Synthesis of 4-arylpiperidines from 1-benzyl-4-piperidone: Application of the shapiro reaction and alkenylsilane cross-coupling

Article abstract of DOI:10.1021/ol070241c

Equation Presented 1-Benzyl-3,4-unsaturated-4-piperidinyl benzyldimethylsilane has been prepared and observed to readily undergo palladium-catalyzed cross-coupling reactions with a variety of aryl iodides and aryl bromides to generate 3,4-unsaturated 4-arylpiperidines, often at ambient temperature.

Full text of DOI:10.1021/ol070241c

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1505-1508
Synthesis of 4-Arylpiperidines from
1-Benzyl-4-piperidone: Application of
the Shapiro Reaction and Alkenylsilane
Cross-Coupling
Christie Morrill* and Neelakandha S. Mani
Department of Drug DiscoVery, Johnson & Johnson Pharmaceutical R&D LLC,
3210 Merryfield Row, San Diego, California 92121
cmorril3@prdus.jnj.com
Received January 30, 2007
ABSTRACT
1-Benzyl-3,4-unsaturated-4-piperidinyl benzyldimethylsilane has been prepared and observed to readily undergo palladium-catalyzed cross-
coupling reactions with a variety of aryl iodides and aryl bromides to generate 3,4-unsaturated 4-arylpiperidines, often at ambient temperature.
The 4-arylpiperidine moiety is commonly employed as a
structural unit in numerous drug discovery programs, includ-
ing those with potential application for the treatment of
asthma,1 hypertension,2 depression,3 migraines,4 bacterial
infections,5 prostate gland enlargement,6 estrogen-related
disorders,7 Alzheimer’s disease,8 neuronal excitotoxicity (e.g.,
epilepsy, Parkinson’s disease),9 cocaine abuse,10 and allergic
rhinitis.11 Both the 4-aryl group and the N-substituent are
frequently used as points of structural diversification.1,3-5,9,11
Because few 4-arylpiperidines are commercially available,
new synthetic routes are desirable. The most common
synthetic methods include the condensation of a 4-piperidone
derivative with an aryl organometallic species (Scheme 1,
eq 1),3-4,8-12 the cross-coupling of a fully saturated piperidine
reagent (eq 2),13 and the cross-coupling of a 3,4-unsaturated
piperidine reagent (eq 3).1-2,5-7,14 The first method is often
undesirable due to its use of strong nucleophiles and acids.
(1) Levell, J.; Astles, P.; Eastwood, P.; Cairns, J.; Houille, O.; Aldous,
S.; Merriman, G.; Whiteley, B.; Pribish, J.; Czekaj, M.; Liang, G.; Maignan,
S.; Guilloteau, J-.P.; Dupuy, A.; Davidson, J.; Harrison, T.; Morley, A.;
Watson, S.; Fenton, G.; McCarthy, C.; Romano, J.; Mathew, R.; Engers,
D.; Gardyan, M.; Sides, K.; Kwong, J.; Tsay, J.; Rebello, S.; Shen, L.;
Wang, J.; Luo, Y.; Giardino, O.; Lim, H-.K.; Smith, K.; Pauls, H. Bioorg.
Med. Chem. 2005, 13, 2859-2872.
(6) Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle,
K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.;
Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang,
R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J. D.; Barrish, A.; Kassahun,
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Johnson, K. M.; Wang, S. Bioorg. Med. Chem. Lett. 2001, 11, 495-500.
(11) Fonquerna, S.; Miralpeix, M.; Page`s, L.; Puig, C.; Cardu´s, A.; Anto´n,
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Bioorg. Med. Chem. Lett. 2005, 15, 1165-1167.
