Synthesis of 3-alkylidene-piperidin-4-ones via one-pot cascade transylidation-olefination

Article abstract of DOI:10.1016/j.tetlet.2009.03.023

3-Alkylidene-piperidin-4-ones with diverse C-5 substitution patterns are synthesized via a one-pot cascade transylidation-olefination sequence. Tributylphosphorus ylides show distinct higher reactivity as compared to triphenyl analogs. t-Butanol is the so

Full text of DOI:10.1016/j.tetlet.2009.03.023

Tetrahedron Letters 50 (2009) 2487–2489
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Synthesis of 3-alkylidene-piperidin-4-ones via one-pot cascade
transylidation–olefination
*
Bing Wang
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Alkylidene-piperidin-4-ones with diverse C-5 substitution patterns are synthesized via a one-pot cas-
cade transylidation–olefination sequence. Tributylphosphorus ylides show distinct higher reactivity as
compared to triphenyl analogs. t-Butanol is the solvent of choice for transylidation, while the Wittig olef-
ination of aliphatic aldehydes requires MeCN as the solvent.
Received 5 February 2009
Revised 3 March 2009
Accepted 6 March 2009
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Alkylidene cycloketone is the structural feature present in
AsPh3, MeCN
reflux
CO2Me
AsPh3Br
3d
many biologically active compounds which exhibited promising
CO2Me
X
antibacterial and antitumor activities.1 In addition, these
a,b-
N
N
Bn
Bn
unsaturated carbonyl compounds are also versatile building blocks
in organic synthesis.2 Conventional methods for the preparation of
this type of compounds relied on Claisen–Schmidt condensation of
cycloketones with aldehydes under basic conditions.3 In general,
aliphatic aldehydes were not ideal substrates due to multiple side
reactions promoted by the base. Bis-condensation was also a seri-
ous side-reaction due to the higher reactivity of mono-condensa-
tion product.4 Recently, catalyzed aldol-dehydration sequences
have emerged as alternative approaches with varying degrees of
success.5 In a different approach, Sato developed an alkyne-based
intramolecular nucleophilic acyl substitution reaction using a low
valent Ti(II) reagent.6 Falck et al. devised an interesting homologa-
tion–condensation cascade to construct the exocyclic C–C double
bond.7 In this connection, classic olefination methods such as Wit-
tig,8 Horner–Wadsworth–Emmons,9 and Julia10 reactions have re-
ceived little attention, probably due to the difficulty in preparing
the corresponding ylids or sulfones, and the intrinsic low reactivity
of these species. Only limited examples have been reported, where
the substrate was restricted to the most reactive formaldehyde and
aromatic aldehydes.11 It should also be mentioned that highly
functionalized ylides, especially those b-hetero-substituted, are
rare due to possible b-elimination. As a part of our continuing pro-
ject in the synthesis of nitrogen heterocycles, particularly substi-
tuted piperidines,12 herein we describe our study on the one-pot
cascade transylidation–olefination protocol for the synthesis of 3-
alkylidene-piperidin-4-ones with a general scope.
1 X = OH
1) MsCl, Et3N
2) LiBr, THF
2 X = Br
R3P, MeCN
reflux
O
t-BuOK
CO2Me
PR3Br
N
N
Tol, reflux
Bn
Bn
PR3
3a R = Ph
4a R = Ph
4b R = Bu
3b R = Bu
3c R = Cy
Scheme 1. Preparation of phosphonium salts and the effect of P-ligands in
transylidation.
effect of the adjacent amino group. The phosphonium salts of inter-
est (3a–c) were synthesized in excellent to quantitative yields by
reacting tertiary phosphines with 2 in acetonitrile under reflux;
however, the analogous arsenium salt 3d was not accessible by this
procedure, due to the low nucleophilicity of triphenylarsine. The
first step in our cascade, namely the transylidation13 of these salts,
was investigated next. Due to the presence of the ester functional-
ity, only hindered non-nucleophilic bases could be employed,
while n-BuLi was precluded. It turned out that the steric factor of
the P-substituents played a major role in this process. We were
pleased to find that 3a and 3b were smoothly deprotonated and
the resulting nonstablized ylides cyclized to afford the correspond-
ing b-keto-ylides 4 using t-BuOK as the base in toluene, as judged
by 31P NMR of the crude reaction mixture. After reacting for 2 h at
60 °C, the original signals of the phosphonium salts were com-
pletely replaced by new signals ꢀ3 ppm upfield (Table 1), consis-
tent with the literature value.14 Notably, this process was not
To begin with, a b-amino-alkylbromide (2) was conveniently
prepared from the corresponding alcohol 1 by routine Finkelstein
reaction (Scheme 1). Compound 2 was sufficiently stable, albeit
its structure was considered quite labile owing to the anchimeric
* Tel./fax: +86 21 54237570.
