Direct N-carbamoylation of 3-monosubstituted oxindoles with alkyl imidazole carboxylates

Article abstract of DOI:10.1021/jo900760r

(Chemical Equation Presented) Regioselective N-carbamoylation of oxindoles was achieved through the use of imidazole carboxylate reagents. This reaction provides ready access to N-carbamoyl-3-monosubstituted oxindoles.

Full text of DOI:10.1021/jo900760r

SCHEME 1. Synthesis of N-Moc Oxindoles
Direct N-Carbamoylation of 3-Monosubstituted
Oxindoles with Alkyl Imidazole Carboxylates
Barry M. Trost,* Yong Zhang, and Ting Zhang
Department of Chemistry, Stanford UniVersity, 337 Campus
DriVe, Stanford, California 94305-5080
bmtrost@stanford.edu
ReceiVed April 16, 2009
frequently employed as a protecting group for nitrogen.8
Surprisingly, very few N-Moc protected oxindoles are known
in the literature and to the best of our knowledge, they have
not been examined as substrates in any catalytic asymmetric
reactions.9 Development of a convenient and general method
for the synthesis of N-Moc protected oxindoles should allow
for the examination of these entities as nucleophiles in asym-
metric synthesis.
Regioselective N-carbamoylation of oxindoles was achieved
through the use of imidazole carboxylate reagents. This
reaction provides ready access to N-carbamoyl-3-monosub-
stituted oxindoles.
We initially examined the preparation of the N-Moc oxindoles
based on the literature reports for the preparation of N-Boc
oxindoles. Direct Boc protection of N-H-3-monosubstituted
oxindoles was reported to be problematic due to competitive
O- and C-reactivity.10 To circumvent the problem, Sodeoka has
developed a three-step sequence involving Grignard addition
to isatin followed by Boc protection and deoxygenation under
hydrogenolysis conditions.4a Alternatively, it has also been
reported that Boc protection of a 3-benzylidene oxindole
followed by hydrogenation of the double bond afforded an
N-Boc-3-benzyl-oxindole.5a We found that both of these
methods can be modified for the synthesis of N-Moc protected
oxindoles by substituting Boc anhydride with chloro methyl-
formate (eqs 1 and 2, Scheme 1). However, both methods have
significant limitations. The approach starting from isatin is
limited by the availability of the Grignard reagent, and the
second method requires an alkylidene-substituted oxindole as
precursor.4 Moreover, both methods employ a hydrogenation
reaction to form the final product and thus functional groups
such as alkene, alkynes, and aromatic halides are not tolerated.
For maximum flexibility, a direct carbamoylation of an N-H
oxindole such as 8 would be most desirable.
Prochiral 3-monosubstituted oxindoles are important precur-
sors for the preparation of oxindole and indoline natural
products.1 Catalytic asymmetric functionalization of 3-mono-
substituted oxindoles via allylic alkylation,2 acyl transfer,3
fluorination,4 hydroxylation,5 aldol reaction,6 or Claisen rear-
rangement7 has allowed the preparation of chiral oxindoles
bearing stereogenic tertiary or quaternary centers at the 3
position. It has been reported that the reactivity and selectivity
of many of these reactions is dependent on the substitution at
nitrogen of the oxindole.1c,4a,5a,6b In several cases, N-carbamoyl,
such as N-Boc, protected oxindoles showed superior selectivity
than those with N-alkyl substitutions (N-methyl or N-benzyl).
The methoxycarbonyl (Moc) group, which is electronically
similar to the Boc group but sterically smaller, has been
(1) (a) Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stean, B. A. J. Am.
Chem. Soc. 2002, 124, 9008. (b) Lakshmaiah, G.; Kawabata, T.; Shang, M.;
Fuji, K. J. Org. Chem. 1999, 64, 1699. (c) Trost, B. M.; Brennan, M. K. Org.
Lett. 2006, 8, 2027. (d) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339. (e)
Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763.
(2) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308. (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (c) Trost,
B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
(3) (a) Shaw, S. A.; Aleman, P.; Vedeis, E. J. Am. Chem. Soc. 2003, 125,
13368. (b) Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 3921.
(4) (a) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sedeoka, M.
J. Am. Chem. Soc. 2005, 127, 10164. (b) Ishimaru, T.; Shibata, N.; Horikawa,
T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008,
47, 4157.
The N-H oxindoles are easily prepared by either oxidation
of the corresponding indoles,12 monoalkylation of the dianions
of the unsubstituted oxindole,13 or cross-coupling chemistry.14
For example, treatment of commercially available oxindole 7
(8) Corey, E. J.; Bock, M. G.; Kozikowski, A. P.; Rao, A. V. R.; Floyd, D.;
Lipshutz, B. Tetrahedron Lett. 1978, 1051.
(5) (a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa,
S. J. Am. Chem. Soc. 2006, 128, 16488. (b) Sano, D.; Nagata, K.; Itoh, T. Org.
Lett. 2008, 10, 1593.
(9) Our group has recently reported the use of N-Moc-3-alkylideneox-
indoles as substrates for asymmetric TMM reactions: Trost, B. M.; Cramer,
N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
(10) Rajeswaran, W. G.; Cohen, L. A. Tetrahedron 1998, 54, 11375.
(11) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043.
(6) (a) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro,
M. Angew. Chem., Int. Ed. 2007, 46, 8666. (b) Tian, X.; Jiang, K.; Peng, J.; Du,
W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583.
(7) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162.
(12) Szabo´-Pusztay, Z.; Szabo´, L. Synthesis 1979, 276.
10.1021/jo900760r CCC: $40.75  2009 American Chemical Society
Published on Web 06/02/2009
J. Org. Chem. 2009, 74, 5115–5117 5115

