Rhodium-catalyzed direct addition of indoles to N-sulfonylaldimines

Article abstract of DOI:10.1002/adsc.201200909

The rhodium-catalyzed addition of indole C-H bonds to a range of aryl- and alkyl-N-sulfonylaldimines is reported. The reaction proceeds with high functional group compatibility and provides easy and rapid access to a wide variety of 2-indolylmethanamine derivatives under mild reaction conditions.

Full text of DOI:10.1002/adsc.201200909

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DOI: 10.1002/adsc.201200909
Rhodium-Catalyzed Direct Addition of Indoles to
N-Sulfonylaldimines
Bing Zhou,a,c,* Yaxi Yang,a,c Sui Lin,b and Yuanchao Lia,*
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, Peopleꢀs
Republic of China
Fax : (+86)-21-5080-7288; e-mail: zhoubing2012@hotmail.com or ycli@mail.shcnc.ac.cn
Fujian Institute of Medical Sciences, Fuzhou 350001, Peopleꢀs Republic of China.
These authors contributed equally.
b
c
Received: October 10, 2013; Published online: January 25, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200909.
Abstract: The rhodium-catalyzed addition of indole
C H bonds to a range of aryl- and alkyl-N-sulfonyl-
aldimines is reported. The reaction proceeds with
high functional group compatibility and provides
easy and rapid access to a wide variety of 2-indolyl-
methanamine derivatives under mild reaction con-
ditions.
across polar C/N multiple bonds, such as imines,[3] iso-
cyanates,[4] and isocyanides,[5] have seen considerably
less progress.[6] Given the prevalence of amines in bio-
À
À
active molecules and drugs, the direct addition of C
À
H bonds to C N bonds to selectively install nitrogen-
based functional groups represents
a
powerful
method for rapid and efficient amine synthesis.
The indole nucleus is a ubiquitous structural motif
in a number of biologically active natural products
and pharmaceutical compounds.[7] In particular, the 2-
indolylmethanamine moiety is a popular structure
core in many bioactive natural and unnatural prod-
ucts.[8] Despite its importance, methods for the synthe-
sis of the 2-indolylmethanamine skeleton remain
À
Keywords: addition reactions; C H activation;
imines; indoles; rhodium
Transition metal-catalyzed direct transformations of rare,[9] and the most typically used are Friedel–Crafts
À
aromatic C H bonds have emerged as powerful alter- reactions of indoles with imines at the C-3 position
natives to traditional reactions that rely heavily on te- [Eq, (1), Scheme 1].[10] Recently, You et al. have de-
dious, stoichiometric, and costly substrate preactiva- veloped an efficient Friedel–Crafts reaction of 4,7-di-
tion.[1] While the transition metal-catalyzed addition hydroindoles with imines followed by oxidation with
À
of C H bonds to alkene and alkyne derivatives has p-benzoquinone to produce the 2-indolylmethan-
been extensively investigated,[2] analogous additions
amine derivatives [Eq. (2), Scheme 1].[9] Given the
ACHTUNGTRENNUNG
Scheme 1. Routes to 3- and 2-indolylmethanamine derivatives.
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Adv. Synth. Catal. 2013, 355, 360 – 364

Rhodium-Catalyzed Direct Addition of Indoles to N-Sulfonylaldimines
Table 1. Optimization of reaction conditions.[a]
Entry
1-Substituted Indole
Catalyst
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
N
CH2Cl2
CH2Cl2
CH2Cl2
DCE
t-BuOH
THF
0
71
57 (66)
70
32
34
15 (50)
<5
30 (40)
40 (48)
28
56 (67)
40 (60)
57
E
E
PhMe
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
9
10
11
12
13[c]
14[d]
15[e]
16[f]
17[g]
18[h]
19
20
21
22
E
65
57 (69)
20 (55)
64
0[i]
0[i]
0[i]
55
[a]
Recation conditions: 1a/2a=1:1.5, 0.3-mmol scale, 5 mol% of catalyst; Rh or Ir/Ag=1:4; 858C for 24 h.
Yield of isolated product; Yield in parentheses is based on recovered starting material.
Rh/Ag=1:2.
The reaction was carried out at 1058C.
The reaction was carried out at 958C.
The reaction was carried out at 758C.
The reaction was carried out at 608C.
Reaction time=36 h.
