2,3-Dihydroisoindolones by cyclisation and rearomatisation of lithiated benzamides

Article abstract of DOI:10.1016/S0040-4039(03)00545-8

Lithiation of tertiary aromatic N-benzyl amides generates [α]-amido benzyllithiums which cyclise with dearomatisation to cyclic extended enolates. Rearomatisation by oxidation, or, in the case of methoxy-substituted enolates, elimination, yields 2,3-dihydroisoindoles. Enantiomerically enriched products may be formed either by using a chiral base to lithiate the starting material or by using a chiral starting material.

Full text of DOI:10.1016/S0040-4039(03)00545-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3059–3062
2,3-Dihydroisoindolones by cyclisation and rearomatisation of
lithiated benzamides
Jonathan Clayden* and Christel J. Menet
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 14 February 2003; revised 24 February 2003; accepted 24 February 2003
Abstract—Lithiation of tertiary aromatic N-benzyl amides generates [a]-amido benzyllithiums which cyclise with dearomatisation
to cyclic extended enolates. Rearomatisation by oxidation, or, in the case of methoxy-substituted enolates, elimination, yields
2,3-dihydroisoindoles. Enantiomerically enriched products may be formed either by using a chiral base to lithiate the starting
material or by using a chiral starting material. © 2003 Elsevier Science Ltd. All rights reserved.
The isoindolone ring system is not the commonest of
the 6,5-fused heterocycles1,2 but can be found in a
number of valuable compounds, including alkaloids
such as nuevamine,3 lennoxamine,3,4 chilenine,5,6 stau-
rosporine,7 aristoyagonine8 and fumaridine,9 and drugs
such as indoprofen9 and DN 2327.10 In this paper, we
describe a modification of our dearomatising cyclisation
reaction of aromatic amides11–14 in which the products
are rearomatised15 to 2,3-dihydroisoindolones. 2,3-
Dihydroisoindolones may bear a stereogenic centre at
C-3, and we describe methods for controlling its abso-
lute stereochemistry.
nitrogen, and that the benzyllithiums 2 undergo cyclisa-
tion to a bicyclic, dearomatised enolate 3.12–14 This
enolate may be protonated or alkylated to yield dearo-
matised products 4, and we have used such reactions in
the synthesis for example of some kainoid amino
acids.16–18 We found that LDA is the most versatile
base for the reaction,14 but if the diisopropylamine is
not rigorously distilled and degassed prior to use, or if
reaction times are extended beyond 2 h, by-products
arising from oxidation of the enolate may be observed.
For example, when the cyclistion of 1 was carried out
with LDA at −40°C for 24 h, the product 4 was
contaminated with a mixture of 5 and 6.
Yields of the oxidised products may be maximised if
the reaction is warmed to 20°C for a minimum of 2 h to
ensure complete cyclisation, and then opened to dry air
(nitrogen line replaced with a drying tube) and stirred
for 12 h. For example, 1, was treated with LDA at 0°C,
allowed to warm to 25°C over 2 h, then opened to dry
air overnight. A single diastereoisomer of the alcohol 5
and the rearomatised 2,3-dihydroisoindolone 6 were
now the sole products, isolated in a 1:1 ratio.19 Com-
pound 5, in common with other partially saturated
isoindolones, is remarkably stable—for example, no
conversion to 6 by elimination of water was observed
even on treatment with acid. However, 5 could be
converted to the dihydroisoindolone 6 by treatment
with methanesulfonyl chloride and triethylamine.
We have previously reported that tertiary benzamides
Application of optimised conditions20 for cyclisation
and rearomatisation of amides to 2,3-dihydroisoin-
dolones are summarised in Table 1. The amides 1 and
7–10 were each lithiated and cyclised by treatment with
bearing N-benzyl groups such as 1 may be lithiated a to
* Corresponding author. Fax: +44 161 275 4939; e-mail: j.p.clayden@
man.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00545-8

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J. Clayden, C. J. Menet / Tetrahedron Letters 44 (2003) 3059–3062
Table 1. Cyclisation–rearomatisation
Entry
S.M.
