Hetero Diels-Alder reactions of acyl phosphonates: Synthesis of glycosyl type phosphonates

Article abstract of DOI:10.1016/j.tet.2011.02.007

We have prepared glycosyl type phosphonates via hetero Diels-Alder (HDA) reactions of acyl phosphonates with electron rich dienes. HDA reactions of acyl phosphonates with Danishefsky's diene required thermal activation to yield the desired dihydropyranone

Full text of DOI:10.1016/j.tet.2011.02.007

Tetrahedron 67 (2011) 2396e2401
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hetero DielseAlder reactions of acyl phosphonates: synthesis of glycosyl type
phosphonates
,
,
*
Sidika Polat-Cakir a b, Ayhan S. Demir b
a Department of Chemistry, Nevs¸ehir University, 50300 Nevs¸ehir, Turkey
b Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
We have prepared glycosyl type phosphonates via hetero DielseAlder (HDA) reactions of acyl phos-
phonates with electron rich dienes. HDA reactions of acyl phosphonates with Danishefsky’s diene re-
quired thermal activation to yield the desired dihydropyranones in good yield (70e91%). The reactions
with Brassard’s diene involved Lewis acid promotion to yield the corresponding lactones, though in
moderate yield (33e69%).
Received 11 November 2010
Received in revised form 13 January 2011
Accepted 1 February 2011
Available online 23 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acyl phosphonates
Hetero DielseAlder
Glycosyl phosphonates
1. Introduction
take part in the glycosylation process.3 The phosphorous group at
the anomeric carbon is considered to be a stable analogue of gly-
The hetero DielseAlder (HDA) reaction is a potent reaction for
the construction of the pyranosyl unit of many biologically active
compounds. There are primarily two types of HDA reactions: (a)
cosyl phosphates that may act as competitive inhibitors of glyco-
syltransferases and may be used in inhibition studies.
electron rich dienes with aldehydes and (b) enal dienes (a,b-un-
2. Results and discussion
saturated aldehydes) with dienophiles. The first HDA reaction is
a normal electron demand, while the second is an inverse. In both
cases high pressure and temperature, or Lewis acid catalysis are
required to promote the reaction.
Acyl phosphonates (R1COPO(OR2)3) are compounds with phos-
phorous directly attached to a carbonyl group and represent a par-
ticular class of functional organophosphorous compounds. They
can be considered as synthetic equivalents of aldehydes with en-
Herein, we present the first hetero DielseAlder (HDA) reactions
of acyl phosphonates with electron rich dienes where the acyl
phosphonate serves as dienophile. This reaction produces glycosyl
type phosphonates as the HDA product in good yield. When elec-
tron rich Danishefsky diene was used, the cycloaddition reaction
was activated by temperature, while Lewis acid instead of thermal
activation was needed in the case of Brassard’s diene.
hanced chemical stability.
used in hetero DielseAlder cycloaddition reactions with electron
a,b-Unsaturated acyl phosphonates are
The required aryl and alkyl acyl phosphonates for the hetero
DielseAlder reaction 1aem were easily prepared in good yield
(over 90%) according to a literature procedure.4 The procedure in-
volved addition of trimethyl phosphites into aryl or alkyl
substituted acyl chlorides at 0 ꢀC (the MichaeliseArbuzov reaction).
The first trial of the HDA reaction of benzoylphosphonate 1a with
1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky’s di-
ene) was thermally activated. When the reaction was heated to
60 ꢀC, no formation of HDA product was observed. The temperature
was increased to 100 ꢀC and then the desired glycosyl type phos-
phonate 2awas obtained in 89% yield. To investigate this reactionwe
used a series of aryl and alkyl substituted acyl phosphonates (entries
2e12 in Table 1). The electronic features of the aromatic moieties did
not significantly affect the product yield. For instance, benzoyl
substrates with electron-donating eOCH3 (entry 2) and an electron-
rich alkenes where the a,b-unsaturated acyl phosphonates serve as
the diene.1 To the best of our knowledge the use of acyl phospho-
nates in hetero DielseAlder reactions as the dienophile is not
reported elsewhere. Our current interest in acyl phosphonate
chemistry2 has led us to employ acyl phosphonates in hetero
DielseAlder reaction as dienophile partner.
Hetero DielseAlder cycloaddition reactions of acyl phospho-
nates with electron rich dienes form glycosyl type phosphonates.
