Chelation-controlled diastereoselective construction of N-aryl-, N-acyl/tosylhydrazono β-substituted aspartate derivatives via Barbier-type reaction

Article abstract of DOI:10.1016/j.tet.2013.05.130

An entry into the stereoselective synthesis of several N-substituted- β-vinyl aspartate and β-alkyl aspartate derivatives having two contiguous stereocenters via the indium-mediated Barbier-type addition of alkyl 4-bromocrotonates or α-halo esters with N-aryl (including N-PMP) α-imino- and N-acyl/tosylhydrazono esters is reported. The formation of β-alkyl aspartate derivatives with exclusively syn stereochemistry in alcohol media revealed the involvement of a chelation-controlled TS. The synthesis of functionalized 1,4-diols, cis piperidine-2,3-dicarboxylate derivative and β-ethyl aspartic acid hydrochloride was performed using the N-substituted β-vinyl aspartates obtained in this work. The stereochemistry of representative products was unambiguously established from the single crystal X-ray structure analyses.

Full text of DOI:10.1016/j.tet.2013.05.130

Tetrahedron 69 (2013) 6598e6611
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Chelation-controlled diastereoselective construction of N-aryl-,
N-acyl/tosylhydrazono b-substituted aspartate derivatives via
Barbier-type reaction
,
a
Nayyar Ahmad Aslam a, Srinivasarao Arulananda Babu a , Arya Jayadev Sudha ,
*
Makoto Yasuda b, Akio Baba b
a Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali,
Manauli P.O., Punjab 140306, India
b Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 April 2013
Received in revised form 25 May 2013
Accepted 29 May 2013
Available online 5 June 2013
An entry into the stereoselective synthesis of several N-substituted-b-vinyl aspartate and b-alkyl as-
partate derivatives having two contiguous stereocenters via the indium-mediated Barbier-type addition
of alkyl 4-bromocrotonates or -halo esters with N-aryl (including N-PMP) -imino- and N-acyl/to-
sylhydrazono esters is reported. The formation of -alkyl aspartate derivatives with exclusively syn
stereochemistry in alcohol media revealed the involvement of a chelation-controlled TS. The synthesis of
functionalized 1,4-diols, cis piperidine-2,3-dicarboxylate derivative and -ethyl aspartic acid hydro-
chloride was performed using the N-substituted -vinyl aspartates obtained in this work. The stereo-
a
a
b
b
Keywords:
b
Amino acids
Aspartic acid
Allylation
chemistry of representative products was unambiguously established from the single crystal X-ray
structure analyses.
Ó 2013 Elsevier Ltd. All rights reserved.
Imines
Stereoselective synthesis
1. Introduction
molecules directed towards a wide range of therapeutic areas
(Fig. 1).3e7
The synthesis and biological evaluation of non-proteinogenic
amino acids, peptides and peptidomimetics are a renowned area
of research in chemical biology and drug discovery.1,2 In this line,
the
important class of non-proteinogenic amino acids and they exhibit
diverse biological and biochemical actions. Furthermore, the -al-
b b
-alkyl aspartates3 and N-substituted -alkyl aspartates4 are an
b
kyl aspartic acid derivatives have significantly attracted the atten-
tion of synthetic chemists due to their occurrence as unusual amino
acids in microorganisms, constituents of various peptides, useful
building blocks of various biologically active natural products and
pharmaceutical agents.3e5 For example, the (2R,3S)-3-methyl
aspartic acid occurs as a component of certain members of the
highly toxic microcystin and nodularin families of natural products
and cyclic peptides (which are known to be powerful inhibitors of
several serine and threonine phosphatases).5 Further, the phar-
Fig. 1. Examples of biologically active b-alkyl aspartic acids.
A survey of the literature revealed that the importance of
-substituted aspartates in amino acid/peptide chemistry con-
b
tinues to flourish, which in turn has inspired the development of
several new methodologies,6,7 such as (a) the alkylation of
unsubstituted-aspartates, (b) hydrogenation of tetrasubstituted
aminoacrylates, (c) cycloaddition chemistry, (d) lactone ring
opening and (e) Mannich-type reactions, etc. for the stereoselective
macological activity of various b-alkyl aspartate molecules has been
recognized by the medicinal chemists for the synthesis of new drug
synthesis of
b-alkyl aspartate derivatives. Notably, a theme based
* Corresponding author. Tel./fax: þ91 172 2240266; e-mail addresses: sababu@
iisermohali.ac.in, srigesbabu@yahoo.com (S.A. Babu).
on the direct Barbier-type stereoselective addition of allylic metals
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.130

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6599
having an ester group at the
cially, N-aryl -imino- and N-acyl/tosylhydrazono esters leading to
the
-alkyl aspartates has not been explored8 (Scheme 1). Mark-
edly, the N-aryl -amino acids are the core structural units in var-
ious medicinal agents.2 Therefore, the development of new
g
-position with C]N systems, espe-
2. Results and discussion
a
b
At the outset, we carried out the indium-mediated addition of
imino ester 1a with ethyl 4-bromocrotonate (2a) under various
reaction conditions. A mixture of -imino ester 1a, ethyl 4-
bromocrotonate (2a, E-geometry) and indium powder in dry DMF
was stirred at 30 ꢀC for 12 h, which furnished the
-adduct 3a (70%,
a-
a
a
synthetic methods leading to the N-aryl a-amino acid derivatives
will be very useful.
g
Scheme 1. Theme of this work. Diastereoselective construction of b-alkyl aspartic acid derivatives.
Recent works on the indium-based stereoselective allylation of
carbonyls and imine systems (aldimines, ketimines, hydrazones,
oximes and sulfonimines) have significantly drawn the attention of
organic chemists and have been recognized as the versatile CeC
bond forming process.9e14 This protocol has an advantage of using
indium powder and allylic halides directly; thereby circumventing
the prior synthesis of allylic metal reagents and the reactions can be
carried out in an aqueous or alcoholic media.
dr 90:10) and the a-adduct 5a (25%, Table 1, entry 1) with moderate
regioselectivity. A similar trend was observed when the reaction
was carried out in dry THF or 1,4-dioxane or toluene (Table 1, en-
tries 2e4). The reaction of
bromocrotonate (2a) and indium powder in 1,2-DCE or MeOH or
DMSO selectively gave the -adduct 3a in 25e63% yields (Table 1,
a-imino ester 1a, ethyl 4-
g
entries 5e7). The reaction in THF-water mixture gave the
(syn isomer) 3a in 46% (dr 98:2, Table 1, entry 8).
g-adduct
The indium-mediated addition of simple as well as
substituted allylic reagents to C]N systems furnishing the
g
-
Successively, we tried the reaction of 1a with 2a in EtOH as the
solvent. We observed that the In-mediated addition reactions un-
derwent smoothly in EtOH (Table 1, entries 11e20). The reaction in
g,d-
unsaturated amino acid derivatives is an interesting area of study.
Kang and co-workers have shown the addition of
0-dimethyl
allylic indium to N-aryl -imino esters for the synthesis of -un-
saturated -amino acid derivatives having
0-dimethyl N-aryl
only one chiral centre. There exists some exceptional reports on the
g,g
EtOH at rt (30 ꢀC) gave the
g-adduct 3a (syn isomer) in 91% yield
a
g,d
(Table 1, entry 12) with very high diastereoselectivity and regio-
b,
b
a
selectivity. Further, the reaction of a-imino ester 1a, ethyl 4-
bromocrotonate (2a) and indium powder in EtOH at ꢁ5 ꢀC or in
In-mediated stereoselective addition of
g
-substituted allylic halides
the presence of NaI as an additive at rt (30 ꢀC) gave the
g-adduct 3a
to C]N bond systems, such as oxime ethers,11 sulfonimines,12
acylhydrazones13 and imines derived from alkyl as well as aryl
amines,14 leading to homoallylic amines with two adjoining ster-
eocenters. In this line, recently, we have reported10 the In-mediated
in 95% yield (dr >95:5, Table 1, entries 14 and 16). Employing other
metals, e.g., Sn, Bi and Zn gave the -adduct 3a in 65, 65 and 25%
g
yields (dr >95:5), respectively (Table 1, entries 21e23).
The scope and generality of the direct Barbier-type addition of
addition of
cyclohexenyl bromides) to N-aryl
and the diastereoselective construction of
substituted N-aryl -amino acid derivatives.
g
-substituted allylic halides (e.g., cinnamyl-, crotyl- and
-imino- and -hydrazono esters
-unsaturated
alkyl 4-bromocrotonates with various N-aryl (including N-PMP) a-
imino- and N-acyl/tosylhydrazono esters using indium metal is
shown in Table 2 and Scheme 2. The indium-employed addition of
a
a
g
,
d
b
-
a
ethyl 4-bromocrotonate with
electron-withdrawing- and donating-group containing anilines in
ethanol afforded the respective -vinyl aspartate derivatives 3bek
-adducts) having two contiguous stereocenters (syn isomers, dr
>95:5, Table 2, entries 1e10). The treatment of methyl 4-
bromocrotonate with -imino esters 1h and 1e gave the carboxyl
group differentiated (orthogonally protected) -vinyl aspartate
a-imino esters synthesized from
In continuation of our research program on the synthesis of
unnatural amino acids10 with multiple stereocenters, we envisaged
b
the addition of alkyl 4-bromocrotonates or
aryl -imino- and N-acyl/tosylhydrazono esters and indium metal
for the production of several examples of N-aryl- and N-acyl/
tosylhydrazono -vinyl aspartate derivatives ( -unsaturated
-amino acid derivatives) having contiguous
a
-halo esters with N-
(g
a
a
b
g
,d
b
-
b
substituted N-aryl
a
derivatives 3l and 3m (syn isomers, dr >95:2, entries 11 and 12,
Table 2). Consequently, the addition of the ethyl 4-bromocrotonate
with N-acylhydrazono esters 1l and 1m using indium metal pow-
stereocenters.
A
review of literature revealed that there exists limited
and only few exceptional examples on the indium-mediated
stereoselective addition of alkyl 4-bromocrotonates to chiral im-
ines of trifluoropyruvate8e and glyoxylic acid oxime ether11c leading
der in EtOH furnished the functionalized
rivatives 3n (81%, dr 90:10) and 3o (50%, dr 70:30, Scheme 2).
Treatment of N-biphenyl -imino ester with ethyl- and methyl 4-
bromocrotonates (2a,b) gave the corresponding N-biphenyl -vi-
nyl aspartates 3p and 3q in very high yields (dr >95:5, Scheme 2).
Next, the addition of ethyl 4-bromocrotonate to hydrazono ester 1o
prepared from ethyl pyruvate gave the adduct 3r in 46% yield
(Scheme 2). In this case, a moderate diastereoselectivity was ob-
served, perhaps due to the involvement of less rigid cyclic TS.
b-vinyl aspartate de-
a
to the corresponding aspartic acid derivatives (
-substituted N-aryl -amino acid derivatives). We herein report
an easy entry into the diastereoselective synthesis of several
examples of N-aryl- and N-acyl/tosylhydrazono -vinyl aspartate
derivatives having contiguous stereocenters, via the addition
of alkyl 4-bromocrotonates or -halo esters with N-aryl -imino-
g
,d-unsaturated
b
b
a
b
a
a
and N-acyl/tosylhydrazono esters mediated by indium metal
Further, the treatment of the
a-imino ester 1p derived from 2-
(Scheme 1).
hydroxyaniline afforded the aspartic acid derivative 3s in 59%

