Parikh-Doering oxidation-dehydration-Ugi cyclization cascade in the development of lactams from formidoalkanols (3>chain length>7)

Article abstract of DOI:10.1016/j.tet.2011.10.050

De novo incorporation of N-formylated aminols as strategic substrates in legendary Ugi cyclization. Lactamization of N-formido alkanols is accomplished by a novel Parikh-Doering oxidation-dehydration-Ugi cyclization cascade leading to the formation of lac

Full text of DOI:10.1016/j.tet.2011.10.050

Tetrahedron 68 (2012) 294e299
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
ParikheDoering oxidationedehydrationeUgi cyclization cascade
in the development of lactams from formidoalkanols (3>chain length>7)
*
Imran A. Khan, Anil K. Saxena
Division of Medicinal and Process Chemistry Division, Central Drug Research Institute (CDRI), CSIR, Chattar Manzil Palace, MG Road, Lucknow 226001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2011
Received in revised form 10 October 2011
Accepted 13 October 2011
Available online 31 October 2011
De novo incorporation of N-formylated aminols as strategic substrates in legendary Ugi cyclization. Lac-
tamization of N-formido alkanols is accomplished by a novel ParikheDoering oxidationedehydrationeUgi
cyclization cascade leading to the formation of lactams up to eight carbons (ring size; n¼1e4) in moderate
yields using formidoaminol, substituted aniline, and aliphatic/aromatic carboxylic acid derivatives as
starting materials.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
ParikheDoering Oxidation
Swern Oxidation
Dehydration
Ugi cyclization
Lactam
1. Introduction
support. None of the reported method for synthesis of such lac-
tams, neither involved multisequential-one pot transformation nor
The essential research theme in modern organic synthesis is
rapid generation of molecular complexity and diversity from simple
the generation of isonitrile and aldehyde functionalities on same
substrate for Ugi cyclization. These lactams possesses the carbon
atom of isonitrile group within the ring thus get constructed, by the
strategic exploitation of Ugi reaction are crucial and constitutes in
the various biologically important scaffolds.12,13
and readily accessible starting materials. Indeed,
a multi-
component reaction combining three or more reactants together
in a single ordered event,1e3 offers not only great molecular com-
plexity and diversity but also the possibility of introducing matched
functionalities suitable for further transformations. A range of re-
actions including condensation,4 ring-closure metathesis,5 cyclo-
addition,6 macrolactonization,7 and intramolecular SNAr reaction,8
etc. have been harnessed along with an isonitrile-based multi-
component reaction (MCR) for the construction of cyclic scaffolds.
Ugi-MCR indeed has gained attentions of organic chemists for its
potential to fulfill the above noted research theme and has been
explicitly exploited to develop chemical libraries. The bifunctional
substrates as starting material have been explored to architect even
2. Results and discussion
In view of above it appeared of interest to explore the scope of
N-formido derivative of higher aminols (chain length ꢀ3) under Ugi
reaction condition to provide cyclization. The perplexity of condi-
tions for sequential oxidationedehydration of N-formidopropanol
to generate a reactive intermediate comprising aldehyde and iso-
cyanide groups at their respective termini was sorted out by
employing ParikheDoering oxidation14 at OH terminal and sub-
sequent dehydration using POCl3 at N-formyl terminal. The func-
tional group inter-conversion from eOH to CHO and eNHCHO to
eNC was confirmed by the observed IR absorption frequencies
1718 cmꢁ1 and 2121 cmꢁ1 for the aldehyde and isonitrile groups,
respectively. These reactive pre-Ugi intermediates with four, five,
six, and seven carbon atoms having eCHO and eNC were employed
for 3CC-Ugi (3-component condensation Ugi) reaction using vari-
ous anilines and aromatic/aliphatic carboxylic acids to yield the
desired respective lactams. This novel methodology involved the
utilization of Ugi condensation of N-formido alkanols as dual
more complex scaffolds. Several groups have used
b-amino acids in
the Ugi reaction to prepare
b
-lactams.9 This approach relies on acyl
transfer in the Mumm’s rearrangement to form the four-membered
ring. Zhang et al.10 have combined aldehydes with carboxylic acids
and used the Ugi reaction to create lactams of various sizes. Short
and Mjalli11 have prepared
g-lactams from keto-acids on solid-
* Corresponding author. Tel.: þ91 522 2612411-18x4268/2624273; fax: þ91 522
2623405/2623938; e-mail addresses: anilsak@gmail.com, ak_saxena@cdri.res.in
(A.K. Saxena).
masked substrate to obtain g-lactams, d-lactams, and caprolactam
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.050

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 294e299
295
Table 1
derivatives from the corresponding three, four, and five-carbon
aminols through ODU (oxidationedehydrationeUgi) cyclization
cascade (Scheme 1).
Conditions used in the optimization of ODU cascade for the preparation of N-(2-
oxopyrrolidin-3-yl)-N-phenylbenzamide
Condition Oxidizing reagents
Dehydrating reagents Yield (%)a
A
B
C
D
E
DMSO/(COCl)2/TEA (1.5:3:6.5) POCl3/TEA (1:4) 16
Py$SO3/DMSO/Py (2:1.5:2)
POCl3/py (1:3.5)
68
32
54
62
DMSO/(COCl)2/TEA (1.5:3:6.5) TsCl/TEA (1:2)
Py$SO3/DMSO/Py (2:1.5:2)
Py$SO3/DMSO/Py (2:1.5:2)
TsCl/py (1:2)
,c
POCl3/KOtBu (1:1.5)b
a
Isolated yields.
b
The condition was employed in the case of aliphatic amines (8gek) to minimize
the amine exchange reaction thus causes to the formation of desired products
(12qeu).
c
These conditions were also used in the case of arylamine but not such increase in
terms of yields were obtained.
