Improving the yield of the exhaustive grignard alkylation of n-benzylphthalimide

Article abstract of DOI:10.1071/CH12528

The tetraalkylation of N-benzylphthalimide is the major yield limiting step in the common synthetic route to isoindoline nitroxides. The progress of this reaction was found to be limited by the formation of previously unobserved mono-and dialkyl side prod

Full text of DOI:10.1071/CH12528

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH12528
Improving the Yield of the Exhaustive Grignard
Alkylation of N-Benzylphthalimide
A
A
Viraj C. Jayawardena, Kathryn E. Fairfull-Smith,
and Steven E. Bottle
A B
,
A
ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, Faculty
of Science and Engineering, Queensland University of Technology, 2 George Street,
Brisbane, Qld 4001, Australia.
B
Corresponding author. Email: s.bottle@qut.edu.au
The tetraalkylation of N-benzylphthalimide is the major yield limiting step in the common synthetic route to isoindoline
nitroxides. The progress of this reaction was found to be limited by the formation of previously unobserved mono- and
dialkyl side products that do not lead to the desired product. The yield for the tetraalkylation of N-benzylphthalimide with
ethylmagnesium iodide could be increased (60 % over two steps) when a stepwise addition sequence was employed. The
new two-step synthesis offers a practical preparative scale alternative to the current approach.
Manuscript received: 28 November 2012.
Manuscript accepted: 6 February 2013.
Published online: 25 March 2013.
Introduction
≡
HC CϪCOOEt
Nitroxides (aminoxyls) are stable free-radical species currently
exploited in a wide range of applications.[1–4] Commercially
available nitroxides containing piperidine or pyrrolidine units
are most commonly used; however, the isoindoline class of
nitroxides can demonstrate some advantages over the com-
mercially sourced compounds. The fused aromatic ring in the
isoindolines provides rigidity, decreasing ring-opening degra-
dation reactions, and enhancing their chemical and thermal
stability in polymers.[5,6] Their linewidths in electron para-
magnetic resonance (EPR) are also often narrower,[7,8] and
substitution onto the aromatic ring of the isoindoline system
facilitates the synthesis of more complex structures.[9,10] Iso-
indoline based nitroxides have found uses as spin traps,[11]
antioxidants,[12,13] alkoxyamines for free radical polymerisa-
tion,[14–16] mediators of polymeric radical exchange reac-
tions,[17] profluorescent probes[18–20] for monitoring the
oxidative capacity of pollution[21,22] or imaging polymer deg-
radation[23] and oxidative stress in biological systems,[24] spin
labels for elucidating structural and dynamic aspects of nucleic
acids,[25] probes for EPR spectrometry,[26] and as potential
redox mediators for dye-sensitised solar cells.[27]
Isoindoline nitroxides have been previously prepared by
three different approaches. Hideg and coworkers have used
the Diels–Alder reaction of diene containing nitroxides with
ethyl propynoate or ethyl 2-butynoate, followed by oxidative
aromatisation to give 5-mono or 5,6-disubstituted isoindoline
nitroxides (Scheme 1).[28] From commercially available starting
materials, this route yields isoindoline nitroxides in seven steps
with an overall yield of 3 %. Hideg has also reported the use of
electrocyclic reactions to form isoindolines starting from a
pyrroline nitroxide (Scheme 2).[29] This route gives isoindoline
nitroxides in five steps from commercially available starting
N
O
ϩ
or
≡
H3CC CϪCOOEt
2 steps
EtOOC
R
R ϭ H or CH3
N
O
Scheme 1. Isoindoline nitroxide preparation using a Diels–Alder reaction.
