Highly regio- and stereoselective dirhodium vinylcarbene induced nitrone cycloaddition with subsequent cascade carbenoid aromatic cycloaddition/N-O cleavage and rearrangement

Article abstract of DOI:10.1002/anie.201201917

An abnormal cascade process provides a selective method for the preparation of tricyclic heterocycles. The cascade involves a metal carbene induced regioselective [3+2] cycloaddition, a Buchner reaction, and a [1,7]-oxygen migration, which occurs with N-O cleavage (see scheme). The products are formed with remarkable specificity. Copyright

Full text of DOI:10.1002/anie.201201917

Angewandte
Chemie
DOI: 10.1002/anie.201201917
Cascade Reactions
Highly Regio- and Stereoselective Dirhodium Vinylcarbene Induced
Nitrone Cycloaddition with Subsequent Cascade Carbenoid Aromatic
ꢀ
Cycloaddition/N O Cleavage and Rearrangement**
Xiaochen Wang, Quentin M. Abrahams, Peter Y. Zavalij, and Michael P. Doyle*
[
7]
Vinylcarbene intermediates derived from vinyldiazoacetates
discovered that the unsubstituted vinyldiazoacetate 6 under-
went dirhodium(II)-catalyzed reactions with nitrones by
a novel and unexpected pathway to produce tricyclic products
by an elaborate cascade pathway.
[
1]
exhibit a high level of selectivity in cyclopropanation and
[
2]
carbon–hydrogen insertion reactions. As evidenced by the
integration of these transformations with the Cope rearrange-
ment, that at least for the combined CꢀH insertion/Cope
Treatment of methyl 2-diazo-3-butenoate (6) with N-(4-
methoxyphenyl)-a-(4-bromophenyl)nitrone (7a) in the pres-
ence of rhodium acetate at room temperature gave immediate
gas evolution and consumption of nitrone. After a reaction
time extending to 20 h two products, accounting for 52%
conversion based on 7a, were isolated. The minor product
(7% conversion) was identified as N-(4-methoxyphenyl)-a-
(4-bromophenyl)imine (8a), formed by deoxygenation of the
reactant nitrone, presumably by the metal carbene inter-
rearrangement appears to be concerted and highly asynchro-
[
3]
nous, the vinyl group broadens the complexity of applica-
tions and enhances the versatility of the process. Their
[
4]
[5]
propensity for formal [3+2] and [4+3] cycloaddition
reactions has also been demonstrated. Recently, we reported
an efficient and highly enantioselective formal [3+3] cyclo-
addition reaction between the vinycarbene from TBS-pro-
tected enoldiazoacetate 1 catalyzed by chiral dirhodium(II)
[
6]
[8]
carboxylates and diverse nitrones (Scheme 1). This reaction
mediate. The NMR spectrum of the major product (45%
conversion) indicated a single compound with the loss of
resonances due to the original anisyl group and new olefinic
protons suggestive of a methoxy-substituted diene, and
structural confirmation of this compound as tricyclic 9a was
[9]
obtained by X-ray diffraction of a single crystal (see the
Supporting Information). This product reveals that extensive
rearrangement has occurred and that the carboxylate group
from the vinyldiazoacetate is now bound to a quaternary
carbon that connects the tricycle.
Different dirhodium carboxylates were examined in
attempts to increase the yield of tricyclic product 9a
(
Table 1). Use of rhodium trifluoroacetate [Rh (TFA) ],
2 4
[10]
which is a stronger Lewis acid than is rhodium acetate,
resulted in a significantly lower conversion into the tricyclic
product, but there was increased conversion into imine 8a.
Rhodium triphenylacetate [Rh (TPA) ] and rhodium capro-
Scheme 1. Formal [3+3] cycloaddition reactions between 1 and 2
catalyzed by chiral dirhodium(II) carboxylates. TBS=tert-butyl dime-
thylsilyl; PTA=N-phthaloylalaninate; TBME=tert-butyl methyl ether.
2
4
lactamate [Rh (cap) ] showed low or negligible reactivities
2
4
toward this transformation under the same conditions.
