A simple and convenient one-pot synthesis of substituted isoindolin-1-ones via lithiation, substitution and cyclization of N'-benzyl-N,N-dimethylureas

Article abstract of DOI:10.3762/bjoc.7.142

Lithiation of N'-benzyl-N,N-dimethylurea and its substituted derivatives with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C followed by reaction with various electrophiles afforded a range of 3-substituted isoindolin-1-ones in high yields.

Full text of DOI:10.3762/bjoc.7.142

A simple and convenient one-pot synthesis of substi-
tuted isoindolin-1-ones via lithiation, substitution and
cyclization of N'-benzyl-N,N-dimethylureas
Keith Smith*1, Gamal A. El-Hiti*1,2, Amany S. Hegazy1 and Benson Kariuki1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1219–1227.
1School of Chemistry, Cardiff University, Main Building, Park Place,
Cardiff CF10 3AT, UK, Fax: +44(0)2920870600; Tel:
+44(0)2920870600 and 2Permanent address: Chemistry Department,
Faculty of Science, Tanta University, Tanta 31527, Egypt
doi:10.3762/bjoc.7.142
Received: 07 February 2011
Accepted: 06 June 2011
Published: 06 September 2011
Email:
Keith Smith* - smithk13@cardiff.ac.uk;
Gamal A. El-Hiti* - el-hitiga@cardiff.ac.uk
This article is part of the Thematic Series "Directed aromatic
functionalization".
* Corresponding author
Guest Editor: V. Snieckus
Keywords:
© 2011 Smith et al; licensee Beilstein-Institut.
License and terms: see end of document.
N'-benzyl-N,N-dimethylureas; isoindolin-1-ones; directed lithiation;
electrophiles; substitution; synthesis
Abstract
Lithiation of N'-benzyl-N,N-dimethylurea and its substituted derivatives with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C
followed by reaction with various electrophiles afforded a range of 3-substituted isoindolin-1-ones in high yields.
Introduction
In recent years there has been a great deal of interest in com- have been developed for the synthesis of substituted isoindo-
pounds possessing an isoindolinone ring system since it repre- lines, of which the most generally useful involve palladium-
sents the core unit of numerous naturally occurring substances catalysed reactions [34-42] or lithiation procedures [43-54].
[1-8]. Also, some members that possess this moiety have shown
interesting biological properties [9-15].
In particular, among the various lithiation methods two useful
approaches to the synthesis of isoindolin-1-ones have been
Several traditional methods are available for the synthesis of reported (Scheme 1 and Scheme 2) [43,45]. One method simply
isoindolinones [16-25], based on the use of Grignard reagents involves lithiation of a preformed isoindolin-1-one ring system
[26], Diels–Alder reactions [27], Wittig reagents [28], reduc- at the 3-position followed by treatment with an electrophile
tion processes [29,30], rearrangement processes [31] and photo- (Scheme 1) [43]. While this approach is straightforward,
chemical reactions [32,33]. However, such methods generally clearly, its general utility depends on the availability of appro-
require multiple reaction steps and are unsatisfactory both in priately substituted analogues of the isoindolin-1-one ring
yield and generality. In recent years several new approaches system.
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Beilstein J. Org. Chem. 2011, 7, 1219–1227.
As a result of our own interest in the use of lithium reagents in
organic synthesis [55-67], we have had occasion to investigate
lithiation of various aromatic compounds containing substi-
tuted amino groups. Factors that influence the site(s) of lithia-
tion of such compounds can be quite subtle. For example, lithia-
tion of N,N-dimethyl-N'-(substituted phenyl)ureas can occur
predominantly on the N,N-dimethyl group (e.g., for the unsub-
stituted, 4-methyl or 4-methoxy-compounds with t-BuLi at
−20 °C) or on the ring next to the urea group (e.g., for the
4-chloro-, 4-fluoro- or 4-trifluoromethyl compounds with either
n-BuLi or t-BuLi at 0 °C) [59]. However, a recent report indi-
cates that replacement of the dimethylamino group by a more
hindered dialkylamino group in the unsubstituted phenyl deriva-
Scheme 1: Lithiation and substitution of isoindolin-1-ones [43].