time. The observed lower yields in the case of aliphatic amine when
conditions (AeD) were employed due to the amine exchange re-
action which decreases the residence time of the amines required
for the in situ formation of Schiff base crucial for the initiation of
the cascade, when tertiary amine were employed as base in the
dehydration step the similar kind of transfer reaction are found
prominent even when pyridine were employed resulted in the
lower yield. Keeping these fact in mind we anticipated that sodium
alkoxides can be a better substitute than the tertiary amines as
there would not be any scope for the amine exchange. Therefore,
potassium tert-butoxides (KOtBu) was used followed by the addi-
tion of Phosphorus Oxychloride (POCl3) resulted to the formation of
isocyanoaldehydes, which was neutralized and added respective
aliphatic amines and carboxylic acid in equimolar amounts gave the
desired lactams (12qeu) in moderate yields. The structure of the
synthesized lactams was confirmed via NMR spectroscopy. In the
case of N-(2-oxopyrrolidin-3-yl)-N-p-tolylbenzamide (12a) a triplet
centered at 4.67 ppm with coupling constant of 8.8 Hz for the
Scheme 1. Representation of ParikheDoering oxidationedehydrationeUgi cyclization
cascade to the formation of a-amido lactams.
Optimization of the three reactions (oxidation, dehydration, and
condensation), two reagents, one oxidizing agent (oxalyl chloride/
DMSO) typical Swern condition15 or Py$SO3/DMSO/pyridine mod-
ified Swern condition14 and other dehydrating agent (POCl3/Py or
TsCl/TEA) and three substrates (N-formidoalkanols, anilines, and
carboxylic acids) was performed using simple aniline, benzoic acid,
and N-formidopronanol. Since the Ugi reaction is either reported in
neutral conditions or in the presence of acidic catalyst. So these
conditions cannot be applied in the present dehydration step
where the dehydrating conditions are basic in nature. Hence the
ratio of the base was especially monitored in the oxida-
tionedehydration step and the Ugi condensation was performed in
situ, with quick neutralization by 1 N hydrochloric acid solution at
Table 2
Yields and time of ODU cyclization reaction cascade with various amines and
carboxylic acids
0
ꢂC relayed with addition of aniline and benzoic acid. The best
Yielda (%)
Timeb (h)
results were obtained under ParikheDoering condition. In both the
cases (i.e., using TsCl or POCl3 as dehydrating agent), the isolated
yields were better than those obtained in the typical Swern oxi-
dation condition as illustrated in Table 1.
Aminols
Reactants
Product
1a
8b
8b
8a
8b
8c
8c
8d
8e
10a
10b
10b
10c
10c
10d
10e
10e
12a
12b
12c
12d
12e
12f
68
62
71
78
62
60
65
75
8.5
12
26
18
20.5
28
The typical Swern oxidation protocol with POCl3/TEA and tosyl
chloride/TEA (condition A and C, Table 1) as dehydrating agent
resulted in low yields (16% and 32%, respectively) in comparison to
the results obtained with modified version of classical Swern oxi-
dation (condition B and D). The moderate yields were obtained due
to the amine exchange reaction16 with the salts of organic bases
present in the reaction mixture. The rate of amine exchange re-
action was slower in the case of anilines than aliphatic amines and
therefore poor or no product was obtained with aliphatic amine.
The yield of the reaction did not depend only on 3CC-Ugi step but
also showed significant dependence on the ring size, which had
effect on the acceleration of movement of Mumm’s rearrangement17
in forward direction.
The optimized methodology was employed with other anilines
and carboxylic acid derivatives to obtain the desired lactams
(Table 2, 12aeh). This methodology was expanded to sculpate six,
seven, and eight membered lactams from N-formidobutanol, N-
fomidopentanol, and N-formidohexanols, respectively, which are
described in Table 2 (12ieu) along with the yields and reaction
12g
12h
26
30
1b
8a
8b
8b
10a
10f
10b
12i
12j
12k
76
78
62
25
28
36
1c
8b
8b
10a
10e
12l
12m
48
51
20
16
1d
8a
8a
8f
8g
8h
8i
10f
10f
10f
10f
10f
10f
10f
10f
12n
12o
12p
12q
12r
12s
12t
12u
54
50
48
36
42
36
51
38
32
25
30
48
42
36
25
50
8j
8k
a
Isolated yields.
b
Time (in h) required for the optimum completion of the reaction as per TLC
(Silica gel 60 F254).

296
I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 294e299
having potential of providing eight membered lactams and thus
may be considered as a powerful technique for Lactamization
which can be further explored for synthesizing new bioactive
entities including natural product containing
as core.
a-amido lactams
4. Experimental
4.1. General method
Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without purification.
Dichloromethane was distilled under nitrogen. Dimethylsulfoxide
was used without distillation. All reactions were carried out under
an atmosphere of dry nitrogen. Solutions were evaporated under
reduced pressure with a rotary evaporator and the residue was
purified by silica gel flash chromatography using an ethyl acetate/
hexane mixture as the eluent unless specified otherwise. NMR
spectra were recorded on 300 MHz spectrometers. Chemical shifts
were reported in parts per million relative to the residual solvent
peak (7.26 ppm for CHCl3) for H spectra and (77.0 ppm for CDCl3)
for 13C spectra. High Resolution Mass spectroscopy data in elec-
tronic impact were recorded with a resolution of 5000 RP at 5%.
Electronic impact (EI) and chemical ionization (CI) mass spectros-
copies were recorded on a HP5989B device. Infrared spectra were
recorded on an FT IR spectrometer in neat for all compounds.
