Unexpected catalytic reactions of silyl-protected enol diazoacetates with nitrile oxides that form 5-arylaminofuran-2(3 H)-one-4-carboxylates

Article abstract of DOI:10.1021/ol203331r

Silyl-protected enol diazoacetates undergo dirhodium(II)-catalyzed reactions with nitrile oxides to form acid-labile ketenimines via dipolar cycloaddition of nitrile oxides to a donor/acceptor cyclopropene and Lossen rearrangement of the dipolar adduct; a

Full text of DOI:10.1021/ol203331r

ORGANIC
LETTERS
2012
Vol. 14, No. 3
800–803
Unexpected Catalytic Reactions of Silyl-
Protected Enol Diazoacetates with Nitrile
Oxides That Form 5-Arylaminofuran-
2(3H)-one-4-carboxylates
Xinfang Xu, Dmitry Shabashov, Peter Y. Zavalij, and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
mdoyle3@umd.edu
Received December 13, 2011
ABSTRACT
Silyl-protected enol diazoacetates undergo dirhodium(II)-catalyzed reactions with nitrile oxides to form acid-labile ketenimines via dipolar
cycloaddition of nitrile oxides to a donor/acceptor cyclopropene and Lossen rearrangement of the dipolar adduct; acid catalysis converts the
ketenimine to the furan product.
In order to understand carbene-like extensions in reac-
tivity and selectivity, we have been investigating catalytic
reactions of 3-(tert-butyldimethylsiloxy)-2-diazo-3-bu-
tenoate esters (1),1 a subset of vinyldiazoacetates2 that
we will refer to as enoldiazoacetates. These diazo com-
pounds, which are conveniently prepared from methyl
diazoacetoacetate and tert-butyldimethylsilyl triflate in
the presence of base,3 are stable to intramolecular dipolar
cycloaddition4 and can be stored for long periods of time.
Dinitrogen extrusion by selected transition metals changes
the polarity of the bound carbon from being susceptible to
electrophilic addition in the diazo compound to undergo
nucleophilic attack in the metal carbene (Scheme 1). The
electrophilic center of the metal carbene formed from
enoldiazoacetates 1 is delocalized which makes possible
not only the expected carbene addition, insertion, and
association reactions but also vinylogous reactions.5,6
Based on our previously reported results that enoldiazo-
acetates undergo formal [3 þ 3] cycloaddition reactions
with N,R-diphenylnitrone catalyzed by Rh(II) catalysts,6
we envisioned an analogous cycloaddition process with
nitrile oxides. Consequently, we were surprised when
treatment of methyl TBS-protected enoldiazoacetate (1a)
with 2,4,6-trimethylbenzonitrile oxide (2a) at 0 °C under
dirhodium acetate catalysis produced γ-lactone 3a in 67%
(1) (a) Xu, X.; Hu, W.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int.
Ed. 2011, 50, 11152. (b) Xu, X.; Hu, W.; Doyle, M. P. Angew. Chem., Int.
Ed. 2011, 50, 6392. (c) Xu, X.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle,
M. P. Org. Lett. 2011, 13, 6122. (d) Liu, Y.; Bakshi, K.; Zavalij, P. Y.;
Doyle, M. P. Org. Lett. 2010, 12, 4304.
(2) Basic understandings of vinyl diazoacetates, including enol diazo-
acetates, in catalytic metal carbene forming reactions have been
developed by Davies and co-workers: (a) Qin, C.; Boyarskikh, V.;
Hansen, J. H.; Hardcastle, K. I.; Musaev, D. G.; Davies, H. M. L. J. Am.
Chem. Soc. 2011, 133, 19198. (b) Lian, Y.; Davies, H. M. L. J. Am. Chem.
Soc. 2011, 133, 11940. (c) Lian, Y.; Hardcastle, K. I.; Davies, H. M. L.
Angew. Chem., Int. Ed. 2011, 50, 9370.
(3) (a) Davies, H. M. L.; Peng, Z.-Q.; Houser, J. H. Tetrahedron Lett.
1994, 35, 8939. (b) Ueda, Y.; Roberge, G.; Vinet, V. Can. J. Chem. 1984,
62, 2936.
(4) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L.
J. Am. Chem. Soc. 1993, 115, 9468.
(5) Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M. L.
J. Am. Chem. Soc. 2010, 132, 12422.
(6) Wang, X.; Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc.
2011, 133, 16402.
r
10.1021/ol203331r
Published on Web 01/24/2012
2012 American Chemical Society

