Organic Letters
Letter
methylene α to the oxygen (38, 7%). BDE and SOMO
calculations did not provide an explanation for this
regioselectivity (see the SI). This observed selectivity could
be due to a polarity-matching effect that favors C−H bonds α
to the nitrogen for the HAT in the presence of the electrophilic
H atom abstractor sulfate radical.
While scale-up of 1a from 2-methylquinoline and Boc-
(2) (a) Su, W.-G.; Dai, G.; Jia, H.; Zhang, Z.; Weng, J.; Venable, J.
D.; Bembenek, S. D.; Chai, W.; Meduna, S. P.; Keith, J. M.; Eccles,
W.; Lebsack, A. D.; Jones, W. M.; Smith, R. C. WO/2016/119707,
Aug 4, 2016. (b) Liang, S. H.; Southon, A. G.; Fraser, B. H.; Krause-
Heuer, A. M.; Zhang, B.; Shoup, T. M.; Lewis, R.; Volitakis, I.; Han,
Y.; Greguric, I.; Bush, A. I.; Vasdev, N. ACS Med. Chem. Lett. 2015, 6,
16
1
025. (c) Smith, E. M.; Sorota, S.; Kim, H. M.; McKittrick, B. A.;
Nechuta, T. L.; Bennett, C.; Knutson, C.; Burnett, D. A.; Kieselgof, J.;
Tan, Z.; Rindgen, D.; Bridal, T.; Zhou, X.; Jia, Y.-P.; Dong, Z.;
Mullins, D.; Zhang, X.; Priestley, T.; Correll, C. C.; Tulshian, D.;
Czarniecki, M.; Greenlee, W. J. Bioorg. Med. Chem. Lett. 2010, 20,
4602.
azetidine gave high reproducibility and yield (85%), scale-up of
2
0 from 2-chloroquinoline was more cumbersome with slow
conversion and hydrolysis of the 2-chloroquinoline. Recently,
the Stephenson group has exemplified advantages of flow over
1
8
(3) Jin, J.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54,
batch for visible-light-induced photoredox catalysis.
A
19
1565.
continuous flow procedure enabled us to transform 4.0
mmol of 2-chloroquinoline in 7 h (residence time of 30 min),
resulting in a productivity of 94 mg/h to prepare 20 using only
(4) Huff, C. A.; Cohen, R. D.; Dykstra, K. D.; Streckfuss, E.;
DiRocco, D. A.; Krska, S. W. J. Org. Chem. 2016, 81, 6980.
(
5) (a) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87.
5
equiv of azetidine (see the SI).
In summary, this protocol allows α-aminoalkylation of
(
b) DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.;
Tudge, M. Angew. Chem., Int. Ed. 2014, 53, 4802. (c) Matsui, J. K.;
Primer, D. N.; Molander, G. A. Chem. Sci. 2017, 8, 3512. (d) Garza-
Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. ACS Catal.
2017, 7, 4057. (e) Cheng, W.-M.; Shang, R.; Fu, M.-C.; Fu, Y. Chem. -
Eur. J. 2017, 23, 2537. (f) Li, G.-X.; Morales-Rivera, C. A.; Wang, Y.;
Gao, F.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2016, 7 (10), 6407.
substituted Boc-protected N-methylamines with a broad range
of functionalized heterocycles. For substituted N-Boc-methyl-
ene amines, reactivity/selectivity plays in favor of constrained
cyclic amine such as azetidines. This coupling does require less
substrate than more traditional Minisci reactions with N-Boc-
azetidine being a particularly active substrate that is selective
toward amine over ethers and allows the use of more complex
(
6) For reviews on the functionalization of N-heteroarenes, see:
(
a) Boubertakh, O.; Goddard, J.-P. Eur. J. Org. Chem. 2017, 2017,
2
2
072. (b) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev.
017, 117 (13), 9302. (c) For a review on α-aminoalkyl radicals in
(
spiro)amines. A broad range of amide or carbamate directing
groups can be used, except trifluoroacetyl, which can be
employed as orthogonal N-protection. A wide variety of
functional groups are tolerated, enabling fine-tuning of
chemical properties important to optimize ADME parameters
in a drug discovery effort. Halo-substituted 6−5, 6−6
heterocycles used routinely in medicinal chemistry projects
can be utilized, hence covering a wide range of pharmaco-
logical space. This protocol is also amenable to building block
synthesis using flow chemistry. Synthetic efforts are currently
directed toward adding those higher Fsp3 structures into our
fragment library with the aim of providing high value starting
points for medicinal chemistry projects.
photoredox, see: Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc.
Chem. Res. 2016, 49, 1946.
(7) Citterio, A.; Gentile, A.; Minisci, F.; Serravalle, M.; Ventura, S. J.
Org. Chem. 1984, 49, 3364.
(8) Caronna, T.; Gambarotti, C.; Palmisano, L.; Punta, C.;
Recupero, F. Chem. Commun. 2003, 2350.
(
(
9) Duncton, M. A. MedChemComm 2011, 2, 1135.
10) Dai, C.; Meschini, F.; Narayanam, J. M. R.; Stephenson, C. R. J.
J. Org. Chem. 2012, 77, 4425. Beatty, J. W.; Stephenson, C. R. J. Acc.
Chem. Res. 2015, 48, 1474.
(
3
(
1
11) (a) Wang, J.; Li, J.; Huang, J.; Zhu, Q. J. Org. Chem. 2016, 81,
017. (b) Zhang, Y.; Teuscher, K. B.; Ji, H. Chem. Sci. 2016, 7, 2111.
12) Okugawa, N.; Moriyama, K.; Togo, H. J. Org. Chem. 2017, 82,
70.
ASSOCIATED CONTENT
Supporting Information
(13) (a) Salamone, M.; Milan, M.; DiLabio, G. A.; Bietti, M. J. Org.
Chem. 2014, 79, 7179. (b) Salamone, M.; Bietti, M. Acc. Chem. Res.
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2
(
015, 48, 2895.
14) (a) Carreira, E. M.; Fessard, C. F. Chem. Rev. 2014, 114, 8257.
(b) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett. 2014,
24, 3673. (c) Rogers-Evans, M.; Knust, H.; Plancher, J.-M.; Carreira,
E. M.; Wuitschik, G.; Burkhard, J.; Li, D. B.; Guer
8, 492.
16) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C.
Nature 2017, 547, 79.
17) Kirichok, A. A.; Shton, I.; Kliachyna, M.; Pishel, I.; Mykhailiuk,
P. K. Angew. Chem., Int. Ed. 2017, 56, 8865.
18) (a) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, C. R.
́
ot, C. Chimia 2014,
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(
(
AUTHOR INFORMATION
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(
(
J. Angew. Chem., Int. Ed. 2012, 51, 4144. (b) Douglas, J. J.; Sevrin, M.
J.; Stephenson, C. R. Org. Process Res. Dev. 2016, 20, 1134.
ORCID
(
19) DMSO/H O (3:1) was used instead of ACN/H O (1:1) to
Notes
2
2
avoid the formation of a biphasic mixture.
The authors declare no competing financial interest.
REFERENCES
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(
2
1) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
013, 113, 5322. (b) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J.
Org. Chem. 2016, 81, 6898. (c) Twilton, J.; Le, C.; Zhang, P.; Shaw,
M. H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1,
0
052.
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Org. Lett. XXXX, XXX, XXX−XXX