Phosphine-Catalyzed Intramolecular Cyclizations of α-Nitroethylallenoates Forming (Z)-Furanone Oximes

Article abstract of DOI:10.1021/acs.orglett.6b01299

A novel and efficient phosphine-catalyzed intramolecular cyclization of α-nitroethylallenic esters is reported. This process appears to be practical for the stereoselective syntheses of (Z)-furan-2(3H)-one oxime derivatives in excellent yields. Mechanisti

Full text of DOI:10.1021/acs.orglett.6b01299

Letter
pubs.acs.org/OrgLett
Phosphine-Catalyzed Intramolecular Cyclizations of
α‑Nitroethylallenoates Forming (Z)‑Furanone Oximes
Qing-Fa Zhou,†,‡ Kui Zhang,‡ Lingchao Cai,‡ and Ohyun Kwon*,‡
†State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 210009,
P. R. China
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: A novel and efficient phosphine-catalyzed intramolecular
cyclization of α-nitroethylallenic esters is reported. This process appears
to be practical for the stereoselective syntheses of (Z)-furan-2(3H)-one
oxime derivatives in excellent yields. Mechanistically, the reaction
involves a phosphine-catalyzed Michael addition of an alkylideneazinate
and rearrangement of the cyclic nitronate to the α-nitrosodihydrofuran.
not, however, exclude the possibility of forming cyclic
ucleophilic phosphine catalysis has recently flourished
Nbecause of its high versatility, operational ease, and low nitronates B through intramolecular Michael addition of the
oxygen anion of the alkylideneazinate intermediate.8b To our
cost. In this context, nucleophilic phosphine-catalyzed cycliza-
surprise, compounds 1 produced, instead, five-membered cyclic
N-hydroxyimidic acid esters 2 as novel products in high yields
under the influence of a tertiary phosphine catalyst. Methods
for the synthesis of cyclic N-hydroxyimidic acid esters are
scarce, with the only known processes being oxidative ring
closure of γ- or δ-hydroxyl oximes,9 rearrangement of
nitronates,10 organoselenium-induced cyclization of β,γ-unsa-
turated hydroxamic acids,11 and tandem reactions of β-
nitrostyrenes with 1,3-dicarbonyl compounds.12 Because of
their potential biological activities,9b herein we report a novel
approach toward five-membered cyclic N-hydroxyimidic acid
esters 2 through highly effective phosphine-catalyzed cycliza-
tions of 2-(2′-nitroethyl)allenic esters 1. This transformation,
which occurs through a mechanistically intriguing cascade
process, appears to be a practical and operationally simple
method for preparing five-membered cyclic N-hydroxyimidic
acid esters under extremely mild conditions.
tions have become extremely multifaceted synthetic method-
ologies for preparing various carbocycles and heterocycles.1
Some notable examples include the intramolecular Morita−
Baylis−Hillman (MBH) reaction,2 the intramolecular Rauhut−
Currier reaction,3 and various annulations based on allenes,4
MBH alcohol derivatives,5 and alkynes.6 In addition to these
cyclization reactions, methods have also been developed for the
syntheses of oxygen-, sulfur-, and nitrogen-containing hetero-
cycles through double-Michael, γ-umpolung−Michael, and
intramolecular γ-umpolung additions of 2,3-butadienoates and
2-butynoates.7
Based on these earlier studies, we hypothesized that 2-(2′-
nitroethyl)allenic esters 1 would undergo intramolecular γ-
umpolung additions in the presence of phosphine catalysts to
yield highly substituted cyclopentenes A (Figure 1).8a We could
To prepare the requisite α-(nitroethyl)allenic esters 1 for this
study, a series of phosphoranes 4 were formed through Michael
additions of carbethoxymethylenetriphenylphosphorane to
nitroalkenes 3 (Scheme 1). Treatment of the stabilized ylides
4 with AcCl and Et3N produced the allenoates 1 for the
subsequent phosphine catalysis reactions.13
With these α-(nitroethyl)allenic esters 1 in hand, ethyl 2-(2-
nitro-1-phenylethyl)buta-2,3-dienoate (1a) was selected for the
initial trial reaction with 20 mol % Ph3P as the catalyst in
CH2Cl2 at room temperature (Table 1). To our delight, the
cyclic N-hydroxyimidic acid ester 2a was obtained with a
synthetically useful level of efficiency (entry 1). To improve the
product yield, various solvents were examined (entries 2−5).
