Examination of the mechanism of Rh2(II)-catalyzed carbazole formation using intramolecular competition experiments

Article abstract of DOI:10.1021/jo901224k

(Chemical Equation Presented) The use of a rhodium(II) carboxylate catalyst enables the mild and stereoselective formation of carbazoles from biaryl azides. Intramolecular competition experiments of triaryl azides suggested the source of the selectivity. A primary intramolecular kinetic isotope effect was not observed, and correlation of the product ratios with Hammett σ⁺ values produced a plot with two intersecting lines with opposite ρ values. These data suggest that electronic donation by the biaryl π-system accelerates the formation of rhodium nitrenoid and that C-N bond formation occurs through a 4π-electron-5-atom electrocyclization.

Full text of DOI:10.1021/jo901224k

pubs.acs.org/joc
Examination of the Mechanism of Rh2(II)-Catalyzed Carbazole
Formation Using Intramolecular Competition Experiments
Benjamin J. Stokes, Kathleen J. Richert, and Tom G. Driver*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
tgd@uic.edu
Received June 10, 2009
The use of a rhodium(II) carboxylate catalyst enables the mild and stereoselective formation of carbazoles
from biaryl azides. Intramolecular competition experiments of triaryl azides suggested the source of the
selectivity. A primary intramolecular kinetic isotope effect was not observed, and correlation of the
product ratios with Hammett σ+ values produced a plot with two intersecting lines with opposite F values.
These data suggest that electronic donation by the biaryl π-system accelerates the formation of rhodium
nitrenoid and that C-N bond formation occurs through a 4π-electron-5-atom electrocyclization.
Introduction
mizing functional group manipulation.1f,3 Dirhodium(II)
complexes have proven to be efficient C-H bond amination
catalysts by stabilizing the nitrene intermediate.1e,4-9 Our
group has used these complexes to catalyze the intramole-
cular formation of C-N bonds from vinyl or aryl azides to
form indoles, pyrroles, and carbazoles.10 Use of the rhodium
catalyst provides a mild and stereoselective alternative to the
thermal- or photochemical reaction (Scheme 1).11 In this
paper, we report mechanistic studies aimed at determining
The development of efficient methods for the selective
transformation of carbon-hydrogen bonds into carbon-
heteroatom bonds remains a goal of synthetic chemistry.1
The direct incorporation of functionality into carbon-
hydrogen bonds improves synthetic efficiency2 by mini-
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Published on Web 08/10/2009
DOI: 10.1021/jo901224k
r
2009 American Chemical Society

Stokes et al.
JOCFeatured Article
SCHEME 1. Comparison of Regioselectivity of Carbazole
Formation from Biaryl Azide 1: Potential Mechanisms for C-N
Bond Formation
SCHEME 2. Comparison of the Reactivity of E- and Z-Isomers
of Styryl Azide 4
aromatic substitution, and electrocyclization of the rhodium
nitrenoid as the mechanism for C-N bond formation.
In contrast to the thorough studies on the mechanism of
thermal or photolytic nitrene formation from o-biaryl
azides,11e,12,13 mechanistic studies on metal nitrenoids gen-
erated from aryl azides are less common.14 The improved
regioselectivity observed when biaryl azide 1 was treated
with rhodium(II) octanoate (as compared to thermolysis)
reveals that the rhodium catalyst is involved in the C-N
bond-forming step of the mechanism. The analogous reac-
tivity of the E- or Z-stilbene isomer of 4 toward rhodium(II)
octanoate indicated that the functionalization of the C-H
bond occurs by a stepwise mechanism (Scheme 2).10b This
behavior contrasts with the metal-free pyrolysis of 4, where
the yield of 2-phenylindole 5 depended on the stereochemis-
try of the styryl azide (88% from E-4; 18% from Z-4).15
These results illustrate the differences between a rhodium
nitrenoid and an arylnitrene and suggest that arylnitrenes
might not be the best models for rhodium arylnitrenoids.
Instead, we anticipated that the rhodium arylnitrenoid
might be more similar to an arylnitrenium ion.16,17 The
the role of the catalyst in promoting and controlling this
regioselective transformation. Our results enable distinction
between a concerted aryl C-H bond insertion, electrophilic
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J. Org. Chem. Vol. 74, No. 17, 2009 6443

Stokes et al.
