Carbonylation of doubly lithiated N′-aryl-N,N-dimethylureas: A novel approach to isatins via intramolecular trapping of acyllithiums

Article abstract of DOI:10.1055/s-2003-41019

Lithiation of N′-(2-bromoaryl)-N,N-dimethylureas with methyllithium and tert-butyllithium under nitrogen in anhydrous THF at 0°C gave doubly lithiated arylurea derivatives, which react with carbon monoxide at 0°C to give isatins in good yields. The scope of the reaction has been demonstrated by application to the synthesis of isatin itself and four substituted isatins beating alkyl, chloro or fluoro groups.

Full text of DOI:10.1055/s-2003-41019

PAPER
2047
Carbonylation of Doubly Lithiated N¢-Aryl-N,N-Dimethylureas: A Novel
Approach to Isatins via Intramolecular Trapping of Acyllithiums
Carbonylation of
D
e
oubly Lith
i
iated
N
t
¢
-Aryl-
h
N
,
N
-Dimethylure
aS
mith,* Gamal A. El-Hiti,1 Anthony C. Hawes
Centre for Clean Chemistry, Department of Chemistry, University of Wales Swansea, Singleton Park, Swansea, SA2 8PP, UK
Fax +44(1792)295261; E-mail: k.smith@swansea.ac.uk
Received 28 May 2003; revised 10 June 2003
HO
tBu
i, BuLi, 0 °C
ii, CO, 0 °C
iii, H3O+
Abstract: Lithiation of N¢-(2-bromoaryl)-N,N-dimethylureas with
X
X
methyllithium and tert-butyllithium under nitrogen in anhydrous
THF at 0 °C gave doubly lithiated arylurea derivatives, which react
with carbon monoxide at 0 °C to give isatins in good yields. The
scope of the reaction has been demonstrated by application to the
synthesis of isatin itself and four substituted isatins bearing alkyl,
chloro or fluoro groups.
O
R
R
N
H
X
NHCOtBu
X
1
X = CH or N
2
Scheme 1
Key words: carbonylation, N,N-dimethylureas, isatins, intramolec-
ular trapping, positron emission tomography
Unfortunately, the presence of a tert-butyl group in com-
pounds 2 greatly restricts the utility of those compounds.
Recently we have also obtained unexpected products from
the carbonylation of 3-pivaloylaminoquinazolin-4(3H)-
one.9 We have therefore sought to replace the pivaloyl-
amino group in the starting material with another group
that would provide products of greater utility.
The carbonylation of organometallics has been reviewed.2
The nature of the reactions depends on the nature of the
organometallics. Although organolithium reagents are
frequently reacted with carbon dioxide for the formation
of carboxylic acids, reactions with carbon monoxide are
much more limited due to the extreme reactivity of the
acyllithium intermediates. This reactivity leads to dimeri-
sation, decomposition, reaction with further carbon mon-
oxide or other reactions, giving rise to a range of
compounds other than those expected for simple electro-
philic trapping.2 A range of acyl anion equivalents has
been developed to overcome this problem,3 but such re-
agents are not without drawbacks. In particular, they re-
quire additional steps to unmask the carbonyl
functionality and they cannot be used for introducing iso-
topically labelled carbon monoxide. It has been shown
that it is possible to trap acyllithiums derived from carbo-
nylation of alkyllithium reagents in situ, given that the re-
action is carried out at very low temperature with a highly
reactive electrophile.4 The conditions are, however, rather
restrictive and the method has only rarely been used with
aryllithiums.5 Therefore, it appeared that intramolecular
trapping of acyllithiums might provide a more generally
useful synthetic approach for carbonylation reactions of
organolithium reagents.6
We tried the reaction of carbon monoxide and doubly
lithiated N-tert-butoxycarbonylaniline, but although the
reaction mixture turned to a deep colour on introduction
of carbon monoxide, as had been the case with doubly
lithiated compounds of type 1, we were unable to isolate
indole derivatives in more than trace amounts after work-
up of the reaction mixture. We had more success with
doubly lithiated N¢-aryl-N,N-dimethylthioureas, which on
carbonylation led to indigotins,10 but these products are
also not very suitable for further modification. We there-
fore turned our attention to doubly lithiated N¢-aryl-N,N-
dimethylureas. We attempted direct lithiation of various
N¢-aryl-N,N-dimethylureas but could not routinely
achieve selective ortho-lithiation under standard condi-
tions.11 Fortunately, this difficulty was easily overcome
by the use of N¢-(2-bromoaryl)-N,N-dimethylureas. In a
preliminary communication we reported that the
carbonylation reaction of N¢-(2-bromoaryl)-N,N-
dimethylureas was useful for the production of isatins.12
We now report the full details of this work.
