One-pot oxidative Mannich-type reaction of lactams with alkyl malonates

Article abstract of DOI:10.1016/j.tetlet.2007.03.025

One-pot substitution of a C-H bond at the position next to the nitrogen atom of lactams with alkyl malonates proceeded effectively by dehydrogenation of lactams with N-tert-butylbenzenesulfinimidoyl chloride, followed by Mannich-type addition of alkyl malonates.

Full text of DOI:10.1016/j.tetlet.2007.03.025

Tetrahedron Letters 48 (2007) 3233–3236
One-pot oxidative Mannich-type reaction of lactams
with alkyl malonates
Jun-ichi Matsuo,* Yumi Tanaki and Hiroyuki Ishibashi*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Received 6 February 2007; revised 3 March 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—One-pot substitution of a C–H bond at the position next to the nitrogen atom of lactams with alkyl malonates proceeded
effectively by dehydrogenation of lactams with N-tert-butylbenzenesulfinimidoyl chloride, followed by Mannich-type addition of
alkyl malonates.
Ó 2007 Elsevier Ltd. All rights reserved.
O
O
A highly substituted lactam moiety is often found in bio-
logically active compounds such as b-lactam antibio-
tics,1 salinosporamide A,2 and lactasystin.3 Formation
of a new carbon–carbon bond onto a lactam ring is a
promising and convenient method for preparing a vari-
ety of lactam derivatives. Direct carbon–carbon bond
formation at the a-position of the carbonyl group of
lactams has been conducted by enolate chemistry. On
the other hand, direct carbon–carbon bond formation
at the a-position of the nitrogen atom of lactams (1 to
2) has remained a challenging subject in organic synthe-
sis since it is difficult to activate the C–H bond of that
position under mild conditions. Oxidation of lactam 1
to cyclic N-acylimine 3 might be considered as one of
the activating methods of the C–H bond. However, it
is known that 3 easily isomerizes to the corresponding
enamides 4,4,5 and some methods for preparation of
the isomerized product 4 such as pyrrolin-2-ones (4a,
n = 1) and dihydro-2-pyridones (4b, n = 2) have been
reported.6 Although cyclic N-acylimines 3 have been
generated at a low temperature from lactams having a
leaving group at the a-position of the nitrogen atom
(e.g., 4-acetoxy-2-azetidinone, 5-acetoxy-2-pyrrolidi-
none and 6-acetoxy-2-piperidinone7) by Lewis acid-
catalysis, preparation of 3 from lactams 1 has not been
reported to date. We have recently developed a mild
and convenient method for oxidation of N-alkyl carb-
NH
H
NH
R
n
n
1
2
O
Cl
S
tBu
N
n
oxidation
R
Ph
N
3
5
H-shift
O
NH
n
4a: n = 1
4b: n = 2
Scheme 1. Carbon–carbon bond formation of 1 to 2 via cyclic N-
acylimine 3.
amates to N-Cbz imines or ketimines using N-tert-butyl-
benzenesulfinimidoyl chloride (5).8,9 We expected that
oxidation of lactam 1 with 5 at a low temperature would
give 3 with minimal isomerization to enamide 4 and that
the thus formed 3 would react with appropriate carbon
nucleophiles to form a new carbon–carbon bond in a
one-pot fashion (Scheme 1). We would like to report
here the one-pot carbon–carbon bond formation at the
a-position of the nitrogen atom of various lactams using
5 and alkyl malonates.
Keywords: Lactam; Oxidation; Mannich-type reaction.
*
Appropriate reaction conditions for oxidative Mannich-
type reaction of lactam were investigated by employing
Corresponding authors. Tel./fax: +81 76 234 4439 (J.M.); e-mail:
jimatsuo@p.kanazawa-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.025

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J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3233–3236
valerolactam (6) and diethyl malonate (Table 1). Lithi-
ated lactam formed by the reaction of 6 and n-BuLi in
THF was treated with 5 at À78 °C followed by the addi-
tion of diethyl malonate and allowing the reaction tem-
perature to rise to room temperature. When diethyl
malonate was reacted for 0.5 h at room temperature,
Mannich product 7 was isolated in 47% yield (entry 1).
Minor improvement in the yield of 7 was observed after
a prolonged reaction time (entry 2), and further
improvement was achieved by employing four equiva-
lents of HMPA as an additive (entry 4).10 An effect of
HMPA was not observed after a short reaction time (en-
tries 1 and 3) but was clearly observed after 6 h (entries 2
and 4). It was assumed that lithiated 6 smoothly reacted
with 5 at À78 °C, and HMPA would accelerate the addi-
tion of diethyl malonate to 3, which was formed during
the rise in reaction temperature from À78 °C to room
temperature. Employment of other bases such as NaH,
NaHMDS, and KHMDS and other additives such as
AcOH and LiCl did not improve the yield of 7.
CO2Et
CO2Et
1)
2)
n-BuLi (1.3 equiv) 3)
Additive
O
O
H
H
N
N
Cl
CO2Et
CO2Et
S
tBu
Ph
N
7
6
5 (1.3 equiv)
THF
Table 1. Effect of HMPA on oxidative Mannich-type reaction of 6 to 7
Entry
Additive (equiv)
Reaction time (h)
Yielda (%)
1
2
3
4
None
None
HMPA (4)
HMPA (4)
0.5
6
0.5
6
47
57
44
71
a Isolated yield.
The scope and limitations of the one-pot oxidative Man-
nich-type reaction of various lactams were next investi-
gated (Table 2). Cyclic N-acylimines generated from
Table 2. One-pot oxidative Mannich reaction of various lactams (6, 8a–e) with malonic acid esters to 9a–ja
Entry
Lactam
Alkyl malonate
CO Et
Product
Yieldb (%)
48c
O
O
2
NH
NH
1
CO Et
2
8a
CO2Et
EtO2C
9a
O
O
Ph
NH
CO Et
2
Ph
NH
CO2Et
2
3
70 (1:1.5)
CO Et
2
CO2Et
8b
9b
O
NH
CO Bn
2
CO2Bn
6
71
CO Bn
2
CO2Bn
9c
O
NH
CO Et
2
CO Et
2
4
5
6
6
Me
58
65
72
CO Et
2
CO Et
2
Me
9d
O
NH
CO Et
2
CO2Et
CO2Et
6
CO Et
2
9e
O
O
8c
NH
CO Et
2
NH
CO2Et
CO Et
2
CO2Et
9f

