Palladium-catalyzed coupling of N-heteroaryl sulfides with organozinc reagents

Article abstract of DOI:10.3987/COM-08-S(F)49

The palladium-catalyzed cross-coupling of N-heteroaryl sulfides with organozinc reagents was developed. Scope and limitation of the reaction regarding generality of zinc reagents and substrate were also investigated.

Full text of DOI:10.3987/COM-08-S(F)49

HETEROCYCLES, Vol. 77, No. 1, 2009
233
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 233 - 239. © The Japan Institute of Heterocyclic Chemistry
Received, 17th July, 2008, Accepted, 27th August, 2008, Published online, 28th August, 2008.
DOI: 10.3987/COM-08-S(F)49
PALLADIUM-CATALYZED
COUPLING
OF
N-HETEROARYL
SULFIDES
WITH ORGANOZINC
REAGENTS†
Takahiro Koshiba,a Tohru Miyazaki,a Hidetoshi Tokuyama,a,b and
Tohru Fukuyama*a
aGraduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
b
Bunkyo-ku, Tokyo 113-0033, Japan. Graduate School of Pharmaceutical
Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578,
Japan. Fax: +81-3-5802-8694, e-mail; fukuyama@mol.f.u-tokyo.ac.jp
Abstract – The palladium-catalyzed cross-coupling of N-heteroaryl sulfides with
organozinc reagents was developed. Scope and limitation of the reaction
regarding generality of zinc reagents and substrate were also investigated.
Transition-metal-catalyzed cross-coupling of organometallic reagents are one of the most versatile and
reliable methods to form carbon-carbon -bond. While a number of reactions using various substrates
including sp2-carbon halides or the corresponding pseudo-halides have been developed,1 only a limited
examples of reactions using sulfur containing substrates have been so far reported, for example,
Ni-catalyzed cross-coupling of alkenyl or aryl sulfides with Grignard reagents.2,3 Among sulfur
containing compounds, thiol esters have recently attracted considerable attention as substrates for
transition-metal-catalyzed cross-coupling.4,5 After the seminal contribution in this area by Marchese and
co-workers who have described Fe(acac)3-catalyzed coupling of thiol esters with Grignard reagents,6 we
have developed a highly chemoselective Pd-catalyzed reduction of thiol esters to aldehyde with Et3SiH7
and cross-coupling of thiol esters with organozinc reagents8 or terminal acetylenes9 (Scheme 1) to form
ketones or alkynyl ketones, respectively.5,10 In addition, Liebeskind and co-workers reported Cu-mediated
Suzuki coupling11 and Stille coupling of thiol esters.12 Mechanistically, these palladium-catalyzed
cross-couplings of thiol esters would be initiated by oxidative addition of the sp2 carbon-sulfur bond to
Pd(0) to generate acyl palladium species,13 followed by transmetallation and reductive elimination
†This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75 years old
birthday.

234
HETEROCYCLES, Vol. 77, No. 1, 2009
reductive
elimination
O
O
Et3SiH
Pd/C
Pd(0)
O
O
O
R
SR''
R
R'
oxidative
addition
acetone, rt
R
R
R
H
R' = H, Alkyl
O
O
R'ZnX
PdCl2(PPh3)2
O
R'
SR''
R
Pd
R
Pd
toluene, rt
R'
R
SEt
R'
PdCl2(dppf)
M = Si, Zn
CuI, Et3N
EtS M
R' M
DMF
transmetallation
R'
Scheme 1. Palladium-catalyzed transformation
Scheme 2. Plausible mechanisms of palladium-
of thiolesters
catalyzed transformation of thiol esters
leading to the corresponding aldehydes or ketones (Scheme 2). We considered that, in analogy to the
reaction of thiol esters, the sp2 carbon-sulfur bond of thioimidates should also oxidatively add to Pd(0),
and subsequent transmetallation and reductive elimination should furnish imine derivatives. This concept
has already been realized using several N-heteroaryl sulfides having C-S bond at the -position to the
nitrogen. For example, Liebeskind demonstrated Suzuki coupling14 and Stille coupling15 with
N-heteroaryl sulfide under the copper-mediated reaction conditions. Casalnuovo reported
palladium-mediated coupling of N-heteroaryl sulfide with benzylzinc reagent.16 While these
methodologies are useful to incorporate sp, sp2, or benzyl group to N-heteroaryl structure, it would be
difficult to apply to introduce highly functionalized alkyl chains. Under these backgrounds, we
investigated a palladium-catalyzed coupling of N-heteroaryl compound having thioimidate structure with
organozinc reagents. We report herein development of the highly versatile and mild coupling reaction of
N-heteroaryl sulfides with organozinc reagents and its general applicability.
By choosing the 2-(ethylthio)quinoline as a test substrate, we initially examined a reaction with EtZnI
under the typical conditions utilized for the ketone synthesis with thiol ester (Table 1).9 As we expected,
2-ethylquinoline was obtained by heating a THF solution of 2-(ethylthio)quinoline and EtZnI in the
presence of catalytic PdCl2(PPh3)2 at 50 °C although the yield was as low as 43% (entry 1). Screening of
various palladium catalysts revealed that the yield was improved to 69% by using Pd(PPh3)4 (entry 2) and
furthermore, to 87% with PdCl2(dppf) (entry 3). Other catalysts such as combinations of Pd2(dba)3 and
DPPF, PCy3, or P(2-fulyl)3 and Pd-C did not provide better results (entries 4-7). In the absence of
palladium catalyst, no product was obtained indicating that the reaction mechanism involves a
Pd-catalysis instead of an addition-elimination process (entry 8). In addition, we observed significant
solvent effects on the rate of the reaction (Table 2). While comparable yields of the desired coupling
product was obtained by reaction in various solvents, more polar solvents required longer time to
complete the reaction.

