Radical (Phenylsulfonyl)difluoromethylation of Isocyanides with PhSO2CF2H under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.6b03013

An atom-economical method for radical (phenylsulfonyl)difluoromethylation of isocyanides with PhSO₂CF₂H under transition-metal-free conditions has been developed. A PhSO₂CF₂ radical is generated through the oxidation of PhSO₂CF₂^- after the deprotonation of PhSO₂CF₂H in one pot. The reaction exhibits excellent functional-group tolerance and the resulting products can be further modified with the removal of a PhSO₂ group to give other CF₂-containing compounds.

Full text of DOI:10.1021/acs.orglett.6b03013

Letter
pubs.acs.org/OrgLett
Radical (Phenylsulfonyl)difluoromethylation of Isocyanides with
PhSO2CF2H under Transition-Metal-Free Conditions
Pan Xiao,†,‡ Jian Rong,† Chuanfa Ni,† Junkai Guo,† Xinjin Li,† Dingben Chen,† and Jinbo Hu*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
S
* Supporting Information
ABSTRACT: An atom-economical method for radical (phenylsulfonyl)difluoromethylation of isocyanides with PhSO2CF2H
under transition-metal-free conditions has been developed. A PhSO2CF2 radical is generated through the oxidation of
−
PhSO2CF2 after the deprotonation of PhSO2CF2H in one pot. The reaction exhibits excellent functional-group tolerance and
the resulting products can be further modified with the removal of a PhSO2 group to give other CF2-containing compounds.
Scheme 1. (Phenylsulfonyl)difluoromethylation of Organic
Molecules with PhSO2CF2H
he phenanthridine core is an important substructure
Texisting in various natural products which possess a wide
range of biological activities and applications.1 Selective
introduction of fluorine-bearing motifs into organic molecules,
including the above-mentioned phenanthridine derivatives, may
effectively enhance the latters’ biological activity due to the
increased lipophilicity and metabolic stability.2 Therefore, it is
highly desirable to develop efficient methods for the
incorporation of fluorinated moieties into diverse organic
structures. Among various fluoroalkyl groups, the gem-
difluoroalkyl group has attracted particular interest, since the
CF2 moiety is known to be isosteric to the ethereal oxygen
atom.3 In this respect, the PhSO2CF2 group is appealing based
on the fact that it is a versatile functional group that can be
converted to other highly useful difluorinated moieties such as
difluoromethyl (−CF2H), difluoromethylene (−CF2−), and
difluoromethylidene (CF2) groups.4 Over the past decades,
nucleophilic (phenylsulfonyl)difluoromethylation of a variety of
electrophiles with PhSO2CF2H has proved to be a powerful
strategy for the synthesis of fluorinated compounds.5,6 For
example, α-difluoromethyl alcohols can be readily prepared by
nucleophilic difluoromethylation of carbonyl compounds with
its anion PhSO2CF2− (Scheme 1, eq 1).6 In addition, a method
for copper-mediated aerobic (phenylsulfonyl)difluoromethyl-
ation of arylboronic acids with PhSO2CF2H has been
developed that proceeds via the in situ generated PhSO2CF2Cu
species (Scheme 1, eq 2).7
there is no report on the direct radical fluoroalkylation with the
readily available PhSO2CF2H reagent.5c Considering that the
generation of PhSO2CF2 radical by the homolytic cleavage of
the F2C−H bond of PhSO2CF2H is a formidable challenge, we
envisioned that the radical could be generated through the
−
oxidation of PhSO2CF2 after the deprotonation of
PhSO2CF2H in one pot. We realized that the difficulty in this
chemistry lies in how to find suitable oxidants and strong bases
and how to make them well compatible in the same reaction
system. Recently, PhI(OAc)2-mediated radical fluoroalkylation
of arenes,12d unactivated alkenes12c,14 or isocyanides12e under
silver-mediated, -catalyzed or -free conditions has been
developed, which inspired us to develop an atom-economical
method for radical (phenylsulfonyl)difluoromethylation with
As very important reactive intermediates, fluoroalkyl radicals
have attracted much attention in recent years,8 and many
reagents, including the Langlois reagent,9 the Togni reagent,10
the Umemoto reagent,11 the Ruppert−Prakash reagent,12 and
fluoroalkyl halides,5c,13 have been used for the radical
fluoroalkylation. However, to the best of our knowledge,
Received: October 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03013
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Letter
PhSO2CF2H using PhI(OAc)2 as a mild oxidant under
transition-metal-free conditions (Scheme 1, eq 3).
