β-amino acids to piperidinones by petasis methylenation and acid-induced cyclization

Article abstract of DOI:10.1021/jo7019948

(Chemical Equation Presented) Ester-imine derivatives of β-amino acids were methylenated with dimethyltitanocene under microwave irradiation and the resulting enol ethers cyclized with Broensted acid or triisopropylaluminium to give 2,6-syn-disubstituted

Full text of DOI:10.1021/jo7019948

â-Amino Acids to Piperidinones by Petasis
SCHEME 1. Methylenation of Esters
Methylenation and Acid-Induced Cyclization
Louis V. Adriaenssens and Richard C. Hartley*
WestCHEM Department of Chemistry, UniVersity of Glasgow,
Glasgow, G12 8QQ, United Kingdom
richh@chem.gla.ac.uk
SCHEME 2. Petasis-Ferrier Rearrangement
ReceiVed September 11, 2007
Ester-imine derivatives of â-amino acids were methylenated
with dimethyltitanocene under microwave irradiation and the
resulting enol ethers cyclized with Br o¨ nsted acid or triiso-
propylaluminium to give 2,6-syn-disubstituted piperidinones
in good yield and diastereoselectivity. The method is
analogous to the Petasis-Ferrier rearrangement of 1,3-
dioxan-4-ones to give tetrahydropyranones.
One application of DMT 1 is in the Petasis-Ferrier rear-
8
9
rangement, which has been shown by Smith and co-workers
to be an exceptionally powerful tool for the total synthesis of
complex natural products. It involves methylenation of a 1,3-
dioxan-4-one 6 with DMT 1 to give an enol ether 7, which
rearranges under Lewis-acidic conditions to give a 2,6-syn-
disubstituted tetrahydropyranone 9 via oxonium ion 8 (Scheme
2). Surprisingly, the nitrogen analogue of this rearrangement,
which would be expected to provide a diastereoselective route
to piperidinones, has not been reported.
Titanium carbenoids are useful reagents for converting
carbonyl groups into alkenes because they are small and
nonbasic, but above all because they will convert carboxylic
acid derivatives into the corresponding hetero-substituted alk-
enes.1 A range of titanium carbenoids have been used to
1
0-12
Concisestereocontrolledroutestopiperidinesareofinterest,
13
as this moiety is considered to be a privileged structure for
the discovery of new drug compounds. Perhaps the best known
2,6-disubstitued piperidene alkaloids are the spiropiperidine,
2
,3
methylenate esters, but the reagent used by Petasis, dimeth-
yltitanocene (DMT) 1, has particular advantages: it is easy to
prepare and handle and is not strongly Lewis acidic, and the
workup following reaction often involves simple precipitation
1
4
histrionicotoxin 10, which is a potent nicotinic receptor
antagonist and lobeline 11, which has been used to treat
nicotine addiction (Figure 1).
1
5
4
of the titanium-containing side products. Indeed, DMT has been
used to methylenate an ester on a 235 Kg scale [with recycling
of the titanocene by precipitation as (Cp2TiMe)2O, conversion
to Cp2TiCl2 with HCl, and regeneration with MeLi]. The active
For our route to piperidinones, we reasoned that chemose-
lective methylenation of the ester group of an imino-ester 12
might be possible using DMT 1 (Scheme 3), because the
titanium atom in titanium methylidene 2 is oxophilic and the
driving force for reaction is the formation of the strong
titanium-oxygen double bond of oxotitanocene 5. Treatment
of the resulting enol ether 13 with a Br o¨ nsted acid would
generate an intermediate 14, which is analogous to the oxonium
ion 8 involved in the Petasis-Ferrier rearrangement. This should
cyclize to give oxonium ion 15, which would be further
protonated to give ammonium salt 16 (or eliminated to give a
related enol ether), which upon hydrolysis would yield piperi-
dinone 17. Similar intramolecular Mannich reactions between
enols or enol ethers and iminium ions have been shown to give
5
titanocene methylidene 2 is generated thermally via R-elimina-
6
tion and this reacts with esters to give oxatitanacylcobutane
7
intermediates 3, which collapse to give the enol ethers 4 and
oxotitanocene 5 (Scheme 1).
