Synthesis of tertiary propargylic phosphonates by addition of trialkynylaluminum reagents to acyl phosphonates and investigation of their antimicrobial activities

Article abstract of DOI:10.3906/kim-1402-6

A series of propargylic alcohols containing phosphonates was synthesized by addition reactions of tris- (propynyl) and tris-(phenylethynyl)aluminum reagents to acyl phosphonates in good yields. Aromatic moieties of the acyl phosphonates with electron-with

Full text of DOI:10.3906/kim-1402-6

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 880 – 893
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1402-6
Research Article
Synthesis of tertiary propargylic phosphonates by addition of trialkynylaluminum
reagents to acyl phosphonates and investigation of their antimicrobial activities
Mohammad Shakhawoat HOSSAIN1, Sıdıka POLAT C¸ AKIR2,∗
,
3
Ay¸se Betu¨l KARADUMAN , Mustafa YAMAC¸ , Ayhan Sıtkı DEMIR
4
1,†
˙
1Department of Chemistry, Middle East Technical University, Ankara, Turkey
2Department of Chemical Engineering, Engineering and Architecture Faculty, C¸anakkale Onsekiz Mart University,
C¸anakkale, Turkey
3Graduate School of Natural and Applied Sciences, Eski¸sehir Osmangazi University, Eski¸sehir, Turkey
4Faculty of Science and Arts, Department of Biology, Eski¸sehir Osmangazi University, Eski¸sehir, Turkey
†Deceased 24 June 2012
Received: 02.02.2014
•
Accepted: 3.05.2014
•
Published Online: 15.08.2014
•
Printed: 12.09.2014
Abstract: A series of propargylic alcohols containing phosphonates was synthesized by addition reactions of tris-
(propynyl) and tris-(phenylethynyl)aluminum reagents to acyl phosphonates in good yields. Aromatic moieties of the acyl
phosphonates with electron-withdrawing groups generally resulted in better isolated chemical yield. Selected propargylic
phosphonates were tested for antimicrobial activities. Compounds 3a and 3h showed noticeable antifungal activity,
especially against molds.
Key words: Acyl phosphonates, alkynyl organoaluminum, propargylic alcohols, tris-(phenylethynyl)aluminum, tris-
(propynyl)aluminum, antimicrobial activity
1. Introduction
Propargylic alcohols are useful synthetic intermediates and can be easily manipulated into a variety of useful
functional groups. For that reason, several methods are available in the literature for their preparation.1−6
Addition of alkyne to either aldehydes or ketones, reduction of ynones, and direct addition of alkynylzinc
reagents to carbonyl compounds are used to obtain related secondary or tertiary propargylic alcohols.1−6 More-
over, alkynylation of α-keto ester provides synthesis of highly functionalized tertiary alcohols, i.e. propargylic
carboxylates.7−12 Propargylic alcohols having C–P bonds are considered close analogues of propargylic car-
boxylates.
Addition of organoaluminum reagents to carbonyl compounds for the synthesis of secondary and tertiary
alcohols is well known.13−16 Organoaluminum reagents are easy to handle and are commercially available. How-
ever, those not commercially available can be easily prepared according to a literature procedure.17 Organoa-
luminum reagents are very attractive for their utilization in asymmetric synthesis.13−16 Trialkyl aluminum
reagents are used as alkyl donor in the addition reaction while trialkynylaluminum reagents are the source of
alkynyl type C-based nucleophiles.
α−Functionalized phosphonates are medicinally important molecules due to their wide range of biological
∗Correspondence: spcakir@comu.edu.tr
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HOSSAIN et al./Turk J Chem
activities. Hence, there are many published procedures for synthesis and investigation of their biological
activities.18−26 For both synthesis and study of their biological activity, tertiary propargylic phosphonates
still need more attention. In continuation of our work on acyl phosphonate chemistry, herein we present
the synthesis of tertiary propargylic phosphonates by simple addition of trialkynyl organoaluminum reagents
to acyl phosphonates and also present our investigation on the antimicrobial activity of selected propargylic
phosphonates.
2. Results and discussion
Recently, we have reported that aryl and alkyl acyl phosphonates 1 can react with trialkyl organoaluminum
reagents such as Me3 Al and Et3 Al to produce the related secondary and tertiary α-hydroxy phosphonates.27
In the same article, we also briefly described the alkynylation reactions of acyl phosphonates with the triethyny-
laluminum reagent to afford the desired α-hydroxy phosphonates 2 in moderate yields, i.e. 67% in the case
of R1 =H, 57% in the case of R1 =Me, and 44% in the case of R1 =Cl (Scheme). Encouraged by the results
obtained from this preliminary study, we have extended our research and investigated the scope of alkynylation
reaction of acyl phosphonates with different trialkynyl organoaluminum reagents to obtain tertiary propar-
gylic phosphonates. In addition, we have studied the capacity of the synthesized propargylic phosphonates as
antimicrobial agents.
O
OH
Al
P(OEt)2
O
3
P(OEt)2
O
toluene, 0oC
15-30 min
R1
R1
1
2
R1= H, Me and Cl
Scheme. Addition of triethynylaluminum reagent to acyl phosphonates.
The acyl phosphonates were prepared by treating the parent chlorides with triethyl phosphites according
to the literature procedure.28 Tris-(propynyl) and tris-(phenylethynyl)aluminum reagents were also prepared by
following the literature procedure,17 i.e. 1-propynyl magnesium bromide solution was reacted with dry AlCl3
to give tris-(propynyl)aluminum.
We initially investigated the addition of tris-(propynyl)aluminum reagent to a variety of acyl phospho-
nates, 1a–m (Table 1). In all cases, the desired tertiary propargylic alcohols were obtained without cleavage of
the C–P bond in good yields. The reaction of benzoyl phosphonate 1a with tris-(propynyl)aluminum gave the
desired tertiary propargylic alcohol 3a in 56% yield. When the electron donation was increased from –CH3 to
–OMe, the yields were lower (entries 2 and 4, Table 1, 53% and 41% yields, respectively).
When the methyl group was at the ortho position (entry 3, Table 1), the desired tertiary propargylic
alcohol 3c was obtained in lower yield (32%) due to the bulkiness around the reactive site. The addition reactions
of compounds 1e and 1h with tris-(propynyl)aluminum were smooth and afforded compounds 3e (70%) and
3h (61%) in good yields. The reaction of 4-trifluoromethyl benzoyl phosphonate with tris-(propynyl)aluminum
proceeded efficiently to give compound 3k in good yield (75%). We also carried out the alkynylation reaction
of alkyl phosphonates 1l and 1m. However, in these cases the corresponding tertiary propargylic alcohols 3l
and 3m were obtained in low yields (32% and 38%, respectively).
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HOSSAIN et al./Turk J Chem
Table 1. Alkynylation of acyl phosphonates with tris-(propynyl)aluminum reagent.
