Synthesis of chromanyl and dihydrobenzofuranyl piperazines

Article abstract of DOI:10.1016/j.tetlet.2007.02.121

The synthesis of a series of regioisomeric chromanyl and dihydrobenzofuranyl piperazines is described.

Full text of DOI:10.1016/j.tetlet.2007.02.121

Tetrahedron Letters 48 (2007) 3039–3041
Synthesis of chromanyl and dihydrobenzofuranyl piperazines
a,
a
David A. Favor,a,* Douglas S. Johnson, James J. Powers,
*
Tingsheng Lib and Rambabu Madabattulab
aPfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
bNAEJA Pharmaceuticals, 4290-091 Edmonton, Canada T6E5V2
Received 20 February 2007; accepted 24 February 2007
Available online 1 March 2007
Abstract—The synthesis of a series of regioisomeric chromanyl and dihydrobenzofuranyl piperazines is described.
Ó 2007 Elsevier Ltd. All rights reserved.
O
4-Arylpiperazines are considered ‘privileged’ templates
in drug discovery.1 This core structure is found in
numerous biologically active compounds and drugs for
a number of indications and mechanisms. Prominent
among these are their activity against monoamine based
GPCRs, namely, dopaminergic,2 serotonergic,3 and
adrenergic4 GPCRs. Subtle structural changes of the
arylpiperazine moiety of a lead molecule are often
desired in order to optimize the potency and selectivity
against these receptors and modulate the physical and
ADME (absorption, distribution, metabolism, and
elimination) properties of the molecule. Often, these
derivatives have similar structural characteristics (i.e.,
MW, cLogP, cLogD, polar surface area) but are pre-
pared using very different starting materials. Herein we
describe the synthesis of a series of regioisomeric chro-
manyl and dihydrobenzofuranyl piperazines, including
1-dihydroisobenzofuranyl- (1), 1-dihydrobenzofuranyl-
(2), 1-isochromanyl- (4 and 5), and 1-chromanyl-pipera-
zine (6). The synthesis of 35,6 and 75 have been disclosed
previously.
O
O
N
N
N
N
H
N
H
N
H
1
2
3
O
O
O
O
N
N
N
N
N
H
4
N
H
5
N
H
6
N
H
7
90% yield of isobenzofuran 10. Reduction of the nitro
group afforded aniline 11 in quantitative yield. The
piperazine was formed by reacting aniline 11 with bis-
(2-chloro-ethyl)-amine in the presence of diisopropylethyl-
amine in refluxing chlorobenzene to afford 1 in moderate
yield.
The synthesis of previously unreported 1-(1,3-dihydro-
isobenzofuran-4-yl)-piperazine (1) began with bromina-
tion of 1,2-dimethyl-3-nitro-benzene (8) as shown in
Scheme 1. The resultant dibromide 9 was converted to
isobenzofuran 10 by exposure to dry alumina and
1 equiv of water using a slightly modified procedure of
Mirhara et al.7 Our modification involved using toluene
instead of the reported hexanes in order to be able to in-
crease the reaction temperature to 120 °C resulting in a
The synthesis of 1-(2,3-dihydro-benzofuran-4-yl)-piper-
azine (2)8 commenced with acylation of m-anisidine with
Boc-anhydride to give 13 (Scheme 2). Directed lithiation
of 13 with tert-butyl lithium followed by quenching with
ethylene oxide at low temperature provided 14.9 Treat-
ment of 14 with PPA at 125 °C resulted in cleavage
of the methyl ether followed by cyclization to provide
4-amino-2,3-dihydrobenzofuran (15).9 The piperazine
was introduced in a similar fashion as described in
Scheme 1 to give 2.
*
Corresponding authors. E-mail addresses: david.favor@pfizer.com;
doug.johnson@pfizer.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.121

