Divergent outcomes of carbene transfer reactions from dirhodium- and copper-based catalysts separately or in combination

Article abstract of DOI:10.1002/anie.201105557

Divergent catalysis: The use of copper and rhodium catalysts separately or in combination directs reactions between vinyldiazoacetates 1 and cinnamaldehydes 2 from formal [4+3] cycloaddition (epoxidation followed by Cope rearrangement), to intramolecular cyclopropanation, to Mukaiyama-aldol reactions. The reactions proceed selectively and in high yield. Copyright

Full text of DOI:10.1002/anie.201105557

Communications
DOI: 10.1002/anie.201105557
Homogeneous Catalysis
Divergent Outcomes of Carbene Transfer Reactions from Dirhodium-
and Copper-Based Catalysts Separately or in Combination**
Xinfang Xu, Wen-Hao Hu, Peter Y. Zavalij, and Michael P. Doyle*
That a reaction pathway can be redirected to a different
product by changing a reactant or reaction conditions is well
known and widely practiced. Such processes are referred to as
“divergent”, and this term is broadly applied to method-
ology,[1] synthesis,[2] reactivity and selectivity,[3] among
others.[4] However, processes in which the same reactant(s)
form different products in synthetically meaningful yields by
application of different catalysts are rare.[5] We and others
have reported exceptionally efficient catalyst-dependent
processes that occur with the same diazo substrates to form
structurally different compounds.[5b,6–8] In the most well-
documented cases, dirhodium(II) catalysts having different
À
ligands differentiate between cyclopropanation and C H
insertion, ylide formation and aromatic substitution, or
À
aromatic cycloaddition and C H insertion with the same
diazoacetates.[6] The exclusive formation of one of two
regioisomeric dihydropyrroles in modest yields from the
reactions between vinyldiazoacetates and imines using dirho-
dium(II) acetate or copper(II) triflate (Scheme 1), due to
either electrophilic metal carbene formation (intermediate 1a
in the case of rhodium) or to initial iminium ion formation
Scheme 1. Divergent pathways to isomeric dihydropyrroles from the
same reactants, but different catalysts.
(intermediate 1b in the case of copper),[7] exemplifies the
critical role of catalyst in product selection. Other examples
include the copper(I)/rhodium(II) product differences in
macrocyclization with diazoacetates.[8] Although both dirho-
dium and copper catalysts are well established catalysts for
dinitrogen extrusion from diazo compounds, there can be
striking differences between them in product outcomes from
the same reactant(s).
Here we report divergent copper- and/or dirhodium-
catalyzed, synthetically relevant processes that occur between
cinnamaldehydes and siloxyvinyl a-diazoacetates which
clearly reveal fundamental differences between these two
catalytic systems. Their applications include the syntheses of
oxepin, furanone, and cyclopropane compounds by intra-
molecular cyclization (Scheme 2) with extraordinary effi-
ciency and atom economy.
We have previously reported that methyl styryldiazoace-
tate undergoes ylide-induced epoxide formation in reactions
with cinnamaldehydes catalyzed by dirhodium tetraacetate,
but product yields were only modest, and mixtures were
formed with the substituted aldehydes.[9] Consequently, we
were surprised when treatment of methylsiloxyvinyldiazo-
acetate (3-Me) with 4-nitrocinnamaldehyde at room temper-
ature, catalyzed by dirhodium carboxylates, gave epoxide 4a
with trans-divinyl substituents in excellent yield (Scheme 3).
[*] Dr. X. Xu, Dr. P. Y. Zavalij, Prof. M. P. Doyle
Department of Chemistry and Biochemistry, University of Maryland
College Park, MD 20742 (USA)
E-mail: mdoyle3@umd.edu
Dr. X. Xu, Prof. W. Hu
Institute of Drug Discovery and Development
East China Normal University
3663 Zhongshan Bei Road, Shanghai 200062 (China)
[**] Support for this research to M.P.D. from the National Institutes of
Health (GM 46503) and National Science Foundation (CHE-
0748121) is gratefully acknowledged. W.H. thanks the National
Science Foundation of China (20932003), and the MOST of China
(2011CB808600).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105557.
Scheme 2. Divergent outcomes from copper- and rhodium-catalyzed
reactions of 3 with cinnamaldehydes.
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Figure 1. X-ray crystal structure of 7a.
gave 4,5-dihydrooxepin 7a in 95% isolated yield.[17] The
structure of 7a was confirmed by single-crystal X-ray
diffraction analysis (Figure 1).
Using these optimum conditions we examined this
