First example of s-BuLi/(-)-sparteine-mediated chiral deprotonation of a piperazine and proof of the sense of induction

Article abstract of DOI:10.1055/s-2008-1042905

This paper describes the first known example of a (-)-sparteine-mediated asymmetric deprotonation of a piperazine. Reaction of tert-butyl 4-tert-butylpiperazine-l-carboxylate with s-BuLi in the presence of (-)-sparteine at -78°C and quenching with carbon

Full text of DOI:10.1055/s-2008-1042905

LETTER
875
First Example of s-BuLi/(–)-Sparteine-Mediated Chiral Deprotonation of a
Piperazine and Proof of the Sense of Induction
s-
BuLi/(–)-Sparte
e
ine-Mediat
n
e
d
Chiral
D
e
j
protonation of
a
Pm
iperazine in P. McDermott,*a Andrew D. Campbell,a Anne Ertanb
a
AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
E-mail: Ben.McDermott@astrazeneca.com
b
AstraZeneca R&D Södertälje, Pharmaceutical & Analytical R&D, 151 85 Södertälje, Sweden
Received 26 November 2007
Analogues of compound 1 having primary or secondary
alkyl groups substituted on the piperazine instead of the
tert-butyl could be readily prepared from commercially
available carboxylic acid 2. Unfortunately, the synthesis
Abstract: This paper describes the first known example of a (–)-
sparteine-mediated asymmetric deprotonation of a piperazine. Re-
action of tert-butyl 4-tert-butylpiperazine-1-carboxylate with s-
BuLi in the presence of (–)-sparteine at –78 °C and quenching with
carbon dioxide proceeded in good yield and with a high degree of of 3 from this material was problematic and an alternative
selectivity (er = 89:11). X-ray crystal structure analysis on a chiral
route was required. Our thoughts therefore turned to the
derivative confirmed the R-enantiomer was the major product. This
synthesis of N-tert-butyl-N-Boc piperazine 4 with a view
methodology was employed as a route to an advanced chiral inter-
to asymmetric deprotonation using (–)-sparteine and
mediate that was used in parallel synthesis of a range of molecules
quenching with CO2 to give carboxylic acid 3. Subsequent
of medicinal interest. Optimisation of the chemistry used to intro-
piperazine coupling would then afford the desired inter-
mediate 1. The use of (–)-sparteine as a chiral ligand for
lithium in asymmetric deprotonations has been reported
extensively and the reactions have proven very success-
ful.1,2 The asymmetric deprotonation of N-Boc pyrroli-
dine using (–)-sparteine/s-BuLi complex, shown in
Scheme 2, was originally achieved by Beak.3 An example
from Beak’s work shows how the organolithium obtained
was quenched with trimethylsilyl chloride to give a good
yield of the corresponding silane 5 with an enantiomeric
ratio of 95:5 (with the R-configuration as the major prod-
uct). However, when the same chiral deprotonation was
repeated on N-Boc piperidine only 8% of the desired
duce a tert-butyl group onto a piperazine nitrogen is also described.
Key words: asymmetric deprotonation, piperazines, lithiation, (–)-
sparteine, N-tert-butylpiperazine synthesis
In the synthesis of a series of key compounds of medicinal
interest we were faced with producing an efficient synthe-
sis of advanced intermediate 1 (Scheme 1). Availability of
this compound would allow rapid parallel synthesis of a
wide range of compounds via coupling of the remaining
secondary piperazine nitrogen with a variety of electro-
philes.
O
O
O
O
O
O
benzylpiperazine
coupling and
debenzylation
O
O
O
N
N
N
N
N
OH
OH
N
NH
N
H
1
3
2
(–)-sparteine-mediated
deprotonation
then CO2
H
H
N
N
H
O
O
H
N
N
(–)-sparteine
4
Scheme 1 Proposed disconnection of target fragment via asymmetric deprotonation of a piperazine
SYNLETT 2008, No. 6, pp 0875–0879
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042905; Art ID: D37807ST
© Georg Thieme Verlag Stuttgart · New York