N¢-(2-Bromoaryl)-N,N-dimethylureas 4 were prepared in
a one-pot reaction involving 4-substituted 2-bromoanil-
ines 3, triphosgene and dimethylamine. Triphosgene is an
alternative to phosgene, with the advantages that it is a
solid, gives three equivalents of phosgene per mole in situ,
is easy to handle and is much more pleasant to use than
phosgene.13 The slow addition of a solution of 3 in THF to
a stirred solution of triphosgene in THF at 0 °C produced
the corresponding arylisocyanate in situ. Reactions of the
aryl isocyanates with dimethylamine at 0 °C gave the cor-
responding N¢-aryl-N,N-dimethylureas 4 (Scheme 2) in
good yield (Table 1). It was found that the corresponding
bis(2-bromoaryl)urea was formed as a by-product in a
As part of our continuing interest in lithiation reactions,7
we have also made use of intramolecular trapping of acyl-
lithiums formed via carbonylation reactions. For example,
we have shown that carbonylation of doubly lithiated N-
pivaloylanilines and N-pivaloylaminopyridines affords 3-
tert-butyl-3-hydroxy-2,3-dihydroindol-2-ones and aza-3-
tert-butyl-3-hydroxy-2,3-dihydroindol-2-ones (2), re-
spectively, in good yields (Scheme 1).8
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 19 08 2003.
Art Id.1437-210X,E;2003,0,13,2047,2052,ftx,en;Z07103SS.pdf.
DOI: 10.1055/s-2003-41019
© Georg Thieme Verlag Stuttgart · New York

2048
K. Smith et al.
PAPER
yield of 4–8% as a result of reaction between 2-bromo- blue colour and after work-up isatin (8) was obtained in
aniline (3) and an aryl isocyanate generated in situ.
66% yield. A series of experiments was conducted in
which the reaction conditions were varied in an attempt to
optimise the yield of 8 (Table 2). It was found that on
treatment of a solution of 4a in THF at 0 °C with MeLi
(1.05 equiv) and t-BuLi (2.1 equiv), followed by reaction
of dilithio-reagent 6 thus formed with carbon monoxide
for 30 minutes, isatin (8) was obtained in 76% isolated
yield.
Scheme 2
O
Table 1 Synthesis of N¢-(2-bromoaryl)-N,N-dimethylureas 4a–e
i, 1.05 MeLi, 0 °C
ii, 2.1 tBuLi, 0 °C
iii, CO, 0.5 h, 0 °C
4
3a
7a
R
5
R
Br
3
According to Scheme 2
O
2
6
Product
4a
R
Yield (%)a
Mp (°C)
85-86
68-69
92-93
71-72
80-81
N
H
NHCONMe2 iv, H3O+
1
7
H
72
65
70
76
71
4a-e
8-12
4b
Me
iPr
Cl
F
Scheme 4
4c
Table 2 Synthesis of Isatin (8) under Various Reaction Conditions
4d
Lithium reagent (mmol) T (°C)a
t (h)b
Yield (%)c
4e
MeLi
–
t-BuLi
3.3
a Yield of isolated, purified product.
–78
–78
0
1
38
54
59
62
66
65
70
69
76
1.2
1.2
1.1
1.1
1.1
2.4
1
As can be seen from Table 1, the yields of compounds 4
are good, proving that the procedure is general for a range
of substituents, and this overcomes the poor availability
and stability of appropriately substituted bromoaryl isocy-
anates. Therefore, it represents a useful one-pot procedure
for the synthesis of N¢-(2-bromoaryl)-N,N-dimethylureas
4.
