PPh3-catalyzed (3 + 3) annulations of 5-acetoxypenta-2,3- dienoate with 1C,3O-bisnucleophiles: Facile entry to stable monocyclic 2H-pyrans

Article abstract of DOI:10.1021/ol302634p

Phosphine-catalyzed (3 + 2) and (3 + 3) annulations between 5-acetoxypenta-2,3-dienoate and 1C,3O-bisnucleophiles are presented. The former cases can be achieved with the assistance of base while the latter is dominant without any additive. A series of de

Full text of DOI:10.1021/ol302634p

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5530–5533
PPh3‑Catalyzed (3 þ 3) Annulations
of 5‑Acetoxypenta-2,3-dienoate with
1C,3O-Bisnucleophiles: Facile Entry
to Stable Monocyclic 2H‑Pyrans
Jian Hu, Wei Dong, Xin-Yan Wu, and Xiaofeng Tong*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, Meilong Road No. 130,
Shanghai, 200237, P. R. China
tongxf@ecust.edu.cn
Received September 24, 2012
ABSTRACT
Phosphine-catalyzed (3 þ 2) and (3 þ 3) annulations between 5-acetoxypenta-2,3-dienoate and 1C,3O-bisnucleophiles are presented. The former
cases can be achieved with the assistance of base while the latter is dominant without any additive. A series of deuterium-labeling experiments
disclosed that the divergence in annulations is likely determined by the involved proton transfer processes.
Tertiary phosphine is an important class of Lewis base
catalysts,1 which has shown great potential for the catalysis
Scheme 1. Phosphine-Catalyzed Reactions of Activated Allene
(E = activated group)
of numerous reactions, such as the MoritaꢀBaylisꢀHillman
reaction,2 RauhutꢀCurrier reaction,3 Michael addition,4
etc.5 In this regard, phosphine catalysis of activated allene
has attracted extensive attention, which strongly relies on,
from the point view of reaction mechanism, the formation
of zwitterionic intermediates A1 and A2 (Scheme 1).5
Recently, we have developed a novel intermediate B1
via a two-step process: addition of a phosphine catalyst to
(1) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560.
(2) For selected reviews, see: (a) Wei, Y.; Shi, M. Acc. Chem. Res.
2010, 43, 1005. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
Rev. 2010, 110, 5447. (c) Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815.
(d) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
811. (e) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
(3) For representative examples, see: (a) Rauhut, M.; Currier, H.
(American Cyanamide Co.) U.S. Patent 3,074,999, 1963. (b) McClure,
J. D. J. Org. Chem. 1970, 35, 3045. (c) Wang, L.-C.; Luis, A. L.; Agapiou,
K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402.
(d) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 2404. (e) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron
2009, 65, 4069 and references therein.
allenoate 1 and subsequent elimination of an acetate group.
B1 has been proven to be a good 1,4-biselectrophilic inter-
mediate for (4 þ 1) annulations (Scheme 1).6 Our continuing
r
10.1021/ol302634p
Published on Web 10/23/2012
2012 American Chemical Society