The other, potentially more useful approach involves genera- tive results in lithiation on the ring [68]. We have also devel-
tion of the heterocyclic ring system during the lithiation step. oped procedures for the lithiation of various substituted benzyl-
For example, lithiation of N-tert-butyl-N-benzylbenzamides amines [69-71]. Similar subtleties over the site(s) of lithiation
gives intermediates that cyclise to form de-aromatised species. are also observed for these compounds. The site(s) of lithiation
Oxidation to re-aromatise the benzenoid system, followed by depend on the substituents at nitrogen, the nature and positions
treatment with trifluoroacetic acid to remove the tert-butyl of substituents on the aryl ring and/or on the nature of the
group, gives the corresponding isoindolin-1-ones (Scheme 2) lithium reagent. For example, lithiation of N-benzylpivalamide
[45]. However, this approach gives more modest yields, with t-BuLi gives a mixture of ring (2-position) and side-chain
requires an additional step to remove the tert-butyl group, and lithiated species, whereas for N'-benzyl-N,N-dimethylurea side-
also involves incorporating the eventual C-3 substituent into the chain lithiation does not occur [69]. Of particular relevance for
starting material, which limits the generality. Moreover, the the present study was the observation that lithiation of N'-(2-
reaction works well only with 3-aryl substituents.
methoxybenzyl)-N,N-dimethylurea (1) with two equivalents of
t-BuLi in THF at −20 °C for 2 h followed by reactions with a
Clayden has improved the yield of isoindolin-1-ones by using range of electrophiles gave mixtures of products (Scheme 3)
2-methoxybenzamides as the starting materials; in this case the involving ring substitution both next to the urea-containing
methoxy group acts as a leaving group, which avoids the need group (o-substitution; 47–51% yields) and next to the methoxy
for an oxidation step [45]. However, this approach still requires group (o'-substitution; 38–40% yields) [69]. Formation of 2 and
an additional step to remove the tert-butyl group and incorpor- 3 presumably involved lithium intermediates 4 and 5,
ation of the 3-substituent into the starting material.
respectively (Figure 1).
Scheme 2: Lithiation and cyclization of N-tert-butyl-N-benzylbenzamides [45].
Scheme 3: Lithiation and substitution of 1 at −20 °C [69].
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Beilstein J. Org. Chem. 2011, 7, 1219–1227.
Indeed, lithiation of 1 with t-BuLi (3.3 equiv) in anhydrous
THF at 0 °C for 6 h, followed by treatment with iodomethane,
gave 9 (i.e., 6, where E = Me) in 79% yield (Table 1). While an
increased yield of 6 (E = Me, i.e., 9, produced from 7) and the
disappearance of 2 (produced from 4) were expected, the disap-
pearance of 3 (produced from 5) was a surprise. It would appear
that at 0 °C, not only did 4 cyclize to give 7, but 5 was also in
equilibrium with 4, allowing its eventual conversion into 7 and
then 8.
Figure 1: Structures of 4–6.
We found that when the lithiation reaction was carried out at This fortuitous finding appeared to offer potential as a general
0 °C rather than at −20 °C, followed by reaction with an elec- synthetic method and the same lithiation procedure was there-
trophile, it produced lower yields of the corresponding substi- fore used with a range of other electrophiles including other
tuted products 2 and 3, along with some residual 1 and a small haloalkanes, water, symmetrical and unsymmetrical ketones,
amount of a new product of structure 6 (Figure 1). By and aldehydes. After work-up of the reaction mixtures, the
increasing the amount of lithiating agent and extending the crude products were triturated and/or washed with diethyl ether
period of the lithiation reaction, we were able to increase the to give products 10–18 in high yields (Table 1).
