One-pot synthesis of substituted isoindolin-1-ones via lithiation and substitution of N′-benzyl-N,N-dimethylureas

Article abstract of DOI:10.1039/b926983e

Lithiation of various N′-benzyl-N,N-dimethylureas with t-BuLi (3.3 mole equivalents) in anhydrous THF at 0 °C followed by reactions with various electrophiles afforded the corresponding 3-substituted isoindolin-1-ones in high yields.

Full text of DOI:10.1039/b926983e

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
One-pot synthesis of substituted isoindolin-1-ones via lithiation and
substitution of N0-benzyl-N,N-dimethylureasw
Keith Smith,* Gamal A. El-Hiti and Amany S. Hegazy
Received (in Cambridge, UK) 22nd December 2009, Accepted 13th February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b926983e
Lithiation of various N0-benzyl-N,N-dimethylureas with t-BuLi
(3.3 mole equivalents) in anhydrous THF at 0 1C followed by
reactions with various electrophiles afforded the corresponding
3-substituted isoindolin-1-ones in high yields.
Although the isoindolinone skeleton was not commonly
encountered in the past, in recent years there has been a great
Scheme 2 Lithiation and cyclization of N-tert-butyl-N-benzylbenz-
deal of interest in such compounds since they represent the
core unit of numerous naturally occurring substances.1 Also,
amides.
The other, potentially more useful, approach involves
generation of the isoindolin-1-one ring system during the
lithiation step. For example, lithiation of N-tert-butyl-N-benzyl-
several members belonging to this family have shown
interesting biological properties.2
Several methods are available for the synthesis of isoindo-
linones,3,4 based on the use of Grignard reagents,5 Diels–Alder
reactions,6 Wittig reagents,7 reduction processes,8 rearrange-
ment processes9 and photochemical reactions.10 However,
such methods generally require multiple reaction steps, and
are often unsatisfactory, in yield and/or generality. In recent
years a number of new approaches have been developed for
the synthesis of substituted isoindolines, of which the most
generally useful involve palladium-catalysed reactions11 or
lithiation procedures.12–15
benzamides gives intermediates that cyclise to form
a
dearomatised species. Oxidation to re-aromatise the system
and treatment with trifluoroacetic acid to remove the tert-butyl
group gives the corresponding 2,3-dihydroisoindolin-1-ones
(Scheme 2).13a However, this approach gives more modest
yields, requires the additional step to remove the t-Bu group,
and also involves incorporating the eventual C-3 substituent
into the starting material, which limits the generality.
Clayden and Menet have improved the yield of 2,3-
dihydroisoindolin-1-ones using 2-methoxy amides as the
starting materials; in this case the methoxy group acts as a
leaving group, avoiding the need for an oxidation step.13a
However, this approach still requires an additional step to
remove the t-Bu group.
In particular, among the methods involving lithiation two
useful approaches to the synthesis of 2,3-dihydroisoindolin-1-
ones have been reported (Schemes 1 and 2).12a,13a One method
simply involves lithiation of a preformed 2,3-dihydroisoindol-l-one
ring system at the 3-position followed by treatment with an
electrophile (Scheme 1).12a Clearly, the general utility of this
approach depends on the availability of appropriately substituted
analogues of the dihydroisoindolin-1-one ring system.
Based on our own experience in the use of lithium reagents
in organic synthesis and in directed lithiation reactions,16 we
felt that it ought to be possible to develop a general, simple
and efficient procedure for the synthesis of 2,3-dihydroisoin-
dolin-1-ones. We now report a new method that involves both
cyclization to give the ring system and incorporation of a C-3
substituent in a single synthetic step via lithiation and sub-
stitution of N0-benzyl-N,N-dimethylureas.
Simple lithiation and substitution of N0-benzyl-N,N-di-
methylureas have been reported previously.17,18 For example,
we have shown that lithiation of N0-(2-methoxybenzyl)-N,N-
dimethylurea (1) with two equivalents of t-BuLi (Scheme 3)
at ꢀ20 1C followed by reaction with 4-anisaldehyde gave 2
(49% yield) and 3 (40%).18b
Scheme 1 Lithiation and substitution of 2,3-dihydroisoindol-1-ones.