Glycosyl phosphates are known as biological glycosyl donors and
* Corresponding author. Tel.: þ90 312 2103242; fax: þ90 312 2103200; e-mail
address: asdemir@metu.edu.tr (A.S. Demir).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.007

S. Polat-Cakir, A.S. Demir / Tetrahedron 67 (2011) 2396e2401
2397
Table 1
Reactions of acyl phosphonates with Danishefsky’s diene
OMe
R1
O
P(OR2)2
O
R1
OTMS
O
1. toluene, 100oC
2. TFA, 0oC, 30 min
P(OR2)2
O
O
Entry
1
Acyl phosphonate
Reaction conditions
and yielda (%)
Product
18 h, 89
O
O
P(OEt)2
O
P(OEt)2
O
1a
O
2a
2
3
18 h, 88
16 h, 90
O
O
P(OEt)2
O
P(OEt)2
O
MeO
MeO
1b
O
2b
O
O
P(OEt)2
O
P(OEt)2
O
1c
O
2c
4
14 h, 80
O
O
P(OEt)2
O
P(OEt)2
O
Cl
Cl
Cl
1d
O
2d
5
6
14 h, 74
O
O
P(OMe)2
O
Cl
P(OMe)2
O
1e
O
2e
16 h, 90
O
Cl
O
P(OMe)2
P(OMe)2
O
O
1f
Cl
O
2f
7
8
14 h, 89
O
O
P(OEt)2
O
P(OEt)2
O
F
F
1g
O
2g
6 h, 70
O
F
O
P(OMe)2
O
P(OMe)2
O
1h
F
O
2h
(continued on next page)

2398
S. Polat-Cakir, A.S. Demir / Tetrahedron 67 (2011) 2396e2401
Table 1 (continued )
Entry
Acyl phosphonate
Reaction conditions
and yielda (%)
Product
9
14 h, 74
O
O
P(OMe)2
O
P(OMe)2
O
F3C
F3C
1i
O
2i
10
16 h, 90
O
O
P(OMe)2
O
P(OMe)2
O
1j
O
2j
11
12
16 h, 91
16 h, 81
O
O
P(OMe)2
O
P(OMe)2
O
1k
O
2k
2l
O
O
P(OMe)2
O
P(OMe)2
O
1l
O
a
Yields refer to purified compounds.
Table 3
Reactions of acyl phosphonates with Brassard’s diene
withdrawing eCH3 groups on the para position both resulted in
similar yields (entry 2 with 88% yield and entry 3 with 90% yield).
When the electron-withdrawing eCl group was used in ben-
zoylphosphonates at three differentpositions (ortho, meta and para),
the yield of HDA product (entries 4e6) did not change considerably
between these three positions. When eF substituted benzoyl-
phosphonates 1g and 1h was employed, glycosyl type phosphonates
2g and 2h were attained in 89% and 70% yields, respectively. Acyl
phosphonate 1i (entry 9) resulted in the corresponding HDA product
2i in 74% yield. We also explored alkyl phosphonates in the HDA
reactions. The corresponding glycosyl phosphonates were obtained
in good yields (entries 10e12 in Table 1).
OTMS
R1
O
EtO
P(OMe)2
R1
O
O
O
OEt
P(OMe)2
Me2AlCl, DCM
O
-78oC- rt, overnight
OEt
Entry
1
Acyl phosphonate
Yielda (%)
69
Product
O
O
P(OMe)2
P(OMe)2
O
O
O
As listed in Table 2, we tested three different Lewis acids as
catalysts for the HDA reactions of benzoylphosphonate 1m with
Danishefsky’s diene. We found that the cycloaddition reaction is
efficiently activated by ZnCl2 and the desired compound 2m was
1m
OEt
3m
2
3
4
52
O
O
P(OMe)2
Table 2
P(OMe)2
O
O
O
Lewis acid screening of benzoylphosphonate 1a with Danishefsky’s diene
1c
OMe
OEt
3c
O
P(OMe)2
65
33
O
O
OTMS
O
O
P(OMe)2
1. Lewis acid
P(OMe)2
O
O
O
P(OMe)2
2. TFA, 0oC, 30 min
O
Cl
Cl
1n
O
2m
1m
OEt
3n
Entry
Lewis acid
Reaction conditions
Yielda (%)
O
O
1
2
3
4
5
6
Me2AlCl (1.1 equiv)
BF3$OEt2 (1.1 equiv)
ZnCl2 (1.1 equiv)
Me2AlCl (1 equiv)
Me2AlCl (1 equiv)
ZnCl2 (1 equiv)
DCM, ꢁ78 ꢀC, 30 min
DCM, ꢁ78 ꢀC, 30 min
DCM, ꢁ78 ꢀC, 30 min
Toluene, 0 ꢀC, 2 h
DCM, 0 ꢀC, 2 h
No formation of 2m
No formation of 2m
41
34
44
81
P(OMe)2
O
1k
3k
Toluene, 0 ꢀC, 2 h
a
Yields refer to purified compounds. In all cases 2 equiv of Danishefsky’s diene
a
Yields refer to purified compounds.
was used except for in entry 1.

S. Polat-Cakir, A.S. Demir / Tetrahedron 67 (2011) 2396e2401
2399
obtained in 81% yield. We tried an un-optimized asymmetric syn-
thesis of compound 2m using a bisoxazolidine type ligand with Cu
(OTf)2 (t-Bu-BOX-CuII) that produced only 33% ee.6
Danishefsky’s diene (2 equiv) was added to the above solution.
After passing with argon, the vial was then sealed with a cap and
heated at 100 ꢀC for the time indicated in the Table 1. The reaction
mixture was cooled to room temperature and then TFA was added
slowly to the reaction mixture at 0 ꢀC and stirred for 30 min. The
reaction mixture was directly purified by flash column chroma-
tography to afford the corresponding product.
In Table 3, we have summarized our results regarding the HDA
reactions of acyl phosphonates with Brassard’s diene.5 Thermal acti-
vation of the reaction between benzoylphosphonate 1m and Bras-
sard’s diene did not afford the expected compound. Based on our
experience through the results obtained from Lewis acid screening of
Danishefsky’s diene, we utilized both ZnCl2 and Me2AlCl to activate
the cycloaddition reaction of benzoylphosphonate 1m with Bras-
sard’s diene. We found that Me2AlCl was an efficient catalyst to pro-
mote the cycloaddition reaction. Before testing Brassard’s diene with
different acyl phosphonates, we performed a solvent screening.
