Visible light photocatalytic decarboxylative monofluoroalkenylation of α-amino acids with: Gem -difluoroalkenes

Article abstract of DOI:10.1039/c7cc05758j

α-Amino acids are among the most common biologically active molecules in nature, and their functionalization has attracted much attention. In this communication, a novel, efficient and general visible-light photocatalytic decarboxylative monofluoroalkenylation of N-protected α-amino acids with gem-difluoroalkenes is reported, affording the corresponding α-amino monofluoroalkenes which might find applications in medical chemistry and materials science. The reaction proceeded at room temperature with high efficiency and tolerance of various functional groups.

Full text of DOI:10.1039/c7cc05758j

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Communication
Visible light photocatalytic decarboxylative monofluoroalkenylation of
αꢀamino acids with gemꢀdifluoroalkenes†
Jingjing Li,a Quentin Lefebvre,b Haijun Yang,a Yufen Zhaoa and Hua Fu*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
αꢀAmino acids are among the most common biologically active molecules in nature, and their functionalization has attracted much
attention. In this communication, a novel, efficient and general visibleꢀlight photocatalytic decarboxylative monofluoroalkenylation of Nꢀ
protected αꢀamino acids with gemꢀdifluoroalkenes is reported, affording the corresponding αꢀamino monofluoroalkenes which might find
applications in medical chemistry and materials sciences. The reaction proceeded at room temperature with high efficiency and tolerance
10 of various functional groups.
Reaction of Nꢀtertꢀbutoxycarbonyl proline (NꢀBocꢀPro) (1a)
with 1ꢀ(2,2ꢀdifluoroꢀ1ꢀphenylethenyl)benzene (2a) was used as
the model to optimize conditions including photocatalysts, bases,
solvents and time (see Table S1 in Supporting Information for the
50 details). The results showed that the optimal photoredox
conditions are as follows: 2.0 mol% Ir[dF(CF3)ppy]2(dtbbpy) (A)
as the photocatalyst, Li2CO3 as the base, and DMSO as the
solvent at room temperature under argon atmosphere. After
establishing the optimal photocatalytic system, we first
55 investigated the scope of Nꢀprotected αꢀamino acids. As shown in
Fluorinated organic compounds play an important role in
pharmaceutical, medicinal1 and agrochemical sciences2 owing to
the small size and high electronegativity of fluorine and the
15 unique chemical and physical properties of fluorineꢀcontaining
structural motifs. About 20ꢀ25% of pharmaceuticals and 30ꢀ40%
of agrochemicals on the market are estimated to be molecules
containing fluorine.3 In addition, these compounds occupy an
important place in materials science.4 Therefore, construction of
20 fluorineꢀcontaining compounds has been a highly topical area of
research. As a typical representative of fluorinated compounds,
monofluoroalkenes are regarded as nonhydrolyzable amide
bioisosteres5 and their lipophilic properties prompt chemists to
develop synthetic approaches to monofluoroalkenes. Among the
25 starting materials for the synthesis of monofluoroalkenes, gemꢀ
difluoroalkenes are readily available and versatile substrates,6 and
their CꢀF bond functionalization with boronic acids,7
heteroarenes,8 alkyl Grignard reagents9 have been explored under
transition metal catalysis. αꢀAmino acids widely occur in nature,
30 are available in large scale, and their chemical transformations
deliver diverse compounds of interest. Recently, visible light
photoredox catalysis as a clean, efficient and accessible strategy
has exhibited great potential in development of novel reactions,10
and our research group has also developed some valuable visibleꢀ
35 light photocatalytic chemical transformations.11 Particularly,
visible light photoredox decarboxylative couplings of Nꢀprotected
αꢀamino acids were reported by MacMillan’s group12 and us.11gꢀl
Very recently, Hashmi and coꢀworkers described a visible light
photoredox C(sp3)ꢀH monofluoroalkenylation of dimethylanilines
40 and trialkyl amines via an oxidation/deprotonation sequence.13
We realized that fluorinated molecules containing amino acid
fragments would be of great interest for further derivatization to
diverse compounds, so we here report our work toward visible
light photoredox decarboxylative monofluoroalkenylation of Nꢀ
45 protected αꢀamino acids with gemꢀdifluoroalkenes.
