Concise synthesis of N3- and N6-monoprotected 3,6-diazabicyclo[3.1.1]heptanes; Useful intermediates for the preparation of novel bridged bicyclic piperazines

Article abstract of DOI:10.1016/j.tetlet.2012.08.156

Bridged bicyclic piperazines are important building blocks in medicinal chemistry research. The bicyclic piperazine 3,6-diazabicylo[3.1.1]heptane is of particular interest as a piperazine isostere because it is achiral and shows similar lipophilicity to that of piperazine based on the c Log P of a derived analog. A concise synthesis of N³- and N⁶-monoprotected 3,6-diazabicyclo[3.1.1]heptanes 2d and 2e, respectively, is described. The seven step sequence begins with inexpensive starting materials and uses straightforward chemistry.

Full text of DOI:10.1016/j.tetlet.2012.08.156

Tetrahedron Letters 53 (2012) 6332–6334
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise synthesis of N3- and N6-monoprotected
3,6-diazabicyclo[3.1.1]heptanes; useful intermediates for the preparation
of novel bridged bicyclic piperazines
⇑
Daniel P. Walker , Matthew W. Bedore
Kalexsyn, Inc., 4502 Campus Drive, Kalamazoo, MI 49008, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Bridged bicyclic piperazines are important building blocks in medicinal chemistry research. The bicyclic
piperazine 3,6-diazabicylo[3.1.1]heptane is of particular interest as a piperazine isostere because it is
achiral and shows similar lipophilicity to that of piperazine based on the cLogP of a derived analog. A
concise synthesis of N3- and N6-monoprotected 3,6-diazabicyclo[3.1.1]heptanes 2d and 2e, respectively,
is described. The seven step sequence begins with inexpensive starting materials and uses straightfor-
ward chemistry.
Received 16 August 2012
Revised 30 August 2012
Accepted 31 August 2012
Available online 19 September 2012
Keywords:
3,6-Diazabicyclo[3.1.1]heptane
Piperazine
Ó 2012 Elsevier Ltd. All rights reserved.
Bicyclic
Heterocycle
Azetidine
Introduction
containing analog (3b) suggest that 3a increases lipophilicity com-
pared to piperazine. The remaining two bicyclic piperazines in Fig-
Piperazines are used extensively in drug discovery research.
Numerous drugs approved by the FDA and other regulatory agen-
cies for the treatment of human diseases contain a piperazine ring.
Some examples are shown in Figure 1, including ciprofloxacin (1,
CiproÒ),1 sildenafil (ViagraÒ),2 ziprasidone (GeodoneÒ),3 and dasat-
inib (SprycelÒ).4 Over the years, several types of bridged bicyclic
piperazines have been developed as piperazine isosteres (Fig. 2);
many of these piperazine isosteres have shown desirable biological
activities for a number of pharmacological targets.5 In some in-
stances, the bicyclic analog showed enhanced biological activity
and/or selectivity compared to the corresponding piperazine
analog.5b,c,e,f
Of the parent bicyclic piperazines shown in Figure 2, 3,6-diaza-
bicyclo[3.1.1]heptane (2a) shows particular promise of becoming a
useful piperazine isostere due to its similarity in structure and
properties to piperazine. For example, cLogP calculations on fluo-
roquinolones 1 and 2b suggest the lipophilicity of 2a is comparable
to that of piperazine. In addition, 2a is achiral, which eliminates the
need to separate and test the individual enantiomers. Of the
remaining piperazines in Figure 2, 3a is also achiral, and a number
of reports have shown its utility as an effective piperazine isoste-
re.5a,c However, cLogP calculations on a derived fluoroquinolone-
ure 2, 4a and 5a, have also been utilized successfully as piperazine
surrogates;5a–f however, both of these piperazines are chiral.
Syntheses of the parent bridged bicyclic piperazines 3a,7 4a,8
and 5a,9 illustrated in Figure 2, have been previously described,
and some mono-N-protected versions of these bicyclic piperazines
O
Me
O
N
O
N
HN
F
O
O
N
OH
S
N
N
N
N
Me
OEt
HN
Cl
1
ciprofloxacin ( )
sildenafil
N
S
H
N
Cl
H
NH
N
N
O
N
N
Me
O
Me
N
N
HO
N
N
S
ziprasidone
dasatinib
⇑
Corresponding author. Tel.: +1 269 488 8471; fax: +1 269 488 8490.
E-mail addresses: dpwalker@kalexsyn.com, quassinoid@earthlink.net (D.P.
Figure 1. Marketed drugs possessing a piperazine ring.
Walker).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.156

