Synthesis of 3-aryl-2-arylamidobenzofurans based on the curtius rearrangement

Article abstract of DOI:10.1021/jo102265b

The synthesis of novel 3-aryl-2-arylamidobenzofurans has been accomplished via a Curtius rearrangement strategy in four steps from benzofuran-2-carboxylic acids. The requisite Suzuki-Miyaura cross-coupling, with benzyl 3-bromobenzofuran-2-ylcarbamate or 2

Full text of DOI:10.1021/jo102265b

ARTICLE
pubs.acs.org/joc
Synthesis of 3-Aryl-2-arylamidobenzofurans Based on the Curtius
Rearrangement
Amandine Carr€er,†,‡ Jean-Claude Florent,†,‡ Emilie Auvrouin, Patricia Rousselle,§ and
Emmanuel Bertounesque**,†,‡
†CNRS UMR 176, 26 rue d’Ulm, 75248 Paris, France
‡Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75248 Paris, France
§Institut de Biologie et de Chimie des Protꢀeines, CNRS UMR 5086, 7, passage du Vercors, 69367 Lyon, France
S Supporting Information
b
ABSTRACT: The synthesis of novel 3-aryl-2-arylamidobenzofurans has been
accomplished via a Curtius rearrangement strategy in four steps from benzo-
furan-2-carboxylic acids. The requisite Suzuki-Miyaura cross-coupling, with
benzyl 3-bromobenzofuran-2-ylcarbamate or 2-arylamido-3-bromobenzofur-
ans, revealed an unusual reductive debromination process due to the presence
of the free NH group. This dehalogenation can be suppressed by N-alkylation. DMAP is an efficient reagent for the one-pot
conversion of benzyl benzofuran-2-ylcarbamates into the corresponding benzofuran-2-arylamides through aroylation, thus acting
both as an acyl transfer reagent and a deprotecting agent of the Cbz group. A mechanism is postulated.
’ INTRODUCTION
Benzo[b]furan derivatives are of considerable interest because
of their widespread occurrence among natural products such as
amurensin H (1), malibatol A (2), and (()-frondosin B (3)
(Figure 1).1,2 In addition, they occupy a prominent place in
medicinal chemistry due to their diverse pharmacological
activities3 such as anti-HIV,4 anticancer,5 and antiinflammatory
(i.e., COX-2 inhibitors).6 Prescribed agents featuring the benzo-
furan scaffold include the antidepressant (-)-BPAP7 and the
antiarrythmic amiodarone.8
Some benzofurans were also identified as 5-lipoxygenase
inhibitors,9 angiotensin II inhibitors,10 calcium entry blockers,11
PTP-1B inhibitors,12 estrogen receptor modulators,13 highly
selective MMP-13 inhibitors,14 PKCθ inhibitors,15 H3
antagonists,16 BLT1 and/or BLT2 antagonists,17 and as direct
inhibitors of thrombin and factor Xa.18 Many other activities have
been reported for benzofurans.19 Recently, a series of structures
containing the benzofuran nucleus, such as SKF-63058 (4) and
SKF-64346 (5), have been identified as efficient inhibitors of β-
amyloid aggregation,20 and 6 as inhibitors of glycogen synthase
kinase-3β (GSK-3β),21 affording a new class of potential multi-
functional drugs for Alzheimer’s disease (Figure 2).
Thus synthetic access to benzofurans is of considerable
interest, and numerous approaches to this scaffold have been dis-
closed in the literature.22 Major synthetic strategies23 utilized
include the dehydrative cyclization of R-(phenoxy)alkyl ketones,
dehydration of o-hydroxybenzyl ketones under acidic conditions,
decarboxylation of o-acylphenoxyacetic acids or esters on treat-
ment with a base, cyclofragmentation of oxiranes, palladium(II)-
catalyzed cyclization of arylacetylenes (C-O cyclization),24
Figure 1. Benzofuran-containing natural products.
copper(I)-catalyzed coupling of acetylenes,25 palladium-cata-
lyzed enolate arylation with o-bromophenols,26 electrophilic
cyclization chemistry developed by Larock and co-workers,27
thermolytic Claisen rearrangement and cyclization of aryl prop-
2-ynyl ethers,28 and intramolecular cyclization via carbon-
carbon bond (C-C) cyclization.29
Received: November 18, 2010
Published: March 10, 2011
r
2011 American Chemical Society
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To the best of our knowledge, 3-aryl-2-arylamidobenzofurans
are not described so far in the literature. Additionally, reports are
very scarce on 2-arylamidobenzofurans. As examples, 3-hydroxy-
efficient method to prepare 3-aryl-2-arylamidobenzofurans 15
(Figure 4).
Several potential strategies could be envisionned to access
2-arylamidobenzofurans directly from the benzofuran skeleton.
We were inspired by the work of Royer and co-workers that
reported, 40 years ago, the transposition of 1-(3-phenylbenzo-
furan-2-yl)ethanone oxime (A) to give N-(3-phenylbenzofuran-
2-yl)ethanamide, but in very low yields (AcOH saturated with
HCl, 5 h, reflux, 20% or PCl5, Et2O, reflux, 10%).35 This
approach would involve the Beckmann transposition of aryl
benzofuranyl oximes (Scheme 1, routes 1 and 2) but under
milder conditions, the benzofuran scaffold being accessible
through a classical synthetic methodology involving cyclodehy-
dration of R-(phenoxy)alkyl aryl ketones (route 1) or Rap-
Stoermer reaction (route 2).36 Importantly, note that 30 years
later, Deprets and Kirsch37 confirmed the shortcomings, in this
context, of applying the Beckmann rearrangement, since it was
unsuccessful from 1-(5-(methylthio)-3-phenylbenzofuran-2-yl)-
ethanone oxime (B) (PPA, toluene, reflux, degradation)—an
analogue of oxime (A) and aryl(3-arylbenzofuran-2-yl)methanone
oximes (C) (Scheme 1)—and successful from 1-(3-phenylbenzo-
[b]thiophen-2-yl)ethanone oxime (83%) or 1-(3-phenylbenzo[b]-
selenophen-2-yl)ethanone oxime (73%).
N-(3-methoxybenzofuran-2-yl)naphthalene-2-carboxamide
7
was mentioned in a patent entitled “Dyed cellulose and protein
textiles” published in 1965.30 At the same time, more functiona-
lized compounds such as 2,6-bis-benzoylamino-benzo[1,2-b;4,5-
b0]difuran-3,7-dicarboxylic acid diethyl ether 8 and its derivative
9 appeared in the context of the chemistry of color reactions.31 A
decade later, derivatives of 2-amino-3-carbethoxy-5-hydroxyben-
zofuran were described such as 10.32 Recently N-7-azabicyclo-
[2.2.1]heptan-2-yl)-2-phenylamidobenzofuran carboxamides 11
and 12 were described for therapeutic use as nicotinic acetylcho-
line receptor agonists.33 In the case of 2-alkylamido- and chiral
2-carbamate benzofurans exemplified by 13 and 14, respectively,
it is worthwhile mentioning an elegant synthesis from a range of
O-anisyl ynamides was described via a Rh(I)-catalyzed demethy-
lation-cyclization (Figure 3).34
As part of our medicinal chemistry program aimed at the search
for novel benzofuran-based bioactive molecules, we were seeking an
The second approach would take advantage of the regioselec-
tive nitration at the 2-position of 3-aryl-2-trimethylstannyl
benzofurans, prepared by lithiation of 3-arylbenzofurans fol-
lowed by reaction with trimethyltin chloride (Scheme 2, route
3).38 The synthesis of 2-arylamidobenzofurans would then be
carried out by a two-step sequence, reduction of the nitro group
into amine followed by N-acylation. The third approach could
benefit from the recent work described by Lebel and Leogane39
Figure 2. Potential multifunctional drugs for Alzheimer’s disease.
Figure 4. N-(3-Arylbenzofuran-2-yl)arylamides 15.
Figure 3. 2-Amidobenzofurans 7-13 and benzofuran-2-ylcarbamate 14.
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Scheme 1. Potential Synthetic Strategies Based on the Beckmann Transposition
Scheme 2. Potential Synthetic Strategies: Regioselective Nitration, Curtius Rearrangement, or Copper-Mediated Reactions
on the Curtius rearrangement of aromatic carboxylic acids, wherein
benzyl benzofuran-2-ylcarbamate (D) was prepared by a one-pot
procedure from benzofuran-2-carboxylic acid (route 4). The Cbz
carbamate group could serve as a precursor of the amido function-
ality after or prior to the installation of the aryl group at the
3-position through the Suzuki-Miyaura reaction. Finally, the fourth
approach would be to attempt the copper-mediated reactions,40
discovered independently by Chan, Evans, and Lam,41 between aryl
amides and benzofuran 2-boronic acid (route 5).
After having briefly examined the application of these attrac-
tive copper-mediated reactions, our choice turned to the devel-
opment of route 4 so as to take advantage of an efficient one-pot
reaction for the formation of the C-N bond at the C2 position of
the benzofuran ring system, and to avoid contamination of toxic
stannyl compounds (route 3). We report herein the synthesis of
3-aryl-2-arylamidobenzofurans 15 via a Curtius rearrangement
from benzofuran-2-carboxylic acid.
’ RESULTS AND DISCUSSION
To the best of our knowledge, the reaction of amines or
amides with benzofuran-2-boronic acid 16a42 as donor has not
been previously mentioned. As an indication of potential feasi-
bility, it should be noted that furan-2-boronic acid and ben-
zothiophene-2-boronic acid have been used to N-arylate tert-
butyl carbazate under catalysis by CuCl at room temperature
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Scheme 3
(pyridine, 1,2-dichloroethane, 3 Å molecular sieves, rt, dry air).43
In addition, copper-catalyzed N-arylation of triazoles with such
boronic acids has been recently reported.44 Therefore, prior to
investigating the Curtius approach, the application of the Cu(II)-
catalyzed N-arylation reaction was evaluated for the coupling of
4-fluorobenzamide with benzofuran-2-boronic acid 16a by using
Scheme 4a
Cu(OAc)2 or Cu(OAc)2 H2O45 (Scheme 3, route 5). Such
41a
3
coupling was not successful whatever the reaction conditions. In
addition, the Cu-catalyzed Goldberg reaction, using N-based chelat-
ing ligands (CuI, K3PO4, N1,N2-dimethylethane-1,2-diamine, diox-
ane, 110 °C, 15 h),46 was tried with no more success with benzamide
and 2-bromo-5-methoxybenzofuran 16b47 as coupling partners.
We then initiated the study of route 4 with the synthesis of
N-(3-phenylbenzofuran-2-yl)benzamide 15a (R1, R2, R3 = H)
from 2-benzofuran carboxylic acid in 4 steps (Scheme 4).
The Curtius rearrangement of 2-benzofuran carboxylic acid
described by Lebel and Leogane39 led to benzyl benzofuran-2-
ylcarbamate 20 in 69% yield, presumably through the formation of
the corresponding benzyl carbonazidate. Subsequent bromination48
at the C-2 position (21a) required the search for reaction conditions.
Indeed, its treatment with bromine49 (1.08 equiv) in CCl4 (0 °C
then room temperature, overnight) led only to the degradation of the
reaction mixture. This reaction carried out in AcOH as solvent in the
presence of AcONa (4 equiv) at room temperature (40 min) gave
benzyl bromo(3-bromobenzofuran-2-yl)carbamate 21b in 65% yield
after flash chromatography (see the Supporting Information). Upon
reduction with 12% aqueous sodium sulfite50 at 5-10 °C(0.5h), the
initially N-bromoadduct formed was transformed in situ into the
desired benzyl 3-bromobenzofuran-2-ylcarbamate 21a in 68% yield.
On the other hand, bromination with NBS51 (1.2 equiv) in THF
(room temperature, overnight) only gave an unidentified compound
in place of the expected bromide. However, low-temperature, acid-
catalyzed C-2 bromination (NBS 1.2 equiv, PTSA 0.1 equiv, THF,
-78 °C, 25 min) provided 21a in 74% yield.
a Reagents: (a) NaN3 (1.7 equiv), CbzCl (1.3 equiv), tBuONa (0.15
equiv), DME, 75 °C, 20 h, 69%; (b) NBS (1.2 equiv), PTSA (0.1 equiv),
THF, -78 °C, 25 min, 74%; (c) Pd(PPh3)4 (5 mol %), CsF (11 equiv),
PhB(OH)2 (5 equiv), dioxane/H2O 4:1 reflux, 1 h, 55%; (d) PhCOCl
(3 equiv), Et3N (6 equiv), DMAP (1.5 equiv), CHCl3, reflux, 16 h, 61%.
product (31-44%). With use of Ba(OH)2, NaOH, or tBuOK
(entries 6-8), the method was ineffecient (4-10% yields). By
choosing CsF as the best base, the search for other palladium
catalysts was disappointing (entries 9-11). PdCl2(dppf) gave
36% yield of 22, and much lower yields were obtained with
Pd(OAc)2-XantPhos and Pd(OAc)2-Cyclohexyl JohnPhos.
On the basis of Pd(PPh3)4 as the catalyst and CsF as the base,
the solvent effect was also examined (entries 12-14). The
reaction is faster in dioxane/H2O (1.5 h, entry 12) as compared
with DME/H2O (entry 5) or toluene/H2O (entry 13), furnish-
ing 22 in a slightly increased yield (46%) along with 20 (39%). In
an attempt to eliminate the formation of the reduced product, the
reaction was conducted in the absence of water as the cosolvent
but failed to give the cross-coupling product (entry 14).
