A C-C bond formation reaction at the α-carbon atom of α-oxo ketene dithioacetals via the Baylis-Hillman type reaction

Article abstract of DOI:10.1016/j.tetlet.2005.04.108

The first example of TiCl₄-mediated Baylis-Hillman type reaction of α-acetyl cyclic ketene dithioacetals with arylaldehydes was described. This methodology adds a new entry to the C-C bond formation at the α-carbon atom of α-oxo ketene dithioacetals.

Full text of DOI:10.1016/j.tetlet.2005.04.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4399–4402
A C–C bond formation reaction at the a-carbon atom of
a-oxo ketene dithioacetals via the Baylis–Hillman type reaction
a,
a
Yan-Bing Yin,a,b Mang Wang,a,* Qun Liu, Jiang-Lei Hu,
*
Shao-Guang Suna and Jing Kanga
aDepartment of Chemistry, Northeast Normal University, Changchun 130024, China
bDepartment of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar 161006, China
Received 28 December 2004; revised 14 April 2005; accepted 18 April 2005
Abstract—The first example of TiCl4-mediated Baylis–Hillman type reaction of a-acetyl cyclic ketene dithioacetals with arylaldehy-
des was described. This methodology adds a new entry to the C–C bond formation at the a-carbon atom of a-oxo ketene
dithioacetals.
ꢀ 2005 Elsevier Ltd. All rights reserved.
As a kind of versatile synthons, a-oxoketene dithioace-
tals 1 have found their wide utilizations in organic syn-
thesis, especially in the synthesis of various aromatic and
heterocyclic compounds.1,2 Compared with the numer-
ous reports involved in the reactions in which a-oxo ke-
tene dithioacetals were taken as 1,3-electrophiles, the
research relevant to the reaction at their a-carbon atom
was poorly investigated. It is clear that the highly polar-
ized push (RS)–pull (R1CO) interaction on the C–C
double bond of these, b,b-dialkylthio-a,b-enones and
analogues makes their a-carbon atom a potential nucleo-
philic centre. Accordingly, the a-functionalization
reaction of 1 has been developed in our group very re-
cently.3 Some heteroatom functional groups such as
Br, I and NO2 have been successfully introduced into
the a-position of the appropriate 1 (R2 = acetyl or car-
boxyl) via halodecarboxylation or similar reaction.3
With the aim to establish a new method for the C–C
bond formation at the a-carbon atom of a-oxo ketene
dithioacetals, on our ongoing research,4 we have become
interested in investigating the reactivity of compounds 2
towards carbon electrophiles.
Based on the C–C coupling of activated alkenes (at the
a-position) with a carbon electrophile, the Baylis–Hill-
man (BH) reaction5 can provide various polyfunctional-
ized molecules and has been applied to the synthesis of
various biologically active compounds and natural
products.6 As a kind of special alkenes with electron rich
a-carbon atom, compounds 2 are expected to proceed
more efficiently than those employed in the BH reaction.
However, the alkenes bearing b-substituent(s) have been
usually proven to be inert due to the steric hindrance to-
wards the attack of the base in the BH reaction.5 To cir-
cumvent this problem, a number of attempts have been
made to provide the BH adducts including the use of
some BH type reactions.7 Recently, we found an unprec-
edented BH type reaction between a-oxo ketene dithio-
acetals 2 and arylaldehydes and the experimental results
are described in this letter.
O
O
2
α
R
2a: R,R=(CH2)2
2b: R,R=(CH2)3
2c: R=CH3
SR
R1
RS
1
β
RS
SR
In our preliminary experiment, the reaction of 2a with 4-
nitrobenzaldehyde 3a (1.0 equiv) in the presence of
DABCO (1–10 equiv) was attempted. Unfortunately,
when the reaction was performed in anhydrous CH2Cl2
at room temperature, no reaction occurred after 3 days
and only 2a and 3a were recovered, respectively. Simi-
larly, DBU and Et3N were also proven to be the
Keywords: a-Oxo ketene dithioacetals; Activated alkenes; C–C Bond
formation; Baylis–Hillman type reaction; Double Baylis–Hillman
products.
