An efficient and novel approach for the synthesis of substituted N-aryl lactams

Article abstract of DOI:10.1039/c2ob26230d

A quick, efficient, one-pot method for the synthesis of substituted N-aryl lactams through the reaction of various kinds of corresponding substituted arenes with a variety of ω-azido alkanoic acid chlorides using a Lewis acid (i.e. EtAlCl₂) at room temperature, through the in situ involvement of a Friedel-Crafts reaction followed by intramolecular Schimdt rearrangement was developed, and afforded good to excellent yields.

Full text of DOI:10.1039/c2ob26230d

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Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 9148
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COMMUNICATION
An efficient and novel approach for the synthesis of substituted N-aryl
lactams
Devdutt Chaturvedi,*a Amit K. Chaturvedi,b Nisha Mishrab and Virendra Mishrab
Received 28th June 2012, Accepted 16th October 2012
DOI: 10.1039/c2ob26230d
low reactivity, requirement of large amounts of catalysts and
ligands, costly, toxic and moisture sensitive nature of catalysts,
harsh reaction conditions, tedious work-up, longer reaction
times, generation of toxic byproducts and a few of them also
involved two or more steps. Therefore, there is continued interest
in developing new, efficient, and safer protocols employing mild
reaction conditions. In the present communication, we report
herein a novel and efficient synthetic route for the synthesis of
substituted N-aryl lactams starting from their corresponding sub-
stituted arenes and a variety of ω-azido alkanoic acid chlorides
catalyzed by a Lewis acid, ethylaluminium dichloride (i.e.
EtAlCl2), at room temperature. To the best of our knowledge,
this is the first report of the efficient and mild synthesis of substi-
tuted N-aryl lactams starting from their corresponding substituted
arenes and ω-azido alkanoic acid chlorides employing a catalytic
amount of EtAlCl2 at room temperature. Furthermore, this is a
one-pot method involving the sequential Friedel–Crafts reaction
followed by Schmidt rearrangement catalyzed by EtAlCl2 and
thus we explore a novel synthetic route for the synthesis of sub-
stituted N-aryl lactams, wherein the chemistry is totally different
from the previously reported various kinds of metal mediated
coupling reactions.
A quick, efficient, one-pot method for the synthesis of substi-
tuted N-aryl lactams through the reaction of various kinds of
corresponding substituted arenes with a variety of ω-azido
alkanoic acid chlorides using a Lewis acid (i.e. EtAlCl2) at
room temperature, through the in situ involvement of a
Friedel–Crafts reaction followed by intramolecular Schimdt
rearrangement was developed, and afforded good to excel-
lent yields.
Substituted N-aryl lactam moieties have been encountered in a
plethora of structurally diverse natural products and drug candi-
dates1 and have also attracted much attention due to their diverse
arrays of potential biological activities such as anti-cancer,2 anti-
microbial,3 anti-diabetic,4 anti-CNS,5 anti-convulsant6 and have
been used as agrochemicals7 etc. Moreover, this structural
moiety has also been explored as a useful synthon for the synth-
eses of structurally diverse complex heterocycles such as benzo-
[a]-quinazolidine-2-ones,8 hexahydropyrido-[3,4-c]-[1,5]-benzo-
thiazepines,9
5-(diethoxyphosphoryl)-1-aryl-2-alkyl/aryl-2,3-
dihydro-4-pyridones,10 3-aminopiperidines,11 methyl-indolo-
[2,3-a]-quinazolidin-2-acetate;12 for the synthesis of various
alkaloids such as guettardine, 15-epiguettardine,13 E-azaburn-
amine,14 makaluvamine A&C,15 veiutamine;16 and for the syn-
thesis of the fundamental tetracyclic skeleton of ervitsine and
20-de-ethylidine-6,16-dihydro analogues.17 In view of their
importance and wide applications, their syntheses have gained
considerable attention, and therefore have become a focus of
synthetic organic chemistry.
