Complete regioselective addition of grignard reagents to pyrazine N-oxides, toward an efficient enantioselective synthesis of substituted piperazines

Article abstract of DOI:10.1021/ol902619h

(Figure presented) A conceptually new one-pot strategy for the synthesis of protected substituted piperazines via the addition of Grignard reagents to pyrazine N-oxides is presented. This strategy is high yielding (33-91% over three steps), step-efficient, and fast. The synthesized N,N-diprotected piperazines are convenient to handle and allow for orthogonal deprotection at either nitrogen for selective transformations. In addition, this Is a synthetic route to enantiomerically enriched piperazines by using a combination of phenyl magnesium chloride and (-)-sparteine, which resulted In enantiomeric excesses up to 83%.

Full text of DOI:10.1021/ol902619h

ORGANIC
LETTERS
2010
Vol. 12, No. 2
284-286
Complete Regioselective Addition of
Grignard Reagents to Pyrazine
N-Oxides, Toward an Efficient
Enantioselective Synthesis of
Substituted Piperazines
Hans Andersson,† Thomas Sainte-Luce Banchelin,† Sajal Das,†
Magnus Gustafsson,‡ Roger Olsson,*,‡,⊥ and Fredrik Almqvist*,†
Department of Chemistry, Umeå UniVersity, SE-90187 Umeå, Sweden, ACADIA
Pharmaceuticals AB, Medeon Science Park S-20512, Malmo¨, Sweden, and Department
of Chemistry, UniVersity of Gothenburg, KemiVa¨gen 10, 41296 Gothenburg
roger@acadia-pharm.com; fredrik.almqVist@chem.umu.se
Received November 12, 2009
ABSTRACT
A conceptually new one-pot strategy for the synthesis of protected substituted piperazines via the addition of Grignard reagents to pyrazine
N-oxides is presented. This strategy is high yielding (33-91% over three steps), step-efficient, and fast. The synthesized N,N-diprotected
piperazines are convenient to handle and allow for orthogonal deprotection at either nitrogen for selective transformations. In addition, this
is a synthetic route to enantiomerically enriched piperazines by using a combination of phenyl magnesium chloride and (-)-sparteine, which
resulted in enantiomeric excesses up to 83%.
Organometallic additions to activated pyrazines have received
little or no attention, whereas the analogous reactions for
pyridines are expedient methods for the synthesis of substi-
tuted pyridines1 and piperidines.2 For the synthesis of
substituted piperazines, this is especially surprising, as
organometallic additions to activated pyrazines potentially
constitute an efficient route to this class of privileged
structures.3 In a recent survey it was shown that piperazines
are among the most frequently occurring structural motifs
in drugs; in fact, more than 60 of the analyzed orally
administrated drugs contained a piperazine fragment.4 Typi-
cally, piperazines are currently obtained by hydrogenation
of substituted pyrazines5 or via various cyclocondensation
† Umeå University.
‡ Acadia Pharmaceuticals AB.
⊥ University of Gothenburg.
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10.1021/ol902619h  2010 American Chemical Society
Published on Web 12/11/2009

