One-pot synthesis of highly substituted tetrahydrofurans from activated propargyl alcohols using Bu3P

Article abstract of DOI:10.1016/j.tetlet.2008.07.180

General and robust synthesis of highly functionalized tetrahydrofuran ring was accomplished with activated propargyl alcohol and reactive Michael acceptors in the presence of catalytic Bu₃P.

Full text of DOI:10.1016/j.tetlet.2008.07.180

Tetrahedron Letters 49 (2008) 6009–6012
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of highly substituted tetrahydrofurans
from activated propargyl alcohols using Bu3P
*
Yakambram Pedduri, John S. Williamson
Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
General and robust synthesis of highly functionalized tetrahydrofuran ring was accomplished with
activated propargyl alcohol and reactive Michael acceptors in the presence of catalytic Bu3P.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 9 June 2008
Revised 28 July 2008
Accepted 31 July 2008
Available online 7 August 2008
Keywords:
Tandem conjugate addition
Double Michael addition
Tributylphosphine
Tetrahydrofuran ring
Highly substituted tetrahydrofurans are ubiquitous in many
natural and unnatural products of biological importance.1,2 Meth-
ylenetetrahydrofurans form a very useful class of skeletal building
blocks, and are derived from extensive synthetic protocols.2,3
Among the methods developed, a formal [3+2] cycloaddition reac-
tion of propargyl alcohols to electrophilic alkene received consider-
able attention.3 Initially, a typical tandem reaction involving
W
OH
R
CO2Et
EWG
W
Lewis Base
EtO2C
W
R
W
O
1
W
3
=
2
Scheme 1. Synthesis of highly functionalized tetrahydrofurans by double Michael
reaction.
conjugate (Michael) additions of activated propargyl alcohol to
t
a
-nitroalkene was reported by Ikeda and others using BuOK.4a,4b
and temperature did not improve the conversion to tetrahydrofu-
ran. In all the cases, minor formation of product was observed,
Lately, Morikawa et al. re-examined the reaction with Lewis acid
catalyst to overcome the instability of activated propargyl alcohol
with limited substrate scope.4c
along with
a new by-product, 4. The new by-product was
characterized as dioxane 4, and was formed by self conjugate addi-
tion of propargyl alcohol 1.5 In addition, reactions conducted at
elevated temperature (>100 °C) led to a considerable decomposi-
tion of starting materials. Interestingly, use of highly nucleophilic
tributylphosphine eliminated the formation of this side product
and gave the tetrahydrofuran 3a exclusively. The catalytic nature
of the reaction was investigated by varying the solvent to find
the optimum loading of Bu3P (10 mol % for complete conversion
under solvent free conditions).6a More importantly, a high compat-
ibility of tributylphosphine to the electrophilic alkene and propar-
gyl alcohol 1 was observed under these reaction conditions. Our
attempts to replace Bu3P catalyst with other phosphines, such as
triphenylphosphine, were not successful.
Having identified the suitable reaction conditions, the scope of
reaction was explored with a range of alkylidene-, arylidene-,
and heteroarylidene malonate/Meldrum’s acid based alkene
derivatives (Table 1). The required Michael acceptors (2a–j) were
prepared by following known literature methods.7 Tandem conju-
gate addition of alkylidene and branched alkylidene malonate
Phosphine-catalyzed reactions using electrophilic alkenes have
emerged as powerful synthetic tool for the construction of N,O-
heterocycles such as tetrahydropyrroles, tetrahydropyridines,
dioxanes, and pyrones.9 We anticipated similar [3+2] cycloaddition
to methylenetetrahydrofurans using Bu3P from activated propargyl
alcohol of type 1 with Michael acceptor 2 (Scheme 1). Accordingly,
we have investigated this useful reaction to increase the substrate
scope and compatibility.
Herein, we report our preliminary results using ethyl 4-
hydroxybut-2-ynoate 1 and electrophilic alkenes such as alkyl-
idene malonate 2. Our early efforts focused on alkene 2a to define
the optimal reaction conditions (Scheme 2). Addition of substrate
2a to propargyl alcohol 1 in the presence of tertiary amines (TEA,
DBU, DABCO, and DMAP) furnished the expected tetrahydrofuran
with slow conversion rate. Manipulation of the solvent, catalyst,
* Corresponding author. Tel.: +1 662 915 7101; fax: +1 662 915 5638.
E-mail address: mcjsw@olemiss.edu (J. S. Williamson).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.180

