Rhodium(II)- and copper(II)-catalyzed reactions of enol diazoacetates with nitrones: Metal carbene versus lewis acid directed pathways

Article abstract of DOI:10.1002/anie.201202525

A complimentary cat.: Copper(II) hexafluoroantimonate catalyzes the formal [3+3] cycloaddition of Lewis acid activated nitrones and vinyl diazoacetates to produce 3,6-dihydro-1,2-oxazines in yields of up to 96 % and diastereoselectivities greater than 25:1 (see scheme). This process compliments the metal carbene pathway that is catalyzed by rhodium(II) species. Copyright

Full text of DOI:10.1002/anie.201202525

Angewandte
Chemie
DOI: 10.1002/anie.201202525
Synthetic Methods
Rhodium(II)- and Copper(II)-Catalyzed Reactions of Enol
Diazoacetates with Nitrones: Metal Carbene versus Lewis Acid
Directed Pathways**
Yu Qian, Xinfang Xu, Xiaochen Wang, Peter J. Zavalij, Wenhao Hu, and Michael P. Doyle*
Access to 1,2-oxazines has proven to be highly valuable for
the preparation of a multitude of biologically active target
compounds,[1] but there are few methods that have been
developed for their syntheses.[2] Of particular interest are the
3,6-dihydro-1,2-oxazines, which are available through nitroso
hetero-Diels–Alder reactions,[3] gold-catalyzed cycloisomeri-
zation with allenes,[4] or (for selected examples) by a one-pot
organocatalytic process involving a-oxyamination and an
intramolecular Wittig reaction.[5] These oxazines have been
valued as synthetic building blocks in organic syntheses,[6] and
they are frequently found as structural skeletons in biologi-
Scheme 1. Rhodium(II) carbene directed [3+3] cycloaddition of 2a
cally active compounds.[7] We have recently reported an
(R3 =H) with nitrones. TBS=tert-butyldimethylsilyl.
efficient and highly enantioselective formal [3+3] cycloaddi-
tion reaction between a variety of nitrones 1 and vinylcarbene
intermediates derived from rhodium(II)-catalyzed reactions
of TBSO-substituted enol diazoacetate (2a, R3 = H).[8] These
high-yielding reactions occur by the vinylogous reaction of
the electrophilic metal carbene with the nucleophilic nitrone
coupled with the intramolecular addition of an iminium ion
and dissociation of the catalyst (Scheme 1). In attempts to
broaden the scope of this transformation by using 2b (R3 =
Ph) and examine the diastereocontrol we discovered that the
rhodium(II) catalysts were inert towards dinitrogen extrusion
from 2b as well as any subsequent reaction. However,
a strongly Lewis acidic copper(II) compound catalyzed this
reaction efficiently and with complete diastereocontrol.
Treatment of TBSO-substituted enol diazoacetate 2b
(R3 = Ph) with rhodium(II) acetate in the presence of nitrone
1a (R1 = p-BrC6H4) at room temperature surprisingly
resulted in no observable reaction over 1 h under conditions
that resulted in 2a (R3 = H) forming the corresponding 3,6-
dihydro-1,2-oxazine 3 in nearly quantitative yield. Heating
the reaction mixture containing [Rh2(OAc)4] in dichloro-
methane to reflux led to a mixture of products, none of which
resulted from [3+3] cycloaddition, but a minor component
was observed that was generated by oxygen transfer from the
nitrone after replacement of the dinitrogen in 2b by oxygen.[9]
Copper(I) catalysts that are alternatives to [Rh2(OAc)4] for
dinitrogen extrusion[9] were surprisingly limiting: only a trace
amount of the [3+3] cycloaddition product was formed with
CuI over 24 h (Table 1, entry 2), but this product was obtained
as a single diastereoisomer (d.r. > 25:1) in 31% yield from
a reaction catalyzed by [Cu(MeCN)4](PF6) (entry 3). Clearly,
traditional catalysts for the formation of metal carbenes[10]
were not suitable to catalyze this transformation effectively.
Encouraged by the observed high diasterocontrol, we
surveyed a variety of Lewis acid catalysts. BF3·OEt2, Sc-
(OTf)3, and In(OTf)3 were ineffective, but 3a was formed,
albeit as a minor product, on using a catalytic amount of
Zn(OTf)2. However, the use of the Lewis acidic copper(II)
triflate led to 3a in 54% yield (Table 1, entry 5); the yield was
further improved to 89% by using AgSbF6 (entry 6) and
a dramatically reduced reaction time of 5 min. Recognizing
that the product yield increased and reaction time decreased
as the Lewis acidity of the catalyst increased, copper(II)
hexafluoroantimonate (Cu(SbF6)2)[11] was tested, and was
found to give superior results (entry 7). Slightly lower yields
were obtained by changing the catalyst loading (entries 8–10).
Notably, when 4 ꢀ molecular sieves were added to the
mixture containing Cu(SbF6)2, a much lower yield was
obtained and a longer reaction time (24 h) was required
(entry 10).