efforts along this line allow us to focus on allenoate 2.7
We envisioned that 2 would also be able to undergo a
similar additionꢀelimination process to form intermedi-
ate B2 which might be labile for further transformations
(Scheme 1). Herein, we report the phosphine-catalyzed
(3 þ 3) annulations between allenoates 2aꢀ2d and 1C,3O-
bisnucleophiles (Tables 1ꢀ3). Moreover, the (3 þ 3)
annulations provide a facile entry to stable monocyclic
2H-pyrans which are greatly challenging targets in organic
synthesis8 since they readily undergo a reversible electro-
cyclic ring opening9 to 1-oxatrienes.
Table 1. Optimization of Reaction Conditions for (3 þ 3)
Annulationsa
run
3
solvent
temp (°C)
5/yieldb
1
3a
3a
3b
3b
3b
3b
3b
3b
3b
toluene
toluene
toluene
toluene
toluene
THF
50
50
50
50
rt
5aa/22%
5aa/58%
5ab/70%
5ab/75%
5ab/92%
5ab/90%
5ab/74%
5ab/20%
5ab/<5%
2c
3c
4
5
Scheme 2. PPh3-Catalyzed (3 þ 2) Annulations
6
rt
7
acetone
DCM
rt
8
rt
9
MeCN
rt
a Reactins were conducted with 1.2 equiv of 2a and 1.0 equiv of 3,
16 h. b Isolated yield. c 1.0 equiv of HOAc was added.
During the course of further optimization of reaction
condition for the (3 þ 2) annulations, it was unexpected
to find that, without any base additive, the furan product
4aa was not detected but the (3 þ 3) annulation product
2H-pyran 5aa was isolated instead (Table 1, run 1).
Surprisingly, addition of HOAc (1 equiv) to the reaction
of 2a and 3a improved the yield of 5aa from 22% to 58%
under otherwise identical conditions (Table 1, run 2).
However, it was found that the HOAc additive had no
similar positive effect on the reaction of 2a and 3b; the
yield of 5ab was 70% in the presence of HOAc while the
corresponding yield was 75% in the absence of HOAc
(Table 2, runs 3 and 4). Without the HOAc additive, the
reaction of 2a and 3b took place smoothly even at room
temperature to afford 5ab in 92% yield (Table 1, run 5).
Further solvent screening proved that toluene was optimal
and other solvents, such as THF, acetone, DCM, and
MeCN, did not exhibit any superior performance in terms
of reaction yield (Table 1, runs 6ꢀ9).
We realized at the outset that the electron-withdrawing
effect of phosphinium and ester groups could enable the
alkene(s) of B being attacked by a nucleophile. Thus, we
began our investigation by treating the mixture of alleno-
ate 2a (1.2 equiv) and PPh3 (20 mol %) with pronucleo-
phile 3a (1.0 equiv) and a base (Scheme 2). After several
attempts, we were pleased to find that the PPh3-catalyzed
(3 þ 2) annulation between 2a and 3a could be achieved
using NaOH (1.2 equiv) as a base in toluene at 80 °C
and furan product 4aa was isolated in 70% yield. This
transformation could be extended to pentane-2,4-dione 3b,
although the corresponding product 4ab could not be
isolated in a pure form (see Supporting Information).
However, other 1,3-dicarbonyl compounds failed to achieve
(3 þ 2) annulations under the conditions and complicated
reactions were found in most cases.
(4) For representative examples, see: (a) White, D. A.; Baizer, M. M.
Tetrahedron Lett. 1973, 14, 3597. (b) Stewart, I. C.; Bergman, R. G.;
Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696. (c) Inanaga, J.; Baba, Y.;
Hanamoto, T. Chem. Lett. 1993, 241. (d) Evans, P. A.; Roseman, J. D.;
Garber, L. T. J. Org. Chem. 1996, 61, 4880. (e) Yavari, I.; Hekmat-
Shoar, R.; Zonouzi, A. Tetrahedron Lett. 1998, 39, 2391. (f) Grossman,
R. B.; Pendharkar, D. S.; Patrick, B. O. J. Org. Chem. 1999, 64, 7178.
(g) Szeto, J.; Sriramurthy, V.; Kwon, O. Org. Lett. 2011, 13, 5420.
(5) For reviews on phosphine catalysis, 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) Lu, X.; Du, Y.; Lu, C. Pure Appl.
Chem. 2005, 77, 1985. (d) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520. (e) Ye, L.-W.;
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (f) Kwong, C. K.-W.;
Fu, M. Y.; Lam, C. S.-L.; Toy, P. H. Synthesis 2008, 2307. (g) Sinisi, R.;
Sun, J.; Fu, G. C. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20652.
(6) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550.
(7) Allenoates 2 can be readily synthesized based on Fu’s procedure:
Suarez, A.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 3580.
Withthese promising results in hand, we then turned our
attentions toward investigating the reaction scope of (3 þ 3)
annulations of 2a with various 1C,3O-bisnucleophiles,
and the results are summarized in Table 2. 1,3-Dicarbonyl
compounds 3c and 3d also smoothly underwent (3 þ 3)
annulations with 2a to afford the corresponding products
in high yields (Table 2, entries 1ꢀ3). It should be noted that
unsymmetrical 1,3-dicarbonyl compound 3c suffered re-
gioselectively, affording two separable isomers 5ac-1 (49%
yield) and 5ac-2 (42%yield) (Table 2, entry 2). 3-Oxo-esters
3eꢀ3h proved to be suitable partners for (3 þ 3) annula-
tions with 2a, leading to the corresponding 2H-pyran
products in high yields (Table 2, entries 4ꢀ7).
(8) (a) Kuthan, J.; Sebek., P.; Boehm, S. Adv. Heterocycl. Chem.
1995, 62, 19. (b) Hepworth, J. D. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J., McKillop, A.,
Eds.; Pergamon: Oxford, U.K., 1984; Vol. 3, p 737.
(9) (a) Kluge, A. F.; Lillya, C. P. J. Am. Chem. Soc. 1971, 93, 4458.
(b) Kluge, A. F.; Lillya, C. P. J. Org. Chem. 1971, 36, 1977. (c) Zhu, Y.;
Ganapathy, S.; Liu, R. S. H. J. Org. Chem. 1992, 57, 1110.
To our delight, a variety of δ-substituted allenoates,
such as 2b, 2c, and 2d, were also suitable substrates for
this process, and the desired (3 þ 3) annulation products
5baꢀ5de were obtained in good to excellent yields (Table3,
entries 1ꢀ8). However, substrate2e, withaphenyl group at
Org. Lett., Vol. 14, No. 21, 2012
5531

