Facile functionalization at the C2 position of a highly substituted benzofuran

Article abstract of DOI:10.1016/j.tetlet.2014.02.051

To expedite an SAR study of the C2 position of a highly substituted benzofuran ring system, we developed a method for the preparation of a key precursor, iodide 10. From iodide 10, a diverse set of compounds with different substituents at the C2 position were prepared efficiently.

Full text of DOI:10.1016/j.tetlet.2014.02.051

Tetrahedron Letters 55 (2014) 2212–2216
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile functionalization at the C2 position of a highly substituted
benzofuran
Shuwen He a, , , Peng Li b, , Xing Dai a, Casey C. McComas c, Chunyan Du b, Ping Wang b, Zhong Lai a,
⇑
Hong Liu a, Jingjun Yin d, Paul G. Bulger d, Qun Dang a, Dong Xiao a, Nicolas Zorn a, Xuanjia Peng b,
Ravi P. Nargund a, Anandan Palani a
a Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
b WuXi Apptec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China
c Discovery Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
d Discovery Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
To expedite an SAR study of the C2 position of a highly substituted benzofuran ring system, we developed
a method for the preparation of a key precursor, iodide 10. From iodide 10, a diverse set of compounds
with different substituents at the C2 position were prepared efficiently.
Received 25 January 2014
Revised 9 February 2014
Accepted 16 February 2014
Available online 24 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuran
Substituted 2-iodobenzofuran
Substituted benzofuran-2-ylboronic acid
Suzuki coupling
The benzofuran motif appears in the structures of many biolog-
ically active natural products and pharmaceutical agents.1 To ex-
plore structure activity relationships (SAR) during a medicinal
chemistry program, we needed to access 5-bromo-N-methyl-6-
series of compounds with different R-groups at the C2 position
(Fig. 1) since this route required installing the C2 group (e.g., 4-flu-
oro-phenyl for 1a) at the beginning of the synthetic sequence. It
was desirable to obtain a common precursor which has the re-
quired substituents at C3, C5, and C6 positions with a handle at
C2 that would allow for the late-stage installation of the C2
substituents.
We envisioned that intermediates 10 and 11 with an iodo or a
boronic acid substitution at the C2 position would serve as the
appropriate precursors (Fig. 2).6–10 Compounds 10 and 11 could
be derived from a C2 unsubstituted precursor 12. Compound 12 it-
self could function as a potential precursor to install the C2 substit-
uents since it has been well-known that the C2-position of the
benzofuran ring can be readily metallated to give the organometal-
lic species,11 which could be employed in further transformations
(N-methyl-methylsulfonamido)benzofuran-3-carboxamide
(1)
with various substitutions at the C2 position (Fig. 1). It was desir-
able to maintain the C5 bromo substitution to allow for additional
SAR development at this position.
Our chemistry effort began with the preparation of compound
1a, which has a 4-F-phenyl at the C2 position (Scheme 1). Claisen
condensation of 1-(4-fluorophenyl)ethanone (2) with diethyl car-
bonate provided ketoester 3 in high yield.2 An iron-catalyzed, oxi-
dative Pechmann condensation of ketoester 3 with 4-bromophenol
formed the benzofuran 4 in moderate yield.3 Nitration followed by
reduction of the nitro group installed an amino group at the C6 po-
sition to give intermediate 6.4 The amino group was sulfonylated to
provide compound 7, which was converted to compound 9 in two
steps. Selective methylation of the sulfonamide nitrogen afforded
compound 1a.5 This synthetic route supplied 1a for our initial
SAR work, however, it would be tedious to apply this route to a
H
N
O
Br
3
5
6
R
2
O
N
Ms = methanesulfonyl
Ms
1
⇑
Corresponding author. Tel.: +1 908 740 0881.
E-mail address: shuwen_he@merck.com (S. He).
These authors contributed equally to this Letter.