HETEROCYCLES, Vol. 77, No. 1, 2009
235
Table 1. Pd-catalyzed coupling reaction of 2-(ethylthio)quinoline with EtZnIa
EtZnI (3.0 eq)
Pd-cat. (20 mol%)
toluene-THF
50 °C
N
SEt
N
Et
entry
time (min)
yield (%)
Pd catalyst
1
2
3
PdCl2(PPh3)2
Pd(PPh3)4
120
100
15
43
69
87
PdCl2(dppf)
Pd2(dba)3, DPPFb,c
no reaction
4
5
6
120
b,d
Pd2(dba)3, PCy3
120
120
26
14
b,d
Pd2(dba)3, P(2-furyl)3
Pd-C
none
7
8
270
120
no reaction
no reaction
a Reaction was carried out with THF solutin of EtZnI (1.0 M ) in toluene under Ar. b Pd2(dba)3 (10 mol%) was used. c DPPF (0.25 equiv)
was used. dLigand (0.5 equiv) was used.
Table 2. Pd-catalyzed coupling reaction of 2-(ethylthio)quinoline with EtZnIa
EtZnI (3.0 eq)
PdCl2(dppf) (20 mol%)
solvent-THF
N
SEt
N
Et
50 °C
entry
time (min)
yield (%)
solvent
1
2
3
4
5
6
7
toluene
benzene
CH2Cl2
CH3CN
Et2O
15
20
87
74
64
62
64
75
75
20
20
30
60
THF
120
DMF
a Reaction was carried out with THF solution of EtZnI (1.0 M) in toluene under Ar.
While we successfully established the coupling conditions, a disadvantage of this reaction for practical
use, namely, unpleasant odor due to ethanethiol during preparation of substrates and work-up, had
remained to be improved. Thus, we then investigated a modification of our protocol using odorless
dodecanethiol.17,18 The 2-(dodecylthio)quinoline, which was prepared from 2-chloroquinoline and
dodecanethiol, was subjected to the coupling conditions with ethylzinc iodide in toluene-THF (Table 3,
entry 1). The desired 2-ethylquinoline was obtained in excellent yield although reaction became relatively
slow.

