Ring expansion and rearrangements of rhodium(II) azavinyl carbenes

Article abstract of DOI:10.1002/anie.201207820

The ring expansion and rearrangement of diazo compounds, specifically rhodium carbenes (derived from the corresponding diazo species), is an efficient and operationally simple method for the construction of structurally unique frameworks.[ 1] Products der

Full text of DOI:10.1002/anie.201207820

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Angewandte
Communications
DOI: 10.1002/anie.201207820
Rhodium(II) Catalysis
Ring Expansion and Rearrangements of Rhodium(II) Azavinyl
Carbenes**
Nicklas Selander, Brady T. Worrell, and Valery V. Fokin*
Dedicated to Professor Michael P. Doyle on the occasion of his 70th birthday
The ring expansion and rearrangement of diazo compounds,
specifically rhodium carbenes (derived from the correspond-
ing diazo species), is an efficient and operationally simple
method for the construction of structurally unique frame-
works.[1] Products derived from these reactions normally
consist of large carbocyclic rings (7, 8, and 9 membered) and
multiple substituted olefins, which are ubiquitous in natural
products and drug molecules.[2] Indeed, these robust methods
have found widespread use in organic synthesis, both for the
synthesis of complex natural products and in pharmaceutical
research.[3] Bolstered by our recent success utilizing readily
available and stable 1-sulfonyl-1,2,3-triazoles 1 as direct
precursors
to
rhodium(II)
azavinyl
carbenes
2
(Scheme 1),[4,5] we hypothesized that these diazo progenitors
Scheme 2. Rhodium(II)-catalyzed ring expansion and rearrangement of
azavinyl carbenes.
Scheme 1. Utility of Rhodium(II) Azavinyl Carbenes.
alcohols.[8] These unique triazoles species (3) were submitted
to a rhodium-catalyzed denitrogenative ring-expansion reac-
tion to form the homologated product. To this end, we reacted
triazole 3a with 0.5 mol% of rhodium(II) octanoate dimer in
chloroform. When the reaction was heated to a minimum of
708C, a rapid evolution of gas occurred and the reaction
proceeded to completion within 15 min. The ring-expanded
product 5a was formed in 91% yield (Table 1, entry 1). A Z-
substituted enaminone (5) was exclusively formed owing to
a facile but selective tautomerization of the acidic a-proton
(the tautomeric ketoimine 4 was not observed). Of note, no
reaction was observed without the addition of a rhodium(II)
catalyst, even under forcing conditions (> 1008C).
could be effective in these ring expansion/rearrangement
reactions, to deliver unique products that are not accessible
via conventional diazo compounds (Scheme 2). Herein, we
report the rhodium(II)-catalyzed ring-expansion and rear-
rangement reactions of azavinyl carbenes (2), to access
various enaminones and substituted olefins, which, in the
case of the expanded enaminones can be further reacted to
form a variety of heterocycles and ketone-based products.[6,7]
We began our investigations with the synthesis of various
1-sulfonyl triazoles bearing cyclic, tertiary alcohols at the 4-
position (Table 1) from the corresponding sulfonyl azide and
commercially available or easily synthesized propargylic
When these reaction conditions were applied to different
sulfonyl triazoles similarly satisfying results were obtained
(Table 1, yields 66–98%). Various cyclic substituents were
smoothly and rapidly (15 min) converted into the expanded
enaminone products, to yield 6, 7, and 8-membered rings (5a–
5c, 91–94%). Triazoles bearing electron-withdrawing, elec-
tron-donating, and aliphatic sulfonyl groups easily underwent
this homologation process to yield the enaminone products
(5d–5 f, 66–95%) in good to excellent yields. Furthermore,
heteroatoms within the ring structure did not affect the
efficiency of this reaction; reactions of both ether 3g and
amide 3h gave the expected products in excellent yields (5g
and 5h, 92–98%). Interestingly, the strained adamantane 3i
[*] Dr. N. Selander, B. T. Worrell, Dr. V. V. Fokin
Department of Chemistry, The Scripps Research Institute
La Jolla, CA 92037 (USA)
E-mail: fokin@scripps.edu
Homepage: http://www.scripps.edu/chem/fokin
[**] This work was supported by the National Science Foundation (CHE-
0848982) and the National Institute of General Medical Science,
National Institutes of Health (GM-087620). N.S. also acknowledges
a postdoctoral fellowship from the Swedish Research Council (VR).
