A novel procedure for the formation of isatins via carbonylation of lithiated N'-aryl-N,N-dimethylureas

Article abstract of DOI:10.1055/s-1999-3085

Isatin and substituted isatins can be formed in very good yields from the appropriate N'(2-bromoaryl)-N,N-dimethylureas via bromine-lithium exchange followed by treatment with carbon monoxide.

Full text of DOI:10.1055/s-1999-3085

LETTER
945
A Novel Procedure for the Formation of Isatins via Carbonylation of Lithiated
N’-Aryl-N,N-dimethylureas
Keith Smith,* Gamal A. El-Hiti,† Anthony C. Hawes
Department of Chemistry, University of Wales Swansea,‡ Swansea, SA2 8PP, UK
Tel +44(1792)295266; Fax +44(1792)295261; E-mail: K.Smith@swansea.ac.uk
Received 8 January 1999
Dedicated to Professor A. Eschenmoser
Abstract: Isatin and substituted isatins can be formed in very good
yields from the appropriate N’-(2-bromoaryl)-N,N-dimethylureas
via bromine-lithium exchange followed by treatment with carbon
monoxide.
Key words: carbonylation, isatins, lithiation, ureas, organolithiums
Scheme 1
Although organolithium compounds are frequently react-
ed with carbon dioxide for the formation of carboxylic ac-
ids, reactions with carbon monoxide are much more
limited due to the extreme reactivity of the acyllithium in-
termediate. This reactivity leads to dimerization, decom-
position, reaction with further carbon monoxide or other
nique which requires the synthesis of biologically-active
compounds labelled with short-lived radioisotopes.7 Un-
fortunately, the presence of a tert-butyl group in com-
pounds 2 greatly restricts the utility of those compounds.
We have therefore sought to replace the pivaloyl group in
the starting material with another group that would pro-
reactions, giving rise to a range of compounds other than
those expected from simple electrophilic trapping.1
A range of acyl anion equivalents has been developed to
overcome this problem,2 but such reagents are not without
drawbacks. In particular they require additional steps to
unmask the carbonyl functionality and they cannot be
used for introducing isotopically labelled carbon monox-
ide. It has been shown by Seyferth et al. that it is possible
to trap acyllithiums derived from carbonylation of alkyl-
lithium reagents given that the reaction is carried out at
very low temperature (typically -130 ºC).3 The conditions
are, however, rather restrictive and the method has only
rarely been used with aryllithiums.4 Therefore, it appeared
that intramolecular trapping of acyllithiums might pro-
vide a more generally useful synthetic approach for carbo-
nylation reactions of organolithium reagents.5
vide products of greater utility. We now report on the suc-
cessful generation of isatins from N’-(2-bromoaryl)-N,N-
dimethylureas.
Initially we tried the reaction of carbon monoxide
and doubly lithiated N-tert-butoxycarbonylaniline,
(PhNHCO2But),8 but although the reaction mixture turned
a deep colour on introduction of carbon monoxide, as had
been the case with doubly lithiated N-pivaloylaniline, 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 in-
digotins,9 but these products are also not very amenable to
further modification. We therefore turned our attention to
doubly lithiated N’-aryl-N,N-dimethylureas. Because of
our own interest in the use of doubly lithiated species and
related compounds for organic synthesis10 we attempted
the direct double lithiation of N,N-dimethyl-N’-pheny-
lurea but could not achieve successful ortho-lithiation in
any conditions we tried. Fortunately, this difficulty was
easily overcome by the use of N’-(2-bromophenyl)-N,N-
dimethylurea (3) which successfully underwent lithiation
on nitrogen to form the monolithio reagent using MeLi,
followed by bromine-lithium exchange using t-BuLi to
give the dilithio reagent 4. To test the extent to which the
dilithio reagent 4 had formed, it was protonated using sat-
urated ammonium chloride solution to give N,N-dimeth-
yl-N’-phenylurea (5) in 90% isolated yield (Scheme 2).
The dilithio reagent 4 thus formed was then exposed to
carbon monoxide. The mixture turned a deep colour and
Early attempts at this approach in our laboratory led to
successful carbonylation of doubly lithiated N-pivaloyla-
nilines (1) and the synthesis of 3-tert-butyldioxindoles (2)
in good yields (Scheme 1).6 The reaction involves a cas-
cade of reactions comprising carbonylation of the original
organolithium reagent, cyclisation of the acyllithium onto
the pivaloylamino group, and then rearrangement to give
the final intermediate, followed by protonation during
workup.