The optimized yield was found to be 55% by stirring 5 mol %
of Pd(PPh3)4, 11 equiv of CsF, and 5 equiv of phenyl boronic
acid for 1 h; however, 34% of the dehalogenated product 20 were
also isolated (entry 15). Finally, the effect of the proportion of
water on the yield of 22 was examined by forcing the reaction
conditions with 5 equiv of PhB(OH)2 in dioxane/H2O 6:1
(entry 15 vs entry 16). It was found that the reactions resulted
The Suzuki-Miyaura (SM) cross-coupling52,53 between 21a
and phenyl boronic acid54 was next investigated by using various
catalysts, bases, and solvants (Table 1). Reaction of 21a with
phenyl boronic acid (1.5 equiv) in the presence of Pd(PPh3)4 (5
mol %) and sodium carbonate (4.5 equiv) in a mixture of
dimethoxyethane/H2O (4:1) for 2 h at reflux gave the desired
coupling product 22 in 22% yield along with the dehalogenated
compound 20 in 34% yield (entry 1). The reaction was then
screened with a variety of base to increase the yield of 22. Thus,
the use of K2CO3, NaHCO3, Cs2CO3, or CsF (entries 2-5)
allowed us to increase the yield, by up to 40% with CsF, but did
not prevent the concomitant formation of 20 as the major
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Table 1. Optimization of the Suzuki-Miyaura Reaction with Phenyl Boronic Acid
yield (%)
entry
PhB(OH)2
1.5 equiv
base
Pd
solvent
time (h)e
22
20
1a
2a
3a
4a
5a
6a
7a
8a
9b
10b
11b
12a
13a
14a
15a
16a
Na2CO3
K2CO3
NaHCO3
Cs2CO3
CsF
Pd(PPh3)4
DME/H2O 4:1
2
1.5
1.5
1.5
3
22
31
32
26
40
4
34
31
41
34
44
14
30
28
44
56
40
39
55
11
34
42
Ba(OH)2
NaOH
tBuOK
CsF
3
3
10
9
3
PdCl2(dppf)
10
10
10
1.5
4
36
8
Pd(OAc)2-ligandc
Pd(OAc)2-ligandd
Pd(PPh3)4
13
46
42
0
DME/H2O 4:1
toluene/H2O 4:1
dioxane
3
5 equiv
5 equiv
11 equiv
11 equiv
dioxane/H2O 4:1
1
55
dioxane/H2O 6:1
1
52
a To a solution of arylbromide (1 equiv), phenyl boronic acid (1.5 or 5 equiv), and base (4.5 or 11 equiv) in degassed solvent/water was added
Pd(PPh3)4 (5 mol %). The mixture was refluxed during 1 to 4 h. b To a solution of arylbromide (1 equiv), phenyl boronic acid (1.5 equiv), and CsF (4.5
equiv) in degassed DME/water 4:1 was added Pd catalyst (5 mol %) and ligand (5% XantPhos or 10% Cyclohexyl JohnPhos). After 5 h at reflux, TLC
control indicated the presence of arylbromide, therefore 0.05 equiv of Pd catalyst was added and the reflux was pursued for 5 h. c XantPhos. d Cyclohexyl
JohnPhos. e The reaction mixture was stirred until the TLC analysis showed the complete disappearance of the starting material.
Scheme 5a
a Reagents: (a) Benzoylation: see Table 3, or alkylation: MeI (1.3 equiv), NaH 60% in mineral oil (1.3 equiv), DMF, 0 °C then room temperature, 3-4 h,
or MOMCl (3 equiv), NaH 60% in mineral oil (3 equiv), Et3N (3 equiv), DMF, 0 °C then 55 °C, overnight; (b) NBS (1.2 equiv), PTSA (0.1 equiv),
THF, 0 °C (27) or -78 °C (28-30); (c) Pd(PPh3)4 (5 mol %), PhB(OH)2 (1.5 equiv), CsF (4.5 equiv), dioxane/H2O 4:1, reflux; (d) TMSCl (4.5
equiv), NaI (4.5 equiv), MeCN, 5 °C, overnight then Et3N (3 equiv), MeOH, 55 °C, 1 h (15a from 34a 55%).
in similar improved yields for 22 but no effect of the water
concentration was found from these two experiments. Finally,
acylation of 22 gave directly access to N-(3-phenylbenzofuran-2-
yl)benzamide 15a via a one-pot process involving initial N-
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acylation followed by in situ Cbz deprotection (PhCOCl 3 equiv,
Et3N 6 equiv, DMAP 1.5 equiv, CHCl3, rt to reflux, 16 h, 61%).
The overall yield of the synthesis of 15a was 17%.
To explain the observed reductive debromination of 21a, the
role of the free NH moiety55,56 was examined by performing the
Suzuki coupling reactions from various N-protected derivatives
27-30 with phenyl boronic acid (Scheme 5).
The Suzuki reaction with 27 bearing a Cbz group, prepared by
bromination of 23a, led only to degradation. The use of Me or
MOM as protecting groups was then investigated. First, methyla-
tion of 20 and 17a followed by bromination with N-bromosucci-
nimide furnished the required compounds 28 and 29, respectively.
Importantly, no reduction of the 3-bromobenzofuran derivatives
could be detected for the Suzuki-Miyaura reactions with 28 or 29
and phenyl boronic acid under the optimized conditions developed
in Scheme 4, and the yield of the cross-coupling products 32 and 33
was high with a 96% yield for both compounds. N-Demethylation of
33 failed by treatment with benzoyl peroxide (CH2Cl2, 80 °C,
overnight),57 only starting material being recovered. Second, similarly
as above, MOM alkylation of 17a followed by bromination gave 30.
Subsequent Suzuki-Miyaura coupling reaction with phenyl boronic
acid resulted exclusively in the formation of 34a in 96% yield.
Attempts to deprotect the latter failed with concentrated HCl58 or
TFA59 leading to degradation. However, the deprotection could be
achieved, with TMSI generated in situ from TMSCl and NaI,60 to
afford N-(3-phenylbenzofuran-2-yl)benzamide 15a in 55% yield.
N-Alkylation turned out to be crucial to suppress the proble-
matic reduction side reaction. Two hypotheses may explain this
unexpected reductive debromination. An intramolecular proton-
transfer process could occur on the palladium benzofuranyl
complex formed by oxidative addition.61 The second explanation
would involve electronic effects due to the free NH group that
could diminish the stability of this organopalladium species, thus
limiting the process of transmetalation from boron to palladium.
To further extend the application of our methodology through
MOM-protection of 17a, we have examined the Suzuki reaction
of 30 with various aryl boronic acids (Table 2). Both electron-
deficient and electron-rich aryl boronic acids smoothly under-
went the coupling process to provide 34b-e in excellent yields
(89-94%).
In a parallel way and simultaneously before the optimization of
the Suzuki reaction conditions were reached, a modified reaction
sequence was carried out to generalize the access to 3-aryl-2-
arylamidobenzofurans, with the free NH group for biological
assays, involving the early one-pot N-acylation-N-Cbz deprotec-
tion sequence (Scheme 6).
Table 2. Suzuki Reaction of 30 with Various Aryl Boronic
Acids
The one-pot reactions of 20 with an excess of benzoyl
chlorides generated 2-arylamidobenzofurans 17a-d in 66-
84% yields (Table 3, method A, entries 1-4). In the case where
this method led to the impossibility of isolating 17e and 17f from
the unreacted starting material 20 by flash chromatography, a
two-step synthesis was then performed (Table 3, method B). It
consisted of N-acylation of 20 (method C, entries 13 and 14) in
the first step (23e,f) followed by hydrogenation over palladium-
on-charcoal to provide 17e and 17f in 59% and 60% yields
(entries 5 and 6), respectively. To complete the study of N-
acylation of 20 with aroyl chlorides (method C, entries 9-11),
compounds 23a-c were also prepared (71-92%).
entry
Ar
product
yield (%)a
1
2
3
4
4-CF3C6H4
34b
34c
34d
34e
93
89
94
91
4-CO2MeC6H4
2-MeOC6H4
3,4,5-(MeO)3C6H4
a Pd(PPh3)4 (5 mol %), ArB(OH)2 (1.5 equiv), CsF (4.5 equiv),
dioxane/H2O 4:1, reflux, 5-6 h.
Next, the Curtius rearrangement of 5-methoxybenzofuran-2-
carboxylic acid 35 and 5-nitrobenzofuran-2-carboxylic acid 36
Scheme 6a
a Reagents: (a) NaN3 (1.7 equiv), CbzCl (1.3 equiv), tBuONa (0.15 equiv), DME, 75 °C, 20 h, 49-69%; (b) DMAP (1.5 equiv), Et3N (6 equiv), NaH
(1.2 equiv), 15 min, 0 °C, THF then Ar1COCl (1.01 to 3 equiv), reflux, 16 h, 66-84% (17a-d, 18, 39); (c) NBS (1.2 equiv) PTSA (0.1 equiv), THF,
-78 °C, 35-60 min, 55-80%; (d) PdCl2dppf (6 mol %), Na2CO3 (2.4 or 4 equiv), Ar2B(OH)2 (1.2 or 2 equiv), DME/H2O (4:1), reflux, 40 min to 6 h,
6-33%; (e) NaH (60% in mineral oil, 3 equiv), THF, 0 °C, 15 min then Ar1COCl (3 equiv), reflux, 16 h; (f) Pd/C 10%, H2, MeOH, room temperature,
4 h (17e,f).
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Table 3. One-Pot N-Acylation/N-Cbz Deprotection Sequence: N-Acylation of 20, 37, and 38
a Method A (one-pot procedure): DMAP (1.5 equiv), Et3N (6 equiv), NaH (1.2 equiv), aroyl chloride (1 to 3 equiv), THF, reflux, overnight. b An
1
inseparable mixture of monoacylated and diacylated products (ratio 79:21 by H NMR) was obtained with 3 equiv of 4-methoxybenzoyl chloride.
Monoacylation took place with 1 equiv of 4-methoxybenzoyl chloride. c Room temperature, 50 min. d Method B (two-step procedure): (a) NaH 60% in
mineral oil (3 equiv), aroyl chloride (3 equiv), THF, reflux, overnight. (b) 10% Pd/C, H2, MeOH, room temperature, 4 h. Overall yield (two steps).
e Method C: NaH 60% in mineral oil (3 equiv), aroyl chloride (3 equiv), THF, reflux, overnight. f Not done. g Yield based on 1H NMR analysis, the
compound 23f being isolated as an inseparable mixture with the starting material 20.
gave benzyl 5-methoxybenzofuran-2-ylcarbamate 37 and benzyl
5-nitrobenzofuran-2-ylcarbamate 38 (low solubility) in 67% and
49% yields, respectively. The N-acylation-deprotection proto-
col applied to 37 and 38 furnished the expected compounds 18
and 39 in 81% and 71% yields, respectively.
obtained in the first reaction sequence (Table 1, entry 15 vs
Table 4, entry 12). As a result, the formation of the coupling
product decreased slightly (22 55% vs 15a 42%) while the
formation of the reductive dehalogenated product increased
almost in the same proportion (20 34% vs 17a 46%). However,
the yield of 15a was slightly improved to 42% by using these
conditions (Table 4, entry 11 vs entry 12). Finally, in this
context, the Suzuki-Miyaura reaction applied to N-(3-bromo-
5-methoxybenzofuran-2-yl)benzamide 41 provided 43, though
also in low yield (entry 20), and was unsuccessful for an
electron-deficient benzofuran such as N-(3-bromo-5-nitroben-
zofuran-2-yl)benzamide 42 leading to the corresponding deha-
logenated product 39 in 88% yield (entry 21).
The mechanistic understanding of this one-pot N-acylation-N-
Cbz deprotection sequence was achieved from 20 (Table 5). It is
worthwhile to mention that the direct conversion of the N-Cbz
carbamate 20 into 2-arylamidobenzofurans 17 is very attractive
because the intermediate 2-aminobenzofuran 45 is unstable and
cannot be isolated (Scheme 7). Indeed, an attempt to reduce
2-nitrobenzofuran 46 to 2-aminobenzofuran 45 exclusively gave the
hydrolysis product benzofuran-2(3H)-one 47 accompanied by
2-benzofuroxime 48.62 Alternatively, hydrogenation of 20 over
Pd/C also failed to provide 45.
Bromination of 17a-d and 17f at the C3 position was accom-
plished with N-bromosuccinimide to give the corresponding bro-
mides 40a-d and 40f in 55-79% yields (Table 4, entries 1-5).