SCHEME 4. Synthesis of Triaryl Azides To Study the
Mechanism of Carbazole Formation
JOCFeatured Article
SCHEME 3. Arylnitrenium Ions as Potential Models for
Rhodium(II) Arylnitrenoids: Mechanistic Conclusions
singlet ground state of an arylnitrenium ion contains exten-
sive delocalization of the positive charge into the adjacent
π-system (Scheme 3).17d,18,19 If rhodium nitrenoid 8 behaved
similarly to 7, the electronic nature of the aryl substituents
would influence the mechanism of N-heterocycle forma-
tion through stabilization of the quinoid resonance struc-
ture 9. Herein, we report the results of our mechanistic
studies, which support this assertion. Our data suggest that
electronic donation by the biaryl π-system accelerates
rhodium nitrenoid formation from 10 and that C-N bond
formation occurs through a 4π-electron-5-atom electrocy-
clization of 11.
dibromoaniline 13 by two consecutive Suzuki cross-coupling
reactions (Scheme 4).22 Carbazoles 17 were also independently
synthesized from carbazole 16 through a Suzuki cross-coupling
reaction to verify the product ratio. Triaryl azides 15 would be
used first to determine if C-H bond cleavage and C-N bond
formation occurred simultaneously and then to investigate the
electronic effect of substituents on the o-aryl group.
Triaryl azide 15a-d5 was used to determine if the reaction
between the rhodium nitrenoid and the o-aryl C-H bond
was concerted (Scheme 5).23,24 If C-N bond formation and
C-H bond cleavage occurred simultaneously (via 20),24
a
primary kinetic isotope effect would result from preferen-
tial reaction of the reactive intermediate with the unlabeled
phenyl substituent.25,26 Exposure of 15a-d5 to rhodium(II)
perfluorobutyrate at 70 °C, however, gave a kinetic iso-
tope effect of 1.01. A similar isotope effect was observed
in 21-d1.10a These experiments show that C-H bond clea-
vage occurs after the product-determining step of the
reaction.27,28 Together with the equal reactivity of Z- and
E-4, these results confirm that a concerted insertion of the
Results and Discussion
Triaryl azides 15 were chosen to study the rhodium-catalyzed
N-heterocycle formation. These substrates allowed the investi-
gation of an intramolecular competition reaction between the
reactive intermediate and the C-H bond on either the phenyl
or aryl substituent. This was necessary because the rate-deter-
mining step of the mechanism was unknown,20,21 and the
intramolecular reaction would allow the ratio of carbazole
products obtained from 15 to offer insight into the mechanism
of the C-N bond-forming event even if it occurred after the
turnover-limiting step. The triaryl azides that were used for the
intramolecular competition experiments were synthesized from
(23) The identity of an intramolecular isotope effect can enable insight
into the mechanism of the product-determining step if it occurs after the rate-
determining step. For a general discussion of the use of product isotope
effects in mechanism determination, see: Carpenter, B. K., Determination of
Organic Reaction Mechanisms; Wiley-Interscience: New York, 1984; pp
101-104.
(24) For leading examples of the use of product isotope effect in
mechanism determination, see: (a) Dai, S.-H.; Dolbier, W. R. J. Am.
Chem. Soc. 1972, 94, 3946. (b) Beak, P.; Berger, K. R. J. Am. Chem. Soc.
1980, 102, 3848. (c) Song, Z.; Chrisope, D. R.; Beak, P. J. Org. Chem. 1987,
52, 3938. (c) Nesheim, J. C.; Lipscomb, J. D. Biochemistry 1996, 35, 10240.
(d) Newcomb, M.; Aebisher, D.; Shen, R.; Chandrasena, R. E. P.; Hollen-
berg, P. F.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064. (e) Singleton, D.
A.; Hang, C.; Szymanski, M. J.; Greenwald, E. E. J. Am. Chem. Soc. 2003,
125, 1176.
(25) 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) Sulikowski, G. A.; Lee, S. Tetrahedron Lett. 1999, 40, 8035. (c)
Clark, J. S.; Wong, Y.-S.; Townsend, R. J. Tetrahedron Lett. 2001, 42, 6187.
(26) For KIE data of related rhodium(II) carbenoid processes, see: (a)
Nowlan, D. T. I.; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J. Am.
Chem. Soc. 2003, 125, 15902. (b) Nowlan, D. T. I.; Singleton, D. A. J. Am.
Chem. Soc. 2005, 127, 6190.
(27) A similar kinetic isotope effect (1.13) was observed in the thermolysis
of 15a-d5. This secondary kinetic isotope effect indicates that C-N bond
formation and C-H bond cleavage are not concerted in the thermal reaction
as well.
(18) McClelland, R. A.; Kahley, M. J.; Davidse, P. A.; Hadzialic, G. J.
Am. Chem. Soc. 1996, 118, 4794.
(19) Cf. (a) Gassman, P. G.; Campbell, G. A. J. Am. Chem. Soc. 1971,
93, 2567. (b) Gassman, P. G.; Campbell, G. A.; Frederick, R. C. J. Am.