Recently, we found that when the reaction was carried out
at 0 1C rather than at ꢀ20 1C it produced lower yields of 2 and
3, along with some residual 1 and a small amount of a new
product, 4, the structure of which was confirmed by X-ray
crystallography (Fig. 1).19 Compound 4 would be expected to
be formed as a pair of racemic diastereoisomers; however, its
NMR spectra showed what appeared to be a single set of
signals, indicating that the isolated product was a single
racemic diastereoisomer.20 It is possible that a small amount
School of Chemistry, Cardiff University, Main Building, Park Place,
Cardiff, UK CF10 3AT. E-mail: smithk13@cardiff.ac.uk,
el-hitiga@cardiff.ac.uk; Fax: +44 (0)2920870600;
Tel: +44 (0)2920870600
w Electronic supplementary information (ESI) available: Experimental
procedure; characterization data; NMR spectra and X-ray
information for representative compounds. CCDC 737415. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b926983e
ꢁc
This journal is The Royal Society of Chemistry 2010
2790 | Chem. Commun., 2010, 46, 2790–2792

View Article Online
Scheme 4 Lithiation, substitution and cyclization of 1.
5 cyclise to give 7, but 6 is also in equilibrium with 5, allowing
its eventual conversion into 7 and then 8.
This fortuitous finding appeared to offer potential as a
general synthesis and the same lithiation procedure was therefore
used with a range of different electrophiles. Following work-up
of the reaction mixtures the crude products were triturated
and/or washed with diethyl ether to give pure products 4 and
9–16 (Scheme 4) in high yields (Table 1).
Scheme 3 Lithiation and substitution of 1.
Compounds 9 and 10 would be expected to be formed as
pairs of racemic diastereoisomers; however, their NMR
spectra each showed what appeared to be just one set of
signals, indicating that the isolated product in each case was
a single racemic diastereoisomer, and the X-ray crystallography
of both compounds confirmed the crystal structures as the
(R*)-3-(S*)- isomers. However, although these compounds
were isolated in high yields, again it seems likely that small
amounts of the other diastereoisomers were formed but
washed out during purification of the crude products by
washing with diethyl ether.
Fig. 1 X-Ray crystal structure of 4.
From the results recorded in Table 1 it was clear that the
reaction with a variety of electrophiles is a general process,
producing 3-substituted 4-methoxyisoindolin-1-ones 4 and
9–16 in high yields.
of the other diastereoisomer was formed but washed out
during the purification process. Indeed, the 1H NMR spectrum
of the crude product showed the presence of an additional
minor diastereoisomer. The X-ray crystallography of
compound 4 confirmed the crystal structure as (R*)-3-((S*)-
hydroxy(4-methoxyphenyl)methyl)-4-methoxyisoindolin-1-one
(Fig. 1).19
The generality of the process was tested further using other
ring-substituted N0-benzyl-N,N-dimethylureas 17 (Scheme 5).
Each substrate was lithiated according to the standard procedure,
and then treated with various electrophiles. Following work-up
as described above pure products 18–23 were obtained in high
yields (Table 2).
Formation of 2 and 3 presumably involves lithium inter-
mediates 5 and 6, respectively (Fig. 2), while 4 would arise
by cyclization of 5 to give 7, followed by further lithiation to
give 8 (Fig. 2), which on reaction with 4-anisaldehyde gives 4.
Therefore, it appeared likely that the yield of 4 could be
increased by the use of a larger quantity of t-BuLi.
In conclusion, we have developed a novel, simple, efficient
and high yielding procedure for the synthesis of isoindolin-1-
ones in a one-step reaction. It allows easy incorporation
of a range of substituents on the initial benzene ring and
incorporation of a range of substituents derived from the electro-
philes used. Isolation of the pure products is also extremely easy,
involving simple trituration and/or washing of the crude product
after work-up. Therefore, this promises to be a very useful new
Indeed, lithiation of 1 with t-BuLi (3.3 mole equivalents) in
anhydrous THF at 0 1C for 6 h, followed by treatment with
4-anisaldehyde (1.1 mole equivalents), gave 4 in high yield.
