy.9 Photocatalysts, commonly derived
from transition-metal complexes or organic dyes,10 are gen-
erally unavoidable as radical initiators in these strategies. In
comparison, photocatalyst-free strategies,9d,11 only mediat-
a) Transition-metal-catalyzed cyclopropanation of indoles
Zhou's work
O
O
O
O
Ph
[Cu] or [Fe]
Ph
N2
N
H
N
Boc
Boc
Pirovano's work
R
COOEt
R
[Cu]
COOEt
N
N2
N
COOEt
COOEt
b) Blue-light-mediated cyclopropanation of indoles (this work)
Ph
COOMe
H
N2
blue LEDs
N
H
Ph
COOMe
N
O
O
Scheme 1 Different routes for cyclopropanation of indole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
X. Zhang et al.
Paper
Synthesis
ed by visible light, are more interesting from a synthetic
perspective; notable achievements have been accomplished
for C–H and N–H insertion,11a intramolecular C(sp3)–H im-
ination,11b and cross-coupling of diazoacetates11c under visi-
ble-light irradiation without the use of other additives.
Such protocols are generally operationally simpler and pro-
ceed under milder conditions, in which visible light is har-
nessed as the only energy source.
Despite the indisputable advances, the photocatalyst-
free cyclopropanation of indoles mediated by visible light
has been rarely reported. Inspired by the aforementioned
progress, we attempted to search for an efficient and sus-
tainable protocol to construct this structure in the absence
of metal salt and other additives. Hence, a blue-light-medi-
ated strategy for a facile access to cyclopropanated indole is
reported. Salient features of this approach include (a) syn-
thetic simplicity, atom efficiency, and an eco-friendly ener-
gy source, (b) moderate to excellent yields and high diaste-
reoselectivities, and (c) broad functional group scope of
substituted indoles and aryl(diazo)acetates.
Our investigation commenced with the analysis of the
UV-vis absorbance spectrum of aryl(diazo)acetate 2a,
which exhibits absorbance in the visible region (Figure 2).
According to the literature, the emission spectrum of blue
LEDs is from 420 nm to 510 nm, indicating that 2a might be
activated under the irradiation of blue LEDs. With this in
mind, we screened various protecting groups (pivaloyl, py-
rimidin-2-yl, tosyl, Boc) and pivaloyl emerged as the opti-
mal group, giving 3aa in 92% yield and excellent diastereo-
selectivities (dr >20:1) (Scheme 2). The structure of 3aa
was confirmed by single-crystal X-ray crystallography.12
Then various solvents were screened for the reaction (Table
1). DCM was found to perform best (entry 1). The solvents
PhCF3, CHCl3, DCE, and MeCN gave slightly inferior results
(entries 2–5) and THF, dioxane, DMF, HFIP, and DMSO in-
Table 1 Optimization of Reaction Conditionsa
H
N2
blue LEDs
COOMe
H
N
COOMe
solvent, r.t.
N
O
O
2a
1a
3aa
Entry
Solvent
Time (h)
Yield (%)b
1
2
DCM
PhCF3
CHCl3
DCE
12
12
12
12
12
12
12
12
12
12
10
8
92
85
86
69
72
7
Figure 2 UV-vis absorbance spectrum of 2a in DCM (0.2 mol/mL)
3
4
Ph
COOMe
H
5
MeCN
THF
N2
blue LEDs
DCM, r.t.
6
H
Ph
COOMe
N
N
7
1,4-dioxane
DMF
N.R.
N.R.
N.R.
N.R.
92
92
92
76
54
0
R
R
2a
1
3
8
9
HFIP
Ph
COOMe
H
H
Ph
H
Ph
COOMe
10
11
12
13
14
15c
16d
DMSO
DCM
COOMe
H
H
H
N
N
N
DCM
Ts
N
O
N
DCM
6
DCM
4
3aa, 92%
3aa-2, 66%
3aa-1, 66%
DCM
6
Ph
H
H
Ph
DCM
6
COOMe
COOMe
H
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), blue light (9 W), sol-
vent (1 mL), air atmosphere, r.t., 12 h.
H
N
N
H
Boc
3aa-3, 65%, dr = 1:1
b Isolated yield (unless mentioned otherwise, dr >20:1); N.R. = No Reaction.
c Green LEDs.
3aa-4, 0%
d In the dark.
Scheme 2 Investigation of protecting groups R (dr >20:1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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X. Zhang et al.
Paper
Synthesis
hibited the cyclopropanation of indole (entries 6–10). Sub-
sequently, reaction time was investigated. The best results
were obtained after 6 hours, with longer reaction times not
improving the results (entries 11–14). However, when we
replaced the light source with green LEDs, the yield
dropped significantly (54%, entry 15); without light, in the
dark, no 3aa was detected (entry 16). This indicates that
blue light is essential in this strategy. Changing the relative
amounts of substrates and solvent did not increase the cy-
clopropanation yield further (see the Supporting Informa-
tion).
Having optimized the reaction conditions, we explored
the scope of the reaction of 1a with various aryl(diazo)ace-
tates 2 (Scheme 3). A broad variety of substituted aryl(di-
azo)acetates were compatible with this blue-light-mediated
method for the cyclopropanation of indoles, regardless of
the electronic properties of the substrates. Halo- and nitro-
substituted substrates were well tolerated, giving the corre-
sponding products in yields of 63–95% (3ad–ah, 3ak–am),
providing the possibility for further applications. Substrates
with electron-donating groups, such as methyl and me-
thoxy substituents at the ortho position of the phenyl ring,
provided the corresponding cyclopropanation products 3ab
and 3ac in 90 and 92% yield with excellent diastereoselec-
tivities under blue light irradiation. Phenyl(diazo)acetates
with methoxy and methyl groups the at the para position
gave the corresponding products 3ai and 3aj in 96 and 95%
yield, respectively. Additionally, disubstituted substrate 2n
afforded the cyclopropane product 3an in excellent yield
(98%). Moreover, naphthalene (2o) and thiophene sub-
strates (2p) were also suitable for this reaction, affording
the cycloaddition products in 88 and 86% yield, respective-
ly. When we replaced the electron-withdrawing carboxy
group (COOMe) of aryl(diazo)acetate with acyl (COMe), the
target product was also obtained in 73% yield (3aq). On the
other hand, 2-diazo-1,2-diphenylethanone, 2-diazo-2-phe-
Ar
H
H
N2
blue LEDs
DCM, r.t., 6 h
COOMe
N
Ar
COOMe
N
O
O
1a
3
2
H
H
H
H
H
H
Cl
Br
Me
COOMe
OMe
F
COOMe
COOMe
COOMe
COOMe
COOMe
H
H
H
H
H
H
N
O
N
N
N
N
N
O
O
O
O
O
3af, 72%
3ae, 70%
3ac, 92%
3ad, 85%
Me
3aa, 92%
3ab, 90%
OMe
Cl
F
Cl
H
H
H
H
H
H
NO2
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
H
H
N
H
N
H
H
H
N
N
N
N
O
O
O
O
O
O
3al, R = Cl, 95%
3am, R = Br, 94%
3ah, 73%
3ag, 63%
3ai, 96%
3aj, 95%
3ak, 84%
OMe
S
H
H
H
H
OMe
COOMe
COOMe
H
COOMe
COMe
H
H
H
N
O
N
N
N
O
O
O
3aq, 73%
3ap, 86%
3ao, 88%
3an, 98%
Scheme 3 Substrate scope of aryl(diazo)acetates (dr >20:1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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X. Zhang et al.