Rhodium octanoate [Rh (Oct) ] provided higher conversion,
2
4
occurs stepwise through vinylogous nucleophilic attack by the
nitrone (2) on the dirhodium vinylcarbene followed by
intramolecular iminium ion addition to the catalyst-activated
vinyl ether (4!5) that, with catalyst dissociation, forms the
cycloaddition product 3. In our efforts exploring potential
cycloaddition reactions with other vinyldiazoacetates we
probably due to its higher solubility in 1,2-dichloroethane
[
11]
compared to rhodium acetate. Extending the reaction time
or increasing the amount of the vinyldiazoacetate reactant to
10 equiv did not significantly increase conversion into 9a.
Since unreacted nitrone remained, and neither reactant was
an inhibitor for the catalyst, we considered that the formation
of a coordinating base could cause inhibition of the catalytic
reaction with 6 and incomplete conversion; and both 8a and
[
*] X. Wang, Q. M. Abrahams, P. Y. Zavalij, Prof. M. P. Doyle
Department of Chemistry and Biochemistry, University of Maryland
College Park, MD 20742 (USA)
9
a, as well as the pyrazoline formed by intramolecular
[
7]
cycloaddition from 6, are suitable bases. To solve this
problem, acidic 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was
E-mail: mdoyle3@umd.edu
[
12]
used as an additive to capture the basic product. When
1 equiv of HFIP was added, and 3 equiv of 6 was used,
complete conversion of nitrone was achieved, resulting in
85% conversion into 9a with 74% yield and the remainder
[**] Support for this research from the National Institutes of Health
(
GM 46503) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201917.
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Table 1: Optimization of reaction conditions for the formation of the
[
a]
tricyclic product 9a.
[
b]
[b]
[c]
[c]
Rh2L4
Additive
Conv. [%]
Conv. [%]
8
a
9a
[
[
[
[
[
[
[
[
Rh (OAc) ]
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
7
24
trace
trace
9
9
10
15
45
17
10
trace
66
70
75
85 (74%)
2
4
Rh (TFA) ]
2
4
Rh (TPA) ]
2
4
Rh (cap) ]
2
4
Rh (Oct) ]
2
4
Rh (Oct) ] (36 h)
2
4
[
d]
Rh (Oct) ]
2
4
[
e]
Rh (Oct) ]
4 ꢀ MS/HFIP
2
4
[a] Reactions were performed by addition of a 1.0 mL solution of the
vinyldiazoacetate 6 (0.75 mmol) in dichloroethane (DCE) dropwise over
h to the mixture of dirhodium carboxylate catalysts (0.0075 mmol), N-
1
(
(
4-methoxyphenyl)-a-(4-bromophenyl)nitrone (0.25 mmol) and 4 ꢀ MS
100 mg) in 1.5 mL of DCE. [b] TFA=trifluoroacetate; TPA=triphenyl-
Scheme 3. Proposed reaction pathway.
acetate; cap=caprolactamate; Oct=octanoate; HFIP=1,1,1,3,3,3-
hexafluoro-2-propanol. [c] Conversions were determined by H NMR
spectroscopy of the reaction mixture before workup. [d] 10 equiv of 6 was
used. [e] Yield of isolated product after column chromatography.
1
panation/rearrangement pathway (Scheme 3) in which the
dirhodium carbene intermediate activates the adjacent vinyl
group for [3+2] cycloaddition by the nitrone. In [3+2]
cycloaddition reactions between diarylnitrones and electron-
deficient alkenes, the concerted reaction prefers endo addi-
tion which explains the exclusive formation of the trans
[13]
(
15%) due to the imine by-product 8a after column
isomer 10. The formation of 13 is consistent with cyclo-
chromatography. An excess of 6 was required due to its
addition of 7a with the metal carbene that forms the
[7]
[13,14]
relatively low stability. Nitrone 7a did not react with
vinyldiazoacetate 6 in the absence of the dirhodium catalyst.
