SmI2-promoted tandem desulfurization and reductive coupling reactions of aromatic lactams with carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(01)02030-5

Treatment of sulfur-substituted aromatic lactams with carbonyl compounds in the presence of samarium(II) diiodide was found to undergo novel tandem desulfurization and reductive coupling reactions to generate α-hydroxyalkylated lactams in high yield. Ster

Full text of DOI:10.1016/S0040-4039(01)02030-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9225–9228
SmI2-promoted tandem desulfurization and reductive coupling
reactions of aromatic lactams with carbonyl compounds
Hidemi Yoda,* Yasuaki Ujihara and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku, Hamamatsu 432-8561, Japan
Received 26 September 2001; revised 22 October 2001; accepted 26 October 2001
Abstract—Treatment of sulfur-substituted aromatic lactams with carbonyl compounds in the presence of samarium(II) diiodide
was found to undergo novel tandem desulfurization and reductive coupling reactions to generate a-hydroxyalkylated lactams in
high yield. Stereochemistry of the coupling products was researched and the results that decreasing the steric bulkiness of the
N-substituents as well as raising the reaction temperature leads to an increase of the erythro-selectivity were observed. The
mechanistic origins of this stereoselectivity are also briefly documented. © 2001 Elsevier Science Ltd. All rights reserved.
Since its introduction by Kagan and co-workers1 SmI2
has been extensively investigated as a powerful electron
donor able to promote a wide range of reductions and
coupling reactions.2 Its use in synthesis has been espe-
cially advantageous for ring closure reactions and CꢀC
bond formation such as hydroxyl-directed addition of
carbonyl to CꢁC double bond and stereocontrolled
intramolecular pinacol reactions.2k,3 The reactions of
acid chlorides4 and acid anhydrides5 with this reagent
have also been researched. In addition, intramolecular
and intermolecular Barbier-type reactions with
haloalkanes toward the carbonyl group of ketones6 and
imides7 have been reported. In this connection recent
disclosures from this laboratory have demonstrated the
first pinacolic cross-coupling reaction between phthal-
imides and carbonyl compounds and its application to
two types of complete threo-selective reactions; CeCl3-
mediated reduction after dehydration of the coupling
products is the first and the second one is direct Lewis
acid-promoted deoxygenation of the coupling sub-
strates with Et3SiH as shown in Scheme 1.8 Although
significant progress, thus, has been made in advancing
the versatility of samarium(II) compounds, the lack of
studies concerning the reactivity toward simple amides
is surprising except in some special cases.9 This should
be attributed to their low reactivity. Herein we report
our successful efforts for the development of novel
SmI2-mediated tandem reaction of sulfur-substituted
aromatic lactams with carbonyl compounds, leading to
the a-hydroxyalkylated products with erythro-
selectivity.
Initial experiments have been performed on a coupling
reaction promoted by SmI2 between g-hydroxy-,
O
N R
NaBH4
H+
O
O
O
O
N R
OH
CeCl3
R1
R1CHO
SmI2
N R
N R
OH
O
HO
R1
R1
Et3SiH
threo-isomer
•
BF3 OEt2
Scheme 1.
Keywords: SmI2; desulfurization; coupling reaction; lactam.
* Corresponding author. Tel.: +81-53-478-1150; fax: +81-53-478-1150; e-mail: yoda@mat.eng.shizuoka.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02030-5

