Mono-acylation of piperazine and homopiperazine via ionic immobilization

Article abstract of DOI:10.1016/j.tetlet.2008.06.044

A method for the selective mono-acylation of piperazine and homopiperazine has been developed. In a flow system, initially the diamine is ionically immobilized on a sulfonic acid funtionalized silica gel, acylated with an appropriate reagent and finally liberated with ammonic methanol. Examples with high yield and purity are presented.

Full text of DOI:10.1016/j.tetlet.2008.06.044

Tetrahedron Letters 49 (2008) 5047–5049
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Tetrahedron Letters
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Mono-acylation of piperazine and homopiperazine via ionic immobilization
*
Wallace Pringle
Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the selective mono-acylation of piperazine and homopiperazine has been developed. In a
flow system, initially the diamine is ionically immobilized on a sulfonic acid funtionalized silica gel, acyl-
ated with an appropriate reagent and finally liberated with ammonic methanol. Examples with high yield
and purity are presented.
Received 16 May 2008
Revised 5 June 2008
Accepted 9 June 2008
Available online 13 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Mono-protected diamines are valuable synthetic intermediates
and have found use in drug-discovery,1 combinatorial2 and macro-
molecule3 synthesis. Traditional methods for the mono-acylation
of diamines in which both nitrogens exhibit similar (or identical)
reactivity often rely upon stoichiometric manipulation—typically
a large excess of the diamine relative to the acylating agent.4,5 This
strategy is less than ideal if the diamine is valuable and/or of lim-
ited supply. Additionally, a large excess of a reactant can lead to
isolation and purification challenges.
The solid-phase immobilization of diamines via covalent bond
formation followed by acylation then cleavage has successfully
produced mono-acylated diamines.6 Unfortunately, there are sev-
eral drawbacks to this approach; notably the expense of function-
alized resins for organic synthesis, the decreased reaction rates on
solid phase (vs solution-phase chemistry), and finally, the need for
two additional synthetic steps (resin binding and cleavage). This
Letter details a new method for the mono-acylation of diamines
which mitigates or eliminates the shortcomings of both solution-
phase and traditional solid-phase approaches.
component(s)—this has been coined ‘catch and release purification’.8
Interestingly, to date there are no known reports of successful
covalent bond formation on SCX ionically immobilized substrates.
In the initial investigations, homopiperazine (1a) in methanol
was loaded into a disposable cartridge of SCX.9 After a rinse se-
quence which transitioned the solvent to 100% DCM, the 1a loaded
cartridge was treated with (Boc)2O (2a). The solvent system was
transitioned back to 100% methanol, and the cartridge was eluted
with ammonia in methanol. Gratifyingly, evaporation of the
ammonic eluent provided essentially pure homopiperazine-1-car-
boxylic acid t-butyl ester (3a). The output of this SCX supported
mono-acylation of 1a was optimized through a series of titra-
tions,10 and iterative solvent and cartridge diameter explora-
tions.11 This exercise resulted in the following general procedure.
General procedure: A SCX cartridge9 was conditioned with MeOH
(2.5 mL),12 then diamine (0.5 M in MeOH, 300
lL, 150 lmol) was
added. The cartridge was rinsed with MeOH (2 ꢀ 2.5 mL), 25%
MeOH/EtOAc (2 ꢀ 2.5 mL), EtOAc (2 ꢀ 2.5 mL), and DCM (2 ꢀ
2.5 mL). The cartridge was then treated with an acylating agent
The past decade has seen tremendous progress in the concepts
and applications of solid-phase extractions (SPE) as purification
techniques.7 Notable among the various solid supports utilized
for SPE has been the emergence of silica-based strong cation
exchange (SCX) chromatography. In a typical SCX application, a
post-reaction mixture in a neutral solvent is passed through a car-
tridge containing a SCX sorbent (often a silica backbone function-
alized with a sulfonic acid containing hydrocarbon). The basic
components within the mixture undergo an acid-base reaction
with the immobilized acid, forming immobilized salts. The acidic
and/or neutral components within the mixture are washed
through the cartridge with neutral solvent. Finally, if the basic
component(s) from the original mixture is desired, the cartridge
is flushed with a solution basic enough to compete off the desired
(1.0 M in DCM, 450 lL, 450 lmol) followed by rinsings with DCM
(2 ꢀ 2.5 mL), EtOAc (2 ꢀ 2.5 mL), 25% MeOH/EtOAc (2 ꢀ 2.5 mL),
and MeOH (2 ꢀ 2.5 mL). Finally, the cartridge was ‘eluted to collect’
with NH3 (2 N in MeOH, 3 mL), and the resulting solution was con-
centrated to dryness and placed under a 2 mmHg vacuum for 1 h.
Using the general procedure specified above, 1a was reacted
with 2a on SCX. In a parallel reaction, piperazine (1b) was reacted
in an identical fashion (Scheme 1). GC analyses of the unconcen-
trated ammonic eluents showed them to both contain the desired
products (3a and 3b, respectively) along with unacylated starting
materials (1a and 1b, respectively). Yet, in both instances, concen-
tration of the ammonic eluents under reduced pressure provided
>97% pure mono-Boc products (yields are based upon 1a or 1b
used, purity gauged by 1H NMR). The yields of this process, using
1a and 2a, were improved to 64% by treating the immobilized di-
amine with two portions of 2a (1.0 M in DCM, 2 ꢀ 450
lL) and
otherwise following the general procedure (similarly, an 81% yield
* Tel.: +1 203 315 4607; fax: +1 203 483 7027.
E-mail address: wcpringle@yahoo.com
was obtained through treatment with three portions of 2a).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.044