Table 1, both NꢀBocꢀPro and NꢀCbzꢀPro (Cbz
=
benzyloxycarbonyl) gave the corresponding products in
satisfactory yields (see 3a and 3b), and the former was a better
substrate. Other NꢀBocꢀprotected amino acids, NꢀBocꢀpipecolic
60 acid, NꢀBocꢀglycine, NꢀBocꢀalanine, NꢀBocꢀphenylalanine, Nꢀ
Bocꢀserine containing hydroxyl and NꢀBocꢀmethionine
containing thioether, were attempted, and they also were good
substrates (see 3cꢀh). Specifically, the fact that naturally
occurring monoprotected amino acids could be used is of high
65 interest for further functionalization and shows the advantage of
our method compared to previous reports. Subsequently, various
substituted
gemꢀdifluoroalkenes
were
screened.
Gemꢀ
difluoroalkenes derived from ketones (see 3iꢀp) provided similar
results to 1ꢀ(2,2ꢀdifluoroꢀ1ꢀphenylethenyl)benzene (2a), and
70 unsymmetrical gemꢀdifluoroalkenes provided tetrasubstituted
monofluoroalkenes as mixtures of E and Z isomers. However,
reaction of Nꢀbenzylꢀproline with 4,4'ꢀ(2,2ꢀdifluoroetheneꢀ1,1ꢀ
diyl)bis(chlorobenzene) afforded the expected product in lower
yield (see 3k). Next, gemꢀdifluoroalkenes derived from aldehydes
75 were explored, and they afforded the corresponding trisubstituted
monofluoroalkenes in good to excellent yields as mixtures of E
and Z isomers (see 3qꢀab) without formation of alkynyes as sideꢀ
products via a dehydrofluorination. Fortunately, E and Z isomers
of most products could be separated by simple silica gel column
80 chromatography (see Supporting Information for the details). We
found that the electronic effects of the substituents on the
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argon atmosphere, Nꢀprotected αꢀamino acid (1) (0.4 mmol), gemꢀ
difluoroalkene (2) (0.2 mmol), PC (A) (4 ꢁmol), Li2CO3 (0.6 mmol),
DMSO (2.0 mL), temperature (rt, ~25 oC), time (36ꢀ72 h) in a sealed
Schlenk tube. Isolated yield. Z/E ratios were determined by H NMR
spectroscopy or yields of the isolated isomers. Cbz = benzyloxycarbonyl.
aromatic units in 2 had no obvious influence on the reaction
efficiency. This visibleꢀlight photocatalytic decarboxylative
monofluoroalkenylation of Nꢀprotected αꢀamino acids showed
tolerance of numerous functional groups including CꢀF, CꢀCl, Cꢀ
Br and CꢀI bonds, amides, hydroxyl, ethers, thioethers, sulfonyl
and sulfonamide groups. Unfortunately, gemꢀdifluoroalkenes
derived from dialkyl ketones and aliphatic aldehydes did not
work under the present conditions.
b
1
5
The reaction could be scaled up from 0.20 mmol to 1.0 mmol
using NꢀBocꢀPro (1a) as partner, and the reaction proceeded well
affording 3j in good yield (326 mg, 75% yield) (Scheme 1a). We
15 also showed that coupling of 2ꢀtetrahydrofuroic acid (4) with 1ꢀ(2,
2ꢀdifluoroꢀ1ꢀphenylethenyl)benzene (2a) was feasible under the
standard conditions and the corresponding product 3ac was
obtained in 78% yield (Scheme 1b).
