Pd-Catalyzed regioselective iminothiolation of alkynes: A remarkable effect of the CF3 group of iminosulfides

Article abstract of DOI:10.1021/ol101289k

Pd-catalyzed iminothiolation of alkynes took place to afford 4-SR substituted 1-azadienes regioselectively.

Full text of DOI:10.1021/ol101289k

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3744-3747
Pd-Catalyzed Regioselective
Iminothiolation of Alkynes: A
Remarkable Effect of the CF3 Group of
Iminosulfides
Yasunori Minami, Hitoshi Kuniyasu,* Atsushi Sanagawa, and Nobuaki Kambe*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
kuni@chem.eng.osaka-u.ac.jp; kambe@chem.eng.osaka-u.ac.jp
Received June 4, 2010
ABSTRACT
Pd-catalyzed iminothiolation of alkynes took place to afford 4-SR substituted 1-azadienes regioselectively.
1-Azadienes have been employed as versatile synthetic building
blocks: electrophiles in 1,2-addition as well as Michael-type
1,4-addition, nucleophiles by a nitrogen atom, and heterodienes
in hetero-Diels-Alder reactions.1 The general method of
preparation is the condensation of R,ꢀ-unsaturated ketones with
primary amines (eq 1). In addition, the transition-metal-catalyzed
iminocarbonvinylcarbon bond-formation reaction is a promising
alternative. Although some catalytic reactions such as the Pd-
catalyzed cross-coupling of imidoyl chlorides with vinyl stan-
nanes and the Pd-catalyzed Mizoroki-Heck-type reaction of
imidoyl iodides with alkenes have been reported,2 the catalytic
introduction of imino groups is still limited. In particular, to
the best of our knowledge, an addition reaction to alkynes is
unprecedented (eq 2).3
saturated bonds.4,5 The Pt(PPh3)4-catalyzed intermolecular
decarbonylative arylthiolation of alkynes using thioesters is
among them (Scheme 1, upper left).4b,5a Recently, CO-
retained aroylthiolation (Scheme 1, lower left) and trifluo-
roacetylthiolation (Scheme 1, upper right) were realized by
Pd/dppe and Pt(PPh3)4 catalyzes, respectively.5e Herein is
reported a new synthetic method of 4-sulfur functionalized
1-azadienes by the iminothiolation of alkynes using imino-
sulfide (Scheme 1, lower right).
(1) For a recent review, see: Groenendaal, B.; Ruijter, E.; Orru, R. V. A.
Chem. Commun. 2008, 5474
.
(2) (a) Kobayashi, T.; Sakakura, T.; Tanaka, M. Tetrahedron Lett. 1985,
26, 3463. (b) Kosugi, M.; Koshiba, M.; Atoh, A.; Sano, H.; Migita, T. Bull.
Chem. Soc. Jpn. 1986, 59, 677. (c) Kosugi, M.; Ogata, T.; Tamura, H.;
Sano, H.; Migita, T. Chem. Lett. 1986, 15, 1197. (d) Uneyama, K.;
Watanabe, H. Tetrahedron Lett. 1991, 32, 1459
.
(3) The reaction of alkynes and nitriles with iodine by using a
stoichiometric amount of zirconium complex to produce ((2)-ꢀ-iodoalk-
enyl)imines has been reported: Coperet, C.; Sugihara, T.; Wu, G.;
Shimoyama, I.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 3422
.
(4) For reviews, see: (a) Kuniyasu, H. In Catalytic Heterofunctional-
ization; Togni, A., Grutzmacher, H., Eds.; Wiley-VCH: Weinheim, 2001;
p251. (b) Kuniyasu, H.; Kurosawa, H. Chem.sEur. J. 2002, 8, 2660. (c)
Kuniyasu, H.; Kambe, N. Chem. Lett. 2006, 35, 1320. (d) Kuniyasu, H.;
Kambe, N. J. Synth. Org. Chem. Jpn. 2009, 67, 701
.
(5) For recent examples, see: (a) Yamashita, F.; Kuniyasu, H.; Terao,
J.; Kambe, N. Org. Lett. 2008, 10, 101. (b) Minami, Y.; Kuniyasu, H.;
Kambe, N. Org. Lett. 2008, 10, 2469. (c) Toyofuku, M.; Fujiwara, S.; Shin-
ike, T.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2008, 130, 10504. (d)
Toyofuku, M.; Murase, E.; Fujiwara, S.; Shin-ike, T.; Kuniyasu, H.; Kambe,
N. Org. Lett. 2008, 10, 3957. (e) Minami, Y.; Kuniyasu, H.; Miyafuji, K.;
We have devoted our attention to the study of transition-
metal-catalyzed carbochalcogenation of carbon-carbon un-
Kambe, N. Chem. Commun. 2009, 3080.
10.1021/ol101289k  2010 American Chemical Society
Published on Web 08/10/2010

