A donor-acceptor cyclopropene as a dipole source for a silver(i) catalyzed asymmetric catalytic [3+3]-cycloaddition with nitrones

Article abstract of DOI:10.1039/c3cc46415f

Silver(i)-catalyzed asymmetric formal [3+3]-cycloaddition of nitrones with a donor-acceptor cyclopropene, formed in situ from dirhodium acetate-catalyzed dinitrogen extrusion/intramolecular cyclization of enoldiazoacetates, effectively generates 3,6-dihydro-1,2-oxazine derivatives in high yield and with exceptional stereocontrol.

Full text of DOI:10.1039/c3cc46415f

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A donor–acceptor cyclopropene as a dipole source
for a silver(I) catalyzed asymmetric catalytic
[3+3]-cycloaddition with nitrones†
Cite this: Chem. Commun., 2013,
49, 10287
Received 21st August 2013,
Accepted 9th September 2013
Xinfang Xu, Peter J. Zavalij and Michael P. Doyle*
DOI: 10.1039/c3cc46415f
www.rsc.org/chemcomm
Silver(I)-catalyzed asymmetric formal [3+3]-cycloaddition of nitrones
with a donor–acceptor cyclopropene, formed in situ from dirhodium
acetate-catalyzed dinitrogen extrusion/intramolecular cyclization of
enoldiazoacetates, effectively generates 3,6-dihydro-1,2-oxazine
derivatives in high yield and with exceptional stereocontrol.
We recently reported that nitrones undergo highly enantioselective
[3+3]-cycloaddition with the dirhodium carbene derived from
methyl 2-diazo-3-(di-tert-butylmethylsilyloxy)-3-butenoate (1a, an
enoldiazoacetate, Scheme 1),1 but that the same dirhodium
catalysts were unreactive towards g-phenyl-enoldiazoacetate 1b.2
Surprisingly, g-phenyl-enoldiazoacetates underwent highly
diastereoselective [3+3]-cycloaddition catalyzed by copper(II)
hexafluoroantimonate that was interpreted to involve a Lewis
acid catalyzed pathway with diazonium ion intermediates
(Scheme 1) since other Lewis acids such as zinc triflate and
copper(II) triflate also catalyzed this reaction.2,3 However,
silver(I) hexafluoroantimonate also catalyzed this reaction and, like
Cu(SbF6)2, did so with a high turnover rate. In an effort to affect
enantiocontrolled cycloaddition with g-aryl-enoldiazoacetates we
reexamined catalysts that might be suitable for reactions with
enoldiazoacetates. Both enoldiazoacetate 1b and the donor–
acceptor cyclopropene (methyl 3-phenyl-2-TBSO-cyclopropene-
carboxylate) derived from it were examined as dipolar reactants.
In this report, we communicate a highly enantioselective and
diastereoselective silver-catalyzed asymmetric [3+3]-cycloaddition
reaction of nitrones that occur with the donor–acceptor cyclopro-
Scheme 1 Divergent pathways for cycloaddition with enoldiazoacetates.
penes derived from g-phenyl-enoldiazoacetate 1b which allows salts of Cu(II) or Ag(I) (Scheme 2).4 However, with 1b (R = phenyl)
dinitrogen loss occurred when catalyzed by dirhodium acetate,
these reactions to occur at À78 1C.
Reactions of 1a (R = H or alkyl) with nitrones gave the [3+3]- but no discernable cycloaddition product was formed; in contrast,
cycloaddition product 3 exclusively when catalyzed by dirhodium the [3+3]-cycloaddition product 3 was isolated in high yield and
acetate,1a but the Mannich addition product 4 was the sole diastereoselectivity using Cu(SbF6)2 or Ag(SbF6).2 Can either
product with catalytic amounts of the hexafluoroantimonate Cu(SbF6)2 or Ag(SbF6) in combination with a chiral ligand
generate [3+3]-cycloaddition products 3 with high stereocontrol
Department of Chemistry and Biochemistry, University of Maryland, College Park,
from the reactions of nitrones with enoldiazoacetates 1b?