Dichloromethane resulted in high yield of HDA product 3m. Non-
chlorinated solvents, such as toluene and THF provided the HDA
product, albeit in low yields. Several substituted aryl and alkyl
phosphonates were also examined in the HDA reaction with Bras-
sard’s diene in acceptable yields (entries 2e4 in Table 3).
4.2.1. Diethyl (4-oxo-2-phenyl-3,4-dihydro-2H-pyran-2-yl)phospho-
nate 2a. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.52e7.49 (m, 2H),
7.40e7.24 (m, 3H), 7.32 (dd, J¼6.1, 1.6 Hz, 1H), 5.36 (dd, J¼6.1, 1.0 Hz,
1H), 4.15e3.91 (m, 4H), 3.43 (dd, J¼16.7, 11.1 Hz, 1H), 3.29 (ddd,
J¼16.7, 5.4 and 1.0 Hz, 1H), 1.25 (q, J¼7.3 Hz, 6H); 13C NMR (CDCl3,
100 MHz):
d
188.2 (d, JCeP¼12 Hz), 159.4 (d, JCeP¼12 Hz), 133.0,
128.6 (d, JCeP¼2.2 Hz), 128.2 (d, JCeP¼2.1 Hz), 126.8 (d, JCeP¼4.3 Hz),
108.2, 83.3 (d, JCeP¼173.6 Hz), 63.9 (br s, (CH3CH2O)2P), 40.6, 16.0
(d, J¼5.1 Hz, (CH3CH2O)2P); 31P NMR (161 MHz, CDCl3): 16.45; IR
(ATR technique, cmꢁ1): 2983, 1735, 1677, 1242, 1013; HRMS: cal-
culated for C15H19O5P 310.0970 and found 310.0977.
3. Conclusion
4.2.2. Diethyl (2-(4-methoxyphenyl)-4-oxo-3,4-dihydro-2H-pyran-
In summary, we disclose the first hetero DielseAlder reactions
of acyl phosphonates with activated dienes where acyl phospho-
nates serve as dionophile. The present work provides a synthesis of
glycosyl type phosphonates via the thermal hetero DielseAlder
reaction of acyl phosphonates with Danishefsky’s diene. The de-
sired glycosyl type phosphonates are obtained in good yields
(70e91%). Although the main objective of the current work was to
employ acyl phosphonates as dienophile in hetero DielseAlder
reactions, a new method for the syntheses of glycosyl type phos-
phonates is also reported. Efforts towards the asymmetric synthe-
ses of these glycosyl type phosphonates are currently in progress.
2-yl)phosphonate 2b. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.42
(dd, J¼9.0, 2.2 Hz, 2H), 7.28 (d, J¼1.0 Hz, 1H), 6.89 (d, J¼9.0 Hz, 2H),
5.36 (dd, J¼6.1, 1.0 Hz, 1H), 4.16e3.94 (m, 4H), 3.8 (s, 3H), 3.39 (dd,
J¼16.7, 10.9 Hz, 1H), 3.25 (ddd, J¼16.7, 4.8 and 1.0 Hz, 1H), 1.25 (q,
J¼6.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz):
d
188.6 (d, JCeP¼12 Hz),
159.8 (d, JCeP¼2.5 Hz), 159.4 (d, J¼12.7 Hz), 128.4 (d, J¼4.2 Hz),
128.4, 113. 7 (d, JCeP¼2.0 Hz), 108.2, 83.0 (d, JCeP¼176.1 Hz), 63.9 (br
s, (CH3CH2O)2P), 55.0, 40.5, 16.1 (d, J¼4.9 Hz, (CH3CH2O)2P); 31P
NMR (161 MHz, CDCl3): 16.65; IR (ATR technique, cmꢁ1): 2981,
2923, 1681, 1599, 1510, 1250, 1014; HRMS: calculated for C16H21O6P
340.1076 and found 340.1081.
4. Experimental section
4.1. General methods
4.2.3. Diethyl (4-oxo-2-p-tolyl-3,4-dihydro-2H-pyran-2-yl)phospho-
nate 2c. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.31 (dd, J¼8.4,
2.2 Hz, 2H), 7.22 (dd, J¼6.1, 1.6 Hz, 1H), 7.11 (d, J¼7.8 Hz, 2H), 5.28
(dd, J¼6.1, 1.0 Hz, 1H), 4.08e3.86 (m, 4H), 3.34 (dd, J¼16.6, 11.0 Hz,
1H), 3.19 (ddd, J¼16.6, 4.9 and 1.0 Hz,1H), 2.26 (d, J¼1.6 Hz, 3H),1.19
Proton (1H) and carbon (13C) NMR spectra were recorded on 400
and100 MHz spectrometers. Chemical shifts inproton and carbon NMR
spectra are reported in parts per million and tetramethylsilane was
used as an internal reference unless otherwise noted. Spin multiplici-
ties in proton NMR spectra are indicated by the following symbols: s
(singlet), t (triplet), dd (doubletof doublet), m (multiplet). Flash column
chromatography was performed using 230e400-mesh silica gel using
ethyl acetate/hexane mixture as eluting solvent. Reactions sensitive to
air and moisture were performed under argon. The progress of all re-
actions was monitored by thin layer chromatography (TLC), which was
carried out on Merck silica gel plates with fluorescent indicator. TLC
plates were initially visualized by UV light source, and then dipped into
an ethanolic solution of phosphomolybdic acid. All commercially
available reagents were used as received unless otherwise reported.