reactions.6 However, although hydrogenation is an efficient
strategy, it has limitations in terms of starting materials
because it requires the corresponding substituted pyrazines
to be available. The catalyst required can also be costly, and
the potential presence of catalyst traces in the product may
complicate its use in late stages of pharmaceutical synthesis.
Furthermore, asymmetric hydrogenation has only been
reported for pyrazine carboxylic acid derivates, with an ee
up to 78%.7 The synthesis of piperazines via cycloconden-
sation reactions often requires multistep synthesis, and the
structural diversity is limited depending on the access of
commercially available starting materials. In 2009, Guercio
et al. reported on an excellent scalable route to a chirally
pure arylpiperazine based on a dynamic kinetic resolution.
This key fragment, used in the synthesis of the NK1
antagonist GW597599, was synthesized after significant
optimization in an overall yield of 60% over nine steps.8
Herein, we report a conceptually new synthesis of sub-
stituted piperazines via the reaction between Grignard
reagents and activated pyrazines (i.e., pyrazine N-oxides (1))
followed by a reduction. After N-Boc protection, the corre-
sponding N,N-diprotected substituted piperazines formed are
easy to handle and can be orthogonally deprotected giving
the opportunity of synthetic modifications on either nitrogen.
This synthetic sequence is performed in one pot with only a
purification of the final product. Finally we show that in the
presence of (-)-sparteine this reaction offers an enantiose-
lective synthesis to substituted piperazines.
Table 1. One-Pot Synthesis of Substituted Piperazinesc
The reaction was explored in studies using pyrazine
N-oxide (1) and phenylmagnesium chloride, which indicated
that addition of pyrazine N-oxide to Grignard reagents at
-78 °C in dichloromethane followed by reduction with
NaBH4 and protection with di-tert-butyl dicarbonate anhy-
dride gave the best results. The N-Boc protected N-hydroxyl
piperazine 2a was isolated in an excellent 91% yield,
considering that it is a three-step, one-pot synthesis. Several
Grignard reagents were reacted with pyrazine N-oxide (1)
to give substituted piperazines (2) in good to high yields
(Table 1).
a Yields of isolated products. b Also performed in gram-scale resulting
in piperazine 2a in a isolated yield of 76%. c Reaction conditions: N-oxide
(1 equiv) in CH2Cl2, Grignard reagent (2.5 equiv), NaBH4 (1.1 equiv) in 2
mL of MeOH, Boc2O (3.0 equiv).
The addition of 4-biphenylmagnesium chloride gave 2h
in 67% yield, whereas the sterically more demanding
2-biphenylmagnesium chloride yielded the corresponding
piperazine 2i in 33% yield (entries 8 and 9, Table 1). Notably,
the steric exerted by an ortho-methyl is well tolerated, and
2e was isolated in 72% yield (entry 5, Table 1). A TMS
substituent was also compatible with the method, and the
4-((TMS)ethynyl)phenyl Grignard reagent yielded piperazine
2g in 53% yield (entry 7, Table 1). The heteroaromatic
thienyl and indole Grignard reagents resulted in 52% and
55% isolated yields, respectively (entries 11 and 12). Last
year (2008), we reported the ortho-metalation of pyridine
N-oxides using alkylmagnesium halides.9 However, when
analogously reacting pyrazine N-oxide with n-butylmagne-
sium chloride we did not observe the expected formation of
an ortho-metalated derivative after trapping experiments.
Instead, the corresponding n-butyl-substituted piperazine 2m
was isolated after reduction and N-Boc protection in 40%
yield (Table 1, entry 13). Finally, the reactivity of the
propenyl Grignard reagent was studied, yielding piperazine
2n in 54% isolated yield over three steps (entry 14, Table
1).
The incorporation of piperazine fragments in pharmaceu-
ticals often requires selective synthetic modifications at either
nitrogen; therefore an orthogonal deprotection of the N-Boc
N-hydroxyl piperazine 2a was developed. Zinc dust in MeOH
and acetic acid selectively removed the N-hydroxyl group,
(5) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781–
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(6) (a) Nordstrom, L. U.; Madsen, R. Chem. Commun. 2007, 5034–
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2286–2287.
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F.; Curti, S. Org. Process Res. DeV. 2008, 12, 1188–1194. (b) Guercio, G.;
Manzo, A. M.; Goodyear, M.; Bacchi, S.; Curti, S.; Provera, S. Org. Process
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Org. Lett., Vol. 12, No. 2, 2010
285

and a subsequent alkylation yielded piperazine 3 in 92% yield
(Scheme 1). Furthermore, a selective N-Boc deprotection was
Table 2. Enantioselective Synthesis of Substituted Piperazinea
Scheme 1. Deprotection of Piperazine 2a
entry Grignard/sparteiene solvent time (h) ee yield (%)b
1
2
3
4
5
6
3/3
4/4
1.5/1.5
1.2/1.2
1.2/1.2
1.5/1.5
DCM
DCM
DCM
DCM
DCM
toluene
2.5
2.5
16.0
2.5
22.0
2.5
62
41
78
82
83
75
26
18
28
21
18
24
a See Supporting Information (SI) for details, including reaction and
HPLC conditions. b Yields of isolated products.
accomplished by using a 4 M HCl saturated dioxane solution,
and piperazine 4 was isolated in 89% yield after the reaction
with benzyl bromide. Deprotection of both nitrogens gave
piperazine 5 in 90% yield (Scheme 1).
fast. We included an N-Boc protection step solely to allow
convenient handling of the products, but it also provides
options for further transformations on either nitrogen. In
addition, we have shown that this is a synthetic route to
enantiomerically enriched piperazines. Although the yields
are not yet optimal, this methodology holds potential,
especially since few methods are currently available for the
synthesis of enantiomerically pure piperazines.
Inspired by Fu and co-worker’s use of Grignard reagents
in combination with (-)-sparteine,10 pyrazine N-oxide was
added to phenylmagnesium chloride in the presence of (-)-
sparteine, which gave a promising ee of 62%. However, the
isolated yield was not satisfactory, mainly due to unconsumed
starting material. Increasing the equivalents of Grignard
reagents and (-)-sparteine resulted in a decrease in % ee
(entry 3, Table 2). Fortunately, decreasing the equivalents
of PhMgCl and (-)-sparteine to 1.2 equiv with 1 equiv of
pyrazine N-oxide substantially increased enantioselectivity,
and (-)-2a was obtained in a high 83% ee (entries 3-5,
Table 2). Prolongation of the reaction time, up to 22 h, gave
no improvement in yield, and the % ee remained more or
less unchanged. Whereas the use of toluene as solvent gave
similar results compared with CH2Cl2, THF or 2-Me THF
gave racemic mixtures.
Acknowledgment. We thank the Swedish Natural Science
Research Council and the Knut and Alice Wallenberg
foundation for financial support. We are also grateful to
Umeå Centre for Microbial Research (UCMR) for financial
support to TSLB.
Note Added after ASAP Publication. The toc/abstract
graphic was incorrect in the version published ASAP
December 11, 2009; the correct version published ASAP
December 15, 2009.
In summary, we have described a conceptually new one-
pot strategy for the synthesis of protected substituted
piperazines. This strategy is high yielding, step-efficient, and
Supporting Information Available: Experimental details
and compound characterizations. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1057–
1059.
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