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Synthesis
nylacetonitrile and diethyl 2-diazomalonate were not com-
patible with this reaction system and did not deliver the
corresponding cyclopropanation products.
N
O
H
H
H
Ph
Ph
Ph
COOMe
Next, we investigated the scope of indole substrates. A
variety of indoles proceed smoothly under the optimized
conditions to afford the corresponding cyclopropane prod-
ucts in moderate to excellent yields and high diastereose-
lectivities. The results are shown in Scheme 4. Substrates
bearing the electron-donating groups methyl and methoxy
(1d and 1e) were compatible with this reaction procedure,
giving the corresponding cyclopropane products 3da and
3ea in 69 and 76% isolated yield, respectively. Nitro- (1i),
cyano- (1j and 1m), and methoxycarbonyl-substituted (1k,
1n) indoles were also tolerated in the cycloaddition reac-
tion, giving the desired products in good to high yields (76–
86%). For substrates bearing fluoro (1f, 1l, 1o), chloro (1b,
1g), and bromo (1c, 1h) groups, the cyclopropanation reac-
tion was also found to proceed smoothly in 78–95% yield
(3ba, 3ca, 3fa–ha, 3la, 3oa).
1p
blue LEDs
COOMe
MeOOC
+
N
N
+
H
H
H
N2
DCM, r.t., 6 h
O
O
Ph
COOMe
2a
4aa
4ab
90% (4aa/4ab = 1:1)
H
H
H
Ph
COOMe
Ph
COOMe
Ph
N2
blue LEDs
MeOOC
+
N
N
H
H
H
Ph
COOMe
DCM, r.t., 6 h
O
O
4aa
2a
4ab 50%
Scheme 5 Cyclopropanation of pyrrole with 2a
Ph
Furthermore, when N-pivaloylpyrrole (1p) was em-
ployed, both monocyclopropane (4aa) and bicyclopropane
(4ab) products were obtained in a 1:1 ratio under the opti-
mized reaction conditions (Scheme 5). The monocyclopro-
pane product were subsequently converted into the bicy-
clopropane product in 50% yield in the presence of aryl(di-
azo)acetate 2a (Scheme 5). Unfortunately, when reactions
with thiophene and furan were attempted, no cyclopro-
pane products were detected.
H
N2
blue LEDs
COOMe
N
H
DCM, r.t., 24 h
COOMe
Ph
N
O
O
1a (1 g, 5 mmol)
2a
3aa (1.54 g, 88%)
Scheme 6 Gram-scale experiment
H
N2
blue LEDs
R
COOMe
R
COOMe
N
H
DCM, r.t., 6 h
N
O
O
2a
3a (
)
1
Br
H
Cl
H
H
H
H
H
Cl
F
MeO
Me
COOMe
COOMe
COOMe
CH2OOMe
COOMe
COOMe
H
H
H
H
H
H
N
N
N
N
N
N
O
O
O
O
O
O
3ba, 95%
3ca, 95%
3da, 69%
3ea, 76%
3fa, 82%
3ga, 78%
H
H
H
H
H
H
R
O2N
Br
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
H
H
N
H
H
H
N
H
N
N
N
O
F
N
O
R
F
O
O
O
O
3ha, 80%
3ia, 76%
3ja, R = CN, 76%
3ka, R = COOMe, 81%
3la, 91%
3ma, R = CN, 84%
3na, R = COOMe, 86%
3oa, 93%
Scheme 4 Substrate scope of indoles (dr >20:1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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Ar
H
H
N2
∗
1
N2
N2
COOMe
hv
Ar
COOMe
Ar
COOMe
N
cyclization
Ar
COOMe
O
∗
2
A
2
3
Scheme 7 Plausible mechanism
To further demonstrate the broad application of the cur-
rent protocol, a gram-scale reaction of 1a with 2a was car-
ried out for 24 hours to afford product 3aa in 88% yield with
excellent diastereoselectivity (dr >20:1) (Scheme 6). Subse-
quently, a 3-substituted indole derivative was obtained by
simple base hydrolysis (see Supporting Information for de-
tails).
Finally, on account of the character of the aryl(diazo)ac-
etates 2, a plausible mechanism for the blue-light-induced
cyclopropanation reaction was proposed based on our ex-
periments and the relevant literature (Scheme 7).11a,11c,13
Firstly, excited state 2* is generated via a photoexcitation
process of aryl(diazo)acetate 2; then N2 is released to afford
singlet-state intermediate carbene A. Then the singlet-state
carbene A is trapped by N-pivaloylindole 1 to give the cyclo-
propanation product 3.
In conclusion, we have developed a metal-free strategy
for constructing cyclopropane-fused indolines mediated by
blue light under ambient temperature conditions. This cy-
clopropanation protocol displays operational simplicity,
with blue light utilized as the sole energy source, to provide
a variety of cyclopropane-fused indoline compounds in
moderate to excellent yields and high diastereoselectivities
under mild conditions. A gram-scale experiment was also
conducted to further demonstrate the applicability of this
strategy; the desired product was obtained in high yield
and diastereoselectivity. The notable features of this proto-
col include that it operates under transition-metal- and
photocatalyst-free conditions, while also being atom-eco-
nomical and environmentally friendly.
was stirred under blue LED irradiation. After completion of the reac-
tion, the mixture was purified by preparative TLC on silica gel. Unless
mentioned otherwise, dr >20:1.
Gram-Scale Synthesis of Product 3aa
N-Pivaloylindole (1a; 1 g, 5 mmol), methyl phenyl(diazo)acetate (2a;
1.8 g, 10 mmol) were added to anhyd DCM (25 mL) under ambient air.
Then the mixture was stirred under 9 W blue LED irradiation for 24 h.
After completion of the reaction, the mixture was concentrated under
vacuum and the residue was purified by flash chromatography (PE–
EtOAc, 20:1) to afford 3aa; yield: 1.54 g (88%); white solid.
Methyl 1-Phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclopropa[b]in-
dole-1-carboxylate (3aa)12
Yield: 64.2 mg (92%); white solid; mp 155–156 °C; Rf = 0.59 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.78 (m, 1 H), 7.37 (dd, J = 7.2, 1.5
Hz, 1 H), 7.06–6.99 (m, 3 H), 6.99–6.91 (m, 4 H), 5.20 (d, J = 7.0 Hz, 1
H), 3.83 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 1.56 (s, J = 2.8 Hz, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.0, 173.4, 144.1, 131.8, 129.9,
128.4, 127.9, 127.6, 127.3, 125.0, 123.5, 117.8, 53.0, 51.8, 40.8, 36.7,
28.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H24NO3: 350.1751; found:
350.1754.