*
Corresponding authors. Tel.: +86 431 5099759; fax: +86 431
5098966; e-mail: liuqun@nenu.edu.cn
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.108

4400
Y.-B. Yin et al. / Tetrahedron Letters 46 (2005) 4399–4402
NO2
O
O
S
Ar
O
S
O
S
Ar
O
OH
TiCl4 / CH2Cl2
0-10°C
CHO
+
+
S
n
ArCHO
TiCl4 / CH2Cl2
0-10°C
O
S
O
S
S
S
n
4aa: n=1
4ba: n=2
S
S
n
+
n
S
S
n
2
3
5
4
NO2
S
S
Scheme 2. The reaction of 2 and 3 in the presence of TiCl4.
n
n
2 (n=1, 2)
3a
Scheme 1. The reaction of 2 and 3a mediated by TiCl4.
a,b
Table 1. The reaction of 2 and 3 in the presence of TiCl4
Entry
2
3
n
Ar
Time Product Yieldc
inefficient basic catalysts for this reaction. According to
the mechanism of the amine-catalyzed BH reaction, the
steric hindrance of the b,b-dialkylthio groups of 2a
should be the reason for why the above reaction was
inert under the typical BH conditions.5
(h)
(%)
1
2
3
4
5
6
7
8
9d
2a 3a
2b 3a
2a 3b
2b 3b
2a 3c
2a 3d
2a 3e
2a 3f
2a 3a
1
2
1
2
1
1
1
1
1
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-ClC6H4
7
8
4aa
4ba
4ab
4bb
4ac
4ad
4ae
4af
72
65
69
66
49
54
44
32
24
23
20
28
9
10
12
9
We then turned to the acidic catalysts and TiCl4 was
chosen to promote the reaction of 2a with 3a with the
consideration that the carbonyl group of an aldehyde
was prone to be more electrophilic under the activation
by the Lewis acid. Indeed, when the reaction was carried
out in anhydrous CH2Cl2 (10 mL) at 0–10 ꢁC for 2 days,
the double BH product 4aa was isolated in 35% yield
with 55% recovery of 3a (Scheme 1).
4-CHOC6H4
4-FC6H4
C6H5
18
30
2
4-NO2C6H4
4aa
5aa
4ad
5ad
10e
2a 3d
1
4-CHOC6H4
1
a Reaction conditions: 2 (2 mmol), 3 (0.5 mmol), TiCl4 (0.6 mmol),
CH2Cl2 (10 mL), 0–10 ꢁC.
b All products 4 and 5 were characterized by IR, 1H NMR, 13C NMR
Since the one-pot synthesis of 4aa presented the first
example of the double BH type reaction, the reaction
conditions were then examined in detail. By changing
the ratio of 2a:3a from 1:1 to 6:1 with a constant amount
of TiCl4 (1.2 equiv), it was found that the ratio of 2a:3a
showed significant effect not only on the product yield
but also on the reaction rate. With the optimized ratio
of 2a:3a (4:1), 4aa was obtained in 72% isolated yield
and the reaction time was shortened to 7 h. Under the
identical conditions, 4ba was obtained in 65% yield from
the reaction of 2b and 3a and its structure was estab-
lished by a single crystal X-ray diffraction study (Fig.
1).8 Interestingly, under the identical conditions, no
reaction occurred between 2c and 3a.
and elemental analysis.
c Isolated yields.
d 2a:3a = 1:3.
e 2a:3d = 1:3.
tron-withdrawing/donating groups, and aliphatic alde-
hyde (pivalaldehyde), were tried under the above
conditions (Scheme 2). The results were summarized in
Table 1.9 Based on these results, it was clear that arylal-
dehydes with strong electron-withdrawing group led to
increased yields and shortened reaction time. Compara-
tively, for arylaldehydes with electron-donating group,
that is, 4-methylbenzaldehyde and 4-methoxylbenzalde-
hyde, only trace amounts of the double BH products
As expected to extend the scope of this novel reaction,
the selected aldehydes, such as arylaldehydes with elec-
1
were found according to the H NMR analysis of the
reaction mixture after recovery of the substrates. For
the case of pivalaldehyde, no reaction occurred even
when the reaction time was prolonged to 3 days. In
our experiment, it was also observed that there was lim-
ited influence on both the yield and the reaction rate
when the amount of TiCl4 was varied from 1.0 to
2.0 mol equiv. However, 0.5 mol equiv of TiCl4 was pro-
ven not enough to complete this double BH type
reaction.
