Copper-mediated C-N bond formation via direct aminolysis of dithioacetals

Article abstract of DOI:10.1021/ol060763c

Mediated by copper acetate, an efficient approach to the C-N bond formation via direct aminolysis of dithioacetals 2 and 5 with ammonia, primary or secondary amines are developed under mild conditions. Enaminones 3 and 6 were thus obtained in high to exce

Full text of DOI:10.1021/ol060763c

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2547-2550
Copper-Mediated C−N Bond Formation
via Direct Aminolysis of Dithioacetals
Jing Kang, Fushun Liang,* Shao-Guang Sun, Qun Liu,* and Xi-He Bi
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, China
liangfs112@nenu.edu.cn
Received March 30, 2006
ABSTRACT
Mediated by copper acetate, an efficient approach to the C−N bond formation via direct aminolysis of dithioacetals 2 and 5 with ammonia,
primary or secondary amines are developed under mild conditions. Enaminones 3 and 6 were thus obtained in high to excellent yields with
high chemoselectivity. This type of aminolysis reaction presents a new synthetic application of the dithioacetal functionality.
Dithioacetals, which are easily obtained by the condensation
of aldehydes/ketones with thiols,1 odorless thiol equivalents,2
or 1,3-propanedithiol copolymers,3 have proven to be very
useful in organic synthesis. Besides its use as a latent
carbonyl,1-3 methylene group4 and an umpolung of the
carbonyl group (dithiane method according to Seebach),5,6
the synthetic potential of the dithioacetal functionality has
been widely expanded in recent years. For example, Luh and
co-workers demonstrated the nickel-catalyzed olefination
reactions of benzylic, allylic, aliphatic, and propargylic
dithioacetals (which function as germinal dication synthons)
with Grignard reagents7 and the synthesis of furans, pyrroles,
and oligoaryls with propargylic dithioacetals as zwitterion
synthons.8 Takeda et al. reported the desulfurizative meta-
lation of dithioacetals to form titanium-alkylidens species
which could produce a C-C double bond with aldehydes,
ketones, and esters.9 Additionally, the dithiane-/trithiane-
based photolabile scaffolds for molecular recognition10 and
some useful transformations11 have also been reported.
In our research on the exploration of the synthetic
applications of functionalized ketene dithioacetals,12,13 a series
(1) (a) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994. (b)
Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999.
(2) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong,
D. J. Org. Chem. 2003, 68, 9148. (b) Yu, H.; Liu, Q.; Yin, Y.; Fang, Q.;
Zhang, J.; Dong, D. Synlett 2004, 999. (c) Dong, D.; Ouyang, Y.; Yu, H.;
Liu, Q.; Liu, J.; Wang, M.; Zhu, J. J. Org. Chem. 2005, 70, 4535-4537.
(3) (a) Bertini, V.; Lucchesini, F.; Pocci, M.; De Munno, A. J. Org.
Chem. 2000, 65, 4839-4842. (b) Bertini, V.; Lucchesini, F.; Pocci, M.;
Alfei, S.; De Munno, A. Synlett 2003, 1201-1203.
(4) Hauptmann, H.; Walter, W. F. Chem. ReV. 1962, 62, 347-404.
(5) For reviews, see: (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1969,
8, 639-649. (b) Grobel, B. T.; Seebach, D. Synthesis 1977, 357-402. (c)
Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258. (d) Bulman
Page, P. C.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643-
7677.
(6) Selected examples: (a) Smith, A. B., III.; Pitram, S. M.; Gaunt, M.
J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 14516. (b) Smith, A. B.,
III.; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.;
Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40,
196. (c) Tyrrell, E.; Skinner, G. A.; Janes, J.; Milsom, G. Synlett 2002,
1073. (d) Nakamura, S.; Ito, Y.; Wang, L.; Toru, T. J. Org. Chem. 2004,
69, 1581-1589.
(7) (a) Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89. (b) Ni, Z.-J.; Luh, T.-Y.
J. Org. Chem. 1991, 56, 4035. (c) Wong, K.-T.; Luh, T.-Y. J. Am. Chem.
Soc. 1994, 116, 8920. (d) Luh, T.-Y. J. Organomet. Chem. 2002, 653, 209.
(e) Luh, T.-Y. Acc. Chem. Res. 1991, 24, 257. (f) Luh, T.-Y.; Leung, M.-
k.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-3204.
(8) For a microreview, see: Luh, T.-Y.; Lee, C.-F. Eur. J. Org. Chem.
2005, 3875-3885.
(9) (a) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am.
Chem. Soc. 1997, 119, 1127. (b) Breit, B. Angew. Chem., Int. Ed. 1998,
37, 453. (c) Takeda, T.; Kuroi, S.; Yanai, K.; Tsubouchi, A. Tetrahedron
Lett. 2002, 43, 5641. (d) Huang, L.-F.; Huang, C.-H.; Stulgies, B.; de
Meijere, A.; Luh, T.-Y. Org. Lett. 2003, 5, 4489.
(10) (a) Wan, Y. Q.; Angleson, J. K.; Kutateladze, A. G. J. Am. Chem.
Soc. 2002, 124, 5610. (b) Kurchan, A. N.; Kutateladze, A. G. Org. Lett.
2002, 4, 4129. (c) Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5,
769. (d) Chiba, K.; Uchiyama, R.; Kim, S.; Kitano, Y.; Tada, M. Org. Lett.
2001, 3, 1245.
(11) (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima,
Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423-
15430. (b) Padwa, A.; Ginn, J. D.; McClure, M. S. Org. Lett. 1999, 1,
1559-1561. (c) Takeda, T.; Yatsumonji, Y.; Tsubouchi, A. Tetrahedron
Lett. 2005, 46, 3157-3160. (d) Chiba, K.; Uchiyama, R.; Kim, S.; Kitano,
Y.; Tada, M. Org. Lett. 2001, 3, 1245-1248.
10.1021/ol060763c CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/16/2006