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10.1021/ol070241c CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/16/2007

containing a benzyldimethylsilyl moiety could be readily
synthesized and successfully employed in cross-coupling
reactions. Herein, we report (1) the application of the Shapiro
reaction to efficiently convert 1-benzyl-4-piperidone into a
benzyldimethylsilyl reagent and (2) the use of cross-coupling
chemistry to subsequently transform this reagent into a
variety of 3,4-unsaturated 4-arylpiperidines.
Scheme 1. Common Methods to Synthesize 4-Arylpiperidines
The Shapiro reaction18 was employed to synthesize the
desired alkenylsilane reagent. This strategy involved the
fragmentation of a tosylhydrazone to generate an alkenyl-
lithium species, which was then trapped with benzyldi-
methylsilyl chloride (BnMe2SiCl). This synthetic route
appeared to be more direct compared to routes involving
precursors such as alkynes or alkenyl halides, which would
have likely involved additional synthetic steps, as well as
problems of regioselectivity.
The first step in this synthesis converted 1-benzyl-4-
piperidone (1) into tosylhydrazone 2 (Scheme 2). The benzyl
The latter two methods represent more general procedures
because they involve mild reaction conditions.
One disadvantage, however, of the methods represented
in eqs 2 and 3 is that the requisite piperidine reagents
generally cannot be carried through multiple synthetic steps.
They must undergo cross-coupling immediately following
their preparation. Thus, the manner in which a 4-arylpiperi-
dine unit can be diversified within a drug discovery program
is limited. This situation exists primarily because tin reagents
introduce issues of toxicity and difficult byproduct removal,
whereas triflate, zinc, and boron reagents introduce issues
of reagent instability and incompatibility.
Organosilanes have recently emerged as alternative cross-
coupling reagents that possess the advantages of low toxicity
and high stability.15 Benzyldimethylsilyl reagents in particular
exhibit notable stability toward acids and bases,16 and they
can be carried through multiple synthetic steps.17 We wanted
to ascertain whether a 3,4-unsaturated piperidine reagent
Scheme 2. Synthesis of Tosylhydrazone 2
protecting group was utilized because of its relatively high
stability toward organometallic reagents such as n-butyl-
lithium (n-BuLi).19 Tosylhydrazone 2 was isolated by filtra-
tion as a crystalline, white solid that was stable for at least
6 months on the bench top. This material was used without
further purification.
The second step involved the Shapiro reaction of 2.
Previous reports described the Shapiro reaction of carbocyclic
tosylhydrazones using excess n-BuLi (4.0-4.3 equiv) and
trimethylsilyl chloride (3.4-4.0 equiv) in TMEDA/hexanes.20
The use of these literature-recommended conditions in the
reaction of 2 with BnMe2SiCl resulted in only a 60% isolated
(13) (a) Bica, K.; Gaertner, P. Org. Lett. 2006, 8, 733-735. (b)
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 11, 1794-
1798. (c) Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.;
Boice, G. J. Org. Chem. 2004, 69, 5120-5123. (d) Powell, D. A.; Fu, G.
C. J. Am. Chem. Soc. 2004, 126, 7788-7789. (e) Billotte, S. Synlett 1998,
4, 379-380.
1
yield of alkenylsilane 4 (Scheme 3). HPLC and H NMR
(14) (a) Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron Lett. 2005,
46, 4261-4263. (b) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner,
A. J. Org. Chem. 2004, 69, 3943-3949. (c) Boice, G. N.; Savarin, C. G.;
Murry, J. A.; Conrad, K.; Matty, L.; Corley, E. G.; Smitrovich, J. H.;
Hughes, D. Tetrahedron 2004, 60, 11367-11374. (d) Dantale, S. W.;
So¨derberg, B. C. G. Tetrahedron 2003, 59, 5507-5514. (e) Bursavich, M.
G.; West, C. W.; Rich, D. H. Org. Lett. 2001, 3, 2317-2320. (f) Eastwood,
P. R. Tetrahedron Lett. 2000, 41, 3705-3708. (g) Kiely, J. S.; Laborde,
E.; Lesheski, L. E.; Bucsh, R. A. J. Heterocycl. Chem. 1991, 28, 1581-
1585. (h) Wustrow, D. J.; Wise, L. D. Synthesis 1991, 11, 993-995.
