Mechanistic studies on the N-formylation of amines with CO2 and hydrosilane catalyzed by a Cu-diphosphine complex

Article abstract of DOI:10.1016/j.tet.2014.07.089

The reaction mechanism, reaction intermediates, and catalytically active species of the Cu-diphosphinecatalyzed N-formylation of amines (R1R2NH) with CO₂ and hydrosilane were investigated. The NMR and kinetic experiments show that the catalytically active species is a Cu-hydride-diphosphine complex, which was generated from the Cu precursor, diphosphine ligand, and hydrosilane. Isotopic experiments using ¹³CO₂ and deuterated hydrosilane revealed the incorporation of the carbonyl group of CO₂ and the H atom of Si-H moiety into the formamide (R¹R²NCHO) product. The formation of a Cu-formate species as an intermediate of the reaction was clarified by in situ ¹H and ¹³C NMR studies.

Full text of DOI:10.1016/j.tet.2014.07.089

Tetrahedron 70 (2014) 6951e6956
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Tetrahedron
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Mechanistic studies on the N-formylation of amines with CO and
2
hydrosilane catalyzed by a Cuediphosphine complex
Ken Motokura, Naoki Takahashi, Akimitsu Miyaji, Yasuharu Sakamoto, Sho Yamaguchi,
Toshihide Baba *
Department of Environmental Chemistry and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2014
Received in revised form 23 July 2014
Accepted 25 July 2014
Available online 30 July 2014
The reaction mechanism, reaction intermediates, and catalytically active species of the Cuediphosphine-
catalyzed N-formylation of amines (R R NH) with CO and hydrosilane were investigated. The NMR and
2
kinetic experiments show that the catalytically active species is a Cu-hydrideediphosphine complex,
1 2
which was generated from the Cu precursor, diphosphine ligand, and hydrosilane. Isotopic experiments
using 13CO
and deuterated hydrosilane revealed the incorporation of the carbonyl group of CO and the
2
2
1
2
H atom of SieH moiety into the formamide (R R NCHO) product. The formation of a Cu-formate species
Keywords:
as an intermediate of the reaction was clarified by in situ 1H and 13C NMR studies.
N-Formylation
Reaction mechanism
Amine
Ó 2014 Elsevier Ltd. All rights reserved.
CO
2
Hydrosilane
Cuediphosphine
1. Introduction
The N-formylation of amines with CO
only for the utilization of CO
the practical synthesis of valuable chemicals. Recently, the use of
hydrosilanes as a reducing agent for CO has received much at-
2
is a useful method not
2
as a chemical feedstock, but also for
1,2
2
tention because of the mild reaction conditions and diverse sub-
strate scope.3 In 2013, we reported the N-formylation of amines
,4
with 1 atm of CO
methylhydrosiloxane (PMHS), a catalytic amount of Cu(OAc)
2
in the presence of a hydrosilane, poly-
$H O,
Scheme 1. Cuediphosphine complex catalyst system for the N-formylation of amines
with CO and PMHS.
2
2
2
5
5
and a diphosphine ligand (Scheme 1). The turnover number
exceeded 10,000. The catalyst system achieved the N-formylation
of various amines including primary and secondary amines, as well
as aliphatic and aromatic amines. However, the reaction pathway,
structure of catalytically active species, and reaction intermediate
are yet to be elucidated.
2
We also reported the hydrosilylation of CO to silyl formate
using the Cuediphosphine complexes and investigated the reaction
mechanism.6 The reaction pathway for the hydrosilylation of CO
,7
Scheme 2. Cu-hydrideediphosphine complex catalyzed hydrosilylation of CO
2
.6
2
is shown in Scheme 2. In this case, the Cu-hydrideediphosphine
complex and Cu-formate were clarified as the catalytically active
species and reaction intermediate, respectively.