(1) For reviews see: (a) Hartley, R. C.; Li, J.; Main, C. A.; McKiernan,
G. J. Tetrahedron 2007, 63, 4825-4864. (b) Hartley, R. C.; McKiernan,
G. J. J. Chem. Soc., Perkin 1 2002, 2763-2793.
(
2) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1
978, 100, 3611-3613. (b) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto,
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C. C.; Lin, K. W.; Wu, Y. H. Org. Lett. 2004, 6, 4965-4967.
(3) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-
1
1
good 2,6-syn selectivity.
6
394.
4) Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T.
R. Org. Synth. 2002, 79, 19-26.
5) Payack, J. F.; Huffman, M. A.; Cai, D.; Hughes, D. L.; Collins, P.
C.; Johnson, B. K.; Cottrell, I. F.; Tuma, L. D. Org. Process Res. DeV.
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6) Hughes, D. L.; Payack, J. F.; Cai, D.; Verhoeven, T. R.; Reider, P.
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003, 5, 1391-1394.
(
(8) Petasis, N. A.; Lu, S. P. Tetrahedron Lett., 1996, 37, 141-144.
(9) Recent examples: (a) Smith, A. B., III; Simov, V. Org. Lett. 2006,
8, 3315-3318. (b) Smith, A. B., III; Mesaros, E. F.; Meyer, E. A. J. Am.
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Meyer, E. A. J. Am. Chem. Soc. 2005, 127, 6948-6949. (d) Smith, A. B.,
III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T. Org. Lett. 2005,
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(
2
(
(
2
1
0.1021/jo7019948 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
J. Org. Chem. 2007, 72, 10287-10290
10287

SCHEME 3. Proposed Route to Piperidinones
FIGURE 1. 2,6-Disbstituted piperidine alkaloids.
The route began from the commercially available racemic
â-amino acids, which were converted into their methyl esters
1
8 in 98-100% yield by using thionyl chloride in methanol.
Imines 19A-C and 19E-K of aldehydes were then prepared
at room temperature with sodium sulfate as desiccant, while
1
6
mixtures were heated to 80 °C with 100 W microwave power
and the temperature maintained for 10 min, but later we found
that heating to 65 °C (approximately 7 min) and maintaining
this temperature for 10 min was sufficient. Indeed, even these
mild conditions were too harsh for electron-rich imines 19C,
F, and G and enaminizable imine J. For these, the pressure
was monitored and when it ceased to rise, after only 3 min at
imines 19D and 19L derived from ketones were prepared by
using azeotropic removal of water (Scheme 4 and Table 1).
1
7
DMT 1 was prepared by Payack’s method as a 1.3 M solution
4
in THF-toluene (1:1), which could be stored at 4 °C.
Methylenation of the esters 19 was carried out in sealed tubes
under microwave irradiation,1
8,19
allowing very short reaction
times and clean conversion to enol ethers 20. Initially, reaction
6
5 °C, the reaction was stopped because we reasoned that
production of methane by R-elimination was complete. This
shorter reaction time gave clean conversion. Clearly, the control
allowed by using microwave heating is key to the success of
the transformations. It is significant that the temperature is no
higher than that employed in conventionally heated Petasis
methylenations, but the reaction time is substantially shorter
than those normally reported. After precipitation of the titanium-
(
10) Review: Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729.
(11) Recent examples of intramolecular Mannich routes to piperidino-
nes: (a) Davis, F. A.; Santhanaraman, M. J. Org. Chem. 2006, 4222-
226. (b) Bariau, A.; Jatoi, W. B.; Calinaud, P.; Troin, Y.; Canet, J.-L.
Eur. J. Org. Chem. 2006, 3421-3433. (c) Davis, F. A.; Yang, B. J. Am.
Chem. Soc. 2005, 127, 8398-8407. (d) Atobe, M.; Yamazaki, N.; Kibayashi,
C. Tetrahedron Lett. 2005, 46, 2669-2673. (e) Rougnon-Glasson, S.;
Tratrat, C.; Canet, J. L.; Chalard, P.; Troin, Y. Tetrahedron: Asymmetry
4
2
004, 15, 1561-1567. (f) Alsarabi, A.; Canet, J. L.; Troin, Y. Tetrahedron
containing residues with hexane, complete reaction of the esters
Lett. 2004, 45, 9003-9006. (g) Davis, F. A.; Zhang, Y.; Anilkumar, G. J.