While an increased yield of 4 was expected, the disappearance
of 3 was a surprise. It would appear that at 0 1C, not only does
Table 1 Synthesis of various 3-substituted 4-methoxyisoindolin-1-
ones 4 and 9–16
Product
Electrophile
E
Yielda (%)
4b
4-MeOC6H4CHO
PhCHO
BuCOMe
Ph2CO
(CH2)5CO
H2O
MeI
4-MeOC6H4CH(OH)
PhCH(OH)
BuC(OH)Me
Ph2C(OH)
(CH2)5C(OH)
H
Me
Et
81
80
78
81
78
82
79
84
72
9b
10b
11
12
13
14
15
16
EtI
BuBr
Bu
a
b
Yield of pure product. The X-ray crystallography confirmed the
crystal structure as (R*)-3-(S*)- isomer.
Fig. 2 Structures of 5–8.
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2790–2792 | 2791

View Article Online
´
P. Grandclaudon, Tetrahedron, 2007, 63, 2664; (d) J. Perard-Viret,
T. Prange, A. Tomas and J. Royer, Tetrahedron, 2002, 58, 5103;
´
(e) T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 1432.
5 W. S. Ang and B. B. Halton, Aust. J. Chem., 1971, 24, 851.
6 A. J. Guticrrez, K. J. Shea and J. J. Svoboda, J. Org. Chem., 1989,
54, 4335.
7 J. Epsztajn, R. Grzelak and A. Jz
8 (a) F. A. Luzzio and D. P. Zacherl, Tetrahedron Lett., 1998, 39, 2285;
(b) M. J. Milewska, T. Bytner and T. Polonski, Synthesis, 1996, 1485.
´ wiak, Synthesis, 1996, 1212.
Scheme 5 Synthesis of isoindolin-1-ones 18–23.
´
9 J. Guillaumel, N. Boccara, P. Demersemann and R. Royer,
J. Chem. Soc., Chem. Commun., 1988, 1604.
Table 2 Synthesis of various 3-substituted isoindolin-1-ones 18–23
10 (a) A. G. Griesbeck, J. Hirt, W. Kramer and P. Dallakian,
Tetrahedron, 1998, 54, 3169; (b) M. A. Weidner-Wells, K. Oda
and P. H. Mazzochi, Tetrahedron, 1997, 53, 3475.
Product
R
Electrophile
E
Yielda (%)
1821
19
20
21
22
23
H
H
Me
Me
OMe
OMe
EtI
Et
77
74
85
72
76
77
11 (a) C. S. Cho and W. X. Ren, Tetrahedron Lett., 2009, 50, 2097;
(b) C. Sun and B. Xu, J. Org. Chem., 2008, 73, 7361; (c) K. Orito,
M. Miyazawa, T. Nakamura, A. Horibata, H. Ushito,
H. Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki and
H. Tokuda, J. Org. Chem., 2006, 71, 5951; (d) S. Couty,
B. Ligault, C. Meyer and J. Cossy, Org. Lett., 2004, 6, 2511;
(e) C. S. Cho, H. S. Shim, H.-J. Choi, T.-J. Kim, S. C. Shim and
M. C. Kim, Tetrahedron Lett., 2000, 41, 3891; (f) C. S. Cho,
L. H. Jiang and S. C. Shim, Synth. Commun., 1998, 28, 849;
(g) C. S. Cho, J. W. Lee, D. Y. Lee, S. C. Shim and T. J. Kim,
Chem. Commun., 1996, 2115; (h) R. Grigg, V. Loganathan,
V. Santhakumar, V. Sridharan and A. Teasdale, Tetrahedron Lett.,
1991, 32, 687; (i) R. C. Larock, C.-L. Liu, H. H. Lau and
S. Varaprath, Tetrahedron Lett., 1984, 25, 4459; (j) M. Mori,
K. Chiba and Y. Ban, J. Org. Chem., 1978, 43, 1684.
Ph2CO
Ph2CO
(CH2)5CQO
MeI
Ph2C(OH)
Ph2C(OH)
(CH2)5C(OH)
Me
BuBr
Bu
a
Yield of pure product.
approach for the synthesis of such compounds. We are currently
conducting further work in order to understand the stereo-
chemical consequences of the reactions.
We thank Dr Benson Kariuki, X-ray crystallography service
at Cardiff School of Chemistry for the crystal structures. A. S.
Hegazy thanks Cardiff University for financial support.
