A straightforward approach towards piperidines via Stille coupling and subsequent 1,4-addition of amines

Article abstract of DOI:10.1055/s-2006-926246

Substituted 4-piperidones are easily obtained from alkynes via molybdenum-catalyzed regioselective hydrostannation and subsequent Stille-coupling of the vinyl stannanes obtained with α,β-unsaturated acyl chlorides. The resulting divinylketones can undergo

Full text of DOI:10.1055/s-2006-926246

LETTER
547
A Straightforward Approach towards Piperidines via Stille Coupling and
Subsequent 1,4-Addition of Amines
P
iperidines via
a
Stille Cou
n
pling and Su
d
bsequent 1,4
r
-Additio
a
n of Amines Dörrenbächer,a Uli Kazmaier,*a Sven Rufb
a
Institut für Organische Chemie, Universitaet des Saarlandes, 66123 Saarbruecken, Germany
b
Chemical Sciences, Sanofi-Aventis, Industriepark Höchst, G838, 65926 Frankfurt am Main, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 7 December 2005
alkynes,10 giving rise to internal vinyl stannanes.11 These
and similar mixed carbonyl/isonitrile complexes were
used previously by Trost et al. for allylic alkylations,12 and
we found that MoBl3 was superior in the hydrostannation
Abstract: Substituted 4-piperidones are easily obtained from
alkynes via molybdenum-catalyzed regioselective hydrostannation
and subsequent Stille-coupling of the vinyl stannanes obtained with
a,b-unsaturated acyl chlorides. The resulting divinylketones can
undergo a double 1,4-addition of amines giving rise to the required reaction to the generally used palladium complexes,13 es-
4-piperidones. The best results are obtained if the Stille couplings
and the 1,4-additions are combined in a one-pot procedure.
pecially with respect to regioselectivity. The internal vinyl
stannanes can subsequently be subjected to Stille cou-
Key words: heterocycles, hydrostannations, piperidines, Stille
couplings
plings, which makes this approach interesting from a
combinatorial point of view. For example, 4-piperidin-
ones should be accessible in three steps from alkynes via
regioselective hydrostannation, Stille coupling with a,b-
Piperidines are an important class of heterocycles, found unsaturated acyl halides, and subsequent double 1,4-addi-
widely in nature, for example in the large group of piperi- tion of amines (Scheme 1).
dine alkaloids.1 Probably the most famous representative
is the poison of the hemlock Conium maculatum, coniin
(1),2 but many other derivatives are highly interesting
from a pharmaceutical point of view as well. Hydroxylat-
ed piperidines such as isofagomine (2)3 and related struc-
tures are important glycosidase inhibitors,4 while
piperidones such as 3 inhibit human platelet aggregation
(Figure 1).5
Scheme 1 Retrosynthetic analysis of substituted 4-piperidones
To prove this synthetic protocol, we subjected protected
propargyl amines 4 to molybdenum-catalyzed hydrostan-
nations (Scheme 2). Under standard reaction conditions,
Figure 1 Natural and pharmaceutically interesting piperidine
three equivalents of Bu3SnH, as reported previously, fur-
nished vinyl stannane 5 in 70–87%. To improve the yield
and obtain more reproducible results, we carefully varied
the reaction conditions and found that the best results
were obtained if only 1.1 equivalents of Bu3SnH were
added slowly over a period of six to seven hours via sy-
ringe pump at room temperature. Under these conditions,
5 was obtained in 95% yield in very pure form [b-product/
g-(E)-product/g-(Z)-product, 93:4:3). As a second sub-
strate, stannylated amino acid 7 was synthesized via a pal-
ladium-catalyzed allylic alkylation of stannylated acetate
611 using a chelated amino acid ester enolate as nucleo-
phile.14
alkaloids
Therefore, substituted 4-piperidones are highly interest-
ing scaffolds for the synthesis of drug-like molecules.
Besides classical approaches such as Dieckmann conden-
sations,6 hetero-Diels–Alder reactions7 and cyclizations
via 1,4-addition of amines towards vinylic ketones8 are
suitable for the synthesis of these heterocycles.
