Asymmeric formal [3 + 3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates

Article abstract of DOI:10.1021/ja207664r

With metal carbene access to dipolar intermediates, 3,6-dihydro-1,2- oxazines are produced in high yields by dirhodium(II) carboxylate catalyzed reactions between nitrones and a β-TBSO-substituted vinyldiazoacetate. High enantiocontrol occurs with catalys

Full text of DOI:10.1021/ja207664r

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Asymmeric Formal [3 + 3]-Cycloaddition Reactions of Nitrones with
Electrophilic Vinylcarbene Intermediates
Xiaochen Wang,† Xinfang Xu,† Peter Y. Zavalij, and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S Supporting Information
b
Scheme 1
ABSTRACT: With metal carbene access to dipolar inter-
mediates, 3,6-dihydro-1,2-oxazines are produced in high
yields by dirhodium(II) carboxylate catalyzed reactions
between nitrones and a β-TBSO-substituted vinyldiazoace-
tate. High enantiocontrol occurs with catalysis by N-phtha-
loyl-(S)-(amino acid)-ligated dirhodium carboxylates for
[3 + 3]-cycloaddition reactions with both acyclic and cyclic
nitrones.
itrones are versatile reagents for cycloaddition reactions that
N
produce cyclic hydroxylamine derivatives.1 Although their
catalytic [2 + 3]-dipolar cycloaddition reactions have been
studied extensively,2 and highly enantioselective reactions with
α,β-unsaturated aldehydes have been reported,3 scarce attention
has been given to their formal [3 + 3]-cycloaddition reactions.
Hayashi reported a palladium-catalyzed [3 + 3]-cycloaddition
reaction between an N,α-diarylnitrone and trimethylenemethane
generated from [2-(acetoxymethyl)-2-propenyl)trimethylsilane
in high yield,4 but nitrones have otherwise been neglected.
Greater attention has been given to azomethine imines and
their reactions with trimethylenemethane (Pd catalysis),4 enals
(N-heterocyclic carbene catalysis),5 and propargyl esters (Au cat-
alysis),6 and other pairings for [3 + 3] cycloaddition show broad
applicability of this annulation transformation.7 However, al-
though there is recognized high potential for [3 + 3]-cycloaddi-
tion between 1,3-dipoles and electrophilic vinylcarbenes, only
the recent communication by Toste has described a [3 + 3]-
annulation process that involves a putative vinylcarbene inter-
mediate.6
formed the [3 + 3]-cycloaddition products (6b and 6c) in high
yields. Structural confirmation for the 3,6-dihydro-1,2-oxazine
products was obtained spectrally and from the X-ray diffraction
of a single crystal from 6c (Figure 1). The core structures of these
compounds, which up to now has been mainly available via
nitroso hetero-DielsÀAlder reactions9 and from a tandem one-
pot process involving organocatalytic α-oxyamination of an en-
amine with nitrosobenzene followed by reaction with a vinyl
phosphonium salt in an intramolecular Wittig process,10 are
versatile intermediates for the synthesis of α-substituted β-amino
acids and related compounds that are not easily accessible by
other methods.9,11 Substituent groups on 6a make this 3,6-dihydro-
1,2-oxazine particularly suitable for further functionalization.
We reasoned that the absence of examples of [3 + 3]-
cycloaddition reactions by catalytic dinitrogen extrusion from
vinyldiazo compounds was due to the limited ability of structure
1b of the vinylcarbene intermediate to capture a dipolar spe-
cies in a stepwise process that is a formal [3 + 3]-cycloaddition
(Scheme 1). This problem has now been resolved with the use of
TBSO-substituted vinyldiazoacetate 58 in catalytic reactions with
nitrones to form 3,6-dihydro-1,2-oxazine derivatives exclusively
and in high yield, and high enantiocontrol has been achieved
from the application of a chiral dirhodium carboxylate catalyst.
Treatment of 1.5 equiv of 5 in the presence of N,α-diphenyl-
nitrone and 1.0 mol % of dirhodium tetraacetate in dichloro-
methane gave immediate dinitrogen extrusion from 5 and pro-
duced 3,6-dihydro-1,2-oxazine 6a within 20 min in 98% isolated
yield (eq 1). No reaction occurred in the absence of catalyst. The
installation of the electron-donating MeO substituent or an
electron-withdrawing Br substituent on the reactant nitrone also
Only one direct chiral catalytic methodology has been ad-
vanced for the synthesis of 3,6-dihydro-1,2-oxazines, and this
process is limited to pyridylnitroso compounds that undergo
cycloaddition with conjugated dienes.12 Ley’s two-step organo-
catalytic route10 provides high enantiocontrol and modest to
good yields but is limited thus far to nitrosobenzene. In view of
the limited availability of catalytic enantioselective methods with
which to access these compounds we sought to employ chiral
dirhodium carboxylate catalysts for the reaction between 5 and
N,α-diphenylnitrone depicted in eq 1. As can be seen by the data
Received: August 13, 2011
Published: September 21, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja207664r J. Am. Chem. Soc. 2011, 133, 16402–16405
|

