Heterocycle formation via palladium-catalyzed intramolecular oxidative C-H bond functionalization: An efficient strategy for the synthesis of 2-aminobenzothiazoles

Article abstract of DOI:10.1021/ol900958z

N-Arylthioureas are converted to 2-aminobenzothiazoles via Intramolecular C-S bond formation/C-H functionalization utilizing an unusual cocatalytic Pd(PPh₃)₄MnO₂ system under an oxygen atmosphere at 80 °C. This method elim

Full text of DOI:10.1021/ol900958z

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2792-2795
Heterocycle Formation via
Palladium-Catalyzed Intramolecular
Oxidative C-H Bond Functionalization:
An Efficient Strategy for the Synthesis
of 2-Aminobenzothiazoles
Laurie L. Joyce and Robert A. Batey*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received April 30, 2009
ABSTRACT
N-Arylthioureas are converted to 2-aminobenzothiazoles via intramolecular C-S bond formation/C-H functionalization utilizing an unusual
cocatalytic Pd(PPh3)4/MnO2 system under an oxygen atmosphere at 80 °C. This method eliminates the need for an ortho-halo substituted
precursor, instead achieving direct functionalization of the ortho-aryl C-H bond. Mechanistic observations, including a large intramolecular
primary kinetic isotope effect of 5.9, reveal a reaction pathway inconsistent with an electrophilic palladation mechanism.
The importance of transition metal-catalyzed C-H “activa-
tion” chemistry has grown rapidly in recent years,1 with
particular interest being afforded to palladium mediated/
catalyzed chelate-directed functionalization reactions.2 While
most examples reported have been intermolecular function-
alizations, only recently, following Buchwald’s report of
Pd(II)/Cu(II) mediated carbazole formation,3 has attention
turned to the use of these oxidative functionalization reactions
for the formation of heterocyclic ring systems Via intramo-
lecular cyclizations.4 Several groups including our own have
explored Pd and Cu catalyzed reactions of ortho-halo-
substituted aromatics for the formation of a variety of benz-
fused heterocycles.5 For example, thiourea 1 undergoes
(1) For selected recent reviews on transition metal-catalyzed C-H
functionalizations, see: (a) Kakiuchi, F.; Chatani, N. AdV. Synth.Catal. 2003,
345, 1077–1101. (b) Goj, L. A.; Gunnoe, T. B. Curr. Org. Chem. 2005, 9,
671–685. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–
2463. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041–
4047. (e) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 3382–3388. (f) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174–238. (g) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. ReV. 2007, 36, 1173–1193. (h) Campeau, L. C.; Stuart, D. R.;
Fagnou, K. Aldrichim. Acta 2007, 40, 35–41.
(2) For selected recent examples using Pd catalysis, see: (a) Dick, A. R.;
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301. (b)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330–7331. (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am.
Chem. Soc. 2006, 128, 9048–9049. (d) Wan, X.; Ma, Z.; Li, B.; Zhang, K.;
Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416–7417. (e)
Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc.
2006, 128, 2528–2529. (f) Wang, J.-R.; Yang, C.-T.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2007, 48, 5449–5453. (g) Deprez, N. R.; Sanford, M. S.
Inorg. Chem. 2007, 46, 1924–2935. (h) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172–1175. (i) Turner, G. L.; Morris, J. A.; Greaney, M. F.
Angew. Chem., Int. Ed. 2007, 46, 7996–8000. (j) Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 11904–11905. (k) Brasche, G.; Garcia-
Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207–2210. (l) Gorelsky,
S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
(3) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560–14561.
(4) (a) Sridharan, V.; Mart´ın, M. A.; Mene´ndez, C. M. Synlett 2006,
15, 2375–2378. (b) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137–3139. (c) Jordan-Hore, J. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 16184–16186.
(5) (a) Takagi, K. Chem. Lett. 1986, 265–266. (b) Brain, C. T.; Bunton,
S. A. Tetrahedron Lett. 2002, 43, 1893–1895. (c) Evindar, G.; Batey, R. A.
Org. Lett. 2003, 5, 133–136. (d) Benedi, C.; Bravo, F.; Uriz, P.; Ferna´ndez,
E.; Claver, C.; Castillo´n, S. Tetrahedron Lett. 2003, 44, 6073–6077. (e)
Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004, 446–447.
(f) Orain, D.; Blumstein, A.-C.; Tasdelen, E.; Haessig, S. Synlett 2008, 2433–
2436.
10.1021/ol900958z CCC: $40.75
Published on Web 05/28/2009
 2009 American Chemical Society