E-mail address: wangbing@fudan.edu.cn
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.023

2488
B. Wang / Tetrahedron Letters 50 (2009) 2487–2489
Table 1
the ester, thus the desired cyclization did not take place. The effect
of base was profound. Treating 3b with the more hindered bases
(NaHMDS or LDA) resulted in complex mixtures, presumably due
31P NMR data for phosphonium salts and ylidsa
Phosphonium salt
d
31P (ppm)
Ylid
d
31P (ppm)
to preferential deprotonation of the a-H on the butyl, while organic
base such as DBU was probably too weak and too bulky for the
3a
3b
+23.7
+30.2
4a
4b
+20.0
+27.1
phosphonium salts.
a
NMR recorded in C6D6, chemical shifts are relative to 85% H3PO4.
Subsequently, when this protocol was extended to the homolo-
gous 5 and 6 possessing relatively acidic a-H of the ester, an inter-
esting solvent effect was found. In toluene, the initial formation of
reactive ylides seemed to be problematic; the characteristic orange
to red color was not observed. This can be ascribed to the stronger
interfered by possible b-elimination of amine. On the other hand,
although the deprotonation of tricyclohexylphosphonium salt 3c
seemed to occur, the resulting ylide may be too hindered to attack
acidity of the ester
a-H compared to that of the phosphonium
salt.15 Additional amounts of the base or higher temperature did
not solve the problem, because the enolate of ester was no longer
an electrophile and thus unable to react with ylides. Fortuitously,
when we accidentally shifted the solvent to t-butanol (reflux
24 h), the transylidation proceeded smoothly. The exact nature of
this solvent effect cannot be determined at present, but it may
be due to that the widely varied basicity of t-BuOK in these two
solvents [pKa(Tol) ꢀ 35, pKa(t-BuOH) ꢀ 19];16 and that t-BuOH, a
protic solvent, promoted the proton exchange between the ester
enolate and phosphonium salt (Scheme 2).
R
H
R
O
R H
t-BuOK
t-BuOK
t-BuOH
OMe
CO2Me
PBu3Br
CO2Me
N
N
N
Toluene
Bn
PBu3Br
Bn
Bn
Bn
PBu3
5 R = Me
6 R = H
R
H
complex
mixture
O
N
PBu3
Next, the key step of Wittig olefination of b-keto-ylides 4a,b
with aldehydes was examined (Scheme 3). It is known that such
cyclic phosphoranes bearing an electron-withdrawing group at
7, 8
Scheme 2. Solvent effect in transylidation.
a-position were deactivated and showed limited reactivity toward
aromatic aldehydes only.11a Indeed, when crude 4a,b were reacted
with 2-methyl-propanal in toluene, virtually no product was de-
tected. In view that Wittig reaction showed marked solvent ef-
fect,17 we turned our attention to polar solvents. To our
satisfaction, in acetonitrile or DMF 4b afforded the desired product
9a (ꢀ50% yield, 36 h) while 4a was still inert. Other solvents such
as THF, CH2Cl2, DMSO, and HMPA were all ineffective. The en-
hanced reactivity of 4b compared to that of 4a is in line with earlier
reports of the phosphorus ligand effect for related nonstablized
tributylphosphorus ylides.18 On the other hand, using 0.3 equiv
PhCOOH19 or excess LiBr20 as additives did not further improve
the yield. As the boiling point of 2-methyl-propanal (63–65 °C) is
even lower than that of the solvent, we then carried out the olefin-
ation in a pressure vessel, and the yield increased to 60% after 24 h
at 100 °C.21 The reactions of 4a,b with aromatic aldehydes were
further tested. Interestingly, olefination of tributylphosphorus
O
O
i-PrCHO, MeCN
100oC, sealed tube
N
N
N
N
N
Bn
Bn
Bn
Bn
Bn
PBu3
60%
9a
9c
4b
O
O
PMPCHO, Tol, reflux
68%
PBu3
PMP
O
4b
4a
PMP = p-Methoxyphenyl
O
PMPCHO, Tol, reflux
N
PPh3
Bn
Ar
Scheme 3. Solvent and P-ligand effects in Wittig olefination.