Figure 1. 5-Bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
(1) with different substitutions at the C2 position.
http://dx.doi.org/10.1016/j.tetlet.2014.02.051
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. He et al. / Tetrahedron Letters 55 (2014) 2212–2216
2213
O
O
EtO
EtO
CO2Et
O
O
Br
CHO
OH
Br
CO2Et
a
b
c
Br
a
b
Br
F
O
F
F
O
O
O2N
2
3
4
13
14
15
18
CO2Y
CO2Et
Br
Br
c
e
HN
EtO
HO
O
O
F
O
F
Ms
f
d
e
Br
H2N
O
Br
H2N
Br
O
N
X
H
5
6
X= NO2
X= NH2
7 Y= Et
8 Y= H
O
O
O
d
f
H2N
16
17
O
O
NH
NH
H
H
N
H
N
N
g
h
Br
Br
O
O
I
O
F
F
Br
Br
Br
h
X
g
O
O
HN
N
Ms
Ms
Ms
O
O
O
N
N
Ms
Ms
N
H
9
1a
19
12
10
Scheme 1. Synthesis of compound 1a. Reagents and conditions: (a) diethyl
carbonate (1.0 equiv), NaH (1.2 equiv), THF, 70 °C, 3 h, 95%; (b) 4-bromophenol
(3.0 equiv), FeCl3Á6H2O (0.15 equiv), (t-BuO)2 (2.2 equiv), reflux, 6 h, 14%; (c) fuming
HNO3 (8.1 equiv), CHCl3, À15 °C, 30 min, 66%; (d) Iron filings (3.0 equiv), NH4Cl
(6.0 equiv), MeOH–THF–H2O (2:2:1), reflux, 3 h, 82%; (e) MsCl (3.0 equiv), pyridine/
CH2Cl2 (1:5), 0 °C to 25 °C, 82%; (f) LiOHÁH2O (5.1 equiv), dioxane–H2O (5:1), 100 °C,
3 h, 96%; (g) HOBt (1.5 equiv), EDC (1.5 equiv), DMF, 25 °C, 2 h, Et3N (4.7 equiv),
CH3NH2ÁHCl (3.0 equiv), 94%; (h) MeI (3.0 equiv), K2CO3 (2.5 equiv), KI (0.02 equiv),
DMF, 80–90 °C, overnight, 94%.
Scheme 2. Preparation of compound 12. Reagents and conditions: (a) ethyl
diazoacetate (1.43 equiv), HBF4ÁEt2O (0.1 equiv), CH2Cl2, <38 °C; then H2SO4 (concd,
1.3 equiv), followed by Na2CO3 (aq), 75%; (b) fuming HNO3 (12.1 equiv), CHCl3,
À20 °C to 0 °C; 85%; (c) Fe filing (3.0 equiv), NH4Cl (6.0 equiv), MeOH–THF–H2O
(2:2:1), 68%; (d) LiOH H2O (5.0 equiv), dioxane–H2O (5.6:1), reflux, 97%; (e) EDC
(1.5 equiv), HOBt (1.5 equiv), DMF, 25 °C, 2 h; Et3N (3.0 equiv), MeNH2ÁHCl
(3.0 equiv), 25 °C, 2 h, 71%; (f) MsCl (2.0 equiv), pyridine (3.0 equiv), CH2Cl2, 0 °C
to 25 °C, 16 h, 70%; (g) K2CO3 (3.0 equiv), MeI (2.0 equiv), DMF, 80 °C, 3 h, 90%; (h)
LDA (5.0 equiv), I2 (6.0 equiv), THF, À78 °C, no required product was observed.
H
H
N
H
N
N
H
N
H
N
HN
O
O
O
O
O
O
Br
Br
Br
Br
Br
Br
a
b
I
B(OH)2
I
B(OH)2
or
O
N
Ms
O
O
O
H2N
O
N
N
Ms
O
H2N
H2N
Ms
18
20
21
10
11
12
H
N
H
N
O
Figure 2. Possible precursors for installing C2 groups: 10 and 11.
O
c
d
Br
Br
I
I
Ms
Ms
O
O
N
to install substituents at the C2-position.12 However, for conve-
nience, we desired a stable intermediate (such as 10), which could
be prepared and stored in bulk, to avoid preparing the organome-
tallic species from 12 separately for each C2 substituent.
Preparation of C2 iodobenzofuran from C2 unsubstituted
benzofuran has been well documented in the literature (Fig. 3).
