A novel approach to the synthesis of 4-aryl-furan-3-ols

Article abstract of DOI:10.1016/S0040-4039(01)01284-9

A novel, yet simple, method for the synthesis of 4-aryl-furan-3-ols is described. The condensation between dimethyl diglycolate 1 and various aryl glyoxylates 2 using KOt-Bu as base furnished a series of 4-aryl-furan-3-ols 4 bearing one tert-butyl ester and one methyl ester substituent. Such a mixed ester allowed easy differentiation of the two esters for selective chemical modification. In addition, these 4-aryl-furan-3-ols could be further transformed to other useful substituted furans through conversion to the triflates and subsequent metal-mediated reduction or coupling.

Full text of DOI:10.1016/S0040-4039(01)01284-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6429–6431
A novel approach to the synthesis of 4-aryl-furan-3-ols
Bruno Tse* and A. Brian Jones
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000 (RY800-C107), Rahway, NJ 07065, USA
Received 21 June 2001; accepted 13 July 2001
Abstract—A novel, yet simple, method for the synthesis of 4-aryl-furan-3-ols is described. The condensation between dimethyl
diglycolate 1 and various aryl glyoxylates 2 using KOt-Bu as base furnished a series of 4-aryl-furan-3-ols 4 bearing one tert-butyl
ester and one methyl ester substituent. Such a mixed ester allowed easy differentiation of the two esters for selective chemical
modification. In addition, these 4-aryl-furan-3-ols could be further transformed to other useful substituted furans through
conversion to the triflates and subsequent metal-mediated reduction or coupling. © 2001 Elsevier Science Ltd. All rights reserved.
Furan moieties exist in numerous natural products,
such as the kallolides1 and the cembranolides,2 as well
as many pharmaceutical products.3 Recently, we were
interested in developing a general method to synthesize
furan-3-ols with various aryl groups substituted at the
4-position. We anticipated that the condensation of
dimethyl diglycolate4 1 with various aryl glyoxylates 2
under basic conditions would be a viable method to
furnish such 4-aryl-furan-3-ols, especially because many
aryl glyoxylates either are commercially available or
can be easily prepared.5 Indeed, when methyl phenyl-
glyoxylate was used with NaOMe as the base (condi-
tion a in Scheme 1), the dimethyl ester 3 (ArꢀPh) was
obtained in 81% yield. An interesting variation of this
reaction was discovered when KOt-Bu was used in a
mixture of toluene6 and t-BuOH (condition b). Instead
of the dimethyl ester 3, a mixed ester 4, bearing one
methyl ester and one tert-butyl ester, was obtained in
72% yield.7 The formation of the mixed ester 4 allowed
for easy differentiation of the two esters for selective
chemical modification. For example, the tert-butyl ester
was expected to be more susceptible to acid hydrolysis
whereas the methyl ester should undergo nucleophilic
attack more readily. In this publication, we would like
to report the application of this novel approach to the
synthesis of 4-aryl-furan-3-ols.
O
O
O
OX
Ar
O
+
MeO
OMe
O
1
2 (X = Me or Et)
O
O
1
O
a or b
RO
OMe
2
5
Ar
OH
3: R = Me (from condition a)
4: R = t-Bu (from condition b)
Scheme 1. Reagents and conditions: (a) NaOMe, MeOH, 70°C, generating 3. (b) KOt-Bu, t-BuOH–toluene (2:1), 70°C, generating
4.
Keywords: furan; 4-aryl-furan-3-ol; mixed-ester; diglycolate; glyoxylate.
* Corresponding author. Fax: (732)-594-9556; e-mail: bruno tse@merck.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01284-9

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B. Tse, A. B. Jones / Tetrahedron Letters 42 (2001) 6429–6431
methyl ester at the 2-position of the furan was reso-
nance-stabilized by the anion of the furan-3-ol, making
this methyl ester resistant to exchange with tert-butox-
ide ion. The methyl ester at the 5-position, however, did
not have such stabilization and was therefore more
reactive. Consequently, only the methyl ester at the
5-position reacted with the excess tert-butoxide ion to
afford 4. The structure of 4 was supported by the NOE
observed between the protons of the tert-butyl group
and those of the phenyl group.
When dimethyl ester 3 obtained from the NaOMe
reaction (condition a) was treated with KOt-Bu (condi-
tion b), 4 was obtained in 79% yield. This result indi-
cated that, under condition b, 3 was likely to be an
intermediate involved during the reaction between 1
and 2 to yield 4. It is noteworthy that only one tert-
butyl ester was formed, even when KOt-Bu was used in
large excess. Under the basic reaction condition b, the
Table 1. Yields of the reaction in Scheme 1 with various
Ar groups
This condensation reaction has also been shown to
work for glyoxylates bearing phenyl groups with vari-
ous substituents and heteroaromatic groups, as shown
in Table 1. The yields were consistently around 60–
70%. Even for a bulky aryl group such as the 2,4,6-
trimethylphenyl group, a yield of 63% was obtained.
This method is therefore useful for the synthesis of
furan-3-ols with various aryl substituents at the 4-
position.
This approach to the synthesis of furan-3-ols can be
further extended to the synthesis of tri-substituted and
tetra-substituted furans. The furan-3-ols can be readily
converted to their corresponding triflates, which in turn
can be converted to H or alkyl groups, via metal-
assisted reduction or coupling, to furnish tri-substituted
and tetra-substituted furans respectively. Such an appli-
cation is demonstrated in the synthesis of carboxylic
acid 9, a key intermediate in the synthesis of the
furo[2,3-c]-isoquinoline alkaloids.8 With the current
discovery, 9 can now be efficiently synthesized from 4
in a five-step sequence and the overall yield is much
higher than that of the method previously reported.8
The furan-3-ol 4 was first converted to its triflate 5
(93%). Upon treatment with Pd(PPh3)2Cl2, NEt3 and
HCOOH in DMF at 80°C, 5 was reduced to the
tri-substituted furan 6 (90%).9 The methyl ester was
expected to be more susceptible to nucleophilic attack
than the tert-butyl ester. Indeed, treatment with super-
hydride in THF selectively reduced the methyl ester to
its corresponding primary alcohol 7 (93%). Alcohol 7
was further reduced to 8 under hydrogenolysis condi-
tions (98%). Finally, acid hydrolysis of the tert-butyl
ester furnished the acid 9 (95%) (Scheme 2).10
In summary, a novel synthesis of 4-aryl-furan-3-ols has
been developed.11 From dimethyl diglycolate which has
two identical methyl esters, a mixed ester furan product
with one tert-butyl ester and one methyl ester was
formed, allowing easy differentiation of these two
esters. This method not only offers a general approach
to the synthesis of furan-3-ols, but can also be extended
to the synthesis of other substituted furans via the
triflates of these furan-3-ols.
Acknowledgements
We thank Ms. Debbie Zink for providing the mass
spectral data.