The ω-azido alkanoic acid chlorides 4, 5, 6 are key intermedi-
ates for this single-step coupling methodology and have been
synthesized from their corresponding cyclic ketones 1, 2, 3
respectively, following the standard reported procedure27
(Scheme 1). Initially, a reaction of 1,2-dimethoxybenzene 7 with
4-azidobutanoic acid chloride 4 (n = 1) using a catalytic amount
of EtAlCl2 in dry CH2Cl2 was tried at room temperature (entry
1) and the corresponding 1,2-dimethoxy N-aryl lactam product
Traditional synthesis of substituted N-aryl lactams involved
the direct coupling reaction of substituted aryl halides with
cyclic amides catalyzed by a transition metal catalyst such as Pd
and Cu.18–20 In recent years, several kinds of efficient ligands
have been used to promote this reaction such as diamines,21 di-
imines,22 amino acids,23 β-ketoesters,24 and diols.25 Some other
multi-step synthetic routes for the synthesis of substituted N-aryl
lactams have also been reported.26 The majority of the above
mentioned routes are associated with several drawbacks such as
aLaboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity
University Uttar Pradesh, Lucknow Campus, Lucknow-226010, U. P.,
India. E-mail: devduttchaturvedi@gmail.com, dchaturvedi@lko.amity.edu
bSynthetic Research Laboratory, Department of Chemistry, B. S. A. P. G.
College, Mathura-281004, U. P., India
Scheme 1 Reagents and conditions: (a) HCOOH–H2O2, water, 97%;
(b) 48% HBr–H2SO4, 94%; (c) NaN3, DMF, 98%; (d) oxalyl chloride,
benzene, 98%.
9148 | Org. Biomol. Chem., 2012, 10, 9148–9151
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Table 1 Conversion of various substituted arenes into substituted
N-aryl lactams of general formula Ia
formation was indeed realized. The formation of the product was
confirmed through the appearance of an amidic peak at
∼1662 cm−1 in the IR spectra and was further confirmed through
various spectroscopic and analytical techniques (see the Experi-
mental section). This reaction was tried in various dry organic
solvents such as chloroform, acetonitrile, methanol, acetone,
DMSO, DMF, CH2Cl2 etc., and thus dry CH2Cl2 was found to
be the best among all in carrying out this transformation at room
temperature. This reaction was also carried out in a variety of
Lewis acids (i.e. BF3OEt2, AlCl3, BF3, CF3SO3H, Me3B,
EtAlCl2) and EtAlCl2 was found to be the best among all in
achieving high yields of the desired products. Then, we opti-
mized the versatility of this method through the reaction of a
variety of 3,4,5-substituted arenes 7 containing electron releas-
ing/electron withdrawing groups with different kinds of ω-azido
alkanoic acid chlorides 4, 5, 6 (Scheme 2) employing a catalytic
amount of EtAlCl2 at room temperature. Thus, a variety of
N-aryl lactams were synthesised and characterized through the
IR, NMR, and mass spectral data. It was further realized that the
yield of the N-aryl lactam was dependent upon the type of sub-
stitution on the aromatic ring of the corresponding arene used. It
was further realized that introducing an electron releasing group
at the aromatic nucleus of the arene led to an increasing yield of
the substituted N-aryl lactam and introducing electron withdraw-
ing groups led to a decrease in the yield as mentioned in Table 1.
We propose that the Lewis acid will facilitate the reaction of
ω-azido alkanoic acid chlorides 4, 5, 6 with the corresponding
substituted arene 7 which will form the acylated intermediate II
through Friedel–Crafts acylation reaction. Nucleophilic attack of
Entry
no.
Time
(min)
Isolated
yield (%)
R1
R2
R3
n
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
OMe
H
OMe
H
OMe
OMe
OMe
H
OMe
Me
H
Me
Me
H
Me
Me
H
H
1
1
1
2
2
2
3
3
3
1
1
1
2
2
2
3
3
3
1
1
1
2
2
2
3
3
3
25
25
20
25
20
25
30
30
25
30
30
25
30
30
25
35
35
30
40
40
50
40
40
50
50
50
50
93
91
98
89
97
85
83
82
89
92
90
94
89
88
95
80
85
87
74
77
71
70
72
68
68
67
65
OMe
OMe
OMe
OMe
H
H
OMe
OMe
H
Me
Me
H
Me
Me
H
Me
Me
COOMe
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me
Me
Me
Me
Me
H
COOMe
COOMe COOMe
COOMe COOMe COOMe
COOMe
COOMe COOMe
COOMe COOMe COOMe
COOMe
COOMe COOMe
H
COOMe
H
H
COOMe
H
COOMe COOMe COOMe
a All the products were characterized by IR, NMR and mass spectral
data.