It was found, by TLC monitoring of the reaction pro-
gress of 2a with 3a that the BH adduct 5aa (according
1
to H NMR analysis of the reaction mixture) was also
produced as a minor product. To obtain the BH adduct
in pure form and to understand the reaction mechanism,
arylaldehydes with strong electron-withdrawing groups,
such as 4-nitrobenzaldehyde 3a and terephthalaldehyde
3d, were selected again to react with 2a with the consid-
eration that the BH adducts derived from them might be
relatively stable to be trapped under an appropriate
Figure 1. The crystal structure of 4ba.

Y.-B. Yin et al. / Tetrahedron Letters 46 (2005) 4399–4402
4401
condition. The experimental results revealed that the in-
creased yield of the BH adduct could be obtained by
increasing the amount of arylaldehyde and shortening
the reaction time. In the 1:3 ratio of 2a:3a under the
identical conditions for 2 h, 4aa (24%) and 5aa (23%)
were able to be separated by flash column chromatogra-
phy (entry 9). Similarly, 4ad and 5ad were obtained in
20% and 28% yields, respectively (entry 10).
and 2b, the carbon sulfur bond between sulfur atom
and b-carbon atom is flexible.
Recently, Minami and co-workers found a Lewis acid-
promoted deoxygenative di[b,b-bis(ethylthio)]vinylation
of silylketene diethylthioacetal with aldehydes.11 Com-
pared with the electron rich alkene with the three
electron-donating groups used in MinamiÕs research,
the alkenes with electron rich a-carbon atom employed
in our work are polarized by the stronger push (RS)–
pull (R1CO) interaction on the C–C double bond and
are apt to the BH type reaction in the presence of Lewis
acids.
In order to understand the reaction mechanism, the BH
adduct 5aa was reacted with 2a under the identical con-
ditions and the double BH adduct 4aa was obtained in
69% isolated yield. It should be mentioned that, neither
the BH nor the double BH product was found when 4ad
was applied as the electrophile to examine its further
reaction with 2a under the same conditions. As the aryl-
aldehyde bearing an electron-donating group on the aryl
ring, this result indicated that 4ad was not reactive to-
wards 2a under the reaction conditions.
In conclusion, we have described a novel Baylis–Hill-
man type reaction between a-oxoketene dithioacetals
and arylaldehydes leading to the polyfunctionalized
1,4-pentadienes.12 As far as we know, this is the first
example in which the activated alkenes having two
b,b-dialkylthio substituents are investigated in the BH
reaction and similar processes. This research represents
a new methodology for the C–C bond formation at
the a-carbon atom of a-oxo ketene dithioacetals. Fur-
ther investigation on this process and the application
of the double BH products are in progress in our
laboratory.
Unlike the mechanism of the TiCl4-catalyzed BH reac-
tion,10 which is believed to proceed through the
Michael-initiated addition–elimination sequence, the
stronger nucleophilicity of the a-carbon atom of 2 might
require only electrophiles to be activated. Based on the
experimental results mentioned above, the mechanism
concerned was thus proposed and depicted in Scheme
3 (with 2a as an example).
Acknowledgements
Initiated by the nucleophilic attack of the electron rich
a-carbon atom of 2a at the carbonyl carbon of the acti-
vated aldehyde, the BH adduct 5 was first produced via
intermediate I. And then the double BH product 4 was
formed from the reaction of intermediate III and 2a with
the aid of TiCl4. Combining the experimental results
with the proposed mechanism, it was indicated that:
(1) the reaction of 2a with arylaldehydes should be the
rate determination step, and (2) the easy formation of
the double BH product was probably due to the higher
stability of the carbocation intermediate III from the
delocalization of the positive charge by the bialkylthio
sulfur atoms. The activated alkene 2b possessed the sim-
ilar property to 2a. The inert of 2c to this process may be
due to the deactivated effect by the formation of a com-
plex between TiCl4 with the lone pair electrons of the
sulfur atoms of 2c because, unlike the rigid cyclic 2a
Financial supports of this research by the NNSFC
(20272008) and the Key Grant Project of Chinese Min-
istry of Education (10412) are greatly acknowledged.
