Highly efficient synthesis of tetrasubstituted 2,3-dihydropyrans by three-component 'one-pot' reaction

Article abstract of DOI:10.1016/j.tetlet.2016.04.008

With ammonium acetate as catalyst, three-component 'one-pot' reaction of β-keto perfluoroalkanesulfones, aldehydes, and vinyl ethers proceeded smoothly and afforded tetrasubstituted 2,3-dihydropyrans in moderate to excellent yields. Both aromatic and alip

Full text of DOI:10.1016/j.tetlet.2016.04.008

Accepted Manuscript
Highly Efficient Synthesis of Tetrasubstituted 2, 3-Dihydropyrans by Three-
component ‘One-pot’ Reaction
Chao Li, Liang-Zhen Cai, Xiao-Dong Liu, Shi-Zheng Zhu, Chun-Hui Xing,
Long Lu
PII:
S0040-4039(16)30349-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.008
TETL 47508
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 February 2016
30 March 2016
5 April 2016
Please cite this article as: Li, C., Cai, L-Z., Liu, X-D., Zhu, S-Z., Xing, C-H., Lu, L., Highly Efficient Synthesis of
Tetrasubstituted 2, 3-Dihydropyrans by Three-component ‘One-pot’ Reaction, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.04.008
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Highly Efficient Synthesis of Tetrasubstituted 2, 3-Dihydropyrans by
Three-component ‘One-pot’ Reaction
Chao Li a, Liang-Zhen Cai a, *, Xiao-Dong Liu a, Shi-Zheng Zhu b, Chun-Hui
Xing b, * and Long Lub
a School of Chemistry and Molecular Engineering, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237, PR China.
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road 200032, Shanghai, PR
China.
Abstract
With ammonium acetate as catalyst, three-component ‘one-pot’ reaction of β-keto
perfluoroalkanesulfones, aldehydes and vinyl ethers proceeded smoothly and afforded
tetrasubstituted 2, 3-dihydropyrans in moderate to excellent yields. Both aromatic and
aliphatic aldehydes, as well as cyclic vinyl ether are compatible with this
methodology. All dihydropyran products were obtained as cis- and
trans-diastereomeric mixtures. The relative configurations were established by
comparing the coupling constants of anomeric protons of both isomers and confirmed
by single-crystal X-ray diffraction analysis.
Keywords: Dihydropyran, Perfluoroalkanesulfone, α, β-Unsaturated ketone，Hetero
Diels-Alder reaction, Three-component
Owing to its strong electron-withdrawing property and multiple reactivity, sulfonyl
groups display manifold roles in reactions and thus serve as a powerful synthetic tool
for constructing various compounds in organic chemistry.1-3 Among all sorts of
sulfonyl groups, perfluoroalkanesulfonyl RfSO2 shows somewhat extraordinary
characters due to the strongly electron-withdrawing inductive effect of the
perfluoroalkyl group.4-6
In our continuing efforts on studying perfluoroalkanesulfone compounds, we have
1

reported that the reaction of β-keto perfluoroalkanesulfones RfSO2CH2COR 1 with
aromatic aldehydes 2 did not terminate at the stage of the normal Knoevenagel
condensation products α-perfluoroalkanesulfonyl-α, β-unsaturated ketones, but made
a step further to undergo Michael addition with another molecular of 1 and resulted in
tetrasubstituted trans-2, 3-dihydrofurans 3 as the final products (Scheme 1).4
Scheme 1 Reaction of β-keto perfluoroalkanesulfones 1 with aromatic aldehydes 2 affords
tetrasubstituted trans-2, 3-dihydrofurans 3.
Scheme 2 Knoevenagel condensation of 1 with 2 for preparing (E)-α-perfluoroalkanesulfonyl-α,
β-unsaturated ketones 4 and its HDA reaction with 5 to synthesize dihydropyran derivatives 6.
Soon after, we found that, with a very weak base AcONH4 as catalyst, the
Knoevenagel condensation reaction between 1 and 2 could stereospecifically generate
(E)-α-perfluoroalkanesulfonyl-α, β-unsaturated ketones 4 in good yields under very
mild conditions (Scheme 2).5 As electrophilic heterodienes, α, β-unsaturated ketones 4
participated hetero Diels-Alder (HDA) reactions with electron-rich olefin vinyl ethers
5 to quantitatively yield tetrasubstituted 2, 3-dihydropyrans 6 under neat condition
(Scheme 2).5 However, this strategy is quite limited because electron-poor aromatic
aldehydes still incline to formation of dihydrofuran derivatives. Besides, the reaction
2