Org. Chem. 2003, 68, 8061-8064. (h) Lamazzi, C.; Carbonnel, S.; Calinaud,
P.; Troin, Y. Heterocycles 2003, 60, 1447-1456.
1
1
9 was confirmed by H NMR spectroscopy of the crude
2
0
mixtures and the sensitive enol ethers 20 were used im-
mediately, without further purification.
(12) Other recent stereocontrolled syntheses of 2- and 2,6-disubstituted
piperidines include: (a) Chen, Y.; Porco, J. A., Jr.; Panek, J. S. Org. Lett.
Initially, aqueous acid was used to combine the cyclization
and hydrolysis steps in Scheme 3. A range of concentrations of
aqueous HCl were investigated (2.4-12 M), and 7 M proved
optimum at ensuring hydrolysis occurred after cyclization, but
not before cyclization. This procedure was effective for pip-
eridinones 21A and 21B derived from the imines 19A and 19B
of benzaldehyde, and can be viewed as an environmentally
benign procedure since it uses no organic solvents (entries 1
and 2, Table 1). Only the 2,6-syn diastereomer was observed
in each case. However, the method was not general and was
poor-yielding for electron-rich imine 20C and ketone-derived
imine 20D (entries 3 and 4). Presumably, in these cases
cyclization is slower and hydrolysis of the imine and enol ether
groups competes.
Using two equivalents of tosic acid under anhydrous condi-
tions in chlorinated solvents overcomes this problem to some
extent. Again, derivatives of benzaldehyde give good yields of
piperidinones (entries 5 and 6), as single syn isomers, following
hydrolysis of the cyclized oxonium ions 16 in aqueous acid,
followed by basification. Modest yields of 2,6-syn piperidinones
21C and 21F, derived from more electron-rich imines 20C and
2
2
9
007, 9, 1529-1532. (b) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem.
007, 72, 2046-2052. (c) Jamieson, A. G.; Sutherland, A. Org. Lett. 2007,
, 1609-1611. (d) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith,
D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 4998-5001. (e) Kokotos, C.
G.; Aggarwal, V. K. Chem. Commun. 2006, 2156-2158. (f) Gandon, L.
A.; Russell, A. G.; G u¨ veli, T.; Brodwolf, A. E.; Kariuki, B. M.; Spencer,
N.; Snaith, J. S. J. Org. Chem. 2006, 71, 5198-5207. (g) de Figueiredo,
R. M.; Fr o¨ hlich, R.; Christmann, M. J. Org. Chem. 2006, 71, 4147-4154.
(h) Amat, M.; Escolano, C.; Lozano, O.; G o´ mez-Esqu e´ , A.; Griera, R.;
Molins, E.; Bosch, J. J. Org. Chem. 2006, 71, 3804-3815. (i) Sales, M.;
Charette, A. B. Org. Lett. 2005, 7, 5773-5776. (j) Goodenough, K. M.;
Raubo, P.; Harrity, J. P. A. Org. Lett. 2005, 7, 2993-2996. (k) Yu, S.;
Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 7364-7370. (l) Robertson, J.;
Stafford, P. M.; Bell, S. J. J. Org. Chem. 2005, 70, 7133-7148.
(13) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246.
(14) Daly, J. W.; Garrafo, H. M.; Spande, T. F. Alkaloids: Chem. Biol.
Perspect. 1999, 13, 2-147.
15) Cunningham, C. S.; Polston, J. E.; Jany, J. R.; Segert, I. L.; Miller,
D. K. Drug Alcohol Depend. 2006, 84, 211-222.
16) Blommaert, A. G. S.; Weng, J.-H.; Dorville, A.; McCort, I.; Ducos,
B.; Durieux, C.; Roques, B. P. J. Med. Chem. 1993, 36, 2868-2877.
17) Eleveld, M. B.; Hogeveen, H.; Schudde, E. P. J. Org. Chem. 1986,
1, 3635-3642.
18) The use of microwave irradiation is a major advance in the Petasis
(
(
(
5
(
20F, could also be obtained (entries 7 and 8). However, reaction
reaction, but is not yet widely used: (a) Cook, M. J.; Fleming, D. W.;
Gallagher, T. Tetrahedron Lett. 2005, 46, 297-300. (b) Gaunt, M. J.;
Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.; Ley, S. V. Org.
