Synthesis of 6-substituted 5-cyano-7-hydroxy-2-carboxybenzofurans

Article abstract of DOI:10.1016/j.tetlet.2010.07.020

Methods for the synthesis of 5-cyano-7-hydroxy-2-carboxybenzofurans bearing a variety of substituents at the 6-position are outlined. The scope and limitations of lithiation processes, electrophilic substitutions, and pericyclic reactions are investigated.

Full text of DOI:10.1016/j.tetlet.2010.07.020

Tetrahedron Letters 51 (2010) 4720–4722
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Tetrahedron Letters
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Synthesis of 6-substituted 5-cyano-7-hydroxy-2-carboxybenzofurans
*
Simon J. Teague , Simon Barber
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Methods for the synthesis of 5-cyano-7-hydroxy-2-carboxybenzofurans bearing a variety of substituents
at the 6-position are outlined. The scope and limitations of lithiation processes, electrophilic substitu-
tions, and pericyclic reactions are investigated.
Received 28 April 2010
Revised 7 June 2010
Accepted 2 July 2010
Available online 8 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Antagonists of the CXCR2 receptor have a number of potential
therapeutic applications.1 Typically they consist of a phenol con-
nected through a urea to a second aromatic ring.2 Our in-house
program toward antagonists of this receptor used a benzofuran
to fix the required groups correctly in space. The synthesis of such
heavily substituted benzofurans required the development of a
number of novel synthetic transformations which are outlined in
this Letter.
and quenched at the 3-position (17% yield plus starting material)
using in situ TMSCl, with excess LiTMP as base and allowing the
reaction mixture to warm from À78 °C to 0 °C.
The ester moiety was reduced and protected to give 2. Disap-
pointingly, lithiation and quenching with methyl chloroformate
gave a 3:1 mixture of the 4- and 6-methyl esters 3 and 4. The
hoped-for directing effect of the methoxy may be offset by in-
creased steric crowding in this heavily substituted system.
Analogous lithiation applied to the monocyclic system 55
(Scheme 2) cleanly gave the desired lithiation regiochemistry and
was quenched with dimethyl disulfide. Demethylation with thio-
late gave a difficult to separate mixture of monophenols 7 and 8.
The activating effect of the para-cyano function appears to be
counterbalanced by the known tendency of 1,2,3-substituted sys-
tems to dealkylate regiospecifically at the 2-position.6 The use of
other reagents such as Me3SiI gave the undesired isomer 7,
regioselectively.
X
R
Cl
HN
X
O
N
N
H
N
H
S
O O
N
H
N
H
F
OH
OH
Cl
Antagonist requirements
O
SB656933 (GSK)
O
O
NC
R
N
N
N
H
OH
O
N
H
O
H
Lithiation and quenching of the silyl-protected ether
9
OH
O
(Scheme 3) gave the required phenol upon deprotection. Duff
formylation gave the aldehyde 11, annulation with methyl bromo-
acetate and oxidation gave the sulfoxide 12. Pummerer rearrange-
ment of this sulfoxide followed by oxidation to the sulfonyl
chloride, using chlorine gas in acetic acid gave the sulfonyl chloride
13. The reaction with Boc-piperidine gave the sulfonamide 14, pos-
SCH52713 (Schering-Plough)
AstraZeneca antagonists
Initially, lithiation at the 6-position of 5-cyano-7-meth-
oxybenzofuran3 1 (Scheme 1) was investigated. Cyano groups are
powerfully ortho-directing, though this property is synthetically
under utilized. Lithiation dominates over addition to the nitrile
when hindered, non-nucleophilic bases are used.4 It was antici-
pated that the complexation/chelation of the lithium species by
the 7-methoxy group would assist in regiochemical control. The
lithiation of 1 failed due to a combination of its insolubility in
THF and/or ether at À78 °C and the presence of a moderately reac-
tive 2-furyl ester. These problems were not overcome by using
alternative bases such as LiTMPÁLiCl or its derivatives. The more
soluble and sterically encumbered t-Bu ester underwent lithiation
sessing
a substitution pattern analogous to that found in
SB656933. The ester was hydrolysed, coupled with aniline, the
methoxy group was converted to the phenol, and the Boc-group
was removed to give the required compound 16.
The sulfonamide could be installed early in the synthesis
(Scheme 4) by quenching the anion with sulfur dioxide and con-
verting the intermediate sulfinic acid salt into the benzotriazole
sulfonamide 18.7 This was converted into stable sulfonamides.
However, all attempts at electrophilic formylation of phenol 19,
which possesses two powerful electron-withdrawing groups, re-
sulted in decomposition.
Frustration at our inability to functionalize directly the 6-posi-
tion in these benzofurans led us to investigate further reactivity
in this system (Scheme 5). The profound deactivation exerted by
* Corresponding author.
E-mail address: simon.teague@astrazeneca.com (S.J. Teague).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.020