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N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
Table 1
Optimization of the reaction conditions for the diastereoselective addition of 2a with a
-imino ester 1aa
Entry
Mt
Solvent (mL)
T (ꢀC)
t (h)
3a/4a Yield (%) (dr¼syn/anti)
5a Yield (%)
1
2
3
4
5
6
7
8
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
In
Sn
Zn
Bi
DMF (1)
THF (1)
30
30
30
30
30
30
30
30
30
30
30
30
30
ꢁ5
80
30
30
30
30
30
30
30
30
12
12
24
24
24
12
12
12
12
12
03
06
24
06
06
06
06
06
06
06
06
06
06
70 (90:10)
40 (70:30)
30 (82:18)
31 (81:19)
25 (76:24)
60 (69:31)
63 (85:15)
46 (98:02)
25
25
13
25
Dioxane (1)
Toluene (1)
DCE (1)
MeOH (1)
DMSO (0.5)
THF (1)/H2O (1)
EtOH (1)/H2O (1)
DMF (1)/H2O (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
23
9
53 (98:02)
60 (98:02)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
66 (>95:05)
91 (>95:05)
90 (>95:05)
95 (>95:05)
51 (>93:05)
95 (>95:05)b
92 (>95:05)c
77 (94:06)d
91 (>95:05)e
84 (>95:05)f
65 (>95:05)
25 (>95:05)
65 (>95:05)
ND
ND
a
All the reactions were done using 1a (0.25 mmol), 2a (0.75 mmol) and indium powder (0.5 mmol). Isolated yields are given.
20 mol % of NaI was added as an additive.
20 mol % of KI was added as an additive.
20 mol % of I2 was added as an additive.
20 mol % of MeCOOH was added as an additive.
b
c
d
e
f
The reaction was carried out using 1a (0.5 mmol), 2a (1.0 mmol) and indium powder (0.75 mmol). ND¼Not detected.
yield. In this case also a moderate diastereoselectivity (dr 76:24)
was observed, probably due to the presence of hydroxyl group in
the aromatic ring affecting the chelation-assisted TS. Interestingly,
formed after the addition of allylic indium reagent. Further, the
observed very high stereoselectivity (>95:5) in these reactions,
revealed that the allylation process was kinetically controlled.
the In-mediated addition of 2a or 2b with the
a
-imino ester 1q
Next, the indium-mediated Reformatsky-type addition of
esters with N-aryl -imino ester using indium metal was explored
(Table 4). The aspartate derivative 9a was obtained in 65% yield in
the reaction of -halo ester 2c with the N-PMP -imino ester 1a in
DMF in the presence of indium metal (Table 4, entry 1). Employing
other metals, such as Zn, Sn and Bi gave the product 9a in 41, 38 and
<5% yields, respectively (Table 4, entries 2e4). The product 9b was
a-halo
derived from 4-acetylaniline afforded the corresponding products
3t and 3u (syn isomers) with very high diastereoselectivity (dr
95:5) and chemoselectivity. In these reactions, the acetyl group was
not affected and the addition took place selectively at C]N bond of
the a-imino ester 1q, which afforded the corresponding products 3t
and 3u (Scheme 2).
a
a
a
Next, we carried out the three component Barbier-type re-
actions of ethyl glyoxalate (6), amines 7 and ethyl 4-bromo
crotonate (2a) using indium metal (Table 3). The one-pot In-me-
diated direct three component reactions of ethyl glyoxalate, various
aryl amines or p-toluenesulfonyl hydrazine and ethyl 4-bromo
obtained in 40% by using the
In this line, the In-mediated addition of 2c with other
esters gave the aspartic acid derivatives 9cee in good yields (Table
a
-halo ester 2d (Table 4, entry 5).
a-imino
4, entries 6e8). Furthermore, the treatment of the substituted
a
-
-
halo ester 2e with the -imino ester 1a in THF/DMF gave the b,b
a
crotonate in EtOH exclusively afforded the respective
b
-alkyl as-
dimethyl aspartate derivative 10a (Table 5, entries 1 and 2). The
indium-mediated reaction of the -halo esters 2f and 2g with 1a
furnished the -difluoro- and
-fluoro aspartates 10b and 10c,15a
respectively (Table 5, entries 3 and 4). The reaction of ethyl 2-
partate derivatives 3a, 3d, 3h and 3v ( -adducts, Table 3, entries
g
a
1e4) with very high regioselectivity and diastereoselectivity (dr
>95:5, syn isomers).
b,
b
b
The stereochemistry of representative products 3p, 3q and 3v
(syn stereochemistry) was unambiguously established from the
single crystal X-ray structure analyses. The stereochemistry of other
adducts listed in Tables 1e3 and Scheme 2 was assigned based on
the X-ray structure analyses of the compounds 3p, 3q and 3v
(Fig. 2).15d The exclusive formation of the syn products 3aev in the
bromobutyrate (2h) with the N-PMP a-imino ester 1a gave the
product 10d15b in 62% yield (dr 65:35, Table 5, entry 5). Similarly,
the reaction of ethyl 2-bromooctanoate (2i) or ethyl 2-
bromopentanoate (2j) with the N-PMP a-imino ester 1a gave the
corresponding products 10e15c (35%, dr 80:20) and 10f (50%, dr
60:40) in low yields (Table 5, entries 6 and 7). In some of these
cases, relatively low diastereoselectivity was observed. This is
perhaps due to the involvement of a less rigid cyclic TS. However,
In-mediated reaction of the a-imino esters 1 with 2a,b could be
explained via a chelation-controlled TS9u,10,15e,f in alcoholic media
(Scheme 3).9v It is well-known that the allylic indium reagents are
tolerant to aqueous and alcoholic media9,10 and in all the reactions
listed in Tables 1e3 and Scheme 2, the alcoholic media contributes
for the rapid quenching of the transient indium amide, which is
the addition of
a-bromo g-butyrolactone (2k) with 1a in the
presence of indium metal furnished the functionalized
b
-
substituted aspartates 10g (67%, dr 73:27) and 10h (72%, dr 82:18,
Scheme 4 and Fig. 3) with relatively good diastereoselectivity.

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6601
Table 2
Diastereoselective addition of 2 with
a
-imino ester 1 and synthesis of N-aryl b-vinyl aspartic acid esters
Entry
eFg
2
Product
Yielda (%) (dr¼syn/anti)
1
2
3
4
5
2a
2a
2a
2a
2a
3b; R1¼H, 83 (>95:05)
3c; R1¼Me, 84 (>95:05)
3d; R1¼Cl, 94 (>95:05)
3e; R1¼Br, 87 (>95:05)
3f; R1¼COOEt, 90 (>95:05)
6
2a
3g; R2¼Me, R3¼Me, 70 (>95:05)
7
8
2a
2a
3h; R2¼Cl, R3¼Cl, 96 (>95:05)
3i; R2¼Me, R3¼Br, 69 (>95:05)
9
2a
2a
3j R4¼Cl, 48 (>95:05)
10
11
3k; 58 (>95:05)
2b
2b
3l; R2¼Cl, R3¼Cl, 72 (>95:05)
3m; R1¼Br, 72 (>95:05)
12
a
All the reactions were carried out using 1 (0.5 mmol), 2 (1.5 mmol) and indium powder (1.0 mmol). Isolated yields are given.
Successively, we focused our attention to show the usefulness of
this synthetic methodology. In this line, initially we carried out the
catalytic hydrogenation of the compound 3a (syn isomer), which
N-acyl/N-tosylhydrazono-
derivatives. We have shown synthesis of functionalized 1,4-diols, cis
piperidine-2,3-dicarboxylate derivative and -ethyl aspartic acid
hydrochloride by using the N-substituted -vinyl aspartates ob-
tained in this method. Further studies are in progress to explore the
b-vinyl aspartate and b-alkyl aspartate
b
gave the N-PMP
Scheme 5). Additionally, the hydrogenation of the compounds 3h
and 3l afforded the N-aryl -ethyl aspartate derivatives 11a and 11b
b
-ethyl aspartate derivative 10d0 (syn isomer,
b
b
potential applications of the N-substituted b-vinyl aspartates ob-
(syn isomers, Scheme 5). The reduction of the ester group of the
representative compounds 3a, 3d, 3h and 3f furnished the corre-
sponding functionalized 1,4-diols 12aed bearing two contiguous
stereocenters (Scheme 5).
Finally, we extended the utility of this synthetic protocol for
constructing the cis piperidine-2,3-dicarboxylate (pipecolic acid)
derivative bearing two contiguous stereocenters (Scheme 6). N-
Allylation of the compound 3a, followed by the RCM reaction16 of
the compound 13 and hydrogenation of the compound 14 gave the
cis piperidine-2,3-dicarboxylate derivative 1517 (Scheme 6). Later,
we carried out the removal of the PMP protecting group followed
tained in this work.
4. Experimental section
4.1. General
Melting points are uncorrected. IR spectra were recorded as thin
films or KBr pellets. 1H and 13C NMR spectra were recorded on
400 MHz and 100 MHz spectrometers, respectively, with TMS as an
internal or external standard. Column chromatography was carried
out on silica gel (100e200 mesh). Reactions were carried out in dry
solvent under nitrogen atmosphere wherever required. Solutions
were dried using anhydrous sodium sulfate. Reagents were added
to the reaction flask with the help of a syringe. Thin layer chroma-
tography (TLC) was performed on silica plates or neutral Al2O3 and
components were visualized by observation under iodine. Isolated
yields of all the products were reported (yields were not optimized)
and total yield of both the diastereomers is reported. Ratios of
by hydrolysis that gave an unnatural amino acid, b-ethyl aspartic
acid hydrochloride 16 (Scheme 6).
3. Summary
In summary, we have reported an entry into the chelation-
controlled stereoselective synthesis of several examples of N-aryl-,

6602
N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
a All the reactions were done using 1 (0.5 mmol), 2 (1.5 mmol) and indium powder (1.0 mmol).
Isolated yields are given. b The reaction was performed using 1 (0.25 mmol), 2 (0.75 mmol) and
indium powder (0.5 mmol).
Scheme 2. Diastereoselective addition of 2 with a-imino ester 1 and the synthesis of b-vinyl aspartic acid esters 3neu.
diastereomers were determined from the 1H and 13C NMR spectra of
crude reaction mixtures or after isolation. In all the reactions, only
the major diastereomer was isolated in pure form (in some excep-
tional cases, the product was isolated as mixture of diastereomers).
The stereochemistry of major isomers was assigned based on the X-
ray structure analysis of representative compounds. In all the re-
actions during the column chromatography, we focused to isolate
the required aspartic acid derivatives in pure form and other minor
impurities/by-products could not be isolated in pure form.
vigorously for 6 h at 30 ꢀC. After this period, the reaction mixture
was quenched with 2 mL of water and transferred to a separating
funnel and extracted using ethyl acetate (3ꢂ15 mL). The combined
organic layers were dried over anhydrous Na2SO4. Then the solvent
was evaporated under vacuum. Purification of the resulting crude
reaction mixture by column chromatography on silica gel (EtOAc/
Hexane as eluent) gave the product 3 (see Tables 1 and 2 and
Scheme 2 for individual entries).
4.3. Procedure B: one-pot synthesis of N-aryl a-amino esters
4.2. Procedure A: In-mediated addition of 4-bromocrotonate
(3a, 3d, 3h, 3v)
(2a or 2b) to a-imino esters 1
Ethyl glyoxylate 6 (0.5 mmol, 1 equiv) and the respective amines
7 (0.5 mmol, 1 equiv) were dissolved in EtOH (2 mL) and stirred for
30 min at rt. To the resulting solution, E-ethyl-4-bromocrotonate
(2a, 1.5 mmol, 3 equiv) and indium powder (1 mmol, 2 equiv)
was added successively while stirring the reaction mixture
To a vigorously stirring solution of
equiv) and E-ethyl-4-bromocrotonate or methyl-4-bromo
crotonate (2, 1.5 mmol, 3 equiv) in EtOH (2 mL) was added in-
dium powder (1 mmol, 2 equiv). The mixture was allowed to stir
a-imino ester 1 (0.5 mmol,
1

