Diastereoselective hydrogenation of α,β-unsaturated but-2-enamides to access the chiral 3-(p-tolyl) butanoic acids

Article abstract of DOI:10.1016/j.tetlet.2016.12.017

An alternative methodology for the synthesis of chiral 3-(p-tolyl) butanoic acids is presented. This was accomplished through the diastereoselective hydrogenation reaction of different chiral N-3-(p-tolyl) but-2-enamides, using Pd/C in EtOH, to produce the corresponding chiral N-3-(p-tolyl) butanamides with high chemical yields and moderate diastereomeric ratios. Removal of the chiral auxiliary from N-3-(p-tolyl) butanamides gave the respective enantiomerically pure acids.

Full text of DOI:10.1016/j.tetlet.2016.12.017

Accepted Manuscript
Diastereoselective hydrogenation of α,β-unsaturated but-2-enamides to access
the chiral 3-(p-tolyl) butanoic acids
Jacqueline Jiménez, Mildred López, Vladimir Carranza, Angel Mendoza, Jenaro
Varela, Estibaliz Sansinenea, Aurelio Ortiz
PII:
S0040-4039(16)31644-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.017
TETL 48429
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 November 2016
28 November 2016
6 December 2016
Please cite this article as: Jiménez, J., López, M., Carranza, V., Mendoza, A., Varela, J., Sansinenea, E., Ortiz, A.,
Diastereoselective hydrogenation of α,β-unsaturated but-2-enamides to access the chiral 3-(p-tolyl) butanoic acids,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.017
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Diastereoselective hydrogenation of ,-
unsaturated but-2-enamides to access the chiral 3-
(p-tolyl) butanoic acids
Jacqueline Jiménez,a Mildred López,a Vladimir Carranza,b Angel Mendoza,b Jenaro Varela,c Estibaliz
Sansineneaa, Aurelio Ortiza *.
a Facultad de Ciencias Químicas, bInstituto de Ciencias, cCentro de vinculación y transferencia de tecnología, Benemérita Universidad
Autónoma de Puebla, Pue. 72570, México.

1
Tetrahedron Letters
Diastereoselective hydrogenation of ,-unsaturated but-2-enamides to access the
chiral 3-(p-tolyl) butanoic acids.
Jacqueline Jiménez,a Mildred López,a Vladimir Carranza,b Angel Mendoza,b Jenaro Varela,c Estibaliz
Sansinenea a, Aurelio Ortiz a 
a Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Pue. 72570, México.
bInstituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Pue. 72570, México.
cCentro de vinculación y transferencia de tecnología, Benemérita Universidad Autónoma de Puebla, Pue. 72570, México
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An alternative methodology for the synthesis of chiral 3- (p-tolyl) butanoic acids is presented.
This was accomplished through the diastereoselective hydrogenation reaction of different chiral
N-3-(p-tolyl) but-2-enamides, using Pd/C in EtOH, to produce the corresponding chiral N-3-(p-
tolyl) butanamides with high chemical yields and moderate diastereomeric ratios. Removal of
the chiral auxiliary from N-3-(p-tolyl) butanamides gave the respective enantiomerically pure
acids.
Available online
2012 Elsevier Ltd. All rights reserved.
Keywords:
Diastereoselective Hydrogenation
Oxazolidinones
Chiral amides
———
 Corresponding author. Tel.: +00-52-222-2295500 ext 7518; fax: +00-52-222-2295584; e-mail: aurelioom@yahoo.com