Methyl 6-Chloro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ba)
Yield: 72.9 mg (95%); white solid; mp 165–166 °C; Rf = 0.55 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.71 (dd, J = 6.9, 2.2 Hz, 1 H), 7.09–7.04
(m, 3 H), 7.02 (dd, 2 H), 6.94–6.86 (m, 2 H), 5.20 (d, J = 7.0 Hz, 1 H),
3.93 (d, J = 7.0 Hz, 1 H), 3.71 (s, 3 H), 1.56 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 145.2, 131.4, 130.7,
129.8, 129.2, 127.9, 127.6, 127.4, 123.4, 116.0, 53.1, 53.1, 51.8, 51.7,
40.9, 35.5, 35.5, 32.3, 28.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H23ClNO3: 384.1361; found:
384.1362.
Unless mentioned otherwise, all materials and solvents were com-
mercially obtained and used without further purification and all the
experiments were performed under ambient air. 1H NMR, 13C NMR,
and 19F NMR spectra were respectively recorded at 400 MHz, 101
MHz, and 376 MHz on a Bruker DPX instrument using Me4Si as an in-
ternal standard. HRMS for new compounds was carried out on a Wa-
ters Q-Tof Micro MS/MS System ESI spectrometer. Melting points
were measured on a WC-1 instrument and are uncorrected. All the
indole14 and aryl(diazo)acetate15 substrates were prepared according
to literature procedures.
Methyl 6-Bromo-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ca)
Purified by preparative TLC (silica gel, PE–EtOAc, 5:1; Rf = 0.55); yield:
81.4 mg (95%); white solid; mp 162–163 °C.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 1 H), 7.11–6.99 (m, 6
H), 6.84 (t, J = 8.1 Hz, 1 H), 5.19 (d, J = 7.0 Hz, 1 H), 3.89 (d, J = 7.0 Hz, 1
H), 3.71 (s, 3 H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 144.9, 131.5, 129.8,
129.4, 129.4, 127.9, 127.5, 126.4, 119.5, 116.5, 53.2, 53.1, 51.5, 51.5,
40.9, 37.4, 37.3, 32.2, 28.1.
Cyclopropanation of Indoles; General Procedure
N-Substituted indole 1 (0.2 mmol), aryl(diazo)acetate 2 (0.4 mmol),
and anhyd DCM (1 mL) were added to a 15 mL oven-dried Schlenk
tube equipped with a stir bar under ambient air. Then the reaction
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X. Zhang et al.
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HRMS (ESI): m/z [M + H]+ calcd for C22H23BrNO3: 428.0856; found:
HRMS (ESI): m/z [M + H]+ calcd for C22H23ClNO3: 384.1361; found:
428.0859.
384.1362.
Methyl 5-Methyl-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
Methyl 5-Bromo-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3da)
propa[b]indole-1-carboxylate (3ha)
Yield: 50.2 mg (69%); white solid; mp 170–171 °C; Rf = 0.47 (PE–EtOAc,
Yield: 68.5 mg (80%); white solid; mp 170–171 °C; Rf = 0.33 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 1 H), 7.16 (s, 1 H),
7.07–7.00 (m, 3 H), 6.97–6.93 (m, 2 H), 6.79 (d, J = 7.2 Hz, 1 H), 5.17
(d, J = 7.0 Hz, 1 H), 3.77 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 2.26 (s, 3 H),
1.54 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 173.4, 141.9, 133.2, 131.7,
130.0, 128.5, 128.4, 127.6, 127.2, 125.5, 125.4, 117.5, 53.0, 52.9, 52.0,
52.0, 40.7, 36.7, 36.6, 32.5, 28.2, 20.9, 20.9.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 1 H), 7.09–7.01 (m, 6
H), 6.84 (t, J = 8.1 Hz, 1 H), 5.19 (d, J = 7.0 Hz, 1 H), 3.89 (d, J = 7.0 Hz, 1
H), 3.71 (s, 3 H), 1.56 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.9, 173.1, 143.2, 131.6, 130.8,
130.6, 129.5, 127.9, 127.8, 127.5, 119.1, 115.9, 53.1, 53.1, 52.0, 51.9,
40.8, 36.1, 36.0, 32.2, 28.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H23BrNO3: 428.0856; found:
428.0860.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO3: 364.1907; found:
364.1909.
Methyl 5-Nitro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
Methyl 5-Methoxy-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocy-
propa[b]indole-1-carboxylate (3ia)
clopropa[b]indole-1-carboxylate (3ea)
Yield: 60.0 mg (76%); white solid; mp 225–226 °C; Rf = 0.31 (PE–EtOAc,
Yield: 57.7 mg (76%); white solid; mp 169–170 °C; Rf = 0.33 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 2.0 Hz, 1 H), 7.95–7.85 (m, 2
H), 7.11–7.02 (m, 3 H), 6.99–6.92 (m, 2 H), 5.28 (d, J = 6.9 Hz, 1 H),
3.90 (d, J = 6.9 Hz, 1 H), 3.72 (s, 3 H), 1.57 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.9, 172.8, 144.0, 133.3, 132.2,
131.0, 129.4, 129.1, 128.3, 128.0, 124.9, 123.7, 121.6, 118.0, 53.0, 51.9,
40.8, 36.6, 31.7, 28.2.
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 9.0 Hz, 1 H), 7.08–7.03 (m, 3
H), 6.99 (m, 2 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.52 (dd, J = 9.0, 2.7 Hz, 1 H),
5.18 (d, J = 6.9 Hz, 1 H), 3.78 (d, J = 6.9 Hz, 1 H), 3.74 (s, 3 H), 3.68 (s, 3
H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.4, 173.3, 156.2, 138.0, 131.6,
129.9, 129.7, 127.7, 127.3, 118.5, 112.7, 111.1, 55.7, 55.7, 53.0, 52.9,
52.1, 52.1, 40.6, 36.6, 36.6, 32.8, 28.3.
HRMS (ESI): m/z [M + H]+ calcd for C22H23N2O5: 395.1602; found:
395.1604.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO4: 380.1857; found:
380.1860.
Methyl 5-Cyano-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ja)
Methyl 5-Fluoro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3fa)
Yield: 56.9 mg (76%); white solid; mp 225–226 °C; Rf = 0.26 (PE–EtOAc,
5:1).
Yield: 60.3 mg (82%); white solid; mp 152–153 °C; Rf = 0.45 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.6 Hz, 1 H), 7.62 (d, J = 1.6
Hz, 1 H), 7.28 (dd, J = 8.3, 1.4 Hz, 1 H), 7.10–7.03 (m, 3 H), 6.93 (m, 2
H), 5.24 (d, J = 7.0 Hz, 1 H), 3.85 (d, J = 7.0 Hz, 1 H), 3.71 (s, 3 H), 1.56
(s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.4, 172.8, 147.4, 132.6, 131.6,
129.7, 129.1, 128.6, 128.1, 127.7, 119.0, 118.0, 106.5, 53.3, 53.2, 52.0,
51.9, 41.1, 35.8, 35.7, 31.9, 28.1.