OH
O
Al(
toluene
0 °C to RT
)
3
R1
P(OEt)2
O
P(OEt)2
O
R1
3
1
R1= Aryl and alkyl
Entry
1
Product
Entry
Product
Entry
10
Product
OH
F
OH
OH
Cl
P(OEt)2
P(OEt)2
O
P(OEt)2
O
O
6
7
8
a
3f, 61%
3j, 62%
3a,
OH
OH
OH
F
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
F3C
2
11
12
3g, 65%
3k, 75%
3b, 53%
OH
OH
OH
P(OEt)2
P(OEt)2
O
P(OEt)2
O
O
Cl
3
4
3h, 61%
3c, 32%
3l, 32%
Cl
OH
OH
OH
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
9
13
MeO
3d, 41%
3m, 38%
3i, 49%
OH
P(OEt)2
O
F
5
3e, 70%
a
Yields refer to purified compound
882

HOSSAIN et al./Turk J Chem
Our next attempt was to use tris-(phenylethynyl) aluminum reagent in alkynylation of the acyl phospho-
nates (Table 2, entries 1–9) to obtain tertiary propargylic phosphonates. The reaction of benzoyl phosphonate
1a with freshly prepared tris-(phenylethynyl)-aluminum gave compound 4a in 61% yield. On the other hand,
Zbiral et al.29 have synthesized compound 4a by direct addition of organolithium reagent PhC≡CLi to benzoyl
phosphonate 1a, reporting 58% chemical yield.
Table 2. Alkynylation of acyl phosphonates with tris-(phenylethynyl)aluminum reagent.
OH
O
Al(
Ph)3
P(OEt)2
O
R1
P(OEt)2
O
R1
toluene
0 °Cto RT
4
1
Ph
Entry
Product
Entry Product
Entry Product
OH
OH
Ph
OH
Ph
F
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
MeO
1
4
7
Ph
4a, 61%a
4d, 39%
4g, 72%
OH
OH
OH
P(OEt)2
P(OEt)2
P(OEt)2
O
O
O
F
Cl
2
5
8
Ph
Ph
Ph
4b, 59%
4e, 68%
4h, 52%
OH
F
OH
OH
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
F3C
Ph
Ph
Ph
3
6
9
4c, 30%
4f, 72%
4k, 60%
a
Yields refer to purified compounds
When the electron-rich benzoyl phosphonates 1b and 1d were used, the corresponding alcohols 4b and
4d were obtained in decreasing yields (Table 2, entries 2 and 4, 59% and 39% yields, respectively). The
electron-poor benzoyl phosphonates entries 5–9 in Table 2 afforded the desired propargylic alcohols in good
yields. We generally obtained better chemical yields with tris-(phenylethynyl)aluminum compared to tris-
(propynyl)aluminum, probably due to the stability of the resulting propargylic phosphonates.
Compounds 4a, 4e, 4k, 4h, 3a, 3e, 3h, and 3k were selected and investigated for antimicrobial activity
against 7 different microorganisms and the results are shown in Table 3. Most of the propargylic phosphonates
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HOSSAIN et al./Turk J Chem
did not show distinctive and wide antimicrobial activity for bacteria. Only 3 compounds, 4a, 4e, and 4h,
showed weak inhibition against 2 of the gram-positive bacteria. On the other hand, while the positive control
did not present any meaningful activity, 2 of the compounds, 3a and 3h, exhibited clear antifungal activity,
especially against molds. When we compare the structures of compounds 4 and 3, we can see that there is a
clear difference in the conjugation of the triple bond with the double bond of benzene. This may change the
dipole moment and may help to explain the better activity of compounds 3.30,31
Table 3. Antimicrobial activity of compounds 4a, 4e, 4k, 4h, 3a, 3e, 3h, and 3k.
Inhibition zone against test organisms (mm)
Compounds
aA
B
C
D
-
E
-
F
-
G
-
-
4a
4e
15.62 9.39
15.16 8.59
-
-
-
-
-
4k
4h
3a
3e
3h
3k
DMSO
bVA
B
-
11.11 6.75
-
-
-
-
-
-
-
-
-
-
-
-
-
7.00
-
7.95
-
-
-
-
-
-
-
-
-
-
-
-
7.34 32.25 33.96
-
-
-
-
-
-
21.86 41.42 31.57
-
-
-
-
-
-
29.46 17.50
34.14 12.07
49.98 28.92
NT
cNT
E
FLU
19.00
-
-
-
-
a A: Micrococcus luteus NRRL B 4375, B: Bacillus cereus LMG 8221, C: Saccharomyces cerevisiae NRRL Y 12632, D:
Candida krusei ATCC 6258, E: Aspergillus parasiticus NRRL 465, F: Aspergillus flavus NRRL 1957, G: Penicillium
chrysogenum NRRL 807 b VA: Vancomycin (30 µg), B: Bacitracin (10 U), E: Erythromycin (30 µg), FLU: Fluconazole
(10 µg) c NT: Not tested
The active compounds against the test organisms were examined to determine their minimum inhibitory
concentration (MIC) values. The MIC values of selected propargylic phosphonate compounds are presented
in Table 4 in comparison to reference antibiotics. All of the studied compounds showed antimicrobial activity
against all test microorganisms studied. Compounds 4a, 4e, and 4h exhibited comparatively low MIC values
in the range of 12.5–25 µg/mL. However, they were less active than the reference antibiotics, vancomycin,
erythromycin, and bacitracin. The MIC value of 3h against Saccharomyces cerevisiae was the same as that of
fluconazole. Compounds 3a and 3h were determined to exhibit potent antifungal activity against 3 molds with
the MIC value of 100 µg/mL. Their activity values were found to be better than those of fluconazole. These
compounds can be potential antifungal drugs, especially for molds.
The current work shows that tertiary propargylic alcohols having a C–P bond can be easily prepared
in good yields by adding trialkynylaluminum reagents to acyl phosphonates. Alkynylation reactions of acyl
phosphonates work better with aryl substituted acyl phosphonates compared to alkyl phosphonates. Moreover,
the electronic features of the aromatic moieties affected the chemical yield in such a way that introduction of
an electron-withdrawing group on the phenyl ring gave a better chemical yield. This route offers a simple
and efficient method for the synthesis of tertiary propargylic alcohols without cleavage of the C–P bond.
Future work will focus on the rearrangement of tertiary propargylic phosphonates. Antimicrobial activities
of selected propargylic phosphonates against Micrococcus luteus NRRL B 4375, Bacillus cereus LMG 8221,
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HOSSAIN et al./Turk J Chem
Saccharomyces cerevisiae NRRL Y 12632, Candida krusei ATCC 6258, Aspergillus parasiticus NRRL 465,
Aspergillus flavus NRRL 1957, and Penicillium chrysogenum NRRL 807 were also investigated. Most of the
propargylic phosphonates did not exhibit any antimicrobial activity for bacteria. However, when we compare
compounds 3a and 3h and the reference antibiotic, compounds 3a and 3h showed good antifungal activity,
especially against molds, according to their MIC values.
Table 4. The minimum inhibitory concentrations (MIC in µg/mL) of compounds 4a, 4e, 4h, 3a, 3h, and 3k.
