An efficient and simple aqueous N-heterocyclization of aniline derivatives: Microwave-assisted synthesis of N-aryl azacycloalkanes

Article abstract of DOI:10.1021/ol050683t

(Chemical Equation Presented) An efficient and clean synthesis of N-aryl azacycloalkanes from alkyl dihalides and aniline derivatives has been achieved using microwave irradiation in an aqueous potassium carbonate medium. The phase separation can simplify the product isolation and reduce usage of volatile organic solvents.

Full text of DOI:10.1021/ol050683t

ORGANIC
LETTERS
2
005
Vol. 7, No. 12
409-2411
An Efficient and Simple Aqueous
N-Heterocyclization of Aniline
2
Derivatives: Microwave-Assisted
Synthesis of N-Aryl Azacycloalkanes
Yuhong Ju and Rajender S. Varma*
Sustainable Technology DiVision, National Risk Management Research Laboratory,
U.S. EnVironmental Protection Agency, 26 West Martin Luther King DriVe, MS 443,
Cincinnati, Ohio 45268
Varma.rajender@epa.goV
Received March 31, 2005
ABSTRACT
An efficient and clean synthesis of N-aryl azacycloalkanes from alkyl dihalides and aniline derivatives has been achieved using microwave
irradiation in an aqueous potassium carbonate medium. The phase separation can simplify the product isolation and reduce usage of volatile
organic solvents.
The concept of “green chemistry” has been widely adopted
to meet the fundamental scientific challenges of protecting
human health and the environment while simultaneously
heteroatom and carbon-carbon bonds has been successfully
demonstrated.
4
Nitrogen-containing heterocycles are known subunits in
many natural products and biologically active pharmaceu-
1
achieving commercial viability. The emerging area of green
5
chemistry envisages minimum hazard as the performance
criteria while designing new chemical processes. One of the
thrust areas for achieving this target is to explore alternative
reaction conditions and reaction media to accomplish the
desired chemical transformations with minimum byproducts
and waste generation, as well as eliminating the use of
volatile and toxic organic solvents.2
ticals. They are prepared via alkylation of primary amines
6
with glycol disulfonate in refluxed anhydrous dioxane, using
7
complicated multistep reactions, under harsh reaction condi-
8
tions, or via coupling reactions using expensive metal
9
catalysts. Developing efficient, selective and eco-friendly
synthetic methods for applications in complex organic
Organic reactions accelerated under the influence of
microwave (MW) irradiation have attracted considerable
attention in the past decade for the efficient and relatively
friendlier synthesis of a variety of organic compounds. The
use of MW irradiation for the formation of several carbon-
(4) (a) Varma, R. S. AdVances in Green Chemistry: Chemical Syntheses
Using MicrowaVe Irradiation; AstraZeneca Research Foundation India:
Bangalore, India, 2002 (free copy available on request from: azrefi@
astrazeneca.com). (b) Varma, R. S. Organic Synthesis using Microwaves
and Supported Reagents. In MicrowaVes in Organic Synthesis; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2002; pp 181-218. (c) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (d) Varma, R. S. J.
Heterocycl. Chem. 1999, 36, 1565.
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Rep. 1986, 10, 239. (b) Craig, P. N. In ComprehensiVe Medicinal Chemistry;
Drayton, C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (c) Kodama,
T.; Tamura, M.; Oda, T.; Yamazaki, Y.; Nishikawa, M.; Takemura, S.;
Doi, T.; Yoshinori, Y.; Ohkuchi, M. U.S. Patent 983928, 2003.
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(7) (a) Lai, G. Synth. Commun. 2001, 31, 565. (b) Verardo, G.; Dolce,
A.; Toniutti, N. Synthesis 1999, 74.
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1) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 1998.
2) (a) Wasserscheid, P., Welton, T., Eds.; Ionic Liquid in Synthesis;
(
Verlag GmbH and Co. KGaA: Weinheim, 2003. (b) Darr, J. A.; Poliakoff,
M. Chem. ReV. 1999, 99, 495. (c) Clifford, A. A.; Rayer, C. M. Tetrahedron
Lett. 2001, 42, 323.
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P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (c)
Varma, R. S. Green Chem. 1999, 1, 43. (d) Gabriel, C.; Gabriel, S.; Grant,
E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. ReV. 1998, 27, 213.
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1
0.1021/ol050683t CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/10/2005