2
The asymmetric synthesis of 3-(p-tolyl) butanoic acid
derivatives has been the subject of interest for many research
groups. It is widely known that these compounds have been
versatile chiral building blocks for the synthesis of bioactive
aromatic sesquiterpenes and diterpenes1. There are different
types of asymmetric methods for introduction of a stereogenic
center in the benzylic position. Asymmetric hydrogenation of
,-unsaturated carboxylic acid derivatives has been an
efficient method for the obtaining of chiral 3-(p-tolyl)butanoic
acid derivatives with high yields and high enantioselectivities.2
However, the high economic or synthetic cost of most
commercial chiral ligands, difficults their use. Organometallic
reagents additions to ,-unsaturated carboxylic acids attached
to chiral auxiliaries have been another method described.3 An
enzymatic process such as, lipase-mediated kinetic resolution
has furnished the enantiomerically enriched chiral 3-(p-
tolyl)butanoic acids, although its disadvantage is that chemical
yield does not exceed 50%.4 The diastereoselective alkylation
carried out in N-acetyloxazolidinone delivers chiral molecules
that easily can be transformed to 3-(p-tolyl)butanoic acids.5
Recently two organocatalytic methods have been described for
the synthesis of 3-(p-tolyl) butanoic acid derivatives.6 The aim
of this work is to describe an alternative method for easy
accessibility to chiral 3-(p-tolyl)butanoic acids. We described a
diastereoselective hydrogenation reaction of different chiral N-
3-(p-tolyl) but-2-enamides, using Pd/C in EtOH, to produce the
corresponding chiral N-3-(p-tolyl) butanamides, where the (S)-
phenylethylamine, (1S, 2R)-ephedrine and oxazolidinones act as
chiral auxiliaries.
Scheme 1. Reagents and conditions. i) NaH, (EtO)2POCH2CO2Et, THF,
rt, 24 h; ii) 0.5N aq. NaOH, MeOH, rt, 12 h, 1M HCl pH 1; to 8, KOH,
DMF-H2O, reflux, 15 h, 1M HCl.
The carboxylic acids 10-13 were linked to (S)-
phenylethylamine, using N, N´-dicyclohexylcarbodiimide
(DCC) and 4-(dimethylamino)pyridine (DMAP) in DCM at
room temperature for 16 hours to give the chiral N-3-(p-tolyl)
but-2-enamides 15-18, in 45%-65% isolated yield3f. On the
other hand, these carboxylic acids 10-13 also were treated under
the same reaction conditions in the presence of (1S,2R)-
ephedrine to deliver the chiral N-3-(p-tolyl) but-2-enamides 19-
22, in 65%-72% yield. The chiral N-3-(p-tolyl) but-2-enamide
23 was accomplished via formation of its respective acyl
chloride, treating the carboxylic acid 14 with oxalyl chloride
and a catalytic amount of DMF at room temperature for 6 hours.
Then, the acyl chloride was treated with (1S,2R)-ephedrine in
the presence of Et3N to afford the compound 23 in 60% yield11,
as shown in Scheme 2.
Our alternative method to the synthesis of chiral 3-(p-
tolyl)butanoic acids, started with the protection of hydroxyl
group
of
commercially
available
2’-hydro-4’-
methylacetophenone with MeI in the presence of KOH gave 2
with 95% yield7a. The protection of 2’-hydro-4’-
methylacetophenone with 2-iodopropane and NaOH in DMF at
Scheme 2. Reagents and conditions. i) DCC, DAMP, DCM, 16h, rt; ii) to
23, Cl2(CO)2, catalytic amount DMF, 6 h, rt, ephedrine, Et3N, DCM, 12 h,
o
70 C for 18 hours7b gave the compound 3 in 98 % yield. The
rt.
acetophenones 1-3 were transformed to their respective ethyl 3-
(p-tolyl)butanoates 4-9 using
NaH and triethyl
Treatment of chiral oxazolidinones with n-butyllithium in
THF at -78 C for 30 minutes and subsequent addition of the
corresponding acyl chloride (described above) and stirring for
18 hours gave the compounds 24-26 in 83-87% yield,10 as
shown in Scheme 3.
o
phosphonoacetate in THF to give the trans-isomers 4, 6 and 8
as the major products in 56-70 % yield and the cis-isomers 5, 7
and 9 in 11-37 % yield. The geometric isomers were separated
by column chromatography using hexane: ethyl acetate (99:1)
as eluent. A change in the stereoselectivity was observed when
this reaction was carried out at reflux giving trans-isomer 6
(35%) and cis-isomer 7 (57%). The hydrolysis reaction of the
ethyl 3-(p-tolyl)butanoates 4-7 was carried out with 0.5 N aq.
NaOH in methanol at room temperature to give the carboxylic
acids 10-13 with high yields after their purification by column
chromatography using silica gel and hexane : ethyl acetate (8:2)
as eluent8. The compound 8 was treated with KOH in DMF-
H2O at reflux for 15 hours to give the carboxylic acid 14 in 65%
yield after its purification as above mentioned, as shown in
Scheme 1.
Scheme 3. i) Reagents and conditions. Cl2(CO)2, catalytic amount DMF, 6
h, rt, nBuLi, THF, -78 oC, 45 min., 18 h, rt.
The chiral N-3-(p-tolyl) but-2-enamides 15-26 were exposed
to hydrogenation reaction conditions using a catalytic amount of
Pd/C in EtOH at room temperature for 16 hours to deliver the
chiral N-3-(p-tolyl) butanamides 27a-34b in high yield (>98%)
and with moderated diastereoselectivity (Tables 1 and 2). The
hydrogenation reaction of 15-E (Table 1, entry 1) afforded the
chiral N-3-(p-tolyl) butanamides 27a and 27b in high yield and
with a diastereomeric ratio of 70:30 (40% d.e.). Both products
27a and 27b were isolated by column chromatography using
hexane/AcOEt (8:2), where the isomer 27a was the major
product. The configuration at newly formed stereogenic center
is (R) for compound 27a as established by X-ray analysis11 (Fig.
1). Hydrogenation reaction of 16-Z (Table 2, entry 1) proceeded
similarly giving the compounds 27a and 27b in high yield and
with the same diastereomeric ratio of 70:30 (40% d.e.).
Surprisingly the compound 27a was also the major product. For
this case the stereoselectivity was unalterable by change in the
geometry of alkenes (15-E, to 16-Z).