Tetrahydrofuran and toluene were distilled from Na/benzophenone
and methylene chloride was freshly distilled from calcium hydride and
freshly distilled prior to use. Acyl phosphonates were easily prepared
according to the published procedure4 and used freshly in the cyclo-
addition reactions. Brassard’s diene for HDA reactions was also pre-
pared by following the literature procedure5 and used freshly in each
experiment. The enantiomeric excess (ee) of the 2mwas determined by
HPLC using Chiralcel OC column with hexane/IPA as the eluent.
(q, J¼7.1 Hz, 6H); 13C NMR (CDCl3, 100 MHz):
d 188.3 (d,
JCeP¼13 Hz),159.3 (d, JCeP¼12.6 Hz),138.5 (d, J¼2.9 Hz),130.6,128.9
(d, JCeP¼2.2 Hz), 126.7 (d, JCeP¼4.3 Hz), 108.1, 83.1 (d,
JCeP¼174.6 Hz), 63.1 (br s, (CH3CH2O)2P), 40.5, 20.7, 16.0 (d,
J¼5.3 Hz, (CH3CH2O)2P); 31P NMR (161 MHz, CDCl3): 16.56; IR (ATR
technique, cmꢁ1): 2982, 1678, 1599, 1248, 1013; HRMS: calculated
for C16H21O5P 324.1127 and found 324.1127.
4.2.4. Diethyl (2-(4-chlorophenyl)-4-oxo-3,4-dihydro-2H-pyran-2-
yl)phosphonate 2d. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.44
(dd, J¼8.8, 2.2 Hz, 2H), 7.36 (d, J¼8.6 Hz, 2H), 7.30 (dd, J¼6.1, 1.6 Hz,
1H), 5.38 (dd, J¼6.1, 1.0 Hz, 1H), 4.17e3.96 (m, 4H), 3.42 (dd, J¼16.7,
11.1 Hz, 1H), 3.22 (ddd, J¼16.7, 5.3 and 1.0 Hz, 1H), 1.27 (dt, J¼7.0,
3.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz):
d
188.0 (d, JCeP¼12 Hz),
159.3 (d, JCeP¼12 Hz), 134.8 (d, J¼3.5 Hz), 132.7, 128.5 (d,
JCeP¼2.1 Hz), 128.3 (d, JCeP¼4.3 Hz), 108.4, 82.9 (d, JCeP¼174.0 Hz),
64.1 (d, J¼6.9 Hz, (CH3CH2O)2P), 64.0 (d, J¼7.2 Hz, (CH3CH2O)2P),
40.6, 16.1 (d, J¼5.5 Hz, (CH3CH2O)2P); 31P NMR (161 MHz, CDCl3):
15.98; IR (ATR technique, cmꢁ1): 2983, 1681, 1599, 1242, 1011;
HRMS: calculated for C15H18ClO5P 344.0580 and found 344.0584.
4.2.5. Dimethyl (2-(3-chlorophenyl)-4-oxo-3,4-dihydro-2H-pyran-2-
4.2. General procedure for the HDA reactions of acyl
phosphonates with Danishefsky’s diene under thermal
conditions (2ael)
yl)phosphonate 2e. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.50e7.49 (m, 1H), 7.38e7.31 (m, 4H), 5.04 (dd, J¼6.1, 1.1 Hz, 1H),
3.75 (d, J¼10.6, 3H), 3.69 (d, J¼10.6, 3H), 3.39 (dd, J¼16.7, 11.1 Hz,
1H), 3.20 (ddd, J¼16.7, 6.1 and 1.0 Hz, 1H); 13C NMR (CDCl3,
A 10-mL vial was charged with acyl phosphonate (200 mg,
1 equiv) and freshly distilled toluene (2 mL) under argon and then
100 MHz):
d
187.6 (d, JCeP¼12.0 Hz), 159.2 (d, JCeP¼12.0 Hz), 136.2,
134.7 (d, J¼2.8 Hz), 129.7 (d, JCeP¼2.3 Hz), 129.1 (d, J¼2.8 Hz), 126.9

2400
S. Polat-Cakir, A.S. Demir / Tetrahedron 67 (2011) 2396e2401
(d, JCeP¼4.2 Hz), 125.1 (d, J¼4.2 Hz), 108.5, 83.0 (d, JCeP¼173.8 Hz),
54.6 (d, J¼7.0 Hz, (CH3O)2P), 54.5 (d, J¼7.2 Hz, (CH3O)2P), 40.6; 31P
NMR (161 MHz, CDCl3): 18.13; IR (ATR technique, cmꢁ1): 2958,
1680, 1258, 1016; HRMS: calculated for C13H14ClO5P 316.0267 and
found 316.0266.
