Iron-Catalyzed Direct Transformation of Benzylic Amines into Carbonyl Compounds in Water

Article abstract of DOI:10.1055/s-0037-1611881

Fe-catalyzed direct transformation of benzylic amines into carbonyl compounds was performed in H ₂ O. The reaction of benzylic amines with formaldehyde in the presence of FeCl ₃ ·6H ₂ O in H ₂ O afforded the corresponding carbonyl compounds (80 °C to reflux conditions; 14 examples, up to 94percent yield). O ¹⁸ -labeling experiments indicated that the O atom in the generated carbonyl is derived from H ₂ O.

Full text of DOI:10.1055/s-0037-1611881

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Synlett
M. Minakawa, T. Sasaki
Letter
Iron-Catalyzed Direct Transformation of Benzylic Amines into
Carbonyl Compounds in Water
Maki Minakawa*
Takashi Sasaki
NH2
O
O
FeCl3·6H2O
H2O
R1
+
R1
+
Me NH2
Ar
Ar
H
H
80 °C to reflux
Department of Applied Chemistry, Chemical Engineering and
Biochemical Engineering, Yamagata University, 4-3-16, Jonan,
Yonezawa, Yamagata 992-8510, Japan
18 h
14 examples
up to 94% yield
minakawa@yz.yamagata-u.ac.jp
Received: 18.05.2019
Accepted after revision: 17.06.2019
Published online: 12.07.2019
NH2
O
O
catalyst: [Fe]
H2O
R
+
R
+
Me NH2
DOI: 10.1055/s-0037-1611881; Art ID: st-2019-u0283-l
H
H
Abstract Fe-catalyzed direct transformation of benzylic amines into
Scheme 2 This work
carbonyl compounds was performed in H O. The reaction of benzylic
2
amines with formaldehyde in the presence of FeCl ·6H O in H O afford-
3
2
2
In this work, the conditions were optimized for the re-
action of (diphenylmethyl)amine (1a) with formaldehyde
(2) (Table 1). The reaction of (diphenylmethyl)amine (1a:
ed the corresponding carbonyl compounds (80 °C to reflux conditions;
18
1
4 examples, up to 94% yield). O -labeling experiments indicated that
the O atom in the generated carbonyl is derived from H O.
2
0
.5 mmol) with formaldehyde (2: 0.6 mmol) in the absence
Key words direct transformation, benzylic amines, carbonyl com-
pounds, iron catalysis, formaldehyde
of any catalyst in H O (0.5 mL) at 80 °C for 18 hours gave
benzophenone (3a) in <1% yield (Table 1, entry 1). The
2
4
transformation reaction with FeCl ·6H O as a catalyst af-
3
2
The direct transformation of amines into carbonyl com-
pounds is a powerful tool for organic synthesis. However,
the synthesis of carbonyl compounds from amines usually
requires stoichiometric quantities or large amounts of ex-
plosive peroxides, toxic oxidizing reagents, and/or expen-
forded the desired product 3a in 74% isolated yield (entry
2). The reaction in the presence of Fe(acac)3 or Fe(NO2)3
gave 3a in yields of 12 and 16%, respectively (entries 3 and
4), whereas FeF as catalyst produced 3a in 54% isolated
3
yield (entry 5). Reactions in the presence of other Fe(II)
complexes resulted in lower yields of 3a (entries 6–8). TsOH
or citric acid as the catalyst afforded 3a in yields of 6 and
7%, respectively (entries 9 and 10). The reaction with other
metal chlorides as catalysts resulted in lower yields of the
desired product 3a (entries 11–13). The reaction at 100 °C
in the presence of FeCl ·6H O generated the desired product
1
sive late-transition metals. In addition, it is widely known
that the reaction of amines with formaldehyde gives ami-
nals via imines and imine salts, as shown in Scheme 1.2
H
O
H
N
H
N
H
H
3
2
OH
N
N
R—NH2
H
H
R
R
R
R
3a in 94% isolated yield (entry 14). In contrast, the reaction
NH2
R
imine salt
aminal
