Ruthenium porphyrin catalyzed diimination of indoles with aryl azides as the nitrene source

Article abstract of DOI:10.1039/c3cc49052a

By using [Ru(TTP)CO] [H₂TTP = meso-tetrakis(4-tolyl)porphyrin] as catalyst and aryl azides as the nitrene source, the sp²(C-H) bonds of a series of indoles undergo oxidative C-N bond formation to give unique 2,3-diimination products in good to high yields. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49052a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Ruthenium porphyrin catalyzed diimination of
indoles with aryl azides as the nitrene source†
Jinhu Wei,‡ab Wenbo Xiao,‡b Cong-Ying Zhouab and Chi-Ming Che*ab
Cite this: Chem. Commun., 2014,
50, 3373
Received 27th November 2013,
Accepted 4th February 2014
DOI: 10.1039/c3cc49052a
www.rsc.org/chemcomm
By using [Ru(TTP)CO] [H2TTP = meso-tetrakis(4-tolyl)porphyrin] as or diimination of indole’s C–H bonds has been reported. Recently,
catalyst and aryl azides as the nitrene source, the sp2(C–H) bonds of we demonstrated that ruthenium porphyrins are effective catalysts
a series of indoles undergo oxidative C–N bond formation to give for C–H amidation of furan, pyrroles and thiophene with PhIQNTs.8
unique 2,3-diimination products in good to high yields.
Herein an efficient ruthenium porphyrin-catalyzed diimination
of indoles with aryl azides as the nitrene source is described.
Indoles are ubiquitous structural motifs present in bioactive natural 2,3-Diiminoindoles and their derivatives have been reported to
products and pharmaceuticals.1 Direct C–H bond functionalization display a broad spectrum of bioactivities.9
of indoles represents a straightforward and atom-economic strategy
In our preliminary study, we found that the reaction of
for the synthesis of indole derivatives. While many methodologies N-methylindole 1a (1 equiv.) and 4-nitrophenyl azide 2a (3 equiv.)
have been developed to functionalize indole’s C–H bonds such as in the presence of [Ru(TTP)CO] (H2TTP = meso-tetrakis(4-tolyl)-
alkylation and arylation,2 the routes to 2- and 3-amino substituted porphyrin) (5 mol%) in 1,2-dichloroethane under reflux for 3 h
indoles via direct C–H bond amination are relatively sparse. gave diiminated product 3a in 80% yield based on 78% substrate
The conventional method to introduce nitrogen atoms into indoles (1a) conversion (Scheme 1). No monoiminated indole or aminated
relies on nitration of indoles with nitric acid.3 This method suffers indole was detected. The structure of 3a was determined by
from the harsh reaction conditions and low product yields. Recently, 1H NMR, 13C NMR, mass spectrometry (see ESI†) and single
Li and coworkers reported a mild Cu(I)-catalyzed oxidative amida- crystal X-ray crystallography. The X-ray crystal structure of 3a
tion of N-methylindole with amide via C–H functionalization.4 By reveals the C(1)–N(2) and C(2)–N(4) distances to be 1.279 Å and
using sulfonyl azides as the nitrogen source, Zhou and coworkers 1.275 Å, respectively, in agreement with the CQN formulation.
described a Rh(III)-catalyzed amidation of indoles via chelation- [Ru(F20TPP)CO] (H2F20TPP = meso-tetrakis(pentafluorophenyl)-
assisted C–H bond activation.5 Dauban and coworkers used porphyrin) and [Ru(TDCPP)CO] (H2TDCPP = meso-tetrakis(2,6-
[Rh2(esp)2] (esp = a,a,a0,a0-tetramethyl-1,3-benzenedipropionic acid) dichlorophenyl)porphyrin) were less efficient than [Ru(TTP)CO]
as catalyst, sulfamate as the nitrene source and PhI(OCOR)2 or PhIO giving 3a in 21% and 47% yields and with 46% and 81% substrate
as an oxidant to achieve oxyamidation of N-phenylsulfonylindole.6 conversion, respectively (see ESI†). [Rh2(OAc)4], [Rh2(esp)2],
Liu and coworkers reported a palladium-/copper-catalyzed inter- [Cu(OTf)2], [Fe(TTP)Cl], and [Co(TTP)] failed to catalyze the diimina-
molecular C–H amination reaction of indoles using chlorosulfo- tion with the recovery of the starting materials or gave low product
namides as the nitrogen source.7 In spite of these advances, yield under similar reaction conditions (see ESI†). With [Ru(TTP)CO]
there are only a few examples of transition metal catalyzed C–H as catalyst, 1,2-dichloroethane was the best solvent (see ESI†).