Table 1 Substrate scope on visibleꢀlight photocatalytic decarboxylative
10 monofluoroalkenylation of Nꢀprotected αꢀamino acids (1)a
3 (Time, Yieldb)
Ph
Ph
F
Ph
H
N
F
Ph
Ph
Ph
Ph
N
Ph
Boc
N
N
F
Boc
F
Ph
3d (96 h, 60%)
Cbz
3b
Boc
3a
3c (36 h, 71%)
(36 h, 75%)
(36 h, 83%)
H
N
F
H
N
F
H
N
F
H
N
F
Ph
Ph
Ph
Boc
Boc
Boc
Boc
Ph
Ph
MeS
Ph
Me Ph
Ph
HO
3e
(48 h, 75%)
3f
(36 h, 84%)
3g
(72 h, 82%)
3h (36 h, 75%)
Cl
20 Scheme 1 (a) Scaleꢀup experiment for coupling of NꢀBocꢀPro (1a) with
4,4'ꢀ(2,2ꢀdifluoroetheneꢀ1,1ꢀdiyl)bis(chlorobenzene) (2c); (b) Coupling of
2ꢀtetrahydrofuroic acid (4) with 1ꢀ(2,2ꢀdifluoroꢀ1ꢀphenylethenyl)benzene
(2a) under the standard conditions.
F
Cl
N
N
F
Cl
N
F
Cl
F
Boc
To explore the mechanism on the visibleꢀlight photocatalyic
25 decarboxylative monofluoroalkenylation of Nꢀprotected αꢀamino
acids, the reaction of NꢀBocꢀproline (1a) with 1ꢀ(2,2ꢀdifluoroꢀ1ꢀ
phenylethenyl)ꢀ4ꢀfluorobenzene (2a) was carried out in the
presence of two equivalents of 2,2,6,6ꢀtetramethylꢀ1ꢀ
piperidinyloxy (TEMPO) as the radicalꢀtrapping agent under the
30 standard conditions, and no reaction was observed, suggesting
that the reaction proceeded via a radical pathway. Given that the
excited state of Ir[dF(CF3)ppy]2(dtbbpy) (A) is a strong oxidant
{E1/2 red[*IrIII/IrII] = + 1.21 V vs SCE},12d the substrate NꢀBocꢀPro
F
Boc
Ph
3k
3i (36 h, 91%)
3j (36 h, 96%)
(36 h, 45%)
Cl
O
F
Ph
F
N
Ph
N
Me
N
Cl
Boc
F
F
Boc
3n
(36 h, 93%)
Z: 22%, E: 71%
3m (36 h, 86%)
Z/E = 2:3
Cl
3l (72 h, 48%)
CH3
CH3
N
N
CH3
O
Boc
F
Boc
F
red
(1a) could be oxidized efficiently (E1/2 = + 0.95 V vs SCE).12d
CF3
S
O
3p
3o
(36 h, 74%)
Z: 20%, E: 54%
(36 h, 91%)
Z/E = 1:1
35 Then, the reduction of 1ꢀ(2,2ꢀdifluoroꢀ1ꢀphenylethenyl)ꢀ4ꢀ
fluorobenzene (2a) (E1/2 = ꢀ 1.04V vs SCE)13 should proceed
red
H
favourably via single electron transfer from the IrII complex {E1/2
red[IrIII/IrII] = ꢀ 1.37 V vs SCE}.13 According to the experimental
results above and previous reports,13 a possible mechanism on the
40 visible lightꢀmediated decarboxylative monofluoroalkenylation is
proposed in Scheme 2. Under irradiation of visible light,
photocatalyst IrIII is excited to *IrIII which is a strong oxdant. The
NꢀBoc proline (1a) is deprotonated by the base (Li2CO3) and
further oxidized by *IrIII delivering the transient αꢀaminoalkyl
45 radical I and IrII via single electron transfer (SET), along with the
departure of carbon dioxide. Subsequently, reduction of gemꢀ
difluoroalkenes by IrII via SET provides a persistent radical anion
that decomposes to the monofluoroalkenyl radical II and a
fluorine anion, possibly under assistance of the lithium cation,
50 regenerating photocatalyst IrIII. Finally, radicalꢀradical crossꢀ
coupling between I and II13 affords the target product (3a).