under similar reaction conditions at 60 °C resulted in a low-
er yield of 3a (entry 15). In the reaction with an excess of
amine, 3a was not detected at 80 °C (entry 16), whereas the
reaction with an excess of formaldehyde gave 3a in 76%
Scheme 1 Reaction of amines with formaldehyde
In our previous study on the N-alkylation of amines,3
we found that the reaction of benzylamine with formalde-
hyde produced benzaldehyde in the presence of an iron(III)
catalyst in water. Here, we describe the direct transforma-
tion of benzylic amines into carbonyl compounds with
formaldehyde in the presence of an iron catalyst in water
under mild reaction conditions (Scheme 2).1
yield (entry 17). Reducing the amount of FeCl ·6H O cata-
5
3
2
lyst to 10 mol% (based on amine) resulted in a lower yield
(entry 18). Thus, the most effective direct transformation
was achieved by the treatment of (diphenylmethyl)amine
(1a: 0.5 mmol) with formaldehyde (2 0.6 mmol) in the
presence of FeCl ·6H O catalyst (20 mol%) in H O at 100 °C.
3
2
2
Moreover, when the transformation reaction was per-
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2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
M. Minakawa, T. Sasaki
Letter
formed with aqueous HCl (0.2 M), 3a was observed in <1%
yield (entry 19). Under similar reaction conditions with 0.6
amine (1f) with 2 produced benzaldehyde (3f) in 62% yield
(entry 6). The reaction of 4-methoxybenzylamine (1g) with
2 led to the corresponding carbonyl compound 3g in 83%
yield (entry 7). The formation of aldehydes from the ben-
zylic amines 4-methylbenzylamine (1h), 3-methylbenzyl-
amine (1i), and 2-methylbenzylamine (1j) and 2, performed
under similar conditions, gave 4-methylbenzaldehyde (3h),
3-methylbenzaldehyde (3i), and 2-methylbenzaldehyde (3j),
respectively (entries 8–10). 4-Fluorobenzylamine (1k) was
converted into 4-fluorobenzaldehyde (3k) in 51% yield (en-
try 11). The reaction of 4-chlorobenzylamine (1l) with 2
gave 4-chlorobenzaldehyde (3l) in 55% yield (entry 12).
6
M aqueous HCl, the reaction gave 3a in 36% yield (entry
7
2
0). Therefore, the Fe catalyst is required for the effective
direct transformation of a benzylic amine with formalde-
hyde to form a carbonyl compound.
Table 1 Direct Transformation of (Diphenylmethyl)amine (1a) into
a
Benzophenone (3a)
NH2
O
O
catalyst
+
H2O (0.5 mL)
H
H
80 °C
1a
2
18 h
3a
Table 2 Direct Transformation of Benzylic Amines with Formaldehyde
To Give Carbonyl Compoundsa
b
Entry
Catalyst (mol%)
–c
Temp (°C)
Yield (%)
NH2
R1
O
1
2
3
4
5
6
7
8
9
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
80
80
80
80
(<1)
(77) 74
(12)
(16)
(60) 54
(2)
O
FeCl3·6H2O (20 mol%)
H O (0.5 mL)
+
R1
Fe(III)Cl
Fe(III)(acac)
Fe(III)(NO
Fe(III)F (20)
Fe(II)(OAc) (20)
Fe(II)Cl ·4H O (20)
Fe(II)SO ·7H O (20)
TsOH (20)
citric acid (20)
AlCl (20)
ZnCl (20)
CuCl (20)
3
·6H
2
O (20)
R2
R2
H
H
2
80 °C to reflux
3
(20)
0.5 mmol
0.6 mmol
18 h
1
2
3
2
)
3
·9H
2
O (20)
3
b
Entry
1
Amine (1)
Product (3)
Yield (%)
2
NH2
O
2
2
(<1)
(<1)
(6)
94
4
2
1
a
3a
3b
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
(7)
NH2
O
3
(4)
2
24
34
13
2
(2)
(<1)
94
1b
Fe(III)Cl
Fe(III)Cl
Fe(III)Cl
Fe(III)Cl
Fe(III)Cl
3
3
3
3
3
·6H
·6H
·6H
·6H
·6H
2
2
2
2
2
O (20)
O (20)
O (20)
O (20)
O (10)
NH2
O
26
3
6d
(<1)
76
Me
1c
Me
3c
7e
8
9
0
(3)
NH2
O
aq HCl (0.2 M)
aq HCl (0.6 M)
(<1)
(36)
4c
2
1
1
d
e
3d
3e
a
Reaction conditions: 1 (0.5 mmol), paraformaldehyde (2: 0.6 mmol), cata-
O (0.5 mL), 80 °C, 18 h.