of 1 with aliphatic aldehydes 7, under the same conditions, only gave complex
mixtures which are difficult to be identified and separated.5
Since dihydropyrans are common subunits in numerous natural and artificial
chemicals,7 compounds 6 might be useful building blocks in organic synthesis.
Therefore, we are interested in exploring new tactics for more efficiently preparing
tetrasubstituted 2, 3-dihydropyrans 6 with broader substrate scope. A three-component
‘one-pot’ sequential reaction method was then developed for this purpose.8 Here, we
report our progress in this field.
Scheme 3 Proposed three-component ‘one-pot’ reaction of 1, 2 and 5.
The key for preparing tetrasubstituted dihydropyrans through three-component
sequential reaction in one pot is to ensure the HDA reaction of in situ formed
intermediates 4 with vinyl ethers 5 surpassing the Michael addition of which with the
anion of 1 (Scheme 3). Thus, a weak basic catalyst is anticipated. It should efficiently
promote the initial Knoevenagel condensation reaction of 1 with aldehydes to
generate the labile intermediates α, β-unsaturated ketones 4, and on the other hand,
the weak basicity of catalyst would restrain the formation of anion of 1 and the
following Michael addition. At the same time, large excessive olefins should be used
to enhance the HDA reaction.
Based on the above considerations, we first investigated a model reaction of 1a,
PhCHO 2a and iso-Butyl vinyl ether 5a. Ammonium acetate was chose as catalyst due
to its weak basicity and acceptable catalytic ability which was already proofed by
3

previous study.5 A large excessive amount iso-butyl vinyl ether 5a was applied in
order to both accelerate the HDA reaction with the intermediate 4a (Rf = ClC4F8, R =
Me, Ar = Ph) and serve as solvent. The reaction was carried out at room temperature.
Gratifyingly, it proceeded smoothly and the expected tetrasubstituted dihydropyran 6a
was obtained as the main product, which is a mixture of cis- and trans-diastereomers
in the ratio of 58:42. At the same time, small amount of byproduct 3a was observed
under this condition (Table 1, Entry 1). Attempts to decrease byproduct by reducing or
increasing reaction temperature were unsuccessful.
Table 1. Three-component ‘one-pot’ reaction of β-keto perfluoroalkanesulfones, aromatic
aldehydes and vinyl ethers.a
6 (Yieldb, c:t c) 3 (Yieldb)
Entry
1 (Rf, R)
2 (Ar)
5 (R’)
5a (iBu)
5b (Et)
5b
Time
2h
1
2
3
4
5
6
7
8
9
1a (Cl(CF2)4, Me) 2a (C6H5)
6a (55, 58:42)e
6b (47, 64:36)e
6c (55, 66:34)e
6d (61, 66:34)e
6e (38, 52:48)f
6f (84, 52:48)e
6g (83, 50:50)e
6h (69, 52:48)g
6i (64, 44:56)g
3a (33)
3b (27)
3c (35)
3d (24)
3e (31)
N. D.d
1a
2a
1h
1a
2b (p-BrC6H4)
2c (p-NO2C6H4)
1h
1a
5b
1h
1a
2d (p-CH3OC6H4) 5b
2e (2-furyl) 5b
2f (C6H5CH=CH) 5b
8h
1a
1h
1a
1h
N. D.d
1b (Cl(CF2)4, Ph)
2b
5a
5a
5b
5a
5a
12h
10h
12h
4h
3h (27)
1b
2c
3i (26)
10 1d (CF3, Me)
11 1d
2a
6j (86, 65:35)e 3j (trace)
2g (C6F5)
6k (97, 71:29)e
6l (63, 55:45)h
N. D.d
N. D.d
12 1e (EtOCOCF2, Ph) 2a
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), 5 (10 mmol), NH4OAc (0.5 mmol, 100 mol%)
and 4Å MS (60-80 meshes, 0.2 g) , stirred at 45 C or r.t. under N2; Isolated yields based on
substrate 1; The ratios of cis-/tran-isomers were detected by H NMR; Dihydrofuan byproduct
was not detected; The reaction was performed at room temperature; The reaction was
performed at room temperature for 4 hours, then 80 oC for 4 hours; g The reaction was performed
at 45 oC; h The reaction was performed at 45 oC for 6 hours, then 80 oC for 12 hours.
18h
o
b
c
1
d
e
f
With this result in hand, three-component ‘one-pot’ reactions of β-keto
perfluoroalkanesulfones 1 with various aromatic aldehydes and vinyl ethers were
explored (Table 1). Benzaldehyde and electron-withdrawing group substituted
aromatic aldehydes reacted with ω-chloro-octafluorobutylsulfone 1a and vinyl ethers
4