2.4
1
2.2
–78
0
1
2.2
1
2.2
–78
0
0.5
0.5
0.5
0.5
N¢-(2-Bromophenyl)-N,N-dimethylurea (4a) underwent 1.1
successful lithiation on nitrogen to form the monolithio-
2.2
1.05
1.05
2.1
–78
0
reagent 5 using methyllithium (1.1 equivalents), followed
by bromine-lithium exchange using tert-butyllithium (2.2
equivalents) to give the dilithio-reagent 6 at 0 °C
(Scheme 3). In order to verify the formation of 6, the mix-
ture was treated with aqueous ammonium chloride solu-
tion to give N,N-dimethyl-N¢-phenylurea (7), mp 135–136
°C (lit.,14 131–133 °C), which was isolated in 90% yield.
2.1
a Temperature of the cooling bath at which lithiation and carbonyl-
ation reactions were carried out.
b Reaction time under carbon monoxide atmosphere.
c Yield of isolated, purified product.
The likely mechanism, involving carbonylation followed
by cyclisation, is shown in Scheme 5.
Br
Br
1.1 MeLi, 0 °C
NMe2
O
Isatin is a useful synthetic intermediate. It reacts with car-
banions to give 3-substituted dioxindoles.15 Therefore, the
reaction was applied to a range of N¢-(2-bromoaryl)-N,N-
dimethylureas (4b–e) under identical reaction conditions,
without optimisation of the individual cases. Indeed, these
reactions afforded the corresponding substituted isatins
9–12 (Scheme 4) in good yields (Table 3).
N
Li
NHCONMe2
4a
5
2.2 tBuLi, 0 °C
Li
aq. NH4Cl
NMe2
O
As can be seen from Table 3, the yields are quite good and
the reaction accommodates a range of substituents in the
isatin moiety. Therefore, it represents a useful new proce-
dure for the formation of isatins.
N
NHCONMe2
Li
7 (90%)
6
Scheme 3
In conclusion, the procedure applied represents a useful
new method for the synthesis of isatins. This work extends
the applicability of our work on the tandem carbonyl-
ation–intramolecular trapping of acyllithiums and is more
Another sample of the dilithio-reagent 6 was then exposed
to carbon monoxide (Scheme 4). The mixture turned to a
Synthesis 2003, No. 13, 2047–2052 © Thieme Stuttgart · New York

PAPER
Carbonylation of Doubly Lithiated N¢-Aryl-N,N-Dimethylureas
2049
THF was distilled from sodium benzophenone ketyl. Other chemi-
cals were obtained from Aldrich Chemical Company and used with-
out further purification. Solvents were purified by standard
procedures.20,21
Synthesis of N¢-(2-Bromoaryl)-N,N-dimethylureas 4; General
Procedure
To a cooled (0 °C) stirred solution of triphosgene (2.36 g, 8.0 mmol)
in CH2Cl2 or THF (30 mL) a solution of the appropriate 4-substitut-
ed 2-bromoaniline (3, 20.0 mmol) and triethylamine (4.44 g, 44.0
mmol) in THF (30 mL) was slowly added in a drop-wise manner
over 30 min. The reaction mixture was stirred at 0 °C for 2 h, after
which a solution of dimethylamine in THF (12.0 mL, 2.0 M, 24.0
mmol) was added. The reaction mixture was stirred at 0 °C for an
extra 1 h. The mixture was poured onto H2O (50 mL) and the organ-
ic layer was separated, washed with H2O (2 × 15 mL), dried
(MgSO4) and the solvent was removed under reduced pressure. The
crude product obtained was purified by column chromatography on
silica gel (hexane–Et2O, 1:2) to give 4. The yields obtained are re-
ported in Table 1.
Scheme 5
Table 3 Synthesis of Substituted Isatins 8–12 According to
Scheme 4
N¢-(2-Bromophenyl)-N,N-dimethylurea (4a)
IR (KBr): 3300, 2910, 1670, 1550, 1510, 1450, 1320, 1255, 1190,
880, 820, 790, 620 cm–1.
1H NMR (CDCl3): d = 8.22 (dd, J = 8.2, 1.3 Hz, 1 H, H6), 7.47 (dd,
J = 8.2, 1.3 Hz, 1 H, H3), 7.28 (apparent dt, J = 8.2, 1.3 Hz, 1 H,
H5), 7.00 (s, exch., 1 H, NH), 6.86 (apparent dt, J = 8.2, 1.3 Hz, 1
H, H4), 3.07 [s, 6 H, N(CH3)2].
