Catalyst-free photoredox addition-cyclisations: Exploitation of natural synergy between aryl acetic acids and maleimide

Article abstract of DOI:10.1002/chem.201304929

Suitably functionalised carboxylic acids undergo a previously unknown photoredox reaction when irradiated with UVA in the presence of maleimide. Maleimide was found to synergistically act as a radical generating photoxidant and as a radical acceptor, negating the need for an extrinsic photoredox catalyst. Modest to excellent yields of the product chromenopyrroledione, thiochromenopyrroledione and pyrroloquinolinedione derivatives were obtained in thirteen preparative photolyses. In situ NMR spectroscopy was used to study each reaction. Reactant decay and product build-up were monitored, enabling reaction profiles to be plotted. A plausible mechanism, whereby photo-excited maleimide acts as an oxidant to generate a radical ion pair, has been postulated and is supported by UV/Vis. spectroscopy and DFT computations. The radical-cation reactive intermediates were also characterised in solution by EPR spectroscopy. UVA photolyses of aryloxy-, arylthio- and arylamino-acetic acids with maleimide yield oxa-, thia- and aza-tricyclo pyrroledione derivatives in the absence of a photoredox catalyst (see scheme). An intriguing mechanism has been proposed and has been supported and supplemented by NMR monitoring experiments, DFT computations and UV/Vis and EPR spectroscopy.

Full text of DOI:10.1002/chem.201304929

Supporting Information
ꢀ
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2014
Catalyst-Free Photoredox Addition–Cyclisations: Exploitation of
Natural Synergy between Aryl Acetic Acids and Maleimide
[a]
[b]
[b]
[a]
David W. Manley,* Andrew Mills, Christopher O’Rourke, Alexandra M. Z. Slawin, and
[a]
John C. Walton*
chem_201304929_sm_miscellaneous_information.pdf

Table of Contents
General Experimental Section
S3
Scheme S1. Preparation of carboxylic acids
Optimisation Studies
S3
S9
Scheme S2. Test reaction for optimisation studies.
Preparative Irradiations
S9
S12
S21
S21
X-ray Crystallography
Fig. S1. The X-ray crystal structure of 5g.
Table S1. Crystal data & structure refinement for 5g
Fig. S2. The X-ray crystal structure of 5i.
S21
S22
Table S2. Crystal data & structure refinement for 5i
Table S3. Coupling Constant between Protons at Ring Junction
In-situ NMR Monitoring
S22
S24
S25
S25
S38
S39
S44
S58
S64
S65
Fig S3. Irradiation setup for in-situ NMR Monitoring
Fig S15. Profile showing Lamp Output and Pyrex Absorbance
EPR Spectroscopy
DFT Optimised Structures
DFT Optimised Energies
References
1
13
H & C NMR Spectra for novel compounds
2

General Experimental Section
All reagents and solvents were purchased from either Sigma Aldrich, Alfa Aesar or TCI Europe and used
without further purification. Tetrahydrofuran was distilled over sodium and dichloromethane was distilled
over calcium hydride. Column chromatography was carried out using Silica 60A (particle size 40-63 µm,
Silicycle, Canada) as the stationary phase, and TLC was performed on precoated silica gel plates (0.20
1
13
mm thick, Sil G UV , Macherey-Nagel, Germany) and observed under UV light. H and C NMR
2
54
spectra were recorded on Bruker AV III 500, Bruker AV II 400 and Bruker AV 300 instruments.
Chemical shifts are reported in parts per million (ppm) from low to high frequency and referenced to the
residual solvent resonance. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations
indicating multiplicity were used as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, q =
quartet, m = multiplet, b = broad. Melting points (M.p.) were determined using a Sanyo Gallenkamp
apparatus and are reported uncorrected. Mass spectrometry was carried out at the EPSRC National Mass
Spectrometry Service Centre, Swansea, UK. UV/Vis spectrometry was carried out using a Cary 50
spectrophotometer (Varian Inc.).
General Procedure for the Preparation of Phenoxy- and Phenylthio-Acetic Acids
To a solution of the phenol/thiol (1 equiv.) in anhydrous THF was added methyl bromo acetate (2 equiv.)
and potassium carbonate (5 equiv.) at room temperature. The resultant mixture was refluxed at 80°C for
4
8-72 hours. The mixture was concentrated under reduced pressure, dissolved in 100 mL CH Cl , washed
2 2
with H O (3 x 100 mL), dried over MgSO and the solvent removed under reduced pressure. To a
2
4
solution of the resultant ester (1 equiv.) in MeOH/H O (3:1 v/v) was added LiOH (5 equiv.) at room
2
temperature and allowed to stir overnight. The reaction mixture was concentrated under reduced pressure,
dissolved in 100 mL saturated (NH ) SO , adjusted to ca. pH3 and extracted with EtOAc (3 x 100 mL).
4
2
4
The combined extracts were dried over MgSO and the solvent removed under reduced pressure.
4
Scheme S1. Preparation of carboxylic acids. Reagents and conditions: (i) K CO , THF, reflux; (ii) LiOH, 3:1
2
3
MeOH/H O, rt.
2
3