4.2. General procedure
The N-formylation of the amino was accomplished by refluxing
the respective aminols in ethylformate (used as solvent and re-
agent) in quantitative yields.19
Condition B for 12a-p: (i) Py-SO3 (2.0 mmol), DMSO (1.5 mmol), Py (2.0
mmol), 1.5 h, 0o-10oC; (ii) POCl3 (1.3 mmol), Py (3.5 mmol), 2.5h, -10oC-
50oC; (iii) HCl (neutralization) at 0oC, RNH2 (1.0mmol), RCOOH(1.0 mmol);
Condition E for 12q-u: (i) Py-SO3 (2.0 mmol), DMSO (1.5 mmol), Py (2.0
mmol), 1.5 h, 0o-10oC;(ii) POCl3 (1.3 mmol), KOtBu (3.0 mmol), 2.5h, -30oC-
60oC in MeOH; (iii) HCl (neutralization) at 0oC, RNH2 (1.0mmol), RCOOH
(1.0 mmol).
Condition A: (Oxidation step) In a 50 ml RB flask, flushed with
nitrogen 10 ml dried DCM was taken and added freshly distilled
oxalyl chloride (3.0 mmol) cooled the reaction mixture to ꢁ60 ꢂC
using liquid nitrogen/ethanol bath followed by the addition of dried
DMSO (1.5 mmol) after 15e30 min of stirring. A solution of for-
midoalkanol (1.0 mmol) dissolved in DCM was added dropwise to
the Swern reagent via syringe. After 30 min of stirring 6.5 mmol of
TEA was added and allowed the reaction to attain room tempera-
ture. (Reduction step) The mixture obtained was again cooled to
ꢁ30 ꢂC and POCl3 (1.2 mmol) was added gradually and allowed the
reaction mixture to stir at 0 ꢂC for 10e30 min and warmed up to
50 ꢂC, after 1.0e1.5 h of stirring the reaction mixture was cautiously
neutralized with the dil HCl solution (if necessary, pH¼6.6). To this
slightly acidic reaction mixture added amine (1.0 mmol) and
RCOOH (1.0 mmol) controlled the reaction by TLC. After the opti-
mum completion of the reaction, solvent was evaporated and pu-
rified by flash chromatography (eluent 10:90; EtOAc/hexane).
Condition B: (Oxidation step) In a dried 25 ml RB, Py/SO3 complex
(2.1 mmol) was taken and diluted with 5 ml DCM, followed by the
addition DMSO (1.5 mmol) and pyridine (2.0 mmol) after 15 min,
formidoalkanols dissolved in DCM was added dropwise to the
stirring mixture. (Reduction step) After 1.5 h, 3.5 mmol, pyridine
was added to the reaction mixture followed by the addition of
phosphorus oxychloride solution (1.3 mmol) after approx. 2.0 h the
neutralization was accomplished and followed by the same process
(as in condition A).
proton at
a
-amido center, protons at
b
-carbon showed a multiplet
carbon got split into
centered at 2.48 ppm, whereas the protons at
d
a double triplet at 3.95 ppm with coupling constant of 6.6 and
1.5 Hz due to the neighboring CH and CH2 centers. In a general
observation the ODU cyclization cascade crops lower amount of
medium sized lactams (seven and eight membered; 12leu) than in
comparison with lower sized ring (five and six membered; 12aek),
the possible explanation points at stereoelectronic preference of
the nucleophile, i.e., isocyano terminal to approach nearly planar to
the plane of imine (9) (exo trig cyclization), which is more prefer-
entially possible in the case smaller ring (Baldwin Rule18) and
decreases as the size of the ring increases. The optimized reaction
conditions were not analyzed for the case of higher for-
midoalkanols (larger than 7-amino heptanol) and substituted de-
rivatives of formidoalkanols but on the basis of the results thus
obtained for the reported examples we can assure the similar
results.
Condition C: (Oxidation step) Same as in condition A. (Reduction
step) As the obtained mixture was not sufficiently basic therefore to
the obtained reaction mixture tosyl chloride (3.0 equiv) was added
three lots at ꢁ20 ꢂC at an interval of 10 min and was allowed to stir
for 2e3 h, followed by the addition of 2.0 mmol of TEA thence made
the reaction mixture to reach room temperature in approximately
30e40 min. After the completion of the dehydration step the pH of
the reaction mixture was maintained to w6.5 by neutralization
3. Conclusions
In conclusion we have found a novel method of employ-
ing aminols with carbon chain length ꢃ3 more for the prepara-
tion of the respective lactams with ring size nþ2. Using the
above mentioned method we have developed a single pot oxi-
dationedehydrationeUgi condensation cascade of reaction

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 294e299
297
with dil HCl. Then the corresponding amine and carboxylic acid
was added. After the completion of the reaction, the solution was
evaporated under vacuo and the crude product was purified by
using flash chromatography.
Condition D: (Oxidation step) Same as in condition B. (Reduction
step) Same as in condition C.
Condition E: (Oxidation step) Same as in condition A where po-
tassium tert-butoxide (3.5 mmol) was used instead of TEA at
ꢁ10 ꢂC. (Reduction step) Same as in condition C.
purified using column chromatography (5% EtOAc/hexane) to give
the title compound 12e (54.0 mg, 62%) as a yellow oil; Rf (10%
EtOAc/hexane) 0.36; IR (neat) cmꢁ1 3506.2, 3333.5, 1705, 1667,
1484.2, 1239.1, 875; 1H NMR (300 MHz, CDCl3)
d
8.27 (2H, d, J¼7.5,
ArH), 7.72e6.91 (7H, m, ArH), 6.19 (1H, s, NH), 4.58 (1H, t, J¼8.8,
CH), 4.35e3.71 (3H, m, ArCH2, CHH), 3.63e3.02 (1H, dt, J¼6.4, 6.5,
CHH), 2.84e1.62 (2H, m, 174.52,
CH2); 13C NMR (75 MHz, CDCl3)
a
b
d
171.68, 148.37, 143.24, 134.56, 129.40, 128.21, 125.48, 124.29, 48.45,
43.12, 40.07, 32.29; ESI-MS (MþH) 340.1 m/z and HRMS calcd mass
for C18H17N3O4 339.1219 found 339.1234.
