Chiron based synthesis of isocoumarins: Reactivity of α-substituted carboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2014.03.019

The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling of homophthalic acid with (S)-N-protected amino acids and α-chloroacids at high temperature by exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with α-chloroacids afforded asymmetric isocoumarins in high yield.

Full text of DOI:10.1016/j.tetasy.2014.03.019

Tetrahedron: Asymmetry 25 (2014) 736–743
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiron based synthesis of isocoumarins: reactivity of
carboxylic acids
a-substituted
b
b
Aisha Saddiqa a, Abdul R. Raza a, , David StC. Black , Naresh Kumar
⇑
a Ibn e Sina Block, Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
b School of Chemistry, University of New South Wales, Sydney 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 January 2014
Accepted 24 March 2014
The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling
of homophthalic acid with (S)-N-protected amino acids and -chloroacids at high temperature by
exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino
a
acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with
acids afforded asymmetric isocoumarins in high yield.
a-chloro-
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
isocoumarins. Herein we report our studies towards the
asymmetric synthesis of functionalized isocoumarins by
employing this chiral pool strategy.
Isocoumarins are an important class of natural products that
have
a wide range of biological properties such as anti-
bacterial1,2 and anti-cancer3,4 activities. The diverse therapeutic
and pharmacological potential5,6 of the coumarin family has
attracted significant research efforts towards the synthesis and
isolation of these molecules.
2. Results and discussion
Our strategy for the asymmetric synthesis of chiral
isocoumarins utilizes a chiral pool methodology. Commercially
available and inexpensive (S)-amino acids 1 are converted into
N-protected (S)-amino acids 3–4, which are subsequently
transformed, in situ, to acid chlorides 5–6. Their coupling with
homophthalic acid 7 produced a mixture of isocoumarin 11 along
with the undesired side-products 8–10 (Scheme 1).
Asymmetric synthesis plays
a central role in synthetic
medicinal chemistry, since typically only one isomer of a drug
possesses the desired pharmacological properties, while the other
isomer(s) may be inactive or exhibit lethal/adverse side-effects.7,8
Consequently it is necessary to develop new synthetic strategies
towards chiral isocoumarins due to the importance of
enantiomeric purity in therapeutic applications.
2.1. Protection of (S)-amino acids
A number of synthetic routes towards substituted isocoumarins
have been reported in the literature. Heynekamp et al.
monoesterified a substituted homophthalic acid and lactonized
the resulting intermediate with PCl5 to obtain chloro and amino
substituted isocoumarins. The amino derivatives were found to
be potent inhibitors of blood coagulation serine proteases.9 Gosh
et al. carried out the asymmetric total synthesis of the
gastroprotective microbial agent 3,4-dihydroisocoumarin, AI-77-
B.10 Saeed et al. reported on the synthesis of 6,8-dimethoxy-3-
The (S)-amino acids 1a–e were N-protected in order to avoid
interference of the NH2-group in the coupling reactions. The
amino acids 1a–e were protected with phthalic anhydride12 or
BnCl13–18 (Scheme 1). In the N-phthaloyl protected amino acids
3a–c,e, the lone pair on the nitrogen atom is delocalized and is
not readily available for nucleophilic attack. On the other hand,
the nitrogen atom is sterically hindered in N-benzyl protected
amino acids 4a–e. Therefore, the nitrogen group should not
interfere with the coupling reaction in both types of N-protected
compounds.
phenylisocoumarin
by
condensation
of
3,5-dimethoxy-
homophthalic acid with BnCl at 200 °C.11 The chiron (also known
as the chiral pool) methodology for asymmetric synthesis has
rarely been used for the stereoselective synthesis of
2.2. Coupling of 5a–c,e and 6a–d with homophthalic acid 7
The protected amino acids 3a–c,e and 4a–d were converted into
their corresponding acid chlorides 5 and 6 by reaction with
SOCl2 at 60 °C. The acid chlorides 5 and 6 were then coupled
⇑
Corresponding author. Tel.: +92 48 600 7432; fax: +92 48 9230 799.
E-mail addresses: roofichemist2012@gmail.com, roofichemist@hotmail.com
(A.R. Raza).
http://dx.doi.org/10.1016/j.tetasy.2014.03.019
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
737
R
1-6
a
R
N(Bn)2
COOH
COOH
Me
f
X
+
R12N
O
COOH
iPr
b
c
iBu
O
7
8
1
2
3
4
R
1 = H, X = OH
1 = Bn, X = OBn
1 = Phth, X = OH
d
e
Bn
a
b
d,e
3'
3
(CH2)2SMe
R
O
R2
c
O
O
5
R3
R
1'
2''
N
3''
9a
R
2 =R3 = H
+
N
N
+
9b R2 = R3 = Me
S
1
O
4''
R
1 = Bn, X = OH
O
8
9c
R
2 = H, R3 = iPr
O
O
O
5 R1 = Phth, X = Cl
6 R1 = Bn, X = Cl
10
O
11
2a 2b 2c 2d 3a 3b 3c 3e 4a 4b 4c 4d
8
9a 9b 9c 10 11
60 67 64 65 70 75 78 80 75 78 82 68 60-64 70 65 60 76 30
*yield (%)
*5 and 6 were synthesized in situ and their yields were calculated.
Scheme 1. (a) BnCl, NaOH; (b) phthalic anhydride,
D, neat conditions; (c) aq KOH, reflux; (d) SOCl2, 60 °C; (e) 5, 200 °C (6 h), neat conditions; (f) 6, 200 °C (6 h), neat
conditions.
with homophthalic acid 7 by heating at 200 °C for 6 h. The major
product in the reactions of acid chlorides 5 with homophthalic
acid 7 were isoindoline-1,3-diones 9a–c, as identified by 1H NMR,
EIMS and X-ray diffraction (XRD). The 1H NMR spectrum of
compound 9a is presented in Figure 1. The other isoindoline-1,3-
diones 9b–c showed very similar 1H NMR spectra to 9a. The
same results were obtained when this reaction was repeated
under identical conditions but in the absence of 7, which
confirmed that 7 does not participate in the formation of 9a–c.