Chem. Soc. 1972, 94, 3884. (c) Novak, M.; Kahley, M. J.; Lin, J.; Kennedy,
S. A.; Swanegan, L. A. J. Am. Chem. Soc. 1994, 116, 11626. (d) Robbins, R.
J.; Yang, L. L.-N.; Anderson, G. B.; Falvey, D. E. J. Am. Chem. Soc. 1995,
117, 6544. (e) Sukhai, P.; McClelland, R. A. J. Chem. Soc., Perkin Trans. 2
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Soc. 1996, 118, 8127. (g) Ren, D.; McClelland, R. A. Can. J. Chem. 1998, 76,
78.
(20) For mechanistic and computational studes of Rh(II)-mediated
carbene transfer reactions, see: (a) Taber, D. F.; Ruckle, R. E. J. Am. Chem.
Soc. 1986, 108, 7686. (b) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.;
See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc.
1993, 115, 958. (c) Pirrung, M. C.; Li, H.; Morehead, A. T. J. J. Am. Chem.
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J.; Hengge, A. C.; Wu, W. Org. Lett. 2007, 9, 1663.
(21) The rate-limiting step for Rh(II)-mediated decomposition of R-
diazoesters is believed to be carbenoid generation; see ref 20.
(22) For recent examples of anilines employed as substrates in the Suzuki
reaction, see: (a) Miura, Y.; Nishi, T.; Teki, Y. J. Org. Chem. 2003, 68, 10158.
(b) Camacho, D. H.; Salo, E. V.; Guan, Z. Org. Lett. 2004, 6, 865. (c) Wu, Y.;
Li, J.; Fu, Y.; Bo, Z. Org. Lett. 2004, 6, 3485. (d) Miura, Y.; Muranaka, Y.;
Teki, Y. J. Org. Chem. 2006, 71, 4786. (e) Arnold, L. A.; Kiplin Guy, R.
Bioorg. Med. Chem. Lett. 2006, 16, 5360.
(28) A modest kinetic isotope effect (KIE=1.9; cyclohexane solvent)
was observed in the photolysis of 2-azidobiphenyl by Sundberg and co-
workers (ref 13d). They imply that this result suggests that the singlet
nitrene does not insert directly into the ortho-C-H bond but rather adds to
the carbon.
6444 J. Org. Chem. Vol. 74, No. 17, 2009

Stokes et al.
JOCFeatured Article
SCHEME 5. Secondary Kinetic Isotope Effect Obtained from Intramolecular Competition Experiments
nitrenoid into the o-aryl C-H bond is not occurring to form
either carbazole or indole products.
TABLE 1. Rhodium-Catalyzed Intramolecular Competition Reactions
of Triaryl Azides
A series of triaryl azides with electron-donating or elec-
tron-withdrawing aryl substituents were screened as substrates
to determine the electronic dependence of the C-H bond
functionalization (Table 1). 4-Substituted aryl groups were
chosen to simplify product analysis by providing only one
regioisomer. The results of these experiments are given in
Table 1 and show that C-N bond formation occurs preferen-
tially with the more electron-rich aryl group.
The product ratios from the reaction of 15 were anal-
yzed using the Hammett equation to determine if an elec-
trophilic aromatic substitution produced the C-N bond
(Scheme 6).29 In this mechanism, nucleophilic attack of the
pendant aryl or phenyl group onto the electrophilic rho-
dium nitrenoid 22 would form arenium ion 23 or 24. If this
mechanism occurs, a linear correlation of the product ratios
from triaryl azides 15 with Hammett σm values should be
observed because the C-N bond is forming meta to the R
group.30,31 Figure 1 clearly shows that the relationship
between σm values and the product ratios from 15 is not
linear. We interpret this result to mean that C-N bond
formation does not occur by electrophilic aromatic sub-
stitution.32 This conclusion is supported by the reactivity
patterns of aryl- and vinyl azides (40, 42, and 43), which will
be discussed below (eq 2 and Scheme 9).
Alternatively, the aryl substituents could affect the for-
mation of rhodium nitrenoid by controlling the amount of
electron density in the π-system (Scheme 7). Overlap of the
π-system with σ*N-N2 best occurs when the N2-leaving
group is oriented orthogonal to the triaryl group (31). If all
three arenes are planar, a destabilizing steric interaction
occurs between the rhodium catalyst and an o-aryl hydrogen
(32). As a result, the more electron-deficient aryl group
(29) For leading discussions of the correlation of the rate of the electro-
philic aromatic substitution reaction with the Hammett equation, see: (a)
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Chem. 1981, 46, 4595.
(30) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(31) For other Hammett correlation diagrams, see the Supporting
Information.
(32) Caution should be exercised in drawing firm conclusions from the
nonlinearity of the Hammett correlation using σ values for electrophilic
reactions. Refer to ref 29 for a detailed discussion.
a As determined using 1H NMR spectroscopy.
