Efficient, one-pot, BF3·OEt2-mediated synthesis of substituted N-aryl lactams

Article abstract of DOI:10.1055/s-0032-1317326

A quick, efficient, one-pot, BF₃·OEt₂-mediated synthesis of substituted N-aryl lactams in good to excellent yields by reaction of various substituted arenes with a variety of ω-azido alkanoic acid chlorides at room temperature is reported.

Full text of DOI:10.1055/s-0032-1317326

LETTER
▌2627
letter
Efficient, One-Pot, BF3·OEt2-Mediated Synthesis of Substituted N-Aryl
Lactams
Substituted N-Aryl Lactams
Devdutt Chaturvedi,*a Amit K. Chaturvedi,b Nisha Mishra,b Virendra Mishrab
a
Laboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226010,
U. P., India
Fax +91(522)2399610; E-mail: devduttchaturvedi@gmail.com; E-mail: dchaturvedi@lko.amity.edu
b
Synthetic Research Laboratory, Department of Chemistry, B. S. A. P. G. College, Mathura 281004, U. P., India
Received: 26.06.2012; Accepted after revision: 06.09.2012
berg reaction is not a popular reaction in organic chemis-
try due to the necessity to use temperatures as high as
210 °C, highly polar aprotic solvents, strong bases such as
alkoxides and NaH, large amounts of the nucleophile, and
often large amounts of copper catalysts. In recent years,
much effort has been directed in order to search for better
catalytic systems for this reaction. Several kinds of effi-
cient ligands have been used to promote this reaction such
as diamines,21 diimines,22 amino acids,23 β-keto esters,24
and diols.25 Some of the other multistep synthetic routes
for the synthesis of substituted N-aryl lactams have also
been reported.26 The majority of the above-mentioned
routes is associated with several drawbacks such as low
reactivity, requirement of large amounts of catalysts and
ligands, costly, toxic, and moisture-sensitive nature of cat-
alysts, harsh reaction conditions, tedious workup, longer
reaction times, generation of toxic byproducts, and few of
them also involved two or more steps. Therefore, there is
a continued interest in developing new, efficient, and safer
protocols employing mild reaction conditions.
Abstract: A quick, efficient, one-pot, BF3·OEt2-mediated synthesis
of substituted N-aryl lactams in good to excellent yields by reaction
of various substituted arenes with a variety of ω-azido alkanoic acid
chlorides at room temperature is reported.
Key words: substituted arenes, ω-azido-alkanoic acid chloride,
Lewis acid, N-aryl lactams
Substituted N-aryl lactam moieties have been encountered
in the plethora of structurally diverse natural products and
drug candidates1 and have also been attracting much at-
tention due to their diverse arrays of potential biological
activities such as anticancer,2 antimicrobial,3 antidiabet-
ic,4 anti-CNS,5 anticonvulsants,6 agrochemicals,7 etc.
Moreover, this structural moiety has also been explored as
a useful synthon for the syntheses of structurally diverse
complex heterocycles such as benzo[a]quinazolidine-2-
ones,8 hexahydropyrido[3,4-c][1,5]benzothiazepines,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 and synthesis of various alka-
loids such as guettardine, 15-epiguettardine,13 (E)-azabur-
namine,14 makaluvamine A and C,15 veiutamine,16 and
synthesis of the fundamental tetracyclic skeleton of ervit-
sine and 20-de-ethylidine-6,16-dihydro analogues.17 In
view of their importance and wide applications, their syn-
thesis has gained considerable attention, and therefore,
become a focus of synthetic organic chemistry.
We report herein an efficient and mild protocol for the
synthesis of substituted N-aryl lactams starting from their
corresponding substituted arenes using a variety of ω-azi-
do alkanoic acid chlorides mediated by a Lewis acid at
room temperature. To the best of our knowledge this is the
first report for the efficient and mild synthesis of substitut-
ed N-aryl lactams from the corresponding substituted
arenes using BF3·OEt2 at room temperature.
The ω-azido alkanoic acid chlorides 2a–c have been syn-
thesized from their corresponding cyclic ketones, in ac-
cordance with the reported procedure.27 Initially, a
reaction of 1,2-dimethoxybenzene (1a) with a 4-azido-
butanoic acid chloride (2a, n = 1) using a catalytic amount
of BF3·OEt2 in anhydrous CH2Cl2 was tried at room tem-
perature (Table 1, entry 1) and the corresponding 1,2-di-
methoxy N-aryl lactam product formation was indeed
realized. The product formation was further confirmed
through the appearance of an amidic peak at ca. 1662 cm–
Traditional synthesis of substituted N-aryl lactams in-
volved the direct coupling reaction of substituted aryl ha-
lides with cyclic amides catalyzed by a transition-metal
catalyst.18 So far significant improvements have been
achieved in Pd-catalyzed amide arylation reactions19 but
the method remains hard to apply to large- and industrial-
scale syntheses due to high cost of palladium and the dif-
ficulty in removing palladium residues from the polar re-
action products. An alternative method for aryl amidation
involves the Cu-catalyzed Goldberg reaction between cy-
clic amides and aryl iodides.20 This method is attractive
from an economic standpoint because copper is much
cheaper than palladium. Despite this advantage, the Gold-
1
in the IR spectrum. The identification of the desired
product was further confirmed through various spectro-
scopic and analytical techniques.28 We proposed that a
Lewis acid will facilitate the reaction of ω-azido alkanoic
acid chlorides 2a–c with the corresponding substituted
arenes 1 which will form the acylated intermediate II
through a Friedel–Crafts acylation reaction. Nucleophilic
attack of one of the nitrogen atoms of the azide group to
SYNLETT 2012, 23, 2627–2630
Advanced online publication: 18.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317326; Art ID: ST-2012-D0547-L
© Georg Thieme Verlag Stuttgart · New York