The synthesis of similar types of compounds has already been
reported by the photolysis of 3a–c.19
electron-deficient nature of the nitrogen atom, which favours the
elimination of CO and HCl to form the stable entity 9a–c
(Scheme 2).
The attempted reaction of acid chloride 5e with 7 yielded 2-
[(3S)-tetrahydrothiolane-2-one-3-yl]-2-benzazole-1,3-dione 10 as
the exclusive product. Since sulfur is a better nucleophile, it is
able to attack the acid chloride moiety of 5e in an intramolecular
fashion to generate a stable five membered heterocyclic ring
(Scheme 3).
Cl
O
O
O
O
Cl
+
S
-MeCl
10
N
N
S
O
O
5e
Scheme 3.
O
2'
The appearance of an intense molecular ion at 247 amu (26%)
and daughter fragments indicated the formation of 10. The XRD
and the presence of five protons (1H integration each) in the
aliphatic region that appeared as two sets of dddd at 2.58
(J = ꢀ12.3, 6.9, 5.4, 1.5 Hz) and 2.88 ppm (in 1:1:3:3:3:3:1:1,
J = ꢀ12.3, 12.3, 12.3, 7.2 Hz), a set of two ddd at 3.45 (J = ꢀ11.1,
7.5, 0.9 Hz) and 3.56 ppm (J = ꢀ11.1, 11.1, 5.4 Hz) and a dd at
N1'
O
9a
0
a
0
0
a
0
5.14 ppm (J = 12.9, 7.2 Hz) corresponding to H4 , Hb4 , H5 , Hb5 and
Figure 1. 1H NMR (300 MHz, CDCl3) signals showing Jcis and Jtrans of the olefinic
protons in 9a.
0
H3 respectively confirmed the structure of this heterocycle 10
(Fig. 2). Such thiolane/thiolactone based heterocycles exhibit a
wide variety of pharmacological activities (such as anticancer,20
insulin signalling inhibitor21,22).
The desired isocoumarin 11 was only produced in trace
amounts in these coupling reactions, except in the case of 5c
where 11 was produced as a minor product in poor yield (30%).
We hypothesized that the acid chlorides 5a–c may have
decomposed into the isoindoline-1,3-diones 9a–c at high
temperature via decarbonylation and dehydrohalogenation
processes (Scheme 2). This mechanism may be facilitated by the
The IR spectrum of isocoumarin 11 displayed
a broad
absorbance signal for both carbonyl groups at 1720 cmꢀ1
indicating the formation of the desired compound. The presence
of a molecular ion and a daughter fragment at 361 (12%) and
318 amu (19%), formed via b-cleavage of an iso-butyl radical,
respectively, in the EIMS is consistent with the proposed
structure of 11. In the NMR spectrum, the characteristic singlet
0
at 6.61 ppm corresponding to H4, the downfield shift of H1
(proton located at the asymmetric centre) to 5.35 ppm and the
O
O
O
R
0
diastereotopy exhibited by H2 (Fig. 3a) confirmed the formation
Cl
H
- CO
of the desired isocoumarin 11, albeit in poor yield (30%). Finally,
the structure of 11 was confirmed by XRD (Fig. 3b). The
synthesis of racemic 11 has already been reported on,24 but no
biological application has yet been reported although it is a
potential candidate for diverse bioactivity.1–6
N
N
- HCl
(200oC)
R
O
O
5a-c
9a-c
Scheme 2.

738
A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
X
H
H
COOH
COX
O
O
Cl
R
COOH
R
Bn2N
H
Bn2N
O
S
O
S
-HCl
7
O
O
8a
O
R = H, (Me)2, iPr, Ph
X = OH or Cl
R
X
O
8b
NBn2
O
S
COOH
-SO2
O
8
a
b
H4
H7
O
O
H5
H6
O
H5'
H5'
Scheme 4.
H4'
S
N
O
H4'
H3'
2.3. Synthesis of (S)-
a-chloro acids 12a–d
The (S)- -chloro acids were synthesized by diazotization of (S)-
a
amino acids 1a–d in very high ee by reaction with HCl and NaNO2
at ꢀ5 °C.26 Proceeding through two consecutive Walden
inversions, via anchimeric assistance of the carboxylic group, the
reaction resulted in a retention of configuration (Scheme 5).
Figure 2. (a) Selected 1H NMR signals of 10 showing extended diastereotopy of H-40
and H-50; (b) ORTEP diagram of 10.23
R
X
Cl
I
II
Y
O
O
R
-N2
R
Cl
O
O
O
1
H
I = first Walden inversion
II = second Walden inversion
X = NH2
X = +N2
12a-d Y = OH
13a-d Y = Cl
a
b
Scheme 5. (a) aq NaNO2, HCl (5 M), ꢀ5 °C (5 h) to ambient (overnight); (b) SOCl2,
60 °C (1 h).
The specific rotation and density of synthesized a-chloro acids
12a–d were measured neat and were consistent with reported
values (Table 1).26 The sign of the rotation confirmed the
predominance of the (S)-isomer of the synthesized acids 12a–d,
Figure 3. (a) Selected 1H NMR signals of 11 showing diastereotopy exhibited by
H
20
; (b) ORTEP diagram of 11.25
while the magnitude of [
a]
in comparison to the literature
D
values indicated the high enantiomeric purity of the products.
The structures of 12a–d were further supported by IR, NMR and
MS techniques. Acids 12a–d were then converted into their
respective acid chlorides 13a–d by heating with SOCl2.
Due to the difficulty in generating the desired isocoumarins
from N-phthaloyl (S)-amino acid chlorides 5a–c,e, the N-benzyl
protection of (S)-amino acids was investigated as an alternative
approach. The coupling of N,N-dibenzyl (S)-amino acid chlorides
6a–d with homophthalic acid 7 at 200 °C produced a single
product, as revealed by TLC analysis, which was established to be
2.4. Coupling of (S)-a-chloro acids 12a–d with 7
the novel N,N-dibenzyl homophthalamide
required isocoumarin. In the EIMS spectrum of 8, the base peak
of the tropylium ion and intense signals of daughter fragments,
8 instead of the
Table 1
Comparison of the yield, density and specific rotation of the reported and synthesized
12a–d
formed by
a-cleavage of the dibenzylamino radical followed by a
20b
26
12
Yielda (%)
Reported Actual
d4
(g/cm3)
[a]
D
loss of CO, at 91 (100%), 163 (33%) and 135 (31%) supports the
proposed structure of 8. Additionally, the structure of 8 was
consistent with the appearance of three singlets (each 2H) at
4.06, 5.07 and 5.22 ppm and a multiplet integrating to 10H at
7.27–7.34 ppm.
