Bifunctional phosphine-catalyzed domino reaction: Highly stereoselective synthesis of cis-2,3-dihydrobenzofurans from salicyl N-thiophosphinyl imines and allenes

Article abstract of DOI:10.1021/ol802453c

A new bifunctional phosphine catalyst, (2'-hydroxy-biphenyl-2-yl)- diethylphosphane (LBBA-1), was developed for the highly stereoselective synthesis of cis-2,3-dihydrobenzofurans via an aza-Morita-Baylis-Hillman/ umpolung addition domino reaction of salic

Full text of DOI:10.1021/ol802453c

ORGANIC
LETTERS
2009
Vol. 11, No. 1
137-140
Bifunctional Phosphine-Catalyzed
Domino Reaction: Highly Stereoselective
Synthesis of cis-2,3-Dihydrobenzofurans
from Salicyl N-Thiophosphinyl Imines
and Allenes
Xiangtai Meng, You Huang,* and Ruyu Chen
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
hyou@nankai.edu.cn
Received October 31, 2008
ABSTRACT
A new bifunctional phosphine catalyst, (2′-hydroxy-biphenyl-2-yl)-diethylphosphane (LBBA-1), was developed for the highly stereoselective
synthesis of cis-2,3-dihydrobenzofurans via an aza-Morita-Baylis-Hillman/umpolung addition domino reaction of salicyl N-thiophosphinyl
imines with electron-deficient allenes. Dual activation of both nucleophile and electrophile by the bifunctional catalyst accounts for the observed
high reactivity and stereoselectivity.
During the past few years, domino reactions catalyzed by
organocatalysts have emerged as a powerful tool in organic
synthesis.1 These reactions can rapidly form complex
molecules from readily available substrates in a single
operation without isolation of intermediates. Therefore,
considerable efforts have been made to develop catalytic
domino transformations by an organocatalyst.2 Most suc-
cessful classes of organocatalysts used for this purpose are
usually secondary amines, especially the prolinol derivatives.3
Other classes of organocatalysts for this purpose are few.4-6
Thus, the development of a new catalyst with high activity
and stereoselectivity is the key issue and remains a great
challenge. Meanwhile, for the purpose of designing a new
organocatalyst, the concept of activating and binding both
reacting partners for a catalytic transformation has been
widely reported using synthetic small molecules.7 Recently,
there has been considerable interest in the unique reactivity
of phosphine catalysts,8 and combining the reactive phos-
phine group with a hydrogen bonding motif in one molecule
is a new direction in designing new bifunctional catalysts.
For example, Shi, Sasai, and Ito reported a series of chiral
phosphine bifunctional catalysts which can efficiently cata-
lyze the asymmetric aza-Morita-Baylis-Hillman (aza-
MBH) reactions.9 Jacobsen developed an efficient phosphi-
nothiourea catalyst for imine-allene [3
+
2]
cycloadditions.10 Miller reported an R-amino acid type
phosphine catalyst for enantioselective [3 + 2] cycloaddi-
tion.11
(1) For reviews on domino reactions, see: (a) Tietze, L. F.; Brasche,
G.; Gericke, K.; Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006. (b) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006,
45, 354. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32,
131. (d) Tietze, L. F. Chem. ReV. 1996, 96, 115.
The reaction of imines with allenic esters catalyzed by
phosphine usually gives [3 + 2]12 or [4 + 2]12a,13 cycload-
ducts. As outlined in Scheme 1, the reaction of salicylic
(2) For recent reviews on organocatalytic domino reactions, see: Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
10.1021/ol802453c CCC: $40.75
Published on Web 11/26/2008
2009 American Chemical Society

Scheme 1
.
