Photoinduced, copper-catalyzed three components cyanofluoroalkylation of alkenes with fluoroalkyl iodides as fluoroalkylation reagents

Article abstract of DOI:10.1039/c7cc07128k

In the past few years, Ru and Ir catalyzed photoredox radical coupling reactions have been widely applied in organic synthesis. In contrast, the applications of Cu catalysts in photoredox organic transformations were limited. We here report the first example of photoinduced, Cu-catalyzed three component cyanofluoroalkylation of alkenes by directly using fluoroalkyl iodides as fluoroalkylation reagents.

Full text of DOI:10.1039/c7cc07128k

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Photoinduced, copper-catalyzed three
components cyanofluoroalkylation of alkenes
with fluoroalkyl iodides as fluoroalkylation
reagents†
Cite this:DOI: 10.1039/c7cc07128k
Received 12th September 2017,
Accepted 25th October 2017
Quanping Guo, Mengran Wang, Yanfang Wang, Zhaoqing Xu * and Rui Wang
*
DOI: 10.1039/c7cc07128k
rsc.li/chemcomm
In the past few years, Ru and Ir catalyzed photoredox radical
coupling reactions have been widely applied in organic synthesis.
In contrast, the applications of Cu catalysts in photoredox organic
transformations were limited. We here report the first example of
photoinduced, Cu-catalyzed three component cyanofluoroalkylation
of alkenes by directly using fluoroalkyl iodides as fluoroalkylation
reagents.
The introduction of fluoroalkyl groups, such as trifluoromethyl
(
–CF ) and perfluoroalkyl (R , (–C F2n+1, n Z 2)), into organic
3 f n
molecules always leads to drastic enhancement of their solubility,
1
metabolic stability, and bioavailability. In this context, the devel-
opments of efficient processes for the construction of C–CF
3
and
C–R bonds have been significant issues in organic synthesis.
f
Scheme 1 ATRA type fluoroalkylation of alkenes.
Atom transfer radical addition (ATRA) reactions provide efficient
ways to construct two vicinal carbon–carbon or carbon–heteroa-
tom bonds in a single step from easily available alkene substrates.
Among them, three-component ATRA reactions represent the with the alkyl radical intermediates and push the reactions into a
most atom- and step-economical methods for difunctionalization three component ATRA fashion. So far, several examples of Pd or Cu
2
of alkenes, and have received much attention.
catalyzed three component ATRA to alkynes by directly using
3
a,b
4
The transition metal catalyzed
component ATRA of fluoroalkyl iodides (CF
alkyl substituted alkenes has been disclosed to generate new
C–CF /C–R and C–I bonds in one step (Scheme 1). In view of
synthetic efficiency, it is ideal to add –CF (or –R ) and a carbon- an alternative strategy for introducing a fluorine-containing motif
or photoinduced two fluoroalkyl iodides as fluoroalkyl radical precursors have been
3
c–g
3
I and R
f
I) across reported,
3
and reports on the three component ATRA of CF I or
5
R
f
I to structurally diversified alkenes are very few.
ꢀ
To avoid the interference of I generated from fluoroalkyl iodides,
3
f
3
f
based functional group across alkenes in a single synthetic opera- (–CF ) into alkenes and realizing the three component ATRA is using
3
6
tion as a three component reaction. However, when fluoroalkyl Togni’s or Umemoto’s reagents. However, all these reagents are
iodides are used in the ATRA of alkenes, the fluoroalkyl radicals and expensive or require multistep synthesis. More importantly, the
ꢀ
7
I are simultaneously formed by the homolytic cleavage of the CF
3
–I reactions were restricted in trifluoromethylation, whereas other
or R –I bonds, which subsequently add to alkenes through radical highly interesting F-containing groups, such as difluoroalkyl and
f
ꢀ
propagation pathways. It is difficult to suppress the coupling of I
perfluoroalkyl, cannot be introduced. Compared with Togni’s and
Umemoto’s reagents, fluoroalkyl iodides and related compounds,
Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
especially CF I, are much cheaper, easily available for various
fluoroalkyl groups, and more practical for large-scale synthesis.
