A Catalyst-Free Process for the Direct Oxidative Synthesis of Form-anilides from Arylamines and Aldehydes under Air Atmosphere

Article abstract of DOI:10.1055/s-0034-1380442

An efficient and catalyst-free process for the direct oxidative synthesis of formanilides from primary aromatic amines and aliphatic aldehydes has been developed under mild aerobic oxidation conditions. The isotope-labeling experiments indicated that the oxygen atom of the formanilide originated from dioxygen.

Full text of DOI:10.1055/s-0034-1380442

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1900–1904
letter
1900
Y. Qin et al.
Letter
Synlett
A Catalyst-Free Process for the Direct Oxidative Synthesis of Form-
anilides from Arylamines and Aldehydes under Air Atmosphere
Yuancheng Qin*a
NHCHO
R2
CHO
NH2
air (O2)
Yuanyuan Chenga
Xubiao Luo*a
Mingjun Lia
Yu Xiea
R1
R1
+
R3
MeCN, 60 °C
R2, R3 = H, alkyl, aryl
48–90%
Yunhua Gaob
a Key Laboratory of Jiangxi Province for Persistant Pollutants Control and
Resources Recycle, Nanchang Hangkong University, Nanchang 330063,
1904P. R. of China
qinyuancheng@hotmail.com
luoxubiao@126.com
b Chinese Academy of Sciences, TIPC, Key Laboratory of Photochemical
Conversion and Optoelectronic Materials, Beijing 100190, P. R. of China
Received: 21.04.2015
Accepted after revision: 17.05.2015
Published online: 09.07.2015
mild aerobic oxidation conditions (Scheme 1). The process
indicated that ketones were byproducts and dioxygen in air
was served as oxidant without any catalyst, which is espe-
cially economic, and the direct use of dioxygen as oxygen
source for functionalization of organic frameworks rep-
resents one of the most ideal strategies for constructing ox-
ygen-containing organic materials. It is believed that this
process provides an interesting and attractive route to syn-
thesize diverse formanilide compounds.
DOI: 10.1055/s-0034-1380442; Art ID: st-2015-w0292-l
Abstract An efficient and catalyst-free process for the direct oxidative
synthesis of formanilides from primary aromatic amines and aliphatic
aldehydes has been developed under mild aerobic oxidation conditions.
The isotope-labeling experiments indicated that the oxygen atom of
the formanilide originated from dioxygen.
Key words catalyst-free, oxidative, formanilides, arylamines, alde-
hydes
R2
CHO
NHCHO
+
NH2
air (O2)
O
R1
R1
(1)
+
R3
R2
R3
MeCN, 60 °C
The formamides are significant intermediates1 in the
construction of various pharmaceutically important com-
pounds in synthetic organic chemistry. They are also em-
ployed as Lewis base to catalyze several organic transfor-
mations.2 Moreover, they are useful reagents in Vilsmeier
formylation reactions.3 The formyl group is also a practical
amino protecting group in peptide synthesis.4
Hence, intense research has been focused on developing
feasible approaches to introduce the N-formylation into
various amines. Generally, formic acid,5 acetic anhydride,6
chloral,7 ammonium formates,8 cyanides and esters,9 car-
bon dioxide and hydrogen,10 N,N-dimethylformamide,11
formyl fluoride,6 enol formate,12 etc. have also been em-
ployed as formylating reagents. Recently, Patcharee et al. re-
ported a nanogold-catalyzed [gold nanoclusters stabilized
by poly(N-vinyl-2-pyrrolidone)] process using methanol or
formalin as the formyl source.13 Formanilides were also ob-
tained from Schiff bases.14 However, these protocols suf-
fered from limitations, such as harsh reaction conditions,
employment of catalysts, tedious procedures, excess of
formylating agents, and formation of toxic byproducts. In
this paper, we report a convenient and catalyst-free process
of the primary aromatic amines and aliphatic aldehydes to
prepare various formanilide derivatives efficiently under
1
2
3
4
Scheme 1
As the initial attempts, p-methoxyaniline (1a) was al-
lowed to react with isobutyraldehyde (2a) under different
experimental conditions to establish the suitable solvents
and temperature for the desired products (Table 1). The re-
action was carried out in different solvents such as cyclo-
hexane, CH2Cl2, DMF, MeOH, THF, DMSO, and MeCN under
identical conditions to obtain the desired products in mod-
erate to good yields (Table 1, entries 1–7). Subsequently, we
modulated the temperature to improve the yields of the re-
actions by using MeCN as the solvent (Table 1, entries 7–
10). At room temperature, a low yield (44%) was obtained
even with prolonged reaction times. The yield was notable-
ly increased (73%) when the temperature raised 40 °C and
the best yield was obtained at 60 °C (88%). But a lower yield
appeared at 80 °C (47%), a possible reason being that the
boiling point of isobutyraldehyde is 63 °C. Meanwhile,
when various metal catalysts were added, the reactions re-
sulted in lower yields (Table 1, entries 11–14). Further ex-
ploration indicated that no desired product was observed
under nitrogen (Table 1, entry 15).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1900–1904

