Highly selective pd-catalyzed intermolecular fluorosulfonylation of styrenes

Article abstract of DOI:10.1021/ja5131676

A novel Pd-catalyzed intermolecular regio- and diastereoselective fluorosulfonylation of styrenes has been developed under mild conditions. This reaction exhibits a wide range of functional-group tolerance in styrenes and arylsulfinic acids to afford various β-fluoro sulfones. Preliminary mechanistic study reveals an unusual mechanism, in which a high-valent L₂Pd^IIIF species side-selectively reacts with a benzylic carbon radical to deliver a C-F bond. This pathway is distinct from a previously reported radical fluorination reaction.

Full text of DOI:10.1021/ja5131676

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Highly Selective Pd-Catalyzed Intermolecular Fluorosulfonylation of Styrenes
Zheliang Yuan, Hao-Yang Wang, Xin Mu, Pinhong Chen, Yin-long Guo, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Feb 2015
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Highly Selective Pd-Catalyzed Intermolecular Fluorosulfonylation of
Styrenes
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Zheliang Yuan, HaoꢀYang Wang, Xin Mu, Pinhong Chen, YinꢀLong Guo and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry and National Center for Organic Mass Spectrometry in Shanghai,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, China, 200032
Supporting Information
Scheme 1. Metalꢀcatalyzed Radical Fluorination of Alkenes.
ABSTRACT: A novel palladiumꢀcatalyzed intermolecular regioꢀ
and diastereoselective fluorosulfonylation of styrenes has been
developed under mild conditions. This reaction exhibits a wide
range of functionalꢀgroup tolerance in styrenes as well as
arylsulfinic acids to afford various βꢀfluoro sulfones. Preliminary
mechanistic study reveals an unusual mechanism, in which a
III
highꢀvalent L Pd F species sideꢀselectively reacts with benzylic
2
carbon radical to deliver CꢀF bond. This pathway is distinct from
previously reported radical fluorination reaction.
As basic structural moieties, sulfones are widely existed in
1
bioactive natural products and pharmaceuticals. Representative
compounds, such as Eletriptan and [2H]ꢀSBꢀ3CT, have been used
for treatment of migraine headaches, or as a potent nonꢀselective
MMPꢀ2 and MMPꢀ9 inhibitor to inhibit human prostate cancer
2
growth. Therefore, efficient incorporation of sulfonyl group into
3
organic molecules has drawn much attention. Recently, the
with excellent regioꢀ and diastereoselectivity, in which a benzylic
carbon radical was involved for the CꢀF bond formation but not
via previous radical fluorination process.
flourishing organofluorine chemistry and its widespread
application in scientific research and industry have demanded
4
more synthetic approaches towards the CꢀF bond formation. We
With our continuing interest in transition metalꢀcatalyzed
speculated that, if both fluorine atom and sulfonyl group can be
simultaneously installed into the C=C bond, a variety of βꢀ
fluorinated sulfones could be easily accessed from simple alkenes.
Recently, radical fluorination has been explored to achieve the
9
difunctionalization of alkenes containing fluorination, we
recently reported a Pdꢀcatalyzed intermolecular fluoroamination
10
and fluoroesterification of styrenes. During the studies, when
CF CO H was replaced by phenylsulfinic acid as an additive
3
2
5
efficient fluorination of alkanes. This strategy was also applied
10b
under standard condition with [Pd(O CCF ) /L1], the reaction
2
3 2
6
for the difunctionalization of alkenes (Scheme 1a). For instance,
afforded fluoroamination product 3a in low yield (entry 1 in Table
). However, when ligand L1 was switched to electronꢀrich
Li and coworkers disclosed a powerful silver catalytic system for
the efficient fluorination of unactivated alkenes by using
1
phenanthroline (Phen) and L2, the reaction gave a major
fluorosulfonylation product 4a with an opposite regioselectivity as
6
aꢀb
SelectFluor as fluorine atom donor.
Zhang and coworkers
reported a Cuꢀcatalyzed aminofluorination of styrenes using NFSI
3
a (entries 2ꢀ3). Different with previous fluoropalladation
6
c
as both fluorine and nitrogen source. With respect to the radical
fluorination process, hydrofluorination of alkenes with Fe and Co
10
pathway, we believed that the opposite regioselectivity might be
stemed from the property of ArSO H, which can be easily
2
7
a
7b
catalyst were developed by Boger and Hiroya respectively. All
of these reactions exhibited excellent regioselectivity, however,
poor diastereoselectivity was obtained due to the nature of carbon
radical intermediate. To overcome these limitations, we
hypothesized that, if carbon radical could sideꢀselectively react
oxidized to give active ArSO2 radical species, resulting rapid
addition to styrenes.