The method has particular potential for the synthesis of
isotopically labelled indole compounds because carbon
monoxide, the source of the additional ring carbon atom,
is easily obtainable in all isotopic forms. Even 11CO, with
a half-life of only 22 minutes, is easily generated, which
gives the reaction potential for use in positron emission
tomography (PET), a non-invasive medical imaging tech-
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946
K. Smith et al.
LETTER
after work-up isatin was obtained. A series of experiments
was conducted in which the reaction conditions were var-
ied in an attempt to optimise the yield. Indeed, when a so-
lution of compound 3 in THF at 0 °C was treated with
MeLi (1.05 equiv.) and then t-BuLi (2.1 equiv.), followed
by reaction of the dilithio reagent 4 thus obtained with car-
bon monoxide, isatin (6) was obtained in 76% isolated
yield.11 The likely mechanism, involving carbonylation
followed by cyclisation, is shown in Scheme 2.
As can be seen from Table 1, the yields are good, and the
reaction accommodates a range of substitutents in the
isatin moiety. Therefore, it represents a useful new proce-
dure for the formation of isatins. This work extends the
applicability of our work on the tandem carbonylation-in-
tramolecular trapping of acyllithiums and is more gener-
ally useful than the reaction of doubly lithiated
pivaloylanilines, the final product having no bulky tert-
butyl group and being much more amenable to modifica-
tion. It should prove more attractive for synthesis of com-
pounds of interest for positron emission tomography.
Acknowledgement
We thank the EPSRC Mass Spectrometry Service, University of
Wales Swansea, for recording mass spectra for us. We also thank
the EPSRC and the University of Wales for grants that enabled the
purchase of NMR equipment used in the course of this work. G. A.
El-Hiti thanks the University of Wales Swansea for financial sup-
port and the Royal Society of Chemistry for an international author
grant.
References and Notes
(†) Permanent address; Department of Chemistry, Faculty of
Science, Tanta University, Tanta, Egypt.
(‡) Formerly known as the University College of Swansea.
(1) Trzupek, L. S.; Newirth, T. L.; Kelly, E. G.; Sbarbarti, N. E.;
Whitesides, G. M. J. Am. Chem Soc. 1973, 95, 8118.
(2) See for example: Seebach, D. Angew. Chem. 1969, 81, 690;
Angew. Chem., Int. Ed. Engl. 1969, 8, 639; Lever, Jr. O. W.
Tetrahedron 1976, 32, 1943; Beak, P.; Reitz, D. R. Chem.
Rev. 1978, 78, 275.
(3) Seyferth, D.; Weinstein, R. M. J. Am. Chem. Soc. 1982, 104,
5534; Seyferth, D.; Weinstein, R. M.; Wang, W.-L. J. Org.
Chem. 1983, 48, 1144; Seyferth, D.; Weinstein, R. M.; Wang,
W.-L.; Hui, R. C. Tetrahedron Lett. 1983, 24, 4907; Seyferth,
D.; Hui, R. C. Organometallics 1984, 3, 1651.
Scheme 2
Isatin is a useful synthetic intermediate. It reacts with
carbanions to give 3-substituted dioxindoles.12 Therefore,
the reaction was applied to a range of N’-(2-bromoaryl)-
N,N-dimethylureas (7) to afford substituted isatins 8-11
(Scheme 3) in very good yields (Table 1).11
(4) Nudelman, N. S.; Vitale, A. A. J. Org. Chem. 1981, 46, 4625;
Seyferth, D.; Hui, R. C.; Wang, W.-L. J. Org. Chem. 1993, 58,
5843.
(5) For other work on intramolecular trapping of acyllithiums, see
Murai, S.; Ryu, I.; Iriguchi, J.; Sonoda, N. J. Am. Chem. Soc.
1984, 106, 2440; Ryu, I.; Hayama, Y.; Hiria, A.; Sonoda, N.;
Orita, A.; Ohe, K.; Murai, S. J. Am. Chem. Soc. 1990, 112,
7061; Orita, A.; Fukudome, M.; Ohe, K.; Murai, S. J. Org.
Chem. 1994, 59, 477; Orita, A.; Ohe, K.; Murai, S.
Organometallics 1994, 13, 1533; Ryu, I.; Yamamoto, H.; So-
noda, N.; Murai, S. Organometallics 1996, 15, 5459; Kai, H.;
Iwamoto, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 1996,
118, 7634; Kai, H.; Yamauchi, M.; Murai, S. Tetrahedron
Lett. 1997, 38, 9027.
