Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: Microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives

Article abstract of DOI:10.1021/jo051878h

The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation is described. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.

Full text of DOI:10.1021/jo051878h

Aqueous N-Heterocyclization of Primary Amines and Hydrazines
with Dihalides: Microwave-Assisted Syntheses of
N-Azacycloalkanes, Isoindole, Pyrazole, Pyrazolidine, and
Phthalazine Derivatives
Yuhong Ju and Rajender S. Varma*
Clean Processes Branch, Sustainable Technology DiVision, National Risk Management Research
Laboratory, U.S. EnVironmental Protection Agency, 26 West Martin Luther King DriVe, MS 443,
Cincinnati, Ohio 45268
Ju.Yuhong@epa.goV; Varma.Rajender@epa.goV
ReceiVed September 7, 2005
The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines
and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs
under microwave irradiation is described. This improved greener synthetic methodology provides a simple
and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted
azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydro-
pyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.
Introduction
of green chemistry envisages minimum hazard as the perfor-
mance criteria while designing new chemical processes. The
target is to explore alternative reaction conditions3 and reaction
media to accomplish the desired chemical transformations with
minimum byproducts or waste generation, as well as to eliminate
the use of conventional organic solvents. The use of alternative
energy sources and alternate reaction media such as supercritical
fluids, poly(ethylene glycol) (PEG), and room ionic liquids is
gaining increasing popularity as well.4 Organic synthesis in an
aqueous medium is a lucrative research area considering its cost,
safety, and significance to environmentally benign process
Heterocycles are abundant in nature and are of great
significance to life because their structural subunits exist in many
natural products such as vitamins, hormones, antibiotics, and
alkaloids, as well as pharmaceuticals, herbicides, dyes, and many
more compounds.1 The concept of “green chemistry” is now
widely adopted to meet the fundamental scientific challenges
of protecting the human health and environment while simul-
taneously achieving commercial viability.2 The emerging area
* To whom correspondence should be addressed. Phone: +1-513-487-2701.
Fax: +1-513-569-7677.
(3) (a) Holbrey, J. D.; Turner, M. B.; Rogers, R. D. Ionic Liquids as
Green SolVents; ACS Symposium Series 856; American Chemical Soci-
ety: Washington, DC, 2003; pp 2-12. (b) 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). (c) Varma, R. S. Organic
Synthesis using Microwaves and Supported Reagents. In MicrowaVes in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany,
2002; pp 181-218. (d) Kappe, C. O.; Stadler, A. In MicrowaVes in Organic
and Medicinal Chemistry; Mannhold, R., Kubinyi, H., Folkers, G., Eds.;
Wiley-VCH: Werlag GmbH & Co. KGaA, Weinheim, Germany, 2005.
(1) (a) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry: 2000, 2nd ed.; Pergamon Press: New York, 2000. (b) Noga,
E. J.; Barthalmus, G. T.; Mitchell, M. K. Cell Biology Int. Rep. 1986, 10,
239. (c) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton, C.
J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (d) Kodama, T.; Tamura,
M.; Oda, T.; Yamazaki, Y.; Nishikawa, M.; Takemura, S.; Doi, T.;
Yoshinori, Y.; Ohkuchi, M. U.S. Patent 983928, 2003. (e) Padwa, A.; Bur,
S. Chem. ReV. 2004, 104, 2401.
(2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, NY, 1998.
10.1021/jo051878h CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/30/2005
J. Org. Chem. 2006, 71, 135-141
135

Ju and Varma
development,5 and the approach needs to be considered for
assembly of heterocyclic compounds.
