One-pot approach to installing eight-membered rings onto indoles

Article abstract of DOI:10.1002/anie.201202971

Ring fusion: The Pd⁰-catalyzed reaction of 2-allyl-3-iodo-1- tosyl-1H-indoles and propargylic bromides affords dihydrocycloocta[b]indoles (see scheme; M.S.=molecular sieves, TFP=tris(2-furyl)phosphine, Ts=4-toluenemethanesulfonyl), and proceeds

Full text of DOI:10.1002/anie.201202971

Angewandte
Chemie
DOI: 10.1002/anie.201202971
Heterocycles
One-Pot Approach to Installing Eight-Membered Rings onto Indoles**
Can Zhu, Xue Zhang, Xiongdong Lian, and Shengming Ma*
Eight-membered rings combined with an aromatic skeleton,
a class of fused eight-membered compounds, have attracted
considerable attention.[1,2] Such units have been found in
various natural products as well as in pharmacologically
active substances:[3,4] Iprindole (1),[5] the first second-gener-
ation antidepressant (TCA), and jolynamine (2),[6] which was
isolated from a dark brown alga belonging to the family
Scytosiphonaceae, contain
a cycloocta[b]indole skeleton
(Figure 1). Very limited methods, especially those involving
the unfavorable formation of eight-membered rings, have
been developed for the synthesis of these type of pro-
ducts.[2b,c,d,7] Thus, new methodologies for the efficient syn-
thesis of this type of skeleton are highly desired.
Scheme 1. One-pot reaction to construct dihydrocycloocta[b]indole.
DMF=N,N-dimethylformamide, Ts=4-methylbenzenesulfonyl.
Interestingly, the reaction in N,N-dimethylformamide (DMF)
at 1008C with 3.0 equivalents of LiI as the additive afforded
the dihydrocycloocta[b]indole 6a in 65% yield, and the
formation of its precursor 5a was not detected.
With the unexpected results in hand, we turned to
optimizing the reaction conditions. Along with the dihydro-
cycloocta[b]indole 6a, the reduced indole 7 was also found in
22% yield (Table 1, entry 1). We reasoned that a trace
amount of water may be critical to the reaction. Thus,
12.5 mgmLꢀ1 of 4 ꢀ molecular sieves (M.S.) was added to
Figure 1. Natural products and pharmaceuticals with the fragment of
cycloocta[b]indole skeleton.
Coupling reactions involving allenylic/propargylic
organometallic reagents have been developed as an efficient
approach for the synthesis of allenes.[8] On this basis, we
envisioned a new approach for the synthesis of 3-allenyl-
indoles by starting from 3-iodoindoles and propargylic
bromides given the fact that propargylic bromide is much
more reactive towards metals forming allenylic/propargylic
organometallic reagents in situ.[9] On the basis of this concept,
the synthesis of 2-allyl-3-(buta-1,2-di-enyl)-1-tosyl-1H-indole
(5a) was attempted by conducting the coupling reaction of 2-
allyl-3-iodo-1-tosyl-1H-indole (3a) with 3-bromobut-1-yne
(4a) in the presence of In and [Pd(PPh3)4] (Scheme 1).
Table 1: Optimization of the reaction conditions for the palladium-
catalyzed cross-coupling reaction and cyclization of 3a with 4a[a]
Entry
Catalyst
6a
7
Yield [%][b]
Yield [%][b]
1[c]
2[d]
3
4
5
6
7
8
9
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Pd(OAc)2
Pd(OAc)2/PPh3
Pd(OAc)2/L1[e]
Pd(OAc)2/L2[f]
Pd(OAc)2/MePPh2
Pd(OAc)2/TFP
Pd(OAc)2/TFP
Pd(OAc)2/TFP
Pd(OAc)2/TFP
65
79
83
53
18
82
32
55
90
79
84
47
22
12
10
31
49
15
58
39
7
[*] C. Zhu, X. Zhang, X. Lian, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032 (P.R. China)
E-mail: masm@sioc.ac.cn
10[g]
11[h]
12[i]
9
6
42
Prof. Dr. S. Ma
Shanghai Key Laboratory of Green Chemistry and Chemical Process
Department of Chemistry, East China Normal University
3663 North Zhongshan Lu, Shanghai 200062 (P.R. China)
[a] The reaction was carried out using 3a (c=0.1m), 4a (3.0 equiv), In
(2.0 equiv), LiI (3.0 equiv), 4 ꢀ M.S. (25.0 mgmLꢀ1), palladium complex
(4 mol%) and ligand (8 mol%) at 1008C in DMF. [b] Determined by
1H NMR analysis with nitromethane as the internal standard. [c] The
reaction was carried out without 4 ꢀ M.S. [d] 12.5 mgmLꢀ1 4 ꢀ M.S. was
added to the reaction mixture. [e] L1=tris(4-methoxyphenyl)phosphine.
