A post aza Baylis-Hillman/Heck coupling approach towards the synthesis of constrained scaffolds

Article abstract of DOI:10.1016/j.tetlet.2006.09.115

An intramolecular Heck coupling of the product of an aza Baylis-Hillman reaction to afford conformationally constrained scaffolds is reported.

Full text of DOI:10.1016/j.tetlet.2006.09.115

Tetrahedron Letters 47 (2006) 8591–8593
A post aza Baylis–Hillman/Heck coupling approach towards
the synthesis of constrained scaffolds
Anil Vasudevan,* Pei-San Tseng and Stevan W. Djuric
Enabling Chemistry Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064, United States
Received 22 August 2006; revised 20 September 2006; accepted 21 September 2006
Available online 17 October 2006
Abstract—An intramolecular Heck coupling of the product of an aza Baylis–Hillman reaction to afford conformationally con-
strained scaffolds is reported.
Ó 2006 Published by Elsevier Ltd.
The Baylis–Hillman reaction, which involves the reac-
tion between a Michael acceptor and an aldehyde to
form highly functionalized a-methylene-b-hydroxy
carbonyl compounds, has been studied extensively.1
The corresponding aza version, which involves the
reaction of a Michael acceptor with an imine as the elec-
trophile, provides a convenient method for the synthesis
of a-methylene-b-amino carbonyl compounds. This pro-
tocol produces the desired compounds in a single reac-
tion step, although the aldimine usually needs to be
preformed and isolated prior to the coupling reaction.
Recently, Balan and Adolfsson have reported an effi-
cient and selective one-pot three-component procedure
for the formation of a-methylene-b-amino acid deriva-
tives using the aza Baylis–Hillman protocol.2 Nucleo-
philic, sterically nonhindered tertiary amines showed
best activity as catalysts, and molecular sieves improved
chemical yields and reaction rates.
tions of conformational constrained compounds.3
Along these lines, we envisioned that the use of an ortho
halo substituted sulfonamide or aldehyde component in
the aza Baylis–Hillman reaction would afford a sub-
strate for an intramolecular Heck coupling to afford
bicyclic scaffolds 2 and 4 (Schemes 1 and 2).4
Initial attempts were directed towards the synthesis of
the aza Baylis–Hillman adducts 1 and 3. A competing
reaction in the synthesis of these products is the forma-
tion of the Baylis–Hillman products. After considerable
experimentation, it was found that using titanium iso-
propoxide, 2-hydroxyquinuclidine and molecular sieves
in i-PrOH afforded respectable yields of the desired
aza Baylis–Hillman products2b (Table 1). Preformation
of the aldimine followed by the addition of the acrylate
did not result in improved yields of the aza Baylis–
Hillman products.
We have been interested in the modifications of products
of multi-component reactions to produce diverse collec-
With the aza Baylis–Hillman products in hand, attempts
to identify suitable conditions for the Heck coupling
O
O
O
S
O
HN
Ar
H
H2N
O
Ar
O
R
O
Heck
S
Ar
O
R
aza-Baylis-Hillman
S
O
R
O
N
O
O
X
H
Coupling
X
O
X=Br, I
1
2
Scheme 1. General scheme for an aza Baylis–Hillman/Heck coupling using a suitably substituted sulfonamide.
*
Corresponding author. Tel.: +1 847 263 3866; fax: +1 847 935 0310; e-mail: Anil.Vasudevan@abbott.com
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.115

8592
A. Vasudevan et al. / Tetrahedron Letters 47 (2006) 8591–8593
Ar
O
S
O
R
NH2
O
HN
S
O
X
Ar
O
O
O
O
O
Heck
aza-Baylis-Hillman
R
O
NH
H
O
Coupling
R
O
S
O
X
Ar
X=Br, I
3
4
Scheme 2. General scheme for an aza Baylis–Hillman/Heck coupling using a suitably substituted aldehyde.
Table 1. Products of the aza Baylis–Hillman (ABH) and Heck coupling
Alkene
Aldehyde
Sulfonamide
ABH Product
Heck Product
Cl
Cl
O
H
N
O
O
O
S
O
O
NH2
S
O
O
O
O
O
S
O
N
Br
Cl
O
H
Br
(10, 52%)
(5, 66%)
OCH3
H3CO
O
H
F
O
F
N
O
O
F
NH2
S
O
O
S
F
O
O
O
O
O
O
F
S
Br
O
O
O
O
N
H3CO
F
O
F
Br
H
F
(11, 60%)
F
(6, 62%)
N
N
O
H
N
O
S
O
O
O
O
NH2
O
S
O
O
S
N
N
O
O
H
Br
Br
(7, 71%)
(12, 45%)
O
S
O
S
O
O
HN
O
O
NH2
O
HN
O
H3CO
O
S
OCH3
OCH3
O
O
Br
Br
(13, 77%)
(8, 74%)
F
F
O
S
O
S
Br
O
O
O
O
NH2
O
HN
O
O
HN
S
O
O
O
O
O
O
O
O
O
O
F
Br
(14, 50%)
(9, 77%)
were commenced. The utility of microwave irradiation to
facilitate organometallic reactions has been reported
extensively.5 Our initial attempts commenced with the
use of Pd(Ph3)4 and triethylamine at various temper-
atures and catalyst concentrations.6 However, the
predominant product observed was the dehalogenated
aza Baylis–Hillman product. Switching to a Pd(OAc)2/
P(o-tolyl)3 catalytic system with triethylamine in