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FIGURE 1. Correlation of log (krel) of the Rhodium-Catalyzed Decomposition of Triaryl Azides 15 with σm Values in the Hammett Equation.
SCHEME 6. Nucleophilic Attack of the Aryl Group as the C-N Bond-Forming Step
would rotate out of the plane to form 27 or 28. Expulsion of
N2 then occurs to form N-rhodiumimine 29 or 30.33,34 If the
electronic nature of the R group affects the rate of nitrenoid
formation, linear correlation of the product ratios from 15
with Hammett σ+ values (or σp values) would be expected
because the reaction is occurring para to the R sub-
stituent. Because electron density is flowing away from the
arene, a F value less than zero should be observed.
The product ratios from 15 were plotted against Hammett
σ+ values29c,35 to test this mechanistic hypothesis (Figure 2).36
Both rhodium perfluorobutyrate and rhodium octanoate gave
plots that contained two intersecting lines (Figure 2). As predicted
by our hypothesis, a negative F value was obtained from triaryl
azides 15b-f. Triaryl azides with stronger electron-withdrawing
groups (15f-h), however, diverged from this trend to provide a
line with a positive F value. The V-shaped Hammett plot suggests
a change in mechanism (or rate-determining step) because the two
lines exhibit opposite F values.37 We did not observe this V-shape
€
(33) Cf. (a) Erker, G.; Fromberg, W.; Atwood, J. L.; Hunter, W. E.
Angew. Chem., Int. Ed. Engl. 1984, 23, 68. (b) Review: Cainelli, G.; Panuzio,
M.; Andreoli, P.; Martelli, G.; Spunta, G.; Giacomini, D.; Bandini, E. Pure Appl.
Chem. 1990, 62, 605. (c) Gilbertson, R. D.; Haley, M. M.; Weakley, T. J. R.;
ꢀ
Weiss, H.-C.; Boese, R. Organometallics 1998, 17, 3105. (d) Hevia, E.; Perez, J.;
Riera, V.; Miguel, D. Angew. Chem., Int. Ed. 2002, 41, 3858.
(34) While 29 and 30 could interconvert, N-metalloimine isomerization
would be slow in comparison to the subsequent C-N bond-forming step.
Z/E thermal isomerization of imines was measured to be approximately
15-25 kcal/mol. See: (a) Roberts, J. D.; Hall, G. E.; Middleton, W. J. J.
Am. Chem. Soc. 1971, 93, 4778. (b) Boyd, D. R.; Jennings, W. B.; Waring, L.
C. J. Org. Chem. 1986, 51, 992. (c) Asano, T.; Furuta, H.; Hofmann, H. J.;
Cimiraglia, R.; Tsuno, Y.; Fujio, M. J. Org. Chem. 1993, 58, 4418. (d)
Yamataka, H.; Ammal, S. C.; Asano, T.; Ohga, Y. Bull. Chem. Soc. Jpn.
2005, 78, 1851.
(35) For a general discussion of the uses of σþ values in the Hammett
reaction, see: (a) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry; Harper-Collins: New York, 1987; pp 149-151. (b) Car-
penter, B. K. Determination of Organic Reaction Mechanisms; Wiley-Inter-
science: New York, 1984; pp 144-148.
(36) While a better linear correlation was obtained using σp values, the
lines did not pass through the origin. See the Supporting Information or
additional Hammett correlation plots.
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FIGURE 2. Hammett correlation of log (krel) with σþ values for the rhodium-catalyzed decomposition of triaryl azides 15.
SCHEME 7. Influence of the Electronic Nature of the R Group on the Formation of the Rhodium Nitrenoid
The V-shape of the Hammett plot suggests that at least
for the metal-free thermolysis of triaryl azides 15, which gave a
single line with a negative F value (-0.66; Figure 3).31,38,39
two mechanisms are occurring in the rhodium-catalyzed
formation of carbazoles.37 The negative F value observed
for triaryl azides 15b-g reveals that electron density is
leaving the aryl π-system in the product-determining step.
(37) U- or V-shaped Hammett plots have been interpreted as evidence for
dual reaction mechanisms. For leading reports, see: (a) Fuchs, R.; Carlton,
D. M. J. Am. Chem. Soc. 1963, 85, 104. (b) Buckley, N.; Oppenheimer, N. J.
J. Org. Chem. 1996, 61, 7360. (c) Tanner, D. D.; Koppula, S.; Kandanar-
achchi, P. J. Org. Chem. 1997, 62, 4210. (d) Huang, R.; Espenson, J. H. J.
Org. Chem. 1999, 64, 6374. (e) Swansburg, S.; Buncel, E.; Lemieux, R. P. J.
