Journal of the American Chemical Society
Page 4 of 5
The reactions with naphthalene-based substrates are interesting.
1
2
3
4
5
6
7
8
With a 2-naphthyl substrate in entry 5, cyclization to the ring 3-
position yielding 4f’ competes with that to the 1-position; another
site competition was observed with the 1-naphthyl substrate, where
cyclization to the peri position en route to a 9-membered ketone
(i.e., 4g’) was significant (entry 6). To our delight, the reaction also
permits a one-step preparation of the tetrahydrobenzo[d]azocinone
4h from a N-propargylsulfonamide (e.g., entry 7). Importantly, the
reaction was surprisingly efficient, and the overall yield (i.e., 78%)
is better than that of its dihydroazepinone counterpart (57% in
Table 2, entry 9). Among the substrates with N or O atoms at other
locations of the tether, phenyl bihomopropargyl ether is the only
one affording a decent yield (entry 8).
(1) a) Zhang, L. Acc. Chem. Res. 2014, 47, 877–888; b) Ye, L.;
Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
3258-3259; c) Wang, Y.; Ji, K.; Lan, S.; Zhang, L. Angew.
Chem., Int. Ed. 2012, 51, 1915-1918; d) Lu, B.; Li, Y.; Wang,
Y.; Aue, D. H.; Luo, Y.; Zhang, L. J. Am. Chem. Soc. 2013,
135, 8512-8524; e) Ji, K.; Zhang, L. Org. Chem. Front. 2014,
1, 34-38; f) Ji, K.; Zheng, Z.; Wang, Z.; Zhang, L. Angew.
Chem., Int. Ed. 2015, 54, 1245-1249; g) Wang, Y.; Zheng,
Z.; Zhang, L. J. Am. Chem. Soc. 2015, 137, 5316–5319.
(2) a) Dateer, R. B.; Pati, K.; Liu, R.-S. Chem. Commun. 2012,
48, 7200-7202; b) Qian, D.; Zhang, J. Chem. Commun. 2012,
48, 7082-7084; c) Davies, P. W.; Cremonesi, A.; Martin, N.
Chem. Commun. 2011, 47, 379-381; d) Henrion, G.; Chavas,
T. E. J.; Le Goff, X.; Gagosz, F. Angew. Chem., Int. Ed. 2013,
52, 6277-6282; e) Wang, T.; Shi, S.; Hansmann, M. M.;
Rettenmeier, E.; Rudolph, M.; Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2014, 53, 3715–3719; f) Sun, N.; Chen, M.;
Liu, Y. J. Org. Chem. 2014, 79, 4055–4067; g) Bhunia, S.;
Ghorpade, S.; Huple, D. B.; Liu, R.-S. Angew. Chem., Int.
Ed. 2012, 51, 2939-2942; h) Chen, M.; Chen, Y.; Sun, N.;
Zhao, J.; Liu, Y.; Li, Y. Angew. Chem., Int. Ed. 2015, 1200-
1204; i) Shu, C.; Liu, R.; Liu, S.; Li, J.-Q.; Yu, Y.-F.; He, Q.;
Lu, X.; Ye, L.-W. Chem. - Asian J. 2015, 10, 91-95; j) Qian,
D.; Zhang, J. Chem. Commun. 2011, 47, 11152-11154; k)
Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.;
Liu, R.-S. Angew. Chem., Int. Ed. 2011, 50, 6911-6914.
(3) Cui, L.; Zhang, G.; Peng, Y.; Zhang, L. Org. Lett. 2009, 11,
1225-1228.
9
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
Of interest is that the sulfonyl groups used to enable rapid
substrate assembly, as in Table 2, entries 3-7, reside β to the nascent
carbonyl group. It is anticipated that they could be eliminated under
basic conditions to yield versatile medium-ring conjugated
enones.13 Indeed, when 3d was treated with DBU in THF in 10 min,
the benzo-fused cycloheptadienone 5 was formed in 71% isolated
yield (Eq.1). Overall, the sulfonyl group acts as a versatile yet
traceless facilitator of the umpolung chemistry.
In conclusion, we have demonstrated that novel N-
alkenoxypyridinium salts exhibit versatile enolate umpolung
reactivities. These intermediates can be readily accessed upon gold-
catalyzed addition of protonated pyridine N-oxide to C-C triple
bonds of unactivated terminal alkynes and easily activated upon
heating to react with tethered arene nucleophiles in an SN2’ manner.
The significant synthetic value of this approach is demonstrated in
this work via expedient one-pot preparation of valuable benzo-
fused medium-ring ketones from easily accessible aryl-substituted
linear alkynes. This novel strategy possesses the potential of
revolutionizing the enolate umpolung reactivities and offering
highly valuable alternatives for the synthesis of various carbonyl
compounds. Studies on challenging intermolecular reactions will
be next pursued.
(4) Noey, E. L.; Luo, Y.; Zhang, L.; Houk, K. N. J. Am. Chem.
Soc. 2011, 134, 1078-1084.
(5) Li, L.; Zhou, B.; Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.;
Ye, L.-W. Angew. Chem. Int. Ed. 2015, 54, 8245–8249.
(6) Graf, K.; Rühl, C. L.; Rudolph, M.; Rominger, F.; Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2013, 52, 12727-12731.
(7) Chen, D.-F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z.
Angew. Chem., Int. Ed. 2012, 51, 12307-12310.
(8) Begue, J. P.; Charpentier-Morize, M. Acc. Chem. Res. 1980,
13, 207-212.
(9) a) Miyata, O.; Miyoshi, T.; Ueda, M. Arkivoc 2013, 2013,
60-81; b) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53-73; c)
Coe, J. W.; Bianco, K. E.; Boscoe, B. P.; Brooks, P. R.; Cox,
E. D.; Vetelino, M. G. J. Org. Chem. 2003, 68, 9964-9970;
d) Edstrom, E. D.; Yu, T. J. Org. Chem. 1995, 60, 5382-5383;
e) Malapel-Andrieu, B.; Mérour, J.-Y. Tetrahedron 1998, 54,
11095-11110; f) Zhdankin, V. V. Arkivoc 2009, 1, 1-62; g)
Parra, A.; Reboredo, S. Chem. - Eur. J. 2013, 19, 17244-
17260.
(10) Scott, P. J. H. Seven-Membered and Larger-Ring Cyclic
Ketones In Science of Synthesis Knowledge Updates; Thieme
Chemistry: 2013; Vol. 4, p 243-299.
(11) Justik, M. W.; Kristufek, S. L.; Protasiewicz, J. D.; Deligonul,
N. Synthesis 2010, 2010, 2345-2347.
(12) Wang, Y.; Wang, Z.; Li, Y.; Wu, G.; Cao, Z.; Zhang, L.
Nature Commun. 2014, doi: 10.1038/ncomms4470.
(13) Jiang, Y.; Ichikawa, Y.; Isobe, M. Synlett 1995, 1995, 285-
288.
Supporting Information
Experimental details, compound characterization and spectra. This
material is available free of charge via the Internet at
Corresponding Author
Notes
†
These authors contributed equally.
The authors declare no competing financial interests.
The authors thank NSF (CHE-1301343) for financial support and
NIH shared instrument grant S10OD012077 for the purchase of a
400 MHz NMR. Dr. Xu Zhou thanks the Overseas Research and
Training Program for University Prominent Young and Middle-
aged Teachers and Presidents of Jiangsu Province.
ACS Paragon Plus Environment