876
B. P. McDermott et al.
LETTER
product 6 was isolated with the same sense of induction successful this would be the first example of its kind. In
(er 87:13).4 In an earlier publication Beak’s group showed our proposed synthesis we were relying on the (–)-
that N-Boc piperidine can be deprotonated in the racemic sparteine/s-BuLi process giving the same sense of induc-
sense (s-BuLi/TMEDA) and quenched with various elec- tion as observed for the asymmetric examples described in
trophiles in high yield.5 This result supports recent work Scheme 2. However, we were aware that if the undesired
by the O’Brien group which shows that significantly fast- enantiomer were to be formed then the use of the O’Brien
er deprotonation occurs with the s-BuLi/TMEDA combi- groups’ (+)-sparteine equivalent should ensure the re-
nation over the (–)-sparteine method.6
quired enantiomer could be made.8
We therefore set about making N-tert-butyl-N-Boc piper-
azine 4.9 Initial synthetic routes to the precursor of our key
asymmetric step are shown in Scheme 3. Amide 7 was
readily obtained by reaction of N-benzylpiperazine with
acetyl chloride in the presence of triethylamine. We then
employed the previously reported modified Bouveault
conditions (MeMgBr, ZrCl4) to access the tert-butyl moi-
ety in 8.10 A simple protecting group switch from a benzyl
to a Boc group afforded our target precursor 4. However,
due to the moderate yield obtained on the Grignard step
and slow filtration of metal residues on scale-up (>100 g)
an alternative method was required. A different approach
starting from dichloroamine 9 was therefore attempted.
(–)-sparteine, s-BuLi
then TMSCl
O
O
O
O
N
N
SiMe3
90%, er = 95:5
5
O
O
O
O
(–)-sparteine, s-BuLi
then TMSCl
N
N
SiMe3
8%, er = 87:13
6
Scheme 2 Beak’s previously published (–)-sparteine/s-BuLi depro-
tonation of N-Boc pyrrolidine and the low-yielding asymmetric de-
protonation of N-Boc piperidine
Cyclisation of 9 with excess tert-butylamine under micro-
wave conditions (130 °C) produced the desired product 8
in moderate yield (69%). However, safety concerns about
preparing the mustard on a larger scale prevented further
work on this route.
Racemic deprotonation of piperazines has been reported
recently by van Marseveen and coworkers.7 In this publi-
cation monoalkylated N-Boc piperazine derivatives can
be deprotonated in the racemic sense using the s-BuLi/
TMEDA combination. The yields vary depending on the
exact conditions used and the choice of electrophile. To
our knowledge, the asymmetric deprotonation of a piper-
azine using (–)-sparteine/s-BuLi has not been reported. If
A far superior route was identified and is outlined in
Scheme 4. Commercially available N-Boc piperazine
could be reacted with acetone in the presence of potassi-
um cyanide and one equivalent of p-toluenesulfonic acid
monohydrate to give the corresponding cyano compound
10. This was then reacted with an excess of Grignard re-
agent (Bruylants reaction)11 to give the desired Boc-pro-
ZrCl4, MeMgBr (3 M in Et2O),
K2CO3, MeCN,
THF, 5 °C
t-BuNH2, 130° C
N
N
N
69%
40%
N
N
Cl
Cl
O
7
8
9
10% Pd/C, H2
(Boc)2O, EtOH
99%
O
O
N
N
4
Scheme 3 Initial routes to tert-butyl piperazine (the precursor to the asymmetric deprotonation)
Synlett 2008, No. 6, 875–879 © Thieme Stuttgart · New York

LETTER
s-BuLi/(–)-Sparteine-Mediated Chiral Deprotonation of a Piperazine
877
O
O
O
O
O
O
acetone, H2O
MeMgBr (3 M in Et2O),
THF, 0 °C
N
N
N
N
KCN, TsOH, 25 °C
N
99%
99%
N
H
CN
10
4
O
O
O
O
O
HATU, DIPEA,
benzyl piperazine
DMF, 25 °C
O
s-BuLi, (–)-sparteine,
CO2, Et2O, –78 °C
N
N
N
N
OH
N
N
Ph
48% over
two stages
er = 89:11
3
11
O
O
O
H2, Pd/C, EtOH
99%
N
N
NH
N
1
Scheme 4 Successful synthesis of our target intermediate involving an asymmetric deprotonation of a piperazine using (–)-sparteine/s-BuLi
tected tert-butyl piperazine 4. This process was both clean Although we strongly suspected that the major enantio-
and high yielding allowing efficient synthesis (>100 g mer was of R-configuration, additional proof was needed
scale) of the precursor to our key asymmetric deprotona- in the form of X-ray crystal structure analysis. Thus,
tion step.
