Dynamic thermodynamic resolution of lithiated N-Boc-N′- alkylpiperazines

Article abstract of DOI:10.1016/j.tetlet.2010.05.019

Deprotonation of N-Boc-N′-alkylpiperazines with sec-BuLi in Et ₂O-TMEDA gave the 2-lithio derivatives which were resolved in the presence of a chiral ligand. The best ligands for the asymmetric substitution were diamino-alkoxides that promoted a dynamic thermodynamic resolution (DTR) of the organolithium at -30 °C. Electrophilic quench gave enantiomerically enriched 2-substituted piperazines. Of a selection of piperazines, the N′-t-butyl derivative gave the best results, with the product N-Boc-N′-t-butyl-2-substituted piperazines being formed with enantiomer ratios up to 81:19.

Full text of DOI:10.1016/j.tetlet.2010.05.019

Tetrahedron Letters 51 (2010) 3642–3644
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dynamic thermodynamic resolution of lithiated N-Boc-N0-alkylpiperazines
Steven P. Robinson a, Nadeem S. Sheikh a, Carl A. Baxter b, Iain Coldham a,
*
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
b Department of Process Research, Merck Sharp and Dohme, Hertford Road, Hoddesdon EN11 9BU, UK
a r t i c l e i n f o
a b s t r a c t
Deprotonation of N-Boc-N0-alkylpiperazines with sec-BuLi in Et2O–TMEDA gave the 2-lithio derivatives
which were resolved in the presence of a chiral ligand. The best ligands for the asymmetric substitution
were diamino-alkoxides that promoted a dynamic thermodynamic resolution (DTR) of the organolithium
at ꢀ30 °C. Electrophilic quench gave enantiomerically enriched 2-substituted piperazines. Of a selection
of piperazines, the N0-t-butyl derivative gave the best results, with the product N-Boc-N0-t-butyl-2-substi-
tuted piperazines being formed with enantiomer ratios up to 81:19.
Article history:
Received 7 April 2010
Revised 29 April 2010
Accepted 7 May 2010
Available online 12 May 2010
Dedicated to Professor S. Florio on the
occasion of his 70th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Lithiation of an acyclic or cyclic N-Boc compound, followed
Recently, the piperazine 8 was treated with sec-BuLi in Et2O and
(ꢀ)-sparteine by McDermott et al. (Scheme 3).9 Asymmetric depro-
tonation, followed by a CO2 quench and coupling with N-benzylpi-
perazine, gave the enantioenriched product 9.
The asymmetric synthesis of 2-substituted piperazines is
important in medicinal chemistry.10 We were therefore interested
in studying the DTR of 2-lithiated piperazines and report here our
initial attempts in this area.
by trapping with an electrophile, is an increasingly common strat-
egy to access synthetically useful 2-substituted nitrogen-contain-
ing molecules.1 Seminal work in this field was carried out by
Beak and co-workers,2 with important contributions from other re-
search groups.3,4
Typically, the base, n-BuLi or sec-BuLi in Et2O and TMEDA, is
used to deprotonate
a- to the nitrogen atom. The chiral ligand
(ꢀ)-sparteine, or other chiral ligands, can sometimes allow asym-
metric deprotonation.5 In contrast to asymmetric deprotonation,
the configurational lability of the lithiated carbanion at tempera-
tures above about ꢀ50 °C can allow a dynamic resolution to induce
asymmetry.6 In this chemistry, the chiral ligand complexes to the
racemic organolithium, giving diastereomeric complexes that can
be resolved under thermodynamic or kinetic control. In dynamic
thermodynamic resolution (DTR), the electrophilic quench is nor-
mally carried out after cooling (to prevent further equilibration).
Recently, we successfully illustrated the application of DTR to
the organolithium derived from deprotonation of N-Boc-piperidine
(1) to give N-Boc-2-substituted piperidines 2 with good yields and
with a good enantiomer ratio (er) (Scheme 1).7 Diamino alkoxide
ligands such as 3 were found to be among the best of those
screened, leading to the products 2 with er up to 87:13.
sec-BuLi, –78 °C
Et2O, TMEDA, 3 h
N
N
E
then L*, hexane, –30 °C, 1 h
Boc
then –78 °C, E+
Boc
2
1
N
er up to 87:13 with L* =
Me2N
OLi
3
Scheme 1. Dynamic resolution of N-Boc-2-lithiopiperidine.