4.2.1. N-(2-Oxopyrrolidin-3-yl)-N-p-tolylbenzamide
(12a). The
crude product obtained using condition A is purified using column
chromatography (5% EtOAc/hexane) to give the title compound 12a
(44.0 mg, 68%) as a yellow oil; Rf (10% EtOAc/hexane) 0.44; IR (neat)
cmꢁ1 3507, 3335, 1705, 1687, 1475, 1233; 1H NMR (300 MHz, CDCl3)
4.2.6. 2-(2-Methoxyphenyl)-N-(4-nitrophenyl)-N-(2-oxopyrrolidin-
3-yl)acetamide (12f). The crude product obtained using condition
A is purified using column chromatography (5% EtOAc/hexane) to
give the title compound 12f (71.0 mg, 60%) as a yellow oil; Rf (10%
EtOAc/hexane) 0.44; IR (neat) cmꢁ1 3507, 3325, 1705, 1687, 1634,
d
8.05e7.62 (2H, m, ArH), 7.44 (3H, dt, J¼4.3, 2.0, ArH), 7.19 (5H, d,
J¼7.5, ArH), 6.30 (1H, s, NH), 4.67 (1H, t, J¼8.8, CH), 3.95 (2H, td,
J¼6.6, 1.5,NHCH2), 3.10e1.86 (5H, m,
CH2, ArCH3). 13C NMR
(75 MHz, CDCl3) 174.52, 170.80, 137.58, 135.48, 134.71, 130.99,
a
1468, 1234, 875; 1H NMR (300 MHz, CDCl3)
d
8.23 (1H, d, J¼7.5,
ArH), 7.56e7.20 (4H, m, ArH), 7.19e6.66 (3H, m, ArH), 6.21 (1H, s,
NH), 4.65 (1H, t, J¼8.8, CH), 4.33e3.90 (1H, m, NHCHH), 3.85 (2H,
s, CH2), 3.78 (3H, s, OCH3), 3.61e3.05 (1H, dt, J¼6.4, 6.5, NHCHH),
2.75e1.72 (2H, m, 174.52,
CH2); 13C NMR (75 MHz, CDCl3)
b
d
a
129.95, 128.57, 124.67, 47.96, 40.07, 32.29, 21.12; 875; ESI-MS
(MþH) 295.1 m/z and HRMS calcd mass for C18H18N2O2 294.1368
found 294.1394.
b
d
171.49, 153.47, 148.37, 143.24, 130.17, 129.89, 126.28, 125.48, 124.29,
123.41, 113.05, 56.78, 48.45, 40.07, 36.91, 32.29; ESI-MS (MþH)
370.1 m/z and HRMS calcd mass for C19H19N3O5 369.1324 found
369.1301.
4.2.2. 2-Methoxy-N-(2-oxopyrrolidin-3-yl)-N-p-tolylbenzamide
(12b). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12b (64.0 mg, 62%) as a yellow oil; Rf (10% EtOAc/hex-
ane) 0.47; IR (neat) cmꢁ1 3510, 3323,1711,1683,1468.5,1232.6, 875;
4.2.7. 2-(Biphenyl-4-yl)-N-(4-chloro-3-fluorophenyl)-N-(2-
oxopyrrolidin-3-yl) acetamide (12g). The crude product obtained
using condition A is purified using column chromatography (5%
EtOAc/hexane) to give the title compound 12g (72.0 mg, 65%) as
a yellow oil; Rf (10% EtOAc/hexane) 0.45; IR (neat) cmꢁ1 3511, 3325,
1H NMR (300 MHz, CDCl3)
d
7.89 (2H, dd, J 6.9, 1.8, ArH), 7.47 (2H,
ddd, J¼6.9, 5.9, 2.1, ArH), 7.25e6.91 (4H, m, ArH), 6.21 (1H, s, NH),
4.71 (1H, t, J¼5.6, CH), 3.81 (3H, s, OCH3), 3.60e3.24 (2H, td, J¼6.8,
4.4, NHCH2), 2.92e1.86 (5H, m, ArCH3,
CH2); 13C NMR (75 MHz,
CDCl3) 174.52, 167.31, 156.86, 137.58, 134.71, 132.47, 131.06, 129.95,
a
b
1705,1657,1468.5,1230, 875; 1H NMR (300 MHz, CDCl3)
d
7.90e7.11
(10H, m, ArH), 6.83 (2H, ddd, J¼7.6, 5.2, 1.4, ArH), 6.22 (1H, s, NH),
4.57 (1H, t, J¼8.8, CH), 4.07 (1H, dt, J¼12.4, 6.8, NHCHH), 3.75 (2H,
s, BiphenylCH2), 3.63e2.99 (1H, m, NHCHH), 2.82e1.56 (2H, m,
CH2); 13C NMR (75 MHz, CDCl3)
174.52, 171.68, 169.50, 152.04,
d
125.45, 124.67, 120.70, 113.66, 56.78, 47.96, 40.07, 32.29, 21.12; ESI-
MS (MþH) 325.2 m/z and HRMS calcd mass for C19H20N2O3
324.1473 found 324.1452.
a
b
d
140.41, 139.08, 138.61, 138.21, 136.82, 131.98, 131.52, 129.17, 128.91,
128.69, 128.33,127.29, 123.76, 123.50, 122.30, 120.50,110.30, 108.50,
48.45, 43.12, 40.07, 32.29; ESI-MS (MþH) 423.5 m/z and; HRMS
calcd mass for C24H20ClFN2O2 422.8792 found 422.8783.
