A Route to α-Fluoroalkyl Sulfides from α-Fluorodiaroylmethanes

Article abstract of DOI:10.1021/acs.orglett.5b03654

α,α-Difluorodiaroylmethane can be used as a nucleophilic difluoromethylation reagent for generating α-thioaryl-α,α-difluoroacetophenones (Ar¹COCF₂SAr) and difluoromethylthiolated arenes (ArSCF₂H) under transition-metal-free conditions. The reaction selectivity is mainly dependent on temperature. The method has also been extended to the synthesis of α-thioaryl-α-monofluoroacetophenones using α-monofluorodibenzoylmethane. Moreover, the benzoyl cation derived from α,α-difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a one-pot process.

Full text of DOI:10.1021/acs.orglett.5b03654

Letter
pubs.acs.org/OrgLett
A Route to α‑Fluoroalkyl Sulfides from α‑Fluorodiaroylmethanes
Ya-mei Lin, Wen-bin Yi,* Wan-zhao Shen, and Guo-ping Lu*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing, 210094, China
S
* Supporting Information
ABSTRACT: α,α-Difluorodiaroylmethane can be used as a
nucleophilic difluoromethylation reagent for generating α-
thioaryl-α,α-difluoroacetophenones (Ar1COCF2SAr) and
difluoromethylthiolated arenes (ArSCF2H) under transition-
metal-free conditions. The reaction selectivity is mainly
dependent on temperature. The method has also been
extended to the synthesis of α-thioaryl-α-monofluoroaceto-
phenones using α-monofluorodibenzoylmethane. Moreover,
the benzoyl cation derived from α,α-difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a
one-pot process.
ecently, the selective introduction of a difluoro(arylthio)-
methyl group (ArSCF2) into organic molecules has been
R
found to be attractive, since compounds containing such a
moiety have potential biological applications,1 such as anti-
HIV-1 reverse transcriptase inhibitors and agrochemical
intermediates. Moreover, the concurrence of the ArSCF2
group and carbonyl group is especially beneficial because the
carbonyl group is of great importance in organic chemistry and
can be transformed into versatile functional groups. Several
Figure 1. Strategies for the preparation of Ar1COCF2SAr and
ArSCF2H.
reports have mentioned the synthesis of this kind of
compounds. SRN1 reactions between arylthiolates and
halodifluoromethyl compounds1b or halogen exchange reac-
tions with the gem-α,α-dichloroalkylsulfenyl carbonyl com-
pounds have been applied to construct these compounds.2
Prakash’s group has developed the TMSCF2SPh as a
nucleophilic (phenylthio)difluoro-methylating reagent to in-
troduce ArSCF2 moieties to ketones.3
However, these strategies suffer from limitations, such as
harsh reaction conditions, use of toxic or hazardous reagents,
and limited substrate scopes. Meanwhile, spurred by the work
of Colby’s group, which used 1 to generate an α,α-
difluoroenolate intermediate for aldol reactions,4 we find that
the stable and easy-to-handle α,α-difluorodiaroylmethane 2
prepared from diaroylmethane and Selecfluor in water can also
generate the same intermediate under basic conditions.5
Therefore, we envision that the Ar1COCF2SAr would be
prepared by the treatment of α,α-difluorodibenzoylmethane
with diaryl disulfides or aryl thiols (Figure 1). Along this line,
we disclose a mild approach for the generation of
Ar1COCF2SAr with harmless and safe α,α-difluorodiaroyl-
methane.
carbinol (CH2OH) unit,7 which may result in pronounced
biological as well as physical and chemical effects.1c−f
Methodologies for electrophilic8 (and, to a lesser extent,
radical9) difluoromethylation of aryl thiolates have been studied
comprehensively, but there is only one example, developed by
Goossen using nucleophilic difluoromethylating reagents, in
which stoichiometric copper is required.10 Thus, the further
exploration of transition-metal-free methods for the synthesis of
ArSCF2H using nucleophilic CF2H sources is still desirable.
