Fe-catalysed oxidative C-H functionalization/C-S bond formation

Article abstract of DOI:10.1039/c1cc16184a

Iron was used as the catalyst for the direct C-H functionalization/C-S bond formation under mild conditions. Various substrates could afford benzothiazoles in moderate to excellent yields. Preliminary mechanistic studies revealed that pyridine played a crucial role for the high yields and selectivities.

Full text of DOI:10.1039/c1cc16184a

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COMMUNICATION
Fe-catalysed oxidative C–H functionalization/C–S bond formationw
Haibo Wang,a Lu Wang,a Jinsai Shang,a Xing Li,a Haoyuan Wang,a Jie Guia and
Aiwen Lei*ab
Received 5th October 2011, Accepted 8th November 2011
DOI: 10.1039/c1cc16184a
Iron was used as the catalyst for the direct C–H functionalization/
C–S bond formation under mild conditions. Various substrates
could afford benzothiazoles in moderate to excellent yields.
Preliminary mechanistic studies revealed that pyridine played a
Scheme 1 Intramolecular C–S bond formation via C–H and S–H
crucial role for the high yields and selectivities.
activation.
progress on iron-salts-catalysed intramolecular C(Ar)–H/X–H
Direct C–H bond functionalization towards C–C and C–
activation/C–S bond formation under mild conditions (Scheme 1).
heteroatom (N, O and S etc.) bond formation promoted by
Aiming at highly efficient iron-catalysed oxidative coupling,
transition metals has attracted extensive attention in the past
decades.1 However, most efforts were focused on noble metal
catalysts, such as Ru,2 Rh,3 Pd,4 etc. Due to the wide existence
we chose 4-chloro-N-phenylbenzothioamide 1a as the model
reaction for initial investigations. Condition optimization
(see details in Tables S1, S2 and S3 of ESIw) showed that
using Na2S2O8 as the oxidant in DMSO with 10% FeCl3 as the
catalyst at 80 1C produced 68% of 2a in 4 h (Table 1, entry 2).
In the absence of Fe catalyst, only 16% of 2a was obtained
(Table 1, entry 1). Additives such as HOAc or Na2CO3 showed
no obvious effect on improving the reaction selectivity. The
breakthrough was achieved when 2 eq. of pyridine was
employed as the additive. Up to 87% of the desired product
2a was obtained with higher selectivity (2a : 3a was 87 : 10)
(Table 1, entry 5). Further optimization of catalyst precursors
in the presence of pyridine gave no obvious improvement
(Table 1, entry 6–8). Even using super pure FeCl3 (99.99%)
as the catalyst, the result showed no significant difference from
commercial FeCl3 (98%) (Table 1, entry 9). By elongating the
reaction time, the reaction could also undergo smoothly at
40 1C (Table 1, entry 10) with the slightly decreased selectivity
of 2a.
and low toxicity of iron compounds, more and more attention
have been paid to the iron-catalysed reaction for organic
synthesis.5 Remarkable results have been reported on iron
promoted ‘‘traditional’’ cross couplings between R1X and R2M.6
Recently, Fe-catalysed direct C–H arylation of unactivated arenes
with aryl halides has also been demonstrated simultaneously by
Charette et al. and our group.7 To the willing of greener and more
atom-economic C–C and C–heteroatom bond formations, the
Fe-catalysed direct oxidative cross-coupling between two C–H
bonds or C–H and X–H bonds would be an ideal approach to
realize this goal. However, few examples have been reported
regarding Fe-catalysed direct oxidative C–H functionalizations.8
Benzothiazoles are a very important class of heterocycles in the
pharmaceutical area.9 Generally, oxidative cyclization is an efficient
approach for the synthesis of thiobenzanilides by using various
oxidants,10 such as quinone,10a bromine,10b and hypervalent
iodine,10d or metal salt.10c,e Meanwhile, Pd-catalyzed C–S bond
formation from thioamides via C–H functionalization has also been
realized.11 Alternatively, cyclization of 2-halophenylthiobenzamides
using Pd or Cu as a catalyst provided another approach to
benzothiazoles.12 However, the pre-functionalization of the
starting materials in this protocol limited its application. It is
no doubt that the direct oxidative intramolecular C–S bonds
formation via C–H functionalization would be an attractive
approach to synthesize benzothiazole. Herein, we report our
Substrate scope of this transformation was further investigated
under the optimal conditions (Table 2). The influence of
the substituent on the aryl group of the thiobenzoyl part
(Ar2, Table 2, substrate 1b–1f) was not the crucial factor for
this transformation. Either with the electronic or steric property
good to excellent yields (72–95%) can be achieved. Halo
substituents (Br, I) can be well tolerated under the reaction
conditions (Table 2, substrates 1e and 1f). Then, the effect of the
substituents on Ar1 was examined (Table 2, substrate 1g–1m).
