Pd-catalyzed direct arylation of nitro(pentafluorosulfanyl)benzenes with aryl bromides

Article abstract of DOI:10.1021/ol4023326

Limited methods for the synthesis of SF₅-substituted compounds significantly restrict their widespread application. A Pd-catalyzed direct arylation of nitro(pentafluorosulfanyl)benzenes with aryl bromides is reported. This protocol provides a facile and straightforward access to diversified SF₅-containing aryl derivatives. The notable features of this reaction are its synthetic simplicity, high reaction efficiency, and good regioselectivity.

Full text of DOI:10.1021/ol4023326

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Pd-Catalyzed Direct Arylation of
Nitro(pentafluorosulfanyl)benzenes with
Aryl Bromides
000–000
Chao Wang, Yan-Bo Yu, Shilu Fan, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xgzhang@mail.sioc.ac.cn
Received August 14, 2013
ABSTRACT
Limited methods for the synthesis of SF -substituted compounds significantly restrict their widespread application. A Pd-catalyzed direct
5
arylation of nitro(pentafluorosulfanyl)benzenes with aryl bromides is reported. This protocol provides a facile and straightforward access to
diversified SF -containing aryl derivatives. The notable features of this reaction are its synthetic simplicity, high reaction efficiency, and good
5
regioselectivity.
Due to the important role of fluorinated compounds in
1
life and material sciences, it is of great interest to develop
high thermal, hydrolytic, and chemical stability, high
lipophilicity, high density, and strong electron-withdrawing
4
character. It is beginning to find many applications in
pharmaceuticals, agrochemicals, and important functional
new and efficient methods to prepare such compounds. In
the past few years, great endeavors have been devoted to
fluorination and trifluoromethylation of (hetero)arenes,
and it has become an intensive topic of organosynthetic
5
materials. However, compared to trifluoromethylation
of (hetero)arenes, only a few methods for the synthesis
of SF -substituted (hetero)aryl derivatives have been re-
2
chemistry. However, to meet the increasing demand of life
5
6
ported so far. This is mainly because of the difficulty in
and materials, the preparation of novel fluorine-containing
compounds remains highly desirable. The pentafluorosul-
fanyl (SF ) group, namely, the “super-trifluoromethyl
5
(4) (a) Verma, R.; Kirchmeier, R.; Shreeve, J. Advances in Inorganic
Chemistry; Elsevier: Amsterdam, 1994; pp 125À169. (b) Lentz, D.;
Seppelt, K. In Chemistry of Hypervalent Compounds; Akiba, K.-Y., Ed.;
Wiley-VCH: New York, 1999; p 295.
3
group”, is one of the fascinating fluorinated groups
bearing specific physicochemical properties, such as its
(
5) For a review, see: (a) Altomonte, S.; Zanda, M. J. Fluorine Chem.
(
1) For selected reviews, see: (a) Smart, B. E. J. Fluorine Chem. 2001,
2012, 143, 57. For selected papers, see: (b) Kirsch, P.; Bremer, M. Angew.
Chem., Int. Ed. 2000, 39, 4216. (c) Welch, J. T.; Lim, D. S. Bioorg. Med.
Chem. 2007, 15, 6659. (d) Wipf, P.; Mo, T.; Geib, S.; Caridha, D.; Dow,
G.; Gerena, L.; Roncal, N.; Milner, E. Org. Biomol. Chem. 2009, 7, 4163.
(e) Stump, B.; Eberle, C.; Schweizer, W. B.; Kaiser, M.; Brun, R.; Kraut-
Siegel, R. L.; Lentz, D.; Diederich, F. ChemBioChem 2009, 10, 79.
(6) (a) Roberts, H. L. J. Chem. Soc. 1962, 3183. (b) Sheppard, W. A.
J. Am. Chem. Soc. 1960, 82, 4751. (c) Sheppard, W. A. J. Am. Chem. Soc.
1962, 84, 3064. (d) Bowden, R. D.; Comina, P. J.; Greenhall, M. P.;
Kariuki, B. M.; Loveday, A.; Philp, D. Tetrahedron 2000, 56, 3399. (e)
Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999, 883. (f)
Umemoto, T. WO 2008/118787, 2008. (g) Beier, P.; Pastyrikova, T.; Vida,
N.; Iakobson, G. Org. Lett. 2011, 13, 1466. (h) Beier, P.; Pastyrikova, T.;
Iakobson, G. J. Org. Chem. 2011, 76, 4681. (i) Frischmuth, A.; Unsinn,
A.; Groll, K.; Stadtmuller, H.; Knochel, P. Chem.;Eur. J. 2012, 18,
10234.
1
09, 3. (b) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93. (c) Special
issue on “Fluorine in the Life Sciences”: ChemBioChem 2004, 5, 557. (d)
M u€ ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (e) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
3
20. (f) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (g) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359.
2) For selected reviews, see: (a) Furuya, T.; Klein, J. E. M. N.; Ritter,
(
T. Synthesis 2010, 1804. (b) Tomashenko, O. A.; Grushin, V. V. Chem.
Rev. 2011, 111, 4475. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
011, 473, 470. (d) Ye, Y.; Sanford, M. S. Synlett 2012, 2005. (e) Besset,
T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 5048. (f)
Qing, F.-L. Chin. J. Org. Chem. 2012, 32, 815. (g) Wang, X.; Zhang, Y.;
Wang, J. Sci. Sin.: Chim. 2012, 42, 1417.
2
(
3) Kirsch, P. Modern Fluoroorganic Chemistry Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, Germany, 2004.
1
0.1021/ol4023326 r XXXX American Chemical Society