1H NMR (400 MHz, CDCl3): δ = 7.78 (dd, J = 9.1, 4.9 Hz, 1 H), 7.09–7.04
(m, 4 H), 7.00–6.94 (m, 2 H), 6.71–6.64 (m, 1 H), 5.21 (d, J = 6.9 Hz, 1
H), 3.80 (d, J = 6.9 Hz, 1 H), 3.69 (s, 3 H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 173.1, 160.3(JC–F = 242.17 Hz),
157.8, 140.2 (JC–F = 1.46 Hz), 131.6, 130.1 ( JC–F = 8.80 Hz), 129.6, 127.8,
118.8 (JC–F = 8.06 Hz), 114.3 (JC–F = 22.76 Hz), 112.1 (JC–F = 24.12 Hz),
53.1, 53.0, 52.2, 52.1, 40.7, 36.2, 32.4, 28.2.
HRMS (ESI): m/z [M + H]+ calcd for C23H23N2O3: 375.1707; found:
375.1705.
19F NMR (376 MHz, CDCl3): δ = –119.14.
HRMS (ESI): m/z [M + H]+ calcd for C22H23FNO3: 368.1657; found:
Dimethyl 1-Phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclopro-
pa[b]indole-1,5-dicarboxylate (3ka)
368.1660.
Yield: 66.0 mg (81%); white solid; mp 147–148 °C; Rf = 0.28 (PE–EtOAc,
5:1).
Methyl 5-Chloro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 1.8 Hz, 1 H), 7.85 (d, J = 8.7
Hz, 1 H), 7.69 (dd, J = 8.7, 1.8 Hz, 1 H), 7.06–7.01 (dd, J = 6.5, 2.7 Hz, 3
H), 6.98–6.93 (m, 2 H), 5.23 (d, J = 7.0 Hz, 1 H), 3.88 (s, 3 H), 3.86 (d, J =
7.0 Hz, 1 H), 3.70 (s, 3 H), 1.57 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.3, 173.1, 166.6, 147.7, 131.7,
130.1, 129.5, 128.7, 127.9, 127.5, 126.4, 125.2, 117.0, 53.2, 53.1, 52.2,
52.2, 52.0, 52.0, 41.0, 36.2, 36.1, 32.1, 28.1.
propa[b]indole-1-carboxylate (3ga)
Yield: 59.9 mg (78%); white solid; mp 184–185 °C; Rf = 0.33 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.8 Hz, 1 H), 7.33 (d, J = 2.2
Hz, 1 H), 7.09–7.04 (m, 3 H), 6.98–6.92 (m, 3 H), 5.20 (d, J = 7.0 Hz, 1
H), 3.79 (d, J = 6.9 Hz, 1 H), 3.69 (s, 3 H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.9, 173.1, 142.7, 131.6, 130.2,
129.6, 128.4, 127.9, 127.5, 124.9, 118.7, 53.1, 53.1, 52.0, 52.0, 40.8,
36.1, 36.1, 32.3, 28.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO5: 408.1806; found:
408.1809.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
X. Zhang et al.
Paper
Synthesis
Methyl 4-Fluoro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
HRMS (ESI): m/z [M + H]+ calcd for C22H23FNO3: 368.1657; found:
propa[b]indole-1-carboxylate (3la)
368.1660.
Yield: 66.9 mg (91%); white solid; mp 155–156 °C; Rf = 0.42 (PE–EtOAc,
5:1).
Methyl 2-Pivaloyl-1-(o-tolyl)-1,1a,2,6b-tetrahydrocyclopro-
pa[b]indole-1-carboxylate (3ab)
1H NMR (400 MHz, CDCl3): δ = 7.59 (dd, J = 11.1, 2.4 Hz, 1 H), 7.29–
7.23 (m, 1 H), 7.09–7.03 (m, 3 H), 6.96–6.93 (m,2 H), 6.72–6.65 (m, 1
H), 5.22 (d, J = 7.0 Hz, 1 H), 3.78 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 1.55
(s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.2, 163.6 (JC–F = 242.17 Hz),
161.2, 145.3, 131.7, 129.7, 127.8, 127.5, 124.1 (JC–F = 2.28 Hz), 110.5
(JC–F = 23.5 Hz), 106.1 (JC–F = 29.4 Hz), 53.0, 53.0, 52.6, 52.6, 40.8, 36.0,
36.0, 32.2, 28.1.
Yield: 65.4 mg (90%); white solid; mp 300–301 °C; Rf = 0.56 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 7.2
Hz, 1 H), 7.03–6.93 (m, 3 H), 6.90 (d, J = 7.04 Hz, 1 H), 6.85 (dd, J =
13.2, 6.8 Hz, 2 H), 5.15 (d, J = 7.0 Hz, 1 H), 3.91 (d, J = 7.0 Hz, 1 H), 3.70
(s, 3 H), 2.20 (s, 3 H), 1.58 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 173.4, 141.9, 133.2, 131.7,
130.0, 128.5, 128.4, 127.6, 127.2, 125.5, 125.4, 117.5, 53.0, 52.9, 52.0,
52.0, 40.7, 36.7, 36.6, 32.5, 28.2, 20.9, 20.9.
19F NMR (376 MHz, CDCl3): δ = –112.56.
HRMS (ESI): m/z [M + H]+ calcd for C22H23FNO3: 368.1657; found:
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO3: 364.1907; found:
368.1658.
364.1910.
Methyl 4-Cyano-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ma)
Methyl 1-(2-Methoxyphenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocy-
clopropa[b]indole-1-carboxylate (3ac)
Yield: 62.9 mg (84%); white solid; mp 164–165 °C; Rf = 0.20 (PE–EtOAc,
Yield: 69.8 mg (92%); white solid; mp 163–164 °C; Rf = 0.44 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 1.4 Hz, 1 H), 7.44 (d, J = 7.8
Hz, 1 H), 7.24 (dd, J = 7.8, 1.4 Hz, 1 H), 7.10–7.02 (m, 3 H), 6.93 (dd, J =
7.9, 1.6 Hz, 2 H), 5.25 (d, J = 6.9 Hz, 1 H), 3.86 (d, J = 6.8 Hz, 1 H), 3.71
(s, 3 H), 1.54 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.2, 172.8, 144.1, 133.6, 131.5,
129.1, 128.0, 127.8, 127.5, 125.6, 121.0, 118.8, 111.4, 53.3, 53.2, 52.0,
52.0, 40.9, 36.4, 36.3, 32.2, 28.1.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.2 Hz, 1 H), 7.24 (d, J = 8.3
Hz, 1 H), 7.04–6.98 (m, 1 H), 6.97–6.91 (m, 2 H), 6.84 (t, J = 7.0 Hz, 1
H), 6.64 (t, J = 7.1 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 5.12 (d, J = 6.9 Hz, 1
H), 3.87 (d, J = 6.8 Hz, 1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 1.56 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.00, 173.65, 158.39, 144.19,
130.78, 129.04, 128.40, 127.60, 124.69, 122.86, 119.56, 118.80,
117.26, 109.89, 55.06, 55.02, 52.83, 52.78, 51.70, 51.67, 40.82, 37.16,
28.21.