[f] L2=tris(2,4,6-trimethoxyphenyl)phosphine. [g] NaI (3.0 equiv) was
used instead of LiI. [h] LiCl (3.0 equiv) was used instead of LiI. [i] No LiI
was added to the reaction mixture.
[**] Financial support from the Major State Basic Research and
Development Program (2011CB808700) and the NSF of China
(21102164 for the DFT calculation) is acknowledged. We thank G.
Chai of our research group for reproducing the results presented in
entries 3 and 14 of Table 2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202971.
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remove moisture and the yield was improved to 79%
(Table 1, entry 2); increasing the loading of the 4 ꢀ M.S. to
25.0 mgmLꢀ1 improved the yield of 6a additionally to 83%,
while the reduced indole 7 was formed in 10% yield (Table 1,
entry 3). Pd(OAc)2 together with different phosphine ligands
was screened (Table 1, entries 4–9), and tris(2-furyl)phos-
phine (TFP) was observed to be the best: The yield of 6a was
improved to 90% with a less than 7% yield of 7 (Table 1,
entry 9). Other additives failed to show better performance
than LiI (Table 1, entries 10–12). Thus, Pd(OAc)2 (4 mol%),
TFP (8 mol%), In (2.0 equiv), LiI (3.0 equiv), and 4 ꢀ M.S.
(25.0 mgmLꢀ1) in DMF at 1008C were defined as the
optimized reaction conditions for additional study.
The scope of the reaction was then investigated by using
the optimal reaction conditions (Table 2). We first studied the
cyclization reaction of iodoindole 3a with different propargyl
bromides. Secondary halides gave good yields (Table 2,
entries 1 and 2). When R1 is H, methyl, or allyl, the reaction
showed moderate to good results (Table 2, entries 3–5). The
reaction worked equally well using a tertiary halide (R2 =
R3 = Me), thus producing 6g in 75% yield (Table 2, entry 6).
Notably, various substituents on the benzene ring turned out
to be compatible under the standard reaction conditions.
Different R groups, such as fluoro, chloro, trifluoromethyl,
bromo, and methyl ester (Table 2, entries 8–12) at the 5-
position and chloro (Table 2, entry 13) at 6-position, may be
introduced to the indole unit, thus leading to the correspond-
ing dihydrocycloocta[b]indole derivatives in good yields.
Further studies showed that the substituent on the nitrogen
atom also has a great influence on the reaction (Table 2,
entries 1, 14, and 15). Finally, it is easy to conduct the reaction
of 3a and 4g to afford 6g in 76% yield on a one gram scale
(Table 2, entry 7). The structures of the products 6a–n were
determined by the single-crystal X-ray diffraction study of 6g
(see the Supporting Information).[10]
As mentioned previously, iprindole (1) is a tricyclic
antidepressant (TCA) used in Europe for the treatment of
depression. We demonstrated the potential of our method by
applying to the synthesis of iprindole:[7] Hydrogenation of our
product 6c produced the hexahydrocycloocta[b]indole 8 in
80% yield and subsequent deprotection and N alkylation led
to 1 in 63% yield after two steps (Scheme 2). The contam-
ination of palladium and indium in the prepared compound
1 was determined by AES (atomic emission spectrometry) to
be less than 0.0001% (1 ppm). The traditional synthetic route
of iprindole is based on the reaction of an aromatic substrate
with cyclooctanone in a Fischer indole synthesis, for exam-
ple.[11] It should be noted that different substituted cyclic
ketones are not readily available. In contrast, our approach
provides diversity in both the eight-membered and benzene
rings, because of the ready availability of both substituted
iodoindoles and propargylic bromides, for the synthesis of
iprindole derivatives, which may display better biological or
pharmacological activities.
