Iron-catalyzed nitrene insertion reaction for facile construction of amide compounds

Article abstract of DOI:10.1055/s-0030-1260531

A facile method for the construction of amide compounds from aldehydes by an iron-catalyzed nitrene insertion reaction has been developed. Both aryl and aliphatic aldehydes can directly afford the corresponding amides with an iron(II)-terpyridine (tpy) complex formed in situ as catalyst, and PhI=NTs as nitrogen source under mild reaction conditions. An ESI-MS study revealed the formation of [Fe(tpy)NTs)]⁺ as a reaction intermediate. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260531

1174
LETTER
Iron-Catalyzed Nitrene Insertion Reaction for Facile Construction of Amide
Compounds
F
acile Constructio
u
n of
A
mide
Co
ompounds -Qiang Chen,a Zhen-Jiang Xu,a Yungen Liu,b Cong-Ying Zhou,b Chi-Ming Che*a,b
a
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai,
P. R. of China
b
State Key Laboratory on Synthetic Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for
Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: cmche@hku.hk
Received 14 January 2011
found to be inactive towards the amidation of benzalde-
hyde, and only a trace amount of amide 2 was detected in
each case (Table 1, entries 3–7).
Abstract: A facile method for the construction of amide com-
pounds from aldehydes by an iron-catalyzed nitrene insertion reac-
tion has been developed. Both aryl and aliphatic aldehydes can
directly afford the corresponding amides with an iron(II)-terpyri-
dine (tpy) complex formed in situ as catalyst, and PhI=NTs as nitro-
gen source under mild reaction conditions. An ESI-MS study
revealed the formation of [Fe(tpy)2(NTs)]2+ as a reaction intermedi-
ate.
Table 1 Screening of Iron Salts for Amidation of Benzaldehyde
with PhI=NTs
O
O
O
S
O
N
[Fe] (10 mol%)
Key words: nitrene, C–H insertion, iron, catalysis, amide
PhI=NTs
+
H
4 Å MS
MeCN, r.t.
2
1
Entrya,b
Catalyst
FeCl2
Yield (%)c
9
The amide group is a fundamental functionality in organic
compounds that is prevalent in biologically active natural
products and pharmaceuticals.1 The most widely used
synthetic route to amides is the coupling of carboxylic ac-
ids and amines;2 however, this method usually requires
addition of activation reagents for carboxylic acids, which
sometimes complicates the reaction. Recently, a straight-
forward approach to amide formation through transition-
metal-catalyzed nitrene insertion directly into the C–H
bond of aldehydes was reported. Rhodium carboxylates,3
ruthenium porphyrins,4 and copper salts5 have proven to
be effective catalysts for this transformation.
1d
2
FeCl3
14
3
Fe(acac)3
trace
trace
trace
trace
trace
4e
5e
6
Fe(ClO4)3·6H2O
Fe(ClO4)2·xH2O
Fe(OAc)2
7
Fe(OTf)2
a Reaction conditions: PhCHO (0.4 mmol), PhI=NTs (0.4 mmol), cat-
alyst (10 mol%), 4 Å MS (120 mg; 30 mg/0.1 mmol substrate),
MeCN (2 mL), r.t.
Due to increasing concerns for the environment and sus-
tainable development, there is growing interest in iron ca-
talysis because of its natural abundance and
biocompatibility.6 We and other groups have demonstrat-
ed that iron complexes can catalyze various nitrene trans-
fer reactions, including aziridination,7 C–H insertion,8 and
imination.9 In view of the importance of amides in organic
chemistry, herein, we report iron-mediated nitrene inser-
tion into the C–H bond of aldehydes for the construction
of amide compounds.
b All the iron salts dissolved well in MeCN except for Fe(OAc)2.
c Isolated yield.
d 5 mol% catalyst loading.
e 240 mg 4 Å MS.
Our previous study showed that [Fe(Cl3terpy)2](ClO4)2 is
effective in the catalysis of alkene aziridination and ni-
trene insertion into saturated C–H bonds, revealing the
important effect of nitrogen-containing ligands on the
iron-catalyzed nitrene transfer reactions.7b Therefore, we
next set out to screen a variety of nitrogen-based ligands;
the results are summarized in Table 2. Terpyridine was
found to be the most effective ligand, affording the prod-
uct in 52% isolated yield (Table 2, entry 4). Chloro-sub-
stituted terpyridine was also effective, albeit with lower
product yield compared with unsubstituted terpyridine
(Table 2, entries 5 and 6). tert-Butyl substitution made the
in situ formed iron catalyst inactive towards the amidation
(Table 2, entry 7). Compared with terpyridine, bipyridine
was less effective, giving the amide in 18% yield (Table 2,
Initially, we investigated the amidation of benzaldehyde
using PhI=NTs as nitrene source. Treatment of benzalde-
hyde with this reagent, in the presence of 5 mol% anhy-
drous FeCl2 in anhydrous MeCN at room temperature,
afforded amide 2 in 9% isolated yield (Table 1, entry 1).
Use of FeCl3 (10 mol%) gave similar results under the
same conditions (Table 1, entry 2). Other iron salts were
SYNLETT 2011, No. 8, pp 1174–1178
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260531; Art ID: W00411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Facile Construction of Amide Compounds
1175
entry 1). The more rigid bidentate nitrogen ligands, 1,10- (Table 2, entries 10–12). However, Me3P promoted the
phenanthroline and 2,9-dimethyl-1,10-phenanthroline, C–H insertion (20% product yield, Table 2, entry 13). The
led to the amide product in 26 and 12% yield, respectively sterically encumbered P(t-Bu)2(o-biphenyl) and P(Cy)2(o-
(Table 2, entries 2 and 3). Reducing the amount of ter- biphenyl-2¢,4¢,6¢-tri-i-Pr) ligands proved to be more effec-
pyridine to 10 mol% had a minor effect on the reaction tive, and the use of these ligands significantly improved
(Table 2, entry 8). Using terpyridine as ligand, changing the reaction yield to 52 and 32%, respectively, albeit at the
the metal source from FeCl2 to FeCl3 led to a slightly low- expense of a longer reaction time (Table 2, entries 14–15).
er product yield (49%; Table 2, entry 9).
Bidentate phosphine ligands such as dppp and dppe led to
lower product yields compared with the sterically hin-
dered monodentate phosphine ligands (Table 2, entries 16
and 17).
Phosphine-based ligands were also screened (Table 2, en-
tries 10–18). The addition of Ph3P, Cy3P, or (n-Bu)3P to
the reaction did not lead to appreciable product yield
Table 2 Ligand Effect on Fe-Catalyzed Amidation of Benzaldehyde with PhI=NTs
O
O
O
FeCl2 (10 mol%)
L (x mol%)
S
O
N
PhI=NTs
H
+
4 Å MS
MeCN, r.t.
1
2
Entrya
1
Ligand
x (mol%)
30
Yield (%)b
18
N
N
N
2
3
30
30
26
12
N
N
N
4
5
20
20
52
44
N
N
N
N
Cl
N
N
Cl
6
7
20
20
10
Cl
Cl
N
N
N
t-Bu
N
trace
t-Bu
t-Bu
N
N
8
10
10
52
49
N
N
N
N
9c
N
N
Synlett 2011, No. 8, 1174–1178 © Thieme Stuttgart · New York