at room temperature gave the corresponding perfluoroalkanesulfonyl substituted
dihydropyrans 6 as the major products (Table 1, Entries 1~4). As for
electron-donating group substituted aromatic aldehyde p-methoxybenzaldehyde 2d, a
modified procedure (r.t. for 4h, then 80 oC for 4h) was required. (Table 1, Entry 5).
However, a small amount of tetrasubstituted dihydrofuran derivatives 3 were always
unavoidable (Table 1, Entries 1~5) for aromatic aldehydes. It should be noticed that
furfural and cinnamaldehyde exhibited perfect chemoselectivity with only
dihydropyran products to be developed in high yields (Table 1, Entries 6 & 7).
Under the same conditions, more sterically hindered substrate 1b was also employed
to react with aromatic aldehyde such as p-BrC6H4CHO 2b and p-NO2C6H4CHO 2c.
Although it formed α, β-unsaturated ketones 4 at the beginning, the desired HDA
reaction was sluggish. Meanwhile the unexpected dihydrofuran byproducts 3 were
formed as intermediates 4 were gradually accumulated in reaction system after a
prolonged period. Increasing the temperature to 80 oC, the reported temperature which
is in favor of HDA reaction between α, β-unsaturated ketone and vinyl ether,5
dihydrofuran derivative was still obtained as major product. After a brief investigation,
o
it was found that the ‘one-pot’ reaction of 1b could be performed at 45 C to obtain
satisfied results (Table 1, Entries 8 & 9).
Compared to 4-chloro-1,1,2,2,3,3,4,4-octafluorobutyl, less electron-withdrawing
fluoroalkyl groups such as trifluoromethyl or ethoxycarbonyldifluoromethyl on
substrates 1 may decrease the Michael addition reaction rate of the corresponding
α-fluoroalkanesulfonyl-α, β-unsaturated ketones 4, and then benefit the HDA reaction
with vinyl ethers, which lead to better chemoselectivity of reactions. This tendency
was confirmed by the reaction of 1d and 1e (Table 1, Entries 10~12).
Encouraged by the success of three-component ‘one-pot’ sequential reaction of β-keto
perfluoroalkanesulfones, aromatic aldehydes and vinyl ethers, we were curious that if
aliphatic aldehydes 7 are compatible with this methodology in spite of the
Knoevenagel reaction of them with 1 is intricate.5 n-Butanal 7a was first selected and
its reaction with 1a in ethyl vinyl ether 5b was then examined (Scheme 4).
5

Scheme 4 Three-component ‘one-pot’ reaction of 1a, 7a and 5b.
To our delighted, the reaction underwent even more smoothly and quickly, and
finished with excellent chemoselectivity in just 5 min at room temperature. The
expected 4-alkyldihydropyran derivative 8a was formed as the sole product and
isolated in high yield. Its six-membered cyclic dihydropyran structure was clearly
confirmed by spectral data (See supplementary data). No dihydrofuran byproduct was
detected in this reaction. Similar result was also acquired with iso-Butanal 7b. Further
study indicates whether ω-chloro-octafluorobutyl or trifluoromethyl sulfones are
suitable to this aliphatic aldehyde participated three-component reaction procedure
(Table 2, Entries 1~5). All reactions completed in minutes, even for cyclic ether
dihydrofuran 5c (Table 2, Entry 5). Compared to aromatic aldehydes, the
three-component reactions of aliphatic aldehydes were much faster and exhibited
excellent
selectivity.
However,
for
less
reactive
substrates
ethoxydifluoromethylsulfones 1e~1g, their three-component reactions with 7 had to
be performed at an elevated temperature with prolonged reaction time (Table 2,
Entries 6~11).
Table 2. Three-component ‘one-pot’ reaction of β-keto perfluoroalkanesulfones, aliphatic
aldehydes and vinyl ethers.a
Entry
1 (Rf, R)
1a (Cl(CF2)4, Me)
1a
7 (R’’)
7a (nPr)
7b (iPr)
7b
5 (R’)
5b (Et)
5b
Time
5min
5min
5min
5min
8 (Yield%, c:t)b
8a (90, 30:70)d
8b (98, 21:79)d
8c (95, 33:66)d
8d (95, 18:82)d
1
2
3
4
1c (CF3, Ph)
1d (CF3, Me)
5b
7b
5b
6