Table 2. Reaction Scope of (3 þ 3) Annulations of 2a with
Table 3. Reaction Scope of (3 þ 3) Annulations of 2bꢀ2e with
1C,3O-Bisnucleophilesa
1C,3O-Bisnucleophilesa
entry
2 (R)
2b (n-Pr)
3
5
yield (%)b
1c
2
3
4
5
6
7
8
9
3a
3b
3d
3e
3b
3d
3e
3e
3e
5ba
5bb
5bd
5be
5cb
5cd
5ce
5de
5ee
48
2b (n-Pr)
2b (n-Pr)
2b (n-Pr)
2c (Bn)
83
95
96
66
2c (Bn)
41
2c (Bn)
68
2d [(CH2)2OTBS]
2e (Ph)
88
trace
a For reaction conditions, see the Supporting Information. b Isolated
yield. c 1.0 equiv of HOAc was added, and the reaction was run at 50 °C.
Scheme 3. Proposed Catalytic Cycles (with 2a and 3a as
substrates)
a Reaction conditions: for details please see the Supporting Informa-
tion. b Isolated yield.
the δ-position, did not give the corresponding product
(Table 3, entry 9). In all cases of the (3 þ 3) annulations, no
(3 þ 2) annulation products were detected.
While the mechanisms of these two unprecedented
annulations, especially the intriguing divergence in annu-
lations, have not been firmly established, we believed that
the reactions were initiated by the addition of PPh3 to 2a,
resulting in zwitterion A3 and A4 formation (Scheme 3).
The installation of an acetate group at the δ-position
would facilitate the process of 1,2-elimination to generate
intermediateB2, which is believed tobe electrophilic due to
the electron-withdrawing effect of phosphinium and ester
groups. Michael addition of 3a to B2 and subsequent
resonance would result in the formation of intermediate
D.10 Under basic conditions, the carbanion of D would
selectively abstract H1 to form zwitterions E1 and E2.
The carbanion of E2 might serve as a base to promote
oxo-Michael addition in 5-endo fashion to generate G via
intermediate F, which was followed by 1,2-elimination of
the PPh3 catalyst to release the (3 þ 2) annulation product.
On the other hand, under acidic conditions, the carbanion
of D would undergo intermolecular hydrogen atom ab-
straction from HOAc to generate H. Selective deprotona-
tion of H2 of intermediate H would result in the formation
of intermediate I. Then, a 6-endo oxo-Michael addi-
tion would occur to form intermediate J, which was
followed by 1,2-proton transfer and 1,2-elimination of
the phosphine catalyst to generate the (3 þ 3) annulation
product.
(10) Wang, Q.; Khoury, M. E.; Schlosser, M. Chem.;Eur. J. 2000, 6,
420.
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Org. Lett., Vol. 14, No. 21, 2012