A. Vasudevan et al. / Tetrahedron Letters 47 (2006) 8591–8593
8593
Cl
References and notes
Cl
O
S
H
O
S
H
N
O
N
O
1. (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 811–891; (b) Aggarwal, V. K.; Emme, I.;
Fulford, S. Y. J. Org. Chem. 2003, 692–700.
5
+
O
N
2. (a) Balan, D.; Adolfsson, H. J. Org. Chem. 2001, 66, 6498;
(b) Balan, D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329;
(c) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44,
2521.
15
16
Scheme 3. Product composition of Heck coupling in N,N-DMF.
3. (a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron
Lett. 2004, 45, 417; (b) Vasudevan, A.; Verzal, M. Tetra-
hedron Lett. 2005, 46, 453.
4. (a) Negishi, E.; Zhang, Y.; O’Connor, B. Tetrahedron Lett.
1988, 29, 2915; (b) Larock, R. C.; Song, H.; Baker, B. E.;
Gong, W. H. Tetrahedron Lett. 1988, 29, 2919; (c)The
synthesis of cyclic compounds from Baylis–Hillman
adducts has been reviewed. Curr. Org. Chem. 2003, 6,
627.
5. (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582;
(b) Kaiser, N. K.; Hallberg, A.; Larhed, M. J. Comb. Chem.
2002, 4, 109; (c) Tan, K. L.; Vasudevan, A.; Bergman, R.
G.; Ellman, J. A.; Souers, A. J. Org. Lett. 2003, 5, 2131; (d)
Larhead, M.; Hallberg, A. Drug Discovery Today 2001, 6,
406; (e) Commercial vendors of single-mode microwave
instrumentation include Biotage AB (www.biotage.com)
and CEM corporation (www.cem.com). Microwave exper-
iments reported in this study were performed either in a
CEM ExplorerÒ or a Biotage Emrys synthesizerÒ.
6. Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org.
Chem. 2005, 70, 3864.
DMF7 afforded 15 and 16 in a 2:3 ratio, presumably
formed from the generation of dimethylamine via
thermal decomposition of N,N-DMF (Scheme 3).
Switching the solvent to THF eliminated the formation
of 15 and 16; however, the reaction had to be heated for
1 h to afford the desired product 10 in acceptable yields.
Speculating that the slower reaction rate could be due to
the sluggish heating profile of THF using microwave
irradiation,5 attempts to dope the reaction with varying
amounts of polar solvents such as 1,2-dichlorobenzene
and ionic liquids8 were attempted. While the addition
of 5% 1,2-dichlorobenzene afforded the desired product,
the reaction time was not shortened. Doping THF with
5% of various ionic liquids, while significantly improv-
ing the heating profile, did not afford any of the desired
product. Hence, the optimal conditions for the Heck
coupling were to heat the aza Baylis–Hillman product,
5 mol % Pd(OAc)2, 2 mol % P(o-tolyl)3 and triethyl-
amine in THF at 160 °C for 1 h.9
7. Smalley, T. L.; Mills, W. Y. J. Heterocyclic Chem. 2005, 42,
327.
8. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
39, 3772; (c) The following ionic liquids were utilized in
these experiments: 1-butyl-3-methylimidazolium chloride,
Aza Baylis–Hillman products obtained using ortho
halobenzaldehydes were heated with Pd(Ph3)4 and
triethylamine6 in THF at 150 °C for 20 min to afford
the conformationally constrained scaffolds 13 and 14.
Efforts to expand the diversity of scaffolds accessible
via the products of the Baylis–Hillman reaction are
ongoing and will be reported in the future.
1-ethyl-3-methylimidazolium
trifluoromethanesulfonate,
1-butyl-3-methylimidazolium tetrafluoroborate.
9. Representative protocol for the intramolecular Heck cou-
pling: A microwave vial was charged with the aza Baylis–
Hillman adduct 8, 50 mg (0.11 mmol), Pd(Ph3)4 (3 mol %)
and triethylamine (3 equiv) in 2 ml THF, sealed and heated
at 150 °C for 20 min. The reaction mixture was diluted with
10 ml water and the crude product extracted with 20 ml
ethylacetate and chromatographed to afford the desired
Acknowledgements
1
Heck product 13 (31.5 mg, 77%). H NMR (DMSO-d6): d
One of the authors (P.T.) thanks the Advanced Technol-
ogy division at Abbott Laboratories for an undergradu-
ate summer fellowship. The assistance of Clara Villamil
with purification is acknowledged.
9.95 (br s, 1H, NH), 7.62 (d, 2H), 7.37 (m, 3H), 7.27 (d,
1H), 6.97 (dd, 1H), 3.71 (s, 3H), 3.59 (s, 3H), 3.52 (s, 2H),
2.35 (s, 3H). MS (ESI) (m/z) 374 (M+H), 372 (MÀH).