Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine

Article abstract of DOI:10.1016/j.tet.2017.11.035

One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.

Full text of DOI:10.1016/j.tet.2017.11.035

Accepted Manuscript
Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-
phthaldialdehydes with alanine
Agathe C.A. D'Hollander, Nicholas J. Westwood
PII:
S0040-4020(17)31183-3
10.1016/j.tet.2017.11.035
TET 29115
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 July 2017
Revised Date: 5 November 2017
Accepted Date: 13 November 2017
Please cite this article as: D'Hollander ACA, Westwood NJ, Assessment of the regioselectivity in the
condensation reaction of unsymmetrical o-phthaldialdehydes with alanine, Tetrahedron (2017), doi:
10.1016/j.tet.2017.11.035.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Assessment of Regioselectivity in the
Leave this area blank for abstract info.
Condensation Reaction of Unsymmetrical
o-Phthaldialdehydes with Alanine
Agathe C.A. D’Hollander and Nicholas J. Westwood
School of Chemistry, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife, KY16 9ST, UK.

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Assessment of the Regioselectivity in the Condensation Reaction of Unsymmetrical o-
Phthaldialdehydes with Alanine
Agathe C.A. D’Hollandera and Nicholas J. Westwooda,
aSchool of Chemistry and Biomedical Sciences Research Complex, University of St Andrews
and EaStCHEM, North Haugh, St Andrews, Fife, KY16 9ST, UK.
Keywords:
o-phthaldialdehyde
Condensation reaction
Regioselectivity
Mechanistic understanding
Abstract:
One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core
structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-
containing nucleophile. This fascinating reaction is revisited here in the context of the use of
o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a
detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-
phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed
across the eleven substrates led to the design of a disubstituted substrate that reacted with
very high control. A gram-scale reaction followed by esterification gave one major
regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel
monodeuterated substrates led to an increased mechanistic understanding.
Corresponding author. Tel.: +44-1334-46-3816; fax: +44-1334-46-2595; e-mail: njw3@st-andrews.ac.uk

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1. Introduction
The isoindolinones make up an important class of bioactive molecules that includes the
known drugs Pazinaclone (1),1a Indoprofen (2)1b and Chlorthalidone (3)1c (Figure 1a).
<<single column figure>>
O
O
O
a)
NH
OH
N
N
SO2NH2
Cl
N
O
N
N
O
Cl
COOH
O
Pazinaclone (1)
Indoprofen (2)
Chlorthalidone (3)
anxiolytic drug antiꢀinflammatory drug
diureticꢀantihypertensive drug
O
b)
NR
5
O
reduction
O
O
O
O
O
O
H
RNH2
condensation
RNH2
aminationꢀ
cyclisation
H
X
or
Lg
NR
H
OH
4
8
7
6
X=OMe, Cl
Lg=leaving group (e.g. Br, Cl)
Figure 1: a) Structure of known bioactive isoindolinone containing drugs;1 b) Overview of
some of the different routes used to prepare the isoindolinone core 4.2-6a
Common methods of obtaining isoindolinones that are unsubstituted in the aromatic ring, for
example compound 4 (Figure 1b), include selective reduction of 5,2 reductive amination-
cyclisation of 63 or 74 with a primary amine (RNH2) and, of interest here, the condensation
reaction of o-phthaldialdehyde (8) with a primary amine (RNH2).5,6a
To date, the majority of studies performed on this condensation reaction have focused on
evaluating the scope of the amine nucleophile that can be tolerated in the reaction5a,5b,5d,6a,6b
and/or proposing potential reaction mechanisms.5a,5b,6 In contrast, examples of the use of this

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condensation reaction with monosubstituted o-phthaldialdehydes are rare (SI1 part I). One
report describes a regioselectivity of 1:1 for the products 11:12 resulting from the
condensation of 9 with 10 (Scheme 1a).7 However, the observed regioselectivity was
measured only after filtration or purification by column chromatography. Isolated yields for
the formation of a single isomer, 14 in most cases, resulting from the condensation of 13 with
various amines have also been reported (Scheme 1b).8 Other studies have provided only
isolated yield(s) after purification (for one or for each isomer), incomplete regioisomeric ratio
(rr) data within a series or have claimed to form a single regioisomer (no yield provided)
without discussing the other possible isomer (SI1 part I).7-9
The work reported here revisits this issue by presenting a detailed study of the regiochemical
outcome of the condensation of alanine (16) with 3-monosubstituted o-phthaldialdehydes 17
(to give 18 and 19, Scheme 1c) and with 4-monosubstituted o-phthaldialdehydes 20 (to give
21 and 22, Scheme 1d). Based on the initial results, the design of a highly regioselective
substrate was achieved consistent with an improved understanding of the reaction. Further
mechanistic insights were provided by the use of novel mono-deuterated substrates.
<<Single column scheme>>

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Scheme 1: a) and b) eported in the literature.7-8 Apparently no regioselectivity was observed
for the condensation of 9 with 10 (ratio of 11:12 of 1:1 obtained after filtration (for R=F, Cl)

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or after purification of the crude reaction mixture by column chromatography (for R=SMe)).7
Condensation of 13 with various amines (RNH2) followed by purification by column
chromatography mainly led to isomer 14 (no comment was made regarding the apparent
change of regioselectivity to give isomer 15 as the major isomer in one case).8 c) and d) A
summary of the study reported in this work to explore in more detail the influence of a
substituent at the 3- or 4-position of the starting o-phthaldialdehyde on the observed
regioselectivity.
2. Results and Discussions
2.1. Synthesis of Monosubstituted o-Phthaldialdehydes
Five 3-substituted o-phthaldialdehydes 17a-e were synthesised using 2-5 step routes
involving either a Swern oxidation of the corresponding diol 23 or an acetal deprotection of
the corresponding monoacetal 24 or diacetal 25 (Scheme 2 and SI1 part II.1 for more details).
It should be noted that the synthesis of pure samples of 17a-e was particularly challenging (in
line with literature reports10) with significant decomposition occurring during purification
attempts and on storage. In several cases freshly prepared crude samples of the dialdehydes
were used (Table 1, footnote c). Additionally, six 4-monosubstituted o-phthaldialdehydes
20a-f were synthesised using 2-3 step routes either involving a Swern oxidation of the
corresponding diol 26 or an acetal deprotection of the corresponding monoacetal 24 (Scheme
2 and SI1 part II.2 for more details).
<<single column scheme>>