In contrast with N-Boc-piperidine, there are only a few reports
of the
R
a
-lithiation of N-Boc-N0-alkylpiperazines, despite the syn-
R
–10 °C, 1 h
TMEDA, Et2O
sec-BuLi,
N
N
thetic and medicinal utility of such compounds. In 2005, van den
Hoogenband, van Maarseveen and co-workers reported the race-
mic lithiation of N-Boc-N0-benzyl- and N-Boc-N0-methylpipera-
zines 4 and 5 followed by electrophilic quench (Scheme 2).8 The
electrophile TMSCl was more successful for the piperazine 4 (to
give 6a), but both substrates gave good yields of the products 6b
and 7b with the electrophile Bu3SnCl.
then –78 °C, E+
N
E
N
Boc
Boc
68% 6a E = SiMe3
71% 6b E = SnBu3
4 R = Bn
5 R = Me
5%
7a E = SiMe3
82% 7b E = SnBu3
* Corresponding author. Tel.: +44 114 222 9428; fax: +44 114 222 9346.
E-mail address: i.coldham@sheffield.ac.uk (I. Coldham).
Scheme 2. Racemic deprotonation–electrophilic quench.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.019

S. P. Robinson et al. / Tetrahedron Letters 51 (2010) 3642–3644
3643
Table 1
i) sec-BuLi, ( )-sparteine
–
Et2O, –78 °C, then CO2
Yields of products ( )-10
N
N
Entry
E+
E
Product
Yield (%)
N
Ph
ii) HATU, DIPEA, DMF
N-benzylpiperazine
1
2
3
4
5
TMSCl
Bu3SnCl
MeI
DMF
CO2
SiMe3
SnBu3
Me
CHO
CO2H
10a
10b
10c
10d
10e
69
77
71
66
65
N
N
N
Boc
Boc
O
8
er 89 : 11
48%
9
Scheme 3. Asymmetric deprotonation of piperazine 8.
Ph
Ph
N-Boc-N0-benzyl- and N-Boc-N0-methylpiperazines
4 and 5
–78 °C,
sec-BuLi, Et2O, TMEDA,
then –10 °C, 1 h
N
N
N
N
were prepared by treatment of commercially available 1-benzylpi-
perazine and 1-methylpiperazine with Boc2O. N-Boc-N0-t-butylpip-
erazine 8 was prepared by mono-Boc protection of piperazine,11
followed by treatment with KCN and acetone and then addition
of MeMgBr according to the reported procedure.9
As the piperazine 8 has not been studied for lithiation, other
than as shown in Scheme 3, we investigated the use of sec-BuLi
in Et2O and TMEDA followed by the addition of several electro-
philes (Scheme 4, Table 1). The products 10 were formed in good
yield. In each case the enantiomers could be resolved by chiral
GC analysis.
Initial studies on the DTR of lithiated piperazines were con-
ducted with N-Boc-N0-benzylpiperazine (4). Deprotonation of the
piperazine 4 with sec-BuLi in Et2O and TMEDA was followed by
the addition of a chiral ligand (L*) at ꢀ78 °C and equilibration at
elevated temperature (Scheme 5). The resolved diastereomeric
complexes were quenched with TMSCl at ꢀ78 °C to give the prod-
uct 6a. The configuration of the major (S)-enantiomer was assigned
on the basis of related chemistry with N-Boc-2-lithiopiperidine.7
With the chiral ligand 3, a good er was obtained after equilibration
at ꢀ30 °C for 1 h or 1.5 h (Table 2, entries 1 and 2). Several other
diamino-alkoxide ligands (11–13)7 were also screened and gave
similar levels of enantioselectivity. At higher temperatures, there
was no improvement in the er suggesting that the thermodynamic
ratio of the diastereomeric complexes had been achieved.
_
SiMe3
–78 °C,
then
L*, hexane
Boc
then Temp (T), time (t)
then –78 °C, TMSCl
Boc
6a
4
N
N
Me2N
Me2N
Me2N
OLi
OLi
OLi
OLi
3
11
N
N
N
Ph
Me
12
13
Scheme 5. Initial DTR studies with the piperazine 4 and ligands 3 and 11–13.
