The first nucleophilic aromatic substitution of suitably activated 2-methoxyfurans with Grignard reagents

Article abstract of DOI:10.1016/S0040-4039(03)01430-8

The reaction of 2-methoxyfuroates 1 with Grignard reagents 2 leads to tertiary alcohols or S_NAr products depending on the position of the alkoxycarbonyl group. OMe-Displacement occurs only for 3-substituted derivatives. It takes place even for 3-acetyl-2-methoxyfuran while the presence of a further ester function at 4 position induces the formation of the sole 4-tertiary alcohol. The OMe-substitution has been verified for a wide range of furans and Grignard reagents and low yields have been found only in the reactions with the benzylic and allylic reagents which are delocalized anions. A mechanistic interpretation is given.

Full text of DOI:10.1016/S0040-4039(03)01430-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5781–5784
The first nucleophilic aromatic substitution of suitably activated
2-methoxyfurans with Grignard reagents
M. Rosaria Iesce,* M. Liliana Graziano, Flavio Cermola, Stefania Montella and Lucrezia Di Gioia
Dipartimento di Chimica Organica e Biochimica, Universita` degli Studi di Napoli Federico II, Complesso Universitario Monte S.
Angelo, via Cinthia, I-80126 Napoli, Italy
Received 6 June 2003; accepted 7 June 2003
Abstract—The reaction of 2-methoxyfuroates 1 with Grignard reagents 2 leads to tertiary alcohols or SNAr products depending
on the position of the alkoxycarbonyl group. OMe-Displacement occurs only for 3-substituted derivatives. It takes place even for
3-acetyl-2-methoxyfuran while the presence of a further ester function at 4 position induces the formation of the sole 4-tertiary
alcohol. The OMe-substitution has been verified for a wide range of furans and Grignard reagents and low yields have been found
only in the reactions with the benzylic and allylic reagents which are delocalized anions. A mechanistic interpretation is given.
© 2003 Elsevier Ltd. All rights reserved.
The furans are versatile building blocks in organic
synthesis for the preparation of many compound
types.1 This versatility is due to the double nature of
1,4-diene and of aromatic compound. So, furans
undergo easy [4+2] cycloaddition as well as electrophilic
aromatic substitution, both reactions representing key
steps in the syntheses of products of applicative and
biological interest.1,2 Conversely, the nucleophilic aro-
matic substitution occurs with difficulty even in the
halogen-substituted derivatives.2,3 In the latter cases,
the introduction of powerful electron-withdrawing
groups, as the nitro substituent or the carboxy or
carbalkoxy function, greatly facilitates the reaction.3
Here we report the first nucleophilic substitution by
Grignard reagents of 2-methoxyfurans activated by carb-
alkoxy or carbonyl substituents. The OMe-displace-
ment by Grignard reagents has been reported to occur
in the benzene4 and naphthalene5 derivatives when suit-
ably substituted with nitro,5a ester4a,5b or oxazoline4b,5c
groups.
Scheme 1.8 Unexpectedly, furan 1a gave the OMe-sub-
stituted derivative 3a in addition to little amount of 4a,
deriving from OMe-substitution followed by addition
of the Grignard reagent to the 3-methoxycarbonyl func-
tion. In the other cases the reaction led exclusively to
the tertiary alcohols 59 and 6 and, for 1d, to lactone 8
evidently via the undetected furan 7.
The peculiar behaviour of 3-substituted furan 1a
prompted us to examine the scope of the reaction by
using several combinations of 3-methoxycarbonyl-2-
methoxyfurans (1e–g,6 1h,10 1i10) and Grignard reagents
(2b–f). The reaction was also carried out on 3-acetyl
derivative 1j.6 As shown in Table 1,8 the OMe-displace-
ment prevails definitely over the addition to the alkoxy-
carbonyl group, even to the carbonyl group (entry 7).
