Synthesis of 2,6-disubstituted piperazines by a diastereoselective palladium-catalyzed hydroamination reaction

Article abstract of DOI:10.1021/ol702891p

(Chemical Equation Presented) A highly diastereoselective intramolecular hydroamination is the key step in a modular synthesis of 2,6-disubstituted piperazines. The requisite hydroamination substrates were prepared in excellent yields by nucleophilic disp

Full text of DOI:10.1021/ol702891p

ORGANIC
LETTERS
2008
Vol. 10, No. 2
329-332
Synthesis of 2,6-Disubstituted
Piperazines by a Diastereoselective
Palladium-Catalyzed Hydroamination
Reaction
Brian M. Cochran and Forrest E. Michael*
Department of Chemistry, UniVersity of Washington, Box 351700,
Seattle, Washington 98195-1700
michael@chem.washington.edu
Received November 30, 2007
ABSTRACT
A highly diastereoselective intramolecular hydroamination is the key step in a modular synthesis of 2,6-disubstituted piperazines. The requisite
hydroamination substrates were prepared in excellent yields by nucleophilic displacement of cyclic sulfamidates derived from amino acids.
A variety of alkyl and aryl substituents at the 2-position were tolerated. The stereochemistry of the piperazines was determined to be trans
by X-ray crystallography, which also showed the preferred conformation of the 2,6-disubstituted piperazine to be a twist-boat due to A1,3
strain.
Piperazines are an important class of nitrogen-containing
heterocycles that are common in pharmaceutical agents. The
1,4-diazacyclohexane ring provides a convenient core from
which many compounds can be derived through convergent
synthesis. This feature makes piperazines great templates for
generating libraries of compounds for the study of structure-
activity relationships (SAR). Piperazine nuclei are found in
a range of biologically active compounds, including 5HT-
anxiolytics,1 dopamine D3 agents,2 Bcl-2 inhibitors,3 cyto-
chrome c inhibitor,4 CNS compounds,5 and HIV protease
inhibitors.6
at the two nitrogen atoms. Although a variety of methods
are suitable for the synthesis of substituted 2,5-diketopip-
erazines,7 leading to the 2,5-substitution pattern, the synthesis
of chiral 2,6-disubstituted piperazines has been relatively
unexplored.8 Jacobsen has successfully synthesized chiral
2,6-disubstituted piperazines by setting the stereocenters of
(2) Leopoldo, M.; Lacivita, E.; Colabufo, N. A.; Contino. M.; Berardi,
F.; Perrone, R. J. Med. Chem. 2005, 48, 7919-7922.
(3) Bruncko, M.; Oost, T. K.; Belli, B. A.; Ding, H.; Joseph, M. K.;
Kunzer, A.; Martineau, D.; McClellan, W. J.; Mitten, M.; Ng, S.-C.;
Nimmer, P. M.; Oltersdorf, R.; Park, C.-M.; Petros, A. M.; Shoemaker, A.
R.; Song, X.; Wang, X.; Wendt, M. D.; Zhang, H.; Fesik, S. W.; Rosenberg,
S. H.; Elmore, S. W. J. Med. Chem. 2007, 50, 641-662.
(4) Bombrun, A.; Gerber, P.; Casi, G.; Terradillos, O.; Antonsson, B.;
Halazy. J. Med. Chem. 2003, 46, 4365-4368.
(5) Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.; Belonga, K. L.; Carter,
D. B.; Im, H. K.; Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander,
P. F.; Petke, J. D.; Zhong, W.-Z.; Mickelson, J. W. J. Med. Chem. 1999,
42, 1123-1144.
One significant drawback to using piperazines as biological
scaffolds is the difficulty of introducing substituents on its
carbon backbone, thus limiting SAR studies to substitution
(1) Ward, S. E.; Harrington, F. P.; Gordon, L. J.; Hopley, S. C.; Scott,
C. M.; Watson, J. M. J. Med. Chem. 2005, 48, 3478-3480.
10.1021/ol702891p CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/22/2007