Am. Chem. Soc. 2000, 122, 6594. (f) Ohshiro, H.; Mitsui, K.; Ando, N.;
Ohsawa, Y.; Koinuma, W.; Takahashi, H.; Kondo, S. i.; Nabeshima, T.;
Yano, Y. J. Am. Chem. Soc. 2001, 123, 2478. (g) Moss, R. A.; Ma, Y.; Sauers,
R. R. J. Am. Chem. Soc. 2002, 124, 13968. (h) Zdilla, M. J.; Dexheimer, J. L.;
Abu-Omar, M. M. J. Am. Chem. Soc. 2007, 129, 11505.
This result is best accommodated by a mechanism where the
(38) Smith and co-workers did not observe any linear correlation with
Hammett substituent constants in the decomposition of 2-azidobiaryls. The
reaction rate depended only on the arene bearing the azide group. See ref 11c.
(39) Theerrorinslopeandinterceptwasdeterminedusingleast-squaresanalysis.
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FIGURE 3. Hammett correlation of log (krel) with σþ values for the thermolysis of triaryl azides 15.
SCHEME 8. Possible 4π-Electron-5-Atom Electrocyclization
Step to Account for C-N Bond Formation
ability of the aryl substituent.40 Falvey and co-workers
interpreted these results as evidence that arylnitrenium ions
can be described as 4-iminocyclohexa-2,5-dienyl cations.40
Electronic donation by the biaryl π-system to form the
rhodium nitrenoid influences the mechanism of C-N bond
formation (Scheme 8). The planar nature of quinoid 35
enables a 4π-electron-5-atom electrocyclization to form the
C-N bond.28,41,42 This pericyclic reaction can be visual-
ized easier by examining 36, the resonance form of 35,
which clearly contains a contiguous, planar array of
π-orbitals.43 Upon formation of 38, a 1,5-hydride shift then
provides carbazole 39.44-46
(41) For recent reviews of 4π-electron-5-atom-electrocyclizations, see:
(a) Harmata, M. Chemtracts 2005, 17, 416. (b) Tius, M. A. Eur. J. Org. Chem.
2005, 2193. (c) Pellissier, H. Tetrahedron 2005, 61, 6479. (d) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577.
(42) Electrocyclization mechanisms have been suggested for the pyro-
lyses of 2-azidobenzophenones and 2-nitroazidobenzenes. For mechanistic
studies, including Hammett correlations, see: (a) Dyall, L. K. In The
Chemistry of Functional Groups. Supplement D: The Chemistry of Halides,
Pseudo-Halides, and Azides; Patai, S., Rappoport, Z., Eds.; Wiley: New York,
1968; Chapter 7. (b) Dyall, L. K. Aust. J. Chem. 1986, 39, 89. (c) Dyall, L. K.;
Karpa, G. J. Aust. J. Chem. 1988, 41, 1231.
(43) A 6π-electron-5-atom electrocyclization was posited as a potential
mechanism in the related deoxygenation of nitroaromatics; see: (a) Davies, I.
W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743. (b) Davies, I. W.;
Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham, V.; Bazaral, C. Tetrahedron
2005, 61, 6425. (c) Leach, A. G.; Houk, K. N.; Davies, I. W. Synthesis 2005,
3463.
(44) In the related thermal nitrene C-H amination reaction, C-N bond
formation is believed to precede N-H bond formation. See: (a) Reference .
(b) Smith, P. A. S. Aryl and heteroaryl azides and nitrenes. In Azides and Nitrenes,
Reactivity and Utility; Scriven, E. F. V., Ed.; Academic Press: London, 1984; p 95
(mechanistic discussion pp 175-182).
(45) A related diradical mechanism was proposed for the isomerization of
aryl-substituted azirines to indoles; see: Taber, D. F.; Tian, W. J. Am. Chem.
Soc. 2006, 128, 1058.
R substituent assists in the extrusion of N2 from the initial
metal-azide complex to form quinoid 35 (Scheme 8). In
support of the potential quinoidal structure of 35, time-
resolved infared spectroscopy of related N-aryl-N-methylni-
trenium ions revealed that the frequency of the CdC bond
stretch increased in proportion to the electron-donating
(40) When N-aryl-N-methylnitrenium ions were substituted with elec-
tron-donating groups, higher frequency aromatic CdC bond stretches were
observed using time-resolved infared spectroscopy. Falvey and co-workers
attributed the longer bond stretch to represent substantial charge delocaliza-
tion in the aromatic system to favor a quinoid structure. See ref 17d.
(46) In triaryl substrates, planarization of the more electron-rich ring
should increase the rate of N2-extrusion. We expect that the resulting
nitrenoid to react faster with this ring than with the more electron-deficient
ring, which is not necessarily in the plane.