accessing pentafluorosulfanylated reagents and lack of key
7
SF -substituted building blocks. Hence, developing new
5
Table 1. Optimization of Palladium-Catalyzed Direct Arylation
of meta-Nitro(pentafluorosulfanyl)benzene 1 with Phenyl
Bromide 3a
and efficient methods to access SF -containing com-
5
pounds for widespread applications is appealing.
The meta- and para-nitro(pentafluorosulfanyl)benzenes
a
(
1 and 2) are readily and commercially available and can
be easily prepared through direct fluorination of bis-
6
nitrophenyl)disulfides on a large scale. Usually, the
d
(
SF -substituted aryl derivatives can be accessed by reduc-
5
tion of the nitro group on (1 and 2) to amine, followed by
6
acylation, electrophilic halogenation, or diazotization.
d,i
ligand,
additive,
5a/4a yield
b
entry
[Pd], x mol %
y mol %
z equiv
(%)
Despite the utility of this method, developing new efficient
and straightforward methods to access diversified struc-
tures would benefit the application of SF -containing
1
2
3
4
5
6
7
8
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
, 10
, 10
, 10
, 10
PPh
3
, 20
NR
L1, 15
L1, 15
L1, 15
L1, 15
L1, 15
L1, 15
PivOH, 1
AcOH, 1
AdOH, 1
PivOH, 1
PivOH, 1
PivOH, 1
PivOH, 1
PivOH, 1
6, 1
31/8
2/trace
3/2
5
compounds in life and material sciences. Considering that
SF and nitro groups are strong electron-withdrawing
5
PdCl , 10
38/3
55/4
51/6
38/4
42/4
71/0
62/8
(82)/(7)
(74)/(7)
(79)/(7)
61/8
NR
2
groups that can acidify their corresponding ortho CÀH
2
(AllylPdCl) , 5
bonds, we envisionedthat withthe aid of a transition-metal
catalyst, such as palladium, the direct arylation of 1 and 2
Pd(dppf)Cl
2
, 10
Pd(MeCN)Cl
2
, 10 L1, 15
8
would be possible, and thus diversified SF -containing
9
Pd(PPh )Cl , 10
L1, 15
L1, 15
L1, 15
L1, 15
L1, 7.5
L1, 7.5
L1, 7.5
L1, 7.5
3
2
5
c
10
(AllylPdCl)
2
, 5
aryl derivatives can be easily accessed via this strategy.
Continuing our study of transition-metal-catalyzed direct
9
functionalization of electron-deficient arenes, herein we
d
11
(AllylPdCl)
(AllylPdCl)
(AllylPdCl)
2
2
2
, 5
6, 1
c,e
c,f
g
1
1
2
3
, 5
6, 0.5
, 2.5
6, 0.3
describe an efficient and straightforward method for
the synthesis of SF -substituted aryl derivatives through
14
15
(AllylPdCl) , 2.5
6, 0.3
2
g
(AllylPdCl)
2
, 2.5
PivOH, 0.3
6, 0.3
5
g
16
17
18
palladium-catalyzed cross-coupling between nitro(penta-
fluorosulfanyl)benzenes and aryl bromides. The notable
features of this protocol are its synthetic simplicity, high
reaction efficiency, and good regioselectivity.
g
(AllylPdCl)
(AllylPdCl)
2
, 2.5
, 2.5
6, 0.3
NR
g
2
L1, 7.5
NR
a
Reaction conditions (unless otherwise specified): 1 (0.3 mmol), 3a
b
(
2.0 equiv), K
2
CO
3
(1.2 equiv), toluene (1 mL), 8 h, 120 °C. NMR yield
determined by F NMR using fluorobenzene as an internal standard
We began this study by choosing meta-nitro(penta-
fluorosulfanyl)benzene 1 and phenyl bromide 3a as model
substrates. Initially, a negative result was obtained with the
use of Pd(OAc) (10 mol %), PPh (20 mol %), and K CO
1
9
c
d
(
isolated yield in parentheses). Reaction conducted at 130 °C. Reac-
e
f
tion conducted at 140 °C. Using 2.4 equiv of K CO . Using 1.8 equiv
2
3
g
of K
(
2
CO
3
.
1 (0.5 mmol), 3a (1.5 equiv), K
3 HBF4
2
CO
3
(1.8 equiv), toluene
; 6, 2,2-dimethylbutyric acid.
2
3
2
3
0.8 mL), 130 °C, 8 h. L1: PCy