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6603
Table 3
One-pot diastereoselective and regioselective synthesis of N-aryl b-vinyl aspartic
acid derivativesa
Entry
1
R
Product
Yielda (%) (syn/anti)
3a; 80 (dr >95:05)
2
3
3d 95 (dr >95:05)
3h; 74 (dr >95:05)
3v; 54 (dr >95:05)
4
a
All the reactions were done using 6 (0.5 mmol), 7 (0.5 mmol), 2a (1 mmol) and In
(0.75 mmol) and isolated yields are given.
vigorously. The stirring was continued for 6 h at 30 ꢀC. After this
period, the reaction mixture was quenched with 2 mL of water and
transferred to a separating funnel and extracted using ethyl acetate
(3ꢂ15 mL). The combined organic layers were dried over anhydrous
Na2SO4. The solvent was then evaporated under vacuum. Purifica-
tion of the resulting crude reaction mixture by column chroma-
tography on silica gel (EtOAc/Hexane as eluent) gave the
corresponding products 3a, 3d, 3h, 3v (see Table 3 for individual
entries).
4.4. Procedure C: In-mediated addition of
(2cek) to -imino esters 1
a-halo esters
a
Fig. 2. X-ray structures of 3p, 3q and 3v.
To a vigorously stirring solution of
a-imino ester 1 (0.5 mmol,
1 equiv) and -halo ester (2cek, 1.5 mmol, 3 equiv) in THF/DMF
a
(1 mL) was added indium powder (1 mmol, 2 equiv). The mixture
was allowed to stir vigorously at 30 ꢀC for given time. After this
period, the reaction mixture was quenched with 2 mL of water and
transferred to a separating funnel and extracted using ethyl acetate
(3ꢂ15 mL). The combined organic layers were dried over anhydrous
Na2SO4. Then the solvent was evaporated under vacuum. Purifica-
tion of the resulting crude reaction mixture by column chroma-
tography on silica gel (EtOAc/Hexane as eluent) gave the product 10
(see Tables 4 and 5 and Scheme 4 for individual entries).
Scheme 3. Plausible mechanism for the formation of syn isomer via chelation-
controlled TS.
4.6. Procedure E: reduction of N-aryl
a-amino esters 3a, 3d,
4.5. Procedure D: hydrogenation of N-aryl
a
-amino esters 3a,
3h and 3f to N-aryl -amino alcohols 12aed
b
3h and 3l
A dry flask was charged with dry THF (4 mL) and the respective N-
aryl
-amino ester 3 (0.5 mmol) under nitrogen atmosphere at 0 ꢀC.
A dry flask containing N-aryl
a-amino ester 3 (0.5 mmol,
a
1 equiv) in dry THF (4 mL) was charged with PdeC (10 mol %) and
the contents are allowed to stir under H2 (1 atm) at rt. After dis-
appearance of starting material (check by TLC) reaction mixture
was filtered through Celite pad and the Celite pad was washed with
EtOAc (20 mL). The solvent was removed by rotary evaporation and
product was purified by column chromatography on silica gel
(EtOAc/Hexane as eluent) to afford the corresponding product 10d0/
11a/11b (Scheme 5).
To this solution was added LiAlH4 (2 mmol) in portions and allowed
to stir overnight at rt EtOH (few drops) and 5% aq NaOH solution
(1e2 mL) were then added sequentially. The resulting white sus-
pensionwas filtered through Celite pad and rinsed with THF (20 mL).
Filtrate was dried over anhydrous Na2SO4 and the solvent was re-
moved by rotary evaporation and product was purified by column
chromatography on silica gel (EtOAc/Hexane as eluent) to afford the
respective N-aryl b-amino alcohols 12 (Scheme 5).

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N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
Table 4
Table 5
Indium-mediated addition of
a
-halo esters with
a
-imino esters and synthesis of
Indium-mediated addition of
substituted aspartic acid esters
a-halo esters with a-imino esters and synthesis of b-
aspartic acid estersa
Entry
1
Solvent
a
-Halo ester
Product
Yielda
(%) (dr)
Entry
eFg
Mt
Product
Yielda
(%)
1
2
1a DMF (0.5 mL)
1a THF (1 mL)
10a; 78
10a; 85
1
2
3
4
In
Zn
Bi
9a; 65
9a; 41
9a; <5
9a; 38
Sn
3
4
1a THF (1 mL)
1a THF (1 mL)
10b; 40b
5
6
7
In
In
9b; 40b
9c; 69
10c; 59
(60:40)b
5
6
1a THF (1 mL)
1a THF (1 mL)
1a THF (1 mL)
10d; 62
(65:35)
In
In
9d; 60c
9e; 67c
10e; 35
(80:20)c
8
a
All the reactions were done using 1 (0.25 mmol), 2 (0.75 mmol) and indium
10f; 50
(60:40)
powder (0.5 mmol). Isolated yields are given.
7
b
The reaction was carried out at 80 ꢀC.
The reaction was carried out at 0 ꢀC for an initial 1 h then at 30 ꢀC for 10 h.
c
a
The reactions were done using 1a (0.5 mmol), 2 (1.5 mmol) and In (1 mmol).
Isolated yields are given.
4.7. Procedure F: N-allylation of N-aryl
a-amino ester 3a
b
The reaction was done at 75 ꢀC.
c
Indium was first allowed to react with 2i for 2 h, then the organoindium was
added to 1a slowly.
To the N-aryl -amino ester 3a (1 mmol,1 equiv) in MeCN (5 mL)
a
was added allyl bromide (6 equiv), NaI (0.1 equiv) and activated
K2CO3 (3 equiv). The resulting reaction mixture was refluxed for
24 h. After completion of the reaction as indicated by the TLC, the
reaction mixture was cooled to rt; water (5e6 mL) was added and
the resulting reaction was transferred to a separating flask and
extracted using ethyl acetate (3ꢂ15 mL). The combined organic
layers were dried over anhydrous Na2SO4. Then the solvent was
evaporated under vacuum. Purification of the resulting crude re-
action mixture by column chromatography on silica gel (EtOAc/
Hexane as eluent) gave the products 13 (see Scheme 6).
4.8. Procedure G: synthesis of 14 by RCM of the compound 13
Scheme 4. In-mediated addition of
thesis of -substituted aspartic acid esters. The reactions were done using
(0.5 mmol), 2 (1.5 mmol) and In (1 mmol).
a-bromo g-butyrolactone (2k) with 1a and syn-
b
1
To the respective compound 13 (0.5 mmol, 1 equiv) in dry DCM
(2 mL) was added Grubbs II generation catalyst (0.05e0.1 equiv),
the resulting reaction mixture was stirred overnight at rt. After
completion of the reaction as indicated by the TLC, the reaction
mixture was subjected to rotary evaporation. Purification of the
resulting crude reaction mixture by column chromatography
on silica gel (EtOAc/Hexane as eluent) gave the products 14
(see Scheme 6).
4.8.1. (2R*,3S*)-Diethyl 2-((4-methoxyphenyl)amino)-3-vinylsucci
nate (3a). Following the general procedure A described above, 3a
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless liquid (146 mg, 91%): Rf
Fig. 3. X-ray structure of 10h (major isomer).

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6605
131.4, 120.6, 115.9, 114.8, 61.3, 61.2, 60.0, 55.7, 53.1, 14.2, 14.2; HRMS:
(ESI) m/z found 344.1471 for C17H23NO5Na (MNaþ), requires
344.1474.
4.8.2. (E)-Diethyl 5-((4-methoxyphenyl)amino)hex-2-enedioate
(5a). Following the general procedure A described above, 5a was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼11:89) as colourless liquid (40 mg, 25%): Rf (20%
EtOAc/Hexane) 0.60; IR (thin film): nmax 3364, 2985, 1730, 1518 and
1032 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.96e6.88 (m, 1H, CH]
CH), 6.77 (d, J¼8.9 Hz, 2H, ArH), 6.61 (d, J¼8.9 Hz, 2H, ArH), 5.91 (d,
J¼15.6 Hz, 1H, CH]CH), 4.22e4.13 (m, 6H, NH, NHCH, OCH2), 3.74
(s, 3H, OCH3), 2.72e2.66 (m, 2H, CH2), 1.30e1.22 (m, 6H, CH2CH3);
13C NMR (100 MHz, CDCl3): dC 173.0,165.9,153.0,142.9, 140.2,124.6,
115.4, 114.9, 61.4, 60.4, 56.8, 55.7, 35.5, 14.2, 14.1. MS (CI): m/z 322
(100%, MHþ).
4.8.3. (2R*,3S*)-Diethyl 2-(phenylamino)-3-vinylsuccinate
(3b). Following the general procedure A described above, 3b was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼09:91) as colourless liquid (120 mg, 83%): Rf (20%
EtOAc/Hexane) 0.65; IR (thin film): nmax 3386, 2983, 1732, 1604 and
1029 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.18 (dd, J1¼8.6 Hz,
J2¼7.4 Hz, 2H, ArH), 6.76 (t, J¼7.4 Hz, 1H, ArH), 6.69 (d, J¼8.6 Hz, 2H,
ArH), 5.94e5.85 (m, 1H, CH), 5.28e5.18 (m, 2H, CH2), 4.52 (t,
J¼6.4 Hz, 1H, NHCH), 4.41 (d, J¼7.8 Hz, 1H, NH), 4.23e4.12 (m, 4H,
OCH2), 3.52 (dd, J1¼9.3 Hz, J2¼6.4 Hz, 1H, CH), 1.27 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.23 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
dC 171.3, 171.1, 146.1, 131.2, 129.4, 120.7, 118.9, 114.1, 61.4, 61.3, 58.6,
52.8, 14.2, 14.2; HRMS: (ESI) m/z found 292.1539 for C16H22NO4
(MHþ), requires 292.1549.
Scheme 5. Scope and functional group transformations. Synthesis of b-ethyl aspartate
derivatives and 1,4-diols.
Scheme 6. Diastereoselective synthesis of cis piperidine-2,3-dicarboxylate derivative and b-ethyl aspartic acid hydrochloride.
(20% EtOAc/Hexane) 0.63; IR (thin film): nmax 3365, 2984, 1731, 1515
and 1035 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.78 (d, J¼9.0 Hz, 2H,
ArH), 6.68 (d, J¼9.0 Hz, 2H, ArH), 5.96e5.86 (m, 1H, CH), 5.29e5.20
(m, 2H, CH2), 4.42 (d, J¼6.8 Hz,1H, NHCH), 4.23e4.13 (m, 4H, OCH2),
3.75 (s, 3H, OCH3), 3.49 (dd, J1¼9.3 Hz, J2¼6.8 Hz, 1H, CH), 1.29 (t,
J¼7.2 Hz, 3H, CH2CH3), 1.24 (t, J¼7.1 Hz, 3H, CH2CH3), 1.30e1.24 (m,
1H, NH); 13C NMR (100 MHz, CDCl3): dC 171.7, 171.2, 153.1, 140.2,
4.8.4. (2R*,3S*)-Diethyl 2-((4-methylphenyl)amino)-3-vinylsuccinate
(3c). Following the general procedure A described above, 3c was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼10:90) as colourless liquid (128 mg, 84%): Rf (20%
EtOAc/Hexane) 0.65; IR (thin film): nmax 3376, 2984, 1731, 1519 and
1031 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.02 (d, J¼8.4 Hz, 2H,
ArH), 6.64 (d, J¼8.4 Hz, 2H, ArH), 5.96e5.87 (m, 1H, CH), 5.30e5.20