Scheme 2 Reagents and conditions: (a) EtAlCl2, dry CH2Cl2, 20–50 min, 65–98%; and proposed mechanism of formation of substituted N-aryl
lactams of general formula I.
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one of the nitrogen atoms of azide on the carbonyl functionality
of acylated intermediate II generated intermediate III which on
subsequent 1,2-shift (i.e. C–N) of aryl migration through
Schmidt rearrangement using the same Lewis acid led to the for-
mation of the desired substituted N-aryl lactam of general
formula I (Scheme 2). Furthermore, the acylated compound II
may also form nitrene intermediate IV which on subsequent
C–H insertion may form intermediate V, electronic rearrange-
ment of V may lead to the formation of the corresponding N-aryl
lactam of general formula I.
reaction, which on treatment with NaN3 afforded 4-azidoacylated
compound III. Treatment of compound III with EtAlCl2
afforded the corresponding N-aryl lactam through the Schmidt
rearrangement (Scheme 3). The spectral data of the synthesized
compound were correlated with the N-aryl lactam compound
(entry 1) synthesized through the direct coupling method.
Another control for the formation of substituted N-aryl lactam
was further confirmed through the reaction of 1,2-dimethoxy
benzene with a previously synthesized ω-azido alkanoic ester
employing a catalytic amount of EtAlCl2 in dry CH2Cl2
(Scheme 4). The formation of the corresponding N-aryl lactam
(entry 1) was confirmed through spectroscopic and analytic tech-
niques and was further confirmed through the data of the pre-
viously synthesized authentic sample.
To further validate this methodology, a reaction of 1,2-
dimethoxybenzene was tried with previously synthesized 4-bromo-
butanoic acid chloride employing EtAlCl2 and this afforded the
corresponding acylated bromo product through Friedel–Crafts
Scheme 3 (a) EtAlCl2 dry CH2Cl2, 50 min, 95%; (b) NaN3, 2 h, DMF, 98%; (c) EtAlCl2, dry CH2Cl2, 25 min, 93%.
Scheme 4 Reagents and conditions: (a) EtAlCl2, CH2Cl2, rt, 25 min, 91%.
9150 | Org. Biomol. Chem., 2012, 10, 9148–9151 This journal is © The Royal Society of Chemistry 2012

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In conclusion, we have developed an efficient and novel one-
pot method for the synthesis of substituted N-aryl lactams
through the reaction of corresponding arenes with a variety of
ω-azido alkanoic acid chlorides employing a catalytic amount of
EtAlCl2 at room temperature. This is a new and efficient method
that afforded high yields (65–98%) of the desired substituted
N-aryl lactams in the shortest reaction time (20–50 min), through
the sequential Friedel–Crafts reaction followed by intramolecular
Schimdt rearrangement, and thus provides a novel synthetic
route for the synthesis of a variety of substituted N-aryl lactams
wherein the chemistry is totally different from the previously
reported metal mediated coupling reactions.
constant encouragement and support for the research. The
authors confirm that there is no conflict of interest with the com-
mercial identities used in the manuscript.
Notes and references
1 (a) M. Rubiralta, E. Giralt and A. Diez, Piperidine: Structure, Prep-
aration and Synthetic Applications of Piperidine and Its Derivatives,
Elsevier, Amsterdam, 1991; (b) G. B. Neurath, in Nicotine Related Alka-
loids, ed. J. W. Gorrod, Chapman, London, 1993; (c) T. A. Muktar and
G. D. Wright, Chem. Rev., 2005, 105, 529–542; (d) D. A. Horton,
G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893–930;
(e) C. Fischer and B. Koening, Beilstein J. Org. Chem., 2011, 7, 59–74;
(f) S. S. Bari and A. Bhalla, Top. Heterocycl. Chem., 2010, 22, 49–99.