Despite these benefits, the use of CF I and R I for three component
3 f
ATRA of alkenes has scarcely been explored. More importantly,
general methods of three component ATRA of alkenes for construct-
3
8
The Institute of Pharmacology, School of Basic Medical Science, Lanzhou University,
1
99 West Donggang Road, Lanzhou 730000, China. E-mail: zqxu@lzu.edu.cn,
wangrui@lzu.edu.cn
Electronic supplementary information (ESI) available. CCDC 1552550 (6e). For
†
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7cc07128k
ing both C–CF
3
and C–R
f
are highly desirable but not yet realized.
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II
I
In the past few years, Ir- and Ru-catalyzed photoredox reac- agents for reducing Cu to Cu in photoinduced oxidative
1
4
tions have widely been applied in organic synthesis, especially in quenching cycles. To our delight, when DIPEA (3 equiv.)
9
radical coupling reactions. In contrast, Cu has scarcely been was employed, the desired product 4a was obtained in 31%
1
0
used as a photoredox catalyst for organic transformations. Very yield without the formation of iodofluoroalkylation product 4aa
recently, Fu, Peters, and Ackermann reported the copper salt (Table 1, entry 1, see the ESI† for details). Introducing 2 equiv.
2
catalyzed radical couplings of organic halides under UV light of H O dramatically increased the yield to 61% (entry 2).
1
1
promotion. Inspired by these precedents, we envisioned that, 365 nm UV light was not as effective as 254 nm (entry 3).
under UV light irradiation, by using a suitable single electron A variety of copper species, including cuprous salts (CuCl,
ꢀ
ꢀ
À
reductant, the conversion of CF
3
I (or R
f
I) to CF
3
(or R
f
) and I
CuBr, CuTc, Cu(MeCN)
, Cu(OAc) , CuF
carefully examined, which indicated that both Cu(I) and Cu(II)
4
PF
6
, and Cu
2
O) and cupric salts
could be realized through the Cu-catalyzed oxidative quenching (Cu(acac)
2
2
2
, CuCl
2
, Cu(OH)
2
, and CuSO ) was
4
4
d,12
cycle without the assistance of Ru or Ir photocatalysts.
More importantly, we assumed that the rapid reduction of worked well (entries 4–6). It gave the best result (87%) when
À
CF I to I could suppress the radical propagations in competing Cu(OAc) was used (entry 5). Significant formation of 4aa was
3
2
two component iodofluoroalkylation of alkenes and facilitate the observed during the survey of amines (Et
3
N, DBU, pyridine,
desired three component reaction. Et NH, TMEDA, DMAP, and DABCO, entry 7). When other
2
Nitriles are widely known as an important class of organic solvents (DMF, THF, toluene, dioxane, or DMSO) were used,
compounds, which are found in numerous pharmaceuticals, the yield did not improve (entry 8). Further varying the amount
agricultural chemicals, and optoelectronic materials. In 2014, of DIPEA indicated that 4 equiv. was optimal (entry 9). The
Liu and co-workers reported the first example of Cu-catalyzed control experiment showed that only a trace amount of 4a was
7
c
cyanotrifluoromethylation of alkenes using Togni’s reagent.
obtained without Cu(OAc) (entry 10). In the absence of DIPEA,
2
Later, remarkable progress has been achieved in the enantio- only iodofluoroalkylation occurred (entry 11). The reaction was
7
d
selective cyanotrifluoromethylation by the same group. We carried out at room temperature for 24 h or 80 1C for 12 h
here report the first example of photoinduced, Cu-catalyzed without light, and no desired product was observed (entry 12).
cyanofluoroalkylation of alkenes using fluoroalkyl iodides as
fluoroalkylation reagents. The reactions were effective for both the scope of the reaction. We first studied the substrate generality
C–CF and C–R bond formation. in terms of aromatic alkenes with different substituents (Table 2).