(15) (a) Denmark, S. E.; Sweis, R. F. Organosilicon Compounds in Cross-
Coupling Reactions. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 163-
216. (b) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835-846.
(c) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531-
1541.
(16) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895-
1898. Note that (2-thienyl)dimethylsilyl reagents also demonstrate significant
acid and base stability: Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett.
2002, 138-139.
(17) (a) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127,
8971-8973. (b) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.;
Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127,
3666-3667. (c) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005,
127, 8004-8005.
Scheme 3. Syntheis of 4 Using Literature Conditions
spectroscopy studies indicated that this low yield was not
the result of either (1) incomplete consumption of 2 or (2)
premature protonation of intermediate 3.
(18) (a) Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16,
55-59. (b) Chamberlin, A. R.; Bloom, S. H. Lithioalkenes from Arene-
sulfonylhydrazones. In Organic Reactions; Paquette, L. A., Ed.; John Wiley
& Sons, Inc.: New York, 1990; Vol. 39, pp 1-83. (c) Shapiro, R. H.
Alkenes from Tosylhydrazones. In Organic Reactions; Dauben, W. G., Ed.;
John Wiley & Sons, Inc.: New York, 1976; Vol. 23, pp 405-507.
(19) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley & Sons, Inc.: New York, 1991; pp 441-
452.
1506
Org. Lett., Vol. 9, No. 8, 2007

Table 1. Optimization of the Shapiro Reaction of 2a
Table 2. Cross-Coupling of 6 with Aryl Iodidesa
entry
R
temp
isolated yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5
rt
rt
rt
50 °C
rt
rt
50 °C
rt
50 °C
rt
rt
rt
rt
rt
rt
rt
50 °C
90%
91%
62%
91%
88%
36%
75%
64%
60%
83%
92%
99%
99%
93%
90%
65%b
61%b
4-MeC6H5
2-MeC6H5
2-MeC6H5
4-MeOC6H5
2-MeOC6H5
2-MeOC6H5
2-thienyl
2-thienyl
3-thienyl
4-FC6H5
4-(CF3)C6H5
4-(MeOC)C6H5
4-(MeO2C)C6H5
4-NCC6H5
4-BrC6H5
b
a 0.2 M; 26 mmol scale. Contaminated with unknown impurities.
Further optimization involved varying the reagent stoichi-
ometries (Table 1). Entry 1 shows the initial reaction
conditions. As the literature suggests,18,20,21 at least 5 equiv
of n-BuLi was required to prevent the formation of 5 (entries
1-3). Moreover, TMEDA was not needed as a cosolvent;
the reaction could be carried out in hexanes with only 5 equiv
of TMEDA (entry 4). Finally, the use of only 1.5 equiv of
BnMe2SiCl significantly increased the isolated yield of 4
(compare entries 4-6). This observation contradicts literature
reports, which suggest that similar amounts of the electro-
phile and n-BuLi must be employed.18,20,21 The use of less
BnMe2SiCl also greatly facilitated the isolation of 4. The
aqueous workup and purification of the reactions shown in
entries 1-4 were plagued with emulsions and abundant
byproducts, but the workup and purification of the reactions
shown in entries 5 and 6 were not. Using the optimized
conditions (entry 5), this reaction was successfully performed
on scales of up to 18 g.
Alkenylsilane 4 was purified by silica gel chromatography,
but it still contained minor impurities. Further purification
was achieved by the conversion of 4 into HCl salt 6 through
reaction with concentrated HCl in isopropanol. Analytically
pure 6 precipitated from the solution overnight, and it was
isolated by filtration in 65% yield as a crystalline, white solid
that was stable for at least 6 months on the bench top.
