A convenient method for the syntheses of tetrahydrofuran moiety from furan by catalytic transfer of hydrogenation with ammonium formate

Article abstract of DOI:10.1016/j.tetlet.2008.02.016

Pd-C/ammonium formate efficiently and selectively reduces hetero-aromatic furan ring to the corresponding tetrahydrofuran moiety. Under this reaction condition, carbon-carbon double bond and α,β-unsaturated ketones also reduced to the corresponding alkanes and saturated ketones.

Full text of DOI:10.1016/j.tetlet.2008.02.016

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2469–2471
A convenient method for the syntheses of tetrahydrofuran
moiety from furan by catalytic transfer of hydrogenation
with ammonium formate
Sandip K. Nandy *, Jiyun Liu, Abeysinghe A. Padmapriya
Organic Chemistry Division, Unigen Pharmaceuticals Inc., 2660 Willamette Dr. NE, Lacey, WA 98516, USA
Received 31 December 2007; revised 2 February 2008; accepted 4 February 2008
Available online 8 February 2008
Abstract
Pd–C/ammonium formate efficiently and selectively reduces hetero-aromatic furan ring to the corresponding tetrahydrofuran moiety.
Under this reaction condition, carbon–carbon double bond and a,b-unsaturated ketones also reduced to the corresponding alkanes and
saturated ketones.
Ó 2008 Elsevier Ltd. All rights reserved.
A large number of biologically active natural products
possess substituted tetrahydrofuran moiety1 such as
acetogenins,2a,b polyether antibiotics,3a,b lignans,4 and
C-glycosides.5a,b Many of which contain substituents at
the 2- and 5-positions of the ring. Due to the medicinal
importance of these compounds, there has been a long-
standing interest in the development of simple and stereo-
selective methods to synthesize the tetrahydrofuran ring
efficiently.1–6 Several reports have also been recorded for
the construction of tetrahydrofuran moiety, most of them
involve metal catalyzed oxycarbonylation reactions on ali-
cyclic precursor.7 Surprisingly, there are no direct methods
or systematic study for the synthesis of tetrahydrofuran
moiety from the readily available hetero-aromatic furan
ring by catalytic transfer hydrogenation (CTH). This
CTH method has recently received considerable attention
to the researchers as the total process is safe, simple, and
ecologically friendly.8
methanol/THF at reflux. Application of ammonium
formate in organic synthesis has been reviewed by Ram
and Ehrenkaufer.9 This versatile, inexpensive, and
nontoxic reagent already was employed in the reduction
of various functional groups such as azide, nitrile, nitro,
aldehyde and ketone, and carbon–carbon double bonds.10
In the course of our studies aiming toward the synthesis
of polyphenol compounds, we employed CTH method for
the reduction of 1 (Scheme 1).
Although the reduction of carbon–carbon double bond
and debenzylation was unexpected, the complete reduction
of hetero-aromatic furan ring to tetrahydrofuran moiety
appeared most intriguing. To the best of our knowledge,
there had been three reports where the authors had
observed the reduction of furan ring to tetrahydrofuran
derivatives by CTH,11 but not systematically investigated.
Herein, we describe a new, simple, and efficient method
for the synthesis of substituted tetrahydrofuran ring from
hetero-aromatic furan by using ammonium formate as a
hydrogen donor with catalytic amount of 10% Pd–C in
OBn
OH
Pd-C/ AMF
BnO
O
HO
O
MeOH: THF (2:1)
reflux, 3 h
1
2
E:Z / 20:80
*
Corresponding author. Tel.: +1 360 486 8200; fax: +1 360 413 9135.
Scheme 1.
E-mail address: snandy@unigenusa.com (S. K. Nandy).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.016