TABLE 1. Optimizations Studies
TABLE 2. Synthesis of N-Moc Protected Oxindoles
entry
1
conditions
yield of 9
∼15%
ClCO2Me (1 equiv), NEt3, DMAP (0.1 equiv),
CH2Cl2, 0 °C
NaHMDS (1 equiv), ClCO2Me, THF, 0 °C
NaHMDS (1 equiv), 10, THF, 0 °C
2
3
∼25%
86%
with excess BuLi in the presence of TMEDA generates the
dianion of 7. Quenching the dianion with allyl bromide afforded
the monoallylated oxindole 8 in good yield (Table 1). Disap-
pointingly, the reaction of oxindole 8 with methyl chloroformate
under a variety of conditions failed to provide the desired N-Moc
product cleanly (entries 1 and 2, Table 1). Similar to previous
reports of Boc protection of 3-monosubstituted-N-H oxindoles,
products of O-acylation and bis-acylation accounted for most
of the mass balance. We reasoned that a “softer” acylating
reagent should help differentiate N from O. Several literature
reports indicate that an imidazole analog of methyl chlorofor-
mate is a “softer” electrophile and thus should favor selective
N-acylation.15,16 Indeed, subjecting the Na salt of oxindole 8
to 1 equiv of imidazole carboxylate 10 at 0 °C in THF afforded
the mono-N-carbamoylated product selectively in 86% yield.
The use of imidazole carboxylate 10 to prepare N-Moc
oxindoles with varying substitution patterns was then investi-
gated (Table 2). Both alkyl and aryl substitution at the 3 position
were tolerated (entry 11h). Oxindoles with ring-substitutions
also performed well (entries 11d and 11f). It should be noted
that more stabilized oxindole anions required higher temperature
to react (entries 11d and 11h).
TABLE 3. Synthesis of N-Carbamate Protected Oxindoles
Alkoxycarbonyl groups other than methoxycarbonyl can also
be installed selectively using the imidazole carboxylate reagents
as the electrophile (Table 3). The required imidazole carboxy-
lates were prepared by simply mixing the corresponding
chloroformate with 2 equiv of imidazole in THF followed by
filtration and removal of the solvent (Scheme 2).16 Treatment
of the resulting imidazole carboxylates with the Na salt of
oxindole 8 furnished N-carbamoyl oxindoles selectively in good
to excellent yields.
SCHEME 2. Synthesis of Imidazole Carboxylate 10
In summary, we have developed a convenient and general
procedure for the synthesis of N-carbamoyl-3-monosubstituted
oxindoles.17 Both the N-H oxindole precursor and the imidazole
carboxylate reagents are readily available.16 The carbamoylation
reaction is highly selective at the N with the imidazole reagent
compared to the reaction with the more commonly employed
chloroformate reagent, where a mixture of products are obtained.
This method does not require the use of a hydrogenation
reaction, and hence is broadly applicable to substrates with
sensitive functional groups. The studies of N-Moc-3-monosub-
stituted oxindoles as nucleophiles in allylic alkylation reactions
are ongoing.18
Experimental Section
(13) Kende, A. S.; Hodges, J. C. Synth. Commun. 1982, 12, 1.
(14) Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 9613.
(15) (a) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 7, 350. (b) Shone,
R. L.; Deason, J. R.; Miyano, M. J. Org. Chem. 1986, 51, 268. (c) Werner, T.;
Barrett, A. G. M. J. Org. Chem. 2006, 71, 4302. (d) Toullec, P. Y.; Bonaccorsi,
C.; Mezzetti, A.; Togni, A.; Trost, B. M. Proc. Natl. Acad. Sci. 2004, 101, 5810.
(e) Trost, B. M.; Xu, J. J. Org. Chem. 2007, 72, 9372.
(16) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211. Alternatively,
imadazole carboxylates can be prepared by reaction of the corresponding alcohol
and 1,1′-carbonyldiimidazole: see ref 14.
(17) In the Supporting Information of ref 4a, Sodeoka reported two examples
of the acylation of 3-(o-anisyl)oxindole in 42 and 70% yield. We thank one of
the referees for alerting us to these two cases.
Synthesis of imidazole carboxylate 10: To a solution of imidazole
(8.55 g, 100 mmol) in THF (120 mL) was added methyl chloro-
formate (5.2 g, 55 mmol) at 0 °C. The resulting solution was stirred
at 0 °C for 3 h before it was filtered under a stream of N2. The
filtrate was concentrated in Vacuo to afford 10 (5.19 g, 82% yield)
as a white solid. IR (film) λmax/cm-1: 3130, 1763, 1475, 1443, 1384,
1291, 1246, 1009. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, b, 1H),
7.44 (s, b, 1H), 7.07 (s, b, 1H), 4.04(s, 3H);13C NMR (125 MHz,
(18) For a standard deprotection procedure of N-Moc-oxindole, see Sup-
porting Information.
5116 J. Org. Chem. Vol. 74, No. 14, 2009

