Rapid synthesis of kahweofuran and its derivatives, the coffee aroma components

Article abstract of DOI:10.1016/j.tetlet.2005.11.087

Kahweofuran, as an impact flavor component of roasted coffee and possesses the 6-methyl-2,3-dihydrothieno[2,3-c]furan structure, was rapidly synthesized from 2-acetyl-3-hydroxymethylthiophene by the formal reductive cyclization using the Wilkinson's catalyst. Similarly, the syntheses of the 4-methyl, 6-ethyl and 4,6-dimethyl derivatives were also achieved in favorable yields.

Full text of DOI:10.1016/j.tetlet.2005.11.087

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 787–789
Rapid synthesis of kahweofuran and its derivatives,
the coffee aroma components
Yanwu Li, Yusuke Murakami and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Hyogo, Japan
Received 24 September 2005; revised 16 November 2005; accepted 18 November 2005
Abstract—Kahweofuran, as an impact flavor component of roasted coffee and possesses the 6-methyl-2,3-dihydrothieno[2,3-c]furan
structure, was rapidly synthesized from 2-acetyl-3-hydroxymethylthiophene by the formal reductive cyclization using the Wilkin-
sonÕs catalyst. Similarly, the syntheses of the 4-methyl, 6-ethyl and 4,6-dimethyl derivatives were also achieved in favorable yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Kahweofuran 1 was isolated1 in 1967 from roasted cof-
fee as an impact flavor component, and its structure was
determined2 in 1971 by spectroscopy and synthesis. The
6-ethyl and 4,6-dimethyl derivatives, 2 and 3, were also
isolated as flavor components from roasted coffee. The
4-methyl derivative 4, the regioisomer of kahweofuran,
is an ideal component and its flavor character is very
interesting. However, full evaluations of their signifi-
cance in aroma research are apparently still lacking,
because they have not been easily synthesized (Fig. 1).
the regioselectivity of the acylation was not admitted
and the overall yield was only 2%. There have been
two other papers on the synthesis of kahweofuran.
RewickiÕs group reported the synthesis starting from
3,4-dibromofuran through the 2-methyl-3-bromo-4-(2-
bromoethyl) furan 6 by the regioselective lithiation of
the furan ring followed by the thiophene ring formation.
The overall yield of this synthesis was 15%.3 In order to
avoid the difficulty of separation from regioisomers,
FugantiÕs group4 prepared compound 7 by the Stobbe
condensation of a-methylcinnamaldehyde with dimethyl
succinate, and carried out a series of reactions involving
the transformation of the carboxyl group to a sulfur
group and then formation of the tetrahydrothiophene
ring by an intramolecular Michael addition to obtain
the key intermediate 8, which was treated with dilute
sulfuric acid to provide kahweofuran (1) in 14 steps
(Fig. 2).
In order to identify the structure of kahweofuran,
BuchiÕs group2 reported its synthesis starting from 3-keto
tetrahydrothiophene through the key intermediate 5 by
acylation and the Grignard reaction followed by acid
treatment. Although this synthesis was only three steps,
O
O
O
S
S
S
S
Et
HO
2
4
1
3
OMe
O
O
Br
S
Br
O
5
7
6
O
O
S
O
Ph
OMe
OH
Figure 1. Structures of kahweofuran and its derivatives.
OMe
MeO
Keywords: Kahweofuran; Reductive cyclization.
Corresponding author. Tel.: +81 79 565 8314; fax: +81 79 565
9077; e-mail: katsumura@ksc.kwansei.ac.jp
8
*
Figure 2. The key intermediates of the previous synthesis.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.087