influenced by placement of a methyl substituent at ortho,
meta, or para positions of the nitrile oxide (entries 4ꢀ6).
Steric hindrance from the aryl group of the nitrile oxide
appears to have little influence on the reaction outcome,
and various esters of the TBS-protected enoldiazoacetate
(entries 2, 7, and 8) provide good yields of lactones.
However, nitrile oxides having electron-withdrawing
substituents react with 1a to produce mixtures of pro-
ducts whose constitution and source(s) are under investi-
gation. Terminal substitution on the vinyl group of the
diazo compound (R1 = Me, Ph: entries 9 and 10) did not
interfere with the formation of 3.
Scheme 1. Polarity Reversal from a Vinyldiazo Compound to
the Corresponding Metal Vinylcarbene
Table 1. Substrate Scope of the Rearrangement Reactiona
isolatedyield after chromatography onsilicagel (eq1). The
structure of this lactone product was confirmed by single-
crystal X-ray diffraction analysis (see the Supporting
Information). Comparing the substrate and product ske-
letons, structural rearrangement has obviously occurred.
We report here the generality of this rearrangement reac-
tion and its cause.
yieldb
To determine the optimum catalysts for this fascinating
rearrangement reaction, a series of Rh(II) compounds was
tested under the same reaction conditions. Dirhodium
catalysts that included those with octanoate, benzoate,
pivalate, and triphenylacetate ligands gave the lactone
product in moderate yields (43ꢀ59%). Interestingly,
CuPF6 catalyzed the reaction as well, providing lactone 3
in modest yield (48%). However, only starting materials
and/or hydrolyzed diazo compound were recovered when
this reaction was performed in the presence of catalytic
amounts of Lewis acids that included Sc(OTf)3, Zn(OTf)2,
and Cu(OTf)2, and no reaction occurred in the absence of
catalyst, which rules out a direct Lewis acid catalyzed
reaction of 1a. Further screening of the catalysts revealed
that rhodium(II) catalysts with electron-withdrawing
ligands (heptafluorobutyrate and trifluoroacetate) were
significantly more active compared with other dirhodium
catalysts, and the highest yield was obtained by controlled
addition of the diazo compound via syringe pump at 0 °C
tothe mixture of nitrile oxideand Rh2(pfb)4 catalyst(83%)
(Supporting Information).
entry
R1/R2 (1)
Ar (2)
product
(%)
1
2
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Bn (1b)
H/t-Bu (1c)
Me/Me (1d)
Ph/Me (1e)
2,4,6-Me3C6H2 (2a)
2-MeOC6H4 (2b)
4-FC6H4 (2c)
3a
3b
3c
3d
3e
3f
67
92
70c
76c
65
76
78
79
54
86
3
4
4-MeC6H4 (2d)
3-MeC6H4 (2e)
2-MeC6H4 (2f)
5
6
7
2-MeOC6H4 (2b)
2-MeOC6H4 (2b)
2-MeOC6H4 (2b)
2,4,6-Me3C6H2 (2a)
3g
3h
3i
8
9
10
3j
a Reaction conditions: diazo compound (1.2 mmol) in DCM
(3.0 mL) was added over 1 h via a syringe pump at 0 °C to mixture of
4 A molecular sieves (100 mg), Rh2(pfb)4 (2.0 mol %), and nitrile oxide
(1.0 mmol) in DCM (5.0 mL) and stirred for another 2 h at room
temperature. The reaction mixture was purified by chromatography on
silica gel. b Isolated yield of 3 based on limiting reagent 2. c Minor
unidentified byproduct was detected.
˚
Although lactones 3 hinted that the methylene group of
1a becomes the methylene group of 3a and that the TBSO-
substituted carbon of 1 becomes the carbon of the lactone
carbonyl group, labeling experiments were performed to
track carbon atom placement in the newly formed skeleton
of 5-arylaminofuran-2(3H)-one 3. Double C-13-labeled
4 was prepared using standard procedures from doubly
labeled ethyl acetoacetate1,3 and then reacted under stan-
dardconditionswith2a(eq 2). The carbonNMR spectrum
of the product showed that the terminal vinyl carbon of 4
had been transformed into the CH2 group of 5, while the
vinyl quaternary carbon of 4 became the lactone carbonyl
carbon of 5. This result hinted at rearrangement of the
metal carbene formed from TBS-protected enoldiazoacetate
1 to cyclopropene 6 and a subsequent dipolar addition
reaction with nitrile oxide. The formation of the analogous
cyclopropene methyl ester that possesses both donor and
acceptor substituents has been reported by Davies from
Examination of the scope of the reaction with substitu-
ent variations in the diazo compound and nitrile oxides
(Table 1) shows that electron-rich nitrile oxides give good
to high yields of lactone products 3. Product yield is not
Org. Lett., Vol. 14, No. 3, 2012
801