Dr. Jessica Raushel’s contribution to the initial ring-expansion
studies is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207820.
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Table 1: Ring expansion of various 1-sulfonyl 4-tertiary alcohol triazoles 3
yielding products 5.[a]
corresponding substituted olefin (7) upon formation of the
rhodium(II) azavinyl carbene. To investigate this hypothesis,
we synthesized 1-sulfonyl triazole 6a bearing the requisite
tert-butyl group at C4 and submitted it to the general reaction
conditions. Gratifyingly, upon heating to 708C in the presence
of 0.5 mol% of rhodium(II) octanoate, the rapid evolution of
gas occurred (20 min) and 6a was smoothly converted into the
expected tetra-substituted olefin 7a in 91% yield (Table 2,
entry 1).
Table 2: Rearrangements of 1-sulfonyl triazoles 6 to give substituted
alkenes 7.[a]
[a] Reaction conditions: 1-sulfonyl triazole (1.0 mmol, 1.0 equiv), rho-
dium(II) octanoate (0.5 mol%), CHCl3 (2.0 mL), 708C, mw, 5–60 min. All
yields shown are of the isolated products. Ts=p-toluenesulfonyl.
[a] Reaction conditions: 1-sulfonyl triazole (1.0 mmol, 1.0 equiv), rho-
dium(II) octanoate (0.5 mol%), CHCl3 (2.0 mL), 708C, mw, 20–80 min.
All yields shown are of the isolated products. Boc=tert-butyloxycarbonyl.
and fluorene 3j triazoles underwent this homologation
reaction effectively (89% and 95% respectively) but instead
of the expected enaminone moiety, they delivered peculiar
enone/imine products 5i and 5j, respectively. It should be
noted that owing to the stability of the 1-sulfonyl triazoles in
Table 1 and the robust nature of the process, no special
precautions were taken regarding the exclusion of air and
moisture. Performing these reactions in a microwave reactor
allows for the reaction progress to be monitored by the
expulsion of dinitrogen; conventional heating is also effective
for this process.
Having shown that 1-sulfonyl triazoles bearing a tertiary
alcohol at the 4-position (e.g. 3) can readily undergo ring
expansion reactions, we sought to explore the use of azavinyl
carbenes in rhodium-catalyzed rearrangements.[1g–n] We
believed that 1-sulfonyl triazoles bearing a quaternary
center at C4 (e.g. 6) would undergo rearrangement to the
We next examined the migratory aptitude of different
atoms and functional groups. When cyclohexyl triazole 6b
was submitted to the reaction conditions, a facile hydride shift
occurred, leading to the formation of alkene 7b in 96% yield.
In contrast to triazoles 3a–e, the reaction of the triazole 6c
bearing a tertiary nontethered alcohol at the 4-position led to
the nonregioselective migration of the alkyl group to give
enaminone 7c in a 3:1 ratio of isomers (Z/E ratio).
Furthermore, for acetoxy triazoles 6d and 6e the exclusive
migration of the acetoxy group, led to formation of the acetyl
enols 7d and 7e in excellent yields (96% and 92%
respectively). Finally and most interestingly, reaction of
piperazine triazole 6 f under our general conditions led to
the selective migration of the nitrogen group to give the stable
imine enamine 7 f in good yield (71%). We believe that this
selective nitrogen transfer is likely to proceed through an
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attack of the nitrogen lone pair of the pendant piperazine
onto the rhodium carbene center, thus forming an aziridinium
ylide intermediate, which upon loss of the rhodium catalyst
leads to the observed product. This rearrangement is, to the
best of our knowledge, unknown, which we account to the
difficulty in preparation of the diazo starting material. All of
the triazoles shown in Table 2 are formed from the commer-
cially available or easily prepared alkynes and tosyl azide,
thus allowing for the simple synthesis of active diazo
progenitors, which would be inaccessible utilizing traditional
diazo chemistry.
ers, at room temperature and in high yields (95% and 82%,
respectively). Additionally, this transamination/cyclization
procedure was further demonstrated by the reaction of
enaminone 5b with sulfamide to obtain heterocycle 10e in
91% yield (Scheme 3b).
The facile rhodium(II)-catalyzed ring-expansion and
rearrangement reactions of 4-substituted 1-sulfonyl-1,2,3
triazoles shown here are experimentally simple and useful
transformations for the synthesis of enaminones and olefins in
high yield and selectivity.[10] Furthermore, the exocyclic
enaminone products can be readily transformed to various
heterocycles and ketone derivatives.