NMR yield (in parentheses) or isolated yield.
No catalyst.
lyst (20 mol% based on 1), H
2
NH2
O
b
c
5c
4
d
e
1
.0 mmol of 1a was used.
1.2 mmol of 2 was used.
With the optimized conditions in hand, we proceeded
to investigate the reaction of various benzylic amines with
formaldehyde (Table 2). Acetophenone (3b) was formed
in 24% yield from (1-phenylethyl)amine (1b) and 2 (entry
NH2
O
6d
H
62
83
8,9
1f
3f
2). The reaction of 1-(4-methylphenyl)ethylamine (1c) with
NH2
O
2
generated 3c in 34% yield (entry 3). The transformations
7d
H
of 1,2,3,4-tetrahydronaphthalen-1-amine (1d) and [1-(1-
naphthyl)ethyl]amine (1e) with 2 produced the corre-
MeO
MeO
3g
1
g
sponding carbonyl compounds 3d and 3e in yields of 13 and
0
4
%, respectively (entries 4 and 5).1 The reaction of benzyl-
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Synlett
M. Minakawa, T. Sasaki
Letter
Table 2 (continued)
the corresponding carbonyl compounds 3a–n in 4–94%
yield (14 examples).
b
Entry
Amine (1)
Product (3)
Yield (%)
Unfortunately, the reaction of (2-phenylethyl)amine (4)
with formaldehyde (2) under similar reaction conditions
gave aldehyde 5 in <1% yield (Scheme 3).11
NH2
NH2
O
H
8d
70
55
66
51
55
Moreover, the treatment of N-(phenylmethylene)meth-
anamine (6) in the presence of FeCl ·6H O in refluxing H O
Me
Me
3h
1
h
3
2
2
for 18 hours afforded benzaldehyde (3f) in 61% yield
(Scheme 4). The reaction without FeCl ·6H O gave 3f in <1%
O
Me
Me
3
2
12
9c,d
H
yield under similar reaction conditions. These results
therefore demonstrate that the direct formation of carbonyl
compounds from benzylic amines with an Fe catalyst pro-
ceeds via intermediate imine 6 derivatives.
1
1
i
j
3i
Me
NH2
Me
O
0d
H
O
1
1
1
1
O
3j
N
FeCl3·6H2O (20 mol%)
H
H2O (0.5 mL)
reflux
NH2
6
3f
18 h
1c,d
H
61%
without FeCl3·6H2O: <1%
F
F
3k
1
k
Scheme 4 Treatment of N-(phenylmethylene)methanamine (6) with
NH2
O
FeCl ·6H O
3
2
2c,d
H
Cl
Cl
3l
The reaction of (diphenylmethyl)amine (1a) with benz-
aldehyde (3f) under similar reaction conditions gave benzo-
1
l
NH2
O
phenone (3a) and N-benzylidene(diphenylmethyl)amine
3
(
7) in yields of 20 and 25%, respectively (Scheme 5).1 In this
3d,e
H
66
52
reaction, benzylamine (1f) was also obtained in 9% yield.