The Cu-hydrideediphosphine catalyst was found to be highly
active for the reduction of CO to the Cu-formate intermediate. In
the case of the N-formylation of amines with CO and hydrosilane,
a combination of Cu salts and diphosphine ligand was also
2
2
*
Corresponding author. E-mail address: tbaba@chemenv.titech.ac.jp (T. Baba).
http://dx.doi.org/10.1016/j.tet.2014.07.089
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
0

6952
K. Motokura et al. / Tetrahedron 70 (2014) 6951e6956
effective.5 Since N-formylation of amines with CO
is a reductive
2
reaction, it can be expected that the formation of an active Cu-
hydrideediphosphine complex for the N-formylation reaction. In
this study, the reaction pathway, catalytically active species, and
reaction intermediates for the N-formylation reaction using a Cu
salt and diphosphine ligand were investigated by kinetic and iso-
topic experiments and in situ NMR analyses.
2
Scheme 3. Direct and stepwise routes to formamide from amine, CO , and hydrosilane.
2
. Results and discussion
2
In the N-formylation reactions of amines with CO using mo-
lecular hydrogen (H
2
) as the reducing agent, the stepwise forma-
As shown in Fig. 1, an induction period was observed for the
formation of formamide and silyl formate. During the induction
period, the formation of silyl acetate (:) was detected. Scheme 4
shows the possible route for the formation of silyl acetate from
tion of the final product, a formamide through the formation of
formic acid or its salt as the reaction intermediate has been widely
accepted.2 Additionally, silyl formate was reported to react with
various amines, affording the corresponding formamides. This
encouraged us to clarify the formation of silyl formate as the re-
action intermediate for the N-formylation of amines catalyzed by
our Cu salt/diphosphine ligand catalyst system. To elucidate the
reaction pathway for the N-formylation reaction, the time course of
the initial period of the N-formylation of piperidine with trie-
4
,8
2 2 3
Cu(OAc) $H O and Et SiH. The Cu-hydride complex should be
formed along with silyl acetate. Thus, the Cu-hydrideephosphine
complex may act as the catalytically active species for the N-for-
mylation of amines.
thylsilane (Et
3 2 2
SiH) using Cu(OAc) $H O and a diphosphine ligand,
1,2-bis(diisopropylphosphino)benzene (Chart 1, 1), was in-
vestigated. The results are shown in Fig. 1. Surprisingly, in this case,
the formations of the corresponding formamide (,) and silyl for-
mate (6) proceeded in a parallel fashion at least for the initial
period of the reaction. This result indicates that N-formylpiperidine
2
was formed directly from piperidine, CO , and hydrosilane. Thus,
the stepwise formation of formamide from the silyl formate in-
termediate and amine is not the major route when this catalyst
system is used (Scheme 3).
Scheme
4. Possible
reaction
pathway
from
2
Cu(OAc) $H
2
O,
1,2-
3
bis(diisopropylphosphino)benzene (1), and Et SiH to Cu-hydride complex and silyl
acetate.
The formation of Cu-hydrideephosphine complex was con-
1
firmed by H NMR analyses in the presence of Cu(OAc)
2
$H
2
O, 1, and
1
Chart 1.
PMHS, as shown in Fig. 2. The H NMR signal for the Cu-hydride
0
0
0
0
0
0
0
0
.35
.30
.25
.20
.15
.10
.05
.00
(
b)
a)
(
-
0.10
-0.20
-0.30
-0.40
1
0
50
100
150
Time / min
200
250
300
350
H Chemical Shift / ppm
Fig. 2. (a) 1H NMR and (b) 31P-decoupled 1H NMR spectra of Cu-hydride with 1,2-
Fig. 1. Time course of formamide synthesis. Formamide (,), silyl formate (6), silyl
acetate (:). Reaction conditions: piperidine (1.4 mmol), Et SiH (3.2 mmol),
bis(diisopropylphosphino)benzene (1) ligand in a dioxane-d
8
solution. Reaction con-
ꢁ
2
ꢁ2
mmol), PMHS (SieH:
3
ditions: Cu(OAc)
0.40 mmol), and 1,4-dioxane-d
mixture was transferred to an NMR tube under Ar atmosphere.
2
$H
2
O
(Cu: 2.5ꢀ10
mmol), 1 (3.8ꢀ10
ꢁ
2
Cu(OAc)
2
2
$H O
(5.0ꢀ10
mmol), ligand 1,2-bis(diisopropylphosphino)benzene (P:
8
(1.0 mL), Ar, rt, and 1 h. Then, ca. 0.4 mL of the reaction
ꢂ
0
.15 mmol), 1,4-dioxane (2.0 mL), CO
2
(1 atm, balloon), and 80 C.

