Journal of the American Chemical Society
AUTHOR INFORMATION
Page 4 of 6
A
CN
Me
CONH2
CO2Et
1
2
3
4
5
6
Corresponding Author
*keary@scripps.edu
5c, 83%
5d, 81%
5e, 55%
β-amino acid precursor
(Ref. 24)
d: 30% H2O2
Na2CO3
c: Pd/C
H2
e: H2SO4
Author Contributions
§These authors contributed equally
Bn
EtOH
CN
f: anthracene
CN
CHO
b: DIBAL–H
FeCl3
7
8
9
4j
5f, 56%
5b, 65%
Notes
g: cat. Ni, Zn
PhthNO2C Me
a: H2SO4
(aq.)
The authors declare no competing financial interests.
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
ACKNOWLEDGMENT
O
N
CO2Bn
Ref. 23
CO2H
CN Me
Me
We gratefully acknowledge The Scripps Research Institute, Pfizer, Inc.,
and NIH (1R35GM125052, R01 CA087660) for financial support. E.
V. V. was supported by the Life Sciences Research Foundation Fellow-
ship. Y. X. was supported by an International Research Scholarship
from Nankai University College of Chemistry. We thank Dr. Milan
Gembicky, Dr. Curtis Moore, and Dr. Arnie Rheingold for X-ray crys-
tallographic analysis.
SAc
5a, 62%
acetorphan
5g, 37%
REFERENCES
(1) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151. (b) Kolb, H. C.; Van-
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. (c) Jen-
sen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083–4088. (d) McDon-
ald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981–3019. (e) Dong, J. J.;
Browne, W. R.; Feringa, B. L. Angew. Chem. Int. Ed. 2015, 54, 734–744. (f) Yin,
G.; Mu, X.; Liu, G. Acc. Chem. Res. 2016, 49, 2413–2423. (g) Chemler, S. R.;
Karyakarte, S. D.; Khoder, Z. M. J. Org. Chem. 2017, 82, 11311–11325.
(2) (a) Segura, J. L.; Martín, N.; Hanack, M. Eur. J. Org. Chem. 1999, 643–651.
(b) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med.
Chem. 2010, 53, 7902–7917. (c) Van Boven, M.; Blaton, N.; Cokelaere, M.;
Daenens, P. J. Agric. Food Chem. 1993, 41, 1605–1607.
(3) Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H. “Nitriles,” in Ullman’s
encyclopedia of industrial chemistry (Wiley-VCH, Weinheim, Germany, ed. 5,
1985), vol. A17, p. 363.
(4) (a) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035–2078. (b) All-
gäuer, D. S.; Jangra, H.; Asahara, H.; Li, Z.; Chen, Q.; Zipse, H.; Ofial, A. R.;
Mayr H. J. Am. Chem. Soc. 2017, 139, 13318–13329.
(5) Zhang, T. Y.; O’Toole, J. C.; Dunigan, J. M. Tetrahedron Lett. 1998, 39,
1461–1464.
(6) Palomo, C.; Aizpurua, J. M.; Garcia, J. M.; Ganboa, I.; Cossio, F. P.; Lecea,
B.; López, C. J. Org. Chem. 1990, 55, 2498–2503.
(7) Zhou, S.; Addis, D.; Das, S.; Junge, K.; Beller, M. Chem. Commun. 2009,
4883–4885.
(8) (a) Cowen, F. M.; Dixon, J. K. Catalytic addition of cyanogen halides to olefins.
US Patent 2653963 A (Sep 29, 1953). (b) Jackson, W. R.; Lovel, C. G. J. Chem.
Soc., Chem. Commun. 1982, 1231–1232. (c) Fitzmaurice, N. J.; Jackson, W. R.;
Perlmutter, P. J. Organomet. Chem. 1985, 285, 375–381.
(9) (a) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc. 2007, 129,
2428–2429. (b) Hirata, Y. Yukawa, T.; Kashihara, N.; Nakao, Y.; Hiyama. T. J.
Am. Chem. Soc. 2009, 131, 10964–10973.
(10) Ye, F.; Chen, J.; Ritter, T. J. Am. Chem. Soc. 2017, 139, 7184–7187.
(11) Chakraborty, S.; Das, U. K.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc.
2017, 139, 11710–11713.
(12) Brenna, E.; Crotti, M.; Gatti, F. G.; Manfredi, A.; Monti, D.; Parmeggiani,
F.; Santangelo, S.; Zampieri, D. ChemCatChem 2014, 6, 2425–2431.
(13) Saylik, D.; Campi, E. M.; Donohue, A. C.; Jackson, W. R.; Robinson, A. J.
Tetrahedron: Asymmetry 2001, 12, 657–667.
(14) (a) Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-
H. Angew. Chem. Int. Ed. 2005, 44, 192–212. (b) Engle, K. M.; Mei, T.-S.; Wang,
X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2011, 50, 1478–1491.
(15) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552–2559.
(16) Schreiber, S. L. J. Am. Chem. Soc. 1980, 102, 6163–6165. (b) Li, J.-H.;
Wang, D.-P.; Xie, Y.-X. Tetrahedron Lett. 2005, 46, 4941–4944. (b) Liwosz, T.
W.; Chemler, S. R. J. Am. Chem. Soc. 2012, 134, 2020–2023.
(17) (a) Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134,
2547–2550; (b) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.;
Figure 2. Synthetic and chemical proteomic applications of alkenyl
nitriles. (A) Representative derivatizations of 4j. (B) Structures (C)
and proteomic reactivity of bis(trifluoromethyl)phenyl compounds
bearing alkenyl nitrile (4y), acrylamide (6), and chloroacetamide (7)
electrophilic groups assessed using the chemical proteomic method
isoTOP-ABPP.23,24 (C) Waterfall plots representing the top 1,500
cysteine-containing peptides and their corresponding reactivity, or
competition ratio (RDMSO/compound), values. High R values correspond to
greater reactivities, where cysteines with R values ≥ 4 (dashed line)
were considered to be liganded by 4y, 6 and 7. (D and E) Representa-
tive MS1 spectra showing examples of cysteines that were generally
(C18 of REEP5) or preferentially liganded (green color) by 4y, 6 and 7
(C152 of GAPDH (7), C146 of PEF1 (4y), and C161 of TIGAR (6)).
In summary, we have developed a catalytic method for oxidative cy-
anation of terminal and select internal alkenes. This transformation
enables direct access to branched alkenyl nitriles that are otherwise
difficult to prepare. The alkenyl nitrile products constitute versatile
electrophiles with applications in both organic synthesis and chemical
biology. In particular, the attenuated and complementary reactivity
displayed by alkenyl nitriles compared to more conventional electro-
philes underscores their attractiveness for their future development as
covalent small-molecule probes and drug candidates.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental details, analytical data, and 1H and 13C NMR spectra
(PDF)
X-ray data for compound 4b (CIF)
X-ray data for compound 4ap (CIF)
NMR data (ZIP)
NMR data (ZIP)
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