Functionalized heterocyclic scaffolds derived from Morita-Baylis-Hillman Acetates

Article abstract of DOI:10.1039/c3cc43285h

Five series of heterocycles with extraordinary structural diversity have been regiospecifically synthesized from the same Morita-Baylis-Hillman Acetates (MBHAs). All four potential electrophilic sites (α, β, γ, δ) of MBHAs are proved to be reactive.

Full text of DOI:10.1039/c3cc43285h

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Functionalized heterocyclic scaffolds derived from
Morita–Baylis–Hillman Acetates†
Cite this: Chem. Commun., 2013,
49, 7738
Huajian Zhu, Nana Shao, Tong Chen and Hongbin Zou*
Received 3rd May 2013,
Accepted 3rd July 2013
DOI: 10.1039/c3cc43285h
www.rsc.org/chemcomm
Five series of heterocycles with extraordinary structural diversity
have been regiospecifically synthesized from the same Morita–
Baylis–Hillman Acetates (MBHAs). All four potential electrophilic
sites (a, b, c, d) of MBHAs are proved to be reactive.
Heterocyclic rings widely exist in Nature and many physio-
logically active substances, such as nucleic acids, antibiotics
and hormones, are composed of the heterocyclic units. Among
them, heterocyclic bioactive pyrroles,1 pyrazoles,2 indolizines,3
and imidazo[1,2-a]pyridines4 have been reported during the
past few decades. Accordingly, substantial attention has been
paid to develop simple and efficient methods for the synthesis of
various functionalized pyrroles,5 pyrazoles,6 indolizines,7 and
Scheme 2 Heterocyclic scaffolds derived from MBHAs.
imidazo[1,2-a]pyridines.8 In this respect, discovery and develop- coworkers8a,9a elegantly demonstrated the potential electro-
ment of highly versatile and efficient heterocyclic synthons philic sites (b or g) involved in further Michael addition to
remain a still very challenging goal.
get A or B (Scheme 1). To better understand the reactivity of
Morita–Baylis–Hillman Acetates (MBHAs)9 are highly versatile MBHAs, we tried several bifunctional nucleophiles and found
substrates which contain at least four potential electrophilic sites that five of them worked successfully. Herein, we report facile
(a, b, g, d) that open in I or II after the first Michael addition by and regiospecific approaches to provide five various functional
the nucleophilic Xꢀ (Scheme 1). Recently, Namboothiri and heterocyclic scaffolds by cyclization of MBHAs with corre-
sponding bifunctional nucleophiles (Scheme 2). We also demon-
strated that all four potential electrophilic sites (a, b, g, d) are
surprisingly highly reactive as shown by the formation of A to D
(Scheme 1).
Initially we optimized the reaction of MBHAs with bifunc-
tional nucleophiles. Different solvents were examined and the
results indicated that solvent selection is crucial for the cycliza-
tion [see the ESI†]. We also tested different bases and found
that the base also plays an important role in the success of
construction of heterocyclic scaffolds (see ESI†). These initial
experiments established the feasibility of the proposed reac-
tion and provided insights for potentially expanding the
scope of the bifunctional nucleophiles. Several bifunctional
nucleophiles were assessed and five of them were found
to be successful in providing functionalized heterocycles (1–5,
Scheme 2). Most of the reactions proceeded under relatively
smooth conditions and gave the desired products with moderate
to high yields after isolation. It was noted that the different
electron-withdrawing groups (EWG) and electron-donating
Scheme 1 Potential electrophilic sites of MBHAs.
Institute of Materia Medica, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, China. E-mail: zouhb@zju.edu.cn;
Fax: +86 571 8820 8835; Tel: +86 571 8820 8835
† Electronic supplementary information (ESI) available: Optimization of reaction
conditions, experimental procedures and spectroscopic data. See DOI: 10.1039/
c3cc43285h
c
7738 Chem. Commun., 2013, 49, 7738--7740
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Table 1 Synthesis of imidazo[1,2-a]pyridines and the proposed mechanisma
Table 2 depicts a number of examples of indolizines 2 that
were synthesized by reacting MBHAs with ethyl 2-pyridylacetate
7a and 2-pyridylacetonitrile 7b respectively. After the first Michael
addition with bifunctional nucleophiles 7, the potential electro-
philic site b (V) participates in subsequent Michael-elimination
and rearrangement to provide indolizines with moderate to high
yields (Table 2). When the EWG was COOEt, the trifluoromethyl
substituted MBHA provided lower isolated yields (Table 2, entry 7).