of the EtOC(O) of 2a and S(p-tolyl) of 1a at the R-carbon
of the Ph of 2a as the E-isomer with anti conformation
regarding the stereochemistry of lone pair of N (Figure 1).8,9
Scheme 1. A Series of Carbothiolations of Alkyne
First, the success of trifluoroacetylthiolation of alkynes by
CF3C(O)SR5e prompted scrutiny of reactions that use an
iminosulfide [1a; CF3C(dNPh)S(p-tolyl)]. Gratifyingly, it
was found that the reaction of 1a (0.5 mmol) with ethyl
phenylpropiolate (2a, 1.0 mmol), which exhibited high
activity for the Pt-catalyzed decarbonylative arylthiolation
by thioesters,5a,6 was catalyzed by Pd(dba)2 (0.025 mmol)
and PPh3 (0.5 mmol) in 1,2-dichloroethane at 100 °C for
3 h under microwave irradiation using a sealed glass vessel.
The desired adduct, E-CF3C(dNPh)C(CO2Et)dC(Ph)[S(p-
tolyl)] (E-3a), was isolated in 91% yield regio- and stereo-
selectively (entry 1, Table 1).7 The structure of E-3a was
unambiguously determined by X-ray crystallography, dem-
onstrating that CF3C(dNPh) of 1a was bound at the R-carbon
Figure 1. ORTEP diagram of E-3a.
The azadiene moiety was not arranged in a planar fashion
(N1-C2-C19-C20 torsion angle is 68.7°), showing that
the imine and vinyl moieties are not conjugated in the solid
state.
In stark contrast, Pd/dppe and Pt(PPh3)4, which work as
good catalysts for aroylthiolation and trifluoroacetylthiolation,
respectively (Scheme 1), hardly promoted the reaction
(entries 2 and 3, Table 1).
The results of the Pd(dba)2/PPh3 catalyzed addition of
various iminosulfides [1; R1C(dNR2)SR3] to 2a are sum-
marized in Table 1. The reactions of 1b and 1c having SPh
and S(p-ClC6H4) as S-aryl groups took place to furnish the
corresponding adducts 3b and 3c in good yields (entries 4
and 5, Table 1). Neither electron-donating nor electron-
withdrawing groups at Y interfered with the reactions (entries
6 and 7, Table 1). A similar transformation was also
accomplished by using 1f with a benzyl group as R3 to
produce 3f in 91% yield (entry 8, Table 1). In the case of
1g (R1 ) Ph), the desired adduct 3g was obtained only in
44% yield even in the presence of 10 mol % of Pd(dba)2/
2P(p-tolyl)3 (entry 9, Table 1). Phenethyl substituted imi-
nosulfide (1h) was not effective; 3h was not synthesized
(entry 10, Table 1). These results demonstrated that CF3
groups as R1 of 1 is quite essential for the successful
transformation.
Table 1. Pd-Catalyzed Iminothiolation of 2a Using Various
Iminosulfides (1)a
The results of the reactions of 1a with a variety of alkynes
are summarized in Table 2. It was found that even the
addition to 4-octyne (2b) took place at 160 °C to give 3i,
albeit in low yield (entry 1, Table 2). The treatment with
3-methoxy-1-phenylpropyne (2c) afforded 3j in 51% yield
(E:Z ) 67:33) at 180 °C (entry 2, Table 2). On the other
hand, terminal alkynes underwent the addition under much
milder conditions (80 °C) than internal alkynes (entries 3-12,
Table 2). Both electron-rich and electron-poor arylalkynes
(2d-g) reacted with 1a to form high yields of 3 (entries
3-6, Table 2). The product of iminothiolation was obtained
in 89% yield (E:Z ) 18:82) when 1-octyne was used (2h)
(entry 7, Table 2). Cyclohexylacetylene (2i) was also applied
a Unless otherwise noted, 1 (0.5 mmol), 2a (1.0 mmol), Pd(dba)2 (0.025
mmol), PPh3 (0.05 mmol), and 1,2-dichloroethane (0.25-0.5 mL) at 100
°C under microwave irradiation for 1-3 h. All reactions were performed
in sealed glass vessels. b Isolated yield. c Pd(dba)2 (0.025 mmol) and dppe
(0.025 mmol). d NMR yield. e Pt(PPh3)4 (0.025 mmol). f Pd(dba)2 (0.05
mmol) and P(p-tolyl)3 (0.1 mmol). dba ) dibenzylideneacetone.
Org. Lett., Vol. 12, No. 17, 2010
3745