53.6 (d, JCeP¼5.8 Hz), 41.4, 19.2; 31P NMR (161 MHz, CDCl3): 22.08;
IR (ATR technique, cmꢁ1): 2961, 1672, 1600, 1309, 1231, 1019, 832;
HRMS: calculated for C8H13O5P 220.0500 and found 220.0491.
4.2.11. Dimethyl
(2-ethyl-4-oxo-3,4-dihydro-2H-pyran-2-yl)phos-
7.26 (d,
phonate 2k. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
4.2.6. Dimethyl (2-(2-chlorophenyl)-4-oxo-3,4-dihydro-2H-pyran-2-
J¼6.2 Hz, 1H), 5.43 (d, J¼6.2 Hz, 1H), 3.86 (d, J¼10.6 Hz, 3H), 3.83 (d,
J¼10.6 Hz, 3H), 2.98 (dd, J¼17.0 and 12.0 Hz, 1H), 2.71 (t, J¼17.0 Hz,
1H), 2.13e1.98 (m, 2H), 1.06 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3,
100 MHz): 188.9 (d, JCeP¼6.6 Hz), 159.8 (d, JCeP¼6.6 Hz), 106.2, 83.1
(d, JCeP¼171.6 Hz), 53.7 (d, J¼6.4 Hz), 53.5 (d, J¼6.5 Hz), 39.5, 26.8,
7.48 (d, JCeP¼5.1 Hz); 31P NMR (161 MHz, CDCl3): 22.59; IR (ATR
technique, cmꢁ1): 2960, 1675, 1601, 1252, 1228, 1021, 831; HRMS:
calculated for C9H15O5P 234.0657 and found 234.0649.
yl)phosphonate 2f. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.59e7.54 (m, 1H), 7.44e7.40 (m, 1H), 7.37 (dd, J¼6.0, 1.2 Hz, 1H),
7.35e7.27 (m, 2H), 5.42 (dd, J¼6.0, 1.1 Hz, 1H), 3.81 (d, J¼10.6 Hz,
3H), 3.74 (d, J¼10.6 Hz, 4H), 3.48 (dd, J¼16.8, 10.1 Hz, 1H); 13C NMR
(CDCl3, 100 MHz):
d
188.3 (d, JCeP¼11.8 Hz), 159.3 (d, JCeP¼12.2 Hz),
132.8 (d, J¼5.0 Hz), 132.7 (d, J¼1.9 Hz), 130.8, 130.2, 130.17 (d,
J¼3.6 Hz), 127.0 (d, J¼4.3 Hz), 108.6, 84.9 (d, JCeP¼173.8 Hz), 54.5 (d,
J¼7.1 Hz, (CH3O)2P), 54.3 (d, J¼7.1 Hz, (CH3O)2P), 41.4; 31P NMR
(161 MHz, CDCl3): 18.10; IR (ATR technique, cmꢁ1): 2981, 2923,
1681, 1599, 1510, 1250, 1014; HRMS: calculated for C13H14ClO5P
316.0267 and found 316.0276.
4.2.12. Dimethyl
(2-isopropyl-4-oxo-3,4-dihydro-2H-pyran-2-yl)
7.27 (d,
phosphonate 2l. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
J¼6.2 Hz, 1H), 5.41 (d, J¼6.2 Hz, 1H), 3.82 (d, J¼10.5 Hz, 3H), 3.79 (d,
J¼10.7 Hz, 3H), 2.91e2.74 (m, 2H), 2.54e2.39 (m, 1H), 1.09 (d,
J¼2.0 Hz, 3H), 1.08 (d, J¼2.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
4.2.7. Diethyl (2-(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-pyran-2-
yl)phosphonate 2g. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.49
d
189.1 (d, J¼3.6 Hz), 160.2 (d, J¼3.3 Hz), 106.0, 83.3 (d, J¼166.0 Hz),
(ddd, J¼8.9, 5.0, 2.2 Hz, 2H), 7.30 (dd, J¼6.1, 1.5 Hz, 1H), 7.07 (t,
J¼8.6 Hz, 2H), 5.38 (d, J¼6.1, 1H), 4.14e3.97 (m, 4H), 3.42 (dd,
J¼16.7, 11.0 Hz, 1H), 3.24 (dd, J¼16.7, 5.2 Hz, 1H), 1.26 (t, J¼7.0 Hz,
53.7 (d, J¼7.5 Hz), 53.2 (d, J¼7.4 Hz), 37.3, 33.4 (d, J¼3.2 Hz), 17.0 (d,
J¼2.7 Hz), 16.9 (d, J¼6.7 Hz); 31P NMR (161 MHz, CDCl3): 23.14; IR
(ATR technique, cmꢁ1): 2968, 1278, 1602, 1404, 1219, 1028, 1009;
HRMS: calculated for C10H17O5P 248.0814 and found 248.0808.
6H); 13C NMR (CDCl3,100 MHz):
d
188.0 (d, JCeP¼12.0 Hz),162.6 (dd,
J¼249.0 and 3.2 Hz), 159.2 (d, JCeP¼12.2 Hz), 128.8 (dd, J¼8.2 and
4.2 Hz), 115.2 (dd, J¼21.8 and 2.1 Hz), 108.2, 82.8 (d, JCeP¼174.8 Hz),
63.9 (d, J¼6.6 Hz, (CH3CH2O)2P), 63.8 (d, J¼5.8 Hz, (CH3CH2O)2P),
40.5, 16.0 (d, J¼5.2 Hz, (CH3CH2O)2P); 31P NMR (161 MHz, CDCl3):
16.18; IR (ATR technique, cmꢁ1): 2983, 1682, 1602, 1238, 1012;
HRMS: calculated for C15H18FO5P 328.0876 and found 328.0866.