3
,5-Dimethoxyphenoxyacetic acid 4g
Prepared from 3,5-dimethoxyphenol (3.01 g, 20 mmol), methyl bromoacetate (6.12 g, 40 mmol) and
potassium carbonate (13.82 g, 100 mmol) in 100 mL THF. The resultant mixture was subjected to column
chromatography on silica gel (eluent 50% CH Cl in pentanes) to yield methyl (3,5-
2
2
1
dimethoxyphenoxy)acetate as an off white solid (4.43g, 97%). H NMR (300 MHz, CDCl , 294 K):  =
3
3
.75 (s, 6H, ArO-CH ), 3.80 (s, 3H, OCH ), 4.59 (s, 2H, ArOCH ), 6.08 (m, 2H, ArH), 6.11 (m, 1H.
3 3 2
1
3
ArH); C NMR (75 MHz, CDCl , 296 K):  = 52.7, 55.8, 65.6, 93.9, 94.3, 160.0, 162.0, 169.6. The ester
3
(
4.2 g, 18.6 mmol) was dissolved 135 mL CH OH and 45 mL H O in and subjected to hydrolysis by
3 2
1
lithium hydroxide (9.48 g, 92.8 mmol) to yield X as an off-white solid (3.47 g, 88%). H NMR (300
MHz, d6-acetone, 294 K):  = 3.75 (s, 6H, ArO-CH ), 4.13 (br-s, 1H, CO H), 4.65 (s, 2H, ArOCH ), 6.11
3
2
2
1
3
(
m, 3H, ArH); C NMR (75 MHz, CDCl , 295 K):  = 55.6, 65.5, 94.2, 94.3, 161.0, 162.6, 170.2. Data
3
1
consistent with literature.
3
,4,5-Trimethoxyphenoxyacetic acid 4h
Prepared from 3,4,5-trimethoxy phenol (3.68 g, 20 mmol), methyl bromoacetate (6.12 g, 40 mmol) and
potassium carbonate (13.82 g, 100 mmol) in 100 mL THF. The resultant mixture was subjected to column
chromatography on silica gel (eluent CH Cl ) to yield methyl 3,4,5-trimethoxyphenoxyacetate as a
2
2
1
colourless solid (3.27 g, 64%). H NMR (300 MHz, CDCl , 294 K):  = 3.70 (s, 3H, OCH ), 3.74 (s, 3H,
3
3
1
3
OCH ), 3.75 (s, 6H, ArOCH ), 4.53 (s, 2H, OCH ), 6.10 (s, 2H, ArH); C NMR (75 MHz, CDCl , 295
3
3
2
3
K):  = 52.6, 56.5, 61.3, 66.1, 92.9, 133.4, 154.1, 154.7, 169.7. The ester (2.86 g, 11.1 mmol) was
dissolved 90 mL CH OH and 30 mL H O in and subjected to hydrolysis by lithium hydroxide (5.67 g,
3
2
5
5.5 mmol) to yield X as an off-white solid which was recrystallized from (1:5) acetone/cyclohexane
1
(
2.36 g, 88%). H NMR (300 MHz, d6-acetone, 294 K):  = 3.64 (s, 3H, ArOCH ), 3.79 (s, 6H,
3
4

1
3
ArOCH ), 4.52 (br-s, 1H, CO H), 4.66 (s, 2H, OCH ), 6.27 (s, 2H, ArH); C NMR (75 MHz, CDCl , 295
3
2
2
3
1
K):  = 56.4, 60.6, 65.8, 93.7, 133.8, 154.8, 155.6, 170.4. Data consistent with literature.
4
-Methoxyphenylthioacetic acid 4j
Prepared from 4-methoxybenzenethiol (2.8 g, 20 mmol), methyl bromoacetate (6.12 g, 40 mmol) and
potassium carbonate (13.8 g, 100 mmol) in 100 mL THF. The resultant mixture was subjected to column
chromatography on silica gel (eluent 50% CH Cl in pentanes) to yield methyl 4-
2
2
1
methoxyphenylthioacetate as a colourless oil (3.64 g, 86%). H NMR (300 MHz, CDCl , 294 K):  = 3.51
3
(
s, 2H, SCH ), 3.68 (s, 3H, OCH ), 3.78 (s, 3H, ArOCH ), 6.83 (d, J = 8.9 Hz, 2H, ArH), 7.40 (d, J = 8.9
2 3 3
1
3
Hz, 2H, ArH); C NMR (75 MHz, CDCl , 296 K):  = 38.5, 52.4, 55.3, 114.7, 124.9, 134.2, 159.7,
3
1
70.4. The ester (3.0 g, 14.1 mmol) was dissolved 105 mL CH OH and 35 mL H O in and subjected to
3 2
hydrolysis by lithium hydroxide (6.56 g, 71 mmol) to yield X as an off-white solid which was
1
recrystallized from (1:10) acetone/cyclohexane (2.77 g, 99%). H NMR (400 MHz, CDCl , 296 K):  =
3
3
1
1
.54 (s, 2H, SCH ), 3.79 (s, 3H, ArOCH ), 6.85 (d, J = 8.9 Hz, 2H, ArH), 7.43 (d, J = 8.9 Hz, 2H, ArH),
2 3
1
3
1.31 (br-s, 1H, CO H); C NMR (75 MHz, CDCl , 295 K):  = 38.6, 55.4, 114.8, 124.6, 134.3, 159.9,
2
3
2
76.3. Data consistent with literature.
4
-(Methylthio)phenoxyacetic acid 4k
Prepared from 4-(methylthio)phenol (2.80 g, 20 mmol), methyl bromoacetate (6.12 g, 40 mmol) and
potassium carbonate (13.80 g, 100 mmol) in 100 mL THF. The resultant mixture was subjected to column
chromatography on silica gel (eluent 50% CH Cl in pentanes) to yield methyl 4-
2
2
1
(
methylthio)phenoxyacetate a colourless oil (3.07 g, 72%). H NMR (400 MHz, CDCl , 294 K):  = 2.43
3
(
s, 3H, ArS-CH ), 3.79 (s, 3H, CO -CH ), 4.61 (s, 2H, ArO-CH ), 6.85 (m, 2H, ArH), 7.24 (m, 2H,
3
2
3
2
5

1
3
ArH); C NMR (75 MHz, CDCl , 295 K):  = 18.0, 52.7, 65.9, 155.8, 130.1, 130.8, 156.6, 169.7. This
3
ester (2.50 g, 11.8 mmol) was dissolved 90 mL CH OH and 30 mL H O in and subjected to hydrolysis
3
2
by lithium hydroxide (5.47 g, 59 mmol) to yield X as an off-white solid which was recrystallized from
1
acetone/cyclohexane (1:10) to yield colorless needles (2.01 g, 86%). M.p. 108 °C. H NMR (400 MHz,
CDCl , 296 K):  = 2.45 (s, 3H, ArS-CH ), 4.67 (s, 2H, ArO-CH ), 6.86 (m, 2H, ArH), 7.26 (m, 2H,
3
3
2
13
ArH), 9.54 (br-s, 1H, CO H); C NMR (75 MHz, CDCl , 297 K):  = 55.6, 65.5, 94.2, 94.3, 161.0,
2
3
+
1
1
62.6, 170.2; LR-ESIMS: m/z = 199 [MH] ; HR-ESIMS: m/z = 199.0424 (calcd. for C H O S,
9 11 3
99.0429).
6