Since nitrone cycloaddition to 6 does not occur in the
absence of catalyst, and dirhodium(II) catalysts are known to
undergo rapid dinitrogen extrusion with vinyldiazoacetates,
the likely intermediate that allows cycloaddition was the
dirhodium vinylcarbene; but instead of the stepwise [3+3]
cycloaddition shown in Scheme 1, stepwise or concerted
electronically favored
3,4-disubstituted regioisomer 10;
the 3,5-disubstituted regioisomer would have been expected if
cycloaddition of 7a occurred directly with vinyldiazoacetate
6. Subsequent intramolecular cyclopropanation and electro-
cyclic opening of the cyclopropane ring (aromatic cyclo-
addition) by the rhodium carbene on the nitrogen-bound aryl
group is proposed to form intermediate 12 that undergoes an
unexpected and unique NꢀO bond cleavage and [1,7]-oxygen
[
3+2] cycloaddition occurs (see Scheme 2 for the general
migration to 13 to complete the overall process. Aromatic
cycloaddition by metal carbenes to form cycloheptatrienes is
a well-known process, widely recognized as the Buchner
representation). We speculate that the overall reaction occurs
through a four-step sequential [3+2] cycloaddition/cyclopro-
[
15]
reaction. Cleavage of a NꢀO bond followed by migration of
oxygen to conjugated olefinic carbon atoms has only been
[
16]
[17]
observed in acylated N-oxides and silyl nitroso acetals,
but [1,3]-migration was the only process reported. Strain in
the intermediate 12 and the proximity of the reacting atoms
could be the driving force of this unusual rearrangement. In
this reaction pathway the dual role of the rhodium carbene,
which first activates the conjugated double bond for dipolar
cycloaddition, and then undergoes aromatic cycloaddition, is
unprecedented, as is the [1,7]-oxygen migration. Alterna-
tively, cleavage of the NꢀO bond in 11 and attack of oxygen at
the cyclopropane with imine formation can lead to 13 in
a single step.
Using the optimized conditions that include HFIP as an
additive we investigated the generality of this process with
Scheme 2. Divergence of reaction pathway dependent on electronic
stabilization by A.
2
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a broad range of nitrones, and the results of this investigation
are reported in Table 2. With diphenylnitrone (7c) an 83%
yield of tricyclic product 9c was produced. Yields for 9 were
Table 2: (Continued)
Com-
Nitrones, 7
Products, 9
Yield
[%]
[
b]
pounds
[
d]
Table 2: Scope of nitrones.
l
88
[a] Reactions were performed by addition of a 1.0 mL solution of the
vinyldiazoacetate 6 (0.75 mmol) in DCE dropwise over 1 h to the mixture
of [Rh (Oct) ] (0.0075 mmol), nitrone (0.25 mmol), 4 ꢀ MS (100 mg), and
2
4
HFIP (0.25 mmol) in 1.5 mL of DCE. [b] Yield of isolated product after
column chromatography. [c] Conversions into imine by-products; for
reactions with nitrones 7c–7l, conversions into imine by-products were
Com-
pounds
Nitrones, 7
Products, 9
Yield
[%]
[
b]
<
5%. [d] 6 equiv of 6 was used, and the reaction time was 48 h.
7
4
a
[
c]
(15)
not obviously dependent on electronic influences from a-aryl
ring since yields ranged from 73% to 85% (products 9c–9g)
with nitrones having electron-donating and electron-with-
drawing substituents. Substituents on the N-aryl ring were
varied in anticipation of activation from electron-donating
substituents and inhibition of addition from electron-with-
7
0
b
c
[
c]
(7)
[
18]
83
73
drawing groups. However, reaction occurred even with the
nitrone having a strongly electron-withdrawing ester group on
the N-aryl group (nitrone 7i). Electron-withdrawing groups
on aromatic rings are known to deactivate the cyclopropana-
d
e
[
18]
tion by metal carbenes on aromatic rings, but with these
substrates (e.g., with 7i) the electron-donating nitrogen has an
overriding activating factor. Also, with meta- and ortho-
substituents on the N-aryl group, cyclopropanation could
have occurred on either side of the N-aryl bond which would
have led to the formation of two regioisomers; however, only
a single regioisomer was formed in good yields (products 9j–
85
75
73
80
9
l). A single diastereomer of 9 was obtained in all cases, and
f
formation of the imine by-product, which was observed in the
optimization process, was variable depending on the nitrone.