4.2.3. 2-Methoxy-N-(2-oxopyrrolidin-3-yl)-N-phenylbenzamide
(12c). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12c (44.0 mg, 71%) as a yellow oil; Rf (10% EtOAc/
hexane)
0.38;
IR
(neat)
cmꢁ1 3501,
3294, 1700,
7.97e7.66 (1H,
4.2.8. 2-(Biphenyl-4-yl)-N-(3-fluorophenyl)-N-(2-oxopyrrolidin-3-
yl)-acetamide (12h). The crude product obtained using condition
A is purified using column chromatography (5% EtOAc/hexane) to
give the title compound 12h (84.0 mg, 75%) as a yellow oil; Rf (10%
EtOAc/hexane) 0.44; IR (neat) cmꢁ1 1694, 1654, 1476, 1302, 1226,
1664,1455,1213,875; 1H NMR (300 MHz, CDCl3)
d
m, ArH), 7.66e6.89 (8H, m, ArH), 6.34 (1H, s, NH), 4.58 (1H, t,
J¼8.7, CH), 4.33e3.68 (4H, m, NHCHH, OCH3), 3.66e3.07 (1H, dt,
J¼6.6, 6.5, NHCHH), 2.90e1.71 (2H, m,
CH2); 13C NMR (75 MHz,
CDCl3) 174.52, 167.31, 156.86, 139.31, 132.47, 131.06, 129.01,
a
b
d
875; 1H NMR (300 MHz, CDCl3)
d
7.95e7.10 (10H, m, ArH), 6.82
(3H, dddd, J¼13.5, 7.1, 3.2, 1.6, ArH), 6.12 (1H, s, NH), 4.78 (1H, t,
J¼8.8, CH), 4.07 (1H, dd, J¼12.4, 6.5, NHCHH), 3.83 (2H, s,
BiphenylCH2), 3.34 (1H, dt, J¼12.4, 6.4, NHCHH), 2.77e1.59 (2H,
m, 174.52, 172.43, 171.68,
CH2); 13C NMR (75 MHz, CDCl3)
127.31, 126.44, 125.45, 120.70, 113.66, 56.78, 47.96, 40.07, 32.29;
ESI-MS (MþH) 311.2 m/z and HRMS calcd mass for C18H18N2O3
310.1317 found 310.1325.
a
b
d
4.2.4. N-(2-Oxopyrrolidin-3-yl)-2-phenyl-N-(p-tolyl)acetamide
(12d). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12d (42.0 mg, 78%) as a yellow oil; Rf (10% EtOAc/hex-
ane) 0.48; IR (neat) cmꢁ1 3507, 3325, 1715, 1681, 1469, 1240, 875;
154.96, 140.41, 139.08, 138.61, 138.21, 136.82, 130.52, 130.05,
129.17, 128.91, 128.69, 128.33, 127.29, 124.32, 124.06, 115.35,
114.36, 113.55, 112.56, 48.45, 43.12, 40.07, 32.29; ESI-MS (MþH)
389.1 m/z and HRMS calcd mass for C24H21FN2O2 388.4341 found
388.4334.
1H NMR (300 MHz, CDCl3)
J¼7.6, ArH), 6.72 (1H, s, NH), 4.72 (1H, t, J¼8.8,
(4H, m, OCH3, NHCH2), 2.82e1.64 (5H, m,
CH2, ArCH3). 13C NMR
(75 MHz, CDCl3) 174.52, 171.68, 137.70, 135.97, 134.56, 130.07,
d
7.69e7.06 (8H, m, ArH), 6.90 (1H, d,
CH), 4.24e3.49
a
4.2.9. N-(2-Oxopiperidin-3-yl)-N-phenylbenzamide (12i). The crude
product obtained using condition A is purified using column
chromatography (5% EtOAc/hexane) to give the title compound 12i
(44.0 mg, 76%) as a yellow oil; Rf (10% EtOAc/hexane) 0.38; IR (neat)
cmꢁ1 3507,3335,1705, 1687, 1475, 1233, 875; 1H NMR (300 MHz,
b
d
129.40, 128.21, 124.25, 48.45, 43.12, 40.07, 32.29, 21.12; ESI-MS
(MþH) 309.6 m/z and HRMS calcd mass for C18H20N2O2 308.1524
found 308.1543.
CDCl3)
NH), 4.44 (1H, t, J¼7.9,
(4H, m,
CH2CH2); 13C NMR (75 MHz, CDCl3)
139.31, 135.48, 130.99, 129.01, 128.57, 127.31, 126.44, 51.80, 40.81,
d
8.01e7.66 (2H, m, ArH), 7.60e6.93 (8H, m, ArH), 6.36 (1H, s,
CH), 3.24 (2H, t, J¼5.2, NHCH2), 2.90e1.49
170.89, 170.44,
a
4.2.5. N-(4-Nitrophenyl)-N-(2-oxopyrrolidin-3-yl)-2-phenylaceta-
mide (12e). The crude product obtained using condition A is
b
d

298
I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 294e299
24.42, 23.99; ESI-MS (MþH) 295.1 m/z and HRMS calcd mass for
129.01, 128.57, 128.57, 127.31, 126.44, 49.72, 41.51, 30.75, 28.64,
26.32, 25.80; HRMS calcd mass for C20H22N2O2 322.1681 found
322.1673.
C18H18N2O2 294.1368 found 294.1394.