13C NMR (CDCl3): d = 155.0 (s, C=O), 137.1 (s, C1), 131.8 (d, C3),
128.3 (d, C5), 123.4 (d, C4), 120.9 (d, C6), 113.0 (s, C2), 36.4 [q,
N(CH3)2].
Prod-
uct
R
Yield
(%)a
Mp (°C)
8
9
H
76
72
71
77
79
201–202 (decomp.)(lit.,16 200–202)
186–187 (lit.,16 185–187)
140
Me
iPr
Cl
F
10
11
12
250–252 (lit.,16 249–251)
223 (lit.,17 223)
EI-MS: m/z (%) = 244 (M+81Br, 22), 242 (M+79Br, 23), 199 (26),
197 (27), 172 (94), 170 (100).
CI-MS: m/z (%) = 262 (M+81Br + NH4, 54), 260 (M+79Br + NH4,
a Yield of isolated, purified product.
55), 245 (MH+81Br, 99), 263 (MH+79Br, 100).
HRMS: m/z (M+) calcd for C9H1179BrN2O, 242.0054; found,
242.0055.
generally useful than the reactions of doubly lithiated N-
pivaloylanilines and N-pivaloylaminopyridines, isatins
having no bulky tert-butyl group and being much more
amenable to modification. It should prove more attractive
for synthesis of compounds of interest for positron emis-
sion tomography.18
Anal. Calcd for C9H11BrN2O: C, 44.47; H, 4.56; N, 11.52. Found:
C, 44.6; H, 4.6; N, 11.6.
N¢-(2-Bromo-4-methylphenyl)-N,N-dimethylurea (4b)
IR (KBr): 3290, 2985, 2495, 1690, 1575, 1520, 1480, 1415, 1370,
1290, 1245, 1185, 1050, 1020, 920, 855, 707, 662, 610 cm–1.
1H NMR (CDCl3): d = 8.07 (d, J = 8.4 Hz, 1 H, H6), 7.31 (d, J = 1.3
Hz, 1 H, H3), 7.09 (dd, J = 8.4, 1.3 Hz, 1 H, H5), 6.89 (s, exch., 1
H, NH), 3.06 [s, 6 H, N(CH3)2], 2.27 (s, 1 H, CH3).
13C NMR (CDCl3): d = 155.1 (s, C=O), 134.5 (s, C1), 133.4 (s, C4),
132.1 (d, C3), 129.0 (d, C5), 120.9 (d, C6), 112.9 (s, C2), 36.4 [q,
N(CH3)2], 20.4 (q, CH3).
EI-MS: m/z (%) = 258 (M+81Br, 2), 256 (M+79Br, 2), 177 (40), 132
(8), 104 (16), 77 (81), 72 (100), 42 (36).
CI-MS: m/z (%) = 259 (MH+81Br, 78), 257 (MH+79Br, 76), 179
(100), 133 (16), 108 (14), 72 (24), 46 (35), 44 (38).
Melting points were determined on an electrothermal digital melt-
ing point apparatus and are reported uncorrected. IR spectra were
recorded on a Perkin-Elmer 1725X spectrometer. 1H and 13C NMR
spectra were recorded on a Bruker spectrometer operating at 400
MHz for 1H and 100 MHz for 13C measurement. Chemical shifts are
reported in parts per million relative to tetramethylsilane. Assign-
ments of signals are based on coupling patterns and expected chem-
ical shift values and have not been rigorously confirmed. Signals
with similar characteristics might be interchanged. For fluoro com-
pounds, C–F doublets in the 13C NMR spectra are recorded as two
lines, identified by the two apparent d values at 100 MHz, as they
appear in the spectral print-out. Low-resolution mass spectra were
recorded on a VG 12-253 spectrometer, electron impact (EI) at 70
eV and chemical ionisation (CI) by use of ammonia as ionising gas.
Accurate mass data were obtained on a VG ZAB-E instrument. El-
emental analyses were obtained from the laboratories of the Univer-
sity of Wales Cardiff. Column chromatography was carried out
using Merck Kieselgel 60 (230–400 mesh). tert-Butyllithium and
methyllithium were obtained from Aldrich Chemical Company and
were estimated prior to use by the method of Watson and Eastham.19
HRMS: m/z (M+) calcd for C10H1379BrN2O, 256.0211; found,
256.0205.