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N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
(m, 2H, CH2), 4.51 (br s, 1H, NH), 4.29 (br s, 1H, NHCH), 4.24e4.14
(m, 4H, OCH2), 3.52 (dd, J1¼9.3 Hz, J2¼6.8 Hz, 1H, CH), 2.26 (s, 3H,
ArCH3), 1.29 (t, J¼7.2 Hz, 3H, CH2CH3),1.25 (t, J¼7.1 Hz, 3H, CH2CH3);
13C NMR (100 MHz, CDCl3): dC 171.5, 171.2, 143.8, 131.3, 129.9, 128.2,
120.6, 114.4, 61.3, 61.2, 59.1, 53.0, 20.4, 14.2, 14.2; HRMS: (ESI) m/z
found 306.1698 for C17H24NO4 (MHþ), requires 306.1705.
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless liquid (173 mg, 96%): Rf
(20% EtOAc/Hexane) 0.64; IR (thin film): nmax 3383, 2982,1731,1595
and 1028 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 7.18 (d, J¼8.7 Hz, 1H,
ArH), 6.76 (d, J¼2.8 Hz, 1H, ArH), 6.51 (dd, J1¼8.7 Hz, J2¼2.8 Hz, 1H,
ArH), 5.90e5.80 (m, 1H, CH), 5.28e5.19 (m, 2H, CH2), 4.58 (d,
J¼9.9 Hz, 1H, NH), 4.39 (dd, J1¼9.9 Hz, J2¼6.1 Hz, 1H, NHCH),
4.21e4.13 (m, 4H, OCH2), 3.50 (dd, J1¼9.3 Hz, J2¼6.1 Hz, 1H, CH),
1.28e1.21 (m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 170.9,
170.8, 145.8, 132.9, 130.9, 130.8, 121.4, 121.0, 115.2, 113.5, 61.7, 61.5,
58.4, 52.5, 14.2, 14.1.
4.8.5. (2R*,3S*)-Diethyl 2-((4-chlorophenyl)amino)-3-vinylsuccinate
(3d). Following the general procedure A described above, 3d was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼10:90) as colourless liquid (153 mg, 94%): Rf (20%
EtOAc/Hexane) 0.64; IR (thin film): nmax 3378, 2983, 1731, 1502 and
1030 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.26 (d, J¼8.5 Hz, 2H,
4.8.10. (2R*,3S*)-Diethyl 2-((4-bromo-3-methylphenyl)amino)-3-
vinylsuccinate (3i). Following the general procedure A described
above, 3i was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼10:90) as colourless liquid
(133 mg, 69%): Rf (20% EtOAc/Hexane) 0.64; IR (thin film): nmax
3376, 2983, 1732, 1479 and 1027 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 7.27 (d, J¼8.6 Hz, 1H, ArH), 6.57 (d, J¼2.8 Hz, 1H, ArH), 6.39 (dd,
J1¼8.6 Hz, J2¼2.8 Hz, 1H, ArH), 5.91e5.82 (m, 1H, CH), 5.27e5.18 (m,
2H, CH2), 4.42 (br s, 2H, NH, NHCH), 4.21e4.12 (m, 4H, OCH2), 3.49
(dd, J1¼9.2 Hz, J2¼5.8 Hz, 1H, CH), 2.29 (s, 3H, ArCH3), 1.28e1.21 (m,
6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 171.1, 171.0, 145.5,
138.5, 132.8, 131.1, 120.8, 116.5, 113.3, 113.0, 61.5, 61.4, 58.6, 52.7,
23.1, 14.2, 14.2; HRMS: (ESI) m/z found 384.0810 for C17H23BrNO4
(MHþ), requires 384.0810.
ArH), 6.56 (d, J¼8.5 Hz, 2H, ArH), 5.91e5.82 (m, 1H, CH), 5.28e5.18
(m, 2H, CH2), 4.45 (br s, 2H, NH, NHCH), 4.22e4.12 (m, 4H, OCH2),
3.49 (dd, J1¼9.1 Hz, J2¼5.0 Hz, 1H, CH), 1.28e1.21 (m, 6H, CH2CH3);
13C NMR (100 MHz, CDCl3): dC 171.0, 145.2, 132.1, 131.0, 120.9, 115.6,
110.6, 61.6, 61.4, 58.6, 52.6, 14.2, 14.2; HRMS: (ESI) m/z found
326.1151 for C16H21ClNO4 (MHþ), requires 326.1159.
4.8.6. (2R*,3S*)-Diethyl 2-((4-bromophenyl)amino)-3-vinylsuccinate
(3e). Following the general procedure A described above, 3e was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼9:91) as colourless liquid (161 mg, 87%): Rf (20%
EtOAc/Hexane) 0.65; IR (thin film): nmax 3374, 2983, 1732, 1477 and
1027 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.26 (d, J¼8.9 Hz, 2H,
ArH), 6.57 (d, J¼8.9 Hz, 2H, ArH), 5.92e5.83 (m, 1H, CH), 5.28e5.18
(m, 2H, CH2), 4.46 (br s, 2H, NH, NHCH), 4.22e4.13 (m, 4H, OCH2),
3.50 (dd, J1¼9.2 Hz, J2¼5.5 Hz, 1H, CH), 1.28e1.21 (m, 6H, CH2CH3);
13C NMR (100 MHz, CDCl3): dC 171.0, 145.2, 132.1, 131.0, 120.9, 115.6,
110.6, 61.6, 61.4, 58.5, 52.6, 14.2, 14.2; HRMS: (ESI) m/z found
370.0658 for C16H21BrNO4 (MHþ), requires 370.0654.
4.8.11. (2R*,3S*)-Diethyl 2-((3,5-dichlorophenyl)amino)-3-vinylsucci
nate (3j). Following the general procedure A described above, 3j
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless liquid (86 mg, 48%): Rf
(20% EtOAc/Hexane) 0.64; IR (thin film): nmax 3375, 2984, 1730,
1594 and 1029 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 6.73 (s, 1H,
;
4.8.7. (2R*,3S*)-Diethyl 2-((4-(ethoxycarbonyl)phenyl)amino)-3-
vinylsuccinate (3f). Following the general procedure A described
above, 3f was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼11:89) as colourless liquid
(163 mg, 90%): Rf (20% EtOAc/Hexane) 0.63; IR (thin film): nmax
3371, 2983, 1731, 1526 and 1031 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 7.90 (d, J¼8.9 Hz, 2H, ArH), 6.67 (d, J¼8.9 Hz, 2H, ArH), 5.92e5.83
(m, 1H, CH), 5.32e5.19 (m, 2H, CH2), 4.93 (d, J¼9.5 Hz, 1H, NH), 4.59
(dd, J1¼9.5 Hz, J2¼5.9 Hz, 1H, NHCH), 4.32 (q, J¼7.1 Hz, 2H, OCH2),
4.25e4.15 (m, 4H, OCH2), 3.56 (dd, J1¼9.5 Hz, J2¼5.9 Hz, 1H, CH),
1.36 (t, J¼7.1 Hz, 3H, CH2CH3), 1.31e1.23 (m, 6H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 171.0, 170.6, 166.6, 149.9, 131.5, 130.8, 121.0,
120.3, 112.6, 61.7, 61.4, 60.3, 57.7, 52.3, 14.4, 14.2, 14.1; HRMS: (ESI)
m/z found 364.1756 for C19H26NO6 (MHþ), requires 364.1760.
ArH), 6.56 (s, 2H, ArH), 5.91e5.82 (m, 1H, CH), 5.31e5.22 (m, 2H,
CH2), 4.69 (d, J¼9.7 Hz, 1H, NH), 4.40 (dd, J1¼9.7 Hz, J2¼6.0 Hz, 1H,
NHCH), 4.23e4.17 (m, 4H, OCH2), 3.52 (dd, J1¼9.1 Hz, J2¼6.0 Hz, 1H,
CH), 1.30e1.24 (m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC
170.9, 170.6, 148.0, 135.6, 130.8, 121.1, 118.5, 112.1, 61.8, 61.5, 58.1,
52.4, 14.2, 14.1; HRMS: (ESI) m/z found 360.0766 for C16H20Cl2NO4
(MHþ), requires 360.0769.
4.8.12. (2R*,3S*)-Diethyl 2-(naphthalen-1-ylamino)-3-vinylsuccinate
(3k). Following the general procedure A described above, 3k was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼10:90) as colourless liquid (99 mg, 58%): Rf (20%
EtOAc/Hexane) 0.64; IR (thin film): nmax 3420, 2983, 1734, 1531 and
1028 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 7.89e7.87 (m, 1H, ArH),
7.79e7.76 (m, 1H, ArH), 7.47e7.43 (m, 2H, ArH), 7.34e7.23 (m, 2H,
ArH), 6.67 (d, J¼7.1 Hz, 1H, ArH), 6.02e5.93 (m, 1H, CH), 5.28e5.18
(m, 3H, CH2, NH), 4.68 (d, J¼6.0 Hz, 1H, NHCH), 4.26e4.15 (m, 4H,
OCH2), 3.66 (dd, J1¼9.2 Hz, J2¼6.0 Hz, 1H, CH), 1.28 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.22 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
dC 171.5, 171.3, 141.4, 134.4, 131.2, 128.6, 126.4, 126.0, 125.1, 123.9,
120.8, 120.2, 118.9, 105.8, 61.6, 61.4, 58.6, 52.4, 14.2; HRMS: (ESI) m/z
found 342.1693 for C20H24NO4 (MHþ), requires 342.1705.
4.8.8. (2R*,3S*)-Diethyl 2-((3,4-dimethylphenyl)amino)-3-vinylsucci
nate (3g). Following the general procedure A described above, 3g
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless liquid (112 mg, 70%): Rf
(20% EtOAc/Hexane) 0.65; IR (thin film): nmax 3375, 2982,1732,1512
and 1030 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.94 (d, J¼8.1 Hz, 1H,
ArH), 6.53 (d, J¼2.5 Hz, 1H, ArH), 6.47 (dd, J1¼8.1 Hz, J2¼2.5 Hz, 1H,
ArH), 5.95e5.86 (m, 1H, CH), 5.28e5.23 (m, 2H, CH2), 4.49 (dd,
J1¼10.0 Hz, J2¼6.6 Hz,1H, NHCH), 4.24e4.13 (m, 5H, NH, OCH2), 3.50
(dd, J1¼10.0 Hz, J2¼6.6 Hz, 1H, CHCH), 2.20 (s, 3H, ArCH3), 2.10 (s,
3H, ArCH3), 1.28 (t, J¼7.2 Hz, 3H, CH2CH3), 1.24 (t, J¼7.2 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 171.6, 171.2, 144.2, 137.4,
131.4, 130.4, 127.0, 120.5, 116.1, 111.5, 61.3, 61.2, 59.1, 53.1, 20.0, 18.8,
14.2, 14.2; HRMS: (ESI) m/z found 320.1870 for C18H26NO4 (MHþ),
requires 320.1862.
4.8.13. (2R*,3S*)-1-Ethyl 4-methyl 2-((3,4-dichlorophenyl)amino)-3-
vinylsuccinate (3l). Following the general procedure A described
above, 3l was obtained after purification by silica gel column chro
matography (EtOAc/Hexane¼10:90) as colourless liquid (124 mg,
72%): Rf (20% EtOAc/Hexane) 0.65; IR (thin film): nmax 3375, 2985,
1730, 1597 and 1020 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 7.22 (d,
;
J¼8.7 Hz, 1H, ArH), 6.79 (d, J¼2.8 Hz, 1H, ArH), 6.54 (dd, J1¼8.7 Hz,
J2¼2.8 Hz, 1H, ArH), 5.92e5.82 (m, 1H, CH), 5.32e5.22 (m, 2H, CH2),
4.57 (d, J¼9.9 Hz,1H, NH), 4.42 (dd, J1¼9.9 Hz, J2¼6.0 Hz,1H, NHCH),
4.22e4.16 (m, 2H, OCH2), 3.76 (s, 3H, OCH3), 3.55 (dd, J1¼9.2 Hz,
4.8.9. (2R*,3S*)-Diethyl 2-((3,4-dichlorophenyl)amino)-3-vinylsucci
nate (3h). Following the general procedure A described above, 3h

