RESEARCH
| RESEARCH ARTICLE
conditions. SiGNa-S1 failed in all the examples
tested (Fig. 4), and Na-dispersion/15-crown-5
(Na-disp./15-c-5) mixture gave only partial con-
version with prolonged reaction times on some
substrates.
The mildness of the reaction conditions was
demonstrated via application to more complex
natural products. Thus, chemo- and regio-
selective reduction gave access to the 1,4-dienyl
derivatives of dextromethorphan (32), dehydroa-
bietic acid (33), and estrone methyl ether (34).
Overall, this methodology was competitive to the
chemical Birch using lithium metal (see supple-
mentary materials for the referenced literature
comparisons).
lated to pragmatism and chemoselectivity. In-
spired by Li-ion battery technology, we have
developed a general set of electrochemical reduc-
tive conditions and demonstrated its practicality,
safety, scalability, and chemoselectivity. We
believe that inspiration from the fast-evolving
research areas of battery technologies and elec-
troactive materials will have an important im-
pact in synthetic organic electrochemistry, in
ways such as the discovery of new oxidative and
reductive mediators, milder access to harsh re-
ducing agents, and generation of low-valent cat-
alytic systems based on transition metals.
37. H. W. Sternberg, R. E. Markby, I. Wender, D. M. Mohilner,
J. Am. Chem. Soc. 89, 186–187 (1967).
38. A. Misono, T. Osa, T. Yamagishi, T. Kodama, J. Electrochem.
Soc. 115, 266–267 (1968).
39. J.-E. Dubois, G. Dodin, Tetrahedron Lett. 10, 2325–2328 (1969).
40. L. A. Avaca, A. Bewick, J. Chem. Soc. Perkin Trans. 2 1972,
1709–1712 (1972).
41. J. P. Coleman, J. H. Wagenknecht, J. Electrochem. Soc. 128,
322–326 (1981).
42. R. A. Misra, A. K. Yadav, Bull. Chem. Soc. Jpn. 55, 347–348
(1982).
43. E. Kariv-Miller, K. E. Swenson, D. Zemach, J. Org. Chem. 48,
4210–4214 (1983).
44. D. Pasquariello et al., J. Phys. Chem. 89, 1243–1245 (1985).
45. F. J. Del Campo et al., J. Electroanal. Chem. 507, 144–151
(2001).
46. C. Combellas, H. Marzouk, A. Thiebault, J. Appl. Electrochem.
21, 267–275 (1991).
REFERENCES AND NOTES
47. P. J. M. van Andel-Scheffer, A. H. Wonders, E. Barendrecht,
J. Electroanal. Chem. 366, 143–146 (1994).
48. Y. Landais, E. Zekri, Eur. J. Org. Chem. 2002, 4037–4053
(2002).
49. K. Liu, Y. Liu, D. Lin, A. Pei, Y. Cui, Sci. Adv. 4, eaas9820
(2018).
1. P. W. Rabideau, Z. Marcinow, in Organic Reactions, Volume 42,
L. A. Paquette, Ed. (Wiley, 1992), pp. 1–334.
2. W. Rabten, C. Margarita, L. Eriksson, P. G. Andersson,
Chemistry 24, 1681–1685 (2018).
3. B. K. Peters et al., J. Am. Chem. Soc. 138, 11930–11935
(2016).
4. J. Liu et al., J. Am. Chem. Soc. 139, 14470–14475 (2017).
5. A. Paptchikhine, K. Itto, P. G. Andersson, Chem. Commun. 47,
3989–3991 (2011).
6. J. L. Dye et al., J. Am. Chem. Soc. 127, 9338–9339 (2005).
7. P. Nandi et al., Org. Lett. 10, 5441–5444 (2008).
8. M. J. Costanzo, M. N. Patel, K. A. Petersen, P. F. Vogt,
Tetrahedron Lett. 50, 5463–5466 (2009).
9. P. Li, S. Guo, J. Fang, J. Cheng, Huaxue Shiji 18, 234–236
(1996).
More broadly, the chemistry of dissolving
metals has been applied to a wide range of re-
ductive transformations, including ring opening
and closing (58), protecting group removal, and
transition metal–mediated reactions, among
others. However, because of the poor solubility
of alkali metals in reductively inert solvents (e.g.,
THF), these reactions have required either the
use of ammonia as a cosolvent or the aid of
polyaromatic hydrocarbons to act as electron
shuttles (59). In contrast, generation of reductive
potential can be precisely controlled in electro-
chemical systems; as a result, the limitations
associated with bulk Li metal are eliminated.
