Organic Letters
Letter
To the best of our knowledge, this is the first general cross-
(5) Selected examples: (a) Stepan, A. F.; Subramanyam, C.;
Efremov, I. V.; Dutra, J. K.; O’Sullivan, T. J.; DiRico, K. J.;
McDonald, W. S.; Won, A.; Dorff, P. H.; Nolan, C. E.; Becker, S. L.;
Pustilnik, L. R.; Riddell, D. R.; Kauffman, G. W.; Kormos, B. L.;
Zhang, L.; Lu, Y.; Capetta, S. H.; Green, M. E.; Karki, K.; Sibley, E.;
Atchison, K. P.; Hallgren, A. J.; Oborski, C. E.; Robshaw, A. E.; Sneed,
B.; O’Donnell, C. J. J. Med. Chem. 2012, 55, 3414−3424.
coupling of various BCP Grignard reagents with primary alkyl
3
3
mesylates and secondary alkyl iodides. This sp −sp cross-
coupling appears to be a promising method for late-stage
introduction of BCP substituents and could thus become an
attractive tool for medicinal chemists for the design and
synthesis of bioactive molecules.
(
b) Nicolaou, K. C.; Vourloumis, D.; Totokotsopoulos, S.;
Papakyriakou, A.; Karsunky, H.; Fernando, H.; Gavrilyuk, J.; Webb,
D.; Stepan, A. F. ChemMedChem 2016, 11, 31. (c) Auberson, Y. P.;
Brocklehurst, C.; Furegati, M.; Fessard, T. C.; Koch, G.; Decker, A.;
La Vecchia, L.; Briard, E. ChemMedChem 2017, 12, 590−598.
ASSOCIATED CONTENT
sı Supporting Information
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(
d) Goh, Y. L.; Cui, Y. T.; Pendharkar, V.; Adsool, V. A. ACS Med.
Chem. Lett. 2017, 8, 516−520. (e) Measom, N. D.; Down, K. D.;
Hirst, D. J.; Jamieson, C.; Manas, E. S.; Patel, V. K.; Somers, D. O.
ACS Med. Chem. Lett. 2017, 8, 43−48.
Experimental procedures and spectral data for all new
(
6) Other syntheses of BCPs including the insertion of a CX group
2
into the middle bond of bicyclo[1.1.0]butane. (a) Bychek, R. M.;
Hutskalova, V.; Bas, Y. P.; Zaporozhets, O. A.; Zozulya, S.; Levterov,
V. V.; Mykhailiuk, P. K. J. Org. Chem. 2019, 84, 15106−15117.
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(
b) Also see ref 5e.
7) Functionalization of [1.1.1]propellane to give 1,3-BCPs, e.g.:
a) Bar, R. M.; Kirschner, S.; Nieger, M.; Brase, S. Chem. - Eur. J.
018, 24, 1373−1382. (b) Bar, R. M.; Heinrich, G.; Nieger, M.; Fuhr,
O.; Brase, S. Beilstein J. Org. Chem. 2019, 15, 1172−1180. (c) Shelp,
R. A.; Walsh, P. J. Angew. Chem., Int. Ed. 2018, 57, 15857−15861.
d) Caputo, D. F. J.; Arroniz, C.; Durr, A. B.; Mousseau, J. J.; Stepan,
A. F.; Mansfield, S. J.; Anderson, E. A. Chem. Sci. 2018, 9, 5295−5300.
e) Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L.
Amandine Guerinot − Molecular, Macromolecular Chemistry
́
Janine Cossy − Molecular, Macromolecular Chemistry and
(
(
2
̈
̈
̈
̈
(
̈
(
R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N.
W.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. Science 2016, 351,
241−246.
Claire Andersen − Molecular, Macromolecular Chemistry and
Materials, ESPCI Paris, CNRS, PSL University, 75005 Paris,
France
Vincent Ferey − Sanofi R&D, 34080 Montpellier, France
Marc Daumas − Sanofi Chimie, 30390 Aramon, France
Patrick Bernardelli − Sanofi R&D, 91380 Chilly-Mazarin,
France
(8) (a) Rehm, J. D. D.; Ziemer, B.; Szeimies, G. Eur. J. Org. Chem.