When the EWG was CN, the MBHAs with electron-rich sub-
stituents proved to be more reactive (Table 2, entries 19 and 20).
Furthermore, MBHAs bearing COOEt usually gave the desired
products with better isolated yields than those with CN (Table 2,
entries 1–6 and 12–17) which might be attributed to the poor
electron-withdrawing property of the CN group. Notably, when
EWG was COOEt or CN extremely high isolation yields were
observed when MBHAs contained a furyl substituent (Table 2,
entries 11 and 21).
Synthesis of substituted pyrroles and pyrazoles was accom-
plished by using ethyl 2-isocyanoacetate 8 and phenylhydrazine 9
as bifunctional nucleophiles (Table 3). Ethyl 2-isocyanoacetate 8
initiates the nucleophilic Michael addition to MBHAs followed by
elimination of acetate in an overall SN20 reaction to generate
intermediate VI, while phenylhydrazine 9 affords VII. Further
intramolecular regioselective Michael addition–elimination at
the g site takes place to afford products 3 and 4 respectively
(Table 3). The regioselectivity observed in the intramolecular
Michael addition might be attributed to geometric factors as
well as the formation of aromatized heterocyclic products 3
and 4. An additional observation was that the isolated yields of 3
did not differ when MBHAs contained either electron-donating
or electron-withdrawing groups (Table 3, entries 1–11).
Entry
R
Yieldb [%]
Entry
R
Yieldb [%]
1
2
3
4
5
Ph
72, 1a
87, 1b
77, 1c
84, 1d
79, 1e
6
7
8
9
3-CF3-Ph
84, 1f
63, 1g
47, 1h
51, 1i
57, 1j
4-Cl-Ph
4-F-Ph
4-Br-Ph
3-Br-Ph
4-OCH3-Ph
4-OAc-Ph
4-N(CH3)2-Ph
2-Furyl
10
a
Reaction conditions: MBHAs (0.3 mmol), 6 (0.3 mmol), K2CO3 (0.3 mmol)
and DMF (2 mL) were stirred at rt for 30 min, then stirred at 115 1C for 1 h.
b
Yield of the isolated product.
groups (EDG) of the aromatic ring of MBHAs have an effect on
the product yields for most of the reactions.
The reactions of a series of MBHAs were first tested with
2-amino-1-ethoxycarbonylmethyl-pyridium 6 (Table 1). We were
surprised to find that the desired cycloaddition did not occur
under mild reaction conditions. With a dramatic increase in
temperature to 115 1C in DMF, the aromatized cyclizations of
MBHAs and 6 were observed. As shown in Table 1, MBHAs
provide the carbon in 6 producing the corresponding substituted
imidazo[1,2-a]pyridines 1 which undergo a Michael-elimination,
rearrangement (III) and subsequently another Michael addition
at the electrophilic site a (IV) followed by an automatic elimina-
tion. All the reactions provided moderate to high yields while the
MBHAs bearing electron-withdrawing groups gave the desired
products with better isolated yields than those with electron-
donating groups (Table 1, entries 2–10).