However, in the latter case, substitution is followed by
addition to the highly reactive carbonyl function so that
the main product is the furan 4g. The reaction mixtures
are generally clean. As an exception, the reaction of 1a
with the benzyl derivative 2e led to a complex mixture
of products among which the only identified compound
was 3k (20% yield with a purity of 85%). It is notewor-
thy that the allylic reagent 2f gave both the SNAr
product 3l and the tertiary alcohol 9l with a large excess
of the latter (15: 85 molar ratio).
The reaction of 2-methoxyfurans 1a,6 1b,6 1c7 and 1d6
bearing an ester function at 3-, 4-, 5- or at 3- and
4-positions with EtMgBr (2a) was carried out under
classical protocols and the results are reported in
The results can be easily interpreted on the basis of
Meyers’ hypothesis4b assuming that the OMe displace-
ment proceeds via an addition–elimination sequence in
which the metal forms a strong complex with the
Keywords: 2-methoxyfuroates; Grignard reagents; nucleophilic aro-
matic substitution.
* Corresponding author. Tel: +39-81-674334; fax: +39-81-674393;
e-mail: iesce@unina.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01430-8

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M. R. Iesce et al. / Tetrahedron Letters 44 (2003) 5781–5784
Scheme 1. Reaction of furans 1a–d with EtMgBr (2a). The yield in parenthesis refers to isolated product except for 6, which was
unchromatographable.
vicinally carbonyl and methoxy groups as depicted in
Scheme 2. The low yields observed in the reactions with
the benzyl reagent 2e and the allylic 2f should be due to
their nature of delocalized anions which makes difficult
the addition step from A to B.4b
solution of the Grignard reagent (2 or 1.5 mmol) was
added under Ar, and the mixture kept at rt under
stirring. After 4 h the reaction was generally complete
and the usual workup (quenching by HCl 2N, extract-
ing with AcOEt, drying with Na2SO4) followed by silica
gel chromatography gave the reaction product except
for the reaction of furan 1c with EtMgBr (Scheme 1)
and of furan 1a with the allylic reagent 2f (Table 1).
Furans 6 (Scheme 1) and 9l (Table 1) undergo rapid
oxidation (6 also polymerization) by air exposition
and/or by chromatography so that their spectroscopic
data and yields were deduced by the crude mixtures; the
yield of 9l was confirmed by that of keto ester 10 to
which it converts quantitatively by oxidation.11
The presence of an alkoxycarbonyl substituent at C-4
addresses the reaction of the Grignard reagent exclu-
sively to the addition to this group. It is possible
therefore to write the following reactivity order of
Grignard reagents towards 2-methoxyfuroates:
addition to the CO-4 or CO-5>substitution of OMe-2
>addition to CO-3.
Our investigation discloses new aspects of furan reactiv-
ity. It, also, suggests a facile and almost general method
for the preparation of a large number of 3-alkoxycar-
bonyl or carbonyl-substituted furans 3 by merely
choosing the appropriate Grignard reagent and starting
2-methoxyfuran, both easily accessible.
Acknowledgements
Financial support from MIUR (PRIN 2001–2003) is
gratefully acknowledged. NMR Spectra were run at the
Centro di Metodologie Chimico-Fisiche, Universita` di
Napoli Federico II.
In a typical experiment, to the furan (1 mmol) dissolved
in dry diethylether (10 mL) the commercially furnished

M. R. Iesce et al. / Tetrahedron Letters 44 (2003) 5781–5784
Table 1. Reactions of different 3-substituted furans and Grignard reagentsa
5783
Entry
Furan
R1
R2
Grignard reagent
R
Product (yield %)b
1
2
3
4
5
6
7
8
1a
1e
1f
1g
1h
1i
OMe
OMe
OMe
OMe
OMe
OMe
Me
OMe
OMe
OMe
OMe
OMe
Ph
4-MeC6H4
4-BrC6H4
3-MeOC6H4
Cyclohexyl
Et
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2a
2a
2b
2b
2a
2b
2c
2d
2e
2f
Et
Et
Et
Et
Ph
Ph
Et
Ph
3a (68) 4a (5)
3b (80)
3c (48)
3d (57)
3e (65)
3f (35)
3g (20), 4g (40)
3h (47)
1j
1a
1a
1a
1a
1a
9
CH3(CH2)4
CH3CHꢀCH
C6H5CH2
CH2ꢀCH-CH2
3i (40)
10
11
12e
3j (55)c
3k (20)d
3l (12)f, 9l (60)g
a All reactions were performed in diethyl ether as solvent at rt using 1.5 equiv. of 2.