Table 2
Optimization of the DTR using piperazine 4
Entry
Ligand
T (°C)
Time (h)
er 6a
The yield of the silane product 6a was reasonable (Scheme 6,
Table 3, entry 1)12 and so we opted to use these conditions for a
selection of substrates and electrophiles. Unfortunately, we have
not yet found a method suitable to determine the er of the prod-
ucts 6 from the electrophilic quench with MeI or Bu3SnCl, so we
turned to the DTR of the piperazine 5. We anticipated that the
piperazine 5 would give similar results and were pleased to find
that deprotonation, then DTR with the chiral ligand 3 followed
by electrophilic quench with MeI gave the product 7c, E = Me with
a reasonable enantioselectivity (Table 3, entry 2). However, addi-
tion of the electrophile Bu3SnCl surprisingly gave a lower er (Table
3, entry 3). The use of DMF as the electrophile (Table 3, entry 4) re-
sulted in a reasonable yield but poor er of the product 7d, E = CHO.
This is most likely due to racemization of the product as a result of
enolization during work-up or purification (the GC of the crude
product showed a higher er than that after column chromatogra-
phy). The best substrate was N-Boc-N0-t-butylpiperazine 8, which,
under the optimized DTR conditions gave reasonable yields and
1
2
3
4
5
3
3
11
12
13
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ10
1
80:20
80:20
80:20
78:22
77:23
1.5
1.5
1.5
1
R
N
R
N
sec-BuLi, Et2O, TMEDA, –78 °C,
5 h (or 1 h at –10 °C)
N
N
E
–78 °C,
then
3, hexane
Boc
then –30 °C, 1 or 1.5 h
then –78 °C, E+
Boc
6
7
10
4 R = Bn
R = Bn
R = Me
5 R = Me
8 R = tBu
R = tBu
Scheme 6. General procedure for DTR of 2-lithiated piperazines.
enantioselectivities of products 10 after equilibration at ꢀ30 °C
for 1.5 h (Table 3, entries 5–8).13
–78 °C,
TMEDA, Et2O
sec-BuLi,
5 h
N
N
Substituted piperazines with differentially protected nitrogen
atoms are likely to find use in medicinal drugs. Therefore we stud-
ied the removal of the N-Boc group from the racemic piperazine
10c (Scheme 7). This was successful and gave the volatile pipera-
zine 14 which was treated with p-toluenesulfonyl chloride to give
the product 15. As yet, we have not found conditions to remove the
N-t-butyl group from the piperazines 14 or 15.
then –78 °C, E+
N
N
E
Boc
Boc
8
10
Scheme 4. Racemic deprotonation–electrophilic quench of 8.

3644
S. P. Robinson et al. / Tetrahedron Letters 51 (2010) 3642–3644
Coldham, I.; Patel, J. J.; Raimbault, S.; Whittaker, D. T. E.; Adams, H.; Fang, G. Y.;
Table 3
Aggarwal, V. K. Org. Lett. 2008, 10, 141–143; (h) Coldham, I.; Leonori, D. Org.
Lett. 2008, 10, 3923–3925; (i) Coldham, I.; Leonori, D.; Beng, T. K.; Gawley, R. E.
Chem. Commun. 2009, 5239–5241.
Yields and er for the DTR of lithiated piperazines with ligand 3
Entry
R
E
Product
Yield (%)
er
5. (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116, 3231; (b)
Kim, D. D.; Lee, S. J.; Beak, P. J. Org. Chem. 2005, 70, 5376–5386; (c) Bailey, W. F.;
Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889–
1896; (d) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006, 2607–
2609; (e) Coldham, I.; O’Brien, P.; Patel, J. J.; Raimbault, S.; Sanderson, A. J.;
Stead, D.; Whittaker, D. T. E. Tetrahedron: Asymmetry 2007, 18, 2113–2119.
6. Coldham, I.; Sheikh, N. S. In Topics in Stereochemistry; Gawley, R. E., Ed.; Verlag
Helvetica Chimica Acta: Zürich, 2010; Vol. 26, pp 253–293.
7. (a) Coldham, I.; Patel, J. J.; Raimbault, S.; Whittaker, D. T. E. Chem. Commun.