EtO2C
R
OHC
N
O
N
O
R
R ϭ H, CH3, n-C6H13
EtO2C
R
N
O
S
Ph,
Scheme 2. Synthesis of isoindoline nitroxides by electrocyclic reactions.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

B
V. C. Jayawardena, K. E. Fairfull-Smith, and S. E. Bottle
materials in a 4 % overall yield. The most common pathway
used to prepare isoindoline nitroxides, however, involves the
treatment of N-benzylphthalimide with an alkylmagnesium
halide, followed by deprotection and oxidation (Scheme 3).[30]
When the atom efficiency is analysed starting from readily
available precursors and calculating the overall yield allowing
for the number of steps involved, the Grignard approach
remains the most effective (36 %, four steps). However, the
major yield limiting step in this route is the reaction between
N-benzylphthalimide and the alkylmagnesium halide, with
typical yields ranging from 28 to 40 %.[30,31]
when N-benzylphthalimide was treated with two equivalents of
MeMgBr followed by four equivalents of PhMgBr (any
2-benzyl-1,1-dimethyl-3,3-diphenylisoindoline formed was not
detected in this reaction). Elimination of OMgX gives the
iminium species 2 which can react with additional alkyl magne-
sium halide to eventually give the tetraalkylated compound 4 via
another iminium ion intermediate 3. As a result of the poor
leaving group qualities of the OMgX, it is expected that the
addition of the third and fourth alkyl groups is difficult and
usually requires high temperature to provide the final tetraalkyl
product 4.
To date, the highest preparative scale yield for N-benzyl-
1,1,3,3-tetraalkylisoindoline has been obtained via the use of
ethylmagnesium halide prepared in methyl-tert-butylether
(41 %).[32] Microwave assisted Grignard reactions can give
higher yields of the product (60 %), but are not practical on
large scales and may present an explosion risk.[31] Despite being
employed for over 30 years by several groups around the world,
little detailed examination of the mechanism of this Grignard
reaction has been undertaken and so it is not clear whether this
reaction can be further optimised. The current accepted mecha-
nism for the tetraalkylation of N-benzylphthalimide is outlined
in Scheme 4. Following the addition of the first equivalent of
alkyl magnesium halide to the carbonyl group of the imide, the
second equivalent adds to the carbonyl group opposite the
alkoxy magnesium salt to form the bis alkoxide intermediate
1. Preferential attack of the alkyl magnesium halide at the 1 and
3 positions of the 5-membered ring was observed by Braslau[33]
We speculated that the presence of better leaving groups, in
place of the current OMgX group, should generate the iminium
ion intermediates 2 and 3 more readily, thereby potentially
delivering the target tetraalkylisoindoline 4 in higher yield.
Herein we explore the effect of leaving group modification
and report
a new approach to the tetraalkylation of
N-benzylphthalimide using a stepwise addition sequence
which delivers improved isolated yields of up to 60 % for the
tetraalkylation over two steps.
Results and Discussion
As the tetraalkylation of N-benzylphthalimide with ethyl mag-
nesium iodide (EtMgI) generally gives higher yields than with
methyl magnesium iodide, EtMgI was used as the Grignard
reagent throughout this study. We initially sought to convert the
hydroxy amide 5 (prepared in good yield using a decreased
EtMgI stoichiometry and milder reaction conditions followed
by aqueous workup) into a better leaving group such as a triflate
or acetate. We then expected to be able to investigate the effect
of this starting point modification on the yield of the final tetra-
ethyl product 8 in the subsequent Grignard reaction. However,
our attempts to isolate the triflate, mesylate, or acetate derivatives
of the hydroxy amide 5 by stirring triflic, mesyl, oracetyl chloride
with 5 in dichloromethane and triethylamine were unsuccessful,
as only the E elimination product 6 could be isolated following
recrystallisation. Less than 10% of the Z isomer was detected in
O
R
R
RMgX
N
O
N
Ph
Ph
R
R
1
the crude reaction products when analysed by H NMR spec-
R
R
R
troscopy. The less reactive methyl ether analogue 7 could,
however, be successfully prepared in good (87 %) yield by the
reaction of the hydroxy amide 5 with sodium hydroxide and
iodomethane in THF (Scheme 5).
R ϭ Me, Et, n-Pr, n-Bu, Ph
N
O
R
Subsequent treatment of methyl ether 7 with six equivalents
of EtMgI in toluene at 808C for 14 h gave the desired tetraethyl
product 8 but in a low yield (11 %). Interestingly, relatively high
Scheme 3. Generation of isoindoline nitroxides via addition of Grignard
reagents to N-benzylphthalimide.
XMgO
XMgO
O
R
R
R
RMgX
RMgX
ϩ
RMgX
N
N
N
R
N
Ph
Ph
Ph
Ph
R
O
XMgO
O
XMgO
1
2
R
R
R
ϩ
R
R
R
N
R
R
N
R
N
Ph
Ph
RMgX
Ph
R
XMgO
4
3
Scheme 4. Mechanism for the tetraalkylation of N-benzylphthalimide to form N-benzyl-1,1,3,3-tetraalkylisoindoline.

