Desulfurization and H-migration of secondary thioamides catalyzed by an iron complex to yield imines and their reaction mechanism

Article abstract of DOI:10.1021/om400304v

Secondary thioamides were converted into imines as the major products using hydrosilane in the presence of an iron catalyst. An iron carbene complex with a silyl thiolato ligand was isolated as one of the intermediates of the catalytic cycle and was characterized by X-ray analysis.

Full text of DOI:10.1021/om400304v

Communication
pubs.acs.org/Organometallics
Desulfurization and H‑Migration of Secondary Thioamides Catalyzed
by an Iron Complex to Yield Imines and Their Reaction Mechanism
Kozo Fukumoto,† Akane Sakai,‡ Kazumasa Hayasaka,‡ and Hiroshi Nakazawa*,‡
†Kobe City College of Technology, Kobe 651-2194, Japan
‡Department of Chemistry, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan
S
* Supporting Information
ABSTRACT: Secondary thioamides were converted into imines as the major
products using hydrosilane in the presence of an iron catalyst. An iron carbene
complex with a silyl thiolato ligand was isolated as one of the intermediates of
the catalytic cycle and was characterized by X-ray analysis.
fficient reduction of amides without the use of strong
hydride reagents is of great interest in the development of
(PhNHC(S)Ph, 0.53 mmol), and triethylsilane (Et3SiH, 2.7
mmol) were charged in a Schlenk tube, and the solution was
heated at 80 °C for 24 h (Table 1, entry 1). The H NMR
E
1
medicines and drug candidates, as these compounds usually
have many other fragments that are also reactive toward strong
hydrides.1 There are a number of reports concerning reduction
of amides to amines by hydrosilanes with the help of a
transition metal catalyst.2 Among the many transition metals
that are suitable as such catalytic centers, iron has attracted
considerable attention because of its high natural abundance,
low cost, and low toxicity. In 2009, Nagashima and co-workers
reported that [Fe(CO)5] and [Fe3(CO)12] were effective
catalysts for thermal and photoassisted reduction of tertiary
amides to tertiary amines, using bifunctional hydrosilane and
polymethylhydrosiloxane (PMHS) as reducing agents.3 Pannell
et al.4 and our group5 recently reported that CpFe(CO)2Me
(1) (Cp = η5-C5H5) served as a catalyst for reactions of tertiary
amides with R3EH (E = Si, Ge) to give amines, and we
proposed that an iron carbene complex was an intermediate.
In other work, the reduction of amides to imines has been
reported,6,7 where Schwartz’s reagent (Cp2ZrHCl) was used as
a reducing agent;5 however, under some reaction conditions
this method led to the production of aldehydes.8 In contrast,
until recently, there were no reports on the reduction of
thioamides. Pannell et al.9 and we10 reported desulfurization of
thioamide (Me2NCHS) by hydrosilane (R3SiH) in the
presence of Mo(CO)6 and 1, respectively, to give amine
(NMe3) and disilathiane (R3SiSSiR3). Herein, we describe the
first example of secondary thioamides being reduced to form
imines as the major or sole product, by hydrosilanes in the
presence of a catalytic amount of 1. The isolation and
characterization of one of the intermediates are also reported.
Catalytic reductions of secondary thioamides were examined
under conditions similar to those previously reported for
tertiary thioamides.5a Tetrahydrofuran (THF, 0.43 mL),
CpFe(CO)2Me (0.053 mmol), N-phenylthiobenzamide
Table 1. Catalytic Desulfurization of Secondary Thioamides
with a Methyl Fe Complex in Et3SiH
a
a
equiv of
Et3SiH condition
TON of TON
entry
sec-thioamide
amine
of imine
b
1
PhNHC(S)Ph
PhNHC(S)Ph
PhNHC(S)Ph
MeNHC(S)Ph
PhNHC(S)Me
PhCH2NHC(S)Ph
PhCH2NHC(S)H
5
5
80 °C
hν
0.6
0
1.7
trace
7.4
2.4
0
b
d
2
c
3
30
30
30
30
30
80 °C
80 °C
80 °C
80 °C
80 °C
1.0
trace
0
c
4
c
5
c
6
2.1
0
6.5
0
c
7
a
b
The value is based on the concentration of CpFe(CO)2Me. 0.060 M
THF solution. In free solvent. Photoirradiation at 5 °C
c
d
spectra and GC-MS analysis of the products demonstrate the
formation of N-benzylaniline (PhNHCH2Ph) and N-benzyli-
deneaniline (PhNCHPh). The formation of (Et3Si)2S was
1
also confirmed by the H NMR results, but the amount could
not be estimated because of its degradation to disiloxane by the
Fe complex.11 This is the first example of desulfurization of sec-
thioamide to give an imine by using a transition metal catalyst,
although the TON was only 1.7. This catalytic reaction is
notable owing to the susceptibility of transition metal catalysts
Received: April 10, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om400304v | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
to be poisoned by S-containing compounds. Desulfurization to
form the imine was also observed using a photoinitiated
reaction; however, only a low efficiency was achieved (entry 2).