Likewise, bromination of the 5-substituted benzofuran derivatives
18 and 39 afforded bromides 41 and 42 in 40% and 81% yields
(entries 9 and 10), respectively. The low yield of 41 was due to its
low solubility, leading to an uneasy purification by flash chroma-
tography. Subsequent Suzuki cross-coupling reactions between
40a-d and 40f and phenyl boronic acid with PdCl2(dppf) led to
15a-d and 15f, respectively, in low yields ranging from 6% to 30%
due to the reductive dehalogenation of the bromides (Table 4,
entries 11 and 13-16). In addition, bromides 40a and 40b were
examined for the Suzuki reaction with an electron-rich aryl
boronic acid as 4-methoxyphenyl boronic acid which, however,
offered no benefit in term of yields (entries 17 and 18). Bromide
40f reacted with (E)-styrylboronic acid to give the correspond-
ing vinylogous derivative 15i in very low yield (not shown in
Scheme 6). Besides, the reactivity of 40a was tested in the
Suzuki-Miyaura reaction for comparison with 21a, under the
best reaction conditions (Pd(PPh3)4, CsF, dioxane/H2O)
As an analogy in methodology, it is interesting to note the one-
pot transformation of N-Boc carbamates into amides by
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Table 4. Bromination and Suzuki-Miyaura Reactions
a Brominated product (1 equiv), boronic acid (1.2 to 2 equiv), sodium carbonate (2.4 to 4 equiv), PdCl2dppf (6 mol %) in DME/H2O 4:1, 85 °C, 40 min
to 6 h. b The reaction mixture was degassed by bubbling with argon and stirred under argon. c Yield of the debrominated product. d Pd(PPh3)4 (5 mol %),
CsF (11 equiv), PhB(OH)2 (5 equiv), dioxane/H2O 4:1, reflux, 1-3.5 h. e No Suzuki cross-coupling was observed.
treatment with acyl halide-methanol mixtures.63 This method
also avoids the isolation of the intermediate amines, which
sometimes can be unstable in some cases.
base (entry 4). The presence of Et3N as a base led to the N-
benzoylation of 20 to give 23a in 93% yield (entry 5). Impor-
tantly, replacement of Et3N by DMAP (3 equiv) as a hypernu-
cleophilic acylation catalyst allowed the exclusive formation of
N-(benzofuran-2-yl)benzamide 17a in 84% yield (entry 6).
Consequently, DMAP64 also acts in this context as a deprotecting
agent.65 Further confirmation could be obtained when the
isolated N,N-bisacylated compound 23a was treated with 3 equiv
of DMAP to lead to both 17a and 20 in 50% and 22% yields,
respectively (Scheme 8).
Taken together, the data provided in Table 5 (entries 1 and 6)
and the results depicted in Scheme 8, a mechanism could be
proposed for the formation of 17a (Scheme 9).
The formation of N-acylpyridinium salt I by the addition of
DMAP to benzoyl chloride is followed by nucleophilic addition
of 20 to salt I, for which the reversibility is possible. Indeed,
DMAP behaves as a nucleophile toward both the carbonyl
Treatment of 20 under the reaction conditions used at first
(i.e., PhCOCl 3 equiv, Et3N 6 equiv, DMAP 1.5 equiv, THF, reflux,
16 h) provided N-(benzofuran-2-yl)benzamide 17a in 66% yield
(Table 5, entry 1) along with 22% of recovered starting material.
Reaction of 20 in THF with benzoylchloride acid (3 equiv) in the
presence of NaH (5 equiv) as base, for 16 h, furnished exclusively
benzyl benzofuran-2-yl(phenylcarbonyl)carbamate 23a in excel-
lent yield (entry 2). The optimized yield for 17a (84%) was
obtained by adding NaH (1.2 equiv) as a strong base, through
improving the formation of the intermediate 23a by anionic
acylation of 20 (entry 3).
The identification of the reagent responsible for the N-Cbz
deprotection reaction was then undertaken. Compound 20 was
found unreactive toward benzoyl chloride with no addition of
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Scheme 7
Table 5. One-Pot N-Acylation/N-Cbz Deprotection
Scheme 8
Sequence
entry
1a
base/catalyst
Ar
product
yield (%)
66
Et3N (6 equiv)
DMAP (1.5 equiv)
NaH (5 equiv)
Ph
17a
2a
3a
Ph
Ph
23a
17a
92
84
Et3N (6 equiv)
DMAP (1.5 equiv)
NaH (1.2 equiv)
’ CONCLUSIONS
In summary, the synthesis of novel 3-aryl-2-arylamidobenzo-
furans has been achieved through a Curtius rearrangement
strategy, in four steps from 2-benzofuran carboxylic acids. The
two reaction sequences outlined above have proved to be of use
in their synthesis. The study of the Suzuki reaction showed that
both benzyl 3-bromobenzofuran-2-ylcarbamate and 2-arylami-
do-3-bromobenzofurans containing a free NH moiety, in the
presence of boronic acids, favor significantly the reductive
debromination process. This dehalogenation can be suppressed
by N-alkylation. A one-pot procedure was discovered to trans-
form benzyl benzofuran-2-ylcarbamates into the corresponding
benzofuran-2-arylamides through N-aroylation, in which DMAP
acts both as an acyl transfer reagent and a deprotecting agent of
the Cbz group. A mechanism is postulated for this transforma-
tion that avoids the isolation of the intermediate 2-aminobenzo-
furans, which are unstable in some cases.
4b
5b
6b
Ph
Ph
Ph
0
93
84
Et3N (3 equiv)
23a
17a
DMAP (3 equiv)
a PhCOCl (3 equiv). b PhCOCl (1.5 equiv).
groups of 23a. Then, the resulting N,N-biacetylated com-
pound 23a can also lead to N-acylpyridinium salt II via the
nucleophilic addition of DMAP to the benzyloxy carbonyl
group.66,67 The benzoxylate anion thus generated is trapped
by benzoyl chloride to form the isolated benzyl benzoate. The
hydrolysis product of II, namely the unstable carbamic acid
derivative 49, loses carbon dioxide to give N-(benzofuran-2-
yl)benzamide 17a. The reaction conditions, that is to say the
number of equivalents of DMAP and benzoyl chloride, allow
the exclusive formation of 17a with no trace of starting
material remaining.
’ EXPERIMENTAL SECTION
From the above results, it appears that the second reaction
sequence (Scheme 6) is equivalent to the first one (Scheme 4) in
terms of overall yield for compound 15a (17% vs 15%, 4 steps
from 19), applying the optimized Suzuki protocol (Table 4, entry
12). In other respects, a MOM protecting group strategy did not
allow an improvement of the yield of 15a (19%, 6 steps from 19).
The Suzuki reaction from 2-arylamido-3-bromobenzofurans
containing free NH groups remains a signicant challenge for
efficient large-scale syntheses.
All reactions were performed under argon atmosphere unless other-
wise noted. THF and DME were dried over Na/benzophenone.
Catalysts Pd(PPh3)4 (99%) and Pd(dppf)Cl2 were purchased from
Aldrich and Alfa Aesar, respectively. All other commercial reagents and
solvents were used as received without additional purification. Reactions
were followed with TLC (0.25 mm silica gel 60-F plates). Visualization
was accomplished with UV light. Flash chromatographies were carried
out on silica gel 320-400 mesh. Yields refer to chromatographically and
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Scheme 9. Postulated Mechanism
spectroscopically pure materials. Melting points were determined by
capillary method and are uncorrected. Infrared spectra were recorded on
a FTIR spectrometer. Low-resolution mass spectra were recorded on a
ESI-QMS instrument and high-resolution mass spectra were recorded
on a TOF-ESI-MS instrument. 1H NMR spectra were recorded on a 300
MHz spectrometer. 13C NMR spectra were recorded at 75 MHz with
complete proton decoupling. Chemical shifts are reported in
ppm relative to the residual solvent peak as the internal reference, and
coupling constants are given in hertz. Peak assignment was unambigu-
ously performed by using HMQC, HMBC, and COSY experiments.
General Procedure for Curtius Rearrangement: Synthesis
of 20, 37, and 38. To a solution of carboxylic acid (1 equiv), sodium
azide (1.7 equiv), and sodium tert-butoxide (0.15 equiv) in anhydrous
DME (0.12 M) at room temperature under argon was added benzyl-
chloroformate (1.3 equiv). After 20 h at 75 °C the mixture was then
quenched with water and extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography over silica gel to afford the desired
product.
General Procedure for Bromination: Synthesis of 21a,
27-30, and 40-42. To a solution of the requisite benzofuran (1
equiv) in THF (0.4 M) at room temperature under argon was added a
solution of PTSA (0.1 equiv) in THF (0.1 M), and at -78 °C, the
resulting mixture was treated by dropwise addition of a solution of NBS
(1.2 equiv) in THF (0.35 M). After being stirred at -78 °C in the
absence of light for the indicated time period, the reaction was quenched
at room temperature with a saturated aqueous solution of NaHCO3
extracted three times with ethyl acetate. The combined organic layers
were washed with a solution of sodium thiosulfate 12% w/v and brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography over
silica gel to afford the desired product. Brominated products are not
stable and are stocked at -30 °C. Beside compounds 21a and 40a,
the brominated products were only described with 1H NMR and
LRMS and directly engaged in the Suzuki-Miyaura reaction due to
their fast degradation.
General Procedure for the Suzuki-Miyaura Reaction
Method A: To a solution of brominated benzofuran 40 (1 equiv),
boronic acid (1.2 to 2 equiv), and sodium carbonate (4 equiv)
in DME/H2O (4:1, 0.1M) at room temperature under argon was
added PdCl2(dppf) (0.06 equiv). After the indicated time period at
85 °C (see Table 4), the mixture was quenched with water and
extracted three times with dichloromethane. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was pur-
ified by flash chromatography over silica gel to afford the desired
product 15.
Method B: To a solution of brominated benzofuran 21a, 40a or 41
(1 equiv), phenyl boronic acid (5 equiv), and cesium fluoride (11 equiv)
in dioxane/H2O (4:1, 0.1 M) at room temperature under argon was
added Pd(PPh3)4 (0.05 equiv). After 1 h at 101 °C (see Table 4), the
mixture was quenched with water and extracted three times with ethyl
acetate. The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography over silica gel to afford the
desired product 22, 15a, or 43, respectively.
Method B0: To a solution of brominated benzofuran 28-30 (1
equiv), phenyl boronic acid (1.5 equiv), and cesium fluoride (4.5 equiv)
in dioxane/H2O (4:1, 0.1 M) at room temperature under argon was
added Pd(PPh3)4 (0.05 equiv). After 5 h at 101 °C, the mixture was
quenched with water and extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography over silica gel to afford the desired
product 32-34, respectively.
General Procedure for N-Methylation: Synthesis of 24 and
25. To a solution of benzofuran derivative 20 or 17a (1 equiv) in DMF
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(0.2 M) was added NaH 60% in mineral oil (1.3 equiv) by portions at 0 °C
under argon. After 15 min at 0 °C, methyl iodide (1.3 equiv) was added at
room temperature and the resulting mixture was stirred during the
indicated time. The reaction was quenched into ice water and extracted
three times with ethyl acetate. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography over
silica gel to afford the desired product 24 or 25, respectively.
21b (17.3 mg, 0.04 mmol) in ethyl acetate (1 mL) at 0 °C was added a
solution of sodium thiosulfate 12% w/v (1.5 mL). After 1 h at 0 °C, the
layers were separated. The aqueous layer was extracted three times with
ethyl acetate. The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure to afford
the desired product 21a (14.3 mg, 0.04 mmol, 100% yield) as a pale yellow
solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.26 (m, 9H), 6.69 (brs, 1H),
5.25 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 152.9, 151.0, 143.3, 135.3,
128.7 (2C), 128.6 (2C), 128.4, 127.7, 125.4, 123.7, 119.5, 111.5, 89.3, 68.2;
MS (ESþ) m/z 346 [M þ H]þ (79Br), 348 [M þ H]þ (81Br).
General Procedure for One-Pot N-Acylation/Deprotec-
tion: Synthesis of 17a-d (Method A). To a solution of benzyl
benzofuran-2-ylcarbamate 20 (1 equiv) in anhydrous THF (0.075 M) at
room temperature under argon was added DMAP (1.5 equiv) and then
sodium hydride 60% in mineral oil (1.2 equiv) by portions (1/3 equiv for
each portion) at 0 °C. After 15 min at 0 °C, the requisite aroyl chloride
(1.01 or 3 equiv) and triethylamine (6 equiv) were added dropwise and the
resulting mixture was stirred at reflux during the indicated time period. The
reaction was quenched into ice water and extracted three times with ethyl
acetate. The combined organic layers were washed with a solution of
saturated sodium bicarbonate and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified by
flash chromatography over silica gel to afford the desired product 17.
General Procedure for N-Acylation: Synthesis of 23a-c,
23e, and 23f (Method B). To a solution of benzyl benzofuran-2-
ylcarbamate 20 (1 equiv) in anhydrous THF (0.075 M) at 0 °C under
argon was added sodium hydride 60% in mineral oil (3 equiv) by
portions. After 15 min at 0 °C, the requisite aroyl chloride (3 equiv) was
added dropwise. After the indicated time period at reflux, the reaction
was quenched into ice water and extracted three times with ethyl acetate.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography over silica gel to afford the
desired product 23.
