Synthesis of 1,1,3,3-tetraalkylisoindolines using a microwave-assisted grignard reaction

Article abstract of DOI:10.1071/CH08008

1,1,3,3-Tetraalkylisoindolines are important intermediates in the preparation of stable nitroxides, such as 1,1,3,3-tetramethylisoindolin-2-oxyl, 1, and 1,1,3,3-tetraethylisoindolin-2-oxyl, 2. The limiting step in their preparation is the Grignard reactio

Full text of DOI:10.1071/CH08008

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CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 168–171
www.publish.csiro.au/journals/ajc
Synthesis of 1,1,3,3-Tetraalkylisoindolines Using
a Microwave-Assisted Grignard Reaction
Richard C. Foitzik,A Steven E. Bottle,B Jonathan M. White,C,D
and Peter J. ScammellsA,E
AMedicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
BSchool of Physical Sciences and Chemical Sciences, Queensland University of Technology,
GPO Box 2434, Brisbane QLD 4001, Australia.
CSchool of Chemistry, University of Melbourne, VIC 3010, Australia.
DBio21 Molecular Science and Biotechnology Institute, University of Melbourne, VIC 3010, Australia.
ECorresponding author. Email: peter.scammells@vcp.monash.edu.au
1,1,3,3-Tetraalkylisoindolines are important intermediates in the preparation of stable nitroxides, such as 1,1,3,3-
tetramethylisoindolin-2-oxyl, 1, and 1,1,3,3-tetraethylisoindolin-2-oxyl, 2. The limiting step in their preparation is the
Grignard reaction between N-benzylphthalimide and the appropriate alkyl magnesium bromide, which typically proceeds
in yields of ∼28–40%. A microwave-assisted variation of this reaction has been optimized to give improved yields and
reduced reaction times (45–60% and 2 h, respectively).
Manuscript received: 11 January 2008.
Final version: 16 February 2008.
The preparation of stable nitroxides has proved in recent
N O
N O
times to be useful for multiple applications, mainly as rad-
ical scavengers,[1–3] and as living polymerization agents for
controlled polymerizations.[4] The isoindoline class of nitro-
xides possess some advantages over other nitroxides including
higher stability and narrower electron paramagnetic resonance
(EPR) linewidths. However, the applications of both the 1,1,3,3-
tetramethylisoindolin-2-oxyl nitroxide 1 (TMIO) (Fig. 1) and
the 1,1,3,3-tetraethylisoindolin-2-oxyl nitroxide 2 (TEIO) have
been limited, in part, by the difficulties in their synthesis, which
involves a low-yielding reaction with an alkyl Grignard reagent.
In this regard, yields of between 28 and 37% have been reported
for the key Grignard reaction involved in the synthesis of the
TMIO precursors.[1,2,5] In 1982, Griffiths et al. reported a yield
of 37%[2] for this reaction, whereas Caldararo et al. patented a
slightly higher yielding procedure (40%) for theTEIO precursor
in 2006.[6]
Microwave-assisted organic synthesis has been a topic of
widespread interest in recent years and microwave heating has
been reported to produce dramatically increased reaction rates,
cleaner reaction profiles, and higher yields for a plethora of dif-
ferent transformations.[7] Although microwave irradiation has
been found to facilitate the formation of Grignard reagents,[8–10]
less attention has been directed toward their subsequent car-
bonyl addition reactions, possibly because reactions of this type
commonly proceed rapidly under mild conditions. In the present
study, we were interested in investigating the use of microwave
irradiation for further improving the yield of the challenging
Grignard reactions involved in the synthesis of TMIO 1 and
TEIO 2.
1
2
Fig. 1. Structure of 1,1,3,3-tetramethylisoindolin-2-oxyl nitroxide
(TMIO 1) and 1,1,3,3-tetraethylisoindolin-2-oxyl nitroxide 2 (TEIO 2).
1
The starting material for our research was N-benzylphtha-
limide 4, which was prepared in quantitative yield by the
microwave-assisted reaction of phthalic anhydride 3 and ben-
zyl amine as described by Vidal et al. (Scheme 1).[11] The
reaction between 4 and the commercially available Grig-
nard reagent methyl magnesium bromide in a mixture of
toluene/tetrahydrofuran (3:1) was the focus of our initial opti-
mizations. A 10-fold excess of the methyl magnesium bromide
and a 2 h reaction time were employed.
Increasing the temperature from 180 to 250◦C increased the
yield of N-benzyl-1,1,3,3-tetramethylisoindoline 5 from 19 to
46% (entries 1–4, Table 1). An increase in the pressure from 3 to
1.5 MPa was associated with the temperature increase across this
range. The formation of gas (methane, ethane, or butane)[12,13]
from the Grignard reagent may have been partially responsible
for this increase in pressure. However, in all cases the reac-
tion pressure was well within the safe operating limits of the
microwave reactor (2.0 MPa). Notably, high pressure is of itself
not an effective means to increase the yield of this alkylation as
heating under pressures of up to 1500 MPa did not improve the
yield.
© CSIRO 2008
10.1071/CH08008
0004-9425/08/030168