Test organisms
Compounds
aA
25
B
25
C
-
D
-
-
E
-
-
F
-
-
-
100
100
G
-
-
4a
4e
4h
3a
3h
VA
B
12.5 12.5
-
25
-
-
12.5
-
-
- -
200 200 100
-
-
50
100
100
1.56 1.56
1.56 200
0.78 0.78
-
bNT
50
E
FLU
100 < 200 < 200 < 200
a All abbreviations used are the same as those in Table 3. b NT: Not tested.
3. Experimental section
All the reactions that were sensitive to air and moisture were performed under argon. Organic solvents used in
the reactions were distilled prior to use; dichloromethane was freshly distilled from calcium hydride; THF and
toluene were distilled from sodium/benzophenone. The progress of all reactions was monitored by TLC, which
was carried out on silica gel plates with fluorescent indicator. Crude compounds were purified by flash column
chromatography using 230–400-mesh silica gel with hexane-EtOAc mixtures as the eluting solvent. Melting
points are uncorrected and were determined on a hot stage microscope. All commercially available reagents
were used as received unless otherwise reported. All NMR spectra were recorded at room temperature on a
Bruker DPX 400 NMR spectrometer operated at 400 MHz for 1 H NMR, 100 MHz for 13 C NMR, and 161 MHz
for 31 P NMR using CDCl3 as the solvent. 1 H NMR and 13 C NMR chemical shifts were reported in parts
per million relative to tetramethylsilane. 31 P NMR chemical shifts were reported in parts per million relative
to H3 PO4 . Tris-(phenylethynyl) aluminum and tris-(propynyl) aluminum reagents were prepared by following
a literature procedure.17 Aryl and alkyl acyl phosphonates were also synthesized according to a literature
procedure.28
3.1. Materials and methods for the antimicrobial activity studies
In vitro antimicrobial susceptibility studies were performed using a panel of gram-positive and -negative bacteria,
yeast, and mold species. The panel consisted of a total of 7 microorganism species, namely Micrococcus luteus
NRRL B 4375, Bacillus cereus LMG 8221, Saccharomyces cerevisiae NRRL Y 12632, Candida krusei ATCC
6258, Aspergillus parasiticus NRRL 465, Aspergillus flavus NRRL 1957, and Penicillium chrysogenum NRRL
807.
First, antimicrobial activities of the synthesized compounds were screened by the disk diffusion method.32
Overnight grown bacteria and yeast cultures were adjusted to 0.5 McFarland turbidity standards to 108 and
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HOSSAIN et al./Turk J Chem
106 cfu/mL, respectively. Mold spore suspensions were prepared as 106 spore/mL. Then 100 µL cell or spore
suspensions were spread on the surfaces of Mueller-Hinton Agar (MHA), Sabouraud Dextrose Agar (SDA), and
Malt Extract Agar (MEA) for bacteria, yeast, and molds, respectively. Propargylic phosphonates 4a, 4e, 4k,
4h, 3a, 3e, 3h, and 3k were dissolved in DMSO and the disks (6 mm dia) including 50 µg of synthesized
compounds were placed on the inoculated media. The petri dishes were incubated at 37 ◦ C for 24 h for bacteria
and at 30 ◦ C for 2–3 days for fungi. Antimicrobial activity was determined by measuring the radius of the
inhibition zones around the disks. Vancomycin (30 µg), erythromycin (30 µg), and bacitracin (10 U) disks
were used as positive controls for bacteria and fluconazole (10 µg) disks were used for fungi. DMSO was also
used as a negative control. The tests were carried out in triplicate and the results are reported as the average
of them. The active compounds in the disk diffusion method were selected to assign MIC values.
In the second step of antimicrobial activity studies, MIC values of selected compounds were determined
by the conventional agar diffusion method.33 To obtain the appropriate concentrations ranging from 200 to 0.78
µg/mL, 2-fold serial dilutions of the selected propargylic phosphonates and reference antibiotics (vancomycin,
erythromycin, and bacitracin for bacteria and fluconazole for fungi) were prepared in MHA, SDA, and MEA for
bacteria, yeast, and molds, respectively. The inoculants’ preparations and incubation conditions were the same
as those in the disk diffusion method. Test media supplemented with solvents and without any phosphonate
compound and antibiotic were also used as controls. MIC values were described as the lowest concentration of
the compound that completely inhibited growth of the test microorganisms on the petri dish.
3.2. General procedure for the synthesis of propargylic phosphonates
To a solution of acyl phosphonate (1 equiv.) in dry toluene (0.5 M) at 0 ◦ C under argon atmosphere was added
trialkynylaluminum (3 equiv., 0.23 M solution) dropwise within 2 min. The resultant mixture was stirred at 0
◦ C, and warmed to room temperature. After the completion of the reaction in 2–3 h, which was monitored by a
TLC plate, the reaction mixture was cautiously hydrolyzed with water. The reaction mixture was filtrated over
Celite and washed with ethyl acetate. The organic layer was then dried over anhydrous MgSO4 , filtered again,
and concentrated under reduced pressure. The crude product was purified by flash column chromatography
using hexane–EtOAc mixtures.
3.2.1. Diethyl 1-hydroxy-1-phenylbut-2-ynylphosphonate (3a)
56% yield as a crystalline white solid; mp 157–158 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.25 (6H, dt, J = 7.0
and 2.9 Hz, –OCH2 CH3), 1.97 (3H, d, J = 5.1 Hz, –C≡C–CH3), 3.66 (1H, d, J = 8.5 Hz, –OH), 3.90–4.22
(4H, m, –OCH2 CH3), 7.27–7.42 (m, 3H), 7.69–7.77 (2H, m). 13 C NMR (CDCl3 , 100 MHz): δ 4.0 (d, JC−P
=
2.7 Hz, –C≡C–CH3), 16.4 (t, JC−P = 4.0 Hz, –OCH2 CH3), 64.4 (dd, JC−P = 73.5 and 4.0 Hz, OCH2 CH3),
71.2 (d, JC−P = 167.4 Hz, quaternary C atom), 77.5 (d, JC−P = 2.3 Hz, C≡C–CH3) 85.0 (d, JC−P = 8.8
Hz, –C≡C–CH3), 126.7 (d, JC−P = 4.2 Hz), 127.8, (d, JC−P = 2.6 Hz), 128.1 (d, JC−P = 3.0 Hz) 137.8 (d,
JC−P = 3.0 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 17.36. IR (ATR technique, cm−1): 3241, 2988, 1228, 1015,
972, 757, 703, 577. HRMS: calculated for C14 H19 O4 P [M], [M+H] = 283.1099 and found 283.1129.