Reaction of Ethyl 2,3-Butadienoate with Salicyl
N-Tosylimine
Figure 1. Structures of the catalysts.
imines with allenic esters catalyzed by DABCO (1,4-
diazabicyclo[2.2.2]octane) or phosphine gives highly func-
tionalized chromenes or [3 + 2] cycloadducts, respectively.14
We have reported a bifunctional phosphine organocatalyst
(LBBA-2) for the novel selective aza-MBH domino reaction
and aza-MBH reaction of N-sulfonated imines with acrolein.6
On the basis of the information on our bifunctional phosphine
as catalyst of the aza-MBH reaction, and the knowledge of
the phosphine as the catalyst of umpolung addition of allenes
and 2-alkynoates,15 we envisioned that the bifunctional
phosphine catalysts may catalyze the salicyl N-thiophosphinyl
imines and allenes to form the 2,3-disubstituted dihydroben-
zofurans through an aza-MBH/umpolung addition domino
reaction. Herein, we wish to report such a novel domino
reaction catalyzed by a new easily synthesized Lewis base
and Brφnsted acid (LBBA-1) bifunctional catalyst (Figure
1) and its application to the highly stereoselective synthesis
of a wide range of cis-2,3-disubstituted dihydrobenzofurans.
Functionalized 2,3-dihydrobenzofurans are common sub-
structures existing in natural products and have been identi-
fied to possess a range of biological activities.16 Various
procedures for synthesis of the 2,3-dihydrobenzofurans have
been developed during the past few years.17 However, a new
method is still needed to rapidly synthesize the highly
functionalized 2,3-dihydrobenzofurans, such as the cis-2,3-
disubstituted dihydrobenzofurans. Up to now, only a few
methods are suitable for the stereoselective synthesis of the
(5) For selected examples of phosphoric acid catalyzed domino reactions,
see: (a) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47,
5836. (b) Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2008, 47, 2458. (c) Terada, M.; Machioka, K.; Sorimachi,
K. J. Am. Chem. Soc. 2007, 129, 10336. (d) Zhou, J.; List, B. J. Am. Chem.
Soc. 2007, 129, 7498. (e) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am.
Chem. Soc. 2006, 128, 13070. (f) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
Chem., Int. Ed. 2006, 45, 4796. (g) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew Chem., Int. Ed. 2006, 45, 3683. (h) Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
84. (i) Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2005, 44, 108.
(3) For recent examples on domino reactions catalyzed by prolinol
derivatives see: (a) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.;
Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.-Eur. J. 2008, 14, 4788. (b)
Zhu, M. K.; Wei, Q.; Gong, L. Z. AdV. Synth. Catal. 2008, 350, 1281. (c)
Zhao, G. L.; Vesely, J.; Rios, R.; Ibrahem, I.; Sunde´n, H.; Co´rdova, A.
AdV. Synth. Catal. 2008, 350, 237. (d) Enders, D.; Hu¨ttl, M. R. M.; Raabe,
G.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 267. (e) Cabrera, S.; Alema´n,
J.; Bolze, P.; Bertelsen, S.; Jφgensen, K. A. Angew. Chem., Int. Ed. 2008,
47, 121. (f) Franke, P. T.; Johansen, R. L.; Bertelsen, S.; Jøogensen, C
K. A. Chem. Asian J. 2008, 3, 216. (g) Franke, P. T.; Richter, B.; Jøgensen,
K. A. Chem.-Eur. J. 2008, 14, 6317. (h) Zu, L.; Xie, H.; Li, H.; Wang, J.;
Yu, X.; Wang, W. Chem.-Eur. J. 2008, 14, 6333. (i) Carlone, A.; Cabrera,
S.; Marigo, M.; Jøgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101.
(j) Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Co´rdova, A.
Chem.-Eur. J. 2007, 13, 574. (k) Hayashi, Y.; Okano, T.; Aratake, S.;
Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (l) Vicario, J. L.;
Reboredo, S.; Bad´ıa, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168.
(m) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jøgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (n) Xie, H.-X.; Zu, L.-S.; Li,
H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886. (o) Li, H.;
Zu, L.-S.; Xie, H.-X.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9,
1833. (p) Wang, J.; Li, H.; Xie, H.-X.; Zu, L.-S.; Shen, X.; Wang, W.