For example, the Larock group demonstrated that quenching of
the lithium species derived from benzofuran with iodine provides
the 2-iodobenzofuran in high yield.7 In an example closely related
to our work, Presidio scientists reported the preparation of a
2-iodobenzofuran compound with a carboethoxy group at C3
position and a methoxy group at C5 position.13
N
H
22
10
Scheme 3. Preparation of compounds 20 and 10. Reagents and conditions: (a) LDA
(4.2 equiv), THF,1 h; B(OMe)3 (4.0 equiv), À78 °C, 1 h; 71%; (b) NIS(1.0 equiv),
MeCN, 0 °C to 25 °C, 79%; (c) MsCl (2.0 equiv), pyridine, 0 °C to 25 °C, 1.5 h,
LiOHÁH2O (7.9 equiv), 25 °C, 30 min, 59%; (d) K2CO3 (3.0 equiv), MeI (2.0 equiv),
DMF, 0 °C, then 80 °C, 1 h, 91%.
procedure described in the literature,13 the reaction failed to pro-
duce the required C2-iodo product 10.
We suspected that the sulfonamide may have interfered with
the metallation of 12. To test this hypothesis, we decided to try
the metallation on compound 18, an intermediate without the sul-
fonamide group (Scheme 3). Unfortunately, treatment of amine 18
with LDA, followed by quenching with iodine produced many
unidentified by-products and a poor yield of the required C2-iodide
21 (ꢀ6% after purification). On the other hand, when the lithium
species was quenched with trimethylborate followed by hydrolysis
of the boronate intermediate, boronic acid 20 was isolated in good
yield.14 Attempts to convert intermediate 20 to compound 11 were
unsuccessful probably due to the limited stability of the boronic
acid moiety. Instead, iododeboronation of boronic acid 20 with
N-iodosucciimide afforded iodide 21 in good yield.15 The methyl
sulfonamide group was then installed according to the chemistry
described above to provide the key intermediate 10.
We set out to prepare the C2 unsubstituted substrate (12) for
iodination/borylation (Scheme 2). The chemistry was similar to
the preparation of compound 1a (Scheme 1). However, when com-
pound 12 was treated with LDA followed by I2 according to the
t-BuLi, -78 o
C
I
ref. 8
O
O
I2
95%
EtO
EtO
O
O
MeO
MeO
LDA (3.5 eq.) -78 oC
I2
ref. 13
I
O
O
Once precursor 10 became available, a variety of substituents at
C2 were installed via Suzuki coupling with the required boronic
acids or boronates to afford compounds 1b–1n (Table 1). Substi-
tuted phenylboronic acids participated well in the Suzuki coupling
83%
Figure 3. Representative examples known for the preparation of C2-iodo benzo-
furan ring system.

2214
S. He et al. / Tetrahedron Letters 55 (2014) 2212–2216
Table 1
Preparation of 1b–1n via the Suzuki coupling of iodide 10
H
N
H
N
O
O
Br
Br
I
R
Ms
Ms
O
O
N
N
10
1b-1n
Entry
1
Boronic acid/boronate
Compound 1
Coupling conditiona (time)
Yield of 1 (%)
HO
O
N
O
B
CF3
Br
HO
F
F
F
F
A
85
O
N
O
O
O
S
O
O
O
1b
F
F
N
F
HO
HO
F
Br
F
B
O
O
2
3
A
B
70
70
O
N
S
1c
OH
B
N
O
OH
Br
F
F
O
N
S
1d
OH
O
NH
B
OH
Br
4
5
6
B
A
C
81
83
79
N
N
O
N
S
O
O
1e
O
F
F
O
N
B
Br
F
O
N
O
O
N
F
N
Ms
1f
O
HO
HO
N
N
B
Br
N
O
O
N
N
S
O
O
O
O
1g
O
OH
B
O
Br
HO
N
7
B
69
O
N
N
N
S
O
N
1h
O
O
O
Br
B
O
O
O
O
8
B
B
B
80
87
70
O
N
S
N
O
O
1i
HO
HO
N
N
O
N
O
B
O
Br
N
N
O
9
O
N
S
O
O
O
O
1j
N
O
O
N
N
B
Br
N
N
10
O
N
S
1k

S. He et al. / Tetrahedron Letters 55 (2014) 2212–2216
2215
Table 1 (continued)
Entry
Boronic acid/boronate
Compound 1
Coupling conditiona (time)
Yield of 1 (%)
O
N
O
N
N
Br
B
N
N
O
11
12
C
78
76
67
O
N
S
O
O
1l
H
N
O
N
S
O
O
Br
B
N
N
O
B
C
O
S
N
S
N
N
O
O
O
O
1m
O
N
Br
O
N
N
B
13
O
N
S
N
N
N
1n
a
Condition A: boronic acid or boronate, Na2CO3, Pd(dppf)Cl2 (cat.), DMF, 50 °C, 12 h; Condition B: boronic acid or boronate, K2CO3, Pd(dppf)Cl2 (cat.), DMF, 100 °C, 1 h;
Condition C: boronic acid or boronate, Na2CO3, Pd(dppf)Cl2 (cat.), DMF, 100 °C, 1 h.