3
Table 1. Diastereoselective hydrogenation of chiral (E)- N-
3-(p-tolyl) but-2-enamides.
Entry
1
27a (70)a
27b (30)a
Figure 1. Molecular structure of the chiral N-3-(p-tolyl) butanamide 27a.
Hydrogenation reaction of 21-E (Table 1, entry 4), under the
same reaction conditions described above, gave the chiral N-3-
(p-tolyl) butanamides 30a and 30b in (>98% yield) and with a
diastereomeric ratio of 70:30 (40% d.e.). The compound 30a (R
configuration) was the mayor product. This was established by
X-ray analysis of 30b where the configuration at the newly
formed stereogenic center is (S)12 (Fig. 2). The hydrogenation
for 22-Z (Table 2, entry 4) gave the compounds 30a and 30b in
high yield and with an opposite diastereomeric ratio of 40:60
(20% d.e.). In this reaction, the compound 30b (S configuration)
was the mayor product.
2
3
28a (44)
29a (53)
28b (56)
29b (47)
4
5
6
30a (70)
31a (50)
32a (62)
30b (30)
31b (50)
32b (38)
7
8
Figure 2. Molecular structure of the chiral saturated butanamide 30b.
33a (37)
34a (33)
33b (63)
34b (67)
Hydrogenation of 17-E, 18-Z, 19-E (Table 1, entries 2 and 3,
Table 2, entry 2) and 23-E (Table 1, entry 5) were carried out
under the same reaction conditions to produce the
corresponding chiral N-3-(p-tolyl) butanamides in high yields
and with poor diastereoselectivity. The hydrogenation of 17-E
(Table 1, entry 2) and 18-Z (Table 2, entry 2) delivered N-3-(p-
tolyl) butanamides 28a, b 44:56 (12% d.e.) and 28a, b 47:53
(6% d.e.) respectively. The relative configuration at newly
formed stereogenic center for compound 28a was confirmed
unambiguously as (S) via single crystal X-ray analysis13 (Fig.
3).
a diastereomeric ratios were determined by 1H NMR on crude of reaction
Figure 3. Molecular structure of the N-3-(p-tolyl) butanamide 28a.
Table 2. Diastereoselective hydrogenation of chiral (Z)- N-
3-(p-tolyl) but-2-enamides
Hydrogenation of 19-E (Table 1, entry 3) and 20-Z (Table 2,
entry 3) gave an inseparable mixture of butanamides 29a and
29b in high yield (>98%) and with no diastereoselectivity, for
19-E 53:47 (6% d.e.) and for 20-Z 60:40 (20% d.e.). The
configuration of the new stereogenic center of the mayor
product 29a was established via comparison of the chemical
1
shifts in the H-NMR spectra of compounds 30a and 30b. An
isopropyl group was placed in the aromatic ring in order to
observe any change in the diastereomeric ratio of the
hydrogenation; however, hydrogenation of 23-E (Table 1, entry
5) gave the N-3-(p-tolyl) butanamides 31a and 31b in high yield
and with a poor diastereoselectivity, compared to the N-3-(p-
tolyl) butanamides 30a and 30b.