236
HETEROCYCLES, Vol. 77, No. 1, 2009
Table 3. Coupling reaction of several organozinc reagentsa
RZnI
PdCl2(dppf) (5 mol%)
N
SC12H25
N
R
toluene-THF, 50 °C
entry
4
eq
time (min) yield (%)
entry
1
eq
time (min) yield (%)
R
R
CO2Et
2.0
90
96
Et
2.0
45
91
4
NPhth
3
2
3
i-Bu
2.0
3.0
240
50
90
47
5
6
2.0
6.0
180
180
82
NHBoc
43 (78)b,c
Me
3
CO2Me
a Reaction was carried out with THF solution of zinc reagent in toluene (0.3 M final concentration corresponding to aryl sulfide) under Ar.
b Yield in the parenthesis is based on the recovered starting material. c >99% ee.
Given the encouraging results, we next examined the reaction with various zinc reagents (Table 3).19 In
addition to alkylzinc reagents (entries 1 and 2), alkenylzinc reagent gave the coupling product in modest
yield. It is notable that functionalized alkylzinc reagents including the one bearing terminal ester (entry 4),
protected primary amine (entry 5), and -amino ester functionalities (entry 6) were amenable to the
coupling reaction providing the corresponding functionalized quinoline derivatives.
The generality of our method has also been tested by using wide range of N-heteroaryl sulfides (Table 4).
Interestingly, not only 2-(dodecylthio)pyridine, but also 3- and 4-(dodecylthio)pyridines smoothly
coupled with the zinc reagent to provide the corresponding product in good to excellent yields (entries
1-3).20 While prolonged reaction time was required, pyridine derivative having electron-withdrawing
group afforded coupling product in good yields (entries 5 and 6). Surprisingly, reactions of a series of
quinoline derivatives revealed that in addition to 2-, 3-, and 4-(dodecylthio)quinoline (entries 6-8),
6-(dodecylthio)quinoline also served as a good substrate for the coupling reaction (entry 10). On the other
hand, no coupling product was obtained proceeded with -(dodecylthio)naphthalene even after 6 hours
(entry 19).21 Furthermore, the reaction conditions was applicable to other N-hetroaryl sulfides such as
pyrazine, pyrimidine, benz[d]oxazole, benzo[d]thiazole, benz[d]imidazole derivatives (entries 13-17).
Most significantly, this protocol is amenable to introduce a substituent on purine moiety of an adenosine
derivative, demonstrating mildness and versatility of the reaction conditions (entry 18).
In conclusion, we have developed the palladium-catalyzed cross-coupling of N-heteroaryl sulfides with
organozinc reagents. The reaction proved to be applicable to introduce functionalized alkyl chains to a
wide range of N-heteroaryl sulfides with a various substitution patterns.22 By using dodecanethiol for the
preparation of substrates, we successfully eliminated the unpleasant odor due to thiol by-products.

HETEROCYCLES, Vol. 77, No. 1, 2009
237
Table 4. Palladium-catalyzed coupling reaction of N-heteroaryl sulfides with IZn(CH2)4CO2Eta
EtO2C(CH2)4ZnI (2 eq)
PdCl2(dppf) (5 mol%)
CO2Et
Ar SC12H25
Ar
toluene-THF, 50 °C
entry
time (min) yield (%)
substrate
entry
11
yield (%)
96
substrate
time (min)
80
Me
1
2
80
40
92
80
N
N
SC12H25
SC12H25
N
SC12H25
MeO
80
95
97
12
N
N
SC12H25
SC12H25
3
60
13
30
74
N
SC12H25
N
N
N
N
4b
14
15
25
90
83
98
45
99
72
MeO
SC12H25
O
SC12H25
SC12H25
O
N
OEt
5c
360
N
N
N
N
SC12H25
O
S
EtO
6
7
8
100
90
85
96
16
17
150
240
88
48
SC12H25
N
SC12H25
Cbz
N
SC12H25
N
SC12H25
SC12H25
SC12H25
45
100
67
N
N
N
120
70
18
N
AcO
SC12H25
O
75
9
N
OAcOAc
C12H25S
C12H25S
10b
45
91
19
no reaction
360
N
aReaction was carried out with THF solution of zinc reagent in toluene (0.3 M final concentration corresponding to heteroaryl sulfide) under
Ar. bThe reaction was carried out at 100 °C. cThe reaction was carried out at 80 °C.
ACKNOWLEDGEMENTS
This work was financially supported by the Ministry of Education, Culture, Sports, Science and
Technology, Japan and the Research Foundation for Pharmaceutical Sciences.