Table 2
One-pot synthesis of 3-alkylidene-piperidin-4-ones
R1 R2
CO2Me
PBu3Br
3b, 5, 6
R1 R2
O
1) t-BuOK, t-BuOH
2) RCHO, solv, 100oC
N
N
Bn
Bn
R
9
Entry
Phosphonium salt
R1, R2
R
Solvent
Timea (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
3b
3b
3b
3b
3b
5
5
5
5
5
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, H
Me, H
Me, H
Me, H
Me, H
H, H
2-Pr
2-Amyl
p-MeOC6H4
p-O2NC6H4
p-ClC6H4
2-Pr
MeCN
DMF
Tol
Tol
Tol
MeCN
MeCN
Tol
Tol
Tol
24
40
36
12
12
20
24
12
12
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
60
58
68
37
42
74
33
55
36
64
68
70
1-Amyl
p-MeOC6H4
p-O2NC6H4
p-ClC6H4
2-Pr
10
11
12
9j
9k
9l
6
6
MeCN
Tol
24
20
H, H
p-MeOC6H4
a
Unoptimized reaction time.
Isolated yields.
b

B. Wang / Tetrahedron Letters 50 (2009) 2487–2489
2489
Kozlowski, J. A.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 169; (g) Perlmutter, P. Conjugate
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Aldrichim. Acta 1990, 23, 39.
O
O
O
X
H2, cat. PtO2
MeOH, 90%
+
N
N
N
Bn
Bn
Bn
9k
10
Scheme 4. Formal alkylation via hydrogenation of exocyclic alkene.
ylide 4b with p-anisaldehyde can be conducted smoothly in tolu-
ene, while triphenylphosphorus ylide 4a, the aza-analog of those
carbocyclic ylides described by House and Babad,11a did not react
under the same conditions.
With the optimized conditions in place, the one-pot condensa-
tion of 3b/5/6 with various aldehydes was carried out (Table 2).
Thanks to the improved nucleophilicity of b-keto-tributylphospho-
rus ylides, a general substrate scope was achieved. For aliphatic
aldehydes, regardless of the boiling points, the olefination should
be run in MeCN or DMF in a pressure vessel, while for aromatic
electrophiles, this step was run in toluene under normal pressure.
Moderate to good yields were obtained in most cases, even for the
hindered 2-methyl-hexanal (entry 2), while the yields for 4-nitro-
benzaldehyde were lower (entries 4 and 9). When this substrate
was added to the ylides, the solution turned into dark green color,
probably due to the formation of ketyl radical in the presence of
excess base (Cannizzarro reaction).22 Dimerization of the product
under basic conditions is another possible cause for the low
yields.23
10. For reviews, see: (a) Dumeunier, R.; Marko, I. E. In Modern Carbonyl Olefination;
Gleiter, R., Hopf, H., Eds.; Wiley-VCH: Weinheim, 2004; (b) Kelly, S. E.. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, p 729.
11. (a) House, H. O.; Babad, H. J. Org. Chem. 1963, 28, 90; (b) Fortiadu, F.; Pardigon,
O.; Buono, G.; LeCorre, M.; Hercouet, A. Tetrahedron Lett. 1999, 40, 867; (c)
Minami, T.; Niki, I.; Agawa, T. J. Org. Chem. 1974, 39, 3236; (d) Minami, T.;
Matsumoto, M.; Suganuma, H.; Agawa, T. J. Org. Chem. 1978, 43, 2149; (e) Lee,
K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58, 5967.
The utility of this cascade reaction was demonstrated by the
synthesis of 10, a compound which cannot be prepared by conven-
12. (a) Liu, R.-H.; Fang, K.; Wang, B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73,
3307; (b) Wang, B.; Fang, K.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 7981; (c) Liu,
R.-H.; Wang, B. Eur. J. Org. Chem. 2009, doi:10.1002/ejoc.2009.0231.
13. (a) Bestmann, H. J.; Arnason, B. Tetrahedron Lett. 1961, 2, 455; (b)
Bestmann, H. J.; Arnason, B. Chem. Ber. 1962, 95, 1513; (c) Wittig, G.;
Schoellkopf, U. Chem. Ber. 1954, 87, 1318; (d) Trippett, S.; Walker, D. M.
J. Chem. Soc. 1961, 1266.
14. (a) Albright, T. A.; Freeman, W. J.; Schweizer, E. E. J. Am. Chem. Soc. 1975, 97,
2942; (b) Miedaner, A. M.; Noll, B. C.; DuBois, D. L. Organometallics 1997, 16,
5779.
tional ketone a-alkylation due to the steric hindrance imposed by
b-branching of the alkylating agents (Scheme 4). Hydrogenation
(1 atm H2/cat. PtO2/MeOH) of the exocyclic C–C double bond in
9k afforded the product in 90% yield.