The cross-coupling reactions of alkenylsilane 6 were
evaluated under the conditions that have been previously
reported for the cross-coupling of alkenyl benzyldimethyl-
silanes.16 Reagent 6 efficiently coupled with a variety of aryl
iodides (Table 2). The only necessary modifications to the
literature procedure were: (1) the use of 4, instead of 2, equiv
of TBAF, presumably to ensure neutralization of 6 and (2)
reaction times of >12 h, as opposed to e4 h. We suspect
that the tertiary amine, which could potentially coordinate
to palladium, is responsible for the longer reaction times.
4-BrC6H5
a 0.2 M in THF; 0.3 mmol scale. No bromo-coupled product isolated.
b
Alkenylsilane
4 also efficiently underwent cross-
coupling: its reaction with iodobenzene, using only 2 equiv
of TBAF, resulted in an 89% yield of the isolated cross-
coupled product. However, because 6 was more readily
obtained in pure form, it was used to evaluate the full
substrate scope of this reaction.
The observed trends matched those previously reported
in alkenylsilane cross-coupling reactions.15,16 Thus, electron-
rich substrates (Table 2, entries 5-10) gave lower yields
than electron-deficient ones (entries 11-15), and ortho-
substituted substrates (entries 3 and 6) gave lower yields than
para-substituted ones (entries 2 and 5). Lower reaction yields
could be improved by raising the temperature to 50 °C in
some cases (entries 4 and 7) but not in others (entries 9 and
17). Finally, entries 16 and 17 show that an aryl iodide is
significantly more reactive than an aryl bromide under these
conditions.
The cross-coupling of 6 with aryl bromides was also
investigated (Table 3). Under the reaction conditions em-
ployed for the aryl iodide couplings, the aryl bromides
afforded extremely low isolated yields (entries 1 and 5).
Attempts to improve these yields by raising the temperature
led to only marginal improvement (entries 2 and 3), except
in the case of a highly electron-deficient substrate bearing a
para-trifluoromethyl group (entries 6 and 7). However, the
use of a PdBr2/2-(di-tert-butylphosphino)biphenyl catalyst
system, which facilitated the cross-coupling of a vinylpoly-
siloxane reagent with aryl bromides,22 led to greatly improved
yields (entries 4 and 8). These reaction conditions promoted
the efficient cross-coupling of 6 with a variety of aryl
(20) (a) Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438-2443.
(b) Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R. J. Org. Chem.
1980, 45, 3017-3028.
(21) Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147-154.
(22) Denmark, S. E.; Butler, C. R. Org. Lett. 2006, 8, 63-66.
Org. Lett., Vol. 9, No. 8, 2007
1507

Table 3. Cross-Coupling of 6 with Aryl Bromidesa
Scheme 4. Transformation of 4 into 7 and Then of 7 into 8
isolated
yield
entry
R
catalyst/ligand
temp
1
2
3
4
C6H5
C6H5
C6H5
C6H5
Pd2dba3-CHCl3/none
Pd2dba3-CHCl3/none
Pd2dba3-CHCl3/none
rt
50 °C
90 °C
0%
26%
42%
74%
reaction. Reagent 6 readily undergoes palladium-catalyzed
cross-coupling reactions with a variety of aryl iodides and
aryl bromides to generate 3,4-unsaturated 4-arylpiperidines.24
Many of these coupling reactions proceed at ambient
temperature. It is also noteworthy that 6 undergoes efficient
cross-coupling, despite its basic tertiary amine. Piperidine-
derived coupling reagents usually possess nonbasic, carbam-
ate-, or amide-protected amines.1,2,5-7,13b-e,14
Because of the low toxicity and high stability of silyl
reagent 6, the coupling reactions of 6 hold some advantages
over those involving analogous tin and boron reagents. Most
notably, because benzyldimethylsilanes can easily be carried
through multiple synthetic steps, piperidenyl silanes such as
6 can be further manipulated prior to undergoing cross-
coupling. Thus, the chemistry demonstrated herein presents
a useful alternative method for 4-arylpiperidine synthesis.