We initiated the investigation by using C F I (1a, 3 equiv.), To our delight, substrates bearing electron-donating and electron-
With the optimal conditions in hand, we set out to explore
3
f
4
9
4-methylstyrene (2a), and TMSCN (3, 3 equiv.) as model sub- withdrawing groups were compatible with the current transforma-
strates, dry CH CN as solvent, and CuI (10 mol%) as the tions (4a–4o). It was worth noting that a series of functional groups,
3
t
3 3
catalyst. The reaction mixture was irradiated under a 25 W such as –Bu , –OCH , –F, –CF , –OAc, and –CN, were all tolerated.
UVC (254 nm) compact fluorescent light bulb at room tem- Compared to terminal alkenes, the internal alkenes 2p exhibited
perature. tert-Amines were reported as single electron transfer slightly lower reactivity (4p, 48%), but in good diastereoselectivity
1
3
a
Table 1 Optimization of reaction conditions
b
Entry
1
Catalyst
Amine
Solvent
Yield (%) (4a/4aa)
CuI
CuI
CuI
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
31/0
61/0
25/0
c
2
3
d
4
5
6
7
8
Other Cu(I) catalysts instead of CuI
Cu(OAc)
Other Cu(II) catalysts instead of Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
57/0–64/0
87/0
59/0–68/0
4/30–66/0
3/0–55/0
92(91)/0
Trace
2
2
2
2
2
2
2
2
Other amines instead of DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
3
Other solvents instead of CH CN
e
9
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
1
1
1
0
1
2
0/12
0
f
a
Unless otherwise noted, the reactions were carried out by using 2a (0.1 mmol), 1a (3.0 equiv.), 3 (3.0 equiv.), amine (3.0 equiv.), solvent (1.0 mL),
b 1
and catalyst (10 mol%), under N , and stirred at room temperature for 2 hours under UV light irradiation. H NMR yields with anisole as internal
standard. 2.0 equiv. of H O was added here and after. 25 W, 365 nm UVC. 4.0 equiv. of DIPEA was used; isolated yield in parentheses. No
2
2
c
d
e
f
light, 24 h at rt or 12 h at 80 1C, respectively.
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a,b
Table 2 Cyanofluoroalkylation reaction of alkenes
Scheme 2 Synthetic applications.
Scheme 3 Mechanistic studies.
a
b
All reactions were conducted in a 0.4 mmol scale. Isolated yields.
The results indicated the general ability of this reaction to
introduce various fluoroalkyl groups by directly using feedstock
(
420: 1). The substrate scopes were then expanded to alkyl- reagents.
substituted alkenes. A range of alkenes with various substituents
The cyanofluoroalkylated products are versatile synthetic
was all suitable for this reaction (6a–6h). Functional groups, intermediates and could be used to prepare fluoroalkylated
such as keto, imide, -O-benzoyl, -O-tert-butyldiphenylsilyl, and compounds, such as amine 9 and carboxylic acid 10 in good
1
5
-
O-P(O)Ph
, were tolerated (6c, 6e, and 6f–6h). Complex mole- yields (Scheme 2, eqn (1)). In addition, the 10 mmol scale
2
cules containing alkenyl groups, namely cinchonine derivatives reactions also proceeded smoothly with high yields (eqn (2)).
5
i and estrone derivatives 5j, afforded products with excellent
To gain some mechanistic insight, several experiments were
carried out (Scheme 3). The reaction was completely shut down
yields (6i, 76%; 6j, 89%).
To further explore the substrate scopes, a variety of fluoro- by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). Meanwhile,
alkyl iodides were examined, including the feedstock agent the radical trapping product 11 was isolated in 45% yield,
CF I (Table 3). To our delight, CF I, ICF CO Et, C F
3 3 2 2 6
13I, and which indicated the formation of a fluoroalkyl radical (eqn (1)).