with incorporation of deuterium at the C1, C2, and C3
positions (eq 1).12 The presence of deuterium at the C1
position of [D3]-5aa partially supported the mechanism of
intermolecular proton transfer of intermediate D under
acidic conditions. Furthermore, the presence of deuterium
at the C2 position inspired us to propose that zwitterions
A3 and A4 would be protonated by AcOH, leading to
the formation of intermediates L and M, respectively
(Scheme 3), which indicated that 1,2-elimination of the
acetate group might be a slow step. The absence of
deuterium at the C1 position of [D1]-4aa implied that
H2O would not be able to promote similar protonation
processes.
Scheme 4. Deuterium-Labelling Studies on (3 þ 2) Annulation
between 2a and 3a
In the absence of AcOH, the carbanion of intermedi-
ate D selectively abstracted H1 likely due to the forma-
tion of more stable zwitterions E1 and E2, leading to
(3 þ 2) annulation. In the presence of AcOH, intermedi-
ate D would undergo intermolecular proton transfer pre-
ferentially to form intermediate H whose H2 was ab-
stracted in turn, resulting in (3 þ 3) annulation. Thus,
AcOH seems to serve as a switch of proton transfer
processes and play essential roles in the divergence in
annulations.13
In summary, we have developed the phosphine-
catalyzed (3 þ 2) and (3 þ 3) annulations between alleno-
ate 2 and 1C,3O-bisnucleophiles; the former are favored
with the assistance of a base additive while the latter are
achieved under acidic reaction conditions. The transfor-
mations provide facile access to two important classes of
heterocycles, furan and 2H-pyran, respectively. The me-
chanistic investigations disclosed that the divergence in
annulations might be strongly dependent on the involved
proton transfer processes. Further understanding of the
mechanism via computational studies and the develop-
ment of an enantioselective variant are being pursued and
will be reported in due course.
To provide more information about the reaction me-
chanism, a series of deuterium-labeling studies were con-
ducted. The reaction of 2a and deuterated 3a-d produced
partially deuterated product [D1]-4aa with incorporation
of deuterium at the C2 position (Scheme 4, entry 1). When
D2O (1 equiv) was added into the reaction of 2a and 3a,
[D1]-4aa with incorporation of deuterium into the C2
position was also obtained (Scheme 4, entry 2). In these
two cases, no deuterium was found to be incorporated at
the C1 position. These results exclude the possibility that
the hydrogen atom of the C1 position stems from 3a or the
reaction medium, which are consistent with the presump-
tion that the carbanion of D would selectively abstract H1
by way of intramolecular H-transfer.11
In the case of (3 þ 3) annulations, the reaction of 2a and
3a in the presence of CD3CO2D (1 equiv) gave [D3]-5aa
(11) For the deuterium-labeling studies as shown in Scheme 4, the
following two issues should be noted: (1) Unfortunately, we failed to
synthesize R-deuterated 2a at this stage. (2) The less deuterium incor-
poration at C1 position might also result from the shorter lifetime of
intermediate D.
(12) 3aꢀd was also employed to probe the (3 þ 3) annulation
mechanism. For details, please see the Supporting Information. How-
ever, we found that 3a was obtained instead when 3aꢀd was stirred
in toluene solution in the presence of AcOH (1 equiv) and NaOAc
(20 mol %) for 1 h.
Acknowledgment. The financial support from NSFC
(No. 21002025), the Fundamental Research Funds for
the Central Universities, Shanghai Rising-Star Program
(11QA1401700), and Specialized Research Fund for the
Doctoral Program of Higher Education (20100074120014)
are highly appreciated.
(13) In recent computational and experimental studies, Yu, Kwon
and their co-workers found that water plays an important role on the
proton transfer processes to facilitate phosphine-catalyzed [3 þ 2]
cycloaddition: (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.;
Huang, F.; Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470.
(b) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T.
Tetrahedron Lett. 2007, 48, 3617. (c) Liang, Y.; Liu, S.; Yu, Z.-X. Synlett
2009, 905.
Supporting Information Available. Experimental pro-
cedures and copies of NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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