Copper-catalyzed formamidation of arylboronic acids: Direct access to formanilides

Article abstract of DOI:10.1055/s-0033-1338453

A new approach for direct synthesis of formanilides starting from structurally varied arylboronic acids is reported. The protocol involves a copper-catalyzed Chan-Lam coupling reaction between arylboronic acids and formamide in the presence of a base at room temperature. The strategy offers a valid and practical alternative to existing transformations of amino, nitro, and azido arenes to formanilides, especially in terms of executing arylboronic acids as easily accessible, stable, and diversified substrates, under mild reaction conditions, and in a simple operation with high efficiency. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338453

LETTER
▌1423
lCettoerpper-Catalyzed Formamidation of Arylboronic Acids: Direct Access to
Formanilides
Formanilides from Arylboronic Acids
Vishnu P. Srivastava,a Deepak K. Yadav,b Arvind K. Yadav,a Geeta Watal,b Lal Dhar S. Yadav*a
a
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
b
Alternative Therapeutic Unit, Drug Development Division, Medicinal Research Lab, Department of Chemistry, University of Allahabad,
Allahabad 211 002, India
Received: 19.03.2013; Accepted after revision: 08.04.2013
EDCI,15b CDMT (chlorodimethoxytriazine),15c KF-alumi-
Abstract: A new approach for direct synthesis of formanilides
na,15d ZnO,15e and PEG.15f Recently, a plethora of catalysts
starting from structurally varied arylboronic acids is reported. The
such as ZnCl2,16a indium,16b iodine,16c thiamine hydro-
protocol involves a copper-catalyzed Chan–Lam coupling reaction
between arylboronic acids and formamide in the presence of a base
chloride (VB1),16d sulfated tungstate,16e and protic ionic
at room temperature. The strategy offers a valid and practical alter- liquid in conjugation with formic acid has been employed
for facilitating formylation of amines.16f Formanilides can
also be synthesized directly from nitro/azido arenes via re-
native to existing transformations of amino, nitro, and azido arenes
to formanilides, especially in terms of executing arylboronic acids
as easily accessible, stable, and diversified substrates, under mild
ductive formylating protocols (Scheme 1, route b).17
reaction conditions, and in a simple operation with high efficiency.
Key words: formamide, formanilides, arylboronic acids, C–N
cross-coupling, N-arylation
previous work
ArNH2
+
formylating
reagents
refs. 13–16
formylation
route (a)
route (b)
ArNHCHO
ArNHCHO
A driving force behind the exploration of new synthetic
methodologies has been the need for simple and efficient
strategies to access structurally complex and diverse mol-
ecules from readily available and simple starting materi-
als. Formanilides are either important constituents present
in valuable classes of pharmaceuticals and other industri-
ally relevant compounds1,2 or used as functional synthetic
intermediates for the synthesis of the same classes of com-
pounds, such as N,N-diarylureas,3 cancer chemotherapeu-
tic agents,4 quinolone antibiotics,5 nitrogen-bridged
heterocycles,6a 1,2-dihydroquinolines,6b and N-arylimid-
azoles.6c They have been also extensively employed in or-
ArX
+
formylating
reagents
ref. 17
reductive formylation
X = NO2, N3
present work
ArB(OH)2
+
NH2CHO
[Cu]
route (c)
ArNHCHO
formamidation
Scheme 1 Approaches to access formanilides
ganic synthesis as a protecting group of amines,7
a
However, many of these methods are deficient in some re-
spect or other. Some of these methods have limited value
due to lower yields, thermal instability, formation of haz-
ardous byproducts, difficult and expensive assembly of
the formylating reagents, sensitivity to moisture, and te-
dious workup procedures. Hence, it is a highly desirable
and preferred endeavor to implement new strategies
which circumvent such limitations towards the prepara-
tion of formanilides.
precursor for the preparation of formamidines8 and isocy-
anides,9 3-aryl-4,5-dimethylthiazolium chloride–carbene
precursors,10 a source of monomethylated amines from
primary amines,11 and can act as a Lewis base catalyst for
allylation or hydrosilylation of carbonyl compounds.12
Consequently, establishing mild and efficient access to
functionalized formanilides is of great significance.