Only the 3-substituted indole derivative was obtained.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
prevalence of 2-indolylmethanamine scaffolds in me- C-2 position of indole.[11] Although the use of 5 mol%
dicinal chemistry, we have developed a Rh(III)-cata- of [Cp*RhCl2]2 proved unsuccessful in catalyzing this
AHCTUNGTRENNUNG
lyzed highly regioselective and efficient addition of reaction (entry 1), [Cp*RhCl2]2 (5 mol%) in the pres-
“inert” indole C H bonds to aryl- and alkyl-N-sulfon- ence of silver salts,[12] AgSbF6 (20 mol%), for exam-
À
ylimines for the rapid preparation of 2-indolylmethan- ple, in CH2Cl2 at 858C provided the desired product
A
ACHTUNGTRENN(UNG III) pre-
A
ACHTUNGTRENNUNG
At first, 1-(N,N-dimethylcarbamoyl)indole (1a) and low conversion of the starting material (entry 3). A
N-tosylimine (2a) were used as the model substrates screen of solvents revealed that using DCE as the re-
to optimize the reaction conditions including catalysts, action solvent led to reactivity similar to that ob-
additives, solvents and reaction temperatures served with CH2Cl2 (entries 2, 4–7). Analogous iridi-
(Table 1). We chose 1-(N,N-dimethylcarbamoyl)indole um-based complexes were found to be inactive for
(1a) as the model substrate for arylation because of this transformation (entry 8). Other halide abstractors
À
its successful history in C H functionalization at the were also explored (entries 9–12), but AgSbF6 proved
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361

Bing Zhou et al.
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to be optimal (entry 4). Moreover, a decrease of the
yield was observed by reducing the ratio of Ag to Rh
(entry 13). Raising the temperature diminished the
yield (entries 14 and 15) and lowering the tempera-
ture led to a low conversion (entries 16 and 17).
Meanwhile, extension of the reaction time did not en-
hance the reactionꢀs efficiency (entry 18). In addition,
the influence of indole protecting group on the prog-
À
ress of the C H arylation of imine 2a was assessed.
Replacement of the N,N-dimethylcarbamoyl group
with acetyl, methyl and Boc groups completely inhib-
ited this transformation (entries 19–21). Different
from the previous results,[3e,13] the use of a cyclic pyr-
rolidine amide directing group, in place of the N,N-di-
methyl substituents in 1a, resulted in a marked de-
crease in yield (entry 22). It is noteworthy to mention
that when using N,N-dimethylcarbamoyl group as
À
protecting group, the C H at the 3-position remained
untouched, although it was found to be active in some
transformations.[14] The regioselectivity of this trans-
formation was further confirmed by removing the
protecting group of 3a in ethanolic KOH to provide
3a-1 in 70% yield (Scheme 2). Comparison of the
physical properties of 3a-1 to those recorded confirms
its identity.[9]
Having established the optimized reaction condi-
tions, we sought to further explore the reaction scope
for 1-(N,N-dimethylcarbamoyl)indole (1a) and
a broad range of N-sulfonylimines (Scheme 3). We
found that the steric bulkiness does not play a signifi-
cant role in reactivity. For example, 2-tolylaldimine
(3f) shows comparable reactivity with 4-tolylaldimine Scheme 3. Investigation of different N-sulfonylaldimines 2.
The reaction was performed with 0.3 mmol of 1a, 0.45 mmol
of 2, 0.015 mmol of [Cp*RhCl2]2 and 0.06 mmol of AgSbF6
at 858C in 1.5 mL of DCE unless otherwise mentioned. The
reported yields are of isolated products.
(3h). Also, the electronic nature of the substituents
on the aromatic imines did not play a key role. Both
electron-rich (3f–3i) and electron-poor (3j–3m) aro-
matic imines gave the corresponding amine products
in moderate to good yields. Substitutions at the ortho
(3f and 3n), meta (3g), and para (3h–3m) positions
were all well tolerated. Moreover, the reaction the corresponding cyclohexyl- and n-butyl-substituted
showed good functional group compatibility. For ex- branched amine producta (3q and 3r).