2007, 4534–4536; (b) Coldham, I.; Raimbault, S.; Chovatia, P. T.; Patel, J. J.;
Leonori, D.; Sheikh, N. S.; Whittaker, D. T. E. Chem. Commun. 2008, 4174–4176;
(c) Coldham, I.; Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.; Leonori, D.;
Patel, J. J.; Sheikh, N. S. Chem. Eur. J. 2010, 16, 4082–4090.
1
2
3
4
5
6
7
8
9
Bn
SiMe3
Me
6a
7c
7b
7d
10a
10b
10c
10d
10e
48
35
34
57
64
75
52
49
30
80:20
77:23
65:35
60:40
77:23
76:24
80:20
60:40
81:19
Me
Me
Me
tBu
tBu
tBu
tBu
tBu
SnBu3
CHO
SiMe3
SnBu3
Me
CHO
CO2H
8. (a) 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.; van Maarseveen, J.
H. Tetrahedron Lett. 2005, 46, 2369–2371; see also: (b) Miller, K. A.; Shanahan,
C. S.; Martin, S. F. Tetrahedron 2008, 64, 6884–6900; (c) Garrido, F.; Mann, A.;
Wermuth, C.-G. Tetrahedron Lett. 1997, 38, 63–64.
N
N
N
N
TsCl, Et3N
TFA
CH2Cl2
9. McDermott, B. P.; Campbell, A. D.; Ertan, A. Synlett 2008, 875–879.
10. See, for example: (a) Guercio, G.; Bacchi, S.; Perboni, A.; Leroi, C.; Tinazzi, F.;
Bientinesi, I.; Hourdin, M.; Goodyear, M.; Curti, S.; Provera, S.; Cimarosti, Z. Org.
Process Res. Dev. 2009, 13, 1100–1110; (b) Lu, R.-J.; Tucker, J. A.; Pickens, J.; Ma,
Y.-A.; Zinevitch, T.; Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.;
Brahmachary, E.; Khasanov, A.; Mikel, C.; Yang, Y.; Liu, C.; Wang, J.; Freel, S.;
Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.; Baker, B.; Sailstad, J.;
Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.; Jeffries, C.;
Chucholowski, A.; Sexton, C. J. Med. Chem. 2009, 52, 4481–4487; (c) Harrison, B.
A.; Whitlock, N. A.; Voronkov, M. V.; Almstead, Z. Y.; Gu, K.; Mabon, R.;
Gardyan, M.; Hamman, B. D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.;
Zhang, Y.; Liu, Y.; Courtney, L. F.; Key, B.; Zhou, J.; Patel, N.; Yates, P. W.; Liu, Q.;
Wilson, A. G. E.; Kimball, S. D.; Crosson, C. E.; Rice, D. S.; Rawlins, D. B. J. Med.
Chem. 2009, 52, 6515–6518; (d) Westaway, S. M.; Brown, S. L.; Fell, S. C. M.;
Johnson, C. N.; MacPherson, D. T.; Mitchell, D. J.; Myatt, J. W.; Stanway, S. J.;
Seal, J. T.; Stemp, G.; Thompson, M.; Lawless, K.; McKay, F.; Muir, A. I.; Barford,
J. M.; Cluff, C.; Mahmood, S. R.; Matthews, K. L.; Mohamed, S.; Smith, B.;
Stevens, A. J.; Bolton, V. J.; Jarvie, E. M.; Sanger, G. J. J. Med. Chem. 2009, 52,
1180–1189.
imidazole
N
Me
N
H
Me
Me
Ts
Boc
10c
72% (2 steps)
14
15
Scheme 7. Removal of the N-Boc group from piperazine 10c.
In summary, the first DTR reactions of various 2-lithiated piper-
azines are reported. Moderate yields and er values were obtained
with a selection of N-Boc-N0-alkylpiperazines using deprotonation
with sec-BuLi in Et2O–TMEDA and resolution with the chiral ligand
3. This has resulted in the synthesis of enantiomerically enriched
2-substituted piperazine products with er up to 81:19.
11. Zheng, H.; Weiner, L. M.; Bar-Am, O.; Epsztejn, S.; Cabantchik, Z. I.;
Warshawsky, A.; Youdim, M. B. H.; Fridkin, M. Bioorg. Med. Chem. 2005, 13,
773–783.