Herein, we have disclosed the first example of a one-pot
formation of ArSCF2H using α,α-difluorodibenzoylmethane as
a nucleophilic CF2H source via a base-induced C−C cleavage
reaction under transition-metal-free conditions (Figure 1).
Initially, we started the investigation by selecting the reaction
of α,α-difluorodibenzoylmethane 2a with di-p-tolyl disulfide 3a
as the model reaction. During the screening of reaction
conditions (Table S1, Supporting Information), we found both
2,2-difluoro-1-phenyl-2-(p-tolylthio)ethanone 4a and (difluoro-
methyl)(p-tolyl)sulfane 5a could be afforded with high
selectivity by controlling the temperature. With the optimized
conditions in hand, a series of diaryl disulfides were applied to
establish the scope and generality of this protocol (Scheme 1).
On the other hand, α-thioaryl-α, α-difluoroacetophenones
(Ar1COCF2SAr) have great potential to be transformed into
difluoromethylthiolated arenes (ArSCF2H) via the Haller−
Bauer reactions.6 ArSCF2H is of particular interest, since the
CF2H moiety not only can act as a hydrogen donor through
hydrogen bonding but also can be isosteric and isopolar to a
Received: December 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Scheme 1. Synthesis of 4 from 2 and 3
Scheme 2. Synthesis of 5 from 2a and 3
a
Method A: 2 0.250 mmol, 3 0.150 mmol, Cs2CO3 0.750 mmol,
b
c
DMSO 1 mL, 80 °C, 12 h, air. Isolated yields of 5. The yield was
determined by GC-MS, and only 19F NMR spectroscopy was available.
d
e
The corresponding thiols instead of disulfides were used. No
f
reaction. Method B: [step I] 2 0.250 mmol, 3 0.150 mmol, Cs2CO3
0.750 mmol, toluene 110 °C, 12 h, air; [step II] KOH 1.25 mmol,
H2O 2.75 mmol, 100 °C, 7 h.
a
b
Isolated yields of 4. The corresponding thiols instead of disulfides
c
were used. Reaction conditions: α,α-difluorodibenzoylmethane 2
0.250 mmol, diaryl disulfide 3 0.250 mmol, Cs2CO3 0.750 mmol,
toluene 1 mL, 110 °C, 12 h, air. The amount of Cs2CO3 is 1.0 equiv.
This reaction was also applicable to heteroarene disulfides (5m,
5n) and diphenyldiselenide (5o). However, no reaction took
place using a disulfide containing a nitro group in the 2 or 4
position of the benzene ring, so another useful strategy was
explored to prepare 5i and 5j through one-pot, two-step
reactions (method B). In some cases, the resulting difluoro-
methylthiolated arenes are volatile (5a−5c, 5m, 5o), which are
only characterized by 19F NMR spectroscopy and MS. The use
of thiols in place of disulfides proved to be also feasible in the
transformation (5g, 5k, 5l, 5n). Remarkably, a disubstituted
product 5p was formed when (2-mercaptophenyl)methanol
was employed, indicating the oxo(phenyl)methylium might be
also utilized by adding a nucleophile.
d
Most diaryl disulfides which have electron-donating and
-withdrawing groups could react with 2a to give the
corresponding adducts in moderate to excellent yields (4a−
4h). However, the diaryl disulfides bearing a nitro group
showed low activities in this reaction due to its strong electron-
withdrawing ability (4i−4k). To further improve the poor
yields of 4i−4k, the reactions were performed in water-
insoluble solvent, in which the hydrolysis of 3i−3k might be
inhibited even under heating conditions.11
Not surprisingly, the moderate yields of 4i−4k were
provided in toluene under reflux conditions. Diheteroaryl
disulfides were also applied in the reaction successfully with
satisfactory results (4l, 4m). It was worth noting that only 1.0
equiv of Cs2CO3 was required when 2,2′-dithiodipyridine was
treated with 1a for the basic nature of pyridine (4l). An
intramolecular cyclocondensation was derived from the treat-
ment of 2,2′-diaminodiphenyl disulfide with 1a through the
subsequent Schiff base reaction to provide a cycloproduct (4n).