H
F
H
N
Boc
N
N
F
Ph
Boc
F
Boc
3s (36 h, 93%)
Z: 52%, E: 41%
3q (36 h, 70%)
Z: 39%, E: 31%
3r
(36 h, 89%)
Z: 54%, E: 35%
H
H
H
OMe
N
N
N
Boc
F
OMe
SMe
F
F
Boc
Boc
3v
(36 h, 74%)
Z: 41%, E: 33%
3t (36 h, 88%)
Z: 44%, E: 44%
3u (36 h, 67%)
Z/E = 3:2
Cl
H
H
H
Br
N
N
N
Cl
F
F
F
Boc
Boc
Boc
3y
3x (36 h, 80%)
Z: 42%, E: 38%
3w (36 h, 58%)
Z/E = 2:3
(36 h, 84%)
Z: 43%, E: 41%
I
H
H
N
F
H
N
Boc
N
COOEt
F
Boc
F
H
Boc
N
Ts
Ph
3aa (36 h, 81%)
Z: 36%, E: 45%
3z
(36 h, 63%)
Z: 29%, E: 34%
3ab (60 h, 56%)
Z: 29%, E: 30%
a
Reaction conditions: irradiation of visible light with 23 W CFL and
2
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University, Beijing 100084, P. R. China. Fax: (+86) 10ꢀ62781695; Eꢀ
mail: fuhua@mail.tsinghua.edu.cn
b School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8
1TS (UK)
35 † Electronic Supplementary Information (ESI) available: Synthetic
1
procedures, characterization data and H, 13C, 19F NMR spectra of these
synthesized compounds. See DOI: 10.1039/b000000x/
1
(a) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed.,
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Mater. Chem., 2005, 15, 4981.
40
45
50
55
60
2
3
4
Scheme
2
A
proposed mechanism for the decarboxylative
monofluoroalkenylation of Nꢀprotected αꢀamino acids.
5
(a) R. J. Sciotti, M. Pliushchev, P. E. Wiedman, D. Balli, R. Flamm,
A. M. Nilius, K. Marsh, D. Stolarik, R. Jolly, R. Ulrich and S. W.
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2009, 7, 2872; (e) C. E. Jakobsche, A. Choudhary, S. J. Miller and R.
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Interestingly, the obtained monofluoroalkenylation products
above contain amino acid fragments which could be further
derivatized after the protective group removal. For example,
deprotection of product 3a with trifluoroacetic acid (TFA) in
CH2Cl2 affords 5, and coupling of 5 with dipeptide NꢀAlaꢀPhe (6)
gave 7 (Scheme 3). Therefore, our monofluoroalkenylation
5
10 method should provide opportunity for synthesis of diverse
fluorinated compounds and peptidomimetics.
6
7
Ph
O
BocHN
OH
N
H
CH3
O
8
9
Ph
F
TFA, CH2Cl2
rt, 3 h
Ph
6
(0.2 mmol)
Ph
Ph
65 10 For selected reviews on visibleꢀlight photoredox catalysis, see: (a) C.
K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013,
113, 5322; (b) D. Ravelli, D. Dondi, M. Fagnoni and A. Albini,
Chem. Soc. Rev., 2009, 38, 1999; (c) J. M. R. Narayanam and C. R. J.
Stephenson, Chem. Soc. Rev., 2011, 40, 102; (d) L. Shi and W. Xia,
EDCI HCl (1.2 equiv)
HOBt H2O(1.2 equiv)
i-Pr2NEt (2.1 equiv)
CH2Cl2, rt, 12 h
N
H
N
98% yield
F
Boc
5 (
0.2 mmol)
3a
Ph
O
70
Chem. Soc. Rev., 2012, 41, 7687; (e) T. P. Yoon, M. A. Ischay and J.