SCHEME 1. Microwave-Accelerated Synthesis of Nitrogen
Heterocycles
Organic reactions assisted by microwave (MW) irradiation
have attracted considerable attention in the past decade for the
efficient and relatively friendlier synthesis of a variety of organic
compounds.6 Use of MW irradiation for the formation of carbon
heteroatoms, especially carbon-nitrogen bonds, has been re-
ported.7 Nitrogen-containing heterocycles are known subunits
in many natural products and biologically active pharmaceuti-
cals. Among these, azacycloalkanes, an important class of
compounds, are prepared via alkylation of primary amines with
glycol disulfonate in refluxed anhydrous dioxane,8 using
complicated multistep reactions,9 under harsh reaction condi-
tions10 or via coupling reactions using expensive metal cata-
lysts.11 The syntheses of dihydroisoindole derivatives include
borane-THF reduction of phthalimide,12 multistep metalation-
alkylation of formamidine,13 reductive amination of phthalde-
hyde by tetracarbonylhydridoferrate,14 and catalytic N-hetero-
cyclization using a Cp*Ir complex.15 The standard preparation
of 4,5-dihydropyrazoles involves the cyclocondensation of
hydrazine derivatives with R,â-unsaturated carbonyl com-
pounds16 or the reaction of hydrazine with substituted cyclo-
propanes,17 often requiring the use of a crown ether as a phase-
transfer catalyst.18 Pyrazolidines are usually prepared by the
condensation reaction of hydrazines with â-diketones or â-ke-
toesters or alternatively by reacting a protected hydrazine, di-
tert-butyldihydrazodiformate, with 1,3-dibromopropane in the
presence of a phase-transfer catalyst ultimately requiring a
sequential deprotection of the Boc group in 4 M HCl.19 To the
best of our knowledge, the direct syntheses of azacycloalkanes,
dihydroisoindole derivatives, 4,5-dihydropyrazoles, pyrazoli-
dines, and 1,2-dihydrophthalazines via a single-step one-pot
heterocyclization of primary amines or hydrazine derivatives
with alkyl dihalides or ditosylates have never been fully
explored.
In a broad program of developing efficient, selective, and
eco-friendly synthetic methods,20 we started exploring the use
of water as reaction media in conjunction with microwave
irradiation as a useful, environmentally benign alternative.21
Initial exploration of the reaction of aniline derivatives with
dihalides proved encouraging as it afforded N-aryl azacyclo-
alkanes,21a and the reaction was also applicable to aliphatic
primary amines. The scope of this general reaction was further
extended to assemble N-substituted 2,3-dihydro-1H-isoindoles
in excellent yields and with a great ease of purification.
Additionally, the application of this double alkylation approach
to hydrazine derivatives generated heterocycles with two
heteroatoms such as 4,5-dihydropyrazoles, pyrazolidines, and
1,2-dihydrophthalazines.21b Our results on the double alkylation
of amines and hydrazine by alkyl dihalides or ditosylates under
microwave irradiation in aqueous media in the presence of a
mild base, which provides a series of nitrogen-containing
heterocycles in a simple and straightforward approach (Scheme
1), are reported here.
(4) (a) Ionic Liquid in Synthesis; Wasserscheid, P., Welton, T., Eds.;
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(20) For reactions in ionic liquid, see: (a) Namboodiri, V. V.; Varma,
R. S. Chem. Commun. 2002, 342. (b) Namboodiri, V. V.; Varma, R. S.
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136 J. Org. Chem., Vol. 71, No. 1, 2006

Aqueous Heterocyclization of Amines and Hydrazines
Results and Discussion
vented, implying the involvement of a specific nonthermal
microwave effect which significantly accelerated the reaction.25
1. Choice of Reaction Media. To choose the most appropri-
ate medium in this heterocyclization reaction, the microwave-
assisted reaction of aniline and 1,4-dibromobutane was examined
under solvent-free condition and using water, poly(ethylene
glycol) with an average molecular weight of 300 (PEG 300),
acetonitrile, N,N-dimethylformamide (DMF), and toluene (Table
1). Reaction under solventless conditions, an approach that is
gaining popularity as it eliminates the use of volatile organic
solvents in synthesis,22 afforded very low yield (less than 20%)
because of the insolubility of the base in the reactants. PEG
300 has proven to be a promising medium as a replacement for
the volatile organic solvents,20f and although it is more expensive
than water, we found that, under microwave irradiation, PEG
300 breaks down to ethylene glycol in the presence of a base.