Benzyl (4-methoxyphenoxy)acetate 15
1
1
0
5 was prepared by stirring (4-methoxyphenoxy)acetic acid (182.2 mg, 1 mmol), benzyl alcohol (119 mg,
.1 mmol), N,N′-dicyclohexylcarbodiimide (413 mg, 1.1 mmol) and 4-dimethylaminopyridine (12 mg,
.1 mmol) in anhydrous CH Cl (25 mL) overnight at room temperature in an argon atmosphere. The
2
2
dicyclohexylurea biproduct was removed by filtration and the filtrate washed with water (3 x 30 mL) 5%
acetic acid solution (3 x 30 mL), again with water (3 x 30 mL) and dried over anhydrous MgSO . The
4
solvent was removed under reduced pressure and the crude reaction mixture purified by column
1
chromatography on silica gel (eluent: CH Cl ) to yield 15 as a clear oil (160.7 mg, 59%). H NMR (400
2
2
MHz, CDCl , 300 K):  = 3.77 (s, 3H, H ), 4.62 (s, 2H, H ), 5.24 (s, 2H, H ), 6.80-6.87 (m, 4H, H ),
3
a
d
e
b,c
1
3
7
1
.33-7.37 (m, 5H, Hf,g,h); C NMR (100 MHz, CDCl , 300 K):  = 55.7, 66.4, 67.0, 114.7, 116.0, 128.5,
3
+
28.5, 128.7, 135.2, 152.0, 154.6, 169.1; LR-ESIMS: m/z = 290 [MNH ] ; HR-ESIMS: m/z = 290.1390
4
(
calcd. for C H NO , 290.1387).
16 20 4
Dibenzyl 2,2'-(1,4-phenylenebis(oxy))diacetate 18
Hydroquinone-O,O’-dicacetic acid (452.4 mg, 2.0 mmol) and benzyl alcohol (0.19 mL, 2.2 mmol) were
dissolved in 20 mL anhydrous DMF. This mixture was cooled to 0°C and to it was added 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide (0.39 ,L, 2.2 mmol) and then DMAP (24.4 mg, 0.2 mmol). The
mixture was then allowed to warm to room temperature and stirred overnight. The mixture was then
concentrated, the resultant residue taken up in 50 mL EtOAc, washed with H O (3 x 100 mL) and dried
2
over MgSO . The solvent was removed under reduced pressure to yield 18 as a clear oil (118.5 mg, 15%).
4
1
H NMR (500 MHz, d6-acetone, 295 K): = 4.73 (s, 4H, ArOCH ), 5.22 (s, 4H, CO CH Ph), 6.88 (s, 4H,
2
2
2
1
3
ArH), 7.35-7.40 (m, 10H, ArH); C NMR (75 MHz, d6-acetone, 297 K): = 66.5, 67.0, 116.5, 128.9,
+
1
29.0, 129.4, 137.0, 153.8, 169.6; LR-ESIMS: m/z = 424 [MNH ] ; HR-ESIMS: m/z = 424.1755 (calcd.
4
for C H NO , 424.1760).
2
4
26
6
7

Optimisation Studies
The reaction between 4-methoxyphenoxyacetic acid 4d and maleimide 1a was used as a test reaction to
determine the optimum reaction conditions. Early work indicated that the reaction generally needed to be
run overnight. However, for the purposes of optimisation a reaction time of 5 hours was adopted.
Scheme S2. Test reaction for optimisation studies.
Reaction Stoichiometry
4
-Methoxyphenoxyacetic acid 4d (47.4 mg, 0.26 mmol) was dissolved in 10 mL anhydrous MeCN along
with various equivalents of maleimide 1. The resultant mixture was degassed for 15 minutes by argon
bubbling before being irradiated for 5 hours by two hemispherical banks of six Philips Cleo 15W tubes.
The solvent was then removed under reduced pressure and the concentration or reagents and products
1
were determined by H NMR in d6-acetone with reference to CH Br internal standard. This data is
2
2
sumarised in the following table:
4
d
1a
(mol eq.)
% Yield
% Yield
%
Conversion
(
mol eq.)
5d
22
33
41
-
7
13
9
5
-
1
1
1
1
1
2
4
28
51
66
a
10
-
[
a] Concentrations of reagents and products could not be determined as the sample repeatedly failed to shim.
Reaction Medium
-Methoxyphenoxyacetic acid 4d (47.4 mg, 0.26 mmol) and maleimide 1 (101.6 mg, 1.04 mmol) were
4
dissolved in a variety solvents. The resultant mixtures were degassed for 15 minutes by argon bubbling
before being irradiated for 5 hours by two hemispherical banks of six Philips Cleo 15W tubes. A 2 mL
aliquot if the reaction mixture was taken at this time, the solvent was then removed under reduced
1
pressure and the concentration or reagents and products were determined by H NMR in d6-acetone with
reference to CH Br internal standard. This data is summarised in the following table:
2
2
8

Solvent
% Conversion
%Yield 5d
% Yield 7
a
MeCN
MeOH
66%
60%
44%
15%
-
41%
40%
37%
12%
-
5%
5%
5%
<1%
-
a
b
t-BuOH
Acetone
c
d
DMF
a
DCM
-
-
-
-
-
-
b
Benzene
H O
-
-
-
2
b
3
5% H O/MeCN
84%
61%
5%
2
[
a] anhydrous, freshly distilled [b] used straight from bottle [c] dried o/n with 4Å mol. sieves [d] purchased anhydrous.
Variation of Maleate
8
-Methoxy-2-methyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione.
N-Methylmaleimide (417 mg, 3.75 mmol) and 4-methoxyphenoxyacetic acid (137mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation a 0.5 mL aliquot was taken from the reaction mixture and the solvent was removed under
1
reduced pressure. H NMR analysis (w.r.t. CH Br standard) of the resultant mixture revealed: 8-
2
2
methoxy-2-methyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione (0.19 mmol, 25%), and
unreacted 4d (0.53 mmol, 70%).
Attempted synthesis of 8-methoxy-2-phenyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-
dione.
N-phenylmaleimide (1299 mg, 7.5 mmol) and 4-methoxyphenoxyacetic acid (137mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation a 0.5 mL aliquot was taken from the reaction mixture and the solvent was removed under
1
reduced pressure. H NMR analysis revealed only starting materials present.
Attempted synthesis of 8-methoxy-3a,4-dihydro-1H-furo[3,4-c]chromene-1,3(9bH)-dione
9