HRMS (ESI): m/z [M + H]+ calcd for C23H23N2O3: 375.4397; found:
375.4396.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO4: 380.1857; found:
380.1858.
Dimethyl 1-Phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclopro-
pa[b]indole-1,4-dicarboxylate (3na)
Methyl 1-(2-Fluorophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ad)
Yield: 70.1 mg (86%); brown oil; Rf = 0.31 (PE–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 1.4 Hz, 1 H), 7.69 (dd, J = 7.8,
1.5 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.06–6.99 (m, 3 H), 6.98–6.92 (m,
2 H), 5.25 (d, J = 6.9 Hz, 1 H), 3.85 (d, J = 6.9 Hz, 1 H), 3.78 (s, 3 H), 3.70
(s, 3 H), 1.57 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.3, 173.1, 166.6, 147.7, 131.7,
130.1, 129.5, 128.7, 127.9, 127.5, 126.4, 125.2, 117.0, 53.2, 53.1, 52.2,
52.2, 52.0, 52.0, 41.0, 36.2, 36.1, 32.1, 28.1.
Yield: 62.5 mg (85%); white solid; mp 165–166 °C; Rf = 0.55 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.2 Hz, 1 H), 7.37 (d, J = 7.4
Hz, 1 H), 7.07–6.93 (m, 3 H), 6.90 (td, J = 7.4, 1.0 Hz, 1 H), 6.82 (dd, J =
7.5, 6.6 Hz, 1 H), 6.77–6.69 (m, 1 H), 5.23 (d, J = 6.9 Hz, 1 H), 3.90 (d, J
= 6.9 Hz, 1 H), 3.71 (s, 3 H), 1.56 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.2, 172.8, 144.1 (JC–F = 242.42 Hz),
133.6, 131.5 (JC–F = 25.31 Hz), 129.1, 128.0 (JC–F = 27.68 Hz), 127.8,
127.5, 125.6, 121.0 (JC–F = 4.75 Hz), 118.8, 111.4, 53.3, 53.2, 52.0, 52.0,
40.9, 36.4, 36.3, 32.2, 28.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO5: 408.1806; found:
408.1810.
Methyl 3-Fluoro-1-phenyl-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3oa)
19F NMR (376 MHz, CDCl3): δ = –113.28.
HRMS (ESI): m/z [M + H]+ calcd for C22H23FNO3: 368.1657; found:
Yield: 68.3 mg mg (93%); white solid; mp 157–158 °C; Rf = 0.34 (PE–
EtOAc, 5:1).
368.1660.
1H NMR (400 MHz, CDCl3): δ = 7.17 (dd, J = 7.5, 0.7 Hz, 1 H), 7.06–7.01
(m, 3 H), 6.99–6.96 (m, 2 H), 6.95–6.88 (m, 1 H), 6.69 (ddd, J = 10.8,
8.3, 0.9 Hz, 1 H), 5.06 (d, J = 6.5 Hz, 1 H), 3.81 (d, J = 6.5 Hz, 1 H), 3.68
(s, 3 H), 1.58 (s, 9 H).
Methyl 1-(2-Chlorophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ae)
Yield: 53.7 mg (70%); white solid; mp 155–156 °C; Rf = 0.59 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.2 Hz, 1 H), 7.43 (d, J = 7.4
Hz, 1 H), 7.09–7.05 (m, 2 H), 7.02–6.94 (m, 3 H), 6.86 (t, J = 7.4 Hz, 1
H), 5.16 (d, J = 6.9 Hz, 1 H), 4.01 (d, J = 6.9 Hz, 1 H), 3.72 (s, 3 H), 1.57
(s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 144.9, 131.5 (JC–F
242.42 Hz), 129.8 (JC–F = 26.53 Hz), 129.4, 129.4, 127.9, 127.5 (JC–F
=
=
22.98 Hz), 126.4, 119.5 (JC–F = 2.39 Hz), 116.5, 53.2, 53.1, 51.5, 51.5,
40.9, 37.4, 37.3, 32.2, 28.1.
19F NMR (565 MHz, CDCl3): δ = –109.89.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
X. Zhang et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 145.2, 131.4, 130.7,
129.8, 129.2, 127.9, 127.6, 127.4, 123.4, 116.0, 53.1, 53.1, 51.8, 51.7,
40.9, 35.5, 35.5, 32.3, 28.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO4: 380.1857; found:
380.1961.
HRMS (ESI): m/z [M + H]+ calcd for C22H23ClNO3: 384.1361; found:
384.1364.
Methyl 2-Pivaloyl-1-(p-tolyl)-1,1a,2,6b-tetrahydrocyclopro-
pa[b]indole-1-carboxylate (3aj)
Yield: 69.1 mg (95%); white solid; mp 151–152 °C; Rf = 0.75 (PE–EtOAc,
5:1).
Methyl 1-(2-Bromophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.5 Hz, 1 H), 7.37 (dd, J = 7.3,
1.4 Hz, 1 H), 7.02–6.92 (m, 2 H), 6.86–6.80 (m, 4 H), 5.17 (d, J = 7.0 Hz,
1 H), 3.80 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 2.15 (s, 3 H), 1.55 (s, 9 H).
propa[b]indole-1-carboxylate (3af)
Yield: 61.7 mg (72%); white solid; mp 138–139 °C; Rf = 0.41 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.3 Hz, 1 H), 7.50–7.46 (m, 1
H), 7.28–7.23 (m, 1 H), 7.07 (dd, J = 7.7, 1.8 Hz, 1 H), 7.04–6.93 (m, 2
H), 6.93–6.82 (m, 2 H), 5.16 (d, J = 6.9 Hz, 1 H), 4.05 (d, J = 6.9 Hz, 1 H),
3.71 (s, 3 H), 1.57 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 144.9, 131.5, 129.8,
129.4, 129.4, 127.9, 127.5, 126.4, 119.5, 116.5, 53.2, 53.1, 51.5, 51.5,
40.9, 37.4, 37.3, 32.2, 28.1.
13C NMR (101 MHz, CDCl3): δ = 177.0, 173.6, 144.2, 136.9, 131.5,
128.5, 127.9, 126.8, 125.0, 123.5, 117.8, 53.0, 51.9, 40.8, 36.7, 32.0,
28.2, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO3: 364.1907; found:
364.1910.
Methyl 1-(4-Fluorophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ak)
HRMS (ESI): m/z [M + H]+ calcd for C22H23BrNO3: 428.0856; found:
428.0861.
Yield: 61.7 mg (84%); white solid; mp 210–211 °C; Rf = 0.61 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 1.4 Hz, 1 H), 7.44 (d, J = 7.8
Hz, 1 H), 7.24 (dd, J = 7.8, 1.4 Hz, 1 H), 7.10–7.02 (m, 3 H), 6.93 (dd, J =
7.9, 1.6 Hz, 2 H), 5.25 (d, J = 6.9 Hz, 1 H), 3.86 (d, J = 6.8 Hz, 1 H), 3.71
(s, 3 H), 1.54 (s, 9 H).