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SCHEME 9. Potential Explanation for Reactivity Differences of Methoxy-Substituted Azidoacrylates
Aryl azide 40, which contains a methylene spacer in
between the two arenes, was examined to test the require-
ment for a contiguous array of π-orbitals (eq 2). Exposure of
40 to reaction conditions did not produce dihydroacridine
41. Instead, >95% of azide 40 was recovered. The lack of
reactivity of 40 agrees with our proposed electrocycliza-
tion mechanism and is inconsistent with an electrophilic
aromatic substitution mechanism, which would not require
a contiguous π-system.
hydride shift appears unlikely, however, because it would
require a nucleophilic rhodium(II) nitrenoid species47-49 and
a reversible N2-extrusion step.21 Alternatively, a different
mechanism could be operating for these substrates. Coordina-
tion of the rhodium carboxylate complex to the nitro or
sulfone group might cause the catalytic system to deviate from
the thermal behavior of these substrates (Scheme 10).50
Triaryl azide 15i (X=NMe3) was used to investigate if the
rhodium carboxylate were functioning as a Lewis acid
through σ-coordination to the X substituent (eq 3).50,51
The electrocyclization mechanism also offers an explanation
for the unusual reactivity trends that we observed with meth-
oxy-substituted azidoacrylates (Scheme 9). In azide 42, the p-
methoxy-substituent is positioned to donate electron density to
accelerate the formation of the nitrenoid species to result in the
efficient formation of indole 44. In contrast, placing the
methoxy group at the 3-position of vinyl azide causes it to act
as an inductive electron-withdrawing group and slow nitrenoid
formation from 45: only 22% of azide 45 was converted into
indole 47 with 5 mol % of catalyst. The remainder of the
mixture was unreacted vinyl azide 45. If an electrophilic aro-
matic substitution mechanism occurred to form indole, azide 45
would be expected to react faster because the methoxy group is
positioned to donate electron density to attack the electron-
deficient rhodium nitrenoid (48).
If this phenomenon was occurring, the product ratio
from 15i would not correlate linearly with substrates 15f-h
because coordination to the trimethylammonium substituent
The V-shape of the Hammett plot indicates that a change in
mechanism occurs for substrates bearing strongly electron-
withdrawing groups (σþ g 0.6). The positive F value for this
portion of the plot reveals that the aryl group accepts electron
density in the product-determining step. Changing the identity
of the product-determining step to the electrocyclization or
(49) While nitrenes and nitrenoids are generally assumed to be electro-
philic (see ref 5e for a discussion of F values), the pKb of singlet phenyl nitrene
was measured to be -2 . See: (a) ref 18. (b) Wang, J.; Burdzinski, G.; Platz, M.
S. Org. Lett. 2007, 9, 5211.
(50) For the use of dirhodium(II) complexes as Lewis acids, see: (a) Doyle,
M. P.;Phillips, I. M.;Hu, W. J. Am. Chem. Soc. 2001, 123, 5366. (b) Anada, M.;
Washio, T.;Shimada,N.;Kitagaki, S.; Nakajima, M.; Shiro, M.;Hashimoto, S.
Angew. Chem., Int. Ed. 2004, 43, 2665. (c) Doyle, M. P.; Valenzuela, M.; Huang,
P. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5391. (d) Wang, Y.; Wolf, J.; Zavalij,
P.; Doyle, M. P. Angew. Chem., Int. Ed. 2008, 47, 1439.
(47) For discussions on the electronic nature of rhodium(II) nitrenoids,
see: refs 5e, 14c, and: Espino, C. G.; Du Bois, J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley: New York, 2005; p
379 (discussion on pp 402-405).
(48) Some nucleophilic group 8 metal nitrenoid complexes have been
reported. For leading examples, see: (a) Ir: Glueck, D. S.; Hollander, F. J.;
Bergman, R. G. J. Am. Chem. Soc. 1989, 111, 2719. (b) Rh: Ge, Y. W.; Sharp,
P. R. J. Am. Chem. Soc. 1990, 112, 3667. (c) Ir: Glueck, D. S.; Wu, J.; Hollander,
F. J.; Bergman, R. G. J. Am. Chem. Soc. 1991, 113, 2041. (d) Co: Jenkins, D. M.;
Betley, T. A.; Peters, J. C. J. Am. Chem. Soc. 2002, 124, 11238.
(51) For leading reports of rhodium(II) η2-π complexes, see: (a) Doyle,
M. P.; Colsman, M. R.; Chinn, M. S. Inorg. Chem. 1984, 23, 3684. (b) Cotton,
F. A.; Falvello, L. R.; Gerards, M.; Snatzke, G. J. Am. Chem. Soc. 1990, 112,
8979. (c) Cotton, F. A.; Dikarev, E. V.; Stiriba, S. E. Organometallics 1999,
18, 2724. (d) Cotton, F. A.; Dikarev, E. V.; Petrukhina, M. A. J. Am. Chem.