MeCN proved to be the most efficient reaction medium,
Figure 1. Phosphine-catalyzed intramolecular cyclizations based on γ-
umpolung and Michael additions.
Received: May 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
required (entry 14). Notably, 1 mol % of catalyst was also
sufficient for this reaction, offering the product in 77% yield
within 40 min under reflux (entries 15 and 16). Only a trace
amount of the product formed when using 0.1 mol % of
catalyst, even at elevated temperature (entries 17 and 18).
Notably, the loading of phosphine catalysts in nucleophilic
phosphine-catalyzed reactions is typically greater than 10 mol
%, so this reaction is a rare example in which 1 mol % of a
phosphine catalyst can effectively promote such a reaction. No
product was obtained when the reaction was performed in the
absence of a phosphine (entry 19).
Scheme 1. Synthesis of α-(Nitroethyl)allenic Esters 1
With the optimal conditions in hand, several 2-(2-nitro-1-
arylethyl)buta-2,3-dienoate esters 1 were converted to their
corresponding five-membered cyclic N-hydroxyimidic acid
esters 2 (Table 2). The yields for these cycloisomerizations
a
Table 1. Optimization of Reaction Conditions
a
Table 2. Synthesis of Cyclic N-Hydroxyimidic Acid Esters
time
yield
b
entry
R1
R2
R3
Et
(min) product
(%)
1
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
40
20
40
15
30
20
30
20
40
30
30
35
180
2a
2b
2c
2d
2e
2f
96
96
94
97
87
93
94
91
93
95
88
96
50
2
4-MeC6H4
4-MeSC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
4
5
6
7
2g
2h
2i
8
4-PhC6H4
3-MeOC6H4
3-BrC6H4
3-ClC6H4
3-FC6H2
9
10
11
12
13
2j
2k
2l
4-(AcO)-3,5-
(MeO)2C6H2
2m
c
14
4-(AcO)-3,5-
(MeO)2C6H2
H
Et
50
2m
79
15
16
17
2-naphthyl
H
Et
30
20
40
720
35
40
40
2n
2o
2p
−
2q
2r
2s
94
86
73
−
93
88
92
5-Me-2-furyl
H
Et
2-thienyl
Ph
H
Et
d
18
Me
H
Et
19
20
21
Ph
Me
Bn
t-Bu
Ph
H
Ph
H
a
All reactions were performed using a β′-nitroalkylallenic ester 1 (0.1
mmol) and MePh2P (5 mol %) in MeCN at room temperature.
Isolated yield. 10 mol % of MePh2P was used. No product was
a
Reaction of 1a (0.1 mmol) was performed in the listed solvent (1
b
c
d
b
mL). Isolated yield.
formed.
providing the cyclic N-hydroxyimidic acid ester 2a in 95%
isolated yield after 1 h (entry 5). Subsequently, the potential of
several commonly used phosphines as catalysts was probed in
MeCN (entries 6−12). MePh2P at 10 mol % was the best
catalyst in terms of product yield and reaction time (entry 13).
Me2PhP, Me3P, and Bu3P also facilitated the cyclization of 1a,
while, surprisingly, Bn3P was ineffective (entries 6−10).
P(OEt)3 did not catalyze this reaction, even when performed
under reflux (entries 11 and 12). Additionally, the loading of
MePh2P could be lowered to 5 mol % without impacting the
product yield, although a slightly longer reaction time was
were generally very high. Both meta- and para-substituted
phenyl moieties, possessing either electron-donating or -with-
drawing substituents, were well tolerated (entries 1−12). For
example, α-(2-nitro-1-arylethyl)allenic esters presenting p- and
m-methoxyphenyl groups underwent their reactions smoothly,
providing the desired products 2d and 2i in 97% and 93%
yields, respectively (entries 4 and 9). Importantly, halogen
substituents (F, Cl, Br) remained intact under the reaction
conditions, providing a handle for subsequent transformations
through various coupling protocols (entries 5−7 and 10−12).