H
N
H
N
O
O
reaction to give the C2 phenyl substituted compounds 1b–1d.
Similarly, substituted pyridyl and pyrimidyl groups were installed
at the C2 position (1e–1j). The Suzuki coupling reaction also
proceeded in good yields for 5-membered heteroaryl boronic
acids/boronates (1k–1m) as well as pyrazolo[1,5-b]pyridazine-3-
boronate (1n). In all cases, the C5 bromo substituent survived the
coupling conditions.
Br
Br
a
B(OH)2
F
O
O
N
H2N
H2N
23
20
H
N
O
Br
As a complementary method, for cases where the boronic acid/
boronate of the desired C2 substituent was not commercially avail-
able, the Suzuki coupling reaction of boronic acid 20 and the corre-
sponding halide could install the C2 group. For example, the
coupling reaction of 20 with 2-bromo-5-fluoropyridine afforded
23 with 5-fluoropyridine-2-yl at C2 position (Scheme 4). The ami-
no group at C6 was then converted to N-methylsulfonamide to pro-
vide compound 1o according to the chemistry described above.
b, c
F
O
N
N
Ms
1o
Scheme 4. Preparation of compound 1o. Reagents and conditions: (a) 2-bromo-5-
fluoropyridine, Pd(dppf)Cl2 (cat.), K3PO4Á3H2O, DMF, 25 °C, 3 h, 51%; (b) MsCl
(2.0 equiv), pyridine, 0 °C to 25 °C, 1.5 h, LiOHÁH2O (7.9 equiv), 25 °C, 30 min, 66%;
(c) K2CO3 (3.0 equiv), MeI (2.0 equiv), DMSO, 0 °C, then 25 °C, 1 h, 70%.
Table 2
Other transformations with iodide 10
H
N
O
H
N
O
Br
Br
I
R
Ms
Ms
O
O
N
N
10
1p-1v
Entry
1
Reagents
Compound 1
Coupling conditiona
Yield of 1 (%)
O
N
Br
O
O
CO, MeOH
D
84
O
N
S
O
O
O
O
O
O
1p
O
NH
NH
Br
HO
NH2
2
3
E
F
60
O
N
S
OH
1q
O
NH
N
Br
N
O
83
HO
O
N
S
1r
(continued on next page)

2216
S. He et al. / Tetrahedron Letters 55 (2014) 2212–2216
Table 2 (continued)
Entry
Reagents
Compound 1
Coupling conditiona
Yield of 1 (%)
O
N
Br
HN
N
N
4
5
6
F
64
O
N
N
S
O
O
O
O
O
O
1s
N
F
O
F
F
F
F
F
Br
N
HN
N
F
F
F
82
55
83
O
N
N
N
S
1t
N
O
N
Br
HN
N
N
N
N
O
N
S
1u
O
NH
N
Br
HN
N
7
O
N
S
O
O
1v
a
Condition D: CO (50 psi), Pd(PPh3)2Cl2, MeOH, DMSO, 50 °C, 16 h; Condition E: amine, pyridine, 60 °C, 3 h; Condition F: reagent, K2CO3, DMF, 80 °C, 10 h.