Maleic anhydride (736 mg, 7.5 mmol) and 4-methoxyphenoxyacetic acid (137mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation a 0.5 mL aliquot was taken from the reaction mixture and the solvent was removed under
1
reduced pressure. H NMR analysis revealed only starting materials present.
Based on this work it was decided to use a five-fold excess of 1a with a variety of acids 4 in 35%
H O/MeCN as the optimum reaction conditions.
2
1
0

General Procedure for Preparative Irradiations
Known amounts of desired reagents were dissolved in a mixture of 35 : 65 H O in MeCN. The resulting
2
mixture was degassed by bubbling with argon for 20 minutes. The mixture was then irradiated with
twelve 29 cm 15 W Philips Cleo tubes (= 350 nm) arranged in two hemispherical banks of six for the
desired reaction time. Following irradiation the solvent was removed under reduced pressure and the
crude reaction mixture was purified if necessary. All reagents were commercially available, MeCN was
used as purchased and H O was deionised.
2
3
a,4-Dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5a (Table 1, Entry 1).
Maleimide (366 mg, 3.75 mmol) and phenoxyacetic acid (114 mg, 0.75 mmol) were dissolved in 13 mL
CH CN and 7 mL H O and irradiated though Pyrex for 18 hours. Following irradiation the reaction
3
2
1
mixture was concentrated under reduced pressure. H NMR analysis revealed that the desired product 5a
had not been formed.
8
-Methyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5b (Table 1, Entry 2)
Maleimide (732 mg, 7.5 mmol) and 4-methylphenoxyacetic acid (124.7 mg, 0.75 mmol) were dissolved
in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 25 hours. Following irradiation the
3
2
reaction mixture was concentrated under reduced pressure and the crude mixture was purified by column
chromatography on silica gel (eluent: 10% EtOAc in CH Cl ) to yield 5b as a colourless solid (46.6 mg,
2
2
1
2
9%). M.p. 172 °C. H NMR (400 MHz, d6-acetone, 295 K):  = 2.27 (s, 3H, H ), 3.59 (m, 1H, H ), 3.93
c
f
(
dd, J = 3.9, 11.3 Hz, 1H, H ), 4.12 (d, J = 9.2 Hz, 1H, H ), 4.51 (dd, J = 2.6, 11.2 Hz, 1H, H ), 6.74 (d, J
g e g’
13
=
8.3 Hz, 1H, H ), 7.00 (d, J = Hz, 1H, H ), 7.30 (s, 1H, H ), 10.15 ( br-s, 1H, H ); C NMR (75 MHz,
a b d h
1
1

d6-acetone, 295 K):  = 20.7, 41.9, 44.3, 64.8, 118.0, 119.4, 131.3, 132.1, 136.0, 154.2, 177.6, 178.5; LR-
+
ESIMS: m/z = 218 [MH] ; HR-ESIMS: m/z = 218.0814 (calcd. for C H NO , 218.0817).
1
2
12
3
8
-(tert-Butyl)-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5c (Table 1, Entry 3)
Maleimide (732 mg, 7.5 mmol) and 4-tert-butylphenoxyacetic acid (156 mg, 0.75 mmol) were dissolved
in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following irradiation the
3
2
reaction mixture was concentrated under reduced pressure and the crude mixture was purified by column
chromatography on silica gel (eluent: 5-10% acetone in CH Cl ) to yield 5b as a colourless solid (104 mg,
2
2
1
5
3
4%). Mp 174 °C. H NMR (400 MHz, d6-acetone, 295 K):  = 1.30 (s, 9H, H ), 3.58-3.62 (m, 1H, H ),
c
f
.95 (dd, J = 4.0, 11.3 Hz, 1H, H ), 4.16 (d, J = 9.2 Hz, 1H, H ), 4.51 (dd, J = 2.7, 11.3 Hz, 1H, H ), 6.78
g
e
g’
(
d, J = 8.5 Hz, 1H, H ), 7.25 (dd, J = 2.5, 8.6 Hz, 1H, H ), 7.55 (d, J = 2.5 Hz, 1H, H ), 10.15 (br-s, 1H,
a b d
1
3
H ); C NMR (75 MHz, d6-acetone, 297 K):  = 31.8, 34.8, 42.0, 44.3, 64.7, 117.7, 118.9, 126.4, 127.8,
h
+
1
45.6, 154.1, 177.7, 178.5 ; LR-ESIMS: m/z = 282 [MNa] ; HR-ESIMS: m/z = 282.1103 (calcd. for
C H NO Na, 282.1106).
15
17
3
8
-Methoxy-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5d (Table 1, Entry 4)
Maleimide (366 mg, 3.75 mmol) and 4-(methoxy)phenoxyacetic acid (137 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 10% EtOAc in CH Cl ) to yield 5d as an off-
2
2
1
white solid (93.9 mg, 54%). M.p. 217 °C. H NMR (300 MHz, d6-acetone, 295 K):  = 3.55-3.60 (m,
H, H ), 3.88 (s, 3H, H ), 3.91 (dd, J = 4.0, 11.2 Hz, 1H, H ), 4.16 (d, J = 9.4 Hz, 1H, H ), 4.50 (dd, J =
1
f
c
g
e
1
2

