Communication
modification of 1,3-diacetylbicyclo[1.1.1]pentane.
of the BCP acyl chloride intermediates (8a–e) with 4-fluoroaniline
under standard amidation conditions subsequently rendered a
ChemComm
27,33
Treatment
9 A. M. Dimlaç, E. Spuling, A. de Meijere and S. Br ¨a se, Angew. Chem.,
Int. Ed., 2017, 56, 5684.
0 K. Semmler, G. Szeimies and J. Belzner, J. Am. Chem. Soc., 1985,
1
107, 6410.
selection of new BCP species 9a–e bearing both an ester and an 11 K. R. Mandanaro and W. P. Dailey, Org. Synth., 1998, 75, 98.
1
1
2 M. D. Levin, P. Kaszynski and J. Michl, Chem. Rev., 2000, 100, 169.
3 K. B. Wiberg and F. H. Walker, J. Am. Chem. Soc., 1982, 104,
amide moiety (Scheme 6). This novel method thus offers an
attractive entry to these valuable building blocks and compared
5239.
to previously reported multi-step routes, our direct method 14 (a) M. Baumann, T. S. Moody, M. Smyth and S. Wharry, Org. Process
Res. Dev., 2020, 24, 1802–1813; (b) M. B. Plutschack, B. Pieber,
K. Gilmore and P. H. Seeberger, Chem. Rev., 2017, 117, 11796;
provides these targets in high step- and atom-economy and
additionally offers variation of the ester functionality without
introducing additional synthetic steps.
(
c) K. F. Jensen, AIChE J., 2017, 63, 858.
15 M. Movsisyan, E. I. P. Delbeke, J. K. E. T. Berton, C. Battilocchio,
S. V. Ley and C. V. Stevens, Chem. Soc. Rev., 2016, 45, 4892.
In conclusion, we have developed a continuous flow platform
for the on-demand synthesis of [1.1.1]propellane. Crucially, this
flow method bridges a gap as it allows to reliably execute this
transformation on laboratory scale (1–10 mmol) whereas the
related batch process is most effectively executed on larger scales
to counteract product losses during the low-temperature distilla-
1
6 (a) M. Baumann, T. S. Moody, M. Smyth and S. Wharry, Eur. J. Org.
Chem., 2020, 7398; (b) F. M. Akwi and P. Watts, Chem. Commun.,
2018, 54, 13894.
1
7 (a) D. Dallinger, B. Gutmann and C. O. Kappe, Acc. Chem. Res., 2020,
53, 1330; (b) L. Degennaro, C. Carlucci, S. De Angelis and R. Luisi,
J. Flow Chem., 2016, 6, 136; (c) B. Gutmann and C. O. Kappe, J. Flow
Chem., 2017, 7, 65.
3
4
18 (a) B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem., Int. Ed.,
tion process as exemplified in recent industrial reports. Appli-
cations to the synthesis of several important BCP derivatives are
2
2
015, 54, 6688; (b) M. Colella, A. Nagaki and R. Luisi, Chem. – Eur. J.,
020, 26, 19.
highlighted, including the multi gram-scale synthesis of BCP-I2. 19 (a) A. Gioiello, A. Piccinno, A. M. Lozza and B. Cerra, J. Med. Chem.,
2
020, 63, 6624; (b) V. R. L. J. Bloemendal, M. A. C. H. Janssen,
J. C. M. van Hest and F. P. J. T. Rutjes, React. Chem. Eng., 2020,
, 1186; (c) R. Porta, M. Benaglia and A. Puglisi, Org. Process Res.
Finally, we disclose the novel synthesis of a range of unsymme-
trical BCP ester/amide structures which offers a more efficient
and direct route to these valuable building blocks compared to
previously published methods.
5
Dev., 2016, 20, 2.
2
0 The patent literature lists one recent continuous method for gen-
erating [1.1.1]propellane, for details please see: K. D. Bunker, et al.,
WO 2019/051038 A1, 2019.