amination of indoles; thus a new methodology for this transforma- Lowering the reaction temperature to room temperature resulted
tion is highly desired. Furthermore, all of these reported methods
only afforded monoaminated indoles, no catalytic diamination
a HKU Shenzhen Institute of Research & Innovation, Shenzhen, China
b State Key Laboratory of Synthetic Chemistry and Department of Chemistry,
The University of Hong Kong, Pokfulam Road, Hong Kong, China.
E-mail: cmche@hku.hk; Fax: +852 2857-1586; Tel: +852 2859-2154
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization. CCDC 973563. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c3cc49052a
Scheme 1
‡ These authors contributed equally to this work.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 3373--3376 | 3373

View Article Online
Communication
ChemComm
Table 1 Substitution effect of aryl azidesa
Table 2 [Ru(TTP)CO]-catalyzed diimination of indoles with 4-nitrophenyl
azide 2a and 3,5-bis(trifluoromethyl)phenyl azide 2ba
Entry
R
Product
Conv.b (%)
Yieldc (%)
1
2
3
3,5-CF3 (2b)
4-Cl (2c)
H (2d)
2-NO2 (2e)
4-NO2 (2a)
3b
3c
3d
3e
3a
84
71
0
97
94
80
25
0
31
90
4
5d
a
Conditions: N-methyl indole (0.2 mmol), aryl azide (0.6 mmol),
[Ru(TTP)CO] (5 mol%), 200 mg of 4 Å MS, 2 mL of DCE, argon,
b
c
d
reflux. Based on indole. Based on substrate conversion. Addition
of aryl azides in two batches was adopted.
in low substrate conversion and product yield. Tosyl azides and
phosphoryl azides failed to react with the indoles under the
[Ru(TTP)CO] catalyzed conditions.
With [Ru(TTP)CO] as catalyst, we examined the substitution
effect of aryl azides on the diimination. As depicted in Table 1,
when 3,5-bis(trifluoromethyl)phenyl azide 2b was used, the corre-
sponding diiminated product 3b was obtained in 80% yield and
84% substrate conversion (entry 1) comparable to those obtained
when 4-nitrophenyl azide 2a was used as the nitrene source. In
contrast, the use of 4-chlorophenyl azide 2c and phenyl azide 2d
led to the diimination product in 25% yield and in a trace
amount, respectively (entries 2 and 3). These results showed that
a strong electron-withdrawing group on aryl azides facilitates the
nitrene transfer to indoles. Compared with 2a, 2-nitrophenyl azide
2e gave lower product yield (31%, entry 4) attributed to the steric
effect of ortho-substitution. Considering the importance of nitro
group in organic synthesis, azide 2a was employed as the nitrene
source for subsequent studies.
In the diimination reaction, a considerable amount of aniline
was produced as the byproduct from the decomposition of aryl
azides. This could be the main cause for the incomplete consump-
tion of indoles. To circumvent this problem, addition of aryl azides
in two batches was adopted. At first, 2 equivalents of aryl azides
were added to the reaction mixture prior to heating. Upon the
a
Conditions: indole (0.2 mmol), aryl azide (0.4 + 0.25 mmol), [Ru(TTP)CO]
(5 mol%), 200 mg of 4 Å MS, 2 mL of DCE, argon, reflux until aryl azide
was completely consumed; conversion is based on indole and yield is
based on substrate conversion.
complete consumption of azides monitored by TLC, another batch reactivity towards the diimination giving 4a–4f in high yields
of aryl azides (one equivalent) was added. The reaction conversion (78%–94%). The reaction of N-acetyl indole gave 4g in 61% yield.
and the product yield were improved to 94% and 90%, respectively When the N–H group of indoles was substituted with a strong
(Table 1, entry 5). Therefore, this optimized addition of aryl azides electron-withdrawing tosyl group, the reaction was completely
was adopted in the subsequent studies.