Encouraged by this realization, we began to ex-
plore the utility of our electroreduction protocol
for non-Birch reductive transformations (Fig.
5A). Ether debenzylation proceeded smoothly
(35→36) without competitive reduction of the
more electron-rich arene (in accord with Birch
guidelines). Similarly, reductive deoxygenation
was accomplished on fluorenone (37→38). Re-
ductive cyclization (39→40), similar to an ap-
proach demonstrated by Wolckenhauer and
Rychnovsky (60), was successfully achieved. Ring
opening of an epoxide (41→42) was facile, as
was furan ring opening (43→44). Remarkably,
McMurry couplings (45→46) could also be ac-
complished at room temperature. Returning to
the sumanirole example outlined in Fig. 1, the
same transformation was readily achieved at
room temperature in 2 hours (1→2, 67% yield).
It is worth noting that the most practical Birch
alternatives available (SiGNa-S1 and Na-disp./
15-c-5) failed to deliver any product, as did all
attempts to use previously reported electrochem-
ical methods (see supplementary materials).
Finally, the scalability of the protocol was
demonstrated in both batch and flow on 12 (the
direct precursor to a key Pfizer intermediate),
without any loss in efficiency. The modular flow
setup (Fig. 5B) is simple and allows an increase
in scale by several orders of magnitude in a safe
and sustainable fashion. Indeed, the very same
transformation could be achieved in flow on 100-g
scale, without major changes to the protocol,
special anhydrous precautions, or loss in yield.
Reductive electrochemical synthesis has been
an approach discussed in the literature for nearly
a century. Despite its obvious conceptual appeal,
adoption of preparative methods in this subfield
has been extremely limited because of issues re-
50. J. Coste, D. Le-Nguyen, B. Castro, Tetrahedron Lett. 31,
205–208 (1990).
51. C. A. Paddon, S. E. W. Jones, F. L. Bhatti, T. J. Donohoe,
R. G. Compton, J. Phys. Org. Chem. 20, 677–684 (2007).
52. J. Burés, Angew. Chem. Int. Ed. 55, 2028–2031 (2016).
53. N. C. L. Wood, C. A. Paddon, F. L. Bhatti, T. J. Donohoe,
R. G. Compton, J. Phys. Org. Chem. 20, 732–742 (2007).
54. B. Zhou et al., Adv. Mater. 29, 1701568 (2017).
55. O. (Youngman) Chusid, E. Ein Ely, D. Aurbach, M. Babai,
Y. Carmeli, J. Power Sources 43, 47–64 (1993).
56. T. J. Donohoe, D. House, J. Org. Chem. 67, 5015–5018
(2002).
57. M. M. Heravi, M. V. Fard, Z. Faghihi, Curr. Org. Chem. 19,
1491–1525 (2015).
58. M. Yus, F. Foubelo, Targets Heterocycl. Syst. 6, 136–171
(2002).
59. R. Luisi, V. Capriati, Eds., Lithium Compounds in Organic
Synthesis: From Fundamentals to Applications (Wiley-VCH,
2014).
60. S. A. Wolckenhauer, S. D. Rychnovsky, Org. Lett. 6, 2745–2748
(2004).
10. P. Lei et al., Org. Lett. 20, 3439–3442 (2018).
11. D. K. Joshi, J. W. Sutton, S. Carver, J. P. Blanchard, Org.
Process Res. Dev. 9, 997–1002 (2005).
12. K. E. Swenson, D. Zemach, C. Nanjundiah, E. Kariv-Miller,
J. Org. Chem. 48, 1777–1779 (1983).
13. R. A. Benkeser, E. M. Kaiser, J. Am. Chem. Soc. 85, 2858–2859
(1963).
14. M. Bordeau, C. Biran, P. Pons, M. P. Leger-Lambert,
J. Dunogues, J. Org. Chem. 57, 4705–4711 (1992).
15. M. Ishifune et al., Electrochim. Acta 48, 2405–2409 (2003).
16. J. B. Goodenough, K.-S. Park, J. Am. Chem. Soc. 135,
1167–1176 (2013).
17. J. B. Goodenough, Y. Kim, Chem. Mater. 22, 587–603
(2010).
18. E. Peled, S. Menkin, J. Electrochem. Soc. 164, A1703–A1719
(2017).