K. Motokura et al. / Tetrahedron 70 (2014) 6951e6956
6953
complex was detected at
signal appeared sharp in the P-decoupled H NMR analysis
Fig. 2b), indicating the coordination of 1 to the Cu salt forming the
Cu-hydride complex. The formation of Cu-hydridee1 complex was
d
ꢁ0.23 ppm in dioxane-d
8
(Fig. 2a). This
31
1
(
1
31
6b
also confirmed by He P HSQC NMR analysis.
Fig. 3 shows the time course of the formamide synthesis using
the Cu-hydridee1 complex.
Cu(OAc) $H O, 1, and Et
A
1,4-dioxane solution of
2 3
Scheme 6. Cu-catalyzed N-formylation of piperidine with CO and Et SiD.
ꢂ
2
2
3
SiH was heated at 80 C under Ar atmo-
sphere for 120 min, affording the Cu-hydridee1 complex. Then, the
Ar gas was replaced with CO . As shown in Fig. 3, the formamide
was formed immediately after the introduction of CO ; thus, no
induction period was observed. This result indicates that the Cu-
hydridee1 complex is the actual catalytically active species for the
2
To elucidate the N-formylation pathway, in situ 13C NMR anal-
yses were conducted as shown in Fig. 4. After the treatment of a 1,4-
2
13
dioxane-d
signal appeared at
carbamic acid or carbamate (:) along with the broadened signal of
8
2
solution of piperidine with CO , a new broadened
d
158 ppm, which was assigned to piperidino
2
N-formylation of piperidine with CO .
1
3
CO solution
2
at
d
125 ppm (6) (Fig. 4b). Then, the 1,4-dioxane-d
8
13
0
0
0
0
0
0
0
0
.35
.30
.25
.20
.15
.10
.05
.00
of Cu-hydridee1 complex (Fig. 4c) was added to the CO -treated
piperidine solution (b). The C NMR spectrum of the mixed solu-
tion was measured, and the spectrum obtained after 8 min of the
2
13
mixing is shown in Fig. 4d. Sharp new signals appeared at
d 158 and
167 ppm, assigned to N-formylpiperidine (,) and Cu-formate (B),
respectively, along with the simultaneous disappearance of the
piperidino carbamic acid/carbamate signal (Fig. 4d). After a pro-
longed reaction time, the Cu-formate signal disappeared, while the
signal for N-formylpiperidine increased (Fig. 4def). These results
indicate the formation of the Cu-formate species from the Cu-
hydride complex and piperidino carbamic acid/carbamate and/or
Addition of CO
2
2
CO . The Cu-formate species reacted with piperidine, affording N-
formylpiperidine. This reaction pathway is consistent with the re-
sult obtained using [Me NCO ][Me NH ] as the substrate.
2 2 2 2
0
50
100
150
Time / min
Fig. 3. Time course of formamide synthesis. Formamide (,), silyl acetate (:). Re-
200
250
300
350
action conditions: piperidine (1.4 mmol), Et
3
SiH (3.2 mmol), Cu(OAc)
2
$H
2
O
5.0ꢀ10ꢁ mmol), ligand 1,2-bis(diisopropylphosphino)benzene (P: 0.15 mmol), 1,4-
2
(
ꢂ
dioxane (2.0 mL), and 80 C under Ar atmosphere. After 120 min, the reactor was
2
replaced by CO (1 atm, balloon).
The incorporation of the C atom of CO
hydrosilane into the formamide product was confirmed by isotopic
experiments using 13CO
and triethylsilane-d (Et SiD), respectively.
As shown in Scheme 5, in the reaction of piperidine with PMHS, the
2
and the H atom of
2
3
1
3
13
12
2 2
C NMR analysis revealed that the use of CO instead of CO
13
afforded N-formylpiperidine with C atoms incorporated at the
carbonyl group. The 1 C content of the formamide product was
3
þ
>
95% as determined by the GCeMS analysis: m/z [M ]: 114(100),
1
13(33). Moreover, the reaction of piperidine using Et
3
SiD under
12
CO
2
atmosphere afforded deuterated N-formylpiperidine: m/z
þ
1
[M ]: 114(100), 113(33). The H NMR analysis of the product
revealed the position of the deuterium atom at the carbonyl group
of the product, as shown in Scheme 6.