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6607
J2¼6.0 Hz, 1H, CH), 1.26 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 171.4, 170.7, 145.8, 133.0, 130.8, 130.7, 121.5,
121.1, 115.3, 113.6, 61.8, 58.4, 52.4, 52.3, 14.1; HRMS: (ESI) m/z found
346.0600 for C15H18Cl2NO4 (MHþ), requires 346.0613.
above, 3q was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼10:90) as colourless solid
(164 mg, 93%): Rf (20% EtOAc/Hexane) 0.63; mp 72e74 ꢀC; IR (KBr):
nmax 3375, 2956, 1723, 1528 and 1019 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): dH 7.49 (d, J¼8.6 Hz, 2H, ArH), 7.42 (d, J¼8.6 Hz, 2H, ArH),
7.35 (t, J¼7.4 Hz, 2H, ArH), 7.23 (t, J¼7.4 Hz, 1H, ArH), 6.74 (d,
J¼8.6 Hz, 2H, ArH), 5.92e5.83 (m, 1H, CH), 5.27e5.17 (m, 2H, CH2),
4.57e4.48 (m, 2H, NH, NHCH), 4.19e4.10 (m, 2H, OCH2), 3.71 (s, 3H,
OCH3), 3.55 (dd, J1¼9.3 Hz, J2¼5.9 Hz, 1H, CH), 1.21 (t, J¼7.1 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 171.7, 171.2, 145.5, 141.0,
131.8, 131.0, 128.7, 128.1, 126.4, 126.3, 121.2, 114.3, 61.6, 58.6, 52.6,
52.4, 14.2; HRMS: (ESI) m/z found 354.1704 for C21H24NO4 (MHþ),
requires 354.1705.
4.8.14. (2R*,3S*)-1-Ethyl 4-methyl 2-((4-bromophenyl)amino)-3-
vinylsuccinate (3m). Following the general procedure A described
above, 3m was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼9:91) as colourless liquid
(128 mg, 72%): Rf (20% EtOAc/Hexane) 0.65; IR (thin film): nmax
3374, 2984, 1730, 1497 and 1021 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 7.28 (d, J¼8.9 Hz, 2H, ArH), 6.59 (d, J¼8.9 Hz, 2H, ArH), 5.92e5.83
(m, 1H, CH), 5.31e5.19 (m, 2H, CH2), 4.47 (d, J¼3.0 Hz, 2H, NH,
NHCH), 4.22e4.14 (m, 2H, OCH2), 3.75 (s, 3H, OCH3), 3.54 (td,
J1¼9.2 Hz, J2¼3.0 Hz, 1H, CH), 1.25 (t, J¼7.2 Hz, 3H, CH2CH3); 13C
NMR (100 MHz, CDCl3): dC 171.5, 170.9, 145.1, 132.1, 130.8, 121.1,
115.7, 110.7, 61.6, 58.5, 52.4, 14.2; HRMS: (ESI) m/z found 356.0486
for C15H19BrNO4 (MHþ), requires 356.0497.
4.8.19. (2R*,3S*)-Diethyl 2-(2-benzoylhydrazinyl)-2-methyl-3-
vinylsuccinate (3r)#. Following the general procedure A described
above, 3r was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼21:79) as colourless oil (80 mg,
46%): Rf (30% EtOAc/Hexane) 0.46; IR (thin film): nmax 3287, 2984,
4.8.15. (2R*,3S*)-Diethyl 2-(2-benzoylhydrazinyl)-3-vinylsuccinate
(3n). Following the general procedure A described above, 3n was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼20:80) as colourless solid (134 mg, 81%): Rf (30%
EtOAc/Hexane) 0.45; mp 87e89 ꢀC; IR (thin film): nmax 3264, 2981,
1721,1451 and 1160 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 7.96 (s,1H,
NH), 7.23 (d, J¼7.0 Hz, 2H, ArH), 7.51 (t, J¼7.0 Hz, 1H, ArH), 7.43 (t,
J¼7.0 Hz, 2H, ArH), 5.98e5.89 (m, 1H, CH), 5.39e5.27 (m, 3H, CH2,
NH), 4.24e4.16 (m, 4H, 2 OCH2), 4.01 (d, J¼7.5 Hz, 1H, NHCH), 3.61
(t, J¼7.5 Hz, 1H, CH), 1.26 (t, J¼7.2 Hz, 6H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 171.3, 170.9, 166.9, 132.5, 132.0, 131.3, 128.7,
127.0, 120.4, 64.8, 61.5, 61.4, 51.5, 14.1, 14.1; HRMS: (ESI) m/z found
335.1590 for C17H23N2O5 (MHþ), requires 335.1607.
1731, 1461 and 1029 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 8.39 (s,
;
1H, NH), 7.76 (d, J¼7.1 Hz, 2H, ArH), 7.53e7.42 (m, 3H, ArH),
6.15e6.06 (m, 1H, CH), 5.41e5.28 (m, 3H, CH2, NH), 4.22e4.09 (m,
4H, OCH2), 3.75e3.68 (m, 1H, CH), 1.41 (s, 3H, CH3), 1.28e1.22 (m,
6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 174.0, 172.2, 166.0,
132.9, 131.7, 130.8, 128.7, 126.9, 121.5, 65.8, 61.7, 61.4, 55.7, 20.1, 14.1,
14.0; HRMS: (ESI) m/z found 371.1578 for C18H24N2O5Na (MNaþ),
requires 371.1583. #The compound was isolated with traces of
minor isomer and the NMR values given here for the major isomer.
4.8.20. (2R*,3S*)-Diethyl 2-(2-hydroxyphenylamino)-3-vinylsucci
nate (3s). Following the general procedure A described above, 3s
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼11:89) as colourless liquid (90 mg, 59%): Rf
(20% EtOAc/Hexane) 0.58; IR (thin film): nmax 3419, 2983, 1731, 1516
4.8.16. (2R*,3S*)-Diethyl 2-((1,3-dioxoisoindolin-2-yl)amino)-3-
vinylsuccinate (3o)#. Following the general procedure A described
above, 3o was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼22:78) as colourless oil (90 mg,
50%): Rf (30% EtOAc/Hexane) 0.43; IR (thin film): nmax 3297, 2984,
1730, 1468 and 1031 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 7.85 (dd,
J1¼5.5 Hz, J2¼3.1 Hz, 2H, ArH), 7.75 (dd, J1¼5.5 Hz, J2¼3.1 Hz, 2H,
ArH), 5.94e5.85 (m, 1H, CH), 5.41e5.28 (m, 3H, CH2, NH), 4.30e4.14
(m, 5H, NHCH, OCH2), 3.54 (t, J¼8.6 Hz, 1H, CH), 1.32 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.26 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
dC 171.9, 171.1, 166.9,135.3, 135.3, 131.8, 131.0, 124.5, 121.9, 65.3, 62.7,
62.5, 53.4, 15.0, 15.0; HRMS: (ESI) m/z found 361.1393 for
C18H21N2O6 (MHþ), requires 361.1400. #The compound was isolated
with traces of minor isomer and the NMR values given here for the
major isomer.
and 1195 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 6.82 (m, 4H, ArH),
;
6.23 (br s, 1H, OH), 5.91e5.82 (m, 1H, CH), 5.28e5.23 (m, 2H, CH2),
4.26e4.11 (m, 6H, NH, NHCH, OCH2), 3.47 (t, J¼8.5 Hz, 1H, CH), 1.28
(t, J¼7.2 Hz, 3H, CH2CH3), 1.20 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 172.3, 172.0, 147.6, 133.8, 131.2, 122.3, 120.8,
120.8, 118.5, 115.6, 60.6, 61.4, 60.8, 53.6, 14.2, 14.1; HRMS: (ESI) m/z
found 330.1300 for C16H21NO5Na (MNaþ), requires 330.1317.
4.8.21. (2R*,3S*)-Diethyl 2-(4-acetylphenylamino)-3-vinylsuccinate
(3t). Following the general procedure A described above, 3t was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼09:91) as colourless liquid (103 mg, 65%): Rf (20%
EtOAc/Hexane) 0.64; IR (thin film): nmax 3379, 2985, 1732, 1599 and
1035 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.83 (d, J¼8.8 Hz, 2H,
ArH), 6.67 (d, J¼8.8 Hz, 2H, ArH), 5.91e5.82 (m, 1H, CH), 5.29e5.19
(m, 2H, CH2), 5.05 (d, J¼9.4 Hz, 1H, NH), 4.59 (dd, J1¼9.4 Hz,
J2¼5.8 Hz, 1H, NHCH), 4.23e4.16 (m, 4H, OCH2), 3.56 (dd, J1¼9.2 Hz,
4.8.17. (2R*,3S*)-Diethyl 2-([1,10-biphenyl]-4-ylamino)-3-vinylsucci
nate (3p). Following the general procedure A described above, 3p
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless solid (167 mg, 91%): Rf
(20% EtOAc/Hexane) 0.62; mp 75e77 ꢀC; IR (KBr): nmax 3349, 2985,
J2¼5.8 Hz, 1H, CH), 2.50 (s, 3H, CH3), 1.29e1.23 (m, 6H, CH2CH3); 13
C
NMR (100 MHz, CDCl3): dC 196.4, 170.9, 170.5, 150.2, 130.8, 128.0,
121.0, 112.5, 61.8, 61.5, 57.6, 52.3, 26.1, 14.1, 14.1; HRMS: (ESI) m/z
found 334.1648 for C18H24NO5 (MHþ), requires 334.1654.
1720, 1527 and 1174 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 7.53 (d,
;
J¼7.5 Hz, 2H, ArH), 7.45 (d, J¼8.6 Hz, 2H, ArH), 7.39 (t, J¼7.5 Hz, 2H,
ArH), 7.27 (t, J¼7.5 Hz, 1H, ArH), 6.77 (d, J¼8.6 Hz, 2H, ArH),
5.96e5.87 (m, 1H, CH), 5.30e5.21 (m, 2H, CH2), 4.57e4.52 (m, 2H,
NH, NHCH), 4.24e4.15 (m, 4H, OCH2), 3.56 (dd, J1¼9.2 Hz, J2¼5.8 Hz,
1H, CH), 1.31e1.23 (m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC
171.3, 171.1, 145.5, 141.0, 131.8, 131.1, 128.7, 128.1, 126.4, 126.3, 120.8,
114.3, 61.5, 61.4, 58.6, 52.8, 14.2, 14.2; HRMS: (ESI) m/z found
368.1850 for C22H26NO4 (MHþ), requires 368.1862.
4.8.22. (2R*,3S*)-1-Ethyl 4-methyl 2-(4-acetylphenylamino)-2-
methyl-3-vinylsuccinate (3u). Following the general procedure A
described above, 3u was obtained after purification by silica gel
column chromatography (EtOAc/Hexane¼09:91) as colourless liq-
uid (91 mg, 57%): Rf (20% EtOAc/Hexane) 0.64; IR (thin film): nmax
3367, 2985, 1731, 1600 and 1276 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 7.80 (d, J¼8.8 Hz, 2H, ArH), 6.63 (d, J¼8.8 Hz, 2H, ArH), 5.86e5.77
(m, 1H, CH), 5.27e5.15 (m, 2H, CH2), 4.97 (d, J¼9.5 Hz, 1H, NH), 4.57
(dd, J1¼9.5 Hz, J2¼5.6 Hz, 1H, NHCH), 4.20e4.11 (m, 2H, OCH2), 3.71
(s, 3H, OCH3), 3.56 (dd, J1¼9.2 Hz, J2¼5.6 Hz, 1H, CH), 2.47 (s, 3H,
4.8.18. (2R*,3S*)-1-Ethyl 4-methyl 2-([1,10-biphenyl]-4-ylamino)-3-
vinylsuccinate (3q). Following the general procedure A described