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Scheme 2: a) General synthesis scheme describing the approaches used to prepare mono-
substituted o-phthaldialdehydes 17 or 20. 17 and 20 were synthesised by Swern oxidation of
23 or 26, or by acetal deprotection of 24 or 25; b) Structures of the monosubstituted o-
phthaldialdehyde substrates 17 and 20 synthesised in this study.
2.2 Regioselectivity of the Condensation Reaction of Mono-substituted o-Phthaldialdehydes
The mono-substituted o-phthaldialdehydes 17a-e and 20a-f were refluxed for 4 h with alanine
(16, 1.2 equivalents) in anhydrous acetonitrile before the reaction was concentrated in vacuo.
The crude reaction mixtures (except when specified, Table 1) were then analysed using a
1
quantitative H NMR experiment. A baseline correction was applied using MestReNova-9
software and integrations were calculated relative to one proton on deconvoluted peaks (see
Figure 2 for an example of the analysis applied to the formation of 18a/19a and SI1 part III.1
for the rest of the NMR analysis; also see the experimental section below for a detailed
explanation of the analytical protocol used).
In two of the condensation reactions the structure of the major regioisomer was identified by
1
comparison with the H NMR spectrum of a pure sample of one of the regioisomers (for
18a/19a, 21a/22a, for the synthesis of authentic isomers see SI1 part III.2). In the rest of the

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cases, advanced NMR techniques (HSQC, HMBC, COSY) applied to the crude reaction
mixture were used to assign the structure of the major regioisomer. Considering the analysis
of the regioisomeric mixture of 18b/19b as an example (Figure 3), the proximity of a
carbonyl was observed to shift the signal corresponding to the aromatic H7 proton in 18b and
the methyl H1’ protons in 19b downfield (Figures 3a and 3b). Identification of H7 in 18b was
further validated by its correlation with C1 in the HMBC analysis of the regioisomeric
mixture (Figure 3a). In contrast, H4 in 19b showed a correlation with C3 in this HMBC
analysis (Figure 3c). Using the correlations observed in the COSY spectrum (Figure 3d), the
signals corresponding to H5 and H6 for 18b and 19b were finally assigned. The value of the
1
integrals in the 1D quantitative H NMR spectra enabled the identification of 18b as major
isomer.
Having assigned the signals corresponding to the two regioisomeric products in each case,
and using as many peaks as possible, an average percentage of the major isomer with its 95%
confidence interval was then calculated for each reaction (SI1 part III.3). The reaction and its
analysis were also carried out in duplicate for each substrate demonstrating high
reproducibility (SI1 part III.3).
<< double column width >>

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1
Figure 2: Quantitative H NMR spectra of the product mixture containing 18a and 19a
formed on reaction of 17a with alanine (16) (Table 1 entry 1). From left to right the spectra
represent the aromatic, the methoxy and the alanine methyl protons. Overlap between the
other signals corresponding to 18a and 19a prevented the use of the other proton signals in
the calculations. The integrals and assignments considered for the calculation of the average
percentage of the major regioisomer with its 95% confidence interval (and therefore the
regioisomeric ratio, see Table 1) are shown here. The top spectra represent the first
experiment and the spectra at the bottom represent the repeat reaction.
<< double column width >>

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Figure 3: NMR data used to identify the structure of the major isomer in the mixture of 18b
and 19b regioisomers. H7 in 18b was identified by its downfield shift, due to the
neighbouring carbonyl group, and its correlation to C1 in the HMBC spectrum mixture
1
(spectrum A). H1’ from 19b was identified by its downfield shift in the H NMR spectrum
due to the neighbouring carbonyl group (spectrum B). H4 from 19b was identified by its
correlation to C3 in the HMBC spectrum of the regioisomeric mixture (spectrum C). Starting
with H4 from 19b, the correlations observed in the COSY spectrum (spectrum D) identified
H5 (arrow 1) then H6 (arrow 2). Similarly, the correlations observed in the COSY spectrum
for H7 from 18b led to the identification H5 and H6 (arrow 3).

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<<single column>>
Table 1: Condensation reaction of monosubstituted o-phthaldialdehydes 17 or 20.
Substrate
Products ; regioisomeric ratio (rr)a
3-substituted series
Yieldb (%)
78%
O
H
49%d
11%f
33%d
60%
H
O
17bc
4-substituted series
90%
93%
90%
73%
55%d

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35%d
a based on analysis of crude reaction before purification (SI1 part III.3). b isolated yield of the
mixture of the two inseparable regioisomers. c crude dialdehyde was used. d extrapolated yield
e
over two steps. a significant amount of impurities in the crude reaction mixture led to an
inaccurate determination of rr (57:43 – 60:40, SI1 part III.1). The rr is reported after
purification by chromatography with collection of as much product as possible. f the batch of
dialdehyde 17c was divided into two portions to carry out the duplicate reactions. The
resulting products were combined to give a yield over two steps.
In both the 3- and 4-substituted series, the regioselectivity of the condensation reaction was
dependent on the substituent employed, as expected. In the 3-substituted series, the presence
of either an electron-donating or an electron-withdrawing substituent favoured the formation
of regioisomer 18 although a decrease in the electron-donating strength led to a clear decrease
in the regioselectivity. In the 4-substituted series it was observed that as the electron-donating
properties of the substituent decreased (OMe > F/Br/Me > CF3 > NO2), the regioselectivity
decreased and then switched from 21 being the major isomer to its regioisomer 22 being the
dominant product. In both series, the methoxy substituent gave the highest regioselectivity
leading to the proposal that a dimethoxysubstituted o-phthaldialdehyde 27 (Scheme 3) should
react with very high regioselectivity.
2.3 Dimethoxysubstituted o-Phthaldialdehyde
As the monomethoxysubstituted substrates 17a and 20a led to the major regioisomers 18a
and 21a respectively, it was proposed that a 3,5-dimethoxysubstituted dialdehyde 27 would

