Rh2(II)-Catalyzed Ring Expansion of Cyclobutanol-Substituted Aryl Azides to Access Medium-Sized N-Heterocycles

Article abstract of DOI:10.1021/jacs.7b01833

A new reactivity pattern of Rh₂(II)-N-arylnitrenes was discovered that facilitates the synthesis of medium-sized N-heterocycles from ortho-cyclobutanol-substituted aryl azides. The key ring-expansion step of the catalytic cycle is both chemosel

Full text of DOI:10.1021/jacs.7b01833

Communication
pubs.acs.org/JACS
Rh2(II)-Catalyzed Ring Expansion of Cyclobutanol-Substituted Aryl
Azides To Access Medium-Sized N‑Heterocycles
Wrickban Mazumdar,† Navendu Jana,† Bryant T. Thurman,† Donald J. Wink,† and Tom G. Driver*,†,‡
†Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
‡Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao University, 668 Jimei Boulevard,
Xiamen, Fujian 361021, People’s Republic of China
S
* Supporting Information
Scheme 1. Trigger Ring-Expansion Reactions Using Metal
N-Aryl Nitrenes
ABSTRACT: A new reactivity pattern of Rh2(II)-N-
arylnitrenes was discovered that facilitates the synthesis
of medium-sized N-heterocycles from ortho-cyclobutanol-
substituted aryl azides. The key ring-expansion step of the
catalytic cycle is both chemoselective and stereospecific.
Our mechanistic experiments implicate the formation of a
rhodium N-arylnitrene catalytic intermediate and reveal
that sp3 C−H bond amination of this electrophilic species
is competitive with the ring-expansion process.
he development of processes that tease new reactivity out
Tof catalytic intermediates continues to spur synthetic
chemists toward innovative solutions that access N-hetero-
cycles.1 Constructing these scaffolds using metal divalent
catalytic intermediates to trigger domino reactions is rare
despite the potential of these reactions to dramatically increase
the complexity of the substrates.2 Azides are emerging as
valuable precursors for nitrenes in transition-metal-catalyzed N-
atom-transfer reactions, but an electron-withdrawing N-
substituent is generally required for the best outcome.3,4 Our
investigations into the reactivity of rhodium N-aryl nitrenes
have established them as valuable electrophilic catalytic
intermediates for the synthesis of complex indoles from readily
accessible styryl azides.5,6 During the course of our studies, we
were curious if the electrophilicity of 2 could be harnessed to
participate in other bond-forming reactions instead of initiating
electrocyclization−migration or C−H bond amination reac-
tions. In particular, we wondered if this electrophilicity could
trigger the release of the strain embedded in the ortho-
substituent of aryl azide 4 to generate an aza-o-quinonoid
reactive intermediate, such as 6, which could further rearrange
(Scheme 1).7−9 If successful, this unprecedented ring expansion
might access medium-sized heterocycles, which are challenging
to construct with existing metal-catalyzed N-atom-transfer
reactions.10 Herein, we report our method development and
mechanistic experiments to form these important N-hetero-
cycles from aryl azides.
Table 1. Optimization of the Ring Expansion
a
entry
catalyst
mol%
T (°C)
yield (%)
1
none
n.a.
5
130
100
100
100
100
120
120
120
120
120
trace
24
2
Rh2(O2CCH3)4
Rh2(O2CC7H15)4
Rh2(O2CCF3)4
Rh2(O2CC3F7)4
Rh2(esp)2
3
5
15
4
5
47
5
5
66
6
5
71
7
Rh2(esp)2
1
80
8
RuBr3·nH2O
CoTPP
1
23
9
5
trace
23
10
[Ir(cod)(OMe)]2
n.a.
a
Isolated yield after silica gel chromatography.
line with our hypothesis, exposure of aryl azide 8a to a Rh2(II)-
carboxylate catalyst triggered a ring expansion to produce
benzazepinone 9a. The yield of this transformation depended
upon the identity of the carboxylate ligand (entries 1−6). While
poor conversion was observed with electron-rich rhodium
carboxylates (entries 2 and 3), perfluorinated complexes were
significantly more active (entries 4 and 5). The highest yield of
the benzazepinone was obtained using Rh2(esp)2 (entry 6).13
The success of Rh2(esp)2 is attributed to its tetradentate
To test our hypothesis, the reactivity of aryl azide 8a toward
commercially available transition metal catalysts was examined
(Table 1). The substrates for our study could be constructed in
three steps from N-phenyl-tert-butyl carbamate: the o-cyclo-
butanol group was installed through o-lithiation of 7a;11
subsequent HCl-mediated Boc-deprotection followed by
azidation using t-BuONO and Me3SiN3 furnished 8a.12 In
Received: February 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b01833
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ligands, which confer enhanced thermal stability relative to
other rhodium carboxylate complexes.14 The catalyst loading of
Rh2(esp)2 could be lowered to 1 mol % if the reaction
temperature was increased to 120 °C (entry 7). Examination of
other established N-atom-transfer catalysts or Lewis acids
revealed the uniqueness of Rh2(II)-carboxylates to trigger this
transformation: no reaction was observed using iron15 or
copper catalysts,16 and diminished conversion to benzazepi-
none 9a was obtained using RuBr3,17 CoTPP or [Ir(cod)-
(OMe)]2 complexes (entries 8−10).18,19 Other common Lewis
acids known to trigger semipinacol rearrangements were found
to lead to deleterious results.20 A solvent screen was performed
to determine if the yield or catalyst loading could be further
reduced. The use of other chlorinated or ethereal solvents,
however, only led to attenuated yields of benzazepinone 9a.20
The scope and limitations of our Rh2(II)-catalyzed ring-