Finally, 2-aminophenol 10 was chosen as the bifunctional
nucleophile and the possible mechanism for the reaction is
Table 2 Synthesis of indolizines and the proposed mechanisma
Table 3 Synthesis of pyrroles,a pyrazolesb and the proposed mechanism
Entry
R
Yieldc [%] Entry
R
Yieldc [%]
Entry R 7ab
Yieldc [%] Entry R 7bb
Yieldc [%]
1
2
3
4
5
6
7
8
Ph
4-Cl-Ph
4-F-Ph
4-Br-Ph
3-Br-Ph
2-Br-Ph
3-CF3-Ph
4-OCH3-Ph
4-OAc-Ph
66, 3a
60, 3b
60, 3c
53, 3d
40, 3e
58, 3f
60, 3g
56, 3h
68, 3i
12
13
14
15
16
17
18
19
20
21
Ph
86, 4a
98, 4b
82, 4c
91, 4d
67, 4e
Trace
93, 4f
1
2
3
Ph
4-Cl-Ph
4-F-Ph
81, 2a
80, 2b
92, 2c
83, 2d
82, 2e
73, 2f
52, 2g
77, 2h
73, 2i
12
13
14
15
16
17
18
19
20
21
Ph
65, 2l
4-Cl-Ph
4-F-Ph
4-Br-Ph
3-Br-Ph
2-Br-Ph
3-CF3-Ph
4-OCH3-Ph 69, 4g
4-OAc-Ph
2-Furyl
4-Cl-Ph
4-F-Ph
4-Br-Ph
3-Br-Ph
2-Br-Ph
3-CF3-Ph
4-OCH3-Ph 78, 2s
4-OAc-Ph
2-Furyl
54, 2m
60, 2n
59, 2o
60, 2p
65, 2q
61, 2r
4
5
6
7
8
9
4-Br-Ph
3-Br-Ph
2-Br-Ph
3-CF3-Ph
4-OCH3-Ph
4-OAc-Ph
9
10
11
64, 4h
75, 4i
76, 2t
95, 2u
4-N(CH3)2-Ph 68, 3j
2-Furyl 62, 3k
10
11
4-N(CH3)2-Ph 73, 2j
2-Furyl 94, 2k
a
Reaction conditions: MBHAs (0.3 mmol), 8 (0.3 mmol), DBU (0.3 mmol)
a
b
Reaction conditions: MBHAs (0.3 mmol), 7 (0.3 mmol), Et3N (0.45 mmol) and toluene (2 mL) were stirred at rt for 2 h. MBHAs (0.3 mmol),
and MeCN (2 mL) were stirred at rt overnight. 7a (EWG: COOEt), 9 (0.3 mmol), MeOH (2 mL) were stirred at 65 1C overnight. Yield of
b
c
c
7b (EWG: CN). Yield of the isolated product.
the isolated product.
c
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Table 4 Synthesis of benzo[b][1,6]oxazocin-2-ones and the proposed mechanisma
Notes and references
1 (a) Y. Arikawa, H. Nishida, O. Kurasawa, A. Hasuoka, K. Hirase,
N. Inatomi, Y. Hori, J. Matsukawa, A. Imanishi, M. Kondo, N. Tarui,
T. Hamada, T. Takagi, T. Takeuchi and M. Kajino, J. Med. Chem.,
2012, 55, 4446; (b) R. B. Thompson, FASEB J., 2001, 15, 1671.
2 (a) K. L. Kees, J. J. Fitzgerald, K. E. Steiner, J. F. Mattes, B. Mihan,
T. Tosi, D. Mondoro and M. L. McCaleb, J. Med. Chem., 1996,
39, 3920; (b) T. D. Penning, J. J. Talley, S. R. Bertenshaw,
J. S. Carter, P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee,
J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu,
G. D. Anderson, E. G. Burton, J. N. Cogburn, S. A. Gregory,
C. M. Koboldt, W. E. Perkins, K. Seibert, A. W. Veenhuizen,
Y. Y. Zhang and P. C. Isakson, J. Med. Chem., 1997, 40, 1347;
(c) S. A. F. Rostom, Bioorg. Med. Chem., 2010, 18, 2767; (d) A. A.
Fadda, E. Abdel-Latif and R. E. El-Mekawy, Eur. J. Med. Chem., 2009,
44, 1250; (e) S. Kiyonaka, K. Kato, M. Nishida, K. Mio, T. Numaga,
Y. Sawaguchi, T. Yoshida, M. Wakamori, E. Mori, T. Numata, M. Ishii,
H. Takemoto, A. Ojida, K. Watanabe, A. Uemura, H. Kurose, T. Morii,
T. Kobayashi, Y. Sato, C. Sato, I. Hamachi and Y. Mori, Proc. Natl.
Acad. Sci. U. S. A., 2009, 106, 5400.