Consistent with prior observations,5 spectroscopic evidence
Maryland, 20742, USA. E-mail: mdoyle3@umd.edu; Fax: +1 301-314-2779
† Electronic supplementary information (ESI) available: Experimental proce-
from control reactions confirmed that Rh2(OAc)4 decomposes
dures, structural proofs, and spectral data for all new compounds. CCDC
the g-phenyl-enoldiazoacetate 1b to generate the moderately
stable donor–acceptor cyclopropene intermediate 5 that upon
953542. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc46415f
c
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with 81% ee in 87% yield (entry 8). An alternative approach to
this procedure is to use the AgSbF6/(S)-t-BuBox catalyst directly
on the enoldiazoacetate in the presence of the nitrones, and under
the same conditions of solvent and temperature as reported in
Table 1 (entry 1), the cycloaddition product 6 was obtained with
56% ee; however, decreasing the reaction temperature to À30 1C
prevented dinitrogen extrusion from 1b and thereby limited stereo-
control. The Cu(SbF6)2/(S)-t-BuBox complex exhibited sluggish reac-
tivity at room temperature in its catalysis of the reaction between
enoldiazoacetate 1b and nitrone 2a, producing the cycloaddition
product in only 26% yield without evidence of any enantio-
selectivity. Attempted optimization through solvent screening
and use of alternative counter anions did not lead to any
improvement in selectivities. However, an increase in enantio-
control from 81 to 93% ee for 7a was achieved using the tert-
butyl g-phenyl-enoldiazoacetate 1c instead of the methyl ester 1b
under the optimized Rh(II)/Ag(I) stepwise catalysis conditions
(Table 2, entry 1).7
Scheme 2 Catalyst influence on product formation in reactions of enoldiazoa-
cetates with nitrones.
treatment of 5 with nitrone 2a and AgSbF6 produced the formal
[3+3]-cycloaddition product 3 that was isolated in 92% yield.6
As was previously reported for reactions of 1b with AgSbF6,2
only the cis-disubstituted cycloaddition product was observed.
This result suggests the viability of silver(I) catalyzed cycloaddition of
nitrones with the rhodium acetate generated cyclopropene (eqn (1)).
Since the donor–acceptor cyclopropene 5 has an asymmetric center,
a critical question in its formation is ‘‘can 5 be formed
asymmetrically?’’ When chiral rhodium catalysts, including
Rh2(S-DOSP)4 and Rh2(S-PTPA)4, were used in the first step
followed by AgSbF6, the resultant cycloaddition product 6
(formed after TBAF removal of the TBS group) showed less
than 5% ee (Table 1, entries 2 and 3). Using the silver catalyst in
the presence of the chiral (S)-t-BuBox ligand in the second step,
these reactions gave the same results as those catalyzed by
achiral Rh2(OAc)4 (entry 1 compared with 4 and 5). Although we
were unable to determine the enantiomeric excess of the in situ
generated cyclopropene 5 catalyzed by chiral rhodium(II), these
results are consistent with 6 being formed as a racemate and with
enantioselectivity being controlled solely by the AgSbF6/(S)-t-BuBox
complex. Furthermore, the advantage of this Rh(II)/Ag(I)-cas-
cade catalyzed process is suitable to broad temperature mani-
pulations to increase both stereoselectivity and yield (entries 6–8);
the Ag(I) catalyzed cycloaddition of 5 with nitrone 2a occurs
smoothly even at À78 1C, which yields the cycloaddition product
(1)
The scope of the enantioselective formal [3+3]-cycloaddition
of 1c with a broad selection of nitrones was explored, and these
results are reported in Table 2. The developed cascade catalysis
system proved to be applicable to a wide range of nitrones, and
the cis-disubstituted 3,6-dihydro-1,2-oxazine derivatives (7)
were obtained in high yield with enantioselectivities above
90%. A lower % ee value was obtained with nitrone 2c that
has an electron-withdrawing substituent on the N-phenyl
group, but nitrones with an electron-donating substituent on
the N-phenyl group with or without an electron-withdrawing
substituent on the a-phenyl group showed higher enantio-
selectivity (up to 97% ee). In addition, the 2-furyl nitrone (2s)
also gave the desired product that was isolated in 95% yield
with 79% ee (entry 19). The (3S,6R)-configuration of the generated
two chiral centers in 3,6-dihydro-1,2-oxazine derivatives was
confirmed by single-crystal X-ray diffraction analysis of 7c,8 and
the configurations of other compounds were assigned by analogy
(Fig. 1).
Despite their synthetic potential, 3,6-dihydro-1,2-oxazines
have been prepared by a limited number of methods, mainly
[4+2] cycloaddition,9 and also by reverse Cope elimination of
hydroxylamine precursors,10 and none of them have afforded
these compounds by enantioselective processes. We have developed
a Rh(II)/Ag(I)-cascade catalytic enantioselective formal [3+3]-
cycloaddition reaction of g-phenyl-enoldiazoacetate with nitrones.
