Intramolecular C-H amination reactions: Exploitation of the Rh 2(II)-catalyzed decomposition of azidoacrylates

Article abstract of DOI:10.1021/ja072219k

Rhodium(II) perfluorobutyrate-mediated decomposition of vinyl azides provides a new, mild entry into Rh₂(II) nitrenoid chemistry. This methodology allows rapid access to a variety of complex, functionalized N-heterocycles in two steps from commercially available starting materials. Copyright

Full text of DOI:10.1021/ja072219k

Published on Web 05/25/2007
Intramolecular C-H Amination Reactions: Exploitation of the
Rh2(II)-Catalyzed Decomposition of Azidoacrylates
Benjamin J. Stokes, Huijun Dong, Brooke E. Leslie, Ashley L. Pumphrey, and Tom G. Driver*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received March 29, 2007; E-mail: tgd@uic.edu
The activation of C-H bonds by dirhodium(II) carbenoids1 and
nitrenoids2 allows access to valuable carbocycles and heterocycles
efficiently and stereoselectively.3 These reactive intermediates are
most commonly accessed through the rhodium(II)-mediated de-
composition of diazo compounds4 or sulfonyliminoiodinanes.5
While metal-mediated nitrogen atom transfer reactions from azides
are well-documented,6 the use of dirhodium(II) carboxylates has
not been shown to be effective despite their proven utility in other
related atom transfer reactions.7 Although nitrenes can be formed
from azides by thermolysis,8 the high temperatures often required
to promote this reaction cause safety concerns,9 which diminish
the usefulness of this method. Since azides are readily available,10-12
the prospect of rhodium nitrenoid generation from them is highly
appealing. Herein, we report a rhodium(II)-mediated C-H bond
amination that transforms vinyl azides into indoles and other
N-heterocycles (Scheme 1).13
withdrawing aryl substituents. Chemoselective formation of the
indole product was observed when R1 ) Me (entry 10). For
substrates containing an R2 substituent, the major regioisomer was
the 5-substituted indole, which resulted from reaction with the
sterically less encumbered C-H bond (entries 13-15).
Table 2. Scope of the Rhodium-Mediated Indole Formation
mol %
entry
R1
R2
R3
[Rh]
temp (
°
C)
% yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Br
OMe
OMe
Me
i-Pr
t-Bu
H
Cl
Br
CF3
H
H
H
H
OMe
OMe
OMe
3
5
5
5
5
5
5
5
5
5
5
5
3
3
3
40
60
60
60
60
60
60
60
60
60
60
60
40
40
40
98
88
91
71
84
85
84
88
91
93
76
97b
92c
98d
88e
Scheme 1
While a variety of metal complexes were examined to convert
vinyl azide 1 to indole 3, only dirhodium(II) carboxylates were
found to be competent for indole formation (Table 1). Employing
metal salts6 (Ag,14 Cu,15 Co,16 and Fe complexes17) or other Lewis
acids known to catalyze nitrenoid chemistry from azides or other
nitrene equivalents led only to recovery of 1.18 The activity of the
rhodium catalyst is dependent upon the electronic nature of its
ligands with higher yields observed with more electron-deficient
carboxylates (entries 2-5). Optimal reactivity was obtained at 40
°C when rhodium(II) perfluorobutyrate was employed. The tem-
perature of the reaction can be lowered, but higher catalyst loading
is required (entry 6). Optimization of solvent revealed that toluene
was superior to chlorinated or ethereal solvents.18
H
a Isolated yield after flash chromatography over SiO2. b Regioselectivity
87:13. c Regioselectivity 79:21. d Regioselectivity 92:8. e Regioselectivity
>95:5.
In addition to indoles, a variety of aromatic N-heterocycles can
be accessed from vinyl azides using rhodium(II) perfluorobutyrate
as a catalyst (Table 3). Both 1- and 2-substituted naphthalene vinyl
azides were transformed into indoles 13 and 14 (entries 1 and 2)
Table 3. Formation of N-Heteroaromatic Compounds
Table 1. Optimization of Catalytic Conditions
entry
metal salt
mol %
temp (
°
C)
% yielda
1
2
3
4
5
6
none
Rh2(OAc)4
Rh2(O2CCF3)4
Rh2(O2CCF3)4
Rh2(O2CC3F7)4
Rh2(O2CC3F7)4
na
10
5
5
3
145
30
30
40
40
30
85b
9
64
>95
>95
>95
5
1
a As determined using H NMR spectroscopy. b After 1 h.
