Efficient iodine catalyzed chemoselective synthesis of aminals - An access to N,N-acetals by the addition of lactams to N-acyl imines

Article abstract of DOI:10.1016/j.tetlet.2013.10.009

A highly efficient protocol has been developed for the synthesis of aminals from γ-butyrolactam and benzaldehyde using iodine as Lewis acid catalyst. The attack of γ-butyrolactam nucleophile to intermediate N-acyliminium ion was more favorable, when aryl

Full text of DOI:10.1016/j.tetlet.2013.10.009

Tetrahedron Letters 54 (2013) 6758–6763
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient iodine catalyzed chemoselective synthesis of aminals—an
access to N,N-acetals by the addition of lactams to N-acyl imines
⇑
Gunasekar Ramachandran, Kulathu I. Sathiyanarayanan
Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient protocol has been developed for the synthesis of aminals from c-butyrolactam and
Received 16 July 2013
Revised 1 October 2013
Accepted 3 October 2013
Available online 10 October 2013
benzaldehyde using iodine as Lewis acid catalyst. The attack of
diate N-acyliminium ion was more favorable, when aryl aldehyde bears the electron donating group
EDG). Iodine plays a key role in these reaction transformations. This current mild protocol is environ-
c-butyrolactam nucleophile to interme-
(
mentally benign and cost-effective method for the synthesis of industrially and pharmaceutically useful
scaffolds.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Iodine
Aminals
N,N-Acetals
N-Acyliminium ion
Table 1
Screening of catalyst and solvent for the condensation reaction of
benzaldehyde
c-butyrolactam and
Aminals, termed as N,N-acetals1a are useful intermediates for
a
the construction of heterocyclic compounds and are also most use-
ful building blocks in numerous organic syntheses. The reactivity
CHO
1
Catalyst
N
O
N
O
and stability of ketene aminals mostly rely on the substitution on
the nitrogen atom with an electron withdrawing group.2 The sta-
bility of the aminals increases if aryl groups are substituted on chi-
ral carbon of aminals. From the literature, it is clearly evident that
there exists a lack of synthetic method for the synthesis of such
N
H
Solvent, rt
O
1
2
4
Entry
Catalyst (mol %)
None
Solvent (ml)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
None
THF
CH CN
3
DMC
n-Butanol
Ethanol
Methanol
IPA
—
FeCl
HgCl
AlCl
ZnCl
SnCl
3
(20)
(20)
(20)
(20)
(20)
69
22
11
56
43
52
91
91
90
81
74
—
67
61
68
45
39
28
22
2
3
2
2
CAN (20)
Iodine (20)
Iodine (15)
Iodine (10)
Iodine (5)
Iodine (3)
Iodine (10)
Iodine (10)
Iodine (10)
Iodine (10)
Iodine (10)
Iodine (10)
Iodine (10)
Iodine (10)
10
11
12
13
14
15
16
17
18
Salinosporamide A (3), B (4)
Lactacystin
Glp-His-Pro-NH2 (TRH)
19
20
Figure 1. Biologically active compound containing c-butyrolactam unit.
a
Reaction conditions:
room temperature (30 °C), time: 4 h.
Isolated yield, DCM-dichloromethane, DMC-dimethyl carbonate, THF-tetrahy-
drofuran, CH CN-acetonitrile, and IPA-isopropyl alcohol.
c-butyrolactam (10 mmol) and benzaldehyde (5 mmol) at
⇑
Corresponding author. Tel./fax: +91 4162243092.
E-mail address: sathiya_kuna@hotmail.com (K.I. Sathiyanarayanan).
b
3
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.009