3.2.2. Diethyl 1-hydroxy-1-p-tolylbut-2-ynylphosphonate (3b)
53% yield as a crystalline white solid; mp 127–128 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.25 (6H, t, JC−P
=
7.1 Hz, –OCH2 CH3), 1.96 (3H, d, JC−P = 5.1 Hz, –C≡C–CH3), 2.34 (3H, d, JC−P = 1.3 Hz, CH3), 3.66
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HOSSAIN et al./Turk J Chem
(1H, t, –OH, JC−P = 12.2 Hz), 3.90–4.30 (m, 4H, –OCH2 CH3), 7.16 (2H, d, JC−P = 8.0 Hz), 7.60 (dd, 2H,
JC−P = 8.3 and 2.2 Hz). 13 C NMR (CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.4 Hz, –C≡C–CH3), 16.4 (t,
JC−P = 4.0 Hz, –OCH2 CH3), 21.0 (s, –CH3), 64.3 (d, JC−P = 7.4 Hz, –OCH2 CH3), 71.1 (d,JC−P = 168.3
Hz, quaternary C atom), 77.6, 84.9 (d, JC−P = 8.4 Hz), 126.6 (d, JC−P = 4.2 Hz), 128.6 (d, JC−P = 4.2
Hz) 128.6 (d, JC−P = 2.4 Hz), 134.9, 137.9 (d,JC−P = 2.8 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 17.52. IR
(ATR technique, cm−1): 3238, 2986, 1231, 1017, 970, 573. HRMS: calculated for C15 H21 O4 P [M], [M+H] =
297.1256 and found 297.1289.
3.2.3. Diethyl 1-hydroxy-1-o-tolylbut-2-ynylphosphonate (3c)
32% yield as a crystalline white solid; mp 104–105 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ1.21 (3H, t, JC−P = 7.1
Hz, –OCH2 CH3), 1.29 (3H, t, JC−P = 7.1 Hz, –OCH2 CH3), 1.95 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 2.69
(d, 3H, JC−P = 1.5 Hz, CH3), 3.25 (1H, d, –OH, JC−P = 8.0 Hz), 3.80–4.30 (m, 4H, –OCH2 CH3), 7.12–7.23
(m, 3H), 7.72–7.82 (m, 1H). 13 C NMR (CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.5 Hz, –C≡C–CH3), 16.4 (dd,
JC−P = 9.3 and 5.5 Hz, –OCH2 CH3), 21.9 (–CH3), 64.2 (t, JC−P = 8.3 Hz, –OCH2 CH3), 71.6 (d, JC−P
=
167.5 Hz, quaternary C atom), 77.6 (d,JC−P = 2.2 Hz), 85.7 (d, JC−P = 9.0 Hz) 125.4 (d, JC−P = 2.3 Hz),
127.7 (d, JC−P = 4.2 Hz), 128.2 (d, JC−P = 2.7 Hz), 132.3 (d, JC−P = 2.3 Hz), 134.8 (d, JC−P = 1.5 Hz),
137.4 (d, JC−P = 4.8 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 18.00. IR (ATR technique, cm−1): 3246, 2982,
1229, 1015, 970. HRMS: calculated for C15 H21 O4 P [M], [M–H] = 295.1099 and found 295.1152.
3.2.4. Diethyl 1-hydroxy-1-(4-methoxyphenyl)but-2-ynylphosphonate (3d)
41% yield as a crystalline white solid; mp 111–112 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.26 (6H, dt, JC−P
=
7.0 and 3.7 Hz, –OCH2 CH3), 1.97 (3H, d, JC−P = 5.1 Hz, –C≡C–CH3), 3.38 (1H, d, –OH, JC−P = 9.0 Hz),
3.81 (s, 3H, –OCH3), 3.92–4.20 (4H, m, –OCH2 CH3), 6.90 (d, 2H, JC−P = 8.7 Hz), 7.64 (m, 2H). 13 C NMR
(CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.6 Hz, –C≡C–CH3), 16.4 (dd, JC−P = 5.2 and 3.6 Hz, –OCH2 CH3),
55.3 (–OCH3), 64.3 (dd, JC−P = 7.3 and 3.5 Hz, –OCH2 CH3), 70.9 (d, JC−P = 169.4 Hz, quaternary C
atom), 77.5, 85.1 (d, JC−P = 8.8 Hz), 113.3 (d, JC−P = 2.3 Hz) 128.1 (d, JC−P = 4.0 Hz), 129.7 (d, JC−P
= 3.4 Hz), 159.6 (d, JC−P = 2.5 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 17.58. IR (ATR technique, cm−1):
3240, 2980, 1225, 1019, 970. HRMS: calculated for C15 H21 O5 P [M], [M+H] = 313.1205 and found 313.1247.
3.2.5. Diethyl 1-(4-fluorophenyl)-1-hydroxybut-2-ynylphosphonate (3e)
70% yield as a crystalline white solid; mp 160–161 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.26 (6H, t, JC−P = 7.1
Hz, –OCH2 CH3), 1.97 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 3.96–4.22 (5H, m, –OCH2 CH3 and –OH), 7.04
(2H, t, J = 8.6 Hz), 7.65–7.75 (m, 2H). 13 C NMR (CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.3 Hz, –C≡C–CH3),
16.4 (dd, JC−P = 5.2 and JC−P = 4.1 Hz, –OCH2 CH3), 64.4 (d, JC−P = 7.4 Hz, –OCH2 CH3), 70.7 (d, J
= 168.9 Hz, quaternary C atom), 77.2, 85.2 (d, JC−P = 8.9 Hz), 114.7 (dd, JC−F = 21.7 Hz and JC−P = 2.6
Hz) 128.7 (dd, JC−F = 8.2 Hz and JC−P =4.2 Hz), 133.8 (t, JC−F = 3.0 Hz) 162.6 (dd, JC−F = 250.0 and
JC−P = 3.3 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.42. IR (ATR technique, cm−1): 3233, 1231, 1021, 971,
804, 572. HRMS: calculated for C14 H18 FO4 P [M], [M+H] = 301.1005 and found 301.1045.
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3.2.6. Diethyl 1-(2-fluorophenyl)-1-hydroxybut-2-ynylphosphonate (3f)
61% yield as a crystalline white solid; mp 145–146 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.23 (3H, t, JC−P
=
7.0 Hz, –OCH2 CH3), 1.31 (3H, t, JC−P = 7.1 Hz, –OCH2 CH3), 1.97 (3H, d, JC−P = 5.1 Hz, –C≡C–CH3),
4.04 (1H, s (broad), –OH), 4.08–4.32 (m, 4H, –OCH2 CH3), 7.05 (1H, dd,JC−F = 11.9 and JC−P = 8.2 Hz),
7.15 (t, 1H, JC−F = 7.6 Hz), 7.25–7.35 (m, 1H), 7.74 (1H, tt, JC−F = 8.0 and JC−P = 2.0 Hz). 13 C NMR
(CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.5 Hz, –C≡C–CH3), 16.3 (d, JC−P = 5.5 Hz, –OCH2 CH3), 64.6
(dd, JC−F = 7.2 and JC−P = 5.1 Hz, –OCH2 CH3), 79.6 (d, JC−P = 168.6 Hz, quaternary C atom), 69.6
(dd, JC−P = 168.6 and JC−F = 2.0 Hz), 76.0 (d, JC−P = 3.8 Hz), 85.3 (dd, JC−P = 8.8 and JC−F = 1.9
Hz), 116.3 (dd, JC−F = 23.0 and JC−P = 2.3 Hz), 123.7 (t, J = 2.3 Hz), 125.1 (dd, JC−F = 9.2 and JC−P
= 2.0 Hz), 129.3 (dd, JC−F = 8.7 and JC−P = 2.7 Hz), 160.2 (dd, JC−F = 250.3 and JC−P = 4.3 Hz). 31 P
NMR (CDCl3 , 161 MHz): δ 16.42. IR (ATR technique, cm−1): 3229, 2983, 1235, 1028, 974, 774, 580. HRMS:
calculated for C14 H18 FO4 P [M], [M+H] = 301.1005 and found 301.1040.
