A practical approach to highly functionalized benzodihydrofurans

Article abstract of DOI:10.1016/S0040-4039(00)00159-3

A number of aromatic dibromides have been treated with 2-3 equivalents of n-butyllithium in order to initiate two sequential chemical events, a Parham cyclization and an intermolecular reaction with DMF. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00159-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2269–2273
A practical approach to highly functionalized
benzodihydrofurans†
Michael Plotkin, Sanyou Chen and P. Grant Spoors ∗
Synthetic Chemistry Department, SmithKline Beecham Pharmaceuticals, PO Box 1539, King of Prussia, PA 19406-0939, USA
Received 10 November 1999; revised 17 January 2000; accepted 20 January 2000
Abstract
A number of aromatic dibromides have been treated with 2–3 equivalents of n-butyllithium in order to initiate
two sequential chemical events, a Parham cyclization and an intermolecular reaction with DMF. © 2000 Elsevier
Science Ltd. All rights reserved.
As part of our ongoing endothelin antagonist program,1 we required an efficient practical preparation
of aldehyde 1 (Fig. 1). The route chosen to support development is illustrated in Scheme 12 and employed
a strategy whereby aromatic bromide 3 was subjected to n-butyllithium in THF at −78°C in order to form
the corresponding lithium anion. The resultant organometallic was allowed to react with DMF to furnish
the aldehyde 1 after acid hydrolysis. On scale-up, however, certain deficiencies were discovered within
the route. Principally, selective bromination of benzodihydrofuran 2 was not an easy task because of its
propensity to dibrominate. Moreover, the purity of 3 was compromized further because of the formation
of regioisomers. These isomers, if not removed by recrystallization, and carried through the entire
process, formed impurities structurally similar to our drug which were extremely difficult to remove.
This imposed a tight specification on the purity of bromide 3 and even though this was achieved, it was
at the expense of yield. For the purpose of supporting development, the short term answer was to arrest
the reaction after 70% of 2 had been consumed (HPLC analysis). This gave 3 in 50% isolated yield
(after recrystallization from hexane) devoid of significant impurities. However, endeavors were initiated
to find a new and more reliable method of making aldehyde 1 as well as an efficient route to highly
functionalized benzodihydrofurans in general.
A review of the literature suggested that a chelation controlled deprotonation of 2 with n-butyllithium
would not be selective.3 Furthermore, when standard formylation procedures were examined, such
as the Vilsmeier reaction and its variants, our efforts were challenged by their lack of selectivity
towards the ring.4 Our next strategy was based on the initial observation of the development route
∗
†
Corresponding author.
Dedicated to the memory of Ken Tubman and Lendon Pridgen.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00159-3
tetl 16439

2270
Fig. 1.
Scheme 1.
that dibromination of these systems was a competing reaction pathway. Therefore we explored an
idea whereby a suitably alkylated phenol would be treated with two equivalents of bromine in order
to allow complete dibromination. The dibromide would then be exposed to two or more equivalents
of n-butyllithium in order to trigger two sequential chemical events, a Parham cyclization5 and an
intermolecular reaction with an electrophile (Scheme 2).
Scheme 2.
In order to investigate this concept, p-methoxyphenol (4) was heated in DMF with 2-chloroethyl-
methanesulfonate (5) and K2CO3 to give 6 in an unoptimized yield of 50%. Ether 6 was exposed to two
equivalents of bromine in dichloromethane in the presence of iron granules to furnish dibromide 7 in
81% yield (Scheme 3).
Scheme 3.
Bradsher has examined the selectivity of n-butyllithium towards aromatic dibromides and observed
that a bromine adjacent to a Lewis basic site will react preferentially with 1 equiv. of n-butyllithium after
1 h at −100°C to initiate a Parham cyclization. After cyclization was achieved he also observed that
addition of a second equivalent of n-butyllithium followed by DMF at −100°C furnishes an aldehyde.6