rearrangement reaction for substrate generality in the two-
step one-pot formal [4+3] cycloaddition of 3 with substituted
cinnamaldehydes, and these results are summarized in
Table 1. Product yields from reactions with cinnamaldehydes
Scheme 3. Divergent catalyst-dependent pathways from cinnamalde-
hydes and methyl siloxyvinyldiazoacetate 3-Me.
Table 1: Substrate generality for the one-pot tandem epoxidation/
Use of chiral catalysts that included Hashimotoꢀs [Rh2(S-
PTPA)4][10] and Daviesꢀ [Rh2(S-DOSP)4][11] did not give
evidence of enantiocontrol in this transformation, and
dirhodium carboxamidates exhibited very low reactivity
towards dinitrogen extrusion of 3. Surprisingly, use of [Cu-
(CH3CN)4]PF6, which is even more reactive towards dinitro-
gen extrusion from diazo compounds than is rhodium
acetate,[12] gave the Mukaiyama-aldol addition product 5 in
high yield when the reaction was performed at 08C without
effecting diazo decomposition (Scheme 3).[13] In this case,
CuPF6 acts as Lewis acid for activation of the aldehyde
towards electrophilic addition to 3 and does not cause
decomposition of the diazoacetate in either the reactant or
the product.
In contrast to their cis-divinylcyclopropane analogues that
undergo [4+3]-cycloaddition at or below room tempera-
ture,[14] and have been key steps in several total syntheses,[15]
trans-divinylepoxides are thermally stable at room temper-
ature but slowly rearrange to 4,5-dihydrooxepins 7.[16] This is
obviously the reason why the conversion of 4 to dihydroox-
epin does not occur under more moderate conditions. Hence
a major challenge of this study has been to develop conditions
suitable to form 4,5-dihydrooxepins in high yield. We initially
applied thermal conditions to effect rearrangement of the
trans-divinylepoxide 4a, and this approach did provide the 4-
nitrophenyl derivative 7a, but the thermal transformation
only occurred at or above 1508C and required long reaction
times. To find the catalytic version of this rearrangement, we
investigated the effects of an array of Lewis acids (CuPF6,
CuOTf, Cu(OTf)2, Sc(OTf)3, Zn(OTf)2) to discover that with
the application of a catalytic amount of [Cu(hfacac)2]
(hfacac = hexafluoroacetylacetonate) the reaction tempera-
ture could be decreased to 1008C while the reaction rate was
drastically increased. Further optimization by carrying out the
two-step reaction in one-pot by performing the catalytic
epoxidation in dichloromethane, replacing that solvent with
toluene, adding [Cu(hfacac)2], and heating at 1258C for 0.5 h
rearrangement reaction.[a]
Entry
3
2, Ar
7
Yield [%][b]
1
2
3
4
5
6
7
8
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Bn
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
C6H5
4-CF3C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
4-NO2C6H4
2-NO2C6H4
C6H5
7a
7b
7c
7d
7e
7 f
7g
7h
7i
95
95
95
82
95
90
88
90
81
95
95
85
95[c]
9
10
11
12
13
7j
7k
7l
3-Bn
3-Bn
Me3-Me
4-NO2C6H4
7m
[a] The reaction was carried out with 3 (0.36 mmol), aldehyde
(0.30 mmol), [Rh2(OAc)4] (2 mol%), [Cu(hfacac)2] (5 mol%), respective
solvent (2 mL). [b] Yield of isolated 7 after chromatography. [c] The
1H NMR spectrum of the reaction mixture showed only one diastero-
isomer, whose stereochemistry was confirmed by NOE analysis (see the
Supporting Information).
having electron-donating substituents were comparable to
those from the nitrocinnamaldehydes (Table 1, entries 4–9).
Benzyl ester analogues (3-Bn) underwent the same two-step
process with isolated yields that were identical to those
obtained with the methyl esters (Table 1, entries 10–12). That
the reaction occurred with the stereospecificity of an electro-
cyclization reaction, whether from a direct Cope rearrange-
ment of rearranged cis-divinyl epoxide[18] or from the
corresponding ylide, with propenyldiazoacetate Me3-Me as
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Communications
the reactant, cis-4,5-disub-
stituted-dihydrooxepine
7m was formed stereospe-
cifically in very high yield.
With the assumption
that copper and rhodium
catalysts act independently,
so that the combination
with vinyldiazoacetate 3-
Me and cinnamaldehydes
could achieve the forma-
tion of 7 under one set of
reaction conditions, we
treated 3-Me with cinna-
maldehyde in the presence
of catalytic amounts of rho-
dium acetate and copper(I)
Scheme 4. Divergent outcomes from copper- and rhodium-catalyzed reactions of 3 with cinnamaldehydes.
hexafluorophosphate
at
room temperature. However, instead of observing either
epoxidation or dihydrooxepine products, use of this catalyst