Comparison of entries 1 and 3 shows that a large excess of
Et3SiH led to high conversion efficiency. Other thioamides
were also converted into the corresponding amines and imines
(entries 4 and 6) via the Fe-catalyzed reaction; however, those
listed as entries 5 and 7 did not react under these conditions.
Therefore, it is speculated that a Ph substituent on the
thioamide C is essential for successful desulfurization. The
effect of the hydrosilane on desulfurization was next examined
under the reaction conditions shown in entry 3 of Table 1, and
it was found that the products were dependent on the particular
hydrosilane used as the reducing agent (Table 2). When Et3SiH
PhNHC(S)Ph then interacts with A to give B in the η2-CS
coordination fashion. The silyl group in B migrates from Fe to
the S atom via a pentavalent Si complex C to produce the Fe−
C−S three-membered-ring complex D. Successive C−S bond
cleavage in the coordination sphere gives amino-carbene
complex E. These reaction sequences are the same as those
for the desulfurization of tertiary thioamides.10 Those are a sort
of a silyl-migration-induced reaction (SiMI reaction).10,12
The subsequent reaction sequences for secondary thioamides
are different from those for tertiary thioamides, where a Si−H
bond of the hydrosilane adds to the FeC double bond. The
N−H bond in the substituent on the carbene carbon in E adds
to the FeC double bond to give F. This step presumably
takes place intramolecularly (E′), although an intermolecular
addition cannot be ruled out. This addition has not been
reported to date; however, it has been shown that an H in an
NHR group on a carbene carbon can be replaced by using an
Table 2. Desulfurization with Hydrosilane under Thermal
Conditions
electrophile.13 Dotz and co-workers reported the alkylation of
̈
PhNHC(S)Ph + 30 equiv R3SiH
the N in an aminocarbene complex by reaction with lithium
diisopropylamide (LDA) and an alkyl halide.13c Complex F
undergoes reductive elimination of the imine PhNCHPh
with formation of H via G. As H is a 16e species, an oxidative
addition of the Si−H bond in Et3SiH takes place to give I,
followed by a reductive elimination of the (Et3Si)2S detected in
the reaction system to give J. A subsequent oxidative addition
of Et3SiH to give K and a reductive elimination of H2 to afford
A then complete the catalytic cycle.
10 mol % CpFe(CO)2Me
⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→⎯ PhNHCH2Ph + PhNCHPh
80 °C, 24 h
a
a
entry
R3SiH
TON of amine
TON of imine
1
2
3
4
Et3SiH
1.0
2.0
0
7.4
0
Me2PhSiH
MePh2SiH
Ph3SiH
2.6
0.8
0
a
The value is based on the concentration of CpFe(CO)2Me.
According to the catalytic cycle, dihydrogen gas (H2) was
expected to be formed. In order to check it, the gas portion in
the reaction of entries 1 and 3 shown in Table 1 was bubbled in
a C6D6 solution individually, and the solutions were subjected
to the 1H NMR measurement. A singlet at 4.48 ppm assignable
to H2 was observed marginally in the former and clearly in the
latter, indicating the formation of dihydrogen in the catalytic
cycle.
was used, PhNCHPh (imine) was formed as a major
product, with PhNHCH2Ph (amine) as a minor product (<1/
7th the yield of PhNCHPh) (entry 1). In contrast, when
Me2PhSiH was used, the corresponding amine was exclusively
formed (entry 2), and when MePh2SiH was used, only the
imine was catalytically formed (entry 3). For Ph3SiH, the imine
was produced exclusively, but not catalytically (entry 4).
Therefore, the results indicate that the selective formation of
secondary amines or imines can be achieved by use of an
appropriate hydrosilane, although the reason for the selectivity
is not yet clear.
Scheme 1 shows a proposed catalytic cycle for the reaction of
1 with Et3SiH and PhNHC(S)Ph. The 16e species, CpFe-
(CO)(C(O)Me), is formed by CO insertion under heating,
followed by the oxidative addition of the Si−H bond in Et3SiH
and the reductive elimination of MeCHO to form A.