References and notes
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O
S
Ar
O
S
TiCl4
O
ArCH=O
TiCl4
H
S
-TiCl4
5
S
2a
I
O
O
Ar
H+
-TiCl3(OH)
TiCl4
-HCl
O
2a
Ar
4
TiCl3
S
S
S
S
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II
Scheme 3. Proposed mechanism.
III

4402
Y.-B. Yin et al. / Tetrahedron Letters 46 (2005) 4399–4402
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to give compound 4aa as a light yellow crystal (eluent:
petroleum ether/ether = 3/1, V/V) in 72% yield. Com-
pounds 4ba, 4ab, 4bb, 4ac, 4ad, 4ae and 4af could also be
formed after the corresponding time mentioned in Table 1
under the similar reaction conditions. When the reaction
time was controlled within 2 h and using the 1:3 ratio of
2:3 under the identical conditions, the BH adducts 5aa
and 5ad could also be obtained in 23% and 28% yields,
respectively, besides the double BH products 4aa (24%)
and 4ad (20%). Compound 4aa: Light yellow crystal; mp:
6. (a) Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A. J. J. Med.
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1
162–164 ꢁC; H NMR (CDCl3, 500 MHz): d 1.93 (s, 6H),
3.28–3.30 (m, 8H), 5.78 (s, 1H), 7.39 (d, J = 7.5 Hz, 2H),
8.15 (d, J = 7.5 Hz, 2H);13C NMR (CDCl3, 125 MHz):
d 23.7, 32.1, 32.6, 48.7, 118.3, 118.7, 124.7, 141.7, 143.6,
159.1, 189.8; IR (KBr): 2924, 1678, 1631, 1516, 1455,
1347, 1238 cmÀ1; Anal. Calcd for C19H19NO4S4: C 50.31,
H 4.22, N 3.09. Found C 50.23, H 4.15, N 2.98.
Compound 5aa: White crystal; mp: 158–160 ꢁC; 1H
NMR (CDCl3, 500 MHz): d 2.07 (s, 3H), 3.08 (d,
J = 4.5 Hz, 1H), 3.36–3.47 (m, 4H), 6.21 (d, J = 4.5 Hz,
8. Crystal data for 4ba: C21H23NO4S4, colourless, M =
481.64, orthorhombic, space group Pca2(1), a = 12.458(3),
3
˚
˚
b = 9.946(2), c = 18.149(4) A, V = 2248.7(8) A , l =
0.451 mmÀ1, Z = 4, T = 293 K, F000 = 1008, R = 0.0337,
wR2 = 0.0585. The CCDC deposition number: 245727.
9. General procedure for the Baylis–Hillman type reaction of 2
and 3: To a solution of 2a (4.0 mmol) and 3a (1.0 mmol) in
dry CH2Cl2 (10 mL) was added dropwise TiCl4
(1.2 mmol) via syringe for 1 min. at 0 ꢁC. The mixture
was allowed to react at 0–10 ꢁC for 7 h till 3a was
consumed (monitored by TLC). Then the reaction was
quenched by NaHCO3 saturated aqueous solution
(10 mL) leading to the white precipitate, which was
filtered off afterwards. The filtrate was extracted with
CH2Cl2 (10 mL · 2) and the organic layer was dried over
anhydrous MgSO4. After removal of the solvent in vacuo,
the residue was purified by flash silica gel chromatography
1H), 7.59 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 8.5 Hz, 2H); 13
C
NMR (CDCl3, 125 MHz): d 29.2, 36.1, 39.1, 74.4, 123.6,
126.4, 126.5, 147.1, 149.1, 166.2, 195.0; IR (KBr): 3446,
2925, 1621, 1518, 1458, 1344, 1245 cmÀ1; Anal. Calcd for
C13H13NO4S2: C 50.15, H 4.21, N 4.50. Found C 50.38, H
4.17, N, 4.58.
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