Anal. Calcd for C10H13BrN2O: C, 46.71; H, 5.10; 12.77; N, 10.89.
Found: C, 46.9; H, 5.1; N, 10.7.
N¢-(2-Bromo-4-iso-propylphenyl)-N,N-dimethylurea (4c)
IR (KBr): 3247, 2930, 1640, 1583, 1520, 1473, 1427, 1375, 1290,
1248, 1190, 1050, 1025, 905, 850, 705, 662, 610 cm–1.
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2050
K. Smith et al.
PAPER
1H NMR (CDCl3): d = 8.08 (d, J = 8.5 Hz, 1 H, H6), 7.34 (d, J = 2.0
Hz, 1 H, H3), 7.14 (dd, J = 8.5, 2.0 Hz, 1 H, H5), 6.89 (s, exch., 1
H, NH), 3.06 [s, 6 H, N(CH3)2], 2.82 [septet, J = 7.0 Hz, 1 H,
CH(CH3)2], 1.21 [d, J = 7.0 Hz, 6 H, CH(CH3)2].
13C NMR (CDCl3): d = 155.1 (s, C=O), 144.5 (s, C4), 134.7 (s, C1),
129.6 (d, C3), 126.4 (d, C5), 121.1 (d, C6), 113.1 (s, C2), 36.4 [q,
N(CH3)2], 33.3 [d, CH(CH3)2], 23.9 [q, CH(CH3)2].
EI-MS: m/z (%) = 286 (M+81Br, 4), 284 (M+79Br, 4), 226 (6), 224
(6), 206 (20), 205 (100), 190 (6), 91 (15), 72 (80), 44 (16).
CI-MS: m/z (%) = 287 (MH+81Br, 50), 285 (MH+79Br, 51), 207
(100), 205 (28), 136 (8), 72 (95).
Bromine-lithium exchange was then effected by the addition of tert-
butyllithium in heptane (2.47 mL, 1.7 M, 4.2 mmol). The mixture
was stirred at 0 °C for 1 h then exposed to carbon monoxide, which
was introduced to the reaction vessel from a balloon fitted with a
needle, via a septum. The dilithio reagent thus obtained was stirred
under CO for 30 min, after which, the mixture was diluted with
EtOAc (10 mL) and then quenched with aq sat. NH4Cl solution (10
mL). The organic layer was separated, dried (MgSO4), and evapo-
rated under reduced pressure. The crude product obtained was puri-
fied by flash column chromatography on silica gel (hexane–Et2O,
1:1) to give the pure isatins 8–12. The yields obtained are recorded
in Table 3.
HRMS: m/z (M+) calcd for C12H1779BrN2O, 284.0466; found,
284.0468.
Isatin (8)
IR (KBr): 3210, 1710, 1610, 1450, 1310, 1200, 1120, 950, 780, 620
cm–1.
Anal. Calcd for C12H17BrN2O: C, 50.54; H, 6.01; N, 9.82. Found: C,
50.4; H, 5.8; N, 10.0.
1H NMR (DMSO-d6): d = 11.02 (s, exch., 1 H, NH), 7.58 (apparent
dt, J = 7.8, 1.3 Hz, 1 H, H6), 7.50 (dd, J = 7.8, 1.3 Hz, 1 H, H7),
7.06 (apparent dt, J = 7.8, 1.3 Hz, 1 H, H5), 6.91 (d, J = 7.8 Hz, 1
H, 4-H).
13C NMR (DMSO-d6): d = 184.4 (s, C3), 159.4 (s, C2), 150.7 (s,
C7a), 138.4 (d, C6), 124.7 (d, C4), 122.8 (d, C5), 117.8 (s, C3a),
112.2 (d, C7).
N¢-(2-Bromo-4-chlorophenyl)-N,N-dimethylurea (4d)
IR (KBr): 3290, 2985, 2495, 1690, 1575, 1520, 1480, 1415, 1370,
1290, 1245, 1185, 1050, 920, 855, 707, 662, 610 cm–1.