Nitrones having the electron-donating methoxy substituent
on the N-aryl group (nitrones 7a and 7b) appeared to
produce the imine by-product with larger conversions, while
for the reactions that produce 9c–9l, imine by-products were
formed only in trace amounts. Therefore, this multistep
cascade process is general and occurs with very high
regiocontrol, and the resulting products are predisposed for
further elaboration.
g
h
In conclusion, we have developed a general and selective
method for preparation of multifunctionalized tricyclic het-
erocycles through an abnormal cascade process. To undergo
this process a metal vinylcarbene activates the vinyl group for
nitrone cycloaddition and then undergoes the Buchner
reaction that is linked to a [1,7]-oxygen migration which
occurs with NꢀO cleavage. The products of the process, which
i
60
have both oxygen and nitrogen-fused rings and a quaternary
carbon in the middle, are formed with remarkable specificity.
Further studies directed to analogous reactions and on an
enantioselective methodology for the reported cascade reac-
tion are underway.
j
86
82
k
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Communications
[
8] Although the imine was isolated and fully characterized,
attempts to isolate the corresponding methyl 2-oxa-3-butenoate
were unsuccessful. However, to establish the validity of this
interpretation 7a was treated with ethyl diazoacetate under
identical conditions; the corresponding imine was isolated in
Experimental Section
A 10 mL Schlenk flask charged with a magnetic stir bar and 4 ꢀ
molecular sieves (100 mg) was placed under high vacuum and heated
by Bunsen burner to dryness. After cooling to room temperature,
[
Rh (Oct) ] (6.0 mg, 3.0 mol%), diarylnitrone (0.25 mmol),
2 4
80% yield, and ethyl glyoxalate was the only other reaction
1
1
,1,1,3,3,3-hexafluoro-2-propanol (27 mL, 0.25 mmol), and 1.5 mL of
,2-dichloroethane were added under the flow of N . The resulting
product.
2
[
9] CCDC 870594 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
green solution was stirred for 5 min, and then the flask was wrapped
with aluminum foil to avoid light. Freshly prepared methyl 2-
diazobut-3-enoate (95 mg, 0.75 mmol) in 1.0 mL of 1,2-dichloro-
ethane was added into the flask via a syringe pump over 1 h. After
complete addition, the mixture was stirred at room temperature for
[
[
10] D. Timmons, M. P. Doyle in Multiple Bonds Between Metal
Atoms, 3rd ed. (Eds.: F. A. Cotton, C. A. Murillo, R. A. Walton),
Springer, New York, 2005, chap. 13.
2
0 h. The solvent from the reaction solution was evaporated, and the
residue was dissolved in a minimal amount of dichloromethane and
loaded onto a silica gel column. Column chromatography with
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3
1
13
that was later analyzed by H NMR and C NMR spectroscopy.
1
[
Received: March 10, 2012
Published online: && &&, &&&&
9
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Keywords: Buchner reaction · cascade reactions · cycloaddition ·
rhodium · vinylcarbenes
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Chemie
Communications
Cascade Reactions
X. Wang, Q. M. Abrahams, P. Y. Zavalij,
M. P. Doyle*
&&&& — &&&&
Highly Regio- and Stereoselective
An abnormal cascade process provides
a selective method for the preparation of
tricyclic heterocycles. The cascade
involves a metal carbene induced regio-
selective [3+2] cycloaddition, a Buchner
reaction, and a [1,7]-oxygen migration
Dirhodium Vinylcarbene Induced Nitrone
Cycloaddition with Subsequent Cascade
Carbenoid Aromatic Cycloaddition/NꢀO
which occurs with NꢀO cleavage (see
scheme). The products are formed with
remarkable specificity.
Cleavage and Rearrangement
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