5048
W. Pringle / Tetrahedron Letters 49 (2008) 5047–5049
Table 1
SCX supported acylation of 1a with various acylating agents
Entry
Acylating agent
Product
Producta/mg
(yieldb/%)
O
O
O
O
O
HN
1
12.0 (56)
N
N
O
O
O
HN
HN
2
3
12.0 (43)
9.6 (31)
O
O
O
N
N
Ph
O
Ph
Ph
O
O
O
O
HN
4
13.8 (39)
Ph
O N
O Bn
O
O
O
O
HN
HN
5c
17.3 (56)
5.8 (28)
N
N
Ph
Ph
CN
Cl
Ph
O
Scheme 1.
6
Ph
Unfortunately, other diamines examined which included
propane-1,3-diamine, N,N0-dimethyl-propane-1,3-diamine, trans-
cyclohexane-1,2-diamine, trans-N,N0-dimethyl-cyclohexane-1,2-
diamine, and trans-cyclohexane-1,4-diamine failed to provide
substantial yields of the desired mono-acylated products (provid-
ing predominantly unreacted starting diamine). The decreased
nucleophilicity of these diamines relative to 1a and 1b is one pos-
sible explanation—while another intriguing possibility (for the 1,2
and 1,3-diamine systems) is that chelation of the otherwise reac-
tive nitrogen with the proximal cationic ammonium precludes
reactivity. Increasing the dwell time of the acylating agents in
the presence of the immobilized diamines has the potential to
overcome this limitation and is currently under investigation.
The use of acid catalysis in the solution-phase t-butoxycarbony-
lation of amines is known13 (including catalysis with a sulfonic
acid functionalized silica gel),5 but this phenomenon is unknown
with alternate (i.e., non-t-butyl) acylating agents. Therefore, it
was of particular interest to explore the scope of this methodology
with a range of acylating agents. Utilizing the general procedure
above with 1a, while varying the acylating agent, provided an
interesting series of results (Table 1).
O
HN
(3c)
7
8
24.8 (75)
(2b)
N
Ph NCO
Ph NCS
HN Ph
S
HN
HN
15.6 (44)
N
N
HN Ph
O
9
19.4 (65)
NCO
HN
O
O
O
O
O
O
HN
HN
OPh
N
N
10
No desired product
No desired product
O
O
O
N
CN
Ph
11
a
Yields average of two runs; all products had >95% purity by 1H NMR.
Yields based upon amount of 1a used.
CAUTION: HCN produced.
Of the 11 acylating agents examined, only two: t-butyl phenyl
carbonate (entry 10) and ‘BOC-ON’, (entry 11) failed to react under
these conditions. These two failures are presumed to be caused by
the acylating agents mitigated reactivity relative to 2a (but it is
also possible that they failed due to their propensity to undergo
acid promoted decomposition). Of all the successful acylating
agents in this process, the lowest yield was obtained with benzoyl
chloride (Table 1, entry 6). Acylation with benzoyl chloride pro-
duces HCl—a strong enough acid to compete with the immobilized
sulfonic acid and cause the premature loss of substrates and
products.
To further demonstrate the utility of this methodology, a
scaled-up procedure was performed using 1a and 2a. This proce-
dure was performed on 50 g of SCX,9 which was loaded into a
34 mm inner diameter flash chromatography column. The general
procedure (above) was then followed at 100ꢀ scale.12 Thus, the
SCX was conditioned with 250 mL of MeOH and treated with 1a
b
c
(0.5 M in MeOH, 30 mL, 15 mmol), then rinsed with MeOH
(2 ꢀ 250 mL). This resulted in a 1.45 g yield of 3a (48% yield,
>97% pure by 1H NMR).14
In conclusion, a novel methodology for the mono-acylation of
diamines has been described. This system combines the selectivity
and purity associated with a traditional solid-phase approach with
the relative speed, yields, and scalability typified by solution-phase
synthesis. Studies of this new methodology continue in an attempt
to improve yields and broaden the scope of applicable diamines—
including investigations of the reactivity of unsymmetrical di-
amines. Additional synthetic transformations which exploit ionic
immobilization are currently under investigation.