2628
D. Chaturvedi et al.
LETTER
the carbonyl functionality of the acylated intermediate II ment using the same Lewis acid, led to the formation of
generated intermediate III, which on subsequent 1,2-shift the desired substituted N-aryl lactam of general formula 3
(i.e., C–N) of aryl migration through Schmidt rearrange- (Scheme 1).
Table 1 Conversion of Various Substituted Arenes into Substituted N-Aryl Lactams 3a,b
R2
R2
R1
R3
R1
R3
Cl
N3
a
n
+
O
N
O
1
2a–c
n
3aa–3ic
R3
Entry
1
R1
R2
2
n
3
Time (min) Isolated yield (%)
1
2
1a
1b
1c
1b
1c
1a
1a
1b
1c
1d
1e
1f
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
OMe
H
H
2a
2a
2a
2b
2b
2b
2c
2c
2c
2a
2a
2a
2b
2b
2b
2c
2c
2c
2a
2a
2a
2b
2b
2b
2c
2c
2c
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
3aa
3ba
3ca
3bb
3cb
3ab
3ac
3bc
3cc
3da
3ea
3fa
3db
3eb
3fb
3dc
3ec
3fc
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
3
OMe
H
4
5
OMe
OMe
OMe
H
6
7
H
8
OMe
OMe
H
9
OMe
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me
Me
Me
H
Me
Me
Me
H
1d
1e
1f
Me
Me
Me
Me
H
Me
Me
Me
H
1d
1e
1f
Me
Me
Me
Me
NO2
H
Me
Me
H
1h
1g
1i
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
3ha
3ga
3ia
NO2
NO2
H
NO2
NO2
H
1h
1g
1i
3hb
3gb
3ib
3hc
3gc
3ic
NO2
NO2
H
NO2
NO2
H
1h
1g
1i
NO2
NO2
NO2
a Reaction conditions: (a) BF3·OEt2, dry CH2Cl2, 20–50 min.
b All the products were characterized by IR, NMR, and mass spectral data.
Synlett 2012, 23, 2627–2630
© Georg Thieme Verlag Stuttgart · New York