1H NMR (CDCl3): d = 8.20 (d, J = 8.0 Hz, 1 H, H6), 7.49 (d, J = 2.4
Hz, 1 H, H3), 7.25 (dd, J = 8.0, 2.4 Hz, 1 H, H5), 6.96 (s, exch., 1
H, NH), 3.07 [s, 6 H, N(CH3)2].
13C NMR (CDCl3): d = 154.7 (s, C=O), 135.9 (s, C1), 131.2 (d, C3),
128.3 (d, C5), 127.5 (s, C4), 121.4 (d, C6), 112.9 (s, C2), 36.4 [q,
N(CH3)2].
EI-MS: m/z (%) = 147 (M+, 22), 119 (84), 92 (100), 64 (47).
CI-MS: m/z (%) = 165 (M+ + NH4, 100), 148 (MH+, 13), 134 (43),
118 (50), 94 (22).
HRMS: m/z (M+) calcd for C8H5NO2, 147.0321; found, 147.0320.
EI-MS: m/z (%) = 280 (M+ 81Br37Cl, 2), 278 (M+81Br35Cl and
M+79Br37Cl, 6), 276 (M+79Br35Cl, 4), 233 (4), 231 (3), 199 (11), 197
(32), 72 (100), 44 (18).
Anal. Calcd for C8H5NO2: C, 65.31; H, 3.43; N, 9.52. Found: C,
65.2; H, 3.3; N, 9.7.
CI-MS: m/z (%) = 281 (MH+81Br37Cl, 12), 279 (MH+81Br35Cl and
M+79Br37Cl, 44), 277 (MH+79Br35Cl, 33), 201 (30), 199 (100), 197
(18), 165 (17), 72 (86).
HRMS: m/z (M+) calcd for C9H1079Br35ClN2O, 275.9665; found,
275.9668.
5-Methylisatin (9)
IR (KBr): 3322, 1750, 1622, 1527, 1433, 1226, 1151, 1150, 1044,
839, 752 cm–1.
1H NMR (DMSO-d6): d = 10.93 (s, exch., 1 H, NH), 7.37 (d, J = 8.0
Hz, 1 H, H6), 7.29 (s, 1 H, H4), 6.76 (d, J = 8.0 Hz, 1 H, H7), 2.24
(s, 3 H, CH3).
13C NMR (DMSO-d6): d = 184.6 (s, C3), 159.5 (s, C2), 148.5 (s,
C7a), 138.8 (d, C6), 132.0 (s, C5), 124.8 (d, C4), 117.8 (s, C3a),
112.0 (d, C7), 20.1 (q, CH3).
Anal. Calcd for C9H10 BrClN2O: C, 38.95; H, 3.63; N, 10.09.
Found: C, 38.8; H, 3.8; N, 10.3.
N¢-(2-Bromo-4-fluorophenyl)-N,N-dimethylurea (4e)
IR (KBr): 3280, 2970, 1670, 1580, 1520, 1480, 1420, 1375, 1290,
1250, 1185, 1050, 1020, 915, 860, 705, 660, 610 cm–1.
EI-MS: m/z (%) = 161 (M+, 21), 133 (21), 104 (41), 78 (43), 51 (72),
1H NMR (CDCl3): d = 8.16 (dd, J = 9.2, 5.9 Hz, 1 H, H6), 7.25 (dd,
J = 7.9, 2.9 Hz, 1 H, H3), 7.03 (ddd, J = 9.2, 8.0, 2.9 Hz, 1 H, H5),
6.84 (s, exch., 1 H, NH), 3.07 [s, 6 H, N(CH3)2].
43 (100).
CI-MS: m/z (%) = 179 (M+ + NH4, 100), 162 (MH+, 10), 150 (20),
148 (33), 132 (30), 108 (15).
13C NMR (CDCl3): d = 158.80, 156.36 (C4), 155.0 (s, C=O),
133.58, 133.55 (C1), 122.14, 122.06 (C6), 118.90, 118.64 (C3),
115.23, 115.01 (C5), 112.93, 112.83 (C2), 36.4 [q, N(CH3)2].
HRMS: m/z (M+) calcd for C9H7NO2, 161.0478; found, 161.0477.
Anal. Calcd for C9H7NO2: C, 67.07; H, 4.38; N, 8.69. Found: C,
67.2; H, 4.5; N, 8.6.