Reported
Actual
Reported (ee)
Actual
a
b
c
64
62
58
—
6
5
4
70
65
60
59
1.265
1.140
1.082
—
1.23
1.10
1.05
1.85
ꢀ14.0 (95.6%)
ꢀ1.4 (97.7%)
ꢀ31.7 (95.8%)
—
ꢀ13.8c
ꢀ1.4c
ꢀ30.9c
ꢀ6.85d
d
In the proposed mechanism for the formation of 8, the nitrogen
atom of 6a–e reacts with SOCl2 to generate
a
Stirring of 1a–d with 2 equiv of NaNO2 and 5 N HCl overnight at ꢀ5 °C to
ambient.
a quaternary
ammonium intermediate. This undergoes an intermolecular
rearrangement reaction with homophthalic acid 7 to yield a
sulfinic anhydride species 8a, which subsequently eliminates 2-
enoic acid 8b and SO2 to generate compound 8 (Scheme 4). The
enoic acid 8b formed (R = Ph, cinnamic acid) was extracted and
isolated from the aqueous layer. Its Rf and melting point were
found to be in agreement with cinnamic acid, which supports the
proposed mechanism. The steric hindrance around the nitrogen
atom in 6a–e did not prevent the atom from acting as an
effective nucleophile.
b
Density of neat and degassed liquid calculated at 34 2 °C.
c
Neat liquids in 1.0 dm cell.
EtOAc in a 1.0 dm cell.
d
To investigate whether the a-nitrogen atom directs the reaction
mechanism for the formation of 8, we investigated the coupling
reaction between homophthalic acid 7 and (S)- -chloro acids
12a–d, which possess the less nucleophilic Cl atom. The acid
chloride 13a–d was heated with 7 for 6 h at 200 °C affording a
single product in each case in good yield (60–70%) (Scheme 6).
a

A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
739
O
11
O
O
+
+
O
9
O
O
O
Y
4a
R
R
COOH
COOH
-R
6
-CO
X
3
c
+
R
8
O
1
O
O
O
O
14a-d
O
O
O
O
1a-d X = OH, Y = NH2
7
a
Cl
R
12
13
1, 12-15
X = OH, Y = Cl
X = Y = Cl
.
b
[M.+
]
A [M-R.]
B
[M-R -CO]
c
a
CH3
R
m/z = 201 amu
m/z = 173 amu
iPr
b
c
O
iBu
Scheme 7. General mass fragmentation pattern of 14a–d.
O
d
15a-d
Bn
Scheme 6. (a) NaNO2, HCl; (b) SOCl2, 60 °C; (c) 200 °C (6 h), neat conditions.
highly stabilized by resonance, which could explain its high
abundance in the EIMS spectra. The spectroscopic data of 14a–d
are summarized in Table 2.
The characteristic singlet for H4 of the isocoumarin scaffold was
not observed in the 1H NMR spectrum of the products, thus
suggesting that the substituent on C4 was not a hydrogen atom.
In the EIMS spectrum, the molecular ion peak appeared 7.5 amu
higher than that expected for the targeted isocoumarins 15a–d.
Furthermore, the absence of the [M] and [M+2] peaks in a 3:1
pattern indicated the absence of the chlorine atom in the
products. Finally, the sharp IR absorption signal at around
It is proposed that the formation of 14 first involves
nucleophilic substitution at the carbonyl carbon of 13 to generate
the intermediate 16, which undergoes two successive
intramolecular cyclization processes accompanied by the
elimination of HCl and H2O to produce 3H-furo[3,4-
c]isochromene-1,5-dione derivatives 14a–d (Scheme 8). The
aromatization of 17 to 14 is anticipated to be the driving force
for the second step of the mechanism. Assuming an
intermolecular cyclization process for 17 involving a Walden
inversion, the probability of racemization in products 14a–d is
likely to be negligible.
1753 cmꢀ1 suggests the presence of
a lactone ring. These
unexpected spectroscopic results indicate that the targeted
isocoumarins 15a–d are not formed, and suggests that the 3H-
furo[3,4-c]isochromene-1,11-dione
derivatives
14a–d
are
Ultimately, the structures of compounds 14a and 14d were
confirmed by X-ray diffraction studies (Fig. 5, Table 3),25 which
clearly showed different bond lengths for pyrone (1.189 and
1.207) and lactone (1.209 and 1.208) C@O bonds for 14a and 14d
respectively. The absolute stereochemistry of the products
observed in the X-ray crystal structures confirmed that in the
second cyclization process, the bicyclic intermediate 17
underwent Walden inversion.
produced instead. Such a compound, where R = H, is already
reported in the literature.27 In the 1H NMR spectrum of 14a–d,
the alkyl group appears at 1.00–3.50 ppm (Fig. 4a), while the
asymmetric proton H9 appears at 5.20–5.45 ppm (Fig. 4b). The
appearance of [M+] and fragment signals, formed by the removal
of an alkyl group (cation A, 201 amu) followed by CO elimination
(cation B, 173 amu) provides strong evidence of the formation of
these isocoumarins 14a–d (Scheme 7, Fig. 4c and d). Cation B is
0
Figure 4. 1H NMR signals showing (a) R substituents of 14c; (b) diastereotopy exhibited by H1 of 14d; EIMS signals for [M]+ and daughter fragments at 201 and 173 amu for
(c) 14c and (d) 14d.