3040
D. A. Favor et al. / Tetrahedron Letters 48 (2007) 3039–3041
In an analogous fashion to 4, previously unreported 1-
Br
Br
b
a
O
isochroman-8-yl-piperazine (5) was synthesized (Scheme
4). The key intermediate, 8-bromo-isochroman (24), was
formed by the TiCl4-promoted cyclization of 1-bromo-
NO2
NO2
NO2
10
8
9
3-(2-((2-methoxyethoxy)methoxy)ethyl)benzene
(23).
Unlike in the isochroman-5-yl-piperazine (4) synthesis,
the ring closure of the oxonium intermediate can occur
to form two different regioisomers 24 and 25. The regio-
selectivity of this cyclization was ꢀ4:1 favoring the
undesired bromo-isochroman 25 over the desired 24
which is presumably driven by sterics. Changes in tem-
perature and Lewis acids had little effect on the regio-
selectivity. Fortunately, these isomers were separable
via column chromatography. Aryl bromide 24 was con-
verted to 5 via a two step sequence of Buchwald amina-
tion followed by removal of the N-Boc group.
d
c
O
O
N
NH2
11
1
N
H
Scheme 1. Reagents and conditions: (a) NBS (2.1 equiv), benzoyl
peroxide, CCl4, 90%; (b) dry alumina, 1 equiv H2O, toluene, 120 °C,
90%; (c) Raney Ni, H2, THF, quant; (d) bis-(2-chloro-ethyl)amine
hydrochloride, iPr2EtN, PhCl, reflux, 54%.
The synthesis of 1-chroman-5-yl-piperazine (6)12 in-
volved a ring-closing metathesis strategy (Scheme 5).13
Stille coupling of 27 with tributylvinyltin provided sty-
rene 28. Subsequent allylation of 28 with allyl bromide
in the presence of K2CO3 afforded the requisite diene
29. Ring-closing metathesis of 29 using Grubbs’ second
generation ruthenium catalyst proceeded smoothly to
give the chromene 30. The alkene and the nitro group
MeO
MeO
MeO
a
b
HO
NHBoc
14
NH2
NHBoc
12
13
O
O
d
c
NH2
15
N
2
O
N
H
b
24 Br
a
+
OH
MEMO
Scheme 2. Reagents and conditions: (a) Boc2O, dioxane, 35 °C, 3 d,
82%; (b) t-BuLi, ethylene oxide, Et2O, À50 to 15 °C, 28%; (c) PPA,
125 °C; (d) bis-(2-chloro-ethyl)amine hydrochloride, iPr2EtN, NaI,
PhCl, cyclohexyl alcohol, 140 °C, 30% over two steps.
O
Br
22
Br
23
Br
25
HN
The synthesis of previously unreported 1-isochroman-5-
yl-piperazine (4) is shown in Scheme 3. Key to the con-
struction of 4 was the formation of the isochroman ring
via an intramolecular oxonium cyclization. The precur-
sor to the cyclization was formed by conversion of 2-
(2-bromo-phenyl)-ethanol (16) to its corresponding
(2-methoxyethoxy)methyl ether 17. This was cyclized
to form isochroman 18 by exposure to TiCl4.10 Aryl bro-
mide 18 was coupled with N-Boc-piperazine (20) under
Buchwald amination11 conditions followed by N-Boc
deprotection to afford 1-isochroman-5-yl-piperazine (4).
N
Boc
O
O
d
20
O
c
N
N
Br
24
26
5
N
N
H
Boc
Scheme 4. Reagents and conditions: (a) MEMCl, Et3N, CH2Cl2, 0 °C,
96%; (b) TiCl4, CH2Cl2, 0 °C, 75% (1:3.4 ratio of isomers); (c)
Pd2(dba)3, NaOtBu, BINAP, toluene, 110 °C, 81%; (d) TFA, CH2Cl2,
0 °C, 90%.
O
HO
Br
HO
O
b
a
b
c
a
MEMO
HO
Br
Br
Br
16
NO2
29
NO2
NO2
17
18
27
28
HN
O
O
O
N
O
O
d
e
Boc
d
O
20
c
N
N
N
N
NO2
NH2
Br
30
31
6
N
H
21
4
18
N
H
Boc
Scheme 5. Reagents and conditions: (a) H2C@CHSnBu3, 10 mol %
Pd(Ph3P)4, toluene, reflux, 44%; (b) H2C@CHCH2Br, K2CO3, acetone,
reflux, 81%; (c) 5 mol % 2nd generation Grubbs catalyst, CH2Cl2, 98%;
(d) H2, 10% Pd/C, MeOH, 100%; (e) bis-(2-chloro-ethyl)amine
hydrochloride, iPr2EtN, NaI, PhCl, cyclohexyl alcohol, 140 °C, 55%.
Scheme 3. Reagents and conditions: (a) MEMCl, Et3N, CH2Cl2, 0 °C,
80%; (b) TiCl4, CH2Cl2, 0 °C, 82%; (c) Pd(OAc)2, NaOtBu, 2-
(dicyclohexylphosphino)biphenyl, toluene, 80–90 °C, 60%; (d) TFA,
CH2Cl2, 0 °C, quant.

