ChemComm
Page 4 of 4
DOI: 10.1039/C5CC08498A
however solely a phenylglyoxal was formed, possibly because of
RS is thankful to DST for the award of research fellowship. SBB
the immediate in-situ oxidation of V. Therefore, αꢀiodo 45 thanks DSTꢀSERB for financial support under FastꢀTrack
acetophenone (V) was prepared via reported method (CuO/I2)7
and was reacted with diamine 2 under optimized conditions,
which resulted in formation of product 3a in excellent yield
(Figure 3B). These results further supported pathway 3 as the
most favourable reaction pathway.
Scheme (grant no. SR/FT/CSꢀ168/2011).
Notes and references
5
1. For biological activities of pyridines, see: (a) M. Horiuch, C.
Murakami, N. Fukamiya, D. Yu, T.ꢀH. Chen, K. F. Bastow, D.ꢀC.
Zhang, Y. Takaishi, Y. Imakura and K.ꢀH. Lee, J. Nat. Prod., 2006,
69, 1271ꢀ1274; (b) S. Follot, J.ꢀC. Debouzy, D. Crouzier, C.
EnguehardꢀGueiffier, A. Gueiffier, F. Nachon, B. Lefebvre and F.
Fauvelle, Eur. J. Med. Chem., 2009, 44, 3509ꢀ3518; (c) V. Onnis,
M. T. Cocco, R. Fadda and C. Congiu, Bioorg. Med. Chem., 2009,
17, 6158ꢀ6165; (d) C. D. Duffy, P. Maderna, C. McCarthy, C. E.
Loscher, C. Godson and P. J. Guiry, ChemMedChem, 5, 517ꢀ522;
(e) G. M. Buckley, N. Cooper, R. J. Davenport, H. J. Dyke, F. P.
Galleway, L. Gowers, A. F. Haughan, H. J. Kendall, C. Lowe, J. G.
Montana, J. Oxford, J. C. Peake, C. L. Picken, M. D. Richard, V.
Sabin, A. Sharpe and J. B. H. Warneck, Bioorg. Med. Chem. Lett.,
2002, 12, 509ꢀ512; (f) B. Vacher, B. Bonnaud, P. Funes, N. Jubault,
W. Koek, M. B. Assie, C. Cosi and M. Kleven, J. Med. Chem.,
1999, 42, 1648ꢀ1660; (g) D. O'Hagan, Nat. Prod. Rep., 2000, 17,
435ꢀ446; (h) Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada,
N. Inamura, M. Asano, I. Aramori, C. Hatori, H. Sawai, T. Oku and
H. Tanaka, J. Med. Chem., 1998, 41, 4062ꢀ4079; (i) S. Zheng, Q.
Zhong, M. Mottamal, Q. Zhang, C. Zhang, E. LeMelle, H. McFerrin
and G. Wang, J. Med. Chem., 57, 3369ꢀ3381; (j) W. M. Eldehna, A.
Altoukhy, H. Mahrous and H. A. AbdelꢀAziz, Eur. J. Med. Chem.,
90, 684ꢀ694.
50
55
60
65
70
75
O
B.
I
N
a
H2N
NH2
+
3a
V
2
10 Figure 3 Experimental evidences to support reaction mechanism pathway
3. (A). LCMS chromatogram of reaction mixture showing presence of
three key iodoꢀintermediates of pathway 3. (B). Reaction of αꢀ
iodoacetophenone V with diamine 2 produces product 3a. Reagents and
conditions: (a) αꢀiodoacetophenone V (1 equiv.), 1,3ꢀdiaminopropane (3
15 equiv.), I2 (8 mol%), HCl (10 µl), DMSO (2 mL), 80 °C, O2, 4 h, 95%.
2. J. A. Bull, J. J. Mousseau, G. Pelletier and A. B. Charette, Chem.
Rev., 112, 2642ꢀ2713.
3.
(a) D. Bora, B. Deb, A. L. Fuller, A. M. Z. Slawin, J. Derek
Woollins and D. K. Dutta, Inorg. Chim. Acta, 363, 1539ꢀ1546; (b)
M.ꢀD. Zhou, K. R. Jain, A. Günyar, P. N. W. Baxter, E. Herdtweck
and F. E. Kühn, Eur. J. Med. Chem., 2009, 2009, 2907ꢀ2914; (c)
Y.ꢀT. Chan, C. N. Moorefield, M. Soler and G. R. Newkome, Chem.
Eur. J., 16, 1768ꢀ1771; (d) S. Lin and X. Lu, Org. Lett., 12, 2536ꢀ
2539.
Next, we conducted reaction of phenylacetones 4a-b with 1,3ꢀ
diaminopropane (2) under optimized reaction conditions. To our
surprise, we observed formation of 3ꢀphenylpyridines 5a-b and
20 not the 2ꢀbenzylpyridine products. The formation of 5a-b clearly
indicated that this reaction must be occurring via CꢀC bond
formation at active methylene group. The plausible mechanism
for formation of 3ꢀphenylpyridine 5a-b from 4a-b is depicted in
Scheme 2. Next, when we performed the reaction of phenyl
25 acetaldehyde with diamine 2, no product was formed. Finally, the
utility of this reaction for large scale synthesis of 2ꢀ
phenylpyridines was investigated (Figure S2). Reaction of 1 g of
1a (8.33 mmol) with diamine 2 (24.99 mmol) afforded 1.1 g of
product 3a (85% yield). This indicated that this reaction could be
30 efficiently scaledꢀup on a gram scale.