yield of 6, and in a preliminary communication we reported that
directed lithiation of various N'-benzyl-N,N-dimethylureas From the results recorded in Table 1, it appeared that the reac-
with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C tion was a general process for production of 3-substituted
followed by reaction with various electrophiles afforded the 4-methoxyisoindolin-1-ones 9–18 in high yields from reactions
corresponding 3-substituted isoindolin-1-ones in high yields with a variety of electrophiles. The identity of the ring system
[72]. We now report full details of that work, extend the scope was confirmed by the crystallization of 12 and subjecting it to
of the reaction and examine the diastereoselectivity of the reac- X-ray crystallography (Figure 2). All the products were
tion with prochiral electrophiles.
analysed by standard spectroscopic methods and showed, for
example, the expected molecular ions in their mass spectra.
Compounds 10–14 were readily identified by their NMR
Results and Discussion
As noted above, when lithiation of 1 was carried out at 0 °C spectra, which showed all the expected signals. In the
rather than at −20 °C prior to reaction with an electrophile, 1H NMR spectra of compounds 10 and 11, the expected
lower yields of 2 and 3 along with some residual 1 and a small diastereotopicity of the two hydrogens of the CH2 groups
amount of 6 were obtained. A possible mechanism for the for- closest to the ring was evident. For compound 13 the two phe-
mation of 6 is shown in Scheme 4. According to this scheme, nyl groups appeared as separated signals in the 13C NMR spec-
compounds of the general structure 6 would arise by cycliza- trum, verifying that they were also diastereotopic, and similarly,
tion of 4 to give 7, followed by further lithiation to give 8, the two sides of the cyclohexane ring in compound 14 also
which on reaction with an electrophile would give 6. It appeared as separated signals. The NMR spectra of products
appeared likely that the yield of 6 could be increased by use of a 15–18 were relatively complex. Therefore, in order to get
larger quantity of t-BuLi and an extended reaction time; there- further information about these products, they were each
fore, we investigated this possibility.
crystallized from ethyl acetate. The 1H NMR spectra of the
Scheme 4: A possible mechanism for the formation of 6.
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Table 1: Synthesis of 3-substituted 4-methoxyisoindolin-1-ones 9–18.
Product
Electrophile
E
Yield (%)a
9
MeI
Me
79
84
72
82
81
78
78
80
81
80
10
11
12
13
14
15
16
17
18
EtI
Et
BuBr
Bu
H2O
H
Ph2CO
(CH2)5CO
BuCOMe
PhCOMe
4-MeOC6H4CHO
PhCHO
Ph2C(OH)
(CH2)5C(OH)
BuC(OH)Me
PhC(OH)Me
4-MeOC6H4CH(OH)
PhCH(OH)
aYield of material isolated by washing or triturating the crude product with diethyl ether.
crystallized materials showed what appeared to be a single The X-ray crystal structures of the isolated crystals of products
component in each case. The crystalline products were there- 15, 17 and 18 showed that they were α-(R*)-3-(S*)-diastereo-
fore subjected to X-ray crystallography. The structures found isomers, while that of 16 showed that it was the α-(R*)-3-(R*)-
are illustrated in Figure 2.
diastereoisomer (Figure 2). With this information in hand, the
Figure 2: X-Ray crystal structures of crystallized compounds 12 and 15–18.
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Beilstein J. Org. Chem. 2011, 7, 1219–1227.
NMR spectra of the initial products obtained by trituration or Table 2). Each substrate was lithiated according to the standard
washing of the original crude products were re-examined. These procedure with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C for
spectra showed the presence of the crystallized product and a 6 h, and then treated with various electrophiles. After work-up,
second component, the identifiable resonances of which were as described above, the substituted isoindolin-1-ones 20–40
consistent with the other diastereoisomer. The two diastereoiso- were obtained in high yields (Table 2).
mers were present in nearly equal proportions (between 47:53
and 42:58), with the α-(R*)-3-(R*)-diastereoisomer being the The 1H NMR spectra of compounds 22–24, 29–31 and 35–38
somewhat predominant diastereoisomer in all cases.