C
8
F
17I all reacted smoothly with uniformly good yields (8a–8l). Addition of butylated hydroxytoluene (BHT) led to a dramatic
decrease of the yield (eqn (2)). These results indicated that a radical
pathway could be involved. In the reaction, the iodofluoroalkylation
a,b
product might possibly form as an intermediate which could then
couple with TMSCN to give the cyanofluoroalkylation product. This
prompted us to carry out several control reactions. In the
absence of TMSCN, no iodoperfluoroalkylation product was
Table 3 Cyanofluoroalkylations with various fluoroalkyl iodides
1
6
observed (eqn (3)). Without DIPEA, 4a was not formed, whereas
aa was isolated in 12% yield, which indicated the crucial role of
4
amine in this multicomponent reaction (eqn (4)). Interestingly,
under standard conditions, 4aa could react with TMSCN and
formed 4a in 87% yield. These control experiments indicated
that even if the iodofluoroalkylation product is a suitable pre-
cursor and participant as an intermediate in this transformation
cannot be completely ruled out, it seems unlikely to be involved
in the main operating pathway.
a
b
All reactions were conducted in a 0.4 mmol scale. Isolated yields.
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and O. Rieser, Angew. Chem., Int. Ed., 2015, 54, 6999; (e) P. Riente and
M. Pericas, ChemSusChem, 2015, 8, 1841; ( f ) J. Gu, Q.-Q. Min, L. Yu and
X. Zhang, Angew. Chem., Int. Ed., 2016, 55, 12270; (g) M. Daniel,
G. Dagousset, P.-A. Klein, B. Tuccio, A.-M. Goncalves, G. Masson and
E. Magnier, Angew. Chem., Int. Ed., 2017, 56, 3997; (h) D. Wang, F. Wang,
P. Chen, Z. Lin and G. Liu, J. Am. Chem. Soc., 2017, 56, 2054.
3
4
(a) Q. Chen, Z. Yang, C. Zhao and Z. Qiu, J. Chem. Soc., Perkin Trans. 1,
1
988, 563; (b) T. Xu, C. W. Cheung and X. Hu, Angew. Chem., Int. Ed.,
2014, 53, 4910; (c) Z. Li, A. G. Dominguez and C. Nevado, J. Am. Chem.
Soc., 2015, 137, 11610; (d) S. Domanski and W. Chaładaj,
ACS Catal., 2016, 6, 3452; (e) Y. He, Q. Wang, L. Li, X. Liu, P. Xu and
Y. Liang, Org. Lett., 2015, 17, 5188; ( f ) Q. Wang, Y. He, J. Zhao, Y. Qiu,
L. Zheng, J. Hu, Y. Yang, X. Liu and Y. Liang, Org. Lett., 2016, 18, 2664;
(g) Y. He, L. Li, Q. Wang, W. Wu and Y. Liang, Org. Lett., 2016, 18, 5158.
(a) A. Ogawa, M. Imura, N. Kamada and T. Hirao, Tetrahedron Lett.,
Scheme 4 Proposed mechanism.
2
6
001, 42, 2489; (b) Z.-M. Qiu and D. J. Burton, J. Org. Chem., 1995,
0, 3465; (c) K. Tsuchii, M. Imura, N. Kamada, T. Hirao and A. Ogawa,
J. Org. Chem., 2004, 69, 6658; (d) C.-J. Wallentin, J. D. Nguyen,
P. Finkbeiner and C. R. J. Stephenson, J. Am. Chem. Soc., 2012,
Based on these investigations and previous reports, a plausible
7c,d
mechanism was proposed (Scheme 4).
exchange delivered a Cu species, which was reduced by the
Firstly, the rapid ligand
1
34, 8875; (e) R. Beniazza, R. Atkinson, C. Absalon, F. Castet, S. A.