Scheme 1
Scheme 2
of 3,5-disubstituted tetronic acid derivatives (TADs) (Scheme
1, compounds 1) with a 1,3-dithiolane- or 1,3-dithian-2-
ylidene moiety at the 3-position of a TAD were obtained in
excellent yields.14 In addition to the biological features, TADs
are useful precursors for syntheses of peptide analogues or
HIV-1 protease inhibitors.15 In continuation of our work, we
are interested in the modification at the 3-position of TADs
1 with a goal to find new synthetic applications for the
dithioacetal moiety and thus improve their activity for
pharmaceutical studies.16 As a result, we have discovered a
new C-N bond-forming reaction via direct aminolysis of
dithioacetals. In this communication, the preliminary results
on the copper-mediated aminolysis of dithioacetals 2 and 5
with ammonia and primary and secondary amines are
described.
Dithianes 2 were prepared from the corresponding TADs
1.14 Upon reduction with NaBH4 (1.1 equiv) in ethanol at 0
°C for about 20 min, dithianes 2a and 2b, with the structure
of 2-hydroxyvinyl dithioacetals, were obtained in 97% and
98% isolated yields, respectively (Scheme 1).17
In our study on the C-N cross-coupling reaction of
dithianes 2 with amines, a model reaction between 2a and
n-butylamine was first examined to optimize the reaction
conditions (Scheme 2). The reaction conditions, including
catalysts (Cu(OAc)2‚H2O; Cu(NO3)2‚3H2O; CuSO4‚5H2O),
solvents (THF, DMF, CH2Cl2), and reaction temperature
(room temperature to 50 °C), were investigated. After
optimization and treatment of 2a (1.0 mmol) with n-
butylamine (1.5 mmol) in the presence of Cu(OAc)2‚H2O
(0.5 mmol) in THF at 50 °C for 1 h, the product, enaminone
3ad (Table 1, entry 4), was obtained in 96% isolated yield.17
Table 1. Copper-Catalyzed C-N Cross-Coupling Reaction
between Dithianes 2 and Amines
time yield
entry substrates
R1
R2
products (h)
(%)a
1b
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
H
H
CH3
C2H5
n-C4H9
PhCH2
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3
84
87
92
96
93
92
96
76
66
85
80
88
91
95
90
92
96
73
64
75
H
H
H
H
2.5
2.5
1
1.5
1.5
2
8
8
2
3
3
2.5
1
1.5
1.5
2
8
8
2
C2H5 C2H5
CH2CH2OCH2CH2
H
H
H
H
H
H
H
H
Ph
p-CH3C6H4
CH2CH2OH
H
CH3
C2H5
10
3aj
11b
12
13
14
15
16
17
18
19
20
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
n-C4H9
PhCH2
C2H5 C2H5
CH2CH2OCH2CH2
H
H
H
Ph
p-CH3C6H4
CH2CH2OH
3bj
a Isolated yields over silica gel chromatography. b 3 equiv of NH4OAc
was adopted.
(12) Reviews: (a) Dieter, R. K. Tetrahedron 1986, 42, 3029. (b) Junjappa,
H.; Tla, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423. (c) Tla, H.; Junjappa,
H.; Barun, O. J. Organomet. Chem. 2001, 624, 34. (d) Elgemeie, G. H.;
Sayed, S. H. Synthesis 2001, 1747.
It should be noted that 0.5 equiv of Cu(OAc)2‚H2O was
enough to accomplish the reaction, but the cases with a low
amount of catalyst, for example, the reaction of 2a with
n-butylamine in the presence of 0.25 equiv of Cu(OAc)2‚
H2O under otherwise the same conditions, gave 3ad in 32%
yield with a longer reaction time (more than 12 h). Under
the optimized conditions as described above, the correspond-
ing enaminones 3 were obtained in high to excellent yields
when TADs 2 reacted with ammonium acetate (Table 1,
entries 1 and 11), primary aliphatic amines (Table 1, entries
2-5 and 12-15), and secondary aliphatic amines (Table 1,
entries 6, 7, 16, and 17). In particular, when the bisnucleo-
philic reagent, 2-aminoethanol, was adopted to react with
2a and 2b, the corresponding enaminones 3aj and 3bj were
obtained in high yields with high chemoselectivity (Table
1, entries 10 and 20), respectively. Moreover, even the less-
(13) Selected examples: (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao,
L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578. (b) Zhao, Y.; Liu, Q.; Zhang,
J.; Liu, Z. J. Org. Chem. 2005, 70, 6913. (c) Dong, D.; Bi, X.; Liu, Q.;
Cong, F. Chem. Commun. 2005, 3580. (d) Zhao, L.; Liang, F.; Bi, X.; Sun,
S.; Liu, Q. J. Org. Chem. 2006, 71, 1094-1098.
(14) Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong, D. Synlett
2005, 49.
(15) (a) Ghosh, N.; Mckee, S. P.; Thompson, W. J.; Darke, P. L.; Zugory,
J. C. J. Org. Chem. 1993, 58, 1025. (b) Hanessian, S.; Park, H.; Yang, R.
Y. Synlett 1997, 351. (c) Hanessian, S.; Park, H.; Yang, R. Y. Synlett 1997,
353.
(16) Selected examples: (a) Pattenden, G. Fortsch. Chem. Org. Naturst.
1978, 35, 133. (b) Rehse, K.; Wagenknecht, J. Arch. Pharm. 1979, 312,
165. (c) Arai, K. Chem. Pharm. Bull. 1989, 37, 3229. (d) Kusumi, T.;
Ichikawa, A.; Kakisawa, H.; Tsunakawa, M.; Konishi, M.; Oki, T. J. Am.
Chem. Soc. 1991, 113, 8947. (e) Ge, P.; Kirk, K. L. J. Org. Chem. 1997,
62, 3340. (f) Langer, P.; Eckardt, T.; Stoll, M. Org. Lett. 2000, 2, 2991.
(g) Sodeoka, M.; Osada, H. J. Med. Chem. 2001, 44, 3216. (h) Roush, W.
R.; Barda, D. A. Org. Lett. 2002, 4, 1539. (i) Kapferer, T.; Bru¨ckner, R.;
Herzig, A.; Ko¨nig, W. A. Chem.-Eur. J. 2005, 11, 2154-2162.
(17) For details for the preparation of dithioacetals 2 and 5 and the C-N
cross-coupling reaction, please see the Supporting Information.
2548
Org. Lett., Vol. 8, No. 12, 2006

