A concise asymmetric synthesis of cis-2,6-disubstituted N-aryl piperazines via Pd-catalyzed carboamination reactions

Article abstract of DOI:10.1021/ol071241f

A concise, modular, asymmetric synthesis of cis-2,6-disubstituted piperazines from readily available amino acid precursors is described. The key step in the synthesis is a Pd-catalyzed carboamination of a N ¹-aryl-N²-allyl-1,2-diamin

Full text of DOI:10.1021/ol071241f

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3279-3282
A Concise Asymmetric Synthesis of
cis-2,6-Disubstituted N-Aryl Piperazines
via Pd-Catalyzed Carboamination
Reactions
Josephine S. Nakhla and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
jpwolfe@umich.edu
Received May 26, 2007
ABSTRACT
A concise, modular, asymmetric synthesis of cis-2,6-disubstituted piperazines from readily available amino acid precursors is described. The
key step in the synthesis is a Pd-catalyzed carboamination of a N1-aryl-N2-allyl-1,2-diamine with an aryl bromide. The products are obtained
in 14−20:1 dr, with >97% ee, and the key cyclizations are the first examples of six-membered ring formation via Pd-catalyzed carboamination
reactions of unsaturated amines with aryl halides.
Substituted piperazines are of profound importance in
medicinal chemistry and drug development. For example, a
2001 survey of biologically relevant templates in the MDDR
revealed 2271 biologically active molecules that contained
substituted N-aryl piperazines: 16 of these compounds were
drugs on the market and an additional 23 were in phase II
or III clinical trials.1 The presence of substituents on C2,
C3, C5, and C6 of the ring has a significant influence on
the biological activity of these molecules, and the ability to
prepare substituted piperazines is of value for the optimiza-
tion of biological properties.2
precursors,3 the stereoselective preparation of enantiomeri-
cally enriched 2,6-disubstituted piperazines remains chal-
lenging, particularly when one of the substituents is not a
carboxylic acid or ester. There are few asymmetric routes
to N,N-disubstituted-2,6-dialkylpiperazines, and the existing
syntheses of these molecules typically require g6 steps.4,5
In this Letter we describe a concise, modular, asymmetric
synthesis of 2,6-disubstituted piperazines that allows the
stereoselective preparation of compounds bearing four dif-
ferent groups at N1, C2, N4, and C6.6
Although the asymmetric synthesis of monosubstituted or
2,5-disubstituted piperazines can be accomplished in a
straightforward manner by using readily available amino acid
(3) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (b) Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297.
(c) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909.
(4) For syntheses of nonracemic 2,6-dialkylpiperazines, see: (a) Schanen,
V.; Cherrier, M.-P.; de Melo, S. J.; Quirion, J.-C.; Husson, H.-P. Synthesis
1996, 833. (b) Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J. Org.
Chem. 1995, 60, 4177. (c) Mickelson, J. W.; Jacobsen, E. J. Tetrahedron:
Asymmetry 1995, 6, 19.
(5) For syntheses of racemic 2,6-dialkylpiperazines, see: (a) Berkheij,
M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.; Terpstra, J. W.; Hiemstra,
H.; Bakker, W. I. I.; van den Hoogenband, A.; van Maarseveen, J. H.
Tetrahedron Lett. 2005, 46, 2369. (b) Mouhtaram, M.; Jung, L.; Stambach,
J. F. Tetrahedron 1993, 49, 1391.
(1) Nilsson, J. W.; Thorstensson, F.; Kvarnstro¨m, I.; Oprea, T.; Sam-
uelsson, B.; Nilsson, I. J. Comb. Chem. 2001, 3, 546.
(2) For examples of biologically active 2,6-disubstituted piperazines,
see: (a) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Zhu, J.; Jones, M. D.;
Crooks, P. A. Bioorg. Med. Chem. 2005, 13, 3899. (b) Chu-Moyer, M. Y.;
Ballinger, W. E.; Beebe, D. A.; Berger, R.; Coutcher, J. B.; Day, W. W.;
Li, J.; Mylari, B. L.; Oates, P. J.; Weekly, R. M. J. Med. Chem. 2002, 45,
511.
10.1021/ol071241f CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/25/2007

Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Substrates from Unprotected Amino
Acids
As shown in Scheme 1, our approach to the construction
of 2,6-disubstituted piperazines employs a key Pd-catalyzed
carboamination reaction,7,8 which generates the heterocyclic
ring and forms two bonds simultaneously. Retrosynthetic
analysis of the carboamination substrates (1) suggested these
compounds could be prepared in a straightforward and
modular fashion from simple precursors: amino acids
(readily available in enantiopure form), allylic amines, and
aryl halides. In addition to the synthetic utility of this strategy,
the key cyclization reaction is a fundamentally interesting
and challenging transformation. The generation of six-
membered rings through Pd-catalyzed carboamination or
carboetherification reactions between heteroatom-tethered
alkenes and aryl/alkenyl halides has not been previously
described, nor has the construction of heterocyclic rings
bearing more than one nitrogen atom been achieved with
this method. Thus, this transformation represents a significant
advance in Pd-catalyzed alkene carboamination methodology.
The starting materials for the carboamination reactions
were prepared from commercially available amino acids by
using one of two 3-4-step sequences. As shown in Scheme
2, the first route employs unprotected amino acid starting
materials, which were subjected to Cu-catalyzed N-phen-
ylation using the anhydrous conditions developed by Ma, to
generate 3 without significant degradation of enantiomeric
purity.9 However, attempts to use biphasic conditions10 for
the N-arylation of unhindered amino acids such as alanine
or phenylalanine provided products with low enantiomeric
purity (ca. 14-50% ee). Amide bond formation was achieved
by coupling 3 with N-(benzyl)allylamine using Goodman’s
DEPBT reagent.11 Reduction of amide 4 with LiAlH4
afforded 1a,b with g98% ee.
Alternatively, in some instances it was advantageous to
employ N-Boc-protected amino acids as starting materials
due to their commercial availability, or due to partial loss
of enantiomeric purity during the Cu-catalyzed N-arylation
reaction.12 These starting materials were converted to 7 in
two steps via DCC-mediated coupling with an allylic amine
followed by reduction with LiAlH4 at 0 °C (Scheme 3).
Scheme 3. Synthesis of Substrates from Protected Amino
Acids
Cleavage of the Boc group was accomplished by treatment
of 7 with HCl/dioxane, and subsequent Pd-catalyzed N-
arylation13 afforded the requisite substrates (1c-e) in high
enantiomeric purity.
With suitable precursors in hand, we initially examined
Pd-catalyzed reactions of phenylalanine-derived substrate 1a
with 4-bromoanisole using a number of different phosphine
ligands. In contrast to the analogous 2,5-disubstituted pyr-
rolidine-forming cyclizations, which were effectively cata-
lyzed by mixtures of Pd2(dba)3 and dppe,7a use of catalysts
supported by P(2-furyl)3 provided optimal results in the
(6) For selected recent approaches to the synthesis of substituted
piperazine derivatives, see: (a) Mercer, G. J.; Sigman, M. S. Org. Lett.
2003, 5, 1591. (b) Ferber, B.; Prestat, G.; Vogel, S.; Madec, D.; Poli, G.
Synlett 2006, 2133. (c) Viso, A.; Fernandez de la Pradilla, R.; Flores, A.;
Garcia, A.; Tortosa, M.; Lopez-Rodriguez, M. L. J. Org. Chem. 2006, 71,
1442 and references cited therein.
(7) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(b) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906. (c) Bertrand,
M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447. (d) Ney, J. E.; Wolfe, J.
P. J. Am. Chem. Soc. 2005, 127, 8644. (e) Yang, Q.; Ney, J. E.; Wolfe, J.
P. Org. Lett. 2005, 7, 2575. (f) Ney, J. E.; Hay, M. B.; Yang, Q.; Wolfe,
J. P. AdV. Synth. Catal. 2005, 347, 1614. (g) Bertrand, M. B.; Wolfe, J. P.
Org. Lett. 2006, 8, 2353. (h) Dongol, K. G.; Tay, B. Y. Tetrahedron Lett.
2006, 47, 927. (i) Bertand, M. B.; Leathen, M. L.; Wolfe, J. P. Org. Lett.
2007, 9, 457. (j) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (k) Peng, J.;
Lin, W.; Yuan, S.; Chen, Y. J. Org. Chem. 2007, 72, 3145.
(8) For examples of Cu-catalyzed intramolecular carboamination, see:
(a) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem.
2007, 72, 3896. (b) Sherman E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O.
Org. Lett. 2004, 6, 1573. For Pd(II)-catalyzed alkoxycarbonylation of alkenes
bearing tethered nitrogen nucleophiles, see: (c) Harayama, H.; Abe, A.;
Sakado, T.; Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru Y. J. Org. Chem.
1997, 62, 2113. For carboamination reactions between alkenes and
N-allylsulfonamides, see: (d) Scarborough, C. C.; Stahl, S. S. Org. Lett.
2006, 8, 3251. For carboamination of vinylcyclopropanes, see: (e) Larock,
R. C.; Yum, E. K. Synlett 1990, 529. For 1,1-carboamination of alkenes,
see: (f) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem.
1994, 59, 4172.
(9) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998,
120, 12459.
(10) Lu, Z.; Twieg. R. J. Tetrahedron Lett. 2005, 46, 2997.
(11) DEPBT ) 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one.
Use of other reagents (e.g., DCC/HOBT or CDI) resulted in partial
epimerization to afford products with ∼85-90% ee. See: Li, H.; Jiang,
X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett. 1999, 1, 91.
(12) Cu-catalyzed N-arylation reactions of alanine afforded products with
e93% ee. See ref 9.
(13) (a) Muci, A. R.; Buchwald, S. L Top. Curr. Chem. 2002, 219, 131.
(b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley,
VCH: Weinheim, Germany, 2002; p 107. (c) Schlummer, B.; Scholz, U.
AdV. Synth. Catal. 2004, 346, 1599.
3280
Org. Lett., Vol. 9, No. 17, 2007