Scheme 3
Synlett 1999, S1, 945–947 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Procedure for the Formation of Isatins
947
(6) Smith, K.; Pritchard, G. J. Angew. Chem. 1990, 102, 298;
Angew. Chem. Int. Ed. Engl. 1990, 29, 282.
(7) Phelps, M. E.; Hoffman, E. J.; Mullani, N. A.; Ter-Pogossian,
M. M. J. Nucl. Med. 1975, 22, 58.
and evaporated under reduced pressure. The crude product
obtained was purified by flash column chromatography
using a 50/50 mixture of diethyl ether and light petroleum
(bp 30-40 ºC) to give the pure isatin. The yields obtained are
recorded in Table 1.
(8) Smith, K. et al., unpublished results.
(9) Smith, K.; Shukla, A. P.; Matthews, I. Sulfur Lett. 1996, 20,
121.
(12) Bettembourg, M.-C.; David, S. Bull. Soc. Chim. Fr. 1962,
772; David, S.; Dauct, M.-C. Bull. Soc. Chim. Fr. 1967, 2152;
Franklin, C. S.; White, A. C. J. Chem. Soc. 1963, 1335;
Bergman, J. Tetrahedron 1971, 27, 1167.
(13) Gassmann, P. G.; Cue, B. W. Jn; Luh, T.-Y. J. Org. Chem.
1977, 42, 1344.
(14) 10: IR (KBr) 3350, 1750, 1620, 1520, 1430, 1220, 1150, 1045,
1040, 850, 770 and 705 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 10.95 (1 H, s, exch.), 7.47 (1 H, dd, J = 1.4 & 8.0 Hz), 7.37
(1 H, d, J = 1.4 Hz), 6.83 (1 H, d, J = 8.0 Hz), 2.86 (1 H, septet,
J = 6.9 Hz), 1.16 (6 H, d, J = 6.9 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 184.62 (s), 159.56 (s), 148.91 (s), 143.16 (d),
136.57 (s), 122.26 (d), 117.84 (s), 112.13 (d), 32.75 (d), 23.72
(q); m/z (EI), 189 (M+, 25%), 161 (53), 146 (100), 91 (76), 63
(50), 41 (53) and 39 (78); m/z (CI), 207 (M+ + NH4, 100%),
190 (MH+, 8), 176 (37), 160 (57), 136 (17) and 77 (12);
HREIMS: found m/z 189.0790 (M+); calcd for C11H11NO2
189.0789).
(10) See for example, Smith, K.; El-Hiti, G. A.; Hamilton, A. J.
Chem. Soc., Perkin Trans. 1, 1998, 4041; Smith, K.;
Anderson, D.; Matthews, I. J. Org. Chem. 1996, 61, 662;
Sulfur Lett. 1995, 18, 79; Smith, K.; El-Hiti, G. A.; Abdel-
Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61, 647,
656; J. Chem. Soc., Perkin Trans. 1, 1995, 1029; Smith, K.;
Lindsay, C. M.; Morris, I. K.; Matthews, I.; Pritchard, G. J.
Sulfur Lett. 1994, 17, 197.
(11) Typical Experimental Procedure: Formation of substituted
isatins. To a cooled solution (0 ºC) of the appropriate N’-(2-
bromoaryl)-N,N-dimethylurea (2.0 mmol) in dry THF (15 ml)
under a nitrogen atmosphere was added a solution of
methyllithium (2.1 ml, 1.0 M, 2.1 mmol) in tetrahydrofuran,
in order to deprotonate the nitrogen. Bromine-lithium ex-
change was then effected by the addition of a solution of t-bu-
tyllithium, (2.47 ml, 1.7 M, 4.2 mmol) in heptane. The
mixture was stirred at 0 ºC 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
was stirred under carbon monoxide for 30 min, after which,
the mixture was diluted with ethyl acetate (10 ml) and then
quenched with aqueous saturated ammonium chloride soluti-
on (10 ml). The organic layer was separated, dried (MgSO4),
(15) O’Sullivan, D. G.; Sadler, P. W. J. Chem. Soc. 1956, 2202.
Article Identifier:
1437-2096,E;1999,0,S1,0945,0947,ftx,en;W00499ST.pdf
Synlett 1999, S1, 945–947 ISSN 0936-5214 © Thieme Stuttgart · New York