Table 2: Palladium-catalyzed one-pot synthesis of dihydrocycloocta-
[b]indole from iodoindoles 3 and propargylic bromides 4.[a]
Entry
3
4
6
R/Pg
R1/R2/R3
Yield [%][b]
1
2
H/Ts (3a)
H/Ts (3a)
H/Ts (3a)
H/Ts (3a)
H/Ts (3a)
H/Ts (3a)
H/Ts (3a)
5-F/Ts (3b)
5-Cl/Ts (3c)
5-Br/Ts (3d)
5-CF3/Ts (3e)
5-CO2Me/Ts (3 f)
6-Cl/Ts (3g)
H/Ms (3h)
H/p-Ns (3i)
H/Me/H (4a)
H/n-Pr/H (4b)
H/H/H (4c)
79 (6a)
75 (6b)
63 (6c)
52 (6d)
67 (6e)
75 (6g)[e]
76 (6g)[e]
75 (6h)
79 (6i)
74 (6j)
69 (6k)
75 (6l)
69 (6m)
67 (6n)
trace (6o)
3[c]
4
Me/H/H (4d)
Allyl/H/H (4e)
H/Me/Me (4g)
H/Me/Me (4g)
H/Me/H (4a)
H/Me/H (4a)
H/Me/H (4a)
H/Me/H (4a)
H/Me/Me (4g)
H/Me/H (4a)
H/Me/H (4a)
H/Me/H (4a)
5[d]
6
7[f]
8
Scheme 2. Approach for the synthesis of iprindole (1).
9
10
11
12
13
14
15
To investigate the mechanism, the reaction was conducted
at a lower temperature, that is, 608C, for 6 hours, and the
coupling product 5c was produced in 33% yield upon
isolation. Heating a solution of 5c in DMF at 1008C produced
dihydrocycloocta[b]indole 6c in 61% yield, thus indicating
the intermediacy of the coupling product 5c for this trans-
formation (Scheme 3).
[a] The reaction was conducted at 1008C in DMF with 3 (c=0.1m), 4
(3.0 equiv), 4 ꢀ M.S. (25.0 mgmLꢀ1), In (2.0 equiv), and LiI (3.0 equiv) in
the presence of Pd(OAc)2 (4 mol%) and TFP (8 mol%). [b] Yield of
isolated product. [c] The reaction was carried out at 1108C for 5 h. [d] The
reaction was carried out at 608C for 30 h and then 1108C for 5 h with
4 mol% [Pd(PPh3)4] as the catalyst. [e] Yield of product isolated after
chromatography on silica gel and then recrystallized from dichloro-
methane and petroleum ether. [f] Gram-scale reaction was conducted
with 3a (1.0942 g) and 4g (1.1025 g) to provide 6g (0.7134 g).
Pg=protecting group, Ms=methanesulfonyl, p-Ns=4-nitrobenzene-
sulfonyl.
DFT calculations[12] have been performed to investigate
the cyclization of 1,2,4Z,7-tetraene 5c to afford 6c. Figure 2
presents the energy profile for the favored pathway of the
cycloisomerization reaction of 5c. It is clear that the rate-
limiting step is the initial [1,5]-H migration step, which is
computed to be exothermic (DH = ꢀ9.7 kcalmolꢀ1) and
requires an activation enthalpy of 26.6 kcalmolꢀ1 as the
2
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gen migration, and electrocyclization, involving overall
a dearomatization and aromatization. Finally, because of the
success of our approach in the efficient synthesis of iprindole,
this chemistry will be of high interest for organic and
medicinal chemists. Further studies in this area are currently
under way in our laboratory.
Experimental Section
Procedure for the preparation of (6Z,10Z)-9,9-Dimethyl-5-tosyl-8,9-
dihydro-5H-cycloocta[b]indole (6g, Table 2, entry 7): Indium powder
(diameterꢁ 32 mm; 572.9 mg, 5.0 mmol), LiI (1.0017 g, 7.5 mmol) in
DMF (6 mL), and 3-bromo-3-methylbut-1-yne (4g; 1.1025 g,
7.5 mmol) in DMF (6 mL) were sequentially added to a flame dried
three-necked flask under an Ar atmosphere. After the mixture was
stirred at room temperature for 15 min, iodoindole 3a (1.0942 g,
2.5 mmol), Pd(OAc)2 (22.4 mg, 0.10 mmol), TFP (47.3 mg,
0.20 mmol), 4 ꢀ molecular sieves (628.0 mg), and DMF (13 mL)
were added to the reaction mixture sequentially. The resulting
mixture was stirred at 1008C and after 5 h the reaction was over as
monitored by TLC. 50 mL of HCl (1.0m) and 200 mL of H2O were
added to the resulting mixture. The water layer was extracted with
Et2O (3 ꢁ 150 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, evaporated, and purified by column
chromatography on silica gel (eluent: n-pentane/ethyl ether= 50:1
then petroleum ether/dichloromethane = 15:1). Recrystallization
from dichloromethane and petroleum ether afforded the desired
product 6g (713.4 mg, 76%): solid; m.p. 206–2088C (petroleum ether/
dichloromethane). 1H NMR (400 MHz, CDCl3): d = 8.21 (d, J =
8.4 Hz, 1H, Ar-H), 7.62 (d, J = 8.0 Hz, 2H, Ar-H), 7.44 (d, J =
7.6 Hz, 1H, Ar-H), 7.36–7.30 (m, 1H, Ar-H), 7.28–7.22 (m, 1H, Ar-
H), 7.11 (d, J = 8.0 Hz, 2H, Ar-H), 7.05 (d, J = 10.8 Hz, 1H, CH =),
Scheme 3. Mechanistic studies.