R=
Product
Yield (%)
Notes
1
2
3
4
5
1
7
8
9
10
4-MeO
2-MeO
4-CN
4-Br
2,3-Benzo
6
11
12
13
–
60
50
71
40
–
a
b
c
a Plus 28% non-rearomatised and 12% 14.
b Plus 39% 14.
c 30% non-rearomatised plus 33% hydroxylated 15.
LDA at 0°C, warming to 20°C over 2 h, and oxidised
by exposure to dry air for 12 h. Treatment of the crude
reaction mixture with MsCl–Et3N promoted elimina-
tion and allowed us to isolate the dihydroisoindoles 6
and 11–13 in moderate to good yields. The main by-
products were due to aromatic substitution (see below)
or incomplete oxidation or elimination.
optically active, but unfortunately we were unable to
quantify its enantiomeric excess. The comparable
dearomatisation proceeds to yield a product with >99%
ee.22 There are few alternatives available for the asym-
metric synthesis of 2,3-dihydroisoindolones.24
During this work, the anionic cyclisation of a phos-
phinyl amide was reported which led to a dihydroisoin-
dole product by nucleophilic aromatic substitution.25
Methoxy groups are well known to be good leaving
groups in nucleophilic aromatic substitutions,26–28 and
we made a collection of amides 19–22 bearing ortho-
methoxy groups for attempted cyclisation to isoindoles.
Table 1 shows that 2-methoxy amide 7 cyclises with
traces of substitution products, but we found that
amides 19–21 which had no choice but to cyclise to
positions carrying methoxy groups underwent nucle-
ophilic aromatic substitution to give isoindoles 11, 23,
24 in good to excellent yield (Table 2). Amide 22 also
undergoes cyclisation with rearomatisation to give 25.
An important feature of the dearomatising cyclisation
leading to 4 is the possibility of introducing asymmetry
by forming the benzyllithium 2 enantioselectively. We
have previously formed similar chiral benzyllithiums in
two ways: by using a chiral lithium amide base to effect
asymmetric deprotonation21 or by using a chiral start-
ing material, which undergoes deprotonation stereospe-
cifically.22 Cyclisation–oxidation reactions were carried
out by both methods, using 1 and 17 as starting materi-
als. Treatment of 1 with 1.1 equiv. the chiral base
(R)-16 and oxidation–elimination gave (−)-6 in 70% ee,
slightly lower than the comparable dearomatising cycli-
sation,21 probably because of partial racemisation of
the product.23 Cyclisation–rearomatisation of both ( )-
and (R)-17 gave the 2,3-dihydroisoindolone 18 in excel-
lent yield, and the product (−)-18 from (R)-17 was
In order to use the isoindolone products in synthesis, it
is necessary to remove the N-t-Bu substituent, a reac-
tion which in dearomatised compounds 4 posed prob-
lems and led to our use of the N-cumyl protecting
group.14,29 However, treatment of 6 and 11 with tri-
fluoroacetic acid resulted in clean de-t-butylation, giv-
ing the N-unsubstituted dihydroisoindolones 26 and 27
Table 2. Cyclisation–substitution
Entry
S.M.
R=
Isoindolone
product
Yield (%)
1
2
3
4
19
20
21
22
6-MeO
11
23
24
25
85
80
66
81
5,6-Benzo
3,4-Benzo
3-MeO

J. Clayden, C. J. Menet / Tetrahedron Letters 44 (2003) 3059–3062
3061
in yields of 80% and 66%, respectively. In a further
demonstration of the potential of the isoindolones in
synthesis, it was also possible to transform isoindolone
11 into the fully unsaturated isoindole 28 by treatment
with a Grignard reagent.30
Tetrahedron Lett. 2001, 42, 3407.
18. Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron
2002, 58, 4727.
19. We speculate that the single diastereoisomer of 5 arises
from non-diastereoselective oxidation followed by
stereoelectronically favoured elimination from one
diastereoisomer only. Assignment of stereochemistry to 5
is speculatively based on the possibility that the
diastereoisomer with H and OH syn eliminates more
slowly.