Grignard Alkylation of N-Benzylphthalimide
C
yields of the re-formed hydroxy amide 5 (54 %) were detected in
the crude reaction mixture using HPLC analysis (Scheme 5;
Table 1, entry 1). Also of note was the presence of the hitherto
unreported dialkyl amide intermediate 9 (26 %), and the singly
ethylated adduct 10 (9 %). At 808C, the yield of 8 could be
doubled using close to twice the reaction time, but dropped off
again if the reaction time was extended further (Table 1, entries 2
and 3). An increase in the reaction temperature from 808C to
1108C on the other hand increased the yield of 8, with the best
yield by HPLC (60 %) obtained after heating for 120 h (Table 1,
entry 9). To support the validity of the HPLC relative yield
analysis, a comparable, actual isolated yield of 55 % of 8 could
be obtained using these reaction conditions. Increasing the
equivalents of EtMgI used at the higher temperature (1108C,
12 equivalents) gave decreased yields of tetraethyl product 8
(Table 1, entries 10 and 11). Such an outcome may result from a
competing Wurtz-like self-coupling reaction for the Grignard
reagents, which is recognised as a major side reaction that
occurs during the formation of organomagnesium halides.[34]
In another attempt to improve the yield of the desired tetraalkyl
product 8, six equivalents of EtMgI were heated at reflux with
methyl ether 7 for 24 h and then an additional 10 equivalents of
EtMgI were added and the mixture was heated at reflux for a
further 72 h. Although an improved yield of tetraalkyl product 8
was not obtained following analysis by HPLC (43 %), the yield
was comparable to that obtained with 6 equivalents of EtMgI
following 96 h at reflux. The replacement of toluene with the
higher boiling xylenes gave slightly improved yields of 8 after
heating at reflux for 24 h (51 %) and 72 h (63 %) (Table 1, entries
12 and 13).
HO
O
a
N
Bn
N
Bn
O
O
5
Both the diethyl compound 9 and monoethyl reduction
product 10 observed in the reactions of methyl ether 7 with
EtMgI have not previously been identified as products from the
tetraethylation of N-benzylphthalimide. The formation of
diethyl species 9 presumably occurs via attack of EtMgI on
the iminium ion 11 instead of reaction at the imide carbonyl
group of 7 (Scheme 6). The hydroxy amide 5 would be expected
to arise from iminium ion 11 on aqueous workup but could also
form by hydrolysis of the corresponding magnesium alkoxide.
The high levels of 5 and 9 formed suggest the influence of an
improved leaving group leads to higher levels of the iminium
b
c
MeO
N
Bn
d
N
Bn
O
O
7
6
H
HO
ϩ
ϩ
ϩ
N
Bn
N
Bn
N Bn
N
Bn
IMgEt
MeO
O
O
O
10
5
ϩ
N Bn
9
8
N
Bn
N
Bn
Scheme 5. Reagents and conditions: (a) EtMgI (2.5 equiv.), toluene, rt,
2 h, 86 %; (b) TfCl, Et3N, CH2Cl2, 08C to rt, 1 h, 82 % or MsCl, Et3N,
CH2Cl2, 08C to rt, 1 h, 37 % or AcCl, Et3N, CH2Cl2, 08C to rt, 1 h, 67 %;
(c) NaOH, MeI, THF, rt, 1.5 h, 87 %; (d) EtMgI (varied equiv.), toluene or
xylene, varied reaction times and temperatures (see Table 1).
O
O
O
7
11
9
Scheme 6. Proposed mechanism for the formation of compound 9.
Table 1. HPLC product ratios from the reaction of 7 with EtMgI under various reaction conditions
Entry
Reaction temperature [8C]
Reaction time [h]
Equiv. EtI
Equiv. Mg
HPLC product ratio [%]
8
9
10
5
1
80
80
14
24
48
3
6
6
8
8
11
22
5
26
29
17
20
26
26
26
19
16
14
20
27
19
17
22
9
16
9
54
33
69
54
49
34
20
20
13
47
35
13
6
2
3
80
6
8
4
110
110
110
110
110
110
110
110
140A
140A
110
110
6
8
24
17
26
43
50
60
25
27
51
63
80
24
5
5
14
24
72
96
120
72
96
24
72
72
72
6
8
8
6
6
8
14
11
11
11
14
18
9
7
6
8
8
6
8
9
6
8
10
11
12
13
14B
15C
12
12
6
16
16
8
6
8
12
–
6
8
3
6
8
1
53
AUsing xylenes as solvent.