Our group is interested in transition metal catalyzed hy-
drostannations and the application of this protocol to nat-
ural product and heterocycle synthesis.9 We found that
Mo(CO)3(CNt-Bu)3 (MoBl3) is a highly efficient catalyst
for the regioselective hydrostannation of terminal
Both vinnylstannanes were than subjected to Stille
couplings15 using cinnamoyl chloride as the coupling
partner. With 5, we investigated the influence of the cata-
lyst system on the outcome of the reaction. Coupling reac-
tions with acyl halides are known to be very fast, and in
SYNLETT 2006, No. 4, pp 0547–0550
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-926246; Art ID: G39705ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
3.
2
0
0
6

548
S. Dörrenbächer et al.
LETTER
that the double 1,4-addition proceeded rather sluggishly.
Even with an excess of benzylamine, the reaction of 8 at
room temperature was not complete after two days
(Scheme 3). Increasing the temperature to 60 °C, resulted
in complete consumption of 8 after one day. Obviously,
the divinyl ketones are far less reactive than expected. We
therefore tried to increase their reactivity by adding Lewis
acids; indeed, in the presence of LiCl, the reaction was
complete after one day at room temperature giving rise to
10 in 29% yield. Under these optimized conditions 9 was
also converted into the corresponding piperidone amino
acid derivative 11a.
Scheme 2 Molybdenum-catalyzed hydrostannations
many cases palladium precipitates (Pds) after a few min-
utes or even seconds, which might be a severe problem.
The results are summarized in Table 1. First we used
Pd2dba3 as catalyst giving rise to 8 in 52%, although the
palladium precipitated after five minutes (Table 1, entry
1). Warming the reaction mixture to 55 °C increased the
yield to 74% (Table 1, entry 2). To suppress the palladium
16
precipitation, we added P(furyl)3 to obtain more stable
complexes. Indeed, no precipitation was observed, but a
very poor yield was achieved. Similar results were ob-
tained with AsPh3 (Table 1, entry 4),17 while with PPh3
the yield could be increased to 83% and palladium precip-
itation was observed after 18 hours (Table 1, entry 5). A
comparable yield could be obtained with [allyl-PdCl]2
(Table 1, entry 6). Under these optimized conditions, sub-
strate 7 reacted to give the same high yield (Table 1, entry
7), even when the amount of catalyst was reduced to 0.5
mol%.
Scheme 3 Synthesis of piperidones via double 1,4-addition of
amines
As mentioned earlier, the Stille couplings proceeded with-
out precipitation of Pd(0) if the reactions were run in the
presence of PPh3. In general, an excess of acyl chloride
(0.5 equiv) was used in the coupling reactions, and there-
fore one might assume that a phosphine complex of the
acyl palladium chloride intermediate could be a relatively
stable Pd(II) source in solution.
With these divinyl ketones in hand, we next investigated
the addition of amines to obtain the desired 4-piperidones.
Our first experiments were disappointing and we found
Table 1 Cross-Coupling of Vinyl Stannanes 5 and 7 with Cinnamoyl Chloride
Entry
Substrate
Catalyst (mol%)
Reaction conditions
THF, r.t., 19 h
Product
Yield (%)
52a
1
2
3
4
5
6
7
5
5
5
5
5
5
7
Pd2dba3 (1)
8
8
8
8
8
8
9
Pd2dba3 (1)
THF, 55 °C, 2.5 h
THF, 55 °C, 2.5 h
THF, 55 °C, 2.5 h
THF, 55 °C, 2.5 h
THF, 60 °C, 2.5 h
THF, 60 °C, <1 h
74a
Pd2dba3 (1), P(fur)3 (2)
Pd2dba3 (1), AsPh3 (2)
Pd2dba3 (1), PPh3 (3)
[allyl-PdCl]2 (2.5), PPh3 (5)
[allyl-PdCl]2 (0.5), PPh3 (1)
43b
45b
83c
86b
86b
a Pds after 5 min.
b No Pds.
c Pds after 18 h.
