Highly Substituted 2,3-dihydroisoxazoles by Et3N-catalyzed tandem reaction of electron-deficient 1,3-conjugated enynes with hydroxylamines

Article abstract of DOI:10.1021/ol100490y

An Et₃N-catalyzed tandem reaction of electron-deficient 1,3-conjugated enynes with hydroxylamines was developed which provided rapid, metal-free, and regioselective access to highly substituted multifunctionalized 2,3-dihydroisoxazoles under mi

Full text of DOI:10.1021/ol100490y

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1876-1879
Highly Substituted 2,3-Dihydroisoxazoles
by Et3N-Catalyzed Tandem Reaction of
Electron-Deficient 1,3-Conjugated
Enynes with Hydroxylamines
Xiuzhao Yu, Bo Du, Kai Wang, and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal UniVersity, 3663 North Zhongshan Road,
Shanghai 200062, P.R. China
jlzhang@chem.ecnu.edu.cn
Received February 26, 2010
ABSTRACT
An Et3N-catalyzed tandem reaction of electron-deficient 1,3-conjugated enynes with hydroxylamines was developed which provided rapid,
metal-free, and regioselective access to highly substituted multifunctionalized 2,3-dihydroisoxazoles under mild conditions. The reactions of
3-(2-arylethynyl)-4H-chromen-4-ones with hydroxylamines afford ꢀ-amino enones under the same reaction conditions.
2,3-Dihydroisoxazoles represent a class of heterocycles that
may be employed as useful building blocks for organic
synthesis1 since the N-O bond can be easily cleaved under
mild reducing conditions leading to 1,3-amino alcohols2,3
or 1,3-amino ketones.2,4 They are also found in many
(2) For selected examples to prepare ꢀ-amino alcohols, see: (a) Pilli,
R. A.; Russowsky, D. J. Chem. Soc., Chem. Commun. 1987, 1053. (b) Pilli,
R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1 1990,
1213. (c) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. L. J.
Org. Chem. 1992, 57, 1219. (d) Keck, G. E.; Truong, A. P. Org. Lett. 2002,
(1) (a) Freeman, J. P. Chem. ReV. 1983, 83, 241. (b) Zhao, B.-X.; Yu,
Y.; Eguchi, S. Tetrahedron 1996, 52, 12049. (c) Padwa, A.; Wong, G. S. K.
J. Org. Chem. 1986, 51, 3125. (d) Padwa, A.; Chiachio, U.; Kline, D. N.;
Perumattan, J. J. Org. Chem. 1988, 53, 2238. (e) Padwa, A.; Norman, B. H.;
Perumattam, J. Tetrahedron Lett. 1989, 30, 663. (f) Padwa, A.; Bullock,
W. H.; Kline, D. N.; Perumattam, J. J. Org. Chem. 1989, 54, 2862. (g)
Adachi, I.; Miyazaki, R.; Kano, H. Chem. Pharm. Bull. 1974, 22, 70. (h)
Aurich, H. G.; Franzke, M.; Kesselheim, H. P.; Rohr, M. Tetrahedron 1992,
48, 669. (i) Lopez-Calle, E.; Keller, M.; Eberbach, W. Eur. J. Org. Chem.
2003, 1438. (j) Friebolin, W.; Eberbach, W. HelV. Chim. Acta 2001, 84,
3822. (k) Ishikawa, T.; Kudoh, T.; Yoshida, J.; Yasuhara, A.; Manabe, S.;
Saito, S. Org. Lett. 2002, 4, 1907. (l) Alcaide, B.; Almendros, P.; Alonso,
J. M.; Aly, M. F.; Pardo, C.; Sa´ez, E.; Torres, M. R. J. Org. Chem. 2002,
67, 7004. (m) Friebolin, W.; Eberbach, W. Tetrahedron 2001, 57, 4349.
(n) Aschwanden, P.; Kværnø, L.; Geisser, R. W.; Kleinbeck, F.; Carreira,
E. M. Org. Lett. 2005, 7, 5741. (o) Canterbury, D. P.; Herrick, I. R.; Um,
J.; Houk, K. N.; Frontier, A. J. Tetrahedron 2009, 65, 3165. (p) Canterbury,
D. P.; Frontier, A. J.; Um, J. M.; Cheong, P. H.-Y.; Goldfeld, D. A.; Huhn,
R. A.; Houk, K. N. Org. Lett. 2008, 10, 4597. For total synthesis of natural
product, see: (q) Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49.
4, 3131
.
(3) ꢀ-Amino alcohols are also commonly used as chiral ligands; see:
(a) ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg, 1999. (b)
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000
.
(4) For general methods to prepare ꢀ-amino ketones, see: (a) Davies,
S. G.; McCarthy, T. D. Synlett 1995, 700. (b) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313. (c)
Kantam, M. L.; Neeraja, V.; Kavita, B.; Neelima, B.; Hussain, S. AdV. Synth.
Catal. 2005, 347, 763. (d) Dondoni, A.; Marra, A.; Boscarato, A.
Chem.sEur. J. 1999, 5, 3562. (e) Kobayashi, S.; Ishitani, H. Chem. ReV.
1999, 99, 1069. (f) Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,
Int. Ed. 1998, 37, 1045. (g) Hart, D. J.; Ha, D. C. Chem. ReV. 1989, 89,
1447. (h) Jafari, A. A.; Moradgholi, F.; Tamaddon, F. Eur. J. Org. Chem.
2009, 1249
.
10.1021/ol100490y  2010 American Chemical Society
Published on Web 03/24/2010