MeS
MeS
3m
1
m
NH2
O
S
S
O
1
4d,e
FeCl3·6H2O (20 mol%)
H
1a
+
3a
0%
+
+
1f
H
N
H2O (0.5 mL)
1
n
3n
100 °C
2
9%
a
Reaction conditions: amine 1 (0.5 mmol), paraformaldehyde (2: 0.6
·6H O (20 mol% based on 1), H O (0.5 mL), 80 °C, 18 h.
Isolated yield.
O–1,4-dioxane (1:1) was used.
Under reflux conditions.
O–1,4-dioxane (1:0.4) was used.
3f
18 h
mmol), FeCl
3
2
2
b
7
25%
c
H
2
d
e
H
2
Scheme 5 Reaction of (diphenylmethyl)amine (1a) with benzaldehyde
(
3f) in the presence of FeCl ·6H O
3 2
Similarly, [4-(methylthio)benzyl]amine (1m) reacted
with 2 to give benzaldehyde 3m in 66% yield (entry 13). The
reaction of (2-thienylmethyl)amine (1n) with 2 afforded
thiophene-2-carbaldehyde (3n) in 52% yield (entry 12).
Thus, our reaction conditions are applicable to the direct
transformation of benzylic amines 1a–n with formaldehyde
The reaction of (diphenylmethyl)amine (1a) with form-
18
aldehyde (2) in the presence of FeCl
·6H O in O -labeled
3
2
18
water (98 atom%) at 100 °C for 18 hours produced O -la-
beled benzophenone (3a′) and benzophenone (3a) (3a′/3a =
1.3:1.0) (Scheme 6).14
(
2) using an iron catalyst (FeCl ·6H O) in water to produce
3 2
O18
O
FeCl3·6H2O (20 mol%)
1a
+
2
+
NH2
O
O
H2O18 (0.5 mL)
FeCl3·6H2O (20 mol%)
+
100 °C
H2O (0.5 mL)
reflux
H
H
H
3a'
3a
18 h
0.5 mmol
0.6 mmol
<1%
100% conversion
18 h
3a'/3a = 1.3:1.0
4
2
5
Scheme 6 O18-Labeling experiment
Scheme 3 Reaction of (2-phenylethyl)amine (4) with formaldehyde (2)
in the presence of FeCl ·6H O
3
2
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2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Synlett
M. Minakawa, T. Sasaki
Letter
A possible reaction pathway (Scheme 7) is proposed on
the basis of the above information and previously published
Funding Information
This research was partially supported by the Asahi Glass Foundation,
and Yamagata University Gender Equality Office.()
4,15,16
results.
The reaction of the benzylic amine 1 with
4
formaldehyde (2) produces an imine intermediate. This co-
ordinates with the Fe catalyst and an H O molecule to give
2
imine intermediate A. The H O molecule coordinated to Fe
Supporting Information
2
could be derived from FeCl ·6H O or from imine formation
3
2
Supporting information for this article is available online at
and it should be readily exchangeable with other H O mole-
2
https://doi.org/10.1055/s-0037-1611881.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
cules of the solvent. The resulting imine A might be con-
15
verted into imine B through isomerization. Subsequently,
the Fe-coordinated H O molecule reacts with the imine to
References and Notes
2
form C. Finally, the release of methylamine from C leads to
product 3 with regeneration of the Fe catalyst.
(
1) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192. (b) Chu, G.; Li, C. Org. Biomol. Chem. 2010,
, 4716. (c) Galletti, P.; Funiciello, F.; Soldati, R.; Giacomini, D.
8
R
Adv. Synth. Catal. 2015, 357, 1840. (d) Patil, V. V.; Gayakwad, E.