BUsing hydroxy amide 5 as starting material.
CUsing N-benzylphthalimide as starting material.

D
V. C. Jayawardena, K. E. Fairfull-Smith, and S. E. Bottle
MeO
MeO
Ph
ϩ
N
Bn
N
Bn
H3C
N
Bn
N
Bn
Et
I
OR
O
CH2
O
ϩ
ϩ
Ϫ
Mg
Mg
Ph
7
R ϭ H or MgI
I
12
14
13
ϪCH2ϭCH2
Chart 1.
MeO
Mg
ϩ
N
Bn
OH
O
O
N
Bn
O
MgI
N
Bn
H
O
MgI
N
H
Bn
O
ϩ
15
5
Scheme 8. Proposed formation of the O-Mg-O bridging complex 16.
ϩ
H
H
N
Bn
and 10 represent ‘dead-end’ side reactions and do not appear
to be intermediates in the pathway to the desired tetraethyl
product 8.
N
Bn
O
O
MgI
10
As our observed increase in the yield of tetraethyl product 8
was obtained from the monoethylated methoxyamide species 7,
we next decided to investigate the influence on the yield of 8 and
the formation of side products when starting from the hydroxy
amide 5. Surprisingly, the treatment of hydroxy amide 5 with six
equivalents of EtMgI gave high amounts of the desired tetra-
alkyl compound 8 by HPLC (80 %) after heating at reflux for
72 h (Table 1, entry 14). The diethyl product 9 (17 %) and
unreacted hydroxy amide 5 (3 %) were also detected, but in
significantly lower levels. Following chromatography, an iso-
lated yield of 70 % was obtained for the tetraethyl target 8. This
yield was significantly higher than that obtained from the methyl
ether 7 (55 %) and none of the previously observed monoethyl
reduction product 10 was detected. This implies that the forma-
tion of the tetraethyl product 8 from the hydroxy amide 5 occurs
via a mechanism unlikely to involve the cyclic iminium ion 11,
but may involve more efficient production of intermediates
further along in the reaction pathway, such as the iminium ion
13 (Chart 1).
The formation of diethyl product 9 following the addition of
excess EtMgI to hydroxy amide 5 prompted us to examine if side
products such as 9 and 10 were present in the standard Grignard
reaction of N-benzylphthalimide with EtMgI. After heating a
solution of N-benzylphthalimide with EtMgI (six equivalents) in
toluene at reflux for 72 h, both 9 and 10 were identified as being
present by HPLC in yields of 22 % and 1 %, respectively, as well
as significant amounts of the hydroxy amide 5 (53 %) (Table 1,
entry 15). From this comparison it can be deduced that the
hydroxy amide 5 is generated on work-up from the iminium ion
11. The hydroxy amide 5 itself is not likely to be present in the
reaction mixture, as there is no source of Hþ to protonate any
alkoxide. Also if it was present we would expect a better yield
of 8. Consequently, starting the reaction by adding the ethyl
Grignard reagent to the hydroxy amide 5 may enable an
additional mechanism to that which occurs when starting from
the N-benzylphthalimide. We propose that the hydroxyl amide 5
may allow the competitive formation of an O-Mg-O bridging
complex 16 (Scheme 8), which has been suggested to play an
important role in some Grignard reactions.[36] The presence of a
Scheme 7. Proposed mechanism for the formation of compound 10.
ion, especially at the lower temperature. However, the overall
production of the tetraethyl product was not improved. The
monoethyl product 10 may arise via reduction of the carbon of
the carbonyl group via a single electron transfer mechanism,
evidence for which is established in literature.[35] In this mecha-
nism one electron is transferred from EtMgI to methyl ether 12
to form a radial anion-radical cation 13 (Scheme 7). This process
relies on the presence of b hydrogens in the alkyl group of the
Grignard reagent. Accordingly, the reaction of methyl ether 7
with MeMgI only gave traces of product 10, at levels which
could be attributed to traces of iodoethane in the commercially
sourced iodomethane.