788
Y. Li et al. / Tetrahedron Letters 47 (2006) 787–789
Thus, a more efficient and rapid synthesis of kahweo-
furan is desired, and we now report the highly efficient
and rapid synthesis of kahweofuran and its derivatives.
hydrogen atmosphere in benzene at 100 °C, kahweo-
furan was directly obtained from hydroxyketone 12 by
the formal reductive cyclization in 51% isolated yield
(Scheme 1). Thus, we succeeded in the highly efficient
and rapid synthesis of kahweofuran.
After a detailed survey of the previous results, we chose
thiophene-3-methanol (9) as the starting material, which
was first protected with 3,4-dihydro-2H-pyran5 to afford
the corresponding ether 10. Regioselective generation of
an anion at the 2-position6 of compound 10 was success-
ful by a chelation-controlled effect with the 3-hydroxy-
methyl tetrahydropyranyl ether. Although the reaction
of the corresponding anion with acetyl chloride gave
the desired 2-acetylated compound 11 in 41% yield
along with the 4-acetylated compound as a by-product
in 11% yield, the rapid addition of acetic anhydride
instead of acetyl chloride into the anion solution at
À78 °C produced the desired compound 11 in 68% yield.
The treatment of 11 with camphorsulfonic acid in
MeOH afforded the corresponding alcohol 12 in 86%
yield, which is present as a hydroxyketone structure.7
Our attempts to partially or completely reduce the thio-
phene ring of 12 were unsuccessful by usual methods.
The thiophene ring was not affected by dissolving metals
in various solvents as well as hydrogenation with palla-
dium on carbon8 and platinum dioxide. Quite fortu-
nately, however, by using WilkinsonÕs catalyst under a
In order to explore the generality of this reductive cycli-
zation with the WilkinsonÕs catalyst, a series of ana-
logues of the hydroxyketone 12 were synthesized, and
attempted the formal reductive cyclization.
Based on the synthesis of compound 12, the correspond-
ing hydroxyketone derivatives 14, 16, and 20 were syn-
thesized as shown in Scheme 2. Hydroxyketone 14 was
prepared using propionic anhydride instead of acetic
anhydride. Compound 16 was prepared from 12 by
MnO2 oxidation9 of the primary alcohol and then the
Grignard reaction of the resulting aldehyde.10 Mean-
while, compound 20 was synthesized from 10 as follows.
Ether 10 was reacted with paraformaldehyde11 to afford
alcohol 17 in 99% yield, which was protected by a 4-
methoxybenzyl group.12 After removal of the THP
group of 17 with an acid treatment in 80% yield, the
obtained alcohol 18 was oxidized with manganese dioxide
followed by the reaction with methyl magnesium bro-
mide to provide 19 in 64% yield in two steps. Compound
20 was obtained by the oxidation of 19 with chromium
trioxide–pyridine complex13 and then removal of the
MPM group of the resulting ketone with DDQ14 in
70% yield. Thus, we obtained four kinds of thiophene
derivatives 12, 14, 16, and 20, containing the hydroxy-
ketone substituents.
OR
OR
O
b
d
51%
O
S
S
S
9 : R = H
10 : R = THP
11 : R = THP
12 : R = H
1
a
c
We then examined the formal reductive cyclization of
the obtained hydroxyketone derivatives using Wilkin-
sonÕs catalyst.15 The corresponding 6-ethyl, 4,6-dimethyl
and 4-methyl derivatives3 of kahweofuran were success-
fully obtained in 54%, 58%, and 43% yields, respectively.
Scheme 1. Reagents and conditions: (a) 3,4-dihydro-2H-pyrane,
pyridinium p-toluenesulfonate, CH2Cl2, rt, 100%; (b) n-BuLi, Ac2O,
À78 °C, 68%; (c) ( )-camphor-10-sulfonic acid, MeOH, rt, 86%; (d)
Rh(PPh3)3Cl, H2, benzene in a sealed tube, 100 °C, 51%.
OTHP
O
OH
O
OTHP
O
c
a
b
54%
S
S
S
S
S
Et
Et
Et
10
13
14
2
3
CHO
O
OH
O
OH
O
e
c
d
f
O
58%
S
S
S
S
S
12
10
15
16
18
OTHP
OH
OTHP
g, h
i, j
OH
OMPM
S
17
OH
O
OH
k, l
O
c
OMPM
43%
S
S
S
19
4
20
Scheme 2. Reagents and conditions: (a) n-BuLi, propionic anhydride, À78 °C, 65%; (b) ( )-camphor-10-sulfonic acid, MeOH, rt, 88%; (c)
Rh(PPh3)3Cl, H2, benzene in a sealed tube, 100 °C; (d) MnO2, CH2Cl2, rt, 99%; (e) CH3MgBr, THF, À78 °C, 56%; (f) n-BuLi, (CH2O)n, À78 °C,
99%; (g) p-MeOC6H4CH2Cl, NaH, THF, 84%; (h) ( )-camphor-10-sulfonic acid, MeOH, rt, 80%; (i) MnO2, CH2Cl2, rt, 90%; (j) CH3MgBr, THF,
À78 °C, 71%; (k) CrO3, pyridine, CH2Cl2, rt, 78%; (l) DDQ, H2O/CH2Cl2 (1:1), rt, 90%.