740
A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
Table 2
Spectroscopic data for 14a–d
22a
14
Yield (%)
Mp (°C)
[
a
]
(c)
logeb (kmax, nm)
mc (C@O)
Selected ionsd (% abundance)
dH of diagnostic protonsf (ppm)
D
´
[M+]
[M+ꢀR]e
[M+ꢀR–CO]
H9
H1
H5g
H6h
H7h
H8g
a
b
c
70
60
65
70
165
67
59
+18.0 (1.0)
+10.0 (1.0)
+26.0 (1.0)
ꢀ14.0 (1.0)
4.0692 (317)
3.4074 (327)
3.8803 (317)
3.2655 (317)
1753
1750
1753
1736
216 (35)
244 (2)
258 (32)
292 (10)
—
201 (2)
201 (84)
201 (2)
173 (89)
173 (59)
173 (100)
173 (36)
5.27
5.20
5.21
5.42
1.67
1.90
1.66, 1.91
3.18, 3.47
8.32
8.58
8.31
8.29
7.62
7.53
7.61
7.59
7.86
7.63
7.86
7.81
8.28
8.51
8.28
8.17
d
90
a
b
c
All specific rotations are calculated in CHCl3 in a 10 cm length cell.
Calculated in CHCl3.
cmꢀ1
.
d
e
f
See Scheme 7.
i
i
R = CH3, Pr, Bu, Bn.
Recorded in CDCl3 on a 400 MHz instrument.
Shows doublet in all cases.
Shows triplet in all cases.
g
h
H
O
O
O
O
O
OH
O
O
OH
R
O
O
R
H
O
R
- HCl
R
- HCl
- H2O
Cl
Cl
Cl
OH
O
Cl
13
H
COOH
O
O
O
16
17
7
14a-d
Scheme 8.
9a–c, whereas N-dibenzyl (S)-amino acid chlorides 6a–d reacted
with homophthalic acid 7 to produce the novel N,N-dibenzyl
homophthalamide 8. (S)-
with homophthalic acid 7 in the presence of SOCl2 to generate
3H-furo[3,4-c]isochromene-1,5-dione derivatives. Therefore,
a-Chlorocarboxylic acids 12a–d coupled
these studies are helpful for selecting the appropriate type of
carboxylic acid required for coupling reactions with
homophthalic acid 7 at high temperature in order generated the
desired products. Further studies on the coupling reactions of
chiral carboxylic acids with homophthalic acid 7 under basic
conditions, at low temperature, are currently under investigation.
4. Experimental
General: TLC was carried out on a pre-coated silica gel (0.25 mm
thick layer over Al sheet, Merck) with a fluorescent indicator. The
spots were visualized under UV lamps (k = 365 and 254 nm, 8 W)
or by KMnO4 dip with heating. The compounds were purified
either on a glass column packed silica gel (0.6–0.2 mm, 60 Å
mesh size, Merck) or by crystallization. All solutions were
concentrated under reduced pressure (25 mm Hg) on a rotary
evaporator (Laborota 4001, Heidolph) at 35–40 °C. Melting points
were determined using a MF-8 (Gallenkamp) instrument and are
uncorrected. The specific rotations were determined using an
automatic AP-300 polarimeter (Atago). The IR-spectra were
recorded on a Prestige 21spectrophotometer (Shimadzu) as KBr
discs. LR EIMS was carried out on a MAT 312 machine. The 1H
NMR was recorded either on an AM-300 or 400 MHz instrument
(Bruker) in CDCl3 or CD3OD using TMS as an internal standard.
Figure 5. ORTEP diagram of 14a (top) and 14d (bottom).
3. Conclusions
In conclusion, the coupling reaction of homophthalic acid 7
with -substituted carboxylic acids and SOCl2 at high
a
4.1. General procedure for the preparation of N-protected
temperature did not, in most cases, lead to the formation of an
isocoumarin. Instead, different products were formed depending
on the manner in which the NH2 moiety was protected, or the
presence or absence of a nitrogen group. The N-phthaloyl (S)-
amino acid chlorides 5a–c,e underwent decarbonylation and
dehydrohalogenation processes to yield isoindoline-1,3-diones
amino acids, 3a–c and 3e
The (S)-amino acids 1a–c and 1e (1 mmol, 1 equiv) and phthalic
anhydride (1.5 mmol, 1.5 equiv) were heated together at 130–
160 °C. After completion of the reaction, the unreacted phthalic
anhydride was scraped off from the walls of the flask and the

A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
741
Table 3
Selected crystal data, geometrical and structure refinement parameters for 14a and 14d25
Geometrical parameters of
14a 14d
Bond distances (Å)
Crystal data and structure refinement parameters
Identification codes
14a
14d
Identification codes
14a
14d
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Monoclinic
P21/c
Monoclinic
P21/c
Theta range
2.4–26.0°
2.7–26.0°
C1AO1
C1AO2
C11AO3
C11AO4
1.189(2)
1.409(2)
1.209(2)
1.363(3)
1.207(6)
1.396(5)
1.208(6)
1.368(6)
Crystal size (mm3)
Absorption correction
Refinement method
Tmin, Tmax
0.35 ꢁ 0.18 ꢁ 0.16
Multi-scan
F2
0.962, 0.982
1902/0/146
0.38 ꢁ 0.20 ꢁ 0.18
Multi-scan
F2
0.963, 0.982
2723/0/202
8.6026(9)
10.4509(11)
10.9791(13)
97.338(4)
978.99(19)
4
14.753(2)
15.390(2)
6.2415(9)
100.531(8)
1393.2(4)
4
Bond angles (°)
O1AC1AO2
C1AO2AC9
O3AC11AO4
O4AC11AC3
b (°)
Reflections/restraints/
parameter
115.5(2)
117.7(1)
121.1(2)
108.8(2)
115.6(4)
118.0(4)
121.1(4)
108.4(4)
Volume (Å3)
Z
R[F2 >2
r
(F2)], wR(F2), S
0.041, 0.111, 1.01
0.17, ꢀ0.17
0.069, 0.187, 0.97
0.44, ꢀ0.22
F(000)
448
608
D
qmax
,
D
qmin (e Åꢀ3
)
Table 4
Conditions for the synthesis of 3a–c and 3e
4.1.4. (2S)-4-Methylthio-2-(1,3-dioxo-2-benzazole-2-yl)butanoic
acid 3e
Colourless prisms. (2.92 g, 80%), mp 132 °C, Rf: 0.71 (EtOH);
D
3
T (°C)
Reaction duration (min)
Crystallization
[a
]
29 = ꢀ60 (c 1.5, EtOAc); mmax (cmꢀ1): 3462 (O–H), 1728 (br s,
Solvent
Ratio
both carboxylic and amido C@O); log
e (kmax, nm): 3.2390
a
b
c
160
121
127
132
90
60
60
EtOH/H2O
8:2
1:2
1:1
7:3
(297.5); dH (400 MHz, CD3OD, in ppm): 2.04 (3H, s, SCH3), 2.5
(4H, m, H3s and H4s), 5.10 (1H, t, J = 7.2 Hz, H2) and 7.81–7.89
(4H, m, aromatic Hs); LR EIMS m/z in amu (% abundance): 279
(7) [M]+Å and 205 (84) [MꢀCH3SCH=CH2, A]+Å.