the piperazine precursor prior to ring closure.9 Conversely,
Quirion used a chiral auxiliary to direct the stereoselective
addition of both the 2- and 6-substituents onto a preformed
piperazine ring in a diastereoselective fashion.10 Unfortu-
nately, both synthetic routes are long, and the yields are
moderate to low. Very recently, Wolfe and co-workers
reported a synthesis of 2,6-disubstituted piperazines that was
highly selective for the cis product.11
Scheme 2. Synthesis of Aminoalkene 3 Followed by
Hydroamination
We recently reported an intramolecular palladium-
catalyzed hydroamination of alkenes that is broadly tolerant
of useful functional groups.12 By taking advantage of this
reaction, a modular and efficient route to enantiopure 2,6-
disubstituted piperazines should be feasible (Scheme 1). In
With this promising result, the effects of other protecting
groups at the 4-position were examined (Table 1). When the
Table 1. Effect of the Protecting Group at the 4-position
Scheme 1. Modular Piperazine Synthesis via Intramolecular
Hydroamination
entry
R
additive
none
none
none
HBF4‚OEt2
none
HBF4‚OEt2
% conversionb
% yieldc
1
2
3
4
5
6
Ts (3a)
100
100
33
100
0
20d
89
97
ND
99
ND
ND
2-Nos (3b)
TFA (3c)
TFA (3c)
Boc (3d)
Boc (3d)
a 5 mol % 1, 10 mol % AgBF4, MgSO4, CH2Cl2, 20 h. b Determined by
1H NMR. c Isolated yields. d The remaining material was Boc-deprotected
aminoalkene. ND ) not determined, 2-Nos ) 2-nitrobenzenesulfonamide.
a retrosynthetic sense, disconnection of two diametrically
opposed C-N bonds via hydroamination and substitution
effectively cuts the piperazine nucleus into two equal
halves: an allylic amine and an enantiopure aminoalcohol-
derived fragment. In the forward sense, coupling of the two
starting materials would give the appropriate hydroamination
substrate, which can then be cyclized using palladium catalyst
1 to provide the desired piperazine (eq 2).
internal nitrogen was protected as a sulfonamide (entries 1
and 2), the aminoalkenes readily underwent hydroamination
to give piperazines 4a and 4b in excellent yields. When the
protecting group was changed to a trifluoroacetamide (TFA,
3c), however, the reaction did not go to completion even
after 2 days. Mechanistic studies of this hydroamination
reaction suggest that mildly basic substituents can slow the
reaction rate by inhibiting the protonolysis step.14 The TFA
protecting group is slightly more basic than the sulfonamides
and could be slowing the reaction in a similar manner. The
addition of cocatalytic acid to the reaction mixture should
help overcome this inhibitory effect and restore catalytic
reactivity. Indeed, when compound 3c was treated under
standard reaction conditions with the addition of tetrafluo-
roboric acid (HBF4‚Et2O), piperazine 4c was formed nearly
quantitatively. In the absence of the palladium catalyst, the
acid failed to promote formation of 4c. When Boc-protected
substrate 4d was used, no reaction was observed under
standard reaction conditions. Addition of acid to the reaction
mixture did result in some conversion to desired product
(entry 6); however, competitive deprotection of the Boc
group also occurred.
To test the tolerance of Pd catalyst 1 for a substrate with
an additional nitrogen in the backbone, model substrate 3a
was chosen for initial studies. Compound 3a was synthesized
by substitution of bromide 2 with allylamine, followed by
protection of the free amine with p-toluenesulfonyl chloride.13
Subjecting compound 3a to standard hydroamination condi-
tions resulted in clean formation of differentially protected
piperazine 4a in 89% yield (Scheme 2).
(6) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Welss, K. M.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 673-676.
(7) For a review on diketopiperazine synthesis, see: Dinsmore, C. J.;
Beshore, D. C. Tetrahedron 2002, 58, 3297-3312.
(8) Method for the synthesis of achiral 2,6-disubstituted piperazines:
Cignarella, G.; Gallo, G. G. J. Heterocycl. Chem. 1974, 11, 985-989.
(9) Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J. Org. Chem. 1995,
60, 417-4183.
(10) Schanen, V.; Cherrier, M.-P.; de Melo, S. J.; Quirion, J.-C.; Husson,
H.-P. Synthesis 1996, 7, 833-837.
(11) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279-3282.
(12) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-
4247.
To synthesize 2,6-disubstituted piperazines, a route to the
appropriate hydroamination substrate 7 was required. Ini-
(13) Basha, F. Z.; DeBernardis, J. F. J. Heterocycl. Chem. 1987, 24,
789-791.
(14) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008. In press.
Org. Lett., Vol. 10, No. 2, 2008
330