In addition, the 1,2-diphenyldiselane could also provide the
desired product under identical conditions (4o). The
corresponding thiols instead of disulfides were also applied in
the reaction with satisfactory yields (4a, 4b, 4d, 4h). However,
the dialkyl disulfides failed to undergo this reaction. In order to
study the scope of 2, we used aryl substituted α,α-difluoro-
diaroylmethane to react with 3a, affording the desired products
in good yields as well (4p−4u).
Furthermore, the versatile synthetic utility of the difluoro-
methylarylsulfanes was studied (Scheme 3). We prepared 6a by
simple oxidation of 5h with m-chloroperbenzoic acid, which
Scheme 3. Transformations of Difluoromethylthiolated
Arenes
Likewise, we used the optimized reaction conditions to
explore the substrate scope of this new strategy for the
preparation of difluoromethylthiolated arenes (Scheme 2).
Both electron-rich and -deficient diaryl disulfides provided the
corresponding products in good to excellent yields (5a−5l).
B
DOI: 10.1021/acs.orglett.5b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
proved to have strong herbicidal activities.12 The method for
the synthesis of 6b and 6c was also found, and 6c was a crucial
intermidiate for the formation of 6e which was a selective
herbicide for rice.13 In addition, a selective oxidation of 5h was
disclosed using selectfluor as the oxidizing reagent to generate
6d as the only product.
α-Thioaryl-α-monofluoroketones, a potentially important
block for a variety of biologically and synthetically interested
SCF2H-containing compounds,14 were generally prepared by
the fluorination of sulfides under extremely strict conditions
with special fluorination reagents.15 Delightedly, our developed
protocol was also efficient for the construction of α-thioaryl-α-
monofluoroketones with α-monofluorodibenzoyl-methane
using DBU or DABCO as the base in toluene (Scheme 4).
process with high yields. In most cases, no obvious influence
was found on the yields of 4a or 5a using nucleophiles in the
transformations. However, a slight lower yield of 4a was noted
when morpholine was added in the reaction of 2a and 3a at 40
°C (entry 2).
The method may be a potential route to utilize the aroyl
cation which used to be a waste during the reaction.
Meanwhile, the formation of corresponding acetophenone
derivatives 9 in the reaction can demonstrate the existence of
decarbonylation processes in the reaction. A small amount of
water proves to be beneficial for the reaction (entries 4 vs 5),
because water can promote the process of decarbonylation to
form aromatic carboxylates (much higher polarity than
products) under basic conditions, which can facilitate the
workup procedure.
To further probe the mechanism, several control experiments
were designed and investigated (Scheme 5). Under the
Scheme 4. Reactions of 7 with 3 To Give α-Thioaryl-α-
monofluoroketones 8
a
Scheme 5. Mechanistic Studies and Control Experiments
a
b
Isolated yields of 8. DABCO instead of DBU was used.
assumption that this reaction involved a free radical pathway,
we chose TEMPO as the radical scavenger to trap the radical
generated in this reaction. The reaction proceeds smoothly to
give the corresponding product 4a without significantly
affecting the efficiency, indicating that the free radical pathway
is not involved in this transformation (eq 1). It has been
reported that thiols can be oxidized to disulfide medicated by
DMSO.16 We hypothesize that a possible dimerization pathway
of benzenethiol formed after the attack of diaryl disulfide by
α,α-difluoroenolates was operative to regenerate disulfide in
DMSO, since 0.5 equiv of diaryl disulfide is enough to undergo
this reaction.
Nevertheless, the synthesis of 4 and 5 from 2 must undergo
debenzoylation, which resulted in very poor atom economy
since the reaction generated 1 or 2 equiv of an aromatic acid.