D. P. Walker, M. W. Bedore / Tetrahedron Letters 53 (2012) 6332–6334
6333
6
N
b
O
O
O
O
a
R'
R'
N
1
R'
3
N
N
R
R
N
R
Cl
Cl
EtO
OEt
ref. 11b
ref. 14b
95%
N
Br Br
3a R = H, R' = H
3bc
2a R = H, R' = H
2bc R = H, R' = Ar
cLogP = -0.60a
10
1 R = H, R' = Ar
clogP = -0.70a
mlogP = -0.94b
9
R = H, R' = Ar
clogP = -0.32a
meso/ d,l = 4:6
2c
2d
2e
2f
R = Bn, R' = H
R = H, R' = BOC
R = Ns, R' = H
R = Ns, R' = BOC
d
e
EtO2C
X
EtO2C
CO2Et
N
H
Y
N
BOC
86%
Bn
85%
8, X=H, Y=CO2Et
c
53%
R'
R'
N
7
, X=CO2Et, Y=H
N
N
N
R
R
4a R = H, R' = H
4bd R = H, R' = Ar
clogP = -0.24a
5a
R = H, R' = H
HO
OH
5bd R = H, R' = Ar
N
BOC
clogP = 0.03a
6
O
O
O2N
O
O
F
S
Scheme 1. Preparation of diol 6. Reagents and conditions: (a) Br2, hm, 80 °C, 6 h;
OH
Ar =
Ns =
EtOH, 0 °C ? rt, 24 h; (b) BnNH2, DMF, 80 °C, 10 h; (c) NaH, toluene–DMF, 80 °C,
24 h; (d) H2, 20% Pd(OH)2/C, Boc2O, EtOH, 60 psi, 24 h; (e) NaBH4 (3.0 equiv), CaCl2
(3.0 equiv), MeOH, 0 ? 10 °C, 5 h.
N
Figure 2. Synthetic targets 2d–f and selected bridged bicyclic piperazine isosteres
(2a–5a) utilized in medicinal chemistry. aLipophilicity (LogPo/w
values were
TsO
OTs
a
b
)
6
calculated based on Molinspiration program predictions (Molinspiration Chemin-
formatics, Bratislava, Slovak Republic, http://www.molinspiration.com/cgi-bin/
properties). bMeasured LogP, see Ref. 6. cAnalogs 2b and 3b are virtual compounds
created to illustrate how their lipophilicities compare to ciprofloxacin (1). dFor the
preparation of analogs 4b and 5b, see Ref. 5b.
N
86%
76%
BOC
11
BOC
c
N
HN
81%
are commercially available. Pinna et al. recently described the
preparation of bicyclic piperazines 2c and 2d, which are N3- and
N6-monoprotected analogs of bicyclic piperazine 2a.10 While Pinna
et al. reported good yields for the preparation of piperazines 2c and
2d,10 the synthetic route is somewhat lengthy, requiring eight-
steps to prepare N3-substituted piperazine 2c and 10-steps to pre-
pare N6-substituted piperazine 2d from commercial material. In
connection with our on-going efforts to prepare isosteres of satu-
rated heterocycles as useful building blocks for medicinal chemis-
try,11 we became interested in developing a more concise synthesis
of N3- and N6-monoprotected analogs of bicyclic piperazine 2a. We
detail below a seven-step synthesis of N3- and N6-monoprotected
bicyclic piperazines 2e and 2d in which either compound is de-
rived from a common intermediate (2f, Fig. 2).
BOC
N
Ns
2d
2e
N
2f
NH
d
Ns
N
89%
Scheme 2. Preparation of bicyclic piperazines 2d and 2e. Reagents and conditions:
(a) Ts2O (2.2 equiv), pyridine, 0 °C rt, 24 h; (b) 2-nitrobenzenesulfonamide
?
(2.0 equiv), DBU (3.0 equiv), CH3CN, reflux, 6 h; (c) C12H25SH (2.0 equiv), LiOHÁH2O
(2.0 equiv), DMF, rt, 2 h; (d) TsOHÁH2O (2.0 equiv), EtOH, reflux, 1 h.
(Scheme 2). In a prior study, we described a method for the forma-
tion of a pyrrolidine ring via a single pot, double N-alkylation of
nitrobenzenesulfonamide.15 We were pleased to find that method-
ology could be extended to the present substrate. Thus, treatment
of bis(tosylate) 11 with 2-nitrobenzenesulfonamide in the pres-
ence of DBU afforded a 76% yield of bicyclic piperazine 2f. With
orthogonally protected bicyclic piperazine 2f in hand, treatment
of 2f with lithium hydroxide and dodecanethiol,16 a low cost and
near-odorless mercaptan, afforded an 81% yield of N6-monopro-
tected piperazine 2d. Fortunately, no by-product resulting from
thiolate addition to the carbon bearing the nitro group could be de-
tected. This result is consistent with observations made by Wuts
et al. who noted that the o-nosyl group is less likely to produce
the nitro group-displacement by-product than the p-nosyl group.17
The spectral properties of our 2d were identical to those reported
in the literature.10 Alternatively, subjection of 2f to p-toluenesul-
fonic acid led to an 89% yield of N3-monoprotected piperazine 2e.
The spectral properties of 2e were in complete agreement with
the desired structure.
Results and discussion
Our synthesis of N3- and N6-monoprotected bicyclic piperazines
2e and 2d commenced from the known azetidinediol
6
(Scheme 1),11b which was originally prepared by Evans et al.12 In
our hands, azetidine 6 was synthesized in 2-steps from cis-azeti-
dine diester 7 using a modified protocol from what Evans originally
reported.11b Employing conditions originally disclosed by Kozi-
kowski et al. on a related substrate,13 a separable 1:1 mixture of
cis/trans-azetidine diesters 7 and 8 was synthesized in 75% yield
from dibromide 9. The overall yield of the cis-isomer (7) could be
increased from 37% to 58% by equilibrating the undesired trans-
isomer (8).11b Dibromide 9 was conveniently prepared in 95% yield
from commercial glutaryl chloride (10) using Guanti and Riva’s
procedure.14
With the availability of azetidinediol 6, efforts were directed at
piperazine ring formation. Toward this end, exposure of diol 6 to p-
toluenesulfonic anhydride gave rise (86%) to bis(tosylate) 11