Entry
R
Yieldb [%]
Entry
R
Yieldb [%]
1
2
3
4
5
Ph
73, 5a
83, 5b
87, 5c
92, 5d
76, 5e
6
7
2-Br-Ph
3-CF3-Ph
4-OCH3-Ph
4-OAc-Ph
4-N(CH3)2-Ph
74, 5f
87, 5g
60, 5h
56, 5i
70, 5j
4-Cl-Ph
4-F-Ph
4-Br-Ph
3-Br-Ph
8c
9c
10c
a
Reaction conditions: MBHAs (0.3 mmol), 10 (0.3 mmol) and MeOH
(2 mL) were stirred at rt for 15 min, then Na2CO3 was added and stirred
at 40 1C. Yield of the isolated product. The mixture should be stirred
at 60 1C.
b
c
3 (a) S. Hagishita, M. Yamada, K. Shirahase, T. Okada, Y. Murakami,
Y. Ito, T. Matsuura, M. Wada, T. Kato, M. Ueno, Y. Chikazawa,
K. Yamada, T. Ono, I. Teshirogi and M. Ohtani, J. Med. Chem.,
1996, 39, 3636; (b) R. Oslund, N. Cermak and M. Gelb, J. Med. Chem.,
2008, 51, 4708.
4 (a) O. Kim, Y. Jeong, H. Lee, S.-S. Hong and S. Hong, J. Med. Chem.,
2011, 54, 2455; (b) A. Kamal, J. S. Reddy, M. J. Ramaiah, D. Dastagiri,
E. V. Bharathi, M. V. P. Sagar, S. N. C. V. L. Pushpavalli, P. Ray and
M. Pal-Bhadra, Med. Chem. Commun., 2010, 1, 355; (c) J. B. Veron,
H. Allouchi, C. E. Gueiffier, R. Snoeck, G. A. E. De Clercq and
A. Gueiffier, Bioorg. Med. Chem., 2008, 16, 9536; (d) A. Scribner,
R. Dennis, J. Hong, S. Lee, D. McIntyre, D. Perrey, D. Feng,
M. Fisher, M. Wyvratt, P. Leavitt, P. Liberator, A. Gurnett, C. Brown,
J. Mathew, D. Thompson, D. Schmatz and T. Biftu, Eur. J. Med. Chem.,
2007, 42, 1334; (e) G. Trapani, M. Franco, L. Ricciardi, A. Latrofa,
G. Genchi, E. Sanna, F. Tuveri, E. Cagetti, G. Biggio and G. Liso,
J. Med. Chem., 1997, 40, 3109.
5 (a) M. Zhang, H. Neumann and M. Beller, Angew. Chem., Int. Ed.,
2013, 52, 597; (b) M. P. Huestis, L. Chan, D. R. Stuart and K. Fagnou,
Angew. Chem., Int. Ed., 2011, 50, 1338; (c) J. Zeng, Y. Bai, S. Cai, J. Ma
and X. Liu, Chem. Commun., 2011, 47, 12855; (d) E. Lourdusamy,
L. Yao and C. M. Park, Angew. Chem., Int. Ed., 2010, 49, 7963;
(e) S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc.,
2010, 132, 9585; ( f ) D. R. Stuart, P. Alsaben, M. Kuhn and K. Fagnou,
J. Am. Chem. Soc., 2010, 132, 18326; (g) X. Xin, D. Wang, X. Li and
B. Wang, Angew. Chem., Int. Ed., 2012, 51, 1693; (h) Y. Jiang,
W. C. Chan and C. M. Park, J. Am. Chem. Soc., 2012, 134, 4104.
6 (a) K. Fuchibe, M. Takahashi and J. Ichikawa, Angew. Chem., Int. Ed.,
2012, 51, 12059; (b) D. J. Babinski, X. Bao, M. E. Arba, B. Chen,
D. A. Hrovat, W. T. Borden and D. E. Frantz, J. Am. Chem. Soc., 2012,
134, 16139; (c) H. Zou, H. Zhu, J. Shao, J. Wu, W. Chen,
M. A. Giulianotti and Y. Yu, Tetrahedron, 2011, 67, 4887; (d) J. Hu,
Y. Cheng, Y. Yang and Y. Rao, Chem. Commun., 2011, 47, 10133;
(e) J. J. Neumann, M. Suri and F. Glorius, Angew. Chem., Int. Ed., 2010,
49, 7790; ( f ) B. S. Gerstenberger, M. R. Rauckhorst and J. T. Starr,
Org. Lett., 2009, 11, 2097.