b Isolated yield.
c Mixture of conformational isomers (3:1 molar ratio).
d With a purity of 85% (1H NMR).
e 3l:9l=15:85 molar ratio.
f With a purity of 70% (1H NMR).
g The yield of product 9l, which was unchromatographable due to its easy air oxidation, was deduced by that of its oxidation product 10.
1998, 2, 59; (d) Rassu, G.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Chem. Soc. Rev. 2000, 29, 109–118.
2. Dean, F. M. Adv. Heterocyclic Chem. 1982, 30, 167–238.
3. Paquette L. A. Principles of Modern Heterocyclic Chem-
istry; The Benjamin/Cummings Publishing Company,
Inc., 1968; p. 102.
4. (a) Kojima, T.; Ohishi, T.; Yamamoto, I.; Matsuoka, T.;
Kotsuki, H. Tetrahedron Lett. 2001, 42, 1709–1712; (b)
Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem.
1978, 43, 1372–1379.
5. (a) Hattori, T.; Takeda, A.; Yamabe, O.; Miyano, S.
Tetrahedron 2002, 58, 233–238; (b) Hattori, T.; Hotta, H.;
Suzuki, T.; Miyano, S. Bull. Chem. Soc. Jpn. 1993, 66,
613–622; (c) Meyers, A. I.; Lutomski, K. A. Synthesis
1983, 105–107.
Scheme 2.
6. Scarpati, R.; Iesce, M. R.; Cermola, F.; Guitto, A. Syn-
lett 1998, 17–25.
7. Manly, D. G.; Amstutz, E. D. J. Org. Chem. 1956, 21,
516–519. We prepared it by reaction, at −60°C, of com-
mercial 2-methoxyfuran with n-BuLi followed by treat-
ment with methoxycarbonyl chloride.
References
1. (a) Kozikowski, A. P. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Perga-
mon Press: New York, 1984; Vol. 1, Part 1, p. 413; (b)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819; (c)
Traulsen, T.; Friedrichsen, W. Targets Heterocyclic Syst.
8. All new products gave satisfactory analytical and/or spec-
tral data. 3b: mp 76–78°C; IR (CHCl3) 1712 cm−1 1H
;
NMR (CDCl3) l 1.32 (t, 3 H, J=7.6, CH3), 2.36 (s, 3 H,
Me-Ar), 3.07 (q, 2 H, J=7.6 Hz, CH2), 3.80 (s, 3 H,

5784
M. R. Iesce et al. / Tetrahedron Letters 44 (2003) 5781–5784
OMe), 6.81 (s, 1 H, H-4), 7.19 and 7.53 (2×d, J=8.1 Hz,
(m, 5 H, Ar); 13C NMR (CDCl3) l 7.9, 13.6, 21.3, 34.5,
75.1, 105.8, 123.7, 124.9, 126.6, 128.5, 131.1, 150.5, 152.9;
MS (EI, 70 eV): m/z 230 (M+), 215, 105. Anal. calcd for
C17H22O2: C, 79.03; H, 8.58. Found: C, 79.0; H, 8.6. 4g:
4 H, Ar); 13C NMR (CDCl3) l 12.3, 21.3 (two overlapping
q and t), 51.3, 104.6, 113.9, 123.6, 127.4, 129.3, 137.5, 151.8,
163.3, 164.4. Anal. calcd for C15H16O3: C, 73.75; H, 6.60.