5
6
1d
7a
7a
7b
7a
7b
7a
7b
5cc
5a (iBu)
5a
15min
5h
8e (70, 38:62)d
8f (74, 28:72)e
8g (54, 45:55)e
8h (62, 39:61)e
8i (58, 45:55)e
8j (65, 36:64)e
8k (57, 47:53)e
1e (EtOCOCF2, Ph)
7
1e
10h
5h
8
1f(EtOCOCF2, p-CH3C6H4)
5a
9
1f
5a
20h
5h
10
11
1g (EtOCOCF2, p-BrC6H4)
5a
1g
5a
10h
a Reaction conditions: 1 (0.5 mmol), 7 (0.6 mmol), 5 (10 mmol), NH4bOAc (0.5 mmol, 100 mol%)
o
and 4Å MS (60-80 meshes, 0.5 g), stirred at r.t. or 45 C under N2; Isolated yields based on 1,
c
d
1
and the ratios of cis-/tran-isomers were detected by H NMR; 5c: 2,3-Dihydrofuran; The
reaction was performed at room temperature; e The reaction was performed at 45 oC.
Scheme 5 The possible reaction procedure of three-component ‘one-pot’ reaction of 1 with
aliphatic aldehydes 7 and vinyl ethers 5.
We speculated that the three-component reaction of aliphatic aldehydes follows the
parallel route of that of aromatic aldehydes (Scheme 5). As the key intermediates,
α-fluoroalkanesulfonyl-β-alkyl-α, β-unsaturated ketones 4’ might be much unstable
and short-lived,9 which impede the Michael additions with the corresponding anion of
1. Without vinyl ether, 4’ would decompose rapidly or transformed to other uncertain
substances. While, the labile 4’ are prominent electron-poor enophiles. Their HDA
reactions were much faster than that of the β-aryl substituted analogues or the
competitive Michael addition reactions. These factors lead to the rapid and selective
construction of dihydropyran derivatives. While, the slow three-component reactions
of 1e~1g might be because of the slow condensation with aldehydes at the first stage
due to their less reactivity.
All tetrasubstituted dihydropyran products 6 and 8 were isolated as cis- and
trans-diastereomeric mixtures. Some of them could be partially separated by column
chromatography. Interestingly, the diastereoselectivity for products 6 and 8 are
contrary to each other, but the reason is not clear right now. The relative configuration
7

might be ascertained by comparing the coupling constant of anomeric protons of both
isomers. According to previous studies, smaller coupling constant corresponds to 2,
4-cis-configutration and vice versa.5, 10 Take dihydropyran product 6i as an example,
the chemical shifts and coupling constants of anomeric protons of two isomers are
5.37 ppm, 3.3 Hz and 5.20 ppm, 6.9 and 3.0 Hz, corresponding to cis-6i and trans-6i
respectively. Identification of relative configuration of tetrasubstituted dihydropyran
products was further confirmed by single-crystal X-ray diffraction analysis of cis-6i
(Figure 1).11
Figure 1. X-ray crystallography of cis-6i
In summary, we developed a three-component ‘one-pot’ sequential reaction of β-keto
perfluoroalkanesulfones, aldehydes and electron-rich olefins to synthesis
tetrasubstituted 2, 3-dihydropyran derivatives. The reaction conditions are very mild.
The
methodology
didn’t
require
the
isolation
of
the
unsteady
α-perfluoroalkanesulfonyl-α, β-unsaturated ketones, which diminished the wastes of
reactions, simplified the operation procedure and increased the synthetic efficiency.
Furthermore, the substrates scope were greatly expanded. Both aromatic and aliphatic
aldehydes are compatible with this process. It should be mentioned that aliphatic
aldehydes, which did not react with β-keto perfluoroalkanesulfones well in the
stepwise procedure, were better substrates in this three-component reaction no matter
what the reaction rate, yields or chemoselectivity. All products were obtained as cis-
8