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Table 1. Optimization of the Enantioselective Formal [3 + 3]
Cycloaddition Reaction between Siloxyvinyldiazoacetate 5
and N,α-Diphenylnitrone Catalyzed by Chiral Dirhodium(II)
Carboxylatesa
T
time
(h)
yield
(%)b
ee
(%)c
Entry
Rh2L4
Solvent
PhMe
(°C)
1
7
23
23
1
80
98
98
76
80
15
85
18
50
<3
60
70
0
30
70
80
62
60
87
64
53
À
2
8a
8a
8a
8b
8c
8d
8e
9a
9b
8d
8d
CH2Cl2
PhMe
0.5
0.5
2
3
23
4
PhMe
À15
À15
À15
À15
À15
À15
À15
À30
À30
Figure 1. X-ray structure of the formal [3 + 3]-cycloaddition reaction
product (6c) formed from 5 and N-phenyl-α-(p-bromophenyl)nitrone.
5
PhMe
2
6
PhMe
2
7
PhMe
2
in Table 1, Rh2(S-DOSP)4 (7)13 catalyzed the formal [3 + 3]-
cycloaddition reaction but did not provide evidence of any
enantiocontrol. However, the phthalimide-amino acid ligated
dirhodium catalysts 8aÀ8d of Hashimoto and co-workers14
produced 6a in good to excellent yields and modest to high
enantioselectivities. Surprisingly, the least sterically encumbered
catalyst (8d) provided the highest level of enantiocontrol; steric
interference by R1 (for 8) and R2 (for 915) appears to be the cause
for lowering the % ee, and the absence of 6a from catalysis by 9b
suggests the absolute limitation for dirhodium carboxylates with
this class of chiral ligand. Notably, bulky substituents in ligands
also decreased the reaction rate, especially for Rh2(S-PTTL)4
(8c) and Rh2(S-PTAD)4 (8e16), which only converted a small
portion of the nitrone into the [3 + 3]-annulation product 6a
resulting in <20% isolated yield. Both solvent and temperature
were varied to reach optimum conditions (entry 14) that included
tert-butyl methyl ether (TBME) as the solvent and À30 °C as the
reaction temperaturefor95%yieldand 93% ee withonly 2.0 mol %
of 8d and a reaction time of 2 h.
8
PhMe
2
9
PhMe
2
10
11
12
PhMe
2
PhMe
2
89
91
PhMe/hexanes
(2:1)
2
13d
8d
8d
PhMe/hexanes
(2:1)
À30
À30
2
2
95
95
91
93
14d
TBME
a Reactions were performed by addition of a 1.0 mL solution of 5
(0.38 mmol) to the suspension of 0.25 mmol of N,α-diphenylnitrone,
0.0025 mmol of catalyst (1.0 mol %), and 100 mg of 4 Å MS with 1.0 mL of
solvent. b Isolated yield; the only othernitrone-derived material observed in
the reaction mixture was unreacted N,α-diphenylnitrone. c Determined by
HPLC (AD-H column). d The diazo compound was added dropwise with
a syringe pump over a time period of 1 h, and 2.0 mol % catalyst was used.
α-substituent was changed to the aliphatic cyclohexyl group
(entry 12), the enantioselectivity was also lower than that with
aryl groups as α-substituents.
Catalytic reactions of 5 with the cyclic nitrone of 3,4-dihy-
droisoquinoline N-oxide (12), which is the geometric equivalent
of a cis-disubstituted nitrone whose stereochemical requirements
would be expected to be different from those of trans-disubsti-
tuted nitrones such as 10, were also examined (eq 3 and Table 3).
In contrast to reactions with 10, catalysis of the reaction between
5 and 12 by Rh2(S-PTA)4 (8d) provided the [3 + 3]-cycloaddi-
tion product in high yield but with only a moderate 54% enantio-
meric excess. However, the sterically demanding catalyst Rh2(S-
PTTL)4 (8c) improved the enantioselectivity to 80% ee without
a significant decrease in product yield. That use of Rh2(S-PTAD)4
(8e) had the same degree of enantiocontrol as Rh2(S-PTTL)4,
but the yield of 13 in this case was much lower, suggests the
subtle nature of steric influences in this catalytic process. Solvent
tert-butyl methyl ether was not used because of its poor mis-
cibility with 3,4-dihydroisoquinoline N-oxide.
The mechanism of this formal [3 + 3]-cycloaddition (Scheme 2)
is in accord with the general process given in Scheme 1. Rhodium
carboxylate catalysts activate the vinyl carbene for nucleophilic
attack by the nitrone at the γ-position of 14 to form adduct 15.
Vinylogous reactivity in catalytic reactions of vinyldiazoacetates