G. Ramachandran, K. I. Sathiyanarayanan / Tetrahedron Letters 54 (2013) 6758–6763
6759
(
)n
aminals of lactams and their derivatives are found in numerous
parts of biologically active compounds and also in numerous natu-
ral products. To develop a more appropriate synthetic route for
CHO
H
N
3
O
N
5
O
Iodine (10 mol%)
O
N
the synthesis of N-substituted
concern for the synthetic community. In numerous biological
compounds, -butyrolactam ring is implanted as a subunit struc-
ture. In numerous natural products, -butyrolactam (2-pyrrolidi-
c-butyrolactam is a great deal of
(
)n
DCM, rt
(
)n
6
R
2
1
R
4
c
7
c
n = 1, R = H; 4-Me; 2-Me; 2-Br; 2-OMe; 3,4,5-OMe; 4-CN;
4
4
-CHO; 3-CHO; 1-naphthaldehyde; 4-benzyloxy;
-OMe; 2-OEt; 4-Cl; 2-Cl; 4F
none) derivatives such as salinosporamides A–B, lactacystin,
dysibetaine, cinnabaramides etc. are found as shown in Figure 1.8
n = 2, R = H; 4-Cl; 2-Cl
n = 3, R = H; 4-Cl
n = 8, R = H
In recent decades, the use of molecular iodine, Lewis acid, has
attracted considerable attention. It requires only a short reaction
9
time, simple work-up, use of simple precursors to synthesize
complex molecules and it is a moisture-stable mild Lewis acid in
9
Scheme 1. Synthesis of aminals from lactams and aryl aldehyde.
synthetic organic chemistry. Molecular iodine enhances the utility
of its catalytic property in organic synthesis emerging as an effec-
tive Lewis acid catalyst to accomplish several organic transforma-
tions. The utility and the importance of this process have been
3
stable aminals. Synthesis of such stable aminals provides a great
potential in synthetic organic chemistry.3
10
drawing attention in recent organic syntheses.
The most efficient bioactive compounds could be synthesized
using a simple starting material in a single step serving a great
potential in synthetic organic chemistry.4 Five membered ring
11
The aminals exist in equilibrium, and in order to shift the
equilibrium toward product side, a classical method is used by
11a
using various drying agent, like boric anhydride,
potassium
Table 2
Condensation reaction of lactams and aromatic aldehyde using iodine as catalyst leading to the formation of product aminals (4)
Entry
Benzaldehyde
Product
Yielda (%)
CHO
O
N
O
2a
1
90
N
4a
CHO
O
N
O
2b
2
3
83
84
N
4b
CHO
CHO
O
O
N
O
N
N
2
c
4
c
N
O
Br 2d
4
5
6
94
—
Br
4d
CHO
O
N
O
Br
N
Br
CHO
O
O
N
O
2e
N
78
O
4e
O
CHO
O
N
O
O
N
O
7
88
O
2f
O
O
4f
(
continued on next page)

6
760
G. Ramachandran, K. I. Sathiyanarayanan / Tetrahedron Letters 54 (2013) 6758–6763
Table 2 (continued)
Entry
Benzaldehyde
CHO
Product
O
Yielda (%)
O
N
NC
2g
8
9
N
78
NC
4g
CHO
F
O
N
O
—
N
F
CHO
O
O
N
N
N
N
OHC
2h
O
1
0
1
89
O
4
h
CHO
O
O
N
N
1
84
89
O
CHO
2i
N
N
O
4
i
O
CHO
N
O
N
1
2
2j
4j
CHO
O
N
O
O
N
1
3
91
O
2k
4k
CHO
O
N
O
O
O
N
1
1
4
5
86
81
2l
O
O
4l
CHO
O
N
O
N
2m
4
m
CHO
O
N
O
Cl
2n
1
1
6
7
N
78
72
Cl
O
4
n
Cl
O
CHO
N
N
2o
Cl
4o

G. Ramachandran, K. I. Sathiyanarayanan / Tetrahedron Letters 54 (2013) 6758–6763
6761
Table 2 (continued)
Entry
Benzaldehyde
CHO
Product
Yielda (%)
O
N
O
F
2p
18
17
18
19
N
76
88
87
81
F
4
p
O
N
2a
2n
2o
N
O
4
q
O
N
N
O
Cl
4r
O
N
N
Cl
N
O
4s
4
O
2
0
1
2a
2n
72
71
N
O
t
O
N
2
N
O
Cl
O
4u
2
2
2a
N
65
N
O
4v
Reaction conditions: lactams (10 mmol), aryl aldehydes (5 mmol) and iodine (10 mol %) at room temperature (30 °C), time: 4 h.
a
Isolated yield.
carbonate11b or method like azeotropic distillation with benzene11c
to make free from water.
2 2
ZnCl and SnCl in this reaction, and we got unsatisfactory yields.
While the same reaction was carried out using 20 mol % of ceric
ammonium nitrate as catalyst, we got 52% yield. In order to attain
better yield, we used highly active Lewis acid catalyst iodine in this
reaction and we got an excellent yield. Molecular iodine remark-
ably played a significant role in this reaction (Table 1).
Thus, to evaluate the catalyst, molar percentage was used in this
reaction to produce excellent yield. We carried out the same reac-
tion with 3 mol % catalyst and increased it upto 20 mol %. Good
yield was obtained when10 mol % of iodine was used in this reac-
tion, whereas the use of increased quantities of catalyst did not
further improve the yield.
Herein, for the first time, we have developed a simple and effi-
cient synthetic method for the synthesis of stable aminals—such as
0
1
,1 -(phenylmethylene)bis(pyrrolidin-2-one) using iodine as cata-
lyst. Addition of lactams to N-acylimininum ion leads to the forma-
0
12
tion of N,N -acetals. The results obtained in the prior studies
using iodine as catalyst for a domino reaction have encouraged
us to study the reaction further involving iodine as catalyst.
Encouraging results were obtained in these studies, and due to
the lack of a synthetic method for the synthesis of aminals, we
have investigated the optimized reaction condition between
c
-butyrolactam and benzaldehyde to assess the efficiency of the
catalyst under various conditions. Initially, we used numerous
3
Lewis acid metal chloride catalysts such as FeCl , HgCl , AlCl ,
So, we carried out all the reactions with 10 mol % of iodine as
the catalyst. To explore the generality of the reaction in other sys-
tems, we carried out the same reaction condition with a diverse
3
2