J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3233–3236
3235
Table 2 (continued)
Entry
Lactam
Alkyl malonate
CO Et
Product
Yieldb (%)
80 (1:1)
O
O
2
7
NH
NH
CO Et
2
CO Et
2
CO Et
t-Bu
2
t-Bu
9g
8d
O
NH
CO Bn
2
CO Bn
8
9
8c
2
80
55
32
CO Bn
2
CO Bn
2
9h
O
NH
CO Et
2
CO Et
8c
Me
2
CO Et
2
CO Et
2
Me
9i
O
O
NH
CO Et
2
NH
CO2Et
10
CO Et
2
CO2Et
8e
9j
a For reaction conditions, see a typical experimental procedure in the text.
b Isolated yield unless otherwise noted. Ratios in parentheses are diastereomeric ratios of the products.
c Determined by 1H NMR analysis.
O
O
O
Pd(OH) /C (cat.)
2
o
H
2
(1 atm)
150
C
NH
NH
NH
CO Bn
CO H
CO H
2
2
2
MeOH
rt,
99%
93%
CO Bn
CO H
2
2
11
10
9h
Scheme 2. Deprotection of Mannich product 9h.
six- and seven-membered lactams reacted with diethyl
malonate to give the corresponding Mannich adducts
in good to high yields (entries 2, 6, and 7), while five-
and eight-membered lactams gave adducts in lower
yields (entries 1 and 10). A substituent on a lactam ring
did not affect the efficiency of the present oxidative
Mannich-type reaction (entries 2 and 7). In addition to
diethyl malonate, the desired carbon–carbon bond was
formed by using dibenzyl malonate, diethyl methylmal-
onate, and diethyl allylmalonate (entries 3, 4, 5, 8, and
9). Deprotection of the benzyl group of Mannich adduct
9h gave diacid 10, and decarboxylation of 10 gave 11 in
93% yield (Scheme 2).
tion was stirred for 15 min. A solution of 5 (247 mg,
1.15 mmol) in THF (1 mL) was added at À78 °C, and
the mixture was stirred for 30 min. Then dibenzyl
malonate (0.29 mL, 1.16 mmol) was added at À78 °C,
and the mixture was stirred at room temperature
for 6 h. Usual workup and purification by column
chromatography on silica gel afforded 9h (281 mg,
0.71 mmol, 80%).
In summary, alkyl malonates reacted with labile cyclic
N-acylimines, which were generated by oxidation of five-
to eight-membered lactams (6 and 8) with 5 under mild
conditions, to afford the corresponding Mannich ad-
ducts in a one-pot manner. This unique oxidative Man-
nich-type reaction enables regioselective introduction of
a variety of carbon–carbon bonds after the construction
of a lactam ring and will contribute to the development
of a strategy for synthesizing various nitrogen-contain-
ing compounds.
A typical experimental procedure (Table 2, entry 8) is
as follows: To a mixture of 8c (100 mg, 0.89 mmol)
and HMPA (0.62 mL, 3.56 mmol) in THF (3 mL) was
added
a solution of n-BuLi (1.58 N in hexane,
0.73 mL, 1.15 mmol) at À78 °C and the resulting solu-

3236
J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3233–3236
ꢀ
3. (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.;
Acknowledgments
Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991,
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44, 113–116; (b) Omura, S.; Fujimoto, T.; Otoguro, K.;
The authors are grateful for the financial support from
Takeda Science Foundation, and this work was partially
supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology of Japan.
Matsuzaki, K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J.
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Supplementary data
Supplementary data including spectral data of the
products (7, 9a–j, and 11) and experimental procedures
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.03.025.
References and notes
8. Review: (a) Matsuo, J. J. Synth. Org. Chem. Jpn. 2004, 62,
574–583; (b) Mukaiyama, T. Angew. Chem., Int. Ed. 2004,
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9. (a) Matsuo, J.; Tanaki, Y.; Kido, A.; Ishibashi, H. Chem.
Commun. 2006, 2896–2898; (b) Matsuo, J.; Tanaki, Y.;
Kido, A.; Ishibashi, H. Org. Lett. 2006, 8, 4371–4374.
10. Addition of ten equiv of HMPA gave the same result as
that obtained by using 4 equiv of HMPA.
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