3.2.7. Diethyl 1-(3-fluorophenyl)-1-hydroxybut-2-ynylphosphonate (3g)
65% yield as a crystalline white solid; mp 152–153 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.27 (6H, dt, JC−P
= 7.0 Hz and JC−F = 5.8 Hz, –OCH2 CH3), 1.97 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 4.03–4.23 (4H, m,
–OCH2 CH3), 4.37 (1H, d, JC−P = 7.5 Hz, –OH), 6.96–7.05 (1H, m), 7.32 (1H, dt, JC−F = 8.0 and 6.10 Hz),
7.45 (1H, ddd, J = 10.4, 4.2, and 2.3 Hz), 7.51 (1H, td, J = 7.9 and 2.4 Hz). 13 C NMR (CDCl3 , 100 MHz):
δ 4.0 (d, JC−P = 4.2 Hz, –C≡C–CH3 ), 16.4 (t, JC−P = 4.2 Hz, –OCH2 CH3), 64.5 (dd, JC−P = 7.4 and
JC−F =2.0 Hz, –OCH2 CH3), 70.8 (dd, JC−P = 167.9 and JC−F = 1.8 Hz, quaternary C atom), 85.2 (d,
JC−P = 8.8 Hz), 114.1 (dd, JC−P = 4.0 and JC−F = 23.9 Hz), 114.9 (dd,JC−F = 21.2 and JC−P = 2.8 Hz),
122.6 (t, J = 3.5 Hz), 129.2 (dd, JC−F = 8.1 and JC−P = 2.7 Hz), 140.8 (dd, JC−F = 7.4 and JC−P
=
3.1 Hz), 162.4 (dd, JC−F = 247.8 and JC−P = 2.9 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.75. IR (ATR
technique, cm−1): 3229, 1228, 1018, 977, 798. HRMS: calculated for C14 H18 FO4 P [M], [M+H] = 301.1005
and found 301.1055.
3.2.8. Diethyl 1-(4-chlorophenyl)-1-hydroxybut-2-ynylphosphonate (3h)
61% yield as a crystalline white solid; mp 124–125 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.26 (6H, dt, JC−P
= 7.0 and JC−P = 1.2 Hz, –OCH2 CH3), 1.96 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 3.95–4.22 (4H, m,
–OCH2 CH3), 4.26 (1H, d, –OH, JC−P = 7.6 Hz), 7.33 (d, 2H, J = 8.6 Hz), 7.66 (2H, dd, J = 8.7 and JC−P
= 2.2 Hz). 13 C NMR (CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.2 Hz, –C≡C–CH3), 16.4 (t, JC−P = 4.5
Hz, –OCH2 CH3), 64.4 (dd, JC−P = 7.3 and 4.2 Hz, –OCH2 CH3), 70.7 (d, JC−P = 168.5 Hz, quaternary C
atom), 85.3 (d, JC−P = 8.8 Hz), 127.9 (d, JC−P = 2.7 Hz), 128.3 (d, JC−P = 4.2 Hz) 134.0 (d, JC−P = 3.7
Hz), 136.7 (d, JC−P = 3.0 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.16. IR (ATR technique, cm−1): 3229,
2986, 1230, 1013, 974. HRMS: calculated for C14 H18 ClO4 P [M], [M+H] = 317.0709 and found 317.0751.
3.2.9. Diethyl 1-(2-chlorophenyl)-1-hydroxybut-2-ynylphosphonate (3i)
49% yield as a crystalline white solid; mp: 137–138 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.24 (3H, t, JC−P
= 7.04 Hz, –OCH2 CH3), 1.31 (3H, t, JC−P = 7.1 Hz, –C≡C–CH3), 1.96 (3H, d, JC−P = 5.2 Hz), 4.07 (1H,
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d, JC−P = 7.7 Hz, –OH,), 4.08–4.32 (4H, m, –OCH2 CH3), 7.20–7.33 (m, 2H), 7.38 (dd, 1H, J = 7.5 and 1.5
Hz), 7.91 (td, 1H, J = 7.8 and 2.1 Hz). 13 C NMR (CDCl3 , 100MHz): δ 4.0 (d, J = 2.4 Hz, –C≡C–CH3),
6.4 (t, JC−P = 5.8 Hz, –OCH2 CH3), 64.5 (dd, JC−P = 7.6 and 1.5 Hz, –OCH2 CH3), 71.3 (d, JC−P = 167.9
Hz, quaternary C atom), 76.3 (d, JC−P = 4.6 Hz), 86.2 (d, JC−P = 9.0 Hz), 126.5 (d, JC−P = 2.1 Hz), 129.4
(d, JC−P = 2.3 Hz), 129.9 (d, JC−P = 4.1 Hz), 131.5 (d, JC−P = 2.0 Hz), 132.4 (d, JC−P = 5.3 Hz), 134.7.
31 P NMR (CDCl3 , 161 MHz): δ 16.79. IR (ATR technique, cm−1): 3221, 2983, 1231, 1022, 972. HRMS:
calculated for C14 H18 ClO4 P [M], [M+H] = 317.0709 and found 317.0774.
3.2.10. Diethyl 1-(3-chlorophenyl)-1-hydroxybut-2-ynylphosphonate (3j)
62% yield as a crystalline white solid; mp 168–169 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.27 (6H, t, JC−P
=
7.1 Hz, –OCH2 CH3), 1.98 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 3.80 (1H, d, JC−P = 7.8 Hz, –OH), 4.0–4.23
(m, 4H, –OCH2 CH3), 7.3 (2H, d, JC−P = 4.8 Hz), 7.55–7.65 (m, 1H), 7.71 (d, 1H, J = 1.5 Hz). 13 C NMR
(CDCl3 , 100 MHz): δ 4.0 (d, JC−P = 2.4 Hz, –C≡C–CH3), 16.4 (t, J = 4.9 Hz, –CH2 CH3), 64.5 (dd, JC−P
= 7.4 and 2.6 Hz, –OCH2 CH3), 70.8 (d, JC−P = 167.8 Hz, quaternary C atom), 77.0, 85.5 (d, JC−P = 8.8
Hz), 125.1 (d, JC−P = 3.9 Hz), 127.0 (d, JC−P = 4.0 Hz), 128.3 (d, JC−P = 2.9 Hz), 129.1 (d, JC−P = 2.8
Hz), 133.8 (d, JC−P = 3.0 Hz), 140.1 (d, JC−P = 3.2 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.64. IR (ATR
technique, cm−1): 3233, 2981, 1231, 1016, 975, 797, 695. HRMS: calculated for C14 H18 ClO4 P [M], [M+H] =
317.0709 and found 317.0765.