Fig. 4. 13C{ H} NMR spectra of (a) 13CO
1
in dioxane-d
, and (c) solution B: Cu-hydride with ligand 1 in dioxane-d
, (b) solution A: 13CO
and pi-
8 2
2
13
peridine in dioxane-d
H} NMR spectra (d)e(f) were obtained at (d) 8, (e) 53, and (f) 180 min after the
8
8
.
C
1
{
mixing of solutions A and B. Solution A: piperidine (0.26 mmol) and 1,4-dioxane-d
8
Scheme 5. Cu-catalyzed N-formylation of piperidine with 13CO
conditions: solution A: piperidine (0.26 mmol) and 1,4-dioxane-d
and PMHS. Reaction
(2.0 mL), under CO
13
, rt, and 1 h. Solution B: Cu(OAc)
(3.8ꢀ10 mmol), PMHS (SieH: 1.0 mmol), and 1,4-dioxane-d
and 1 h. Then, 0.4 mL of each solution was mixed in an NMR tube to start the N-for-
O (Cu: 2.5ꢀ10 mmol), 1
ꢁ2
2
2
2 2
$H
ꢁ
2
8
(2.0 mL), under
8
(2.0 mL), under Ar, rt,
13
ꢁ2
ꢁ2
CO
PMHS (SieH: 1.0 mmol), and 1,4-dioxane-d
.4 mL of each solution was mixed in an NMR tube to start the N-formylation reaction.
The reaction mixture was transferred to the NMR tube under Ar atmosphere.
2
, rt, and 1 h. Solution B: Cu(OAc)
2
$H
2
O (Cu: 2.5ꢀ10 mmol), 1 (3.8ꢀ10 mmol),
13
8
(2.0 mL), under Ar, rt, and 1 h. Then,
2
mylation reaction. Spectra (d)e(f) show the conversion of CO (6) and piperidine
0
(and/or piperidino carbamic acid/carbamate (:)) to N-formylpiperidine product (,)
through copper formate (B).

6954
K. Motokura et al. / Tetrahedron 70 (2014) 6951e6956
Previously, we reported the formation of N,N-dimethylformamide
from [Me NCO ][Me NH ] using the Cuediphosphine complex and
2
2
2
2
5
PMHS under Ar atmosphere, indicating the direct formation of Cu-
formate from the Cu-hydride complex and an amine carbamate.
13
The stepwise transformation by the addition of CO
dine, and hydrosilane to the 1,4-dioxane-d solution of the Cu-
hydride complex was also monitored by H NMR analyses. The
regions,
4e9 and ꢁ1.0 to 0.2 ppm, are shown in Figs. 5 and 6,
respectively. As shown in Fig. 5a and b, after the addition of CO
2
, piperi-
8
1
d
1
3
to
(d)
2
the solution of the Cu-hydride complex, the formation of silyl for-
mate (-) was observed in the absence of piperidine. This result is
9
in agreement with our previous report on the hydrosilylation of
6
CO
2
.
During the hydrosilylation of CO
2
, the Cu-hydride complex
(
c)
signal (
d
ꢁ0.25 ppm) was maintained as shown in Fig. 6b. This
result is also in agreement with the previous report, indicating that
the rate-determining step of the hydrosilylation is the insertion of
to a CueH bond.6 After the addition of an excess amount of
b
CO
2
piperidine and prolonged reaction time, N-formylpiperidine (,)
was formed, and the hydrosilane (SieH, 4.7 ppm) was consumed
(b)
d
completely (Fig. 5c). As shown in Fig. 5c, the Cu-formate signal (B)
was observed even in the presence of piperidine. Then, an excess
amount of hydrosilane was added to the solution. The Cu-formate
signal disappeared along with the increase in the signal assigned
(
a)
10
to N-formylpiperidine (Fig. 5d). The Cu-hydride complex signal
was regenerated at
d
ꢁ0.25 ppm after the addition of the hydro-
0
.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
silane (Fig. 6d). These results indicate that (i) the formation of N-
formylpiperidine from Cu-formate and piperidine is assisted by
hydrosilane, and (ii) Cu-hydride complex can be regenerated after
the formation of N-formylpiperidine.
