Palladium-catalyzed insertion reactions of isocyanides into thiocarbamates and selenocarbamates

Article abstract of DOI:10.1246/cl.141141

The insertion reaction of isocyanides with thiocarbamates and selenocarbamates in the presence of a Pd(0) catalyst to selectively give 2-oxoethanimidothioates and -selenoates is reported. This is the first example of the insertion of an isocyanide into a

Full text of DOI:10.1246/cl.141141

Received: December 11, 2014 | Accepted: January 2, 2015 | Web Released: January 9, 2015
CL-141141
Palladium-catalyzed Insertion Reactions of Isocyanides
into Thiocarbamates and Selenocarbamates
1
2
2
1
1
1
Daisuke Shiro, Shin-ichi Fujiwara,* Susumu Tsuda, Takanori Iwasaki, Hitoshi Kuniyasu, and Nobuaki Kambe*
1
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871
2
Department of Chemistry, Osaka Dental University, Hirakata, Osaka 573-1121
(
E-mail: fujiwara@cc.osaka-dent.ac.jp, kambe@chem.eng.osaka-u.ac.jp)
The insertion reaction of isocyanides with thiocarbamates
and selenocarbamates in the presence of a Pd(0) catalyst to
selectively give 2-oxoethanimidothioates and -selenoates is
reported. This is the first example of the insertion of an
isocyanide into a carbon­heteroatom bond using a transition-
metal catalyst. DFT calculations suggest that the reaction
proceeds through a thiopalladation pathway at the migratory
insertion process.
Table 1. Pd-catalyzed insertion of an isocyanide to 1a using
various ligands
[Pd(dba)2] (5 mol%)
ligand (Y mol%)
O
O
O
SPh
SPh
+
XyNC
Me N
+
Me2N
2
Me2N
1
SPh
equiv
toluene (0.5 M)
NXy
NXy
110°C, 5 h
2
1
a
2a
3a
4a
Conv.
Conv.
Yield
Yield
Entry Ligand
Y
a
a
a
a
of 1a/% of 2a/% of 3a/% of 4a/%
1
2
3
4
5
6
7
8
9
PPh3
P(p-tolyl)3
P(p-CF3-C6H4)3 10
PCy3
10
10
42
39
20
53
51
17
66
54
63
44
38
74
57
51
60
57
70
40
75
87
84
53
58
100
32
35
18
32
45
6
60
54
55
40
27
61
1
n.d.
2
The transition-metal-catalyzed insertion of an unsaturated
organic molecule into a carbon­heteroatom bond is one of the
most straightforward and atom-economical methods for the
synthesis of heteroatom compounds with the concomitant
extension of the carbon skeleton. However this transformation
is difficult to achieve efficiently in comparison to similar
10
10
5
5
5
5
5
5
5
5
P(OEt)3
n.d.
n.d.
n.d.
1
5
6
b
dppe
b
dppp
dppb
dpppen
dpphex
dcypp
b
1
b
insertion reactions involving heteroatom­heteroatom bonds or
2
b
heteroatom­hydrogen bonds. This is due, in part, to fact that the
10
b
1
1
1
n.d.
n.d.
cleavage of carbon­heteroatom bonds by the oxidative addition
to transition metals is not as efficient as the reaction of
heteroatom­heteroatom and heteroatom­hydrogen bonds. Un-
saturated compounds that have been employed in such trans-
formations include alkynes, allenes, carbon monoxide, isocya-
nides, etc. Among them, the insertion of alkynes into carbon­
2c dppp
a
b
Determined by GC, and the yields are based on 2a. dppe: 1,2-
bis(diphenylphosphino)ethane; dppp: 1,3-bis(diphenylphosphino)-
propane; dppb: 1,4-bis(diphenylphosphino)butane; dpppen: 1,5-
bis(diphenylphosphino)pentane; dpphex: 1,6-bis(diphenylphos-
phino)hexane; dcypp: 1,3-bis(dicyclohexylphosphino)propane.
3
heteroatom bonds (C­Z, Z = Si, Sn, P, S, Se, etc.) has been
c
DMF was employed as a solvent.
exploited extensively as a two carbon homologation reaction
during the past two decades. Recently, several examples of the
insertion of allenes into carbon­heteroatom bonds have been
We initially examined the reaction of a thiocarbamate (1a,
Me2NC(O)SPh) with an isocyanide 2a. When a toluene solution
4
reported.