expansion reaction was explored using the optimal conditions
(Table 2). While our reaction is currently limited to aryl
Table 3. Investigation of the Scope and Selectivity
Table 2. Scope and Limitations of Benzazepinone Formation
a
entry
R1
R2
R3
yield (%)
1
a
b
c
d
e
f
H
H
H
80
80
2
OMe
Me
CF3
OCF3
H
H
H
b
3
H
H
91
4
H
H
74
71
85
80
78
86
80
74
5
H
H
a
6
OMe
Me
F
H
Isolated yield of 11 after silica gel chromatography; only product
b
c
7
g
h
i
H
H
obtained. d.r. > 95:5. Diastereoselectivity of the product confirmed
by X-ray crystallographic analysis. Cambridge Crystallographic Data-
base number for 11j is CCDC 1525486.
8
H
H
9
H
CF3
F
H
10
11
j
Me
H
H
k
H
OMe
substrate submitted to the reaction conditions produced the
medium-ring N-heterocycle as a single constitutional isomer.
Aryl azides 10e and 10f exhibited exclusive migration of the
benzyl carbon over the methylene (entries 5 and 6), while only
allyl carbon migration was observed with aryl azide 10g to
provide benzazepinone 11g as the only product (entry 7). Our
reaction could even differentiate between the methylene and
methine carbons present on the o-cyclobutanol substituent: aryl
azides 10h and 10i produced only the benzazepinone resulting
from migration of cycloalkyl fragment (entries 8 and 9). Finally,
the stereospecificity of the [1,2] migration step was established
with aryl azide 10j (entry 10). Exposure of the cis-substituted
10j to reaction conditions produced benzazepinone 11j as a
single diastereomer, suggesting that the [1,2] migration is
concerted.
The reactivity trends of the o-cyclobutanol-substituted aryl
azides suggest that the benzazepinone product is formed
through the catalytic cycle outlined in Scheme 2. First, the
substrate reacts with the Rh2(II) carboxylate catalyst to form
the metal N-aryl nitrene 12.6,23 Formation of this electrophilic
species triggers the selective and stereospecific ring expansion
of the o-cyclobutanol substituent to produce metallo aza-
quinonoid 13.9,24 After proton transfer to the metalloimine,
aromaticity is re-established by generation of acylium ion 15,
which is attacked by the proximal nitrogen nucleophile to form
16. Loss of the rhodium carboxylate produces the benzazepi-
none product. Alternatively, the key [1,2] migration step could
a
b
Isolated after silica gel chromatography. Cambridge Crystallographic
Database number for 9c is CCDC 1525478.
azides,21 both electron-donating and electron-withdrawing R1
and R2 substituents on the aryl azide were tolerated without
attenuating the benzazepinone yield (9a−9e). In contrast to
our previously reported aryl azide methods,5,6 aryl azide 8k
could be substituted with an additional ortho-substituent and
still furnish benzazepinone 9k using the optimal reaction
conditions without significant diminishment of the yield.
Next, the identity of the o-cycloalkanol substituent of the aryl
azide was varied to investigate the scope and selectivity of
benzazepinone formation (Table 3). First, aryl azide 10a
established the generality of this phenomenon by revealing that
the strain embedded in an o-cyclopropanol substituent could be
released to access dihydroquinolone 11a (entry 1). Aryl azide
10b revealed that our reaction tolerated the presence of an
oxygen heteroatom in the strained ortho-substituent to access
medium-ring N-heterocycle 11b, albeit in a slightly diminished
yield (entry 2). The o-cyclobutanol substituent could be
substituted with an alkyl or aryl substituent to enable access to
4-substituted benzazepinones (entries 3 and 4). The specificity
of the [1,2] migration step was investigated with aryl azides
10e−10j (entries 5−10). In contrast to related ring-expansion
reactions of substituted cyclobutanols containing N2 as the
leaving group,22 our reaction proved to be selective: each
B
DOI: 10.1021/jacs.7b01833
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Journal of the American Chemical Society
Communication
chemoselective and stereospecific to enable predictable
formation of a broad range of benzazepinones. Future
experiments will be aimed at exploring the reactivity of the
strained indoline C−H bond amination product as well as
developing domino reaction sequences to access more complex
medium-ring N-heterocycles.
Scheme 2. Possible Mechanism for Rh2(II)-Catalyzed
Benzazepinone Formation
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b01833.
■
S
Experimental procedures; spectroscopic and analytical
data for the products (PDF)
X-ray crystallographic data for 9c (CIF)
X-ray crystallographic data for 11j (CIF)
AUTHOR INFORMATION
Corresponding Author
*tgd@uic.edu
■
occur at the same time as loss of dinitrogen: coordination of the
rhodium carboxylate to the γ-nitrogen in 17 activates the
substrate for a semipinacol ring expansion with concomitant
loss of N2 to produce 13.22
Support for a mechanism via a rhodium N-aryl nitrene was
obtained from the reactivity of aryl azides 18 and 21 (Scheme
3). To assay the importance of ring-strain to the success of the
ORCID
Tom G. Driver: 0000-0001-7001-342X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 3. Mechanistic Support for the Intermediacy of a
Rhodium N-Aryl Nitrene
We are grateful to the National Science Foundation CHE-
1564959, University of Illinois at Chicago, Office of the Vice-
Chancellor for Research, Huaqiao University Xiamen, and the
Fujian Hundred Talents Plan for their generous financial
support.
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