II
Denisov, N. D. McClenaghan, D. Last ´e couer `e s and J.-M. Vincent,
Adv. Synth. Catal., 2016, 358, 2949; Y. Wang, J. Wang, G.-X. Li, G. He
and G. Chen, Org. Lett., 2017, 19, 1442.
electron rich tert-amine and formed an amine radical cation and
I 14
I
Cu . Under UV light irradiation, Cu was excited to its triplet state
5
Ni-Catalyzed three component aryldifluoroalkylation of enamides using
I
11
[
Cu ]*. The following oxidative quenching step converted R I into
Br/ClCF
6 (a) P. Eisenberger, S. Gischig and A. Togni, Chem. – Eur. J., 2006, 12, 2579;
b) T. Umemoto and S. Ishihara, J. Am. Chem. Soc., 1993, 115, 2156.
2 2
CO Et was reported by Zhang and co-workers, see: ref. 2f.
f
ꢀ
À
II 10
ꢀ
Rf and I along with recycling of Cu . Meanwhile, R attacked
f
(
alkene to give the radical intermediate A. Then, it reacted with
7
(a) S. Mizuta, S. Verhoog, K. M. Engle, T. M. Khotavivattana, O. Duill,
K. Wheelhouse, G. Rassias, M. M ´e debielle and V. Gouverneur, J. Am.
Chem. Soc., 2013, 135, 2505; (b) Y. He, L. Li, Y. Yang, Z. Zhou, H. Hua,
X. Liu and Y. Liang, Org. Lett., 2014, 16, 270; (c) Z. Liang, F. Wang, P. Chen
and G. Liu, J. Fluorine Chem., 2014, 167, 55; (d) F. Wang, D. Wang, X. Wan,
L. Wu, P. Chen and G. Liu, J. Am. Chem. Soc., 2016, 138, 15547; (e) N. Zhu,
F. Wang, P. Chen, J. Ye and G. Liu, Org. Lett., 2015, 17, 3580; ( f ) Z. Liang,
F. Wang, P. Chen and G. Liu, Org. Lett., 2015, 17, 2438; (g) L. Wu,
F. Wang, X. Wan, D. Wang, P. Chen and G. Liu, J. Am. Chem. Soc., 2017,
139, 2904; (h) X.-L. Yu, J.-R. Chen, D.-Z. Chen and W.-J. Xiao, Chem.
Commun., 2016, 52, 8275; (i) W. Zhang, F. Wang, S. D. McCann, D. Wang,
P. Chen, S. S. Stahl and G. Liu, Science, 2016, 353, 1014.
II
III
Cu (CN)
n
and formed a Cu species, B. The subsequent reductive
elimination provided the desired cyanofluoroalkylation product. It
I
II
should be noted that both Cu and Cu salts showed good catalytic
activities (Table 1, entries 4 and 6). These results indicated that
II
I
the catalytic cycle could be initiated either from Cu or from Cu .
+
À
Unstable species TMS and I undergo rapid hydrolysis and then
neutralized by amine, which promoted a complete conversion.
17
In conclusion, the first example of photoinduced, Cu-catalyzed
three component cyanofluoroalkylation of alkenes was disclosed.
The reactions were effective for the introduction of both perfluoro-
alkyl and trifluoromethyl groups by directly using the fluoroalkyl
iodides. A 25 W UVC compact fluorescent light bulb irradiation was
sufficient for functionalization of a broad range of simple and
complex alkenes at room temperature. Compared with previously
reported cyanotrifluoromethylation of alkenes, our method showed
8
9
3
CF I is a feedstock reagent which could be supplied as 100 kg per
pack, and the price is B$900 per kg (Alibaba). In sharp contrast, the
price of Togni’s reagent is B$150 per g (Acros, the biggest pack-size
is 5 g); the price of Umemoto’s reagent is $108 per g (Sigma-Aldrich,
the biggest pack-size is 1 g). C
4 9
F I is B$450 per kg (Alibaba) and
could be supplied in 1 kg per pack.