Therefore, encouraged by the result of 5p, initial attempts were
made to eliminate the issue (Table 1). The results indicated the
benzoyl cation derived from 2a can react with different
nucleophiles to afford the desired products 9 in a one-pot
Table 1. Transformations of 2a, 3a, and Nucleophiles
Thus, we treated benzenethiol with standard reaction
conditions, which showed that benzenethiol could be oxidized
to disulfide 3a in DMSO (eq 2). The reaction is inhibited in a
N2 atmosphere, indicating that air may promote the oxidation
of diaryl disulfide and benzenethiolate (eq 3).17 Based on these
results, we proposed a plausible mechanism for this reaction
shown in Figure 2. Initially, the α,α-difluorodibenzoylmethane
2a is attacked by Cs2CO3 to form α,α-difluoroenolate
intermediate 11, which reacts with disulfide 3 subsequently to
generate product 4 and benzenethiolate 12. The product 4 is
finally transformed into difluoromethylthiolated arene 5
through the base-induced Haller−Bauer reaction while the
benzenethiolate 12 is oxidized to a disulfide and merged into
the reaction cycle.
ab
,
bc
,
entry
NuH
NH3
yield (4a/9, %)
yield (5a/9, %)
d
1
2
3
4
5
75/80 (9a)
64/91 (9b)
79/86 (9c)
81
98 /87 (9a)
d
morpholine
97 /93 (9b)
d
benzyl alcohol
99 /95 (9c)
e
d
H2O
99
f
d
none
59
trace
a
Conditions: 2a 0.250 mmol, 3a 0.250 mmol, NuH 0.300 mmol (NH3
0.750 mmol), Cs2CO3 0.500 mmol, DMSO 1 mL, 40 °C, 12 h, air.
Isolated yields. Conditions: 2a 0.250 mmol, 3a 0.150 mmol, NuH
0.600 mmol (NH3 1.50 mmol), Cs2CO3 0.750 mmol, DMSO 1 mL, 80
b
c
In summary, we have developed a transition-metal-free
protocol to afford the α-thioaryl-α,α-difluoroacetophenones
and difluoromethylthiolated arenes from α,α-difluorodibenzoyl-
methane. The broad scope of diaryl disulfides and further
d
e
°C, 12 h, air. The yield was determined by GC-MS. 3 equiv of H2O
f
were added in dry DMSO. Dry DMSO.
C
DOI: 10.1021/acs.orglett.5b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011,
133, 5802. (b) John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163.
(c) Zhang, P.; Wolf, C. J. Org. Chem. 2012, 77, 8840.
(5) Stavber, G.; Stavber, S. Adv. Synth. Catal. 2010, 352, 2838.
(6) Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983.
(7) (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882.
(b) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863. (c) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995,
60, 1626. (d) Ojima, I. Fluorine in Medicinal Chemistry and Chemical
Biology; Blackwell: Oxford, 2009. (e) Zhu, D.; Gu, Y.; Lu, L.; Shen, Q.
J. Am. Chem. Soc. 2015, 137, 10547. (f) Wu, J.; Gu, Y.; Leng, X.; Shen,
Q. Angew. Chem., Int. Ed. 2015, 54, 7648.
(8) (a) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009, 11, 2109.
(b) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.; Olah, G. A. J.
Fluorine Chem. 2011, 132, 792. (c) Langlois, B. R. J. Fluorine Chem.
1988, 41, 247. (d) Van Poucke, R.; Pollet, R.; De Cat, A. Tetrahedron
Lett. 1965, 6, 403. (e) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15,
5036. (f) Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Tetrahedron 2009, 65,
5278. (g) Thomoson, C. S.; Dolbier, W. R. J. Org. Chem. 2013, 78,
8904.