Benzyl Bromo(3-bromobenzofuran-2-yl)carbamate
21b. To a solution of benzyl benzofuran-2-ylcarbamate 20 (75 mg,
0.28 mmol) in acetic acid (2 mL, 0.14 M) at room temperature under
argon was added successively sodium acetate (92 mg, 1.12 mmol) and a
solution of bromine in acetic acid (750 μL, C = 0.1 g/mL, 0.48 mmol)
dropwise. After 40 min at room temperature, the mixture was quenched
at 0 °C with a solution of sodium hydroxide 30% w/v until pH 8 and
extracted three times with ethyl acetate. The combined organic layers
were washed with a solution of sodium hydroxide 10% w/v, a solution of
sodium thiosulfate 12% w/v, and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography over silica gel (cyclohexane/EtOAc/triethyla-
mine 98:2:0.2) to afford the desired product 21b (77 mg, 0.18 mmol,
65% yield) as an orange powder: 1H NMR (300 MHz, CDCl3) δ 7.66
(dd, J = 7.6, 1.1 Hz, 1H), 7.47-7.35 (m, 6H), 7.27 (dt, J = 7.6, 1.0 Hz,
1H), 7.02 (d, J = 8.2 Hz, 1H), 5.34 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 161.8, 157.9, 150.5, 135.0, 132.7, 130.2, 128.61 (3C), 128.60 (2C),
125.9, 125.8, 111.5, 69.0; MS (ESþ) m/z 424 [M þ H]þ (C16H11-
79Br2NO3), 426 [M þ H]þ (C16H1179Br81BrNO3), 428 [M þ H]þ
(C16H1181Br2NO3).
Benzyl 3-Phenylbenzofuran-2-ylcarbamate 22. Following
the general procedure for the Suzuki-Miyaura reaction (method B), a
mixture of the brominated product 21a (100 mg, 0.29 mmol), phenyl
boronic acid (176 mg, 1.44 mmol), Pd(PPh3)4 (16.7 mg, 0.014 mmol),
and CsF (483 mg, 3.18 mmol) was stirred in dioxane/H2O (3.6 mL, 4:1)
at 101 °C for 1 h. After workup, the crude product was purified by flash
chromatography over silica gel (toluene/cyclohexane 50:50 to 100:0) to
afford the desired product 22 (54.5 mg, 0.16 mmol, 55% yield) as a
yellow solid: mp 102 °C (recrystallized from heptane to give off-white
needles); IR (CH2Cl2) νmax 3399, 3066, 3037, 1746, 1641, 1503, 1480,
General Procedure for Deprotection: Synthesis of 17e and
17f (Method B). A solution of protected 2-arylamidobenzofuran 23e
or 23f (1 mmol) in methanol (0.02 M) at room temperature was stirred
with 10% Pd/C under hydrogen atmosphere. After the indicated time
period, the resulting reaction was filtered and the filtrate was concen-
trated under reduced pressure. The crude product was purified by flash
chromatography over silica gel to afford the desired product 17e or 17f,
respectively.
1
1470, 1455, 1309, 1216, 1059 cm-1; H NMR (300 MHz, CDCl3) δ
Benzyl Benzofuran-2-ylcarbamate 20. Following the general
procedure for Curtius rearrangement,39 a mixture of benzofuran-2-
carboxylic acid 19 (1.00 g, 6.17 mmol), sodium azide (682 mg, 10.49
mmol), sodium tert-butoxide (89 mg, 0.93 mmol), and benzylchlor-
oformate (970 μL, 6.79 mmol) was stirred in DME (50 mL) at 75 °C for
20 h. After workup, the crude product was purified by flash chromatog-
raphy over silica gel (cyclohexane/EtOAc 95:5) to afford the desired
product 20 (1.14 g, 4.26 mmol, 69% yield) as a pale yellow powder: mp
97 °C (recrystallized from heptane to give pale yellow crystals); IR
(CH2Cl2) νmax 3410, 3052, 2960, 1745, 1624, 1524, 1457, 1284, 1244,
1206, 1186, 1059 cm-1; 1H NMR (300 MHz, MeOD) δ 7.43-7.28 (m,
7H), 7.16-7.07 (m, 2H), 6.42 (brs, 1H), 5.21 (s, 2H); 13C NMR (75
MHz, MeOD) δ 153.0, 150.2, 149.4, 136.2, 129.5, 128.2 (2C), 127.7
(2C), 127.9, 122.7, 121.9, 119.3, 109.5, 87.6, 66.9; MS (ESþ) m/z 290
[M þ Na]þ, (ES-) m/z 266 [M - H]-.
7.64 (d, J = 7.01 Hz, 1H), 7.55-7.43 (m, 5H), 7.39-7.24 (m, 8H), 6.64
(brs, 1H), 5.19 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.0, 151.7,
141.6, 135.5, 131.0, 129.0 (3C), 128.6 (2C), 128.5 (2C), 128.3, 127.8,
127.6 (2C), 124.8, 123.2, 120.1, 112.5, 111.4, 68.0; HRMS (ESþ) m/z
calcd for C22H17NO3Na [M þ Na]þ 366.1106, found 366.1100.
N-(3-Phenylbenzofuran-2-yl)benzamide 15a from 22. To
a solution of benzyl 3-phenylbenzofuran-2-ylcarbamate 22 (50 mg, 0.15
mmol) in CHCl3 (1 mL) at room temperature under argon was added
successively DMAP (26.7 mg, 0.22 mmol), triethylamine (0.12 mL, 0.87
mmol), and benzoyl chloride (0.05 mL, 0.44 mmol). The resulting
mixture was stirred at reflux for 16 h. The reaction was quenched into ice
water and extracted three times with ethyl acetate. The combined
organic layers were washed with a solution of saturated sodium
bicarbonate and brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography over silica gel (toluene/cyclohexane 50:50 to 100:0)
to afford the desired product 15a (27.8 mg, 0.09 mmol, 61% yield).
N-(3-Phenylbenzofuran-2-yl)benzamide 15a from 40a.
Following the general procedure for the Suzuki-Miyaura reaction
(method B), a mixture of the brominated product 40a (183 mg, 0.58
mmol), phenyl boronic acid (354 mg, 2.90 mmol), Pd(PPh3)4 (33.4 mg,
0.029 mmol), and CsF (970 mg, 6.38 mmol) was stirred in dioxane/
H2O (7.1 mL, 4:1) at 101 °C for 1 h. After workup, the crude product
Benzyl 3-Bromobenzofuran-2-ylcarbamate 21a from
20. Following the general procedure for bromination, a mixture of
benzyl benzofuran-2-ylcarbamate 20 (600 mg, 2.25 mmol), PTSA
(43 mg, 0.23 mmol), and NBS (480 mg, 2.7 mmol) was stirred in
THF at -78 °C for 25 min. After workup, the crude product was purified
by flash chromatography over silica gel (toluene) to afford the desired
product 21a (575 mg, 1.66 mmol, 74% yield) as a pale yellow solid.
Benzyl 3-Bromobenzofuran-2-ylcarbamate 21a from
21b. To a solution of benzyl bromo(3-bromobenzofuran-2-yl)carbamate
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was purified by flash chromatography over silica gel (toluene/cyclohex-
ane 50:50 to 100:0) to afford the desired product 15a (76 mg, 0.24
mmol, 42% yield) as a pale yellow solid: mp 175 °C (recrystallized from
heptane to give a pale yellow powder); IR (CH2Cl2) νmax 3409, 3065,
2927, 1697, 1635, 1502, 1464, 1271, 1251, 1181 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.87 (brs, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.70-7.67 (m,
1H), 7.61-7.44 (m, 8H), 7.39-7.25 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.9, 152.1, 142.2, 132.9, 132.5, 131.2, 129.0 (2C), 128.8
(2C), 128.4 (2C), 127.75, 127.62, 127.56 (2C), 124.7, 123.2, 120.0,
112.9, 111.5; HRMS (ESþ) m/z calcd for C21H15NO2Na [M þ Na]þ
336.1000, found 336.1009.
yl)benzamide 17a (430 mg, 1.81 mmol) and MeI (0.15 mL, 2.36 mmol)
in DMF (9 mL) was treated with NaH 60% in mineral oil (94 mg, 2.36
mmol) by portions at 0 °C. The reaction mixture was stirred at room
temperature for 4 h. After workup, the crude product was purified by
flash chromatography over silica gel (cyclohexane/ethyl acetate 97:3) to
afford the desired product 25 (416 mg, 1.66 mmol, 92%) as a pale yellow
oil: 1H NMR (300 MHz, CDCl3) δ 7.45-7.15 (m, 9H), 6.04 (s, 1H),
3.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.6, 152.4, 151.7, 134.9,
130.6, 128.1 (2C), 128.0, 127.9 (2C), 124.4, 123.1, 121.0, 111.1, 99.5,
36.3; HRMS (ESþ) m/z calcd for C16H13NO2Na [M þ Na]þ 274.0844,
found 274.0856.
N-(Benzofuran-2-yl)benzamide 17a. Following the general
procedure for one-pot N-acylation/deprotection, to a solution of benzyl
benzofuran-2-ylcarbamate 20 (100 mg, 0.37 mmol) in anhydrous THF
(5 mL) at room temperature under argon was added DMAP (68.5 mg,
0.56 mmol) and then sodium hydride 60% in mineral oil (18 mg, 0.45
mmol) by portions at 0 °C. After 15 min at 0 °C, benzoyl chloride (0.13
mL, 1.12 mmol) and triethylamine (0.31 mL, 2.25 mmol) were added
and the resulting mixture was stirred at reflux overnight. After workup,
the crude product was purified by flash chromatography over silica gel
(toluene/cyclohexane 50:50) to afford the desired product 17a (75 mg,
0.31 mmol, 84% yield) as a pale yellow solid: mp 128 °C (recrystallized
from heptane to give white crystals); IR (CH2Cl2) νmax 3421, 3055,
1689, 1610, 1600, 1520, 1491, 1456, 1249, 1189 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.6 (brs, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.61-7.47 (m,
4H), 7.33 (d, J = 7.9 Hz, 1H), 7.26-7.17 (m, 2H), 6.94 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 163.6, 149.7, 147.8, 133.1, 132.5, 129.5,
129.0 (2C), 127.2 (2C), 123.3, 122.9, 120.5, 110.2, 90.7; HRMS (ESþ)
m/z calcd for C15H12NO2 [M þ H]þ 238.0868, found 238.0858.
Benzyl Benzofuran-2-yl(benzoyl)carbamate 23a. Follow-
ing the general procedure for N-acylation, to a solution of benzyl
benzofuran-2-ylcarbamate 20 (100 mg, 0.375 mmol) in anhydrous THF
(5 mL) at 0 °C under argon was added sodium hydride 60% in mineral oil
(75 mg, 1.87 mmol) by portions. After 15 min at 0 °C, benzoyl chloride
(0.13 mL, 1.12 mmol) was added dropwise. Stirring at reflux overnight was
followed by workup. The crude product was purified by flash chromatog-
raphy over silica gel (toluene) to afford the desired product 23a (129 mg,
0.35 mmol, 93% yield) as a pale yellow solid: mp 91 °C (recrystallized from
heptane to give a white powder); IR (CH2Cl2) νmax 3685, 3068, 3037,
N-(Benzofuran-2-yl)-N-(methoxymethyl)benzamide 26.
To a solution of N-(benzofuran-2-yl)benzamide 17a (381.0 mg, 1.61
mmol, 1 equiv) in DMF (8 mL, 0.2 M) was added sodium hydride
60% in mineral oil (193 mg, 4.82 mmol, 3 equiv) by portions at 0 °C
under argon. After 15 min at 0 °C, triethylamine (0.67 mL, 4.82
mmol, 3 equiv) and chloro(methoxy)methane (0.37 mL, 4.82 mmol,
3 equiv) were added at room temperature and the resulting mixture
was stirred overnight at 55 °C. The reaction was quenched into ice water
and extracted three times with ethyl acetate. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography over silica gel (toluene/EtOAc 99:1 to 97:3) to afford
the desired product 26 (353.0 mg, 1.26 mmol, 78%) as a yellow oil: 1H
NMR (300 MHz, CDCl3) δ 7.51 (d, J = 6.9 Hz, 2H), 7.42-7.15 (m, 7H),
6.27 (s, 1H), 5.29 (s, 2H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.8, 151.9, 150.4, 134.4, 130.9, 128.0 (2C), 127.9, 127.8 (2C), 124.4,
123.0, 120.9, 111.1, 100.9, 79.0, 56.9; HRMS (ESþ) m/z calcd for
C17H16NO3 [M þ H]þ 282.1130, found 282.1143.
Benzyl Benzoyl(3-bromobenzofuran-2-yl)carbamate 27.
Following the general procedure for bromination, a mixture of benzyl
benzofuran-2-yl(benzoyl)carbamate 23a (330 mg, 0.89 mmol), PTSA
(17.0 mg, 0.09 mmol), and NBS (190 mg, 1.07 mmol) was stirred in
THF at 0 °C for 90 min. After workup, the residue was purified by flash
chromatography over silica gel (toluene/cyclohexane 70:30) to afford
the desired product 27 (297 mg, 0.66 mmol, 74% yield) as a yellow solid:
1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 6.9 Hz, 2H), 7.53-7.26 (m,
10H), 7.19-7.16 (m, 2H), 5.22 (s, 2H); MS (ESþ) m/z 472 [M þ Na]þ
(79Br), 474 [M þ Na]þ (81Br)
1
1752, 1715, 1613, 1453, 1330, 1238, 1162, 1047 cm-1; H NMR (300
Benzyl-3-bromobenzofuran-2-yl(methyl)carbamate 28.