n-Hexane/EtOAc
MeOH/H2O
MeOH/H2O
e
120
crude acid that remained in the flask was purified by
crystallization, from different solvents, to afford pure crystals of
3a–c, e (Table 4).
4.1.5. (2S)-2-Dibenzylaminocarboxylic esters and acids 4a–d13
4.2. General procedure for the coupling of homophthalic acid 7
with 5a–d
4.1.1. (2S)-2-(1,3-Dioxo-2-benzazole-2-yl)propanoic acid 3a
Colourless prisms (2.5 g, 70%), mp 160 °C, Rf: 0.28 (EtOAc);
A mixture of (2S)-N protected carboxylic acids 3a–d (1 mmol,
1 equiv) and SOCl2 (1.1 mmol, 1.1 equiv) was heated at 60 °C for
1 h under dry conditions to afford acid chlorides 5a–c.
Homophthalic acid 7 (0.25 mmol, 0.25 equiv) was added and the
reaction mixture was heated at 200 °C for 6 h. The crude product
was poured into chilled water (20 mL) and partitioned with
EtOAc (3 ꢁ 25 mL). The organic phase was dried over anhydrous
Na2SO4, the mixture was filtered, and the solvent was removed
under reduced pressure. The residue was subjected to column
chromatography with EtOAc and n-hexane as the mobile phase
to give crystals of 9a–c, 10 and 11.
[
a
]
29 = ꢀ32.0 (c 1.5, EtOAc); mmax (cmꢀ1): 1720 (C@O); log
e (kmax,
D
nm): 3.2003 (295.5); dH (400 MHz, CD3OD, in ppm): 1.65 (3H, d,
J = 7.2 Hz, H3), 4.94 (1H, q, J = 7.2 Hz, H2) and 7.80–7.90 (4H, m,
aromatic Hs); LR EIMS m/z in amu (% abundance): 219 (21) [M]+Å,
175 (86) [MꢀCO2]+Å and 174 (100) [MꢀÅOHꢀCO]+.
4.1.2. (2S)-3-Methyl-2-(1,3-dioxo-2-benzazole-2-yl)butanoic
acid 3b
White needles. (5.12 g, 75%), mp 121 °C, Rf: 0.5 (EtOAc);
[a]
29 = +28.5 (c 1.5, EtOAc); mmax (cmꢀ1): 3489 (br s, O–H), 1732
D
(br s, both carboxylic and amido C@O); log
e (kmax, nm): 3.3449
(298.5); dH (400 MHz, CD3OD, in ppm): 0.88 (3H, d, J = 6.8 Hz,
H4), 1.14 (3H, d, J = 6.4 Hz, CH3 at C3), 2.69 (1H, 8 signals with
1:7:21:35:35:21:7:1 ratio, J = 6.8 Hz, H3), 4.52 (1H, d, J = 8 Hz, H2)
and 7.82–7.89 (4H, m, aromatic Hs); LR EIMS m/z in amu (%
abundance): 247 (13) [M]+Å, 205 (14) [Mꢀpropene]+, 204 (10)
4.2.1. 2-Ethenyl-2-benzazole-1,3-dione 9a
The crude product was purified by column chromatography and
elution with 2% EtOAc in n-hexane (500 mL) afforded 9a (4.00 g,
70%) as colourless prisms. Rf: 0.72 (EtOAc/n-hexane, 2:8); mmax
(cmꢀ1): 1710 (C@O); dH (300 MHz, CDCl3, in ppm): 5.09 (1H, d,
i
[Mꢀ PrÅ]+, 203 (34) [MꢀCO2, A]+Å, 202 (100) [MꢀÅOHꢀCO]+Å and
0
0
i
160 (35) [Aꢀ PrÅ]+.
J = 9.9 Hz, H2 cis), 6.13 (1H, d, J = 16.5 Hz, H2 trans), 6.92 (1H, dd,
0
J = 16.2, 9.6 Hz, H1 ), 7.77–7.82 (2H, m, H4and7) and 7.89–7.93 (2H,
m, H5and6); LR EIMS m/z in amu (% abundance): 173 (30) [M]+Å.
4.1.3. (2S)-4-Methyl-2-(1,3-dioxo-2-benzazole-2-yl)pentanoic
acid 3c
White needles. (2.75 g, 78%), mp 127 °C, Rf: 0.47 (EtOAc);
D
4.2.2. 2-(20-Methylprop-10-enyl)-2-benzazole-1,3-dione 9b
The crude product was purified by column chromatography by
using 1% EtOAc in n-hexane as eluent, which afforded 9b (720 mg,
65%) as colourless needles. mp 65 °C, Rf: 0.64 (EtOAc/n-hexane,
[
a]
29 = ꢀ44 (c 1.5, EtOAc); mmax (cmꢀ1): 3483 (O–H), 1718 (br s,
both caboxylic and amido C@O); log
e (kmax, nm): 2.4659 (297)
2.2357 (253); dH (400 MHz, CD3OD, in ppm): 0.92 (3H, d, J = 6.8,
H5), 0.94 (3H, d, J = 6.8 Hz, Hz, CH3 at C4), 1.47 (1H, m, H4), 1.93
2:8); mmax (cmꢀ1): 1720 (C@O); log
e (kmax, nm): 3.2249 (298.5);
0
(1H, ddd, J = ꢀ14.4, 10.0, 4.4 Hz, H3), 2.31 (1H, ddd, J = ꢀ14.2,
a
dH (400 MHz, CDCl3, in ppm): 1.65 (3H, d, J = 1.2 Hz, H3 ), 1.90
11.4, 4.4 Hz, H3b), 4.90 (1H, dd, J = 11.6, 4.4 Hz, H2), 7.81–7.85 (2H,
10
0
0
´
m, H5 s) and 7.86–7.89 (2H, m, H4 s); LR EIMS m/z in amu (%
abundance): 261 (16) [M]+Å, 217 (35) [MꢀCO2, A]+Å, 216 (94)
[MꢀÅOHꢀCO]+ and 205 (36) [Mꢀmethylpropene]+Å.