1
1
Found: C, 73.7, H 6.7. 3c: oil; IR (CHCl3) 1713 cm−1; H
oil, IR (CHCl3) 3590 cm−1; H NMR (CDCl3) l 0.91 (t,
NMR (CDCl3) l 1.31 (t, 3 H, J=7.1 Hz, CH3), 3.02 (q,
2 H, J=7.1 Hz, CH2), 3.85 (s, 3 H, OMe), 6.90 (s, 1 H,
H-4), 7.50 (br s, 4 H, Ar); 13C NMR (CDCl3) l 12.3, 21.3,
51.4, 106.0, 114.0, 121.4, 125.2, 130.4, 131.8, 150.6, 163.0,
164.2. Anal calcd for C14H13BrO3: C, 54.39; H, 4.24, Br,
3 H, J=7.1 Hz, CH3), 1.30 (t, 3 H, J=7.1 Hz, CH3), 1.54
(s, 3 H, CH3), 1.80 (q, 2 H, J=7.1 Hz, CH2), 2.80 (q, 2
H, J=7.1 Hz, CH2), 6.48 (s, 1 H, H-4), 7.20–7.60 (m, 5 H,
Ar); 13C NMR (CDCl3) l 8.5, 13.5, 21.8, 29.2, 36.3, 72.2,
105.2, 122.1, 123.7, 126.7, 128.6, 131.1, 150.4, 152.3. Anal.
calcd for C16H20O2: C, 78.65; H, 8.25. Found: C, 78.7; H,
8.2. 6 (with a purity of 85%, 1H NMR): 1H NMR (CDCl3)
l 0.76 (t, 6 H, J=7.1 Hz, 2×CH3), 1.70 (m, 4 H, 2×CH2),
3.74 (s, 3 H, OMe), 4.70 (brs, 1 H, OH), 4.98 and 5.98 (2×d,
2 H, J=3.7 Hz, H-3 and H-4); 13C NMR (CDCl3) l 7.8,
31.2, 57.7, 74.2, 83.2, 106.3, 148.1, 160.5. 8: mp 80–82°C;
IR (CHCl3) 1745 and 1623 cm−1; 1H NMR (CDCl3): l 0.90
(t, 6 H, J=7.1 Hz, 2×CH3), 2.1 (m, 4 H, 2×CH2), 4.36 (s,
3 H, OMe), 7.20–7.45 (m, 5 H, Ar); 13C NMR (CDCl3) l
7.9, 31.3, 60.7, 89.4, 95.2, 123.6, 127.1, 128.8, 129.0, 130.4,
134.0, 156.0, 163.4. Anal. calcd for C17H18O4: C, 71.31; H,
6.34. Found: C, 71.2; H, 6.4. 9l: 1H NMR (CDCl3) l 2.47
and 2.63 (2×m, 4 H, 2×CH2), 4.01 (s, 3 H, OMe), 5.13 (m,
4 H, 2×CH2ꢀ)*, 5.80 (m, 2 H, 2×CHꢀ), 6.53 (s, 1 H, CH),
7.20–7.60* (m, Ar) [*overlapping with signals of the other
products (3l and polymeric material)]. 10: oil; IR (CHCl3)
3601, 1718 and 1669 cm−1; 1H NMR (CDCl3): l 2.37 (brs,
1 H, OH), 2.43 and 2.70 (2 dd, J=13.0, 7.7, 6.1 Hz, 4 H,
2×CH2), 3.72 (s, 3 H, OMe), 5.21 (m, 4 H, 2×CH2ꢀ), 5.90
(m, 1 H, CH), 7.10 (s, 1 H, H-3), 7.45–7.95 (m, 5 H, Ar);
13C NMR (CDCl3): l 44.0, 52.3, 74.9, 120.2, 126.5, 128.3,
128.6, 132.5, 133.3, 137.0, 151.5, 168.4, 190.0. Anal. calcd
for C18H20O4: C, 71.98; H, 6.71. Found: C, 71.9; H, 6.8.
Furans 3a (Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini,
F. Synlett 1994, 373–374), 3h (Miyashita, A.; Matsuoka,
Y.; Numata, A.; Higashino, T. Chem. Pharm. Bull. 1996,
44, 448–450) and 59 were known compounds.