Following the general procedure for bromination, a mixture of benzyl
benzofuran-2-yl(methyl)carbamate 24 (480 mg, 1.70 mmol), PTSA (32
mg, 0.17 mmol), and NBS (364 mg, 2.04 mmol) was stirred in THF at -
78 °C for 25 min. After workup, the residue was purified by flash
chromatography over silica gel (toluene) to afford the desired product
MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 2H), 7.54-7.45 (m, 3H), 7.37 (t, J =
7.5 Hz, 2H), 7.32-7.26 (m, 4H), 7.26-7.15 (m, 3H), 6.6 (s, 1H), 5.21 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 169.9, 153.0, 152.8, 146.0, 134.5,
133.9, 132.8, 128.9 (2C), 128.51 (3C), 128.47 (2C), 128.1 (2C), 127.8,
125.0, 123.2, 121.4, 111.4, 103.2, 69.2; HRMS (ESþ) m/z calcd for
C23H18NO4 [M þ H]þ 372.1236, found 372.1227.
1
28 (469 mg, 1.30 mmol, 76% yield) as a colorless oil: H NMR (300
MHz, CDCl3) δ 7.52-7.49 (m, 1H), 7.44-7.26 (m, 8H), 5.20 (s, 2H),
3.33 (s, 3H); MS (ESþ) m/z 360 [M þ H]þ (79Br), 362 [M þ H]þ
(81Br), 382 [M þ Na]þ (79Br), 384 [M þ Na]þ (81Br).
Benzyl Benzofuran-2-yl(methyl)carbamate 24. Following
the general procedure for N-methylation, to a solution of benzyl
benzofuran-2-ylcarbamate 20 (500 mg, 1.87 mmol) in DMF (10 mL)
at 0 °C under argon was added sodium hydride 60% in mineral oil (97
mg, 2.43 mmol) by portions. After 15 min at 0 °C, MeI (0.55 mL, 2.43
mmol) was added. The reaction mixture was stirred at room temperature
for 3 h. After workup, the crude product was purified by flash
chromatography over silica gel (toluene/cyclohexane 90:10) to afford
the desired product 24 (481 mg, 1.71 mmol, 91% yield) as a pale yellow
solid: IR (CH2Cl2) νmax 3685, 3035, 1721, 1597, 1456, 1394, 1359,
1275, 1249, 1154, 1142 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.50-
7.47 (m, 1H), 7.41-7.33 (3, 6H), 7.23-7.20 (m, 2H), 6.50 (s, 1H), 5.26
(s, 2H), 3.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.1, 150.9 (2C),
135.9, 128.6 (4C), 128.3, 128.0, 123.1 (2C), 120.5, 110.6, 94.7, 68.1,
35.0; HRMS (ESþ) m/z calcd for C17H15NO3Na [M þ Na]þ 304.0950,
found 304.0940.
N-(3-Bromobenzofuran-2-yl)-N-methylbenzamide 29.
Following the general procedure for bromination, a mixture of 2-aryla-
midobenzofuran 25 (317 mg, 1.26 mmol), PTSA (24 mg, 0.13 mmol),
and NBS (270 mg, 1.51 mmol) was stirred in THF at -78 °C for 20 min.
After workup, the crude product was purified by flash chromatography
over silica gel (cyclohexane/EtOAc 98:2) to afford the desired product
29 (296 mg, 0.90 mmol, 71% yield) as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 7.49-7.46 (m, 2H), 7.40-7.23 (m, 5H), 7.21-7.16 (m, 2H),
3.45 (s, 3H); MS (ESþ) m/z 352 [M þ Na]þ (79Br), 354 [M þ Na]þ
(81Br).
N-(3-Bromobenzofuran-2-yl)-N-(methoxymethyl)benza-
mide 30. Following the general procedure for bromination, a mixture
of 2-arylamidobenzofuran 26 (250 mg, 0.89 mmol), PTSA (17.0 mg,
0.09 mmol), and NBS (190 mg, 1.07 mmol) was stirred in THF at -78 °C
for 20 min. After workup, the residue was purified by flash chromatography
N-(Benzofuran-2-yl)-N-methylbenzamide 25. Following the
general procedure for N-methylation, to a solution of N-(benzofuran-2-
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ARTICLE
over silica gel (toluene/EtOAc 98:2) to afford the desired product 30 (243
mg, 0.68 mmol, 76% yield) as an orange oil: 1H NMR (300 MHz, CDCl3)
δ 7.51 (d, J = 6.9 Hz, 2H), 7.45-7.42 (m, 1H), 7.38-7.18 (m, 6H), 5.32
(s, 2H), 3.59 (s, 3H); MS (ESþ) m/z 382 [M þ Na]þ (79Br), 384
[M þ Na]þ (81Br).
(s, 2H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4, 151.6, 146.9,
134.1, 133.8, 130.8, 129.5 (q, J = 32.4 Hz), 128.4 (2C), 127.7 (2C), 127.3
(2C), 127.0, 125.7 (2C, q, J = 3.75 Hz), 125.5, 124.0 (q, J = 270 Hz),
123.6, 119.9, 113.9, 111.6, 78.9, 57.9; HRMS (ESþ) m/z calcd for
C24H18NO3F3Na [M þ Na]þ 448.1136, found 448.1147.
Benzyl Methyl(3-phenylbenzofuran-2-yl)carbamate
32. Following the general procedure for the Suzuki coupling
(method B0), a mixture of the brominated product 28 (105.0 mg, 0.29
mmol), phenyl boronic acid (53.0 mg, 0.43 mmol), Pd(PPh3)4 (16.7 mg,
0.015 mmol), and cesium fluoride (198 mg, 1.30 mmol) was stirred in
dioxane/H2O (3.5 mL, 4:1) at 101 °C for 5 h. After workup, the crude
product was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 98:2) to afford the desired product 32 (100.0
mg, 0.28 mmol, 96% yield) as a pale yellow oil: IR (CH2Cl2) νmax 3066,
3036, 2954, 1721, 1636, 1454, 1390, 1333, 1151 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.70 (d, J = 6.9 Hz, 1H), 7.50-7.10 (m, 13H), 5.06 (s,
2H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.3, 151.7, 146.7,
135.9, 131.1, 128.9 (4C), 128.4, 128.1, 127.80, 127.6 (4C), 125.0, 123.1,
120.4, 113.1, 111.4, 68.0, 36.7; HRMS (ESþ) m/z calcd for C23H19NO3-
Na [M þ Na]þ 380.1263, found 380.1267.
Methyl 4-(2-(N-(Methoxymethyl)benzamido)benzofuran-
3-yl)benzoate 34c. Following the general procedure for the Suzuki
coupling (method B0), a mixture of the brominated product 30 (200 mg,
0.56 mmol), 4-(methoxycarbonyl)phenylboronic acid (150.0 mg, 0.83
mmol), Pd(PPh3)4 (32 mg, 0.028 mmol), and cesium fluoride (376 mg,
2.48 mmol) was stirred in dioxane/H2O (6.7 mL, 4:1) at 101 °C for 5 h.
After workup, the crude product was purified by flash chromatography
over silica gel (toluene/EtOAc 100:0 to 95:5) to afford the desired
product 34c (205.0 mg, 0.49 mmol, 89% yield) as an orange solid: IR
(CDCl3) νmax 3064, 2953, 1717, 1675, 1454, 1290, 1185, 1096 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.1 Hz,
1H), 7.44-7.35 (m, 2H), 7.26-7.18 (m, 4H), 7.02-6.97 (m, 4H), 5.36
(s, 2H), 3.95 (s, 3H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4,
166.7, 151.6, 146.8, 135.0, 133.9, 130.6, 129.9 (2C), 128.9, 128.0 (2C),
127.6 (2C), 127.2 (2C), 126.9, 125.3, 123.4, 120.0, 114.3, 111.5, 78.9,
57.9, 52.1; HRMS (ESþ) m/z calcd for C25H21NO5Na [M þ Na]þ
438.1317, found 438.1321.
N-Methyl-N-(3-phenylbenzofuran-2-yl)benzamide 33.
Following the general procedure for the Suzuki coupling (method B0),
a mixture of the brominated product 29 (191.5 mg, 0.58 mmol), phenyl
boronic acid (106.0 mg, 0.87 mmol), Pd(PPh3)4 (33.4 mg, 0.029 mmol),
and cesium fluoride (396 mg, 2.61 mmol) was stirred in dioxane/H2O
(7.1 mL, 4:1) at 101 °C for 4 h. After workup, the residue was purified by
flash chromatography over silica gel (toluene/EtOAc 100:0 to 90:10) to
afford the desired product 33 (181.6 mg, 0.56 mmol, 96% yield) as a pale
yellow solid: mp 136 °C (recrystallized from heptane to give white
crystals); IR (CH2Cl2) νmax 3063, 1665, 1634, 1454, 1388, 1349, 1125,
1099 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52-7.45 (m, 2H), 7.38-
7.29 (m, 4H), 7.25-7.12 (m, 2H), 7.02-6.92 (m, 6H), 3.56 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.6, 151.6, 148.2, 134.8, 130.5, 130.1,
128.9 (2C), 127.9 (2C), 127.53, 127.47 (2C), 127.4, 127.2 (2C), 125.1,
123.2, 120.3, 113.9, 111.4, 36.2; HRMS (ESþ) m/z calcd for
C22H17NO2Na [M þ Na]þ 350.1157, found 350.1160.
N-(Methoxymethyl)-N-(3-(2-methoxyphenyl)benzofuran-
2-yl)benzamide 34d. Following the general procedure for the
Suzuki coupling (method B0), a mixture of the brominated product 30
(200 mg, 0.56 mmol), 2-methoxyphenyl boronic acid (127 mg, 0.83
mmol), Pd(PPh3)4 (32 mg, 0.028 mmol), and cesium fluoride (376 mg,
2.48 mmol) was stirred in dioxane/H2O (6.7 mL, 4:1) at 101 °C for 6 h.
After workup, the crude product was purified by flash chromatography
over silica gel (toluene/EtOAc 100:0 to 95:5) to afford the desired
product 34d (202.0 mg, 0.52 mmol, 94% yield) as an orange solid: IR
(CDCl3) νmax 3064, 3001, 2939, 1671, 1455, 1298, 1248, 1095, 1079,
1032 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz, 1H),
7.33-7.14 (m, 5H), 7.09-6.99 (m, 4H), 6.87-6.79 (m, 3H), 5.34 (s,
2H), 3.62 (s, 3H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.5,
156.5, 151.5, 147.4, 134.5, 130.8, 130.3, 129.2, 128.4, 127.5-127.4 (5C),
124.5, 122.8, 120.7, 120.5, 118.5, 111.2, 110.5, 79.0, 57.4, 54.9; HRMS
(ESþ) m/z calcd for C24H21NO4Na [M þ Na]þ 410.1368, found
410.1383.
N-(Methoxymethyl)-N-(3-(3,4,5-trimethoxyphenyl)benzo-
furan-2-yl)benzamide 34e. Following the general procedure for
the Suzuki coupling (method B0), a mixture of the brominated product
30 (200 mg, 0.56 mmol), 3,4,5-trimethoxyphenyl boronic acid (176.5
mg, 0.83 mmol), Pd(PPh3)4 (32 mg, 0.028 mmol), and cesium fluoride
(376 mg, 2.48 mmol) was stirred in dioxane/H2O (6.7 mL, 4:1) at
101 °C for 6 h. After workup, the crude product was purified by flash
chromatography over silica gel (toluene/EtOAc 95:5 to 85:15) to afford
the desired product 34e (225.0 mg, 0.50 mmol, 91% yield) as a pale
yellow solid: IR (CDCl3) νmax 3005, 2940, 1675, 1581, 1510, 1455, 1357,
1301, 1129, 1096 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 8.1
Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.26-7.16 (m,
2H), 7.04-7.00 (m, 4H), 6.34 (s, 2H), 5.34 (s, 2H), 3.89 (s, 3H), 3.76 (s,
6H), 3.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.5, 153.5 (2C),
151.5, 146.3, 137.3, 134.2, 130.4, 127.5 (2C), 127.42 (2C), 127.37, 125.6,
125.1, 123.3, 120.1, 114.7, 111.4, 105.1 (2C), 78.8, 60.9, 57.8, 56.0 (2C);
HRMS (ESþ) m/z calcd for C26H25NO6Na [M þ Na]þ 470.1580,
found 470.1602.
N-(Methoxymethyl)-N-(3-phenylbenzofuran-2-yl)benz-
amide 34a. Following the general procedure for the Suzuki
coupling (method B0), a mixture of the brominated product 30
(180 mg, 0.50 mmol), phenyl boronic acid (91.5 mg, 0.75 mmol),
Pd(PPh3)4 (29 mg, 0.025 mmol), and cesium fluoride (342 mg, 2.25
mmol) was stirred in dioxane/H2O (6.1 mL, 4:1) at 101 °C for 6 h. After
workup, the crude product was purified by flash chromatography over silica
gel (toluene) to afford the desired product 34a (177.0 mg, 0.495 mmol,
99% yield) as a yellow oil: IR (CDCl3) νmax 3064, 2938, 1673, 1454, 1394,
1350, 1297, 1187, 1094, 1081 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52
(d, J= 8.4 Hz, 1H), 7.45 (d, J= 7.8 Hz, 1H), 7.38-7.30 (m, 4H), 7.26-7.16
(m, 2H), 7.10-7.09 (m, 2H), 7.01-6.99 (m, 4H), 5.35 (s, 2H), 3.59 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 170.8, 151.6, 146.2, 134.3, 130.5,
130.2, 128.7 (2C), 128.2 (2C), 127.5-127.3 (6C), 125.1, 123.2, 120.3,
115.0, 111.4, 79.0, 57.8; HRMS (ESþ) m/z calcd for C23H20NO3 [M þ
H]þ 358.1443, found 358.1440.