Figure 2. A proposed mechanism for the synthesis of 4 and 5 from
α,α-difluoro-dibenzoylmethane 2a.
applications of these products are demonstrated. The
seclectivity between α-thioaryl-α,α-difluoroacetophenones and
difluoromethylthiolated arenes can be controlled by temper-
ature. This method has been successfully extended for the
synthesis of α-thioaryl-α-monofluoroacetophenones using α-
monofluorobenzoylmethane. In addition, nucleophiles can react
with the benzoyl cation in the protocol with high yields without
inhibiting the fluoridations. Further investigations to apply α-
fluorodibenzoylmethane for other processes are currently
underway.
(9) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon,
D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc.
2012, 134, 1494.
(10) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J. Angew.
Chem., Int. Ed. 2015, 54, 5753.
(11) Ge, S.; Chaładaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136,
4149.
(12) Karabanov, Y. V.; Borisenko, V. P.; Gandel’sman, L. Z.;
Abramova, K. A.; Sedova, L. N.; Gridasova, V. I.; Akkerman, V. P.;
Dombrovskaya, I. Fiziologicheski Aktivnye Veshchestva 1976, 8, 61.
(13) Aya, M.; Fukazawa, N.; Kamochi, S. Jpn. Pat. 50076234A, 1975.
(14) (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 48, 7465.
(b) Karagas, M. R.; Cushing, G. L.; Greenberg, E. R.; Mott, L. A.;
Spencer, S. K.; Nierenberg, D. W. Br. J. Cancer 2001, 85, 683.
(15) Ayuba, S.; Yoneda, N.; Fukuhara, T.; Hara, S. Bull. Chem. Soc.
Jpn. 2002, 75, 1597.
(16) (a) Yiannios, C. N.; Karabinos, J. V. J. Org. Chem. 1963, 28,
3246. (b) Wallace, T. J. J. Am. Chem. Soc. 1964, 86, 2018. (c) Zhang,
C.; McClure, J.; Chou, C. J. J. Org. Chem. 2015, 80, 4919. (d) Yang, Y.;
Dong, W.; Guo, Y.; Rioux, R. M. Green Chem. 2013, 15, 3170. (e) Yan,
S.-Y.; Liu, Y.-J.; Liu, B.; Liu, Y.-H.; Shi, B.-F. Chem. Commun. 2015, 51,
4069.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03654.
■
S
Experimental details; copies of H, 13C, and 19F NMR
spectra of all products (PDF)
1
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yiwb@njust.edu.cn.
*E-mail: glu@njust.edu.cn.
Notes
(17) Taniguchi, N. Tetrahedron 2009, 65, 2782.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Fundamental Research Funds
for the Central Universities (30920140122003), Natural
Science Foundation of China (21402093, 21476116) and
Jiangsu (BK20140776, BK20141394), Chinese Postdoctoral
Science Foundation (2015M571761), and the Center for
Advanced Materials and Technology in Nanjing University of
Science and Technology for financial support.
REFERENCES
(1) (a) Burkholder, C. R.; Dolbier, W. R., Jr; Med
Fluorine Chem. 2000, 102, 369. (b) Burkholder, C.; Dolbier, W. R., Jr;
■
́
ebielle, M. J.
́
Medebielle, M.; Ait-Mohand, S. Tetrahedron Lett. 2001, 42, 3459.
(c) Shimizu, K. Jpn. J. Antibiot. 1988, 12, 1809. (d) Ito, M.; Ishigami,
T. Infection 1991, 19, S253. (e) Fourie, J. J.; Horak, I. G.; de la Puente
Redondo, V. Vet. Rec. 2010, 167, 442. (f) Yoshimura, T.; Nakatani, M.;
Asakura, S.; Hanai, R.; Hiraoka, M.; Kuwahara, S. J. Pestic. Sci. 2011,
36, 212.
́
(2) Gouault, S.; Guerin, C.; Lemoucheux, L.; Lequeux, T.; Pommelet,
J.-C. Tetrahedron Lett. 2003, 44, 5061.
(3) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. J. Fluorine Chem.
2005, 126, 527.
D
DOI: 10.1021/acs.orglett.5b03654
Org. Lett. XXXX, XXX, XXX−XXX