4.2.10. 4-Nitro-N-(2-oxopiperidin-3-yl)-N-p-tolylbenzamide
(12j). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12j (97.0 mg, 78%) as a yellow oil; Rf (10% EtOAc/hexane)
0.35; IR (neat) cmꢁ1 3507, 3335, 1705, 1687, 1475, 1233, 875; 1H
4.2.15. 4-Nitro-N-(2-oxoazocan-3-yl)-N-phenylbenzamide
(12o). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the
title compound 12o (56.0 mg, 50%) as a yellow oil; Rf (10%
EtOAc/hexane) 0.30; IR (neat) cmꢁ1 3507, 3335, 1687, 1648,
NMR (300 MHz, CDCl3)
ArH), 7.48e6.92 (4H, m, ArH), 6.31 (1H, s, NH), 4.76e4.13 (1H, m,
CH), 3.48e3.02 (2H, m, NHCH2), 2.92e1.50 (7H, m, CH2CH2,
ArCH3); 13C NMR (75 MHz, CDCl3)
170.89, 170.44, 148.54, 140.12,
d
8.33 (2H, d, J¼7.6, ArH), 8.11 (2H, d, J¼7.6,
14,735, 1236, 873; 1H NMR (300 MHz, CDCl3)
d
8.45e8.24 (2H,
m, ArH), 8.24e8.04 (2H, m, ArH), 7.70e6.66 (5H, m, ArH), 6.17
(1H, s, NH), 4.44 (1H, t, J¼4.6, CH), 3.45 (2H, dd, J¼7.9, 3.9,
NHCH2), 2.54e1.25 (8H, m, 4CH2); 13C NMR (75 MHz, CDCl3)
171.53, 170.89, 148.54, 140.12, 139.31, 129.01, 127.31, 126.44,
a
b
d
a
137.58, 134.71, 129.95, 129.01, 124.67, 123.99, 51.80, 40.81, 24.42,
23.99, 21.12; ESI-MS (MþH) 354.2 m/z and HRMS calcd mass for
C19H19N3O4 353.1375 found 353.1364.
d
123.99, 49.72, 41.51, 30.75, 28.64, 26.32, 25.80; ESI-MS (MþH)
368.6 m/z and HRMS calcd mass for C20H21N3O4 367.1532 found
367.1524.
4.2.11. 2-Methoxy-N-(2-oxopiperidin-3-yl)-N-p-tolylbenzamide
(12k). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12k (41.0 mg, 62%) as a dark yellow oil; Rf (15% EtOAc/
hexane) 0.40; IR (neat) cmꢁ1 3527, 3313,1687,1641,1374,1232, 875;
4.2.16. N-(4-Methoxyphenyl)-4-nitro-N-(2-oxoazocan-3-yl)benza-
mide (12p). The crude product obtained using condition A is pu-
rified using column chromatography (5% EtOAc/hexane) to give the
title compound 12p (43.0 mg, 48%) as a yellow oil; Rf (10% EtOAc/
hexane) 0.32; IR (neat) cmꢁ1 3507, 3335, 1705, 1687, 1475, 1233,
1H NMR (300 MHz, CDCl3)
(7H, m, ArH), 6.19 (1H, s, NH), 4.66e4.20 (1H, m, NCH), 3.83 (3H, s,
OCH3), 3.46e3.02 (2H, m, NHCH2), 2.85e2.14 (4H, m, ArCH3,
NCCHH), 2.10e1.48 (3H, m, NHCH2CHH); 13C NMR (75 MHz, CDCl3)
d
7.87 (1H, dd, J¼6.8, 1.6, ArH), 7.69e6.91
875; 1H NMR (300 MHz, CDCl3)
d
8.34 (2H, d, J¼7.6, ArH), 8.12 (2H,
d, J¼7.6, ArH), 7.29 (2H, t, J¼3.7, ArH), 6.95 (2H, d, J¼7.5,ArH), 6.33
d
170.44, 167.93, 156.86, 137.58, 134.71, 132.47, 131.06, 129.95,
(1H, s, NH), 4.44 (1H, t, J¼4.6,
aCH), 3.81 (3H, s, OCH3), 3.46 (2H, t,
125.45, 124.67, 120.70, 113.66, 56.78, 51.80, 40.81, 24.42, 23.99,
21.12; ESI-MS (MþH) 339.1 m/z and HRMS calcd mass for
C20H22N2O3 338.1630 found 338.1621.
J¼6.0, NHCH2), 2.64e1.17 (8H, m, 4CH2); 13C NMR (75 MHz, CDCl3)
d
171.53, 170.89, 156.85, 148.54, 140.12, 132.19, 129.01, 127.40,
123.99, 114.97, 56.03, 49.72, 41.51, 30.75, 28.64, 26.32, 25.80; ESI-
MS (MþH) 398.4 m/z and HRMS calcd mass for C21H23N3O5
397.1637 found 397.1652.
4.2.12. N-(2-Oxoazepan-3-yl)-N-p-tolylbenzamide (12l). The crude
product obtained using condition A is purified using column
chromatography (5% EtOAc/hexane) to give the title compound 12l
(34.0 mg, 48%) as a yellow oil; Rf (10% EtOAc/hexane) 0.42; IR (neat)
cmꢁ1 3537, 3325, 1667, 1455, 1235, 875; 1H NMR (300 MHz, CDCl3)
4.2.17. N-(4-Methoxybenzyl)-4-nitro-N-(2-oxoazocan-3-yl)benza-
mide (12q). The crude product obtained using condition A is
purified using column chromatography (8% EtOAc/hexane) to
give the title compound 12q (35.0 mg, 36%) as a yellow oil; Rf
(10% EtOAc/hexane) 0.34; IR (neat) cmꢁ1 1677, 1653, 1474, 1234,
d
8.05e7.64 (2H, m, ArH), 7.44 (3H, dt, J¼4.2, 1.9, ArH), 7.34e7.03
(4H, m, ArH), 5.02e4.62 (1H, m,
NHCH2), 3.17 (1H, dt, J¼12.6, 5.4,
a
CH), 4.47 (2H, dd, J¼10.3, 5.0,
b
CHH), 2.87e1.93 (5H, m, ArCH3,
875; 1H NMR (300 MHz, CDCl3)
d
8.38 (2H, d, J¼7.6, ArH), 8.14
(2H, d, J¼7.6, ArH), 7.51e7.11 (2H, m, ArH), 6.92 (2H, d, J¼7.6,
ArH), 6.03 (1H, s, NH), 4.64e4.21 (3H, m, CH, AnisylCH2),
b
CHHCH2), 1.90e0.73 (4H, m, CH2CH2); 13C NMR (75 MHz, CDCl3)
d
170.89, 169.46, 137.58, 135.48, 134.71, 130.99, 129.95, 128.57,
a
124.67, 55.32, 42.43, 30.90, 29.87, 24.32, 21.12; ESI-MS (MþH) 323.1
m/z and HRMS calcd mass for C20H22N2O2 322.1681 found
322.1643.