Acetonitrile and DMF are ideal polar aprotic solvents for
nucleophilic substitution that enhance the reaction rate of SN2
reactions.23 However, volatile acetonitrile gave a poor yield
because of its low boiling point, and use of DMF gave rise to
side reactions and therefore low product yields (∼40%). The
reaction in nonpolar toluene was a failure, as the yield was less
than 25%. Water is a good absorber for microwave energy24
and has been successfully employed as a solvent for various
organic syntheses; it turned out to be one of the best choices,
in view of its relatively environmental-friendly characteristics,
as a “cleaner” reaction medium.
SCHEME 2. Model Reaction Comparing MW Heating and
Conventional Heating
TABLE 2. Reaction Conversion under Conventional Heating
(Oil Bath)a
conversion based on
reaction time
(h)
ethyl 4-aminobenzoate
entry
(%)b
1
2
3
4
5
6
7
8
0.33
1.0
1.5
3.0
5.0
0
26
34
41
56
8.0
64 (58)c
63 (57)c
95 (91)c
24.0
0.33 (MW)d
a The temperature of the oil bath was 120 °C. b Conversions based on
quantitative GC-MS analyses. c Isolated yields in parentheses. d MW power
of 80-100 W at 120 °C for 20 min.
3. Microwave-Assisted Synthesis of Azacycloalkanes. The
microwave-accelerated heterocyclization reaction was applicable
to both aromatic and aliphatic primary amines and dihalides or
ditosylates. As exemplified in Table 3, the reactions proceeded
smoothly to completion within 20 min and furnished the
expected N-aryl and N-alkyl azacycloalkanes in fair to excellent
yields. The scope of this reaction in terms of using substituted
anilines, aliphatic primary amines, and functionalized dihalides
and ditosylates was examined, and the reaction was found to
tolerate various functionalities; acyl (entries 6, 10, and 11), ester
(entries 12-15) substituents, and reactive hydroxyl groups (entry
4) were unaffected in the course of the reaction. This feature
rendered the reaction even more practically useful to construct
the azacycloalkane moiety without tedious functional group
protection/deprotection procedures. Shorter reaction times,
simpler procedures, higher product yields, tolerance of functional
groups, and an aqueous nontoxic reaction medium are distin-
guished advantages over conventional transitional-metal-
catalyzed synthesis of heterocycles.26
4. Simple and Efficient Synthesis of 2,3-Dihydro-1H-
isoindoles. To broaden the scope of this MW-accelerated
heterocyclization approach, the assembly of an isoindoline
nucleus from reaction of primary amines with R,R-bishalo-o-
xylenes under aqueous MW irradiation was investigated. The
strategy turned out to be practically useful for the syntheses of
2,3-dihydro-1H-isoindoles and N-substituted 2,3-dihydro-1H-
isoindoles. This MW-assisted protocol greatly simplified the
workup procedure because the product precipitates out from the
aqueous reaction medium, and no flash column chromatography
was needed to separate the synthesized product. A simple
filtration and washing with cold hexanes afforded analytically
pure products. A variety of pharmaceutically significant 2,3-
dihydro-1H-isoindoles27 were prepared in good to excellent
yields by this novel MW approach (Table 4).
TABLE 1. Choice of Reaction Media
conversion
entry
reaction media
water
(%)
comments
1
2
3
89
19
30
media of choice
base insoluble in reactants
breaks down
none
poly(ethylene glycol)
(PEG 300)
4
5
acetonitrile
N,N-dimethylformamid
(DMF)
32
45
lower reaction temp
side reaction
6
toluene
24
base insoluble in toluene
2. Advantage of Using Microwave Heating. The reaction
between ethyl 4-aminobenzoate and 1,4-dibromobutane under
conventional and MW heating was investigated to demonstrate
the specific microwave effect that might be involved in the
reaction (Scheme 2). The reaction remained largely incomplete,
afforded very low product yields under conventional heating
conditions during a short reaction period, and gave rise to
undesired byproducts upon prolonged heating. However, the
same reaction under microwave irradiation for only 20 min
afforded excellent product yields (91%). As can be seen from
the results (Table 2), microwave irradiation exhibited several
advantages over the conventional heating by not only signifi-
cantly reducing the reaction time but also by improving the
reaction yield dramatically and, in the process, eliminating the
side reactions. Thus, the hydrolysis of esters to carboxylic acid
and alcohol and the transformation of bromides to hydroxides
under an alkaline reaction medium, which were both observed
in the reactions under conventional heating, could be circum-
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Hoz, A.; D´ıaz-Ortiz, AÄ .; Moreno, A. Chem. Soc. ReV. 2005, 34, 164. (c)
Jachuck, R. J. J.; Selvaraj, D. K.; Varma, R. S. Green Chem. 2006, 8,
Advanced Article. DOI: 10.1039/b512732g.