Table 1. Optimization Studies
Table 2. Asymmetric Synthesis of 2,6-Disubstituted
Piperazinesa
conversion
product
ratiod
isolated
yield (%)
entry
ligandb
dppee
Dpe-Phos
Xantphos
P(o-tol)3
(%)c
1
2
3
4
5
50
97
82
87
97
68:0:32
56:23:21
50:35:15
9:17:74
71:7:21
P(2-furyl)3
62e
a Reagents and conditions: 1.0 equiv of 1a, 1.2 equiv of Ar1Br, 1.2 equiv
of NaOtBu, 1 mol % of Pd2(dba)3, 4 mol % of chelating ligand or 8 mol
% of monodentate ligand, toluene (0.2 M), 105 °C, 8 h. b Dppe ) 1,2-
bis(diphenylphosphino)ethane, Dpe-Phos ) 1,1-bis(diphenylphosphinophen-
yl)ether, Xantphos ) 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
c Conversion refers to % starting material consumed; 9-11 were the sole
products detected in the crude reaction mixture. d Determined by 1H NMR
analysis of crude reaction mixtures. e This yield was obtained after complete
conversion.
piperazine-forming reactions (Table 1). Use of a 4:1 ratio
of phosphine to Pd led to complete consumption of the
diamine starting material, whereas reactions that employed
a 2:1 L:Pd ratio frequently halted at ca. 85-90% conversion.
The major side products generated in these transformations
were unsaturated piperazines 10 and 11. Resubjection of 11
to the reaction conditions did not result in the formation of
9 or 10, and 9 was not converted to 10 under the reaction
conditions.
As shown in Table 2, the carboamination reactions are
effective for transformations involving derivatives of several
different amino acids including phenylalanine (1a), valine
(1b), serine (1c), and alanine (1d-e). The reactions are
tolerant of functionalized aryl groups on N1 (e.g., p-
chlorophenyl and p-cyanophenyl) and several different
protecting groups on N4 (e.g., benzyl, allyl, and p-methox-
yphenyl).14 Electron-rich, -neutral, and -poor aryl bromides
can be employed as coupling partners, although use of
â-bromostyrene provided low yields (ca. 25%) of the desired
allylpiperazine derivative. In most cases the cyclizations
afforded cis-2,6-disubstituted piperazines with >20:1 dr,
although cyclizations of 1c proceed with slightly lower (14:
1) diastereoselectivity.15,16
A plausible mechanism for the Pd-catalyzed piperazine-
forming reactions is shown below (Scheme 4). These
transformations appear to be mechanistically analogous to
previously described carboamination reactions of γ-ami-
a Reagents and conditions: 1.0 equiv of amine, 1.2 equiv of ArBr, 1.2
equiv of NaOtBu, 1 mol % of Pd2(dba)3, 8 mol % of P(2-furyl)3, toluene
(0.2 M), 105 °C, 8-10 h. b Average isolated yields obtained from two or
more experiments. c The reaction was conducted with 2 mol % of Pd2(dba)3
and 16 mol % of P(2-furyl)3.
(14) Initial studies on carboaminations of amides such as 4 or 6 suggest
these transformations may be feasible, but further optimization is required;
low yields (ca. 10-20%) of the desired products were obtained.
(15) Diastereomeric ratios observed in crude reaction mixtures were
identical with those obtained upon isolation. In some cases the minor
diastereomer could be separated by careful chromatography. See the
Supporting Information for complete details.
(16) Preliminary efforts to employ a N1 Boc-protected substrate resulted
in the formation of a 1:1 mixture of diastereomers. Attempts to cyclize
substrates bearing N1 Piv or Ac groups have thus far been unsuccessful.
noalkenes with aryl bromides,7 and are likely initiated by
oxidative addition of the aryl bromide to Pd(0) to generate
20. This intermediate can react with the amine and NaOtBu
to provide palladium (aryl)(amido) complex 21, which can
undergo syn-aminopalladation7a,d to afford 22. Carbon-
carbon bond-forming reductive elimination would then yield
the observed piperazine product.
Org. Lett., Vol. 9, No. 17, 2007
3281