M.; Shankarling, G. S. J. Org. Chem. 2016, 81, 781. (e) Wang, Y.;
Kaboyashi, H.; Yamaguchi, K.; Mizuno, N. Chem. Commun. 2012,
R
O
NH2
3
[Fe]
2
+
48, 2642. (f) Gaspa, S.; Porcheddu, A.; Valentoni, A.; Garroni, S.;
MeNH2
1
Enzo, S.; De Luca, L. Eur. J. Org. Chem. 2017, 5519. (g) Iqbal, N.;
Cho, E. J. Adv. Synth. Catal. 2015, 357, 2187. (h) Ratnikov, M. O.;
Farkas, L. E.; McLaughlin, E. C.; Chiou, G.; Choi, H.; El-Khalafy, S.
H.; Doyle, M. P. J. Org. Chem. 2011, 76, 2585. (i) Hamamoto, H.;
Suzuki, Y.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2007, 48,
R
OH
NH
Fe]
R
4239. (j) Golime, G.; Bogonda, G.; Kim, H.; Oh, K. ACS Catal.
N
2018, 8, 4986. (k) Telvekar, V. N.; Chaudhari, H. K. Synth.
[
C
[
Fe] OH2
A
Commun. 2013, 43, 1155. (l) Hudwekar, A. D.; Reddy, G. L.;
Verma, P. K.; Gupta, S.; Vishwakarma, R. A.; Sawant, S. D. Chem-
istrySelect 2017, 2, 4963. (m) Srogl, J.; Voltrova, S. Org. Lett.
H2O
2009, 11, 843. (n) Knowles, D. A.; Mathews, C. J.; Tomkinson, N.
C. O. Synlett 2008, 2769. (o) Miyazawa, A.; Tanaka, K.; Sakakura,
T.; Tashiro, M.; Tashiro, H.; Prakash, G. K. S.; Olah, G. A. Chem.
Commun. 2005, 2104.
R
N
(
2) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemis-
try; Oxford University Press: Oxford, 2001.
[
Fe]
H2O
(
3) (a) Minakawa, M.; Okubo, M.; Kawatsura, M. Bull. Chem. Soc.
Jpn. 2015, 88, 1680. (b) Minakawa, M.; Okubo, M.; Kawatsura,
M. Tetrahedron Lett. 2016, 57, 4187. (c) Minakawa, M.;
Watanabe, K.; Toyoda, S.; Uozumi, Y. Synlett 2018, 29, 2385.
4) (a) Issleib, K.; Döpfer, K.; Balszuweit, A. Z. Naturforsch., B 1981,
36, 1392. (b) Sugimoto, H.; Nakamura, S.; Ohwada, T. Adv. Synth.
Catal. 2007, 349, 669. (c) Cele, Z. E. D.; Pawar, S. A.; Naicker, T.;
Maguire, G. E. M.; Arvidsson, P. I.; Kruger, H. G.; Govender, T.
Eur. J. Org. Chem. 2014, 2253.
B
Scheme 7 A possible reaction pathway
(
In conclusion, we have demonstrated a Fe-catalyzed di-
rect transformation of benzylic amines into carbonyl com-
pounds in H O. The benzylic amines were converted into
carbonyl compounds in the presence of formaldehyde with
a Fe catalyst in H O without stoichiometric quantities or
large amounts of explosive peroxide, toxic oxidizing re-
agents, and/or expensive late-transition metals. The ex-
pected intermediate (internal imine), N-(phenylmethy-
lene)methanamine, led to the corresponding carbonyl com-
pound (benzaldehyde) in the presence of FeCl ·6H O in H O
under refluxing conditions. The reaction in the absence of
Fe catalyst did not proceed under similar reaction condi-
tions. The reaction of (diphenylmethyl)amine with benzal-
dehyde under similar reaction conditions afforded benzo-
phenone, an imine intermediate [N-benzylidene(diphenyl-
2
(
5) The reaction with an excess of amine to give an aminal seems to
predominate over the conventional reaction (Scheme 1). On the
other hand, the reaction with an excess of formaldehyde pre-
vented the formation of an aminal in the presence of
2
FeCl ·6H O.
3 2
(
(
(
6) 0.2 M aq HCl. The concentration was calculated for 1.0 mol
equiv of HCl formed from FeCl ·6H O (20 mol% based on amine).