2. All new compounds were characterized by NMR (see Supplementary material
for details).
produced compounds with other C2 substituents (Table 2). Car-
3. Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
Beyond the Suzuki coupling, other reactions involving iodide 10
bonylation of 10 gave the ester 1p, which could be further deriva-
tized. The reaction of 2-aminoethanol with 10 under basic
conditions introduced a 2-hydroxyethylamino group at the C2 po-
sition (1q).16 Heteroaryl C–N coupling afforded access to a variety
of N-linked compounds (1r–1v). Again, in all cases, the C5 bromo
substituent survived the coupling conditions.
In summary, we have developed a method to prepare a com-
mon precursor, iodide 10, and demonstrated its utility in installing
a variety of substituents at the C2 position of a highly substituted
benzofuran ring system in a highly efficient fashion. This effort
produced a diverse set of compounds to support the extensive
SAR interrogation for this series. Further manipulation of these
compounds into biologically active compounds as well as their
activity on the biological target will be disclosed in due course.
4. The position of nitro group was confirmed by NMR analysis. Under the
optimized condition detailed in the experimental section, the di-nitro product
was not observed.
5. For an example of selective alkylation of sulfonamide NH over amide NH, see:
Giannotti, D.; Viti, G.; Sbraci, P.; Pestellini, V.; Volterra, G.; Borsini, F.; Lecci, A.;
Meli, A.; Dapporto, P.; Paoli, P. J. Med. Chem. 1991, 34, 1356.
6. For an example utilizing 2-iodobenzofuran in the Negishi coupling reaction,
see: Negishi, E.; Xu, C.; Tan, Z.; Kotora, M. Heterocycles 1997, 46, 209.
7. For an example utilizing 2-iodobenzofuran in the Sonogashira coupling
reaction, see: Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048.
8. For an example utilizing 2-iodo-3-phenylbenzofuran in the Heck reaction, see:
Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14327.
9. For an example utilizing 2-iodobenzofuran in the Suzuki coupling reaction, see:
Carter, M. D.; Hadden, M.; Weaver, D. F.; Jacobo, S. M. H.; Lu, E. PCT Int. Appl.
2006125324, 30 Nov 2006.
10. For an example utilizing benzofuran-2-ylboronic acid in the Suzuki coupling
reaction, see: Lee, J. H.; Park, E. S.; Yoon, C. M. Tetrahedron Lett. 2001, 42, 8311.
11. For an early report on metallating the C2 position of benzofuran ring, see:
Gschwend, H. W.; Rodriguez, H. R. Org. React. (Hoboken, NJ, United States) 1979,
26, 1.
12. For an example employing benzofuran-2-zinc species in the Negishi coupling
with an aryl bromide, see: Aoyagi, Y.; Mizusaki, T.; Hatori, A.; Asakura, T.;
Aihara, T.; Inaba, S.; Hayatsu, K.; Ohta, A. Heterocycles 1995, 41, 1077.
13. Zhong, M.; Li, L. PCT Int. Appl. 2012058125, 03 May 2012.
14. Miller, C. P.; Collini, M. D.; Kaufman, D. H.; Morris, R. L.; Singhaus, R. R.; Ullrich,
J. W.; Harris, H. A.; Keith, J. C.; Albert, L. M.; Unwalla, R. J. PCT Int. Appl.
2003051860, 26 Jun 2003.
15. Iododeboronation of benzofuran-2-ylboronic acid has not been reported in the
literature, for a related example of iododeboronation of triolborates, see: Akula,
M. R.; Yao, M.-L.; Kabalka, G. W. Tetrahedron Lett. 2010, 51, 1170.
16. For couplings of a substituted 2-bromo benzofuran with an amine or NH-
containing heterocycles, see: Gill, G. S.; Grobelny, D. W.; Chaplin, J. H.; Flynn, B.
L. J. Org. Chem. 2008, 73, 1131.
Supplementary data
Supplementary data (the experimental procedures and charac-
terization data for all new compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.02.051.
References and notes
1. Dawood, K. M. Expert Opin. Ther. Patents 2013, posted online on May 17, 2013.
(doi:http://dx.doi.org/10.1517/13543776.2013.801455).