6010
Y. Pedduri, J. S. Williamson / Tetrahedron Letters 49 (2008) 6009–6012
EtO2C
MeO2C
MeO2C
tert-Amine
CO2Et
O
O
Me
OH
or
Bu3P
Me
MeO2C
CO2Me
O
EtO2C
CO2Et
4
2a
3a
1
Scheme 2. Synthesis of tetrahydrofuran using alkene 2a and propargyl alcohol 1.
Table 1
Entry
Michael acceptor
Product
Solvent (temp.)
Neat (rt)
Time (h)
4
Yielda (E:Z)
Me
O
CO2Me
Me
1
2
3
4
5
86% (1:1.7)
CO2Me
CO2Me
2a
EtO2C
CO2Me
nPr
3a
CO2Me
O
nPr
iPr
Neat (rt)
Neat (rt)
Neat (rt)
Neat (rt)
6
8
8
8
80% (1:1.6)
80% (1:1.6)
92% (1:2)
CO2Me
CO2Me
2b
EtO2C
EtO2C
EtO2C
EtO2C
CO2Me
3b
i
Pr
CO2Me
O
CO2Me
CO2Me
CO2Me
2c
3c
O
iBu
CO2Me
iBu
CO2Me
CO2Me
CO2Me
nHept
2d
3d
O
CO2Me
n-Hept
75% (1:1.5)
CO2Me
CO2Me
2e
CO2Me
3e
Ph
CO Me
O
2
Ph
6
7
Toluene (80 °C)
Toluene (80 °C)
6
4
78% (1:1.6)
89% (1:4.1)
CO2Me
CO2Me
CO2Me
EtO2C
EtO2C
2f
3f
OMe
CO2Me
CO2Me
O
O
O
MeO
MeO
2g
O
O
3g
OMe
OMe
OMe
O
CO Me
2
8
9
O
O
Toluene (80 °C)
8
83% (1:3.1)
CO2Me
EtO2C
O
O
2h
3h
Br
Br
CO2Me
CO2Me
O
O
O
Toluene (80 °C)
Toluene (80 °C)
6
4
85% (1:5.1)
87% (1:3.1)
EtO2C
EtO2C
O
2i
O
O
3i
CO2Me
O
S
O
O
S
CO2Me
10
O
2j
3j
a
Isolated yields.