preparations is the ultimate goal of several research groups,
1
0
including ours. Among alternative, friendlier solvents, water
Table 1. Microwave-Accelerated Synthesis of N-Aryl
Azacycloalkanes from Alkyl Dihalides
1
1
is very benign and has been utilized in combination with
microwave irradiation12 wherein activation of reactions can
be achieved. We wish to report here that the double alkylation
of aniline derivatives by alkyl dihalides occurs in mildly basic
aqueous media upon microwave irradiation and affords a
series of N-aryl azacycloalkanes in a simple and straight-
forward manner (Scheme 1). Although theoretically feasible,
this simple approach has not been explored previously.
a
Scheme 1. Microwave-Accelerated Synthesis of
Azacycloalkanes
The reaction between ethyl 4-aminobenzoate and 1,4-
dibromobutane under conventional and MW heating condi-
tions was investigated to demonstrate the specific microwave
effect. We found that under conventional heating conditions,
the reaction did not proceed within 20 min and gave rise to
a moderate yield (58%) within 8 h of reaction time. However,
the same reaction under microwave irradiation for only 20
min afforded excellent product yield (91%). Microwave-
assisted reaction exhibited several advantages over the
conventional heating by not only significantly reducing the
reaction time but also by improving the reaction yield
dramatically and, in the process, eliminating the side reac-
tions. Thus, the hydrolysis of esters to carboxylic acid and
alcohol and transformation of bromides to hydroxides in an
alkaline reaction medium,13 which were both observed in
the separate controlled experiments, could be avoided, thus
implying the involvement of a specific nonthermal micro-
wave effect.
a
All reactions were carried out at 1 mmol scale, microwave power )
b
8
0-100 W, and T ) 120 °C for 20 min. NMR spectra of all synthesized
N-aryl azacycloalkane products are in accord with the literature. Isolated
yields based on starting aniline derivatives.
c
to alkyl chlorides, bromides, and iodides. A detailed exami-
nation of this reaction revealed that the mild reaction
conditions tolerated a variety of functional groups such as
hydroxyls, carbonyls, and esters (entries 4, 5, and 7 in Table
1
K
) in the presence of a mild base, potassium carbonate
CO . This advantageous attribute renders the reaction
2
3
useful to build the N-aryl cycloalkane moiety without tedious
functional group protection/deprotection sequences.
The experimental observations are consistent with the
mechanistic postulation wherein the polar transition state of
the reaction is favored by microwave irradiation with respect
to the dielectric polarization nature of microwave energy
transfer. As proposed in Scheme 2, the charge developed
in intermediates 4 and 7 induces a specific microwave
enhancement, thus lowering the activation energy due to a
greater stabilization of the transition state 6 by the dipole-
dipole interaction between the more polar, ionic intermediate
and the microwave electric field when compared to the less
This microwave-accelerated double-alkylation reaction was
applicable to a variety of aniline derivatives and dihalides
to furnish N-aryl azacycloalkanes in good to excellent yields
expeditiously within 20 min under microwave irradiation
1
5
14
(
Table 1). The reaction was general in nature and applicable
(9) (a) Lo, Y. S.; Causey, D. H.; Shamblee, D. A.; Mays, R. P. Eur. Pat.
Appl. EP 279543, 1988. (b) Tsuji, Y.; Yokoyama, Y.; Huh, K. T.; Yoshihisa,
Y. Bull. Chem. Soc. Jpn. 1987, 60, 3456. (c) Tararov, V. I.; Kadyrov, R.;
Borner, A.; Riermeier, T. H. Chem. Commun. 2000, 1867. (d) Desmarets,
C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67, 3029.
16
polar ground state.
(
10) (a) Varma, R. S. MicrowaVe TechnologysChemical Applications:
Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed.; John Wiley
Sons: New York, 2004. (b) Namboodiri, V. V.; Varma, R. S. Green
Chem. 2001, 3, 146.
(14) In a representative reaction, 1.0 mmol of aniline derivatives, 1.1
mmol of dihalides, and 1.1 mmol of potassium carbonate in 2 mL of distilled
water were placed in a 10 mL crimp-sealed, thick-walled reaction tube
equipped with a pressure sensor and a magnetic stirrer. The reaction tube
was placed in the microwave cavity (CEM Discover Focused Microwave
Synthesis System with a built-in infrared temperature sensor), operated at
120 ( 5 °C, 80-100 W, and a pressure of 65-70 psi for 20 min. After
completion of the reaction, the organic portion was extracted into ethyl
acetate. Removal of the solvent under reduced pressure and flash column
chromatography furnished the desired product.
&
(
11) (a) Li, C. J. Chem. ReV. 1993, 93, 2023. (b) Li, C. J.; Chen, T. H.
Organic Reactions in Aqueous Media; Wiley: New York, 1997. (c) Wei,
W.; Keh, C. C. K.; Li, C. J.; Varma, R. S. Clean Technol. EnViron. Policy
005, 7, 62.
2
(
12) An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J.
Org. Chem. 1997, 62, 2505.
13) March, J. AdVanced Organic Chemistry; John Wiley & Sons: New
York, 1992; pp 375-386.
(
(15) Loupy, A.; Perreux, A. Tetrahedron 2001, 57, 9199.
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Org. Lett., Vol. 7, No. 12, 2005