Angew. Chem., Int. Ed. 2007, 46, 9050. (q) Zu, L.-S.; Li, H.; Xie, H.-X.;
Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007,
46, 3732. (r) Wang, W.; Li, H.; Wang, J.; Zu, L.-S. J. Am. Chem. Soc.
2006, 128, 10354. (s) Brandau, S.; Maerten, E.; Jøgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 14986. (t) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.
Nature 2006, 441, 861. (u) Marigo, M.; Schulte, T.; Franze´n, J.; Jøgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 15710.
(6) For bifunctional phosphine-catalyzed domino reactions see: Meng,
X.; Huang, Y.; Chen, R. Chem.-Eur. J. 2008, 14, 6852.
(7) (a) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005,
1491. (b) Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566. (c)
Qi, M.-J.; Ai, T.; Shi, M.; Li, G. Tetrahedron 2008, 64, 1181. (d) Shi,
Y.-L.; Shi, M. AdV. Synth. Catal. 2007, 349, 2129. (e) Liu, Y.-H.; Chen,
L.-H.; Shi, M. AdV. Synth. Catal. 2006, 348, 973. (f) Shi, M.; Chen, L.-H.;
Teng, W.-D. AdV. Synth. Catal. 2005, 347, 1781. (g) Matsui, K.; Takizawa,
S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680. (h) Balan, D.; Adolfsson,
H. Tetrahedron Lett. 2003, 44, 2521. (i) Shi, M.; Xu, Y.-M.; Shi, Y.-L.
Chem.-Eur. J. 2005, 11, 1794. (j) Shi, M.; Xu, Y.-M. Angew. Chem., Int.
Ed. 2002, 41, 4507.
(8) For reviews, see: (a) Ye, L. W.; Zhou, J.; Tang, Y. Chem. Soc. ReV.
2008, 37, 1140. (b) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004,
346, 1035. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(9) (a) Shi, M.; Chen, L.-A.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127,
3790. (b) Matsui, K.; Sasai, T. H. Synlett. 2006, 761. (c) Ito, K.; Nishida,
K.; Gotanda, T. Tetrahedron Lett. 2007, 48, 6147.
(10) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660.
(11) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(12) (a) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.;
de Leon, P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843.
(b) Fleury-Bregeot, N.; Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron
2007, 63, 11920. (c) Jean, L.; Marinetti, A. Tetrahedron Lett. 2006, 47,
2141. (d) Scherer, A.; Gladysz, J. A. Tetrahedron Lett. 2006, 47, 6335. (e)
Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276. (f) Xu,
Z.; Lu, X. J. Org. Chem. 1998, 63, 5031. (g) Zhu, G.; Chen, Z.; Jiang, Q.;
Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (h) Xu,
Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461.
(4) For selected examples of Cinchona Alkaloid, amine thiourea
catalyzed domino reactions, see: (a) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang,
W. Angew. Chem., Int. Ed. 2008, 47, 4177. (b) Dodda, R.; Goldman, J. J.;
Mandal, T.; Zhao, C.-G.; Broker, G. A.; Tiekink, E. R. T. AdV. Synth. Catal.
2008, 350, 537. (c) Zu, L.-S.; Xie, H.-X.; Li, H.; Wang, J.; Jiang, W.; Wang,
W. AdV. Synth. Catal. 2007, 349, 1882. (d) Wang, B.; Wu, F.; Wang, Y.;
Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (e) Zu, L.-S.; Wang,
J.; Li, H.; Xie, H.-X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129,
1036. (f) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
129, 3830. (g) Wang, Y.; Liu, X.-F.; Deng, L. J. Am. Chem. Soc. 2006,
128, 3928. (h) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto,
Y. Tetrahedron 2006, 62, 365. (i) Hoashi, Y.; Yabuta, T.; Takemoto, Y.
Tetrahedron Lett. 2004, 45, 9185.