The available approaches for the preparation of formani-
lides are based on formylation reactions of amino arenes
(Scheme 1, route a).4,13–16 The literature is enumerated
with an array of formylating methods, and these include
use of formylating reagents/systems such as DMF–
NaOMe,14a formamide–NaOMe,14b activated formic es-
ters,14c,d acetic formic anhydride,14e chloral,14f ammonium
formate,14g 2,2,2-trifluoroethyl formate,14h N-formylsac-
charin,14i formic acid in combination with DCC,15a
In 1998, the groups of Chan, Lam, and Evans indepen-
dently developed the copper-mediated oxidative C–N
cross-coupling of amines, amides, imides, and C–O cross-
coupling of phenols with arylboronic acids,18 which of-
fered a valuable alternative to traditional cross-couplings
in the construction of carbon–heteroatom bonds. In recent
years, arylboronic acids and their derivatives have be-
come the reagents of choice as aryl donors towards car-
bon–heteroatom bond formations and in other reactions
owing to the advantages of these reagents regarding sta-
bility, substrate diversity, commercial availability, and
low toxicity compared to other organometallics.19 Subse-
SYNLETT 2013, 24, 1423–1427
Advanced online publication: 08.05.2013
0
9
3
6
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5
2
1
4
1
4
3
7
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2
0
9
6
DOI: 10.1055/s-0033-1338453; Art ID: ST-2013-D0250-L
© Georg Thieme Verlag Stuttgart · New York

1424
V. P. Srivastava et al.
LETTER
quently, they have been widely used as precursors in sev- sufficient to reach completion of reaction (Table 1, entry
eral functional-group transformations showing excellent 14). At a lower catalyst loading (<10 mol%) or decreasing
compatibility with the wide range of substrates and re- molar ratio of K2CO3 (<1.0 equiv), the reaction took a lon-
agents required to make aromatic compounds (e.g., ger time and was not complete even after stirring for sev-
ArB(OH)2 → ArNH2, ArNR1COR2, ArNO2, ArN3, ArSR, eral hours (Table 1, entries 15, 17, and 18). No reaction
ArSCF3, ArSO2R, ArOR, ArOH, ArCN, ArCF3, ArCl, occurred in the absence of a copper catalyst (Table 1, en-
ArBr, and ArI).20–22 However, to the best of our knowl- try 16).
edge, there is no example for the preparation of formani-
lides by coupling reactions of arylboronic acids with
formamide (ArB(OH)2 → ArNHCHO, Scheme 1, route
Table 1 Reaction of Phenylboronic Acid (1a) with Formamide in
Different Conditionsa
c). In continuation of our recent program on devising pot-
efficient strategies for useful organic transformations,23
catalyst [Cu], base
B(OH)2
NH2CHO
+
NHCHO
we report a new approach for the synthesis of formani-
lides 2 starting from arylboronic acids 1 and formamide in
the presence of catalytic amounts of a simple copper salt
and a base in open air at room temperature (Scheme 2).
solvent, r.t.