Initially we assumed that the diethyl species 9 would be an
intermediate in the pathway towards the desired tetraethyl
product 8. Notably however, when 9 was treated with four
equivalents of EtMgI and heated at reflux for 96 h, only traces
(,2 %) of the desired tetraethyl product 8 could be detected by
HPLC with the major component present being unreacted
diethyl compound 9. The steric crowding imposed by the two
ethyl groups across the ring may prevent the correct approach by
EtMgI needed to attack the remaining amide carbonyl group.
Interestingly, no further alkylation products, including both the
tetraethyl compound 8 and the diethyl compound 9 could be
identified following the treatment of the monoethyl reduction
product 10 with EtMgI after heating at reflux for 72 h. After this
time no starting material remained, as determined by HPLC, and
the NMR spectrum of the complex reaction mixture did not
show any typical alkylisoindoline signals. It is possible that any
Grignard alkylation products formed from 10 may not be stable
under these conditions, as the presence of the hydrogen atom
may allow degradation through various ring opening and elimi-
nation reactions. A decrease in the electrophilicity of the lactam
carbonyl due to delocalisation of the lone pair of electrons on the
nitrogen could also explain the low reactivity observed for 9 and
10. Based on these results, it can be concluded that compounds 9

Grignard Alkylation of N-Benzylphthalimide
E
better leaving group such as the methoxide seen in the methoxy
amide 7 would be expected to lead more readily to the formation
of the iminium ion 11, which in turn may form the 2,2-diethyl
adduct 9 as a ‘dead-end’ product unable to give rise to further
alkylation. The significance of the bridging intermediate 15 may
be important in explaining the regiospecific formation of
Braslau’s 1,3-dimethyl-1,3-diphenylisoindoline 14, where both
initial methyl Grignard additions occurred on carbons 1 and 3
and no 1,1-addition products were detected.
distillation until a temperature of 80–908C was reached. The
reaction mixture was allowed to cool to 648C and a solution of
N-benzylphthalimide (1.00 g, 0.004 mol) in dry toluene (20 mL)
was added. Once addition was completed, the mixture was
stirred for 2 h at room temperature. Saturated ammonium
chloride solution (50 mL) was added and the reaction mixture
was stirred until all the solids dissolved. The organic layer was
separated and the remaining aqueous layer extracted with
chloroform (4 ꢀ 50 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated at reduced
pressure to give brown coloured solid. Purification by column
chromatography (hexane : ethyl acetate 1 : 1) and recrystallisa-
tion from hexane/ethyl acetate gave title compound 5 as white
coloured crystals (0.97 g, 86 %). mp 148–1508C (lit.[38] 1598C).
dH (400 MHz, CDCl3) 0.27 (t, J 7.2, 3H), 2.15–2.00 (m, 2H),
3.37 (s, 1H), 4.46 (d, J 15.2, 1H), 4.57 (d, J 15.2, 1H), 7.30–7.22
(m, 3H), 7.51–7.44 (m, 4H), 7.58 (t, J 7.6, 1H), 7.73 (d, J 7.6,
1H). dC (100 MHz, CDCl3) 7.5, 29.3, 41.9, 92.5, 121.8, 123.3,
127.3, 128.4, 128.7, 129.4, 131.1, 132.4, 138.2, 146.6, 168.0.
m/z (HR-ESI) calc. for C17H18NO2 (MþH)þ 268.1332; found
268.1337. Anal. Calc. for C17H17NO2: C 76.38, H 6.41, N 5.24;
found C 76.66, H 6.43, N 5.22.
Conclusion
In summary, the exhaustive Grignard alkylation of N-
benzylpthalimide provides an efficient one-step route to tetra-
alkylisoindolines, however the reaction may be limited by the
formation of mono- and dialkylation side reactions that do not
lead to the desired product. Starting with partially alkylated
species that are further along the reaction pathway provides
higher yields, even though two steps are required. This approach
provides a practical preparative scale improvement over the
existing synthesis.