EI-MS: m/z (%) = 262 (M+81Br, 9), 260 (M+79Br, 9), 181 (78), 109
(18), 108 (18), 82 (14), 72 (100), 56 (19), 44 (22).
5-iso-Propylisatin (10)
CI-MS: m/z (%) = 280 (M+81Br + NH4, 9), 278 (M+79Br + NH4, 9),
263 (MH+81Br, 100), 261 (MH+79Br, 94), 183 (8), 181 (9), 72 (85),
44 (22).
HRMS: m/z (M+) calcd for C9H1079BrFN2O, 259.9961; found,
259.9960.
IR (KBr): 3351, 1752, 1620, 1522, 1431, 1149, 1046, 1041, 848,
770, 706 cm–1.
1H NMR (DMSO-d6): d = 10.95 (s, exch., 1 H, NH), 7.47 (dd,
J = 8.0, 1.4 Hz, 1 H, H6), 7.37 (d, J = 1.4 Hz, 1 H, H4), 6.83 (d,
J = 8.0 Hz, 1 H, H7), 2.86 [septet, J = 6.9 Hz, 1 H, CH(CH3)2], 1.16
[d, J = 6.9 Hz, 6 H, CH(CH3)2].
13C NMR (DMSO-d6): d = 184.6 (s, C3), 159.6 (s, C2), 148.9 (s,
C7a), 143.2 (d, C6), 136.6 (s, C5), 122.3 (d, C4), 117.8 (s, C3a),
112.1 (d, C7), 32.7 [d, CH(CH3)2], 23.7 [q, CH(CH3)2].
Anal. Calcd for C9H10BrFN2O: C, 41.40; H, 3.86; N, 10.73. Found:
C, 41.6; H, 3.9; N, 10.6.
Formation of Isatins 8–12 from N¢-(2-Bromoaryl)-N,N-dimeth-
ylureas 4; Typical Procedure
EI-MS: m/z (%) = 189 (M+, 25), 161 (53), 146 (100), 91 (76), 63
To a cooled solution (0 °C) of the appropriate N¢-(2-bromoaryl)-
N,N-dimethylurea 4 (2.0 mmol) in anhydrous THF (15 mL) under a
nitrogen atmosphere was added a solution of methyllithum in Et2O
(2.1 mL, 1.0 M, 2.1 mmol), in order to deprotonate the nitrogen.
(50), 41 (53), 39 (78).
CI-MS: m/z (%) = 207 (M+ + NH4, 100), 190 (MH+, 8), 176 (37),
160 (57), 136 (17), 77 (12).
Synthesis 2003, No. 13, 2047–2052 © Thieme Stuttgart · New York

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Carbonylation of Doubly Lithiated N¢-Aryl-N,N-Dimethylureas
2051
HRMS: m/z (M+) calcd for C11H11NO2, 189.0789; found, 189.0790.
References
Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C,
70.0; H, 5.7; N, 7.5.
(1) Permanent address: G. A. El-Hiti, Department of Chemistry,
Faculty of Science, Tanta University, Tanta 31527, Egypt.
(2) (a) Trzupek, L. S.; Newirth, T. L.; Kelly, E. G.; Sbarbati, N.
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G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
(4) (a) Seyferth, D.; Weinstein, D. R. J. Am. Chem. Soc. 1982,
104, 5534. (b) Seyferth, D.; Weinstein, R. M.; Wang, W.-L.
J. Org. Chem. 1983, 48, 1144. (c) Weinstein, R. M.; Wang,
W.-L. J. Org. Chem. 1983, 48, 3367. (d) Seyferth, D.;
Weinstein, R. M.; Wang, W.-L.; Hui, R. C. Tetrahedron
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5-Chloroisatin (11)
IR (KBr): 3190, 2950, 2390, 1780, 1710, 1610, 1430, 1240, 1205,
1132, 1041, 842, 770 cm–1.
1H NMR (DMSO-d6): d = 11.15 (s, exch., 1 H, NH), 7.60 (dd,
J = 8.3, 1.3 Hz, 1 H, H6), 7.54 (d, J = 1.3 Hz, 1 H, H4), 6.91 (d,
J = 8.3 Hz, 1 H, H7).
13C NMR (DMSO-d6): d = 183.4 (s, C3), 159.2 (s, C2), 149.2 (s,
C7a), 137.3 (d, C6), 126.8 (s, C5), 124.2 (d, C4), 119.2 (s, C3a),
113.9 (d, C7).