(3H, d, J = 1.2 Hz, CH3 at C2), 5.87 (1H, m, H ), 7.70–7.72 (2H, m,
H5and6) and 7.84–7.86 (2H, m, H4and7); LR EIMS m/z in amu (%
abundance): 201 (100) [M]+Å.

742
A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
4.2.3. 2-(30-Methylbut-10-enyl)-2-benzazole-1,3-dione 9c
The crude product was purified by column chromatography and
elution with 1% EtOAc in n-hexane afforded 9c (3.53 g, 60%) as
yellow crystalline solid. mp 68 °C, Rf: 0.85 (EtOAc/n-hexane, 1:1);
4.4. General procedure for the synthesis 2-chlorooacids 12a–d23
The (S)-amino acids (10mmol, 1 eq) were dissolved in HCl
(26mL of 13M) and temperature of solution was maintained
below ꢀ5 oC. The chilled aq. NaNO2 (20mmol, 2.0eq) was added
as drops to this solution and temperature was controlled below
0 °C and stirred for 5h in ice bath. The ice bath was removed and
the solution was stirred overnight, extracted with EtOAc
(3 ꢁ 25mL) at highly acidic pH. The organic extract was
concentrated which afforded yellow oily products 12a–d which
was further concentrated under N2.
mmax (cmꢀ1): 1713 (C@O); log
e (kmax, nm): 2.4461 (336), 2.8978
(297); dH (300 MHz, CDCl3, in ppm): 1.12 (6H, d, J = 6.9 Hz, CH3 at
0
0
0
C30 and H4 s), 2.45 (1H, m, H3 ), 6.61 (1H, J = 2.4 Hz, H1 ), 6.62 (1H,
0
J = 3.3 Hz, H2 ), 7.74 (2H, m, H4 and H7) and 7.87 (2H, m, H5 and
H6); LR EIMS m/z in amu (% abundance): 215 (44) [M]+Å, and 200
(100) [MꢀÅCH3]+.
4.2.4. 2-[(30S)-2-Oxothiolan-30-yl]-2-benzazole-1,3-dione 10
The crude product was purified by column chromatography and
elution with 6% EtOAc in n-hexane afforded 10 (1.04 g, 76%) as
4.4.1. (2S)-2-Chloro-3-methylbutanoic acid 12a23
4.4.2. (2S)-2-Chloro-3-methylbutanoic acid 12b
colourless needles. mp 164 °C, Rf: 0.66 (CHCl3); [
a
]
24 = ꢀ4.0 (c
Colorless oil (0.85 mL, 0.96 g, 71%); d (g/cm3): 1.14; Rf: 0.39
D
1.0, CHCl3); mmax (cmꢀ1): 1701 (bs, C@O); log
e
(kmax, nm): 3.3771
(EtOAc/ n-hexane 7:3); [a]
30 = –29.4 (c 1.90, EtOAc); tmax (cm-1):
D
(297.5); dH (300 MHz, CD3OD, in ppm): 2.58 (1H, dddd, J = ꢀ12.3,
3435 (OAH), 1728 (C@O), 694 (CACl); dH (300 MHz, CDCl3, in
ppm) 0.97 (3H, d, J = 6.6 Hz, CH3), 0.99 (3H, d, J = 6.6 Hz, CH3),
2.01 (1H, hep, J = 6.6 Hz, H3), 3.42 (1H, d, J = 6.6 Hz, H2), 11.53
(1H, s, OH); ESI MS (m/z, amu): 137.0358 [M+H]+ & 139.0536
[(M+2)+H]+ in 3:1.
0
6.9, 5.4, 1.5 Hz, H5 ), 2.88 (1H, dddd, J = ꢀ12.3, 12.3, 12.3, 7.2 Hz,
a
0
0
H5 b), 3.45 (1H, ddd, J = ꢀ11.1, 7.5, 0.9 Hz, H4 ), 3.56 (1H, ddd,
a
0
0
J = ꢀ11.1, 11.1, 5.4 Hz, H4 b), 5.14 (1H, dd, J = 12.9, 7.2 Hz, H3 )
and 7.84–7.92 (4H, m, aromatic Hs); LR EIMS m/z in amu (%
abundance): 247 (26) [M]+Å and 219 (100) [MꢀCO]+Å.
4.4.3. (2S)-2-Chloro-4-methylpentanoic acid 12c
Colorless oil (0.77 mL, 0.83 g, 80%); d (g/cm3): 1.09; Rf: 0.54
4.2.5. (10S)-3-[30-Methyl-10-(100,300-dioxo-2-benzazole-2-yl)butyl]
isocoumarin 11
(EtOAc/ n-hexane 1:1); [
a
]
30 = ꢀ34.4 (c 1.80, EtOAc); tmax (cm-1):
D
2954 (OAH), 1725 (C@O), 732 (CACl); dH (300 MHz, CDCl3, in
ppm): 0.96 (3H, d, J = 6.6 Hz, CH3), 0.99 (3H, d, J = 6.3 Hz, CH3),
1.53–1.60 (3H, m, H3 & H4), 4.21 (1H, dd, J = 8.7, 4.8 Hz, H2),
10.60 (1H, s, OH).
