3
entry 6), 48%, and 43% yields, respectively. In addition, the
1
hydrogenation of 2-(pent-1’-ynyl)-pyridine 1d in MeOH
monoiodopyridines and alkynes was successfully conducted to
produce the corresponding monoalkylpiperidines in moderate to
excellent yields. The optimal conditions for the hydrogen
3
produced the corresponding alkylpiperidine 2d in 44% yield,
while a complex mixture was obtained in the case of 4-(pent-1’-
ynyl)-pyridine 1f. Furthermore, for 2-, 3-, and 4-substituted
pyridines bearing alkynyl amino acids, hydrogenation of pyridine
ring and the alkyne moiety with removal of the benzyl group at
the carboxylic acid moiety gave 2-(S)-[(tert-butoxycarbonyl)-
amino]-5-(piperidin-2’-yl)-pentanoic acid 2g, 2-(S)-[(tert-
butoxycarbonyl)-amino]-5-(piperidin-3’-yl)-pentanoic acid 2h,
2
reaction were H (1 atm) and 10 wt% Pd/C (5 eq) in either AcOH
or MeOH at room temperature, rendering our conditions milder
than those of similar previously reported hydrogenation
reactions. We therefore expect that these mild conditions will be
suitable for the quick and easy preparation of other
monoalkylpiperidines both in the laboratory and in industry.
Further synthetic studies of preparation of alkylpiperidines are
now in progress in our laboratory.
and
pentanoic acid 2i in 66%, 48%, and 42% yield in MeOH, and
00%, 80%, and 73% yield in AcOH, respectively. The yields
2-(S)-[(tert-butoxycarbonyl)-amino]-5-(piperidin-4’-yl)-
1
Acknowledgments
obtained in AcOH were significantly higher than those obtained
for the pyridine moieties bearing alkynyl alcohol groups.
We thank Mr. Takanori Sugimura (Sophia University) for
preliminary experiments. This work was supported in part by a
Grant-in-Aid for Young Scientist (B) from the Japan Society for
the Promotion of Science (JSPS; KAKENHI Grant No.
H2 (1 atm)
Pd/C (5 eq)
2
5750388).
Supplementary Material
Supplementary data
R
N
R
AcOH or MeOH
rt, 6 h
N
H
(experimental
procedures
and
OH
OH
characterization data) associated with this article can be found, in
the online version, at http://
OH
N
N
HN
H
H
2a, 57% (AcOH)
2b, 48% (AcOH)
2c, 43% (AcOH)
References and notes
HN
N
H
1. (a) Viegas, C.; Bolzani, V. S.; Furlan, M.; Barreiro, E. J.; Young,
M. C. M.; Tomazela, D.; Eberlin, M. N. J. Nat. Prod. 2004, 67,
2d, 44% (MeOH)
2f, complex mixture (MeOH)
908–910; (b) Kishore, C. A.; Reddy, S.; Yadav, J. S.; Ressy, B. V.
S. Tetrahedron Lett. 2012, 53, 4551-4554.
NHBoc
NHBoc
CO2H
6% (MeOH)
NHBoc
CO2H
42% (MeOH)
2i
2. (a) Smalberger, T. M.; Rall, G. J. H.; Wall, H. L. Tetrahedron
1968, 24, 6417-6421; (b) Kurogome, Y.; Kogio, M.; Looi, K. K.;
Hattori, Y.; Konno, H.; Hirota, M.; Makabe, H. Tetrahedron 2013,
CO2H
HN
N
H
N
H
6
9, 8349-8352.
6
48% (MeOH)
80% (AcOH)
2
g
2h
quant (AcOH)
73% (AcOH)
3. Kitbunnadaj, R.; Zuiderveld, O. P.; De Esch, I. J. P.; Vollinga, R.
C.; Bakker, R.; Lutz, M.; Spek, A. L.; Cavoy, E.; Deltent, M. F.;
Menge, W. M. P. B.; Timmerman, H.; Leurs, R. J. Med. Chem.
Scheme 3. Hydrogenation of monoalkynylpyridines in AcOH or
MeOH
2
003, 46, 5445-5457.
4
5
.
.
Boekelheide, V.; Rothchild, S. J. Am. Chem. Soc. 1948, 70, 864.
Thompson, S. K.; Priestley, T.; Smith, R.; Saha, A.; Rudara, S.;
Hajra, A. K.; Chatterjee, D.; Behrens, C. H.; He, Y.; Li, H. Y.
PCT Int. Appl., 2012112969, 23 Aug 2012.
The above results therefore indicate that the presence of an
acidic proton promotes the hydrogenation reaction. In addition, it
appears that the reactivity of the substituents on the pyridine
rings follows the order: 2 > 3 > 4. This tendency is probably due
to the closer distance between the nitrogen atom of the pyridine
moiety and the alkyne group of the 2-alkynylpyridines, which
results in strong π-electron interactions, thereby promoting the
simultaneous hydrogenation of the pyridine ring and the alkyne
moiety. Compared with the substrates shown in Scheme 1, the
conjugated π-electron system present in the alkynylpyridines
promoted the hydrogenation reaction even under the mild
6
7
.
.
Siegel, M. G.; Chaney, M. O.; Bruns, R. F.; Clay, M. P.; Schober,
D. A.; van Abbema, A. M.; Johnson, D. W.; Cantrell, B. E.; Hahn,
P. J.; Hunden, D. C.; Gehlert, D. R.; Zarrinmayeh, H.; Ornstein, P.
L.; Zimmerman, D. M.; Koppel, G. A. Tetrahedron 1999, 55,
1
1619-11639.
Qu, B.; Mangunuru, H. P. R.; Wei, X.; Fandrick, K. R.;
Desrosiers, J.-N.; Sieber, J. D.; Kurouski, D.; Haddad, N.;
Samankumara, L. P.; Lee, H.; Savoie, J.; Ma, S.; Gringerg, N.;
Sarvestani, M.; Yee, N. K.; Song, J. J.; Senanayake, C. H. Org.
Lett. 2016, 18, 4920-4923.
Koseki, Y.; Sugimura, T.; Ogawa, K.; Suzuki, R.; Yamada, H.;
Suzuki, N.; Masuyama, Y.; Lin, Y. Y.; Usuki, T. Eur. J. Org.
Chem. 2015, 18, 4024-4032.
8
9
.
.
2
conditions examined herein (i.e., H (1 atm) with Pd/C at room
Paleo, M. R.; Calaza, M. I.; Grana, P.; Sardina, F. J. Org. Lett.
2004, 6, 1061-1063.
10. Usuki, T.; Yamada, H.; Hayashi, T.; Yanuma, H.; Koseki, Y.;
temperature). Furthermore, based on the improved yield obtained
following the addition of glycine (entry 3, Table 1) and the
improved yields observed for the pyridine substrates bearing
alkynyl amino acids (Scheme 3, bottom), it appears that the
presence of an intramolecular amino acid function is crucial for
enhancing the hydrogenation of alkynylpyridines and improving
product yields.
Suzuki, N.; Masuyama, Y.; Lin, Y. Y. Chem. Commun. 2012, 12,
3
233-3235.
1
1
1. Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
2. Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.; Kappe, C. O.
Eur. J. Org. Chem. 2009, 9, 1327-1334.
13. As 2-(pent-1’-ynyl)-pyridine and 4-(pent-1’-ynyl)-pyridine were
not soluble in AcOH, the reaction was conducted in MeOH.
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Conclusion
In conclusion, the hydrogenation of the monoalkynylpyridines
prepared via a Sonogashira cross-coupling reaction between