1
3
2
.5, 11.2 Hz, 1H, H ), 6.79 (m, 2H, Ar-H), 7.06 (m, 1H, Ar-H), 10.18 (br-s, 1H, H ); C NMR (75 MHz,
g h
d6-acetone, 295 K):  = 42.2, 44.3, 56.0, 65.0, 115.3, 115.4, 118.9, 120.4, 150.3, 155.6, 177.5, 178.6; LR-
+
EIMS: m/z = 233 [M] ; HR-ESIMS: m/z = 233.0680 (calcd. for C H NO , 233.0683).
1
2
11
4
7
-Methoxy-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione
5e
&
9-methoxy-3a,4-
dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5e’ (Table 1, Entry 5)
Maleimide (366 mg, 3.75 mmol) and 3-(methoxy)phenoxyacetic acid (137 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 5% EtOAc in CH Cl ) to yield 5e as an off-
2
2
1
white solid (111 mg, 64%). M.p. 156 °C. H NMR (300 MHz, d6-acetone, 295 K):  = 3.55-3.60 (m, 1H,
H ), 3.74 (s, 3H, H ), 3.95 (dd, J = 4.0, 11.4 Hz, 1H, H ), 4.08 (d, J = 9.2 Hz, 1H, H ), 4.53 (dd, J = 2.7,
f
b
g
e
1
1.3 Hz, 1H, H ), 6.42 (d, J = 2.6 Hz, 1H, H ), 6.61 (dd, J = 2.8, 8.7 Hz, 1H, H ), 7.39 (d, J = 8.3 Hz, 1H,
g’ a c
1
3
H ), 10.14 (br-s, 1H, H ); C NMR (75 MHz, d6-acetone, 296 K):  = 41.2, 44.1, 55.7, 64.7, 103.1,
d
h
+
1
2
09.9, 111.5, 131.7, 157.2, 161.0, 178.1, 178.6; LR-ESIMS: m/z = 234 [MH] ; HR-ESIMS: m/z =
1
34.0765 (calcd. for C H NO , 234.0766). As above to yield 5e’ as a yellow oil (28.2 mg, 16%). H
1
2
12
4
NMR (300 MHz, d6-acetone, 294 K):  = 3.52-3.57 (m, 1h, H ), 3.79 (dd, J = 4.3, 11.2 Hz, 1H, H ), 3.87
f
g
(
s, 3H, H ), 4.54 (dd, J = 1.8, 11.2 Hz, 1H, H ), 4.60 (d, J = 9.7 Hz, 1H, H ), 6.50 (d, J = 8.2 Hz, 1H, Ar-
d g’ e
1
3
H), 6.71 (d, J = 8.3 Hz, 1H, Ar-H), 7.15 (t, J = 8.2 Hz, 1H, Ar-H), 10.14 (br-s, 1H, H ); C NMR (75
h
MHz, d6-acetone, 294 K):  = 37.5, 45.0, 56.4, 66.7, 106.3, 110.9, 139.4, 158.5, 160.1, 176.7, 179.0; LR-
+
EIMS: m/z = 234 [MH] ; HR-ESIMS m/z = 234.0763 (calcd. for C H NO , 234.0766).
1
2
12
4
3
a,4-Dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5a (Table 1, Entry 6)
1
3

Maleimide (366 mg, 3.75 mmol) and 2-(methoxy)phenoxyacetic acid (137 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 10% EtOAc in CH Cl ) to yield 5a as a
2
2
1
colourless solid (81.5 mg, 54%). H NMR (300 MHz, d6-acetone, 295 K):  = 3.61-3.67 (m, 1H, H ), 4.00
f
(
dd, J = 4.2, 11.5 Hz 1H, H ), 4.19 (d, J = 9.2 Hz, 1H, H ), 4.55 (dd, J = 3.1, 11.4 Hz 1H, H ), 6.87 (d, J
g e g’
=
8.2 Hz, 1H, H ), 7.03 (t, J = 8.2 Hz, 1H, H ), 7.22 (t, J = 8.0 Hz, 1H, H ), 7.51 (d, J = 7.8 Hz, 1H, H ),
d c b a
3
1
0.18 (br-s, 1H, H ). Consistent with literature.
h
7
,9-Dimethoxy-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5g (Table 1, Entry 7)
Maleimide (366 mg, 3.75 mmol) and 3,5-dimethoxyphenoxyacetic acid (159.2 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 10-20% EtOAc in CH Cl ) to yield 5g as a
2
2
1
colourless solid (161 mg, 82%). M.p. 236 °C. H NMR (300 MHz, d6-acetone, 296 K):  = 3.52-3.58 (m,
1
1
H, H ), 3.79 (s, 3H, OCH ), 3.82 (dd, J = 4.3, 11.2 Hz, 1H, H ), 3.89 (s, 3H, OCH ), 4.50 (d, J = 9.7 Hz,
f 3 g 3
H, H ), 4.55 (dd, J = 1.8, 11.2 Hz, 1H, H ), 6.12 (d, J = 2.3 Hz, 1H, ArH), 6.32 (d, J = 2.3 Hz, 1H,
e
g,
1
3
ArH), 10.14 (br-s, 1H, H ); C NMR (75 MHz, d6-DMSO, 297 K): = 35.9, 43.5, 55.2, 55.8, 65.7, 93.6,
h
+
9
4.7, 101.6, 157.6, 159.2, 177.2, 179.2; LR-ESIMS: m/z = 264 [MH] ; HR-ESIMS: m/z = 246.0869
(
calcd. for C H NO , 264.0872).
13 14 5
7
,8,9-Trimethoxy-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5h (Table 1, Entry 8)
Maleimide (366 mg, 3.75 mmol) and 3,4,5-trimethoxyphenoxyacetic (181.7 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 64 hours. Following
3
2
1
4