Y. Pedduri, J. S. Williamson / Tetrahedron Letters 49 (2008) 6009–6012
6011
O
R
O
O
O
OH
O
10 mol% Bu3P
EtO2C
R
n
CHO
O
O
Toluene, 80 ˚C
O
EtO2C
O
R =
-Heptyl
1
3g
: R = 4-MeOPh
3h: R = 1,2-diMeOPh
3k: R= -Heptyl
= 1,2-diMeOPh
= 4-MeOPh
n
Scheme 3. Three component coupling reaction for the synthesis of highly substituted tetrahydrofuran ring.
acceptors underwent clean transformation to provide the 3-alkyl-
idene tetrahydrofurans (3), as a separable E:Z mixture, in good
yield (entries 1–6). The arylidene and heteroarylidene malonate
esters were found to be inert under the same reaction conditions,
and further optimization of reaction conditions varying the tem-
perature and solvent did not yield the required product. The more
reactive arylidene and heteroarylidene alkenes derived from Mel-
drum’s acid provided the tetrahydrofuran ring through modifica-
tion of reaction conditions (entries 7–10).6b The spectral data of
each of the products showed a characteristic olefin proton for the
E-isomer in between d 6.01 and 6.50 ppm, whereas the Z-olefinic
proton appeared in the region of d 5.80–6.09 ppm.3,6c
Considering the instability and highly reactive nature of alkyl-
idene Meldrum’s acids, the anticipated tandem conjugate addition
reaction was planned using the in situ generation of alkene from
the aldehyde and Meldrum’s acid (Scheme 3). The mixture of Mel-
drum’s acid, octanal and ethyl 4-hydroxybut-2-ynoate 1 was trea-
ted with Bu3P. Heating the reaction mixture at 80 °C in toluene led
to the formation of tetrahydrofuran 3k as a E:Z (2:1) isomeric mix-
ture in 40% yield.8 Increasing the amount of catalyst Bu3P and vary-
ing the solvent did not improve the yield. This multicomponent
reaction was further examined using additional aldehydes includ-
ing p-anisaldehyde and 1,2-dimethoxy benzaldehyde (3g and 3h)
where products were found in low yields (42% and 46% respec-
tively, Scheme 3). It is likely that the thermal instability of enoliz-
able Meldrum’s acid was the reason for observed lower yields.
Further optimization of reaction conditions of this three-compo-
nent reaction system is currently in progress.
Bu3P on 1) with electrophilic alkene 2, leading to meth-
ylenetetrahydrofuran 3 (Scheme 4).3,9 In the proposed mechanistic
path, path a accounts for the catalytic nature of reaction. Comple-
mentary catalytic cycles (path b and path c) are expected to com-
pete with path a in the case of solvent-free reaction conditions.
The strong basic nature of enolate intermediates I or V could trig-
ger the catalytic cycles path b and path c by proton abstraction
from propargyl alcohol 1. The proposed mechanism also explains
the observed poor olefin regioselectivity of product 3 by the inter-
mediacy of allene I and/or V. Absence of Michael addition product
IV (protonated) further supports the derived mechanism.
In conclusion, we have demonstrated efficient and simple
methodology to highly functionalized tetrahydrofuran rings from
readily available starting materials using catalytic amount of tri-
butylphosphine. In the course of the reaction, we have also devel-
oped a promising one-pot, three-component coupling reaction for
the same.
Acknowledgments
The authors would like to thank Drs. Amar Chittiboyina,
Mahesh Gundluru, and Paulo Carvalho for their suggestions in edit-
ing the manuscript. This work was funded in part by the Center for
Disease Control and Prevention (CDC cooperative agreements
1UO1 CI000211-03 and 1UO1 CI000362-01). The preceding inves-
tigations were conducted in a facility remodeled with support from
a National Center for Research Resources, National Institutes of
Health (C06 Rr-14503-01).
In connection with previous reports, we propose the probable
mechanism as
a formal [3+2] cycloaddition of zwitterionic
Supplementary data
intermediate II (formed by the initial attack of the nucleophilic
Supplementary data (spectral data of all the products) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.07.180.
R
CO2R
CO2R
PBu3
O
2
References and notes
a
HO
R
O
1. Dean, F. M.; Sargent, M. V. In Comprehensive Heterocyclic Chemistry; Katrizky, A.
R., Rees, C. W., Eds.; Oxford: Pergamon, 1984; Vol. 4, pp 31–712.
2. Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
CO2R
CO2R
3
O
EtO2C
C
II
Bu3P
RO
PBu3
3. Yamazaki, S. Chem. Eur. J. 2008, 14, 6026–6036.
4. (a) Yakura, T.; Tsuda, T.; Matsumura, Y.; Yamada, S.; Ikeda, M. Synlett 1996, 985–
986; (b) Yakura, T.; Yamada, S.; Shima, M.; Iwamoto, M.; Ikeda, M. Chem. Pharm.
Bull. 1998, 46, 744–748; (c) Morikawa, S.; Yamazaki, S.; Tsukada, M.; Izuhara, S.;
Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2007, 72, 6459–6463.
Bu3P
I
EtO2C
OH
5. Spectral data of 4 (major isomer): 1H NMR (500 MHz, CDCl3): d 5.06 (s, 1H), 4.75
(s, 2H), 4.17 (q, J = 7.1, 2H), 1.28 (t, J = 7.1, 3H); 13C NMR (126 MHz, CDCl3) d
164.50, 160.04, 94.65, 77.29, 77.03, 76.78, 65.52, 59.90, 14.26. HRMS: 279.0852
for C12H16O6Na (Calcd mass 279.0845). Compound 4 (minor isomer): 1H NMR
(500 MHz, CDCl3) d 5.50 (s, 2H), 5.46 (s, 1H), 5.01 (s, 1H), 4.60 (s, 2H), 4.17 (m,
4H), 1.28 (m, 6H); 13C NMR (126 MHz, CDCl3) d 166.59, 164.60, 164.31, 160.46,
97.11, 94.17, 77.28, 77.02, 76.77, 64.78, 61.80, 60.10, 59.89, 14.28. HRMS:
279.0839 for C12H16O6Na (Calcd mass 279.0845).
c
O
b
CO2R
1
III
O
RO2C
R
1
RO2C
RO2C
2
C
O
OR
R
O
V
6. (a) General procedure A: To a mixture of olefin (2a–f, 0.5 mmol) and alkynoate 1
(0.5 mmol) was added catalytic Bu3P (0.05 mmol) at room temperature under
argon. After the completion of reaction, the crude mixture was dissolved in ethyl
acetate, washed with aq NaHSO3, dried, and concentrated. Purification on silica
gel gave pure E and Z isomers of 3a-f, and were characterized by 1D-NMR (1H,
13C, DEPT), 2D-NMR (COSY, NOESY, HSQC, HMBC), HRMS and IR.
RO2C
RO2C
CO2R
IV
(b) General procedure B: To a degassed solution of olefin (2g–j, 0.5 mmol) and
alkynoate 1 (0.5 mmol) in toluene (1 mL) was added catalytic Bu3P (0.05 mmol)
Scheme 4. Probable mechanism for the tandem conjugate addition reaction.