Further screening of palladium catalysts revealed that other
Pd(II) catalysts, such as Pd(OAc) , PdCl and Pd(acac) , gave
2
2
2
comparable or worse yields than Pd(O CCF ) (entries 4ꢀ6).
2
3 2
with
a highꢀvalent metal fluoride complex, the highly
However, cationic palladium catalysts, such as [Pd(CH CN) ]X
2
3
4
diastereoselective fluorination might be expected. Recently,
(
X = BF and OTf), were more reactive to afford product 4a in
4
V
Groves demonstrated that the highꢀvalent (TMP)Mn F species
good yields, and formation of the side product 3a was completely
inhibited (entries 7ꢀ8). Encouraged by these results, more
bidentate nitrogenꢀcontaining ligands were tested, and
phenanthroline type ligands L3 and L4 exhibited a slightly better
can react with alkyl radical to generate CꢀF bond with good
8
diastereoselectivity (around 10:1). Herein, we reported the first
intermolecular antiꢀspecific fluorosulfonylation of styrenes using
palladium catalyst to deliver vicinal Fꢀsubstituted sulfones
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a
reactivity (entries 9ꢀ10). However, steric hindered ligands L5-L6
Table 2. Substrate Scope.
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bearing orthoꢀmethyl group were ineffective (entries 11ꢀ12).
Compared with dioxane, reaction carried out in THF provided a
better reproducible result (entry 13). Finally, no reaction ocurred
in the absence of palladium catalyst or ligand (entries 14ꢀ15).
Notably, the reaction also afforded small amount of side products
PhSO F and
β
ꢀsulfonylstyrene.
2
a
Table 1. Optimization of the Reaction Condition.
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a
Table 3. The Fluorosulfonylation of Internal Alkenes.
With the optimized condition in hand, the scope of sulfinic
acids was investigated. As shown in Table 2, gratifyingly, a series
of arylsulfinic acids bearing both electronꢀdonating groups (R =
t
Bu, Me) and electronꢀwithdrawing groups (R = F, Cl, Br, NO2)
were compatible to the reaction condition providing the desired
products 4b-4g in satisfactory yields. However, electronꢀrich
arylsulfinic acid presented higher reactivity than electronꢀpoor
substrates. Moreover, 2ꢀnaphthylsulfinic acid was also effective to
give the corresponding product 4h (64%). Additionally,
thiophenyl sulfinic acid (for 4i) and aliphatic sulfinic acid (for 4j)
were also suitable for this reaction. Unfortunately, combination of
CF SO Na and HOAc failed to generate product 4k. Subsequently,
3
2
a range of styrenes were surveyed under standard reaction
condition. Both electronꢀrich and electronꢀpoor styrenes were
viable to produce 4l-5b in good yields. Most importantly, a series
of functional groups, such as halides, ester, aldehyde, ketone,
amide, nitrile, nitro, and CF , were compatible for the reaction
3
condition. Notably, the allyl group in styrene also survived to give
product 4y in 62% yield. Finally, 1,1ꢀdisubstituted styrenes were
also tested, and these substrates had moderate reactivity to give
desired products 5c-5d in satisfactory yields. However,
unactivated substrate 1ꢀoctene was ineffective, and only trace
amount of the desired product was detected.
Next, we turned our attention to more challenging internal
alkenes. Eꢀ and Zꢀ(β)ꢀ methyl styrenes were initially surveyed and
both reactions proceeded smoothly to give antiꢀspecific
fluorosulfonylation product 5e in good yields with excellent
diastereoselectivity, which is obviously distinct from previous
11
radical fluorination. Furthermore, similar results were obtained
in the reactions of Eꢀ and Zꢀcinnamyl alcohol to deliver product
antiꢀ5f efficiently with an intact hydroxyl group. In addition,
cinnamyl alcohol, acetate and imide were also suitable to react
with various sulfinic acids to produce antiꢀ5gꢀ5j in good yields. In
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contrast, electronꢀdeficient cinnamyl ester was ineffective toward
the fluorosulfonylation reaction. Furthermore, the reaction with
O . In fact, the fluorosulfonylation of styrene under aerobic
condition did afford product 10b in 57% yield, combined with
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homoallylic alcohol and homoallylic ketone also provided antiꢀ5l
and antiꢀ5m in moderate yields with excellent d.r. ratio. Finally,
the cyclic alkene substrates were studied, and we are delighted to
find that the desired products antiꢀ5n and antiꢀ5o could be
synthesized efficiently with high diastereoselectivity in
satisfactory yields. The configurations of products 5e and 5n were
only trace amount of product 10a (eq 4), which argues against this
possibility. In addition, the classic free radical fluorination
process generally exhibits a poor diastereoselectivity (range from
6,7
1
:1 to 4:1). The excellent d.r. ratio in current reaction also ruled
out the possibility of the radical fluorination pathway.