4.07e3.46 (4H, m, NHCHH, OCH3), 3.18 (1H, dt, J¼12.5, 4.6,
NHCHH), 2.61e1.28 (8H, m, 4CH2); 13C NMR (75 MHz, CDCl3)
d
174.62, 170.61, 159.85, 146.84, 141.05, 129.13, 128.11, 127.36,
123.84, 113.80, 56.03, 52.92, 47.89, 41.51, 29.96, 28.64, 26.32,
25.80; ESI-MS (MþH) 412.1 m/z and HRMS calcd mass for
C22H25N3O5 411.1794 found 411.1773.
4.2.13. 2-(Biphenyl-4-yl)-N-(2-oxoazepan-3-yl)-N-p-tolylacetamide
(12m). The crude product obtained using condition A is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12m (46.0 mg, 51%) as a yellow oil; Rf (10% EtOAc/
hexane) 0.48; IR (neat) cmꢁ1 3507, 3335, 1705, 1687, 1475, 1233,
4.2.18. N-(3,4-Dimethoxyphenethyl)-4-nitro-N-(2-oxoazocan-3yl)
benzamide (12r). The crude product obtained using condition E
is purified using column chromatography (7% EtOAc/hexane) to
give the title compound 12r (47.0 mg, 42%) as a yellow oil; Rf
(14% EtOAc/hexane) 0.37; IR (neat) cmꢁ1 3507, 3347, 1715, 1689,
875; 1H NMR (300 MHz, CDCl3)
(2H, d, J¼7.6, ArH), 4.63e4.26 (2H, m, NH,
BiphenylCH2), 3.19 (2H, t, J¼4.6, NHCH2), 2.93e2.17 (4H, m, ArCH3,
CHH), 2.15e0.95 (5H, m,
CHH, CH2CH2); 13C NMR (75 MHz,
d
7.94e7.08 (11H, m, ArH), 6.93
CH), 3.92 (2H, s,
a
b
b
1468, 1243, 875; 1H NMR (300 MHz, CDCl3)
d
8.36 (2H, d, J¼7.6,
ArH), 8.09 (2H, d, J¼7.6, ArH), 6.89 (3H, s, ArH), 5.98 (1H, s, NH),
5.07e4.61 (1H, m,
CDCl3) precluded due to lesser concentration; ESI-MS (MþH) 413.2
m/z and HRMS calcd mass for C27H28N2O2 412.2151 found
412.2134.
a
CH), 4.44 (1H, t, J¼7.4, NCHH), 4.13e3.76
(7H, m, NCHH, 2eOCH3), 3.74e3.41 (1H, m, NHCHH), 3.29e2.75
(3H, m, NHCHH, ArCH2), 2.58e1.09 (8H, m, 4CH2); 13C NMR
4.2.14. N-(2-Oxoazocan-3-yl)-N-phenylbenzamide (12n). The crude
product obtained using condition A is purified using column chro-
matography (5% EtOAc/hexane) to give the title compound 12n
(38.0 mg, 54%) as a yellow oil; Rf (10% EtOAc/hexane) 0.40; IR (neat)
cmꢁ1 3507, 3335, 1705, 1687, 1475, 1233, 875; 1H NMR (300 MHz,
(75 MHz, CDCl3) d 174.62, 170.82, 148.92, 148.78, 146.84, 141.05,
133.21, 128.11, 123.84, 122.38, 113.11, 112.80, 56.78, 51.44, 42.97,
41.51, 35.14, 29.96, 28.64, 26.32, 25.80; ESI-MS (MþH) 456.1 m/z
and HRMS calcd mass for C24H29N3O6 455.2056 found
455.2044.
CDCl3) d 8.17e7.67 (2H, m, ArH), 7.64e6.78 (8H, m, ArH), 6.29 (1H, s,
NH), 4.44 (1H, t, J¼4.1,
a
CH), 3.80 (1H, dt, J¼12.5, 4.7, NHCHH), 3.21
4.2.19. N-Allyl-4-nitro-N-(2-oxoazocan-3-yl)benzamide (12s). The
crude product obtained using condition E is purified using column
chromatography (5% EtOAc/hexane) to give the title compound
(1H, dt, J¼12.5, 4.6, NHCHH), 2.56e1.14 (8H, m, 4CH2); 13C NMR
(75 MHz, CDCl3)
d 171.53, 170.89, 139.31, 135.48, 130.99, 129.01,

I.A. Khan, A.K. Saxena / Tetrahedron 68 (2012) 294e299
299
12s (40.0 mg, 36%) as a yellow oil; Rf (10% EtOAc/hexane) 0.28; IR
Kushwaha, Mr. Zahid Ali for their technical support. The CDRI
communication number allotted to this manuscript is 8147.