1999, 1999, 2079−2085. (b) Messner, M.; Kozhushkov, S. I.; de
Meijere, A. Eur. J. Org. Chem. 2000, 2000 (7), 1137−1155.
(9) Hughes, J. M. E.; Scarlata, D. A.; Chen, A. C.-Y.; Burch, J. D.;
Gleason, J. L. Org. Lett. 2019, 21, 6800−6804.
(10) One single example from 1988 shows the use of a BCP cuprate
in coupling with octyl iodide: Wiberg, K. B.; Waddell, S. T.
Tetrahedron Lett. 1988, 29, 289−292.
(11) Very recently, a dual copper-photoredox reaction was
developed to access disubstituted BCP from [1.1.1]propellane; see:
Zhang, X.; Smith, R. T.; Le, C.; McCarver, S. J.; Shireman, B. T.;
Carruthers, N. I.; MacMillan, D. W. C. Nature 2020, 580, 220.
Notes
The authors declare no competing financial interest.
(12) For a recent iron-catalyzed Kumada cross-coupling between
iodo-BCPs and (het)aryl Grignard reagents, see: Nugent, J.; Shire, B.
R.; Caputo, D. F. J.; Pickford, H. D.; Nightingale, F.; Houlsby, I. T.
T.; Mousseau, J. J.; Anderson, E. A. Angew. Chem., Int. Ed. 2020, 59,
ACKNOWLEDGMENTS
We thank Sanofi for financial support.
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11866.
(13) In order to obtain [1.1.1]propellane 2 in Et O after the
2
REFERENCES
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addition of phenyllithium on 1, a distillation under vacuum was
necessary. During this step, some of the formed [1.1.1]propellane was
(
1) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem.
014, 57, 5845−5859.
2
lost to avoid contamination with significant amounts of Bu O or
2
(
1
2) (a) Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009,
4, 1011−1020. (b) Fournier, J.-F.; Bouix-Peter, C.; Duvert, D.; Luzy,
A.-P.; Ouvry, G. J. Med. Chem. 2018, 61, 3231−3236.
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c) Mykhailiuk, P. Org. Biomol. Chem. 2019, 17, 2839.
4) (a) The distance between carbon C1 and carbon C4 in a phenyl
phenyl bromide (>50 mbar), resulting in moderate yields around 40%
in 2. See the SI for details.
(14) Recently, a flexible and fast access to aryl BCP zinc reagents
(
6
through a sequence encompassing a ring opening of [1.1.1]propellane
with aryl Grignard reagents and a transmetalation using ZnCl was
(
2
developed (see ref 4c). The use of high temperature (100 °C) using
(
Et O as the sole solvent seemed to be a high risk profile synthesis. We
group is around 2.82 Å, whereas the distance between carbon C1 and
carbon C3 in a BCP group is around 1.85 Å, which corresponds to a
5% reduction in length. Mykhailiuk, P. K. Org. Biomol. Chem. 2019,
2
therefore tried to optimize the conditions without the need for high
temperature. See the SI for details.
3
1
7, 2839−2849. (b) BCP can also be a bioisostere of a tert-butyl
(15) An addition of p-methoxyphenylmagnesium bromide as well as
the p-tolylmagnesium bromide on 2 was also attempted, resulting in
comparable mixtures of BCP and aryl Grignard reagents; see the SI
for details.
group: Westphal, M. V.; Wolfstadter, B. T.; Plancher, J.-M.; Gatfield,
̈
J.; Carreira, E. M. ChemMedChem 2015, 10, 461−469. (c) BCP can
also be a bioisostere of an alkynyl group: Makarov, I. S.; Brocklehurst,
C. E.; Karaghiosoff, K.; Koch, G.; Knochel, P. Angew. Chem., Int. Ed.
(16) Andersen, C.; Ferey, V.; Daumas, M.; Bernardelli, P.; Guer
A.; Cossy, J. Org. Lett. 2019, 21, 2285−2289.
́
inot,
2
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Org. Lett. XXXX, XXX, XXX−XXX