Scheme 2. Possible Reaction Pathway
Figure 1. Favorable transition of product to the upper layer.
It is noteworthy that this reaction is not a homogeneous
single-phase reaction system, as neither reactant was soluble
in aqueous alkaline reaction medium. We postulate that
selective absorption of microwaves by polar molecules and
intermediates in a multiphase system could substitute as a
phase transfer catalyst without using any phase transfer
reaction time significantly and utilizes readily available
aniline and alkyl dihalide derivatives to assemble two C-N
bonds in a simple S 2-like sequential heterocyclization
N
protocol that has never been fully realized under conventional
reaction conditions. The protocol circumvents the difficulty
associated with running multistep reactions to assemble
N-aryl azacycloalkanes and avoids the use of expensive metal
catalysts in building aryl C-N bonds. Further, reactive
functional groups such as carbonyl, ester, and hydroxyl
groups, etc., remain unaffected under these mild reaction
conditions.
1
7
reagent, thereby providing the observed acceleration.
In large-scale experiments, the phase separation of the
desired product in either solid or liquid form from the
aqueous media can facilitate product purification by simple
filtration or decantation instead of tedious column chroma-
tography, distillation, or extraction processes and reduces the
usage of volatile organic solvent required for extraction or
column chromatography. A distinct phase separation is
exhibited in Figure 1 wherein the lower 1,4-dibromobutane
and aniline layer transition to the upper layer of 1-phenylpyr-
rolidine as the reaction proceeds to completion.
In brief, an efficient synthesis of N-aryl azacycloalkanes,
an important class of building blocks in natural products and
pharmaceuticals, has been discovered via double N-alkylation
of aniline derivatives accelerated under microwave irradiation
conditions in an aqueous medium. The method shortens the
Acknowledgment. This research was supported, in part,
by Postgraduate Research Program at the National Risk
Management Research Laboratory administered by the Oak
Ridge Institute for Science and Education through an
interagency agreement between the U.S. Department of
Energy and the U.S. Environmental Protection Agency.
Supporting Information Available: NMR, MS, HRMS,
and procedures for the synthsis of compounds 3a-k. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
16) de la Hoz, A.; D ´ı az-Ortiz, AÄ .; Moreno, A. Chem. Soc. ReV. 2005,
3
4, 164.
(17) Varma, R. S.; Naicker, K. P.; Kumar, D. J. Mol. Catal. A: Chem.
1
999, 149, 153.
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