Table 2. Pd-Catalyzed Iminothiolation of Various Alkynes (2)
Using 1aa
As mentioned, for the synthesis of 3, the conversion of
CF3C(O)C(R4)dC(R5)(SR3) (5)5e into 3 is conceivable. Thus,
the reaction of 5a (R3 ) p-tolyl, R4 ) H, R5 ) n-C6H13)
with PhNH2 was attempted (eq 5). The reaction selectively
furnished CF3C(OH)dC(H)C(n-C6H13)-(dNC6H5) (6a) in
81% yield, elucidating that the present Pd-catalyzed imi-
nothiolation of 2 by 1 is complementary to the formation of
6 via 5.
entry
2
temp (°C)
time (h)
3
(%)b (E:Z)
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
160c
180c
80
80
80
80
80
80
80
1
3
1
1
1
1
1
3
1
2
2
1
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
14 (5:95)
51 (67:33)
92 (2:98)
95 (14:86)
74 (2:98)
83 (1:>99)
89 (18:82)
76 (14:86)
81 (13:87)
81 (14:86)
87 (13:87)
89 (1:>99)
A plausible mechanism of the present reaction of imino-
sulfides (1) with alkynes (2) is depicted in Scheme 2. The
9
2j
2k
2l
10
11
12d
80
80
80
Scheme 2. Plausible Mechanism for the Pd-Catalyzed
Iminothiolation of Alkynes (2) Using Iminosulfides (1)
2m
a Unless otherwise noted, 1a (0.5 mmol), 2 (0.6-3.0 mmol), Pd(dba)2
(0.025 mmol), PPh3 (0.5 mmol) and 1,2-dichloroethane (0.25-0.5 mL) for
1-3 h. In the case of runs 1 and 2, reactions were performed in sealed
glass vessels. b Isolated yield. c Microwave irradiation. d Pd(PPh3)4 (0.025
mmol). Pr ) propyl, MOM ) methoxymethyl, THP ) 2-tetrahydro-pyranyl.
to this reaction (entry 8, Table 2). Functional groups such
as chlorine (2j), methoxy carbonyl (2k), and 2-tetrahydro-
pyranyl (2l) aptly furnished the corresponding adducts 3p-s
in high yields as cis-rich stereoisomers (entries 9-11, Table
2). In the case of the reaction with 2-methyl-3-butyn-2-ol
(2m), Z-3t was selectively obtained in 89% yield (entry 12,
Table 2).
oxidative addition of 1 to the Pd(0)Ln complex triggers the
reaction to afford PdLn[C(dNR2)R1](SR3) (7).11 Subsequent
regio- and stereoselective insertion of 2 into the Pd-S bond
of 7 generates cis-PdLn[C(dNR2)R1][Z-C(R4)dC(R5)(SR3)]
(Z-8).12 Finally, the reductive elimination of 3 from 8 with
(7) When the reaction of 1a and 2a was performed at 100 °C in a sealed
vessel without a microwave irradiation, 3a was obtained in a E to Z ratio
of 93:7 with the same yield, indicating that following isomerization of the
adducts was partly prevented by the microwave irradiation.
(8) Crystal data for E-3a: space group Pbca (No. 61) with a )
15.2284(7) Å, b ) 17.6487(8) Å, c ) 17.8733(9) Å, ꢀ ) 96.385(2)°, Z )
8, F ) 1.298 g/cm3, R ) 0.0661, and Rw ) 0.189. See Supporting
Informaion for crystal data for E-3a.
(9) The NMR spectra of 3 showed temperature dependence due to the
fluxional movement of the molecules. The 1H NMR spectra of E-3a in
toluene-d8 solution at -40 °C appeared as a mixture of two stereoisomers
by slow inversion of the N lone pair on the imino group in a ratio of 75:25
(stereochemistry undetermined).
(10) For the utility of furan derivatives, see: Eicher, T., Hauptmann, S.
In The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and
Applications; Wiley-VCH: Weinheim, 2003 and references therein.
(11) (a) Bowman, W. R.; Lyon, J. E.; Pritchard, G. J. Synlett 2008, 2169.
(b) Takeda, H.; Ishida, T.; Takemoto, Y. Chem. Lett. 2009, 38, 772.
(12) (a) Sugoh, K.; Kuniyasu, H.; Kurosawa, H. Chem. Lett. 2002, 31,
106. (b) Kuniyasu, H.; Yamishita, F.; Terao, J.; Kambe, N. Angew. Chem.,
Int. Ed. 2007, 46, 5929. (c) Kuniyasu, H.; Takekawa, K.; Yamashita, F.;
Miyafuji, K.; Asano, S.; Takai, Y.; Ohtaka, A.; Tanaka, A.; Sugoh, K.;
Kurosawa, H.; Kambe, N. Organometallics 2008, 27, 4788.
Interestingly, the reaction of 1i containing an N-tosyl group
with 2m selectively produced furan derivative 4a in 89%
yield,indicatingthatthecis-to-transisomerizationofCF3C(dNTs)-
C(H)dC(C(Me)2OH)(S-p-tolyl) (3u) and the following cy-
clization facilely occurred (eq 3).10 A similar transformation
was realized by the treatment of 3t with AcOH to form 4b
in 84% yield (eq 4).
(6) The high reactivity and regioselectivity would be attributed to the
oxygen atom at the propargyl moiety in alkynes; see ref 5a.
3746
Org. Lett., Vol. 12, No. 17, 2010

