N-heterocyclic carbene-catalyzed domino hydroacylation/stetter reactions of salicyl alkynylphosphonates and aromatic aldehydes

Article abstract of DOI:10.3998/ark.5550190.p008.158

1,4-Dicarbonyl compounds 2 carrying a phosphonate group were obtained by utilizing a dually N-heterocyclic carbene (NHC) catalyzed domino reaction involving the intramolecular hydroacylation of salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction with aromatic aldehyde at room temperature. In addition, 2 can also be applied for the synthesis of benzopyranopyrrole carrying a phosphonate group 4 in one pot and in moderate yield. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.p008.158

General Papers
ARKIVOC 2013 (iv) 88-97
N-Heterocyclic carbene-catalyzed domino hydroacylation/Stetter
reactions of salicyl alkynylphosphonates and aromatic aldehydes
Zhen-Qiang Wang, Ying Wang, and De-Qing Shi*
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430 079, P. R. China
E-mail: chshidq@mail.ccnu.edu.cn
Abstract
1,4-Dicarbonyl compounds 2 carrying a phosphonate group were obtained by utilizing a dually
N-heterocyclic carbene (NHC) catalyzed domino reaction involving the intramolecular
hydroacylation of salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction
with aromatic aldehyde at room temperature. In addition, 2 can also be applied for the synthesis
of benzopyranopyrrole carrying a phosphonate group 4 in one pot and in moderate yield.
Keywords: N-Heterocyclic carbene; domino reaction; hydroacylation; Stetter reaction;
1,4-dicarbonyl compound; phosphonate
Introduction
During the past decades, domino reactions, which can rapidly form complicated molecule
skeletons from readily available substrates in a single operation without isolation of
intermediates, have received more and more attention of organic chemists. So, considerable
efforts have been made to develop organocatalytic domino transformations.1 1,4-Dicarbonyl
compounds are versatile intermediates in the synthesis of cyclopentenones2 and a variety of
heterocycles such as furan,3 pyrrole,4 thiophene,5 and pyrrolidine.6 Recently, N-heterocyclic
carbenes (NHCs) have been widely used, not only as ligands in organometallic chemistry, but
also as efficient nucleophilic organocatalysts in a variety of organic reactions, such as benzoin
condensation, Stetter reaction, a3 to d3 umpolung, and so on, so the development of NHCs in
organic synthesis has attracted more and more attention.7 Glorius and coworkers have pioneered
the development of a powerful NHC-catalyzed hydroacylation of unactivated alkynes leaded to
the formation of α,β-unsaturated chromanones,8 while intramolecular hydroacylation reactions of
activated alkynes were reported recently.9
Recently, an effective N-heterocyclic carbene catalyzed intramolecular hydroacylation
reaction of salicyl alkynylphosphonates was reported in our group, in which both exocyclic and
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endocyclic tautomers can be obtained at different temperatures.9b Because α,β-unsaturated
ketones (exocyclic tautomers) are the major products at lower temperatures (15-17 ºC), this
prompted us to investigate the possibility of developing a dually NHC-catalyzed domino reaction
involving the intramolecular hydroacylation of salicyl alkynylphosphonates and a subsequent
intermolecular Stetter reaction to prepare 1,4-dicarbonyl compounds 2 carrying a phosphonate
group at room temperature (Scheme 2), which can be very important intermediates for the
synthesis of biologically active phosphonyl heterocyclic compounds.10 Although Glorius and
coworkers reported the NHC-catalyzed cascade hydroacylation/Stetter reactions of salicyl
alkynes,8 the groups linking with alkynes are usually H or a Me group, other groups such as
aromatic group, ester group linking with alkynes are not reported. As for activated alkynes, no
domino hydroacylation/Stetter reaction is reported because in which endocyclic tautomers are
the major product. In this paper, we report the first cascade hydroacylation/ Stetter reaction of
activated alkynes 1 containing a phosphonyl group derived from substituted salicylaldehydes
(Scheme 1).
Scheme 1. Domino hydroacylation/Stetter reaction of activated alkynes containing a phosphonyl
group.
Results and Discussion
First of all, we used substrate 1a and 4-chlorobenzaldehyde as a model in order to optimize the
reaction condition. The initial screening was carried out at 15-17 °C with 5 mol% of catalyst and
10 mol% of K2CO3 in THF (Table 1, entries 1-6). When thiazolium salt 3a was used as the
catalyst and K2CO3 as the base, 2a was obtained in 81% yield (Table1, entry 1), and 3a is the
most effective catalyst, however, the triazolium salt 3d is not so effective (Table1, entry 4);
Secondly, the effects of various bases (Table 1, entries 7-11) were explored using catalyst 3a as a
control, the moderate base (K2CO3) afforded the products in higher yields than other bases.