At the onset of our investigation, isocyanide 1a was used as a
model substrate, LiHMDS/THF as a base, and PhI(OAc)2 as
an oxidant and DMF as solvent, respectively, for the radical
(phenylsulfonyl)difluoromethylation with PhSO2CF2H (Table
1, entry 1). We were pleased to find that the desired product 3a
PhI(OAc)2 and t-BuONa/DMF to 6.0 equiv and adding some
additives (Table 1, entries 11−20), which turned out to be
useful to inhibit the generation of side product 5 to some extent
(for details, see the SI). Furthermore, the addition of weak
bases could increase the conversion of PhSO2CF2H (Table 1,
entries 12−15 and 18−20), and the reaction could be further
promoted in the presence of I2 (Table 1, entries 17, 18, and
20). Finally, the optimal yield of 3a (78% yield) was obtained
when employing Cs2CO3 (1.0 equiv) as a base and I2 (0.2
equiv) as an additive (Table 1, entry 18).
a
Table 1. Optimization of Reaction Conditions
With the optimized reaction conditions in hand, we further
investigated the substrate scope of the current method and
found that a variety of isocyanides 1 could be transformed into
the corresponding products 3 in moderate to good yields
(Scheme 2). Both electron-withdrawing groups (3b−f) and
electron-donating groups (3g,h) on the para-position of the R2-
substituted phenyl ring were compatible under the reaction
b
entry
base
additive (1.0 equiv) temp (°C) 3a, yield (%)
Scheme 2. Radical (Phenylsulfonyl)difluoromethylation of
Isocyanides
a
1
2
3
4
LiHMDS
NaHMDS
t-BuOK
−50
−50
−50
−50
−50
−60
−40
−30
−10
rt
13
7
19
41
0
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
c
5
6
39
39
34
21
5
7
8
9
10
d
11
−50
−50
−50
−50
−50
−50
−50
−50
−50
−50
54
58
61
70
62
58
67
78
66
74
d
12
NaHCO3
Na2CO3
Cs2CO3
K3PO4
d
13
d
14
d
15
d
e
16
BQ
d
e
17
I2
d
e
e
18
Cs2CO3/I2
d
19
K3PO4/BQ
d
e
20
Na2CO3/I2
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (2.0 equiv),
PhI(OAc)2 (4.0 equiv), base (4.0 equiv), DMF (1.0 mL), Ar, 1 h.
b
Yields were determined by 19F NMR spectroscopy using PhCF3 as an
c
internal standard. t-BuONa (solid) and PhI(OAc)2 were mixed
together before the addition of 2. PhI(OAc)2 (6.0 equiv) and t-
BuONa/DMF (2.0 mol/L, 6.0 equiv) were used. 0.2 equiv of additive
d
e
was added.
was formed in 13% yield. Further optimization of the reaction
conditions showed that t-BuONa/DMF solution (2.0 M) gave
a higher yield than other bases (Table 1, entries 1−4). It was
noteworthy that no desired product 3a could be detected when
mixing t-BuONa (solid) and PhI(OAc)2 together before the
addition of 2 (Table 1, entry 5), indicating that charging
sequence is very important. The reaction was quite sensitive to
temperature, and the yield was gradually increased as the
temperature decreased; we found that −50 °C was the optimal
temperature for the reaction (Table 1, entries 4 and 6−10). At
the same time, we found that although the side product 4 can
be diminished at low temperatures, another side product 5 (via
homocoupling of the radical intermediate) was increasingly
formed (for details, see the Supporting Information). The yield
was further improved effectively by increasing the amount of
a
General conditions: isocyanides 1 (0.2 mmol), PhSO2CF2H (0.4
mmol), PhI(OAc)2 (1.2 mmol), t-BuONa/DMF (2.0 M, 0.6 mL),
Cs2CO3 (0.2 mmol) and I2 (0.04 mmol) in 1.3 mL of DMF at −50 to
b
−60 °C for 1 h. Isolated yields were given by column
c
chromatography on silica. Isolated yields were given by recrystalliza-
d
tion. Yields were determined by 19F NMR spectroscopy using PhCF3
e
as an internal standard. Yields were determined by 19F NMR
spectroscopy using PhOCF3 as an internal standard.