1176
G.-Q. Chen et al.
LETTER
Table 2 Ligand Effect on Fe-Catalyzed Amidation of Benzaldehyde with PhI=NTs (continued)
O
O
O
FeCl2 (10 mol%)
L (x mol%)
S
O
N
PhI=NTs
H
+
4 Å MS
MeCN, r.t.
1
2
Entrya
10d
11d
12d
13d
14d
15d
16d
17d
18d
Ligand
x (mol%)
Yield (%)b
trace
trace
trace
20
Ph3P
20
20
20
20
20
20
10
10
10
PCy3
P(n-Bu)3
PMe3
P(t-Bu)2(o-biphenyl)
52
P(Cy)2(o-biphenyl-2¢,4¢,6¢-tri-i-Pr)
32
dppp
27
dppe
23
P(t-Bu)2(o-biphenyl)
49
a Reaction conditions: PhCHO (0.4 mmol), PhI=NTs (0.4 mmol), FeCl2 (10 mol%), ligand, 4 Å MS (120 mg, 30 mg/0.1 mmol substrate), MeCN
(2 mL), r.t., 8 h.
b Isolated yield.
c With FeCl3 (10 mol%) as metal source.
d Reaction run at r.t. for 24 h.
Table 3 FeCl2/Terpyridine-Catalyzed Amidation of Various Alde-
hydes with PhI=NTs (continued)
Among the N and P donor ligands examined, terpyridine
and P(t-Bu)2(o-biphenyl) gave the best results. We chose
terpyridine for further study because of its ease of prepa-
ration and high stability. With 10 mol% FeCl2 and 10
mol% terpyridine as catalyst, the effect of solvent on the
nitrene C–H bond insertion reaction was investigated, and
acetonitrile was the best solvent (see Table S1 in the Sup-
porting Information).
FeCl2 (10 mol%)
O
tpy (10 mol%)
RCHO
Entrya
6
+
PhI=NTs
MeCN
r.t.
R
NHTs
Aldehyde
Yield (%)b
CHO
68
48
Table 3 FeCl2/Terpyridine-Catalyzed Amidation of Various Alde-
hydes with PhI=NTs
FeCl2 (10 mol%)
O
CHO
tpy (10 mol%)
7
RCHO
+
PhI=NTs
MeCN
r.t.
R
NHTs
8
9
71
76
CHO
CHO
Entrya
1
Aldehyde
Yield (%)b
CHO
63
66
CHO
10
89
MeO
CHO
CHO
11
12
13
79
88
72
2
OMe
CHO
CHO
OMe
3
4
5
83
40
CHO
a Reaction conditions: aldehyde (0.4 mmol), PhI=NTs (0.4 mmol),
FeCl2 (10 mol%), tpy (10 mol%), 4 Å MS (120 mg, 30 mg/0.1 mmol
substrate), MeCN (2 mL), r.t.
CHO
b Isolated yield.
CHO
c No desired product detected after 24 h.
c
–
Cl
Synlett 2011, No. 8, 1174–1178 © Thieme Stuttgart · New York