(13) (a) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632.
(b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (c) Zhu,
X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(14) Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 3057.
(15) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (b)
Zhang, C.; Lu, X. Synlett 1995, 645. (c) Lu, C.; Lu, X. Org. Lett. 2002, 4,
4677.
(16) (a) Reynaud, J.; Guilet, D.; Terreux, R.; Lussignol, M.; Walchshofer,
N. Nat. Prod. Rep. 2005, 22, 504. (b) Maurya, R.; Yadav, P. P. Nat. Prod.
Rep. 2005, 22, 400. (c) Apers, S.; Vlietinck, A.; Pieters, L. Phytochem.
ReV. 2003, 2, 201.
(17) Kuethe, J. T.; Wong, A.; Journet, M.; Davies, I. W. J. Org. Chem.
2005, 70, 3727, and references therein.
138
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Screening Catalysts and Solvents for the Domino
Reactionsa
Figure 2. ORTEP representation of 2a.
yield (%)
2a 3a
entry
catalyst
solvent
time (h)
1
2
3
4
LBBA-2
LBBA-1
LBBA-1
LBBA-1
LBBA-1
LBBA-1
LBBA-1
PPh3
toluene
CH3CN
CH2Cl2
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
6
6
6
6
4
1
24
6
6
0
60
65
83
88
90
89
0
0
0
0
0
0
0
0
0
0
Table 2. Scope of the Aza-MBH/oxa-Michael Domino
Reactiona
5
6b
7c
8
9d
10e
11e
nBu3P
51
0
0
DABCO
DBU
95
10
entry
R1
R2
time (h)
yield (%)
24
a The reaction was carried out in 0.5 mmol scale in solvent (2 mL).
The ratio of the 1a/allene is 1/1.5. b 30 mol % catalyst was used. c The
reaction temperature is 50 °C. d cis- and trans-isomers were determined by
31P NMR spectroscopic analysis. C/T ) 1:1. e oxa-Michael addition product
3a.
1
5-CH3
5-tBu
5-Br
3-CH3
4-CH3
3-Cl
5-CH3O
3,5-tBu
H
3-CH3
5-CH3
5-tBu
5-Cl
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
tBu
6
6
12
6
6
12
1
1
6
8
88 (2a)
88 (2b)
72 (2c)
92 (2d)
90 (2e)
65 (2f)
75 (2g)
95 (2h)
90 (2i)
83 (2j)
85 (2k)
87 (2l)
70 (2m)
68 (2n)
2
3b
4
5
6b
7
cis-2,3-disubstituted dihydrobenzofurans by the intramolecu-
lar cyclization reaction.18
8
9
The reaction of salicyl N-thiophosphinyl imines 1a (see
Supporting Information) and ethyl 2,3-butadienoate with
LBBA-2 as catalyst was first tested (entry 1), but no desired
product was obtained. However, with LBBA-1, the analogue
of LBBA-2, as the catalyst, the reaction proceeded smoothly
and gave exlcusively the cis-2,3-disubstituted dihydroben-
zofuran 2a in different solvent systems (Table 1, entries
2-5). This domino reaction with toluene as solvent gave
the best result (88% yield, entry 5). Reaction temperature
and catalyst amount were also examined as shown in Table
1 (entries 6 and 7). The optimal reaction condition is with
20 mol % of LBBA-1 as catalyst in toluene at room
temperature. Other phosphine catalysts, such as PPh3, were
not effective for this domino reaction (entry 8). The reaction
10
11
12
13b
14b
tBu
8
8
18
18
tBu
tBu
5-Br
tBu
a The reaction was carried out in 0.5 mmol scale in solvent (2 mL).
The ratio of the 1a/allene is 1/1.5. b The reaction temperature is 50 °C.
c All of the products are cis isomer only.
and configuration of the product 2a were unequivocally
confirmed by single-crystal X-ray analysis. The ORTEP
diagram is shown in Figure 2.