[*] Dr. Y. Qian, Dr. X. Xu, Dr. X. Wang, Dr. P. J. Zavalij, Prof. M. P. Doyle
Department of Chemistry and Biochemistry
University of Maryland
College Park, MD 20742 (USA)
E-mail: mdoyle3@umd.edu
Dr. Y. Qian, Prof. W. Hu
Shanghai Engineering Research Center for Molecular Therapeutics
and Institute of Drug Discovery and Development and
Department of Chemistry, East China Normal University
3663 Zhongshan Bei Road, Shanghai 200062 (China)
[**] Support to M.P.D. from the National Institutes of Health
(GM46503) is gratefully acknowledged. W.H. thanks MOSTof China
(2011CB808600) and the NSFC (21125209, 20932003) for spon-
sorship.
The scope of this reaction was evaluated under these
optimized conditions by changing the nitrone 1; as can be seen
from Table 2, both high yields and high diastereoselectivities
for 3 were obtained. Neither electron-withdrawing (e.g.,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202525.
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Table 1: Catalyst screening and optimization of reaction conditions.[a]
atom (R2) from phenyl to substituted phenyl (entries 2, 10,
and 11) and to alkyl (entries 12 and 13) similarly had no
adverse effect on the reactivity or selectivity. In all cases, only
the syn diastereomer was observed. The stereochemistry of
the product was determined by single-crystal X-ray analysis of
3j.[12]
Modification of the vinyl substituent (R3 in Scheme 1) led
to unexpected results in Cu(SbF6)2-catalyzed reactions with
diphenylnitrone 1b [Eq. (1)]. The Mukaiyama–Mannich
products 4a or 4b were formed in high yields, instead of
Entry
MLn
t[b]
MLn [mol%]
3a yield[%][c]
1
2
3
4
5
6
7
8
[Rh2(OAc)4]
CuI
[Cu(MeCN)4](PF6)
Zn(OTf)2
Cu(OTf)2
AgSbF6
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
Cu(SbF6)2
1 h
24 h
24 h
24 h
5
5
5
5
5
5
5
10
2
mixture
trace
31
6
54
89
95
92
88
24 h
5 min
5min
5 min
30 min
24 h
9
10[d]
5
73
[a] Reactions were performed by the dropwise addition of a solution of
freshly prepared Cu(SbF6)2 (5.0 mol%) in CH2Cl2 (1 mL) to the mixture
of enol diazoacetate 2b (200 mg, 0.6 mol) and nitrone 1a (0.5 mmol) in
CH2Cl2 (3 mL). [b] The time for complete conversion of 2b into
product(s) was monitored by TLC. [c] Yield of isolated product after
column chromatography; the diastereoselectivity was determined by
1H NMR spectroscopic analyses of the unpurified reaction mixture and
was greater than 25:1 in all cases. [d] With 4 ꢀ molecular sieves added.
[3+3] cycloaddition products, when R3 = H (2a) and R3 = Me
(2c). This reaction process is characteristic of Lewis acid
catalysis and has been observed in reactions between 2a and
nitrones catalyzed by [Cu(MeCN)4](PF6).[13]
The anisyl-substituted aryl enol diazoacetate 2d was
isolated as a mixture of E and Z isomers (Z/E = ca. 6:1),
instead of the exclusive formation of the Z isomers, as
observed in the synthesis of 2b and 2c. Chromatographic
separation of (Z)-2d from (E)-2d and treatment of both
individually with diphenylnitrone in the presence of a catalytic
amount of Cu(SbF6)2 resulted in the exclusive production of
the [3+3] cycloaddition product 3n with high diastereoselec-
tivity. Thus, the stereochemistry of the reactant enol diazo-
acetate was not retained in the product [Eq. (2)].
entry 5) nor electron-donating substituents (e.g., entries 4 and
6) on R1 had an impact on the product yields, although
reactions occurred at a faster rate when nitrone 1 contained
electron-withdrawing substituents in R1. Similarly, R1 can be
naphthyl, furyl, or styryl without diminishing the reactivity or
selectivity. Changing the substituent on the nitrone nitrogen
Table 2: Cu(SbF6)2-catalyzed [3+3] cycloaddition reactions of enol
diazoacetate 2b with nitrones.[a]
Entry R1
R2
3
t [min][b] Yield d.r.