ample, aromatic imines with methyl (3f–3h), methoxy
The substrate scope was further extended to a varie-
(3i), nitro (3j), chloro (3m), fluoro (3n) and ester (3l) ty of substituted indoles (Scheme 4). It was found that
groups were effective coupling partners under opti- the electronic nature of the substituents on the indole
mized conditions. In addition, 2-naphthyl- and 2- ring did not play a key role. Both electron-donating
thienyl-substituted branched amine products (3o and (3s–3w) and electron-withdrawing (3x and 3y) indoles
3p) were also obtained from the corresponding imine were readily converted to the corresponding products
substrates. Particularly remarkable is the participation in moderate to good yields. Notably, the tolerance of
of alkyl-N-sulfonylimines in this reaction, providing the bromo group (3x) offers the opportunity for fur-
ther functionalization. Steric bulkiness on the indole
ring was also tested. To our delight, all the reactions
with a methyl group at the 3- to 6-positions of the
indole ring showed good reactivities (3s–3v), thus
showing the high tolerance for steric hindrance. It
should be noted that the reaction exclusively afforded
the 2-indolylmethanamine products in all cases, and
no 3-indolylmethanamine products were observed by
Scheme 2. Deprotection of 3a.
1H NMR or GC-MS analysis.
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Adv. Synth. Catal. 2013, 355, 360 – 364

Rhodium-Catalyzed Direct Addition of Indoles to N-Sulfonylaldimines
Scheme 5. Proposed catalytic cycle.
Experimental Section
General Procedurs for Rhodium-Catalyzed Direct
Addition of Indole to N-Sulfonylaldimines
Scheme 4. Scope of indoles. The reaction was performed
with 0.3 mmol of 1, 0.45 mmol of 2a, 0.015 mmol of
[Cp*RhCl2]2 and 0.06 mmol of AgSbF6 at 858C in 1.5 mL of
DCE unless otherwise mentioned. The reported yields are
of isolated products.
In a N2-filled glovebox, [Cp*RhCl2]2 (9.3 mg, 0.015 mmol),
AgSbF6 (21.0 mg, 0.06 mmol), substrate 1a (0.3 mmol), and
2a (0.45 mmol, 1.5 equiv.) were added to a screw-capped
vial followed by addition of a stir bar and DCE (1.5 mL).
The vessel was sealed and heated at 858C (oil bath tempera-
ture) for 24 h. The resulting mixture was cooled to room
temperature, filtered through a short silica gel pad and
transferred to silica gel column directly to give product 3a.
The mechanism of this transformation is proposed
as Scheme 5. The reaction is initiated by the N,N-di-
À
methylcarbamoyl-directed C H bond activation to
form a relatively stable five-membered rhodacycle A
and is accompanied by the release of one equivalent
of proton (H+).[15] Coordination of the N-sulfonyl-
References
À
[1] a) G. Dyker, Handbook of C H Transformations: Ap-
ACHTUNGTRENNUNGimine would then activate the imine for nucleophilic
plication in Organic Synthesis, Wiley-VCH: Weinheim,
À
addition to form the N Rh species C. C is protonated
by the acid that is generated in situ at the initiating
step, thus producing the desired product 3a and re-
generating the catalyst.
À
2005; b) J. Q. Yu, Z. J. Shi, C H Activation, Springer:
Berlin, 2010.
À
[2] For selected recent reviews on C H bond functionali-
zation, see: a) G. Song, F. Wang, X. Li, Chem. Soc. Rev.
2012, 41,3651; b) D. A. Colby, A. S. Tsai, R. G. Berg-
man, J. A. Ellman, Acc. Chem. Res. 2012, 45, 814;
c) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem.
Rev. 2010, 110, 624; d) X. Chen, K. M. Engle, D. H.
Wang, J. Q. Yu, Angew. Chem. 2009, 121, 5196; Angew.
Chem. Int. Ed. 2009, 48, 5094; e) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147; f) I. A. I. Mkhalid,
J. H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hart-
wig, Chem. Rev. 2010, 110, 890; g) T. Satoh, M. Miura,
Chem. Eur. J. 2010, 16, 11212; h) R. B. F. Shi, K. M.
Engle, N. Maugel, J. Q. Yu, Chem. Soc. Rev. 2009, 38,
3242; i) Y. J. Park, J. W. Park, C. H. Hun, Acc. Chem.
Res. 2008, 41, 222; j) J. C. Lewis, R. G. Bergman, J. A.