Synthesis of Tetraalkylisoindolines
169
H2N
O
O
O
R R
N
RMgBr
N
R R
O
O
3
4
5 R ϭ Me
6 R ϭ Et
Scheme 1. Synthesis of N-benzyl-1,1,3,3-tetraalkylisoindolines.
Table 1. Synthesis of N-benzyl-1,1,3,3-tetramethylisoindoline 5
N-Benzylphthalimide(0.422 mmol)intoluene(1 mL)wastreatedwith1.4 M
CH3MgBr in toluene/THF (3:1)
a significantly higher yield of 60% was achieved. Ether sol-
vents are necessary for the stabilisation of alkyl magnesium
halide Grignard reagents;[14] however, once formed, the bulk
of the ether solvent may be removed. In this case, the removal of
the ether clearly improved productivity, even though microwave
irradiation heats through dipole interaction, which would be
expected to be decreased in the less polar toluene. We believe
that the microwave radiation may directly heat the intermedi-
ate iminium ion, leading to dissociation and facilitating further
reaction with the Grignard reagent to give the second alkylation.
Although the evaporation of the ether improved the yield, these
conditions exceeded the pressure limit of the microwave reaction
vials on some occasions and were not explored further.
The optimized reaction conditions for the synthesis of N-
benzyl-1,1,3,3-tetraethylisoindoline 6 are shown in Table 3. The
reaction between N-benzylphthalimide 4 and 3.0 M ethyl mag-
nesium bromide at 200◦C for 1.25 h proceeded in 60% yield
(entry 1, Table 3). The use of 1.0 M ethyl magnesium bromide
in t-butyl methyl ether gave similar results (59%, cf. entries 1
and 2).
The reaction of N-methylphthalimide 7 with methyl magne-
siumbromide(12equiv.)at200◦Cfor2 hproducedaninteresting
outcome. In this case, the desired Grignard reaction proceeded
with concomitant ring opening to afford 2-[2-(1-hydroxy-1-
methylethyl)phenyl]propan-2-ol 8 as the major product, isolated
in 45% yield (Scheme 2). The structure of this product was
confirmed by X-ray crystallography (Fig. 2). This unexpected
product presumably resulted from the cleavage of the carbon–
nitrogen bond rather than the carbon–oxygen bond on reaction
of the second equivalent of the Grignard reagent at each of the
imide carbonyls. However, further investigation is required to
determine why the N-methylphthalimide proceeded in this fash-
ion, whereas the N-benzylphthalimide produced the expected
Grignard reaction product under the same conditions.
The current investigation indicates that the synthesis of 5 and
6 can be effectively achieved using microwave irradiation and
that this method of heating offers substantial improvements over
the established synthetic methodology.The optimized conditions
for the microwave-mediated alkylations to give tetraalkylisoin-
dolines employed 10–12 equivalents of a Grignard reagent and a
2 h reaction time at high temperature.These conditions improved
the yield of 5 and 6 to 45 and 60%, respectively. Notably
the microwave reactions described here did not generate sig-
nificant levels of other side reactions, which facilitated the
purification of the product and is a further advantage of this pro-
cedure.Themaximumvialsizeaccommodatedbythemicrowave
reactor may be a limiting factor in larger scale preparations;
however, either manual or automated batch processing can be
employed as a viable alternative to direct scaling up. In contrast,
when N-methylphthalimide 7 was treated with methyl magne-
sium bromide under the same general conditions, the Grignard
reactions proceeded with concomitant ring opening to afford
2-[2-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol 8.
Entry Temp. [◦C] Grignard Reaction time Pressure Yield [%]A
reagent
[equiv.]
[h]
[MPa]
1
2
3
4
5
6
7
8
180
200
225
250
200
200
200
200
200
200
200
200
200
10
10
10
10
10
10
10
10
6
2
2
2
2
1
2
5
20
2
2
0.3
0.5
1.1
1.3–1.5
0.5
19
34
37
46
30
34
35
35
22
24
34
39
35
0.5
0.5–0.6
0.5–1.1
0.4
0.4–0.5
0.5
9
10
11
12
13
8
10
12
14
2
2
2
0.6
0.6
AIsolated yield of crude 5.
Increasing the reaction time had a very small effect on the
yieldof 5(entries5–8,Table1). Extendingthetimefrom1to20 h
only increased the percentage yield from 30 to 35%. The use of
even longer reaction times (>20 h) afforded slightly lower yields
of the desired product. Such extended reaction times also gener-
ated significant increases in the pressure, which may have arisen
from alkane formation as the excess Grignard reagent scavenged
protons and formed dimers by radical addition processes.[13]
The molar equivalence of the Grignard reagent was also opti-
mized (entries 9–13, Table 1). In the original synthesis of TMIO
1, six molar equivalents of methyl magnesium iodide were used
in the preparation of N-benzyl-1,1,3,3-tetramethylisoindoline 5
and the authors noted that the yield was unaffected by the pres-
ence of a large excess (9 equiv.) of the Grignard reagent.[1] In
this present case, a significant improvement in the isolated yield
was achieved when 10 or more molar equivalents of the Grignard
reagent were used (i.e. from 22% with 6 equiv. to 34% with 10
equiv.).
From this initial optimization, it was concluded that the best
conditions for this specific reaction were to have 10–12 equiva-
lents of Grignard reagent reacting for 2 h at the highest possible
temperature. The effects of the reaction solvent and the concen-
tration of the Grignard reagent were also briefly investigated
(Table 2). An increase in yield from 34 to 44% was observed
when N-benzylphthalimide was treated with methyl magnesium
bromide (1.4 M in toluene/THF, 3:1) in the absence of additional
solvent (cf. entries 1 and 2).The use of a more concentrated Grig-
nard reagent (3.0 M in diethyl ether) produced a similar outcome
when either THF or toluene was used as a co-solvent (entries
3 and 4, Table 2). When toluene was used as a cosolvent and
the diethyl ether was evaporated before microwave irradiation,