tially, enantiopure protected bromoamine 6 was synthesized
from L-phenylalanine 5 using known methods (Scheme 3).15
Table 3. Hydroamination of Aminoalkenes 9a-f
Scheme 3. Initial Synthesis of Aminoalkene 7
R
% yieldb
configuration
drc
Me (10a)
iPr (10b)
iBu (10c)
Bn (10d)
Ph (10e)
tBu (10f)
98
95
94
93
88
NRd
(S,S)
(R,R)
(S,S)
(S,S)
(R,R)
-
>20:1
>20:1
19:1
>20:1
5:1
Unfortunately, treatment of compound 6 with allylamine
afforded only poor yields of substrate 7. Multiple byproducts
resulting from attack on the Cbz protecting group by
allylamine were detected. Poor yields were also obtained
when N-allyltoluenesulfonamide was used as a nucleophile
under basic conditions.
-
a 5 mol % 1, 10 mol % AgBF4, MgSO4, CH2Cl2, 20 h. b Isolated yields.
c Determined by 1H NMR. d No Reaction. Only starting material 9f was
isolated.
product was slightly diminished. Surprisingly, tert-butyl-
substituted aminoalkene 9f failed to produce any of the
desired product, most likely due to the steric bulk of the
tert-butyl group.
Table 2. Synthesis of Aminoalkenes 9a-f from Cyclic
Sulfamidates 8a-f
The relative stereochemistry of the piperazine product was
determined to be trans by single-crystal X-ray diffraction
of 10a (Figure 1a). Unexpectedly, the preferred conformation
R
% yielda
configuration
Me (9a)
iPr (9b)
iBu (9c)
Bn (9d)
Ph (9e)
tBu (9f)
95
81
74
94
89
89
S
R
S
S
R
S
a Isolated yields.
An improved route to aminoalkene 7, or a protected
version thereof, was required. Cyclic sulfamidates 8a-f were
readily synthesized from the corresponding enantiopure
amino alcohols16 in good yields using a modification of
literature conditions.17 Treatment of 8a-f with N-allyltolu-
enesulfonamide and KOH in acetonitrile resulted in clean
displacement to give the desired aminoalkenes 9a-f in good
yields after acidic work up (Table 2).
Figure 1. (a) ORTEP of 10a. Thermal ellipsoids shown at 50%
probability. (b) Ring flip from chair to boat.
These substituted aminoalkene precursors (9a-f) were
then subjected to standard hydroamination conditions (Table
3). Substrates 9a-d readily cyclized to the corresponding
piperazines 10a-d in high yields and with excellent dias-
tereoselectivities. Phenyl-substituted piperazine 10e was also
formed in high yield, although the diastereoselectivity of the
of the piperazine ring is a twist-boat, rather then the typical
chair conformation. This preference is a result of allylic strain
between the alkyl substituents and the carbamate protecting
group. In the chair conformation, one of the two alkyl
substituents is forced to adopt an equatorial position adjacent
to the carbamate protecting group, which would result in a
strong A1,3-interaction (Figure 1b). In the twist-boat confor-
mation, however, both alkyl groups can adopt axial confor-
mations to avoid allylic strain with the carbamate moiety.
Typical values for the cost of adopting a twist-boat confor-
(15) (a) Piper, J. R.; Stringfellow, C. R., Jr.; Johnston, T. P. J. Med.
Chem. 1966, 9, 911-920. (b) Kano, S.; Yokomatsu, T.; Iwasawa, H.;
Shibuya, S. Heterocycles 1987, 26, 2805-2809. (c) Han, M. S.; Oh, D. J.;
Kim, D. H. Bioorg. Med. Chem. Lett. 2004, 14, 701-705.
(16) The amino alcohols were derived from enantiopure amino acids by
methods described in ref 15.
(17) Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J. Org. Chem. 2002,
67, 5164-5169.
Org. Lett., Vol. 10, No. 2, 2008
331