amine 1 was coupled with N-tosyl (R)-proline to form
amide 1313 in excellent yield. Slow crystallisation from a
DCE–isohexanes mixture afforded a sample of sufficient
quality for X-ray crystal structure analysis that confirmed
A solution of the N-Boc piperazine 4 in diethyl ether was
treated with s-BuLi in the presence of (–)-sparteine at
–78 °C for five hours and the resulting anion was
quenched with CO2. Rather than isolating the carboxylic
acid 3 the crude reaction mixture was subjected to a
HATU coupling with benzyl piperazine to give amide
11.12 Comparison to the racemate showed an enantiomeric
ratio of 89:11 by chiral HPLC. To our knowledge this was
the first reported example of a chiral deprotonation and
electrophile quench with a piperazine using this (–)-spar-
teine methodology. The yield over the two steps was also
very impressive when compared with the piperidine ex-
ample shown in Scheme 2. For our convenience the re-
maining undesired enantiomer was then removed using
chiral prep HPLC to give enantiomerically pure material.
Debenzylation (H2, Pd/C) then afforded our desired inter-
mediate 113 in excellent yield. Scheme 5 shows an exam-
ple of how we reacted 1 with a phenyl carbamate to give,
after Boc deprotection, final compound 12.13 The interme-
diate 1 was reacted in this way with a series of isocyanates
(if available) or masked isocyanates such as the phenyl
carbamate shown to provide a diverse library of com-
pounds for biological testing.
Figure 1 X-ray crystal structure, confirming R-stereochemistry on
the piperazine
Synlett 2008, No. 6, 875–879 © Thieme Stuttgart · New York

878
B. P. McDermott et al.
LETTER
O
H
N
O
N
N
N
S
O
N
N
N
N
59%
two steps
Cl
O
S
Cl
Et3N, THF
60 °C
12
O
O
O
then TFA, CH2Cl2
N
N
N
NH
HATU, DIPEA
DMF
O
O
1
O
HO
N
N
S
N
O
O
N
O
N
N
90%
S
O
O
O
13
Scheme 5 Example of the use of our key chiral intermediate 1 in the synthesis of molecules of biological interest and the coupling with a
substituted proline to enable X-ray crystal structure analysis
2002, 423. (f) Papillon, J. N.; Taylor, R. J. K. Org. Lett.
2002, 4, 119. (g) Deiters, A.; Hoppe, D. J. Org. Chem. 2001,
66, 2842. (h) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am.
Chem. Soc. 2001, 123, 1004. (i) Coldham, I.; Copley, R. C.
B.; Haxell, T. F. N.; Howard, S. Org. Lett. 2001, 3, 3799.
(j) Kobayashi, S.; Shiraishi, N.; Lam, W. W.-L.; Manabe, K.
Tetrahedron Lett. 2001, 42, 7303. (k) Laufer, R. S.; Veith,
U.; Taylor, N. J.; Snieckus, V. Org. Lett. 2000, 2, 629.
(l) Hodgson, D. M.; Gras, E. Angew. Chem. Int. Ed. 2002,
41, 2376.
the piperazine had the required C21 R-stereochemistry. A
crystal structure diagram is shown in Figure 1.14
In summary we have shown that asymmetric deprotona-
tion of a piperazine is possible using (–)-sparteine and s-
BuLi. We have also proven that deprotonation of pipera-
zine 4 proceeds with the same sense of induction as ob-
served in other ring systems (Scheme 2).
Further work will explore other piperazine examples to
show, for example, if the bulky tert-butyl substitution en-
forces a subtle conformational effect allowing asymmet-
ric control? Also, can the enantiomeric ratio be improved
with alternative conditions and can the yield be improved
by subjecting the substrate to longer deprotonation times?
We also have not yet explored the possibility of introduc-
ing electrophiles other than CO2.
(3) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem.
Soc. 1994, 116, 3231. (b) Whisler, M. C.; MacNeil, S.;
Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43,
2206.
(4) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Sunghoon, M.;
Wilberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889.
(5) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(6) O’Brien, P.; McGrath, M. J.; Bilke, J. L. Chem. Commun.
2006, 2607.