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react to give 28 with an increased regioselectivity compared to 17a and 20a (Scheme 3). A 6-
step route was developed to obtain 27 (SI1 part IV.1) and pleasingly, its subsequent reaction
with alanine (16) gave 28 as the major regioisomer in a 88:12 ratio of 28:29 (Scheme 3 and
SI1 part IV.2).
<<single column>>
O
1''MeO
6
1
O
O
N
H
H
OR
OR
a
3
4
NR
O
O
1'
OMe
O
28
30
c
MeO
OMe
18a MAJOR
OMe O
H
H
a or b
17a
+
O
3
MeO
O
5
1''
MeO
MeO
N
OMe O
H
H
a
NR
27
1
7
O
1'OMe
21a MAJOR
R=CH(CH3)COOH
29
31
O
20a
c
Scheme 3: Rationale behind the design of substrate 27, a 3,5-dimethoxysubstituted o-
phthaldialdehyde expected to favour the regioisomer 28 with a high regioselectivity.
Reagents and conditions: a) alanine (16), anhyd. MeCN, reflux, 4 h, 93% yield of 28:29 with
rr 88:12 (from 0.03 g of 27), 90% yield of 28 and 29 (1.2 g, from 0.97 g of 27); (b) alanine
(16), anhyd. MeCN, rt, 29 h, quant. yield of 28:29 with rr 97:3 (from 0.03 g of 27); (c)
SOCl2, anhyd. MeOH, rt, 12 h, 84% (1.06 g) for 30, 16% (0.20 g) for 31.
On scaling up the condensation reaction of 27 (0.97 g instead of 30 mg initially used), the
1
quantitative H NMR analysis of the crude reaction mixture was not carried out in this case
due to the low solubility of the isoindolinone products requiring a large amount of deuterated
solvent for their complete dissolution (Scheme 3). Purification by column chromatography

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led to the pure and inseparable regioisomers 28 and 29 in good yield (90%, 1.2 g).
Derivatisation using thionyl chloride and methanol gave the now separable regioisomeric
esters isolated in 1.06 g for ester 30 (84% yield) and 0.2 gram for ester 31 (16% yield)
respectively. The overall esterification yield was quantitative and thus the initial ratio of 28
and 29 for the larger scale was calculated as 84:16 which was comparable to the small scale
result (88:12 of 28:29). Inspired by this result, the condensation reaction was attempted on a
small scale (30 mg of 27) at room temperature (as opposed to reflux) and led to an excellent
regioselectivity of 97:3 of 28:29 (Scheme 3 and SI1 part IV.3).
2.4 Mechanism Discussion
A continuing discussion on the likely mechanism of this condensation reaction has occurred
in the literature over the last decade.5-6 The early stages of the proposed mechanisms can be
divided into two categories involving either an isoindolinediol intermediate5 (such as 32 from
20a) or imine intermediates6 (such as 33 and 34 from 20a) (Scheme 4).
<<single column>>

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Scheme 4: Considering the two most frequently proposed mechanisms in the literature5-6: (i)
if the reaction proceeds via 32, the electron-donating properties of the methoxy-substituent
should favour the displacement of the C1-hydroxyl in 32, leading to the major isomer 21a (as
observed) or (ii) if the reaction proceeds via 33 and 34, the electron-donating properties of the
methoxy-substituent should decrease the reactivity of the C1-formyl in 20a, favouring 34 and
leading to 22a as the major product (not observed).
Whilst drawing clear mechanistic conclusion from the 3-monosubstituted o-phthaldialdehyde
series proved challenging (see SI1 part V.1. for a more detailed discussion), the results
obtained with the 4-substituted series proved insightful (Table 1). Considering 20a as an
example (Scheme 4), the electron-donating properties of the methoxy-substituent should
favour the displacement of the C1-hydroxyl group in the proposed isoindolinediol
intermediate 32 leading to the predicted formation of regioisomer 21a as the major product
(as observed, see Table 1). In contrast, the electron-donating properties of the methoxy-
substituent would be expected to decrease the reactivity of the C1-formyl group11 in 20a

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favouring the formation of the proposed imine intermediate 34 over imine 33 and therefore
predicting that 22a should be the major product (not observed). In this study, 21a was
obtained as the major regioisomer providing evidence to support the initial conversion of 20a
to the isoindolinediol intermediate 32. The same reasoning could explain the switch for the
formation of the regioisomer 22e as the major product when the strongly electron-
withdrawing nitro-substituent was used (substrate 20e, Table 1 and SI1 part V.2 for a more
detailed discussion). This conclusion is also supported by Pan et al. and Jones et al.’s studies
1
reporting the ESI-MS² and the H NMR spectroscopy detection of an isoindolinediol
intermediate in a related transformation.5a, 5b
Assuming an isoindolinediol intermediate is initially formed in this reaction, two routes have
been proposed in the literature to form the final isoindolinones.5a,5c,5e,5f One of these involving
a [1,3]-hydride shift was ruled out based on stereoelectronic arguments (see reference 5(f) for
additional comment). Detailed consideration of the other possible mechanism and inspired by
the reaction of the mono-substituted o-phthaldialdehyde 17a, it was proposed that the use of a
mono-deuterated mono-methoxysubstituted substrate such as 35 (Scheme 5) could potentially
5d
provide additional mechanistic information. If the proposed reaction pathway5a,
was
followed, the isoindolinediol intermediate 36 formed from 35 could undergo either a loss of
HDO leading to 37, and subsequently to 18a, or a loss of water leading to 38, and
subsequently to the deuterated 19a’ (Scheme 5). In this case, only one of the two predicted
products is deuterated. Analogous reasoning can be applied to the reaction of mono-
deuterated 39 (Scheme 6) and would predict the formation of one mono-deuterated isomer
18a’ along with the non-deuterated 19a.
<<Single column>>