aromaticity of the indole ring is lost.[13] This initial [1,5]-H
migration step leads to the formation of the intermediate
(2E,3Z)-2,3-diallylidene-1-tosylindoline (A) having two s-
trans allylidenes. Conformer A then undergoes two single-
bond rotations to afford the 8p-electrocyclization precursor
C, which has both allylidenes in the s-cis conformation. The
computed enthalpy difference of 9.8 kcalmolꢀ1 between A
and C, with the former species being favored, results from the
steric effect between the two terminal methylene groups of
conformer C. There is an approximately 11 kcalmolꢀ1 barrier
for interconversion of these two structures. At last, the final
product dihydrocycloocta[b]indole (6c) is formed by the 8p-
electrocyclization of C, which requires an activation enthalpy
of only 1.2 kcalmolꢀ1 as a result of the rearomatization.
Overall, the cycloisomerization reaction of 5c is calculated to
occur irreversibly, as the final product 6c is about 27 kcal
molꢀ1 below the energy of the starting material, and the [1,5]-
H migration is the rate-limiting step.
=
=
6.47–6.38 (m, 1H, CH ), 6.15 (d, J = 13.2 Hz, 1H, CH ), 5.76 (d, J =
=
12.8 Hz, 1H, CH ), 2.29 (s, 3H, Ar-CH3), 2.14 (d, J = 8.0 Hz, 2H,
CH2), 1.10 ppm (s, 6H, 2 ꢁ CH3). 13C NMR (CDCl3, 100.5 MHz): d =
144.7, 144.6, 136.8, 135.9, 135.4, 131.9, 131.1, 129.5, 126.7, 125.1, 123.7,
123.4, 119.7, 119.1, 115.0, 114.6, 38.9, 38.5, 31.8, 21.5 ppm. MS (EI):
+
~
m/z 377 (M , 29.90), 222 (100). IR (KBr): n ¼3040, 2956, 2925, 2862,
1597, 1494, 1471, 1455, 1371, 1306, 1292, 1224, 1195, 1186, 1174, 1151,
1121, 1090, 1025 cmꢀ1. Anal. (%) calcd for C23H23NO2S: C 73.18; H
6.14; N 3.71; S 8.49. Found: C 73.36; H 6.15; N 3.46; S 8.63.
Received: April 18, 2012
Revised: May 11, 2012
Published online: && &&, &&&&
Keywords: allenes · cyclization · heterocycles · indium ·
.
palladium
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Figure 2. Reaction coordinate for the cycloisomerization reaction of
5c. Enthalpies are given in kcalmolꢀ1 and are relative to 5c.
In conclusion, we have developed a one-pot reaction for
the synthesis of dihydrocycloocta[b]indoles from 2-allyl-3-
iodoindoles and propargyl bromides. This coupling/cycliza-
tion reaction is highly efficient, and proceeds through
palladium(0)-catalyzed carbon–carbon coupling, [1,5]-hydro-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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9.4240(9), b = 14.7239(14), c = 14.2847(14) ꢀ, a = 90, b =
101.7000(10), g = 908, V= 1940.9(3) ꢀ3, T= 133 (2) K, Z = 4,
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Cambridge Crystallographic Data Center. CCDC 875477 con-
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These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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4
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Chemie
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Heterocycles
C. Zhu, X. Zhang, X. Lian,
S. Ma*
&&&& — &&&&
One-Pot Approach to Installing Eight-
Membered Rings onto Indoles
Ring fusion: The Pd0-catalyzed reaction of
2-allyl-3-iodo-1-tosyl-1H-indoles and
propargylic bromides affords dihydrocy-
cloocta[b]indoles (see scheme; M.S.=
molecular sieves, TFP=tris(2-furyl)phos-
phine, Ts=4-toluenemethanesulfonyl),
and proceeds by carbon–carbon cou-
pling, [1,5]-hydrogen migration, and
electrocyclization. The newly established
method was used to efficiently access
iprindole.
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