6334
D. P. Walker, M. W. Bedore / Tetrahedron Letters 53 (2012) 6332–6334
T.; Inigo, I.; Johnston, K.; Kamath, A.; Kan, D.; Klei, H.; Marathe, P.; Pang, S.;
In summary, we have developed a concise synthesis of N3- and
Peterson, R.; Pitt, S.; Schieven, G. L.; Schmidt, R. J.; Tokarski, J.; Wen, M.-L.;
Wityak, J.; Borzilleri, R. M. J. Med. Chem. 2004, 47, 6658.
N6-monoprotected 3,6-diazabicyclo[3.1.1]heptanes 2e and 2d. The
seven step synthesis features straightforward chemistry starting
from inexpensive glutaryl chloride. The overall yields of 2d and
2e were 14% and 15%, respectively.18 Given the similarities in
structure and predicted lipophilicity between bicyclic piperazine
2a and piperazine, it is anticipated that monoprotected bicyclic
piperazines 2d and 2e will become useful building blocks in medic-
inal chemistry research.
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Acknowledgment
We thank Greg Cavey of the Southwest Michigan Innovation
Center Core Lab for accurate mass measurement, which is sup-
ported, in part, by the Michigan Economic Development Corpora-
tion (MEDC).
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Supplementary data
11. (a) Wishka, D. G.; Beagley, P.; Lyon, J.; Farley, K. A.; Walker, D. P. Synthesis 2011,
2619; (b) Walker, D. P.; Eklov, B. M.; Bedore, M. W. Synthesis 2012,
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Supplementary data (experimental procedures and character-
ization data for all new compounds (11, 2d–f) and copies of NMR
spectra) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.156.
References and notes
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18. By subjecting the undesired trans-isomer
8 to one iteration of cis/ trans
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and 22%, respectively.