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Scheme 5: The predicted products formed from mono-deuterated 35 considering the likely
isoindolinediol intermediate 36. Loss of HDO or water from 36 would lead to 37 or 38 and
then to 18a and 19a’ respectively via tautomerisation. An alternative mechanism proposed in
the literature5a,5c,5e,5f involving a a [1,3]-deuteride or a [1,3]-hydride shift was ruled out based
on stereoelectronic considerations in response to a comment during the review of this paper
(see reference 5(f)).
Mono-deuterated 35 and 39 were successfully synthesised with the key deuterium
incorporation step being achieved using sodium borodeuteride reduction of lactones 40 and
41 (Figure 4a, SI1 part II.1.1. and part VI.2.)12 followed by Swern oxidation13 of 42 and 43
1
respectively. H NMR spectra of 35 and 39 confirmed the presence of a monodeuterated
aldehyde (Figure 4b). However, a signal consistent with potential traces of non-deuterated
17a was observed in the 13C NMR spectrum of 39 (see SI2 for spectrum). Analysis of the
condensation of 35 and 39 with alanine (16) at reflux was carried out by 13C NMR
spectroscopy (Figure 4c). The spectra associated with both purified reaction mixtures differed
from that of pure 18a and 19a in the signals that corresponded to the CH2 carbon only (red
circle, Figure 4c). The 13C NMR analysis of the reaction of 35 (spectrum ii) showed a major

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isomer with a singlet corresponding to the CH2 signal of 18a (c.f. spectrum i and ii). The
observed triplet (blue bars, spectrum ii) suggested that the minor isomer was monodeuterated
13
and thus corresponded to 19a’. Similarly, C NMR analysis of the reaction of 39 (spectrum
iii) showed the presence of the undeuterated minor isomer 19a (singlet, c.f. spectrum iv with
iii) and the monodeuterated major isomer 18a’ (triplet, blue bars, spectrum iii) with a small
additional signal (labelled * in spectrum iii) assigned to the formation of trace amounts of
undeuterated 18a (c.f. spectrum iii with i). Therefore, in both reactions, only one
monodeuterated product was formed consistent with the reaction occurring as shown in
Scheme 5. Further evidence to support this comes from work previously published by Pan et
al.5a The presence of trace amounts of undeuterated 18a when using substrate 39 could
potentially be explained by the initial contamination of substrate 39 with traces of
undeuterated substrate 17a or by the reversibility of the final tautomerisation step.
Interestingly, the regioisomeric ratios obtained with substrates 35 and 39 were slightly
affected by the presence of a deuterium atom suggesting a kinetic isotope effect (SI1 part
VI.3.).
3. Conclusions
Although unstable and challenging to obtain, eleven monosubstituted o-phthaldialdehydes
were successfully synthesised. The result of their condensation reaction with alanine (16) led
to the design of a disubstituted analogue 27 that reacted with 16 in a highly regioselective
manner (rr of 88:12 on 30 mg scale). A gram-scale reaction using this substrate 27 followed
by esterification led to the isolation of pure isoindolinone regioisomers in high yield and
selectivity (rr of 84:16). Performing this condensation at room temperature provided an
excellent regioisomeric ratio of 97:3.

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<< single column>>
Figure 4: a) Synthesis of monodeuterated substrates 35 and 39. Reagents and conditions: (a)
NaBD4, ZnCl2, N,N-dimethylaniline, anhyd. THF, reflux, 20 h, 62% for 42, 49% for 43; (b)
(COCl)2, anhyd. DCM, anhyd. DMSO, Et3N, rt, 15‒17 h, 67% for 35, 86% for 39; b)
1
Aldehyde region of the H NMR spectra of 17a, 35 and 39. Only one aldehyde signal is
present in the 1H NMR spectra of 35 and 39 (red lines) compared to the 1H NMR spectrum of
13
17a supporting the formation of monodeuterated substrates; C) CH2 region of the C NMR
spectrum of: i) 18a; ii) the purified mixture of isoindolinones obtained from the condensation
of 35 with alanine (16); iii) the purified mixture of isoindolinones obtained from the
condensation of 39 with alanine (16); iv) 19a. The condensation reaction of 35 led to a major
isomer with a singlet corresponding to 18a and a minor isomer with a triplet (blue bars,
spectrum ii) corresponding to monodeuterated 19a’. Similarly, the condensation reaction of
39 led to a minor isomer with a singlet corresponding to 19a and a major isomer with a triplet

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(blue bars, spectrum iii) corresponding to monodeuterated 18a’. *13C NMR signal consistent
with traces of undeuterated 18a.
In addition, the structure of the major regioisomers of the condensation reactions of 4-
monosubstituted substrates supported the view that this reaction most likely occurs through
an isoindolinediol intermediate (44 from 8,Scheme 6). Two routes have been proposed in the
literature to form the final isoindolinone product from such an intermediate.5a,5c,5d The
synthesis and condensation reaction of two additional monodeuterated substrates supported a
mechanism that most likely occurs via loss of water from 44 and a subsequent
tautomerisation of 45 to give the more thermodynamically stable 4 (Scheme 6).
<< single column>>
Scheme 6: Proposed condensation reaction mechanism based on this study. Addition of
amine RNH2 to o-phthaldialdehyde (8) leads to isoindolinediol intermediate 44. A water loss
followed by tautomerisation of 45 would then provide the desired product 4.
4. Experimental section
General methods: All solvents and chemicals were purchased from Sigma Aldrich, Alfa
Aeser, Acros Organics, Fluorochem, Apollo Scientific or Fisher Scientific and used without
further purification. All air or moisture sensitive reactions were carried out in flame or oven-