W. Pringle / Tetrahedron Letters 49 (2008) 5047–5049
10. Titration example: the amounts of 2a and 2b (both 450
5049
l
mol) and SCX (0.50 g)
Acknowledgments
were held constant while increasing amounts of 1a were used. The yields of
products (3a and 3c) obtained are plotted against the amount of 1a used.
Special thanks are given to Mark Kershaw, Kevin Hodgetts,
Chris Lombardi, and Jeff Noonan for their insightful discussions
and support.
120%
100%
80%
60%
40%
20%
0%
3c
3a
References and notes
1. Lead in reference: Prante, O.; Tietze, R.; Hocke, C.; Loeber, S.; Huebner, H.;
Kuwert, T.; Gmeiner, P. J. Med. Chem. 2008, 51, 1800.
2. Lead in reference: Bettinetti, L.; Loeber, S.; Huebner, H.; Gmeiner, P. J. Comb.
Chem. 2005, 7, 309.
3. Lead in reference: Troshina, O. A.; Troshin, P. A.; Peregudov, A. S.; Kozlovski, V.
I.; Lyubovskaya, R. N. Chem.-Eur. J. 2006, 12, 5569.
4. Carpino, L. A.; Mansour, E. M. E.; Cheng, C. H.; Williams, J. R.; MacDonald, R.;
Knapczyk, J.; Carman, M.; Lopusinski, A. J. Org. Chem. 1983, 48, 661.
5. For a non-traditional example see: Das, B.; Venkateswarlu, K.; Krishnaiah, M.;
Holla, H. Tetrahedron Lett. 2006, 47, 7551.
0
100
200
Mol 1a loaded
300
400
μ
6. Oliver, M.; Jorgensen, M. R.; Miller, A. D. Synlett 2004, 453.
7. Poole, C. F.; Poole, S. K. In Solid-Phase Extraction: Principles, Techniques and
Applications; Simpson, N. J. K., Ed.; Marcel Dekker: New York, 2000; pp 183–
221.
8. Organ, M. G.; Dixon, C. E.; Mayhew, D.; Parks, D. J.; Arvanitis, E. A. Comb. Chem.
High Throughput Screen. 2002, 5, 211.
9. SCX cartridges purchased from United Chemicals Technologies, Inc. Bristol, PA
USA. Product name: ‘CUBCX1 (Benzenesulfonic acid)’. Specifications: 500 mg in
a 3 mL cartridge (loading = 0.7 meq/g). Loose SCX (i.e., not prepackaged in
cartridge format) was purchased from the same supplier (and had the same
loading).
11. In the reaction of 1a with 2a under the otherwise standard reaction conditions,
the smaller the diameter of the reaction tube (i.e., the longer the SCX bed), the
higher the yield of 3a.
12. With the small SCX cartridges (0.5–1.0 g SCX), the solvents were allowed to
‘gravity drain’. Upon scale-up, the solvent was forced through the SCX bed with
positive nitrogen pressure.
13. Suryakiran, N.; Prabhakar, P.; Reddy, T. S.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 8039.
14. Drying time under a 2 mmHg vacuum extended to 20 h.