Subsequently, we turned our attention to the influence of different solvents on the reaction
(Table 1, entries 12-17) and found THF to be the most effective, the more polar EtOH and DMF
being less so. Different temperatures have some obvious effects on the reaction. The lower
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temperature (15-17 °C) is more beneficial to the reaction than the higher one (30-35 °C); when
the reaction with 3a and K2CO3 in THF was tested at 30-35 °C, the yield of 2a is only 32%.
Finally, the optimized conditions were established as following: thiazolium salt 3a as the
pre-catalyst (5 mol%), K2CO3 (10 mol%) as the base, THF as the solvent, and stirring at
15-17 °C for 3 h.
Table 1 Optimization of the reaction conditionsa
Entry
1
NHC-HX
3a
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
DBU
Solvent
THF
Yield of 2a [%] b
81
75
70
20
34
57
65
40
38
71
58
72
40
65
68
30
76
2
THF
3b
3c
3
THF
4
THF
3d
3e
5
THF
6
THF
3f
7
THF
3a
8
THF
3a
9
DABCO
NaH
THF
3a
10
11
12
13
14
15
16
17
THF
3a
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
3a
Dioxane
EtOH
Toluene
CH3CN
DMF
DCM
3a
3a
3a
3a
3a
3a
a
General conditions: 1a (0.5 mmol), NHC-HX (5 mol%), base (10 mol%), solvent (2.0 ml),
room temperature (15-17 °C), 3h;
b Isolated yields.
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With the optimised conditions thus established, we tested different substrates to give good
results in the NHC catalyzed cascade reaction of hydroacylation and Stetter reaction. For salicyl
alkynylphosphonates with both electron-donating groups and electron-withdrawing ones on the
phenyl ring, the reactions proceeded smoothly and gave the corresponding 2 in good yields at
room temperature. However, when benzaldehyde was used, the yield was very low (Table 2,
entry 7); the reason for this is not clear.
Table 2 Scope of the domino hydroacylation/Stetter reactions. a
S
ClO4
N
3a
O
O
Ar
O
O
(5 mol%)
H
ArCHO
+
PO(OEt)2
K2CO3 (10 mol%)
THF, 15-17 oC
O
R
R
PO(OEt)2
2
1
Entry
R
Ar
Yield of 2 [%] b
81 (2a)
84 (2b)
83 (2c)
71 (2d)
77 (2e)
69 (2f)
1
2
3
4
5
6
7
H (1a)
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
C6H5
4-MeO (1b)
4-F (1c)
4-t-Bu (1d)
6-Me (1e)
4,6-di-t-Bu (1f)
H (1a)
<5
a General conditions: 1 (0.5 mmol, 1.0 equiv), 3a (0.025 mmol, 5 mol%), K2CO3 (0.05 mmol, 10 mol%),
ArCHO (0.5 mmol, 1.0 equiv), THF (2.0 ml), 15-17 ºC, 3h; b Isolated yields
In order to prepare novel heterocycles containing a phosphonyl group with potent biological
activities, 2 can be applied to the synthesis of benzopyranopyrrolephosphonate 4 successfully via
a one-pot reaction in 50% yield (Scheme 2).
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Scheme 2 Preparation of the benzopyranopyrrolephosphonate 4 by a one-pot reaction.
Conclusions
In conclusion, 1,4-dicarbonyl compounds 2 carrying a phosphonate group were obtained by
utilizing a dually NHC-catalyzed domino reaction involving the intramolecular hydroacylation of
salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction with aromatic
aldehyde in good yields at room temperature. In addition, 2 can be also applied successfully for
the synthesis of benzopyranopyrrole containing a phosphonyl group 4 in one-pot reaction in
moderate yield.
Experimental Section
General. All reagents and solvents for reactions were used as received with the following
exceptions. THF, toluene and dioxane were distilled from Na/benzophenone. Dichloromethane,
acetonitrile and N,N-dimethylformamide (DMF) were distilled from calcium hydride. Ethanol
and n-butyl alcohol were distilled form Mg turnings. K2CO3 was dried by heating at 110 °C for
12 h and left to cool under Ar. N-Heterocyclic carbene (NHC) precursors 3 were prepared
according to the literature.11 The substituted salicyl alkynylphosphonates 1 were synthesized
according to the the reported method.9b All other commercially available solvents and reagents
were used without further purification. All reactions were performed in oven-dried apparatus
under N2 or Ar atmosphere. Reactions were monitored by thin layer chromatography (TLC) and
visualized by UV light or KMnO4 staining solution followed by heating.
