A controlled selective synthesis of dihydropyrans through tandem reaction of alkynes with diazo compounds

Article abstract of DOI:10.1039/C7CC01616F

We report here an effective protocol to prepare highly functionalized dihydropyrans via sequential reaction of cross-coupling-intramolecular Michael addition of functionalized terminal alkynes and diazo compounds under mild reaction conditions. Importantly, by choosing different ligands, the configuration of exocyclic double bonds of dihydropyrans can be selectively controlled.

Full text of DOI:10.1039/C7CC01616F

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A controlled selective synthesis of dihydropyrans
through tandem reaction of alkynes with diazo
compounds†
Cite this:DOI: 10.1039/c7cc01616f
Received 2nd March 2017,
Accepted 25th March 2017
Junxiang Min, Guangyang Xu and Jiangtao Sun
*
DOI: 10.1039/c7cc01616f
rsc.li/chemcomm
We report here an effective protocol to prepare highly functionalized
dihydropyrans via sequential reaction of cross-coupling-intramolecular
Michael addition of functionalized terminal alkynes and diazo
compounds under mild reaction conditions. Importantly, by choosing
different ligands, the configuration of exocyclic double bonds of
dihydropyrans can be selectively controlled.
Five- and six-membered oxygen-containing heterocycles are
common motifs found in a variety of bioactive natural products
and pharmaceuticals.1 Numerous efforts have been devoted to
development of efficient protocols for the stereoselective synthesis of
these compounds. However, despite great advances, highly
substituted six-membered oxacycles, including pyrans and
dihydropyrans, remain difficult to access. Thus, new methodologies
are highly needed.
On the other hand, metal–carbene mediated cyclizations have
received much attention due to their versatility in constructing
synthetically useful molecular scaffolds.2 Many valuable methodo- Scheme 1 Previous report and our protocol.
logies have been developed to prepare various ring systems
including oxacycles via metal-catalyzed intermolecular reactions
of diazo compounds with readily available substrates.3 Such
Recently, we developed a copper-catalyzed protocol to synthesize
methods for the construction of 5-membered oxygenated hetero- five-membered heterocycles from diazoacetates and terminal alkynes
cycles are many, including tetrahydrofurans4 and dihydrofurans.5 under base free conditions.7a We envisaged that this protocol could
In contrast, approaches to synthesize 6-membered oxacycles are be improved or modified to synthesize six-membered dihydropyrans
´
less. Recently, Saa and co-workers described an elegant protocol by choosing specific functionalized alkynes. Thus, our plan starts
for synthesizing dihydropyrans from readily available alkynals and from the copper-catalyzed cross-coupling reaction of terminal alkyne
alkynones through ruthenium-catalyzed cyclizations (Scheme 1a).6 1a with diazoacetate 2a (Scheme 2). This reaction would result in the
In continuation of our interest in carbene chemistry,7 we now report formation of an allenoate intermediate in the presence of a base
a novel controlled stereoselective synthesis of dihydropyrans from (from alkynes)8 even under base-free conditions. Moreover, as a good
diazo compounds and alkynyl–carbonyl compounds (Scheme 1b).
Michael acceptor, this allenoate intermediate could undergo three
types of cyclizations under different reaction conditions. First, in the
absence of base, the direct intramolecular oxo-Michael addition of
carbonyl oxygen atoms to allenoate would generate zwitterionic
intermediate II, followed by H-migration to afford cycloaddition
product 3a (Scheme 2, path A). Alternatively, treatment of allenoate
I with base would furnish nucleophilic enol anion III or carbon
anion IV, respectively. We anticipated that these different addition
modes would selectively yield dihydropyrans (3a or 4a) through path
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology,
and School of Pharmaceutical Engineering & Life Science, Changzhou University,
Changzhou 213164, P. R. China. E-mail: jtsun@cczu.edu.cn, jtsun08@gmail.com;
Fax: +86 519 86334598; Tel: +86 519 86334597
† Electronic supplementary information (ESI) available. CCDC 1528333. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7cc01616f
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Table 1 Selected optimizationa
Entry
Ligand
Base
Solvent
T (1C)
3a/4a/6ab (%)
1
2
3
4
5
6
7
8
—
—
—
—
—
—
—
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
LiOtBu
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
50
50
50
50
50
50
25
25
25
25
25
25
25
25
25
25
—
—
L1–L10
L11
L12
L13
L14
L15
—
L1–L2
L3
L4
L5–L9
L10
L11–L15
L4
L4
L4
55/36/9
49/40/11
51/32/17
(70)/10/8
35/30/35
(33)/(27)/7
o5
Scheme 2 Our strategy.