LETTER
Substituted N-Aryl Lactams
2629
R2
OMe
OMe
R2
R1
OMe
R3
R1
OMe
+
R3
Cl
a
Cl
Br
n
N3
a
+
O
O
Br
O
N
O
2
1a
1
n
Lewis acid
3
Friedel–Crafts acylation
b
Schmidt
rearrangement
R2
Lewis acid
OMe
OMe
R2
OMe
R1
R3
OMe
O
R3
R1
c
O
O
O
N
N
N
N
N
N
N
N
N
N
n
III
II
n
3aa
III
Scheme 2 Reagents and conditions: (a) BF3·OEt2 anhdrous CH2Cl2,
10 min, 95%; (b) NaN3, 2 h, DMF, 98%; (c) BF3·OEt2, anhydrous
CH2Cl2, 15 min, 93%.
Scheme 1 Proposed mechanism of formation of substituted N-aryl
lactams of general formula
This reaction was also tried in various anhydrous organic
solvents such as chloroform, acetonitrile, methanol, ace-
tone, DMSO, DMF, CH2Cl2, etc., and thus anhydrous
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.,
BF3·OEt2, AlCl3, BF3, Me3B) and BF3·OEt2 was found to
be the best among all in achieving high yields of the de-
sired products. Then, we optimized the versatility of this
method through the reaction of a variety of 3,4,5-substi-
tuted arenes 1 containing electron-donating/electron-
withdrawing groups with different kinds of ω-azido alka-
noic acid chlorides 2a–c using BF3·OEt2 at room temper-
ature. Thus, a variety of N-aryl lactams were synthesized
and characterized through IR, NMR, and mass spectral
data. It was further realized that the yield of the N-aryl lac-
tam was dependent on the type of substitution of the aro-
matic ring of the corresponding arene used. It was further
realized that the introduction of an electron-donating
group at the aromatic nucleus of the arene led to an in-
creasing yield of the substituted N-aryl lactam. The intro-
duction of electron-withdrawing groups led to a decrease
in yield as depicted in Table 1.
1a–i with ω-azido alkanoic acid chlorides 2a–c employ-
ing BF3·OEt2 at room temperature. This is a new and one-
pot method using a catalytic amount of BF3·OEt2 that
gives high yields (65–98%) of the desired substituted N-
aryl lactams in a short reaction time (20–50 min) and thus
dominates over the reported procedures in respect of mild-
er reaction conditions, high yields, and shorter reaction
times.
Acknowledgement
The corresponding author wishes to thank Pro-Vice Chancellor and
Dean, Research (Science and Technology), Amity University Uttar
Pradesh, Lucknow Campus, Lucknow, for his constant encourage-
ment and support for research. The authors confirm that there is no
conflict of interest with the commercial identities used inside the
manuscript.
References and Notes
(1) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation and Synthetic Applications of Piperidine and Its
Derivatives; Elsevier: Amsterdam, 1991. (b) Neurath, G. B.
In Nicotine and Related Alkaloids; Gorrod, J. W.; Wahren,
J., Eds.; Chapman: London, 1993. (c) Muktar, T. A.; Wright,
G. D. Chem. Rev. 2005, 105, 529. (d) Horton, D. A.; Bourne,
G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893. (e) Fischer,
C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59. (f) Bari,
S. S.; Bhalla, A. Top. Heterocycl. Chem. 2010, 22, 49.
(2) (a) Dimmock, J. R.; Jha, A.; Zello, G. A.; Quail, J. W.; Oloo,
E. O.; Nienaber, K. H.; Kowalczyk, E. S.; Allen, T. M.;
Santos, C. L.; De Clercq, E.; Balzarini, J.; Manavathu, E. K.;
Stables, J. P. Eur. J. Med. Chem. 2002, 961. (b) Jha, A.;
Mukherjee, C.; Prasad, A. K.; Parmar, V. S.; De Clercq, E.;
Balzarini, B.; Stables, J. P.; Manavathu, E. K.; Srivastava,
A.; Sharma, R. K.; Nienaber, K. H.; Zello, Z. H.; Dimmock,
J. R. Bioorg. Med. Chem. 2007, 15, 5854.
To further validate this methodology, a reaction of 1,2-di-
methoxybenzene (1a) with previously synthesized 4-bro-
mobutanoic acid chloride employing BF3·OEt2 afforded
the corresponding acylated bromo product through Frie-
del–Crafts reaction, which on treatment with NaN3 afford-
ed 4-azidoacylated compound III. Treatment of
compound III with BF3·OEt2 gave the corresponding N-
aryl lactam through the Schmidt rearrangement (Scheme
2). The spectral data of the synthesized compound was
correlated with the N-aryl lactam compound (Table 1, en-
try 1) synthesized through the direct coupling method.
(3) (a) Schwartz, R. E.; Helms, G. L.; Bolessa, E. A.; Wilson, K.
E.; Giacobbe, R. A.; Tkacz, J. S.; Bills, G. F.; Liesch, J. M.;
Zink, D. L.; Curotto, J. E.; Pramanik, B.; Onishi, J. C.
Tetrahedron 1994, 50, 1675. (b) Das, U.; Das, S.; Bandy, B.;
Stables, J. P.; Dimmock, J. R. Bioorg. Med. Chem. 2008, 16,
In conclusion, we have developed an efficient and novel
method for the syntheses of substituted N-aryl lactams
3aa–ic through the reaction of the corresponding arenes
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2627–2630