6012
Y. Pedduri, J. S. Williamson / Tetrahedron Letters 49 (2008) 6009–6012
at room temperature under argon. The reaction mixture was heated to 80 °C.
7. (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazaccani, A.; Sartori, G. Tetrahedron
Lett. 2001, 42, 5203–5205; (b) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Gianotti,
M.; Tolomelli, A. Synth. Commun. 2003, 33, 1587–1594.
8. General Procedure C: To the degassed solution of aldehyde (0.5 mmol),
Meldrum’s acid (0.5 mmol) and ethyl 4-hydroxybut-2-ynoate 1 (0.5 mmol) in
toluene (2 mL) was added Bu3P (0.05 mmol) under argon and heated at 80 °C.
After the completion, reaction mixture was diluted with ethyl acetate and
washed with aq NaHSO3, dried, and concentrated. The isomeric E:Z mixture of
product (3g, 3h, and 3j) was subjected to silica gel chromatography and
characterized by NMR, HRMS, and IR.
After the completion of reaction, crude mixture was diluted with ethyl acetate,
washed with aq.NaHSO3, dried, concentrated, and purified on silica gel using
ethyl acetate and hexane to give the E:Z mixture of 3g–j.
(c) The (Z) and (E) structures were confirmed by NOE correlations of OCH2 (ring
protons) and olefin proton as shown below (A, B and C) for 3g, 3h, and 3a.
EtO2C
H
H
O
RO2C
H
O
CO2Et
MeO2C
MeO2C
CO2Et
O
O
RO2C
9. Zhu, X. F.; Henry, C. E.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 6722–6723 and
references cited therein.
H
H
O
R
O
O
R
R
(
Z
)
(
E
)
(Z
)