12 (a) A. Couture, E. Deniau, D. Lonescu and P. Grandclaudon,
Tetrahedron Lett., 1998, 39, 2319; (b) A. Couture, E. Deniau and
P. Grandclaudon, Tetrahedron, 1997, 53, 10313.
13 (a) J. Clayden and C. J. Menet, Tetrahedron Lett., 2003, 44, 3059;
(b) J. Clayden, C. J. Menet and D. J. Mansfield, Org. Lett., 2000, 2,
4229; (c) J. Clayden and K. Tchabanenko, Chem. Commun., 2000,
317; (d) A. Ahmed, J. Clayden and S. A. Yasin, Chem. Commun.,
1999, 231; (e) J. Clayden, F. E. Knowles and I. R. Baldwin, J. Am.
Chem. Soc., 2005, 127, 2412.
Notes and references
1 (a) A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau and
V. Rys, Tetrahedron Lett., 2002, 43, 2207; (b) N. J. Lawrence,
J. Liddle, S. M. Bushell, M. I. Page and A. M. Z. Slawin, J. Org.
Chem., 2002, 67, 457; (c) J. R. Fuchs and R. L. Funk, Org. Lett.,
2001, 3, 3923; (d) M. Linder, D. Hadler and S. Hofmann, Human
Psychopharmacol., 1997, 12, 445; (e) R. A. Abramovitch, I. Shinkai,
B. J. Mavunkel, K. M. More, S. O’Connor, G. H. Ooi,
W. T. Pennington, P. C. Srinivason and J. R. Stowers, Tetrahedron,
1996, 52, 3339; (f) J. L. Wood, B. M. Stoltz and P. N. Goodman,
J. Am. Chem. Soc., 1996, 118, 10656; (g) F. G. Fang and
S. J. Danishefsky, Tetrahedron Lett., 1989, 30, 2747;
(h) E. Valencia, A. J. Freyer, M. Shamma and V. Fajardo,
Tetrahedron Lett., 1984, 25, 599; (i) V. Fajardo, V. Elango,
B. K. Cassels and M. Shamma, Tetrahedron Lett., 1982, 23, 39.
2 (a) C. Maugeri, M. A. Alisi, C. Apicella, L. Cellai, P. Dragone,
E. Fioravanzo, S. Florio, G. Furlotti, G. Mangano, R. Ombrato,
R. Luisi, R. Pompei, V. Rincicotti, V. Russo, M. Vitiello and
N. Cazzolla, Bioorg. Med. Chem., 2008, 16, 3091; (b) H. M. B. Cid,
14 (a) J. Epsztajn, A. Jo
I. D. Wilkowska, Tetrahedron, 2000, 56, 4837; (b) J. Epsztajn,
A. Jo wiak and A. K. Szczesniak, Synth. Commun., 1994, 24, 1789;
(c) J. Epsztajn, A. Jo wiak and A. K. Szczesniak, Tetrahedron,
1993, 49, 929; (d) J. Epsztajn, A. Jo wiak, K. Czech and
A. K. Szczesniak, Monatsh. Chem., 1990, 121, 909.
´
z´ wiak, P. Ko"uda, I. Sadokierska and
´
z´
´
´
z´
´
´
z´
´
15 M. Lamblin, A. Couture, E. Deniau and P. Grandclaudon,
Tetrahedron: Asymmetry, 2008, 19, 111.
16 See for example: (a) K. Smith, G. A. El-Hiti, M. A. Abdo and
M. F. Abdel-Megeed, J. Chem. Soc., Perkin Trans. 1, 1995, 1029;
(b) K. Smith, G. A. El-Hiti, M. F. Abdel-Megeed and M. A. Abdo,
J. Org. Chem., 1996, 61, 647; (c) K. Smith, G. A. El-Hiti,
M. F. Abdel-Megeed and M. A. Abdo, J. Org. Chem., 1996, 61,
656; (d) K. Smith, G. A. El-Hiti and A. P. Shukla, J. Chem. Soc.,
Perkin Trans. 1, 1999, 2305; (e) K. Smith, G. A. El-Hiti and
M. F. Abdel-Megeed, Synthesis, 2004, 2121; (f) K. Smith,
G. A. El-Hiti and A. S. Hegazy, Synthesis, 2005, 2951;
(g) K. Smith and M. L. Barratt, J. Org. Chem., 2007, 72, 1031.