3.2.11. Diethyl 1-(4-(trifluoromethyl)phenyl)-1-hydroxybut-2-ynylphosphonate (3k)
75% yield as a crystalline white solid; mp 119–120 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.26 (6H, dt, JC−P
= 7.0 and JC−P = 5.5 Hz, –OCH2 CH3), 1.97 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 4.0–4.26 (4H, m, –
OCH2 CH3), 4.62 (1H, d, OH, JC−P = 6.8 Hz), 7.61 (d, 2H, JC−P = 8.6 Hz), 7.85 (2H, dd, J = 1.5 and J
= 8.3 Hz). 13 C NMR (CDCl3 , 100 MHz): δ 3.9 (d, JC−P = 2.2 Hz, –C≡C–CH3), 16.3 (t, JC−P = 4.9 Hz,
–OCH2 CH3), 64.5 (t, JC−P = 7.6 Hz, –OCH2 CH3), 70.9 (d, JC−P = 167.3 Hz, quaternary C atom), 77.2,
85.4 (d, JC−P = 8.9 Hz), 124.7 (t, JC−F = 6.7), 124.1 (d, JC−F = 271.2 Hz), 127.2 (d, JC−P = 3.8 Hz), 129.8
(q, JC−F = 32.2 Hz, –CF3), 142.3 (d, JC−F = 1.7 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 15.84. IR (ATR
technique, cm−1): 3220, 1238, 1016, 972,883. HRMS: calculated for C15 H18 F3 O4 P [M], [M+H] = 351.0973
and found 351.1018.
3.2.12. Diethyl 3-hydroxy-2-methylhex-4-yn-3-ylphosphonate (3l)
32% yield as a crystalline white solid; mp 68–69 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.09 (6H, d, J = 6.7 Hz,
CH3), 1.36 (6H, t, J = 7.1 Hz, –OCH2 CH3), 1.91 (3H, d, JC−P = 5.2 Hz, –C≡C–CH3), 2.08–2.12 (m, 1H,
–CH), 2.85 (1H, d, OH, JC−P = 4.7 Hz), 4.10– 4.33 (m, 4H, –OCH2 CH3). 13 C NMR (CDCl3 , 100MHz): δ
3.8 (d, JC−P = 2.6 Hz, –C≡C–CH3), 16.5 (d, JC−P = 5.2 Hz, –OCH2 CH3), 17.0 (d, JC−P = 9.5 Hz), 18.4
(d, JC−P = 1.9 Hz), 34.5 (d, JC−P = 1.0 Hz), 63.8 (dd, JC−P = 20.4 and 7.4 Hz), 73.4 (d, JC−P = 168.7
Hz, quaternary C atom), 75.2, 85.0 (d, JC−P = 9.6 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 20.92. IR (ATR
technique, cm−1): 3270, 2986, 1228, 1021, 962. HRMS: calculated for C11 H21 O4 P [M], [M+H] = 249.1256
and found 249.1300.
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3.2.13. Diethyl 1-cyclohexyl-1-hydroxybut-2-ynylphosphonate (3m)
38% yield as a crystalline white solid; mp 62–63 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.08–1.30 (5H, m), 1.36
(6H, t, JC−P = 7.0 Hz, –OCH2 CH3), 1.66 (1H, d, J = 10.3 Hz), 1.72–1.88 (3H, m), 1.91 (d, 3H, JC−P = 5.3
Hz, –C≡C–CH3), 2.04 (2H, t, J = 9.3 Hz), 2.72 (s (broad), 1H, –OH), 4.18–4.32 (m, 4H, –OCH2 CH3). 13 C
NMR (CDCl3 , 100 MHz): δ 3.9 (d, JC−P = 2.8 Hz, –C≡C–CH3), 16.5 (d, JC−P = 5.5 Hz, –OCH2 CH3),
26.2 (d, JC−P = 9.5 Hz, CH2), 26.5 (d, JC−P = 8.6 Hz, CH2), 28.1 (d, JC−P = 2.1 Hz, CH2), 44.2, 63.8
(dd, JC−P = 17.1 and 7.5 Hz, –OCH2 CH3), 72.9 (d, JC−P = 167.8 Hz, quaternary C atom), 75.8, 84.9 (d,
JC−P = 9.5 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 20.71. IR (ATR technique, cm−1): 3263, 2921, 1224, 1017,
983, 939. HRMS: calculated for C14 H25 O4 P [M], [M+H] = 289.1569 and found 289.1630.
3.2.14. Diethyl 1-hydroxy-1,3-diphenylprop-2-ynylphosphonate (4a)
61% yield as a crystalline white solid; mp 120–121 ◦ C. 1 H NMR (CDCl3 , 400MHz): δ 1.14 (t, 3H, JC−P
=
7.1 Hz, –OCH2 CH3), 1.20 (t, 3H, JC−P = 7.1 Hz, –OCH2 CH3), 4.0–4.14 (m, 4H, –OCH2 CH3), 4.4–4.6 (s
(broad), 1H, –OH), 7.20–7.36 (m, 6H), 7.40–7.46 (dd, 2H, J = 7.5 and 1.7 Hz), 7.70–7.75 (m, 2H). 13 C NMR
(CDCl3 , 100 MHz): δ 15.3 (t, JC−P = 5.6 Hz, –OCH2 CH3), 63.6 (dd, JC−P = 7.2 and 4.1 Hz, –OCH2 CH3),
70.5 (d, JC−P = 166.9 Hz, quaternary C atom), 86.2 (d, JC−P = 2.1 Hz, –C≡C–Ph), 87.0 (d, JC−P = 9.0 Hz,
–C≡C–Ph), 121.1 (d, JC−P = 3.2 Hz) 125.8 (d, JC−P = 3.9 Hz), 126.9 (d, JC−P = 2.7 Hz), 127.2 (d, JC−P
= 2.9 Hz), 127.3, 127.9, 130.9 (d, JC−P = 2.8 Hz), 136.7 (d, JC−P = 3.6 Hz). 31 P NMR (CDCl3 , 161 MHz):
δ 16.13. IR (ATR technique, cm−1): 3187, 2978, 1227, 1049, 1010, 952, 758, 693, 579. HRMS: calculated for
C19 H21 O4 P [M], [M+H] = 345.1255 and found 345.1313.
3.2.15. Diethyl 1-hydroxy-3-phenyl-1-p-tolylprop-2-ynylphosphonate (4b)
59% yield as a crystalline white solid; mp 118–119 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.20 (3H, t, JC−P
= 7.0 Hz, –OCH2 CH3), 1.28 (3H, t, JC−P = 7.0 Hz, –OCH2 CH3), 2.35 (3H, d, JC−P = 1.6 Hz, –CH3),
4.05–4.22 (4H, m, –OCH2 CH3), 4.66 (1H, d, J = 7.4 Hz, –OH), 7.18 (2H, d, J = 8.4 Hz), 7.28–7.38 (3H, m),
7.51 (2H, dd, J = 7.5 Hz and 1.9 Hz), 7.68 (2H, dd, JC−P = 8.3 and 2.2 Hz). 13 C NMR (CDCl3 , 100 MHz):
δ 16.4 (t, JC−P = 5.6 Hz, –OCH2 CH3), 21.2 (–CH3), 64.6 (t, JC−P = 7.5 Hz, –OCH2 CH3), 71.4 (d, J =
167.4 Hz, quaternary C atom), 87.4, 88.0 (d, JC−P = 9.5 Hz), 122.2 (d, JC−P = 3.3 Hz) 126.7 (d, JC−P = 4.2
Hz), 128.3, 128.7 (d, JC−P = 2.5 Hz), 128.8, 132.0 (d, JC−P = 2.6 Hz), 134.7 (d, JC−P = 3.7 Hz), 138.0 (d,
JC−P = 3.1 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.96. IR (ATR technique, cm−1): 3199, 2979, 1225, 1050,
1018, 952, 757, 691, 573. HRMS: calculated for C20 H23 O4 P [M], [M+H] = 359.1412 and found 359.1481.