N-(Methoxymethyl)-N-(3-(4-(trifluoromethyl)phenyl)ben-
zofuran-2-yl)benzamide 34b. Following the general procedure
for the Suzuki coupling (method B0), a mixture of the brominated
product 30 (200 mg, 0.56 mmol), 4-(trifluoromethyl)phenyl boronic
acid (158.0 mg, 0.83 mmol), Pd(PPh3)4 (32 mg, 0.028 mmol), and
cesium fluoride (376 mg, 2.48 mmol) was stirred in dioxane/H2O (6.7
mL, 4:1) at 101 °C for 5 h. After workup, the crude product was purified
by flash chromatography over silica gel (toluene/EtOAc 100:0 to 98:2)
to afford the desired product 34b (219.0 mg, 0.52 mmol, 93% yield) as a
pale yellow solid: IR (CDCl3) νmax 3064, 2940, 1675, 1454, 1325, 1297,
1171, 1130, 1069 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.57-7.54 (m,
3H), 7.42-7.36 (m, 2H), 7.28-7.18 (m, 4H), 7.02-6.94 (m, 4H), 5.36
Benzyl 5-Methoxybenzofuran-2-ylcarbamate 37. Follow-
ing the general procedure for Curtius rearrangement, a mixture of
5-methoxybenzofuran-2-carboxylic acid 35 (2.37 g, 12.34 mmol), so-
dium azide (1.36 g, 20.92 mmol), sodium tert-butoxide (178 mg, 1.85
mmol), and benzylchloroformate (2.3 mL, 13.58 mmol) was stirred in
DME (45 mL) at 75 °C for 20 h. After workup, the crude product was
purified by flash chromatography over silica gel (cyclohexane/EtOAc
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ARTICLE
90:10 to 70:30) to afford the desired product 37 (2.45 g, 8.25 mmol, 67%
yield) as an orange powder: mp 103 °C (recrystallized from heptane to
give pale orange crystals); IR (CDCl3) νmax 3425, 2958, 1743, 1614, 1525,
1478, 1315, 1207, 1177, 1061 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.43-
7.36 (m, 5H), 7.20 (d, J= 8.7 Hz, 1H), 7.09 (brs, 1H), 6.94 (d, J=2.7Hz,1H),
6.74 (dd, J = 2.7, 8.7 Hz, 1H), 6.47 (brs, 1H), 5.26 (s, 2H), 3.83 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ156.1, 151.8, 148.4, 144.8, 135.3, 130.1, 128.6 (2C),
128.5, 128.3 (2C), 110.5, 110.4, 103.2, 89.1, 67.8, 55.8; HRMS (ES-)
m/z calcd for C17H14NO4 [M - H]- 296.0923, found 296.0918.
Benzyl 5-Nitrobenzofuran-2-ylcarbamate 38. Following the
general procedure for Curtius rearrangement, a mixture of 5-nitroben-
zofuran-2-carboxylic acid 36 (2.55 g, 12.32 mmol), sodium azide (1.36 g,
20.92 mmol), sodium tert-butoxide (178 mg, 1.85 mmol), and benzyl-
chloroformate (2.3 mL, 6.79 mmol) was stirred in DME (45 mL) at
75 °C for 20 h. After workup, the crude product was purified by flash
chromatography over silica gel (cyclohexane/EtOAc 90:10 to 50:50) to
afford the desired product 38 (1.87 g, 5.99 mmol, 49% yield) as a yellow
powder: mp 150 °C (recrystallized from EtOAc/heptane to give yellow
crystals); IR (CDCl3) νmax 3420, 3068, 1747, 1617, 1524, 1347, 1257,
1209, 1158, 1068 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s,
1H), 8.45 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 2.4, 8.7 Hz, 1H), 7.68 (d, J =
8.7 Hz, 1H), 7.46-7.33 (m, 5H), 6.65 (s, 1H), 5.24 (s, 2H); 13C NMR
(75 MHz, DMSO-d6) δ 152.6, 152.4, 152.0, 143.9, 135.8, 130.2, 128.5-
128.2 (5C), 117.9, 115.6, 110.8, 87.7, 66.8; HRMS (ES-) m/z calcd for
C16H11N2O5 [M - H]- 311.0668, found 311.0681.
N-(Benzofuran-2-yl)-4-methoxybenzamide 17b. Following
the general procedure for one-pot N-acylation/deprotection, to a
solution of benzyl benzofuran-2-ylcarbamate 20 (2.50 g, 9.36 mmol)
in anhydrous THF (85 mL) at room temperature under argon was
added DMAP (1.71 g, 14 mmol) and then sodium hydride 60% in
mineral oil (375 mg, 9.37 mmol) by portions at 0 °C. After 15 min at
0 °C, 4-methoxybenzoyl chloride (1.27 mL, 9.36 mmol) and triethyla-
mine (7.8 mL, 56 mmol) were added and the resulting mixture was
stirred at reflux overnight. After workup, the crude product was purified
by flash chromatography over silica gel (toluene/cyclohexane 60:40 to
100:0) to afford the desired product 17b (1.92 g, 7.18 mmol, 77% yield)
as a pale yellow solid: mp 147 °C (recrystallized from heptane to give off-
white crystals); IR (CDCl3) νmax 3682, 3436, 2966, 2937, 2842, 2250,
1683, 1605, 1527, 1503, 1456, 1249, 1177, 1031 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.49 (brs, 1H), 7.88 (d, J = 8.7 Hz, 2H), 7.51-7.48 (m,
1H), 7.35-7.32 (m, 1H), 7.25-7.15 (m, 2H), 6.97 (d, J = 8,7 Hz, 2H),
6.91 (s, 1H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 163.0,
149.7, 148.1, 129.7, 129.2 (2C), 125.3, 123.3, 122.8, 120.5, 114.2 (2C),
110.1, 90.4, 55.5; HRMS (ESþ) m/z calcd for C16H14NO3 [M þ H]þ
268.0974, found 268.0961.
N-(Benzofuran-2-yl)-4-chlorobenzamide 17c. Following
the general procedure for one-pot N-acylation/deprotection, to a
solution of benzyl benzofuran-2-ylcarbamate 20 (1.0 g, 3.75 mmol) in
anhydrous THF (50 mL) at room temperature under argon was added
DMAP (685 mg, 5.62 mmol) and then sodium hydride 60% in mineral
oil (230 mg, 5.62 mmol) by portions at 0 °C. After 15 min at 0 °C,
4-chlorobenzoyl chloride (1.44 mL, 11.24 mmol) and triethylamine (3.1
mL, 22.5 mmol) were added and the resulting mixture was stirred at
reflux overnight. After workup, the crude product was purified by flash
chromatography over silica gel (toluene/cyclohexane 50:50 to 100:0) to
afford the desired product 17c (678 mg, 2.50 mmol, 66% yield) as a
yellow solid: mp 176 °C (recrystallized from heptane to give pale yellow
crystals); IR (CH2Cl2) νmax 3686, 3420, 3055, 1693, 1608, 1595, 1522,
1487, 1456, 1260, 1188, 1101, 1014 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.38 (brs, 1H), 7.86 (dt, J = 8.9, 2.2 Hz, 2H), 7.53 (m, 1H), 7.50 (dt, J =
8.9, 2.2 Hz, 2H), 7.37 (m, 1H), 7.22 (m, 2H), 6.94 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 162.5, 149.8, 147.5, 139.0, 131.4, 129.4, 129.3 (2C),
128.6 (2C), 123.4, 123.1, 120.6, 110.2, 91.0; HRMS (ESþ) m/z calcd for
C15H10NO2NaCl [M þ Na]þ 294.0298, found 294.0298.
N-(Benzofuran-2-yl)-4-nitrobenzamide 17d. Following the
general procedure for one-pot N-acylation/deprotection, to a solution of
benzyl benzofuran-2-ylcarbamate 20 (100 mg, 0.37 mmol) in anhydrous
THF (5 mL) at room temperature under argon was added DMAP (68.5
mg, 0.56 mmol) and then sodium hydride 60% in mineral oil (18 mg, 0.45
mmol) by portions at 0 °C. After 15 min at 0 °C, 4-nitrobenzoyl chloride
(208 mg, 1.12 mmol) and triethylamine (0.31 mL, 2.25 mmol) were added
and the resulting mixture was stirred at room temperature for 50 min. After
workup, the crude product was purified by flash chromatography over silica
gel (toluene/cyclohexane 80:20 to 100:0) to afford the desired product 17d
(77 mg, 0.27 mmol, 73% yield) as an orange solid: mp 210 °C
(recrystrallized from heptane to give an orange powder); IR (CH2Cl2)
νmax 3397, 1747, 1641, 1503, 1470, 1452, 1394, 1307, 1216, 1177, 1059
cm-1; 1H NMR (300 MHz, acetone-d6) δ 10.93 (brs, 1H), 8.40 (d, J = 9.1
Hz, 2H), 8.35 (d, J = 9.1 Hz, 2H), 7.59-7.55 (m, 1H), 7.43-7.38 (m, 1H),
7.26-7.19 (m, 2H), 6.98 (d, J = 0.9 Hz, 1H); 13CNMR (75 MHz, acetone-
d6) δ 162.1, 150.1, 149.8, 149.1, 139.0, 129.4, 129.2 (2C), 123.7 (2C),
123.3, 123.0, 120.4, 110.1, 90.7; HRMS (ESþ) m/z calcd for C15H11N2O4
[M þ H]þ 283.0719, found 283.0727.
N-(Benzofuran-2-yl)-4-fluorobenzamide 17e. Following the
general procedure for deprotection, a solution of protected 2-arylami-
dobenzofuran 23e (430 mg, 1.10 mmol) in methanol (60 mL) at room
temperature was stirred with 10% Pd/C under hydrogen atmosphere.
After 3 h, the resulting reaction was filtered and the filtrate was
concentrated under reduced pressure. The crude product was purified
by flash chromatography over silica gel (toluene) to afford the desired
product 17e (201.5 mg, 0.79 mmol, 72% yield) as a pale yellow solid: mp
160 °C (recrystallized from heptane to give off-white crystals); IR
(CDCl3) νmax 3433, 3065, 2250, 1687, 1603, 1526, 1502, 1456, 1248,
1187, 1160 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.38 (brs, 1H), 7.96-
7.92 (m, 2H), 7.54-7.50 (m, 1H), 7.38-7.35 (m, 1H), 7.26-7.18 (m,
4H), 6.94 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 165.3 (d, J = 252 Hz),
162.5, 149.8, 147.7, 129.7 (2C, d, J = 9.2 Hz), 129.5, 129.3 (d, J = 3.1
Hz), 123.4, 123.1, 120.6, 116.2 (2C, d, J = 22 Hz), 110.2, 90.9; HRMS
(ESþ) m/z calcd for C15H10NO2FNa [M þ Na]þ 278.0593, found
278.0590.
N-(Benzofuran-2-yl)-4-(trifluoromethyl)benzamide 17f.
Following the general procedure for N-acylation, to a solution of benzyl
benzofuran-2-ylcarbamate 20 (2.0 g, 7.5 mmol) in anhydrous THF (80
mL) at 0 °C under argon was added sodium hydride 60% in mineral oil
(540 mg, 22.5 mmol) by portions. After 15 min at 0 °C, 4-(trifluoro-
methyl)benzoyl chloride (4.7 g, 22.5 mmol) was added dropwise.
Stirring at reflux overnight was followed by workup. The crude product
was purified by flash chromatography over silica gel (toluene/cyclohex-
ane 50:50 to 100:0) to afford the product 23f as an inseparable mixture
with the starting material 20 (2.39 g, 5.44 mmol, 73% yield based on 1H
NMR analysis). Following the general procedure for deprotection, a
solution of the mixture of 23f and 20 in methanol (300 mL) at room
temperature was stirred with 10% Pd/C under hydrogen atmosphere.
After 4 h, the resulting reaction was filtered and the filtrate was
concentrated under reduced pressure. The crude product was purified
by flash chromatography over silica gel (toluene) to afford the desired
product 17f (1.36 g, 4.46 mmol, 60% overall yield, two steps) as a pale
yellow solid: mp 181 °C (recrystallized from heptane to give white
cotton); IR (CDCl3) νmax 3693, 3430, 3065, 2250, 1691, 1609, 1525,
1508, 1456, 1326, 1250, 1177, 1139, 1067 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.46 (brs, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz,
2H), 7.56-7.53 (m, 1H), 7.39-7.36 (m, 1H), 7.27-7.22 (m, 2H), 6.98
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 162.3, 149.8, 147.3, 136.3, 134.2
(q, J = 32.7 Hz), 129.3, 127.7 (2C), 126.1 (2C, q, J = 3.7 Hz), 123.5,
123.4 (q, J = 271 Hz), 123.3, 120.7, 110.3, 91.4; HRMS (ESþ) m/z calcd
for C16H11NO2F3 [M þ H]þ 306.0742, found 306.0746.