3
2
3
2
2
7) 0.6 M aq HCl. The concentration was calculated for 3.0 mol
equiv of HCl formed from FeCl ·6H O (20 mol% based on amine).
8) Benzophenone (3a); Typical Procedure (Table 2, Entry 1)
A vial was charged with (diphenylmethyl)amine (1a; 91.6 mg,
3
2
0.5 mmol), FeCl ·6H O (27.0 mg, 20 mol%), and paraformalde-
3 2
hyde (2; 19.2 mg, 0.6 mmol) under air. H O (0.5 mL) was added
2
1
8
and the mixture was stirred at 100 °C for 18 h. The aqueous
phase was then extracted with EtOAc (×3) and dried (Na SO ).
methyl)amine],
and
benzylamine.
O -Labeling
2
4
experiments demonstrated that the O atom in the generat-
The extract was filtered through paper and concentrated in
vacuo. The residue was purified by flash column chromatogra-
ed carbonyl is derived from H O.
2
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
Synlett
M. Minakawa, T. Sasaki
Letter
phy [silica gel, EtOAc–hexane (1:10)] to give a white solid; yield:
(13) The yields were determined by 1H NMR analysis of the crude
mixtures (based on an internal standard). After the reaction,
benzaldehyde (3f) was also detected in 35% yield.
(14) The products ratio (O /O ) was determined by GC–MS analy-
sis.
(15) (a) Casey, C. P.; Johnson, J. B. J. Am. Chem. Soc. 2005, 127, 1883.
(b) Brune, H. A.; Unsin, J.; Hemmer, R.; Reichhardt, M.
J. Organomet. Chem. 1989, 369, 335. (c) Gangadasu, B.; Narender,
P.; China Raju, B.; Jayathira Rao, V. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 2005, 44, 2598. (d) Guthrie, R. D.;
Meister, W.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 5288.
(e) Guthrie, R. D.; Jaeger, D.; Meister, W.; Cram, D. J. J. Am. Chem.
Soc. 1971, 93, 5137.
8
5.2 mg (94%); mp 47.5–49.0 °C.
1
H NMR (500 MHz, CDCl ):  = 7.49 (t, J = 6.2 Hz, 4 H), 7.58–7.61
3
13
18
16
(m, 2 H), 7.81 (d, J = 6.2 Hz, 4 H). C NMR (125 MHz, CDCl ):  =
3
1
28.4, 130.2, 132.6, 137.7, 196.9.
9) When amines or imine intermediates were insoluble in water,
,4-dioxane was added.
(
1
(
10) Although amines were consumed, the desired products were
obtained in low yields.
11) Although the reactions of (pyridin-4-ylmethyl)amine, (pyrazin-
(
2-ylmethyl)amine, and furfurylamine with formaldehyde were
also performed under similar reaction conditions, the corre-
sponding carbonyl compounds were not obtained. In addition,
4
-nitrobenzylamine with formaldehyde gave 4-nitrobenzalde-
(16) (a) Pi, D.; Jiang, K.; Zhou, H.; Sui, Y.; Uozumi, Y.; Zou, K. RSC Adv.
2014, 4, 57875. (b) Jiang, K.; Pi, D.; Zhou, H.; Liu, S.; Zou, K.
Tetrahedron 2014, 70, 3056. (c) Zhou, Y.; Shen, G.; Sui, Y.; Zhou,
H. Tetrahedron Lett. 2016, 57, 3396. (d) Shen, G.; Zhou, H.; Sui,
Y.; Liu, Q.; Zou, K. Tetrahedron Lett. 2016, 57, 587. (e) He, R.; Cui,
P.; Pi, D.; Sun, Y.; Zhou, H. Tetrahedron Lett. 2017, 58, 3571.
hyde in 7% yield under similar reaction conditions.
(
12) Without FeCl ·6H O, N-(phenylmethylene)methanamine (6)
3
2
was detected in quantitative yield after the reaction.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E