intramolecular cross-coupling to give 2-aminobenzothiazoles6
3 (Figure 1).5c The requirement for an ortho-halo substituted
precursor (such as 1) would be eliminated if a direct C-H
bond functionalization/cyclization could be achieved, thus
opening up a much wider range of more readily accessible
precursors for benz-fused heterocycle synthesis.7 Herein, we
report the successful realization of this strategy using
palladium catalysis under oxidative conditions,8,9 for the
conversion of N-arylthiourea substrates 2 into 3 (Scheme 1).10
(9-53% yield), while reaction in the absence of a terminal
oxidant afforded just a 6% yield of 3a. Evidence of substrate
acetoxylation, however, seen with the Cu(OAc)2 co-oxidant,
led us to investigate the use of alternative co-oxidants. A
broad screen of catalytic co-oxidants revealed both Cu(acac)2
and CuCl salts to be effective, giving 72 and 59% yields,
respectively. Activated MnO2 was unexpectedly the most
efficient co-oxidant giving a quantitative yield of 3a at half
the loading of Pd(PPh3)4, and with a higher rate of conver-
sion; use of MnO2 (5 mol %) alone did not result in product
formation. These results highlight the importance of the
combination of Pd(PPh3)4 and activated MnO2 for these
oxidative cyclizations.
Scheme 1
.
Metal Catalyzed Cyclization Strategies for
2-Aminobenzothiazole Formation
The optimized reaction conditions were evaluated for a
range of substituted precursors 2 (Table 1). Para-substituted
Table 1. Effect of Aryl Substituents on 2-Aminobenzothiazole
Formation
Initial optimization studies using model substrate 2a
(NR1R2 ) morpholino and R3 ) H) under catalytic oxidative
conditions were not encouraging. However, overnight screen-
ing reactions of stoichiometric Pd complexes in acetonitrile
under a N2 atmosphere, at 75 °C, revealed that whereas Pd(II)
complexes11 afforded product 3a in low 12-31% yields, use
of zerovalent Pd(PPh3)4 led to an improved 47% yield. This
result was unexpected as most oxidative functionalizations
make use of Pd(II) catalysts, typically Pd(OAc)2. Reaction
of 2a under an O2 atmosphere using 10 mol % Pd(PPh3)4 in
MeCN solvent at 80 °C gave a 40% yield of 3a after 2 h.12
Introduction of the catalytic co-oxidant Cu(OAc)2·H2O (10
mol %) under otherwise identical conditions further improved
the yield to 72% after 2 h. Other terminal oxidants such as
p-benzoquinone, NMO, and DMSO, were less efficient
(6) A class of heterocycles having significant pharmaceutical importance.
For examples, seeFrentizole (immunosuppressant): (a) Paget, C. J.; Kisner,
K.; Stone, R. L.; DeLong, D. C. J. Med. Chem. 1969, 12, 1016–1018.
Zolantidine (centrally acting H2-receptor histamine antagonist): (b) Young,
R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, C. R.; Griffiths, R.; Jones,
M.; Rana, K. K.; Saunders, D.; Smith, I. R.; Sore, N. E.; Wilks, T. J. J. Med.
Chem. 1988, 31, 656–671.
a Conversion determined by 1H NMR spectroscopy. b Yields after silica
gel column chromatography. c 22% starting material recovered; complete
conversion and 88% yield are obtained after a reaction time of 24 h. d Ratio
of 9:1 5-F/7-F products. e 39% starting material recovered. f 16% starting
material recovered and 3% of 3a. g 68% starting material recovered and
11% of 3a.
(7) For a general overview of synthetic methods to benzthiazoles, see:
(a) Ulrich, H. in Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; Schaumann, E., Ed.; Thieme: Stuttgart, 2001; Vol. 11,
pp 835-912.
(8) This work was presented in part at 234th American Chemical Society
National Meeting, Boston, MA, August 19-23, 2007. Abstract #325.
(9) During the course of our studies two examples on copper catalyzed
benzimidazole and benzoxazole formation via C-H functionalization were
reported, see: (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 1932–1934. (b) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed.
aryl thioureas worked well; however, the more electron-rich
p-MeO-substituted precursor 2e reacted in lower yield (Table
1, entries 2-5). Meta-substituted substrates cyclized chemose-
lectively to give the 5-substituted products 3g-3i exclusively,
except for the m-F substrate which gave a 9:1 mixture of
5-substituted:7-substituted products 3f (Table 1, entries 6-9).
Incorporation of two meta-substituents resulted in very poor
conversions for 2j and 2k, and only modest conversion was
achieved for 2l (Table 1, entries 10-12). While the majority
2008, 47, 6411–6413
.
(10) The precursors 2 are readily synthesized through the facile reaction
of commercially available phenylisothiocyantes with secondary amines in
less than 10 min, in typically quantitative yields.
(11) Pd(II) sources tested: PdCl2(CH3CN)2, Pd(OAc)2, and PdCl2(1,5-
C8H12).
(12) This and subsequent optimization reactions were monitored Via
HPLC using a naphthalene internal standard as a reference.
Org. Lett., Vol. 11, No. 13, 2009
2793