Because 4-arylpiperidines are one of the basic heterocyclic
building blocks for drug candidates, this chemistry provides
new opportunities for drug discovery programs.
PdBr2/2-(tBu2P)biphenyl 50 °C
5
6
7
8
4-(CF3)C6H5
4-(CF3)C6H5
4-(CF3)C6H5
4-(CF3)C6H5
Pd2dba3-CHCl3/none
Pd2dba3-CHCl3/none
Pd2dba3-CHCl3/none
rt
50 °C
90 °C
21%
64%
74%
80%
t
PdBr2/2-( Bu2P)biphenyl 50 °C
9
10
11
12
13
14
15
4-MeC6H5
4-MeOC6H5
3-thienyl
4-FC6H5
4-(MeOC)C6H5
4-(MeO2C)C6H5 PdBr2/2-(tBu2P)biphenyl 50 °C
4-NCC6H5
PdBr2/2-(tBu2P)biphenyl 50 °C
PdBr2/2-(tBu2P)biphenyl 50 °C
PdBr2/2-(tBu2P)biphenyl 50 °C
PdBr2/2-(tBu2P)biphenyl 50 °C
PdBr2/2-(tBu2P)biphenyl 50 °C
89%
78%
45%
69%
99%
84%
94%
PdBr2/2-(tBu2P)biphenyl 50 °C
a 0.2 M in THF or 0.1 M in 1,4-dioxane/THF (for 90 °C reactions), 2
mol % of Pd2dba3-CHCl3, 5 mol % of PdBr2, 10 mol % of 2-(t-
Bu2P)biphenyl; 0.3 mmol scale.
bromides (entries 9-15). Both electron-rich substrates
(entries 9-11) and electron-deficient substrates (entries 8
and 12-15) gave yields comparable to those of the corre-
sponding aryl iodides, with the exception of the thiophene
substrate (entry 11). Common functional groups such as
ketones, esters, and nitriles were tolerated.
The N-substituent of 4 and 6 can be manipulated prior to
undergoing cross-coupling. For example, the N-benzyl group
of 4 was selectively removed through reaction with 1-chloro-
ethyl chloroformate.23 The resultant secondary amine was
subsequently converted into Boc-protected amine 7, which
readily underwent cross-coupling to form 8 (Scheme 4). Such
a transformation would be challenging with the correspond-
ing boronic acid or pinacol boronic ester reagents.
Acknowledgment. The authors wish to thank Prof. Scott
E. Denmark, University of Illinois at UrbanasChampaign,
for helpful discussions and Dr. Jiejun Wu, Heather
McAllister, David J. Tognarelli, and Raymond Rynberg for
analytical support.
Supporting Information Available: Experimental details
and characterization data for compounds 2, 4, 6, 7, and all
compounds reported in Tables 2 and 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070241C
In summary, we have demonstrated that piperidine reagent
6, which contains a benzyldimethylsilyl moiety, can be easily
synthesized from 1-benzyl-4-piperidone via the Shapiro
(24) Procedures to convert 1-benzyl-4-aryl-1,2,3,6-tetrahydropyridines
into their 4-arylpiperidine analogues with retention of the N-benzyl
protecting group have been reported. See: (a) Sakamuri, S.; Enyedy, I. J.;
Kozikowski, A. P.; Zaman, W. A.; Johnson, K. M.; Wang, S. Bioorg. Med.
Chem. Lett. 2001, 11, 495-500. (b) Czibula, L.; Nemes, A.; Sebo¨k, F.;
Sza´ntay, C., Jr.; Ma´k, M. Eur. J. Org. Chem. 2004, 3336-3339.
(23) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T.
J. Org. Chem. 1984, 49, 2081-2082.
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Org. Lett., Vol. 9, No. 8, 2007