2470
S. K. Nandy et al. / Tetrahedron Letters 49 (2008) 2469–2471
Table 1
Tetrahydrofuran synthesis
ponding triphenyl phosphonium salt by Wittig reactions
with commercially available furan aldehydes. In a typical
experiment, the substrates (3–5) (Table 1) were hydroge-
nated in refluxing methanol/THF (2:1) in the presence of
10% Pd–C catalyst and excess amount of ammonium
formate.
In all cases, we noticed that the reduction of carbon–
carbon double bond and debenzylation was accompanied
by the complete reduction of the hetero-aromatic furan
to tetrahydrofuran ring. In the case of 4, nitro group also
reduced to corresponding amine.
Substratea
Product
Yieldb (%)
OBn
OH
H
O
69
O
BnO
HO
H
3
6
7
O
O
O
H
O
O
65
72
O
H
Then, we extended our newly observed methodology to
the reduction of substrates, 9–12, which were obtained
through Grignard addition reactions on the corresponding
furaldehydes (Table 2).
NO2
NH2
4
HO
OH
BnO
OBn
O
As in the previous cases, the second series of compounds
(Table 2, 9–12) underwent smooth reductions, when
exposed to 10% Pd–C catalyst and excess amount of
ammonium formate at reflux. In all the cases, two diastere-
oisomers were obtained with the same ratio. The mixtures
of diastereoisomers12 (Table 2, 13 and 14) were separated
by careful column chromatography and the structure and
stereochemistry was determined by a combination of
high-field 1D and 2D NMR experiments. It is noteworthy
that no dehydroxylation was observed in this condition.
Furthermore, we extended the scope of this reagent to
achieve the chemoselective reduction of a,b-unsaturated
ketones. Different chalcone derivatives were selected as
substrates (Table 3). Remarkable chemoselective carbon–
O
5
8
a
Substrates, 3 and 4, were synthesized by Wittig reactions from the
corresponding triphenylphosphonium salts with aldehydes. In all cases, we
found 80:20 (E:Z) isomer.
b
Isolated yield after column purifications.
These observations prompted us to begun a systematic
study of the CTH method of a series of unsaturated
furan derivatives. Our previous interest in the synthesis of
substituted biaryl compounds allowed access to a series
of unsaturated furan derivatives. These compounds were
synthesized using common procedures from the corres-
Table 2
Tetrahydrofuran synthesis
Substratea
Product
Yieldb (%)
OH
H
OH
OH
H
H
O
O
O
+
O
O
85
78
79
75
H3CO
H3CO
H3CO
13
14
9
(1:1)
OH
OH
OH
H
H
O
H
+
H3CO
H3CO
H3CO
16
15
10
(1:1)
OH OH
OBn OH
OH OH
H
H
O
O
+
O
HO
BnO
HO
18
(1:1)
11
17
OH OH
OBn OH
OH OH
H
H
+
O
O
O
HO
BnO
HO
20
(1:1)
12
19
a
Substrates, 9–12, were synthesized by Grignard addition reactions with the corresponding commercially available furaldehydes.
Isolated yield after column purifications.
b