Synlett 2006, No. 4, 547–550 © Thieme Stuttgart · New York

LETTER
Piperidines via Stille Coupling and Subsequent 1,4-Addition of Amines
549
In contrast to Pd(0) complexes, those of Pd(II) show sig- Cleavage under standard conditions using hydrazine or
nificant Lewis acid activity,18 which suggested to us that primary amines resulted in a complex mixture of prod-
the Stille coupling and the subsequent amine addition ucts, probably because of the participation of the keto
could be conducted in a one-pot procedure. We reacted group. To avoid these side reactions, we decided to cleave
vinyl stannane 7 under the optimized conditions (Table 1, the protecting group under reductive conditions (includ-
entry 7) with cinnamoyl chloride, and after three hours ing reduction of the keto group) using NaBH4. The best re-
two equivalents of benzylamine were added. This two- sults were obtained in isopropanol–water (6:1) giving rise
step process, gave 11a in as high a yield as the simple ad- to intermediate 12, which undergoes cleavage to 13 via
dition step, and the amine addition was complete after two lactonization under acidic conditions.20
hours (Table 2, entry 1).19 The amine hydrochloride pre-
In summary, we have shown that piperidines can easily be
cipitation was monitored, the amine reacted first with the
obtained by a domino Stille coupling/Michael addition
excess of cinnamoyl chloride and afterwards with the di-
sequence starting from easily available vinyl stannanes.
vinyl ketone 9 formed. No palladium precipitated before
9 was completely consumed. To prove the generality of
Acknowledgment
this approach, we used other amines, including an amino
acid ester, and varied the acyl halide (Table 2).
Financial support by the Deutsche Forschungsgemeinschaft as well
as from Sanofi-Aventis is gratefully acknowledged.
Table 2 Direct Synthesis of Piperidinones 11 from Vinyl
Stannane 7
References and Notes
(1) Alkaloids: Chemical and Biological Perspectives, Vol. 10;
Pelletier, S. W., Ed.; Pergamon Press: New York, 1996.
(2) Römpp Lexikon: Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
(3) Jespersen, T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.;
Lundt, I.; Bols, M. Angew. Chem. Int. Ed. 1994, 33, 1778;
Angew. Chem. 1994, 106, 1858.
(4) (a) Persson, M. P.; Butt, W. M.; Joergensen, M.;
Christensen, P.; Hansen, L. T. Tetrahedron Lett. 1996, 37,
2097. (b) Ichikawa, M.; Igaroshi, Y.; Ichikawa, Y.
Tetrahedron Lett. 1995, 36, 1767. (c) Liu, H.; Liang, X.;
Soehoel, H.; Buelow, A.; Bols, M. J. Am. Chem. Soc. 2001,
123, 5116.
Entry
R1
R2
Product
11a
Yield (%)
1
2
3
4
5
6
Ph
CH2Ph
70
69
53
52
54
67
Ph
CH2CH=CH2
CH2COO-t-Bu
CH2Ph
11b
11c
Ph
Me
Me
Me
11d
11e
(5) Blasko, G.; Blasko, G.; Szantay, C. Arzneim.-Forsch. 1987,
37, 667.
CH2CH=CH2
CH2COO-t-Bu
(6) Ruzicka, L.; Fornasier, V. Helv. Chim. Acta 1920, 3, 806.
(7) Hattori, K.; Yamamoto, H. Tetrahedron Lett. 1993, 1749.
(8) (a) Jackson, R. F.; Graham, L. J.; Rettie, A. B. Tetrahedron
Lett. 1994, 35, 4417. (b) Barco, A.; Benetti, S.; De Risi, C.;
Manchetti, P.; Pollini, G. P.; Zanirato, V. Eur. J. Org. Chem.
2001, 975.
11f
This one-pot protocol was also used for the synthesis of
piperidinone 10b, which is an interesting scaffold for drug
targeting, providing that the phthaloyl protecting group
(Phth) can be removed reasonably easily (Scheme 4). In
the presence of the keto group, this proved not to be a
trivial issue.
(9) Braune, S.; Pohlman, M.; Kazmaier, U. J. Org. Chem. 2004,
69, 468.
(10) For a recent review of hydrostannations, see: Smith, N. D.;
Mancuso, J.; Lautens, M. Chem. Rev. 2000, 100, 2413.