9
10
11
12
13
14
15
16
17
0/(52)/5
0/(65)/7
o5
B (oxo-Michael addition), or carbocycle 5a through path C (C–C bond
formation). Nevertheless, it should be noted that this type of alkyne
is prone to undergo Conia-ene reaction resulting in the formation of
6a in the presence of a copper complex.9
9/(60)/7
o5
0/53/8
0/19/12
7/22/o5
Upon the above hypothesis, we started our investigation by
using 1a and 2a as starting materials and CuCl as the catalyst to
optimize the reaction conditions. Initially, we observed that the
reaction did not give the cycloaddition products in acetonitrile
at 50 1C in the absence of a ligand and base (Table 1, entry 1).
a
Reaction conditions: 1g (0.2 mmol), 2a (0.24 mmol), CuCl (10 mmol%),
ligand (12 mmol%), at 50 1C for 12 h (entries 1 to 7). Then base (0.24 mmol)
was added and the reaction mixture was continuously stirred for another 2 h
b
(entries 8 to 17). NMR yields. Isolated yields in parentheses.
The combination of CuCl with nitrogen-containing ligands L1 observed in the absence of base (this intermediate is unstable, see
to L10 also did not furnish any product under the same the ESI† for details). The above optimization revealed that 3a and
conditions as in entry 1. However, when phosphine ligand 4a with opposite double bond configuration could be selectively
L11 was added, the yield of 3a was improved to 55% associated obtained as the major products by changing the reaction
with 36% yield of 4a and 9% yield of 6a (entry 3). The use of L12 conditions. The experiment results disclosed that the addition
and L13 gave similar results (entries 4 and 5). Gratifyingly, of a base favored the formation of the E-isomer of the dihydro-
the combination of phosphine ligand L14 with CuCl resulted pyran. It should be noted that compound 5a (described in
in 70% isolated yield of 3a with a small amount of 4a and 6a Scheme 2, path C) was not detected in the whole screening
(entry 6). When diphosphine ligand L15 was employed, the process. Moreover, the use of CuI, CuBr and other copper salts
reaction selectivity was poor (entry 7). Next, we examined the resulted in very low yields of the dihydropyrans.
role of base in the reaction. The use of CuCl followed by
With the optimal reaction conditions in hand, we then used
addition of Cs2CO3 gave 3a and 4a in 33% and 27% isolated the combination of CuCl and L14 to investigate the substrate
yield associated with a small amount of Conia-ene product 6a scope (Table 2). Both alkynes and diazo compounds were
in dichloromethane at room temperature (entry 8). However, examined. Gratifyingly, a wide range of aryl diazoacetates with
the addition of L1 or L2 to the reaction gave very low conversion different substitution patterns could be utilized in this reaction,
(entry 9). To our delight, using L3 as a ligand, the reaction providing the corresponding dihydropyrans in moderate to excellent
furnished 4a in 52% yield, without the detection of 3a (entry 10). yields. Either electron-donating or electron-withdrawing groups were
The isolated yield of 4a was further improved to 65% when tolerated on the aryl ring of the diazoacetates (3a to 3e). The reaction
2,20-bipyridine ligand L4 was used (entry 11). Ligand L10 gave 4a of 1a with thiophene derived diazoacetate 2h furnished 3f in 64%
in 60% yield associated with a small amount of 3a and 6a yield. Alkyl diazoacetate 2i was tolerated in the reaction and the
(entry 13). Other ligands did not promote the reaction (entries 12 corresponding product 3g was isolated in 59% yield. The ketone
and 14). Next, screening other bases did not give better results diazo compound 2j also reacted well and 3h was isolated in 56%
(entries 15 to 17). The formation of an allenoate intermediate was yield. Moreover, the reaction of 1b with phenyl diazoacetate 2a
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Table 2 Substrate scope for dihydropyrans 3a,b
Table 3 Scope for dihydropyrans 4a,b
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), CuCl (0.02 mmol),
L4 (0.024 mmol), in CH2Cl2 (3 mL) at RT for 12 h; then Cs2CO3
b
(0.24 mmol) was added and stirred for another 2 h. Isolated yields.
In conclusion, we have developed an efficient protocol to
prepare polysubstituted dihydropyrans in a stereoselective mode.