regeneration of Pd(0)Ln completes the catalytic cycle.13 The
reason that iminosulfide 1 with a CF3 group exhibited high
activity for iminothiolation is presumably due to the facile
oxidative addition of a carbon-sulfur bond to the Pd(0)
complex.
In conclusion, the present study substantiated the imi-
nothiolation of alkynes with iminosulfides giving rise to the
formation of 1-azadiene derivatives, where the introduction
of a CF3 group to the imino-carbon moiety is key to
achieving the reaction. Furthermore, the facile syntheses of
furan derivatives through 1-azadienes were also presented.
Acknowledgment. Thanks are due to the Instrumental
Analysis Center, Faculty of Engineering, Osaka University
for assistance in obtaining mass spectra with the JEOL JMS-
DX303 instrument. Y.M. would like to thank the JSPS
Research Fellowship for Young Scientist for financial support
and the Global COE (center of excellence) Program “Global
Education and Research Center for Bio-Environmental
Chemistry” of Osaka University.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Monitoring the reaction of 1a with 2h at room temperature showed
that the cis:trans ratio of 3o stayed the same during the course of the
reaction, implicating that trans-3 was produced through isomerisation of
cis-8 to trans-8 prior to the reductive elimination.
OL101289K
Org. Lett., Vol. 12, No. 17, 2010
3747