3
(
1.2 equiv) in toluene at 120 °C (Table 1, entry 1). After a
survey of different reaction parameters, such as phos-
phane ligands, solvents, and additives, it was found that
the reaction is sensitive to the ligands and solvents. The use
of PCy HBF L1 and nonpolar solvent toluene in con-
junction with PivOH showed better catalytic effect, albeit a
mixture of 5a and 4a was obtained in 31 and 8% yield,
respectively (Table 1, entry 2) (for details see Supporting
Information). Further, to improve the reaction efficiency
by investigation of different palladium sources (Table 1,
entries 5À9), it turned out that (AllylPdCl) is the optimal
2
precatalyst with 55% yield of 5a as the major product
obtained (Table 1, entry 6). We were delighted to find that
increasing the reaction temperature to 130 °C in combina-
tion with bulky carboxylic acid 2,2-dimethylbutyric acid 6
could improve the yield of 5a to 71% without observation
of 4a (Table 1, entry 10). Further optimization revealed
that 79% yield of isolated product 5a was afforded by
3
3
4
decreasing the (AllylPdCl) loading to 2.5 mol % with use
2
(
7) SF
can be used to introduce the SF
However, SF Cl is a gaseous and highly toxic reagent. See: Ait-Mohand,
S.; Dolbier, W. D., Jr. Org. Lett. 2002, 4, 3013.
8) For selected transition-metal-catalyzeddirectarylation ofelectron-
5
Cl is presently the only commercially available “reagent” that
5
substituent into aliphatic compounds.
of PCy HBF (7.5 mol %), 6 (0.3 equiv), and K CO (1.8
3
3
4
2
3
5
equiv) in high concentration at 130 °C (Table 1, entry 14).
The use of PivOH diminished the yield (Table 1, entry 15).
Without Pd catalyst or phosphane ligand, no desired
product was obtained (Table 1, entries 16 and 17), thus
implying that a Pd(0/II) catalytic cycle is involved in the
reaction. Furthermore, the absence of additive 6 failed to
afford any desired product, thus demonstrating the essen-
tial role of carboxylic acid for the reaction efficiency
(
deficient (hetero)arenes with aryl halides, see: (a) Lafrance, M.; Rowley,
C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754.
b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c)
Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533. (d)
Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
27, 18020.
(
1
(
9) (a) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.;
Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (b) He, C.-Y.; Fan, S.;
Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. (c) Fan, S.; Chen, F.;
Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 5918. (d) Fan, S.; Yang, J.;
Zhang, X. Org. Lett. 2011, 13, 4374. (e) Fan, S.; He, C.-Y.; Zhang, X.
Chem. Commun. 2010, 46, 4926. (f) Chen, F.; Feng, Z.; He, C.-Y.; Wang,
H.-Y.; Guo, Y.-l.; Zhang, X. Org. Lett. 2012, 14, 1176. (g) Chen, F.;
MinQ.-Q.; Zhang, X. J. Org. Chem. 2012, 77, 2992. (h) He, C.-Y.; Min,
Q.-Q.; Zhang, X. Organometallics 2012, 31, 1335. (i) Yu, Y.-B.; Fan, S.;
Zhang, X. Chem.;Eur. J. 2012, 18, 14643.
(10) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754. (b) Lafrance, M.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 16496. (c) Garcia-Cuadrado, D.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129,
6880. (d) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 14570.
B
Org. Lett., Vol. XX, No. XX, XXXX