In order to obtain further experimental evidence supporting
this proposed cycle, isolation of carbene Fe complex E was
attempted. The isolation of E from the reaction mixture of 1,
Et3SiH, and PhNHC(S)Ph was unsuccessful. However,
reactions of R1NHC(S)Ph (R1 = Ph, Me) with CpFe(CO)-
(py)(SiR2 ) (py = pyridine; R2 = Et (2), Ph (3)), considered as
3
a synthon of a 16e complex CpFe(CO)(SiR3),5,12c−e resulted in
the isolation of amino-carbene complexes. Treatment of 2 with
PhNHC(S)Ph in toluene for 2 h gave 4 in a high yield
according to the NMR measurement, but the isolation as a solid
Scheme 1. Proposed Reaction Sequence
B
dx.doi.org/10.1021/om400304v | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
was not successful (Scheme 2). In contrast, 6 obtained in the
reaction of 3 with MeNHC(S)Ph could be isolated as an
orange powder in 40% yield.
complex was also investigated. Complex 5, prepared according
to Scheme 2, was treated with MeNHC(S)Ph and Et3SiH at 80
°C for 24 h and was found to generate MeNCHPh with a
TON of 3.2 (eq 1). These results demonstrate that a sec-amino-
carbene complex is an intermediate in the desulfurization of
MeNHC(S)Ph.
Scheme 2. Synthesis of sec-Amino-carbene Iron Complexes
MeNHC(S)Ph + 30 equiv Et3SiH
10 mol % 5, 80 °C
⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ MeNCHPh
(1)
24 h
TON 3.2
Reaction of pyridine−Fe complex 2 with partially deuterated
sec-thioamide PhNDC(S)Ph was also examined in C6D6 at
room temperature for 24 h. The NMR and GC-MS spectra of
the reaction mixture suggest the formation of the correspond-
ing imine, PhNCDPh, and a carbene complex (Scheme 3).
The unprecedented sec-amino-carbene Fe complex was
confirmed using X-ray analysis (Figure 1). The Fe was seen
Scheme 3. Reaction of 2 with Deuterated Thioamide
In conclusion, this study constitutes the first example of
desulfurization of a sec-thioamide to imine by an Fe-methyl
complex. A sec-amino-carbene complex was isolated in the
reaction of a pyridine−Fe complex with a sec-thioamide and
characterized by X-ray analysis. The carbene complex was
demonstrated to be an intermediate in the reaction pathway,
enabling elucidation of the mechanism of the Fe complex-
mediated transformation.
Figure 1. ORTEP drawing of carbene complex 6.
ASSOCIATED CONTENT
* Supporting Information
■
to take a distorted three-legged piano-stool structure. The bond
distance of Fe1−C1 (1.9036(17) Å) agrees with that of a
typical FeC bond in a Fischer-type carbene.14 The structures
of 6 and the corresponding amino-carbene complex CpFe-
(CO){C(NMe2)H}(SSiPh3) (7)10 were found to be similar: (i)
the N1−C1−Fe1 angle was 123.01(15)° for 6 and 135.96(12)°
for 7, being larger by 13° presumably due to the steric repulsion
between the Me group and the Fe center; (ii) the C1−N1−C2
angle was 127.5(2)° for 6 and 123.56(13)° for 7; and (iii) the
torsion angle of C2−N1−C1−Fe1 was −174.52(13)° for 6 and
169.06(12)° for 7. As the N of 7 could be seen to have a planar
geometry that indicates sp2 hybridization, it is highly likely that
N1 of 6 was also sp2 hybridized, although the position of H1
could not be determined by the X-ray analysis. The position of
H1 was obtained using calculations assuming the sp2 hybrid-
ization of N1. The distance between N1 and Fe1 was found to
be 2.8357(12) Å, which is shorter than the sum of the van der
Waals radius of N (1.55 Å)15 and the atomic radius of Fe (1.56
Å).16 Therefore, some interaction between H1 on N1 and Fe1
or between the N1−H1 bond and Fe1 is indicated, meaning
that the barrier of H1 migration to Fe1 would be lower.
Complex 6 was dissolved in C6D6 and heated at reflux
temperature for 24 h, and the formation of MeNCHPh in
9% yield was observed by 1H NMR. This yield is approximately
equal to the amount of MeNCHPh in the thermal reaction
of 1 with 1 equiv of Ph3SiH and 1 equiv of MeNHC(S)Ph in
C6D6 for 24 h. The catalytic activity of a sec-amino-carbene
S
Text giving detailed experimental procedures and the character-
ization data for the products and a CIF file giving crystallo-
graphic data for 6. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nakazawa@sci.osaka-cu.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Challenging Exploratory
Research grant (No. 23655056) from the Ministry of
Education, Culture, Sports, Science and Technology and a
Grant-in-Aid for Young Scientists (B) (No. 23750067) from
the Japan Society for the Promotion of Science (JSPS).
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