irradiation the reaction mixture was concentrated under reduced pressure, diluted with 100 mL CH Cl ,
2
2
washed with saturated aqueous NaHCO (100 mL), deionised water (2 x 100 mL), dried over anhydrous
3
1
MgSO and the solvent evaporated to yield 5h as a yellow solid (52.2 mg, 24%). Mp 165 °C. H NMR
4
(
400 MHz, d6-acetone, 295 K):  = 3.48-3.52 (m, 1H, H ), 3.74 (dd-overlapped, J = 4.4, 11.2 Hz, 1H,
c
H ), 3.75 (s-overlapped, 3H, Ar-OCH ), 3.79 (s, 3H, Ar-OCH ), 4.04 (s, 3H, Ar-OCH ), 4.49 (d-
d
3
3
3
overlapped, J = 9.7 Hz, 1H, H ), 4.50 (dd-overlapped, J = 1.7, 11.2 Hz, 1H, H ), 6.31 (s, 1H, H ), 10.21
b
d’
a
1
3
(
br-s, 1H. H ); C NMR (75 MHz, d6-acetone, 297 K):  = 37.7, 44.9, 56.3, 60.7, 61.7, 67.0, 98.1, 107.1,
e
+
1
36.0, 138.6, 153.7, 154.6, 177.4, 179.2; LR-ESIMS: m/z = 294 [MH] ; HR-ESIMS: m/z = 294.0975
1
(
calcd. for C H NO , 294.0978). Analysis of the reaction mixture by H NMR prior to chromatography
1
4
16
6
revealed 71% unreacted 3,4,5-trimethoxyphenoxyacetic (0.53 mmol w.r.t. 5h) indicating that the reaction
had achieved only 29% conversion.
3
a,4-Dihydrothiochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5i (Table 1, Entry 9)
Maleimide (366 mg, 3.75 mmol) and phenylthioacetic acid (126 mg, 0.75 mmol) were dissolved in 13 mL
CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following irradiation the reaction
3
2
mixture was concentrated under reduced pressure and the crude mixture was purified by column
chromatography on silica gel (eluent: 7.5% EtOAc in CH Cl ) to yield 5i as a colourless solid (62.9 mg,
2
2
1
3
9%). Mp 157 °C. H NMR (300 MHz, d6-acetone, 295 K):  = 2.91 (dd, J = 4.9, 13.3 Hz, 1H, H ), 3.26
g
(
dd, J = 2.4, 13.3 Hz, 1H, H ), 3.82-3.88 (m, 1H, H ), 4.35 (d, J = 9.5 Hz, 1H, H ), 7.20-7.30 (m, 3H,
g’ f e
13
ArH), 7.43-7.49 (m, 1H. ArH),10.37 (br-s, 1H, H ).; C NMR (75 MHz, d6-acetone, 295 K):  = 30.1,
h
+
4
6.4, 47.2, 127.3, 128.4, 129.9, 132.5, 133.1, 135.4, 177.3, 179.3; LR-ESIMS: m/z = 237 [MNH ] ; HR-
4
ESIMS: m/z = 237.0696 (calcd. for C H N O S, 237.0698).
1
1
13
2
2
8
-Methoxy-3a,4-dihydrothiochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5j (Table 1, Entry 10)
1
5

Maleimide (366 mg, 3.75 mmol) and 4-methoxyphenyltioacetic acid (148.6 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 72 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 10-20% EtOAc in CH Cl ) to yield 5j as a
2
2
1
yellow oil (67.5 mg, 36%). H NMR (300 MHz, d6-acetone, 296 K):  = 2.85 (dd, J = 4.9, 13.3 Hz, 1H,
H ), 3.23 (dd, J = 2.3, 13.3 Hz, 1H, H ), 3.77-3.83 (m, overlapped, 1H, H ), 3.81 (s, overlapped, 3H, H ),
g
g’
f
c
4
8
1
2
.31 (d, J = 9.4 Hz, 1H, H ), 6.84 (dd, J = 2.8, 8.7 Hz, 1H, H ), 7.05 (d, J = 2.7 Hz, 1H, H ), 7.20 (d, J =
e b d
1
3
.6 Hz, 1H, H ), 10.37 (br-s, 1H, H ) ; C NMR (75 MHz, d6-acetone, 297 K):  = 30.7, 46.2, 47.6, 55.8,
a
h
+
14.2, 118.8, 126.1, 130.9, 133.8, 159.4, 177.2, 179.4; LR-ESIMS: m/z = 250 [MH] ; HR-ESIMS: m/z =
50.0535 (calcd. for C H NO S, 250.0538).
1
2
12
3
8
-(Methylthio)-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5k (Table 1, Entry 11)
Maleimide (366 mg, 3.75 mmol) and 4-methylthiophenoxyacetic acid (148.6 mg, 0.75 mmol) were
dissolved in 13 mL CH CN and 7 mL H O and irradiated though pyrex for 72 hours. Following
3
2
irradiation the reaction mixture was concentrated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (eluent: 10% EtOAc in CH Cl ) to yield 5k as a off-
2
2
1
white solid (27.3 mg, 14%). M.p. 160 °C. H NMR (400 MHz, d6-acetone, 300 K):  = 2.46 (s, 3H, H ),
c
3
1
.61-3.64 (m, 1H, H ), 3.98 (dd, J = 4.1, 11.3 Hz, 1H, H ), 4.18 (d, J = 9.2 Hz, 1H, H ), 4.53 (dd, J = 2.8,
f g e
1.3 Hz, 1H, H ), 6.84 (d, J = 8.5 Hz, 1H, H ), 7.16 (dd, J = 2.3, 8.5 Hz, 1H, H ), 7.47 (d, J = 2.3 Hz, 1H,
g
a
b
1
3
H ), 10.16 (br-s, 1H, H ); C NMR (100 MHz, CDCl , 296 K):  = 17.2, 40.8, 43.2, 63.8, 117.7, 118.5,
d
h
3
+
1
28.9, 129.0, 131.9, 153.4, 175.7, 176.6; LR-ESIMS: m/z = 272 [MNa] ; HR-ESIMS: m/z = 272.0354
1
(
calcd. for C H NO SNa, 272.0357). Analysis of the reaction mixture by H NMR prior to
1
2
11
3
1
6

chromatography revealed 47% unreacted 4-methylthiophenoxyacetic acid (0.35 mmol w.r.t. 5k)
indicating that the reaction had achieved only 53% conversion.
3
a,4,5,9b-Tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione 5l (Table 1, Entry 12)
Maleimide (366 mg, 3.75 mmol) and N-phenylglycine (113.4 mg, 0.75 mmol) were dissolved in 13 mL
CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following irradiation the reaction
3
2
mixture was concentrated under reduced pressure and the crude mixture was purified by column
chromatography on silica gel (eluent: 20% EtOAc in CH Cl ) to yield 5l as an off-white solid (135 mg,
2
2
1
8
3
9%). M.p. 173-176 °C. H NMR (500 MHz, d6-acetone, 293 K):  = 3.12 (dd, J = 4.4, 11.3 Hz, 1H, H ),
g
.47-3.51 (m, 1H, H ), 3.54 (dt, J = 3.0, 11.3 Hz, 1H, H ), 4.04 (d, J = 9.3 Hz, 1H, H ), 5.00 (br-s, 1H,
f
g
e
H ), 6.68 (d, J = 7.9 Hz, 1H, ArH), 6.72 (t, J = 7.5 Hz, 1H, ArH), 7.01 (t, J = 7.4 Hz, 1H, ArH), 7.36 (d, J
h
1
3
=
7.6 Hz, 1H, ArH), 10.04 (br-s, 1H, H ); C NMR (75 MHz, d6-acetone, 298 K):  = 41.9, 43.5, 45.2,
i
+
1
2
16.2, 118.5, 119.5, 128.5, 131.1, 148.1, 178.2, 179.9; LR-ESIMS: m/z = 203 [MH] ; HR-ESIMS: m/z =
03.0815 (calcd. for C H N O , 203.0821).
1
1
10
2
2
8
-Chloro-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione 5m (Table 1, Entry 1).
Maleimide (366 mg, 3.75 mmol) and 4-chlorophenoxyacetic acid (140 mg, 0.75 mmol) were dissolved in
3 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following irradiation the
1
3
2
1
7