The copper(I)-catalyzed synthesis of 1-sulfonyl triazoles
and their subsequent rhodium(II)-catalyzed ring expansion or
rearrangement can be combined into a sequential one-pot
procedure, thus eliminating the requirement for purification
of the starting 1-sulfonyl triazole. This efficient procedure was
demonstrated on a 10 mmol scale for the conversion of
commercial alkyne 8 and tosyl azide 9 into the 7-membered
enaminone 5b, to deliver 2.5 g of material in an overall 85%
yield using only 0.1 mol% of the rhodium catalyst for the
ring-expansion step (Scheme 3a). With this unique enami-
none (5b) building block in hand, we sought to transform it
into useful ketone and heterocyclic-based products. As
enaminones are well-studied and versatile intermediates in
organic synthesis,[9] the subsequent functionalization was
easily accomplished. Indeed, enaminone 5b can easily
undergo transamination by the addition of an amine nucle-
ophile with loss of tosyl amine, to give products 10a and 10b
at room temperature in excellent yields (88% and 87%,
respectively). When enaminone 5b was reacted with hydra-
zines, pyrazoles 10c and 10d were formed as single regioisom-
Received: September 28, 2012
Published online: November 19, 2012
Keywords: click chemistry · heterocycles · rearrangement ·
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rhodium(II) catalysis · ring expansion
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Am. Chem. Soc. 2011, 133, 8834; Rhodium(II)-catalyzed rear-
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2009, 131, 18034; e) N. P. Grimster, L. Zhang, V. V. Fokin, J. Am.
Chem. Soc. 2010, 132, 4870; f) S. Chuprakov, J. A. Malik, M.
Zibinsky, V. V. Fokin, J. Am. Chem. Soc. 2011, 133, 10352; g) T.
Miura, T. Biyajima, T. Fujii, M. Murakami, J. Am. Chem. Soc.
2012, 134, 194; h) N. Selander, B. T. Worrell, S. Chuprakov, S.
Velaparthi, V. V. Fokin, J. Am. Chem. Soc. 2012, 134, 14670.
Scheme 3. A) One-pot large-scale synthesis of 5b. Reaction conditions:
8 (10 mmol, 1 equiv), 9 (10 mmol, 1 equiv), CuTc (5 mol%), CHCl3
(15 mL), RT, 4 h; then rhodium(II) octanoate (0.1 mol%), 708C, 2 h.
B) Functionalization of 5b. Reaction conditions: a) PhNH2 (3 equiv),
MeOH, RT, 6 h; b) 3-azidopropan-1-amine (2 equiv), MeOH, RT, 2 h;
c) hydrazine hydrate (5 equiv), MeOH, RT, 1 h; d) phenyl hydrazine
hydrochloride (1.1 equiv), MeOH, RT, 5 h; e) sulfamide (1.1 equiv), p-
TsOH (10 mol%), MeOH, 708C, 36 h. See the Supporting Information
for reaction details.
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[5] For a recent review of denitrogenative reactions of 1-sulfonyl
triazoles, see: B. Chattopadhyay, V. Gevorgyan, Angew. Chem.
2012, 124, 886; Angew. Chem. Int. Ed. 2012, 51, 862.
[6] Initial experiments were performed by Dr. Jessica Raushel; J.
Raushel, Diss. Abstr. Int. B 2009, 69, 4763 (Ph.D Dissertation,
The Scripps Research Institute, La Jolla, CA, 2009).
[7] For a recent study of the ring expansion of 4-cyclopropyl-1-
sulfonyl-1,2,3-triazoles to substituted cyclobutenes under silver-
catalyzed conditions, see: R. Liu, M. Zhang, G. Winston-
McPherson, W. Tang, Chem. Commun. 2012, DOI: 10.1039/
c2cc34609e.
[9] Selected applications of enaminones in synthesis: a) J. V. Green-
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[10] While this manuscript was under review, the following account
describing a similar transformation of 1-sulfonyl triazoles to
substituted enaminones was published: T. Miura, Y. Funakoshi,
M. Morimoto, T. Biyajima, M. Murakami, J. Am. Chem. Soc.
2012, 134, 17440.
[8] J. Raushel, V. V. Fokin, Org. Lett. 2010, 12, 4952.
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