B
DOI: 10.1021/acs.orglett.6b03013
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conditions, with no significant influence on the yields of
products. In the case of R1-substituted isocyanides, the desired
products were obtained in slightly lower yields when the
substituents were on the meta- or para-positions (3i−n). Those
with two substituents in the same or different aromatic rings
gave good yields of products (3o−s). In addition to biphenyl
derivatives, those fused to other aryl (3t,u) and heteroaryl
(3v,w) moieties also worked well in the reaction, albeit
providing the products in moderate yields. Compared with 3h,
the 2-methyloxy-substituted isocyanide 1x was transformed to
product 3x in poor yield (12%), which might be because only
one reactive site was available on the aryl ring. It was
noteworthy that under optimized conditions the reaction can
be easily scaled up; for example, when 10 mmol of 1a (1.79 g)
was used, 54% of isolated yield of 3a (1.99 g) could be obtained
after repeated recrystallization.
Scheme 4. Plausible Reaction Mechanism
To gain more insights into this transition-metal-free radical
(phenylsufonyl)difluoromethylation reaction, we carried out
some control experiments. First, in the absence of isocyanide
1a, the homocoupling product PhSO2CF2CF2SO2Ph (5) was
formed in 11% yield, and a peak at −111.1 ppm was observed
in a crude sample by 19F NMR spectroscopy using PhCF3 as an
internal standard (Scheme 3, eq 1). Second, the inhibition
Scheme 3. Control Experiments
the absence of I2, which suggested that PhSO2CF2I might not
participate in the reaction. Therefore, we propose that the
iodide ion formed from the reaction between PhSO2CF2 anion
and I2 may serve as an additional initiator to promote the
generation of PhSO2CF2 radical from the hypervalent iodine
intermediate B (Scheme 4).
Based on the aforementioned results, a plausible reaction
mechanism is proposed in Scheme 4. After the deprotonation
of PhSO2CF2H, the hypervalent iodine intermediate B is
generated from PhSO2CF2 anion (A) and PhI(OAc)2. Single-
electron transfer (SET) from an initiator (such as the iodide
ion in situ produced from A and I2) to B gives PhSO2CF2
radical and thus initiates the reaction. Then the PhSO2CF2
radical adds to 1 to give the imidoyl radical D, which
subsequently undergoes intramolecular radical cyclization to
afford the radical intermediate E. Deprotonation of E by t-
BuO− provides radical anion F,10a,13b,16 which reacts with
intermediate B through a SET process to generate product 3
and to regenerate PhSO2CF2 radical. A secondary path that
involves the generation of PhSO2CF2 radical from PhSO2CF2I
is less likely due to the inhibition effect of PhSO2CF2I on the
reaction.
It was reported that the PhSO2 group in some fluoroalkyl
sulfones could be removed by the nucleophilic attack of
alkoxide or hydroxide, and the generated fluoroalkyl anions
were able to react with different electrophiles such as carbonyl
compounds and disulfides.6b,17 We assumed that a similar type
of S−C bond cleavage could occur with our products 3. As
expected, the transformation of PhSO2 group to PhS and PhSe
group was accomplished successfully (Scheme 5, eqs 1 and 2).