Experimental
(E)-2-Benzyl-3-ethylideneisoindolin-1-one (6)
General Methods
A solution of 2-benzyl-3-ethyl-3-hydroxyisoindolin-1-one
(5) (0.29 g, 0.001 mol) and triethylamine (0.30 mL, 0.002 mol,
2 equiv.) in dry dichloromethane (10.0 mL) was prepared and
purged with argon at room temperature. Acetyl chloride
(0.20 mL, 0.002 mol, 2 equiv.) was added dropwise to this
solution at 08C over a period of 5–10 min. The ice bath was
removed and the mixture was allowed to reach room tempera-
ture and then stirred for 1 h. The resulting solution was washed
with 2 M HCl (2 ꢀ 40 mL), saturated NaHCO3 solution
(2 ꢀ 40 mL), and saturated brine solution (2 ꢀ 40 mL). The
combined layers were dried over anhydrous Na2SO4 and evap-
orated at reduced pressure to give a cream coloured solid which
was purified by recrystallisation (ethanol) to give title com-
pound 6 as white coloured needles (0.18 g, 67 %). mp
128–1298C (lit.[38] 1298C). dH (400 MHz, CDCl3) 2.15 (d,
J 7.6), 5.03 (s, 2H), 5.50 (q, J 7.6, 1H), 7.25–7.34 (m, 5H),
7.53 (t, J 7.6, 1H), 7.62 (t, J 7.6, 1H), 7.86 (d, J 7.6, 1H), 7.98
(d, J 7.6, 1H). dC (100 MHz, CDCl3) 13.1, 42.9, 107.2, 123.5,
123.6, 126.9, 127.2, 128.56, 128.64, 130.3, 131.9, 135.5, 135.7,
137.2, 166.5. m/z (HR-ESI) calc. for C17H16NO (MþH)þ
250.1226. Found 250.1236. Anal. Calc. for C17H15NO:
C 81.90, H 6.06, N 5.62; found C 81.78, H 6.11, N 5.60. The
stereochemistry around the double bond was confirmed using a
NOESY spectrum.
All air-sensitive reactions were carried out under an atmosphere
of ultra-high purity argon. Tetrahydrofuran was freshly distilled
from sodium benzophenone ketal and dichloromethane was
freshly distilled from calcium hydride. Toluene and diethyl
ether were dried by storage over sodium wire and triethylamine
by storage over potassium hydroxide. N-benzylphthalimide was
synthesised using established literature procedures and the
obtained NMR data matched that previously reported.[37] All
other reagents were purchased from commercial suppliers and
used without further purification. 1H and 13C NMR spectra were
recorded on a 400 MHz spectrometer and referenced to the
relevant solvent peak (CDCl3; dH ¼ 7.26 ppm, dC ¼ 77.0 ppm).
Electrospray ionisation (ESI) high resolution mass spectra were
obtained using a QTOF LC mass spectrometer which utilised
electrospray ionisation (recorded in the positive mode) with a
methanol mobile phase. Electron impact (EI) high resolution
mass spectra were recorded on a double focusing magnetic
sector mass spectrometer in the positive mode. Fourier trans-
form infrared (FTIR) spectra were recorded on a FTIR spec-
trometer equipped with a Deuterated Tri-Glycine Sulfate
Thermoelectric Cooler detector and an Attenuated Total
Reflectance objective. Melting points were measured on a
Variable Temperature apparatus by the capillary method and are
uncorrected. Analytical HPLC was carried out on a HPLC
system using a Prep-C18 scalar column (4.6 ꢀ 150 mm, 10 mm)
with a flow rate of 1 mL minꢁ1 in the stated mixtures of meth-
anol and water with detection at 254 nm. TLC was done using
silica gel 60 F254 TLC plates and preparative column chroma-
tography was performed using silica gel 60 (230–400 mesh).