This protocol tolerated a wide range of functionalized terminal
alkynes as well as diazo substrates. Importantly, by choosing
suitable ligands and catalytic systems, dihydropyrans with opposite
exocyclic double bonds can be synthesized in a controlled manner.
We gratefully acknowledge the National Natural Science
Foundation of China (21572024), the Natural Science Foundation
of Jiangsu Province (BK20151184) and Jiangsu Key Laboratory of
Advanced Catalytic Materials and Technology (BM2012110) for
their financial support.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), CuCl (0.02 mmol),
b
L14 (0.024 mmol), in MeCN (3 mL) at 50 1C for 12 h. Isolated yields.
provided 3b in 65% yield. The structure of 3b was confirmed by
X-ray crystallographic analysis.10 Then, the alkyne substrates
bearing methyl groups at different positions (1c to 1f) were
employed in the reaction. The corresponding products were
obtained in moderate to good yields (3i to 3m). Moreover, alkyne
with di-ketone moieties (1g) was also tolerated and 3n was
obtained in 55% yield.
Next, by using CuCl and L4 in dichloromethane followed by
addition of Cs2CO3 under standard reaction conditions, the
tandem reactions of alkynes 1 and diazo compounds 2 were
conducted to prepare dihydropyrans 4 (Table 3). As observed,
the reaction tolerated a series of aryl diazoacetates bearing
either electron-donating or electron-withdrawing substituents
on the aryl ring, and the corresponding dihydropyrans were
obtained in moderate yields (4a to 4e). Different alkynes were
also subjected to reaction and the corresponding products
were isolated in moderate yields too (4g to 4i). It should be
noted that for alkynes 1e and 1f, the products were obtained as
Notes and references
1 For leading reviews, see: (a) A. Deiters and S. F. Martin, Chem. Rev.,
2004, 104, 2199; (b) R. Jacques, R. Pal, N. A. Parker, C. E. Sear,
P. W. Smith, A. Ribaucourt and D. M. Hodgson, Org. Biomol. Chem.,
2016, 14, 5875.
2 For selected reviews, see: (a) M. P. Doyle, R. Duffy, M. Ratnikov and
L. Zhou, Chem. Rev., 2010, 110, 704; (b) H. M. L. Davies and
D. Morton, Chem. Soc. Rev., 2011, 40, 1857; (c) X. Zhao, Y. Zhang
and J. Wang, Chem. Commun., 2012, 48, 10162; (d) Y. Xia, Y. Zhang
and J. Wang, ACS Catal., 2013, 3, 2586; (e) A. Ford, H. Miel, A. Ring,
C. N. Slattery, A. R. Maguire and M. A. McKervey, Chem. Rev., 2015,
115, 9981.
3 For selected examples, see: (a) O. A. Davis and J. A. Bull, Angew.
Chem., Int. Ed., 2014, 53, 14230; (b) O. A. Davis, R. A. Croft and
J. A. Bull, Chem. Commun., 2015, 51, 15446; (c) Z. Liu, H. Tan,
L. Wang, T. Fu, Y. Xia, Y. Zhang and J. Wang, Angew. Chem., Int. Ed.,
2015, 54, 3056; (d) V. V. Pagar and R.-S. Liu, Angew. Chem., Int. Ed.,
2015, 54, 4923; (e) M.-Y. Wu, W.-W. He, X.-Y. Liu and B. Tan, Angew.
Chem., Int. Ed., 2015, 54, 9409; ( f ) Z. Yu, H. Qiu, L. Liu and J. Zhang,
Chem. Commun., 2016, 52, 2257; (g) W.-W. Tan and N. Yoshikai,
J. Org. Chem., 2016, 81, 5566; (h) A. C. Hunter, S. C. Schlitzer and
I. Sharma, Chem. – Eur. J., 2016, 22, 16062; (i) A. R. Reddy, C.-Y.
Zhou, Z. Guo, J. Wei and C.-M. Che, Angew. Chem., Int. Ed., 2014,
a
mixture of two isomers in 1.2 : 1 and 1.3 : 1 ratios,
´
´
53, 14175; ( j) D. Sole, F. Mariani, M.-L. Bennasar and I. Fernandez,
Angew. Chem., Int. Ed., 2016, 55, 6467; (k) Y. Zhu, C. Zhai, Y. Yue,
respectively.