mation (5.3 kcal/mol in cyclohexane)18 and the magnitude
of A1,3-strain (∼3.4-4.7 kcal/mol)19 would indicate that this
tradeoff should be slightly unfavorable. However, in this
system the twist-boat conformation is likely to be more stable
due to the presence of two sp2-hybridized nitrogen atoms in
the ring, reducing the torsional strain. Excluding ketopip-
erazines, this is the first report of a 2,6-disubstituted
piperazine that prefers a boat conformation to our knowl-
edge.20 By analogy, the major diastereomers of piperazines
10b-e are also presumed to be trans isomers adopting twist-
boat confomations.21
substituent at the 2-position is too large, as in compound 9f
(R ) tert-butyl), the group cannot be accommodated in either
the pseudoequatorial position or the pseudoaxial position.
Hence, 9f fails to cyclize at all.22 After protonolysis of the
palladium-carbon bond of the alkyl complex, the piperazine
is released from the catalytic cycle, and in the case of the
trans-substituted piperazine, the chair conformation flips to
the thermodynamically more favorable twist-boat conforma-
tion. It is worth noting that, in both the piperazine cyclization
reported by Wolfe11 and the lanthanide-catalyzed hydroami-
nations23 to give piperidines, the cis isomers were favored,
whereas this system affords preferentially the trans isomers.
This difference in selectivity likely arises from the presence
of an aryl group or a hydrogen on the cyclizing nitrogen
rather than a carbamate, which therefore avoids the possibility
of allylic strain.
In conclusion, a short, high-yielding, and stereoselective
route to enantiopure trans-2,6-disubstituted piperazines with
differentially protected nitrogen atoms has been developed.
Both sulfonamide and TFA protecting groups at N-4 as well
as a variety of alkyl and aryl-substituents at C-2 were
tolerated. An improved synthesis of the requisite 2-substituted
aminoalkenes was developed using cyclic sulfamidates
derived from enantiopure amino acids. Hydroamination of
these aminoalkenes gave excellent yields of the desired
piperazines with good to excellent diastereoselectivity for
the trans isomer. The trans-substituted piperazines adopt an
unusual twist-boat conformation both in solution and in the
solid state.
A model that correctly predicts the diastereoselectivity and
reactivity of aminoalkenes 9a-f is illustrated in Scheme 4.
Scheme 4. Model for the Diastereoselectivity and Reactivity of
Aminoalkenes 9a-f
The palladium catalyst binds to the alkene, thereby activating
it toward attack by the carbamate, generating a palladium-
alkyl intermediate. In the chairlike transition state for the
cyclization, the substituent in the 2-position will adopt a
pseudoaxial orientation to avoid allylic strain with the
carbamate group. Cyclization will preferentially occur with
the alkenyl group in a pseudo-equatorial (A) position, rather
than in a pseudoaxial (B) position, leading to selective
formation of the trans diastereomer. Additionally, when the
Acknowledgment. WernerKaminskyandJohnFreudenthal
(University of Washington) are acknowledged for X-ray
crystallography, and the University of Washington is ac-
knowledged for financial support.
Supporting Information Available: Detailed reaction
conditions and experimental data for synthesis of all new
starting materials and products, details of the X-ray crystal
1
structure of 10a, and a detailed analysis of the H NMR
spectrum of compound 10d. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons: New York, 1994; p 689.
(19) (a) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860. (b) Johnson,
F. Chem. ReV. 1968, 68, 375-413.
OL702891P
(20) For an example of a 2,5-disubstituted piperazine boat, see: Tsub-
oyama, K.; Uzawa, J.; Koda, R.; Mitsunori, N.; Kobayashi, K.; Sakurai, T.
Tetrahedron Lett. 1977, 18, 2895-2898.
(22) Corey, E. J.; Feiner, N. F. J. Org. Chem. 1980, 45, 765-780.
(23) (a) Hong, S.; Marks, T. Acc. Chem. Res. 2004, 37, 673-686. (b)
Kim, Y. K.; Livinghouse, T.; Horino, Y. J. Am. Chem. Soc. 2003, 125,
9560-9561.
(21) This assumption is supported by 1H coupling constants. See
Supporting Information for a detailed analysis of compound 10d.
332
Org. Lett., Vol. 10, No. 2, 2008