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J. Org. Chem, Vol. 71, No. 1, 2006 137

Ju and Varma
TABLE 3. Microwave-Accelerated Synthesis of Azacycloalkanesa
TABLE 4. Microwave-Accelerated Synthesis of
2,3-Dihydro-1H-isoindolesa
a All reactions were carried out at 1 mmol scale with a MW power of
80-100 W at 120 °C for 20 min. b The NMR spectra of all synthesized
isoindoles are in accord with the literature. c Isolated yields based on starting
amines. d Unknown compounds.
SCHEME 3. Double Alkylation of Hydrazines
dine, and 1,2-dihydrophthalazine derivatives via double alky-
lation of hydrazine derivatives by alkyl dihalides or ditosylates
in aqueous media under microwave irradiation were demon-
strated (Scheme 3). The general microwave protocol enabled
the synthesis of a wide variety of useful precursors for phar-
macologically active heterocycles using water as the reaction
medium in the absence of a phase-transfer agent and could be
an ideal substitute for hazardous organic solvents. The easy
experimental protocol utilizing readily available unprotected
hydrazine derivatives and alkyl dihalides/ditosylates are some
of the salient features. (Table 5).
6. Mechanistic Postulations. A plausible mechanism for the
heterocyclization reaction to form azacycloalkanes is proposed
in Scheme 4. 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,
a All reactions were carried out at 1 mmol scale with a MW power of
80-100 W at 120 °C for 20 min. b The NMR spectra of all synthesized
azacycloalkanes are in accord with the literature. c Isolated yields based on
starting amines. d Unknown compounds.
(27) Austin, N. E.; Avenell, K. Y.; Boyfield, I.; Branch, C. L.; Hadley,
M. S.; Jeffrey, P.; Johnson, C. N.; Macdonald, G. J.; Nash, D. J.; Riley, G.
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5. Syntheses of Pyrazole, Pyrazolidine, and Phthalazine
Derivatives. 4,5-Dihydropyrazoles,28 pyrazolidines,29 and 1,2-
dihydrophthalazines30 are important classes of heterocycles that
are useful as pesticides, anticonvulsants, and potent vasorelaxing
agents. The direct syntheses of 4,5-dihydropyrazole, pyrazoli-
138 J. Org. Chem., Vol. 71, No. 1, 2006

Aqueous Heterocyclization of Amines and Hydrazines
TABLE 5. Aqueous Cyclocondensation of Hydrazines with
Dihalides and Ditosylates Using Microwave Irradiationa
SCHEME 4. Possible Reaction Pathway Favored by MW
Irradiation
SCHEME 5. Proposed Mechanism for Cyclocondensation
Reactions
It is noteworthy to mention that these reactions are not
homogeneous, single-phase reaction systems, as neither reactant
is soluble in an 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 reagent,
thereby providing the observed acceleration similar to that of
ultrasound irradiation.31 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 by tedious column
chromatography, distillation, or extraction processes, thus reduc-
ing the use of volatile organic solvents for extraction or column
chromatography. In most of the reactions discussed herein, we
observed the completion of reactions simply indicated by phase
transition of lower-layered reactants to upper-layered products.