4.3. General procedure for the HDA reactions of
benzoylphosphonate 1m with Danishefsky’s diene in the
presence of Lewis acids
To a solution of benzoylphosphonate 1m (200 mg, 1 equiv) in
either DCM or toluene (2 mL) was added Lewis acid (either 1.1 equiv
or 1.0 equiv) at ꢁ78 ꢀC under argon atmosphere. After stirring for
10 min, Danishefsky’s diene (2 equiv) was added to the reaction
mixture at the same temperature as the time indicated in Table 2.
TFA was added slowly to the reaction mixture and stirred for 30 min.
The reaction mixture was carefully quenched byadding few drops of
water at 0 ꢀC and then filtrated over Celite and concentrated. The
crude product was purified by flash column chromatography.
4.2.8. Dimethyl (2-(2-fluorophenyl)-4-oxo-3,4-dihydro-2H-pyran-2-
yl)phosphonate 2h. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.52e7.47 (m, 1H), 7.38e7.31 (m, 2H), 7.18 (t, J¼7.6 Hz, 1H), 7.08
(dd, J¼12.4, 8.3 Hz, 1H), 5.40 (dd, J¼6.1, 1.0 Hz, 1H), 3.78 (d,
J¼10.6 Hz, 3H), 3.76 (d, J¼10.6 Hz, 3H), 3.53 (dd, J¼16.5 and 7.0 Hz,
1H), 3.42 (ddd, J¼16.5, 10.4, 1.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d
188.3 (d, JCeP¼12.1 Hz), 160.4 (dd, J¼251.6 and 4.2 Hz), 159.2 (d,
JCeP¼12.0 Hz), 131.1 (dd, J¼8.9, 2.8 Hz), 129.3 (dd, J¼3.7, 2.7 Hz),
124.2 (t, J¼2.9 Hz), 120.9 (dd, J¼10.0, 1.4 Hz), 117.1 (dd, J¼24.2,
2.1 Hz),108.5, 83.0 (dd, JCeP¼175.3, 4.2 Hz), 54.5 (d, J¼7.0 (CH3O)2P),
54.4 (d, J¼7.1 (CH3O)2P), 40.8 (d, J¼8.6 Hz); 31P NMR (161 MHz,
CDCl3): 18.03; IR (ATR technique, cmꢁ1): 2960, 1682, 1599, 1242,
1013; HRMS: calculated for C13H14FO5P 300.0562 and found
300.0560.
4.3.1. Dimethyl (4-oxo-2-phenyl-3,4-dihydro-2H-pyran-2-yl)phos-
phonate 2m. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.52e7.49 (m,
2H), 7.41e7.34 (m, 3H), 7.31 (dd, J¼6.1 and 1.4 Hz, 1H), 5.37 (d,
J¼6.1 Hz, 1H), 3.71 (d, J¼10.6 Hz, 3H), 3.65 (d, J¼10.6 Hz, 3H), 3.43
(dd, J¼16.7 and 11.1 Hz, 1H), 3.29 (ddd, J¼16.7, 5.6 and 0.7 Hz, 1H);
13C NMR (CDCl3, 100 MHz):
d
188.1 (d, J¼12.4 Hz), 159.3 (d,
J¼12.3 Hz), 133.7, 128.9 (d, J¼2.3 Hz), 128.5 (d, J¼2.0 Hz), 126.9 (d,
J¼4.3 Hz), 108.4, 83.5 (d, J¼174.5 Hz), 54.5 (t, J¼7.4 Hz), 40.6; 31P
NMR (161 MHz, CDCl3): 18.07; IR (ATR technique, cmꢁ1): 2959,
1675, 1597, 1243, 1015, 832; HRMS: calculated for C13H15O5P
282.0657 and found 282.0654. Determination of enantiomeric ex-
cess (ee) values for racemic 2m: Chiralcel OC, hexane/IPA¼95:5,
flow¼1 mL/min t¼12.29 and 13.34 min. The asymmetric compound
2m was prepared according to the procedure in literature (Ref. 6).
(S,S)-2,20-Methylenebis(4-tert-butyl-2-oxazoline) was used as the
ligand. Determination of enantiomeric excess (ee) values for
asymmetric 2m: Chiralcel OC, hexane/IPA¼95:5, flow¼1 mL/min
t¼12.11 and 13.80 min.