With the identification of the optimal reaction conditions, the
scope of the reaction was investigated (Table 2).19 The reaction
tolerated substrates with both electron-donating and electron-
a Isolated yield after flash chromatography over SiO2. b Regioselectivity
>95:5.
9
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J. AM. CHEM. SOC. 2007, 129, 7500-7501
10.1021/ja072219k CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Taber, D. F.; Joshi, P. V. J. Org. Chem. 2004, 69, 4276. (b) Davies,
H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060. (c)
Bykowski, D.; Wu, K.-H.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128,
16038.
(2) (a) Fruit, C.; Mu¨ller, P. Tetrahedron: Asymmetry 2004, 15, 1019. (b)
Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378. (c) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem.
Soc. 2005, 127, 14198. (d) Liang, C.; Robert-Peillard, F.; Fruit, C.; Mu¨ller,
P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2006, 45, 4641. (e)
Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013. (f) Fiori, K. W.;
Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562.
(3) For demonstrations of Rh(II)-mediated atom transfer reactions in total
synthesis, see: (a) Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org. Chem.
2002, 67, 2954. (b) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 11510. (c) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem.
Soc. 2006, 128, 2485. (d) Mej´ıa-Oneto, J. M.; Padwa, A. Org. Lett. 2006,
8, 3275.
(4) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091.
(5) (a) Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728. (b)
Mansuy, D.; Mahy, J.-P.; Dure´ault, A.; Bedi, G.; Battioni, P. Chem.
Commun. 1984, 1161.
(6) For recent reviews on the formation and reactivity of metal nitrenoids
formed from the reaction of metal complexes and azides, see: (a) Katsuki,
T. Chem. Lett. 2005, 34, 1304. (b) Cenini, S.; Gallo, E.; Caselli, A.;
Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem. ReV. 2006, 250,
1234.
(7) Photolysis of NsN3 produces nitrene, which was reported to react with
styrene in the presence of a Rh(II) bis(naphthol)phosphate catalyst to
produce an aziridine in 9% yield. In the absence of hν, no aziridine was
produced. See: Mueller, P.; Baud, C.; Naegeli, I. J. Phys. Org. Chem.
1998, 11, 597.
(8) For leading reviews, see: (a) Moody, C. J. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Ley, S., Eds.; Pergamon: Oxford,
1991; Vol. 7, p 21. (b) So¨derberg, B. C. G. Curr. Org. Chem. 2000, 4,
727.
(9) For a discussion of the safety issues of processes involving azides, see:
Wiss, J.; Fleury, C.; Onken, U. Org. Process Res. DeV. 2006, 10, 349.
(10) The vinyl azides employed herein were synthesized by the condensation
of an aromatic or heteroaromatic aldehyde with methyl azidoacetate.
(11) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed.
2005, 44, 5188.
though the 2-substituted naphthalene substrate required slightly
harsher conditions. While 2-substituted benzofurans, furans, and
thiophenes can be efficiently converted (entries 3 and 4), protection
of the pyrrole nitrogen with a Piv or Boc group was necessary to
access N-heterocycles 18 and 19 (entry 5). Presumably, the
protecting group must inhibit coordination of the nitrogen to the
coordinatively unsaturated rhodium catalyst.
The mechanism is believed to be similar to that proposed for
the rhodium(II)-mediated C-H bond functionalization by R-diazo
esters (Scheme 2).20,21 Following this model, initial coordination
of the dirhodium(II) carboxylate with the R-nitrogen of azide 1
produces 20,22 the presumed resting state of the catalyst.20a Upon
rhodium nitrenoid (2) formation from 20, C-N bond formation
could occur by two pathways: a concerted20 insertion of 2 into an
ortho-C-H bond (21) or a stepwise23 electrophilic aromatic
substitution via arenium ion 22. Interrogation of this step by
submission of deuterium-labeled vinyl azide 23 to reaction condi-
tions revealed a product isotope effect of 1.0 (eq 1).24 The magnitude
of the isotope effect suggests that a stepwise substitution reaction
is occurring.25 When this reaction was run to 75% completion, re-
isolation of the labeled vinyl azide showed no H/D exchange at
the labeled ortho-position, indicating that C-N bond formation
happened after the irreversible loss of N2.