In summary, we have developed a one-pot cascade transylida-
tion–olefination sequence for the synthesis of 3-alkylidene-piperi-
din-4-ones with diverse C-5 substitution patterns. tert-Butanol is
the solvent of choice for transylidation of substrates possessing
15. Pearson, R. G.; Dillon, R. L. J. Am. Chem. Soc. 1953, 75, 2439.
16. Pearson, D. E.; Buehler, C. A. Chem. Rev. 1974, 74, 45.
acidic a-protons of the ester. Only tributylphosphorus ylides pro-
17. Greenwald, R.; Chaykovsky, M.; Corey, E. J. J. Org. Chem. 1963, 28, 1128.
18. (a) Johnson, A. W.; LaCount, R. B. Tetrahedron 1960, 9, 130; (b) Johnson, A. W.
Ylide Chemistry; Academic Press: New York, 1966; (c) Heathcock, C. H.;
Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989, 54, 1548.
19. (a) Ruchardt, C.; Panse, P.; Eichler, S. Chem. Ber. 1967, 100, 1144; (b) Fliszar, S.;
Hudson, R. F.; Salvadory, G. Helv. Chim. Acta 1964, 47, 159.
duced the desired Wittig olefination products due to its higher
nucleophilicity, while the triphenylphosphorus analogs were unre-
active. Both aliphatic and aromatic aldehydes are suitable sub-
strates; for low-boiling aldehydes, the olefination can be
conveniently carried out in a re-sealable pressure vessel. Applica-
tion of this protocol to the synthesis of bioactive natural products
is in progress.
20. (a) Hooper, L.; Garagan, S.; Kayser, M. M. J. Org. Chem. 1994, 59, 1126; (b) Takai,
K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59, 2668.
21. Representative procedures: The dried tributylphosphonium salt (0.65 mmol)
was placed in a re-sealable pressure vessel equipped with a side-arm under Ar.
To this were added t-BuOH (6 mL) and t-BuOK (0.78 mL of 1.0 M solution in t-
BuOH, 0.78 mmol) at rt, and the solution was refluxed for 24 h, cooled, and the
volatiles were removed in vacuo. To the residue were added MeCN or Tol
(4 mL) and aldehyde (0.73–3.3 mmol), the vessel was sealed and stirred at
100 °C for 8–24 h. After cooling, the reaction was diluted with ether (20 mL)
and washed successively with water and brine, dried (Na2SO4), concentrated,
and purified by silica gel flash column chromatography. Compound 5: 1H NMR
(CDCl3, 300 MHz) d 7.40–7.20 (m, 5H), 3.85–3.60 (m, 4H), 3.71 (s, 3H), 3.00–
2.60 (m, 4H), 2.50–2.40 (m, 1H), 2.36–2.05 (m, 6H), 1.50–1.25 (m, 12H), 1.18 (d,
J = 6.6 Hz, 3H), 0.92 (t, J = 7.1 Hz, 9H) ppm. ESI m/z (MÀBr) 436.2. Compound 9f:
1H NMR (CDCl3, 300 MHz) d 7.40–7.23 (m, 5H), 6.47 (dt, J = 9.9, 2.1 Hz, 1H),
3.75–3.60 (AB, JAB = 12.9 Hz, 2H), 3.70–3.15 (AB-d, JAB = 14.4 Hz, J = 2.4 Hz, 2H),
2.97 (ddd, J = 10.8, 5.7, 1.5 Hz, 1H), 2.62–2.50 (m, 1H), 2.50–2.35 (m, 1H), 2.33
(dd, J = 11.4, 9.6 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 3.9 Hz, 3H), 0.99 (d,
J = 3.9 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz) d 201.3, 145.7, 137.9, 130.9,
128.8, 128.4, 127.3, 62.3, 57.4, 54.0, 42.9, 27.0, 21.8, 21.7, 14.4. HR-ESI-MS m/z
calcd for C17H23NO (M+H+) 258.1858, Found 258.1852. Compound 9j: 1H NMR
(CDCl3, 300 MHz) d 7.45 (t, J = 1.8 Hz, 1H), 7.40–7.19 (m, 9H), 3.91 (dt, J = 14.7,
1.8 Hz, 1H), 3.72–3.58 (AB, JAB = 13.2 Hz, 2H), 3.51 (dd, J = 14.7, 2.4 Hz, 1H),
2.99 (ddd, J = 11.4, 6.0, 2.1 Hz, 1H), 2.70–2.58 (m, 1H), 2.38 (dd, J = 11.4, 9.0 Hz,
1H), 1.15 (d, J = 6.9 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz) d 201.5, 137.7,
134.8, 134.0, 133.7, 133.4, 131.4, 128.8, 128.7, 128.3, 127.3, 62.3, 57.0, 56.1,
43.2, 14.6.
Acknowledgments
The author is indebted to Professor Guo-Qiang Lin for valuable
suggestions and generous support. Financial support from the Na-
tional Natural Science Foundation of China (20602008, 20832005)
is gratefully acknowledged.
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