(
0.8 mL) containing 2,6-xylyl isocyanide (2a) (0.4 mmol), 1a
cat. [Pd(PPh3)4]
PhS
SPh
(
PhS)2
+
ArNC
(0.4 mmol), [Pd(dba)2] (5 mol %), and PPh3 (10 mol %) was
heated at reflux for 5 h, the insertion product, amino 2-
oxoethanimidothioate 3a, was obtained in 32% yield (Table 1,
Entry 1). Unlike the reaction with a disulfide shown in eq 1, this
reaction is selective and the possible 1:2 addition product 4a was
formed in only 1% yield and other multiple insertion products
such as 1:3 addition products were not detected. We examined
the reaction using other monodentate and bidentate phosphine
ligands and the results are summarized in Table 1. The use of a
triarylphosphine bearing an electron-donating group, trialkyl-
phosphine, and phosphite afforded similar results as PPh3
(Entries 1, 2, 4, and 5), however, a triarylphosphine derivative
containing an electron-withdrawing CF3 group was not a
suitable ligand (Entry 3). Bidentate tetraphenylbisphosphine
ligands with a different tether unit afforded 3a in similar yields
(Entries 7­10), but the use of an analogous tetracyclohexyl-
bisphosphine resulted in a decreased product yield (Entry 11).
When DMF was employed as a solvent, the isocyanide 2
was completely consumed, but the yield of 3a was not improved
(Entries 7 and 12). We postulated that the oxidative addition of
m
NAr
ð1Þ
Ar = 4-Methylphenyl
Carbon monoxide has been utilized as a one-carbon
homologating agent for introduction into C­O, C­N, and C­S
bonds giving rise to lactones, lactams, thioesters, thiolactones,
5
etc. Similarly several examples of the insertion of an isocyanide
into heteroatom compounds are available,6 whereas transition-
metal-catalyzed reactions have been limited to the following two
examples. Ito and co-workers reported on the Pd-catalyzed
disilylation of isocyanides with Me3SiSiMe3.10 Kurosawa and
co-workers revealed the reaction of a disulfide with an isocy-
anide in the presence of a Pd catalyst to give 1:1, 1:2, and 1:3
addition products (m = 1­3) (eq 1).11 The analogous insertion
of isocyanides into carbon­heteroatom bonds has never been
attained. Herein, we report on the first example of the palladium-
catalyzed insertion of isocyanides 2 into carbon­sulfur and
carbon­selenium bonds of thio- or selenocarbamates 1 or 5
giving rise to the 1,1-insertion products 3 or 6, respectively, with
high selectivities.
­9
Chem. Lett. 2015, 44, 465–467 | doi:10.1246/cl.141141
© 2015 The Chemical Society of Japan | 465

Table 2. Screening of the amount of thiocarbamate 1a
Table 3. Syntheses of several kinds of amino-2-oxoethanimi-
dothioate 3
[
Pd(dba)2] (5 mol%)
dppp (5 mol%)
O
O
O
SPh
SPh
[Pd(dba)2] (5 mol%)
dppp (5 mol%)
O
+
XyNC
Me N
+ Me N
2
2
O
Me2N
SPh
DMF (0.5 M)
YAr
NR'
NXy
NXy
+
XyNC
110°C, 5 h
R2N
X equiv
1 equiv
2
DMF (0.5 M)
110°C
R2N
YAr
1
a
2a
3a
4a
1
, 1.0 mmol
2a, 0.4 mmol
3
Conv.
Conv.
Yield
Yield
of 4a/%
a
Entry
X
Entry
1
1
Time/h
3
Yield /%
of 1a/%a
of 2a/%a
of 3a/%a
a
O
O
1
2
3
4
1
2
2.5
3
74
41
35
30
100
100
100
100
61
72
87 (83 )
n.d.
n.d.
2
1b
1c
5
7
SPh
NXy
3b, 75
Et2N
N
SPh
Et2N
N
b
O
O
74
n.d.
2
SPh
NXy
3c, 81
SPh
a
b
Determined by GC based on 2a. Isolated yield.