Ellman, Acc. Chem. Res. 2008, 41, 1013; k) K. Godula,
In summary, we have developed a RhACTHNUTRGNE(NUG III)-catalyzed
addition of indoles to a variety of aromatic or alkyl-
À
N-sulfonylimines via C H bond functionalization to
give 2-indolylmethanamine derivatives. The Rh-cata-
lyzed reaction exhibits high regioselectivity, functional
group tolerance, and broad substrate scope under rel-
atively mild conditions and provides an efficient,
practical and rapid method to synthesize 2-indolylme-
thanamine derivatives. Mechanistic studies and syn-
thetic applications of the Rh-catalyzed reaction are
underway.
Adv. Synth. Catal. 2013, 355, 360 – 364
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
363

Bing Zhou et al.
COMMUNICATIONS
D. Sames, Science 2006, 312, 67. For selected recent ex-
amples, see: l) L. Yang, B. Qian, H. Huang, Chem. Eur.
J. 2012, 18, 9511; m) B. Qian, D. Shi, L. Yang, H.
Huang, Adv. Synth. Catal. 2012, 354, 2146; n) H.
Komai, T. Yoshino, S. Matsunaga, M. Kanai, Org. Lett.
2011, 13, 1706; o) P. Zhao, R. Niu, F. Wang, K. Han, X.
Li, Org. Lett. 2012, 14, 4166; p) P. Zhao, F. Wang, K.
Han, X. Li, Org. Lett. 2012, 14, 5506; q) P. Zhao, F.
Wang, K. Han, X. Li, Org. Lett. 2012, 14, 3400; r) Y.
Su, M. Zhao, K. Han, G. Song, X. Li, Org. Lett. 2010,
12, 5462; s) H. Li, K.-H. He, J. Liu, B.-Q. Wang, K.-Q.
Zhao, P. Hu, Z.-J. Shi, Chem. Commun. 2012, 48, 7028;
t) B.-J. Li, H.-Y. Wang, Q.-L. Zhu, Z.-J. Shi, Angew.
Chem. 2012, 124, 4014; Angew. Chem. Int. Ed. 2012, 51,
3948; u) H. Li, Y. Li, X.-S. Zhang, K. Chen, X. Wang,
Z.-J. Shi, J. Am. Chem. Soc. 2011, 133, 15244; v) F.
Wang, G. Song, X. Li, Org. Lett. 2010, 12, 5430.
Yang, C. A. Correia, C. J. Li, Adv. Synth. Catal. 2011,
353, 1269; g) A. Flores-Gaspar, R. Martin, Adv. Synth.
Catal. 2011, 353, 1223; h) Y. Li, X. S. Zhang, K. Chen,
K. H. He, F. Pan, B. J. Li, Z. J. Shi, Org. Lett. 2012, 14,
636; i) S. Sharma, E. Park, J. Park, I. S. Kim, Org. Lett.
2012, 14, 906; j) B. Zhou, Y. Yang, Y. Li, Chem.
Commun. 2012, 48, 5163; k) Y. Lian, R. G. Bergman,
J. A. Ellman, Chem. Sci. 2012, 3, 3088; l) Y. Yang, B.
Zhou, Y. Li, Adv. Synth. Catal. 2012, 354, 2916; m) X.
Shi, C.-J. Li, Adv. Synth. Catal. 2012, 354, 2933.
[7] a) J. A. Joule, K. Mills, Heterocyclic Chemistry, Black-
well Science Ltd., Oxford, 2000; b) T. Eicher, S. Haupt-
mann, The Chemistry of Heterocycles, Wiley-VCH,
Weinheim, 2003; c) D. A. Horton, G. T. Bourne, M. L.
Smythe, Chem. Rev. 2003, 103, 893; d) G. R. Humphrey,
J. T. Kuethe, Chem. Rev. 2006, 106, 2875; e) K. Higuchi,
T. Kawasaki, Nat. Prod. Rep. 2007, 24, 843.
[3] a) A. S. Tsai, M. E. Tauchert, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2011, 133, 1248; b) Y. Li,
B.-J. Li, W.-H. Wang, W.-P. Huang, X.-S. Zhang, K.
Chen, Z.-J. Shi, Angew. Chem. 2011, 123, 2163; Angew.
Chem. Int. Ed. 2011, 50, 2115; c) B. Qian, S. Guo, J.
Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am.
Chem. Soc. 2010, 132, 3650; d) K. Gao, N. Yoshikai,
Chem. Commun. 2012, 48, 4305; e) K. D. Hesp, R. G.
Bergman, J. A. Ellman, Org. Lett. 2012, 14, 2304; f) Y.