of ortho-substituted precursors effectively underwent reaction
(Table 1, entries 13-15), o-chloro and -bromo substituted
compounds (Table 1, entries 16-17) led to lower conversions
and competitive cyclization to the dehalogenated cyclized
product 3a. The reaction of other trisubstituted aminophe-
nylthioureas generally proceeded well, giving excellent
conversions and high yields (Table 2).
absence of the ligand. In situ catalyst formation by addition
of free PPh3 (4 or 10 equiv) to Pd(OAc)2 under an O2
atmosphere was also successful giving yields of 34 and 81%,
respectively. These results demonstrate the importance of
using a Pd(0)/phosphine based catalyst system.13,14 The
utility of similar systems have been reported in the oxidative
homocoupling of arylboronic esters15 and acids,16 as well
as in the oxidation of allylic alcohols to R,ꢀ-unsaturated
carbonyl compounds.17
As with many oxidative C-H functionalization reactions,
a full mechanistic understanding of the reaction has yet to
be established, however, some observations can be made.
Addition of a free-radical trap (galvinoxyl, 30 mol %) was
found to have no effect on the reaction, suggesting that a
radical pathway does not operate.18 Competition experiments
reveal that substrates bearing electron-withdrawing groups
at the para-position (e.g., p-CN or p-NO2) undergo cycliza-
tion more rapidly than 2a, whereas substrate 2e bearing an
electron donating p-OMe group undergoes cyclization more
slowly. The effects are similar, although less pronounced,
with meta-substituted examples. The higher reactivity of the
more electron deficient substrates is inconsistent with an
electrophilic palladation mechanism.
Table 2. C-S Bond Forming Cyclization Reaction Substrate
Scope
Treatment of mono-ortho-deuterium enriched N-phenyl-
benzothiourea with Pd(PPh3)4 (10 mol %) and MnO2 (20
mol %) in CH3CN for 5.5 h under an O2 atmosphere at 80
°C resulted in complete conversion to the cyclized product
2-phenylbenzothiazole. This transformation occurred with a
high intramolecular primary KIE of 5.9, showing preferential
functionalization of the C-H bond over a CsD bond. An
intramolecular primary KIE of 5.9 is similar to isotope effects
observed in aromatic palladation reactions and intramolecular
palladium-catalyzed cyclizations.19-23 This comparison pro-
vides further support to suggest that an electrophilic palla-
dation mechanism does not operate, as such reactions
typically do not exhibit primary KIEs because aryl depro-
tonation is fast relative to the formation of an arenium
σ-complex.24
a Conversion determined by 1H NMR spectroscopy. b Yields after silica
gel column chromatography.
A catalyst system comprising Pd2(dba)3 (1 mol %), PPh3
(8 mol %) and MnO2 (10 mol %) is also effective giving 3a
in quantitative yield after 4 h under an O2 atmosphere.
Lowering the amount of PPh3 ligand led to lowered reactivity
and yields of 3a, with no product being obtained in the
The chemoselectivity of cyclization of substrates 2f-2i
and the poor reactivity of 2j and 2k suggest that the reaction
(13) Screening of a variety of other phosphines under the same
conditions led to lowered yields of 3a: PCy3, P(o-tol)3, and P(2-fur)3
ranging from 3-5%; Buchwald ligands DavePhos, JohnPhos, and Ph
XPhos from 1-12%; and bidentate ligands DPPB, DPPF, and XantPhos
from 17-32%.
Scheme 2
. Potential Mechanistic Overview of
(14) The superiority of PPh3 as a ligand may reflect its greater stability
towards oxidation, as ligand loss through oxidation results in termination
of the catalytic cycle. See Iyer, S.; Kulkarni, G. M.; Ramesh, C. Tetrahedron
2004, 60, 2163–2172.
Aminobenzothiazole Formation
(15) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2003, 44, 1541–1544.
(16) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2000, 42, 4087–
4089.
(17) Gomez-Bengoa, E.; Noheda, P.; Echavarran, M. A. Tetrahedron
Lett. 1994, 35, 7097–7098.
(18) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330–7331.
(19) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636–
5637 (kH/kD ) 3.5).
(20) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880–6886. (kH/kD
5.0-6.7).
)
(21) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
12634–12635 (kH/kD ) 3.0-7.0).
(22) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586–1587 (kH/kD ) 3).
2794
Org. Lett., Vol. 11, No. 13, 2009