4.2.9. Dimethyl (4-oxo-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-
2H-pyran-2-yl)phosphonate 2i. Yellow oil; 1H NMR (CDCl3,
400 MHz):
d
7.65 (br t, J¼10 Hz, 4H), 7.33 (dd, J¼6.1, 1.3 Hz, 1H), 5.40
(dd, J¼6.1 and 0.8 Hz,1H), 3.77 (d, J¼10.6 Hz, 3H), 3.70 (d, J¼10.6 Hz,
3H), 3.47 (dd, J¼16.7 and 11.3 Hz, 1H), 3.28 (dd, J¼16.7, 5.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz):
d
187.6 (d, JCeP¼12.0 Hz), 159.2 (d,
JCeP¼12.0 Hz), 138.4, 131.2 (dq, J¼32.8, 2.9 Hz), 127.4 (d, J¼4.1 Hz),
125.5 (t, J¼3.2 Hz), 123.7 (dd, J¼272.2 and 1.2 Hz), 108.8, 83.4 (d,
J¼173.9 Hz), 54.8 (d, J¼6.8 Hz, (CH3O)2P), 54.7 (d, J¼6.7 Hz,
(CH3O)2P), 40.8; 31P NMR (161 MHz, CDCl3): 17.96; IR (ATR tech-
nique, cmꢁ1): 3283, 2969, 2911, 1675, 1178, 1056, 1009; HRMS:
calculated for C14H14F3O5P 350.0531 and found 350.0532.
4.4. General procedure for the HDA reactions of acyl
phosphonates with Brassard’s diene in the presence of
Me2AlCl (3m, 3c,d and 3k)
4.2.10. Dimethyl (2-methyl-4-oxo-3,4-dihydro-2H-pyran-2-yl)phos-
phonate 2j. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.26 (d,
J¼6.2 Hz, 1H), 5.44 (d, J¼6.2 Hz, 1H), 3.88 (d, J¼10.5 Hz, 6H), 3.08
(dd, J¼16.7 and 12.1 Hz, 1H), 2.55 (dd, J¼16.7 and 11.5 Hz, 1H), 1.65
To a solution of acyl phosphonate (200 mg, 1 equiv) in DCM
(2 mL) was added Me2AlCl (1.1 equiv) at ꢁ78 ꢀC under argon at-
mosphere. After stirring for 10 min, freshly prepared Brassard’s
(d, J¼15.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 188.2 (d,
JCeP¼9.9 Hz), 159.3 (d, JCeP¼9.4 Hz), 105.9, 79.9 (d, JCeP¼176.3 Hz),

S. Polat-Cakir, A.S. Demir / Tetrahedron 67 (2011) 2396e2401
2401
diene (2 equiv) was added to the reaction mixture at the same
temperature and left it overnight. The reaction mixture was care-
fully quenched by adding few drops of water at 0 ꢀC and then fil-
trated over Celite and concentrated. The crude product was purified
by flash column chromatography to give the desired HDA product.
1H), 4.02e3.95 (m, 2H), 3.85 (d, J¼3.3 Hz, 3H), 3.83 (d, J¼3.2 Hz,
3H), 2.92 (dd, J¼17.8 and 12.7 Hz, 1H), 2.60 (dd, J¼19.7 and 17.9 Hz,
1H), 2.14e1.95 (m, 2H), 1.40 (t, J¼7.0 Hz, 3H), 1.05 (t, J¼7.5 Hz, 3H);
13C NMR (CDCl3,100 MHz):
d
169.2 (d, J¼8.3 Hz), 164.8 (d, J¼5.0 Hz),
89.9, 80.1 (d, J¼169.8 Hz), 64.7, 53.8 (d, J¼7.2 Hz), 53.7 (d, J¼7.4 Hz),
30.7 (d, J¼2.8 Hz), 28.8 (d, J¼1.4 Hz), 13.8, 7.5 (d, J¼5.4 Hz); 31P NMR
(161 MHz, CDCl3): 23.04; IR (ATR technique, cmꢁ1): 2958, 2922,
1710, 1628, 1214, 1021; HRMS: calculated for C11H19O6P 278.0919
and found 278.0909.
4.4.1. Dimethyl (4-ethoxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-
yl)phosphonate 3m. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d
7.57e7.54 (m, 2H), 7.41e7.34 (m, 3H), 5.01 (d, J¼1.3 Hz, 1H), 3.85
(d, J¼10.5 Hz, 3H), 3.84 (q, J¼12.4 Hz, 2H), 3.48 (d, J¼10.4 Hz, 3H),
3.46 (ddd, J¼17.3, 11.5 and 1.5 Hz, 1H), 3.09 (dd, J¼17.3 and 5.2 Hz,
1H), 1.32 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 169.3 (d,
Acknowledgements
J¼17.7 Hz), 164.5 (d, J¼11.1 Hz), 136.0, 128.4, 128.4 (d, J¼2.1 Hz),
126.0 (d, J¼4.0 Hz), 90.6, 80.6 (d, J¼171.7 Hz), 64.8, 54.5 (t, J¼7.9 Hz),
33.1, 13.6; 31P NMR (161 MHz, CDCl3): 18.50; IR (ATR technique,
cmꢁ1): 2955, 1720, 1624, 1229, 1013, 840; HRMS: calculated for
C15H19O6P 326.0919 and found 326.0908.
Financial support from the Scientific and Technological Research
€
€
Council of Turkey (TUBITAK), Turkish Academy of Science (TUBA)
and the Middle East Technical University (METU) are all apprecia-
tively acknowledged.