Li, X.-S. Zhang, Q.-L. Zhu, Z.-J. Shi, Org. Lett. 2012,
14, 4498. For selected example of Lewis acid-catalyzed
[8] a) J. Bosch, M.-L. Bennasar, Synlett 1995, 587; b) D. J.
Faulkner, Nat. Prod. Rep. 2002, 19, 1; c) S. Agarwal, S.
Caemmerer, S. Filali, W. Froehner, J. Knoell, M. P.
Krahl, K. R. Reddy, H.-J. Knoelker, Curr. Org. Chem.
2005, 9, 1601; d) S. E. OꢀConnor, J. J. Maresh, Nat.
Prod. Rep. 2006, 23, 532.
[9] Q. Kang, X.-J. Zheng, S.-L. You, Chem. Eur. J. 2008,
14, 3539.
[10] Selected examples of Friedel–Crafts reactions, see:
a) B.-L. Wang, J.-X. Zhang, N.-K. Li, G.-G. Liu, Q.
Shen, X.-W. Wang, Tetrahedron Lett. 2011, 52, 4671;
b) Q. Kang, Z.-A. Zhao, S.-L. You, J. Am. Chem. Soc.
2007, 129, 1484; c) P. Yu, J. He, C. Guo, Chem.
Commun. 2008, 44, 2355; d) W. Xie, K. M. Bloomfield,
Y. Jin, N. Y. Dolney, P. G. Wang, Synlett 1999, 498.
[11] a) D. J. Schipper, M. Hutchinson, K. Fagnou, J. Am.
Chem. Soc. 2010, 132, 6910; b) B. Zhou, Y. Yang, Y. Li,
Chem. Commun. 2012, 48, 5163.
[12] T. Nishikata, Y. Yamamoto, N. Miyaura, Angew. Chem.
2003, 115, 2874; Angew. Chem. Int. Ed. 2003, 42, 2768.
[13] Y. Shibata, Y. Otake, M. Hirano, K. Tanakka, Org.
Lett. 2009, 11, 689.
À
C H bond functionalization, see: g) B. Qian, S. Guo, C.
Xia, H. Huang, Adv. Synth. Catal. 2010, 352, 3195;
h) B. Qian, P. Xie, Y. Xie, H. Huang, Org. Lett. 2011,
13, 2580; i) M. Rueping, N. Tolstoluzhsky, Org. Lett.
2011, 13, 1095.
[4] a) K. D. Hesp, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2011, 133, 11430; b) Y. Kuninobu, Y. Toku-
naga, A. Kawata, K. Takai, J. Am. Chem. Soc. 2006,
128, 202; c) P. Hong, H. Yamazaki, K. Sonogashira, N.
Hagihara, Chem. Lett. 1978, 535.
[5] C. Zhu, W. Xie, J. R. Falck, Chem. Eur. J. 2011, 17,
12591.
[14] S. Yanagisawa, T. Sudo, R. Noyori and K. Itami, J. Am.
À
[6] Recent examples of direct addition of C H bonds to
Chem. Soc. 2006, 128, 11748.
aldehydes, see: a) C. W. Chan, Z. Zhou, W.-Y. Yu, Adv.
Synth. Catal. 2011, 353, 2999; b) Y. Yuan, D. Chen, X.
Wang, Adv. Synth. Catal. 2011, 353, 3373; c) C. Li, L.
Wang, P. Li, W. Zhou, Chem. Eur. J. 2011, 17, 10208;
d) B. J. Li and Z. J. Shi, Chem. Sci. 2011, 2, 488; e) J.
Park, E. Park, A. Kim, Y. Lee, K. W. Chi, J. H. Kwak,
Y. H. Jung, I. S. Kim, Org. Lett. 2011, 13, 4390; f) L.
[15] a) L. Li, Y. Jiao, W. W. Brennessel, W. D. Jones, Orga-
nometallics 2010, 29, 4593; b) L. Li, W. W. Brennessel,
W. D. Jones, Organometallics 2009, 28, 3492; c) L. Li,
W. W. Brennessel, W. D. Jones, J. Am. Chem. Soc. 2008,
130, 12414; d) D. L. Davies, O. Al-Duaij, J. Fawcett, M.
Giardiello, S. T. Hilton, D. R. Russell, Dalton Trans.
2003, 4132.
364
asc.wiley-vch.de
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Adv. Synth. Catal. 2013, 355, 360 – 364