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Besides the fact we had two Lewis basic sites on the aromatic ring to which the alkyl lithium could
coordinate, this low temperature procedure was too impractical for our purposes and so we explored a
modification of this operation at −40°C. To our dismay we discovered that sequential addition of 2 equiv.
of n-butyllithium and DMF to dibromide 3 at −40°C led to a complex mixture which contained only a
small quantity of the desired product. This result was also observed when the reaction was conducted
at −78°C and at −25°C.7 The reaction was improved slightly when dibromide 7 and DMF were
stirred together at −40°C and sec-butyllithium was added last. However, after some experimentation,
we discovered that treating a pre-cooled mixture of n-butyllithium with dibromide 7 (inverse addition) at
−40°C resulted in clean conversion to aldehyde 1 in 75% yield after addition of DMF (Scheme 4).8
Scheme 4.
The scope and utility of this procedure was demonstrated further when applied to a number of readily
available dibrominated phenols. Each phenol was alkylated with 2-chloroethyl-methanesulfonate (5) and
the resultant ether was sequentially exposed to 3 equivalents of n-butyllithium and DMF. The results
from these studies are presented in Table 1.9
In general, this procedure worked extremely well and provided synthetically useful yields of substi-
tuted benzodihydrofurans. More importantly, it provided a practical route to 1 of a purity that could be
used in our supply route without the need of further purification.
Conclusion: This dianion strategy provides ready access to highly functionalized benzodihydrofurans
in a short number of steps. Furthermore, this chemistry can be applied to a range of other electrophiles
some already investigated by us.10 This method will be applied to other heterocycles and the results will
be reported in due course.
Acknowledgements
We are indebted to SB for financial support for M.P. We would also like to thank Lew Kilmer for mass
spectral data, Richard Matsuoka, David Stevenson and Brian Rattigan for helpful discussions.

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Table 1
Reaction of aromatic dibromides with n-BuLi and DMF at −40°C
References
1. (a) Elliot, J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.; Erhard, K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar,
C.; Lee, J. A.; Bean, J. W.; DeBrosse, C. W.; Eggleston, D. S.; Brooks, D. P.; Feuerstein, G.; Ruffolo Jr., R. R.; Weinstock,
J.; Gleason, J. G.; Peishoff, C. E.; Ohlstein, E. H. J. Med. Chem. 1994, 37, 1553–1557. (b) Endothelin Receptors: From the
Gene to the Human; Ruffolo Jr., R. R., Ed.; CRC: Boca Raton, 1995.
2. Hammond, M. L.; Zambias, R. A.; Chang, M. N.; Jensen, N. P.; McDonald, J.; Thompson, K.; Boulton, D. A.; Kopka, I. E.;
Hand, K. M.; Opas, E. E.; Luell, S.; Bach, T.; Davies, P.; MacIntyre, D. E.; Bonney, R. J.; Humes, J. L. J. Med. Chem. 1990,
33, 908–918.
3. (a) Paquette, L. A.; Schulze, M. M.; Bolin, D. G. J. Org. Chem. 1994, 59, 2043–2051. (b) Alabaster, R. J.; Cottrel, I. F.;
Hands, D.; Humphrey, G. R; Kennedy, D. J.; Wright H. B. Synthesis 1989, 8, 598–603.
4. Nichols, D. E.; Hoffman, A. J.; Oberlander, R. A.; Riggs, R. M.; J. Med. Chem. 1986, 29, 302–304; Monte, A. P.; Marona.
D. L.; Parker, M. A.; Wainscott, D. B.; Nelson, D. L.; Nichols, D. E. J. Med. Chem. 1996, 39, 2953–2961.
5. Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem. 1976, 41, 1184–1186.
6. Bradsher, C. K.; Reames, D. C. J. Org. Chem. 1981, 46, 1384–1388.
7. It was observed that when lithiated species 8 was allowed to warm to 0°C (or rt) and then recooled, a mixture of isomeric
aldehydes was obtained after sequential addition of DMF and 1.0 M HCl. This is probably due to scrambling of the aryl
lithium anion on the ring. This could be avoided if the reaction temperature is maintained below −25°C. At this temperature,
the isomerization is suppressed to a level of less than 5%. Therefore the temperature profile of the reaction, prior to DMF
addition, should never exceed −25°C.
8. A precooled solution of the dibromide (1.73g, 4.67 mmol, entry 3) in THF (4 mL) was added dropwise to a precooled
solution of n-BuLi (5.61 mL, 14.0 mmol) in 15 mL of THF at −40°C. Upon completion of the addition, DMF (0.76 mL,
9.82 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to rt. After the starting