strained (due to rehybridization of the C2-carbon from sp3
to sp2) than the analogous transition state for conversion of
the six-membered ring 22 to 23.
Scheme 4. Catalytic Cycle
The stereochemical outcome of the piperazine-forming
reactions contrasts with our model for the analogous pyrro-
lidine-forming processes, which are believed to proceed via
a transition state in which the C1-substutient is placed in a
pseudoaxial orientation to minimize A(1,3) strain between the
C1-group and the N-substituent (Ar, Boc, or Cbz).7a,g,j
A
similar transition state structure (27) should afford trans-
2,6-disubstituted piperazines, which are not the major
products in these reactions. Our current working hypothesis
for piperazine formation involves cyclization via transition
state 28, in which the N1-Ar group is rotated such that N1
is pyramidalized. This eliminates the A(1,3) interaction and
allows pseudoequatorial orientation of R1, which leads to
the cis-2,6-disubstitued stereoisomers. This hypothesis is
consistent with the observation that cyclizations of substrates
bearing N1-(p-cyanophenyl) or N1-Boc groups, which should
have a decreased degree of N1-pyramidalization, proceed
with lower selectivity.16
Side products 10 and 11 most likely derive from a common
intermediate (23) that results from competing â-hydride
elimination of 22. Compound 11 could be generated by
insertion of the alkene into the Pd-H bond of 23 followed
by â-hydride elimination from the C5 position of 24.
Alternatively, displacement of Pd from 23 would afford 25,
which could be converted to the more thermodynamically
stable derivative 11 by reaction with NaOtBu. Side product
10 most likely results from Heck-type arylation of 25,
although formation of 10 via carbopalladation of 23 followed
by C5 â-hydride elimination from 26 cannot be ruled out.17
The generation of 10 and 11 provides further evidence to
support the mechanism of 2,6-disubstituted piperazine for-
mation shown above, rather than a mechanism involving
alkene carbopalladation of 21.7a,d
In conclusion, we have developed a new, stereoselective,
asymmetric synthesis of N-aryl-2,6-disubstituted piperazines.
This strategy allows the modular construction of a number
of derivatives containing different substituents at C2, C6,
N1, and N4 from simple starting materials. The key cycliza-
tions are the first examples of six-membered-ring formation
in Pd-catalyzed carboamination reactions between alkene-
tethered amines and aryl halides. Further studies on the scope,
stereochemical outcome, and applications of these transfor-
mations are currently underway.
Acknowledgment. The authors thank the NIH-NIGMS
(GM 071650) for financial support. Additional funding was
provided by the Camille and Henry Dreyfus Foundation
(New Faculty Award, Camille Dreyfus Teacher Scholar
Award), Research Corporation (Innovation Award), Eli Lilly,
Amgen, and 3M. We also thank the Vedejs research group
at the University of Michigan for sharing chiral HPLC
columns.
Interestingly, the production of undesired compounds
resulting from â-hydride elimination of 22 is much more
problematic in the N-arylpiperazine-forming reactions than
the analogous N-arylpyrrolidine-forming reactions.7a,18 This
may be due to the fact that the transition state for â-hydride
elimination from the five-membered pyrrolidine ring is more
(17) Alkene insertion into late M-H bonds is usually much faster than
alkene insertion into late M-C bonds. See: (a) Brookhart, M.; Hauptman,
E.; Lincoln, D. M. J. Am. Chem. Soc. 1992, 114, 10394. (b) Siegbahn, P.
E. M.; Stromberg, S.; Zetterberg, K. Organometallics 1996, 15, 5542.
(18) The formation of unsaturated five-membered heterocycles analogous
to 10 and 11 is generally not observed in N-aryl-2-benzylpyrrolidine-forming
reactions. Instead, the generation of regioisomeric N-aryl-2-methyl-3-
arylpyrrolidine side products, which result from reversible â-hydride
elimination/reinsertion processes, is observed. These side products are
usually formed in ca. 10% yield, whereas the combined yields of 10 and
11 is usually ca. 20-30%. For further discussion, see refs 7a and 7j.
Supporting Information Available: Characterization
data for all new compounds in Schemes 2 and 3 and Tables
1 and 2, and descriptions of stereochemical assignments. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL071241F
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Org. Lett., Vol. 9, No. 17, 2007