(7) van Maarseveen, J. H.; Berkheij, M.; van der Sluis, L.;
Sewing, C.; den Boer, D. J.; Terpstra, J. W.; Hiemstra, H.;
Iwema Bakker, W. I.; van den Hoogenband, A. Tetrahedron
Lett. 2005, 46, 2369.
(8) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870.
(9) N-(tert-Butyl)piperazine is advertised as a commercially
available compound. A sample ordered and received by us
was, in fact, identified as N-(n-butyl)piperazine. Another
company advertising the compound has now discontinued
this product.
(10) (a) Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306.
(b) Denton, S. M.; Wood, A. Synlett 1999, 55.
Acknowledgment
We thanks to Howard Beeley and the spectroscopy team for NMR
analysis, Madeleine Vickers for mass spectra work, and also the
HPLC team for the chiral analysis. Thanks are also due to Trystan
Nicholls and the RSL team at AstraZeneca for the large-scale work
performed on this synthesis.
References and Notes
(1) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2282.
(2) Some examples: (a) Johnson, T. A.; Curtis, M. D.; Beak, P.
Org. Lett. 2002, 4, 2747. (b) Lim, S. H.; Beak, P. Org. Lett.
2002, 4, 2657. (c) Wilkinson, J. A.; Rossington, S. B.;
Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron 2006, 62,
1833. (d) Metallinos, C.; Snieckus, V. Org. Lett. 2002, 4,
1935. (e) Majumdar, S.; de Meijere, A.; Marek, I. Synlett
(11) Bruylants, P. Bull. Soc. Chim. Belg. 1924, 33, 467.
(12) (R)-tert-Butyl 2-(4-Benzylpiperazine-1-carbonyl)-4-tert-
butylpiperazine-1-carboxylate (11)
To a solution of tert-butyl 4-tert-butylpiperazine-1-carb-
oxylate (500 mg, 2.1 mmol) and (–)-sparteine (0.62 mL, 2.7
mmol) in Et2O (20 mL) at –78 °C under argon was added s-
Synlett 2008, No. 6, 875–879 © Thieme Stuttgart · New York

LETTER
s-BuLi/(–)-Sparteine-Mediated Chiral Deprotonation of a Piperazine
879
BuLi (1.92 mL, 2.7 mmol) dropwise. The resulting
H), 1.38 (s, 9 H), 2.11 (td, J = 11.4, 4.2 Hz, 1 H), 2.38 (dd,
J = 12.0, 4.8 Hz, 1 H), 2.68–2.76 (m, 4 H), 3.08 (dt, J = 12.2,
2.5 Hz, 1 H), 3.33–3.51 (m, 6 H), 3.61 (dt, J = 12.3, 3.1 Hz,
1 H), 4.67–4.70 (m, 1 H). 13C NMR (126 MHz, DMSO): d =
18.49, 25.58, 27.98, 42.34, 45.01, 45.64, 47.05, 53.00,
55.98, 78.58, 155.11, 169.06. ESI-HRMS: m/z calcd for
C25H41N4O3: 355.27037; found: 355.27036 [M + H]+.
Compound 12: white solid; mp 165 °C; [a]D20 +11.0 (c 1.00,
EtOH). 1H NMR (400 MHz, CDCl3): d = 1.07 (s, 9 H), 2.01–
2.18 (m, 2 H), 2.22 (s, 3 H), 2.83–3.13 (m, 4 H), 3.35–3.89
(m, 10 H). 13C NMR (101 MHz, CDCl3): d = 13.90, 25.44,
41.53, 43.62, 44.00, 44.67, 45.08, 46.78, 49.32, 113.18,
140.17, 154.54, 158.18, 170.07. ESI-HRMS: m/z calcd for
C25H41N4O3: 429.18340; found: 429.18344 [M + H]+.
Compound 13: white solid; mp 208 °C; [a]D20 +31.0
(c = 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 0.79–
0.90 (m, 1 H), 1.04 (s, 9 H), 1.21–1.32 (m, 1 H), 1.45 (s, 9
H), 1.72–1.82 (m, 1 H), 1.88–2.28 (m, 4 H), 2.41–2.54 (m, 1
H), 2.43 (s, 3 H), 2.85–3.19 (m, 2 H), 3.35–3.87 (m, 10 H),
4.63–4.91 (m, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.2
Hz, 2 H). 13C NMR (176 MHz, CDCl3): d = 21.48, 24.81,
25.76, 28.34, 30.63, 38.55, 42.23, 43.16, 45.38, 45.72,
47.53, 48.31, 53.67, 57.88, 80.19, 127.47, 129.59, 135.67,
143.57, 155.57, 169.94, 170.13. ESI-HRMS: m/z calcd for
C25H41N4O3: 606.33198; found: 606.33167 [M + H]+.