D. A. Favor et al. / Tetrahedron Letters 48 (2007) 3039–3041
3041
were both reduced via catalytic hydrogenation to give
References and notes
aminochroman 31. Finally the piperazine was formed
by reacting 31 with bis-(2-chloro-ethyl)-amine in the
presence of diisopropylethylamine and sodium iodide
in refluxing chlorobenzene with a small amount of cyclo-
hexanol to afford 6 in moderate yield.
1. Coudert, P.; Rubat, C.; Bastide, M.; Malhuret, R.;
Chopineau, J. J. Pharm. Belg. 1995, 50, 445–454.
2. (a) Soskic, V.; Joksimovic, J. Curr. Med. Chem. 1998,
5, 493–512; (b) Zhang, A.; Kan, Y.; Li, F. Exp.
Opin. Ther. Pat. 2006, 16, 587–630; (c) Zhang, A.;
Neumeyer, J. L.; Baldessarini, R. J. Chem. Rev. 2007,
107, 274–302.
3. Pessoa-Mahana, H.; Araya-Maturana, R.; Claudio Saitz,
B.; Pessoa-Mahana, C. D. Mini-Rev. Med. Chem. 2003, 3,
77–93.
4. Manetti, F.; Corelli, F.; Strappaghetti, G.; Botta, M. Curr.
Med. Chem. 2002, 9, 1303–1321.
5. Kerrigan, F.; Martin, C.; Thomas, G. H. Tetrahedron
Lett. 1998, 39, 2219–2222.
6. Kling, A.; Lange, U. E. W.; Mack, H.; Bakker, M. H. M.;
Drescher, K. U.; Hornberger, W.; Hutchins, C. W.;
Moeller, A.; Mueller, R.; Schmidt, M.; Unger, L.; Wicke,
K.; Schellhaas, K.; Steiner, G. Bioorg. Med. Chem. Lett.
2005, 15, 5567–5573.
In summary, we have expanded the toolbox of 2,3-bi-
cyclic arylpiperazines. In many cases, incorporation of
these piperazines (1–7) into lead molecules resulted in
an improved solubility and metabolic stability profile
especially when compared with the corresponding indan-
yl- and tetrahydro-naphthalenyl-piperazines 32 and 33.
This is partially due to the reduced lipophilicity of 1–7
where incorporation of the oxygen atom lowers the
clogP by approximately 1–2 log units.14,15
O
decrease
clogP
7. Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M.
Synlett 2002, 1526–1528.
N
N
N
8. Jpn. Kokai Tokkyo Koho. JP 61,152,655 A2, 1986.
9. Marburg, S.; Tolman, R. L. J. Heterocycl. Chem. 1980, 17,
1333.
10. Mohler, D. L.; Thompson, D. W. Tetrahedron Lett. 1987,
28, 2567–2570.
N
H
32
N
H
33
N
H
1 - 7
11. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158–1174.
Acknowledgments
12. Van Hes, R.; Smid, P.; Kruse, C. G.; Tulp, Martinus T.
M. PCT Int. Appl., WO 2006061374 A1, 2006.
13. (a) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321–
5324; (b) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
864–866.
We would like to acknowledge Andrew White, Joseph
Repine and Michael Stier for helpful discussions.
14. van de Waterbeemd, H.; Gifford, E. Nat. Rev. Drug Dis.
2003, 2, 192–204.
Supplementary data
15. Thomas, V. H.; Bhattachar, S.; Hitchingham, L.; Zochar-
ski, P.; Naath, M.; Surendran, N.; Stoner, C. L.; El-
Kattan, A. Expert Opin. Drug Metab. Toxicol. 2006, 2,
591–608.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.121.