1
H Chemical Shift / ppm
Fig. 6. 1H NMR spectra for the stepwise addition of 13CO , piperidine, and PMHS to
a solution of Cu-hydride. The analysis conditions are shown in Fig. 5.
2
Fig. 5. 1H NMR spectra for the stepwise addition of 13CO
a solution of Cu-hydride. (a) 1,4-Dioxane-d solution of Cu-hydride complex; (b)
at rt; (c) after the addition of piperidine; (d) after the addition of an
excess amount of PMHS. Spectra (a)e(d) show the conversion of Cu-hydride to
, piperidine, and PMHS to
2
Scheme 7. Proposed reaction mechanism.
8
13
treated with CO
2
13
CueO C(O)H (B) and catalytic formation of silyl formate (-) from PMHS (SieH) and
13
2
CO . Then, after the addition of piperidine, N-formylpiperidine (,) was obtained
complex from the Cu precursor, ligand 1, and hydrosilane (i). After
the formation of the Cu-hydride complex, the catalytic N-for-
mylation of amines is initiated. The Cu-hydride complex reacts with
from the reaction of silyl formate with piperidine. After the addition of PMHS, the Cu-
formate (B) was converted to N-formylpiperidine (,). All the signals assigned as
formyl protons are doublets because of the 1He C spin interactions.
13
2
CO and/or piperidino carbamic acid/carbamate, affording a Cu-
Overall, the proposed reaction mechanism for the N-formylation
formate (ii). Then, the Cu-formate reacts with piperidine in the
presence of hydrosilane (iii), giving the N-formylpiperidine product
and Cu-hydride complex (iv). The results obtained for the stepwise
2
of amines with CO and hydrosilane is shown in Scheme 7. The
initial step involves the formation of a Cu-hydrideediphosphine

K. Motokura et al. / Tetrahedron 70 (2014) 6951e6956
6955
addition of reactants to the Cu-hydride solution (Figs. 5 and 6) in-
dicate that the reaction of Cu-formate with piperidine is assisted by
hydrosilane. The proposed transition state involving Cu-formate,
triethylsilyl formate, and acetyl group of triethylsilyl acetate (
d
2.07,
1
3H, s) were used. H chemical shift was referenced to 1,4-dioxane
solvent ( 3.71).
d
11
piperidine, and hydrosilane is also shown in Scheme 7.
. Conclusion
The reaction mechanism of the Cuediphosphine-catalyzed N-
1
4
.4. Measurement of H NMR of Cu-hydridee1 complex
3
(Fig. 2)
To a glass reactor equipped with an Ar balloon were added
ꢁ
2
ꢁ2
formylation of piperidine was investigated by kinetic and isotopic
experiments as well as in situ NMR analyses. The major reaction
route did not include the formation of a silyl formate intermediate.
The time course of the N-formylation reaction indicates the direct
Cu(OAc)
2
$H
2
O (Cu: 2.5ꢀ10 mmol), 1 (3.8ꢀ10 mmol), PMHS
(SieH: 0.40 mmol), and 1,4-dioxane-d
8
(1.0 mL), Ar, room tem-
perature, and 1 h. Then, ca. 0.4 mL of the reaction mixture was
1
transferred to an NMR tube under Ar atmosphere for H NMR and
31
1
formation of the formamide product from piperidine, CO
2
, and
P-decoupled H NMR measurements.
hydrosilane. The catalytically active species was determined to be
a Cu-hydrideediphosphine complex, which is generated from the
Cu precursor, diphosphine ligand, and hydrosilane. The formation
of a Cu-formate species as the intermediate for the N-formylation
reaction was established. The reaction of Cu-formate with piperi-
dine, affording the formamide product and the Cu-hydride com-
plex, was assisted by hydrosilane.