(11) (a) Kazmaier, U.; Schauß, D.; Pohlman, M. Org. Lett. 1999,
1, 1017. (b) Kazmaier, U.; Schauß, D.; Pohlman, M.;
Raddatz, S. Synthesis 2000, 914. (c) Kazmaier, U.;
Pohlman, M.; Schauß, D. Eur. J. Org. Chem. 2000, 2761.
(d) Kazmaier, U.; Schauß, D.; Raddatz, S.; Pohlman, M.
Chem. Eur. J. 2001, 7, 456. (e) Kazmaier, U.; Braune, S. J.
Organomet. Chem. 2002, 641, 26. (f) Kazmaier, U.;
Wesquet, A. Synlett 2005, 1271.
(12) Trost, B. M.; Merlic, C. A. J. Am. Chem. Soc. 1990, 112,
9590.
(13) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1867.
(14) (a) Rewiew: Kazmaier, U. Curr. Org. Chem. 2003, 317.
(b) Kazmaier, U.; Pohlman, M. In Metal Catalyzed C-C and
C-N Coupling Reactions; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004, 531–583.
Scheme 4 Synthesis of free piperidines
Synlett 2006, No. 4, 547–550 © Thieme Stuttgart · New York

550
S. Dörrenbächer et al.
LETTER
(15) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508;
Angew. Chem. 1986, 98, 504. (b) Pereyne, M.; Quintard, J.
P.; Rahm, A. In Tin in Organic Synthesis; Butterworth:
London, 1986. (c) Davies, A. G. Organotin Chemistry;
Wiley-VCH: Weinheim, 2004.
(16) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic
Reactions, Vol. 50; Paquette, L., Ed.; John Wiley & Sons:
New York, 1997, 1–652.
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(18) (a) Albrecht, M.; van Koten, G. Angew. Chem. Int. Ed. 2003,
40, 3750; Angew. Chem. 2001, 113, 3866. (b) Solin, M.;
Kjellgren, J.; Szabo, K. J. Angew. Chem. Int. Ed. 2003, 42,
3656; Angew. Chem. 2003, 115, 3784.
3J = 7.9 Hz, 1 H), 2.68 (dd, 2J = 12.3 Hz, 3J = 5.7 Hz, 1 H),
2.63 (dd, 2J = 14.0 Hz, 3J = 4.9 Hz, 1 H), 2.45 (dd, 2J = 13.9
Hz, 3J = 5.7 Hz, 1 H), 1.12 (d, 3J = 6.7 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): d = 15.8, 37.1, 47.0, 47.9, 51.9, 55.5,
57.5, 123.3, 127.1, 128.4, 128.5, 131.9, 133.9, 138.8, 168.2,
209.2. HRMS (EI): m/z calcd for C22H22N2O3: 362.4322;
found: 362.1602. Diastereomer B: 1H NMR (500 MHz,
CDCl3): d = 7.75–7.78 (dd, 3J = 3.9 Hz, 4J = 7.2 Hz, 2 H),
7.66–7.68 (dd, 3J = 3.9 Hz, 4J = 6.6 Hz, 2 H), 7.24–7.29 (m,
2 H), 7.13–7.21 (m, 2 H), 7.06–7.10 (m, 1 H), 4.15 (dd,
2J = 14.2 Hz, 3J = 6.6 Hz, 1 H), 3.86 (d, 2J = 13.6 Hz, 1 H),
3.58 (dd, 2J = 14.2 Hz, 3J = 8.4 Hz, 1 H), 3.46 (d, 2J = 13.3
Hz, 1 H), 2.90–2.99 (m, 3 H), 2.59 (dd, 2J = 14.2 Hz, 3J = 4.1
(19) One-Pot Stille Couplings and 1,4-Additions; General
Procedure
Hz, 1 H), 2.29–2.35 (m, 2 H), 1.19 (d, 3J = 6.3 Hz, 3 H). 13
C
NMR (125 MHz, CDCl3): d = 18.4, 36.6, 47.9, 48.2, 53.6,
56.1, 57.3, 123.3, 127.0, 128.2, 128.7, 131.8, 134.0, 138.5,
168.1, 208.7. HRMS (EI): m/z calcd for C22H22N2O3:
362.4322; found: 362.1640.