N-(5-Methoxybenzofuran-2-yl)benzamide 18. Following
the general procedure for one-pot N-acylation/deprotection, to a
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solution of benzyl 5-methoxybenzofuran-2-ylcarbamate 37 (297 mg,
1.00 mmol) in anhydrous THF (15 mL) at room temperature under
argon was added DMAP (183 mg, 1.50 mmol) and then sodium hydride
60% in mineral oil (48 mg, 1.20 mmol) by portions at 0 °C. After 15 min
at 0 °C, benzoyl chloride (0.12 mL, 1.01 mmol) and triethylamine (0.83
mL, 6.00 mmol) were added and the resulting mixture was stirred at
reflux overnight. After workup, the crude product was purified by flash
chromatography over silica gel (toluene/EtOAc 98:2) to afford the
desired product 18 (213.0 mg, 0.80 mmol, 80% yield) as a pale yellow
solid: mp 138 °C (recrystallized from heptane/EtOAc to give off-white
crystals); IR (CDCl3) νmax 3432, 2956, 1688, 1601, 1521, 1477, 1209,
1187, 1030 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.42 (brs, 1H), 7.91
(d, J = 6.9 Hz, 2H), 7.63-7.58 (m, 1H), 7.55-7.50 (m, 2H), 7.25 (d, J =
9.0 Hz, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.90 (s, 1H), 6.79 (dd, J = 2.7, 9.0
Hz, 1H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.8, 156.2,
148.5, 144.5, 133.0, 132.4, 130.1, 128.8 (2C), 127.2 (2C), 111.0, 110.5,
103.4, 91.1, 55.8; HRMS (ESþ) m/z calcd for C16H14NO3 [M þ H]þ
268.0974, found 268.0986.
N-(5-Nitrobenzofuran-2-yl)benzamide 39. Following the
general procedure for one-pot N-acylation/deprotection, to a solution
of benzyl 5-nitrobenzofuran-2-ylcarbamate 38 (624 mg, 2.00 mmol) in
anhydrous THF (24 mL) at room temperature under argon was added
DMAP (366 mg, 3.00 mmol) and then sodium hydride 60% in mineral
oil (96 mg, 2.40 mmol) by portions at 0 °C. After 15 min at 0 °C, benzoyl
chloride (0.23 mL, 2.02 mmol) and triethylamine (1.7 mL, 12.00 mmol)
were added and the resulting mixture was stirred at reflux overnight.
After workup, the crude product was purified by flash chromatography
over silica gel (toluene/EtOAc 100:0 to 90:10) to afford the desired
product 39 (402.0 mg, 1.43 mmol, 71% yield) as a yellow solid: mp
224 °C (recrystallized from EtOAc/heptane to give a pale yellow
powder); IR (CDCl3) νmax 3431, 1696, 1609, 1526, 1491, 1347, 1260,
1070 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.54 (s,
1H), 8.12 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 8.7 Hz,
1H), 7.68-7.63 (m, 1H), 7.59-7.54 (m, 2H), 7.09 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 164.3, 152.4, 152.2, 144.0, 132.7, 132.4, 130.0,
128.5 (2C), 128.0 (2C), 118.4, 116.1, 110.8, 90.4; HRMS (ES-) m/z
calcd for C15H9N2O4 [M - H]- 281.0562, found 281.0563.
Benzyl Benzofuran-2-yl(4-methoxybenzoyl)carbamate
23b. Following the general procedure for N-acylation, to a solution
of benzyl benzofuran-2-ylcarbamate of 20 (500 mg, 1.87 mmol) in
anhydrous THF (20 mL) at 0 °C under argon was added sodium hydride
60% in mineral oil (135 mg, 5.62 mmol) by portions. After 15 min at
0 °C, 4-methoxybenzoyl chloride (0.76 mL, 5.62 mmol) was added
dropwise. Stirring at reflux overnight was followed by workup. The crude
product was purified by flash chromatography over silica gel (toluene) to
afford the desired product 23b (533 mg, 1.33 mmol, 71% yield) as a pale
yellow solid: mp 128 °C (recrystallized from heptane to give off-white
crystals); IR (CH2Cl2) νmax 3067, 3037, 2968, 2939, 2843, 1748, 1706,
1605, 1512, 1454, 1421, 1381, 1328, 1312, 1275, 1252, 1170, 1045, 1028
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.78 (dt, J = 8.7, 1.6 Hz, 2H), 7.51
(d, J = 7.6 Hz, 1H), 7.48 (d, J = 9.6 Hz, 1H), 7.33-7.26 (m, 4H), 7.26-
7.20 (m, 3H), 6.84 (dt, J = 8.7, 1.8 Hz, 2H), 6.58 (s, 1H), 5.24 (s, 2H),
3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.9, 163.6, 153.2, 152.7,
146.5, 134.7, 131.7 (2C), 128.51 (2C), 128.46, 128.1 (2C), 127.9, 125.8,
124.9, 123.1, 121.4, 113.9 (2C), 111.4, 102.5, 69.1, 55.5; HRMS (ESþ)
m/z calcd for C24H19NO5Na [M þ Na]þ 424.1161, found 424.1158.
Benzyl Benzofuran-2-yl(4-chlorobenzoyl)carbamate 23c.
Following the general procedure for N-acylation, to a solution of benzyl
benzofuran-2-ylcarbamate of 20 (250 mg, 0.94 mmol) in anhydrous
THF (11 mL) at 0 °C under argon was added sodium hydride 60% in
mineral oil (68 mg, 2.81 mmol) by portions. After 15 min at 0 °C,
4-chlorobenzoyl chloride (0.36 mL, 2.81 mmol) was added dropwise.
Stirring at reflux overnight was followed by workup. The crude product
was purified by flash chromatography over silica gel (toluene/
cyclohexane 50:50 to 100:0) to afford the desired product 23c (345
mg, 0.85 mmol, 90% yield) as a yellow solid: mp 118 °C (recrystallized
from heptane to give pale yellow crystals); IR (CH2Cl2) νmax 3416,
3068, 3037, 2964, 1753, 1713, 1613, 1593, 1522, 1488, 1454, 1402, 1380,
1329, 1252, 1162, 1092, 1046, 1015 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.67 (dt, J = 8.6, 2.1 Hz, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.6
Hz, 1H), 7.35-7.29 (m, 6H), 7.26-7.16 (m, 3H), 6.60 (s, 1H), 5.21 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 169.0, 152.8 (2C), 145.7, 139.3,
134.4, 132.3, 130.2 (2C), 128.8 (2C), 128.7, 128.6 (2C), 128.3 (2C),
127.7, 125.2, 123.3, 121.5, 111.4, 103.4, 69.4; HRMS (ESþ) m/z calcd
for C23H17NO4Cl [M þ H]þ 406.0846, found 406.0857.
Benzyl Benzofuran-2-yl(4-fluorobenzoyl)carbamate 23e.
Following the general procedure for N-acylation, to a solution of benzyl
benzofuran-2-ylcarbamate 20 (500 mg, 1.87 mmol) in anhydrous THF
(25 mL) at 0 °C under argon was added sodium hydride 60% in mineral
oil (135 mg, 5.62 mmol) by portions. After 15 min at 0 °C, 4-fluoro-
benzoyl chloride (0.66 mL, 5.62 mmol) was added dropwise. Stirring at
reflux overnight was followed by workup. The crude product was
purified by flash chromatography over silica gel (toluene) to afford
the desired product 23e (602 mg, 1.54 mmol, 83% yield) as a yellow
solid: mp 111 °C (recrystallized from heptane to give pale yellow
crystals); IR (CH2Cl2) νmax 3068, 3037, 2964, 1753, 1712, 1603, 1508,
1453, 1380, 1329, 1238, 1158, 1045 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.77 (ddt, J = 8.9, 5.25, 2.1 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.46 (d,
J = 8.3 Hz, 1H), 7.38-7.29 (m, 4H), 7.26-7.18 (m, 3H), 7.02 (tt, J =
8.8, 2.1 Hz, 2H), 6.59 (s, 1H), 5.22 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 168.7, 165.5 (d, J = 253.4 Hz), 152.9, 152.8, 145.9, 134.5, 131.6 (2C, d,
J = 9.3 Hz), 130.0 (d, J = 3.2 Hz), 128.7, 128.6 (2C), 128.2 (2C), 127.8,
125.1, 123.3, 121.5, 115.8 (2C, d, J = 22.1 Hz), 111.4, 103.2, 69.3; HRMS
(ESþ) m/z calcd for C23H16NO4FNa [M þ Na]þ 412.0961, found
412.0956.
Benzyl Benzofuran-2-yl(4-(trifluoromethyl)benzoyl)car-
bamate 23f. To a solution of 2-arylamidobenzofuran 17f (250 mg,
0.82 mmol) in anhydrous THF (5 mL) at 0 °C under argon was added
sodium hydride 60% in mineral oil (50 mg, 1.2 mmol). After 15 min at
0 °C benzylchloroformate (130 μL, 0.9 mmol) was added dropwise and
the resulting mixture was stirred at room temperature during 6 h. The
reaction was dropped on icy water. The aqueous layer was extracted
three times with ethyl acetate. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography over silica
gel (toluene/cyclohexane, 75:25) to afford the desired product 23f (330
mg, 0.75 mmol, 92% yield) as a pale yellow solid: mp 127 °C
(recrystallized from hexane to give white needles); IR (CH2Cl2) νmax
3685, 3053, 1722, 1622, 1596, 1458, 1440, 1394, 1360, 1276, 1154, 1095
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.61 (d,
J = 8.2 Hz, 2H), 7.57-7.54 (m, 1H), 7.49-7.46 (m, 1H), 7.37-7.23 (m,
5H), 7.15 (dd, J = 5.6, 1.9 Hz, 2H), 6.64 (d, J = 0.8 Hz, 1H), 5.20 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 169.0, 152.9, 152.7, 145.3, 137.5, 134.1,
134.0 (q, J = 33 Hz), 128.84 (2C), 128.80, 128.6 (2C), 128.3 (2C),
127.7, 125.5 (2C, q, J = 3.5 Hz), 125.3, 123.4, 123.4 (q, J = 271 Hz),
121.6, 111.5, 103.7, 69.6; HRMS (ESþ) m/z calcd for C24H16NO4F3Na
[M þ Na]þ 462.0929, found 462.0919.
N-(3-Bromobenzofuran-2-yl)benzamide 40a. Following the
general procedure for bromination, a mixture of 2-arylamidobenzofuran
17a (440mg, 1.86 mmol), PTSA (35 mg, 0.18 mmol), andNBS (397 mg,
2.23 mmol) was stirred in THF at -78 °C for 35 min. After workup, the
residue was purified by flash chromatography over silica gel (toluene) to
afford the desired product 40a (467 mg, 1.48 mmol, 79% yield) as a pale
yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.87
(brs, 1H), 7.64-7.59 (m, 1H), 7.54-7.45 (m, 4H), 7.35-7.31 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 165.9, 151.2, 143.9, 132.7, 132.6, 128.8
(2C), 127.75, 127.69 (2C), 125.3, 123.6, 119.5, 111.5, 90.0; MS (ESþ)
m/z 316 [M þ H]þ (79Br), 318 [M þ H]þ (81Br).
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N-(3-Bromobenzofuran-2-yl)-4-methoxybenzamide 40b.
Following the general procedure for bromination, a mixture of 2-aryla-
midobenzofuran 17b (1.92 g, 7.19 mmol), PTSA (0.14 g, 0.72 mmol),
and NBS (1.54 g, 8.63 mmol) was stirred in THF at -78 °C for 60 min.
After workup, the crude product was purified by flash chromato-
graphy over silica gel (toluene/EtOAc 100:0 to 99:1) to afford the
desired product 40b (1.37 g, 3.96 mmol, 55% yield) as an orange solid:
1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.7 Hz, 2H), 7.78 (brs, 1H),
7.51-7.44 (m, 2H), 7.37-7.29 (m, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.89
(s, 3H).
N-(3-Bromobenzofuran-2-yl)-4-chlorobenzamide 40c.
Following the general procedure for bromination, a mixture of 2-arylami-
dobenzofuran 17c (1.23 g, 4.50 mmol), PTSA (86 mg, 0.45 mmol), and
NBS (0.97 g, 5.45 mmol) was stirred in THF at -78 °C for 45 min. The
residue was purified by flash chromatography over silica gel (toluene) to
afford the desired product 40c (1.25 g, 3.57 mmol, 79% yield) as an orange
solid: 1H NMR (300 MHz, CDCl3) δ 8.06 (brs, 1H), 7.84 (d, J = 8.4 Hz,
2H), 7.49-7.46 (m, 1H), 7.44-7.39 (m, 3H), 7.37-7.28 (m, 2H); MS
(ES-) m/z 348 [M - H]- (79Br), 350 [M - H]- (81Br).
