Efficient microwave-assisted three-component one-pot preparation of 1-aryl-4-(2-acetoxyethyl)piperazines and 1-aryl-4-(2-acetoxyethyl)piperidines

Article abstract of DOI:10.1016/j.tetlet.2009.04.027

A highly efficient one-pot, three-component microwave-assisted procedure has been developed for the preparation of 1-(para-substituted-aryl)-4-(2-acetoxyethyl)piperazines and 1-(para-substituted-aryl)-4-(2-acetoxyethyl)piperidines. Microwave-accelerated h

Full text of DOI:10.1016/j.tetlet.2009.04.027

Tetrahedron Letters 50 (2009) 3813–3816
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Efficient microwave-assisted three-component one-pot preparation of
1-aryl-4-(2-acetoxyethyl)piperazines and 1-aryl-4-(2-acetoxyethyl)piperidines
*
*
S. Gabrielle Gladstone , William G. Earley , Jared K. Acker , Gregory S. Martin
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient one-pot, three-component microwave-assisted procedure has been developed for the
preparation of 1-(para-substituted-aryl)-4-(2-acetoxyethyl)piperazines and 1-(para-substituted-aryl)-4-
(2-acetoxyethyl)piperidines. Microwave-accelerated heating of electron-deficient aryl halides and potas-
sium acetate with either 1,4-diazabicyclo[2.2.2]octane (DABCO) or quinuclidine at 180 °C for 120 min
provided the title products in good yields and with general substrate scope. Similarly, subjection of potas-
sium pthalimide instead of potassium acetate to the same conditions provided good yields of 1-arylpip-
erazines and 1-arylpiperidines containing a 2-phthalimidoethyl substituent at the C-4 position.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 9 March 2009
Revised 2 April 2009
Accepted 6 April 2009
Available online 14 April 2009
1. Introduction
O
N
O
N
F3C
In medicinal chemistry, any given active pharmaceutical ingre-
dient (API) is directed at hundreds of biological targets. In an era of
rising competition and research costs, the desire for molecules that
are both biologically active and therapeutically versatile is strong.
Thus emerges the ‘privileged structure’ concept,1 in which particu-
lar small molecules (MW <500 Da) can bind to multiple receptors,
resulting in a great potential for diverse uses. Aryl piperazines and
aryl piperidines are such structures, with applications across sev-
eral therapeutic areas.2–7 This basic structure can be used both as
a substituent and as a series core in combinatorial libraries (Fig. 1).
In 1963, Ross and Finkelstein reported on the observation that a
high-temperature reaction between 4-chloronitrobenzene (1) and
1,4-diazabicyclo[2.2.2]octane (DABCO, 2) in benzyl alcohol did
not lead to the expected N-aryl quaternary ammonium salt 3, but
instead exclusively produced the quaternary ammonium salt 4
(Scheme 1).10 This product 4 was thought to arise from the addi-
tion of excess DABCO to the initial SNAr salt product 3, proceeding
through a ring-opening N-dealkylative process. Over two decades
later, Ibata et al.11 reported that a similar aromatic nucleophilic
substitution reaction of 1 with N-substituted pyrrolidines 5 under
high pressure gave the ring-opening salt products 6 as well as N-
dealkylation 4-pyrrolidinonitrobenzene products 7 in a ratio that
depended on the steric bulk and electronics of the amine substitu-
ent R.
H3CO
H3CO
oxypertine
N
N
HN
N
N
CF3
antrafenine
CH3
H
Figure 1. Two 4-arylpiperazine APIs: antrafenine, an analgesic,8 and oxypertine, a
neuroleptic.9
ent is an acetate or a phthalimide group tethered by a two-meth-
ylene unit. The corresponding piperidine congeners are also
prepared by this method. The procedure uses the microwave syn-
thesizer to efficiently achieve the appropriate reaction conditions
reported by thermal methods,12 but under very short times.
2. Preliminary reactions
Recently we reported a procedure in which the reaction be-
tween DABCO, activated hetaryl chlorides (e.g., 8) and an excess
of a third nucleophile can undergo a three-component, one-pot
microwave-assisted reaction to generate 1-hetaryl-4-(alkyl)piper-
azines 10, in which the alkyl group on nitrogen was a 2-substituted
ethyl group (Scheme 2).13 Although this two-step procedure was
conducted without isolation of the intermediates, it is possible that
any one of the three structures 9a–c are viable adducts from the
first step, and would be capable of reacting with a second nucleo-
phile (or excess DABCO) to generate products 10.
In this Letter we demonstrate the ability to create 1-(para-
substituted-aryl)-4-(alkyl)piperazines in which the alkyl substitu-
* Corresponding authors. Tel.: +1 518 512 2407; fax: +1 518 512 2085 (W.G.E.).
E-mail address: William.Earley@amriglobal.com (W.G. Earley).
Undergraduate Research Intern, May–August 2008.
Based on the results of the thermal reaction depicted in Scheme
1, we sought to adapt our microwave-based protocol in order to
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.027