bioactive molecules and pharmaceuticals.5 Among many
methods developed in past years, 1,3-dipolar cycloaddition
reactions between nitrones and alkynes or metal acetylides
under the catalysis of transition metals or Lewis acids are
the most common synthetic methods for the construction of
2,3-dihydroisoxazoles.6 However, metal-catalyzed 1,3-dipolar
cycloadditions often furnish regioisomeric mixtures of ad-
ducts, proceed in low yield,6g-i or have functional group
tolerance.6a-c Herein, we report a base-catalyzed tandem
reaction7 of electron-deficient 1,3-conjugated enynes with
substituted hydroxylamines, providing a metal-free, efficient,
and regioselective approach to highly substituted 2,3-
dihydroisoxazoles.
Table 1. Screening Conditions for Tandem Reaction of 1a with 2a
entrya base (20 mol %) solvent temp (°C) yield of 3aaf (%)
1
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DCM
DCE
40
40
40
40
40
40
60
rt
rt
rt
0
77
44
<5
19
32
72
64
83
80
66
87
86
88
91
2
3b
4
DBU
NaHCO3
PhCO2Na
Et3N
Et3N
Et3N
DABCO
DMAP
Et3N
Et3N
Et3N
Recently, our group8 and others9 have demonstrated that
electron-deficient 1,3-conjugated enynes are readily available
and attractive precursors for the construction of various
acyclic and cyclic compounds. During these studies, we
envisaged that 2,3-dihydroisoxazoles might be prepared from
the corresponding electron-deficient 1,3-enynes and hydroxyl-
amines by tandem inter- and intramolecular nucleophilic
addition.
To test this hypothesis, enyne 1a and N-benzylhydroxyl-
amine 2a were subjected to DMF at 40 °C in the presence
of Et3N (20 mol %). Gratifyingly, the desired product 3aa
was obtained in 77% isolated yield after 4 h (Table 1, entry
1). Interestingly, the reaction gives 44% yield of 3aa without
any additional base, indicating that hydroxylamine itself can
play the role of a base (Table 1, entry 2). Other organic and
inorganic bases such as DBU, DABCO, DMAP, PhCO2Na,
5
6c
7
8
9d
10e
11
12
13
14
0
0
0
Et3N
a All reactions were carried out using 1a (0.3 mmol) and 2a (0.45 mmol)
in the presence of base under N2 atmosphere in solvent (2.5 mL) for 1-12
h. b DBU ) 1,8-diazabicyclo[5.4.0]undecen-7-ene. c 10 mol % of Et3N.
d DABCO ) 1,4-diazabicyclo[2.2.2]octane. e DMAP ) 4-dimethylaminopyri-
dine. f Isolated yield.
and NaHCO3 were next tested. In contrast with the previous
result,8c DBU here failed to give the desired product (Table
1, entry 3), while DABCO (entry 9) or DMAP (entry 10)
catalyzed this reaction at ambient temperature, providing 3aa
in 80% and 66% yield, respectively. Both NaHCO3 (entry
4) and PhCO2Na (entry 5) are less effective. Furthermore,
the reaction temperature and catalyst loading were also
examined (Table 1, entries 6-8, 14). There is little solvent
effect on this tandem reaction (Table 1, entries 11-14).
Finally, we were pleased to find that 3aa could be isolated
in 91% yield after stirring at 0 °C in DCE for 1.5 h with 20
mol % of Et3N as catalyst (Table 1, entry 14, standard
conditions).
With the optimized conditions in hand, we next examined
the scope of this tandem reaction with various substituted
electron-deficient 1,3-conjugated enynes 1 and various N-
substituted hydroxylamines (Scheme 1). Several points are
noteworthy: (1) In general, highly substituted 2,3-dihy-
droisoxazoles can be prepared in moderate to excellent yields
