Revision of the stereochemistry of the reductive Heck cyclisation of 1-(2-iodobenzoyl)-4-substituted-1.4-dihydro-pyridine-3-carbaldehyde aminals

Article abstract of DOI:10.1016/S0040-4039(03)01384-4

The stereochemistry of reductive and non reductive Heck cyclisations of 4-substituted-1.4-dihydropyridines is reexamined. The both reactions occur mainly via an anti (from the C₄ substituent) 5-exo process without any epimerisation of the C

Full text of DOI:10.1016/S0040-4039(03)01384-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5719–5722
Revision of the stereochemistry of the reductive Heck cyclisation
of 1-(2-iodobenzoyl)-4-substituted-1.4-dihydro-pyridine-
3-carbaldehyde aminals
Pierre Mangeney* and Christophe Pays
Laboratoire de Chimie Organique, UMR 7611 Universite´ P. et M. Curie, 4 place Jussieu, F-75252 Paris cedex 05, France
Received 27 March 2003; accepted 27 May 2003
Abstract—The stereochemistry of reductive and non reductive Heck cyclisations of 4-substituted-1.4-dihydropyridines is reexam-
ined. The both reactions occur mainly via an anti (from the C4 substituent) 5-exo process without any epimerisation of the C4-H.
© 2003 Elsevier Ltd. All rights reserved.
We recently reported unexpected results obtained by
Heck cyclisations of a functionalised 1,4-dihydropy-
ridine 1.1 It was claimed in this paper that a non
reductive (Heck) cyclisation afforded, after removal of
the aminal, a compound 2 resulting from an anti carbo-
palladation and that a reductive Heck cyclisation
yielded to a compound 3 resulting from a syn carbopal-
ladation with an epimerisation of the C4-H (Scheme 1).
The structures of these two cyclised products 2 and 3
were established on the basis of X ray analysis of the
aminals 2A and 3A.2 This unexpected interesting result
impelled us to study the possible influence of the nature
of the substituent R on the stereochemistry of these
reactions.
Accordingly, two dihydropyridines 4 (R=Et) and 5
(R=Ph) were prepared (Scheme 2). The addition of
EtCu to the pyridine aminal 6 in the presence of
ortho-iodobenzoyl chloride gave a complex mixture
resulting from a non regio- and diastereoselective addi-
tion. Several attempts to increase these selectivities by
changing the nature of the copper salt were ineffective
affording the same surprising result. Indeed, we have
never observed, in similar reaction, such poor selectivi-
ties using primary alkyl copper reagents.3 As a last
resort, the dihydropyridine 4 was prepared from 7,
easily prepared from 6, by a selective addition of EtCu
in the presence of acetyl chloride and then transac-
ylation according Scheme 2.4 The dihydropyridine 5
Scheme 1.
Keywords: dihydropyridines; chiral aminals; Heck reactions; isoindolone synthesis.
* Corresponding author. Fax: +33-1-44 27 75 67; e-mail: mangeney@ccr.jussieu.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01384-4

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P. Mangeney, C. Pays / Tetrahedron Letters 44 (2003) 5719–5722
Scheme 2.
pound were found to be identical to those obtained in
our previous study but an X-ray analysis (Fig. 2)6
showed that it was not the result of a syn carbopallada-
tion with epimerisation of the C4-H, but similarly to 10,
of an anti carbopalladation without epimerisation of
the C4-H to give a C4-(R) and C6-(S) adduct. An acidic
hydrolysis gave the corresponding aldehyde 12 which
optical rotation was found to be identical to the one
reported previously.1
was obtained by a selective addition of PhCu to 6 in the
presence of ortho-iodobenzoyl chloride.
A Heck cyclisation (Scheme 3) was attempted on dihy-
dropyridines 4 and 5. A clean reaction was observed
with 4 affording a mixture of Z and E cyclised products
8 (de>90%, 1H NMR, Scheme 3). Under the same
conditions, 5 gave a complex mixture. In reductive
conditions two cyclised adducts 9 were produced from
4, as a mixture (9/1) of trans and cis diastereomers
This aldehyde 12 was then treated by the R,R diamine
1
1
(de>90% each, H NMR) and from 5 only one com-
13 to give the aminal 14 (Scheme 4). The H NMR
pound 10 was obtained (de>90%, 1H NMR). The
results observed with 4 were apparently similar to those
reported in our previous report starting from 1, but this
was not the case with the phenyl-dihydropyridine 5.
Therefore, the structure of 10 was determined by X ray
analysis.5 As shown in Figure 1, the absolute stereo-
chemistry of this compound was found to be C4-(R)
and C6-(S) starting from an aminal of S,S configura-
tion. Therefore, 10 was the result of an anti carbopalla-
dation without epimerisation of the C4-H. This
disturbing result was attributed, in first analysis, to the
spectra of 11 and 14 were found to be different to each
other.
presence of
a phenyl substituent. Therefore, we
attempted to crystallise the trans 9 for X-ray analysis
but without success. Finally, we decided to reproduce
the reductive Heck cyclisation with 1 as described in
our previous paper (Scheme 3). Two cyclised products
11 were obtained as a trans and cis mixture in a 7/3
1
ratio (de>90% for each, H NMR). The major trans
diastereomer was purified by chromatography and crys-
tallised. The NMR spectra (1H and 13C) of this com-
Figure 1.
Scheme 3. ‘Heck’: Pd(OAc)2 10%, AcOK, DMF, 90°C, 4 h; ‘reductive Heck’: Pd(OAc)2(PPh3)2 10%, HCOOH, piperidine,
CH3CN, 80°C, 4 h.