6
762
G. Ramachandran, K. I. Sathiyanarayanan / Tetrahedron Letters 54 (2013) 6758–6763
range of aryl aldehyde and lactams. A schematic representation for
1
the formation of aminals is shown in Scheme 1. The obtained re-
sults are summarized in Table 2. The arrangement of atoms of a
N
H
O
compound 4d was further confirmed by the single crystal X-ray
O
H
I2
12b
diffraction analysis as shown in Figure 3.
The scope and the lim-
3
I2
itation of this reaction were also examined. We also tried with var-
ious lactams to check whether the reaction yields aminals and
found that the reaction with other lactams also proceeds smoothly.
When the same reaction was carried out with aliphatic aldehyde,
reaction did not proceed to form product. We tried to prepare
2
N
N
O
N
O
H
O
int1
unsymmetrical aminal derivatives by reacting 1 equiv of
c-lactam,
OH
1
equiv of d-lactam and benzaldehyde, to create a chiral asymmet-
ric carbon in the molecules but we got a mixture of 4a and 4q as
shown in Scheme 2.
4
a
H
N
H+
The substitution in phenyl ring and the orientation of the phe-
nyl ring of benzaldehyde influenced the outcome of the reaction
(Table 2). We carried out the reaction with aryl aldehyde bearing
electron withdrawing (EWG) and electron donating groups
(EDG), but excellent yield was obtained only when EDG on aryl
aldehyde was used.
The initial step of the mechanism was the attack of iodine cat-
alyst on the carbonyl oxygen of aryl aldehyde, and this gave rise to
the formation of intermediate, int1 (1-(hydroxy (phenyl) methyl)
pyrrolidin-2-one). The transformation of intermediate, int1 to
int2 was obtained by the removal of water molecule. Thereby, N-
acyliminium cation (int2) was formed. Nucleophile attack of one
more lactam on the N-acyliminium cation int2 led to the formation
of the desired product (4). The most feasible mechanism for the
formation of product 4 is proposed in Figure 2.
N
O
O
H
H
int2
H O
2
Figure 2. Most feasible mechanism for the formation of product via N-acyliminium
ion.
In summary, we successfully developed an efficient method for
the synthesis of aminals from lactams and aryl aldehyde using io-
dine as an efficient catalyst. Iodine played a remarkable role in this
reaction transformation that provided better yield. Nucleophile at-
tack of lactams on N-acyliminium ion intermediate was more fea-
sible pathway for the formation of aminals. Further increase in the
ring of lactam motifs was also used to raise diversity for preparing
a library of 20 novel derivatives in good yields and high purities
without column chromatography. Thus the present modest proce-
dure affords numerous advantages like simple synthetic method,
excellent yield, convenient work-up and no column
chromatography.
Acknowledgment
The DST-FIST NMR facility at VIT University is greatly
acknowledged.
Figure 3. ORTEP diagram of compound 4d.
O
O
N
N
N
N
O
O
CHO
4
a, 44%
Iodine (10 mol%)
4q, 42%
O
N
H
N
H
O
DCM, rt
O
N
N
*
O
Scheme 2. Synthesis of unsymmetrical aminals bearing chiral asymmetric carbon.

G. Ramachandran, K. I. Sathiyanarayanan / Tetrahedron Letters 54 (2013) 6758–6763
6763
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