1
13
Melting points were determined with a WRS-1B digital melting point apparatus. H NMR, C
NMR spectra and 31P NMR spectra were obtained with a Varian Mercury PLUS 600
spectrometer. Chemical shift in ppm, internal standard TMS or CHCl3, multiplicity (s = singlet, d
13
= doublet, t = triplet, q = quartet, and m = multiplet), coupling constants Hz. C NMR chemical
shifts are reported in ppm from CDCl3 (taken as 77.0 ppm). 31P NMR spectra were recorded with
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85% H3PO4 as external standard. The mass spectra (ESI) were obtained using an Applied
Biosystems API 2000 LC/MS/MS (ESI-MS) spectrometer. Elemental analyses were performed
with an Elementar Vario ELШ CHNSO elemental analyzer.
Synthesis of 2-phosphonyl 1,4-diketones 2: general procedure. To an oven-dried
round-bottomed flask equipped with a magnetic stirring bar was added diethyl
3-(2-formylphenoxy)prop-1-ynylphosphonate 1 (0.5 mmol, 1.0 equiv), pre-catalyst 3a (9 mg,
0.025 mmol, 0.05 equiv), substituted benzaldehyde (0.5 mmol, 1.0 equiv), dry THF (2 ml) and
dry K2CO3 ( 6.9 mg, 0.05 mmol, 0.10 equiv) under a N2 or Ar atmosphere at 15-17 °C. The
resulting mixture was then stirred for 3h at the same temperature. The progress of the reaction
was monitored by TLC. Upon completion, the mixture was pre-absorbed on silica gel and
purified by flash column chromatography on silica gel (eluent: hexane/ AcOEt 1:1) to afford 2 as
a white solid.
Diethyl 2-(4-chlorophenyl)-1-(4-oxochroman-3-yl)-2-oxoethylphosphonate (2a). Prepared
according to the general procedure. The product was obtained as a white solid (81% yield), mp
1
102-104 °C. H NMR (600 MHz, CDCl3): δ 8.01 (d, J 8.4 Hz, 2H), δ 7.75 (d, J 7.8 Hz, 1H), δ
7.49 (d, J 7.8 Hz, 3H), δ 6.98 (d, J 8.4 Hz, 2H), δ 5.17 (dd, J 15.0 Hz, J 5.4 Hz, 1H), δ 4.38-4.43
(m, 2H), δ 4.01-4.16 (m, 5H), δ 1.28 (t, J 7.2 Hz, 3H), δ 1.17 (t, J 7.2 Hz, 3H). 13C NMR (150
MHz, CDCl3): δ 193.3, 192.2, 161.5, 139.4, 136.3, 135.6, 130.2, 128.8, 127.3, 121.5, 119.8,
117.6, 69.6, 63.2, 46.9, 44.3 (d, J 128.4 Hz), 16.1. 31P NMR (243 MHz, CDCl3): δ 18.8. ESI-MS:
m/z 437 [M+H]+, 459 [M+Na]+, 475 [M+K]. Anal. calcd for C21H22ClO6P: C, 57.74; H, 5.08.
Found: C, 56.83; H, 5.01 %.
Diethyl 2-(4-bromophenyl)-1-(6-methoxy-4-oxochroman-3-yl)-2-oxoethylphosphonate (2b).
Prepared according to the general procedure. The product was obtained as white solid (84%), m
p 126-127 °C. 1H NMR (600 MHz, CDCl3): δ 7.93 (d, J 8.4 Hz, 2H), δ 7.64 (d, J 8.4 Hz, 2H), δ
7.16 (s, 1H), δ 7.08 (d, J 9.6 Hz, 1H), δ 6.93 (d, J 9.6 Hz, 1H), δ 5.13 (dd, J 11.4 Hz, J 4.8 Hz,
1H), δ 4.34-4.39 (m, 2H), δ 4.03-4.16 (m, 5H), δ 3.71 (s, 3H), δ 1.28 (t, J 6.6 Hz, 3H), δ 1.18 (t,
J 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 193.4, 192.3, 156.3, 154.0, 136.1, 131.8, 130.5,
130.2, 128.2, 125.6, 119.1, 107.3 (d, J 101.4 Hz), 69.7, 63.1, 55.6, 46.9, 43.9 (d, J 130.4 Hz),
16.1. 31P NMR (243 MHz, CDCl3): δ 16.4. ESI-MS: m/z 512 [M+H]+, 434 [M+Na]+, 550
[M+K]. Anal. calcd for C22H24BrO7P: C, 51.68; H, 4.73. Found: C, 51.86; H, 4.84 %.