O
O
O
O
O
O
3
4
1d
1e
7
5
SPh
NXy
3d, 72
3e, 37
the carbon­sulfur bond of the desired product 3a towards Pd
might proceed in DMF and this further reaction resulted in the
loss of the product 3a. Thus, we conducted the reaction using
excess amounts of the thiocarbamate 1a to suppress the further
reaction of 3a and the results are shown in Table 2. As expected,
the use of an excess of 1a improved the yields, and 3a was
obtained in 87% yield when 2.5 equiv of 1a was employed in the
reaction (Entry 3). The product 3a was isolated as a single
stereoisomer by column chromatography and the Z-configura-
tion with respect to C=N double bond was confirmed by X-ray
analysis.
This insertion reaction was carried out using several
different thio- and selenocarbamates under the same conditions
and the results are given in Table 3. The N,N-diethylthiocarba-
mate 1b and morpholinocarbothioate 1c also afforded the
corresponding amino 2-oxoethanimidothioates 3b and 3c in
high yields (Entries 1 and 2). The thiocarbamate 1d containing a
bulkier diisopropyl amino group yielded the product in good
yield (Entry 3). However, the presence of a phenyl group(s) on
the nitrogen led to lower yields (Entries 4 and 5).
i-Pr N
SPh
SPh
i-Pr N
2
2
Ph
N
Ph
N
SPh
Me
Me NXy
O
O
O
O
b
5
6
1f
18
8
3f (3 )
SPh
Ph2N
Me2N
SPh
Ph2N
NXy
O
O
b
5a
6a, 41 (63 )
SePh
NXy
SePh
NXy
SePh
Me2N
b
7
8
5b
1g
24
4
6b, 64 (71 )
N
SePh
N
O
O
O
O
O
O
3g, 60
S(p-OMe-C6H4)
NXy
S(p-CF3-C6H4)
NXy
Me2N
Me2N
S(p-OMe-C6H4)
Me2N
Me2N
9
1h
7
7
3h, 94
3i, 62
S(p-CF3-C6H4)
O
O
1
0c
1a
SPh
We then examined the influence of aryl groups on the sulfur
of thiocarbamates and on the nitrogen of isocyanides. The
reaction of 1h having a p-trifluoromethyl group on the aromatic
ring afforded the expected adduct 3h in high yield (94%),
however, the presence of a p-methoxy group resulted in a lower
yield of 60% (Entries 8 and 9). Although the reaction of the 2,6-
diisopropylphenyl isocyanide (2b) with the thiocarbamate 1a
afforded the corresponding product 3i in 62% yield (Entry 10),
the desired products were not obtained from cyclohexyl,
adamantyl, p-methoxyphenyl, o-tolyl, and 3,5-xylyl isocyanides.
These results suggest that this reaction proceeds only with aryl
isocyanides that contain substituents at both ortho positions.
When the selenocarbamates 5a and 5b were employed as
substrates, the corresponding products 6a and 6b were obtained
in moderate yields (Entries 6 and 7), probably due to the partial
decomposition of the products during their isolation by column
chromatography.
Plausible reaction pathways of thiocarbamates 1 are shown
in Scheme 1. The catalytic cycle is initiated by the oxidative
addition of the carbamoyl­S bond of 1 to Pd(0), affording the
carbamoyl­Pd­S complex A. The coordination of an isocyanide
to the palladium gives complex B. Insertion of the coordinated
isocyanide into the Pd­S bond generates a thiopalladation
intermediate C1, or the insertion into the carbamoyl­Pd bond
affords a carbopalladation intermediate C2. Finally, reductive
elimination from C1 or C2 produces the addition product 3.
Me2N
SPh
Me2N
NDipp
aIsolated yield. b 1H NMR yield. c2,6-Diisopropylphenyl isocya-
nide (2b) was used instead of 2,6-xylyl isocyanide.
O
O
SAr
NR'
Pd(0)
R2N
R2N
SAr
1
3
O
O
SAr
Pd
NR'
R2N
Pd
SAr
O
or R N
2
NR'
R2N
Pd
thiopalladation
carbopalladation
SAr
A
C1
C2
O
R'NC
2
R2N
R'NC
Pd
SAr
B
Scheme 1. Plausible reaction pathway for the formation of 3.