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View Article Online
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´
´
L. Yang and W. Hu, Chem. Commun., 2009, 1362; (l) F. Cambeiro,
6 F. Cambeiro, S. Lopez, J. A. Varela and C. Saa, Angew. Chem., Int. Ed.,
2014, 53, 5959.
´
´
S. Lopez, J. A. Varela and C. Saa, Angew. Chem., Int. Ed., 2012,
´
´
´
51, 723; (m) E. Lopez, G. Lonzi, J. Gonzalez and L. A. Lopez, Chem.
7 (a) K. Liu, C. Zhu, J. Min, S. Peng, G. Xu and J. Sun, Angew. Chem.,
Int. Ed., 2015, 54, 12962; (b) D. Zhang, G. Xu, D. Ding, C. Zhu and
J. Sun, Angew. Chem., Int. Ed., 2014, 53, 11070; (c) L. Qiu, D. Huang,
G. Xu, Z. Dai and J. Sun, Org. Lett., 2015, 17, 1810; (d) G. Xu, C. Zhu,
W. Gu, J. Li and J. Sun, Angew. Chem., Int. Ed., 2015, 54, 883;
(e) C. Zhu, G. Xu, K. Liu, L. Qiu, S. Peng and J. Sun, Chem. Commun.,
2015, 51, 12768; ( f ) C. Zhu, G. Xu and J. Sun, Angew. Chem., Int. Ed.,
2016, 55, 11867.
8 (a) Q. Xiao, Y. Xia, H. Li, Y. Zhang and J. Wang, Angew. Chem., Int. Ed.,
2011, 50, 1114; (b) M. Hassink, X. Liu and J. M. Fox, Org. Lett., 2011,
13, 2388; (c) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013,
46, 236; (d) Y. Tang, Q. Chen, X. Liu, G. Wang, L. Lin and X. Feng,
Angew. Chem., Int. Ed., 2015, 54, 9512; (e) J.-S. Poh, D. N. Tran,
C. Battilocchio, J. M. Hawkins and S. V. Ley, Angew. Chem., Int. Ed.,
2015, 54, 7920; ( f ) W.-D. Chu, L. Zhang, Z. Zhang, Q. Zhou, F. Mo,
Y. Zhang and J. Wang, J. Am. Chem. Soc., 2016, 138, 14558.
9 (a) C.-L. Deng, R.-J. Song, S.-M. Guo, Z.-Q. Wang and J.-H. Li, Org.
Lett., 2007, 9, 5111; (b) T. Yang, A. Ferrali, F. Sladojevich,
L. Campbell and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 9140.
10 CCDC 1528333 (3b).
´
´
´
´
Commun., 2016, 52, 9398; (n) E. Lopez, J. Gonzalez and L. A. Lopez,
Adv. Synth. Catal., 2016, 358, 1428; (o) C. Gonzalez-Rodrıguez,
´
´
´
J. R. Suarez, J. A. Varela and C. Saa, Angew. Chem., Int. Ed., 2015,
54, 2724; (p) M. Tang, D. Xing, H. Huang and W. Hu, Chem.
Commun., 2015, 51, 10612; (q) J. Kalepu and S. Katukojvala, Angew.
Chem., Int. Ed., 2016, 55, 7831.
4 (a) X. Xu, X. Han, L. Yang and W. Hu, Chem. – Eur. J., 2009,
15, 12604; (b) Y. Hashimoto, K. Itoh, A. Kakehi, M. Shiro and
H. Suga, J. Org. Chem., 2013, 78, 6182; (c) F. Urabe, S. Miyamoto,
K. Takahashi, J. Ishihara and S. Hatakeyama, Org. Lett., 2014,
16, 1004; (d) S. M. Nicolle, W. Lewis, C. J. Hayes and C. J. Moody,
Angew. Chem., Int. Ed., 2015, 54, 8485; (e) C. Jing, D. Xing, L. Gao,
J. Li and W. Hu, Chem. – Eur. J., 2015, 21, 19202.
5 (a) S. Son and G. C. Fu, J. Am. Chem. Soc., 2007, 129, 1046; (b) C.-R.
Liu, B.-H. Zhu, J.-C. Zheng, X.-L. Sun, Z. Xie and Y. Tang, Chem.
Commun., 2011, 47, 1342; (c) J. Wang, X. Yao, T. Wang, J. Han,
J. Zhang, X. Zhang, P. Wang and Z. Zhang, Org. Lett., 2015, 17, 5124;
(d) T. Shi, X. Guo, S. Teng and W. Hu, Chem. Commun., 2015,
51, 15204.
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