1901
Y. Qin et al.
Letter
Synlett
Table 1 Reaction of p-Methoxyaniline and Isobutyraldehyde under Dif-
With the optimal conditions in hand, the generality and
ferent Experimental Conditionsa
limitation of this useful method has been examined differ-
ent aldehydes and anilines (Table 2).15 Various aldehydes
were attempted (Table 2, entries 1–5), the results indicated
that the aliphatic aldehydes with two substituents at the α-
position provided the products in good yields (Table 2, en-
tries 1, 3, and 5) while the yields significantly decreased
with the monosubstituted aldehydes at the 2-position (Ta-
ble 2, entries 2 and 4). It was remarkable that no desired
products were observed when aromatic aldehydes were
used as substrates, such as benzaldehyde. Meanwhile, vari-
ous anilines were examined to further probe the scope of
this approach (Table 2, entries 6–18). Electronic effect was
observed when different substituents located on the phenyl
ring of aromatic amines. Those containing electron-donat-
ing groups gave the desired products in high yields (Table 2,
entries 5–11). However, amines bearing electron-with-
drawing groups generated comparatively lower yields of the
targets (Table 2, entries 12, 14, and 16). ortho-Substituted
amines also gave relatively lower yields, because of the ste-
ric effect (Table 2, entry 13). Some heterocyclic amines
were also attempted, for example, 6-amino-1,4-benzodiox-
an and pyridin-2-amine, and gave the corresponding prod-
ucts 3b and 3n in 85% and 67% yields, respectively (Table 2,
entries 6 and 18). It is notable that no different yields were
observed when all materials were redistilled (Table 2, en-
tries 5, 11, and 17). However, none of the desired products
were generated when the secondary aromatic amines or al-
iphatic amines were served as substrates.
air
CHO
MeO
NH2
+
MeO
NHCHO
21 h
1a
Solvent
2a
3a
Entry
Temp (°C)
Catalyst
Yield (%)b
1
2
cyclohexane
CH2Cl2
DMF
60
60
60
60
60
60
60
r.t.
40
80
60
60
60
60
60
60
–
82
–
81
3
–
80
4
MeOH
THF
–
84
5
–
55
6
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
71
7
–
88
8
–
44c
73c
47
9
–
10
11
12
13
14
15
16
–
PdCl2
CuI
AuCl3
FeCl3
–
67
trace
19
trace
traced
89e
–
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), solvent (1.5 mL), under
air, 21 h.
b Isolated yields.
c 32 h.
d Under N2.
e Under O2.
Table 2 Scope of the Reaction
R2
CHO
NH2
NHCHO
air
R1
R1
+
MeCN, 60 °C
R1
2a–e
1a–n
3a–n
Entry
1
Arylamine
Aldehyde
Product
Isolated yield (%)a
79
MeO
NHCHO
NHCHO
MeO
NH2
NH2
CHO
2a
2b
3a
1a
MeO
MeO
CHO
2
3
48
82
1a
3a
CHO
MeO
NH2
MeO
NHCHO
1a
3a
2c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1900–1904

1902
Y. Qin et al.
Letter
Synlett
Table 2 (continued)
Entry
Arylamine
Aldehyde
Product
Isolated yield (%)a
53
CHO
MeO
NH2
MeO
NHCHO
NHCHO
4
1a
3a
2d
2e
CHO
MeO
1a
NH2
MeO
3a
5
6
88 (84)b
O
NHCHO
O
NH2
CHO
CHO
85
O
O
2e
1b
3b
MeO
NHCHO
NHCHO
MeO
NH2
7
8
9
90
89
87
MeO
3c
MeO
1c
2e
2e
2e
NH2
CHO
CHO
1d
1e
3d
3e
NH2
NHCHO
MeS
NH2
CHO
CHO
CHO
MeS
NHCHO
10
11
12
88
1f
3f
2e
2e
2e
NHCHO
NH2
89 (85)b
3g
1g
O
O
NH2
NHCHO
57
1h
1i
3h
3i
CHO
CHO
CHO
13
14
15
71
66
70
NH2
NHCHO
2e
2e
2e
Cl
NH2
Cl
NHCHO
1j
3j
NH2
NHCHO
Br
Br
1k
3k
NH2
NHCHO
CHO
16
60
O2N
1l
O2N
3l
2e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1900–1904