170
R. C. Foitzik et al.
Table 2. Further optimization of the synthesis of N-benzyl-1,1,3,3-tetramethylisoindoline 5
Entry Time [h] Temp. [◦C] Solvent
Grignard reagent
Pressure Yield [%]A
[MPa]
1
2
3
4
5
2
2
2
2
2
200
200
180
200
200
Toluene (1 mL)
–
THF (5 mL)
Toluene (5 mL)
Toluene (5 mL)
CH3MgBr in toluene/THF (3:1) (1.4 M, 10 equiv.)
CH3MgBr in toluene/THF (3:1) (1.4 M, 10 equiv.)
CH3MgBr in Et2O (3.0 M, 10 equiv.)
CH3MgBr in Et2O (3.0 M, 10 equiv.)
CH3MgBr in Et2O (3.0 M, 10 equiv.)B
0.5
0.5
1.8–2.1
1.5–2.1
1.2–2.0
34
44
45
45
60
AIsolated yields following purification.
BEt2O was evaporated before the microwave reaction.
Table 3. Synthesis of N-benzyl-1,1,3,3-tetraethylisoindoline 6
Entry Time [h] Temp. [◦C] Solvent
Grignard reagent
Pressure Yield [%]A
[MPa]
1
2
1.25
2
200
180
Toluene:THF 9:1 (2 mL) EtMgBr in diethyl ether (3.0 M, 12 equiv.)
1.3–1.9
1.4–1.9
60
59
–
EtMgBr in t-butyl methyl ether (1.0 M, 12 equiv.)
AIsolated yields following purification.
O
C9
MeMgBr
OH
OH
N
CH3
C8
O
C2
7
8
C7
C3
O1
Scheme 2. Microwave Grignard reaction of N-methylphthalimide 7 with
C1
methyl magnesium bromide.
Experimental
C4
C6
O2
Melting points were determined on an Electrothermal melt-
ing point apparatus and are uncorrected. A Biotage Initiator
2.0 Microwave Synthesiser was used for all microwave reac-
tions. High-pressure reactions were undertaken in a PSIKA
dual-piston high-pressure reactor. Thin-layer chromatography
C5
C10
C12
C11
was performed on 0.2 mm plates using Merck silica gel 60 F254
.
Column chromatography was achieved using Merck silica gel 60
(70–230 mesh). NMR spectra were recorded on a BrukerAvance
DPX 300 spectrometer, and 1H and 13C NMR spectra were
recorded at 300.1 and 75.4 MHz, respectively. Unless otherwise
stated, spectra were acquired in CDCl3. High-resolution mass
spectra were collected on a Waters Micromass LCT Premier
XE TOF mass spectrometer fitted with an electrospray ioniza-
tion (ESI) ion source. Crystallography data were collected with
an Oxford XCalibur X-ray diffractometer with Saphire charge
coupled device detector using CuKα radiation (graphite crystal
monochromator; λ 1.54184 Å). Data were reduced and corrected
for absorption (Gaussian).[15] The structure was solved by direct
methods and difference Fourier synthesis with the SHELX suite
of programs[16] as implemented within WINGX software.[17]
Fig. 2. ORTEP diagram of the X-ray crystal structure of
2-[2-(1-hydroxy-1-methylethyl)phenyl]propan-2-ol 8.
acetateastheeluentandtheorganicsolventswereremovedunder
reduced pressure to yield the crude product. Purification for the
N-benzyl products 5 and 6 was achieved by column chromato-
graphy (silica gel) using hexane as the eluent, whereas 2-[2-(1-
hydroxy-1-methylethyl)phenyl]propan-2-ol 8 was recrystallized
from toluene.
N-Benzyl-1,1,3,3-tetramethylisoindoline 5
Mp 60–62◦C. δH 1.37 (s, 12H, CH3), 4.06 (s, 2H, CH2), 7.18–
7.20 (m, 2H, ArH), 7.27–7.32 (m, 5H, ArH), 7.35 (d, 2H, ArH).
δC 28.5, 46.3, 65.3, 121.4, 126.4, 126.8, 128.0, 128.4, 143.5,
147.9.
General Procedure for the Microwave Grignard Reaction
The N-protected phthalimide (0.42 mmol) was dissolved in the
appropriate solvent in a 2–5 mL Biotage microwave tube. Alkyl
magnesium bromide (5.06 mmol) was injected and the mixture
was reacted at 200◦C in the microwave for 2 h.The crude mixture
was passed through a plug of silica gel using 1:1 hexane/ethyl
N-Benzyl-1,1,3,3-tetraethylisoindoline 6
δH 0.84 (s, 12H, CH3), 1.55–1.67 (m, 4H, CH2), 1.92–
2.05 (m, 4H, CH2), 4.07 (s, 2H, CH2), 7.10–7.14 (m, 2H,