3814
S. G. Gladstone et al. / Tetrahedron Letters 50 (2009) 3813–3816
O2N
O2N
Cl
O2N
N
PhCH2OH
Cl
N
N
N
Cl
160 °C, 70 h
N
95%
N
N
3
N
1
2
4
(not isolated)
O2N
O2N
O2N
R
0.75 GPa
R
N
N
N
THF, 80 °C
N
R
Cl
Cl
48 h
6
7
5
1
Scheme 1. First reported ring-opening reactions of quaternary salts generated thermally by SNAr reactions with tertiary amine nucleophiles.
Cl
Cl
N
N
N
N
N
2
1. DABCO ( ), THF
N
N
N
N
N
Cl
160 C, 15 min
°
9b
9a
microwave irradiation
N
N
8
N
N
Cl
9c
N
2. nucleophile
160 C, 15–45 min
N
N
Nuc
°
N
microwave irradiation
10
Scheme 2. Possible intermediates generated in the reaction of aryl halide 1 with DABCO (4).
Table 1
O2N
N
N
O2N
Cl
2
Optimization of reagent equivalents and solvent
DABCO ( ), CH3CN
N
180 °C, 30 min
microwave irradiation
Cl
O2N
DABCO (2)
10 equiv KOAc
N
1
4
O2N
7%
N
OAc
solvent, 180 °C
microwave irradiation
Cl
Scheme 3. Formation of quaternary ammonium product 4.
N
1
11
1 (equiv)
2 (equiv)
Solvent
Time (min)
Yield (%)
1
1
1
1
1
1
1
2
2
2
3
3
DMF
DMF
DMF
CH3CN
DMF
DMF
40
40
60
40
40
60
43
56
57
56
59
74
increase the utility of this transformation. In our initial studies, we
heated a 1:1 mixture of DABCO and 4-chloronitrobenzene in aceto-
nitrile at 180 °C in the microwave for 30 min. HPLC analysis of the
resulting mixture showed 93% of the recovered starting material 1
with only a 7% yield of the desired quaternary ammonium product
4 (Scheme 3).
We decided to investigate these reactions using a three-compo-
nent procedure, whereby interception of intermediates 9a and/or
9b with other nucleophiles would generate products akin to 10
in Scheme 2.
Upon further investigation of the ability of 4-halonitrobenzenes
12 to facilitate the reaction, bromide proved to be the best leaving
group, followed by chloro, then iodo and least of all fluoro, which
gave very poor yields of the desired product 11 (Table 2). The
3. Results and discussion
Table 2
Optimization of 4-halonitrobenzenes 12
We first decided to investigate the SNAr/ring-opening reaction
using DABCO and 4-chloronitrobenzene in various solvents with
potassium acetate to serve as our secondary nucleophile (Table
1). Our procedure was anticipated to prepare 2-[4-(4-nitro-
phenyl)piperazin-1-yl]ethyl acetate (11), which to date has only
been synthesized by a route using bromoethyl acetate.14 Our
hypothesis was that a suitable excess of potassium acetate would
allow a high enough concentration to act as our second nucleophile
onto the initial reaction intermediates (cf. Scheme 2). We soon dis-
covered that the reaction worked moderately well in DMF, and
progressed best when 3 M equiv of DABCO was used with 10 M e-
quiv of potassium acetate (Table 1). In practice, however, we
decided to limit the amount of DABCO to 2 equiv to better mimic
the utility of the reagent in practical use.15
O2N
O2N
2 equiv 2,10 equiv KOAc
N
OAc
180 °C, microwave irradiation
X
N
12
11
12 (equiv)
2 (equiv)
X
Solvent
Time (min)
Yield (%)
1
1
1
1
1
2
2
2
2
2
Cl
Br
I
F
OAc
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
57
68
37
NPa
NPa
a
No desired product isolated.