We are grateful to the School of Chemistry for providing a
postgraduate scholarship (to KD). SFI is acknowledged for 21 R. Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R. Malins,
L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego, N. W. Sach,
J. E. Spangler, H. Zhu, J. Zhu and P. S. Baran, Science, 2016, 351,
support through the 2018 Infrastructure Call (18/RI/5702) and
the European Development Fund (12/RC2275_P2).
241.
22 A. Ghanem, T. Lemenand, D. Della Valle and H. Peerhossaini,
Chem. Eng. Res. Des., 2014, 92, 205.
2
3 (a) R. M. B ¨a r, S. Kirschner, M. Nieger and S. Br ¨a se, Chem. – Eur. J.,
Conflicts of interest
2
018, 24, 1373; (b) R. M. B ¨a r, G. Heinrich, M. Nieger, O. Fuhr and
S. Br ¨a se, Beilstein J. Org. Chem., 2019, 15, 1172.
4 K. B. Wiberg and S. T. Waddell, J. Am. Chem. Soc., 1990, 112,
There are no conflicts to declare.
2
2194.
Notes and references
25 Y. L. Goh, E. K. W. Tam, P. H. Bernardo, C. B. Cheong,
C. W. Johannes, A. D. William and V. A. Adsool, Org. Lett., 2014,
16, 1884.
1
2
P. K. Mykhailiuk, Org. Biomol. Chem., 2019, 17, 2839.
R. Pellicciari, M. Raimondo, M. Marinozzi, B. Natalini, 26 K. B. Wiberg and N. McMurdle, J. Am. Chem. Soc., 1994, 116, 11990.
G. Costantino and C. Thomsen, J. Med. Chem., 1996, 39, 2874. 27 P. Kaszynski and J. Michl, J. Org. Chem., 1988, 53, 4593.
A. F. Stepan and C. Subramanyam, et al., J. Med. Chem., 2012, 28 J. Nugent, C. Arroniz and B. R. Shire, et al., ACS Catal., 2019, 9, 9568.
5, 3414. 29 S. Kim and S. Y. Jon, Tetrahedron Lett., 1998, 39, 7317.
I. S. Makarov, C. E. Brocklehurst, K. Karaghiosoff, G. Koch and 30 For an example amongst patents: Y. Suzuki, D. Jimenez-Teja,
P. Knochel, Angew. Chem., Int. Ed., 2017, 56, 12774.
C. Salom ´e and T. Fessard, WO 2017/157932 A1, 2017.
M. V. West, J. Plancher, J. Gatfield and E. M. Carreira, ChemMed- 31 For recently published examples from our lab using this high-power
3
4
5
5
Chem, 2015, 10, 461.
LED lamp, please see: (a) S. Bonciolini, M. Di Filippo and
M. Baumann, Org. Biomol. Chem., 2020, 18, 9428; (b) M. Di Filippo
and M. Baumann, Eur. J. Org. Chem., 2020, 6199.
6
7
F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752.
X. Zhang, R. T. Smith, C. Le, S. J. McCarver, B. T. Shireman,
N. I. Carruthers and D. W. C. MacMillan, Nature, 2020, 580, 220.
32 C. Michelin and N. Hoffmann, ACS Catal., 2018, 8, 12046.
8
(a) X. Ma and L. N. Pham, Asian J. Org. Chem., 2020, 9, 8; 33 S. O. Kokhan, Y. B. Valter, A. V. Tymtsunik, I. V. Komarov and
b) M. M. D. Pramanik, H. Qian, W.-J. Xiao and J.-R. Chen, O. O. Grygorenko, Eur. J. Org. Chem., 2017, 6450.
Org. Chem. Front., 2020, 7, 2531; (c) J. Kanazawa and 34 C. Zarate and M. Ardolino, et al., Org. Process Res. Dev., 2021, DOI:
M. Uchiyama, Synlett, 2019, 1. 10.1021/acs.oprd.0c00446.
(
2874 | Chem. Commun., 2021, 57, 2871ꢀ2874
This journal is The Royal Society of Chemistry 2021