S. J. Teague, S. Barber / Tetrahedron Letters 51 (2010) 4720–4722
4721
O
OMe
NC
NC
NC
MeO
Br
O
O
b, c
a
d
NC
+
O
OMe
O
OSiMe2tBu
O
OSiMe2tBu
O
OMe
O
OSiMe2tBu
OMe
OMe
OMe
OMe
O
OMe
1
2
4
3
Scheme 1. Reagents and conditions: (a) Zn(CN)2, (Ph3P)4Pd, N2, DMF, 85 °C, 70%; (b) LiBH4, THF, 60 °C, 99%; (c) ClSiMe2tBu, DMF, imidazole, 25 °C, 95%; (d) LiTMP, THF, À78 °C
then ClCO2Me, 36%.
NC
NC
b
NC
a
NC
+
OMe
OMe
MeS
OMe
OMe
OMe
MeS
MeS
OH
OMe
OH
7
8
6
5
Scheme 2. Reagents and conditions: (a) LiTMP, THF, À78 °C then MeSSMe, 49%; (b) NaSMe, DMF, 50 °C, 74%, 7: 8 = 2:1.
NC
NC
NC
c
NC
a, b
O
NC
f
O
d, e
O
Cl
O
OMe
O
OMe
OSiMe2tBu
MeS
OH
OMe
MeS
OH
OMe
S
O
S
OMe
OMe
O O
OMe
13
10
9
11
12
NC
O
NC
O
NC
O
h, i
j, k
g
O
O
O
O
NHPh
O
OMe
OMe
S
S
O
NHPh
S
N O
N O
OMe
N O
OH
16
N
N
N
H
Boc
15
Boc
14
Scheme 3. Reagents and conditions: (a) LiTMP, THF, À78 °C then MeSSMe, 82%; (b) TBAF, THF, 100%; (c) HMTA, TFA, 80 °C, 80%; (d) BrCH2CO2Me, K2CO3, DMF, rt then 100 °C,
70%; (e) mCPBA, CH2Cl2, rt, 95%; (f) TFAA then Cl2, AcOH, 50 °C, 80%; (g) Boc-piperazine, neat, 90%; (h) LiOH, THF, H2O, 90%; (i) PhNH2, TBTU, DMF, Hünig’s base, 70%; (j) LiI,
collidine, 120 °C, 70%; (k) TFA neat, rt, 100%.
NC
NC
a
b, c
NC
NC
O
S
N
N
O
S
N
O
S
OLi OMe
OSiMe2tBu
OMe
OH
OMe
OSiMe2tBu
OSiMe2tBu
17
O
O
OMe
N
N
18
19
Scheme 4. Reagents and conditions: (a) LiTMP, THF, À78 °C then SO2 at À78 °C followed by BtCl and warming to 25 °C, 24%; (b) NMe-piperazine, 100%; (c) TBAF, THF, 100%.
Br
a
NC
Br
O
NC
NC
O
NC
O
+
O
OtBu
O
OtBu
O
OtBu
OMe
OMe
20
OMe
21
22
Br
b
NC
Br
O
NC
Br
O
O
+
O
OtBu
O
O
OtBu
OtBu
OH
OH
23
OH
25
24
Scheme 5. Reagents and conditions: (a) 3 equiv Br2, NaOAc, AcOH, 80 °C, 8 h; (b) Br2, t-BuNH2, toluene, CH2Cl2, À78 °C, 69% yield for isomer 25.
the 5-cyano group can easily be underestimated. Forcing condi-
tions and prolonged reaction times are required for mono-bromin-
ation of the anisole 20 even with excess bromine. The reaction is
selective for the unwanted 4-bromo isomer over the 6-isomer,
ratio 3:1. The reactivity of the system can be greatly increased by
demethylation to the phenol 23. Conventional bromination
conditions (Br2, NaOAc, HOAc, 25 °C) gave mixtures of the starting
materials together with 6- and 4,6-dibrominated materials. Regio-
selective ortho, mono-substitution in phenols has been extensively
investigated.8 These conditions eventually allowed the production
of the required regioisomer 25, in a good yield. Attempts to intro-
duce a variety of other electrophilic substitutions on phenol 23
using reagents such as MeSSMe/AlCl3, ClSO3H, and HMTA/TFA un-
der a variety of conditions failed.
Remarkably the exceptions to this rule were Mannich processes
and hydroxymethylation using paraformaldehyde with a dialkyl