and trans-diastereomeric mixtures. The relative configurations of which were
established by comparing their coupling constants of anomeric protons and affirmed
by single-crystal X-ray diffraction analysis.
Acknowledgments
Support from the National Natural Science Foundation of China (21272257) is
gratefully acknowledged.
Supplementary data: Supplementary data associated with this article can be found in
the online version.
References and notes
1. Simpkins, N. S. Sulphones in Ortganic Synthesis; Pergamon: Oxford, 1993.
2. Patai, S.; Rappoport, Z.; Stirling, C. The Chemistry of Sulphones and Sulphoxides;
John Wiley & Sons: New York, 1988.
3. (a) Markitanov, Y. M.; Timoshenko, V.; Shermolovvich, Y. G. J. Sulfur Chem.
2014, 35, 188; (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org.
Chem. 2003, 68, 1443; (c) Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1984,
106, 7260.
4. Xing, C.; Zhu, S. J. Org. Chem. 2004, 69, 6486;
5. Xing, C.; Li, X.; Zhu, S.; Zhao, J.; Zhu, S. Tetrahedron Lett. 2006, 47, 4951.
6. (a) Shibata, N.; Matsuzaki, K.; Xu, X. H. Chem. Rev. 2015, 115, 731; (b) Zhu, S.
Synthesis, 1994, 261. ; (c) Eugene, F.; Langlois, B.; Laurent, E. J. Fluorine Chem.
1994, 66, 301; (d) Hanack, M.; Bailer, G.; Hackenberg, J.; Subramanian, L. R.
Synthesis 1991, 1205.
7. (a) Yang, D.; Shi, L.; Huang, H.; Zhang, J, Gan, L. J. Org. Chem. 2010, 75, 4567;
(b) Christoph, O.; Dirk, S.; Jose, M. V.; Jose, L. D.; Jorg, H.; Bemhard, W. J. Med.
Chem. 2008, 51, 6531; (c) Gunatilaka, A. A. L. J. Nat. Prod. 2006, 69, 509; (d)
Liu, R. H.; Zhang, W. D.; Gu, Z. B.; Zhang, C. Su, J.; Xu, X. K. Nat. Prod. Res.
2006, 20. 866; (e) Nakata, T. Chem. Rev. 2005, 105, 4314; (f) Faulkner, D. J. Nat.
Prod. Rep. 2000, 17, 7.
8. Some examples for synthesis of Dihydropyrans: (a) Feng, J.; Fu, X.; Chen, Z.; Lin,
L.; Liu, X.; Feng, X. Org. Lett. 2013, 15, 2640; (b) Chen, X. Y.; Sun, L. H.; Ye, S.
9

Chem. Eur. J. 2013, 19, 4441; (c) Guo, B.; Schwarzwalder, G.; Njardason, J.
Angew. Chem. Int. Ed. 2012, 51, 5675; (d) Wang, X.; Fang, T.; Tong, X. Angew.
Chem. Int. Ed. 2011, 50, 5361; (e) Yao, C.; Feng, X.; Wang, C.; Jiang, B.; Yu, C.;
Wang, X.; Li, T.; Tu, S. J. Heterocyclic Chem. 2011, 48, 1111; (f) Li, X.; Song, L.;
Xing, C.; Zhao, J.; Zhu, S. Tetrahedron 2006, 62, 2255; (g) Jung, F. J.; Park, P. H.;
Lee, Y. R. Green Chem. 2010, 12, 2003; (h) Pena, J.; Moro, R. F.; Basabe, P.;
Marcos, I. S.; Diez, D. RSC Adv. 2012, 2, 8041.
9. The configuration of carbon-carbon double bond of 4’ was not identified since it
could not be separated or captured from the reaction mixtures.
10. Tietze, L. F.; Meier, H.; Nutt, H. Chem. Ber. 1989, 122, 643.
11. Crystal data for compound cis-6c: C25H22ClF8NO6S, MW = 651.95, orthorhombic,
Pbca, Mo K, final R indices [I > 2(I)], R1 = 0.0804, wR2 = 0.2217, a = 8.2393(5)
Å, b = 18.3576(11) Å, c = 38.482(2) Å,  = 90,  = 90,  = 90, V = 5820.5(6) Å3,
T = 293(2) K, Z = 8, reflections collected/unique: 29084/5408 (Rint = 0.0646),
F(000) = 2656, parameters 405.
10

Graphical abstract



Highly efficient multicomponent reaction
Mild reaction conditions
Wide substrates scope
Highlights
 Highly efficient three-component ‘one-pot’ sequential reaction.
 Very mild reaction conditions, very simple operation procedure.

Wide substrates scope.
11