12
confirmed by single crystal Xꢀray crystallography.
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As mentioned above, single isomers antiꢀ5e and antiꢀ5f were
obtained from the reactions of Zꢀ and Eꢀstyrenes (Table 3), which
reveals the reaction should involve a benzylic radical or carbon
cation intermediate. To test the possibility of radical intermediate,
compound 6 was introduced to the standard reaction condition as
In order to gain further insights on the mechanism, the
catalytic reaction was monitored by ESIꢀMS spectroscopy. We are
delighted to find that two signals at m/z 289 and 446.5,
2
+
corresponding
[(L4) Pd(F)N(SO
reaction rate was highly dependent on the ratio of L4 and Pd
to
the
mass
] , were detected.
2
of
[(L4)
Furthermore, the
Pd]
and
2
2
+
12
a
radical scavenger. The fluorosulfonylation reaction was
2
Ph)
2
significantly suppressed. Instead, sulfonyloxygenation product 7
was obtained as major product in 65% yield (eq 1). In addition,
when the radical clock substrate 8 was treated under standard
reaction condition, the cyclopropyl group was completely opened
to give product 9 (eq 2). These observations implied that the
reaction could involve a benzylic radical species. Based on above
analysis, there are three scenarios to address the final CꢀF bond
formation (Scheme 2): (1) a radical pathway involving a carbon
2
+
catalyst (range from 1:1 to 4:1). In addition, [(L4) Pd] (OTf)
2 2
13
was also an efficient catalyst, and the reaction gave the identical
rate with the catalyst of Pd:L4 = 1:2 (Figure 1, left). Thus, we
2+
believed that cationic [(L4) Pd] should be the catalytically
2
active species, thus Pd catalysts having coordinative Xꢀtype
ligands (OAc, Cl) may impede the formation of such active
species, meanwhile L5-L6 bearing orthoꢀmethyl group also
+
2+
radical to attack F reagent NFSI (path a); (2) a highꢀvalent
prevent the formation of bisꢀbidentate Pd species [(L) Pd] .
2
palladium fluoride involved as the electrophilic fluorine reagent to
react with benzylic radical (path b); (3) a benzylic carbon cation
1
00
60
50
ꢀ
involved as key species to react with F to give CꢀF bond (path c).
80
60
40
4
0
0
3
20
20
0
1
0
Scheme 2. The possible mechanism for CꢀF bond formation.
0
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
Reaction Time (min)
Reaction Time (min)
In order to differentiate these three possibilities, the
electronic effect of styrenes was further evaluated under standard
condition. A much small Hammett ρꢀvalue ꢀ0.029 (see the SI) was
observed, which implied that the carbon cation pathway (path c) is
less likely.
[Pd] : L4 = 2:2
[Pd] : L4 = 2:3
[Pd] : L4 = 2:6
[Pd] : L4 = 2:8
[(L4) Pd](BF )
4 2
ArSO2H (1 eq.)
ArSO2H (2 eq.)
ArSO2H (3 eq.)
ArSO2H (4 eq.)
[Pd] : L4 = 2:4
2
Figure 1. The effect on the reaction of 1n and ArSO
H (Ar =
BuC H ): Left, L4/[Pd] ratio effect, [Pd] = [Pd(CH CN) ] (BF )
4 2
2
t
Lei and coworkers recently proved that a benzylic radical
6
4
3
4
(2 mol %), L4 (2ꢀ8 mol%); Right, [ArSO H] effect.