1
reaction mixture was concentrated under reduced pressure. H NMR analysis revealed peaks that could be
attributed to the desired product 5m (0.025 mmol; 3%).
Attempted Synthesis of 9
Maleimide (732 mg, 7.5 mmol) and hydroquinone-O,O’-diacetic acid (169.7 mg, 0.75 mmol) were
dissolved in 26 mL CH CN and 7 mL H O and irradiated though pyrex for 18 hours. Following
3
2
1
irradiation the reaction mixture was concentrated under reduced pressure. H NMR and GC-MS analyses
revealed that the desired product 9 had not been formed.
1
8

X-ray Crystallography
Fig. S1. The X-ray crystal structure of 5g.
Table S1. Crystal data & structure refinement for 5g.
Identification code
CCDC code
5g
962517
C H NO
5
Empirical Formula
Formula Weight
Crystal Colour, Habit
Crystal Dimensions
Crystal System
13
13
263.25
colourless prism
0.200 mm x 0.100 mm x 0.030 mm
monoclinic
Lattice Type
Primitive
Lattice Parameters
a = 7.925(4) Å
b = 8.466(3) Å
c = 17.187(6) Å
 = 92.336(8)°
3
Volume
1152.2(8) Å
Space Group
Z value
P2 /n(#14)
4
1
Density (calculated)
F(000)
μ(CuKα)
1.517 g/mL
552.00
9.993 cm
-1
Diffractometer
Radiation Voltage
Current Temperature
Detector Aperture
Pixel Size
Saturn70
CuK ( = 1.54187 Å)
173 K
70 x 70 mm
0.034 nm
2
θmax
136.7°
No. of Reflections Measured
Corrections
Structure Solution
Refinement
Function Minimized
Least Squares Weights
Total: 15,295, Unique: 2084 (R = 0.0431)
int
Lorentz-polarization
Direct Methods
2
Full-matrix least-squares on F
2
2 2
 w (Fo - Fc )
2
2
2
w = 1/[ (Fo ) + (0.1051P) + 2.9953P]
2
2
where P = (Max(Fo , 0) + 2Fc )/3
2
θmax cutoff
136.7°
Anomalous Dispersion
No. Observations
All non-hydrogen atoms
(All reflections) 2084
No. Variables
176
Reflection/Parameter Ratio
Residuals: R1 (I>2.00σ(I))
Residuals: R (All reflections)
11.9
0.0361
0.0389
1
9

Residuals: wR2 (All reflections)
Goodness of Fit
0.1115
0.956
Indicator Max Shift/Error in Final Cycle
Maximum peak in Final Diff. Map
Minimum peak in Final Diff. Map
0.000
0.22 e /Å
-0.20 e /Å
3
3
Fig. S2. The X-ray crystal structure of 5i.
Table S2. Crystal data & structure refinement for 5i.
Identification code
CCDC code
5i
962518
C H NO S
Empirical Formula
Formula Weight
Crystal Colour, Habit
Crystal Dimensions
Crystal System
1
1
9
2
219.26
colourless prism
0.100 mm x 0.060 mm x 0.030 mm
monoclinic
Lattice Type
C-centered
Lattice Parameters
a = 12.590(7) Å
b = 11.384(5) Å
c = 27.890(13) Å
 = 96.690(12)°
3
Volume
3970(3) Å
Space Group
Z value
Cc(#9)
16
Density (calculated)
F(000)
μ(CuKα)
1.467 g/mL
1824.00 -
1
3.016 cm
Diffractometer
Radiation Voltage
Current Temperature
Detector Aperture
Pixel Size
Mercury70
MoK ( = 0.71075)
93 K
70 x 70 mm
0.068 mm
50.8°
2
θmax
No. of Reflections Measured
Corrections
Total: 10656, Unique: 5199 (R = 0.0744)
Lorentz-polarization
int
Structure Solution
Refinement
Function Minimized
Least Squares Weights
Charge Flipping (Superflip)
Full-matrix least-squares on F
2
2
2 2
 w (Fo - Fc )
2
2
2
w = 1/[ (Fo ) + (0.1051P) + 2.9953P]
2
2
where P = (Max(Fo , 0) + 2Fc )/3
50.8°
2
θmax cutoff
Anomalous Dispersion
No. Observations
No. Variables
All non-hydrogen atoms
(All reflections) 5199
557
2
0

Reflection/Parameter Ratio
9.33
Residuals: R1 (I>2.00σ(I))
0.0738
0.0979
0.1927
1.073
Residuals: R (All reflections)
Residuals: wR2 (All reflections)
Goodness of Fit
Indicator Max Shift/Error in Final Cycle
Maximum peak in Final Diff. Map
Minimum peak in Final Diff. Map
0.000
0.52 e /Å
-0.43 e /Å
3
3
2
1

Table S3. Coupling Constant between Protons at Ring Junction
3
Entry
Product
JH-H (Hz)
1
4a
4b
4c
4d
-
2
3
4
9.2
9.2
9.4
a
5
6
7
4e
4f
9.2 ; 9.7
9.2
4g
9.7
8
9
4h
9.7
4i
4j
9.5
9.4
9.3
1
1
0
1
4k
1
2
4l
9.3
a
7
-methoxy and 9-methoxy regioisomers respectively.
2
2