showed diastereotopicity features similar to those for com-
pounds reported in Table 1. The NMR spectra of 25, 26, 32, and
We have shown previously that lithiation of N'-benzyl-N,N- 38–40 showed the presence of two racemic diastereoisomers in
dimethylurea and N'-(4-substituted benzyl)-N,N-dimethylureas unequal proportions (up to ca. 38:62). However, the NMR
with t-BuLi (two equiv) in THF at −78 °C for 4 h followed by spectra of the products after crystallization from ethyl acetate all
reactions with a variety of electrophiles gave high yields of exhibited one set of signals, indicating that the isolated crys-
products involving substitution at the 2-position [69]. There- talline product in each case was a single racemic diastereoiso-
fore, it was of interest to investigate further the scope of the mer. X-ray crystallography of the isolated crystals of com-
process represented in Table 1 with other ring-substituted pounds 38 and 39 showed them to be the α-(R*)-3-(R*)-dia-
N'-benzyl-N,N-dimethylureas 19 (R = H, 4-OMe, 4-Me; stereoisomers (Figure 4). The 1H NMR spectra of the isolated
Table 2: Synthesis of various substituted isoindolin-1-ones 20–40.
Product
R
Electrophile
E
Yield (%)a
20
H
H2O
H
71
75
77
76b
74
73
78
70
76
78
77
72
75
75
78
75
72
85
77
79
83
21
H
MeI
Me
22
H
EtI
Et
23
H
BuBr
Bu
24
H
Ph2CO
PhCHO
4-MeOC6H4CHO
H2O
Ph2C(OH)
25c
26d
27
H
PhCH(OH)
H
4-MeOC6H4CH(OH)
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
H
28
MeI
Me
29
EtI
Et
30
BuBr
Bu
31
Ph2CO
4-MeOC6H4CHO
H2O
Ph2C(OH)
4-MeOC6H4CH(OH)
H
32c
33
34
MeI
Me
35
EtI
Et
36
(CH2)5C=O
Ph2CO
MeCOBu
PhCHO
4-MeOC6H4CHO
(CH2)5C(OH)
Ph2C(OH)
MeC(OH)Bu
PhCH(OH)
4-MeOC6H4CH(OH)
37
38e
39e
40d
aYield of product isolated by trituration or washing of the initial reaction mixture with diethyl ether. bCompound 41 (Figure 3) was obtained in 5% yield.
cThe 1H NMR spectrum of the solid after crystallization showed the structure to be the α-(R*)-3-(R*)-isomer. dThe 1H NMR spectrum of the solid after
crystallization showed the structure to be the α-(R*)-3-(S*)-isomer. eX-Ray crystallography showed the product isolated by crystallization to be the
α-(R*)-3-(R*)-isomer (Figure 4).
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Beilstein J. Org. Chem. 2011, 7, 1219–1227.
Figure 3: Structures of compounds 41–44.
Conclusion
We have developed a novel, simple, efficient, general and high
yielding procedure for synthesis of isoindolin-1-ones in a one-
step reaction. It allows easy addition of a range of substituents
to the initial benzene ring and incorporation of a range of
substituents derived from the electrophiles used. Isolation of the
pure products is also extremely easy, involving simple tritura-
tion and/or washing of the crude product after work up, except
in the cases where two diastereoisomers are produced. In such
cases the α-(R*)-3-(R*)-isomer is somewhat predominant
(ratios of ca. 47:53 to 38:62); crystallization of these mixtures
produces one pure diastereoisomer in all cases. The method
promises to be a very useful new approach for synthesis of
substituted isoindolin-1-ones.