3.2.16. Diethyl 1-hydroxy-3-phenyl-1-o-tolylprop-2-ynylphosphonate (4c)
30% yield as a crystalline white solid; mp 111–112 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.25 (dt, 6H, JC−P
=
7.1 Hz and 16.0 Hz, –OCH2 CH3), 2.76 (d, JC−P = 1.5 Hz, –CH3), 3.65 (unresolved q, 1H, –OH), 3.92–4.25
(4H, m, –OCH2 CH3), 7.12–7.24 (m, 3H), 7.27–7.38 (3H, m), 7.47 (2H, dd, J = 7.5 and 1.9 Hz), 7.79–7.88 (m,
1H). 13 C NMR (CDCl3 , 100 MHz): δ 16.4 (t, JC−P = 5.5 Hz, –OCH2 CH3), 22.0 (–CH3), 64.5 (dd, JC−P
= 7.5 Hz and 3.9 Hz, –OCH2 CH3), 71.8 (d, JC−P = 166.7 Hz), 87.2 (d, JC−P = 2.1 Hz), 88.7 (d, JC−P
9.5 Hz), 122.2 (d, JC−P = 3.4 Hz), 125.5 (d, JC−P = 2.3 Hz), 127.6 (d, JC−P = 3.9 Hz), 128.3 (d, JC−P
=
=
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2.8 Hz), 128.4, 128.9, 131.7 (d, JC−P = 2.8 Hz), 132.4 (d, JC−P = 2.2 Hz), 134.6 (d, JC−P = 2.2 Hz), 137.4
(d, JC−P = 5.0 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 17.43. IR (ATR technique, cm−1): 3187, 2979, 1212,
1053, 1012, 947, 758, 694. HRMS: calculated for C20 H23 O4 P [M], [M+H] = 359.1412 and found 359.1477.
3.2.17. Diethyl 1-hydroxy-1-(4-methoxyphenyl)-3-phenylprop-2-ynylphosphonate (4d)
39% yield as a crystalline white solid; mp 115–116 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.22 (3H, t, JC−P
= 7.0 Hz, –OCH2 CH3), 1.28 (3H, t, JC−P = 7.1 Hz, –OCH2 CH3), 3.81 (s, 3H, –OCH3), 4.0–4.22 (4H, m,
–OCH2 CH3), 4.24–4.40 (s (broad), 1H, –OH), 6.91 (d, J = 8.7 Hz, 2H), 7.28–7.38 (3H, m), 7.51 (2H, dd, J
= 7.5 and 1.9 Hz), 7.72 (dd, 2H, J = 9.0 and 2.3 Hz). 13 C NMR (CDCl3 , 100 MHz): δ 16.4 (t, JC−P = 4.2
Hz, –OCH2 CH3), 55.3 (–OCH3 ), 64.5 (dd, JC−P = 7.3 and 2.6 Hz, –OCH2 CH3), 71.2 (d, JC−P = 168.6 Hz,
quaternary C atom), 87.2, 88.1 (d, JC−P = 9.1 Hz), 113.4 (d, JC−P = 2.2 Hz), 122.1 (d, JC−P = 2.9 Hz),
128.2 (d, JC−P = 4.0 Hz), 128.3, 128.9, 129.6, 131.9 (d, JC−P = 2.7 Hz), 159.6 (d, JC−P = 2.6 Hz). 31 P
NMR (CDCl3 , 161 MHz): δ 17.05. IR (ATR technique, cm−1): 3199, 2980, 1225, 1051, 1015, 953, 758, 573.
HRMS: calculated for C20 H23 O5 P [M], [M+H] = 375.1361 and found 375.1426.
3.2.18. Diethyl 1-(4-fluorophenyl)-1-hydroxy-3-phenylprop-2-ynylphosphonate (4e)
68% yield as a crystalline white solid; mp 115–116 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.17 (3H, t, JC−P
=
7.0 Hz, –OCH2 CH3), 1.27 (3H, t, JC−P = 7.0 Hz, –OCH2 CH3), 4.04–4.22 (4H, m, –OCH2 CH3), 5.11 (1H,
d, JC−P = 6.3 Hz, –OH), 7.05 (2H, t, J = 8.6 Hz), 7.28–7.40 (3H, m), 7.51 (2H, dd, J = 7.7 and 1.7 Hz),
7.73–7.81 (2H, m). 13 C NMR (CDCl3 , 100 MHz): δ 16.4 (t, JC−P = 6.3 Hz, –OCH2 CH3), 64.6 (dd,JC−P
= 9.4 and 7.5 Hz, –OCH2 CH3), 71.0 (d, J = 168.2 Hz, quaternary C atom), 87.0 (d, JC−P = 1.1 Hz), 88.2
(d, JC−P = 9.0 Hz), 114.6 (d, J = 2.3 Hz), 114.9.7 (d, J = 2.5 Hz), 122.0 (d, J = 3.0 Hz), 128.3, 128.8 (dd,
JC−F = 8.3 and JC−P = 4.1 Hz), 129.0, 132.0 (d, J = 2.6 Hz), 133.7 (t, J = 3.3 Hz), 162.0 (dd, JC−F
=
249.7 Hz and JC−P =3.4 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 15.84. IR (ATR technique, cm−1): 3203,
2981, 1233, 1050, 1017, 951, 762, 695, 572. HRMS: calculated for C19 H20 FO4 P [M], [M+H] = 363.1162 and
found 363.1223.