The crude product was purified by column chromatography and
elution with 7% EtOAc in n-hexane afforded 11 as a colourless
crystalline solid. (300 mg, 30%), mp 173 °C, Rf: 0.70 (EtOAc/n-
hexane, 1:4); [
s, of both lactonic and lactamic C@O); log
a
]
25 = ꢀ22.0 (c 0.2, DMSO); mmax (cmꢀ1): 1720 (br
D
e (kmax, nm): 3.5559
4.4.4. (2S)-2-Chloro-3-phenylpropanoic acid 12d
(323) and 3.5746 (306 nm); dH (300 MHz, CDCl3, in ppm): 1.02
Colorless oil (6.0 mL, 7.60 g, 83%); d (g/cm3): 1.27; Rf: 0.35
0
0
(6H, d, J = 6.3 Hz, Me at C30 and H4 ), 1.64 (1H, m, H3 ), 1.99 (1H,
30 = ꢀ6.00 (c 2.10, EtOAc); tmax (cmꢀ1):
0
ddd, J = ꢀ13.2, 9.0, 4.2 Hz, H2 ), 2.55 (1H, ddd, J = ꢀ13.8, 11.1,
(EtOAc/n-hexane 7:3); [
3437 (OAH), 1730 (C@O), 702 (CACl); log
a
]
D
a
0
0
4.5 Hz, H2 b), 5.35 (1H, dd, J = 11.3, 4.2 Hz, H1 ), 6.61 (1H, s, H4),
7.44 (1H, d, J = 7.8 Hz, H5), 7.50 (1H, ddd, J = 7.5, 7.5, 0.9 Hz, H7),
e (kmax, nm): 4.09849
(260); dH (300 MHz, CDCl3, in ppm) 3.27 (1H, dd, J = ꢀ14.4,
7.8 Hz, H3 ), 3.48 (1H, dd, J = ꢀ14.1, 6.6 H3b), 4.60 (1H, t, J = 7.5,
7.71 (1H, ddd, J = 7.5, 7.5, 1.2 Hz, H6), 7.76 (2H, m, H4 and H700),
00
a
H2), 7.32–7.44 (5H, m, Ph), 11.54 (1H, bs, OH).
7.88 (2H, m, H5 and H600) and 8.25 (1H, d, J = 7.8 Hz, H ); LR
8
00
EIMS m/z in amu (% abundance): 361 (12) [M]+Å, 318 (19)
[Mꢀ PrÅ]+, 304 (14) [Mꢀ BuÅ]+ and 214 (17) [Mꢀphthalamide]+Å.
i
i
4.5. General procedure for the coupling of homophthalic acid 7
with 13a–d
4.3. General procedure for the coupling of homophthalic acid 7
with 6a–d
A
mixture of (2S)-2-alkyl-2-cholorocarboxylic acids 12a–d
(1 mmol, 1 equiv) and SOCl2 (1.1 mmol, 1.1 equiv) was heated at
60 °C for 1 h under dry conditions to afford acid chlorides 13a–d;
the excess SOCl2 was removed in vacuo. Homophthalic acid 7
(1.0 g, 5.5 mmol, 1 equiv) and 13a–d (22 mmol, 4 equiv) were
heated to 200 °C at reflux for 6 h with continuous stirring. The
reaction mixture was cooled and partitioned between H2O
(20 mL) and EtOAc (3 ꢁ 25 mL). The combined organic extract
was dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residual mass was purified by
column chromatography on silica gel using 2% EtOAc in n-hexane
as the mobile phase to afford 14a–d as a crystalline product.
A mixture of 4a–d (1 mmol), prepared by a previously described
method,14,15 and SOCl2 (1.2 mmol) was heated at 60 °C for 1 h and
concentrated in vacuo to remove the excess SOCl2 to afford 6a–d.
The reaction mixture was used in the next step without further
purification. Homophthalic acid 7 (0.25 mmol) was added and
the reaction mixture was heated at 200 °C at reflux for 6 h with
continuous stirring. The reaction mixture was partitioned
between H2O (20 mL) and EtOAc (3 ꢁ 25 mL). The combined
organic extract was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residual mass was
purified by column chromatography on silica gel using 1% EtOAc
in n-hexane as the mobile phase to afford 2-[(N,N-
dibenzylcarbamoyl)methyl]benzoic acid 8 (60–64%) as a white
powder. mp 90 °C, Rf: 0.70 (EtOAc/n-hexane, 2:8); mmax (cmꢀ1):
4.5.1. (9R)-9-Methyl-3H-furo[3,4-c]isochromene-1,11-dione 14a
White cubical crystals (940 mg, 70%), mp 165 °C, Rf: 0.50
(EtOAc/n-hexane, 1:2.3); [
a]
22 = +18.0 (c 1.0, CHCl3); mmax (cmꢀ1):
D
1753 (lactonic C@O); log
e
(kmax, nm): 4.0692 (317) and 3.3916
3040 (OAH), 1734 (HOC@O), 1680 (NC@O); log
e (kmax, nm):
0
´
3.6594 (318); dH (400 MHz, CDCl3, in ppm): 4.06 (2H, s, H1 ), 5.07
(2H, s, N–CH2), 5.22 (2H, s, NACH2), 7.27–7.34 (10H, m, aromatic
Hs of Bn), 7.35–7.38 (2H, m, H3 and H5), 7.46 (1H, ddd, J = 7.6,
7.6, 1.2 Hz, H4) and 8.40 (1H, d, J = 7.2 Hz, H6); LR EIMS m/z in
amu (% abundance): 163 (33) [MꢀÅNBn2, A]+, 135 (31)
[MꢀAꢀCO]+ and 91 (100) [PhCH2]+.