combination unexpectedly produced the two diastereoiso-
mers[19] of bicyclo[3.1.0]hexane 8a[20] in high yield (Table 2).
Substrates with electron-donating substituents showed higher
reactivity (Table 2, entries 2 and 3), and this reactivity pattern
was opposite to that observed for epoxidation. Reversal of
diastereoselectivity from up to 9:1 to < 1:20 was achieved by
using a b-substituted cinnamaldehyde in this transformation
(Table 2, entry 5); interaction with the syn-phenyl substituent
that occupies position 6 in 8 forces the OTBS group to favor
the cis geometry. With dirhodium catalysts and Ar= Ph,
diastereoselectivity ranged from 82:18 (with rhodium capro-
lactamate) to 27:73 (with rhodium trifluoroacetate).
product 5 to the complete exclusion of epoxide 4. The product
of the Mukaiyama-aldol reaction, catalyzed by CuPF6, which
gave optimum results, when treated with rhodium acetate
gave cyclopropanation products 8a. Alternatively, by per-
forming the reaction of 3-Me and cinnamaldehyde with
CuPF6 as catalyst at 408C (3 h), instead of at or below room
temperature, the two-step process can be accomplished in one
pot (77% yield, d.r. = 90:10).[17] Obviously, the role of CuPF6
as a Lewis acid in these reactions is pronounced, and the
possibility exists that coordination of 5 with CuPF6 inhibits its
use as a catalyst for dinitrogen extrusion. The advantage of
the cooperative rhodium- and copper-catalyzed bicyclization
is that the overall transformation can be conducted at room
temperature. Furanone 6 formation (Scheme 2) from diazo-
acetoacetates has been previously reported,[21] although not
with the structural diversity that is available by this method-
ology.
Table 2: Cooperative rhodium- and copper-catalyzed bicyclization of
vinyldiazoacetates 3 with a,b-unsaturated aldehydes.[a]
In summary, the use of copper and rhodium catalysts
separately and in combination directs the reaction between
vinyldiazoacetates 3 and cinnamaldehydes to a broad diver-
sity of products selectively and in high yield (Scheme 4). The
basis for this catalyst-based selectivity lies in the differences in
Lewis acidity between copper and rhodium catalysts and the
bidentate coordinating ability of copper catalysts. That copper
and dirhodium catalysts can work cooperatively for product
formation is demonstrated.
Entry
3
2, Ar/R’’
8
d.r.[b]
(trans/cis)
Yield
[%][c]
1
2
3
4
5
3-Me
3-Me
3-Me
3-Bn
3-Bn
C6H4/H
8a
8b
8c
8d
8e
85:15
75:25
90:10
70:30
<5:95
80
87
32
86
65
4-MeOC6H4/H
2-NO2C6H4/H
C6H4/H
Experimental Section
Diazo compound 3 (0.36 mmol) in CH2Cl2 (1.0 mL) was added over
1 h through a syringe pump at room temperature to an oven-dried
C6H4/C6H4
flask containing
a magnetic stirring bar, cinnamaldehyde 2
[a] Reaction in 0.3 mol scale: 3 (0.36 mmol), aldehyde (0.30 mmol),
[Rh2(OAc)4] (2 mol%), CuPF6 (5 mol%), solvent (2 mL). [b] Determined
by 1H NMR spectroscopy of the crude reaction mixture. [c] Yield of
isolated 8 (trans and cis) after chromatography.
(0.3 mmol), and [Rh2(OAc)4] (2.0 mol%) in CH2Cl2 (1.0 mL). The
reaction mixture was stirred for another 2 h, then CH2Cl2 was
removed under reduced pressure, and toluene (2.0 mL) was added.
The solution was transferred to the reaction tube containing a
magnetic stirring bar; the tube was suited for use under high pressure.
The reaction tube was sealed after [Cu(hfacac)2] (5.0 mol%) was
added, and the temperature of the reaction was warmed to 1258C in
an oil bath with stirring. After complete consumption of the
intermediate epoxide 4 (about 1 h), monitored by 1H NMR spectros-
copy (epoxide and the product oxepin overlap on thin-layer
Treatment of 3-Me and cinnamaldehyde with both
copper(I) and copper(II) compounds in catalytic amounts
resulted in the formation of the Mukaiyama-aldol reaction
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Angew. Chem. Int. Ed. 2011, 50, 11152 –11155

chromatography), the reaction mixture was purified by column
chromatography on silica gel (eluent hexanes/EtOAc = 50:1 to 30:1)
to give the pure products oxepin 7 in greater than 80% yield.
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Received: August 5, 2011
Published online: October 6, 2011
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[13] The Zn(OTf)2 catalysis forms the Mukaiyama-aldol reaction
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Keywords: copper · [4+3]-cycloaddition ·
intramolecular cyclopropanation · Mukaiyama-aldol reaction ·
rhodium
.
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Angew. Chem. Int. Ed. 2011, 50, 11152 –11155
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