S. G. Gladstone et al. / Tetrahedron Letters 50 (2009) 3813–3816
3815
Table 3
A = CH) can be used in the transformation with aryl bromides to
Examination of other nucleophiles
prepare
1-(para-substituted-aryl)-4-(acetoxyethyl)piperidines
16b.
O2N
We were also interested to see the method applied to reactions
with heterocyclic substrates, and were pleased to find that an acti-
vated bromopyridine 17 and two electron-deficient halothioph-
enes 19 and 21 provided desired products, albeit in moderate
yields (Schemes 4 and 5). Combination of 5-bromopicolinonitrile
(17) with 2 equiv of quinuclidine (15) resulted in the formation
of the requisite 3-piperidino product 18 in good yield. Similarly,
the reaction of 2-bromo-5-nitrothiophene (19) with 1 equiv of 15
generated piperidine 20 in 57% yield.
Combination of 2 equiv of DABCO with 3-chloro-2-cyanothi-
ophene (21) under the optimized conditions did provide the 3-pip-
erazinothiophene 22, albeit in moderate yield after 3.5 h (Scheme
5). This product 22 with an electron-withdrawing functionality at
the ortho-position relative to the piperazine is noteworthy, as our
attempts to generate N-arylated piperazine products from the dis-
placement of 2-halonitrobenzene and 3-halonitrobenzene were
unsuccessful. We were, however, able to react DABCO with 4-bro-
mo-3-chloronitrobenzene (23) and potassium acetate to provide
the difunctional N-aryl adduct 24, albeit in moderate yield.
In conclusion, we have demonstrated that it is possible to inter-
cept the quaternary ammonium salt generated from 4-chloronitro-
benzene and DABCO or quinuclidine with nucleophiles to provide
1-(para-substituted-aryl)-4-(alkyl)piperazines or 1-(para-substi-
tuted-aryl)-4-(alkyl)piperidines in which the alkyl substituent is
an acetate or a phthalimide group tethered by a two-methylene
O2N
2, nucleophile
N
Nuc
DMF, 180 °C
microwave irradiation
Br
N
12
1 (equiv)
13
2 (equiv)
Nucleophile (Amt.)
Potassium acetate (10 equiv)
Potassium phthalimide (5 equiv)
Potassium cyanide (10 equiv)
Potassium hydroxide (10 equiv)
Sodium methoxide (10 equiv)
Yield (%)
1
1
1
1
1
3
2
3
3
2
69
68
NPa
NPa
NPa
a
No desired product isolated.
acetate was unreactive, eliminating the possibility of acetate add-
ing then being displaced.
Other alkali salts were examined for their ability to serve as
secondary nucleophiles (Table 3). Of the other nucleophiles tested,
potassium phthalimide was the only one which gave the desired
product 13 (Nuc = phthalimide).
The evaluation of different electron-withdrawing groups on the
para-position of the aryl bromide 14 was next explored to prepare
a series of 1-(para-substituted-aryl)-4-(acetoxyethyl)piperazines
16a (Table 4). This study provided an opportunity not only to ob-
serve the influence of different aryl substituents, but also to reveal
that in addition to the use of DABCO (2, A = N), quinuclidine (15,
Table 4
Examination of aryl para-substitution
EWG
N
A
EWG
10 equiv KOAc
N
OAc
DMF, 180 °C
microwave irradiation
Br
A
14
16a (A = N) or
16b (A = CH)
2 (A = N) or
15 (A = CH)
EWG
Amine
Time (h)
Yield (%)
NO2
NO2
COCH3
CN
CN
COPh
COPh
SO2CH3
SO2CH3
CF3
CF3
CO2CH3
CO2H
2 (A = N), 2 equiv
15 (A = CH), 2 equiv
2 (A = N), 2 equiv
2 (A = N), 2 equiv
15 (A = CH), 2 equiv
2 (A = N), 1 equiv
15 (A = CH), 1 equiv
2 (A = N), 2 equiv
15 (A = CH), 2 equiv
2 (A = N), 2 equiv
15 (A = CH), 2 equiv
2 (A = N), 2 equiv
2 (A = N), 2 equiv
1
1
3
2
4
1
3
2
2
1.5
4
2
2
68
62
16
52
60
24
33
43
51
9
49
NPa
NPa
a
No desired product isolated.
NC
N
N
10 equiv KOAc
NC
N
DMF, 180 °C, 3 h
microwave irradiation
N
OAc
Br
15
18
17
O2N
(2 equiv)
65%
O2N
N
10 equiv KOAc
S
S
DMF, 180 °C, 1 h
microwave irradiation
N
OAc
Br
15
20
19
(1 equiv)
57%
Scheme 4. Reaction of substituted heterocyclic halides with quinuclidine.