When the substituent group was the electron-donating group,
either ortho or para-position did not influence the reaction.
Excellent yields (84–93%) were obtained (Table 2, substrates
1g, 1h and 1l). The reaction of N-naphthalene substituted
benzothioamide gave excellent yields (97%) of the cyclization
product (Table 2, substrate 1m). However, electron-withdrawing
groups decreased the yields dramatically, only moderate
yield was obtained when the NO2 substituent was introduced
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072, P. R. China. E-mail: aiwenlei@whu.edu.cn;
Fax: +86-27-68754672; Tel: +86-27-68754672
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000, Lanzhou, P. R. China
w Electronic supplementary information (ESI) available: General
procedures, spectral data and other supplementary information. See
DOI: 10.1039/c1cc16184a
c
76 Chem. Commun., 2012, 48, 76–78
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Table 1 Reaction parameters of 1aa
(Table 3, product 5a–5c). However, when N-phenyl alkylthio-
amide bore a less hindered substituted group, only low yields
were obtained. For instance, only 21% desired product 5d and
even no 5e were obtained. When thioureas were employed as
substrates, the reaction of 1,1-dibutyl-3-phenylthiourea (4f) and
1,1-diethyl-3-phenylthiourea (4g) gave corresponding products
in good (5f, 70%) and moderate (5g, 57%) yields. When R was
NHPh and NHBn, 50% of 5h and 22% of 5i were obtained,
respectively.
Yield [%]
2a
3a
Entry Cat.
Additive
Conversion 1a [%]
To gain preliminary mechanistic information about this
transformation, isotopic effect experiments have been carried
out. The reaction of deuterium-1o (1o-D) under the standard
condition provided a mixture of the products deuterium-2o
(2o-D) and 2o in 93% combined yields, in which the ratio of
2o-D : 2o was 1.3 (eqn (1)). The KIE values revealed that the
C–H bond cleavage is not the rate-determining-step. When
running the reaction in the presence of a radical scavenger
(TEMPO) at the same condition, only 19% product was
obtained (as shown in eqn (2)) indicating that the reaction
might proceed via a radical process.
1
No
—
—
100
100
100
99
16
68
65
64
87
82
46
30
85
83
81
28
30
34
10
15
33
32
15
13
2
3
4
5
6
7
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
FeBr2
HOAc (2 eq)
Na2CO3 (2 eq)
Pyridine (2 eq) 100
Pyridine (2 eq) 100
Pyridine (2 eq) 100
90
Pyridine (2 eq) 100
Pyridine (2 eq) 100
8
Fe(acac)3 Pyridine (2 eq)
FeCl3
FeCl3
9b
10c
a
Reaction conditions: 1a (0.5 mmol), Na2S2O8 (0.5 mmol) and
catalyst (0.05 mmol) in 2 mL of DMSO at 80 1C for 4 h. The purity
of FeCl3 is 98% unless otherwise indicated. Yields were determined by
b
c
HPLC with an internal standard. 99.99% FeCl3. 40 1C for 10 h.
ð1Þ
Table 2 Synthesis of substituted 2-arylbenzothiazolesa
ð2Þ
Furthermore, a series of stoichiometric reactions were carried
out monitored by in situ IR. The profiles of ConcIRT vs. time
shown in Fig. 1 represent the relative concentrations vs. time
for individual species. Clearly, no reaction occurred when
Na2S2O8, pyridine and FeCl3 were sequentially added. How-
ever, as soon as 1a was added, we could see the consumption
of Na2S2O8, 1a and the formation of 2a was in accordance
Table 3 Synthesis of 2-substituted benzothiazolesa
a
Reaction conditions: 1 (0.5 mmol), Na2S2O8 (0.5 mmol), pyridine
(1 mmol) and FeCl3 (0.05 mmol) in 2 mL of DMSO at 80 1C for 4 h.