As exemplified by the reaction of aniline with 1,4-dibromobu-
tane, a distinct phase separation was exhibited (Figure 1)
wherein the lower 1,4-dibromobutane and the aniline layer
transitioned to the upper layer of 1-phenylpyrrolidine as the
reaction proceeded to completion.
a Reaction was carried out on a 1 mmol scale with a MW power of
70-100 W at 120 °C and a pressure of 40-80 psi for 20 min. b Isolated
yields based on starting hydrazines. c Structure isomer ratio determined by
NMR. d Yields based on quantitative GC-MS analysis of starting dihalides.
ionic intermediate and the microwave electric field when
compared to the less polar ground state. In a very similar manner
(Scheme 5), the double alkylation of hydrazine is favored by
MW irradiation because the increased polarity of 4′ and 6′ drives
the reaction to form 1-phenylpyrazolidine, 7′. The ease of
generation of a carbon-nitrogen double bond to finally afford
1-phenyl-4,5-dihydro-1H-pyrazole 3′ was explored in two
control experiments by introducing oxygen into the system or,
alternatively, by using activated palladium on carbon as a
dehydrogenation catalyst. It was found that oxygen in the air
plays a critical role in promoting the formation of a C-N double
bond instead of a C-N bond in the observed product via a
dehydrogenation mechanism, as was the case observed for
palladium-catalyzed dehydrogenation processes.
Conclusion
In conclusion, an efficient synthesis of azacycloalkanes,
isoindolidines, pyrazole, pyrazolidine, and phthalazine deriva-
tives, important classes of building blocks in natural products
and pharmaceuticals, was accomplished via double N-alkylation
(31) Varma, R. S.; Naicker, K. P.; Kumar, D. J. Mol. Catal. A: Chem.
1999, 149, 153.
J. Org. Chem, Vol. 71, No. 1, 2006 139

Ju and Varma
3.46 (m, 1H), 3.24 (m, 1H), 2.05 (m, 3H), 1.80 (m, 1H), 1.36 (q,
3H, J ) 7.0 Hz), 1.18 (d, 3H, J ) 6.5 Hz); 13C NMR (75.5 MHz,
CDCl3/TMS) δ ppm 167.2, 150.2, 131.0, 116.5, 110.8, 60.0, 53.7,
47.9, 32.9, 23.1, 18.9, 14.5; MS (EI) m/z (relative intensity, %)
233 (M, 29), 219 (16), 218 (100), 190 (36), 188 (19), 145 (7); HR-
MS (ESI) calcd (M + H)+ for C14H19NO2 234.1494 (C14H20NO2+),
found (M + H)+ 234.1508.
1-Benzylpyrrolidine (3s). The reaction of benzylamine (1.0
mmol, 0.106 g) and 1,4-dibromobutane (1.1 mmol, 0.231 g) was
carried out as described earlier and produced 0.143 g (89%) of
1
1-benzylpyrrolidine as a yellow oil: H NMR (300 MHz, CDCl3/
TMS) δ ppm 7.24 (m, 5H), 3.53 (s, 2H), 2.42 (m, 4H), 1.70 (m,
4H, J ) 4.6 Hz); 13C NMR (75.5 MHz, CDCl3/TMS) δ ppm 139.4,
128.9, 128.2, 126.9, 60.8, 54.2, 23.5; MS (EI) m/z (relative intensity,
%) 161 (M, 69), 160 (M+, 96), 91 (100), 84 (56), 70 (34), 42 (19);
HR-MS (ESI) calcd (M + H)+ for C11H15N 162.1283 (C11H16N+),
found (M + H)+ 162.1286.