Methyl 1-(2-Nitrophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ag)
Yield: 49.7 mg (63%); white solid; mp 221–223 °C; Rf = 0.25 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 2.0 Hz, 1 H), 7.95–7.85 (m, 2
H), 7.11–7.02 (m, 3 H), 6.99–6.92 (m, 2 H), 5.28 (d, J = 6.9 Hz, 1 H),
3.90 (d, J = 6.9 Hz, 1 H), 3.72 (s, 3 H), 1.57 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.9, 173.1, 143.2 (JC–F = 242.42 Hz),
131.6, 130.8, 130.6, 129.5 (JC–F = 54.32 Hz), 127.9, 127.8, 127.5 (JC–F
=
3.52 Hz), 119.1 (JC–F = 2.73 Hz), 115.9, 53.1, 53.1, 52.0, 51.9, 40.8, 36.1,
36.0, 32.2, 28.2.
19F NMR (376 MHz, CDCl3): δ = –109.89.
HRMS (ESI): m/z [M + H]+ calcd for C22H23FNO3: 368.1657; found:
368.1660.
13C NMR (101 MHz, CDCl3): δ = 177.1, 173.1, 145.2, 131.4, 130.7,
129.8, 129.2, 127.9, 127.6, 127.4, 123.4, 116.0, 53.1, 53.1, 51.8, 51.7,
40.9, 35.5, 35.5, 32.3, 28.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H23N2O5: 395.1602; found:
395.1605.
Methyl 1-(4-Chlorophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
Methyl 1-(3-Chlorophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3al)
propa[b]indole-1-carboxylate (3ah)
Yield: 72.9 mg (95%); white solid; mp 154–155 °C; Rf = 0.48 (PE–EtOAc,
Yield: 56.1 mg (73%); white solid; mp 124–125 °C; Rf = 0.53 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 1 H), 7.09–7.01 (m, 6
H), 6.84 (t, J = 8.1 Hz, 1 H), 5.19 (d, J = 7.0 Hz, 1 H), 3.89 (d, J = 7.0 Hz, 1
H), 3.71 (s, 3 H), 1.56 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.2, 172.8, 144.1, 133.6, 131.5,
129.1, 128.0, 127.8, 127.5, 125.6, 121.0, 118.8, 111.4, 53.3, 53.2, 52.0,
52.0, 40.9, 36.4, 36.3, 32.2, 28.1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 8.3, 0.9 Hz, 1 H), 7.39 (dd,
J = 7.3, 1.5 Hz, 1 H), 7.05–6.93 (m, 5 H), 6.86–6.82 (m, 1 H), 5.20 (d, J =
7.0 Hz, 1 H), 3.83 (d, J = 7.0 Hz, 1 H), 3.70 (s, 3 H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 173.1, 160.3, 157.8, 140.2,
131.6, 130.1, 129.6, 127.8, 118.8, 114.3, 112.1, 53.1, 53.0, 52.2, 52.1,
40.7, 36.2, 32.4, 28.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H23ClNO3: 384.1356; found:
384.1356.
HRMS (ESI): m/z [M + H]+ calcd for C22H23ClNO3: 384.1361; found:
384.1362.
Methyl 1-(4-Bromophenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
Methyl 1-(4-Methoxyphenyl)-2-pivaloyl-1,1a,2,6b-tetrahydrocy-
propa[b]indole-1-carboxylate (3am)
clopropa[b]indole-1-carboxylate (3ai)
Yield: 80.5 mg (94%); white solid; mp 187–188 °C; Rf = 0.47 (PE–EtOAc,
Yield: 72.9 mg (96%); white solid; mp 197–198 °C; Rf = 0.41 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.1 Hz, 1 H), 7.38–7.33 (m, 1
H), 7.18–7.14 (m, 2 H), 7.05–7.01 (m, 1 H), 6.99–6.96 (m, 1 H), 6.85–
6.80 (m, 2 H), 5.19 (d, J = 7.0 Hz, 1 H), 3.82 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3
H), 1.55 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.5 Hz, 1 H), 7.37 (dd, J = 7.3,
1.4 Hz, 1 H), 7.02–6.92 (m, 2 H), 6.86–6.80 (m, 4 H), 5.17 (d, J = 7.0 Hz,
1 H), 3.80 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 2.15 (s, 3 H), 1.55 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.0, 173.7, 158.5, 144.2, 132.8,
128.4, 128.0, 124.9, 123.5, 121.8, 117.8, 113.2, 54.9, 53.0, 51.9, 40.8,
36.8, 31.7, 28.2.
13C NMR (101 MHz, CDCl3): δ = 176.9, 172.8, 144.0, 133.3, 132.2,
131.0, 129.4, 129.1, 128.3, 128.0, 124.9, 123.7, 121.6, 118.0, 53.0, 51.9,
40.8, 36.6, 31.7, 28.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
X. Zhang et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C22H23BrNO3: 428.0856; found:
HRMS (ESI): m/z [M + H]+ calcd for C22H24NO2: 333.1729; found:
428.0861.
333.1731.
Methyl 1-(2,4-Dimethoxyphenyl)-2-pivaloyl-1,1a,2,6b-tetrahydro-
Methyl 1-Phenyl-2-(pyrimidin-2-yl)-1,1a,2,6b-tetrahydrocyclo-
cyclopropa[b]indole-1-carboxylate (3an)
propa[b]indole-1-carboxylate (3aa-1)
Yield: 80.3 mg (98%); white solid; mp 136–137 °C; Rf = 0.18 (PE–EtOAc,
Yield: 45.3 mg (66%); white solid; mp 210–211 °C; Rf = 0.36 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 1 H), 7.38–7.34 (m, 1
H), 6.60–6.54 (m, 2 H), 6.60–6.54 (m, 2 H), 6.39 (d, J = 1.5 Hz, 1 H),
5.18 (d, J = 7.0 Hz, 1 H), 3.80 (d, J = 7.0 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3
H), 3.63 (s, 3 H), 1.55 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 8.55 (d, J = 4.7 Hz, 2 H), 7.97 (d, J = 8.2
Hz, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.06–7.00 (m, 1 H), 6.99–6.94 (m, 1
H), 6.90 (t, J = 7.4 Hz, 3 H), 6.86–6.79 (m, 3 H), 5.40 (d, J = 6.8 Hz, 1 H),
3.85 (d, J = 6.8 Hz, 1 H), 3.69 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.93, 173.57, 148.01, 147.98,
144.28, 128.48, 128.10, 124.79, 124.36, 123.47, 122.10, 117.93,
115.18, 110.33.
13C NMR (101 MHz, CDCl3): δ = 174.1, 159.4, 157.7, 142.8, 132.3,
130.6, 129.5, 127.6, 127.4, 127.0, 125.3, 121.7, 115.5, 113.1, 52.7, 51.8,
35.3, 32.0.