All yields are isolated yields.
(Table 2, substrate 1k). C–Br and C–I could also be well
tolerated (Table 2, substrates 1i and 1j). Interestingly, the
reaction of 1n proceeded smoothly to give 2n with high
selectivity.
Furthermore, N-aryl alkylthioamides and thioureas were
also employed as substrates (Table 3). N-Aryl tert-penta-
nethioamide bearing both electron-donating and withdrawing
groups could undergo the C–H activation/C–S bond for-
mation smoothly in moderate to excellent yields (71–92%)
a
Reaction conditions: 4 (0.5 mmol), Na2S2O8 (0.5 mmol), pyridine
(1 mmol) and FeCl3 (0.05 mmol) in 2 mL of DMSO at 80 1C for 4 h.
c
All yields are isolated yields. 40 1C for 10 h.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 76–78 77

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Notes and references
1 For recent reviews on transition metal-catalyzed C–H functiona-
lization, see: (a) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147; (b) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540;
(c) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009,
38, 2447; (d) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem.
Res., 2009, 42, 1074; (e) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094.
2 For selected recent examples, see: (a) F. Pozgan and P. H. Dixneuf,
Adv. Synth. Catal., 2009, 351, 1737; (b) I. Oezdemir, S. Demir,
B. Cetinkaya, C. Gourlaouen, F. Maseras, C. Bruneau and
P. H. Dixneuf, J. Am. Chem. Soc., 2008, 130, 1156;
(c) N. A. Foley, T. B. Gunnoe, T. R. Cundari, P. D. Boyle and
J. L. Petersen, Angew. Chem., Int. Ed., 2008, 47, 726.
3 For selected recent examples, see: (a) Q. Li and Z.-X. Yu, J. Am.
Chem. Soc., 2010, 132, 4542; (b) A. S. Tsai, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 6316; (c) M. Shen,
B. E. Leslie and T. G. Driver, Angew. Chem., Int. Ed., 2008,
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4 For selected recent examples, see: (a) D. A. Candito and
M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 6713;
(b) L.-C. Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-
Laperle, E. Villemure, H.-Y. Sun, S. Lasserre, N. Guimond,
M. Lecavallier and K. Fagnou, J. Am. Chem. Soc., 2009,
131, 3291; (c) N. Lebrasseur and I. Larrosa, J. Am. Chem. Soc.,
2008, 130, 2926; (d) H. A. Chiong, Q.-N. Pham and O. Daugulis,
J. Am. Chem. Soc., 2007, 129, 9879.
Fig. 1 The 2D-kinetic profiles of the stoichiometric reaction of
Na2S2O8 (0.2 M), pyridine (4 M), FeCl3 (0.02 M) and 1a (0.2 M)
added to 5 mL DMSO at 40 1C one by one; the reaction was
monitored by in situ IR.
obviously. Other stoichiometric reactions varying the addition
sequences of these species (see Fig. S8 and S9 in ESIw) also
indicated that the C–H activation and C–S bond formation
required the co-existence of oxidant, FeCl3 and the substrates.
Further kinetic investigation showed that the reaction was
first order in [1a], and zero order in the oxidant [Na2S2O8]
(see Table S4 and Fig. S10–S17 in ESIw).
5 (a) S. Enthaler, K. Junge and M. Beller, Angew. Chem., Int. Ed.,
2008, 47, 3317; (b) C. Bolm, J. Legros, J. Le Paih and L. Zani,
Chem. Rev., 2004, 104, 6217.
Finally, in order to clarify the role of FeCl3 and pyridine in
the reaction, comparison experiments were carried out and
monitored by in situ IR. We found that pyridine is crucial for
the high selectivity of C–H activation/C–S bond formation
(for detailed information see Fig. S18–S20 in ESIw).
According to all above results, we proposed a mechanism
shown in Scheme 2. The substrate N-phenyl benzothioamide
was oxidized by Fe(III) through path A and lost an electron and
H+ to form the thioyl radical intermediate, in the meantime
Fe(III) was reduced to Fe(II). Fe(II) species was re-oxidized by
Na2S2O8 to regenerate Fe(III). Then, the cyclization of the thioyl
radical intermediate followed by oxidation in the presence of
Na2S2O8 gave the product 2-phenyl benzothiazole.