6608
N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
CH3), 1.21 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC
196.5, 171.4, 170.4, 150.1, 130.8, 130.5, 128.1, 121.3, 112.5, 61.9, 57.5,
52.5, 52.1, 26.1, 14.1; HRMS: (ESI) m/z found 320.1480 for C17H22NO5
(MHþ), requires 320.1498.
(m, 4H, OCH2), 4.08e4.04 (m, 1H, NHCH), 2.87 (d, J¼5.3 Hz, 2H,
CH2CH), 1.30e1.24 (m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC
171.7,170.8,167.1,132.5,132.0,128.7,127.0, 61.6, 61.1, 59.3, 35.6,14.1;
HRMS: (ESI) m/z found 331.1266 for C15H20N2O5Na (MNaþ), re-
quires 331.1270.
4.8.23. (2R*,3S*)-Diethyl 2-(2-tosylhydrazinyl)-3-vinylsuccinate
(3v). Following the general procedure B described above, 3v was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼19:81) as colourless solid (103 mg, 54%): Rf (20%
EtOAc/Hexane) 0.33; mp 107e109 ꢀC; IR (KBr): nmax 3261, 2987,
4.8.28. Diethyl 2-([1,10-biphenyl]-4-ylamino)succinate (9e). Following
the general procedure
C described above, 9e was obtained
after purification by silica gel column chromatography (EtOAc/
Hexane¼09:91) as yellow colour liquid (114 mg, 67%): Rf (20% EtOAc/
Hexane) 0.60; IR (thin film): nmax 3395, 2982, 1734, 1609 and
1722, 1320 and 1161 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 7.76 (d,
;
J¼8.3 Hz, 2H, ArH), 7.28 (d, J¼8.3 Hz, 2H, ArH), 6.54 (s, 1H, NH),
5.86e5.77 (m, 1H, CH), 5.21e5.17 (m, 2H, CH2), 4.35 (dd, J1¼10.3 Hz,
J2¼2.9 Hz, 1H, NH), 4.19e4.13 (m, 2H, OCH2), 4.09 (q, J¼7.0 Hz, 2H,
OCH2), 3.78 (dd, J1¼10.3 Hz, J2¼5.5 Hz, 1H, NHCH), 3.45 (dd,
J1¼8.8 Hz, J2¼5.5 Hz, 1H, CH), 2.41 (s, 3H, ArCH3), 1.25e1.19 (m, 6H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 172.1, 170.9, 144.0, 134.9,
131.4, 129.5, 128.3, 119.9, 65.1, 61.7, 61.4, 51.2, 21.6, 14.1, 14.0; HRMS:
(ESI) m/z found 385.1410 for C17H25N2O6S (MHþ), requires 385.1433.
1229 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 7.51e7.49 (m, 2H, ArH),
;
7.42 (d, J¼8.6 Hz, 2H, ArH), 7.36 (t, J¼7.5 Hz, 2H, ArH), 7.23 (t,
J¼7.5 Hz, 1H, ArH), 6.72 (d, J¼8.6 Hz, 2H, ArH), 4.46 (t, J¼5.7 Hz, 1H,
NHCH), 4.31e4.16 (m, 3H, NH, OCH2), 4.14 (q, J¼7.2 Hz, 2H, OCH2),
2.86 (dd, J1¼5.8 Hz, J2¼2.5 Hz, 2H, CH2CH), 1.24 (dt, J1¼7.1 Hz,
J2¼2.5 Hz, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 172.3, 170.6,
145.7, 141.0, 131.6, 128.7, 128.1, 126.4, 126.3, 114.0, 61.7, 61.1, 53.5, 37.5,
14.2; HRMS: (ESI) m/z found 364.1525 for C20H23NO4Na (MNaþ),
requires 364.1525.
4.8.24. Diethyl 2-(4-methoxyphenylamino)succinate (9a). Following
the general procedure C described above, 9a was obtained after
purification by silica gel column chromatography (EtOAc/
Hexane¼10:90) as colourless liquid (94 mg, 65%): Rf (20% EtOAc/
Hexane) 0.56; IR (thin film): nmax 3368, 2983, 1730, 1512 and
4.8.29. Diethyl 3-((4-methoxyphenyl)amino)-2,2-dimethylsuccinate
(10a). Following the general procedure C described above, 10a
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼9:91) as colourless liquid (137 mg, 85%): Rf
(20% EtOAc/Hexane) 0.61; IR (thin film): nmax 3371, 2982, 1728, 1512
and 1238 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.75 (d, J¼9.0 Hz, 2H,
ArH), 6.68 (d, J¼9.0 Hz, 2H, ArH), 4.24 (br s, 1H, NH), 4.24e4.10 (m,
5H, NHCH, OCH2), 3.72 (s, 3H, OCH3), 1.29e1.24 (m, 9H, CH3,
CH2CH3), 1.20 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
dC 175.6, 172.2, 153.1, 141.4, 116.1, 114.7, 64.7, 61.2, 61.0, 55.7, 45.9,
22.5, 21.6, 14.2, 14.1; HRMS: (ESI) m/z found 324.1797 for C17H26NO5
(MHþ), requires 324.1811.
1029 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 6.77 (d, J¼9.0 Hz, 2H,
ArH), 6.65 (d, J¼9.0 Hz, 2H, ArH), 4.34 (t, J¼6.0 Hz, 1H, NHCH),
4.22e4.13 (m, 4H, OCH2), 3.73 (s, 3H, OCH3), 2.82 (d, J¼6.0 Hz, 2H,
CH2CH), 1.27e1.22 (m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC
172.7, 170.6, 153.1, 140.4, 115.8, 114.8, 61.5, 61.0, 55.7, 55.0, 37.7, 14.2,
14.1; HRMS: (ESI) m/z found 296.1509 for C15H22NO5 (MHþ), re-
quires 296.1498.
4.8.25. 4-tert-Butyl 1-ethyl 2-(4-methoxyphenylamino)succinate
(9b). Following the general procedure C described above, 9b was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼10:90) as colourless liquid (64 mg, 40%): Rf (20%
EtOAc/Hexane) 0.57; IR (thin film): nmax 3385, 2979, 1731, 1514 and
4.8.30. Diethyl 2,2-difluoro-3-((4-methoxyphenyl)amino)succinate
(10b). Following the general procedure C described above, 10b was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼11:89) as colourless liquid (66 mg, 40%): Rf (20%
EtOAc/Hexane) 0.55; IR (thin film): nmax 3363, 2988, 1745, 1514 and
1155 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 6.75 (d, J¼8.9 Hz, 2H,
ArH), 6.62 (d, J¼8.9 Hz, 2H, ArH), 4.26 (t, J¼5.9 Hz, 1H, NHCH),
4.19e4.12 (m, 2H, OCH2), 3.71 (s, 3H, OCH3), 2.71 (d, J¼5.9 Hz, 2H,
CH2CH), 1.42 (s, 9H, C(CH3)3), 1.23e1.20 (m, 4H, NH, CH2CH3); 13C
NMR (100 MHz, CDCl3): dC 172.8, 169.8, 153.0, 140.6, 115.7, 114.9,
114.8, 81.4, 61.4, 55.7, 55.1, 38.8, 28.1, 28.1, 14.2; HRMS: (ESI) m/z
found 324.1791 for C17H26NO5 (MHþ), requires 324.1811.
1199 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 6.77 (d, J¼9.1 Hz, 2H,
ArH), 6.71 (d, J¼9.1 Hz, 2H, ArH), 4.64 (dd, J1¼15.8 Hz, J2¼10.0 Hz,
1H, NHCH), 4.63e4.19 (m, 5H, NH, OCH2), 3.73 (s, 3H, OCH3), 1.32 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.26 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 167.5 (JCeF¼3.2 Hz), 162.4 (JCeF¼30.7 Hz),
154.0, 139.6, 116.7, 114.8, 63.4, 62.6, 61.6 (JCeF¼23.2 Hz), 61.3
(JCeF¼23.0 Hz), 55.7, 14.0, 13.9; HRMS: (ESI) m/z found 332.1300 for
C15H20F2NO5 (MHþ), requires 332.1310.
4.8.26. Diethyl 2-(4-chlorophenylamino)succinate (9c). Following
the general procedure C described above, 9c was obtained after
purification by silica gel column chromatography (EtOAc/
Hexane¼10:90) as colourless liquid (104 mg, 69%): Rf (20% EtOAc/
Hexane) 0.58; IR (thin film): nmax 3382, 2982, 1732, 1498 and
4.8.31. Diethyl
2-fluoro-3-((4-methoxyphenyl)amino)succinate
(10c). Following the general procedure C described above, 10c was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼11:89) as colourless liquid (92 mg, 59%): Rf (20%
EtOAc/Hexane) 0.55; IR (thin film): nmax 3369, 2963,1746, 1515 and
1033 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.75e6.69 (m, 2H, ArH),
6.64e6.60 (m, 2H, ArH), 5.40e5.14 (m, 1H, NHCH), 4.57e4.45 (m,
1H, CHF), 4.31e4.14 (m, 4H, OCH2), 3.68 (s, 3H, OCH3), 1.30e1.18
(m, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 169.6
(JCeF¼2.3 Hz), 168.4 (JCeF¼6.7 Hz), 167.1 (JCeF¼8.4 Hz), 166.9
(JCeF¼4.2 Hz), 153.7, 153.4, 140.3, 139.6, 116.7, 115.8, 115.0, 114.7,
90.0 (JCeF¼80.0 Hz), 88.1 (JCeF¼81.8 Hz), 62.3, 62.2, 62.1, 62.0, 60.6
(JCeF¼19.7 Hz), 60.2 (JCeF¼21.5 Hz), 55.7, 55.6, 14.1, 14.0; HRMS:
(ESI) m/z found 314.1391 for C15H21FNO5 (MHþ), requires
314.1404. 13C data given here for the mixture of diastereomers.
1202 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.04 (d, J¼8.8 Hz, 2H,
ArH), 6.51 (d, J¼8.8 Hz, 2H, ArH), 4.29 (t, J¼5.8 Hz, 1H, NHCH),
4.15e4.04 (m, 4H, OCH2), 2.76 (dd, J1¼5.8 Hz, J2¼3.2 Hz, 2H, CH2CH),
1.16 (t, J¼7.1 Hz, 6H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 172.1,
170.5, 145.0, 129.2, 123.3, 114.9, 61.7, 61.1, 53.6, 37.3, 14.1, 14.1;
HRMS: (ESI) m/z found 300.0999 for C14H19NO4Cl (MHþ), requires
300.1003.
4.8.27. Diethyl 2-(benzamido)succinate (9d). Following the general
procedure C described above, 9d was obtained after purification by
silica gel column chromatography (EtOAc/Hexane¼20:80) as col-
ourless oil (92 mg, 60%): Rf (20% EtOAc/Hexane) 0.31; IR (thin film):
nmax 3291, 2928, 1733, 1529 and 1028 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): dH 8.09 (br s, 1H, NH), 7.76e7.74 (m, 2H, ArH), 7.54e7.50 (m,
1H, ArH), 7.43 (t, J¼7.7 Hz, 2H, ArH), 5.45 (br s, 1H, NH), 4.28e4.14
4.8.32. (2S*,3R*)-Diethyl 2-ethyl-3-((4-methoxyphenyl)amino)succi-
nate (10d0). Following the general procedure C described above,