Lett. 2003, 5, 4819-4822.
was slower (sometimes requiring elevated temperature, entries
6 and 8) and was most conveniently carried out overnight. The
efficiency of cyclization improved (compare entries 7 and 9)
when using more polar solvents, DME and DMSO (entries
(19) Reviews of microwave-assisted organic synthesis: (a) Kappe, C.
O.; Dallinger, D. Nat. ReV. Drug DiscoVery 2006, 5, 51-63. (b) MicrowaVes
in Organic Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH: Weinheim,
Germany, 2006. (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-
(20) The presence of the enol ether is confirmed by two broad 1H singlets
1
6
284. (d) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos,
in the range of 3.5-4.0 ppm in the H NMR spectrum, and the signals for
D. M. P. Chem. Soc. ReV. 1998, 27, 213-223. (e) Strauss, C. R.; Trainor,
CH2C(OMe)dCH2 appear 0.2-0.3 ppm upfield from the signals for CH2-
R. W. Aust. J. Chem. 1995, 48, 1665-1692. (f) Caddick, S. Tetrahedron
CO2Me of the starting ester, so that complete conversion from starting
1
1
995, 51, 10403-10432.
material can be confirmed by H NMR spectroscopy.
1
0288 J. Org. Chem., Vol. 72, No. 26, 2007

TABLE 1. Summary of Reaction Conditions and Yields for the Synthesis of Piperidinones
a
piperidinones 21
cyclization conditions
temp, time,
yieldb
from 19,
%
yield of
imine 19,
entry compd
%
R1
Me
Ph
Ph
Me
Me
R2
R3
acid
7 M HCl
7 M HCl
7 M HCl
solvent
°C
h
hydrolysis
d
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
A
B
C
D
A
E
C
F
C
G
H
I
75c
89
Ph
Ph
H
H
H
H2O
H2O
H2O
H2O
20
20
20
20
20
40
20
60
20
20
20
20
20
28
28
28
28
28
28
28
28
0.5
0.5
17
61
62
12
d
d
94
74
75
2,4-MeOC6H3
Ph
Ph
e
Me 7 M HCl
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
trace
61
61
40
37
51
58
48
58
34
61
68
70
66
64
51
c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2 equiv of TsOH
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DME
DME
DME
DME
DME
DMSO
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
1 M HCl (0.5 h)
83
94
87
PhCH2 Ph
2 equiv of TsOH
2 equiv of TsOH
2 equiv of TsOH
2 eq.uiv of TsOH
2 equiv of TsOH
2 equiv of TsOH
2 equiv of TsOH
2 equiv of TsOH
Ph
Me
Ph
Me
Me
Ph
Ph
Ph
Me
Ph
Ph
2,4-MeOC6H3
(E)-4-MeOC6H4CHdCH
2,4-MeOC6H3
2,4-MeOC6H3
3-Br C6H4
c
94
61
58
90
1
1
1
1
1
1
1
1
1
1
2
2
t
Bu
f
J
91
Et
B
A
B
C
K
F
72
75
Ph
Ph
Ph
2 equiv of TsOH
c
i
2 equiv of Al( Bu)3 DMSO
2 equiv of Al( Bu)3 DMSO
2 equiv of Al( Bu)3 DMSO
2 equiv of Al( Bu)3 DMSO
i
72
94
55
i
2,4-MeOC6H3
2-F C6H4
(E)-4-MeOC6H4CHdCH
Ph
i
Me
Me
Me
Ph
c
i
87
2 equiv of Al( Bu)3 DMSO
e
i
g
D
L
74
Me 2 equiv of Al( Bu)3 DMSO
69
i
73
-(CH2) 5-
2 equiv of Al( Bu)3 DMSO
52
a
Isolated yield from amines 18 after purification. b Isolated yield after purification; except where otherwise indicated, only the 2,6-syn isomer was detected
by NMR of the crude mixture and only this isomer was isolated; relative stereochemistry was assigned by NOE, except for 21B, which was assigned by
comparison with the literature. Yield based on aldehyde. Isolated as HCl salt. e E:Z ratio was 93:7. 19:18:propionaldehyde 80:13:7. g dr (2,6-syn:2,6-
c
d
f
anti) ) 89:11 in both crude mixture and isolated material.