(14) C30H47N5O6S.C2H4Cl2, Mr = 704.75, colourless block.
Crystal dimensions: 0.20 × 0.15 × 0.03 mm, monoclinic,
space group P21, a = 6.0241(3) Å, b = 19.1591(7) Å,
c = 15.9244(8) Å, b = 99.631(2)°, V = 1812.03(14) Å3,
Z = 2, Dx = 1.292 Mg m–3. Reflections collected: 25197;
independent reflections: 8012 (Rint = 0.042), final R[F2 > 2s
(F2)] = 0.052, R (all data) = 0.1249, wR(F2) = 0.137. Flack
parameter: –0.01 (7). Crystallographic data for this structure
has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
668196. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road Cambridge, CB2 1EZ,
UK [fax: +44 (1223)336033; e-mail:
suspension was stirred at –78 °C for 5 h and then CO2 was
bubbled through the mixture via syringe for 30 min. After
the addition of one pellet of CO2 the reaction was allowed to
warm to 0 °C and then quenched with H2O (0.5 mL). The
mixture was diluted with CH2Cl2 and Na2SO4 was added.
The mixture was stirred for 5 min then filtered and
concentrated at reduced pressure to give a light yellow oil.
To a solution of this material in DMF (15 mL) at r.t. was
added benzylpiperazine (0.30 mL, 1.7 mmol), DIPEA (0.58
mL, 3.3 mmol), and finally HATU [O-(7-azabenzotriazol-1-
yl)-N,N,N¢,N¢-tetramethyluronium hexafluorophosphate,
627 mg, 1.7 mmol]. After 2 h H2O (50 mL) was added and
the mixture was stirred for 2 h. The mixture was then
extracted with EtOAc (150 mL) and the organic layer
washed with brine (3 × 50 mL), dried (Na2SO4), and
concentrated at reduced pressure. The residue was purified
via silica column chromatography (40 g silica) eluting with
0–10% MeOH in CH2Cl2 to give (R)-tert-butyl 2-(4-
benzylpiperazine-1-carbonyl)-4-tert-butylpiperazine-1-
carboxylate as a white solid (442 mg, 48% over two steps);
mp 105 °C; [a]D20 +12.8 (c 1.00, EtOH). 1H NMR (500
MHz, DMSO, 373 K): d = 0.98 (s, 9 H), 1.37 (s, 9 H), 2.09
(td, J = 11.6, 3.7 Hz, 1 H), 2.34–2.44 (m, 5 H), 2.84–2.92 (m,
1 H), 3.05–3.10 (m, 1 H), 3.39–3.53 (m, 5 H), 3.52 (s, 2 H),
3.60 (dt, J = 12.2, 3.1 Hz, 1 H), 4.68–4.71 (m, 1 H), 7.22–
7.27 (m, 1 H), 7.29–7.33 (m, 4 H). 13C NMR (126 MHz,
DMSO, 373 K): d = 25.09, 27.55, 42.08, 42.91, 44.52, 46.70,
51.99, 52.37, 52.60, 61.31, 78.21, 126.22, 127.41, 128.16,
137.22, 154.41, 168.54. ESI-HRMS: m/z calcd for
C25H41N4O3: 445.31732; found: 445.31726 [M + H]+. Chiral
HPLC conditions: er = 89:11; Instrument: HP1100 System
2; column: 5 mm Chiralpak AD-H (250 mm × 4.6 mm) No.
FE168; eluent: i-hexane–EtOH (50:50); ambient
temperature; flow 1 mL/min; wavelength 210 nm; tR (R) =
3.25 min; tR (S) = 6.52 min.
(13) Selected Analytical Data
Compound 1: white solid; mp 89 °C; [a]D20 +9.5 (c 1.00,
EtOH). 1H NMR (500 MHz, DMSO, 373 K): d = 1.00 (s, 9
deposit@ccdc.cam.ac.uk].
Synlett 2008, No. 6, 875–879 © Thieme Stuttgart · New York