inhibited. It is noteworthy that the reaction of N-allyl indole
With the optimized reaction conditions, the scope of indoles for exhibited an excellent chemoselectivity giving only diimination
the [Ru(TTP)CO]-catalyzed diimination was examined. As depicted product 4a in 89% yield without the detection of nitrene insertion
in Table 2, a variety of indoles reacted with 4-nitrophenyl azide 2a into the a C–H bond or aziridination of the allyl group.
in the presence of [Ru(TTP)CO] to give corresponding diimination
We next examined the effect of substitution on indoles toward
products 4a–4p in good to high yields (50–94%) and with quanti- the diimination. The indoles bearing electron-donating groups
tative substrate conversions. This reaction shows good functional (methyl or methoxy groups) exhibited high reactivity giving 4i–4l
group tolerance as various functionalities including alkene, in 83–90% yields and with the reaction completed within 5 h.
acyl, silane, methoxy, halide and ester groups are compatible Electron-withdrawing groups (ester, bromo, chloro) render indoles
with the protocol.
less reactive than their electron-donating counterparts leading to
The N-substitution effect on the Ru(II)-catalyzed diimination 4m–4p in 50–85% yields and a long reaction time of 15 h was
was first examined. N-Alkyl and -phenyl indoles displayed high required. These findings revealed that the reaction intermediate is
3374 | Chem. Commun., 2014, 50, 3373--3376
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
electrophilic and prefers to react with electron-rich indoles.
3,5-Bis(trifluoromethyl)phenyl azide 2b is also an effective nitrene
source for the diimination giving the corresponding products 4q–4t
in good to excellent yields. No reaction was observed when 2- or
3-methyl indole was used under the same reaction conditions.
It should be noted that only 2,3-diimination products of
indoles were isolated as depicted in Tables 1 and 2. No mono-
iminated or aminated indole was obtained or detected by ESI-MS
analysis of the reaction mixture. The underlying reason for this
observation is not clear. Attempts to synthesize monoiminoindole
or aminoindole were unsuccessful. For example, performing the
reactions of 1a and 2a in a ratio of 1 : 1 or 1 : 2 under the optimized
reaction conditions only led to 3a in 26% and 53% product yields,
respectively, without the mono-iminated or the mono-aminated
product being detected.
Scheme 3
To gain insight into the reaction mechanism, [Ru(TPP)(NAr)2]
(Ar = 3,5-bis(trifluoromethyl)phenyl) 5 was synthesized by the
reaction of [Ru(TPP)CO] and 3,5-bis(trifluoromethyl)phenyl azide
according to the literature10 and employed in the stoichiometric
reaction with indoles. Treatment of 5 (1 equiv.) with 1a (2 equiv.) in
1,2-dichloroethane under reflux for 1.5 h gave 3b in 35% yield
(Scheme 2). No mono-iminated or aminated product was obtained.
This finding suggests that the bis(imido)ruthenium complex
[Ru(TPP)(NAr)2] might be involved in the Ru(II)-catalyzed
diimination.
Dauban and coworkers recently reported an Rh(II)-catalyzed
oxyamidation of N-phenylsulfonylindole in which initial aziridina-
tion of indoles with subsequent ring opening by methanol or
carboxylic acid was proposed.6 However, when acetic acid or
methanol was added in our reaction, only a diimination product
was obtained though in very low yield without oxyamidation of
indoles being detected.
To examine whether the aniline, which was generated as the
byproduct in the reaction course, was responsible for the diimina-
tion, a control experiment was performed. Treatment of 1a (1 equiv.),
2b (2 equiv.) and 4-nitroaniline (2 equiv.) in the presence of
[Ru(TTP)CO] (5 mol%) in 1,2-dichloroethane under reflux gave 3b
in 65% yield based on 80% conversion of indoles (Scheme 3). The
dissymmetric imination product 6 was not observed. This result does
not support the involvement of aniline in the diimination.
A tentative reaction mechanism is proposed. As depicted in
Scheme 4, [Ru(TTP)CO] decomposes aryl azides to give metal–nitrene
intermediate I or II, both of which can undergo aziridination with
indoles to give III. A similar reaction mechanism was reported by
Kumar in which 1-(phenylsulfonyl)indole or 2-substituted indoles
reacted with phthalimidonitrene generated in situ by the oxidation
of N-aminophthalimide with lead tetraacetate to give aziridination
products in good yields.11 Intermediate III may undergo rapid
ring-opening followed by subsequent nitrene C–H insertion to
Scheme 4
give diamination product IV. Hydrogen atom abstraction of IV
by I or II gives the diimination product. The dehydrogenation of
amines to imines was reported previously.12–14 The exclusive
formation of the diimination product could be attributed to the
high reactivity/instability of intermediate III.