P. Mangeney, C. Pays / Tetrahedron Letters 44 (2003) 5719–5722
5721
Additionally, we have checked that the presence of a
chiral aminal did not change the stereochemical out-
come of the reaction by performing reductive and non
reductive Heck cyclisations on the aldehyde 157
obtained by acidic hydrolysis of 1 (Scheme 5).
A change of the conditions for the non reductive Heck
cyclisation of the aldehyde 15 was needed due to the
fast cleavage of the amide bond by AcOK yielding to
16 (Scheme 5). In the presence of 10% of
Pd(OAc)2(PPh3)2 and 2 equiv. of iPr2NEt in acetonitrile
at 82°C, 15 yielded to a mixture of two cyclised prod-
ucts (3/1 ratio) in a very good yield. The major one
(ee>90%) was found to be identical with 2, the cyclised
product obtained from 1 by a non reductive Heck
cyclisation and hydrolysis of the aminal. A catalytic
hydrogenation of the minor compound 177 (ee>90%)
afforded an aldehyde 187 identical with the aldehyde
obtained by acidic hydrolysis of cis11 (Scheme 6).
Figure 2.
The only conclusion it was possible to draw back from
all these results is that our previous observation of a
stereodivergence between reductive and non reductive
Heck cyclisations1 was not confirmed. In fact, the two
reactions occur mainly via an anti carbopalladation
(from the C4 substituent).
Under the reductive conditions, two aldehydes in a 3/1
ratio were obtained in poor yield (Scheme 5). The
major one was identical with 12 and the minor one with
18. Therefore, the stereochemical outcome of the reduc-
tive and non reductive cyclisations was not influenced
Scheme 4.
Scheme 5. a=Pd(OAc)2(PPh3)2 10% AcOK, DMF, 90°C, 4 h. b=Pd(OAc)2(PPh3)2 10%, 2 equiv. iPr2NEt, CH3CN, 82°C, 1 h.
c=Pd(OAc)2(PPh3)2 10%, 4 equiv. piperidine, 3 equiv. HCOOH, CH3CN, 82°C, 1 h.
Scheme 6.

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P. Mangeney, C. Pays / Tetrahedron Letters 44 (2003) 5719–5722
by the presence of the aminal even if a loss of the
enantiomeric purity was observed.
References
1. Pays, C.; Mangeney, P. Tetrahedron Lett. 2001, 42, 589–
592.
2. Probably on a wrong sample.
In conclusion, we have observed a strong effect of the
nature of the acyl chloride used for the preparation of
the 1,4-dihydropyridine 4. We have found that the
intramolecular Heck reactions, applied to such dihy-
dropyridines, are always regioselective. We have never
observed the formation of products resulting from a
cyclisation onto the C2ꢀC3 double bond. Furthermore,
contrary to our affirmation in our first report, they
occur both mainly via an anti (from the C4 substituent)
5-exo process without any epimerisation of the C4-H.
This stereochemistry is independent of the presence of
the aminal.
3. We have always obtained regio and diastereoselective
additions of alkyl copper reagents on acyl pyridinium salts
derived from 6. See: Mangeney, P.; Gosmini, R.; Raussou,
S.; Commerc¸on, M.; Alexakis, A. J. Org. Chem. 1994, 59,
1877–1888; Mangeney, P.; Hamon, L.; Raussou, S.;
Urbain, N.; Alexakis, A. Tetrahedron 1998, 54, 10349–
10362. In one case, with an ethoxyvinyl copper reagent, we
have observed that the selectivities were dependent of the
nature of the acyl chloride, see Ref. 3.
4. Raussou, S.; Gosmini, R.; Mangeney, P.; Alexakis, A.;
Commerc¸on, M. Tetrahedron Lett. 1994, 35, 5433–5436.
5. Crystallographic data have been deposited at the Cam-
bridge Data (no. CCDC 199720).
Acknowledgements
6. Crystallographic data have been deposited at the Cam-
bridge Data (no. CCDC 199721).
7. 15: [h]2D5=−110 (c=0.4, CHCl3), 17: [h]2D5=−9 (c=0.5,
CHCl3), 18: [h]2D5=−387 (c=0.9, CHCl3).
We thank Carine Guyard-Duhayon for the crystal
structure determinations.