Acknowledgements
We would like to thank the EPSRC (Grant EP/F000340/1), the
University of Sheffield and Merck Sharp and Dohme for funding.
12. sec-BuLi (0.67 mL, 1.3 M in hexanes) was added to piperazine 4 (100 mg,
0.36 mmol) and TMEDA (0.13 mL, 0.86 mmol) in Et2O (0.8 mL) at ꢀ78 °C. The
mixture was warmed to ꢀ10 °C for 1 h, then cooled to ꢀ78 °C and a solution of
the ligand 3 [prepared by adding sec-BuLi (0.39 mL, 1.3 M in hexanes) to the
alcohol precursor of 37 (107 mg, 0.47 mmol) in Et2O (0.8 mL)] and then hexane
(0.39 mL) was added. The mixture was warmed to ꢀ30 °C for 1 h, then cooled
to ꢀ78 °C and Me3SiCl (0.16 mL, 1.27 mmol) was added. The mixture was
allowed to warm to room temperature over 16 h then aqueous NH4Cl (1 mL)
was added and the mixture was extracted with CH2Cl2 (2 ꢁ 10 mL). The
organic layers were dried (MgSO4) and evaporated. Purification by column
chromatography, eluting with petrol/EtOAc/NEt3 (90:10:1), gave the
References and notes
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piperazine 6a (60 mg, 48%) as an oil; ½ ꢂ
a 2D1 +11.5 (0.26, CHCl3); 1H NMR
(400 MHz, CDCl3) d = 7.38–7.22 (5H, m), 5.58 (1H, br s), 3.79 (1H, br s), 3.73
(1H, d, J 13.5 Hz), 3.45 (1H, d, J 13.5 Hz), 3.37 (1H, br td, J 12, 3 Hz), 2.89 (1H, br
d, J 12 Hz), 2.82 (1H, br d, J 12 Hz), 2.18 (1H, td, J 12, 3 Hz), 2.08 (1H, dd, J 12,
2 Hz), 1.49 (9H, s), 0.13 (9H, s); 13C NMR (100 MHz, CDCl3) d = 154.0, 137.4,
129.1, 128.2, 127.1, 80.1, 62.5, 58.3, 52.6, 29.7, 28.4, 0.14; HRMS (ES) found
349.2308, C19H33N2O2Si requires MH+ 349.2311; HPLC analysis (Phenomenex
Lux Amylose-2, 0.5% iPrOH in hexanes) showed the enantiomers eluting at
18.3 min (major) and 22.3 min (minor).
13. In the same way as that for the piperazine 6a,12 except that the deprotonation
was maintained at ꢀ78 °C for 5 h (and not warmed to ꢀ10 °C), sec-BuLi
(0.85 mL, 1.3 M in hexanes), piperazine
8 (200 mg, 0.83 mmol), TMEDA
(0.16 mL, 1.08 mmol), the ligand 3 [prepared by adding sec-BuLi (0.89 mL,
1.3 M in hexanes) to the alcohol precursor of 37 (247 mg, 1.08 mmol) in Et2O
(1.7 mL)], hexane (1.6 mL) and Me3SiCl (0.32 mL, 2.5 mmol) gave, after
purification by column chromatography, eluting with petrol/EtOAc (90:10),
the piperazine 10a (166 mg, 64%) as an oil; ½a D21
ꢂ
+11.7 (1.03, CHCl3); 1H NMR
(400 MHz, CDCl3) d = 4.03 (1H, br s), 3.81 (1H, br s), 3.53 (1H, br s), 2.97 (1H, br
s), 2.86 (1H, br s), 2.32 (1H, br s), 2.07 (1H, br s), 1.44 (9H, s), 1.02 (9H, s), 0.10
(9H, s); 13C NMR (100 MHz, CDCl3) d 154.6, 78.9, 53.6, 46.9, 46.2, 45.9, 42.3,
28.5, 25.9, ꢀ0.62; HRMS (ES) found 315.2468, C16H35N2O2Si requires MH+
315.2474; GC analysis (b-cyclodextrin-permethylated, 125 °C) showed the
enantiomers eluting at 16.6 min (minor) and 17.5 min (major).