Soc. 2001, 123, 11655.
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FIGURE 4. Hammett correlation of log (krel) with σp values for the rhodium-catalyzed decomposition of triaryl azides 15f-i.
considered to be an electron-donating group. We interpreted
these results as evidence for two different mechanisms.
Electron-rich substrates appear to react through a mechan-
ism in which electronic donation by an aryl R substituent
assists in the formation of a planar arylnitrenoid that under-
goes a 4π-electron-5-atom electrocyclization to form the new
C-N bond. In agreement with our mechanistic hypothesis,
substrates that lack a contiguous π-system are unreactive.
While our experimental results prevent definitive conclu-
sions for the mechanism operating in electron-deficient
substrates, our data does suggest that the rhodium carbox-
ylate does not σ-coordinate to the R group. We believe that
these studies provide new models for azide reactivity toward
rhodium carboxylates, and that the mechanistic insight
gained herein will guide future methodology development
that builds on our understanding of the interactions of metal
complexes and azides.
SCHEME 10. Possible Mechanism Involving Coordination of
Rhodium to Arene
Experimental Section
is not possible. The product ratio from 15i, however, does
correlate linearly with the azides 15f-h using Hammett σp
values. This relationship reveals that σ-coordination of the R
substituent to the rhodium(II) carboxylate is not occurring in
the mechanism for substrates bearing strongly electron-with-
drawing groups (Figure 4).
2-Bromo-4-methyl-6-phenylaniline. In a dry 500 mL round-
bottom flask, phenylboronic acid (5.00 g, 43.0 mmol, 1.3 equiv),
K2CO3 (21.50 g, 156 mmol, 4.0 equiv), and Pd(PPh3)4 (2.00 g,
1.73 mmol, 0.1 equiv) were dissolved in 150 mL of toluene,
100 mL of H2O, and 50 mL of EtOH. 2,6-Dibromo-4-methyla-
niline (10.48 g, 39.8 mmol, 1.0 equiv) was added, and the
resulting mixture was heated to 95 °C for 16 h. After cooling,
the biphasic solution was diluted with 100 mL of saturated
aqueous NH4Cl and 100 mL of CH2Cl2 and separated. The
aqueous phase was extracted with an additional 2 ꢀ 100 mL
of CH2Cl2, and the combined organic phases were washed 1 ꢀ
100 mL of water and 1 ꢀ 100 mL of saturated aqueous
NaHCO3. The organic phase was dried over Na2SO4 and
filtered. The filtrate was concentrated in vacuo to afford a
brown oil. Purification by MPLC (15:85 benzene/hexanes)
afforded 2-bromo-4-methyl-6-phenylaniline as a white powder
(4.90 g, 47%): mp 58 °C; Rf = 0.31 (15:85 benzene/hexanes,
visualized by 254 nm UV light); 1H NMR (CDCl3, 500 MHz) δ
Conclusions
The mechanism of N-heterocycle formation from aryl and
vinyl azides was examined through intramolecular competi-
tion experiments. The lack of a primary intramole-
cular kinetic isotope effect suggests that the C-H(D) bond
cleavage does not occur in the product-determining step.
Correlation of the product ratios obtained from a series of
substituted triaryl azides with the Hammett equation gener-
ated plots with two intersecting lines. The best linear correla-
tion was obtained when the methoxy substituent was
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Stokes et al.
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7.50-7.45 (m, 4H), 7.42-7.38 (m, 1H), 7.31 (s, 1H), 6.93 (s, 1H),
4.04 (s, 2H), 2.30 (s, 3H); 13C NMR (CDCl3, 125 MHz) 139.3
(C), 139.0 (C), 132.1 (CH), 130.4 (CH), 129.1 (CH), 128.9 (CH),
128.7 (C), 128.5 (C), 127.7 (CH), 109.9 (C), 20.2 (CH3); IR (thin
film) 3477, 3385, 3045, 3028, 2924, 1619, 1593, 1473, 1441, 1302,
1234, 1073, 1058, 861, 638, 575 cm-1; HRMS (EI) m/z calcd for
C13H12NBr (Mþ) 261.0153, found 261.0154.