S. K. Nandy et al. / Tetrahedron Letters 49 (2008) 2469–2471
2471
Table 3
Tetrahydrofuran synthesis
References and notes
Substratea
Product
Yieldb
(%)
1. Hou, X.-L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl. Chem. 2002,
14, 139–179.
2. (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504–540; (b) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J.
R.; Cortes, D. Phytochemistry 1998, 48, 1087–1117.
3. (a) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407; (b) Polyether
Antibiotics: Naturally Occurring Acid Ionophores; Westley, J. W., Ed.;
M. Dekker: New York, 1982; Vols. 1 and 2.
4. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96.
5. (a) Nicorta, F. Top. Curr. Chem. 1997, 187, 55–83; (b) Postema, M. H.
D. Tetrahedron 1992, 48, 8545–8599.
6. (a) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301–2323; (b)
Harmanage, J. C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4,
1711–1754.
7. (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106,
1496–1498; (b) Hay, M. B.; Hadrin, A. R.; Wolfe, J. P. J. Org. Chem.
2005, 70, 3099–3107 and references cited therein.
OBn O
OH
O
O
O
83
88
79
BnO
HO
HO
24
21
OBn O
OH
OH
O
O
O
O
BnO
25
22
OBn O
H
O
H
O
8. Rao, H. S. P.; Reedy, K. S. Tetrahedron Lett. 1994, 35, 171.
9. Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91–95.
BnO
HO
26
23
10. (a) Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929 and later
publications; (b) Adger, B. M.; O’Farrell, C.; Lewis, N. J.; Mitchell,
M. B. Synthesis 1987, 53; (c) Carpino, L.; Tunga, A. J. Org. Chem.
1986, 11, 1930; (d) Ram, S.; Ehrenkaufer, R. E. Synthesis 1986, 133;
(e) Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745. For a
review see: (f) Ranu, B. C.; Sarkar, A.; Guchhait, S. K.; Ghosh, K. J.
Ind. Chem. Soc. 1998, 75, 690. CTH reaction with polymer-supported
formats, see: (g) Basu, B.; Bhuiyan, Md. M. H.; Das, P.; Hossain, I.
Tetrahedron Lett. 2003, 44, 8931–8934.
11. (a) Albright, J. D.; Howell, C. F.; Sum, F. W. Heterocycles 1993, 35,
737–754; (b) Albright, J. D.; Howell, C. F. U.S. Patent 5,459,131,
1991; (c) Sharma, A.; Kumar, V.; Sinha, A. K. Adv. Synth. Catal.
2006, 348, 354–360.
Conditions: a Chalcone derivatives were synthesized by aldol condensation
reaction following the known procedures with benzyl protected
acetophenone and corresponding substituted furaldehyde.
b
In all cases, yield was obtained after column purifications.
carbon double bond reductions along with complete reduc-
tion of furan ring were observed in all cases and sensitive
functionalities like ketones were unaffected under this
condition.13
In summary, the ammonium formate/Pd–C system
proved to be very efficient and versatile for the one-step
reduction of unsaturated furan derivatives to saturated
tetrahydrofuran derivatives wherein the sensitive func-
tional group such as the keto group remains intact. The
reaction workup procedure was very simple and the prod-
ucts were easily obtained in excellent yield without the need
for high pressure equipment and explosive hydrogen gas.
Application of this newly developed methodology and the
asymmetric version of this reaction are under active
investigations.
12. All the compounds gave satisfactory spectroscopic data. Data for the
selected compounds are given below: 9: 1H NMR (CDCl3, 300 MHz):
d 7.39–7.32 (m, 3H), 6.92–6.87 (m, 2H), 6.31 (dd, J1 = 2.1 Hz,
J2 = 3.3 Hz, 1H), 6.11 (dt, J1 = 2.4 Hz, J2 = 0.6 Hz, 1H), 5.76 (s, 1H),
3.80 (s, 3H); 13: 1H NMR (CDCl3, 300 MHz): d 7.27 (d, J = 8.1 Hz,
2H), 6.86 (d, J = 9.0 Hz, 2H), 4.81 (d, J = 2.1 Hz, 1H), 4.05–3.95 (m,
1H), 3.91–3.83 (m, 1H), 3.82–3.71 (m, 4H), 2.85 (s, 1H), 1.90–1.70 (m,
3H), 1.70–1.51 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 159.128 (1C),
133.156 (1C), 127.519 (2C), 113.873 (2C), 83.418 (1C), 74.091(1C),
69.157 (1C), 55.446 (1C), 26.212 (1C), 25.338 (1C), 14: 1H NMR
(CDCl3, 300 MHz): d 7.28 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 9.0 Hz,
2H), 4.37 (d, J = 7.5 Hz, 1H), 4.03–3.92 (m, 1H), 3.92–3.81 (m, 1H),
3.81–3.71 (m, 4H), 3.17 (s, 1H), 1.92–1.70 (m, 2H), 1.70–1.49 (m, 2H);
13C NMR (CDCl3, 75 MHz): d 159.524 (1C), 133.102 (1C), 128.420
(2C), 113.988 (2C), 83.780 (1C), 76.820 (1C), 68.619 (1C), 55.465 (1C),
28.154 (1C), 26.261 (1C).
Acknowledgments
13. Reduction of chalcone to saturated alcohol, see: (a) Andrade, C. K.
Z.; Silvia, W. A. Lett. Org. Chem. 2006, 3, 39–41. Reduction of a,b-
unsaturated ketones to saturated ketones, see: (b) Ahamed, N.; Lier,
J. E. V. J. Chem. Res. 2006, 584–585; (c) Berthold, H.; Schotten, T.;
Hong, H. Synthesis 2002, 1607–1610.
We are pleased to acknowledge Danielle Berry and
Catherine Maurseth for NMR spectra, Jifu Zhao for Mass
spectra.