17 (a) G. Katsoulos and M. Schlosser, Tetrahedron Lett., 1993, 39, 6263;
(b) G. Simig and M. Schlosser, Tetrahedron Lett., 1988, 29, 4277.
18 (a) K. Smith, G. A. El-Hiti and A. S. Hegazy, Synlett, 2009, 2242;
(b) A. S. Hegazy, PhD thesis, Cardiff University, UK, 2009.
19 Crystal data for 4: colourless, C17H17NO4, T = 293(2) K, centro-
symmetric, space group P-1, a = 7.5240(3) A, b = 9.4100(3) A,
c = 11.9960(5) A, a = 83.877(2)1, b = 77.311(2)1, g = 68.559(2)1,
5071 reflections collected, 3513 independent reflections, R = 0.0570,
wR = 0.1277, Rint = 0.0334. CCDC 737415.
C. Traenkle, K. Baumann, R. Pick, E. Mies-Klomfass, E. Kostenis,
¨
K. Mohr and U. Holzgrabe, J. Med. Chem., 2000, 43, 2155;
(c) T. R. Belliotti, W. A. Brink, S. R. Kesten, J. R. Rubin,
D. J. Wustrow, K. T. Zoski, S. Z. Whetzel, A. E. Corbin,
T. A. Pugsley, T. G. Heffner and L. D. Wise, Bioorg. Med. Chem.
Lett., 1998, 8, 1499; (d) Z.-P. Zuang, M.-P. Kung, M. Mu and
H. F. Kung, J. Med. Chem., 1998, 41, 157; (e) E. C. Taylor,
P. Zhou, L. D. Jenning, Z. Mao, B. Hu and J.-G. Jun, Tetrahedron
Lett., 1997, 38, 521; (f) I. Takahashi, E. Hirano, T. Kawakami and
H. Kitajima, Heterocycles, 1996, 43, 2343; (g) I. Takahashi,
T. Kawakami, E. Hirano, H. Yokota and H. Kitajima, Synlett,
1996, 353; (h) E. De Clercq, J. Med. Chem., 1995, 38, 2491;
(i) I. Pendrak, S. Barney, R. Wittrock, D. M. Lambert and
W. D. Kingsbury, J. Org. Chem., 1994, 59, 2623; (j) W. Lippmann,
US Pat., 4267189, 1981 (Chem. Abs., 1981, 95, 61988m).
20 Analytical data for 4: mp: 199–201 1C; 1H NMR (400 MHz,
DMSO-d6): d 8.77 (s, exch., 1H), 7.31 (app. t, J = 8 Hz, 1H), 7.16
(d, J = 8 Hz, 1H), 6.93 (d, J = 8 Hz, 1H), 6.89 (d, J = 9 Hz, 2H),
6.58 (d, J = 9 Hz, 2H), 5.73 (d, J = 3 Hz, exch., 1H), 5.39 (app. t,
J = 3 Hz, 1H), 4.89 (d, J = 3 Hz, 1H), 3.97 (s, 3H), 3.60 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d 169.7, 158.4, 155.0, 134.9, 131.6,
131.5, 130.1, 128.3, 114.9, 113.6, 112.5, 71.6, 61.5, 56.0, 55.1; HRMS
3 (a) G. E. Marinicheva and T. I. Gubina, Chem. Heterocycl.
Compd., 2004, 40, 1517; (b) R. Bonnett and S. A. North, Adv.
Heterocycl. Chem., 1981, 29, 341; (c) J. D. White and M. E. Mann,
Adv. Heterocycl. Chem., 1969, 10, 113.
4 (a) C. F. Marcos, S. Marcaccini, G. Menchi, R. Pepino and
pez-Valdez,
T. Torroba, Tetrahedron Lett., 2008, 49, 149; (b) G. Lo
´
S. Olguın-Uribe and L. D. Miranda, Tetrahedron Lett., 2007,
(CI): calcd for C17H18NO4 [MH+
FT (FT): nmax 3304, 2872, 1677, 1604, 1512, 1273, 1048 cmꢀ1
21 E. Deniau and D. Enders, Tetrahedron, 2001, 57, 2581.
] 300.1230; found 300.1231;
´
48, 8285; (c) M. Lamblin, A. Couture, E. Deniau and
.
ꢁc
This journal is The Royal Society of Chemistry 2010
2792 | Chem. Commun., 2010, 46, 2790–2792