2
intermediate can be trapped by dioxygen to provide
hydroxysulfones (eq 3). We hypothesized that, if the radical
βꢀ
3a
Further kinetic studies exhibited a first order dependence on
fluorination process was responsible for the CꢀF bond formation
2
+
the concentration of [(L4) Pd] (OTf) and NFSI, and zeroth
5
2
2
in current transformation (path a), addition of extraneous NFSI to
1
2
order dependence on the styrene (see the SI). Surprisingly, the
reaction rate was inverse dependence on the concentration of
arylsulfinic acid (Figure 1, right). NMR studies clarified that
(L4) Pd] (OTf) catalyst could convert to ineffective
2 2
(L4)Pd(SO Ar) ] (n = 1 or 2) species and release ligand L4 in the
Lei’s reaction should also afford the fluorosulfonylation product.
However, the reaction only afforded oxygenation product 10a, but
without fluorination product 10b (eq 3). This result addressed that
either path a is not involved, or trapping of benzylic radical by O2
is much faster than NFSI. If the latter is true, the
fluorosulfonylation reaction should be inhibited in the presence of
2+
[
[
2
n
presence of ArSO H, but could be further regenerated in the
2
presence of excess amount of ligand L4 (see the SI). These
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observations implied that the sulfonylpalladation of styrenes
should not be involved in the catalytic cycle.
ACKNOWLEDGMENT
We are grateful for financial support from 973 program (No.
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Based on above analysis, the proposed mechanism was
illustrated in Scheme 3: the initial oxidation of cationic
2
011CB808700), NSFC (Nos. 21225210, 21202185, 21421091
and 21121062) and the CAS/SAFEA International Partnership
Program for Creative Research Teams.
2
+
2+
[
(L4) Pd] by NFSI provided [(L4) Pd(F)N(SO Ph) ] , which
2 2 2 2
could react with arylsulfinic acid via a SET process to generate
III
14,15
REFERENCES
ArSO radical and (L4) Pd F species.
The former could react
2
2
with styrene to give benzylic radical species, which directly attack
III
Pd F complex to give the fluorination product (dash line).
III
Alternatively, the benzylic radical could also be trapped by Pd F
IV
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complex to give alkylꢀPd F species, which undergoes direct
reductive elimination to form CꢀF bond selectively (plain cycle).
The first order on the [Pd] and NFSI revealed that the oxidation of
palladium catalyst occurs as turnꢀover limiting step. For the CꢀF
bond forming step, it is difficult to differentiate above two
possible mechanisms at this stage. Compared to good
(1) a) Fromtling, R. A. Drugs. Future. 1989, 14, 1165. b) Oida, S.;
Tajiam, Y.; Konosu, T.; Nakamura, Y.; Somada, A.; Tanaka, T.; Habuki,
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Pharm. Bull. 2000, 48, 694.
(
2) a) Willems, E.; Vries, P. De; Heiligers, J. P. C.; Saxena, P. R.
Naunyn Schmiedeberg's Arch. Pharmacol. 1998, 358, 212. b) Lee, M.;
Ikejiri, M.; Klimpel, D.; Toth, M.; Espahbodi, M.; Hesek, D.; Forbes, C.;
Kumarasiri, M.; Noll, B. C.; Chang, M.; Mobashery, S. ACS Med. Chem.
Lett. 2012, 3, 490.
V
diastereoselectivity (d.r. ~10:1) from highꢀvalent (TMP)Mn F
8
species, Governeur recently demonstrated that
a tandem
stereospecific cisꢀhydropalladation and direct reductive
(3) For some recent examples, see: a) Liu, Q.; Zhang, J.; Wei, F.; Qi, Y.;
IV
elimination of Pd (F)R complex for hydrofluorination of styrenes
Wang, H.; Liu, Z.; Lei, A. Angew Chem., Int. Ed. 2013, 52, 7156. b) Liu,
Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A. J. Am. Chem.
Soc. 2013, 135, 11481. c) Shen, T.; Yuan, Y.; Song, S.; Jiao, N. Chem.
Commun. 2014, 50, 4115. d) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu,
W.; Jiang, H. Angew Chem., Int. Ed. 2014, 53, 4205.
16,17
could dilever excellent diastereoselectivity (d.r. >20:1).
Thus,
we though the current fluorosulfonylation reaction is more likely
IV
to involve
a
(L4) Pd (F)R species for highly selective
2
III
fluorination, and the bezylic radical is possibly trapped by Pd
species on the opposite side of sulfonyl group with high
selectivity due to the steric hindrance of ligand L4.