Synthesis of 2,3-Dihydro-1H-isoindoles. Aniline (1.0 mmol,
0.093 g), 1.1 mmol 1,2-bisbromomethylbenzene (0.270 g), and 1.1
mmol potassium carbonate (0.162 g) in 2 mL of distilled water
were placed in a 10 mL crimp-sealed thick-walled glass tube
equipped with a pressure sensor and a magnetic stirrer. The reaction
tube was placed in a focused microwave synthesis system and
operated at 120 ( 5 °C using a power of 80-100 W and a pressure
of 40-80 psi for 20 min. After completion of the reaction, the
solid product was separated from the aqueous phase, filtered, and
washed with cold hexanes three times. This afforded the off-white,
solid, analytically pure 2-phenyl-2,3-dihydro-1H-isoindole in 92%
FIGURE 1. Favorable transition of the product to the upper layer.
of primary amines and hydrazine derivatives assisted by
microwave irradiation in an aqueous medium. This MW-
accelerated general approach shortened the reaction time
significantly and utilized readily available amines and hydrazines
with alkyl dihalides or ditosylates to assemble two C-N bonds
in a simple SN2-like sequential heterocyclization experimental
protocol which has never been fully realized under conventional
reaction conditions. Obtaining good to excellent product yields,
avoiding multistep reactions and functional group protection/
deprotection sequences to construct useful heterocycles, and
eliminating the use of expensive phase transfer- and transition-
metal catalysts are some of the salient features of this approach.
1
yield. Satisfactory H and 13C NMR data was obtained and was
consistent with those found in the literature.
2-(4-Ethylphenyl)-2,3-dihydro-1H-isoindole (3ad). The reaction
of 4-ethylaniline (1.0 mmol, 0.121 g) and 1,2-bischloromethylben-
zene (1.1 mmol, 0.195 g) was carried out as described earlier and
produced 0.196 g (88%) of 2-(4-ethylphenyl)-2,3-dihydro-1H-
isoindole as a yellow solid: 1H NMR (300 MHz, CDCl3/TMS) δ
ppm 7.29 (m, 4H), 7.14 (d, 2H, J ) 8.4 Hz), 6.62 (d, 2H, J ) 8.5
Hz), 4.61 (s, 4H), 2.57 (q, 2H, J ) 7.8 Hz), 1.22 (t, 3H, J ) 7.8
Hz); 13C NMR (75.5 MHz, CDCl3/TMS) δ ppm 145.4, 138.2, 132.0,
128.8, 127.1, 122.6, 111.7, 54.0, 28.0, 16.1; MS (EI) m/z (relative
intensity, %) 223 (M, 71), 222 (M+, 100), 208 (33), 206 (11), 193
(4), 165 (4), 104 (6), 90 (5), 77 (4); HR-MS (ESI) calcd (M + H)+
for C16H17N 224.1439 (C16H18N+), found (M + H)+ 224.1440.
2-Indan-5-yl-2,3-dihydro-1H-isoindole (3ae). The reaction of
indanyl-5-amine (1.0 mmol, 0.133 g) and 2-bischloromethylbenzene
(1.1 mmol, 0.195 g) was carried out as described earlier and
produced 0.197 g (84%) of 2-indan-5-yl-2,3-dihydro-1H-isoindole
as a light-yellow solid: 1H NMR (300 MHz, CDCl3/TMS) δ ppm
7.29 (m, 4H), 7.14 (m, 1H), 6.54 (s, 2H), 6.49 (t, J ) 8.2 Hz),
4.63 (s, 4H), 2.86 (t, 4H, J ) 9.8 Hz), 2.04 (m, 2H); 13C NMR
(75.5 MHz, CDCl3/TMS) δ ppm 146.2, 145.6, 138.1, 132.2, 127.1,
124.9, 122.5, 110.1, 108.0, 54.3, 33.4, 31.9, 25.8; MS (EI) m/z
(relative intensity, %) 235 (M, 61), 234 (M+, 100), 233 (14), 115
(9), 104 (4), 91 (4); HR-MS (ESI) calcd (M + H)+ for C17H17N
236.1439 (C17H18N+), found (M + H)+ 236.1436.
Syntheses of 4,5-Dihydropyrazole, Pyrazolidine, and 1,2-
Dihydrophthalazine Derivatives. 1,2-Diethylhydrazine dihydro-
chloride (1 mmol, 0.161 g), 1,2-bischloromethylbenzene (1 mmol,
0.175 g), 2 M sodium hydroxide (1 mL), and potassium carbonate
(1 mmol, 0.138 g) in water (1 mL) were placed in a 10 mL crimp-
sealed thick-walled glass tube equipped with a pressure sensor and
a magnetic stirrer. The reaction tube was placed inside the cavity
of a focused microwave synthesis system and operated at 120 ( 5
°C (temperature monitored by a built-in infrared sensor) using a
power of 70-100 W and a pressure of 40-80 psi for 20 min. After
completion of the reaction, the biphasic system was allowed to stir
in the air for 6 h, and the product was extracted into ethyl acetate.