N-(3-Bromobenzofuran-2-yl)-4-nitrobenzamide 40d. Fol-
lowing the general procedure for bromination, a mixture of 2-arylami-
dobenzofuran 17d (1.55 g, 5.50 mmol), PTSA (0.10 g, 0.55 mmol), and
NBS (1.17 g, 6.60 mmol) was stirred in THF at -78 °C for 1 h. After
workup, the residue was purified by flash chromatography over silica gel
(toluene/EtOAc 100:0 to 90:10) to afford the desired product 40d (1.37
g, 3.79 mmol, 69% yield) as a bright yellow solid: 1H NMR (300 MHz,
CDCl3) δ 8.36 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.92 (brs,
1H), 7.54-7.51 (m, 1H), 7.49-7.46 (m, 1H), 7.41 to 7.32 (m, 2H); MS
(ESþ) m/z 359 [M þ H]þ (79Br); 361 [M þ H]þ (81Br).
mixture of the brominated product 40b (350 mg, 1.01 mmol), phenyl
boronic acid (247 mg, 2.02 mmol), PdCl2(dppf) (50 mg, 0.06 mmol),
and sodium carbonate (430 mg, 4.05 mmol) was stirred in DME/H2O
(10 mL, 4:1) at 85 °C for 40 min. After workup, the crude product was
purified by flash chromatography over silica gel (toluene/EtOAc 100:0
to 95:5) to afford the desired product 15b (90 mg, 0.26 mmol, 26%
yield) as a pale yellow solid: mp 165 °C (recrystallized from heptane to
give white cotton); IR (CH2Cl2) νmax 3687, 3412, 3063, 2940, 2842,
1
1693, 1607, 1456, 1253, 1174 cm-1; H NMR (300 MHz, CDCl3) δ
7.91 (brs, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.58 (d,
J = 7.2 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.36-
7.25 (m, 3H), 6.90 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.4, 163.0, 152.1, 142.5, 131.3, 129.6 (2C), 129.0 (2C),
128.4 (2C), 127.8, 127.5, 125.1, 124.6, 123.1, 120.0, 114.0 (2C), 112.7,
111.5, 55.5; HRMS (ESþ) m/z calcd for C22H18NO3 [M þ H]þ
344.1287, found 344.1277.
4-Chloro-N-(3-phenylbenzofuran-2-yl)benzamide 15c. Fol-
lowing the general procedure for the Suzuki coupling (method A), a
mixture of the brominated product 40c (310 mg, 0.88 mmol), phenyl
boronic acid (129 mg, 1.06 mmol), PdCl2(dppf) (43.3 mg, 0.05 mmol),
and sodium carbonate (235 mg, 2.21 mmol) was stirred in DME/H2O (8.1
mL, 4:1) at 85 °C for 4 h. After workup, the crude product was purified by
flash chromatography over silica gel (toluene) to afford the desired product
15c (41 mg, 0.12 mmol, 14% yield) as a pale yellow solid: mp 176 °C
(recrystallized from heptane to give a white powder); IR (CH2Cl2) νmax
3687, 3406, 2360, 1699, 1636, 1596, 1502, 1456, 1257, 1182, 1096, 1014
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92 (brs, 1H), 7.75 (d, J = 8.2 Hz,
2H), 7.68-7.65 (m, 1H), 7.57-7.26 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 166.0, 152.1, 141.8, 138.9, 131.2, 131.1, 129.08 (2C), 129.05
(2C), 128.97 (2C), 128.3 (2C), 127.7, 127.6, 124.9, 123.3, 120.1, 113.1,
111.5; HRMS (ESþ) m/z calcd for C21H15NO2Cl [M þ H]þ 348.0791,
found 348.0787.
N-(3-Phenylbenzofuran-2-yl)-4-(trifluoromethyl)benzamide
15f. Following the general procedure for the Suzuki coupling (method A),
a mixture of the brominated product 40f (350 mg, 0.91 mmol), phenyl
boronic acid (134 mg, 1.09 mmol), PdCl2(dppf) (44.6 mg, 0.05 mmol),
and sodium carbonate (242 mg, 2.28 mmol) was stirred in DME/H2O (9.1
mL, 4:1) at 85 °C for 6 h. After workup, the crude product was purified by
flash chromatography over silica gel (toluene/cyclohexane 50:50 to 100:0)
to afford the desired product 15f (22 mg, 0.058 mmol, 6% yield) as a pale
yellow solid: mp 192 °C (recrystallized from heptane to give a white
powder); IR (CDCl3) νmax 3693, 3415, 3065, 2257, 1701, 1467, 1454,
1326, 1177, 1138, 1067 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.95-7.90
(m, 3H), 7.71-7.66 (m, 3H), 7.56-7.43 (m, 5H), 7.39-7.27 (m, 3H);
13CNMR(75 MHz, CDCl3) δ165.8, 152.1, 141.5, 136.1, 134.1 (q, J = 33.0
Hz), 131.0, 129.1 (2C), 128.3 (2C), 128.0 (2C), 127.8, 127.6, 125.8 (2C, q,
J = 3.6 Hz), 125.0, 123.5 (q, J = 252.1 Hz), 123.4, 120.2, 113.4, 111.5;
HRMS (ESþ) m/z calcd for C22H15NO2F3 [M þ H]þ 382.1055, found
382.1062.
N-(3-Bromobenzofuran-2-yl)-4-(trifluoromethyl)benzamide
40f. Following the general procedure for bromination, a mixture of
2-arylamidobenzofuran 17f (1.00 g, 3.28 mmol), PTSA (62 mg, 0.33
mmol), and NBS (700 mg, 3.93 mmol) was stirred in THF at -78 °C for
40 min. After workup, the crude product was purified by flash chromatog-
raphy over silica gel (toluene/cyclohexane 90/10) to afford the desired
product 40f (700 mg, 1.82 mmol, 55% yield) as a yellow solid: 1H NMR
(300 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz, 2H), 7.90 (brs, 1H), 7.78 (d, J =
8.4 Hz, 2H), 7.53-7.50 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.31 (m, 2H);
MS (ESþ) m/z 384 [M þ H]þ (79Br), 386 [M þ H]þ (81Br), (ES-) m/z
382 [M - H]- (79Br), 384 [M - H]- (81Br).
N-(3-Bromo-5-methoxybenzofuran-2-yl)benzamide 41.
Following the general procedure for bromination, a mixture of 2-aryla-
midobenzofuran 18 (400 mg, 1.50 mmol), PTSA (28.5 mg, 0.15 mmol),
and NBS (320 mg, 1.80 mmol) was stirred in THF at -78 °C for 20 min.
After workup, the residue was purified by flash chromatography over
silica gel (toluene/EtOAc 95:5 to 50:50) to afford the desired product
1
41 (207.5 mg, 0.60 mmol, 40% yield) as a pale brown solid: H NMR
(300 MHz, CDCl3) δ 7.94 (d, J = 6.9 Hz, 2H), 7.86 (brs, 1H), 7.64-
7.59 (m, 1H), 7.55-7.49 (m, 2H), 7.35 (d, J = 9.6 Hz, 1H), 6.95-6.91
(m, 2H), 3.88 (s, 3H); MS (ES-) m/z 344 [M - H]- (79Br), 346 [M -
H]- (81Br).
N-(3-(4-Methoxyphenyl)benzofuran-2-yl)benzamide 15g.
Following the general procedure for the Suzuki coupling (method A), a
mixture of the brominated product 40a (210 mg, 0.67 mmol), 4-methoxy-
phenyl boronic acid (193 mg, 1.33 mmol), PdCl2(dppf) (32.5 mg, 0.04
mmol), and sodium carbonate (282 mg, 2.66 mmol) was stirred in DME/
H2O (6.3 mL, 4:1) at 85 °C for 3 h. After workup, the crude product was
purified by flash chromatography over silica gel (toluene/cyclohexane
50:50 to 100/0) to afford the desired product 15g (75 mg, 0.22 mmol,
33% yield) as a pale yellow solid: mp 160 °C (recrystallized from heptane to
give an off-white powder); IR (CH2Cl2) νmax 3684, 3408, 3065, 3040,
N-(3-Bromo-5-nitrobenzofuran-2-yl)benzamide 42. Fol-
lowing the general procedure for bromination, a mixture of 2-arylami-
dobenzofuran 39 (282 mg, 1.00 mmol), PTSA (19 mg, 0.10 mmol),
and NBS (214 mg, 1.20 mmol) was stirred in THF at -78 °C for
20 min. After workup, the residue was purified by flash chromatography
over silica gel (toluene/EtOAc 100:0 to 95:5) to afford the desired
product 42 (293 mg, 0.81 mmol, 81% yield) as a pale yellow solid:
1H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 2.4 Hz, 1H), 8.27
(dd, J = 2.4, 9.0 Hz, 1H), 8.02 (brs, 1H), 7.95 (d, J = 7.2 Hz, 2H),
7.68-7.52 (m, 4H); MS (ES-) m/z 359 [M - H]- (79Br), 361 [M -
H]- (81Br).
1
2961, 2940, 1696, 1609, 1517, 1464, 1250, 1175 cm-1; H NMR (300
MHz, CDCl3) δ7.90 (brs, 1H), 7.85 (d, J= 7.5 Hz, 2H), 7.65 (d, J=7.3Hz,
1H), 7.56-7.46 (m, 6H), 7.34-7.25 (m, 2H), 6.98 (d, J = 8.8 Hz, 2H),
3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.9, 159.1, 152.0, 141.6,
133.0, 132.5, 129.6 (2C), 128.8 (2C), 128.0, 127.5 (2C), 124.7, 123.4,
4-Methoxy-N-(3-phenylbenzofuran-2-yl)benzamide 15b.
Following the general procedure for the Suzuki coupling (method A), a
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The Journal of Organic Chemistry
ARTICLE
123.1, 120.0, 114.5 (2C), 112.7, 111.5, 55.3; HRMS (ESþ) m/z calcd for
C22H18NO3 [M þ H]þ 344.1287, found 344.1285.
’ AUTHOR INFORMATION
Corresponding Author
*Email: emmanuel.bertounesque@curie.fr.
4-Methoxy-N-(3-(4-methoxyphenyl)benzofuran-2-yl)ben-
zamide 15h. Following the general procedure for the Suzuki coupling
(method A), a mixture of the brominated product 40b (350 mg, 1.01
mmol), 4-methoxyphenyl boronic acid (205 mg, 1.34 mmol), PdCl2-
(dppf) (50 mg, 0.06 mmol), and sodium carbonate (430 mg, 4.05 mmol)
in DME/H2O (10 mL, 4:1) was stirred at 85 °C for 40 min. After
workup, the crude product was purified by flash chromatography over
silica gel (toluene/EtOAc 100:0 to 90:10) to afford the desired product
15h (81 mg, 0.22 mmol, 22% yield) as a pale yellow solid: mp 175 °C
(recrystallized from heptane to give a white-off powder); IR (CH2Cl2)
νmax 3686, 3411, 3010, 2939, 2841, 1691, 1607, 1516, 1456, 1251, 1175,
1032 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 2H),
7.81 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.49 (d, J =
7.3 Hz, 1H), 7.35-7.24 (m, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.8
Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
166.4, 163.0, 159.0, 152.0, 142.0, 129.6 (4C), 128.0, 125.2, 124.5, 123.5,
123.0, 120.0, 114.5 (2C), 114.0 (2C), 112.5, 111.4, 55.5, 55.3; HRMS
(ESþ) m/z calcd for C23H19NO4Na [M þ Na]þ 396.1212, found
396.1231.
’ ACKNOWLEDGMENT
This work was supported by the Agence Nationale de la
Recherche (Grant ANR-08-PCVI-0031-CHEMISPIKE), CNRS,
and Institut Curie.
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silica gel (toluene/cyclohexane 50:50 to 100:0) to afford the desired
product 15i (16.8 mg, 0.04 mmol, 8% yield) as an orange solid: mp
212 °C (recrystallized from heptane/EtOAc to give a yellow powder); IR
(CDCl3) νmax 3410, 2959, 1702, 1455, 1326, 1178, 1139, 1067 cm-1; 1H
NMR (300 MHz, CDCl3) δ 8.16 (brs, 1H), 8.03 (d, J = 7.9 Hz, 2H), 7.91-
7.88 (m, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.44-7.39
(m, 1H), 7.36-7.31 (m, 4H), 7.28-7.24 (m, 1H), 7.21 (d, J = 16.5 Hz,
1H), 7.08 (d, J = 16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.5,
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126.5, 126.3 (2C), 126.0 (2C, q, J = 3.5 Hz), 125.0, 123.5, 123.5 (q, J = 271
Hz), 121.0, 117.8, 111.4, 110.3; HRMS (ESþ) m/z calcd for C24H17NO2F3
[M þ H]þ 408.1211, found 408.1230.
N-(5-Methoxy-3-phenylbenzofuran-2-yl)benzamide 43.
Following the general procedure for the Suzuki coupling (method B),
a mixture of the brominated product 41 (144 mg, 0.42 mmol), phenyl
boronic acid (254 mg, 2.08 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol),
and CsF (696 mg, 4.58 mmol) was stirred in dioxane/H2O (5.2 mL,
4:1) at 101 °C for 3.5 h. After workup, the crude product was purified
by flash chromatography over silica gel (toluene/EtOAc 100:0 to
97:3) to afford the desired product 43 (47.5 mg, 0.14 mmol, 33%
yield) as a pale yellow solid: mp 175 °C (recrystallized from heptane
to give white crystals); IR (CDCl3) νmax 3418, 3065, 2957, 2836,
1694, 1601, 1502, 1476, 1259, 1229, 1189, 1156 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.87 (brs, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.59-7.55
(m, 3H), 7.49-7.34 (m, 6H), 7.11 (d, J = 2.7 Hz, 1H), 6.94 (dd, J =
2.4, 9.0 Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.7,
156.2, 146.9, 142.8, 132.9, 132.5, 131.3, 129.0 (2C), 128.8 (2C), 128.3
(2C), 128.2, 127.54, 127.50 (2C), 113.2, 112.9, 112.0, 102.6, 55.9;
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found 366.1117.
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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