4.5. N-Formylation of piperidine with 13CO
(Scheme 5)
and PMHS
2
To a glass reactor equipped with an Ar balloon were added
ꢁ
2
ꢁ2
Cu(OAc)
2
$H
2
O (Cu: 2.5ꢀ10
mmol), 1 (3.8ꢀ10
(2.0 mL). To another glass re-
actor equipped with a balloon were added piperidine
8
(0.26 mmol) and 1,4-dioxane-d (2.0 mL). Both solutions were stirred
mmol), PMHS
(SieH: 1.0 mmol), and 1,4-dioxane-d
8
1
3
CO
2
4
4
. Experimental section
at room temperature for 1 h. Then, 0.4 mL of each solutionwas mixed
in an NMR tube to start the N-formylation reaction at room tem-
perature. The reaction mixture was transferred to the NMR tube
.1. General methods
The H and 13C NMR spectra were recorded in CDCl
1
or dioxane-
under Ar atmosphere. The reaction was monitored by H and
1
13
C
3
13
d
8
using a Bruker AVANCE 400 spectrometer operating at 400 and
NMR. The incorporation of C atom to the formamide product was
13
1
1
00.61 MHz, respectively. A Shimadzu QP2010 instrument equip-
ped with a DB-1 column was used for the GCeMS analyses.
Cu(OAc) $H (Cu content>99.99%) was purchased from
detected by GCeMS and C NMR. For yield calculation, H NMR
signal of formyl proton (
8.01, 1H, d, J¼191.0 Hz) of N-for-
mylpiperidine product was used. In this case, the formyl proton
d
2
2
O
13
Aldrich Inc. PMHS was purchased from WAKO Pure Chemicals (FW:
ca. 1900). Unless otherwise noted, all the other materials were
purchased from Wako Pure Chemicals, Tokyo Kasei Co., Kanto
Kagaku Co., and Aldrich Inc. Mesitylene or 1,3,5-
triisopropylbenzene was used as the internal standard.
signal was obtained as doublet because of the spin couplingof CeH.
2 3
4.6. N-Formylation of piperidine with CO and Et SiD
(Scheme 6)
To a glass reactor equipped with a CO
Cu(OAc) $H
2 2
2
balloon were added
O (Cu: 5.0ꢀ10 mmol), 1,2-bis(diisopropylphosphino)
benzene (1, P: 0.15 mmol), piperidine (1.4 mmol), Et SiD
3.2 mmol), and 1,4-dioxane (2.0 mL). The resulting reaction mix-
ꢁ
2
4
.2. Typical procedure for the formylation of amines under
CO
2
with PMHS
3
(
ꢂ
To a glass reactor equipped with a CO
2
balloon were added
O (Cu: 5.0ꢀ10 mmol),1,2-bis(diisopropylphosphino)
SiH
3.2 mmol), and 1,4-dioxane (2.0 mL). The resulting reaction mix-
ture was stirred vigorously at 80 C for 180 min. The reaction was
ꢁ
2
1
13
Cu(OAc)
2
$H
2
monitored by H and C NMR. The incorporation of deuterium to
1
benzene (1, P: 0.15 mmol), piperidine (1.4 mmol), Et
3
the formamide product was detected by GCeMS and H NMR. For
1
(
yield calculation, H NMR signal of proton at 2-C position (
d
3.31,
ꢂ
1
ture was stirred vigorously at 80 C. The products were confirmed
2H, t, J¼5.5 Hz) of N-formylpiperidine product was used.
H
1
13
by the comparison of their GCeMS spectra and/or H and C NMR
chemical shift was referenced to 1,4-dioxane solvent ( 3.71).
d
spectra with those of authentic data. The yields were determined
by the internal standard technique using a CDCl
3
solution of the
4.7. In situ 13C NMR measurement of N-formylation of pi-
13
reaction mixture. Mesitylene or 1,3,5-triisopropylbenzene was used
2
peridine with CO and PMHS (Fig. 4)
1
as the internal standard. For yield calculation, H NMR signal of
formyl proton (
d 8.01, 1H, s) of N-formylpiperidine product was
To a glass reactor equipped with an Ar balloon were added
used. 1H chemical shift was referenced to 1,4-dioxane solvent (
d
Cu(OAc)
$H
O (Cu: 2.5ꢀ10 mmol), 1 (3.8ꢀ10 mmol), PMHS
(2.0 mL) (solution A). To an-
ꢁ2
ꢁ2
2
2
3
.71).