2 (a) J. R. Dimmock, A. Jha, G. A. Zello, J. W. Quail, E. O. Oloo,
K. H. Nienaber, E. S. Kowalczyk, T. M. Allen, C. L. Santos,
E. D. Clercq, J. Balzarini, E. K. Manavathu and J. P. Stables, Eur. J. Med.
Chem., 2002, 37, 961–972; (b) A. Jha, C. Mukherjee, A. K. Prasad,
V. S. Parmar, E. D. Clercq, J. Balzarini, J. P. Stables, E. K. Manavathu,
A. Srivastava, R. K. Sharma, K. H. Nienaber, Z. H. Zello and
J. R. Dimmock, Bioorg. Med. Chem., 2007, 15, 5854–5865.
3 (a) R. E. Schwartz, G. L. Helms, E. A. Bolessa, K. E. Wilson,
R. A. Giacobbe, J. S. Tkacz, G. F. Bills, J. M. Liesch, D. L. Zink,
J. E. Curotto, B. Pramanik and J. C. Onishi, Tetrahedron, 1994, 50,
1675–1686; (b) U. Das, S. Das, B. Bandy, J. P. Stables and
J. R. Dimmock, Bioorg. Med. Chem., 2008, 16, 3602–3607; (c) M. Das,
J. Molnar, Z. Barath, Z. Bata and J. R. Dimmock, Bioorg. Med. Chem.
Lett., 2008, 18, 3484–3487.
Experimental
Typical experimental procedure for the synthesis of substituted
N-aryl lactams
An equimolar amount of substituted arene and the corresponding
ω-azido alkanoic acid chloride were taken in dry CH2Cl2
(25 ml), and stirred for 10 min at room temperature. To this, a
1/10th molar amount (with respect to arene) of Lewis acid (i.e.
EtAlCl2) was added slowly in 2–3 small portions at room temp-
erature. The reaction was continued until completion (cf.
Table 1) as confirmed by TLC. The reaction mixture was then
poured into distilled water (50 ml) and extracted with dichloro-
methane. The organic layer was separated and dried over anhy-
drous sodium sulphate and then concentrated to afford the
desired substituted N-aryl lactam compound.
4 P. Coutrot, S. Claudel, C. Didierjean and C. Grison, Bioorg. Med. Chem.
Lett., 2006, 16, 417–420.
5 P. W. Baures, D. S. Eggleston, K. F. Erhard, L. B. Cieslinski, T. J. Torphy
and S. B. Christensen, J. Med. Chem., 1993, 36, 3274.
6 (a) B. Ho, A. M. Crider and J. P. Stables, Eur. J. Med. Chem., 2001, 36,
265–286; (b) A. L. Tiran, J. P. Stables and H. Kohn, Bioorg. Med. Chem.,
2001, 9, 2693–2708.
7 G. Mitchell, N. J. Barnes, J. M. Cox, I. R. Matthews, D. R. Parry,
D. P. J. Pearson and S. C. Smith, ACS Symposium Series, 2001, vol. 800,
ch. 3, pp. 18–29.
Data of selected compounds
8 M. Rubiralta, A. Diez, A. Balet and J. Bosch, Tetrahedron, 1987, 43,
3021–3030.
9 R. R. Kumar and S. Perumal, Tetrahedron, 2007, 63, 7850–7857.
10 D. L. Commins and C. G. Ollinger, Tetrahedron Lett., 2001, 42, 4115–
4118.
11 A. Diez, A. Voldoire, I. Lopez, M. Rubiralta, V. Segarra, L. Pages and
J. M. Palacois, Tetrahedron, 1995, 51, 5143–5156.
12 M. Rubiralta, A. Diez, C. Vila, J. L. Bettiol, Y. Troin and M. E. Sinibaldi,
Tetrahedron Lett., 1992, 33, 1233–1236.