(
4 ) a) Hiyama, T. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000. (7). b) Ojima, I. Fluorine in Medical
Chemistry and Chemical Biology; WileyꢀBlackwell, U.K., 2009.
(
5) For radical fluorination process, see: a) Sibi, M. P.; Landais, Y.;
Angew. Chem. Int. Ed. 2013, 52, 3570. b) Xia, J.ꢀB.; Zhu, C.; Chen, C. J.
Am. Chem. Soc. 2013, 135, 17494. c) RuedaꢀBecerril, M.; Sazepin, C. C.;
Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J.ꢀF.; Sammis, G.
M. J. Am. Chem. Soc. 2012, 134, 4026. d) Bloom, S.; Pitts, C. R.; Miller,
D. C.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem.
Int. Ed. 2012, 51, 10580.
Scheme 3. Proposed Mechanism.
(6) a) Zhang, C.; Li, Z.; Zhu, L.; Yu, L.; Wang, Z.; Li, C. J. Am. Chem.
Soc. 2013, 135, 14082. b) Li, Z.; Song, L.; Li, C.; J. Am. Chem. Soc. 2013,
1
35, 4640. c) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.; Zhang, Q. Angew.
Chem. Int. Ed. 2014, 53, 11079.
7) a) Baker, T. J.; Boger, D. L.; J. Am. Chem. Soc. 2012, 134, 13588. b)
Shigehisa, H.; Nishi, E.; Fujisawa, M.; Hiroya, K. Org. Lett. 2013, 15,
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8) a) Liu, W.; Huang, X.; Cheng, M.ꢀJ.; Nielsen, R. J.; Goddard III, W.
(
5
(
A.; Groves, J. T. Science 2012, 337, 1322. b) Huang, X.; Liu, W.; Ren, H.;
Neelamegam, R.; Hooker, J. M.; Groves, J. T. J. Am. Chem.
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In conclusion, we have developed a Pdꢀcatalyzed antiꢀselective
intermolecular fluorosulfonylation of styrenes. The reaction
exhibits excellent regioꢀ and diasteroselectivity to provide various
vicinal fluorinated sulfone products. Preliminary mechanistic
study reveals that the radical species is involved, but significantly
different with previous radical fluorination process. Instead, the
(10) a) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.ꢀL.; Liu, G. J. Am. Chem. Soc.
2
010, 132, 2856. b) Peng, H.; Yuan, Z.; Wang, H.ꢀY.; Guo, Y.ꢀL.; Liu, G.
Chem. Sci. 2013, 4, 3172.
11) For the internal substrates, ligand L4 provided a better yield than
L3. For product 5e, 57% yield was given by L3, and 64% by L4.
(
(
(
12) See the Supporting Information (SI) for detail.
13 ) With [(L4) Pd] (OTf) (3 mol %) as catalyst, the reactions
2 2
III
sideꢀselectively combination of benzylic carbon radical with Pd
2+
IV
complex and the direct reductive elimination of L Pd (F)R
afforded product 4j in 80% yield, 5g in 65% yield (>20:1 d.r.) and 5h in
60% yield (>20:1 d.r.). For more detail, see the SI.
2
intermediate was proposed to address the high diastereoselectivity.
We envisioned that this unusual pathway may be operational in
other alkene difunctionalization reactions.
II
IV
III
2
(14) For the oxidation of L Pd by NFSI and from Pd to Pd via SET
process, see: a) Mazzotti, A. R.; Campbell, M. G.; Tang, P.; Murphy, J. M.;
Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012. b) Boursalian, G. B.; Ngai,
M.ꢀY.; Hojczyk, K. N.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 13278.
Supporting Information
2
(15) In this reaction, the ArSO radical is efficiently generated in the
Synthetic procedures, characterization and additional data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
presence of palladium catalyst. For more discussions, see the SI.
(16) Emer, E.; Pfeifer, L.; Brown, J. M.; Gouverneur, V. Angew. Chem.
Int. Ed. 2014, 53, 4181.
(17) For the evidence for selective reductive elimination of highꢀvalent
Corresponding Author
metal fluoride complexes, see: a) Zhao, S.ꢀB.; Becker, J. J.; Gagńe, M. R.
Organometallics 2011, 30, 6039. b) Mankad, N. P.; Toste, F. D. Chem. Sci.
gliu@mail.sioc.ac.cn
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012, 3, 72.
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