(12) An alkyl azide is a key intermediate in the Roche Tamiflu synthesis. See:
Federspiel, M.; et al. Org. Process Res. DeV. 1999, 3, 266.
(13) For leading reports on the thermal version of the reaction, see: (a)
Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1970, 101,
161. (b) Moody, C. J. Stud. Nat. Prod. Chem. 1988, 1, 163. (c) Moody,
C. J.; Warrellow, G. J. J. Chem. Soc., Perkin Trans. 1 1990, 2929.
(14) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210.
(15) Dauban, P.; Sanie`re, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc.
2001, 123, 7707.
(16) Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Gotti, C. L.; Lapadula, M.;
Mangioni, E.; Cenini, S. Chem.sEur. J. 2003, 9, 249.
(17) Bach, T.; Schlummer, B.; Harms, K. Chem.sEur. J. 2001, 7, 2581.
(18) See Supporting Information for a complete listing of the reaction conditions
employed.
In conclusion, we have developed a new, mild way to access
rhodium(II) nitrenoids from azides. This methodology allows rapid
access to a variety of complex, functionalized N-heterocycles in
two steps from commercially available starting materials. Currently,
we are working to broaden our understanding of the unique
reactivity of these azidoacrylates and to apply our mechanistic
conclusions in the development of new methods that form N-
heterocycles from azides by rhodium-mediated nitrogen atom
transfer.
(19) In the absence of catalyst, no indole product was formed at this
temperature.
(20) For mechanistic and computational studies of related Rh(II)-mediated
carbene transfer reactions, see, respectively: (a) Pirrung, M. C.; Liu, H.;
Morehead, A. T., Jr. J. Am. Chem. Soc. 2002, 124, 1014. (b) Nakamura,
E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
(21) For a study of the mechanism of the intramolecular C-H bond insertion
of aryl nitrenes, see: Murata, S.; Tsubone, Y.; Kawai, R.; Eguchi, D.;
Tomioka, H. J. Phys. Org. Chem. 2005, 18, 9.
(22) For reports of Lewis acid coordination to the R-nitrogen of an azide, see:
(a) Takeuchi, H.; Maeda, M.; Mitani, M.; Koyama, K. Chem. Commun.
1985, 287. (b) Olah, G. A.; Ramaiah, P.; Wang, Q.; Prakash, G. K. S. J.
Org. Chem. 1993, 58, 6900. (c) Wrobleski, A.; Aube´, J. J. Org. Chem.
2001, 66, 886.
Acknowledgment. We are grateful to the University of Illinois
at Chicago for their generous support. We thank Profs. David Crich,
Vladimir Gevorgyan, Martin E. Newcomb, and Duncan J. Wardrop
for insightful discussions and chemicals. We thank Dr. Dan
McElheny for assistance with NMR spectroscopy, and Dr. John
A. Anderson and Dr. Carrie Ann Crot for mass spectrometry data.
(23) For a related Rh(II)-mediated C-H functionalization reaction postulated
to occur in a stepwise fashion, see: Clark, J. S.; Dossetter, A. G.; Wong,
Y.-S.; Townsend, R. J.; Whittingham, W. G.; Russell, C. A. J. Org. Chem.
2004, 69, 3886.
(24) For related isotope studies of C-H bond functionalization by rhodium
carbenoids, see: (a) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116,
3296. (b) Clark, J. S.; Wong, Y.-S.; Townsend, R. J. Tetrahedron Lett.
2001, 42, 6187.
(25) For a discussion on the isotope effects observed in electrophilic aromatic
substitution, see: Perrin, C. L. J. Org. Chem. 1971, 36, 420.
Supporting Information Available: Complete ref 12, experimental
procedures, spectroscopic, and analytical data for the products (PDF).
JA072219K
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J. AM. CHEM. SOC. VOL. 129, NO. 24, 2007 7501