has ample precedent.17 Intramolecular iminium ion addition to
the catalyst-activated vinyl ether functional group of 15 forms, in
a stepwise or concerted fashion, the [3 + 3]-cycloaddition
product 11. Iminium ion addition is facilitated by stabilization
provided by the TBSO group, and release of the catalyst from 16
With the optimal conditions in hand, the generality of this
enantioselective formal [3 + 3]-cycloaddition reaction (eq 2) was
further investigated, and the results of this investigation are given
in Table 2. Product yields were high, and 3,6-dihydro-1,2-oxazines
11 were the sole reaction products; however, enantioselectivities
of reactions with nitrones having electron-donating or -with-
drawing groups all occurred with a 3À16% lower enantiomeric
excess than did N,α-diphenylnitrone, indicating little depen-
dence on the electronic nature of aryl substituents. Instead,
the size of the α-substituent appears to be a determining factor
in the enantioselectivity of these reactions. All substituents on
the α-phenyl group decreased the enantioselecitivity relative to
N,α-diphenylnitrone, but 90% ee and 89% ee were achieved with
α-2- and α-3-furyl nitrones (entries 9 and 10), albeit in a lower
% conversion of 10 and lower isolated yield of 11. When the
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Journal of the American Chemical Society
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Table 2. Effects of Nitrone Substituents on Enantiocontrol
Scheme 2. Mechanism of the Formal [3 + 3]-Cycloaddition
Reaction of Siloxyvinyldiazoacetate 5 and Nitrone 10
for the Formal [3 + 3]-Cycloaddition Reactiona
T
time
(h)
yield
(%)b
ee
(%)c
Entry
R
(°C)
1
C6H5
À30
À30
À15
À15
À15
À30
À15
0
2
2
3
4
4
2
3
3
3
3
3
2
95
95
96
65
92
94
89
73
53
66
81
85
93
87
78
80
77
90
85
80
90
89
80
77
2
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-FC6H4
m-MeC6H4
m-ClC6H4
2-naphthyl
2-furyl
3
4
5
6
occur in high yields and selectivities. The convenience of this
methodology, the absence of a background reaction, and the
potential suitability of a spectrum of 1,3-dipoles and β-substituted
vinyldiazoacetates for this transformation suggest broad applic-
ability. The high level of dependence of catalyst ligands on en-
antioselectivity in product formation provides opportunities for
new catalyst developments. Further studies exploring these pro-
cesses are underway.
7
8
9
0
10
11
12
3-furyl
0
2-thienyl
0
cyclohexyl
À30
a Reactions were performed by slow addition (over 1 h) of 1.0 mL solu-
tion of 5 (0.38 mmol) to the suspension of 0.25 mmol of nitrone 10,
0.0050 mmol of catalyst (2.0 mol %), and 100 mg of 4 Å MS with 1.0 mL
of TBME. b Isolated yield of 11; the only other nitrone-derived material
observed in the reaction mixture was unreacted 10. c Determined by
HPLC (AD-H or OD-H column).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
compound characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Table 3. Formal [3 + 3]-Cycloaddition Reactions of
’ AUTHOR INFORMATION
3,4-Dihydroisoquinoline N-Oxide with 5a
Corresponding Author
mdoyle3@umd.edu
Author Contributions
†These authors contributed equally.
’ ACKNOWLEDGMENT
catalyst
yield (%)b
ee (%)c
Support for this research from the National Institutes of
Health (GM 46503) and the National Science Foundation
(CHE- 0748121) is gratefully acknowledged.
Rh2(S-PTA)4 (8d)
Rh2(S-PTTL)4 (8c)
Rh2(S-PTAD)4 (8e)
Rh2(S-NTTL)4 (9b)
a Reactions were performed by slow addition (over 1 h) of the diazo
compound (0.38 mmol) in 1.0 mL of toluene to the suspension of
0.25 mmol of 3,4-dihydroisoquinoline N-oxide, 0.0050 mmol of catalyst
(2.0 mol %), and 100 mg of 4 Å MS in 1.0 mL of toluene. b Isolated yield;
the only other nitrone-derived material observed in the reaction mixture
was unreacted 12. c Determined by HPLC (AD-H column).
97
86
50
75
54
80
80
60
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