The removal of the solvent under reduced pressure (rotary evapora-
tor) and flash column chromatography using hexane/ethyl acetate
Experimental Section
Synthesis of Azacycloalkanes. Aniline (1.0 mmol, 0.093 g), 1.1
mmol 1,4-dibromobutane (0.237 g), and 1.1 mmol potassium
carbonate (0.162 g) in 2 mL of distilled water were placed in a 10
mL crimp-sealed thick-walled glass tube equipped with a pressure
sensor and a magnetic stirrer. The reaction tube was placed in a
focused microwave synthesis system and operated at 120 ( 5 °C
using a power of 70-100 W and a pressure of 40-80 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 using hexane/ethyl
acetate (90:10) as eluent afforded the product, 1-phenylpyrrolidine,
1
in 89% yield. Satisfactory H and 13C NMR data are consistent
with those found in the literature.
1-(4-Ethylphenyl)pyrrolidine (3h). The reaction of 4-ethyl-
aniline (1.0 mmol, 0.121 g) and 1,4-butanediol ditosylate (1.1 mmol,
0.418 g) was carried out as described earlier and produced 0.154 g
(88%) of 1-(4-ethylphenyl)pyrrolidine as a yellow oil: 1H NMR
(300 MHz, CDCl3/TMS) δ ppm 7.04 (dd, 2H, J ) 8.4, 4.1 Hz),
6.51 (d, 2H, J ) 8.5, 4.2 Hz), 3.23 (t, 4H, J ) 6.6 Hz), 2.50 (q,
2H, J ) 7.5 Hz), 1.94 (t, 4H, J ) 6.6 Hz), 1.18 (t, 3H, J ) 7.5
Hz); 13C NMR (75.5 MHz, CDCl3/TMS) δ ppm 146.4, 131.3, 128.6,
111.9, 47.9, 28.0, 25.5, 16.2; MS (EI) m/z (relative intensity, %)
175 (M, 53), 174 (M+, 30), 160 (100), 119 (11), 118 (9), 91 (6),
77 (5); HR-MS (ESI) calcd (M + H)+ for C12H17N 176.1439
(C12H18N+), found (M + H)+ 176.1433.
4-(2-Methylpyrrolidinyl)benzoic Acid Ethyl Ester (3l). The
reaction of 4-aminobenzoic acid ethyl ester (1.0 mmol, 0.165 g)
and 1,4-dibromopentane (1.1 mmol, 0.253 g) was carried out as
described earlier and produced 0.207 g (89%) of 4-(2-methylpyr-
rolidinyl)benzoic acid ethyl ester as a yellow oil: 1H NMR (300
MHz, CDCl3/TMS) δ ppm 7.91 (d, 2H, J ) 8.5 Hz), 6.52 (d, 2H,
J ) 8.4 Hz), 4.32 (q, 2H, J ) 7.2 Hz), 3.96 (q, 1H, J ) 6.4 Hz),
140 J. Org. Chem., Vol. 71, No. 1, 2006

Aqueous Heterocyclization of Amines and Hydrazines
(9:1) as eluent afforded the product, 2,3-diethyl-1,2,3,4-tetrahy-
drophthalazine (0.114 g, 60% yield).
Mills, and Xuejun Pan are thanked for support of the HR-MS
analysis.
Acknowledgment. This research was supported, in part, by
the 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. Dr.’s Brian Boulanger, Marc
Supporting Information Available: Experimental procedures,
NMR spectrum, and HR-MS data for compounds 3h, 3l, 3s, 3ad,
and 3ae. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO051878H
J. Org. Chem, Vol. 71, No. 1, 2006 141