13 A. Diez, M. Tona and M. Rubiralta, Tetrahedron, 1990, 46, 4393–4406.
14 I. Lopez, A. Diez and M. Rubiralta, Tetrahedron, 1996, 52, 8581–8600.
15 D. C. Radisky, E. S. Radisky, L. R. Barrows, B. R. Copp, R. A. Kramer
and C. M. Ireland, J. Am. Chem. Soc., 1993, 115, 1632–1634.
16 D. A. Venables, L. R. Barrows, P. Lassota and C. M. Ireland, Tetrahedron
Lett., 1997, 38, 721–724.
17 M. Rubiralta, M. P. Marco, J. Bolos and J. Trape, Tetrahedron, 1991, 47,
5585–5602.
18 J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046–2455.
19 A. Klappars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem.
Soc., 2001, 123, 7727–7729.
1-(3,4-Dimethoxyphenyl)piperidin-2-one (Table 1, entry 1,
C13H17O3N). Colorless oil; 1H NMR (300 MHz, CDCl3) δ =
1.92–1.95 (m, 4H), 2.55 (t, J = 6.2 Hz, 2H), 3.61 (t, J = 5.5 Hz,
2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.77–6.78 (m, 2H), 6.86–6.88
(m, 1H); 13C NMR (75 MHz, CDCl3) δ = 21.3, 23.4, 32.7, 52.0,
55.7, 55.8, 110.0, 111.2, 118.0, 136.4, 147.6, 149.0, 170.0; MS
(EI) m/z 235 (M+, 100), 220, 166; HRMS (EI) m/z calcd for
C13H17O3N (M+) 235.1208, found 235.1208.
1-(3,5-Dimethoxyphenyl)pyrrolidin-2-one (Table 1, entry 2,
C12H15NO3). White solid, m. p. = 85–86 °C; IR (CH2Cl2): ν =
1069, 1154, 1208, 1249, 1275, 1324, 1347, 1393, 1478, 1598,
1697, 2841, 2958 cm−1; 1H NMR (300 MHz, CDCl3, TMS): δ =
2.14 (tt, J = 8.4 Hz, J = 6.6 Hz, 2H, CH2), 2.61 (t, J = 8.4 Hz,
2H, CH2), 3.80 (s, 6H, OCH3), 3.83 (t, J = 6.6 Hz, 2H, CH2),
6.27 (t, J = 2.4 Hz, 1H, Ar), 6.86 (d, J = 2.4 Hz, 2H, Ar); 13C
NMR (75 MHz, CDCl3, TMS): δ = 17.8, 32.9, 48.9, 55.3, 96.4,
98.3, 141.1, 160.7, 174.3; MS (EI) m/z: 221 (M+, 100),
192 (23), 178 (9), 166 (75), 162 (7), 151 (5), 136 (12), 122 (6),
108 (5); Anal. Calcd for C12H15NO3: C, 65.14, H, 6.83, N,
6.33%; Found: C, 64.99, H, 6.85, N, 6.25.
20 W. Deng, Y. F. Wang, Y. Zou, L. Liu and Q.-X. Guo, Tetrahedron Lett.,
2004, 45, 2311–2315.
21 A. Klapars, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2002,
124, 7421–7428.
22 Q. Cai, W. Zhu, H. Zhang, Y. D. Zhang and D. W. Ma, Synthesis, 2005,
496–499.
23 X. Guo, H. Rao, H. Fu, Y. Jiang and Y. Zhao, Adv. Synth. Catal., 2006,
348, 2197–2202.
24 X. Lv and W. Bao, J. Org. Chem., 2007, 72, 3863–3867.
25 F. Y. Kwong, A. Klapars and S. L. Buchwald, Org. Lett., 2002, 4, 581–
584.
26 Y.-H. Yang and M. Shi, J. Org. Chem., 2005, 70, 8645–8648.
27 S. Sankaranarayan and S. Chattopadhyay, Tetrahedron: Asymmetry, 1998,
9, 1345–1350.
Acknowledgements
The corresponding author wishes to thank the Pro-Vice Chancel-
lor and Dean, Research (Science and Technology), Amity Uni-
versity Uttar Pradesh, Lucknow Campus, Lucknow, for his
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9148–9151 | 9151