80 4.
(a) C. Liu and W. Yang, Chem. Commun., 2009, 6267ꢀ6269; (b) A.
V. Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan, Chem.
Rev., 113, 3084ꢀ3213; (c) O. M. Kuzmina, A. K. Steib, J. T.
Markiewicz, D. Flubacher and P. Knochel, Angew. Chem. Int. Ed.,
52, 4945ꢀ4949; (d) R. S. Senaiar, D. D. Young and A. Deiters,
Chem. Commun., 2006, 1313ꢀ1315; (e) I. Nakamura and Y.
Yamamoto, Chem. Rev., 2004, 104, 2127ꢀ2198.
85
5.
(a) K. Wu, Z. Huang, C. Liu, H. Zhang and A. Lei, Chem.
Commun., 2015, 51, 2286ꢀ2289; (b) L.ꢀY. Xi, R.ꢀY. Zhang, S.
Liang, S.ꢀY. Chen and X.ꢀQ. Yu, Org. Lett., 2014, 16, 5269ꢀ5271.
(a) S. Mohammed, R. A. Vishwakarma and S. B. Bharate, J. Org.
90 6.
I
N
Chem., 2015, 80, 6915ꢀ6921;
(b) S. Mohammed, R. A.
N
a
+
R
R
R
Vishwakarma and S. B. Bharate, RSC Adv., 2015, 5, 3470ꢀ3473; (c)
J. B. Bharate, S. Abbat, P. V. Bharatam, R. A. Vishwakarma and S.
B. Bharate, Org. Biomol. Chem., 2015, 13, 7790ꢀ7794; (d) R.
Mudududdla, R. Sharma, S. Abbat, P. V. Bharatam, R. A.
Vishwakarma and S. B. Bharate, Chem. Commun., 2014, 50, 12076ꢀ
12079; (e) J. B. Bharate, S. B. Bharate and R. A. Vishwakarma,
ACS Comb. Sci., 2014, 16, 624–630; (f) J. B. Bharate, A. Wani, S.
Sharma, S. I. Reja, M. Kumar, R. A. Vishwakarma, A. Kumar and
S. B. Bharate, Org. Biomol. Chem., 2014, 12, 6267ꢀ6277; (g) J. B.
Bharate, R. Sharma, B. Singh, S. Aravinda, V. K. Gupta, S. B.
Bharate and R. A. Vishwakarma, RSC Adv., 2013, 3, 21736–21742;
(h) J. B. Bharate, S. K. Guru, S. K. Jain, S. Meena, P. P. Singh, S.
Bhushan, B. Singh, S. B. Bharate and R. A. Vishwakarma, RSC
Adv., 2013, 3, 20869–20876; (i) S. B. Bharate, A. Padala, B. A.
Dar, R. R. Yadav, B. Singh and R. A. Vishwakarma, Tetrahedron
Lett., 2013, 54, 3558ꢀ3561; (j) R. Mudududdla, S. K. Jain, J. B.
Bharate, A. P. Gupta, B. Singh, R. A. Vishwakarma and S. B.
Bharate, J. Org. Chem., 2012, 77, 8821ꢀ8827; (k) S. B. Bharate, R.
Mudududdla, J. B. Bharate, N. Battini, S. Battula, R. R. Yadav, B.
Singh and R. A. Vishwakarma, Org. Biomol. Chem., 2012, 10,
5143ꢀ5150.
H2N
NH2
O
5a: R = 2ꢀCl
4a: R = 2ꢀCl
XV
2
5b: R = 4ꢀOMe
4b: R = 4ꢀOMe
95
O
I
I
HO
I
I
+ 2
N
N
R
R
R
NH2
N
R
O
XI
XII
XIII
XIV
100
Scheme 2 Reaction of phenylacetones 4a-b with 1,3ꢀdiaminopropane (2).
Reagents and conditions: (a) 4a-b (1 equiv.), 2 (3 equiv.), I2 (8 mol%),
HCl (10 µl), DMSO (2 mL), 80 °C, O2, 4 h, 75ꢀ80%.
35 In conclusion, we have reported a new scalable metalꢀfree
approach for oxidative cyclization of aryl ketones with 1,3ꢀ
diaminopropanes for synthesis of 2 and 3ꢀarylpyridines in good
yields. The distinct features of this method are metalꢀfree nature,
high reaction yields, excellent yields, particularly for heteroaryl
40 ketones, and feasibility at gram scale. Using quantum chemical
calculations and LCMS analysis, mechanism of the reaction has
been established.
105
110
7. M. Gao, Y. Yang, Y.ꢀD. Wu, C. Deng, L.ꢀP. Cao, X.ꢀG. Meng and
A.ꢀX. Wu, Org. Lett., 2010, 12, 1856ꢀ1859.
Acknowledgements
4
|
Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]