reactive amines, such as aniline and p-toluidine, could afford
the corresponding enaminones 3ah, 3ai, 3bh, and 3bi in good
yields (Table 1, entries 8, 9, 18, and 19), although the reaction
time was prolonged to 8 h. All the results described above
indicate the efficiency of this C-N cross-coupling reaction
and the generality of this reaction to amines. Also, it is
noticeable that this reaction presents an alternative synthetic
route to useful enaminones.18
Figure 1. Dithioacetals with more general structures in the explored
aminolysis reaction mediated by the Cu(II) catalyst.
As an extension of the new C-N coupling reaction,
dithioacetals 5a-g were then synthesized via the reduction
of 4a-g19 by magnesium in methanol20 (Scheme 3) and were
I is proposed to be formed by reaction of 2 with Cu(OAc)2
in which one of the sulfur atoms of the dithioacetal unit
coordinates to the Cu(II) ion.21 The formation of I activates
the C-S bond coordinated to the copper(II) ion, and thus,
the thionium ion intermediate II (or the sulfur-stabilized
carbocation intermediate) would be formed by the C-S bond
cleavage. After that, the amine attacking at the carbon atom
of thionium II leads to the formation of enaminones 3.
Scheme 3
subjected to the reaction sequence. Under conditions identical
to those above, the C-N cross-coupling reaction of 5a-g
with n-butylamine (Scheme 3) was proven to be successful
and the corresponding enaminones 6a-g were synthesized
in high to excellent yields (Table 2). To understand the scope
Scheme 4. Proposed Mechanism for the Copper-Catalyzed
C-N Cross-Coupling Reaction
Table 2. Copper-Catalyzed C-N Cross-Coupling Reaction
between Dithioacetals 5 and n-Butylamine
time yield
entry substrates
R3
R4
products (min) (%)a
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
CH2CH2CH2CO
CH2C(Me)2CH2CO
6a
6b
6c
6d
6e
6f
15
30
60
30
20
20
20
90
89
94
95
70
84
84
Me
Me
OEt
Me
Me
COMe
CO2Et
CO2Et
CONH2
CN
The C-N coupling reaction is important in organic
synthesis.22,23 To know more details about the reaction
mechanism, the reaction of 2a with n-butylamine was then
carried out under optimized conditions with anhydrous Cu-
(OAc)2 as the catalyst in absolute THF and monitored by
TLC. The reaction was completed at 50 °C within 8 h and
gave 3ad in 81% isolated yield. By comparison, in another
experiment without n-butylamine added, substrate 2a was
almost entirely recovered (contaminated with traces of the
corresponding aldehyde; yield <3%) under the above condi-
tions for 8 h.24 The results, together with the reaction of
2-aminoethanol with 2a and 2b (Table 1, entries 10 and 20),
5g
6g
a Isolated yields over silica gel chromatography.
of the aminolysis reaction explored here, dithioacetals 7a
and 7b were selected to react with n-butylamine. As a result,
no reaction was found for 7a (the substrate was recovered
quantitatively). As for 7b, an inseparable mixture was
produced (Figure 1).
On the basis of the above results, a possible mechanism
for the copper(II)-catalyzed C-N cross-coupling reaction is
tentatively proposed as depicted in Scheme 4 (with the
aminolysis of 2 as an example). Initially, a copper complex
(21) Viski, P.; Waller, D. P.; Zuraw, M. J. Org. Chem. 1996, 61, 7631-
7632.
(22) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400-5449. (b) Muzart, J. Tetrahedron 2005, 61, 4179-
4212.
(23) Selected examples: (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40,
1513. (b) Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079.
(24) The corresponding aldehyde, produced by the hydrolysis of 2a, is
likely formed during the workup process. This process was difficult to
monitor because dithiane 2a and the corresponding aldehyde have the same
Rf value on TLC and the amount of aldehyde was calculated based on the
1H NMR spectra of the mixture (see the Supporting Information).
(18) For reviews, see: (a) Abdel-Zaher, A. E.; Adel, A. E.-K. Tetrahe-
dron 2003, 59, 8463. (b) Stanovnik, B.; Svete, J. Chem. ReV. 2004, 104,
2433.
(19) (a) Ouyang, Y.; Dong, D.; Yu, H.; Liang, Y.; Liu, Q. AdV. Synth.
Catal. 2006, 348, 206. (b) Pak, C. S.; Choi, E. B. Synthesis 1992, 1291-
1294.
(20) (a) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1988, 792. (b)
Mellor, J. M.; Schofield, R.; Korn, S. R. Tetrahedron 1997, 53, 1711-
17162.
Org. Lett., Vol. 8, No. 12, 2006
2549