Experimental
General information
Melting point determinations were performed by the open capil-
lary method with a Gallenkamp melting point apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on a
Bruker AV400 or AV500 spectrometer at 400 or 500 MHz for
1H and 100 or 125 MHz for 13C measurements. Chemical shifts
δ are reported in parts per million (ppm) relative to TMS and
coupling constants J are in Hz and have been rounded to the
nearest whole number. 13C multiplicities were revealed by
Figure 4: X-ray crystal structures of compounds 38 and 39.
crystalline products 26, 32 and 40 indicated that the crystals DEPT signals. Assignments of signals are based on integration
were α-(R*)-3-(S*)-diastereoisomers, while the 1H NMR spec- values, coupling patterns and expected chemical shift values
trum of the crystallized product 25 showed it to be α-(R*)-3- and have not been rigorously confirmed. Signals with similar
(R*)-isomer. With the help of the NMR spectra of the crystal- characteristics might be interchanged. Low-resolution mass
lized diastereoisomers, re-examination of the spectra of the ma- spectra (see Supporting Information File 1) were recorded on a
terials obtained by simple trituration or washing of the original Quattro II spectrometer, electron impact (EI) at 70 eV and
crude product allowed calculation of the proportions of the two chemical ionization (CI) at 50 eV by the use of NH3 as ioniza-
diastereoisomers and in all cases the major diastereoisomer was tion gas. Atmospheric pressure chemical ionization (APCI)
again the α-(R*)-3-(R*)-isomer, as was the case when mass spectra were measured on a Waters LCT Premier XE
2-methoxybenzyl-N,N-dimethylurea was the starting material. instrument. Electrospray (ES) analyses were performed on a
ZQ4000 spectrometer in positive and negative ionisation
Compound 41 (Figure 3) was obtained as a side product in 5% modes. Accurate mass data were obtained on a MAT900 instru-
yield when 1-bromobutane was used as the electrophile. Com- ment. IR spectra (see Supporting Information File 1) were
pound 41 arose due to further lithiation at position 3 of 42, recorded on a Perkin Elmer Spectrum One FT-IR spectrometer
produced in situ from 43, to generate the lithium intermediate or a Perkin Elmer 1600 series FT-IR spectrometer. Micro-
44 (Figure 3). Reaction of the latter with a further equivalent of analyses for representative compounds were performed by
1-bromobutane affords 41.
Warwick analytical service at the University of Warwick. The
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Beilstein J. Org. Chem. 2011, 7, 1219–1227.
X-ray single-crystal diffraction data were collected on a Nonius NMR spectra. Elemental composition of a molecular ion or
Kappa CCD diffractometer using graphite-monochromated pseudo molecular ion confirmed the formula.
Mo-Kα, (λ = 0.71073 Å) radiation. Crystal and structure refine-
ment data are shown in the Supporting Information File 1. The
Supporting Information
structures were solved by direct methods using SHELXS-96
[73] and refined with all data on F2 full-matrix least squares
Supporting Information File 1
using SHELXL-97 [74]. Non-hydrogen atoms were generally
refined anisotropically. Hydrogen atom positions were located
from difference Fourier maps and a riding model with atomic
displacement parameters 1.2 times (1.5 times for methyl
groups) those of the atom to which they are bonded were used
for subsequent refinements. Full crystallographic data have
been deposited with the CCDC, reference numbers 737411
(compound 12), 762624 (compound 15), 766180 (compound
16), 737415 (compound 17), 762623 (compound 18), 766182
(compound 38) and 766181 (compound 39), and can be
obtained free of charge via http://www.ccdc.cam.ac.uk/
data_request/cif. Alkyl lithiums were obtained from Aldrich
Chemical Company and were estimated prior to use by the
method of Watson and Eastham [75]. Other reagents and
starting materials were obtained from Aldrich Chemical
Company and used without further purification. THF was
distilled from sodium benzophenone ketyl.
Characterization data of all compounds given in the article
and NMR spectra and X-ray information for representative
compounds. CCDC 737411, 737415, 762623, 762624,
766180, 766181 and 766182.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-142-S1.pdf]
Acknowledgements
A. S. Hegazy thanks Cardiff University for the financial
support.
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