mixture was warmed to ambient temperature and stirred for
30 min. The solution was diluted with 20 mL of water and 20 mL
of CH2Cl2 and basified by the slow addition of K2CO3 until
bubbling ceased. The phases were separated, and the aqueous
phase was extracted with an additional 2 ꢀ 20 mL of CH2Cl2. The
combined organic phases were washed 1 ꢀ 20 mL of water and
1 ꢀ 20 mL of brine. The resulting organic phase and dried over
Na2SO4 and filtered. The filtrate was concentrated in vacuo to
afford an oil. Purification by MPLC (100% hexanes) afforded
azide 15b as a faint yellow oil (0.080 g, 97%): Rf=0.55 (10:10:80
benzene/EtOAc/hexanes, visualized by 254 nm UV light);
1H NMR (CDCl3, 500 MHz) δ 7.53-7.52 (m, 2H), 7.49-7.45
(m, 4H), 7.42-7.39 (m, 1H), 7.13 (m, 2H), 7.03-7.00 (m, 2H),
3.88 (s, 3H), 2.42 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.2
(C), 138.7 (C), 136.4 (C), 136.1 (C), 135.2 (C), 132.1 (C), 131.1
(CH), 131.0 (C), 130.8 (CH), 130.5 (CH), 129.4 (CH), 128.4 (CH),
127.6 (CH), 113.9 (CH), 55.4 (CH3), 20.9 (CH3); IR (thin film)
2-(4-Chlorophenyl)-4-methyl-6-phenylaniline. Toa dry100mL
round-bottom flask equipped with a stir bar were added
2-bromo-4-methyl-6-phenylaniline (0.500 g, 1.90 mmol, 1.0
equiv), 4-chlorophenylboronic acid (0.343 g, 2.09 mmol, 1.3
equiv), K2CO3 (1.050 g, 7.63 mmol, 4.0 equiv), and Pd(PPh3)4
(0.110 g, 0.950 mmol, 0.1 equiv). Toluene (30 mL), 20 mL of H2O,
and 10 mL of EtOH were added, and the resulting mixture was
heated to 95 °C for 16 h. After cooling, the biphasic solution was
diluted with 100 mL of saturated aqueous NH4Cl and
100 mL of CH2Cl2 and separated. The organic phase was washed
1 ꢀ 100 mL of water and 1 ꢀ 100 mL of saturated aqueous
NaHCO3. The organic phase was dried over Na2SO4 and filtered.
The filtrate was concentrated in vacuo to afford a brown oil.
Purification by MPLC (0:10:90-10:10:80 EtOAc/benzene/
hexanes) afforded 2-(4-chlorophenyl)-4-methyl-6-phenylaniline
as a white powder (0.463 g, 83%): mp 101 °C; Rf = 0.56
(10:10:80 benzene/EtOAc/hexanes, visualized by 254 or 365 nm
2122, 2093, 1513, 1455, 1422, 1290, 1265, 1179, 1033, 896 cm-1
;
HRMS (EI) m/z calcd for C20H17ON3 (Mþ) 315.13717, found
315.13679.
Acknowledgment. We are grateful to the National Insti-
tutes of Health NIGMS (R01GM084945), Petroleum Research
Fund administered by the American Chemical Society (46850-
G1), and the University of Illinois at Chicago for their generous
support. We thank Professors Martin E. Newcomb (UIC),
Laura L. Anderson (UIC), Douglass Taber (U Delaware), and
1
UV light); H NMR (CDCl3, 500 MHz) δ 7.55-7.45 (m, 8H),
7.42-7.39 (m, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.98 (d, J=1.6 Hz,
1H), 3.67 (br s, 2H), 2.36 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
139.7 (C), 138.4 (C), 138.2 (C), 133.2 (C), 130.8 (CH), 130.7 (CH),
130.3 (CH), 129.4 (CH), 129.0 (CH), 128.9 (CH), 128.4 (C), 127.6
(C), 127.4 (CH), 126.9 (C), 20.5 (CH3); IR (thin film) 3455, 3386,
3053, 2985, 2923, 2859, 2305, 1615, 1599, 1492, 1466, 1438, 1392,
1265, 1092, 1015, 896, 872, 837, 749, 704 cm-1; HRMS (EI) m/z
calcd for C19H16NCl (Mþ) 293.0971, found 293.0973.
ꢀ ꢁ
Helene Lebel (U Montreal) for helpful discussions. We also
thank Dr. Dan McElheny (UIC) for assistance with NMR
spectroscopy and Mr. Furong Sun (UIUC) for mass spectro-
metry data. The 70-VSE mass spectrometer (UIUC) was
purchased in part with a grant from the Division of Research
Resources, National Institutes of Health (RR 04648).
Azide 15b. In a 20 mL scintillation vial, 2-(4-methoxyphenyl)-
4-methyl-6-phenylaniline (0.076 g, 0.253 mmol, 1.0 equiv)
was dissolved in 3 mL of HOAc and chilled in an ice bath.
NaNO2 (0.026 g, 0.367 mmol, 1.45 equiv) was added slowly, and
the resulting mixture was stirred at 0 °C for 1 h. NaN3 (0.393 g,
0.393 mmol, 1.55 equiv) was then added slowly, and the resulting
Supporting Information Available: Complete experimental
procedures and spectroscopic and analytical data for the pro-
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 17, 2009 6451