(Table 1, entry 18). On the basis of previous studies, we
supposed that 2,2-dimethylbutanoate generated by the
Scheme 2. Pd-Catalyzed Direct Arylation of para-Nitro(penta-
fluorosulfanyl)benzene 2 with Aryl Bromides 3
reaction of 6 with K CO may serve as a suitable base to
2
3
a
1
0
assist the CÀH cleavage for compound 1.
Under optimal reaction conditions, the substrate scope
of direct arylation of meta-nitro(pentafluorosulfanyl)-
benzene 1 was investigated (Scheme 1).
Scheme 1. Pd-Catalyzed Direct Arylation of meta-Nitro-
(
a
pentafluorosulfanyl)benzene 1 with Aryl Bromides 3
a
Reaction conditions (unless otherwise specified): 1 (0.5 mmol,
1
.0 equiv), 3 (1.5 equiv), (AllylPdCl)
2 3 4
(2.5 mol %), PCy HBF
3
(
(
7.5 mol %), K CO (1.8 equiv), and 2,2-dimethylbutyric acid 6
3
0.3 equiv) in toluene (0.8 mL) at 130 °C for 15 h.
2
a
Reaction conditions (unless otherwise specified): 2 (0.2À0.3 mmol,
1
K
.0 equiv), 3(2.5 equiv), (AllylPdCl)
CO
2
(2.5mol%),PCy
3
HBF
4
(7.5mol%),
3
2
3
(1.8 equiv), and 2,2-dimethylbutyric acid 6 (0.3 equiv) in toluene
(1 mL) at 130 °C for 15 h.
The present method allowed the direct arylation of 1
with a variety of aryl bromides, and high regioselectivity
was observed with aryl groups ortho to the nitro group.
Generally, the reaction efficiency depends on the nature of
the substituents on the aryl bromides. Substrates bearing
an electron-donating group afforded higher yields than
those substituted with an electron-withdrawing group.
However, for the heteroaryl bromide, a reasonable yield
was obtained (5g).
hydrochloric acid afforded SF -substituted aniline 8 in
5
11
good yield, thus providing a good opportunity for
further applications of this key SF -substituted building
5
block in life and materials sciences.
Scheme 3. Transformation of Compound 5c
To probe the applicability of this method further, cou-
plings of para-nitro(pentafluorosulfanyl)benzene 2 with
aryl bromides 3 were also tested (Scheme 2). Interestingly,
diarylated compounds 6 were obtained as major products
when 2.5 equiv of 3 was used. Similarly, the coupling of
compound 2 with electron-rich aryl bromides provided
yields of compounds 6 higher than those of electron-
deficient ones. The position of the substituents on the
phenyl bromide also affected reaction efficiency, and
meta-substituted phenyl bromides furnished their corre-
sponding products in higher yields (6c and 6e). For elec-
tron-deficient aryl bromides, more monoarylated 7 was
afforded (6eÀh). 2-Bromonaphthalene also underwent the
reaction smoothly, providing 6j in 75% yield along with a
To understand the working mode of the present reac-
tion, a kinetic isotope effect (KIE) experiment was con-
ducted (Scheme 4). The intermolecular competition reac-
tions between 1 and d-1 showed a KIE of 1.91. Although
the exact mechanism of the reaction is still not clear, on the
1
0
basis of theresults reportedbyothers and thepreliminary
kinetic data and the fact that a Pd(0/II) is involved in the
catalytic cycle (Table 1, entries 16 and 17), we proposed
that the catalytic cycle could be initiated from oxidation
of Pd(0) to aryl bromides. The resulting Pd(II) intermedi-
ate subsequently goes through the concerted metalationÀ
1
7% yield of 7j (6j), but for 6-bromoquinoline, a mixture
of 6k and 7k (6k/7k = 1.36) was obtained in moderate
yield (6k).
To demonstrate the utility of this method, a transforma-
tion of 5c was performed. As shown in Scheme 3, reduction
ofthenitrogroup on 5cwithironpowderandconcentrated
1
0
deprotonation (CMD) process with 1 or 2 to form a
(11) Welch, J. T.; Lim, D. S. Bioorg. Med. Chem. 2007, 15, 6659.
Org. Lett., Vol. XX, No. XX, XXXX
C

requirement of several synthetic steps to prepare cross-
coupling partners. Because of the high reaction efficiency,
high regioselectivity, and the ease of conducting such
reactions, this protocol provides a useful and facile access
Scheme 4. Kinetic Isotope Effect Study
to SF -substituted aryl derivatives of interest in life and
5
materials sciences.
Acknowledgment. The National Basic Research Pro-
gram of China (973 Program) (No. 2012CB821600), the
NSFC (No 21172242), and SIOC are greatly acknowl-
edged for funding this work.
diarylpalladium complex. Finally, reductive elimination
provides the finalproductand releasesPd(0). However, the
detailed reaction mechanism remains a point of discussion.
In conclusion, we have developed a straightforward
and convenient method for Pd-catalyzed direct arylation
of meta- and para-nitro(pentafluorosulfanyl)benzenes
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(1 and 2). The reaction makes direct use of simple and
readily available SF -substituted benzenes without the
The authors declare no competing financial interest.
5
D
Org. Lett., Vol. XX, No. XX, XXXX