25.85. Found: C, 54.2; H, 4.3. 3d: oil; IR (CHCl3) 1710 cm−1
;
1H NMR (CDCl3) l 1.30 (t, 3 H, J=7.1 Hz, CH3), 3.15
(q, 2 H J=7.1 Hz, CH2), 3.80 (s, 6 H, 2×OMe), 6.87 (s,
1 H, H-4), 6.80–7.35 (m, 4 H, Ar); 13C NMR (CDCl3) l
12.3, 21.3, 51.4, 55.3, 105.7, 109.1, 113.3, 114.0, 116.2, 129.8,
131.3, 151.8, 159.8, 163.6, 164.3. Anal. calcd for C15H16O4:
C, 69.22; H, 6.20. Found: 69.1, H 6.2. 3e: oil; IR (CHCl3)
1703 cm−1; 1H NMR (CDCl3) l 1.5–2.0 (m, 10 H, C5H10),
2.65 (m, 1 H, CH), 3.83 (s, 3 H, OMe), 6.43 (s, 1 H, H-4),
7.35–8.00 (m, 5 H, Ar); 13C NMR (CDCl3) l 25.7, 25.9,
31.2, 36.9, 51.4, 106.0, 113.8, 127.1, 126.0, 128.7, 141.2,
155.6, 159.8, 164.4. Anal. calcd for C18H20O3: C, 76.03; H,
7.09. Found: C, 75.9; H, 7.1. 3f: oil; IR (CHCl3) 1700 cm−1
;
1H NMR (CDCl3) l 1.30 (t, 3 H, J=7.6 Hz, CH3), 2.71
(q, 2 H, J=7.6 Hz, CH2), 3.82 (s, 3 H, OMe), 6.43 (s, 1
H, H-4), 7.35–8.00 (m, 5 H, Ar); 13C NMR (CDCl3) l 11.8,
21.3, 51.4, 107.1, 113.9, 128.0, 128.9 (two overlapping d),
130.0, 155.9, 156.7, 164.3. Anal. calcd for C14H14O3: C,
73.02; H, 6.13. Found: C, 72.9; H, 6.2. 3g: oil; IR (CHCl3)
1
1673 cm−1; H NMR (CDCl3) l 1.34 (t, 3 H, J=7.1 Hz,
CH3,), 2.48 (s, 3 H, COCH3), 3.11 (q, 2 H, J=7.1 Hz, CH2),
6.87(s, 1H, H-4), 7.20–7.70(m, 5H, Ar); 13CNMR(CDCl3)
l 12.0, 21.8, 29.2, 105.2, 109.6, 123.7, 127.7, 128.6, 130.0,
151.6, 162.9, 187.0. Anal. calcd for C14H14O2: C, 78.48; H,
6.59. Found: C 78.3; H 6.6. 3i: oil; IR (CHCl3) 1709 cm−1
;
1H NMR (CDCl3): l 0.90–1.80 (m, 9 H, C4H9), 3.05 (t, 2
H, J=7.7 Hz, CH2-2), 3.85 (s, 3 H, OMe), 6.89 (s, 1 H,
H-4), 7.30–7.60 (m, 5 H, Ar); 13C NMR (CDCl3): l 13.5,
21.9, 27.2, 27.3, 30.9, 50.8, 104.9, 114.2, 123.2, 127.2, 128.3,
129.7, 151.3, 162.5, 163.9. Anal. calcd for C17H20O3: C,
74.97; H, 7.40. Found: C, 74.9; H 7.4. 3j as a 3:1 mixture
9. Formation of tertiary alcohols with Grignard reagents has
been described previously for 1b and other 4-methoxycar-
bonyl or 4-acetyl-2-methoxyfurans. See: Iesce, M. R.;
Cermola, F.; De Lorenzo, F.; Orabona, I.; Graziano, M.