The reaction is initiated by dirhodium-catalyzed intramolecular
Table 1 Rh(II)/Ag(I)-cascade catalyzed enantioselective formal [3+3]-cycloaddi-
tion of 1b with nitrone 2aa
6a, Yieldb
(%)
6a, eec
(%)
Entry
Rh(II)
Ligand
T (1C)
1
2
3
4
5
6
7
8
Rh2(OAc)4
(S)-t-BuBox
—
0
0
0
0
0
68
75
81
61
66
69
74
87
63
o5
o5
63
64
67
Rh2(S-DOSP)4
Rh2(S-PTPA)4
Rh2(S-DOSP)4
Rh2(S-PTPA)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
—
(S)-t-BuBox
(S)-t-BuBox
(S)-t-BuBox
(S)-t-BuBox
(S)-t-BuBox
À25
À40
À78
76
81
a
Reactions were carried out in a 0.2 mmol scale: 1b (0.24 mmol),
2a (0.20 mmol), in 1.0 mL DCM (the silver catalyst [10 mol% AgSbF6
+
12 mol% (S)-t-BuBox] was stirred in 1.0 mL DCM at room temperature
b
for 0.5 h before use). Isolated yield of 6a based on limiting reagent 2a.
c
Determined by HPLC analysis using chiral OD–H columns (hexanes :
i-PrOH = 98 : 2, 254 nm, 0.5 mL minÀ1, t1 = 8.9, t2 = 21.0).
c
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Table 2 Enantioselective formal [3+3]-cycloaddition of donor–acceptor cyclo-
propene 5c with nitrones 2a
[3+3]-cycloaddition between 5 and nitrones that results in the
exclusive formation of cis-disubstituted 3,6-dihydro-1,2-oxazine
derivatives 7 in high yield with exceptional enantiocontrol.
While it is attractive to propose that a silver carbene species
is involved in the cycloaddition process, a Lewis acid-promoted
pathway cannot be excluded from consideration.11–13 Efforts
are underway to determine the mechanism of this process and
to extend the methodology to other cycloaddition reactions.
Entry Ar1/Ar2 (2)
7
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Ph/4-BrC6H4 (2a)
7a
89
93
4-MeOC6H4/Ph (2b)
4-BrC6H4/4-ClC6H4 (2c)
Ph/Ph (2d)
2-MeOC6H4/Ph (2e)
Ph/2-MeOC6H4 (2f)
Ph/4-CF3C6H4 (2g)
Ph/2-ClC6H4 (2h)
7b 85
7c 92
7d 93
7e
7f
7g
7h 77
7i
7j
7k
7l
7m 88
7n 85
91
Notes and references
82 (>99.5)d
90
92
90
90
93
90
94
90
94
92
96
93
94
97
93
79
1 For [3+3]-cycloaddition reactions: (a) X. Wang, X. Xu, P. Y. Zavalij
and M. P. Doyle, J. Am. Chem. Soc., 2011, 133, 16402; (b) X. Xu,
Y. Qian, P. Y. Zavalij and M. P. Doyle, J. Am. Chem. Soc., 2013,
135, 1244; (c) X. Xu, P. J. Zavalij, W. Hu and M. P. Doyle, Chem.
Commun., 2012, 48, 11522; (d) X. Xu, P. J. Zavalij and M. P. Doyle,
Angew. Chem., Int. Ed., 2012, 51, 9829; (e) X. Xu, X. Xu, P. Y. Zavalij
and M. P. Doyle, Chem. Commun., 2013, 49, 2762.
2 Y. Qian, X. Xu, X. Wang, P. J. Zavalij, W. Hu and M. P. Doyle, Angew.
Chem., Int. Ed., 2012, 51, 5900.
3 M. P. Doyle, M. Yan, W. Hu and L. S. Gronenberg, J. Am. Chem. Soc.,
2003, 125, 4692.
95
91
88
9
Ph/3-ClC6H4 (2i)
Ph/4-ClC6H4 (2j)
80
91
95
92
10
11
12
13
14
15
16
17
18
19
Ph/4-MeC6H4 (2k)
Ph/4-FC6H4 (2l)
Ph/2-naphthyl (2m)
2-MeOC6H4/4-BrC6H4 (2n)
2-MeOC6H4/2-BrC6H4 (2o)
2-MeOC6H4/2-CF3C6H4 (2p)
2-MeOC6H4/4-MeO2CC6H4 (2q) 7q 82
4-MeOC6H4/4-BrC6H4 (2r)
Ph/2-furyl (2s)
7o
7p 85
75
4 X. Xu, M. O. Ratnikov, P. Y. Zavalij and M. P. Doyle, Org. Lett., 2011,
13, 6122.
5 (a) H. M. L. Davies, J. H. Houser and C. Thornley, J. Org. Chem., 1995,
60, 7529; (b) H. M. L. Davies, G. Ahmed and M. R. Churchill, J. Am.