6 (a) X.-F. Wu and C. Darcel, Eur. J. Org. Chem., 2009, 4753;
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2009, 351, 1732; (d) O. Bistri, A. Correa and C. Bolm, Angew.
Chem., Int. Ed., 2008, 47, 586.
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49, 2004; (b) F. Vallee, J. J. Mousseau and A. B. Charette, J. Am.
Chem. Soc., 2010, 132, 1514.
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46, 6505; (b) Z. Li, R. Yu and H. Li, Angew. Chem., Int. Ed., 2008,
47, 7497; (c) J. Norinder, A. Matsumoto, N. Yoshikai and
E. Nakamura, J. Am. Chem. Soc., 2008, 130, 5858; (d) J. Wen,
J. Zhang, S.-Y. Chen, J. Li and X.-Q. Yu, Angew. Chem., Int. Ed.,
2008, 47, 8897; (e) Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin and Z.-J. Shi,
Angew. Chem., Int. Ed., 2009, 48, 3817; (f) C.-X. Song, G.-X. Cai,
T. R. Farrell, Z.-P. Jiang, H. Li, L.-B. Gan and Z.-J. Shi, Chem.
Commun., 2009, 6002; (g) N. Yoshikai, A. Matsumoto, J. Norinder
and E. Nakamura, Angew. Chem., Int. Ed., 2009, 48, 2925.
9 For selected recent examples, see: (a) S. Massari, D. Daelemans,
M. L. Barreca, A. Knezevich, S. Sabatini, V. Cecchetti,
A. Marcello, C. Pannecouque and O. Tabarrini, J. Med. Chem.,
2010, 53, 641; (b) L. A. Black, M. D. Cowart, G. A. Gfesser,
B. D. Wakefield, R. J. Altenbach, H. Liu, C. Zhao and
G. C. Hsieh, WO 2009085945, 2009; (c) S. Aiello, G. Wells,
E. L. Stone, H. Kadri, R. Bazzi, D. R. Bell, M. F. G. Stevens,
C. S. Matthews, T. D. Bradshaw and A. D. Westwell, J. Med.
Chem., 2008, 51, 5135.
In conclusion, we have developed an efficient iron-catalysed
C–H functionalization/C–S bond formation under mild conditions.
This transformation could be conveniently carried out affording
various benzothiazoles in moderate to excellent yields. Preliminary
mechanistic studies revealed that the reaction required the
co-existence of substrate, oxidant, FeCl3 and pyridine. Kinetic
studies indicated that pyridine was crucial for the high selectivity
of this transformation and the reaction was first order in the
substrate and zero-order in oxidant Na2S2O8.
10 For selected recent examples, see: (a) D. S. Bose and M. Idrees,
Tetrahedron Lett., 2007, 48, 669; (b) D. S. Bose and M. Idrees,
J. Org. Chem., 2006, 71, 8261; (c) X.-J. Mu, J.-P. Zou, R.-S. Zeng
and J.-C. Wu, Tetrahedron Lett., 2005, 46, 4345;
(d) F. M. Moghaddam and H. Z. Boeini, Synlett, 2005, 1612;
(e) D.-F. Shi, T. D. Bradshaw, S. Wrigley, C. J. McCall,
P. Lelieveld, I. Fichtner and M. F. G. Stevens, J. Med. Chem.,
1996, 39, 3375; (f) F. M. Moghaddam and D. Zargarani, J. Sulfur
Chem., 2009, 30, 507.
This work was support by the National Natural Science
Foundation of China (20702040, 20832003, 20972118).
11 (a) K. Inamoto, C. Hasegawa, K. Hiroya and T. Doi, Org. Lett.,
2008, 10, 5147; (b) L. L. Joyce and R. A. Batey, Org. Lett., 2009,
11, 2792.
12 For selected recent examples, see: (a) M. D. Vera and
J. C. Pelletier, J. Comb. Chem., 2007, 9, 569; (b) G. Evindar and
R. A. Batey, J. Org. Chem., 2006, 71, 1802; (c) C. Benedi, F. Bravo,
P. Uriz, E. Fernandez, C. Claver and S. Castillon, Tetrahedron
Lett., 2003, 44, 6073.
Scheme 2 Proposed mechanism.
c
78 Chem. Commun., 2012, 48, 76–78
This journal is The Royal Society of Chemistry 2012