4722
S. J. Teague, S. Barber / Tetrahedron Letters 51 (2010) 4720–4722
a
Despite considerable synthetic challenges, we were eventually
NC
O
NC
O
N
able to introduce a variety of functional groups into the 6-position
of 5-cyano-7-hydroxybenzofurans. These were used to modulate
the biological and physical properties of these therapeutically
interesting molecules.
N
O
OtBu
O
OtBu
OH
OH
27
26
b
NC
O
NC
O
Supplementary data
O
OMe
O
OMe
OH OH
OH
29
28
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.020.
Scheme 6. Reagents and conditions: (a) paraformaldehyde, LiCl, NMP, NMe-
piperazine, 50 °C, 43%; (b) Et2AlCl, paraformaldehyde, DCE, 25 °C, 24 h, 92%.
References and notes
1. Chapman, R. W.; Phillips, J. E.; Hipkin, R. W.; Curran, A. K.; Lundell, D.; Fine, J. S.
Pharmacol. Ther. 2009, 121, 55–68.
a
NC
O
NC
O
2. Busch-Petersen, J.; Wang, Y. Expert Opin. Ther. Patents 2008, 18, 629–637.
O
OAllyl
O
OAllyl
3. The CuCN (Rosenmund-von Braun) displacement was due to
a highly
O
OH
capriciously producing product, demethylation product, and acyl cyanide in
various proportions. The zinc cyanide/Pd(0) reaction is highly oxygen sensitive
and requires >30 min N2 sparging and careful maintenance of the inert
atmosphere.
31
30
Scheme 7. Reagents and conditions: (a) xylene reflux, 40 h, 100%.
4. Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276–9287; Lysen, M.;
Hansen, H. M.; Begtrup, M.; Kristensen, J. L. J. Org. Chem. 2006, 71, 2518–2520.
5. Brasholz, M.; Luan, X.; Reissig, H.-U. Synthesis 2005, 3571–3579.
6. The closest analog in the literature, 2,3,4-trimethoxybenzaldehyde is cleaved in
the order o > p > m so the mesomeric effect dominates in this case, see: Hansson,
C.; Wickberg, B. Synthesis 1975, 191.
7. Katritzky, A. R.; Rodriguez-Garcia, V.; Nair, S. K. J. Org. Chem. 2004, 69, 1849–
1852.
8. Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967, 32, 2358–2360.
9. Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S. J. J.
Am. Chem. Soc. 2005, 127, 4596–4598.
aluminum Lewis acid catalyst9 (Scheme 6). The latter may be dri-
ven by precipitation of the intermediate aluminate complex. The
steric crowding present in this system is demonstrated by the fac-
ile loss of the 6-substituent when these products are isolated by
concentration from formic- or TFA-containing, reverse phase chro-
matography fractions, if these had not first been neutralized. Final-
ly the 6-position could be allylated cleanly using the Claisen
rearrangement (Scheme 7).