clearly support the proposed mechanism of copper(II)-
mediated direct aminolysis of dithioacetals (Scheme 4),
although the reaction rate between 2a and n-butylamine is a
little slower under anhydrous conditions than that with Cu-
(OAc)2‚H2O as the catalyst.25
In conclusion, a new C-N bond formation reaction where
a thionium ion intermediate was trapped by an amine was
realized. This copper(II)-mediated C-N bond formation
reaction of a dithioacetal unit with amines could proceed
under mild conditions with high chemoselectivity. The
functional groups such as carbonyl, cyano, ethoxycarbonyl,
and lactone are tolerable to the reaction conditions. This
type of aminolysis reaction represents a new synthetic
application of the dithioacetal functionality. Further work
on the scope of this C-N coupling reaction is underway in
our laboratory.
Acknowledgment. Financial support from the Key Grant
Project of the Chinese Ministry of Education (10412) and
the National Natural Sciences Foundation of China (20272008)
is gratefully acknowledged.
Supporting Information Available: Experimental details
1
and spectral data for compounds 2 and 3 and 5 and 6. H
NMR spectrum for the mixture of 2a and the corresponding
aldehyde, and the HMBC, HMQC, and 1H-1H COSY spectra
of compound 3aa. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) The substrates 2 were slightly soluble in THF. When even one drop
of water was added to the THF of 2, the solution would become clear
immediately. The reason for the prolonged reaction time of 2a under
anhydrous conditions was mainly attributed to the poor solubility of 2a in
absolute THF.
OL060763C
2550
Org. Lett., Vol. 8, No. 12, 2006