2-Benzyl-3-ethyl-3-methoxyisoindolin-1-one (7)
Finely ground sodium hydroxide (0.60 g, 0.015 mol,
4 equiv.) was added to a solution of 2-benzyl-3-ethyl-3-
hydroxyisoindolin-1-one (5) (0.95 g, 0.004 mol) in dry THF
(15 mL) under an atmosphere of argon. Iodomethane
(1.00 mL, 0.016 mol, 4 equiv.) was added dropwise and the
mixture was stirred for 1.5 h at room temperature. After evapo-
rating to dryness, the obtained residue was dissolved in CH2Cl2
(25 mL) and washed with deionised water (2 ꢀ 25 mL). The
CH2Cl2 layer was dried over anhydrous Na2SO4 and concen-
trated at reduced pressure. The resulting residue was purified by
recrystallisation (hexane) to give title compound 7 as white
crystals (0.87 g, 87 %). mp 62–648C. dH (400 MHz, CDCl3) 0.30
Specific Experimental Procedures
2-Benzyl-3-ethyl-3-hydroxyisoindolin-1-one (5)
Ethyl iodide (1.00 mL, 0.010 mol, 2.5 equiv.) was added
dropwise to a suspension of pre-dried magnesium turnings
(0.25 g, 0.010 mol, 2.5 equiv.) in anhydrous diethyl ether
(15 mL). The mixture was stirred at room temperature for 1 h
until all the activity had subsided and was then concentrated by

F
V. C. Jayawardena, K. E. Fairfull-Smith, and S. E. Bottle
(t, J 7.6, 3H), 2.04–2.14 (m, 2H), 2.58 (s, 3H), 4.52 (d, J 14.8,
1H), 4.67 (d, J 14.8, 1H), 7.25–7.34 (m, 3H), 7.40 (td, J 7.4, 0.88,
1H), 7.50–7.61 (m, 3H), 7.89 (td, J 7.5, 0.88, 1H). dC (100 MHz,
CDCl3) 7.4, 29.4, 42.1, 50.3, 96.9, 122.0, 123.5, 127.4, 128.3,
129.2, 129.6, 132.2, 133.0, 137.9, 143.0, 168.4. m/z (HR-ESI)
calc. for C18H20NO2 (MþH)þ 282.1489; found 282.1498. Anal.
Calc. for C18H19NO2: C 76.84, H 6.81, N 4.98; found C 76.70,
H 6.82, N 4.91.
combined ethyl acetate layers were dried over anhydrous
Na2SO4 and concentrated at reduced pressure. The resulting
residues from the toluene and ethyl acetate layers were com-
bined and purified by column chromatography (hexane : ethyl
acetate 4 : 1) to give title compound 8 as a white solid (0.06 g,
55 %). mp 72–748C (lit.[39] 768C). dH (400 MHz, CDCl3) 0.79 (t,
J 7.6, 12H), 1.53–1.59 (m, 4H), 1.92–1.97 (m, 4H), 4.03 (s, 2H),
7.06–7.09 (m, 2H), 7.21–7.23 (m, 2H), 7.26–7.34 (m, 3H), 7.47
(d, J 6.0, 2H). dC (100 MHz, CDCl3) 9.8, 30.5, 46.9, 71.5, 123.6,
125.8, 126.7, 128.0, 129.5, 142.6, 144.8. m/z (HR-ESI) Calc. for
C23H32N (MþH)þ 322.2589; found 322.2571. The obtained
spectroscopic data was in agreement with that previously
reported.[30] Three other compounds were also isolated from
this reaction:
2-Benzyl-3,3-diethylisoindolin-1-one (9) (cream coloured
solid, 0.022 g, 22 %). mp 37–398C. dH (400 MHz, CDCl3) 0.19
(t, J 7.2, 6H), 1.86–1.92 (m, 4H), 4.61 (s, 2H), 7.25–7.32 (m,
4H), 7.44 (t, J 7.2, 1H), 7.53 (d, J 7.2, 3H), 7.89 (d, J 7.6, 1H).
dC (100 MHz, CDCl3) 7.1, 30.4, 43.0, 70.7, 120.7, 123.5, 127.4,
127.8, 128.3, 129.0, 131.7, 132.9, 138.1, 147.7, 169.6. m/z
(HR-ESI) Calc. for C19H22NO (MþH)þ 280.1700; found
280.1720.