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HETEROCYCLES, Vol. 77, No. 1, 2009
REFERENCES AND NOTES
1.
G. Pattenden, ‘Carbon-Carbon -Bond Formation,’ in ‘Comprehensive Organic Synthesis,’ Vol. 3,
ed. by B. M. Trost, Pergamon Press, Oxford, 1991, pp. 481-562.
2.
A review on Ni-catalyzed coupling of alkenyl sulfides, see: K. Tamao, ‘Coupling Reactions
Between sp3 and sp2 Carbon Centers,’ in ‘Comprehensive Organic Synthesis,’ Vol. 3, ed. by B. M.
Trost, Pergamon Press, Oxford, 1991, pp. 446-450.
3.
4.
5.
H. Takei, M. Miura, H. Sugimura, and H. Okumura, Chem. Lett., 1979, 1447.
T. Mukaiyama, M. Araki, and H. Takei, J. Am. Chem. Soc., 1973, 95, 4763.
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Synthesis, 2006, 2975.
6.
(a) C, Cardellicchio, V. Fiandanese, G. Marchese, and L. Ronzini, Tetrahedron Lett., 1985, 26,
3595. (b) C. Cardellicchio, V. Fiandanese, G. Marchese, and L. Ronzini, Tetrahedron Lett.,
1987, 28, 2053.
7.
8.
9.
H. Tokuyama, S. Yokoshima, T. Yamashita, S.-C. Lin, and T. Fukuyama, J. Braz. Chem. Soc.,
1998, 9, 381.
(a) T. Fukuyama, S.-C. Lin, and L. Li, J. Am. Chem. Soc., 1990, 112, 7050. (b) H. Tokuyama, S.
Yokoshima, S.-C. Lin, L. Li, and T. Fukuyama, Synthesis, 2002, 1121.
H. Tokuyama, S. Yokoshima, T. Yamashita, and T. Fukuyama, Tetrahedron Lett., 1998, 39, 3189.
10. H. Tokuyama, T. Miyazaki, S. Yokoshima, and T. Fukuyama, Synlett, 2003, 1512.
11. (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260. (b) H. Prokopcová, L.
Pisani, and C. O. Kappe, Synlett, 2007, 43.
12. R. Wittenberg, J. Srogl, M. Egi, and L. S. Liebeskind, Org. Lett., 2003, 5, 3033.
13. R. Kakino, S. Yasumi, I. Shimizu, and A. Yamamoto, Bull. Chem. Soc. Jpn., 2002, 75, 137.
14. L. S. Liebeskind and J. Srogl, Org. Lett., 2002, 4, 979.
15. M. Egi and L. S. Liebeskind, Org. Lett., 2003, 5, 801.
16. M. E. Angiolelli, A. L. Casalnuovo, and T. P. Selby, Synlett, 2000, 905.
17. M. Node, K. Kumar, K. Nishide, S. Ohsugi, and T. Miyamoto, Tetrahedron Lett., 2001, 42, 9207.
18. T. Miyazaki, Y. Han-ya, H. Tokuyama, and T. Fukuyamaꢀ , Synlett, 2004, 477.
19. General procedure for the coupling reaction of N-heteroaryl sulfide with zinc reagent: Under
an argon atmosphere, a 0.95 M solution (1.29 mL, 1,22 mmol) of (5-ethoxy-5-oxopentyl)zinc(II)
iodide in tetrahydrofuran was added to a mixture of 2-(dodecylthio)quinoline (202 mg, 0.61 mmol,
prepared from 2-chloroquinoline and 1-dodecanethiol with NaH in DMF at 0 °C to reflux, 92%
isolated yield) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg, 0.031
mmol) in 0.75 mL of toluene. The mixture was stirred and heated at 50 °C for 90 min. The reaction

HETEROCYCLES, Vol. 77, No. 1, 2009
239
mixture was diluted with EtOAc and the reaction was quenched by addition of a saturated aqueous
sodium hydrogen carbonate. The aqueous layer separated was extracted with EtOAc three times.
The combined organic extracts were washed with brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by flash column chromatography on
silica gel (30% EtOAc-hexane) to provide ethyl 5-(quinolin-2-yl)pentanoate (150 mg, 0.58 mmol,
96%) as a pale yellow oil. IR (neat, cm-1): 2943, 1732, 1606, 1502, 1375, 1306, 1184, 827, 760; 1H
NMR (400 MHz, CDCl3):  8.07 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz,
1H), 7.68 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.49 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.30 (d, J = 8.4 Hz,
1H), 4.12 (q, J = 7.2 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 1.92-1.82 (m, 2H),
13
1.81-1.70 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3):  173.5, 162.3, 147.8,
136.2, 129.3, 128.8, 127.4, 126.7, 125.7, 121.3, 60.2, 38.8, 34.1, 29.3, 24.7, 14.2; HRMS (FAB):
Calculated for C16H20NO2 (M+H)+, 258.1494; Found 258.1495.
20. Casalnuovo and co-workers also examined coupling reaction of a series of 2-, 3-, and
4-(methythio)pyridines with benzylzinc bromide (Ref. 16). However, they reported that no reaction
was observed in the case of 3-(methylthio)pyridine.
21. To the best of our knowledge, this is the first example of palladium-mediated coupling of
N-heteroaryl sulfide, which has alkylthio group on the carbocyclic ring. While the presence of
nitrogen atom in the ring is indispensable for the coupling reaction (Table 4, entry 10 vs. 19), a
detailed explanation of this observation is not possible at this point.
22. The reaction we have established in this work was also applicable to simple thioimidates to form
the corresponding imines.
EtZnI (2 eq)
N
N
PdCl2(dppf) (5 mol%)
Et
SC12H25
toluene-THF
50 °C, 45 min
79%
Ph
Ph