Furthermore, in the absence of other electrophiles, 3a could
react with another molecule of itself to give rise to a structurally
symmetrical product 4 (Scheme 5, eq 3), which is the side
product observed during our optimization of reaction
conditions (see Table 1 and the SI). The formation of 4
from 3a/t-BuOK/DMF is intriguing and needs further study to
understand its reaction mechanism.
experiment of 1a with TEMPO (2,2,6,6-tetramethyl-1-piper-
idinyloxy, 3.0 equiv), which is known as an efficient radical
scavenger, was conducted under the standard reaction
conditions, and the reaction was almost shut down (Scheme
3, eq 2). Similarly, when 3.0 equiv of 1,3-dinitrobenzene, which
easily undergoes one electron reduction,15 was added into the
standard reaction system, no desired product 3a could be
detected. Third, a large amount of PhI was obtained by column
chromatography on silica gel when the desired products were
isolated, indicating that PhI(OAc)2 was reduced. Fourthly, the
attempt to capture the protonated product (6) of the
intermediate G failed (Scheme 3, eq 3, and Scheme 4), thus
ruling out the path of the oxidation of G. These experiments
support the involvement of a PhSO2CF2 radical species in the
current fluoroalkylation reaction. Finally, we probed the role of
the additive I2 in this reaction. Because a trace amount of
PhSO2CF2I was detected after the completion of the reaction,
we initially thought that PhSO2CF2I could serve as a PhSO2CF2
radical source in this reaction and the formation of PhSO2CF2I
via iodination of PhSO2CF2 anion by I2 could improve the
generation of PhSO2CF2 radical. In fact, when I2 was replaced
by PhSO2CF2I (0.2 equiv), the consumption of the latter
resulted in a relatively low yield (53%), even lower than that in
C
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(f) Bernardo, P. H.; Wan, K.-F.; Sivaraman, T.; Xu, J.; Moore, F. K.;
Hung, A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem.
2008, 51, 6699. (g) Dubost, E.; Dumas, N.; Fossey, C.; Magnelli, R.;
Butt-Gueulle, S.; Ballandonne, C.; Caignard, D. H.; Dulin, F.; Santos, J.
S. d.-O.; Millet, P.; Charnay, Y.; Rault, S.; Cailly, T.; Fabis, F. J. Med.
Chem. 2012, 55, 9693.
Scheme 5. Transformation of PhSO2 Group to Other
Functionalities
(2) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(d) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(3) (a) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc.,
Perkin Trans. 1 1984, 1, 1119. (b) Berkowitz, D. B.; Bose, M. J. J.
Fluorine Chem. 2001, 112, 13. (c) O’Hagan, D.; Wang, Y.; Skibinski,
M.; Slawin, A. M. Z. Pure Appl. Chem. 2012, 84, 1587. (d) Kirsch,
P.Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications;
Wiley-VCH: Weinheim, 2013.
(4) (a) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68,
4457. (b) Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew.
Chem., Int. Ed. 2003, 42, 5216. (c) Prakash, G. K. S.; Hu, J.; Wang, Y.;
Olah, G. A. Org. Lett. 2004, 6, 4315. (d) Prakash, G. K. S.; Hu, J.;
Wang, Y.; Olah, G. A. Angew. Chem., Int. Ed. 2004, 43, 5203. (e) Ni,
C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273. (f) Surya Prakash, G. K.;
Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org. Chem. 2005, 2005, 2218.
(g) Zhu, J.; Wang, F.; Huang, W.; Zhao, Y.; Ye, W.; Hu, J. Synlett
2011, 2011, 899. (h) Li, X.; Zhao, J.; Hu, M.; Chen, D.; Ni, C.; Wang,
L.; Hu, J. Chem. Commun. 2016, 52, 3657.
(5) (a) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921.
(b) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (c) Hu,
J. J. Fluorine Chem. 2009, 130, 1130. (d) Ni, C.; Hu, J. Synlett 2011,
2011, 770.
(6) (a) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. (b) Prakash, G. K.
S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2003, 42,
5216. (c) Liu, J.; Ni, C.; Li, Y.; Zhang, L.; Wang, J.; Hu, J. Tetrahedron
Lett. 2006, 47, 6753.