LETTER
Facile Construction of Amide Compounds
1177
Having established the optimal reaction conditions, we into the C–H bond of an aldehyde. Attempts were made to
then explored the scope of the reaction with respect to al- characterize the reaction intermediate by monitoring the
dehydes; the results are depicted in Table 3. Methoxy- reaction mixture comprising of PhI=NTs, FeCl2, and
substituted benzaldehydes reacted smoothly with terpyridine with ESI mass spectrometry. As depicted in
PhI=NTs under the optimal reaction conditions to afford Figure 1, a prominent cluster peak (in positive-ion mode)
the insertion products regardless of substitution position at m/z 345.4 with peak separation of 0.5 units was
(Table 3, entries 1–3). 2,4,6-Trimethylbenzaldehyde also observed. The cluster peak was consistent with
underwent the reaction smoothly to afford the product, al- [Fe(tpy)2(NTs)]2+ formulation
beit with a lower yield, probably because of steric hin- C37H29N7O2SFe: 345.6).
drance (Table 3, entry 4). For p-chlorobenzaldehyde, no
(m/z calcd. for
O
desired product was detected in the reaction mixture after
24 h (Table 3, entry 5). Both a- and b-naphthaldehydes af-
forded the corresponding product amides in 68 and 48%
isolated yield, respectively (Table 3, entries 6 and 7). In-
terestingly, the catalytic system seemed to be more suit-
able for preparing amides from aliphatic aldehydes than
from aryl aldehydes, and various substituted aliphatic al-
dehydes underwent the reaction well to afford the inser-
tion products in up to 89% yield (Table 3, entries 8–13). It
is noteworthy that when 3-phenylpropanal was used as
substrate, no intermolecular benzylic C–H bond insertion
product was found (Table 3, entry 13).
[Fe]n+
R
NHTs
PhI=NTs
PhI
≠
O
R
Ts
N
H
NTs
n+2
n+2
Fe
Fe
RCHO
A plausible reaction mechanism was proposed as shown
in Scheme 1. Similar to previous reports,5 the iron cata-
lysts could decompose PhI=NTs to generate an iron imido/
nitrene intermediate, which undergoes nitrene insertion
Scheme 1 Plausible reaction mechanism of iron-catalyzed nitrene
C–H insertion reaction.
Figure 1 ESI-MS spectrum attributed to [Fe(tpy)2(NTs)]2+ (C37H29N7O2SFe). (a) Observed isotope pattern; (b) simulated isotope pattern.
In conclusion, we have developed a simple and efficient
method for the construction of amide derivatives by iron-
catalyzed nitrene insertion into the C–H bond of alde-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
hydes. Both aryl and aliphatic aldehydes undergo the in-
termolecular nitrene C–H bond insertion reaction with
inexpensive and biocompatible iron complex as catalyst
to afford the corresponding amide derivatives under mild
reaction conditions.
Acknowledgment
We gratefully acknowledge financial support from The University
of Hong Kong (University Development Fund), Hong Kong Re-
search Grants Council (HKU 1/CRF/08), the University Grants
Council of HKSAR (Area of Excellence Scheme: AoE 10/01P),
Synlett 2011, No. 8, 1174–1178 © Thieme Stuttgart · New York

1178
G.-Q. Chen et al.
LETTER
CAS-GJHZ200816 and CAS-Croucher Funding Scheme for Joint
Laboratory. G.-Q. Chen thanks the Croucher Foundation of Hong
Kong for a postgraduate studentship.
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