rhodium acetate catalyzed dinitrogen extrusion from 1a;7
this cyclopropene was unstable but, as also reported by
Davies, could be trapped as a DielsꢀAlder adduct.8
Scheme 2. Possible Intervention of a Ketenimine
Careful examination of the 1H NMR data for the
reaction mixture from Rh2(pfb)4 catalysis of 1a with 2a
prior to chromatography provided evidence that the che-
mical shifts of the CH2 group protons of the product
are different from those of 3a, suggesting that an inter-
mediate in the reaction mixture is transformed into 3
during the chromatographic isolation procedure. A pro-
duct crystallized from this reaction mixture (prior to
chromatography, open to the atmosphere) and was identi-
fied as 7a. The connectivity of 7a suggests the intervention
of ketenimine 8a that could arise from ring-opening of the
product (9) from dipolar cycloaddition of the nitrile oxide
to cyclopropene 10a (Scheme 2).9 The conversion of 9a to
8a that involves migration of the aryl group from carbon to
nitrogen is an example of the rarely reported Lossen
rearrangement which is facilitated by aryl group elec-
tron-donating substituents.10
(“click” chemistry),12 the isocyanideꢀNefꢀPerkow reac-
tion sequence,13 from ynamides by Pd(0)-catalyzed N-to-
C allyl transfer,14 and even by pulsed pyrolysis of isoxazole.15
Their structural diversity is dependent on the methods for
their formation, and structure 8 is unique. Is ketenimine 8a
an actual intermediate along the pathway to either 3 or 7?
To answer this question we prepared the triisopropylsilyl
(TIPS)-protected enol diazoacetate 1f and subjected this
compound to reaction with 2a catalyzed by Rh2(pfb)4.
Ketenimine 8b was the only product formed and was
isolated in 62% yield (eq 3). Treatment of 8b with aqueous
trifluoroacetic acid gave the product identical to amide 7
except for the silyl group. These observations confirm that
dirhodium(II) catalysis of the reaction between enoldiazo-
acetates form a highly reactive cyclopropene intermediate that
undergoes reaction with nitrile oxides to form ketenimine
products. That the ketenimine is formed from a cyclopropene
intermediate was established by preparing the stable BHT
ester 1112 and then adding 2a with and without the presence of
rhodium acetate catalyst. Although reaction was slow in both
cases, presumably because of steric inhibition, ketenimine 12
was detected in about 30% yield in the reaction mixture by
NMR (eq 4), and its formation confirmed that cyclopropenes
with donor and acceptor groups are precursors to ketenimines
formed by cycloaddition with nitrile oxide.
Ketenimines (RR0CdCdNR00) are versatile reaction
intermediates in organic synthesis, and their formation
and reactions have been the subjects of intense interest.11
They are accessible via azide cycloaddition with acetylenes
(7) (a) Davies, H. M. L.; Houser, J. H.; Thornley, C. J. Org. Chem.
1995, 60, 7529. (b) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am.
Chem. Soc. 1996, 118, 10774.
(8) When this reaction was performed in the presence of 2a (1.0 equiv)
and 1,3-diphenylisobenzofuran (1.0 equiv), 3a and the DielsꢀAlder
adduct were obtained in a 2:1 ratio.
(9) An analogous rearrangement of a 2-oxa-3-azabicyclo[3.1.0]-
hex-3-ene system (one example) involving ketenimine formation has
been reported: Nesi, R.; Giomi, D.; Papaleo, S.; Dapporto, P.; Paoli, P.
J. Chem. Soc. Chem. Commun. 1990, 1675.
ꢀ
(10) (a) Dube, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org. Lett.
2009, 11, 5622. (b) Berndt, D. C.; Shechter, H. J. Org. Chem. 1964, 29,
916.
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Finnerty, J. J.; Wentrup, C. J. Org. Chem. 2011, 76, 6024. (c) Wang, J.;
Wang, J.; Zhu, Y.; Lu, P.; Wang, Y. Chem. Commun. 2011, 47, 3275.
(d) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem. Commun. 2011, 47, 5623.
(e) Alajarin, M.; Bonillo, B.; Ortin, M.-M.; Orenes, R.-A.; Vidal, A. Org.
Biomol. Chem. 2011, 9, 6741. (f) Cheng, Y.; Ma, Y.-G.; Wang, X.-R.;
Mo, J.-M. J. Org. Chem. 2009, 74, 850. (g) Larksarp, C.; Sellier, O.;
Alper, H. J. Org. Chem. 2001, 66, 3502.
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Kim, S. H.; Park, S. H.; Choi, J. H.; Chang, S. Chem. Asian J. 2011, 6,
2618. (c) Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011, 13, 4312. (d) Li, S.; Luo,
Y.; Wu, J. Org. Lett. 2011, 13, 3190. (e) Namitharan, K.; Pitchumani, K.
Org. Lett. 2011, 13, 5728.
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1825.
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Dai, H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76,
5092. (b) DeKorver, K. A.; Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org.
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The question that now arises is how are ketenimine
intermediates converted to 3? Is acid catalysis involved?
(15) Nunes, C. M.; Reva, I.; Pinho e Melo, T. M. V. D.; Fausto, R.;
ꢁ
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802
Org. Lett., Vol. 14, No. 3, 2012

