T. Miura et al. / Tetrahedron Letters 54 (2013) 2674–2678
2677
H
H
Acknowledgments
PCy2
N
R2
P
R2
P
KOtBu
< 0 °C
CO
L
CO
L
H
Ru
Ru
This work was supported by Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’, MEXT. T.M. and S.O. acknowledge IGER
in chemistry at Nagoya University (NU) and JSPS for financial sup-
port. The authors wish to thank Dr. K. Oyama and Y. Maeda (Chem-
ical Instrument Facility of RCMS) for NMR and ESI-MS
measurements and Professor R. Noyori (NU & RIKEN) for fruitful
discussions.
N
N
KCl, tBuOH
Cl
1d
6a
Figure 1. Milstein’s mechanism for pyridine dearomatization (L = Et2N or iPr2P) and
the ligand used here, 6a.
Supplementary data
H2
H H
H
P
7 H2
P
2a
1a
H
Supplementary data associated with this article can be found, in
N
Ru
P
Ru
P
N
Milstein's
mechanism
H N
N
H
IA
H
catA
References and notes
1. a Challis, B. C.; Challis, J. A. In The Chemistry of Amides; Zabicky, J., Patai, S., Eds.;
John Wiley & Sons: London, 1970; pp 731–857; b Beckwith, A. L. J. In The
Chemistry of Amides; Zabicky, J., Patai, S., Eds.; John Wiley & Sons: London,
1970; pp 73–185; (c) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996,
61, 4196–4197; (d) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb.
Chem. 1999, 1, 55–68; (e) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1999, 42,
5095–5099; (f) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–
10852; (g) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337–2347; (h) Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72,
7473–7476. and references cited therein; (i) Burk, R. M.; Woodward, D. F. Drug
Dev. Res. 2007, 68, 147–155; (j) Gunanathan, C.; Ben-David, Y.; Milstein, D.
Science 2007, 317, 790–792; (k) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew.
Chem., Int. Ed. 2008, 47, 2876–2879.
H
∗
+
∗
X
Ru
P
H
N
N
H
N
H
PCy2
PCy2
O
H
catB
7
8
Figure 2. Plausible pathway giving prospective catalytic species catA/catB via
formation of IA. Hydrogen atoms may occupy ꢃ positions afterward.
2. (a) Murahashi, S.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988, 110, 8256–
8258; (b) Beller, M.; Zapf, A. Chem. Eur. J. 2001, 7, 2908–2915; (c) Eldred, S. E.;
Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422–3423;
(d) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556–6557;
(e) Botella, L.; Nájera, C. J. Org. Chem. 2005, 70, 4360–4369; (f) Smith, S. M.;
Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734–3735; (g) Nakao,
Y.; Idei, H.; Kanyvia, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 5070–5071;
(h) Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2009,
131, 10003–10008; (i) Smith, S. M.; Takacs, J. M. J. Am. Chem. Soc. 2010, 132,
1740–1741.
3. (a) Greenberg, A.; Moore, D. T. J. Mol. Struct. 1997, 413–414, 477–485; (b)
Fersner, A.; Karty, J. M.; Mo, Y. J. Org. Chem. 2009, 74, 7245–7253.
4. (b) Núñez Magro, A. A.; Eastham, G. R.; Cole-Hamilton, D. J. Chem. Commun.
2007, 3154–3156.
5. (a) Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. J. Am. Chem. Soc. 2007, 129,
290–291; (b) Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.;
Ikariya, T. Angew. Chem., Int. Ed. 2009, 48, 1324–1327; (c) Ito, M.; Kobayashi, C.;
Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2010, 132, 11414–11415; (d) Ito, M.;
Ootsuka, T.; Watari, R.; Shiibashi, A.; Himizu, A.; Ikariya, T. J. Am. Chem. Soc.
2011, 133, 4240–4242.
(4a: ꢀ55% with hydrogenation conditions: 140 °C, PH2 = 4 MPa,
12 h).