N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
6609
10d0 (minor isomer) was obtained after purification by silica gel
column chromatography (EtOAc/Hexane¼9:91) as colourless liquid
(100 mg, 62%): Rf (20% EtOAc/Hexane) 0.63; IR (thin film): nmax
3379, 2976, 1731, 1515 and 1034 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 6.69 (d, J¼9.0 Hz, 2H, ArH), 6.56 (d, J¼9.0 Hz, 2H, ArH), 4.17e4.01
(m, 6H, NH, NHCH, OCH2), 3.66 (s, 3H, OCH3), 2.77e2.66 (m,1H, CH),
1.75e1.66 (m, 1H, CH), 1.57e1.47 (m, 1H, CH), 1.19 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.14 (t, J¼7.1 Hz, 3H, CH2CH3), 0.88 (t, J¼7.4 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 173.2, 172.8, 152.9, 140.7,
115.5, 114.8, 61.2, 60.8, 59.6, 55.7, 49.9, 22.0, 14.3, 14.2, 12.0; HRMS:
(ESI) m/z found 324.1809 for C17H26NO5 (MHþ), requires 324.1811.
The major isomer 10d could not be separated from the minor
isomer.
(400 MHz, CDCl3): dH 7.51 (d, J¼8.5 Hz, 2H, ArH), 7.43 (d, J¼8.6 Hz,
2H, ArH), 7.37 (t, J¼7.5 Hz, 2H, ArH), 7.25 (t, J¼7.5 Hz, 1H, ArH), 6.88
(d, J¼8.6 Hz, 2H, ArH), 4.64e4.56 (m, 2H, NH, NHCH), 4.42e4.37 (m,
1H, OCH2), 4.26 (t, J¼8.3 Hz, 1H, OCH2), 4.21 (q, J¼7.1 Hz, 2H, OCH2),
3.15 (dt, J1¼9.7 Hz, J2¼3.4 Hz, 1H, CH), 2.35e2.29 (m, 2H, CH2), 1.25
(t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 176.4,
170.9, 145.9, 140.9, 132.1, 128.7, 128.2, 126.4, 114.0, 66.7, 62.3, 56.4,
42.5, 24.9, 14.1; HRMS: (ESI) m/z found 340.1535 for C20H22NO4
(MHþ), requires 340.1549.
4.8.37. (2S*,3R*)-Diethyl 2-ethyl-3-((4-methoxyphenyl)amino)succi-
nate (10d0). Following the general procedure D described above,
10d0 was obtained after purification by silica gel column chroma-
tography (EtOAc/Hexane¼10:90) as colourless liquid (142 mg, 88%).
Characterization data (has been given above) same as the product
obtained in Table 5.
4.8.33. (2S*,3R*)-Diethyl 2-hexyl-3-((4-methoxyphenyl)amino)suc-
cinate (10e)#. Following the general procedure C described above,
10e was obtained after purification by silica gel column chroma-
tography (EtOAc/Hexane¼9:91) as colourless liquid (65 mg, 35%): Rf
(20% EtOAc/Hexane) 0.64; IR (thin film): nmax 3374, 2925, 1732, 1515
and 1036 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.69 (d, J¼9.0 Hz, 2H,
ArH), 6.56 (d, J¼9.0 Hz, 2H, ArH), 4.17 (d, J¼6.1 Hz, 1H, NHCH),
4.12e3.87 (m, 5H, NH, OCH2), 3.66 (s, 3H, OCH3), 2.77e2.72 (m, 1H,
CH), 1.81e1.72 (m, 1H, CH2), 1.58e1.50 (m, 1H, CH2), 1.21e1.12 (m,
14H, CH2, CH2CH3), 0.82e0.77 (m, 3H, CH2CH3); 13C NMR (100 MHz,
CDCl3): dC 173.0,172.5,153.0,140.8,115.7,114.8, 61.3, 60.9, 59.9, 55.7,
48.5, 31.6, 29.1, 28.0, 27.6, 22.6, 14.2, 14.2, 14.1; HRMS: (ESI) m/z
found 380.2450 for C21H34NO5 (MHþ), requires 380.2437. #The
compound was isolated with minor isomer and the NMR values
given here for the major isomer.
4.8.38. (2R*,3S*)-Diethyl 2-(3,4-dichlorophenylamino)-3-ethylsucci
nate (11a). Following the general procedure D described above,
11a was obtained after purification by silica gel column chroma-
tography (EtOAc/Hexane¼10:90) as colourless liquid (117 mg, 65%):
Rf (20% EtOAc/Hexane) 0.64; IR (thin film): nmax 3380, 2978, 1731,
1599 and 1193 cmꢁ1 1H NMR (400 MHz, CDCl3): dH 7.20 (d,
;
J¼8.7 Hz, 1H, ArH), 6.75 (d, J¼2.8 Hz, 1H, ArH), 6.51 (dd, J1¼8.7 Hz,
J2¼2.8 Hz, 1H, ArH), 4.73 (d, J¼9.8 Hz, 1H, NHCH), 4.22e4.16 (m, 5H,
NH, OCH2), 2.85e2.79 (m,1H, CH),1.86e1.75 (m,1H, CH2),1.65e1.55
(m, 1H, CH2), 1.29e1.23 (m, 6H, CH2CH3), 0.97 (t, J¼7.3 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 173.1, 171.8, 146.3, 132.9,
130.7, 121.0, 114.8, 113.3, 61.6, 61.0, 57.8, 49.2, 22.1, 14.2, 14.2, 12.0;
HRMS: (ESI) m/z found 384.0728 for C16H21NO4Cl2Na (MNaþ), re-
quires 384.0745.
4.8.34. Diethyl 2-([1,10-biphenyl]-4-ylamino)-3-propylsuccinate
(10f). Following the general procedure C described above, 10f
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼10:90) as colourless liquid (96 mg, 50%): Rf
(20% EtOAc/Hexane) 0.63; IR (thin film): nmax 3384, 2962, 1732,
1528 and 1027 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 7.52e7.50 (m,
2H, ArH), 7.42 (d, J¼8.6 Hz, 2H, ArH), 7.37 (t, J¼7.4 Hz, 2H, ArH), 7.25
(t, J¼7.4 Hz, 1H, ArH), 6.71 (d, J¼8.6 Hz, 2H, ArH), 4.39 (br s, 2H, NH,
NHCH), 4.21e4.13 (m, 4H, OCH2), 2.90e2.85 (m, 1H, CH), 1.90e1.81
(m, 1H, CH2), 1.65e1.57 (m, 1H, CH2), 1.48e1.30 (m, 2H, CH2),
1.28e1.22 (m, 6H, CH2CH3), 0.92 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 172.9, 172.1, 146.1, 141.0, 131.6, 128.7, 128.0,
126.4, 126.3, 114.1, 61.5, 61.0, 58.4, 48.3, 30.3, 20.9, 14.2, 14.2, 14.0;
HRMS: (ESI) m/z found 384.2180 for C23H30NO4 (MHþ), requires
384.2175.
4.8.39. (2R*,3S*)-1-Ethyl 4-methyl 2-(3,4-dichlorophenylamino)-3-
ethylsuccinate (11b). Following the general procedure D described
above, 11b was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼10:90) as colourless liquid
(166 mg, 96%): Rf (20% EtOAc/Hexane) 0.65; IR (thin film): nmax
3382, 2970, 1735, 1599 and 1201 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 7.11 (d, J¼8.7 Hz, 1H, ArH), 6.66 (d, J¼2.8 Hz, 1H, ArH), 6.42 (dd,
J1¼8.7 Hz, J2¼2.8 Hz, 1H, ArH), 4.61 (d, J¼8.2 Hz, 1H, NHCH),
4.14e4.07 (m, 3H, NH, OCH2), 3.64 (s, 3H, OCH3), 2.78e2.73 (m, 1H,
CH), 1.75e1.66 (m, 1H, CH2), 1.56e1.46 (m, 1H, CH2), 1.16 (t, J¼7.1 Hz,
3H, CH2CH3), 0.87 (t, J¼7.4 Hz, 3H, CH2CH3); 13C NMR (100 MHz,
CDCl3): dC 173.6, 171.7, 146.3, 132.9, 130.7, 121.1, 114.9, 113.3, 61.7,
57.8, 52.1, 49.1, 22.0, 14.2, 12.0; HRMS: (ESI) m/z found 370.0570 for
C15H19NO4Cl2Na (MNaþ), requires 370.0589.
4.8.35. (R*)-Ethyl 2-((4-methoxyphenyl)amino)-2-((R*)-2-oxotetra
hydrofuran-3-yl)acetate (10g). Following the general procedure C
described above, 10g was obtained after purification by silica gel
column chromatography (EtOAc/Hexane¼13:87) as colourless liq-
uid (98 mg, 67%): Rf (20% EtOAc/Hexane) 0.60; IR (thin film): nmax
3368, 2916, 1739, 1597 and 1036 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 6.76e6.70 (m, 4H, ArH), 4.37e4.31 (m, 2H, NH, NHCH), 4.23e4.11
(m, 1H, CH2), 4.21 (t, J¼8.2 Hz, 1H, OCH2), 4.14 (q, J¼7.1 Hz, 2H,
OCH2), 3.68 (s, 3H, OCH3), 3.06 (dt, J1¼9.6 Hz, J2¼3.5 Hz, 1H, CH),
2.27e2.21 (m, 2H, CH2), 1.19 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): dC 177.0,172.4,153.8,140.6,117.3,114.7, 66.8, 61.9,
59.1, 55.7, 42.7, 23.7, 14.2; HRMS: (ESI) m/z found 294.1338 for
C15H20NO5 (MHþ), requires 294.1341.
4.8.40. (2R*,3S*)-2-((4-Methoxyphenyl)amino)-3-vinylbutane-1,4-
diol (12a). Following the general procedure E described above, 12a
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼30:70) as colourless oil (59 mg, 50%): Rf (20%
EtOAc/Hexane) 0.18; IR (thin film): nmax 3377, 2930, 1513, 1241 and
1038 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 6.78 (d, J¼9.0 Hz, 2H,
ArH), 6.69 (d, J¼9.0 Hz, 2H, ArH), 5.75e5.66 (m, 1H, CH), 5.23e5.18
(m, 2H, CH2), 3.81e3.74 (m, 2H, OCH2), 3.74 (s, 3H, OCH3), 3.68 (dd,
J1¼11.0 Hz, J2¼5.0 Hz, 2H, OCH2), 3.56 (dd, J1¼11.0 Hz, J2¼5.0 Hz, 1H,
NHCH), 3.48e3.44 (m, 1H, CH), 2.60e2.52 (m, 1H, CH); 13C NMR
(100 MHz, CDCl3): dC 153.2, 141.0, 136.0, 119.0, 116.8, 115.0, 64.8,
61.8, 59.1, 55.7, 48.5; HRMS: (ESI) m/z found 238.1449 for
C13H20NO3 (MHþ), requires 238.1443. (OH protons could not be
detected perhaps due to the rapid exchange among each other.)
4.8.36. (R*)-Ethyl 2-([1,10-biphenyl]-4-ylamino)-2-((R*)-2-oxotetra
hydrofuran-3-yl)acetate (10h). Following the general procedure C
described above, 10h was obtained after purification by silica gel
column chromatography (EtOAc/Hexane¼14:86) as yellow solid
(122 mg, 72%): Rf (20% EtOAc/Hexane) 0.62; mp 113e115 ꢀC; IR
4.8.41. (2R*,3S*)-2-((3,4-Dichlorophenyl)amino)-3-vinylbutane-1,4-
diol (12b). Following the general procedure E described above, 12b
was obtained after purification by silica gel column chromatogra-
phy (EtOAc/Hexane¼30:70) as colourless oil (81 mg, 59%): Rf (20%
(KBr): nmax 3351, 2984, 1757, 1530 and 1025 cmꢁ1 1H NMR
;