L. J. Org. Chem. 2001, 66, 4732–4735.
1
of isomers (*refers to minor isomer): H NMR (CDCl3):
1.98* (dd, 3 H, J=7.4, 1.2 Hz, CH3), 2.25 (dd, 3 H, J=7.4,
1.2 Hz, CH3), 3.87 (s, 6 H, 2×OMe), 6.03 (dq, 1 H, J=14.8,
7.4 Hz, CHꢀ), 6.61* (dq, 1 H, J=14.8, 7.4 Hz, CHꢀ), 6.92*
(s, 1 H, H-4), 6.99 (s, 1 H, H-4), 7.30–7.70 (m, 12 H,
2Ar+2CHꢀ); 13C NMR: l 29.7, 30.3*, 51.6, 106.1, 106.2*,
115.9, 116.9, 119.1*, 123.8, 123.9, 127.9, 128.0, 128.7, 128.8,
130.0, 131.2, 152.0, 152.3, 156.2, 157.0, 165.8. Anal. calcd
for C15H14O3: C, 74.36; H, 5.83. Found: C, 74.2; H 5.9. 3k
(with a purity of 85%, 1H NMR): 1H NMR (CDCl3) l 3.88
(s, 3 H, OMe), 4.42 (s, 2 H, CH2), 6.91 (s, 1 H, H-4),
7.20–7.60 (m, 10 H, 2×Ar); 13C NMR (CDCl3) l 48.7, 51.4,
105.4, 115.3, 123.7, 126.6, 127.0, 128.0, 128.5, 128.6, 136.3,
137.4, 152.4, 159.8, 164.2; MS (EI, 70 eV) for C19H16O3:
m/z 292 (M+), 277, 260. 3l (with a purity of 70%, 1H NMR):
1H NMR (CDCl3) l 2.80 (m, 2 H, CH2), 3.96 (s, 3 H, OMe),
5.20 (m, 2 H, ꢀCH2), 5.45 (m, 1 H, ꢀCH), 7.02 (s, 1 H, H-4),
7.20–7.60 (m, 5 H, Ar). MS (EI, 70 eV) for C15H14O3: m/z
10. The new furans 1h and 1i were prepared by a previous
procedure6 by heating a mixture of the corresponding
2-alkyl-4-methyl-5-methoxyoxazoles and methyl propio-
late at 80°C. 1h: oil; IR (CHCl3) 1715 cm−1 1H NMR
;
(CDCl3) l 1.5–2.0 (m, 10 H, 5 CH2), 2.43 (m, 1 H,
cyclohexyl-H), 3.74 (s, 3 H, OMe), 4.04 (s, 3 H, OMe), 6.10
(s, 1 H, H-4); 13C NMR (CDCl3) l 25.5, 25.9, 30.8, 36.5,
50.1, 57.9, 90.9, 103.9, 150.3, 160.8, 163.6. Anal. calcd for
C13H18O4: C, 65.53; H, 7.61. Found: C 65.6, H 7.6. 1i: oil;
1
IR (CHCl3) 1713 cm−1; H NMR (CDCl3) l 1.17 (t, 3 H,
J=7.1 Hz, CH3), 2.54 (q, 2 H, J=7.1 Hz, CH2), 3.76 (s,
3 H, OMe), 4.05 (s, 3 H, OMe), 6.15 (s, 1 H, H-4); 13C NMR
(CDCl3) l 11.5, 20.8, 51.0, 57.9, 91.2, 105.1, 147.3, 161.0,
163.6. Anal. calcd for C9H12O4: C, 58.69; H, 6.57. Found:
C, 58.5; H, 6.5.
11. Sensitivity to chromatographic procedures and/or to air
oxidation has been reported for other 2-alkoxyfurans, and
has been found to be enhanced by the presence of electron-
donating substituents on the furan nucleus. See: Wulff, W.
D.; Gilbertson, S. R.; Springer, J. P. J. Am. Chem. Soc. 1986,
108, 520–522.
1
232 (M+), 217. 4a: oil; IR (CHCl3) 3591 cm−1; H NMR
(CDCl3) l 0.89 (t, 6 H, J=7.7 Hz, 2×Me), 1.32 (t, 3 H,
J=7.7 Hz, CH3), 1.65 (brs, 1 H, OH), 1.78 (m, 4 H, 2×CH2)
2.89 (q, 2 H, J=7.7 Hz, CH2-2), 6.42 (s, 1 H, H-4), 7.25–7.70