(258 nm); dH (400 MHz, CDCl3, in ppm): 1.67 (3H, d, J = 6.8 Hz,
0
H1 s), 5.27 (1H, q, J = 6.8 Hz, H9), 7.62 (1H, t, J = 7.6 Hz, H7), 7.86
(1H, t, J = 7.2 Hz, H6), 8.28 (1H, d, J = 7.2 Hz, H5) and 8.32 (1H, d,
J = 7.2 Hz, H8); dC (100 MHz, CDCl3, in ppm): 176.2, 169.1 (C1,
C11), 160.1 (C3), 137.5 (C8a), 136.2 (C8), 134.7 (C4a), 131.1 (C6),
130.8 (C4), 129.6 (C5), 123.1 (C7), 73.9 (C9) and 17.5 (Me at C9);

A. Saddiqa et al. / Tetrahedron: Asymmetry 25 (2014) 736–743
743
LR EIMS m/z in amu (% abundance): 216 (35) [M]+Å and 173 (89)
Acknowledgments
[MꢀÅCH3ꢀCO]+.
The authors are obliged to the Higher Education Commission,
Government of Pakistan for their generous support of a research
project (HEC 1419), fellowship, IRSIP award to Ms. Aisha Saddiqa
(053-00063-Ps3-283) and financial assistance for EIMS and NMR-
analyses. The authors are also grateful to the Department of Phys-
ics, University of Sargodha for a single crystal XRD facility.
4.5.2. (9R)-9-(10-Methylethyl)-3H-furo[3,4-c]isochromene-1,
11-dione 14b
White needles (980 mg, 60%), mp 67 °C, Rf: 0.62 (EtOAc/n-
hexane, 1:2.3); [a] e (kmax, nm):
22 = +10.0 (c 1.0, CHCl3); log
D
3.4074 (327); mmax (cmꢀ1): 1753 (C@O); dH (400 MHz, CDCl3, in
0
0
ppm): 1.69 (6H, d, J = 6.4 Hz, H2 and CH3 at C1 ), 2.95 (1H, m,
0
H1 ), 5.20 (1H, d, J = 6.4 Hz, H9), 7.53 (1H, t, J = 7.6, H6), 7.63 (1H,
t, J = 7.4 Hz, H7), 8.40 (1H, d, J = 7.2 Hz, H5) and 8.51 (1H, d,
J = 8.4 Hz, H8); dC (100 MHz, CDCl3, in ppm): 170.0, 168.0 (C1,
C11), 160.5 (C3), 136.0 (C8), 135.0 (C6), 129.6 (C4), 127.0, 122.5
References
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was obtained by Prof. Dr. Muhammad Nawaz Tahir, Department of Physics,
University of Sargodha, Sargodha, Pakistan. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
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´
(C5, C7), 119.6 (C8a), 103.5 (C4a), 60 (C9), 45.0 (C1), 25.0 and
+Å
´
23.9 (C2, Me); LR EIMS m/z in amu (% abundance): 244 (2) [M] ,
201 (2) [Mꢀ PrÅ]+ and 173 (59) [Mꢀ PrÅꢀCO]+.
i
i
4.5.3. (9R)-9-(20-Methylpropyl)-3H-furo[3,4-c]isochromene-1,
11-dione 14c
White cubical crystals (950 mg, 65%), mp 59 °C, Rf: 0.60 (EtOAc/
n-hexane, 1:2.3); [a] e (kmax, nm):
22 = +26.0 (c 1.0, CHCl3); log
D
3.8803 (317); mmax (cmꢀ1): 1753 (lactonic C@O); dH (400 MHz,
0
CDCl3, in ppm): 1.02 (3H, d, J = 6.4 Hz, H3 ), 1.04 (3H, d, J = 6.8 Hz,
10
´
CH3 at C2), 1.66 (1H, ddd, J = ꢀ14.8, 9.6, 5.2 Hz, H ), 1.91 (1H,
a
0
0
ddd, J = ꢀ14.0, 8.4, 3.6 Hz, H1 b), 2.03 (1H, m, H2 ), 5.21 (1H, dd,
J = 9.6, 3.2 Hz, H9), 7.61 (1H, t, J = 7.6, H6); 7.86 (1H, t, J = 7.6 Hz,
H7), 8.28 (1H, d, J = 8.0 Hz, H5) and 8.31 (1H, d, J = 8.0 Hz, H8); dC
(100 MHz, CDCl3, in ppm): 173.0, 167.0 (C1, C11), 160.0 (C3),
136.2 (C8), 131.0 (C6), 130.7 (C4), 129.6, 123.1 (C5, C7), 119.1
´
´
(C8a), 102.5 (C4a), 57.1 (C9), 41.0 (C1), 25.1 (C2), 23.0 and 21.9
(C3, Me); LR EIMS m/z in amu (% abundance): 258 (32) [M] , 201
+Å
´
i
i
(84) [Mꢀ BuÅ]+ and 173 (100) [Mꢀ BuÅꢀCO]+.
4.5.4. (9R)-9-Benzyl-3H-furo[3,4-c]isochromene-1,11-dione 14d
White needles (1.20 g, 70%), mp 70 °C, Rf: 0.64 (EtOAc/n-hexane,
1:2.3); [
a
]
22 = ꢀ14.0 (c 1.0, CHCl3); log
e (kmax, nm): 3.2655 (317);
mmax (cmꢀ1D): 1735 (C@O); dH (400 MHz, CDCl3, in ppm): 3.18 (1H,
0
0
dd, J = ꢀ14.8, 6.4 Hz, H1 ), 3.47 (1H, dd, J = ꢀ14.0, 6.8 Hz, H1 b),
a
5.42 (1H, dd, J = 6.4, 4.0 Hz, H9), 7.59 (1H, t, J = 7.2 Hz, H6); 7.81
(1H, t, J = 7.2 Hz, H7), 8.17 (1H, d, J = 8.0 Hz, H5) and 8.29 (1H, dd,
J = 8.0 Hz, H8); dC (100 MHz, CDCl3, in ppm): 171.3, 171.1 (C1,
C11), 161.0 (C3), 132.4, 132.3 (C8, C6), 131.1 (C5), 129.4 (C4),
129.7 (C1}), 128.6, 128.3 (2ꢁ, C2}, C3}), 128.2 (C4}), 127.5 (C7),
´
117.0 (C8a), 108.3 (C4a), 66.4 (C9) and 40.6 (C1); LR EIMS m/z in
amu (% abundance): 292 (10%) [M]+Å, 201 (2%) [MꢀÅCH2Ph]+ and
173 (36%) [MꢀÅCH2PhꢀCO]+.