19. A. M. Haregewoin, A. S. Wotango, B.-J. Hwang, Energy Environ.
Sci. 9, 1955–1988 (2016).
20. K. Mizushima, P. C. Jones, P. J. Wiseman, J. B. Goodenough,
Mater. Res. Bull. 15, 783–789 (1980).
21. Y. Kawamata et al., J. Am. Chem. Soc. 139, 7448–7451
(2017).
22. S. Behr, K. Hegemann, H. Schimanski, R. Fröhlich, G. Haufe,
Eur. J. Org. Chem. 2004, 3884–3892 (2004).
23. A. Kirste, B. Elsler, G. Schnakenburg, S. R. Waldvogel,
J. Am. Chem. Soc. 134, 3571–3576 (2012).
24. J. Mihelcic, K. D. Moeller, J. Am. Chem. Soc. 126, 9106–9111
(2004).
25. Y. Ashikari, T. Nokami, J. Yoshida, Org. Lett. 14, 938–941
(2012).
26. T. Nokami et al., J. Am. Chem. Soc. 130, 10864–10865
(2008).
27. R. J. Perkins, D. J. Pedro, E. C. Hansen, Org. Lett. 19,
3755–3758 (2017).
28. G. Sun, S. Ren, X. Zhu, M. Huang, Y. Wan, Org. Lett. 18,
544–547 (2016).
29. C. Edinger, S. R. Waldvogel, Eur. J. Org. Chem. 2014,
5144–5148 (2014).
30. R. D. Little et al., J. Org. Chem. 53, 2287–2294 (1988).
31. J. Mortensen, J. Heinze, Angew. Chem. Int. Ed. Engl. 23, 84–85
(1984).
ACKNOWLEDGMENTS
We thank W. Qiao for assistance in setting up scale-up reactions.
We also thank D. Blackmond for assistance in interpreting the
kinetics data. Funding: Financial support for this work was
provided by NSF (CCI Phase 1 grant 1740656) to M.N., S.D.M.,
and P.S.B. Financial support was also provided by Pfizer and
Asymchem. B.K.P. and K.X.R. acknowledge the Swedish
Research Council (Vetenskapsrådet, VR 2017-00362) and
National Institutes of Health (PA-18-586), respectively, for
funding their postdoc fellowships. Y.K. acknowledges the
Hewitt Foundation for a postdoctoral fellowship. S.H.R.
acknowledges an NSF GRFP (#2017237151) and a Donald
and Delia Baxter Fellowship. Author contributions: B.K.P.
and P.S.B. conceived of the project. B.K.P., K.X.R., S.H.R.,
S.B.B., D.P.H., Y.K., M.C., J.S., S.U., K.K., T.J.G., S.L.A., M.N.,
S.D.M., and P.S.B. designed the experiments. B.K.P., K.X.R.,
S.H.R., S.B.B., D.P.H., L.C., S.U., and K.K. ran the experiments.
B.K.P., K.X.R., S.H.R., S.B.B., D.P.H., Y.K., M.C., J.S., S.U.,
K.K., T.J.G., S.L.A., M.N., S.D.M., and P.S.B. analyzed the data.
B.K.P., K.X.R., S.H.R., D.P.H., S.U., M.N., S.D.M., and P.S.B.
wrote the manuscript. Competing interests: P.S.B. serves
on a scientific advisory panel for Asymchem. Data and
materials availability: Detailed experimental and analytical
procedures and full spectral data are available in the
supplementary materials.
SUPPLEMENTARY MATERIALS
Materials and Methods
Supplementary Text
Figs. S1 to S83
Tables S1 to S7
32. M. P. S. Mousavi, S. Kashefolgheta, A. Stein, P. Buhlmann,
J. Electrochem. Soc. 163, H74–H80 (2016).
33. A. J. Birch, Nature 158, 60 (1946).
34. N. M. Alpatova, S. E. Zabusova, A. P. Tomilov, Russ. Chem. Rev.
55, 99–112 (1986).
35. H. W. Sternberg, R. Markby, I. Wender, J. Electrochem. Soc.
110, 425–429 (1963).
36. R. A. Benkeser, E. M. Kaiser, R. F. Lambert, J. Am. Chem. Soc.
86, 5272–5276 (1964).
NMR Spectra
References (61–112)
28 September 2018; accepted 23 January 2019
10.1126/science.aav5606
Peters et al., Science 363, 838–845 (2019)
22 February 2019
8 of 8