HRMS (ESI): m/z [M + H]+ calcd for C24H28NO5: 410.1962; found:
HRMS (ESI): m/z [M + H]+ calcd for C21H18N3O2: 344.1394; found:
410.1963.
344.1396.
Methyl 1-(Naphthalen-1-yl)-2-pivaloyl-1,1a,2,6b-tetrahydrocyclo-
Methyl 1-Phenyl-2-tosyl-1,1a,2,6b-tetrahydrocyclopropa[b]in-
propa[b]indole-1-carboxylate (3ao)
dole-1-carboxylate (3aa-2)
Yield: 78.3 mg (88%); white solid; mp 195–196 °C; Rf = 0.47 (PE–EtOAc,
Yield: 55.4 mg (66%); white solid; mp 210–211 °C; Rf = 0.30 (PE–EtOAc,
5:1).
5:1).
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.6 Hz, 1 H), 7.79 (d, J = 8.3
Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.50–7.44 (m,
1 H), 7.36 (dd, J = 11.0, 4.0 Hz, 1 H), 7.23 (dd, J = 7.1, 1.2 Hz, 1 H), 7.19–
7.14 (m, 1 H), 6.95 (d, J = 7.4 Hz, 1 H), 6.76 (dd, J = 11.5, 4.3 Hz, 1 H),
6.52–6.46 (m, 1 H), 5.28 (d, J = 7.0 Hz, 1 H), 4.17 (d, J = 7.0 Hz, 1 H),
3.63 (s, 3 H), 1.63 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 176.9, 173.8, 144.0, 133.5, 132.7,
128.7, 128.6, 128.4, 127.7, 127.2, 126.6, 125.9, 125.3, 125.3, 124.5,
124.1, 122.8, 117.2, 53.0, 52.0, 40.9, 38.1, 29.6, 28.3.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.3 Hz, 2 H), 7.32–7.28 (m, 1
H), 7.20 (dd, J = 7.7, 5.2 Hz, 3 H), 7.12–7.03 (m, 5 H), 6.97–6.93 (m, 1
H), 6.92–6.89 (m, 1 H), 4.93 (d, J = 6.6 Hz, 1 H), 3.64 (s, 3 H), 3.60 (d, J =
6.6 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.2, 144.4, 141.3, 135.4, 132.4,
129.9, 129.6, 129.5, 127.8, 127.6, 127.3, 126.9, 125.6, 123.6, 114.3,
53.1, 52.9, 35.2, 30.7, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C24H22NO4S: 420.1264; found:
420.1267.
HRMS (ESI): m/z [M + H]+ calcd for C26H26NO3: 400.1907; found:
400.1907.
2-tert-Butyl-1-methyl-1-phenyl-1,6b-dihydrocyclopropa[b]in-
dole-1,2(1aH)-dicarboxylate (3aa-3)
Methyl 2-Pivaloyl-1-(thiophen-2-yl)-1,1a,2,6b-tetrahydrocyclo-
propa[b]indole-1-carboxylate (3ap)
Yield: 47.5 mg (65%); white solid; mp 210–211 °C; Rf = 0.55 (PE–EtOAc,
5:1).
Yield: 61.1 mg (86%); white solid; mp 140–141 °C; Rf = 0.50 (PE–EtOAc,
5:1).
1H NMR (400 MHz, CDCl3) two rotamers (dr = 1:1), δ = 7.4–7.32 (m, 2
Ha + 2 Hb), 7.06–7.01 (m, 3 Ha + 3 Hb), 7.00–6.92 (m, 3 Ha + 3 Hb), 6.91–
6.82 (m, 1 Ha + 1 Hb), 5.00–4.90 (d, J = 6.44 Hz, 1 Ha), 4.89–4.79 (d, J =
6.44 Hz, 1 Hb), 3.76–3.68 (m, 1 Ha + 1 Hb), 3.66 (s, 3 Ha), 3.64 (s, 3 Hb),
1.64 (s, 9 Ha), 1.57 (s, 9 Hb).
13C NMR (101 MHz, CDCl3) two rotamers (dr = 1:1), δ = 173.6, 173.4,
152.9, 151.7, 142.4, 141.3, 132.3, 132.1, 130.3, 129.2, 128.8, 128.5,
128.0, 127.9, 127.6, 127.3, 125.6, 125.1, 122.4, 122.3, 114.6, 114.4,
82.6, 81.8, 52.7, 52.2, 50.7, 50.6 35.5, 34.6, 32.1, 31.8, 28.5, 28.3.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.2 Hz, 1 H), 7.39–7.34 (m, 1
H), 7.10–6.96 (m, 3 H), 6.65 (dd, J = 5.2, 3.6 Hz, 1 H), 6.55 (dd, J = 3.6,
1.2 Hz, 1 H), 5.22 (d, J = 7.0 Hz, 1 H), 3.94 (d, J = 7.0 Hz, 1 H), 3.74 (s, 3
H), 1.53 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.0, 172.7, 144.7, 131.7, 130.8,
128.3, 127.8, 126.0, 125.7, 125.1, 123.7, 117.8, 53.3, 53.2, 40.8, 39.0,
28.1, 27.5.
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO3S: 356.1315; found:
HRMS (ESI): m/z [M + Na]+ calcd for C22H23NO4Na: 388.1519; found:
356.1319.
388.1520.
1-[1-Acetyl-1-phenyl-1,6b-dihydrocyclopropa[b]indol-2(1aH)-yl]-
2,2-dimethylpropan-1-one (3aq)
Methyl 6-Phenyl-2-pivaloyl-2-azabicyclo[3.1.0]hex-3-ene-6-car-
boxylate (4aa)
Yield: 48.6 mg (73%); white solid; mp 155–156 °C; Rf = 0.65 (PE–EtOAc,
Yield: 29.9 mg (45%); white solid; mp 122–123 °C; Rf = 0.50 (PE–EtOAc,
5:1).
10:1).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.78 (m, 1 H), 7.37 (dd, J = 7.2, 1.5
Hz, 1 H), 7.06–6.99 (m, 3 H), 6.99–6.91 (m, 4 H), 5.20 (d, J = 7.0 Hz, 1
H), 3.83 (d, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 1.56 (s, J = 2.8 Hz, 9 H).
1H NMR (400 MHz, CDCl3): δ = 7.25–7.17 (m, 3 H), 7.08–7.04 (m, 2 H),
6.26 (s, 1 H), 5.31 (dd, J = 3.8, 2.9 Hz, 1 H), 4.91 (d, J = 6.7 Hz, 1 H), 3.62
(s, 3 H), 3.24 (dd, J = 6.6, 2.5 Hz, 1 H), 1.10 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.0, 173.4, 144.1, 131.8, 129.9,
128.4, 127.9, 127.6, 127.3, 125.0, 123.5, 117.8, 53.0, 51.8, 40.8, 36.7,
28.2.