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dried glassware under a positive pressure of nitrogen. Thin layer chromatography (TLC)
analysis was performed using glass plates coated with silica gel (with fluorescent indicator
UV254). Developed plates were air dried and analysed under a UV lamp (254/365 nm). Flash
chromatography was performed using silica gel (40-62 ꢁm, Fluorochem). Melting points
were measured using Electrothermal 9100 capillary melting point apparatus. Values are
quoted to the nearest 1 °C and are uncorrected. Fourier Transform infra-red spectra (FT IR)
were acquired on a Shimadzu IR Affinity-1 Fourier transform IR spectrophotometer using
thin films, a Pike MIRacle ATR accessory and Shimadzu IR solution v1.50 for analysis.
Absorption maxima (νmax) are reported in wavenumbers (cm-1). Broad signals were assigned
with as br. Nuclear magnetic resonance (NMR) spectra were acquired at room temperature on
a Brüker Advance 500 (1H, 500 MHz; 13C, 125 MHz), a Brüker Advance 400 (1H, 400 MHz;
13C, 100 MHz) or a Brüker Advance 300 (1H, 300 MHz; 13C, 75 MHz) instruments.
1
Deuterium solvents were used as lock for all NMR spectra and H NMR shifts were
13
internally referenced to the solvent. Chemical shifts are expressed as δ in units of ppm. C
NMR spectra were recorded using the PENDANT sequence mode. Data processing was
carried out using MestReNova 9.0 NMR program (Brüker UK Ltd). Signals for protons and
carbons were assigned, as far as possible, by using the following two-dimensional NMR
1
spectroscopy techniques: [1H, H] COSY (COrrelation SpectroscopY), [1H, 13C] HSQC
(Heteronuclear Single Quantum Coherence) and [1H, 13C] HMBC (Heteronuclear Multiple
Bond Connectivity). For 1H NMR, the multiplicity is indicated by the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. = broad. The
CH2 proton NMR signals corresponding to the isoindolinone ring appeared as a singlet, a
multiplet or as two apparent doublets with a roofing effect which are referred to as doublets
hereafter. All 13C NMR signals were singlets (except for compounds containing F) and
correspond to one carbon unless otherwise stated. Mass spectrometric analysis (electrospray

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mode, ES, or atmospheric solids analysis probe mode, ASAP) was carried out on a high
performance orthogonal acceleration reflecting TOF (Time Of Flight) mass spectrometer
operating in positive and negative mode, coupled to a Waters 2975 HPLC.
General procedures
General procedure A: Swern oxidation
To a solution of (COCl)2 (2.6 equiv.) in anhydrous DCM (1.4 mL per mmol of diol) was
added dropwise a solution of anhydrous DMSO (5.2 equiv.) in anhydrous DCM (2.2 mL per
mmol of diol) at ‒78 °C and under a nitrogen atmosphere. After 10 mins. stirring at ‒78 °C, a
solution of diol (1.0 equiv.) in anhydrous DCM (2.2 mL per mmol of diol) was added at this
temperature. The reaction mixture was stirred at ‒78 °C for 1 h under a nitrogen atmosphere
before Et3N (1.4 mL per mmol of diol) was added dropwise. The reaction mixture was
warmed to rt and stirred for 2‒18 h under a nitrogen atmosphere. The reaction was then
quenched by addition of H2O. The organics were extracted with DCM, combined, washed
with water, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the
desired o-phthaldialdehyde.
General procedure B: Condensation reaction
Alanine (16, 1.2 equiv.) was added to a solution of unsymmetrical o-phthaldialdehyde (1.0
equiv.) in anhydrous MeCN (3.8 mL per mmol of o-phthaldialdehyde). The reaction mixture
was heated at reflux for 4 h under a nitrogen atmosphere. The solution was then cooled to rt
before being concentrated in vacuo to afford the crude mixture of regioisomers.
Quantitative 1H NMR analysis (SI1 part III.1) was carried out on this crude reaction mixture
to obtain the average percentage of the major regioisomer with its 95% confidence interval
(SI1 part III.3) and subsequently the regioisomeric ratio (rr, Table 1). The NMR spectrum
was processed using MestReNova 9.0 as follows: (i) the baseline was corrected using the
Whittaker smoother; (ii) the peaks were selected by manual threshold following a Global

24
ACCEPTED MANUSCRIPT
Spectral Deconvolution (GSD) with a refinement level of 4 (20 fitting cycles). When the
peaks were too overlapped to allow an accurate deconvolution, they were not used in the
subsequent steps; (iii) the integral for each peak was calculated using the peaks method and
applying an automatic integration; (iv) when the integrals of two distinguishable signals were
overlapping, manual removal of one signal allowed the integral of the remaining signal to be
obtained. For each signal, the contribution was calculated relative to one proton (CH2
integrals were divided by 2, CH3 integrals were divided by 3 and the integration of an
aromatic signal corresponding to two protons belonging to the same regioisomer was divided
by 2). Using as many signals as possible, an average regioisomeric ratio with its standard
deviation was then calculated using Excel Microsoft Office software. The desired 95%
confidence
interval
was
then
calculated
using
the
following
formula:
=CONFIDENCE.NORM(0,05;standard deviation; number of ratio calculated). The crude
product was then purified by column chromatography (0‒10% MeOH in DCM then 0‒10%
MeOH in DCM with 1% CH3COOH) to afford the pure regioisomeric mixture and to enable
calculation of the yield.
General procedure C: Reduction of lactone using NaBD4
To a solution of lactone (1 equiv.) in anhydrous THF (1 mL per mmol of lactone) under a
nitrogen atmosphere were added cautiously NaBD4 (2 equiv.), ZnCl2 (1 equiv.) and N,N-
dimethylaniline (1 equiv.). The reaction was refluxed for 20 h under a nitrogen atmosphere
before being cooled to 0 °C and quenched cautiously with an aqueous solution of NH4Cl
(10%). The grey solid formed was filtered off and washed with DCM. The filtrate was
extracted with DCM. The organics were combined, washed with water, washed with brine,
dried over MgSO4 and concentrated in vacuo to afford the crude product. Purification by