is very sensitive to steric effects at the ortho-position adjacent
to the C-H bond undergoing functionalization. In combina-
tion these observations may suggest that a σ-bond metathesis
mechanism occurs, wherein an anionic peroxo/peroxide-Pd-
bound ligand aids in proton abstraction (Scheme 2).
While the role of MnO2 remains unclear, it may serve as
a catalyst for hydrogen peroxide decomposition. The het-
erogeneous surface of may also aid in the generation of a
peroxo-Pd(II) species or enhance catalyst stability. Interest-
ingly, another heterogeneous additive, 4 Å molecular
sieves,25 also had a beneficial effect on overall reaction
conversions (in the absence of MnO2). However, much larger
amounts of 4 Å molecular sieves were required relative to
MnO2, rendering this approach less practical.
C-H functionalization. Further studies on related systems
and the broader use of mixed Pd/Mn based oxidative catalysis
are currently underway.
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC). We thank Dr. A. B. Young (University
of Toronto) for mass spectrometric analysis.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900958Z
In summary, we have established a Pd/Mn based catalyst
system for 2-aminobenzothiazole formation via an oxidative
(25) Several groups have demonstrated the beneficial effect of molecular
sieves on aerobic palladium(II) catalyzed oxidation of alcohols. See for
example:(a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem.
1999, 64, 6750–6755. (b) Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.;
Sigman, M. S. J. Org. Chem. 2005, 70, 3343–3352. (c) Steinhoff, B. A.;
King, A. E.; Stahl, S. S. J. Org. Chem. 2006, 71, 1861–1868.
(23) Shue, R. S. J. Am. Chem. Soc. 1971, 93, 7116–7117 (kH/kD ) 5).
(24) Campeau, C.-L.; Fagnou, K. Chem. Commun. 2006, 1253–1264.
Org. Lett., Vol. 11, No. 13, 2009
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