Diethyl 2-(4-bromophenyl)-1-(6-fluoro-4-oxochroman-3-yl)-2-oxoethylphosphonate (2c).
Prepared according to the general procedure. The product was obtained as white solid (83%), mp
97-99 °C. 1H NMR (600 MHz, CDCl3): δ 7.92 (d, J 8.4 Hz, 2H), δ 7.64 (d, J 8.4 Hz, 2H), δ
7.39 (dd, J 8.4 Hz, J 3.0 Hz, 1H), δ 7.20 (t, J 3.0 Hz, 1H), δ 6.98 (dd, J 4.2 Hz, J 9.0 Hz, 1H), δ
5.17 (dd, J 11.4 Hz, J 5.4 Hz, 1H), δ 4.40 (m, 2H), δ 4.03-4.14 (m, 5H), δ 1.27 (t, J 7.2 Hz, 3H),
δ 1.18 (t, J 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 193.3, 191.3, 161.4, 157.8, 135.9,
131.9, 131.6 (d, J 32 Hz), 130.3 (d, J 30 Hz), 128.4, 123.9 (d, J 25 Hz), 119.4, 112.2 (d, J 23 Hz),
69.8, 63.3 (t, J 41.2 Hz), 46.8, 43.8 (d, J 129 Hz), 16.2 (d, J 16 Hz). 31P NMR (243 MHz,
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CDCl3): δ 19.5. ESI-MS: m/z 499 [M+H]+, 521 [M+Na]+, 537 [M+K]. Anal. calcd for
C21H21BrFO6P: C, 50.52; H, 4.24. Found: C, 50.41; H, 4.35 %.
Diethyl 2-(4-bromophenyl)-1-(6-tert-butyl-4-oxochroman-3-yl)-2-oxoethylphosphonate (2d).
Prepared according to the general procedure. The product was obtained as white solid (71%), m
p 99-101 °C. 1H NMR (600 MHz, CDCl3): δ 7.95 (d, J 7.8 Hz, 2H), 7.74 (s, 1H), δ 7.65 (d, J
7.8 Hz, 2H), δ 7.54 (d, J 7.2 Hz, 1H), δ 6.93 (d, J 9.0 Hz, 1H), δ 5.13 (dd, J 12.0 Hz, J 6.0 Hz,
1H), δ 4.32-4.38 (m, 2H), δ 4.03-4.15 (m, 5H), δ 1.29 (t, J 7.2 Hz, 3H), δ 1.25 (t, J 7.2 Hz, 3H).
13C NMR (150 MHz, CDCl3): δ 193.5, 192.7, 159.5, 144.5, 136.1, 134.2, 130.5, 128.8, 128.2,
123.4, 119.0, 117.3, 69.6, 63.2, 47.2, 43.5, 34.3, 31.2 (d, J 142.6 Hz), 16.3. 31P NMR (243 MHz,
CDCl3): δ 13.2. ESI-MS: m/z 537 [M+H]+, 559 [M+Na]+, 575 [M+K]. Anal. calcd for
C25H30BrO6P: C, 55.88; H, 5.63. Found: C, 55.71; H, 5.57 %.
Diethyl 2-(4-bromophenyl)-1-(8-methyl-4-oxochroman-3-yl)-2-oxoethylphosphonate (2e).
Prepared according to the general procedure. The product was obtained as white solid (77%), m
p 109-110 °C. 1H NMR (600 MHz, CDCl3): δ 7.93 (d, J 8.4 Hz, 2H), δ 7.65 (d, J 8.4 Hz, 2H), δ
7.59 (d, J 8.4 Hz, 1H), δ 7.34 (d, J 7.2 Hz, 1H), δ 6.88 (t, J 7.8 Hz, 1H), δ 5.20 (dd, J 11.4 Hz, J
5.4 Hz, 1H), δ 4.36-4.41 (m, 2H), δ 4.04-4.17 (m, 5H), δ 1.29 (t, J 7.2 Hz, 3H), δ 1.19 (t, J 7.2
Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 193.5, 192.4, 159.8, 137.2, 136.1, 131.8, 130.3, 128.2,
127.0, 124.9, 120.9, 119.4, 63.2, 46.9, 44.3, 43.5, 16.2, 15.5. 31P NMR (243 MHz, CDCl3): δ
15.1. ESI-MS: m/z 495 [M+H]+, 517 [M+Na]+, 533 [M+K]. Anal. calcd for C22H24BrO6P: C,
53.35; H, 4.88. Found: C, 53.19; H, 4.64 %.