B. Tse, A. B. Jones / Tetrahedron Letters 42 (2001) 6429–6431
6431
O
O
O
O
O
O
a, b
t-BuO
t-BuO
OMe
OMe
Ph
R1
Ph
OH
5: R1 = OTf
6: R1 = H
4, Ar = Ph
O
O
O
t-BuO
e
O
R2
c, d
HO
Ph
H
Ph
H
7: R2 = OH
8: R2 = H
9
Scheme 2. Reagents and conditions: (a) Tf2O, i-Pr2NEt, CH2Cl2, −78°C. (b) Pd(PPh3)2Cl2, NEt3, HCOOH, DMF, 80°C. (c)
LiHBEt3, THF, rt. (d) H2 (balloon), Pd(OH)2, MeOH, rt. (e) HCOOH, rt.
References
9. Chen, Q.; He, Y.; Yang, Z. J. Chem. Soc., Chem. Com-
mun. 1986, 1452.
1
1. Look, S. A.; Burch, M. T.; Fenical, W.; Qi-tai, Z.;
Clardy, J. J. Org. Chem. 1985, 50, 5741.
2. Fenical, W.; Okeeda, R. K.; Basnadurraga, M. M.; Cul-
ver, P.; Jacobs, R. S. Science 1981, 212, 1512.
3. For a list of methods to synthesize furans, see: Wipf, P.;
Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63,
7132 and references cited therein.
4. Dimethyl diglycolate 1 was prepared from diglycolyl
chloride, MeOH and NEt3 in CH2Cl2 in 95% yield.
5. For example, see: Rossi, R.; Carpita, A.; Pazzi, P.; Man-
nina, L.; Valensin, D. Tetrahedron 1999, 55, 11343.
6. As tert-butanol has a relatively low melting point (25°C),
toluene was used as a co-solvent to ensure homogeneity
of the reaction mixture, especially during the additions of
reagents.
7. The dimethyl ester 3 existed as a minor product in 5%.
8. A discussion of the syntheses and biological activities of
furo[2,3-c]isoquinolines and furo[2,3-b]quinoline alka-
loids can be found in: Ito, K.; Yakushijin, K.; Yoshina,
S. J. Heterocyclic Chem. 1978, 15, 301 and references
cited therein.
10. Data for 9: H NMR (CD3OD) l 2.39 (3H, s), 6.36 (1H,
s), 7.33–7.58 (5H, m); 13C NMR (CD3OD) l 12.4, 111.0,
115.3, 127.7, 127.8, 129.2, 132.6, 136.3, 136.7, 156.1. IR
3018, 1674, 1541, 1494. HRMS calcd for C12H10O3
202.0630, found 202.0635.
11. A typical procedure to prepare 4 is as follows: to a
solution of 1 (1.0 g, 6.2 mmol) in toluene (20 mL) and
tert-butanol (40 mL) was added methyl phenylglyoxylate
2 (ArꢀPh) (1.05 mL, 7.4 mmol) followed by KOt-Bu
(24.7 mL of a 1 M solution in t-BuOH, 24.7 mmol) at
room temperature. The mixture was stirred at 70°C for 2
hours. After acidification with cold 0.1N HCl and
aqueous work-up (EtOAc), the mixture was subjected to
chromatography to yield 1.41 g of 4 with ArꢀPh (72%)
and 85 mg of 3 (5%). 4: 1H NMR (CD3OD) l 1.36 (s,
9H), 3.92 (3H, s), 7.38–7.42 (5H, m); 13C NMR (CD3OD)
l 27.0, 51.0, 82.9, 123.6, 125.8, 127.7, 128.1, 129.2, 130.2,
141.3, 151.4, 158.0, 160.1. IR 3372, 1720, 1675, 1621,
1550, 1500. HRMS calcd for C17H18O6 318.1103, found
318.1107.