2630
D. Chaturvedi et al.
LETTER
(23) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth.
3602. (c) Das, M.; Molnar, J.; Barath, Z.; Bata, Z.;
Dimmock, J. R. Bioorg. Med. Chem. Lett. 2008, 18, 3484.
Catal. 2006, 348, 2197.
(4) Coutrot, P.; Claudel, S.; Didierjean, C.; Grison, C. Bioorg.
Med. Chem. Lett. 2006, 16, 417.
(5) Baures, P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L.
B.; Torphy, T. J.; Christensen, S. B. J. Med. Chem. 1993, 36,
3274.
(6) (a) Ho, B.; Crider, A. M.; Stables, J. P. Eur. J. Med. Chem.
2001, 265. (b) Tiran, A. L.; Stables, J. P.; Kohn, H. Bioorg.
Med. Chem. 2001, 9, 2693.
(24) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
(25) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
4, 581.
(26) Yang, Y.-H.; Shi, M. J. Org. Chem. 2005, 70, 8645.
(27) Sankaranarayan, S.; Chattopadhyay, S. Tetrahedron:
Asymmetry 1998, 9, 1345.
(28) Typical Experimental Procedure for the Synthesis of
Substituted N-Aryl Lactams
(7) Mitchell, G.; Barnes, N. J.; Cox, J. M.; Matthews, I. R.;
Parry, D. R.; Pearson, D. P. J.; Smith, S. C. Synthesis and
Structure-Activity Relationships in a Novel Class of N-Aryl
Lactam Herbicides; ACS Symposium Series 80:
Washington, 2001, Chap. 3; 18–29.
(8) Rubiralta, M.; Diez, A.; Balet, A.; Bosch, J. Tetrahedron
1987, 43, 3021.
(9) Kumar, R. R.; Perumal, S. Tetrahedron 2007, 63, 7850.
(10) Commins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42,
4115.
(11) Diez, A.; Voldoire, A.; Lopez, I.; Raburalta, M.; Segarra, V.;
Pages, L.; Palacois, J. M. Tetrahedron 1995, 51, 5143.
(12) Rubiralta, M.; Diez, A.; Vila, C.; Bettiol, J. L.; Troin, Y.;
Sinibaldi, M. E. Tetrahedron Lett. 1992, 33, 1233.
(13) Diez, A.; Tona, M.; Rubiralta, M. Tetrahedron 1990, 46,
4393.
(14) Lopez, I.; Diez, A.; Rubiralta, M. Tetrahedron 1996, 52,
8581.
(15) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. J. Am. Chem. Soc. 1993, 115,
1632.
(16) Venables, D. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M.
Tetrahedron Lett. 1997, 38, 721.
(17) Rubiralta, M.; Marco, M. P.; Bolos, J.; Trape, J. Tetrahedron
1991, 47, 5585.
(18) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(19) Klappars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727.
(20) Deng, W.; Wang, Y. F.; Zou, Y.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2004, 45, 2311.
An equimolar amount of substituted arene and the
corresponding ω-azido alkanoic acid chloride were taken in
anhyd CH2Cl2 (25 mL) and stirred for 10 min at r.t. To this
mixture, BF3·OEt2 (0.1 mol, with respect to arene) was
added slowly in 2–3 small portions at r.t. The reaction was
continued until completion (cf. Table 1) as confirmed by
TLC. The reaction mixture was then poured into distilled
H2O (50 mL) and extracted with CH2Cl2. The organic layer
was separated and dried over anhyd Na2SO4 and then
concentrated to afford the desired substituted N-aryl lactam
compound.
Data of Selected Compounds
1-(3,4-Dimethoxyphenyl)piperidin-2-one (3aa)
Colorless oil. 1H NMR (300MHz, CDCl3): δ = 1.92–1.95 (m,
4 H), 2.55 (t, J = 6.2 Hz, 2 H), 3.61 (t, J = 5.5 Hz, 2 H), 3.86
(s, 3 H), 3.87 (s, 3 H), 6.77–6.78 (m, 2 H), 6.86–6.88 (m, 1
H). 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 (100) [M+], 220, 166. HRMS (EI):
m/z calcd for C13H17O3N [M+]: 235.1208; found: 235.1208.
1-(3,5-Dimethoxyphenyl)pyrrolidin-2-one (3ba)
White solid; mp 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, 6.6 Hz, 2 H, CH2), 2.61 (t, J = 8.4 Hz, 2
H, CH2), 3.80 (s, 6 H, OCH3), 3.83 (t, J = 6.6 Hz, 2 H, CH2),
6.27 (t, J = 2.4 Hz, 1 H, Ar), 6.86 (d, J = 2.4 Hz, 2 H, 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
(100) [M+], 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.
(21) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421.
(22) Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y. D.; Ma, D. W.
Synthesis 2005, 496.
Synlett 2012, 23, 2627–2630
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.