EI-MS: m/z (%) = 183 (M+37Cl, 5), 181 (M+35Cl, 14), 155 (21), 153
(33), 125 (13), 91 (34), 84 (33), 49 (95), 43 (100).
CI-MS: m/z (%) = 199 (M+35Cl + NH4, 100), 182 (MH+35Cl, 10),
178 (18), 165 (22), 152 (50), 151 (65), 118 (53), 77 (79).
Organometallics 1984, 3, 327. (f) Seyferth, D.; Hui, R. C.
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M.; Hui, R. C.; Wang, W.-L.; Archer, C. M. J. Org. Chem.
1992, 57, 5620.
HRMS: m/z (M+) calcd for C8H437ClNO2, 182.9904; found,
182.9901.
Anal. Calcd for C8H4ClNO2: C, 52.92; H, 2.22; N, 7.71. Found: C,
52.9; H, 2.3; N, 7.9.
5-Fluoroisatin (12)
(5) (a) Nudelman, N. S.; Vitale, A. A. J. Org. Chem. 1981, 46,
4625. (b) Seyferth, D.; Hui, R. C.; Wang, W.-L. J. Org.
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IR (KBr): 3341, 1750, 1625, 1521, 1434, 1156, 1041, 845, 771
cm–1.
(6) See for example: (a) Orita, A.; Fukudome, M.; Ohe, K.;
Murai, S. J. Org. Chem. 1994, 59, 477. (b) Orita, A.; Ohe,
K.; Murai, S. Organometallics 1994, 13, 1533. (c) Kai, H.;
Iwamoto, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 1996,
118, 7634. (d) Ryu, I.; Yamamoto, H.; Sonoda, N.; Murai, S.
Organometallics 1996, 15, 5459. (e) Kai, H.; Yamauchi,
M.; Murai, S. Tetrahedron Lett. 1997, 38, 9027.
1H NMR (DMSO-d6): d = 11.02 (s, exch., 1 H, NH), 7.44 (m, 1 H,
H6), 7.38 (dd, J = 7.2, 2.7 Hz, 1 H, H4), 6.91 (dd, J = 8.5, 4.0 Hz, 1
H, H7).
13C NMR (DMSO-d6): d = 183.9 (s, C3), 159.53, 159.31 (C5),
156.9 (s, C2), 147.0 (s, C7a), 124.66, 124.43 (C6), 118.56, 118.49
(C3a), 113.54, 113.47 (C7), 111.54, 111.30 (C4).
EI-MS: m/z (%) = 165 (M+, 40), 137 (100), 109 (53), 82 (42).
CI-MS: m/z (%): 183 (M+ + NH4, 100), 166 (MH+, 4), 151 (24), 136
(f) Fukuyama, T.; Chatani, N.; Kakiuchi, F.; Murai, S. J.
Org. Chem. 1997, 62, 5647. (g) Ryu, I.; Matsu, K.;
Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120,
5838. (h) Ryu, I. Chem. Soc. Rev. 2001, 30, 16.
(21), 76 (10).
HRMS: m/z calcd for C8H4FNO2 (M+), 165.0226; found, 165.0226.
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Abdel-Megeed, M. F. J. Chem. Soc., Perkin Trans. 1 1995,
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(e) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo,
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(8) (a) Smith, K.; Pritchard, G. J. Angew. Chem., Int. Ed. Engl.
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Soc., Perkin Trans. 1 1999, 2299.
Anal. Calcd for C8H4FNO2: C, 58.19; H, 2.44; N, 8.48. Found: C,
58.3; H, 2.5; N, 8.3.
Acknowledgements
We thank the EPSRC Mass Spectrometry Service, University of
Wales Swansea, for recording mass spectra for us. We also thank
the EPSRC, the Higher Education Funding Council for Wales
(ELWa-HEFCW) and the University of Wales Swansea for grants
that enabled the purchase and upgrading of NMR equipment used
in the course of this work. G. A. El-Hiti thanks the University of
Wales Swansea for financial support and the Royal Society of Che-
mistry for an international author grant.
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K. Smith et al.
PAPER
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Synthesis 2003, No. 13, 2047–2052 © Thieme Stuttgart · New York