4
Entry
27a (70)a
28a (47)
27b (30)a
28b (53)
1
2
Scheme 5. Conformers of 25-E.
The chiral auxiliary ephedrine was removal from 30b and
31b under acid hydrolysis conditions described by Myers.11
Compound 30b was treated with 9N aq. H2SO4 solution/dioxane
1/1, reflux for 6 hours and a subsequent addition of saturated aq.
NaOH solution for the extraction of ephedrine and addition of
3M aq. HCl solution to give the known (S)-3-(2-methoxy-4-
methylphenyl) butanoic acid4b,4d in 87% yield, []20D = +16.6 (c
2, CHCl3). To avoid degradation of compound 31b, it was
treated with 4N aq. H2SO4 solution /dioxane 1/1, reflux for 4
hours and subsequent addition of saturated aq. NaOH solution
for the extraction of ephedrine and addition of 3M aq. HCl
solution to give the new (S)-3-(2-isopropyl-4-methylphenyl)
butanoic acid 35 in 80% yield, which its absolute configuration
was assigned by comparison with the carboxylic acid above
3
4
29a (60)
30a (40)
29b (40)
30b (60)
a diastereomeric ratios were determined by 1H NMR on crude of reaction
described, []25 = +10.4 (c 0.94, CHCl3). On the other hand,
D
Hydrogenation
reaction
of
N-3-(p-tolyl)butenoyl
the compounds 32a, 33b, and 34b were treated under hydrolysis
oxazolidinones 24-26 was carried out under the same reaction
conditions with a catalytic amount of Pd/C in EtOH at room
temperature for 16 hours to deliver the chiral N-3-(p-
tolyl)butanoyl oxazolidinones 32a-34b in high yield (>98%)
and with a moderated diastereoselectivity. The compound 24-E
(Table 1, entry 6) gave the products 32a and 32b with a
diastereomeric ratio of 62:38 (24% d.e.) The configuration of
new stereogenic center of the mayor product 32a is (R).
Although both chiral oxazolidinone moieties within 24-E and
25-E have the same phenyl substituent group and the same
configuration at C(4), an unexpected result was observed for
hydrogenation of compound 25-E (Table 1, entry 7), which
gave the products 33a-(R) and 33b-(S) as white solids in high
yield (>98%) and with a diastereomeric ratio of 37:63 (26%
d.e.). Hydrogenation of 25-E gave the product 33b-(S) as mayor
compound, therefore the gem-dimethyl groups at C(5) within
the oxazolidinone structure in 25-E have an important role in
the stereocontrol of the hydrogenation.14 The compound 26-E
(Table 1, entry 8) afforded the products 34a-(R) and 34b-(S) in
high yield and with a diastereomeric ratio of 33:67 (34% d.e.)
The mayor product is the compound 34b-(S). The
stereoselectivity of the major products 32a-(R) and 34b-(S) can
be rationalized by the conformational preference of anti-s-cis
rotamers,15 where hydrogenation of 24-E is carried out in the Si-
face, which is opposite to the phenyl group substituent at C4.
Hydrogenation for 26-E was carried out in the Re-face, which is
opposite side to the isopropyl group substituent at C4, as shown
in Scheme 4.
conditions described by Evans,16 using LiOH, H2O2 in
o
THF/H2O at 0 C for 2 hours to furnish the known (R)-3-(p-
tolyl)butanoic acid in 72% yield, []25 = -36.4 (c 1.92,
D
CHCl3), lit. []25 = -31.1 (c 3.1, CHCl3)5a, and (S)-3-(p-
D
tolyl)butanoic acids in 93% and 95% respectively, []25
=
D
+34.8 (c 1.92, CHCl3), lit. []25 = +34.2 (c 1.92, CHCl3).4b,4c
D
The recovery of the chiral auxiliaries oxazolinedines and
ephedrine was in high yield 85% to 90%, as shown in Scheme
6.
Scheme 6. Reagents and conditions: i) 30b, 9N aq. H2SO4 soln. dioxane,
reflux 6h, NaOH soln. pH 10, HCl pH 1. 31b, 4.0 N aq. H2SO4 soln.
dioxane, reflux 4h, NaOH soln. pH 10, HCl pH 1. ii) LiOH, H2O2 30%,
THF/H2O, 0 oC to rt, 2h, HCl soln. pH 1.
We realized a study of the hydrogenation reaction of N-3-(p-
tolyl) but-2-enamides carring (S)-phenylethylamine, (1S,2R)-
ephedrine and oxazolidinones as chiral auxiliaries. (S)-
phenylethylamine produced the highest diastereoselectivity
(40% d.e.); however, its removal from chiral N-3-(p-tolyl)
butanamides, under soft reaction conditions was not possible.
Hydrogenation of both geometric isomers (Z)-N-3-(p-tolyl) but-
2-enamides or (E)- N-3-(p-tolyl) but-2-enamides joined to (S)-
phenylethylamine or (1S,2R)-ephedrine gave the same
diastereoselectivity. The best reaction conditions to achieve
chiral 3-(p-tolyl)butanoic acids are those in which the
oxazolidinones were used as chiral auxiliaries. Hydrogenation
of their Z-N-3-(p-tolyl) but-2-enamides produced the chiral N-3-
Scheme 4. Conformers of 24-E and 26-E.
Hydrogenation of 25-E can be rationalized by the
conformational preference of anti-s-trans rotamer, where its
hydrogenation is carried out in the Re-face, which is opposite to
the phenyl group substituent at C4, as shown in Scheme 5.