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H. Yoda et al. / Tetrahedron Letters 42 (2001) 9225–9228
phenylthio-, or phenylsulfonyl-substituted phthalides
or the smaller methyl functions (entries 8–13) together
with a change from the sulfur- to the seleno-substituent
in 2 (entry 6). Although the reason why such unusual
desulfurization and subsequent coupling reactions were
observed in the use of lactams is not clarified at present,
the presence of a nitrogen atom in the substrate has a
decisive role and is indispensable for these reactions.
and iodobutane with a variety of additives such as
6b,10
HMPA, CuCl2, FeCl3, or NiI2
in expectation of
new CꢀC bond formation.11 The reactions, however,
did not proceed under any conditions even in the use of
excess SmI2. Next, we examined the same type of
reactions employing similarly sulfur-substituted N-benz-
yllactams 212 prepared from imides 1 (Table 1) and
iodobutane, which, in turn, changed the results and
unexpectedly gave the desulfurized lactam alone in high
yield (up to 89%) without coupling adducts.
We further found that the use of both aliphatic (entries
1–4 shown in Table 2) and sterically more hindered
aromatic ketones (entries 5 and 6) also underwent fast
reactions (5 min) to afford the corresponding desulfur-
ized coupling products with good to high yields in
With the above desulfurization method in hand, we
researched the tandem reaction followed by CꢀC bond
formation of 2 employing more reactive aldehyde than
haloalkane. The results from our survey are summa-
rized in Table 1. To begin with, treatment of N-benzyl-
phenylthiolactam 2a with heptanal in the presence of 2
equiv. of SmI2 at ambient temperature for 1 h rapidly
provided the desired tandem reaction products 3 but in
low yield (entry 1) due to the formation of the alde-
hyde-self-coupling compounds. The use of excess SmI2
(3 equiv.), however, had a dramatic effect on the rate,
giving 3 in 86% isolated yield within 5 min (entry 3).
The same beneficial results were again obtained in
reaction employing the phenylsulfonyllactam 2b (80%
in entry 4). We were delighted to find that 5 equiv. of
this reagent (entry 5) could effect these reactions in
excellent yield (98%) without byproducts except the
aldehyde-dimerized substances. This procedure is also
applicable for the production of a wide range of a-
hydroxyalkylated lactams through replacement of the
N-benzyl group by the larger diphenylmethyl (entry 7)
Table 2. SmI2-promoteda tandem reactions of lactams 2
with ketonesa
O
O
SmI2
N CH2Ph
OH
N CH2Ph
R1COR2, THF
rt
S(O)nPh
R1
R2
2
4
Entry
n
R1
R2
Yield (%)b
1
2
3
4
5
6
0
2
0
2
0
2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
n-C3H7
n-C3H7
Ph
50
85
71
79
72
85
Ph
a Reactions employed 3 equiv. of SmI2 and ketones, respectively.
b Isolated yield.
Table 1. SmI2-promoted tandem reactions of lactams 2 with aldehydea
O
O
O
O
SmI2
1) NaBH4
2) XH,
N R
N R
N R
OH
N R
+
n-C6H13CHO
OH
O
X
•
THF
cat. BF3 OEt2
n-C6H13
n-C6H13
erythro-3
threo-3
2a: X = SPh
2b: X = SO2Ph
2c: X = SePh
1
m-CPBA
Entry
X
R
SmI2 (equiv.)
Temp. (°C)
Yield (%)b
erythro/threoc
1
2
3
4
5
6
7
8
SPh
SO2Ph
SPh
SO2Ph
SO2Ph
SePh
SPh
SPh
SO2Ph
SPh
SO2Ph
SPh
SO2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CHPh2
CH3
CH3
CH3
CH3
CH3
2.0
2.0
3.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
rt
rt
rt
rt
rt
rt
rt
−20
−20
0
0
rt
22
42
86
80
98
58
39
63
69
71
73
69
90
–
–
83/17
79/21
79/21
–
55/45d
76/24d
68/32d
82/18d
84/16d
92/8d
92/8d
9
10
11
12
13
CH3
rt
a All reactions employed 3.0 equiv. of heptanal.
b Isolated yield.
c Isolated ratio after chromatographic separation unless otherwise indicated and stereochemistry determined according to our preceding report.8
d Determined by 1H NMR.

H. Yoda et al. / Tetrahedron Letters 42 (2001) 9225–9228
9227
contrast to the fact that direct SmI2-promoted reaction
Acknowledgements
of phthalimides with ketones did not provide any
desired coupling adduct.8 This strategy will find conve-
nient usage and proved to be a superior CꢀC bond
formation method accompanying the desulfurization
reaction.
This work was partially supported by a Grant-in-Aid
(No. 13640530) from the Ministry of Education, Sci-
ence, Sports and Culture of Japan.
In addition to the development of novel tandem reac-
tion described here, we investigated the stereochemistry
of these products, since the stereodefined construction
of threo- or erythro-heterocyclic moieties with a
hydroxyl-containing side chain attracts considerable
attention due to their presence in the framework of
natural products.13
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It will particularly be of interest to note that decreasing
the steric bulkiness of the N-substituents as well as
raising the reaction temperature14 up to rt led to an
increase of the erythro-selectivity (from 55:45 to 92:8 as
shown in Table 1) contrary to our previous threo-selec-
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