open flask
1a
2a
Entry Catalyst (mol%)
Base (1
equiv)
Solventb Time Yield
(h) (%)c
NHCHO
B(OH)2
1
2
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (100)
CuSO4·5H2O (100)
Cu2O (100)
Et3N
CH2Cl2 24 19
CH2Cl2 24 22
CH2Cl2 24 30
MeOH 24 63
MeOH 24 53
MeOH 24 53
MeOH 24 42
MeOH 24 40
MeCN 24 59
Cu(OAc)2⋅H2O (10 mol%)
pyridine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
Ar
Ar
+
NH2CHO
K2CO3 (1 equiv), r.t., 8–16 h
open flask
3
1
2
4
Scheme 2 Copper-catalyzed direct formamidation of arylboronic ac-
ids
5
6
Our intention to execute arylboronic acids as substrates to
access formanilides emanated from a recent surge in the
literature towards demonstrating their lucrative applica-
tions in a variety of functional-group transformations
yielding useful aromatic compounds under very mild con-
ditions.20a,b,21,22 Nevertheless, none of the previous studies
has utilized formamide as a coupling partner with arylbo-
ronic acids 1 leading to formanilides 2 (Scheme 2).18,20d At
the outset, it was unclear whether the C–N cross-coupling
reaction, formally a formamidation of arylboronic acids,
could proceed with formamide, which was previously em-
ployed as either an ammonia or formyl surrogate.24 Thus,
it seems clear that the viability of such design would offer
an attractive alternative to existing methods to deliver for-
manilides (Scheme 1, routes a and b). In order to realize
the envisaged protocol, phenylboronic acid (1a) was cho-
sen as the model substrate to design an array of reaction
conditions in a systematic fashion (Table 1). As shown in
Table 1, among the copper salts such as Cu(OAc)2·H2O,
CuSO4·5H2O, Cu2O, CuCl, and CuI investigated, Cu(II)
salts, particularly Cu(OAc)2·H2O in combination with
K2CO3, has shown potential efficiency in polar organic
solvents (Table 1, entries 4 and 9). On the other hand, a
less polar solvent, such as dichloromethane, is not a suit-
able solvent to mediate the coupling reaction (Table 1, en-
tries 1–3). Interestingly, use of formamide both as a
solvent and coupling partner provided the highest yield in
7
CuCl (100)
8
CuI (100)
9
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (40)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (5)
–
10
11
12
13
14
15
16
17
18
19
20
21
H2O
–
24 35
10 90
10 90
10 90
10 90
18 60
–
–
–
–
–
18
–
Cu(OAc)2·H2O (10)
CuSO4·5H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
–
18 69d
18 40
–
K2CO3
K2CO3
K2CO3
–
10 tracee
10 90f
10 90g
–
–
a Reaction procedure: A mixture of phenylboronic acid (1a, 1 mmol),
formamide (1 mmol), copper salt, and base (1.0 equiv) in 2 mL of sol-
vent was vigorously stirred at r.t. open to air (without bubbling air).
b In entries 11–21: excess formamide (2 mL) was used to act as both
relatively short reaction time as compared to polar sol- coupling partner and solvent instead of use in stoichiometric amounts.
c Yields of isolated pure compound 2a.
vents (Table 1, entry 11). Based on the fact that under an
aerobic atmosphere, Cu(0)/Cu(I) could reoxidize back to
Cu(II) establishing a catalytic cycle, the reaction was also
monitored with different catalyst loadings. To our satis-
faction, the results revealed that 10 mol% of
Cu(OAc)2·H2O along with 1.0 equivalent of K2CO3 was
d Conditions: 0.5 equiv of K2CO3 were used.
e Run under a nitrogen atmosphere.
f Conditons: 1.0 equiv of K2CO3 in combination with 1.0 equiv of
1,10-phenanthroline were used.
g Conditons: 1.0 equiv of K2CO3 in combination with 1.0 equiv of
2,2′-bipyridine were used.
Synlett 2013, 24, 1423–1427
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formanilides from Arylboronic Acids
1425
Table 2 Synthesis of Formanilides from Arylboronic Acidsa
Trace amounts of product were observed in the absence of
air (in a nitrogen atmosphere, Table 1, entry 19), which in-
dicated that an oxidative process was involved in the for-
mation of the products. Since the reaction is catalyzed by
Cu(II), the effect of different ligands such as 1,10-phen-
anthroline and 2,2′-bipyridine was investigated under the
reaction conditions but no improvement was observed in
reaction efficiency (Table 1, entries 20 and 21). There-
fore, our optimal reaction conditions for most of the con-
versions of phenylboronic acid (1a) into the title product
2a are as follows: Cu(OAc)2·H2O (10 mol%) as the cata-
lyst, K2CO3 (1.0 equiv) as a base, formamide (2 mL) as
the solvent and formamido source, and the reaction is car-
ried out in air (without bubbling air) at room temperature
(Table 1, entry 14). The reaction can be monitored visual-
ly as the indigo blue reaction mixture that turns into light
green when the reaction reaches completion.