A mixture of [allylPdCl]2 (1.8 mg, 0.005 mmol) and PPh3
(2.6 mg, 0.01 mmol) was dissolved in anhyd THF (1 mL)
and stirred for at least 15 min at r.t. The freshly prepared,
pale-yellow catalyst solution was added to a solution of b-
stannylated allylic substrate (1 mmol) and acyl chloride (1.5
mmol) in anhyd THF (2 mL) at 60 °C. After complete cross-
coupling (ca. 30–60 min) the reaction mixture was stirred for
an additional 2 h at 60 °C, then amine (2 mmol) was added.
After the reaction was complete (2–3 h), the solvent was
evaporated, the residue was dissolved in EtOAc, and then
stirred vigorously with a sat. solution of KF (2 mL) for at
least 12 h. After extraction of the aqueous layer, the organic
layer was washed with H2O (× 2) and dried over Na2SO4.
The crude product was purified by chromatography over
silica gel (hexanes–EtOAc).
11a: Mixture of diastereomers. 1H NMR (500 MHz, CDCl3):
d = 7.80 (d, 3J = 5.7 Hz, 0.5 H), 7.44 (d, 3J = 7.9 Hz, 2 H),
7.22–7.38 (m, 8.5 H), 4.43–4.46 (m, 0.5 H), 4.23–4.28 (m,
0.5 H), 3.82 (d, 2J = 13.7 Hz, 0.5 H), 3.80 (d, 2J = 13.7 Hz,
0.5 H), 3.54 (t, 3J = 3.2 Hz, 0.5 H), 2.52 (t, 3J = 3.2 Hz, 0.5
H), 3.24 (dd, 2J = 11.3 Hz, 3J = 6.0 Hz, 0.5 H), 3.12 (dd,
2J = 11.4 Hz, 3J = 6.0 Hz, 0.5 H), 2.89 (d, 2J = 13.9 Hz, 0.5
H), 2.86 (d, 2J = 13.6 Hz, 0.5 H), 2.70–2.83 (m, 2 H), 2.58
(dd, 2J = 6.4 Hz, 3J = 3.4 Hz, 0.5 H), 2.55 (dd, 2J = 6.3 Hz,
3J = 3.5 Hz, 0.5 H), 2.20–2.27 (m, 1 H), 2.07–2.13 (m, 1 H),
1.53–1.59 (m, 1 H), 1.38–1.47 (m, 9 H). 13C NMR (125
MHz, CDCl3): d = 27.82/27.85/27.94, 28.16/28.60, 46.67/
47.89, 50.44/50.49, 51.79/53.11, 57.65/57.84, 58.13, 69.13/
69.18, 83.07/83.10, 115.75 (q, 3J = 288 Hz), 127.16/127.20,
127.21, 128.02/128.04, 128.33/128.37, 128.52/128.45,
129.06, 138.34/138.50, 141.91/141.95, 157.08 (q, 3J = 38
Hz), 168.98/169.23, 209.69/210.00. HRMS (EI): m/z calcd
for C27H31N2O4F3: 504.5543; found: 504.2259.
10b: Diastereomer A: 1H NMR (500 MHz, CDCl3):
d = 7.78–7.80 (dd, 3J = 5.4, 5.8 Hz, 4J = 3.2 Hz, 5J = 2.8 Hz,
2 H), 7.67–7.69 (dd, 3J = 5.4 Hz, 4J = 3.2 Hz, 2 H), 7.31 (d,
3J = 7.3 Hz, 2 H), 7.23–7.28 (dd, 3J = 7.3 Hz, 2 H), 7.16–
7.21 (t, 3J = 7.3 Hz, 1 H), 4.25 (dd, 2J = 14.2 Hz, 3J = 7.3 Hz,
1 H), 3.91 (d, 2J = 13.6 Hz, 1 H), 3.61 (dd, 2J = 14.2 Hz,
3J = 7.9 Hz, 1 H), 3.44 (d, 2J = 13.2 Hz, 1 H), 3.06–3.12 (m,
1 H), 2.96–3.02 (q, 3J = 7.3 Hz, 1 H), 2.85 (dd, 2J = 12.3 Hz,
(20) Osby, J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett.
1984, 25, 2093.
Synlett 2006, No. 4, 547–550 © Thieme Stuttgart · New York