13C NMR (101 MHz, CDCl3): δ = 175.5, 173.7, 132.8, 130.9, 130.1,
127.8, 127.3, 109.9, 52.6, 50.3, 39.1, 31.0, 27.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
300.1598.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

J
X. Zhang et al.
Paper
Synthesis
Dimethyl-3,7-Diphenyl-5-pivaloyl-5-azatricyclo[4.1.0.02,4]hep-
tane-3,7-dicarboxylate (4ab)
A.; Ravasio, N.; Zaccheria, F. Org. Biomol. Chem. 2013, 11, 4327.
(d) Liu, K.; Xu, G.; Sun, J. Chem. Sci. 2018, 9, 634. (e) Zhang, B.;
Wee, A. G. Org. Biomol. Chem. 2012, 10, 4597.
Yield: 40.3 mg (45%); white solid; mp 212–213 °C; Rf = 0.43 (PE–EtOAc,
(5) For selective examples of cyclopropanation of indoles with N-
tosylhydrazones, see: Reddy, A. R.; Hao, F.; Wu, K.; Zhou, C. Y.;
Che, C. M. Angew. Chem. Int. Ed. 2016, 55, 1810.
(6) Xu, H.; Li, Y. P.; Cai, Y.; Wang, G. P.; Zhu, S. F.; Zhou, Q. L. J. Am.
Chem. Soc. 2017, 139, 7697.
(7) Pirovano, V.; Brambilla, E.; Tseberlidis, G. Org. Lett. 2018, 20,
405.
(8) Chen, W.; Ji, D.-S.; Luo, Y.-C.; Wang, Z.-Y.; Xu, P.-F. Org. Chem.
Front. 2018, 5, 1768.
5:1).
1H NMR (400 MHz, CDCl3): δ = 7.41–7.27 (m, 9 H), 7.25–7.19 (m, 2 H),
3.57 (s, 3 H), 3.49 (s, 3 H), 3.38 (d, J = 6.5 Hz, 1 H), 3.30 (d, J = 6.4 Hz, 1
H), 2.79 (d, J = 6.6 Hz, 1 H), 2.44 (d, J = 6.4 Hz, 1 H), 1.20 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 177.7, 171.8, 171.7, 132.0, 131.4,
131.3, 130.8, 128.7, 128.6, 128.0, 127.8, 52.9, 52.6, 50.3, 50.2, 39.2,
38.6, 37.3, 34.3, 30.6, 27.9.
HRMS (ESI): m/z [M + H]+ calcd for C27H30NO5: 448.2119; found:
(9) For selective visible-light-induced functionalization, see:
(a) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Nature 2018, 559,
83. (b) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan, D. W.
C. Science 2018, 360, 1010. (c) Gandeepan, P.; Mo, J.;
Ackermann, L. Chem. Commun. 2017, 53, 5906. (d) Hari, D. P.;
Schroll, P.; Konig, B. J. Am. Chem. Soc. 2012, 134, 2958.
(e) Mateos, J.; Cherubini-Celli, A.; Carofiglio, T.; Bonchio, M.;
Marino, N.; Companyo, X.; Dell’Amico, L. Chem. Commun. 2018,
54, 6820. (f) Pagire, S. K.; Hossain, A.; Traub, L.; Kerres, S.; Reiser,
O. Chem. Commun. 2017, 53, 12072. (g) Shen, Z. C.; Yang, P.;
Tang, Y. J. Org. Chem. 2016, 81, 309. (h) Tang, X.; Studer, A.
Angew. Chem. Int. Ed. 2018, 57, 814. (i) Xiao, T.; Li, L.; Lin, G.;
Mao, Z. W.; Zhou, L. Org. Lett. 2014, 16, 4232. (j) Yang, J. C.;
Zhang, J. Y.; Zhang, J. J.; Duan, X. H.; Guo, L. N. J. Org. Chem. 2018,
83, 1598. (k) Zhao, Y. N.; Luo, Y. C.; Wang, Z. Y.; Xu, P. F. Chem.
Commun. 2018, 54, 3993. (l) Ye, C.; Zhang, Y.; Ding, A.; Hu, Y.;
Guo, H. Sci. Rep. 2018, 8, 2205. (m) Li, H.; Jin, R.; Li, Y.; Ding, A.;
Hao, X.; Guo, H. Sci. Rep. 2017, 7, 16559. (n) Zhu, M.; Zhou, K.;
Zhang, X.; You, S.-L. Org. Lett. 2018, 20, 4379. (o) Cheng, Y.-Z.;
Zhou, K.; Li, L.-A.-C.; Zhang, X.; You, S.-L. Chem. Eur. J. 2018, 24,
12519. (p) Liu, Y.-Y.; Yu, X.-Y.; Chen, J.-R.; Qiao, M.-M.; Qi, X.;
Shi, D.-Q.; Xiao, W.-J. Angew. Chem. Int. Ed. 2017, 56, 9527.
(q) Xia, X.-D.; Ren, Y.-L.; Chen, J.-R.; Yu, X.-L.; Lu, L.-Q.; Zou, Y.-
Q.; Wan, J.; Xiao, W.-J. Chem. Asian J. 2014, 9, 1.
448.2123.
2-(1H-Indol-3-yl)-2-phenylacetic Acid (5a)
Yield: 30.2 mg (60%); brown solid; mp 310–312 °C; Rf = 0.43 (DCM–
EtOAc, 2:1).
1H NMR (400 MHz, DMSO): δ = 12.57 (br, 1 H), 10.99 (s, 1 H), 7.42–
7.34 (m, 4 H), 7.32–7.27 (m, 2 H), 7.25–7.20 (m, 2 H), 7.08–7.03 (m, 1
H), 6.95–6.90 (m, 1 H), 5.18 (s, 1 H).
13C NMR (101 MHz, DMSO): δ = 173.9, 139.7, 136.2, 128.3, 128.1,
126.7, 126.3, 123.5, 121.1, 118.6, 118.5, 112.7, 111.5, 48.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H14NO2: 252.1019; found:
252.1017.
Funding Information
This work was supported by the National Natural Science Foundation
of China (Nos. 21772179, 21502173, 21672192) and the Outstanding
Young Talent Research Fund of Zhengzhou University (No.
1521316002).
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Supporting Information
(10) (a) Strieth-Kalthoff, F.; James, M. J.; Teders, M.; Pitzer, L.;
Glorius, F. Chem. Soc. Rev. 2018, 47, 7190. (b) Xuan, J.; Xiao, W. J.
Angew. Chem. Int. Ed. 2012, 51, 6828. (c) Romero, N. A.;
Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (d) Prier, C. K.;
Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
(11) For selective metal- and photocatalyst-free functionalization
see: (a) Jurberg, I. D.; Davies, H. M. L. Chem. Sci. 2018, 9, 5112.
(b) Li, J.; Zhang, P.; Jiang, M.; Yang, H.; Zhao, Y.; Fu, H. Org. Lett.
2017, 19, 1994. (c) Xiao, T.; Mei, M.; He, Y.; Zhou, L. Chem.
Commun. 2018, 54, 8865. (d) Ni, K.; Meng, L. G.; Wang, K.; Wang,
L. Org. Lett. 2018, 20, 2245. (e) Li, X.; Gu, X.; Li, L.; Li, P. ACS
Catal. 2014, 4, 1897.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610668.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J