The 31P{1H} NMR (toluene-d8, ppm) spectrum (Fig. S1) of the
reaction mixture obtained after the optimal induction period of
the catalyst showed a medium intensity singlet at d ꢁ15.2 corre-
sponding to 7 (Fig. 2), with an additional set of small signals (d
45.8, 71.0, 73.3, 88.1), which are all different from that of 1a (d
66.2) and the free ligand 6a (d 4.3) (Fig. 1).14 A 1H NMR of the same
sample lacks signals in the 6–9 ppm region which would corre-
spond to the protons of the original Py of 1a or of partially decom-
posed products. In order to further confirm the identity of the
catalytic species involving 7, the reaction mixture was quenched
with excess BH3ꢂTHF (25 °C, 12 h) and was analyzed via electro-
spray ionization mass spectroscopy (ESI-MS).14 The base peak
obtained matched fully hydrogenated 7 complexed with BH3
(Found: m/z = 310.2837; Calcd for 7ꢂBH3+H+: 310.2829)
(Fig. S2).21 The mixture obtained following a shorter induction per-
iod (1 h) showed a negligible ESI-MS signal for 7ꢂBH3 and an in-
tense signal consistent with unreacted 1a (Found: m/z =
750.2335; Calcd for 1a+: 750.2334) (Fig. S4). These results, with
the Hg test, suggest that catA or catB is likely to be responsible
for the hydrogenation of amides.22 Based on the fact that at least
2 equiv of 2a relative to 1a was required to ensure a high reaction
rate,23 1a is first converted into IA (16e complex) upon
6. (a) Balaraman, E.; Gnanaprakasam, B.; Shimon, L. J. W.; Milstein, D. J. Am. Chem.
Soc. 2010, 132, 16756–16758. carbamate hydrogenaiton:; (b) Balaraman, E.;
Gunanathan, C.; Zhang, J.; Shimon, L. J. W.; Milstein, D. Nat. Chem. 2011, 3, 609–
614. urea hydrogenation:; (c) Balaraman, E.; Ben-David, Y.; Milstein, D. Angew.
Chem., Int. Ed. 2011, 50, 11702–11705.
7. (a) Takebayashi, S.; John, J. M.; Bergens, S. H. J. Am. Chem. Soc. 2010, 132,
12832–12834; (b) John, J. M.; Bergens, S. H. Angew. Chem., Int. Ed. 2011, 50,
10377–10380.
8. Significantly higher electrophilicity of the carbonyl carbon of
a-alkoxy
carbonyl compounds over -unsubstituted ones due to substituent field/
a
inductive effects: (a) Das, G.; Thoronton, E. R. J. Am. Chem. Soc. 1990, 112, 5360–
5362; (b) Das, G.; Thoronton, E. R. J. Am. Chem. Soc. 1993, 115, 1302–1312.
9. (a) Hirosawa, C.; Wakasa, N.; Fuchikami, T. Tetrahedron Lett. 1996, 37, 6749–
6752; (b) Stein, M.; Breit, B. Angew. Chem., Int. Ed. 2013, 125, 2287–2290.
10. (a) Saito, S.; Noyori, R.; Miura, T.; Held, I. E.; Suzuki, M.; Iida, K. JP patent Appl.
#2011-012316, Filed: Jan. 24, 2011.; (b) Oishi, S.; Saito, S. Angew. Chem., Int. Ed.
2012, 51, 5395–5399; (c) Foo, S. W.; Oishi, S.; Saito, S. Tetrahedron Lett. 2012,
53, 5445–5448.
11. (a) Ashby, M. T.; Halpern, J. J. Am. Chem. Soc. 1991, 113, 589–594; (b) Brown, J.
M.; Maddox, P. J. Chirality 1991, 3, 345–354; (c) Hadzovic, A.; Song, D.;
MacLaughlin, C. M.; Morris, R. H. Organometallics 2007, 26, 5987–5999; (d)
Donald, S. M. A.; Vidal-Ferran, A.; Maseras, F. Can. J. Chem. 2009, 87, 1273–
1279; (e) O, W. W. N.; Lough, A. J.; Morris, R. H. Organometallics 2011, 30, 1236–
1252.
g
2-coordination of H2. The olefins of the two partially decomposed
Pys of IA are in turn hydrogenated (intramolecularly), and finally,
the structure is fully saturated, giving piperidines as in catA, catB,
and 7 during the induction period of catalyst (Fig. 2).
In summary, a sterically congested and coordinatively saturated
Ru complex 1a (catalyst precursor), combined with a bulky base,
has been demonstrated to be effective for the hydrogenation of a
range of unactivated amides. A novel structural change involving
multiple hydrogenation of the interior Py of 1a during the catalyst
induction period was also clarified. Such insight into a catalytic
species reinforces the promise of further improvement of molecu-
lar catalysts for the hydrogenation of even more kinetically inert
and thermodynamically stable unsaturated chemical bonds.
12. Alkylphosphines are better than arylphosphines for
p
p
back-donation from a
back-donation is more
metal to the dꢃP—C . The pyridine structure ensures the
effective than that which occurs to dNꢃ ðsp3Þ—C
.
Due to the supplementary
interaction with the pꢃN—C orbital, a pyridine ligand is twice as strong a
p