6610
N.A. Aslam et al. / Tetrahedron 69 (2013) 6598e6611
EtOAc/Hexane) 0.18; IR (thin film): nmax 3379, 2923, 1596, 1511 and
CH2CH3), 1.11 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
dC 170.6, 170.0, 153.2, 143.4, 125.8, 122.1, 116.6, 114.5, 61.0, 60.9, 59.0,
55.6, 45.6, 43.7, 14.2, 14.1; HRMS: (ESI) m/z found 334.1660 for
C18H24NO5 (MHþ), requires 334.1654.
1038 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.16 (d, J¼8.7 Hz, 1H,
ArH), 6.74 (d, J¼2.8 Hz, 1H, ArH), 6.51 (dd, J1¼8.7 Hz, J2¼2.8 Hz, 1H,
ArH), 5.78e5.69 (m, 1H, CH), 5.25e5.18 (m, 2H, CH2), 3.77e3.67 (m,
3H, NHCH, OCH2), 3.62e3.52 (m, 2H, OCH2), 2.82 (br s, 1H, CH),
2.56e2.49 (m, 1H, CH); 13C NMR (100 MHz, CDCl3): dC 147.1, 135.7,
132.9, 130.8, 120.4, 119.3, 115.0, 113.7, 63.6, 62.1, 56.3, 48.7; HRMS:
(ESI) m/z found 276.0548 for C12H16NO2Cl2 (MHþ), requires
276.0558. (OH protons could not be detected perhaps due to the
rapid exchange among each other.)
4.8.46. (2R*,3S*)-Diethyl 1-(4-methoxyphenyl)piperidine-2,3-dicar
boxylate (15). Following the general procedure
D described
above, 15 was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼10:90) as colourless liquid
(109 mg, 65%): Rf (20% EtOAc/Hexane) 0.63; IR (thin film): nmax
2940, 1732, 1512, 1242 and 1037 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 6.93 (d, J¼9.1 Hz, 2H, ArH), 6.83 (d, J¼9.1 Hz, 2H, ArH), 4.82 (d,
J¼5.0 Hz, 1H, NCH), 4.18 (q, J¼7.1 Hz, 2H, OCH2), 4.07e3.98 (m, 2H,
OCH2), 3.76 (s, 3H, OCH3), 3.32e3.19 (m, 2H, OCH2), 2.93e2.88 (m,
1H, NCH2), 2.07e2.02 (m, 1H, NCH2), 1.89e1.75 (m, 2H, CH2),
1.72e1.62 (m, 1H, CH), 1.28 (t, J¼7.1 Hz, 3H, CH2CH3), 1.10 (t,
J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3): dC 172.3, 170.4,
153.5, 144.7, 118.6, 114.3, 61.7, 60.6, 60.5, 55.6, 44.5, 44.3, 24.5, 22.0,
14.2, 14.1; HRMS: (ESI) m/z found 336.1807 for C18H26NO5 (MHþ),
requires 336.1811.
4.8.42. (2R*,3S*)-2-(4-Chlorophenylamino)-3-vinylbutane-1,4-diol
(12c). Following the general procedure E described above, 12c was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼31:69) as colourless oil (54 mg, 45%): Rf (20%
EtOAc/Hexane) 0.17; IR (thin film): nmax 3373, 2926, 1599, 1496 and
1048 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 7.08 (d, J¼8.8 Hz, 2H,
ArH), 6.57 (d, J¼8.8 Hz, 2H, ArH), 5.74e5.65 (m, 1H, CH), 5.21e5.14
(m, 2H, CH2), 3.75e3.63 (m, 3H, NHCH, OCH2), 3.58e3.50 (m, 2H,
OCH2), 2.85 (br s, 1H, CH), 2.55e2.48 (m, 1H, CH); 13C NMR
(100 MHz, CDCl3): dC 146.0, 135.8, 129.3, 122.9, 119.2, 115.4, 63.9,
62.1, 56.8, 48.8; HRMS: (ESI) m/z found 242.0951 for C12H17ClNO2
(MHþ), requires 242.0948. (OH protons could not be detected
perhaps due to the rapid exchange among each other.)
4.8.47. (2R*,3S*)-2-Amino-3-ethylsuccinic acid hydrochloride (16)*.
To the N-aryl
a
-amino ester 10d0 (0.2 mmol, 1 equiv) in MeCN
(2 mL) was added aqueous solution of both (NH4)2S2O8 (2 equiv)
and ammonium ceric (III) nitrate (0.1 equiv) at 0 ꢀC. The resulting
reaction mixture was stirred for 3 h at 35 ꢀC. After this period, the
reaction mixture was washed with DCM (2 mL) and treated with
Na2CO3 to obtain the pH 7. Then, the product was extracted using
DCM (5ꢂ1 mL). The combined organic layers were dried over an-
hydrous Na2SO4. The solvent was evaporated under vacuum, which
gave a crude mixture. To this crude reaction mixture 6 N HCl (5 mL)
was added and refluxed for 3 h. After completion of the reaction,
the reaction mixture was cooled to rt and the solvent was removed
under vacuum that gave the product as colourless viscous liquid
(20 mg, 50%): IR (thin film): nmax 3562, 3060e2575, 1715 and
4.8.43. (2R*,3S*)-2-(p-Tolylamino)-3-vinylbutane-1,4-diol
(12d). Following the general procedure E described above, 12d was
obtained after purification by silica gel column chromatography
(EtOAc/Hexane¼29:71) as colourless oil (78 mg, 71%): Rf (20%
EtOAc/Hexane) 0.19; IR (thin film): nmax 3369, 2923, 1617, 1518 and
1256 cmꢁ1
;
1H NMR (400 MHz, CDCl3): dH 6.98 (d, J¼8.0 Hz, 2H,
ArH), 6.62 (d, J¼8.0 Hz, 2H, ArH), 5.75e5.66 (m, 1H, CH), 5.22e5.17
(m, 2H, CH2), 3.75 (dd, J1¼10.9 Hz, J2¼6.8 Hz, 1H, NHCH), 3.71e3.65
(m, 2H, OCH2), 3.58e3.51 (m, 2H, OCH2), 2.57e2.50 (m, 1H, CH),
2.23 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3): dC 144.9, 136.0,
130.0, 128.2,119.0,115.0, 64.5, 62.0, 57.7, 48.8, 20.4; HRMS: (ESI) m/z
found 222.1498 for C13H20NO2 (MHþ), requires 222.1494. (OH
protons could not be detected perhaps due to the rapid exchange
among each other.)
1273 cmꢁ1
;
1H NMR (400 MHz, D2O): dH 4.17 (d, J¼4.0 Hz, 1H,
NHCH), 3.07e3.02 (m, 1H, CH), 1.80e1.71 (m, 1H, CH2), 1.59e1.52
(m, 1H, CH2), 0.91 (t, J¼8.0 Hz, 3H, CH2CH3); 13C NMR (100 MHz,
D2O): dC 175.7, 53.1, 46.2, 21.1,11.0; MS (CI): m/z 162 (100, MHþ),144
(12), 101 (10%). HRMS: (ESI) m/z found 162.0777 for C6H12NO4
(MHþ), requires 162.0766. *(OH protons could not be detected
perhaps due to the rapid exchange among each other.) *The NMR
values given here for the major isomer and the NMR spectrum were
having some traces of minor diastereomer.
4.8.44. (2R*,3S*)-Diethyl 2-(allyl(4-methoxyphenyl)amino)-3-
vinylsuccinate (13). Following the general procedure F described
above, 13 was obtained after purification by silica gel column
chromatography (EtOAc/Hexane¼08:92) as colourless liquid
(90 mg, 50%): Rf (20% EtOAc/Hexane) 0.64; IR (thin film): nmax 2983,
1730, 1513, 1154 and 1036 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH 6.91
(d, J¼9.0 Hz, 2H, ArH), 6.75 (d, J¼9.0 Hz, 2H, ArH), 5.84e5.75 (m, 1H,
CH), 5.66e5.57 (m, 1H, CH), 5.27 (d, J¼17.1 Hz, 1H, CH2), 5.18 (d,
J¼10.2 Hz, 1H, CH2), 5.07 (d, J¼17.1 Hz, 1H, CH2), 5.00 (d, J¼10.2 Hz,
1H, CH2), 4.46 (d, J¼11.2 Hz, 1H, NCH), 4.09e3.91 (m, 5H, CH, OCH2),
3.83e3.73 (m, 2H, NCH2), 3.71 (s, 3H, OCH3), 1.17e1.12 (m, 6H,
CH2CH3); 13C NMR (100 MHz, CDCl3): dC 171.4, 169.3, 154.0, 142.1,
135.6, 131.9, 120.4, 120.3, 116.5, 114.0, 66.9, 61.0, 60.6, 55.4, 51.7,
49.5, 14.3, 14.1; HRMS: (ESI) m/z found 362.1959 for C20H28NO5
(MHþ), requires 362.1967.
Acknowledgements
This work was funded by the Fast Track Young Scientist Scheme,
DST, New Delhi. We thank the NMR and X-ray facilities of IISER-M.
N. A. A. and A. J. S. thank UGC and DST, New Delhi respectively, for
fellowships. We thank IICT-Hyderabad, CDRI-Lucknow and NIPER-
Mohali for providing the mass spectral data.
Supplementary data
Supplementary data (copy of 1H, 13C NMR, charts of all the
compounds and X-ray structure data of the compounds 3p, 3q, 3v
and 10h). Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.05.130.
4.8.45. (2R*,3S*)-Diethyl 1-(4-methoxyphenyl)-1,2,3,6-tetrahydro
pyridine-2,3-dicarboxylate (14). Following the general procedure
G described above, 14 was obtained after purification by silica gel
column chromatography (EtOAc/Hexane¼10:90) as colourless oil
(153 mg, 92%): Rf (20% EtOAc/Hexane) 0.63; IR (thin film): nmax
2983, 1736, 1512, 1248 and 1032 cmꢁ1; 1H NMR (400 MHz, CDCl3):
dH 6.90 (d, J¼9.3 Hz, 2H, ArH), 6.85 (d, J¼9.3 Hz, 2H, ArH), 6.25e6.21
(m, 1H, CH), 5.92e5.87 (m, 1H, CH), 5.04 (d, J¼5.0 Hz, 1H, NCH), 4.22
(q, J¼7.1 Hz, 2H, OCH2), 4.12e3.95 (m, 2H, OCH2), 3.79e3.75 (m, 2H,
NCH2), 3.77 (s, 3H, OCH3), 3.67 (br s, 1H, CH), 1.30 (t, J¼7.2 Hz, 3H,
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