In summary, we have developed an atom-economical method
for radical (phenylsulfonyl)difluoromethylation of isocyanides
with PhSO2CF2H reagent under transition-metal-free con-
ditions. This new strategy shows an unusual role of
PhSO2CF2H, from which a PhSO2CF2 radical is formed in
the presence of PhI(OAc)2. The reaction tolerates many
functional groups, and the transformation of PhSO2 group to
other groups mediated by t-BuOK is accomplished. Further
exploration of the synthetic applications of fluoroalkyl sulfones
is currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) Li, X.; Zhao, J.; Hu, M.; Chen, D.; Ni, C.; Wang, L.; Hu, J. Chem.
Commun. 2016, 52, 3657.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03013.
(8) (a) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (b) Koike,
T.; Akita, M. Top. Catal. 2014, 57, 967. (c) Alonso, C.; Martinez de
Marigorta, E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
(d) Belhomme, M. C.; Besset, T.; Poisson, T.; Pannecoucke, X. Chem.
- Eur. J. 2015, 21, 12836. (e) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem.
Rev. 2015, 115, 683. (f) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115,
765. (g) Ni, C.; Zhu, L.; Hu, J. Huaxue Xuebao 2015, 73, 90.
(h) Zhang, B.; Studer, A. Chem. Soc. Rev. 2015, 44, 3505.
(9) (a) Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Chem. Sci.
2013, 4, 3160. (b) Cui, L.; Matusaki, Y.; Tada, N.; Miura, T.; Uno, B.;
Itoh, A. Adv. Synth. Catal. 2013, 355, 2203.
Experimental procedures and characterization data for
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinbohu@sioc.ac.cn.
ORCID
(10) (a) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A.
̈
Jinbo Hu: 0000-0003-3537-0207
Notes
Angew. Chem., Int. Ed. 2013, 52, 10792. (b) Tomita, R.; Yasu, Y.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2014, 53, 7144.
(11) (a) Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012,
51, 9567. (b) Tomita, R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed.
2015, 54, 12923.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) (a) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464.
This work was supported by the National Basic Research
Program of China (2015CB931900), the National Natural
Science Foundation of China (21632009, 21372246, 21421002,
21472221), the Chinese Academy of Sciences, Shanghai
Academic Research Leader Program (15XD1504400), Shang-
hai Rising-Star Program (16QA1404600), and the Youth
Innovation Promotion Association CAS (2014231).
(b) Hafner, A.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 3713. (c) Wu,
̈
X.; Chu, L.; Qing, F.-L. Angew. Chem., Int. Ed. 2013, 52, 2198. (d) Seo,
S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2013, 49, 6385.
(e) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846.
(13) (a) Sun, X.; Yu, S. Org. Lett. 2014, 16, 2938. (b) Zhang, B.;
Studer, A. Org. Lett. 2014, 16, 3990. (c) Gu, J. W.; Min, Q. Q.; Yu, L.
C.; Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 12270.
(14) Ma, G.; Wan, W.; Li, J.; Hu, Q.; Jiang, H.; Zhu, S.; Wang, J.;
Hao, J. Chem. Commun. 2014, 50, 9749.
REFERENCES
■
(15) Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734.
(16) Rong, J.; Deng, L.; Tan, P.; Ni, C.; Gu, Y.; Hu, J. Angew. Chem.,
Int. Ed. 2016, 55, 2743.
(17) (a) Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5,
3253. (b) Li, X.; Zhao, J.; Zhang, L.; Hu, M.; Wang, L.; Hu, J. Org. Lett.
2015, 17, 298.
(1) (a) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223.
(b) Ishikawa, T. Med. Res. Rev. 2001, 21, 61. (c) Abdel-Halim, O. B.;
Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M. J. Nat. Prod.
2004, 67, 1119. (d) Zhu, S.; Ruchelman, A. L.; Zhou, N.; Liu, A. A.;
Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2005, 13, 6782. (e) Sripada,
L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6, 263.
D
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