2-Benzyl-3-ethylisoindolin-1-one (10) (colourless oil,
0.003 g, 3 %). dH (400 MHz, CDCl3) d 0.54 (t, J 8.0, 3H),
1.97–2.06 (m, 2H), 4.11 (d, J 15.2, 1H), 4.45 (t, J 4.0, 1H),
5.44 (d, J 14.8, 1H), 7.28–7.37 (m, 6H), 7.48 (t, J 7.2, 1H), 7.54
(t, J 7.2, 1H), 7.91 (d, J 7.6, 1H). dC (100 MHz, CDCl3) 6.3, 22.9,
43.7, 59.0, 122.0, 123.8, 127.6, 128.0, 128.2, 128.7, 131.4,
132.7, 137.2, 144.9, 168.7. m/z (HR-ESI) Calc. for C17H18NO
(MþH)þ 252.1400; found 252.1393. These data are in agree-
ment with those previously reported.[40]
2-Benzyl-1,1,3,3-tetraethylisoindoline (8) – from
2-Benzyl-3-ethyl-3-hydroxyisoindolin-1-one (5)
Ethyl iodide (0.18 mL, 2 mmol, 6 equiv.) was added drop-
wise to a suspension of pre-dried magnesium turnings (0.07 g,
3 mmol, 8 equiv.) in anhydrous diethyl ether (8 mL). The mixture
was stirred at room temperature for 1 h and then concentrated
by distillation until a temperature of 80–908C was reached. The
reaction mixture was allowed to cool to 648C and a solution
of 2-benzyl-3-ethyl-3-hydroxyisoindolin-1-one (5) (0.10 g,
0.37 mmol) in dry toluene (8 mL) was added. Once the addition
was complete, the mixture was heated at reflux at 1108C for
3 days. Saturated ammonium chloride solution (50 mL) was then
added and the mixture was stirred until all the solids had
dissolved. The toluene layer was separated and evaporated to
dryness. The remaining aqueous layer was extracted with ethyl
acetate (4 ꢀ 50 mL). The combined ethyl acetate layers were
dried over anhydrous Na2SO4 and concentrated at reduced
pressure. The resulting residues from the toluene and ethyl
acetate layers were combined (0.096 g) and purified by silica
column chromatography (hexane : ethyl acetate 4 : 1) to give 8 as
a white solid (0.084 g, 0.26 mmol, 70 %). mp 72–748C (lit.[39]
mp 768C); dH (400 MHz, CDCl3) d 0.79 (t, J 7.6, 12H),
1.53–1.59 (m, 4H), 1.92–1.97 (m, 4H), 4.03 (s, 2H), 7.06–7.09
(m, 2H), 7.21–7.23 (m, 2H), 7.26–7.34 (m, 3H), 7.47 (d, J 6.0,
2H); dC (100 MHz, CDCl3) d 9.8, 30.5, 46.9, 71.5, 123.6, 125.8,
126.7, 128.0, 129.5, 142.6, 144.8; HRMS: Calc. for C23H32N
[MH]þ 322.2589, found 322.2571. The obtained spectroscopic
data was in agreement with that previously reported.[30] The
other compound isolated from this reaction was: 2-benzyl-3,3-
diethylisoindolin-1-one (9) (cream coloured solid, 0.010 g,
0.03 mmol, 8 %). Mp 37–398C; dH (400 MHz, CDCl3) d 0.19
(t, J 7.2, 6H), 1.86–1.92 (m, 4H), 4.61 (s, 2H), 7.25–7.32
(m, 4H), 7.44 (t, J 7.2, 1H), 7.53 (d, J 7.2, 3H), 7.89 (d, J 7.6,
1H); dC (100 MHz, CDCl3) d 7.1, 30.4, 43.0, 70.7, 120.7, 123.5,
127.4, 127.8, 128.3, 129.0, 131.7, 132.9, 138.1, 147.7, 169.6;
HRMS: Calc. for C19H22NO [MH]þ 280.1700; found 280.1720.
2-Benzyl-3-ethyl-3-hydroxyisoindolin-1-one (5) (white crys-
talline solid, 0.013 g, 13 %). Data shown above.
Supplementary Material
(1) 1H NMR spectra of compounds 5–10; (2) 13C NMR spectra
of compounds 5–10; (3) HPLC chromatograms for compounds
5–10 and example reaction mixtures from Table 1; and (4)
example reaction conditions for larger scale generation of
compound 8 are all available on the Journal’s website.
Acknowledgements
This work was supported by the Australian Research Council Centre of
Excellence for Free Radical Chemistry and Biotechnology (CE 0561607)
and Queensland University of Technology.
2-Benzyl-1,1,3,3-tetraethylisoindoline (8) – from
2-Benzyl-3-ethyl-3-methoxyisoindolin-1-one (7)
References
Ethyl iodide (0.20 mL, 0.002 mol, 6 equiv.) was added drop-
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solution (50 mL) was then added and the mixture was stirred
until all the solids had dissolved. The toluene layer was
separated and evaporated to dryness. The remaining aqueous
layer was extracted with ethyl acetate (4 ꢀ 50 mL). The
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