3816
S. G. Gladstone et al. / Tetrahedron Letters 50 (2009) 3813–3816
CN
CN
Cl
S
N
10 equiv KOAc
S
DMF, 180 °C, 3.5 h
microwave irradiation
N
OAc
N
2
N
22
21
(2 equiv)
38%
O2N
Cl
N
N
O2N
Cl
Br
10 equiv KOAc
DMF, 180 °C, 3 h
OAc
N
2
microwave irradiation
N
24
23
(2 equiv)
34%
Scheme 5. ortho-Substituted aryl halide substrates.
unit. We have also shown that different electron-withdraw-
ing groups can be used in place of the nitro moiety, and that het-
erocyclic aromatic compounds can react similarly to form
N-pyridinyl- and N-thiophenyl-piperidine adducts as well as N-
thiophenyl-piperazine derivatives. Thus, we have demonstrated
the successful microwave-assisted method for the synthesis of
cores useful for the generation of privileged structures.
7. (a) For example, as antibacterial agents: Matsui, M.; Adachi, M.; Mikamiyama,
H.; Matsumara, A.; Tsuno, N. PCT Int. Pat. Publ. WO 2007/099828, 2007.; (b)
Tsubochi, H.; Sasaki, H.; Kuroda, H.; Itotani, M.; Hasegawa, T.; Haraguchi, Y.;
Kuroda, T.; Matsuzaki, T.; Tai, K.; Komatsu, M.; Matsumoto, M.; Hashizume, H.;
Tomishige, T.; Seike, Y.;. Kawasaki, M.; Sumida, T.; Miyamura., S. PCT Int. Pat.
Publ. WO 2004033463, 2004.
8. Giudicelli, D.P.R.L.; Najer, H.; Manoury, P.M.J.; Dumas, A.P.F. US Pat. 3,935,229,
1976.
9. Archer, S.; Wylie, D. W.; Harris, L. S.; Lewis, T. R.; Schulenberg, J. W.; Bell, M. R.;
Kullnig, R. K.; Arnold, A. J. Am. Chem. Soc. 1962, 84, 1306–1307.
Acknowledgment
10. (a) Ross, S.; Finkelstein, M. J. Am. Chem. Soc. 1963, 85, 2603–2607; (b) Petersen,
R. C. J. Am. Chem. Soc. 1963, 85, 3999–4003.
11. Ibata, T.; Shang, M.-H.; Demura, T. Bull. Chem. Soc. Jpn. 1995, 68, 2941–2949.
12. For recent examples involving thermal protocols, see: (a) Reddy, N. D.; Elias, A.
J.; Vij, A. J. Chem. Soc., Dalton Trans. 1999, 1515–1518; (b) Axelsson, O.; Peters,
D. J. Heterocycl. Chem. 1997, 34, 461–463.
The authors would like to thank AMRI colleague R. Jason Herr
for his helpful advice and insight.
13. Wang, H.-J.; Earley, W. G.; Lewis, R. M.; Srivastava, R. R.; Zych, A. J.; Jenkins, D.
M.; Fairfax, D. J. Tetrahedron Lett. 2007, 48, 3043–3046.
References and notes
14. Wurster, S.; Engstrom, M.; Savola, J.; Hoeglund, I.; Sallinen, J.; Haapalinna, A.;
Tauber, A.; Hoffren, A.; Salo, H. WO 2001064645, 2001.
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15. Representative experimental procedure: Preparation of 2-[4-(4-nitro-
phenyl)piperazin-1-yl]ethyl acetate (11). All reactions were run on a 100 mg
scale of aryl halide. A 10 mL microwave reactor vial containing a magnetic stir
bar was charged with a 4-chloronitrobenzene (1, 0.634 mmol), DABCO (2,
1.27 mmol), potassium acetate (6.34 mmol), and DMF (6 mL). The vial was
sealed and irradiated in a SmithCreatorTM microwave reactor to reach 180 °C
over a 2-min ramp and held at 180 °C for up to 4 h. Reaction progress was
monitored with a PESciex API 150ex mass spectrometer with a Shimadzu LC-
10AD liquid chromatograph and LC SPD 10A UV–Vis detector. Upon
completion of the reaction, the solids were removed by vacuum filtration
4. For example, as serotonin reuptake inhibitors: Broekkamp, C. L. E.; Leysen, D.;
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through
a
Hirsch funnel, washing with dichloromethane (ꢀ20 mL). The
solvents were removed and the amorphous residue was purified by
chromatography on silica gel using a Teledyne-Isco CombiFlash unit. The
corresponding fractions were collected, the solvents were removed, and the
product was analyzed using a Bruker AV 300 MHz NMR spectrometer. Data for
compound 11: 1H NMR (300 MHz, CDCl3) d 8.13 (d, J = 9.3 Hz, 2H), 6.82 (d,
J = 9.3 Hz, 2H), 4.23 (t, J = 5.2 Hz, 2H), 3.43 m, 4H), 2.70–2.64 (m, 6H), 2.08 (s,
3H); APCI MS m/z 294 [M+H]+.
6. For example, as rhinovirus protease inhibitors: Reich, S. H.; Johnson, T.;
Wallace, M. B.; Kephart, S. E.; Fuhrman, S. A.; Worland, S. T.; Matthews, D.
A.; Hendrickson, T. F.; Chan, F.; Meador, J., III; Ferre, R. A.; Brown, E. L.;
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