under standard conditions from the corresponding electron-
deficient conjugated enynes and hydroxylamines. The yield
of 3ra is low because of the unstable substrate 1r. (2) Various
electron-withdrawing groups (EWG) such as ketone
(3ba-na), aldehyde (3ra), ester (3qa and 3uc), and amide
(3oa) can be effectively introduced to the products. (3) The
substituent on the alkene moiety (R1) can be an aryl
(3aa-3ad), alkyl (3ea), styryl (3la), or ester (3qa) group.
(4) The substituent (R2) on the alkyne moiety can also be
an aryl or alkyl (3ea) group. (5) Besides 2a, we also tested
other substituted or unsubstituted hydroxylamines such as
N-(naphthalen-1-ylmethyl) hydroxylamine (2b), MeNH(OH)·
(5) (a) Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med. Chem.
2001, 44, 2921. (b) FraleyM. E. Garbaccio, R. M.; Hartman, G. D. Patent
WO 2006023440, 2006.
(6) (a) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000,
2, 2331. (b) Stoner, E. J.; Roden, B. A.; Chemburkar, S. Tetrahedron Lett.
1997, 38, 4981. (c) Fabio, M.; Ronzini, L.; Troisi, L. Tetrahedron 2008,
64, 4979. (d) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry.
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, 2002. (e) Tufarillio, J. J. In 1,3-Dipolar Cycload-
dition Chemistry; Padwa, A. Ed.; Wiley: New York, 1984; Vol. 2. (f)
Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.; Pardo, C.; Sa´ez, E.;
Torres, M. R. Org. Lett. 2002, 4, 1463. (g) Gonza´lez-Cruz, D.; Tejedor,
D.; de Armas, P.; Garc´ıa-Tellado, F. Chem.sEur. J. 2007, 13, 4823. (h)
Gonza´lez-Cruz, D.; Tejedor, D.; Armas, P.; Morales, E. Q.; Garc´ıa-Tellado,
F. Chem. Commun. 2006, 2798. (i) Benfatti, F.; Cardillo, G.; Contaldi, S.;
Gentilucci, L.; Mosconi, E.; Tolomelli, A.; Juaristi, E.; Reyes-Rangel, G.
Tetrahedron 2009, 65, 2478. (j) Cantagrel, F.; Pinet, S.; Gimbert, Y.;
Chavant, P. Y. Eur. J. Org. Chem. 2005, 2694. (k) Abbiati, G.; Arcadi, A.;
Marinelli, F.; Rossi, E.; Verdecchia, M. Eur. J. Org. Chem. 2009, 1027. (l)
Canterbury, D. P.; Frontier, A. J.; Um, J. M.; Cheong, P. H.-Y.; Goldfeld,
D. A.; Huhn, R. A.; Houk, K. N. Org. Lett. 2005, 7, 5147. (m) Debleds,
O.; Dal Zotto, C.; Vrancken, E.; Campagne, J.-M.; Retailleau, P. AdV. Synth.
Catal. 2009, 351, 1991.
(7) For representative reviews on cascade or domino reactions, see: (a)
Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Tietze, L. F.; Lieb, M. E. Curr.
Opin. Chem. Biol. 1998, 2, 363. (c) Rodriguez, J. Synlett 1999, 505. (d)
Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (e) Multicomponent reactions often
involve domino process, see: Multicomponent Reactions; Zhu, J., Bienayme´,
H., Eds.; Wiley-VCH: Weinheim, 2005.
(8) (a) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903. (b)
Yu, X.; Ren, H.; Xiao, Y.; Zhang, J. Chem.sEur. J. 2008, 14, 8481. (c)
Xiao, Y.; Zhang, J. Chem. Commun. 2009, 3594. (d) Liu, F.; Zhang, J.
Angew. Chem., Int. Ed. 2009, 48, 5505. (e) Liu, R.; Zhang, J. Chem.sEur.
J. 2009, 15, 9303. (f) Gao, H.; Zhao, X.; Yu, Y.; Zhang, J. Chem.sEur. J.
2010, 16, 456. (g) Xiao, Y.; Zhang, J. Chem. Commun 2010, 46, 752.
(9) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679.
(c) Liu, Y. H.; Zhou, S. Org. Lett. 2005, 7, 4609. (d) Patil, N. T.; Wu, H.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 4531.
Org. Lett., Vol. 12, No. 8, 2010
1877