Y. Li et al. / Tetrahedron Letters 47 (2006) 787–789
789
References and notes
S
OH
OH
O
O
a
+
1. Stoll, M.; Winther, M.; Gautschi, F.; Flament, I.;
Willhalm, B. Helv. Chim. Acta 1967, 50, 628.
2. Buchi, G.; Degen, P.; Gautschi, F.; Willhalm, B. J. Org.
S
S
S
OH
¨
21
22
23
Chem. 1971, 36, 199.
3. Gorzynski, M.; Rewicki, D. Liebigs Ann. Chem. 1986, 625.
4. Brenna, E.; Fuganti, C.; Serra, S.; Dulio, A. J. Chem. Res.
(S) 1998, 74.
Scheme 3. Reagents and conditions: (a) Rh(PPh3)3Cl, H2, benzene,
100 °C, 22: 47%, 23: 49%.
5. Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J.
J. Org. Chem. 1979, 44, 1438.
Thus, the rapid and efficient syntheses of the kahweo-
furan derivatives were achieved.
6. Buttery, C. D.; Cameron, A. G.; Dell, C. P.; Knight, D.
W. J. Chem. Soc., Perkin Trans. 1 1990, 1601.
7. NMR date of compound 12 1H NMR (400 MHz, CDCl3)
d 7.49 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 4.74
(d, J = 5.6 Hz, 2H), 4.24 (t, J = 5.6 Hz, OH, 1H), 2.58 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 192.43, 149.98,
136.57, 130.91, 130.51, 59.98, 29.09.
8. Mozingo, R.; Harris, S. A.; Wolf, D. E.; Haffhine, C. E.;
Easton, N. R.; Folkers, K. J. Am. Chem. Soc. 1945, 67,
2092.
9. Ernst, L.; Hopf, H.; Krause, N. J. Org. Chem. 1987, 52,
398.
10. Ko, K. Y.; Eliel, E. L. J. Org. Chem. 1986, 51, 5353.
11. Screttas, C. G.; Screttas, M. M. J. Org. Chem. 1978, 43,
1064.
12. Marco, J. L.; Hueso-Rodriquez, J. A. Tetrahedron Lett.
1988, 29, 2459.
13. Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 3, 4000.
14. Horita, K.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron Lett. 1986, 42, 3021.
15. Typical procedure: To a solution of 14 (312 mg, 2 mmol)
in benzene (10 ml) was added tris(triphenylphosphine)
rhodium(I) chloride (92 mg, 0.1 mmol). The reaction
mixture was stirred at 100 °C under a 1 MPa hydrogen
atmosphere for 24 h. The reaction mixture was then
concentrated. The obtained residue was separated by
chromatography on silica gel (pentane/ether 100:1) to
obtain 1 (142 mg, 51%) as a colorless oil. Since the desired
molecules 1–4 are very volatile, their isolated yields tend to
be lower than the TLC aspects.
On the other hand, the treatment of the THP derivative
derived from 12 with the WilkinsonÕs catalyst under the
same reaction conditions gave a complex mixture. The
treatment of the dihydroxy compound 21, which was
quantitatively prepared by the LAH reduction16 of com-
pound 12, using the WilkinsonÕs catalyst under the same
reaction conditions gave dimer 22 and reduced com-
pound 23 in 47% and 49% yields, respectively (Scheme
3). Obviously, both the hydroxy and ketone groups of
the substituents at the 2- and 3-positions in the thio-
phene ring are necessary for the successful furan ring
formation. It is quite interesting that this formal reduc-
tive cyclization produces furan derivatives and not thio-
phene derivatives.
In conclusion, we achieved the highly efficient and novel
synthesis of kahweofuran and its derivatives by the for-
mal reductive cyclization using the WilkinsonÕs catalyst.
This synthetic method can be used to prepare a wide
variety of substituted kahweofuran derivatives.
Acknowledgements
This work was partially supported by The Japan Food
Chemical Research Foundation.
16. Rei, M.-H. J. Org. Chem. 1979, 44, 2760.