SCHEME 4. Synthesis of Piperidinones
9
-14), presumably because these, like water, can stabilize the
ketone (yielding a spirocyclic piperidine 21L, entry 21). The
Lewis acidic conditions are superior to those using protic acid,
both for easily cyclized substrates (compare entries 1, 5, and
15) and for more demanding electron-rich imines (compare
entries 3, 7, 9, and 17). The 2,6-syn isomers were the only
products, except in the case of trisubstituted piperidinone 21D,
where the syn:anti ratio was 89:11, which was only a small
decline on the E:Z ratio of the starting imines 19D.
developing positive charge of the oxonium ion 15 (Scheme 3).
The imine derivatives 19J and 20J of propionaldehyde were
unstable and difficult to handle, due to their propensity to form
reactive enamine intermediates, and this accounts for the low
yield of piperidinone 21J (entry 13) compared to piperidinone
2
2
1I (entry 12). Indeed, in spite of steric interactions, bulky imine
0I cyclizes efficiently.
Petasis and co-workers had found that triisobutylaluminium
In summary, we report a highly diastereoselective route to
2,6-disubstituted piperidinones that is analogous to the Petasis-
Ferrier rearrangement, having microwave-assisted Petasis me-
thylenation and Lewis acid-induced cyclization as the key steps.
This diastereoselective route should be applicable to the
preparation of enantiopure piperidinones from enantiopure
â-amino esters, which are straightforward to prepare.21
at low temperature in toluene induced Ferrier rearrangement of
vinyl acetals derived from 1,3-dioxan-4-ones, but that the
resulting tetrahydropyranones were reduced under the reaction
8
conditions to give 4-hydroxytetrahydropyrans. We found that
enol ethers 20 were cleanly converted into piperidinones 21
using this Lewis acid in DMSO, followed by hydrolysis in good
yield and with excellent selectivity. The choice of such a polar
solvent is unusual when using a Lewis acid, but reaction in
dichloromethane was slower and led to the formation of complex
mixtures. As before, we reason that stabilization of developing
carbocation character in the transition state leading to a cyclized
oxonium ion is important. No reduced product is observed
because the ketone is only formed in the hydrolysis step and
the oxygen atom in the oxonium ion intermediates is too poor
a Lewis base to associate with the triisobutylaluminum in
DMSO.
Experimental Section
Microwave-Assisted Petasis Methylenation. A 1.30 M solution
of Cp TiMe 1 (1.8-2.1 equiv) in toluene-THF (1:1 by mass) was
2 2
added to an imino-ester 19 (1 equiv), and the solution was sealed
in a 10 mL microwave tube under argon. This was irradiated
under 100 W microwave power to raise the internal temperature to
65 °C (ca. 7 min), and the temperature was maintained with
microwave irradiation for a further 2.5-10 min (the exact times
and maximum internal pressures observed are included for indi-
vidual transformations in the Supporting Information) before
A range of imines cyclized well, including those derived from
aromatic aldehydes (entries 15-18), an R,â-unsaturated alde-
hyde (entry 19), an alkyl aryl ketone (entry 20), and a dialkyl
(
21) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004,
1, 1111-1239.
J. Org. Chem, Vol. 72, No. 26, 2007 10289

cooling. The resultant black solution was concentrated under
reduced pressure and hexane added to precipitate most titanium-
containing impurities. The hexane extract was filtered and concen-
trated under reduced pressure to yield the crude enol ether 20, which
was used directly in the cyclization reactions.
4 2 4
organic extract was washed with NH Cl(aq), dried over Na SO , and
concentrated under reduced pressure to give the crude piperidinone
21, which was purified by column chromatography.
Supporting Information Available: Full experimental proce-
Lewis Acid-Induced Cyclization. Triisobutylaluminium (1.0 M
in hexanes, 2 equiv) was added to the crude enol ether 20 (1 equiv,
1
13
dures, spectroscopic data, and scanned H NMR and C NMR
spectra for compounds 18 (Me, Ph and Bn), 19A-L (with the
exception of 19J, which was unstable), and 21A-L. This material
is available free of charge via the Internet at http://pubs.acs.org.
0
2
.03 M) in dry DMSO, under Ar. The solution was stirred at
8 °C for 17 h, and then quenched by careful addition of 1 M HCl(aq)
(35 equiv). The reaction mixture was stirred for a further 45 min,
then it was basified with NaOH(aq) and extracted with EtOAc. The
JO7019948
1
0290 J. Org. Chem., Vol. 72, No. 26, 2007