25
ACCEPTED MANUSCRIPT
column chromatography (0‒100% EtOAc in petroleum ether) afforded the desired deuterated
diol.
Compounds synthesised
3-Methoxyphthalaldehyde (17a)13
17a was synthesised according to general procedure A using (3-methoxy-1,2-
phenylene)dimethanol (23a, 1.0 equiv., 500 mg, 2.97 mmol), (COCl)2 (2.6 equiv., 0.66 mL,
7.73 mmol), DMSO (5.2 equiv., 1.10 mL, 15.40 mmol). Additional DMSO (1 mL) was
required to help 23a solubilisation. The reaction was stirred at rt for 17 h. Pure 17a was
obtained after recrystallisation from EtOAc as a yellow gum (249 mg, 1.52 mmol, 51%).
1H NMR (400 MHz, CDCl3) δH 10.62 (s, 1H, H1’’), 10.41 (s, 1H, H1’), 7.63 (t, J = 8.0 Hz,
1H, H5), 7.42 (d, J = 8.0 Hz, 1H, H6), 7.23 (d, J = 8.0 Hz, 1H, H4), 3.97 (s, 3H, OCH3).
Spectral data in accordance with those reported in the literature.13
2-(4-Methoxy-1-oxoisoindolin-2-yl)propanoic acid (18a) with 2-(7-methoxy-1-
oxoisoindolin-2-yl)propanoic acid (19a)
A mixture of 18a and 19a was synthesised according to general procedure B using 4-
methoxyphthalaldehyde (17a, 1.0 equiv., 30 mg, 0.18 mmol) and alanine (16, 1.2 equiv., 19
mg, 0.22 mmol). A pure regioisomeric mixture of 18a and 19a was obtained as a light yellow
solid (32 mg, 0.14 mmol, 78%). Each regioisomer was also synthesised in pure form via a
different method (SI1 part III.2) and their characterisation is reported here.
18a: Mp: 205‒208 °C; IR νmax cm-1 (thin film) 2943 (O-H stretch), 1721 (C=O stretch), 1628
1
(C=O stretch), 1605 (C=C stretch), 1497 (C=C stretch), 1275 (C-O stretch), 1061, 806; H
NMR (400 MHz, CD3OD) δH 7.48 (t, J = 8.0 Hz, 1H, H6), 7.36 (d, J = 7.8 Hz, 1H, H7), 7.19
(d, J = 8.0 Hz, 1H, H5), 4.99 (q, J = 7.5 Hz, 1H, CH), 4.53 (d, J = 17.5 Hz, 1H, H3), 4.47 (d,
13
J = 17.5 Hz, 1H, H3), 3.93 (s, 3H, OCH3), 1.62 (d, J = 7.5 Hz, 3H, CH3); C NMR (100
MHz, CD3OD) δc 174.7 (COOH), 171.0 (C1), 156.2 (C4), 134.5 (C7a), 131.4 (C3a), 131.1

26
ACCEPTED MANUSCRIPT
(C6), 116.2 (C7), 114.6 (C5), 56.1 (OCH3), 51.0 (CH), 46.3 (C3), 15.9 (CH3); HRMS (ES+)
m/z calculated for C12H14NO4 [M+H]+: 236.0917; found: 236.0918. See SI1 part IX for
experimental procedure and SI2 for 1H and 13C NMR spectra.
19a: Mp: 218‒220 °C; IR νmax cm-1 (thin film) 2934 (O-H stretch), 1728 (C=O stretch), 1636
(C=O stretch), 1612 (C=C stretch), 1489 (C-H bend), 1456 (C-H bend), 1279 (C-N stretch),
1204 (C-O stretch), 1180 (C-O stretch), 1084, 773; 1H NMR (500 MHz, CD3OD) δH 7.55 (t,
J = 8.0 Hz, 1H, H5), 7.11 (d, J = 8.0 Hz, 1H, H4), 7.02 (d, J = 8.0 Hz, 1H, H6), 4.96 (q, J =
7.5 Hz, 1H, CH), 4.54 (d, J = 17.5 Hz, 1H, H3), 4.47 (d, J = 17.5 Hz, 1H, H3), 3.91 (s, 3H,
13
OCH3), 1.59 (d, J = 7.5 Hz, 3H, CH3); C NMR (125 MHz, CD3OD) δc 174.9 (COOH),
170.0 (C1), 158.8 (C7), 146.3 (C3a), 135.0 (C5), 120.1 (C7a), 116.2 (C4), 111.2 (C6), 56.0
(OCH3), 50.7 (CH), 48.0 (C3), 15.8 (CH3); HRMS (ES+) m/z calculated for C12H14NO4
[M+H]+: 236.0917; found: 236.0917. See SI1 part IX for experimental procedure and SI2 for
1H and 13C NMR spectra.
2-(4-Methyl-1-oxoisoindolin-2-yl)propanoic acid (18b) with 2-(7-methyl-1-oxoisoindolin-
2-yl)propanoic acid (19b) via 3-methylphtalaldehyde (17b)
17b was synthesised according to general procedure A using (3-methyl-1,2-
phenylene)dimethanol (23b, 1.0 equiv., 100 mg, 0.66 mmol), (COCl)2 (2.6 equiv., 0.15 mL,
1.77 mmol) and DMSO (5.2 equiv., 0.24 mL, 3.43 mmol). The reaction was stirred at rt for 2
h. Crude 17b was obtained contaminated with a small amount of impurities (73 mg, 0.49
mmol, 75% assuming pure 17b) Characterisation was performed on this slightly impure
mixture with the 1H and 13C NMR signals reported for 17b only.
IR νMax cm-1 (Thin Film) 2922 (C-H stretch), 1690 (C=O stretch), 1481 (C-H bend), 1358,
1260, 1086, 1067, 1038; 907, 866, 775; 1H NMR (500 MHz, CDCl3) δH 10.59 (s, 1H, H1’’),
10.21 (s, 1H, H1’), 7.72 (d, J = 7.5 Hz, 1H, H6), 7.57 (t, J = 7.5 Hz, 1H, H5), 7.49 (d, J = 7.5
13
Hz, 1H, H4), 2.59 (s, 3H, CH3); C NMR (125 MHz, CDCl3) δC 193.7 (C1’’), 192.8 (C1’),