Cu(OAc)2⋅H2O
(10 mol%)
ArB(OH)2
ArNHCHO
2a–pb
(75–94%)c
NH2CHO
+
K2CO3 (1 equiv), r.t.
open flask
1a–p
8–16 h
NHCHO
NHCHO
NHCHO
NHCHO
OMe
OMe
OMe
2d from 1d
(12 h, 88%)
2a from 1a
(10 h, 90%)
2c from 1c
(8 h, 92%)
2b from 1b
(8 h, 94%)
NHCHO
NHCHO
NHCHO
NHCHO
With the stipulated conditions in hand, the scope of the
method was extended by conversion of various structur-
ally diverse arylboronic acids 1a–p bearing electron-
neutral, electron-donating, and electron-withdrawing sub-
stituents into formanilides 2a–p as summarized in Table 2
(see also Scheme 2). The substituted arylboronic acids
containing electron-deficient groups showed slightly low-
er reactivity than those containing electron-rich or neutral
groups. For example, 4-nitrophenyl boronic acid (1j) with
an electron-withdrawing group furnished N-(p-nitrophe-
nyl)formamide in slightly lower yield (Table 2, product
2j) than arylboronic acids with an electron-donating
group. Higher reactivity was observed for 4- and 3-me-
thoxyphenylboronic acids (1b,c) and 1-naphthylboronic
acid (1p, Table 2, products 2b,c,p). Furthermore, sterical-
ly hindered substrates were also applicable, with 2-substi-
tuted arylboronic acids providing the desired products in
good yields (Table 2, products 2d,f). The reaction tolerat-
ed a range of functional groups on the aryl ring because
the coupling occurs in the presence of carbon–halogen
bonds (Table 2, products 2g–i), an ester group (Table 2,
product 2k), a ketone carbonyl group (Table 2, product
2l), a carboxyl group (Table 2, product 2n), a nitrile and
an aldehyde group (Table 2, products 2m,o).
Based on the literature precedents26 along with our obser-
vations (Table 1), a plausible catalytic cycle for the cop-
per-catalyzed Chan–Lam coupling reaction between
arylboronic acids and formamide is depicted in Scheme 3,
which consists of an initial transmetalation of the aryl
group from arylboronic acid to Cu(II)OAc2 to afford a
ArCu(II)OAc species. The resulting ArCu(II)OAc is oxi-
dized by another equivalent of Cu(II)OAc2 providing the
ArCu(III)OAc2 intermediate that can easily facilitate the
reductive elimination pathway furnishing the C–N bond.
Subsequently, the rapid aerobic oxidation of Cu(I)OAc re-
generates Cu(II)OAc2 establishing an efficient catalytic
cycle.
F
Cl
2f from 1f
(10 h, 88%)
2g from 1g
(15 h, 79%)
2h from 1h
(15 h, 83%)
2e from 1e
(9 h, 92%)
NHCHO
NHCHO
NHCHO
NHCHO
Br
NO2
2j from 1j
(16 h, 75%)
COOMe
COMe
2i from 1i
(16 h, 81%)
2k from 1k
(14 h, 85%)
2l from 1l
(13 h, 84%)
NHCHO
NHCHO
NHCHO
NHCHO
CN
CHO
COOH
2p from 1p
(9 h, 93%)
2o from 1o
(11 h, 86%)
2m from 1m
(16 h, 80%)
2n from 1n
(16 h, 83%)
a See ref.25 for the General Procedure.
b All are known compounds and were characterized by comparison of
their melting points, IR and 1H NMR data with those of authentic
samples.14–17
c Yields of isolated pure compounds.