Scheme 1. Synthesis of Multifuncionalized
2,3-Dihydroisoxazoles 3a
Figure 1. X-ray crystal structures and line drawings of 3na (top)
and 5ab (bottom).
When R is H, imines 6a-c were obtained by further
isomerization.
One plausible mechanism that accounts for this Et3N-
catalyzed tandem process is proposed (Scheme 3). The
regioselective and chemoselective nucelophilic addition of
the hydroxylamine 2 via the N-atom1k produces 1,2-allenyl
ketone intermediate A,8b which undergoes an intramolecular
addition with the O-atom to give an allylic carboanion B
under the catalysis of the base. Subsequent protonation
Scheme 2. Tandem Reactions of Enynes 4 and 2
a MeNH(OH)·HCl or HONH2·HCl and 170 mol % of Et3N were used
for 3ac, 3uc, 3jc, and 3ad. b The designation 3aa for the product indicates
that the reactants used were 1a and 2a, respectively.
HCl (2c), HONH2·HCl (2d), and the N-phenylhydroxylamine
(2e). (6) Due to its weak nucleophilicity, only 2e cannot react
with electron-deficient 1,3-enynes. (7) The structure of the
products was confirmed by single-crystal X-ray analysis of
representative 3na (Figure 1).10
It is interesting and surprising that in contrast to the
2-(phenylethynyl)cyclohex-2-enone (Scheme 1, 3ta), the re-
action of 4a with N-benzylhydroxylamine (2a) under the
same conditions produced novel ꢀ-amino enone 5aa rather
than the expected product (Scheme 2), the structure of which
was aslo established by single-crystal X-ray diffraction
analysis of 5ab (Figure 1).10 Phenyl-bearing electron-rich
and electron-withdrawing groups on the alkyne moiety (R2)
could be introduced and have little effect on the reaction.
(10) CCDC 763753 (3na) 763754 (5ab) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1878
Org. Lett., Vol. 12, No. 8, 2010

which provides a rapid, efficient, and metal-free approach
to multifunctionalized, highly substituted 2,3-dihydroisox-
azoles. This method is a complementary approach to those
metal or Lewis acid catalyzed 1,3-dipolar cycloadditions of
nitrones with alkynes. For those 3-(2-arylethynyl)-4H-
chromen-4-ones, the reaction undergoes further rearrange-
ment to give ꢀ-amino enones. Further studies including
synthetic applications, the asymmetric catalysis of this
reaction, and examination of other binucleophiles are ongoing
in this laboratory.
Scheme 3. Plausible Mechanism Accounts for this
Et3N-Catalyzed Tandem Process
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20702015, 20972054)
and Shanghai Municipal Committee of Science and Technol-
ogy (08dj1400101) is greatly appreciated.
Supporting Information Available: Experimental pro-
cedures, X-ray data for 3na and 5ab (CIF), as well as
characterization data of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
affords product 3, which undergoes further rearrangement
to give the final product 5.6c
In summary, we have developed an Et3N-catalyzed tandem
intermolecular and intramolecular nucelophilic addition of
N-hydroxyamines to electron-dificient 1,3-conjugated enynes,
OL100490Y
Org. Lett., Vol. 12, No. 8, 2010
1879