1903
Y. Qin et al.
Letter
Synlett
Table 2 (continued)
Entry
Arylamine
Aldehyde
Product
Isolated yield (%)a
70 (71)b
NH2
CHO
CHO
NHCHO
17
2e
1m
3m
18
67
N
NH2
N
NHCHO
2e
3n
1n
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), MeCN (1.5 mL), under air, at 60 °C, 24 h.
b 1 (1.0 mmol, redistilled), compound 2e (1.2 mmol, redistilled), MeCN (2 mL, redistilled), under air, at 60 °C, 24 h.
It is worth noting that the reaction can also be effective-
ly scaled-up with the similar efficiency. For example, a
gram-scale test for the synthesis of N-(4-methoxyphenyl)
formamide from p-methoxyaniline (0.81 mol, 10 g) and cy-
clohexanecarbaldehyde (0.9 mol, 11 mL) was carried out
under the standard conditions and generated the product
3a in high yield (83%).
To gain insights into the reaction mechanism, the iso-
tope-labeling experiments using 18O2 and H218O were con-
ducted in the reaction of p-methoxyaniline (1a) and 2-
phenylpropanal (2d), respectively (Scheme 2, eq. 1 and 2).
The compounds 3a and 4d were absolutely labeled by 18O
when the reaction proceeded under 18O2 atmosphere
(Scheme 2, eq. 1). Neither 3a nor 4d was labeled when 1a
and 2d reacted under the standard conditions with addition
of five equivalents H218O (Scheme 2, eq. 2). The above re-
sults indicated that the carbonyl oxygen atoms of N-(4-me-
thoxypheny)formamide (3a) and acetophenone (4d) both
originated from molecular oxygen.
Photoinitiated singlet oxygen was usually existing in
aerobic oxidation reaction system,16 To investigate whether
photosensitized singlet oxygenation was involved in the ox-
idation reaction, singlet-oxygen inhibitor 1,4-diazabicy-
clo[2,2,2]octane (DABCO) was added to the model reaction
of p-methoxyaniline (1a) and 2-phenylpropanal (2d), and
the isolated yield was obtained (86%). Moreover, 80% of the
product was obtained in the dark. Based on the above re-
sults, we deduced that the participation of singlet oxygen
might not be involved in the present reaction system.
The detailed mechanism is not clear, however, based on
the preliminary studies and previous reported about the
oxidation of imines or enamines,17 a possible reaction
mechanism was proposed as shown in Scheme 3. Initially,
aniline 1a reacted with aldehyde 2d to generate imine 5 or
enamine 6. Subsequently, the autoxidation of the corre-
sponding imine 5 or enamine 6 would lead to the formation
of the hydroperoxide intermediate 7,14,17f which decom-
posed rapidly to yield N-(4-methoxyphenyl)formamide
(3a) and acetophenone (4d).
NHCH18
O
OMe
In summary, an economic and green method for the
construction of various formanilides from primary aryl-
amines and aliphatic aldehydes employing O2 as oxidant in
the absence of catalyst has been developed. The detailed re-
action mechanism is still not clear at the present stage. Fur-
ther investigations of the reaction mechanism and applica-
tion are ongoing.
18O
18O2 (ballon)
MeCN, 60 °C
CHO
(1)
+
+
NH2
OMe
3a (84%)
100% 18O-labeled
1a
(1.0
2d
(1.2 mmol)
4d (81%)
mmol)
OMe
H218O
(5 equiv),
air
NHCHO
O
Acknowledgment
CHO
+
(2)
+
MeCN, 60°C
The work was financially supported by Aviation Science Fund of China
(no. 2013ZF56025) and Natural Science Foundation of Jiangxi Prov-
ince (Grant no. 20142BAB213015).
NH2
OMe
3a (77%)
1a
(0.5
2d
4d (72%)
no18O-labelled
(0.6 mmol)
mmol)
Supporting Information
Scheme 2
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380442.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1900–1904