In-situ NMR Monitoring
A 5 mL stock solution of 37.5 mM of the acid 4 and 187.5 mM of maleimide 1a was prepared in a 65 : 35
mixture of CD CN and D O. The solution was purged with argon for 5 minutes before transferring 1 mL
3
2
to an NMR tube. The tube was irradiated using a 12 x 8 W BLB photoreactor (λmax = 365 nm).
Overhead Stirrer
(turned on its side)
NMR Tube
UVA Photoreactor
(12 x 8 W BLB Bulbs)
Figure S3. Irradiation setup for in-situ NMR monitoring.
Data for each reaction studied is provided below.
2
3

Reaction of phenoxyacetic acid 4a and maleimide 1a (Table 2, Entry 1).
Time
[4a]
(mM)
37.50
35.65
33.02
29.43
22.97
17.91
14.38
10.73
7.62
[1a]
[5a]
(mM)
0.00
0.14
0.21
0.51
0.86
1.74
1.85
1.97
2.45
2.33
[7]
(mM)
0.00
0.00
0.01
0.03
0.05
0.13
0.10
0.24
0.30
0.44
(
min)
(mM)
187.50
171.17
157.75
139.37
107.69
84.31
69.29
54.02
40.13
26.11
0
1
3
6
0
0
0
1
1
2
3
4
5
20
80
40
00
20
40
4.56
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
a
a
5
.00
.00
0
0
100
200
300
Time (min.)
400
500
Figure S4. Reaction profile for 4a
2
4

Reaction of 4-methylphenoxyacetic acid 4b and maleimide 1a (Table 2, Entry 2).
Time
[4b]
(mM)
37.50
32.45
26.93
18.27
12.70
8.71
[1a]
(mM)
187.50
126.83
115.05
83.96
67.49
63.70
43.47
41.87
31.62
27.27
[5b]
(mM)
0.00
[7]
(mM)
0.00
0.61
1.44
2.12
2.80
4.31
4.61
6.38
5.41
6.49
(
min)
0
1
2
4
6
9
0
0
0
0
0
1.12
3.31
5.19
7.28
11.56
12.05
15.53
14.61
12.18
1
1
1
2
20
50
80
40
4.76
1.94
0.71
0.91
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
b
b
5
.00
.00
0
0
50
100
Time (min.)
150
200
-
5.00
Figure S5. Reaction profile for 4b
2
5

Reaction of 4-t-butylphenoxyacetic acid 4c and maleimide 1a (Table 2, Entry 3)
Time
[4c]
(mM)
37.50
33.79
26.82
19.15
9.32
[1a]
(mM)
187.50
144.36
98.87
54.63
15.53
5.61
[5c]
(mM)
0.00
[7]
(mM)
0.00
0.40
1.28
2.40
4.00
4.50
4.69
4.82
4.74
5.00
(
min)
0
1
3
6
0
0
0
1.50
4.52
8.01
1
1
2
3
4
5
20
80
40
00
20
40
12.09
14.14
14.81
14.68
14.74
17.27
5.80
4.06
2.68
2.76
2.17
1.82
1.34
0.12
2.98
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
c
c
5
.00
.00
0
0
100
200
300
Time (min.)
400
500
Figure S6. Reaction profile for 4c
2
6

Reaction of 4-methoxyphenoxyacetic acid 4d and maleimide 1a (Table 2, Entry 4).
Time
[4d]
(mM)
37.50
33.42
26.17
20.15
15.72
11.33
8.17
[1a]
(mM)
187.50
122.23
93.80
74.21
58.60
42.21
32.04
26.34
23.36
14.13
11.75
[5d]
(mM)
0.00
[7]
(mM)
0.00
0.47
0.96
1.72
2.41
3.03
3.80
3.95
5.26
5.14
5.31
(
min)
0
1
2
4
6
9
0
0
0
0
0
1.94
3.87
6.64
9.31
12.18
14.35
15.60
18.84
22.06
20.89
1
1
1
2
3
20
50
80
40
00
5.96
4.85
0.00
0.03
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
d
d
5
.00
.00
0
0
50
100
150
200
250
300
Time (min.)
Figure S7. Reaction profile for 4d
2
7

Reaction of 3-methoxyphenoxyacetic acid 4e and maleimide 1a (Table 2, Entry 5).
Time
[4e]
(mM)
37.50
32.13
27.03
18.80
12.13
6.39
[1a]
(mM)
187.50
119.52
106.46
96.69
75.00
48.31
35.31
37.91
[5e]
(mM)
0.00
[5e’]
(mM)
0.00
1.37
2.11
3.68
4.05
4.78
6.76
5.34
[7]
(mM)
0.00
0.60
1.13
2.31
3.40
4.32
5.92
6.18
(
min)
0
1
3
6
9
5
0
0
0
3.40
6.38
12.45
17.57
22.08
28.33
28.42
1
1
2
20
80
40
-0.15
0.04
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
5
e
e
e'
5
.00
.00
0
0
50
100
150
200
Time (min.)
Figure S8. Reaction profile for 4e
2
8

Reaction of 2-methoxyphenoxyacetic acid 4f and maleimide 1a (Table 2, Entry 6).
Time
[4f]
(mM)
37.50
25.86
20.90
12.12
5.17
[1a]
(mM)
187.50
118.09
84.36
45.82
19.51
8.58
[5f]
(mM)
0.00
[7]
(mM)
0.00
0.37
0.66
0.99
1.14
1.43
1.64
(
min)
0
1
3
6
5
0
0
6.05
10.60
16.26
20.15
18.93
20.17
1
1
2
20
80
40
2.12
0.67
4.58
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
f
f
5
.00
.00
0
0
50
100
Time (min.)
150
200
Figure S9. Reaction profile for 4f
2
9

Reaction of 3,5-dimethoxyphenoxyacetic acid 4g and maleimide 1a (Table 2, Entry 7).
Time
[4g]
(mM)
37.50
34.59
28.57
21.60
9.68
[1a]
[5g]
(mM)
0.00
[7]
(mM)
0.00
0.37
1.07
2.08
3.69
4.98
5.11
0.00
(
min)
(mM)
187.50
166.71
143.33
114.31
75.93
0
1
3
6
0
0
0
3.15
8.26
15.56
26.83
34.99
36.92
0.00
1
1
2
20
80
40
0
2.25
54.30
0.28
42.99
37.50
187.50
40.00
35.00
30.00
25.00
20.00
15.00
10.00
4
5
7
c
c
5
.00
.00
0
0
50
100
Time (min.)
150
200
Figure S10. Reaction profile for 4g
3
0