outlined in Table 4. The reaction is initiated by Michael addition
of the primary amino group of 10 as the nucleophilic center to
MBHAs. This is followed by elimination of acetate in an overall
SN20 reaction and two-step rearrangements to generate the
intermediate VIII. Subsequently, the phenolic hydroxyl serves
as another nucleophile attacking the carbonyl (d site) to form IX
followed by an elimination to afford the eight-membered
heterocyclic benzo[b][1,6]oxazocin-2-ones which have not been
reported before (Table 4). As shown in Table 4, an increase
in reaction temperature from 40 1C to 60 1C is required for
the MBHAs with the electron-donating groups (entries 8–10).
Even so the isolated yields are lower than those with electron-
withdrawing groups. Unexpectedly, the corresponding target
compound cannot be achieved when MBHAs contain a furyl
substituent.
In summary, we have developed facile and regiospecific
routes to synthesize five series of heterocycles with extraordinary
structural diversity starting from the same highly efficient synthons
as MBHAs. Interestingly, the benzo[b][1,6]oxazocin-2-one scaf-
fold has never been reported. Notably, after the first Michael
addition at the a position of MBHAs, all of the four subsequent
potential electrophilic sites (a, b, g, d) can undergo another
nucleophilic attack to form heterocyclic compounds, such as
imidazo[1,2-a]pyridines (1, a/a), indolizines (2, a/b), pyrroles
(3, a/g), pyrazoles (4, a/g), and benzo[b][1,6]oxazocin-2-ones
(5, a/d). The results described herein provide insights into the
property of MBHAs and give an excellent opportunity to con-
struct diversified heterocycles by reaction with a broad range of
bifunctional nucleophiles.
¨
7 (a) H. Zhu, J. Stockigt, Y. Yu and H. Zou, Org. Lett., 2011, 13, 2792;
´
´
(b) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lopez and M. Tomas, J. Am.
Chem. Soc., 2010, 132, 13200.
8 (a) D. K. Nair, S. M. Mobin and I. N. Namboothiri, Org. Lett., 2012,
`
14, 4580; (b) O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacapere and
This work was supported by National Natural Science Foun-
dation of China (21272207), Natural Science Foundation of
Zhejiang Province (LY12H30006), and Zhejiang Qianjiang talent
M. Y. Balakirev, J. Am. Chem. Soc., 2011, 133, 10058; (c) N. Chernyak
and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2743; (d) L. Ma,
X. Wang, W. Yu and B. Han, Chem. Commun., 2011, 47, 11333.
9 (a) D. K. Nair, S. M. Mobin and I. N. N. Namboothiri, Tetrahedron
Lett., 2012, 53, 3349; (b) R. J. Reddy and K. Chen, Org. Lett., 2011,
13, 1458; (c) W. Y. Huang, Y. C. Chen and K. Chen, Chem.–Asian J.,
2012, 7, 688; (d) L. F. Yeh, S. Anwar and K. Chen, Tetrahedron, 2012,
68, 7317; (e) K. Kaur and I. N. Namboothiri, Chimia, 2012, 66, 913;
( f ) T. Kumar, S. M. Mobin and I. N. Namboothiri, Tetrahedron, 2013,
69, 4964.
¨
plan (2011R10023). We thank Prof. Dr Joachim Stockigt, Prof.
Dr Yongping Yu and Prof. Dr Sunliang Cui (Zhejiang University,
China) for valuable discussions and Dr Marc A. Giulianotti
(Torrey Pines Institute for Molecular Studies, USA) for proof-
reading the manuscript.
c
7740 Chem. Commun., 2013, 49, 7738--7740
This journal is The Royal Society of Chemistry 2013