In summary, an efficient ruthenium porphyrin-catalyzed
diimination of sp2 C–H bonds of indoles has been developed. With
[Ru(TTP)CO] as catalyst and aryl azides as the nitrene source, a
variety of indoles were diiminated to give unique 2,3-diimination
products in good to high yields. The reaction displays high func-
tional group tolerance and excellent chemoselectivity. Furthermore,
the stoichiometric reaction of bis(imido)ruthenium complex
[Ru(por)(NAr)2] with indoles gave a product identical to that
observed in the catalytic reaction.
We are grateful for the financial support from the National
Natural Science Foundation of China (NSFC 21272197) and the
Hong Kong Research Grant Council (HKU 700813).
Notes and references
1 (a) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev.,
2010, 110, 4489; (b) M. Somei and F. Yamada, Nat. Prod. Rep., 2005,
22, 73; (c) Atta-ur-Rahman and A. Basha, Indole Alkaloids, Harwood
Academic, Chichester, UK, 1998; (d) R. J. Sundberg, Indoles,
Academic Press, London, 1996.
2 (a) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009,
48, 9608; (b) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007,
36, 1173; (c) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873.
3 (a) W. E. Noland, L. R. Smith and K. R. Rush, J. Org. Chem., 1965, 30, 3457;
(b) J. B. Hendrickson and J. G. de Vries, J. Org. Chem., 1985, 50, 1688;
(c) A. R. Mackenzie, C. J. Moody and C. W. Rees, Tetrahedron, 1986, 42, 3259.
4 Q. Shuai, G. Deng, Z. Chua, D. S. Bohle and C.-J. Li, Adv. Synth.
Catal., 2010, 352, 632.
5 J. Shi, B. Zhou, Y. Yang and Y. Li, Org. Biomol. Chem., 2012, 10, 8953.
6 S. Beaumont, V. Pons, P. Retailleau, R. H. Dodd and P. Dauban,
Angew. Chem., Int. Ed., 2010, 49, 1634.
Scheme 2
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 3373--3376 | 3375

View Article Online
Communication
ChemComm
7 X.-Y. Liu, P. Gao, Y.-W. Shen and Y.-M. Liang, Org. Lett., 2011, 10 S. Fantauzzi, E. Gallo, A. Caselli, F. Ragaini, N. Casati, P. Macchi and
13, 4196. S. Cenini, Chem. Commun., 2009, 3952.
8 L. He, P. W. H. Chan, W.-M. Tsui, W.-Y. Yu and C.-M. Che, Org. Lett., 11 P. R. Kumar, Heterocycles, 1987, 26, 1257.
2004, 6, 2405.
12 S. K.-Y. Leung, W.-M. Tsui, J.-S. Huang, C.-M. Che, J.-L. Liang and
N. Zhu, J. Am. Chem. Soc., 2005, 127, 16629.
9 (a) B. Krivogorsky, A. C. Nelson, K. A. Douglas and P. Grundt, Bioorg.
Med. Chem. Lett., 2013, 23, 1032; (b) D. P. Singh, K. Kumar, C. Sharma 13 J. Sankaranarayanan, S. Rajam, C. M. Hadad and A. D. Gudmundsdottir,
and K. R. Aneja, J. Enzyme Inhib. Med. Chem., 2010, 25, 544; J. Phys. Org. Chem., 2010, 23, 370.
(c) P. P. Bandekar, K. A. Roopnarine, V. J. Parekh, T. R. Mitchell, 14 V. Lyaskovskyy, A. I. O. Suarez, H. Lu, H. Jiang, X. P. Zhang and B. de
M. J. Novak and R. R. Sinden, J. Med. Chem., 2010, 53, 3558. Bruin, J. Am. Chem. Soc., 2011, 133, 12264.
3376 | Chem. Commun., 2014, 50, 3373--3376
This journal is ©The Royal Society of Chemistry 2014