Du, Nat. Chem., 2010, 2, 527; (f) J. W. Tucker and C. R. J.
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Chem. Int., Ed., 2012, 51, 6828; (i) D. P. Hari and B. König, Angew.
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Asian J. Org. Chem., 2017, 6, 368.
BocHN
N
N
Ph
Ph
H
CH3
O
F
7
(72% yield)
Scheme 3 Application of the synthesized product (3a).
75
In summary, we have developed a mild and practical visibleꢀ
15 light photocatalytic decarboxylative monofluoroalkenylation of
Nꢀprotected αꢀamino acids with gemꢀdifluoroalkenes. The
reaction smoothly proceeded under visibleꢀlight photocatalysis.
Both αꢀamino acids and gemꢀdifluoroalkenes are readily available
or can be prepared on scale with high efficiency. In addition, the
20 resulting products, αꢀamino monofluoroalkenes, are useful
building blocks in pharmaceutics, agrochemical and materials
sciences.
11 (a) M. Jiang, H. Li, H. Yang and H. Fu, Angew. Chem., Int. Ed.,
2017, 56, 874; (b) J. Li, H. Tian, M. Jiang, H. Yang, Y. Zhao and H.
Fu, Chem. Commun., 2016, 52, 8862; (c) C. Gao, J. Li, J. Yu, H.
Yang and H. Fu, Chem. Commun., 2016, 52, 7292; (d) M. Jiang, H.
Yang and H. Fu, Org. Lett., 2016, 18, 5248; (e) J. Li, P. Zhang, M.
Jiang, H. Yang and H. Fu, Org. Lett., 2017, 19, 1994; (f) J. Yang, M.
Jiang, Y. Jin, H. Yang and H. Fu, Org. Lett., 2017, 19, 2758; (g) M.
Jiang, Y. Jin, H. Yang and H. Fu, Sci. Rep., 2016, 6, 26161; (h) Y. Jin,
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H. Yang and H. Fu, Org. Lett., 2016, 18, 1968; (j) Y. Jin, H. Yang
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Yang and H. Fu, Org. Lett., 2016, 18, 6400.
12 Using NꢀBoc αꢀamino acids as the radical precursors, see: (a) L. Chu,
C. Ohta, Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc., 2014,
136, 10886; (b) A. Noble and D. W. C. MacMillan, J. Am. Chem.
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Chem. Soc., 2014, 136, 5257; (d) Z. Zuo, D. T. Ahneman and L. Chu,
J. A. Terrett, A. G. Doyle and D. W. C. MacMillan, Science, 2014,
345, 437.
80
85
Acknowledgements
90
We thank Dr. Haifang Li in Department of Chemistry at
25 Tsinghua University for her great help in analysis of mass
spectrometry, and the National Natural Science Foundation of
China (Grant Nos. 21372139 and 21772108) for financial support.
95
Notes and references
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
13 Ji. Xie, J. Yu, M. Rudolph, F. Rominger and A. S. K. Hashmi, Angew.
Chem., Int. Ed., 2016, 55, 9416.
30 Biology (Ministry of Education), Department of Chemistry, Tsinghua
100
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Graphical abstract
Visible light photocatalytic decarboxylative monofluoroalkenylation
of αꢀamino acids with gemꢀdifluoroalkenes
Jingjing Li, Quentin Lefebvre, Haijun Yang, Yufen Zhao and Hua Fu*
A novel, efficient and general visibleꢀlight photocatalytic decarboxylative monofluoroalkenylation
of Nꢀprotected αꢀamino acids with gemꢀdifluoroalkenes is reported, affording the corresponding
αꢀamino monofluoroalkenes. The reaction proceeded at room temperature with high efficiency and
tolerance of various functional groups.