4.4.2. Dimethyl (4-ethoxy-6-oxo-2-p-tolyl-3,6-dihydro-2H-pyran-2-
yl)phosphonate 3c. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 7.42
Supplementary data
(dd, J¼8.4 and 2.2 Hz, 2H), 7.19 (d, J¼8.1 Hz, 2H), 5.00 (d, J¼1.4 Hz,
1H), 3.85 (d, J¼10.4 Hz, 3H), 3.81 (q, J¼11.8 Hz, 2H), 3.50 (d,
J¼10.4 Hz, 3H), 3.43 (ddd, J¼17.2, 11.5 and 1.5 Hz, 1H), 3.07 (dd,
J¼17.3 and 4.8 Hz, 1H), 2.34 (d, J¼1.4 Hz, 3H), 1.32 (t, J¼7.0 Hz, 3H);
Supplementary data (the copies of 1H, 13C and 31P NMR spectra
of these synthesized compounds are presented) associated with
this article can be found online at doi:10.1016/j.tet.2011.02.007.
These data include MOL files and InChIKeys of the most important
compounds described in this article.
13C NMR (CDCl3, 100 MHz):
d
169.4 (d, J¼18.2 Hz), 164.8 (d,
J¼11.4 Hz), 138.4 (d, J¼3.2 Hz), 133.0, 129.2 (d, J¼2.2 Hz), 126.9 (d,
J¼4.0 Hz), 90.7, 80.6 (d, J¼172.8 Hz), 64.8, 54.7 (d, J¼7.5 Hz), 54.6 (d,
J¼7.4 Hz), 33.1, 20.9, 13.7; 31P NMR (161 MHz, CDCl3): 18.68; IR (ATR
technique, cmꢁ1): 2957, 1716, 1625, 1221, 1028, 748; HRMS: calcu-
lated for C16H21O6P 340.1076 and found 340.1069.
References and notes
1. (a) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122,
1635e1649; (b) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120,
4895e4896; (c) Samanta, S.; Krause, J.; Mandal, T.; Zhao, C. Org. Lett. 2007, 9,
2745e2748.
2. (a) Demir, A. S.; Aybey, A.; Emrullahoglu, M. Synthesis 2009, 1655e1658;
(b) Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. J. Org. Chem. 2008,
4.4.3. Dimethyl
2H-pyran-2-yl)phosphonate 3n. Yellow oil; 1H NMR (CDCl3,
400 MHz):
(2-(4-chlorophenyl)-4-ethoxy-6-oxo-3,6-dihydro-
d
7.48 (dd, J¼8.8 and 2.2 Hz, 2H), 7.37 (d, J¼8.6 Hz, 2H),
5.01 (d, J¼1.4 Hz, 1H), 3.86 (d, J¼10.5 Hz, 5H), 3.56 (d, J¼10.4 Hz,
73, 8992e8997; (c) Erturk, E.; Demir, A. S. Tetrahedron 2008, 64,
€
3H), 3.47 (ddd, J¼17.2, 11.4 and 1.5 Hz, 1H), 3.04 (dd, J¼17.3 and
€
€ €
7555e7560; (d) Demir, A. S.; Reis, B.; Reis, O; Eymur, S.; Gollu, M.; Tural,
S.; Saglam, G. J. Org. Chem. 2007, 72, 7439e7442; (e) Demir, A. S.; Eymur,
S. J. Org. Chem. 2007, 72, 8527e8530; (f) Demir, A. S.; Reis, O.; Esiringue,
I.; Reis, B.; Baris, S. Tetrahedron 2007, 63, 160e165; (g) Demir, A. S.; Reis,
5.1 Hz,1H),1.32 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3,100 MHz):
d 169.2
(d, J¼17.6 Hz), 164.3 (d, J¼11.0 Hz), 134.8 (d, J¼3.6 Hz), 128.7 (d,
J¼2.3 Hz), 127.6 (d, J¼4.2 Hz), 90.6, 80.3 (d, J¼172.3 Hz), 65.0, 54.75
(d, J¼5.4 Hz), 54.68 (d, J¼5.9 Hz), 33.1, 13.7; 31P NMR (161 MHz,
CDCl3): 18.10; IR (ATR technique, cmꢁ1): 2958, 1728, 1624, 1239,
1220, 1027, 852; HRMS: calculated for C15H18ClO6P 360.0530 and
found 360.0524.
€
O; Kayalar, M.; Eymur, S.; Reis, B. Synlett 2006, 3329e3333; (h) Demir, A.
S.; Reis, O.; Igdir, A. C.; Esiringu, I.; Eymur, S. J. Org. Chem. 2005, 70,
10584e10587.
3. (a) Dondoni, A.; Daninos, S.; Marra, A.; Formaglio, P. Tetrahedron 1998, 54,
9859e9874; (b) Dondoni, A.; Marra, A.; Scherrmann, M. C.; Bertolasi, V. Chem.
dEur. J. 2001, 7, 1371e1382.
4. Berlin, K. D.; Taylor, H. A. J. Am. Chem. Soc. 1964, 86, 3862e3866.
5. Du, H.; Zhao, D; Ding, K. Chem.dEur. J. 2004, 10, 5964e5970.
6. Johannsen, M.; Yao, Y.; Jørgensen, K. A Chem. Commun. 1997, 2169e2170 (S,S)-
2,20-Methylenebis(4-tert-butyl-2-oxazoline) was used as the ligand.
4.4.4. Dimethyl (4-ethoxy-2-ethyl-6-oxo-3,6-dihydro-2H-pyran-2-
yl)phosphonate 3k. Yellow oil; 1H NMR (CDCl3, 400 MHz):
d 5.14 (s,