Diethyl 2-(4-bromophenyl)-1-(6,8-di-tert-butyl-4-oxochroman-3-yl)-2-oxoethylphosphonate
(2f). Prepared according to the general procedure. The product was obtained as white solid
1
(69%), mp 114-116 °C. H NMR (600 MHz, CDCl3): δ 7.93 (d, J 8.4 Hz, 2H), δ 7.65 (d, J 8.4
Hz, 2H), δ 7.63 (s, 1H), δ 7.53 (s, 1H), δ 5.19 (dd, J 11.4 Hz, J 5.4 Hz, 1H), δ 4.31-4.35 (m, 2H),
δ 4.04-4.16 (m, 5H), δ 1.40 (s, 9H), δ 1.26 (t, J 7.2 Hz, 3H), δ 1.23 (s, 9H), δ 1.17 (t, J 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3): δ 193.5, 183.8, 158.7, 143.4, 138.2, 136.2, 131.8, 131.1,
31
130.3, 128.1, 121.4, 119.7, 63.2 (d, J 30 Hz), 47.0, 44.4, 43.5, 35.0, 34.4, 31.2, 29.6, 16.2. P
NMR (243 MHz, CDCl3): δ 12.6. ESI-MS: m/z 593 [M+H]+, 615 [M+Na]+, 631 [M+K]. Anal.
calcd for C29H38BrO6P: C, 58.69; H, 6.45. Found: C, 58.82; H, 6.51 %.
Synthesis of diethyl [2-(4-chlorophenyl)-1,4-dihydro-chromeno[4,3-b]pyrrole-3- phosphonate
(4): To an oven-dried round-bottom flask equipped with a magnetic bar was added 1a (296 mg,
1.0 mmol, 1.0 equiv), pre-catalyst 3a (18 mg, 0.05 mmol, 0.05 equiv), 4-chlorobenzaldehyde
(140 mg, 1.0 mmol, 1.0 equiv), anhydrous THF (2 ml), and dry K2CO3 ( 14 mg, 0.1 mmol, 0.10
equiv.) under a N2 or Ar atmosphere at r.t. The resulting mixture was then stirred for 3 h at
15-17 °C. The progress of the reaction was monitored by TLC. NH4OAc (231 mg, 3 mmol) and
gacial AcOH (3 ml) were added under N2 atmosphere, the mixture was allowed to be stirred
under reflux for 12 h. Upon completion, the mixture was cooled to r.t. The workup involved
addition of ice water (20 ml) and extraction of the product mixture into CHCl3 (3 × 20 ml),
washing with sat. aq. NaHCO3 and sat. brine. After phase separation, drying over Na2SO4,
filtration and evaporation, the crude product was purified by chromatography on silica using a
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mixture of petroleum ether and AcOEt (2:1) as an eluent to give 4 as white solid (208.5 mg,
50%). Mp 106-107 °C. 1H NMR (600 MHz, CDCl3): δ 10.33 (s, 1H), δ 7.50 (d, J 7.8 Hz, 2H), δ
7.39 (d, J 7.2 Hz, 1H), δ 7.18 (d, J 7.2 Hz, 2H), δ 7.07 (t, J 7.8 Hz, 1H), δ 6.85-6.89 (m, 2H), δ
5.43 (s, 2H), δ 3.85-3.92 (m, 4H), δ 1.13 (t, J 7.2 Hz, 6H ). 13C NMR (150 MHz, CDCl3): δ 158.4,
156.5, 149.3, 138.4, 136.5, 135.7, 134.1, 131.7, 129.8, 128.5, 126.2, 122.7, 122.2, 116.7, 66.5,
62.6, 16.4. 31P NMR (243 MHz, CDCl3): δ 15.57. ESI-MS: m/z 418 [M+H]+, 440 [M+Na]+, 456
[M+K]. Anal. calcd for C21H21ClNO4P: C, 60.37; H, 5.07; N, 3.35. Found: C, 60.24; H, 5.15; N
3.21 %.
Acknowledgements
This work was supported by the Natural Science Foundation of China (No. 20872046) and the
Fundamental Research Funds for the Central Universities (No. CCNU09A02013).
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