20. General procedure for cyclisation–rearomatisation: The
amide 1 (0.43 g, 2.52 mmol) in dry THF (30 ml) was
added to a solution of freshly prepared LDA (2.75 mmol)
in THF (10 ml) at 0°C under nitrogen. After 2 h at 20°C,
the nitrogen line was replaced with a drying tube and
stirring was continued for 12 h. The mixture was concen-
trated and CH2Cl2 (30 ml) was added. The solution was
cooled to 0°C, and triethylamine (6.3 mmol) and
methanesulfonyl chloride (3.04 mmol) were added. After
1 h at 0°C water was added, the layers were separated
and the aqueous phase was extracted with CH2Cl2. The
combined organic fractions were dried (MgSO4) and con-
centrated to yield the crude product. Purification by flash
chromatography, eluting with 7:3 petrol–EtOAc, afforded
the dihydroisoindolone 6 as a white solid (0.23 g, 60%).
Mp=140–141°C. Found: M+H+ 296.1654; C19H22NO2
requires M, 296.1650; m/z (EI) 296 (M+H+, 100%); lH
(300 MHz, CDCl3) 7.75 (1H, d, J 8.5, H7), 7.4–7.2 (5H,
m, ArH), 6.93 (1H, dd, J 8.5, 2, H6), 6.52 (1H, d, J 2,
H4), 5.65 (1H, s, H3), 3.77 (3H, s, CH3O), 1.48 (9H, s,
tert-butyl); lC (75 MHz, CDCl3) 169.8, 162.6, 148.7,
141.1, 128.9, 127.7, 126.1, 124.7, 124.4, 114.5, 107.2, 64.6,
55.7, 55.4, 28.6; wmax (film)/cm−1 1677 (CꢀO).
Acknowledgements
We are grateful to Aventis (C.J.M.) for support, and to
Dr. Darren Mansfield for helpful discussions.
References
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Data for 11: Mp=178–179°C; Found: M+ 295.1581;
C19H21NO2 requires M, 295.1572 (Found: C 76.94%, H
7.26%, N 4.74%; calc. C 77.26%, H 7.17%, N 4.74%); m/z
(CI) 296 (M+H+, 100%), 295 (M+, 40%), 280 (M+−CH3,
40%); lH (300 MHz, CDCl3) 7.4–7.2 (6H, m, ArH), 6.82
(1H, d, J 8, ArH), 6.62 (1H, d, J 7.5, ArH), 5.62 (1H, s,
CH), 3.99 (3H, s, CH3O), 1.47 (9H, s, tert-butyl); lC (75
MHz, CDCl3) 172.2, 156.8, 149.3, 132.9, 128.9, 128.0,
127.7, 126.4, 126.1, 114.6, 109.5, 103.8, 64.2, 55.8, 55.7,
28.4; wmax(film)/cm−1 1683 (CꢀO).
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Data for (−)-18: [h]D22=−32 (c=1.38 in CHCl3). Mp=
143–145°C. Found: M+ 295.1570; C19H21NO2 requires M,
295.1571; m/z (EI) 295 (M+, 80%), 280 (M−Me, 100%),
237 (50%); lH (300 MHz, CDCl3) 7.78 (1H, d, J 8.5, H7),
7.3 (5H, m, PhH), 6.95 (1H, dd, J 8.5, 2, H6), 6.51 (1H,
d, J 2.5, H4), 3.78 (3H, s, MeO), 3.35 (1H, sept, J 7,
CH(CH3)2), 1.92 (3H, s, CH3), 1.50 (3H, d, J 7, CH3CH),
1.28 (3H, d, J 7, CH3CH); lC (75 MHz, CDCl3) 167.8,
162.8, 154.1, 140.2, 128.3, 127.8, 126.8, 124.6, 124.5,
114.3, 106.5, 67.7, 55.4, 45.5, 23.1, 20.7, 19.7; wmax(film)/
cm−1 1678 (CꢀO), 1609 (Ar).
11. Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun.
1998, 297.
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1999, 231.
13. Clayden, J.; Tchabanenko, K.; Yasin, S. A.; Turnbull, M.
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2000, 2, 4229.
15. Some nucleophilic additions to aromatic rings unavoid-
ably yield aromatic products by rearomatisation (see
Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4, 787
and references cited therein). By contrast we have found
the partially saturated products of our dearomatising
cyclisations to be surprisingly resistant to rearomatisation
(Ref. 14).