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material was consumed the reaction was quenched with 1.0 M HCl (20 mL) and the solvent volume was reduced (in vacuo).
The organics were extracted with TBME (4×20 mL), washed with brine (25 mL), dried (MgSO4), filtered and concentrated
to produce a crude yellow solid, which was purified by chromatography to give the substituted benzaldehyde (0.87g, 91%) as
a white solid: 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 4.72 (t, J=8.7 Hz, 2H), 3.24 (t, J=8.7
Hz, 2H), 1.30 (s, 9H); 13C NMR (100.62 MHz, CDCl3) δ 189.20, 160.37, 143.83, 129.28, 128.61, 123.29, 118.69, 72.81,
34.37, 31.42, 28.83; IR (KBr disc, cm−1) 3100, 2762, 1675, 1460, 888; MS(ESP) 205 (M+H),+ 149 (M+H-(tBu)+H)+.
1
9. Data for entry 2. H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 7.35 (s, 1H), 7.21 (s, 1H), 4.69 (t, J=8.8 Hz, 2H), 3.19 (t,
J=8.8 Hz, 2H), 2.29 (s, 3H); 13C NMR (100.62 MHz, CDCl3) δ 189.00, 160.4, 131.9, 130.0, 129.5, 126.9, 119.1, 72.7, 28.7,
20.5; IR (KBr disc, cm−1) 3428, 2771, 1675, 1613, 871; MS(CI) 163 (M+H)+, 177 (M+CH5)+. Data for entry 4. 1H NMR
(400 MHz, CDCl3) δ 10.15 (s, 1H), 7.35 (s, 1H), 7.24 (ddt, J=8.9, 2.7, 1.3, 1H), 7.14 (ddt, J=7.5, 2.7, 1.3, 1H), 4.75 (t,
J=8.7 Hz, 2H), 3.25 (ddt, J=8.7, 1.3, 1.0 Hz, 2H); 13C NMR (100.62 MHz, CDCl3) δ 187.7, 158.8, 157.1, 131.5, 118.9,
118.9, 111.3 73.1, 22.8; IR (KBr disc, cm−1) 2777, 1680, 1620, 1173 (C-F), 875; MS(CI) 167 (M+H)+. Data for entry 5. 1H
NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 4.76 (t, J=8.7 Hz, 2H), 3.25 (t, J=8.7 Hz, 2H); IR (KBr
disc, cm−1) 2778, 1680, 1591, 1070 (C-Br), 868; 1675, 1613, 871; MS(CI) 227 (M+H)+, 148 (M+H-Br)+. Data for entry 7.
1H NMR (360 MHz, CDCl3) δ 10.03 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 4.67 (t, J=8.7 Hz, 2H), 3.15 (t, J=8.7 Hz, 2H); IR
(KBr disc, cm−1) 1668, 1584, 1434, 1097 (C-I), 870; MS(CI) 275 (M+H)+, 148 (M+H-Br)+. Data for entry 8. 1H NMR (400
MHz, CDCl3) δ 10.08 (s, 1H), 8.28 (d, J=1.6 Hz, 1H), 7.94 (dd, J=8.6, 1.6 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.6
Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 4.82 (t, J=9.0 Hz, 2H), 3.52 (t, J=9.0 Hz, 2H); 13C NMR (100.62 MHz, CDCl3) δ 192.0,
160.7, 135.6, 134.0, 131.6, 131.2, 131.2, 128.1, 123.8, 123.8, 119.5, 72.3, 28.3; MS(CI) 199 (M+H)+, 227 (M+C2H5)+.
10. Unpublished results.