27
ACCEPTED MANUSCRIPT
140.0 (C3), 137.3 (C1), 136.7 (C4), 135.9 (C2), 132.4 (C5), 129.3 (C6), 19.5 (CH3); HRMS
(ES+) m/z calculated for C9H9O2 [M+H]+: 149.0597; found: 149.0595. See SI2 for 1H and 13C
NMR spectra.
A portion of this impure mixture (1.0 equiv., 30 mg, 0.20 mmol assuming pure 17b) was
treated according to general procedure B using alanine (16, 1.2 equiv., 22 mg, 0.24 mmol). A
pure regioisomeric mixture of 18b and 19b was obtained as a light yellow solid (29 mg, 0.13
1
mmol, 49% extrapolated yield over 2 steps). The H and 13C NMR signals integration are
given assuming a mixture of 18b:19b with a ratio of 1:1 for clarity.
IR νMax cm-1 (Thin Film) 2916 (O-H stretch), 2361 (C-H stretch), 1734 (C=O stretch), 1636
(C=O stretch), 1609 (C=C stretch), 1456 (O-H bend), 1211 (C-O stretch), 1175 (C-O stretch);
1H NMR (400 MHz, CD3OD) δH 7.60 (dd, J = 6.0, 2.9 Hz, 1H, H7 in 18b), 7.45 (t, J = 7.5
Hz, 1H, H5 in 19b), 7.42-7.38 (m, 2H, H5 and H6 in 18b), 7.36 (d, J = 7.5 Hz, 1H, H4 in
19b), 7.22 (d, J = 7.5 Hz, 1H, H6 in 19b), 5.02 (q, J = 7.5 Hz, 1H, CH in 18b), 4.98 (q, J =
7.5 Hz, 1H, CH in 19b), 4.58-4.45 (m, 4H, H3 in 18b, H3 in 19b), 2.65 (s, 3H, H1’ in 19b),
2.39 (s, 3H, H1’ in 18b), 1.64 (d, J = 7.5 Hz, 3H, CH3 in 18b), 1.60 (d, J = 7.5 Hz, 3H, CH3
13
in 19b); C NMR (175 MHz, CD3OD) δC 175.0 (COOH in 19b), 174.8 (COOH in 18b),
171.6 (C1 in 19b), 171.4 (C1 in 18b), 144.2 (C3a in 19b), 142.5 (C4 in 18b), 138.4 (C7 in
19b), 134.4 (C3a or C7a in 18b), 133.9 (C5 in 18b), 132.7 (2C, C5 in 19b, C3a or C7a in
18b), 130.9 (C6 in 19b), 130.1 (C7a in 19b), 129.4 (C6 in 18b), 121.73 (C4 in 19b or C7 in
18b), 121.67 (C4 in 19b or C7 in 18b), 51.0 (CH in 18b), 50.7 (CH in 19b), 47.8 (C3 in 19b),
47.7 (C3 in 18b), 17.52 (C1’ in 18b or 19b), 17.45 (C1’ in 18b or 19b), 16.0 (CH3 in 18b),
15.9 (CH3 in 19b); HRMS (ES-) m/z calculated for C12H12NO3 [M-H]-: 218.0823; found:
218.0823. See SI2 for 1H and 13C NMR spectra.

28
2-(1-Oxo-4-(trifluoromethyl)isoindolin-2-yl)propanoic acid (18c) with 2-(1-oxo-7-
ACCEPTED MANUSCRIPT
(trifluoromethyl)isoindolin-2-yl)propanoic
(trifluoromethyl)phthalaldehyde (17c)
acid
(19c)
via
3-
To a solution of 2-(1,3-dioxolan-2-yl)-6-(trifluoromethyl)benzaldehyde (24c, 1 equiv., 100
mg, 0.41 mmol) in DCM (5 mL) was added an aqueous solution of HCl (2 M, 5 mL). The
reaction was stirred at rt for 15 h. Water was added and the organics were extracted with
DCM, combined, washed with brine, dried over MgSO4 and concentrated in vacuo. 17c was
obtained impure (24 mg). The considerable amount of impurities prevented any
characterisation. Instead, this impure mixture (1.0 equiv., 24 mg, 0.12 mmol assuming pure
17c) was directly treated according to general procedure B using alanine (16, 1.2 equiv., 13
mg, 0.14 mmol). A pure regioisomeric mixture of 18c and 19c was obtained as a light brown
oil (12 mg, 0.04 mmol, 11% yield over 2 steps). The small amount of product available did
not allow the identification of the 13C NMR signals corresponding to C4, CF3 in 18c and C7,
1
13
CF3 in 19c and allowed the visibility of grease impurities in the H and C NMR spectra.
Additionally, the 13C NMR signals corresponding to COOH in 18c and in 19c were
1
extrapolated from the HMBC spectrum (SI1 part VII). The H and 13C NMR signal
integration are given assuming a mixture of 18c:19c with a ratio of 1:1 for clarity.
IR νMax cm-1 (Thin Film) 2922 (O-H stretch), 2359 (C-H stretch), 1684 (br. C=O stretch),
1
1558 (C=C stretch), 1456 (O-H bend), 1325 (C-F stretch), 1117 (C-F stretch); H NMR (400
MHz, CD3OD) δH 8.04 (d, J = 7.5 Hz, 1H, H7 in 18c), 7.93 (d, J = 7.5 Hz, 1H, H5 in 18c),
7.86 (d, J = 7.5 Hz, 1H, H4 in 19c), 7.82 (d, J = 7.5 Hz, 1H, H6 in 19c), 7.78-7.72 (m, 2H,
H5 in 19c, H6 in 18c), 5.03-4.97 (m, 2H, CH in 18c, CH in 19c), 4.83 (d, J = 18.0 Hz, 1H,
H3 in 18c), 4.74 (d, J = 18.0 Hz, 1H, H3 in 18c), 4.70 (d, J = 17.5 Hz, 1H, H3 in 19c), 4.62
(d, J = 17.5 Hz, 1H, H3 in 19c), 1.64 (d, J = 7.5 Hz, 3H, CH3 in 18c), 1.63 (d, J = 8.0 Hz, 3H,
13
CH3 in 19c); C NMR (175 MHz, CD3OD) δC 174.0 (2C, COOH in 18c, COOH in 19c,