Data for 23: Found: M+ 315.1624; C22H21NO requires M,
315.1623; m/z (CI) 316 (M+H+, 100%), 315 (M+, 60%);
lH (300 MHz, CDCl3) 8.67 (1H, d, J 8.5, ArH), 7.83 (1H,
d, J 9, ArH), 7.63 (1H, d, J 8, ArH), 7.5–7.4 (2H, m,
ArH), 7.4–7.1 (6H, m, ArH), 4.75 (1H, s, CH), 1.42 (9H,
s, tert-butyl); lC (75 MHz, CDCl3) 197.8, 164.0, 138.1,
138.0, 131.1, 129.7, 128.9, 127.9, 127.6, 126.9, 126.2,
123.6, 122.7, 114.5, 71.5, 56.3, 29.6; wmax(film)/cm−1 1677
(CꢀO).
16. Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317.
17. Ahmed, A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K.

3062
J. Clayden, C. J. Menet / Tetrahedron Letters 44 (2003) 3059–3062
Data for 24: Found: M+ 315.1622; C22H21NO requires M,
(1H, d, J 8, ArH), 6.81 (1H, d, J 7.5, ArH), 6.62 (1H, b,
NH), 5.59 (1H, s, CH2), 4.03 (3H, s, CH3O); lC (75 MHz,
CDCl3) 170.1, 157.9, 151.8, 138.6, 134.0, 128.9, 128.4,
126.7, 115.3, 110.1, 60.1, 55.9; wmax(film)/cm−1 3200 (NH),
1690 (CꢀO).
315.1623; m/z (CI) 316 (M+H+, 100%), 315 (M+, 60%);
lH (300 MHz, CDCl3) 8.0–7.8 (4H, m, ArH), 7.5–7.2
(7H, m, ArH), 6.11 (1H, s, CH), 1.52 (9H, s, tert-butyl);
lC (75 MHz, CDCl3) 169.9, 144.0, 139.9, 135.3, 130.1,
129.4, 129.1, 128.7, 127.9, 127.0, 126.7, 126.1, 123.2,
119.5, 64.5, 56.0, 28.6; wmax(film)/cm−1 1679 (CꢀO).
Data for 25: Found: M+ 295.1581; C19H21NO2 requires
M, 295.1572; m/z (CI) 296 (M+H+, 100%), 295 (M+,
40%), 280 (M+−CH3, 40%); lH (300 MHz, CDCl3) 7.5–
7.2 (7H, m, ArH), 6.88 (1H, d, J 8, ArH), 5.75 (1H, s,
CH), 3.66 (3H, s, CH3O), 1.46 (9H, s, Boc); lC (75 MHz,
CDCl3) 169.8, 153.7, 139.3, 134.4, 133.9, 129.7, 128.0,
127.4, 127.3, 115.1, 113.3, 63.0, 55.8, 55.3, 28.3;
wmax(film)/cm−1 1678 (CꢀO), 1608 (Ar).
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23. Using 2 equiv. of 16 further reduced the ee of (−)-6 to
only 50%.
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Data for 26: Mp=200–202°C. Found: M+ 239.0944;
C15H13NO2 requires M, 239.0946; m/z (CI) 240 (M+H+,
100%); lH (300 MHz, CDCl3) 7.82 (1H, d, J 7.5, H7),
7.18 (5H, m, PhH), 7.05 (1H, b, NH), 7.0 (1H, d, J 7.5,
H6), 6.72 (1H, s, H4), 5.60 (1H, s, H3), 3.81 (3H, s,
MeO); lC (75 MHz, CDCl3) 171.3, 163.6, 150.7, 138.9,
129.3, 128.8, 127.1, 125.4, 123.7, 115.3, 108.2, 60.9, 55.9;
wmax(film)/cm−1 3200 (NH), 1688 (CꢀO), 1610 (Ar).
Data for 27: Mp=179–181°C; Found: M+ 239.0947;
C15H13NO2 requires M, 239.0946; m/z (CI) 240 (M+H+,
100%); lH (300 MHz, CDCl3) 7.5–7.2 (6H, m, ArH), 6.93