(neat) cmꢁ13517, 3405, 2224, 1687, 1654, 1468, 1233, 1103, 875; 1H
NMR (300 MHz, CDCl3)
J¼7.5,ArH), 6.27e5.44 (2H, m, CH, NH), 5.19 (1H, d, J¼2.2, CH2),
5.07e4.83 (1H, m,
CH), 4.46 (2H, dd, J¼9.5, 6.7,NCH2), 3.97 (1H, d,
J¼5.9, NHCHH), 3.87e3.46 (1H, m, CHH), 3.20 (1H, dt, J¼12.5, 5.4,
NHCHH), 2.57e0.87 (8H, m, 4CH2); 13C NMR (75 MHz, CDCl3)
174.62, 171.63, 146.84, 141.05, 133.56, 128.11, 123.84, 118.87,
d
8.33 (2H, d, J¼7.5, ArH), 7.99 (2H, d,
Supplementary data
a
b
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.10.050.
d
52.08, 46.77, 41.51, 29.96, 28.64, 26.32, 25.80; ESI-MS (MþH) 295.1
m/z and HRMS calcd mass for C17H21N3O4 331.1532 found
331.1524.
References and notes
1. (a) Domling, A. Comb. Chem. 1998, 1, 1e22; (b) Armstrong, R. W.; Combs, A. P.;
Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123e131; (c)
Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449e472; (d)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210.
4.2.20. Ethyl-5-(4-nitro-N-(2-oxoazocan-3-yl)benzamido)pent-2-
enoate (12t). The crude product obtained using condition E is
purified using column chromatography (5% EtOAc/hexane) to
give the title compound 12t (27.0 mg, 51%) as a yellow oil; Rf
2. (a) Ugi, I. Heterocycles 1984, 21, 271e277; (b) Ugi, I. Pure Appl. Chem. 2001, 73,
187e191; (c) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810e819.
ꢀ
3. (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.dEur. J. 2000, 6,
3321e3329; (b) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709e712.
(10% EtOAc/hexane) 0.30; 1H NMR (300 MHz, CDCl3)
d
8.37 (2H,
d, J¼7.6, ArH), 8.10 (2H, d, J¼7.6, ArH), 7.19e5.79 (3H, m, CHCH,
NH), 4.68e4.02 (4H, m,
€
4. Domling, A. Chem. Rev. 2006, 106, 17e89.
5. (a) Grubb, R. H. Tetrahedron 2004, 60, 7117e7119; (b) Connon, S. J.; Blechert, S.
Angew. Chem, Int. Ed. 2003, 42, 1900e1923; (c) Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360e11370.
6. Sara, M. H. J. Chem. Educ. 2006, 83, 940e942.
7. (a) Trost, B. M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881e6882; (b) Trost, B. M.;
Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4743e4763.
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42, 4963e4968; (b) Umkehrer, M.; Kolb, J.; Burdack, C.; Ross, G.; Hiller, W.
Tetrahedron Lett. 2004, 45, 6421e6424.
a
CH, NHCHH), 3.23 (3H, dddd, J¼16.8,
12.5, 10.8, 6.1, NHCHH, NCH2), 2.47 (2H, dd, J¼13.7, 7.2),
2.23e1.12 (11H, m, 4CH2,CH3). Due lesser concentration of
the compound 13C NMR was percluded; ESI-MS (MþH) 418.2
m/z and HRMS calcd mass for C21H27N3O6 417.1899 found
417.1874.
9. (a) Pitlik, J.; Townsend, C. A. Bioorg. Med. Chem. Lett. 1997, 7, 3129e3134; (b)
Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725e2728; (c) Gedey, S.;
Eycken, J. V. D.; Fulop, F. Org. Lett. 2002, 4, 1967e1969.
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Tidwell, T. T. Org. React. 1990, 39, 297e309.
15. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651e1660; (b) Mancuso, A. J.;
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Swern, D. Synthesis 1981, 03, 165e185; (d) Mancuso, A. J.; Huang, S.-L.; Swern,
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4.2.21. Ethyl-6-(4-nitro-N-(2-oxoazocan-3-yl)benzamido)hexanoate
(12u). The crude product obtained using condition E is purified
using column chromatography (5% EtOAc/hexane) to give the title
compound 12u (44.0 mg, 38%) as a yellow oil; Rf (10% EtOAc/hex-
ane) 0.33; IR (neat) cmꢁ1 3507, 3335, 1735, 1687, 1636, 1465, 1232,
874; 1H NMR (300 MHz, CDCl3)
d
8.32 (2H, d, J¼7.6, ArH), 8.02 (2H,
d, J¼7.6, ArH), 5.46 (1H, s, NH), 4.29 (3H, dt, J¼11.8, 6.6, NHCHH,
NCH2), 3.99e3.47 (2H, m), 3.46e2.93 (2H, m, CH2), 2.35 (2H, t,
J¼5.2, CH2), 2.23e0.95 (16H, m, 8CH2); 13C NMR (75 MHz, CDCl3)
d
174.62, 174.11, 170.82, 146.84, 141.05, 128.11, 123.84, 61.17, 51.44,
43.03, 41.51, 34.02, 29.96, 28.62, 26.52, 26.32, 25.80, 25.33, 14.69
ESI-MS (MþH) 434.5 m/z and HRMS calcd mass for C22H31N3O6
433.2212 found 433.2236.
16. (a) Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc. 1948, 70, 4233e4234; (b) Craig, J. C.;
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Thomas, R. C.; Kruse, L. I.; Siberman, L. J. Org. Chem. 1977, 42, 3846e3852; (c)
David, L. L.; Morrow, C. J.; Rapoport, H. J. Org. Chem. 1974, 39, 893e902; (d)
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Acknowledgements
19. (a) Moffatt, J.; Newton, M. V.; Papenmeier, G. J. J. Org. Chem. 1962, 27, 4058; (b)
Dhake, K. P.; Tambade, P. J.; Singhal, R. S.; Bhanage, B. M. Green Chem. Lett. Rev.
2011, 4, 151e157.
I.A.K. is thankful to UGC, New Delhi for the award of SRF and
acknowledges Mr. R.K. Purshottam, Mr. D.N. Viswakarma, Mr. A.S.