To shed light on the mechanism of the insertion process
from intermediate B, DFT calculations were performed with
methyl isocyanide and Me NC(O)SMe as substrates and PH as
2
3
the ligand for the palladium. Complex B¤ shown in Scheme 2 is
466 | Chem. Lett. 2015, 44, 465–467 | doi:10.1246/cl.141141
© 2015 The Chemical Society of Japan

thiopalladation TS1
C1'
TS2
O
O
O
PH3
PH3
PH3
Pd PH3
SMe
3'
Me2N
Pd
Me N
2
Pd PH3
Me N
2
O
SMe
PH3
B'
Me N
MeNC
MeN
+ 2.4
SMe
MeN
SMe
NMe
O
Me2N
+
PH3
+
7.9
+ 15.8
Pd
2
TS4
+
SMe
TS3
C2'
MeNC
H3P
H3P
+
PH3
O
O
H3P
PH3
PH3
Pd
PH3
O
PH3
Pd
0
.0
Pd
(
kcal mol−1)
Me2N
MeNC
Pd
Me N
2
SMe
SMe
Me N
2
SMe
PH3
- 17.5
NMe
- 14.9
carbopalladation
NMe
- 1.0
+
+
20.5
B3LYP/LANL2DZ for Pd, 6-31G(d,p) for the rest
Scheme 2. Computational calculations for isocyanide insertion and reductive elimination.
e) E. Shirakawa, Y. Nakao, T. Tsuchimoto, T. Hiyama, Chem. Commun.
002, 1962. f) R. Hua, M. Tanaka, Tetrahedron Lett. 2004, 45, 2367. g) Y.
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Iwasaki, H. Kuniyasu, N. Kambe, Tetrahedron 2012, 68, 10523.
C­O: a) M. D. Wang, S. Calet, H. Alper, J. Org. Chem. 1989, 54, 20. C­N:
b) H. Alper, C. P. Perera, F. R. Ahmed, J. Am. Chem. Soc. 1981, 103, 1289.
c) H. Alper, C. P. Mahatantila, Organometallics 1982, 1, 70. d) H. Alper, F.
Urso, D. J. H. Smith, J. Am. Chem. Soc. 1983, 105, 6737. e) S. Calet, F.
Urso, H. Alper, J. Am. Chem. Soc. 1989, 111, 931. f) D. Roberto, H. Alper,
J. Am. Chem. Soc. 1989, 111, 7539. g) M. D. Wang, H. Alper, J. Am. Chem.
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an optimized model for the isocyanide coordinated intermediate.
The intermediate B¤ undergoes thiopalladation or carbopalla-
dation to give C1¤ or C2¤, respectively. The relative energies
of C1¤, C2¤, and the transition states TS1­TS4 shown in
Scheme 2 suggest that C­S bond-forming steps are more facile
2
2
than C­C bond-forming steps in either pathway and overall the
thiopalladation pathway would be more likely.12
5
In summary, we report the first example of the transition-
metal-catalyzed insertion of isocyanides into carbon­sulfur
bonds. This protocol could also be applied to the insertion of
isocyanides into carbon­selenium bonds. DFT calculations
indicate that the reaction proceeds via a thiopalladation pathway
and not a carbopalladation pathway.
1
994, 59, 1414. j) C. M. Crudden, H. Alper, J. Org. Chem. 1995, 60, 5579.
D.S. expresses his special thanks to the JSPS Japanese-
German Graduate Externship Program on “Environmentally
Benign Bio- and Chemical Processes” for financial support for
the stay in RWTH Aachen.
k) M. Furuya, S. Tsutsuminai, H. Nagasawa, N. Komine, M. Hirano, S.
Komiya, Chem. Commun. 2003, 2046.
Cationic, anionic, and radical insertion reactions of isocyanides into
carbon­heteroatom bonds have already been reported.
a) S. Yoshioka, M. Oshita, M. Tobisu, N. Chatani, Org. Lett. 2005, 7, 3697.
b) M. Tobisu, M. Oshita, S. Yoshioka, A. Kitajima, N. Chatani, Pure Appl.
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7
8
9
6
7
Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 465–467 | doi:10.1246/cl.141141
© 2015 The Chemical Society of Japan | 467