Synthesis of Tetraalkylisoindolines
171
ArH), 7.22–7.36 (m, 5H, ArH), 7.49–7.54 (d, 2H, ArH).
δC 9.6, 30.4, 56.0, 71.4, 123.4, 125.6, 126.6, 127.8, 129.3,
142.5, 144.6.
References
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2-[2-(1-Hydroxy-1-methylethyl)phenyl]propan-2-ol 8
Yield45%;mp154–155◦C. δH 1.80(s, 12H, CH3), 7.22–7.25(m,
2H, ArH), 7.38–7.40 (m, 2H, ArH). δC 33.9, 75.0, 126.3, 128.2,
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orthorhombic, space group Pc21b, 14.7203(6), 8.1827(4),
8.9421(5) Å, 1077.09(9) Å3, Z 4, Dc 1.198 mg m−3, µ(CuKα
)
0.630 mm−1, F(000) 424, crystal size 0.8 × 0.4 × 0.18 mm3.
3210 reflections measured, 1564 independent reflections (Rint
0.052), thefinalRwas0.0434[I > 2σ(I)]andwR(F2)was0.1319
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High-Pressure Reactions
High pressure reactions were conducted in Teflon vessels under
an argon atmosphere at varying pressures up to 1500 MPa for
12–18 h. Temperatures ranged from room temperature to 80◦C.
In each case, workup of the reaction mixture gave only minor
amounts of the targeted tetraalkylisoindoline, indicating that
high pressures do not have a major influence on the product
yields.
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Commun. 2007, 2066. doi:10.1039/B617861H
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Acknowledgements
The authors thank the Australian Research Council Centre of Excellence
for Free Radical Chemistry and Biotechnology for financial support, and
Associate Professor David Young from Griffith University for assistance
with the high-pressure reactions.
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