With the optimal reaction conditions in hand, we next
explored the scope of this domino reaction using a variety
of salicyl N-thiophosphinyl imines and ethyl 2,3-butadienoate
(Table 2). The corresponding cis-2,3-dihydrobenzofurans
were obtained in good to excellent yields. For imines with
electron-withdrawing groups on the phenyl rings, a prolonged
reaction time and higher temperature were needed, and the
yields were slightly low (entries 3, 6, 13, and 14). The reason
is that the electron-withdrawing groups decrease the nucleo-
philicity of the oxygen atom. In contrast, for imines with
electron-donating groups on the phenyl rings, the reaction
was completed in a short time to give the corresponding
n
under Bu3P led to the target molecule as a mixture of cis-
and trans-isomers without stereoselectivity (entry 9). Em-
ploying DABCO (entry 10) and DBU (entry 11) as the
catalysts did not give the desired product; instead, an
umpolung addition product 3a was obtained. The structure
(18) (a) Bertolini, F.; Crotti, P.; Bussolo, V. D.; Macchia, F.; Pineschi,
M. J. Org. Chem. 2007, 72, 7761. (b) Enders, D.; Niemeier, O.; Straverb,
L. Synlett 2006, 3399. (c) Cheung, W.-H.; Sheng, S.-L.; Yu, W.-Y.; Zhou,
G.-C.; Che, C.-M. Org. Lett. 2003, 5, 2535. (d) Saito, H.; Oishi, H.; Kitagaki,
S.; Nakamura, S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4, 3887.
Org. Lett., Vol. 11, No. 1, 2009
139

bifunctional phosphine catalyst LBBA-1 first reacts with the
allene19 and meanwhile activates the imine by the hydrogen
bond to form A. The subsequent aza-MBH reaction was
carried out by a γ addition to 1a affording intermediate
B,12f,20 which forms intermediate C via two proton
transfers.12f The hydrogen bonding interaction between the
OH group of the bifunctional phosphine catalyst and the
substrate RNHP(S)Ph2 group fixes the conformation of
intermediate C and thus ensures generation of the cis-isomer.
Then an intramolecular umpolung addition of the oxygen
anion to the γ carbon in C from the backside of the
RNHP(S)Ph2 group leads to the cyclized cis intermediate
D,15a followed by another proton transfer to afford E.12f
Finally, the reaction gives the cis-2,3-disubstituted dihy-
drobenzofuran 2a with the regeneration of LBBA-1 to
complete the catalytic cycle.
Scheme 2. Possible Catalytic Cycle
In summary, we have developed a novel bifunctional
phosphine-catalyzed aza-MBH/umpolung addition domino
reaction to generate the cis-2,3-dihydrobenzofurans from
salicyl N-thiophosphinyl imines and allenic esters with high
stereoselectivity. Our future efforts will focus on an asym-
metric version of this reaction and applying this new method
to the construction of natural products.
product with excellent yields (entries 1, 2, 4, 5, 7-12,).
Surprisingly, when a sterically hindered substrate (1h) was
used (entry 8), the reaction proceeded smoothly to give the
corresponding product in good yield with a short reaction
time. Similarly, tert-butyl 2,3-butadienoate can also react with
various salicyl N-thiophosphinyl imines under identical
conditions to give the desired cis-2,3-disubstituted dihy-
drobenzofurans in good yields.
The detailed mechanism of the above domino reaction has
not been clarified. According to these experimental results
and some literature for the bifunctional phosphine-catalyzed
reactions,6,9a we proposed a possible mechanism for this
novel aza-MBH domino reaction as follows (Scheme 2). The
Acknowledgment. We thank the National Natural Science
Foundation of China (20772061) and the Natural Science
Foundation of Tianjin (05YFJMJC00600) for financial sup-
port.
Supporting Information Available: Detailed experimen-
tal procedures, spectral data for all new compounds, and
X-ray crystal structure CIF files. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802453C
(19) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289.
(20) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686
.
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