B(OH)3
ArB(OH)2
Cu[II]OAc2
1/2 O2
AcOH
BOAc(OH)2
Cu[I]OAc
1
Cu[II]OAc2
Cu[I]OAc
•
AcOH
+
ArB(OH)2
Cu(I) Cu(II) Cu(III)
NHAr
O
H
2
BOAc(OH)2
NH2
H
Ar Cu[II]OAc
Ar Cu[III]OAc2
Cu[I]OAc
O
Cu[II]OAc2
In summary, we have developed a simple and highly effi-
cient ligand-free Cu(II)-catalyzed method for the synthe-
sis of formanilides by couplings of easily accessible,
Scheme 3 Plausible catalytic cycle for Chan–Lam coupling of aryl-
boronic acid with formamide
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1423–1427

1426
V. P. Srivastava et al.
LETTER
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Acknowledgment
V.P.S. is grateful to the Department of Science and Technology
(DST) Govt. of India, for the award of a DST-Inspire Faculty posi-
tion (Ref. IFA-11CH-08) and financial support. We sincerely thank
the SAIF, Punjab University, Chandigarh, for providing spectra.
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Synlett 2013, 24, 1423–1427
© Georg Thieme Verlag Stuttgart · New York

LETTER
Neelima, B.; Reddy, C. V.; Neeraja, V. J. Mol. Catal. A:
Formanilides from Arylboronic Acids
1427
(1.0 mmol) in formamide (2 mL) were added Cu(OAc)2·H2O
(19.9 mg, 10 mol%) and K2CO3 (138.2 mg, 1 mmol), and the
mixture was stirred vigorously at r.t. under air (without
bubbling air) for 8–16 h (Table 2). After completion of the
reaction (indicated by TLC), the reaction mixture was
treated with EtOAc (5 mL) and H2O (5 mL). The organic
layer was separated, and the aqueous layer was extracted
with EtOAc (3 × 5 mL). The combined organic phase was
washed with H2O (2 × 5 mL), dried over anhyd Na2SO4, and
concentrated to yield a residue, which was purified by flash
chromatography (prepacked silica cartridges) to afford the
clean product 2 as a mixture of rotamers.27 All the products
are known compounds and were characterized by
comparison of their melting points and spectral data with
those reported in the literature.14–17 As a typical example, the
data for 2a are given.
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1383.
N-Phenylformamide (2a, Table 2)
Isolated as a pale brownish solid (109 mg, 90%); mp 48–
49 °C [lit.17a 47–48 °C]. 1H NMR (400 MHz, CDCl3): δ =
9.12 (br s, 1 H, NH), 8.70 (d, J = 11.4 Hz, 1 H, CHO), 8.39
(s, 1 H, CHO), 8.10 (br s, 1 H, NH), 7.54 (d, J = 7.8 Hz, 2 H,
ArH), 7.39–7.31 (m, 4 H, ArH), 7.20–7.14 (m, 2 H, ArH),
7.09 (d, J = 7.7 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3):
δ = 163.1, 159.5, 137.0, 136.7, 129.8, 128.9, 125.0, 124.6,
119.9, 118.6. IR (KBr): 3252, 3048, 1686, 1602, 1550, 1430,
1352, 758, 710, 696 cm–1. MS (EI): m/z = 122 [M+ + 1].
Anal. Calcd for C7H7NO: C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.16; H, 5.96; N, 11.48.
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Brunold, T. C.; Stahl, S. S. Organometallics 2012, 31, 7948.
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353, 2599.
(27) Manea, V. P.; Wilson, K. J.; Cable, J. R. J. Am. Chem. Soc.
1997, 119, 2033.
(25) General Procedure for the Synthesis of Formanilides 2
To an open flask containing a solution of arylboronic acid 1
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Synlett 2013, 24, 1423–1427

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