B
DOI: 10.1021/acs.orglett.6b01299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Mechanism of Phosphine-Catalyzed Formation of N-Hydroxyimidic Acid Esters 2
The yield was low when the aryl group was trisubstituted (entry
13), but it improved when using a higher catalyst loading (10
mol %; entry 14). The reaction was equally effective at
producing the corresponding product in good yield when a 2-
naphthyl group was present (entry 15). Gratifyingly, the
benzene ring of the substrates 1 could be replaced by heteroaryl
groups, providing the furyl- and thienyl-substituted five-
membered cyclic N-hydroxyimidic acid esters 2o and 2p in
86% and 73% yields, respectively (entries 16 and 17). γ-
Substituted allenoates did not participate in this process (entry
18), presumably because the steric bulk lowered the electro-
philicity. Variation of the ester group had no obvious effect on
the reaction, with the cyclized products again obtained in high
yield (entries 19−21). The structures of the products were
confirmed through X-ray crystallographic analysis of compound
2m (Figure 2).14
to five-membered cyclic N-hydroxyimidic acid esters in high
yields. This transformation is a rare example of the rearrange-
ment of cyclic nitronates to furanone oximes.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01299.
Crystallographic data for compound 2m (CIF)
Experimental procedures and characterization data for
the starting materials 1 and the products 2 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ohyun@chem.ucla.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH (GM071779) for financial support.
■
REFERENCES
■
(1) For selected reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal.
2004, 346, 1035. (c) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520. (d) Ye, L.-W.;
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (e) Cowen, B. J.;
Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (f) Marinetti, A.; Voituriez,
A. Synlett 2010, 2010, 174. (g) Wei, Y.; Shi, M. Acc. Chem. Res. 2010,
43, 1005. (h) Wang, S.-X.; Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Synlett
2011, 2011, 2766. (i) Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi, M. Chem.
Commun. 2012, 48, 1724. (j) Fan, Y. C.; Kwon, O. Chem. Commun.
2013, 49, 11588. (k) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014,
43, 2927. (l) Xiao, Y.; Guo, H.; Kwon, O. Aldrichimica Acta 2016, 49,
3.
Figure 2. ORTEP representation of the solid state structure of 2m.
Scheme 2 presents a proposed mechanism to account for the
formation of the cyclic N-hydroxyimidic acid esters 2.
Conjugate addition of the phosphine to the α-(nitroethyl)-
allenic ester 1 leads to the formation of the zwitterionic
intermediates 5↔6. 1,5-Proton transfer of the intermediate 6
yields the α-nitro anion 7, the alternative resonance form (the
alkylideneazinate 8) of which undergoes cyclization to form the
nitronate 9. β-Elimination of the phosphine from the
zwitterionic intermediate 9 produces the cyclic nitronate B,
which rearranges to produce the 2-nitrosodihydrofuran
intermediate 10,10 with tautomerization giving the five-
membered cyclic N-hydroxyimidic acid ester 2.
In conclusion, we have observed the unprecedented
chemoselective phosphine-catalyzed intramolecular cyclization
of α-nitroethylallenic esters to five-membered cyclic N-
hydroxyimidic acid esters. This catalytic process, performed
under mild and seemingly general conditions, provides access
́
(2) Roth, F.; Gygax, P.; Frater, G. Tetrahedron Lett. 1992, 33, 1045.
(3) (a) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
2002, 124, 2404. (b) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402. (c) Aroyan, C. E.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256. (d) MacKay, J. A.;
Landis, Z. C.; Motika, S. E.; Kench, M. H. J. Org. Chem. 2012, 77,
7768.
(4) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.;
Lu, X. J. Org. Chem. 1998, 63, 5031. (c) Xu, Z.; Lu, X. Tetrahedron Lett.
1999, 40, 549. (d) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc.
2003, 125, 4716. (e) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron
2005, 61, 6276. (f) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
12234. (g) Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O.
Org. Lett. 2005, 7, 1387. (h) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.;
Kwon, O. Org. Lett. 2005, 7, 2977. (i) Jean, L.; Marinetti, A.
C
DOI: 10.1021/acs.orglett.6b01299
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tetrahedron Lett. 2006, 47, 2141. (j) Meng, X.; Huang, Y.; Chen, R.
Org. Lett. 2009, 11, 137. (k) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.;
Ma, J.; Chen, R. Org. Lett. 2009, 11, 991. (l) Wang, T.; Ye, S. Org. Lett.