For leading reviews, see: (a) C. K. Prier, D. A. Rankic and
D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322; (b) D. Ravelli,
S. Protti and M. Fagnoni, Chem. Rev., 2016, 116, 9850.
significant advantages: (i) using less costly and feedstock CF
instead of expensive Togni’s or Umemoto’s reagent is more prac-
tical for large-scale synthesis; and (ii) besides CF , a variety of
fluoroalkyl groups (–C , –C 13, –C 17, and –CF CO Et) could be
introduced with high yields.
3
I
10 For reviews, see: (a) S. Paria and O. Reiser, ChemCatChem, 2014,
, 2477; (b) O. Reiser, Acc. Chem. Res., 2016, 49, 1990.
6
1
1 (a) T. S. Ratani, S. Bachman, G. C. Fu and J. C. Peters, J. Am. Chem.
Soc., 2015, 137, 13902; (b) C. Uyeda, Y. Tan, G. C. Fu and J. C. Peters,
J. Am. Chem. Soc., 2013, 135, 9548; (c) D. T. Ziegler, J. Choi,
J. M. Mu n˜ oz-Molina, A. C. Bissember, J. C. Peters and G. C. Fu,
J. Am. Chem. Soc., 2013, 135, 13107; (d) H.-Q. Do, S. Bachman,
A. C. Bissember, J. C. Peters and G. C. Fu, J. Am. Chem. Soc., 2014,
136, 2162; (e) F. Yang, J. Koeller and L. Ackermann, Angew. Chem.,
Int. Ed., 2016, 55, 4759; ( f ) J. M. Ahn, T. S. Ratani, K. I. Hannoun,
G. C. Fu and J. C. Peters, J. Am. Chem. Soc., 2017, 139, 12716.
2 D. A. Nagib, M. E. Scott and D. W. C. MacMillan, J. Am. Chem. Soc.,
3
4
F
9
6
F
8
F
2
2
We are grateful for the grants from the NSFC (No. 21432003)
and Fundamental Research Funds for the Central Universities
lzujbky-2017-127).
(
1
1
1
2009, 131, 10875.
Conflicts of interest
3 A 25 W UVC bulb was used, which can be purchased from a
supermarket (B$9 for each).
4 (a) A. Baralle, L. Fensterbank, J.-P. Goddard and C. Ollivier, Chem. –
Eur. J., 2013, 19, 10809; (b) B. Michelet, C. Deldaele, S. Kajouj,
C. Moucheron and G. Evano, Org. Lett., 2017, 19, 3576.
5 CCDC 1552550 (6e)†.
There are no conflicts to declare.
Notes and references
1
1
P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, 16 For detailed information and additional experiments, see the ESI†.
Applications, Wiley, New York, 2nd edn, 2013.
For reviews, see: (a) K. H. Jensen and M. S. Sigman, Org. Biomol. Chem.,
17 Other examples using stoichiometric amounts of tert-amines as electron
transfer agents in photoredox reactions, see ref. 14 and also (a) J. L. Jeffrey,
F. R. Petronijevic and D. W. C. MacMillan, J. Am. Chem. Soc., 2015,
137, 8404; (b) F. R. Petronijevic, M. Nappi and D. W. C. MacMillan, J. Am.
Chem. Soc., 2013, 135, 18323; (c) A. G. Amador, E. M. Sherbrook and
T. P. Yoon, J. Am. Chem. Soc., 2016, 138, 4722.
2
2
008, 6, 4083; (b) C. K. Prier, D. A. Rankic and D. W. C.
MacMillan, Chem. Rev., 2013, 113, 5322; (c) J. M. R. Narayaman and
C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102. For recent examples,
see: (d) D. B. Bagal, G. Kachkovskyi, M. Knorn, T. Rawner, B. M. Bhanage
Chem. Commun.
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