Is the ketenimine intermediate converted to a carboxylic
acid that then cyclizes? To answer these questions, various
Lewis acids were screened under strictly anhydrous condi-
tions in reactions using preformed 8a as the substrate
(eq 5). Although all of these Lewis acids catalyze the
formation of 3a, reactions occurred at different catalyst-
dependent rates, and 3 was prone to hydrolysis at extended
reaction times. CuPF6 and Zn(OTf)2 showed lower reac-
tion rates but gave 3a without hydrolysis over the extended
reaction times, and reactions with or without Rh2(pfb)4
present gave the same result. The use of CsF, which is
known to effect removal of TBS,16 had no effect on 8a in
dichloromethane during a 12 h exposure.
Scheme 3. Possible Pathways from Ketenimine 8 to Lactone 3
Scheme 4. Proposed Mechanism for the Catalytic Cascade
Reaction of Enoldiazoacetates with Nitrile Oxides
To ascertain the sequence through which conversion of8
to 3 has occurred (Scheme 3);either directly from Lewis
acid coordinated 8 with silyl group transfer to nitrogen
then hydrolysis (path A) or after initial hydrolysis of the
trialkylsilyl-ester then cyclization (path B);the TMS-
protected enoldiazoacetate (1g) was prepared and sub-
jected to reaction with Rh2(pfb)4. Ketenimines 8a and 8b
are stable to lactone formation in the presence of Rh2(pfb)4.
However, lactone product 3a was formed directly in reac-
tions of TMS-protected enoldiazoacetate, indicating that
silyl group transfer (path B) is the barrier in the conversion
of ketenimine 8 to lactone 3.
In summary, the mechanism for formation of 3 from
catalytic reactions between1 and 2 is describedinScheme4.
Rhodium-catalyzed dinitrogen extrusion from diazo com-
pound 1 forms cyclopropene 10 that undergoes uncata-
lyzed dipolar cycloaddition with nitrile oxide to form
the unstable 2-oxa-3-azabicyclo[3.1.0]hex-3-ene (9). Ring-
opening via the Lossen rearrangement (9f8) forms kete-
nimine 8 that undergoes catalytic cyclization to form
5-arylaminofuran-2(3H)-one 3. Catalysis in the formation
of 3 occurs either with Lewis acids or on silica gel during
chromatography. Both 8 and 10 have been intercepted
along this mechanistic pathway.
Acknowledgment. Support for this research from the
National Institutes of Health (GM 46503) and the Na-
tional Science Foundation (CHE-0748121) is gratefully
acknowledged.
Supporting Information Available. General experimental
procedures, X-ray structures of 3a and 7a, and spectro-
scopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(16) (a) Bellassoued, M.; Lensen, N.; Bakasse, M.; Mouelhi, S.
J. Org. Chem. 1998, 63, 8785. (b) Bellassoued, M.; Ennigrou, R.;
Gaudemar, M. J. Organomet. Chem. 1988, 338, 149.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
803