1904
Y. Qin et al.
Letter
Synlett
OMe
OMe
OMe
MeO
NH2
MeO
NHCHO
1a
3a
H
O2
HN
N
O
O
N
+
+
– H2O
CHO
O
2d
5
6
7
4d
Scheme 3 Possible mechanism
References and Notes
(11) (a) Pettit, G.; Kalnins, M.; Liu, T.; Thomas, E.; Parent, K. J. Org.
Chem. 1961, 26, 2563. (b) Djuric, S. W. J. Org. Chem. 1984, 49,
1311.
(12) Neveux, M.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc., Perkin
Trans. 1 1991, 1197.
(13) Preedasuriyachai, P.; Kitahara, H.; Chavasiri, W.; Sakurai, H.
Chem. Lett. 2010, 39, 1174.
(14) Witkop, B. J. Am. Chem. Soc. 1956, 78, 2873.
(1) (a) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545.
(b) Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun.
1995, 1319. (c) Chen, B.-C.; Bednarz, M. S.; Zhao, R.; Sundeen, J.
E.; Chen, P.; Shen, Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahe-
dron Lett. 2000, 41, 5453. (d) Kobayashi, K.; Nagato, S.;
Kawakita, M.; Morikawa, O.; Konishi, H. Chem. Lett. 1995, 24,
575. (e) Kakehi, A.; Ito, S.; Hayashi, S.; Fujii, T. Bull. Chem. Soc.
Jpn. 1995, 68, 3573. (f) Gim, H.; Kang, B.; Jeon, R. Arch. Pharm.
Res. 2007, 30, 1055. (g) Lohray, B. B.; Baskaran, S.; Srinivasa Rao,
B.; Yadi Reddy, B.; Nageswara Rao, I. Tetrahedron Lett. 1999, 40,
4855.
(2) (a) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620.
(b) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 25,
407. (c) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahe-
dron 1999, 55, 977.
(3) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahe-
dron 1993, 49, 4015.
(4) Sheehan, J. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 1154.
(5) (a) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71,
6652. (b) Desai, B.; Danks, T. N.; Wagner, G. Tetrahedron Lett.
2005, 46, 955. (c) Das, B.; Krishnaiah, M.; Balasubramanyam, P.;
Veeranjaneyulu, B.; Nandan Kumar, D. Tetrahedron Lett. 2008,
49, 2225. (d) Brahmachari, G.; Laskar, S. Tetrahedron Lett. 2010,
51, 2319.
(6) Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1960, 82, 2380.
(7) Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933.
(8) (a) Ganapati Reddy, P.; Kishore Kumar, G. D.; Baskaran, S. Tetra-
hedron Lett. 2000, 41, 9149. (b) Pratap, T. V.; Baskaran, S. Tetra-
hedron Lett. 2001, 42, 1983.
(9) Bao, K.; Zhang, W.; Bu, X.; Song, Z.; Zhang, L.; Cheng, M. Chem.
Commun. 2008, 5429.
(10) (a) Jessop, P. G.; Hsiao, Y.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 344. (b) Tumma, H.; Nagaraju, N.; Reddy, K. V. J. Mol.
Catal. A: Chem. 2009, 310, 121.
(15) General Procedure
To a mixture of p-methoxyaniline (1a, 0.5 mmol) and cyclohex-
anecarboxaldehyde (2e, 0.6 mmol), and MeCN (1.5 mL) in a
25mL round-bottomed flask at 60 °C under air, the reaction
vessel was allowed to stir at 60 °C for 24 h. After reaction, the
resulting mixture was isolated by column chromatography on
silica gel with EtOAc–PE (1:2) to obtain product 3a as brown
solid; yield 88%. 1H NMR (600 MHz, CDCl3): δ = 8.51 (d, 1 H, J =
11.3 Hz), 8.31 (s, 1 H), 8.17 (br s, 1 H), 7.49 (br s, 1 H), 7.45–6.85
(m, 8 H, ArH), 3.80 (s, 3 H), 3.78 (s, 3 H). 13C NMR (151 MHz,
CDCl3): δ = 163.2, 159.1, 157.6, 156.7, 130.0, 129.6, 121.8, 121.6,
114.9, 114.2, 55.6, 55.5. ESI-HRMS: m/z [M + Na+] calcd for
C8H9NNaO2: 174.0525; found: 174.0529.
(16) (a) Wasserman, H. H.; Terao, S. Tetrahedron Lett. 1975, 16, 1735.
(b) Ando, W.; Saiki, T.; Migita, T. J. Am. Chem. Soc. 1975, 97,
5028. (c) Sivaguru, J.; Solomon, M. R.; Poon, T.; Jockusch, S.;
Bosio, S. G.; Adam, W.; Turro, N. J. Acc. Chem. Res. 2008, 41, 387.
(d) Christ, T.; Kulzer, F.; Bordat, P.; Basché, T. Angew. Chem. Int.
Ed. 2001, 40, 4192.
(17) (a) Snider, B. B.; Ron, E. J. Am. Chem. Soc. 1985, 107, 8160.
(b) Yamaguchi, K.; Yabushita, S.; Fueno, T.; Houk, K. N. J. Am.
Chem. Soc. 1981, 103, 5043. (c) Saito, I.; Matsugo, S.; Matsuura,
T. J. Am. Chem. Soc. 1979, 101, 7332. (d) Achmatowicz, O.;
Szymoniak, J. J. Org. Chem. 1980, 45, 4774. (e) Orfanopoulos, M.;
Stratakis, M.; Elemes, Y.; Jensen, F. J. Am. Chem. Soc. 1991, 113,
3180. (f) Malhotra, S. K.; Hostynek, J. J.; Lundin, A. F. J. Am.
Chem. Soc. 1968, 90, 6565.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1900–1904