(SieH: 1.0 mmol), and 1,4-dioxane-d
8
1
3
2
other glass reactor equipped with a CO balloon were added pi-
4
.3. N-Formylation of amines under CO
2
with Et
3
SiH (Fig. 1)
peridine (0.26 mmol) and 1,4-dioxane-d (2.0 mL) (solution B). Both
8
solutions were stirred at room temperature for 1 h. Then, 0.4 mL of
each solution was mixed in an NMR tube to start the N-formylation
reaction at room temperature. The reaction mixture was transferred
to the NMR tube under Ar atmosphere. The reaction was monitored
To a glass reactor equipped with a CO
Cu(OAc) $H
2 2
benzene (1, P: 0.15 mmol), piperidine (1.4 mmol), Et
2
balloon were added
O (Cu: 5.0ꢀ10 mmol),1,2-bis(diisopropylphosphino)
SiH
3.2 mmol), and 1,4-dioxane (2.0 mL). The resulting reaction mix-
ꢁ
2
3
13
(
by C NMR at 8, 53, and 180 min after the mixing.
ꢂ
ture was stirred vigorously at 80 C. The products were confirmed
1
13
1
by the comparison of their GCeMS spectra and/or H and C NMR
spectra with those of authentic data. The yields were determined
4.8. In situ H NMR measurement for stepwise addition of
13
2
CO , piperidine, and PMHS to Cu-hydridee1 solution (Figs. 5
by the internal standard technique using a CDCl
3
solution of the
and 6)
reaction mixture. Mesitylene was used as the internal standard. For
1
yield calculation, H NMR signals of formyl proton (
d
8.01, 1H, s) of
To a glass reactor equipped with an Ar balloon were added
O (Cu: 5.0ꢀ10ꢁ mmol), 1 (7.5ꢀ10
2
ꢁ2
mmol), PMHS
N-formylpiperidine product, formyl proton ( 8.13, 1H, s) of
d
Cu(OAc)
2
$H
2

6956
K. Motokura et al. / Tetrahedron 70 (2014) 6951e6956
(
SieH: 0.81 mmol), and 1,4-dioxane-d
8
(2.0 mL). The solution was
4. Itagaki, S.; Yamaguchi, K.; Mizuno, N. J. Mol. Catal. A: Chem. 2013, 366, 347.
5. Motokura, K.; Takahashi, N.; Kashiwame, D.; Yamaguchi, S.; Miyaji, A.; Baba, T.
Catal. Sci. Technol. 2013, 3, 2392.
stirred at room temperature for 1 h. Then, 0.4 mL of solution was
1
transferred to the NMR tube under Ar atmosphere. After the
NMR measurement, to the solution were stepwisely added 13CO
bubbling), piperidine, and an excess amount of PMHS. Each step
H
6. (a) Motokura, K.; Kashiwame, D.; Miyaji, A.; Baba, T. Org. Lett. 2012, 14, 2642; (b)
Motokura, K.; Kashiwame, D.; Takahashi, N.; Miyaji, A.; Baba, T. Chem.dEur. J.
2
2013, 19, 10030.
(
7
. Recent reports on Cu-catalyzed reductive reactions: for reviews, see: (a) Díez-
Gonz aꢀ lez, S.; Nolan, S. P. Synlett 2007, 2158; (b) Deutsch, C.; Krause, N.; Lipshutz,
B. H. Chem. Rev. 2008, 108, 2916; (c) Lipshutz, B. H. Synlett 2009, 509 see also:
1
was monitored by H NMR as shown in Figs. 5 and 6.
(
d) Lipshutz, B. H.; Frieman, B. A. Angew. Chem., Int. Ed. 2005, 44, 6345; (e)
Acknowledgements
Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed. 2007, 46, 1650; (f)
Baker, B. A.; Bo ꢁs kovi ꢀc , Z. V.; Lipshutz, B. H. Org. Lett. 2008, 10, 289; (g) Yoo, K.;
Kim, H.; Yun, J. Chem.dEur. J. 2009, 15, 11134; (h) Moser, R.; Bo ꢁs kovi ꢀc , Z. V.;
Crowe, C. S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 7852; (i) Issenhuth, J.-T.;
Notter, F.-P.; Dagorne, S.; Dedieu, A.; Bellemin-Laponnaz, S. Eur. J. Inorg. Chem.
This study was supported by Japan Society for the Promotion of
Science KAHENHI (grant nos. 24686092 and 25630362).
2
010, 529; (j) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew. Chem., Int.
References and notes
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