29
ACCEPTED MANUSCRIPT
extrapolated from the HMBC spectrum, SI1 part VII), 169.2 (C1 in 18c), 167.4 (C1 in 19c),
146.4 (C3a in 19c), 140.7 (C3a in 18c), 135.1 (C7a in 18c), 132.9 (C5 in 19c), 130.3 (C6 in
18c), 129.9-129.8 (m, C5 in 18c), 128.5 (C4 in 19c), 128.3 (C7 in 18c), 126.8 (C7a in 19c),
126.6-126.5 (m, C6 in 19c), 51.7 (CH in 18c or 19c), 51.5 (CH in 18c or 19c), 48.2 (C3 in
19c), 47.9 (C3 in 18c), 16.03 (CH3 in 18c or 19c), 16.00 (CH3 in 18c or 19c); HRMS (ES-)
1
13
m/z calculated for C12H9NO3F3 [M-H]-: 272.0540; found:272.0540. See SI2 for H and C
NMR spectra.
2-(4-Chloro-1-oxoisoindolin-2-yl)propanoic acid (18d) with 2-(7-chloro-1-oxoisoindolin-
2-yl)propanoic acid (19d) via 3-chlorophtalaldehyde (17d)
17d was synthesised according to general procedure A using (3-chloro-1,2-
phenylene)dimethanol (23d, 1.0 equiv., 100 mg, 0.58 mmol), (COCl)2 (2.6 equiv., 0.13 mL,
1.51 mmol) and DMSO (5.2 equiv., 0.21 mL, 3.02 mmol). The reaction was stirred at rt for 2
h. Crude 17d was obtained with small impurities (51 mg, 0.30 mmol, 52% assuming pure
1
17d) Characterisation was performed on this slightly impure mixture with the H and 13C
NMR signals reported for 17d only.
IR νMax cm-1 (Thin Film) 2924 (C-H stretch), 1695 (C=O stretch), 1591 (C=C stretch), 1460
1
(C-H bend), 1354, 1292, 1175, 1144, 1078, 910, 862, 773; H NMR (500 MHz, CDCl3) δH
10.64 (s, 1H, H1’’), 10.32 (s, 1H, H1’), 7.81 (d, J = 8.0 Hz, 1H, H6), 7.69 (d, J = 8.0 Hz, 1H,
H4), 7.64 (t, J = 8.0 Hz, 1H, H5); 13C NMR (125 MHz, CDCl3) δC 191.3 (C1’ or C1’’), 191.2
(C1’ or C1’’), 139.0 (C1), 137.5 (C3), 135.1 (C4), 134.3 (C5), 133.8 (C2), 127.7 (C6);
35
HRMS (ES+) m/z calculated for C8H6O2 Cl [M+H]+: 169.0051; found: 169.0046. See SI2
for 1H and 13C NMR spectra.
A portion of this impure mixture (1.0 equiv., 30 mg, 0.18 mmol assuming pure 17d) was
treated according to general procedure B using alanine (16, 1.2 equiv., 19 mg, 0.21 mmol). A
pure regioisomeric mixture of 18d and 19d was obtained as a yellow gum (27 mg, 0.11

30
ACCEPTED MANUSCRIPT
1
mmol, 33% extrapolated yield over 2 steps). The H and 13C NMR signals integration are
given assuming a mixture of 18d:19d with a ratio of 1:1 for clarity.
IR νMax cm-1 (Thin Film) 2922 (O-H stretch), 2359 (C-H stretch), 1653 (br. C=O stretch),
1558 (C=C stretch), 1456 (O-H bend), 1206 (C-O stretch), 1173 (C-O stretch); 1H NMR (400
MHz, CD3OD) δH 7.74 (d, J = 7.5 Hz, 1H, H7 in 18d), 7.64 (d, J = 8.0 Hz, 1H, H5 in 18d),
7.59-7.51 (m, 3H, H4 in 19d, H5 in 19d, H6 in 18d), 7.45 (d, J = 7.5 Hz, 1H, H6 in 19d),
5.03-4.94 (m, 2H, CH in 18d, CH in 19d), 4.66 (d, J = 17.5 Hz, 1H, H3 in 18d), 4.63 (d, J =
17.5 Hz, 1H, H3 in 19d), 4.57 (d, J = 17.5 Hz, 1H, H3 in 18d), 4.54 (d, J = 17.5 Hz, 1H, H3
13
in 19d), 1.65 (d, J = 7.5 Hz, 3H, CH3 in 18d), 1.62 (d, J = 7.5 Hz, 3H, CH3 in 19d); C
NMR (175 MHz, CD3OD) δC 175.4 (2C, COOH in 18d, COOH in 19d), 169.8 (C1 in 18d),
168.4 (C1 in 19d), 146.5 (C3a in 19d), 141.6 (C3a in 18d), 135.4 (C7a in 18d), 134.0 (C5 in
19d), 133.0 (C5 in 18d), 132.0 (C7 in 19d), 131.2 (C6 in 18d), 130.6 (C6 in 19d), 130.4 (C4
in 18d), 129.1 (C7a in 19d), 123.1 (C4 in 19d), 123.0 (C7 in 18d), 51.6 (CH in 18d), 51.4
(CH in 19d), 47.71 (C3 in 18d), 47.68 (C3 in 19d), 16.1 (CH3 in 18d), 15.9 (CH3 in 19d);
HRMS (ES-) m/z calculated for C11H9NO3 Cl [M-H]-: 238.0276; found: 238.0277. See SI2
35
for 1H and 13C NMR spectra.
3-Fluorophthalaldehyde (17e)
To a solution of 2,2'-(3-fluoro-1,2-phenylene)bis(1,3-dioxolane) (25e, 1 equiv., 100 mg, 0.42
mmol) in DCM (5 mL) was added an aqueous solution of HCl (2 M, 5 mL). The reaction was
stirred at rt for 3 h. Water was added and the organics were extracted with DCM, combined,
washed with brine, dried over MgSO4 and concentrated in vacuo. Pure 17e was obtained as a
light orange gum (31 mg, 0.20 mmol, 49%).
IR νMax cm-1 (Thin Film) 2928 (C-H stretch), 1694 (C=O stretch), 1603 (C=C stretch), 1479
1
(C-H bend), 1248 (C-F stretch), 1094, 917, 783; H NMR (500 MHz, CDCl3) δH 10.56 (s,
1H, H1’’), 10.49 (s, 1H, H1’), 7.75-7.69 (m, 2H, H5, H6), 7.45-7.41 (m, 1H, H4); 13C NMR