CDCl3) δ 149.0, 136.9, 130.4, 116.9, 54.5. This material underwent
slow decarboxylation at rt and was stored at -20 °C.
MgSO4, and concentrated in Vacuo. Purification through silica gel
(20% EtOAc-pentane) afforded 9 as a clear oil (400 mg, 86%).
IR (film) λmax/cm-1: 2964, 2878, 1771, 1735, 1607, 1467, 1439,
Synthesis of N-Moc-3-allyl oxindole 9. To a solution of oxindole
(400 mg, 3 mmol) in THF (20 mL) was added TMEDA (1.5 mL,
10 mmol), and the resulting solution was cooled to -78 °C. BuLi
(2.6 mL, 2.5 M in hexane) was added dropwise and the resulting
solution was stirred for 30 min allyl bromide (600 mg, 5 mmol)
was then added dropwise and the solution was slowly warmed up
to -20 °C and stirred for 3 h at that temperature. The reaction was
then quenched with aq. NH4Cl (20 mL) and extracted with ethyl
acetate (3 × 25 mL). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in Vacuo. Purifica-
tion through silica gel (30% EtOAc-pentane) afforded 3-allylox-
indole (340 mg, 67%). On a 30 mmol scale, an 85% yield was
obtained as detailed in the Supporting Information.
3-Allylloxindole (340 mg, 2.0 mmol) was dissolved in 15 mL
dry THF and cooled to -20 °C. A freshly prepared solution of
NaHMDS (420 mg, 2.2 mmol, 95%) in THF (5 mL) was added
dropwise. The resulting solution was stirred for 30 min and a
solution of 10 (280 mg, 2.2 mmol) in THF (3 mL) was added
dropwise. The resulting solution was slowly warmed up to 0 °C
and stirred for 3 h. The reaction was quenched with dropwise
addition of AcOH (0.5 mL) in THF (2 mL) and then 20 mL water.
The mixture was extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine, dried over
1
1354, 1297, 1242, 1155, 1094, 1052, 1024, 911, 761; H NMR
(500 MHz, CDCl3): δ 7.91(d, J ) 8.5, 1H), 7.36-7.28(m, 2H),
7.18(t, J ) 7.5, 1H), 5.75-5.67 (m, 1H), 5.12(dm, J ) 17, 1H),
5.07(dm, J ) 10, 1H), 4.02 (s, 3H), 3.67(t, J ) 5.5, 1H), 2.87-2.81
(m, 1H), 2.70-2.63(m, 1H),;13C NMR (125 MHz, CDCl3) δ 175.4,
151.6, 139.7, 133.1, 128.4, 127.4, 124.7, 119.0, 115.1, 54.0, 45.8,
35.6. HRMS (MNa+): calcd for C13H13NO3: 231.0895; found:
231.0892.
Acknowledgment. We thank the National Science Founda-
tion and the National Institute of Health, Gneral Medical
Sciences Grant GM 13598, for their generous support of our
programs. Dr. Jiayi Xu is acknowledged for giving us imidazole
carboxylate reagent 12a. Dr. Benjamin Taft is acknowledged
for proofreading the manuscript.
Supporting Information Available: Full experimental de-
tails, spectral data, and characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900760R
J. Org. Chem. Vol. 74, No. 14, 2009 5117