[%][c] (syn/anti)[d]
1
2
3
4
5
6
7
8
4-BrC6H4
Ph
3-ClC6H4
2-MeOC6H4
2-NO2C6H4
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d 12 h
3e
3 f 60
3g
3h
3i
5
5
5
95
88
90
95
96
93
80
85
92
93
82
78
75
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
To rule out a metal carbene pathway similar to that shown
in Scheme 1 for this [3+3] cycloaddition reaction we initially
sought to trap any intermediate metal carbene by cyclo-
propanation. However, the use of neither [Rh2(OAc)4] nor
Cu(SbF6)2 in reactions between diphenylnitrone and 2b in the
presence of styrene led to the production of cyclopropane
compounds. The outcome of the reaction with benzyl alcohol
as the additive was different in the presence of [Rh2(OAc)4]
and Cu(SbF6)2 catalysts: only the [Rh2(OAc)4] catalyst
5
3,4-(MeO)2C6H3 Ph
b-naphthyl
2-furyl
trans-styryl
Ph
Ph
Ph
Ph
Ph
Ph
5
5
5
5
5
30
9
10
11
12
13
p-BrC6H4 3j
PMP
Bn
3k
3l
3m 30
À
produced the O H insertion product (Scheme 2), but its
yield was less than 30%. The most convincing evidence that
Cu(SbF6)2 catalyzed the [3+3] cycloaddition reaction as
a Lewis acid came from experiments in which 2b and
Cu(SbF6)2 were combined in dichloromethane, and the
nitrone was added last. This approach resulted in 2b retaining
its identity, only undergoing intramolecular dipolar cyclo-
addition to 5,[14] and with slow enol hydrolysis observed even
Ph
Me
[a] Reactions were performed as described in Table 1. [b] The time for
complete conversion of 2b into product(s) was monitored by TLC.
[c] Yield of isolated product after column chromatography. [d] The
diastereoselectivity was determined by H NMR spectroscopic analyses
of the unpurified reaction mixtures and was greater than 25:1 in all cases.
1
PMP=p-methoxyphenyl, Bn=benzyl.
2
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dirhodium(II) species and inhibited from occurring with enol
diazoacetate 2b, and illustrates that a duality of mechanistic
pathways can account for the same transformation. Although
there are several examples of divergent outcomes from Lewis
acid catalysis and metal carbene pathways,[15] the enol
diazoacetate/nitrone process reported here is the first in
which the same transformation (a formal [3+3] cycloaddition)
is reached by both Lewis acids and catalysts that generate
metal carbenes, albeit with enol diazoacetates having an aryl
(2b) rather than a hydrogen (2a) substituent.
Scheme 2. Catalyst-dependent products.
Experimental Section
General procedure: Nitrone 1a (137.5 mg, 0.50 mmol), enol diazo-
acetate 2b (200 mg, 0.6 mol), and CH2Cl2 (3.0 mL) were added under
a flow of N2 to a 10 mL Schlenk flask charged with a magnetic stir bar.
The CH2Cl2 solution (1 mL) of the freshly prepared Cu(SbF6)2
(5.0 mol%) was added into the flask. Once the diazo compound
was consumed (determined by TLC), the crude products were
subjected to 1H NMR spectroscopic analysis to determine the
diastereoselectivity. The reaction mixture was purified by flash
chromatography on silica gel (eluent: hexanes/EtOAc = 40:1 to
20:1) to give pure product 3a.
after 29 hours (see the Supporting Information). However,
the addition of nitrone 1b to the reaction mixture containing
2b and Cu(SbF6)2 caused immediate evolution of gas and the
formation of the cycloaddition product. Additionally, when
the nitrone was combined with an equivalent amount of
catalyst, chemical shifts consistent with coordination of the
nitrone to the Cu(SbF6)2 were observed in the NMR spectrum
(see the Supporting Information).
On the basis of these determinations the [3+3] cyclo-
addition reaction between 2b and nitrones is proposed to
occur through Lewis acid catalysis (Scheme 3) rather than via
a metal carbene. The catalyst first activates the nitrone
Received: March 31, 2012
Published online: && &&, &&&&
Keywords: copper · cycloaddition · homogeneous catalysis ·
.
nitrones · oxazines
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the diazo carbon atom of 2b to generate diazonium ion
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7b) are shown. The more stable conformation (7b) is that in
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diazonium ion and OTBS groups are in proximity, and it is
through this conformation that the major isomer is formed.
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atom, which occurs with addition to the double bond coupled
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catalyze formal [3+3] cycloaddition of Lewis acid activated
nitrones and vinyl diazoacetates. The process is complimen-
tary to its metal carbene counterpart, which is catalyzed by
[8] X. Wang, X. Xu, P. Y. Zavalij, M. P. Doyle, J. Am. Chem. Soc.
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4
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Communications
Synthetic Methods
Y. Qian, X. Xu, X. Wang, P. J. Zavalij,
W. Hu, M. P. Doyle*
&&&& — &&&&
Rhodium(II)- and Copper(II)-Catalyzed
Reactions of Enol Diazoacetates with
Nitrones: Metal Carbene versus Lewis
Acid Directed Pathways
A complimentary cat.: Copper(II) hexa-
fluoroantimonate catalyzes the formal
[3+3] cycloaddition of Lewis acid acti-
vated nitrones and vinyl diazoacetates to
produce 3,6-dihydro-1,2-oxazines in
yields of up to 96% and diastereoselec-
tivities greater than 25:1 (see scheme).
This process compliments the metal
carbene pathway that is catalyzed by
rhodium(II) species.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!