2010, 12, 4168. (m) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.;
Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III;
Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (n) Hu, J.;
Dong, W.; Wu, X.-Y.; Tong, X. Org. Lett. 2012, 14, 5530. (o) Xie, P.;
Lai, W.; Geng, Z.; Huang, Y.; Chen, R. Chem. - Asian J. 2012, 7, 1533.
(5) (a) Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481. (b) Zheng, S.; Lu,
X. Org. Lett. 2009, 11, 3978. (c) Xie, P.; Huang, Y.; Chen, R. Org. Lett.
2010, 12, 3768. (d) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org.
Chem. 2011, 76, 2374.
(6) (a) Winterfeldt, E.; Dillinger, H.-J. Chem. Ber. 1966, 99, 1558.
(b) Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996, 61,
4516. (c) Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 3129. (d) Nair, V.; Nair, J. S.; Vinod, A. U.
Synthesis 2000, 2000, 1713. (e) Meng, L.-G.; Cai, P.; Guo, Q.; Xue, S.
J. Org. Chem. 2008, 73, 8491. (f) Hu, J.; Wei, Y.; Tong, X. Org. Lett.
2011, 13, 3068. (g) Nasiri, F.; Bayzidi, M.; Zolali, A. Mol. Diversity
2012, 16, 619. (h) Xie, P.; Li, E.; Zheng, J.; Li, X.; Huang, Y.; Chen, R.
Adv. Synth. Catal. 2013, 355, 161. (i) Zhou, Q.; Chu, X.; Ge, F.;
Cheng, L.; Lu, T. Mol. Diversity 2013, 17, 563. (j) Zhou, Q.-F.; Chu,
X.-P.; Ge, F.-F.; Wang, Y.; Lu, T. Adv. Synth. Catal. 2013, 355, 2787.
(7) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819.
(b) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (c) Liu, B.; Davis, R.; Joshi,
B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595. (d) Sriramurthy, V.;
Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928.
(e) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225.
(f) Sriramurthy, V.; Kwon, O. Org. Lett. 2010, 12, 1084. (g) Szeto, J.;
Sriramurthy, V.; Kwon, O. Org. Lett. 2011, 13, 5420. (h) Zhou, R.;
Wang, J.; Duan, C.; He, Z. Org. Lett. 2012, 14, 6134. (i) Lundgren, R.
J.; Wilsily, A.; Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew.
Chem. 2013, 125, 2585. (j) Andrews, I. P.; Blank, B. R.; Kwon, O.
Chem. Commun. 2012, 48, 5373.
(8) (a) Boyce, G. R.; Liu, S.; Johnson, J. S. Org. Lett. 2012, 14, 652.
(b) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069.
(9) (a) Stubbs, K. A.; Zhang, N.; Vocadlo, D. J. Org. Biomol. Chem.
2006, 4, 839. (b) Goddard-Borger, E. D.; Stubbs, K. A. J. Org. Chem.
2010, 75, 3931.
(10) (a) Denmark, S. E.; Dappen, I. M. S.; Cramer, C. J. J. Am. Chem.
Soc. 1986, 108, 1306. (b) Denmark, S. E.; Hurd, A. R. J. Org. Chem.
2000, 65, 2875. (c) Smirnov, V. O.; Khomutova, Y. A.; Ioffe, S. L.
Mendeleev Commun. 2008, 18, 255.
(11) Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini, F. J. Chem. Soc.,
Chem. Commun. 1994, 221.
(12) (a) Barange, D. K.; Raju, B. R.; Kavala, V.; Kuo, C.-W.; Tu, Y.-
C.; Yao, C.-F. Tetrahedron 2010, 66, 3754. (b) Wu, M.-Y.; Li, K.; He,
T.; Feng, X.-W.; Wang, N.; Wang, X.-Y.; Yu, X.-Q. Tetrahedron 2011,
67, 2681.
(13) For examples of Michael additions of carbethoxymethylene-
triphenylphosphorane to nitroalkenes, see: (a) Asunskis, J.; Schechter,
H. J. Org. Chem. 1968, 33, 1164. (b) Connor, D. T.; von Strandtmann,
M. J. Org. Chem. 1973, 38, 1047.
(14) CCDC 1004071 contains the supplementary crystallographic
data for compound 2m. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
D
DOI: 10.1021/acs.orglett.6b01299
Org. Lett. XXXX, XXX, XXX−XXX