Chem. Soc., 1996, 118, 10774; (c) X. Xu, D. Shabashov, P. Y. Zavalij
and M. P. Doyle, J. Org. Chem., 2012, 77, 5313; (d) X. Xu,
D. Shabashov, P. Y. Zavalij and M. P. Doyle, Org. Lett., 2012, 14, 800.
6 Cycloaddition was not observed in the absence of AgSbF6 or in the
presence of other metal catalysts, including Sc(OTf)3, Zn(OTf)2,
Yb(OTf)3, In(OTf)3, Mg(OTf)2 and Pd2Cl2(allyl)2.
7r
7s
71
95
a
Reactions were carried out in a 0.2 mmol scale: 1c (0.24 mmol),
2 (0.20 mmol), in 1.0 mL DCM (the silver catalyst [10 mol% AgSbF6
+
12 mol% (S)-t-BuBox] was stirred in 1.0 mL DCM at room temperature
b
for 0.5 h before use). Isolated yield of 7 based on limiting reagent 2.
c
d
Determined by HPLC analysis with chiral columns. Enantioselectivity
7 For review on relay catalysis: (a) G. Dong, P. Teo, Z. K. Wickens and
R. H. Grubbs, Science, 2011, 333, 1609; (b) V. Jeso and G. C.
Micalizio, Nature, 2013, 494, 179; (c) J. Yu, F. Shi and L. Gong,
Acc. Chem. Res., 2011, 44, 1156; (d) And recent examples: Z. Han,
D. Chen, Y. Wang, R. Guo, P. Wang, C. Wang and L. Gong, J. Am.
Chem. Soc., 2012, 134, 6532(e) D. Qian and J. Zhang, Chem.–Eur. J.,
2013, 19, 6984; ( f ) X. Xu, W. Hu, P. Y. Zavalij and M. P. Doyle, Angew.
Chem., Int. Ed., 2011, 50, 11152; (g) H. Huang, X. Ji, W. Wu and
H. Jiang, Chem. Commun., 2013, 49, 3351; (h) S. Zhu and M. Rueping,
Chem. Commun., 2012, 48, 11960; (i) M. Rueping, J. Dufour and
M. S. Maji, Chem. Commun., 2012, 48, 3406.
in the brackets resulted after recrystallization of 7 from a mixture of
DCM, ethyl acetate and hexanes.
8 CCDC 953542 (7c)†.
9 (a) S. M. Weinreb, Heterodienophile Additions to Dienes, in Comp. Org.
Synth., ed. B. M. Trost, Pergamon, Oxford, 1991, vol. 5, pp. 417–422;
(b) G. Calvet, N. Blanchard and C. Kouklovsky, Org. Lett., 2007, 9, 1485.
`
10 E. Dumez, R. Faure and J.-P. Dulcere, Eur. J. Org. Chem., 2001, 2577.
11 References for silver carbene: (a) J. Urbano, A. A. C. Braga,
´
´
´
F. Maseras, E. Alvarez, M. M. Dıaz-Requejo and P. J. Peerez, Orga-
nometallics, 2009, 28, 5968; (b) J. H. Hansen and H. M. L. Davies,
Chem. Sci., 2011, 2, 457; (c) J. L. Thompson and H. M. L. Davies,
J. Am. Chem. Soc., 2007, 129, 6090.
12 Enol metal carbene in situ generated from cyclopropene catalyzed by
Au or Ru: (a) D. Benitez, N. D. Shapiro, E. Tkatchouk, Y. Wang,
W. A. Goddard and F. D. Toste, Nat. Chem., 2009, 1, 482;
(b) H. Nishiyama, M. Konno, K. Aoki and H. M. L. Davies, Organo-
metallics, 2002, 21, 2536.
Fig. 1 (3S,6R)-Configuration of 7c. ORTEP view showing product stereochem-
istry. Ellipsoids are shown at 30% probability.
13 Evidence for the Lewis acid pathway: (a) A. Padwa, T. J. Blacklock
and R. Loza, J. Am. Chem. Soc., 1981, 103, 2404; (b) D. T. H. Phan and
V. M. Dong, Tetrahedron, 2013, 69, 5726; (c) Y. Yue, Y. Wang and
W. Hu, Tetrahedron Lett., 2007, 48, 3975.
cyclization of the metal carbene formed from g-phenyl-enoldia-
zoacetate to produce donor–acceptor cyclopropene 5, followed
by chiral AgSbF6/(S)-t-BuBox complex-catalysis of the formal
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10287--10289 10289