5
(p-tolyl) butanamides in high yield > 98 % and with moderated
diastereoselectivity. This methodology has the advantage that
the products were crystalline and easy to separate by column
chromatography. In addition, mild reaction conditions were
used to remove the oxazolidinone moiety.
Acknowledgments
We thank VIEP (ORMJ-NAT16-G) and CONACyT
(258647).
References and notes
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2.
a) Sansinenea E.; Cabrera-Vivas B. M.; Ortiz A. Current Org. Synth.,
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Biomol. Chem., 2014, 12, 2049-2052. h) Sun, X.; Zhou, L.; Wang,
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Dong, K.; Li, Y.; Wnag, Z.; Ding, K. Org. Chem Front., 2014, 1,
155-160. j) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem. Int.
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M.; Hong, X.; Barnes, C.L. Tetrahedron Lett., 2003, 44, 7261-7264.
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F. Org. Lett., 2010, 12, 4268-4270.
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Tetrahedron Asymmetry, 2007, 18, 2547-2553. c) Kamal, A.; Malik,
M., S.; Azeza, S.; Bajee, S.; Shaik, A. A. Tetrahedron Asymmetry,
2009, 20, 1267-1271. d) Serra, S. Tetrahedron Asymmetry, 2011, 22,
619-628. e) Deasy, R. E.; Brossat, M.; Moody, T. S.; Mangure, A. R.
Tetrahedron Asymmetry, 2011, 22, 47-61.
5.
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a) Mori, K. Tetrahedron Asymmetry, 2005, 16, 685-692. b) Yadav, J.
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6
Highlights

Alternative methodology for the synthesis of
chiral 3- (p-tolyl) butanoic acids is described
Diastereoselective hydrogenation reaction
Easy removal of chiral auxiliaries.