3.2.19. Diethyl 1-(2-fluorophenyl)-1-hydroxy-3-phenylprop-2-ynylphosphonate (4f)
72% yield as a crystalline white solid; mp 122–123 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.13 (3H, t, JC−P
=
7.0 Hz, –OCH2 CH3), 1.32 (3H, t, JC−P = 7.1 Hz, –OCH2 CH3), 4.05–4.22 (2H, m, –OCH2 CH3), 4.31 (2H,
p, J = 7.1 Hz, –OCH2 CH3), 5.2 (s (broad), 1H, –OH), 7.06 (1H, dd, J = 11.7 and 8.2 Hz), 7.16 (1H, t, J
= 7.6 Hz), 7.22–7.37 (m, 4H), 7.51 (dd, 2H, J = 7.5 and 1.9 Hz), 7.78–7.87 (m, 1H). 13 C NMR (CDCl3 , 100
MHz): δ 16.3 (dd, JC−P = 13.8 and 5.8 Hz, –OCH2 CH3), 64.9 (dd, JC−P = 12.3 and 7.3 Hz, –OCH2 CH3),
69.3 (dd, JC−P = 168.2 Hz and JC−F = 2.0 Hz, quaternary C atom), 85.8 (d, JC−P = 2.7 Hz), 87.9 (dd,
JC−P = 9.3 and JC−F = 2.5 Hz), 116.3 (dd, JC−F = 22.9 and JC−P =2.2 Hz), 122.2 (d, J = 3.1 Hz), 123.8
(t, J = 2.8 Hz), 125.0 (dd, JC−F =9.3 Hz and JC−P =2.7 Hz), 128.3, 128.8, 129.1 (dd, JC−F =4.0 Hz and
JC−F =2.0 Hz), 130.1 (dd, JC−F =8.6 and JC−P =2.8 Hz), 131.8 (d, J = 2.7 Hz), 160.0 (dd, JC−F = 251.0
and JC−P =4.2 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 16.01. IR (ATR technique, cm−1): 3189, 2979, 1224,
1051, 1015, 952, 760, 692. HRMS: calculated for C19 H20 FO4 P [M], [M+H] = 363.1162 and found 363.1227.
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3.2.20. Diethyl 1-(3-fluorophenyl)-1-hydroxy-3-phenylprop-2-ynylphosphonate (4g)
72% yield as a crystalline white solid; mp 113–114 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.15 (3H, t, J =
7.1 Hz, –OCH2 CH3), 1.28 (3H, t, J = 7.1 Hz, –OCH2 CH3), 4.05–4.27 (4H, m, –OCH2 CH3), 5.45–5.60 (s
(broad), 1H, –OH), 7.01 (t, 1H, J = 8.3 Hz), 7.27–7.40 (4H, m), 7.47–7.63 (m, 4H). 13 C NMR (CDCl3 , 100
MHz): δ 16.4 (dd, J = 10.5 and 5.6 Hz, –OCH2 CH3), 64.8 (dd, J = 7.4 and 14.4 Hz, –OCH2 CH3), 71.0 (d,
JC−P = 167.0 Hz, quaternary C atom), 86.8 (d, JC−P = 1.3 Hz), 88.2 (d, J = 9.4 Hz), 114.6 (d, J = 3.8
Hz), 114.3 (d, J = 4.1 Hz), 114.9 (d, J = 2.7 Hz) 115.1 (d, J = 2.9 Hz), 121.9 (d, J = 3.1 Hz), 122.7 (d, J
= 3.4 Hz), 128.4, 129.0, 129.3 (dd,JC−F = 8.0 and JC−P = 2.6 Hz), 132.0 (d, J = 2.6 Hz), 140.7 (dd, JC−F
= 7.5 and JC−P = 3.6 Hz), 161.3 (dd, JC−F = 242.0 and JC−P =3.1 Hz). 31 P NMR (CDCl3 , 161 MHz): δ
16.20. IR (ATR technique, cm−1): 3186, 2977, 1226, 1015, 964, 759. HRMS: calculated for C19 H20 FO4 P [M],
[M+H] = 363.1162 and found 363.1226.
3.2.21. Diethyl 1-(4-chlorophenyl)-1-hydroxy-3-phenylprop-2-ynylphosphonate (4h)
52% yield as a crystalline white solid; mp 102–103 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.15 (3H, t, J = 7.0
Hz, –OCH2 CH3), 1.26 (3H, t, J = 7.1 Hz, –OCH2 CH3), 4.02–4.24 (4H, m, –OCH2 CH3), 5.34 (d, J = 5.9
Hz, –OH), 7.28–7.40 (m, 5H), 7.50 (2H, dd, J = 7.8 and 1.6 Hz), 7.73 (2H, dd, J = 8.8 and 2.3 Hz). 13 C
NMR (CDCl3 , 100 MHz): δ 16.4 (dd, JC−P = 8.5 and 5.7 Hz, –OCH2 CH3), 64.7 (dd, JC−P = 14.2 and
7.5 Hz, –OCH2 CH3), 71.0 (d, JC−P = 167.8 Hz, quaternary C atom), 86.8 (d, JC−P = 1.52 Hz), 88.2 (d,
JC−P = 8.9 Hz) 121.9 (d, JC−P = 3.0 Hz), 128.0 (d, JC−P = 2.7 Hz), 128.4, 129.0, 132.0 (d, JC−P = 2.8
Hz), 134.1 (d, JC−P = 3.5 Hz), 136.6 (d, JC−P = 3.6 Hz). 31 P NMR (CDCl3 , 161 MHz): δ 15.60. IR (ATR
technique, cm−1): 3201, 2985, 1230, 1053, 1012, 949, 754, 688. HRMS: calculated for C19 H20 ClO4 P [M],
[M+H] = 379.0866 and found 379.0935.
3.2.22. Diethyl 1-(4-(trifluoromethyl)phenyl)-1-hydroxy-3-phenylprop-2-ynylphosphonate (4k)
60% yield as a crystalline white solid; mp 88–89 ◦ C. 1 H NMR (CDCl3 , 400 MHz): δ 1.15 (3H, t, J = 7.1 Hz,
–OCH2 CH3), 1.28 (3H, t, J = 7.1 Hz, –OCH2 CH3), 4.08–4.25 (4H, m, –OCH2 CH3), 5.59 (1H, d, J = 5.5
Hz, –OH), 7.3–7.4 (3H, m), 7.52 (2H, dd, J = 7.8 and 1.5 Hz), 7.62 (2H, d, J = 8.3 Hz), 7.92 (d, 2H, J = 8.2
Hz). 13 C NMR (CDCl3 , 100 MHz): δ 16.3 (dd, J = 10.5 and 5.5 Hz, OCH2 CH3), 64.8 (dd, J = 16.4 and
7.5 Hz, OCH2 CH3), 71.2 (d, J = 166.7 Hz, quaternary C atom), 86.6 (d, JC−P = 2.1 Hz), 88.3 (d, JC−P
=
9.2 Hz), 121.8 (d, JC−P = 3.2 Hz), 121.4 (q, JC−F = 272.0 Hz, –CF3), 124.8 (t, J = 3.2 Hz), 127.3, (d, J
= 3.8 Hz), 128.3, 129.1, 129.9 (qd, JC−F = 32.2 Hz and JC−P = 2.9 Hz), 132.0 (d, J = 2.8 Hz), 142.2. 31 P
NMR (CDCl3 , 161 MHz): δ 15.30. IR (ATR technique, cm−1): 3180, 2988, 1227, 1067, 1018, 952, 755, 687.
HRMS: calculated for C20 H20 F3 O4 P [M], [M+H] = 413.1130 and found 413.1226.
Acknowledgments
¨
Financial support from the Scientific and Technological Research Council of Turkey (TUBITAK), Turkish
˙
¨
Academy of Sciences (TUBA), and Middle East Technical University (METU) is appreciatively acknowledged.
¨
Helpful suggestions from Prof. Dr. Ozdemir Do˘gan are appreciated.
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