B(C6F5)3 as a highly effective catalyst for the phosphoryl transfer reaction

Article abstract of DOI:10.1002/cjoc.201200264

The phosphoryl transfer reactions of diphenyl chlorophosphate with a wide range of alcohols were catalyzed by tris(pentafluorophenyl)boron [B(C ₆F₅)₃], giving the corresponding phosphate esters in excellent yields. This me

Full text of DOI:10.1002/cjoc.201200264

FULL PAPER
DOI: 10.1002/cjoc.201200264
B(C6F5)3 as a Highly Effective Catalyst for the Phosphoryl
Transfer Reaction
Xue, Weihua*,a(薛伟华)
Zhang, Lifenb(张立芬)
a School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China
b School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
The phosphoryl transfer reactions of diphenyl chlorophosphate with a wide range of alcohols were catalyzed by
tris(pentafluorophenyl)boron [B(C6F5)3], giving the corresponding phosphate esters in excellent yields. This meth-
odology has advantages over older ones because it employs the easily handled B(C6F5)3, avoids the side reaction,
and has shorter reaction time.
Keywords phosphorylation of alcohols, B(C6F5)3, phosphate esters
fecting many organic transformations.[7] We now dis-
close the new utility of commercially available B(C6F5)3
highly effectively catalyzing the phosphoryl transfer
reaction.
Introduction
Phosphate esters are of great synthetic interest be-
cause of their wide distribution in nature, useful bio-
logical activities,[1] and significant medicinal applica-
tion.[2] There are some reports available for the synthe-
sis of phosphate esters in the literature. The most used
methods include the oxidation of phosphite[3] and the
phosphorylation of alcohols. The former has well-
recognized drawbacks, namely that it requires the care-
fully handling of the phosphitylating reagents fairly
sensitive to moisture or air, and especially lacks
chemoselectivity when substrates containing active
functional groups such as alkenes and thioether groups
susceptible to oxidation. The latter is a more concise
route involving the reaction of alcohol with chloro-
phosphate in the presence of the base or Lewis acid.
Under the base-mediated phosphorylation condition,
large excess of chlorophosphate has to be frequently
consumed to achieve the satisfactory yield.[4] In addition,
strong alkalis have potential effect on some functional-
ities in substrates. Phosphorylation of alcohols to phos-
phate esters through Lewis acid-catalyzed procedures
was recently reported.[5] The catalytic methods feature
the mild conditions, the handsome yields and the broad
functional group tolerance, but suffer from evident dis-
advantages such as the severe side reaction, the long
reaction time, or the use of sensitive catalysts or expen-
sive additives. Therefore, considerable interest exists in
developing efficient methods for Lewis acid-catalyzed
phosphorylation reaction. Tris(pentafluorophenyl)-
boron[B(C6F5)3] is a relatively stable solid and is solu-
ble in organic systems.[6] The previous study showed
that the Lewis acid B(C6F5)3 is a useful catalyst for ef-
Experimental
General methods
NMR spectra were recorded on a Varian Mercury
1
Plus 400 spectrometer (400 MHz for H, 100 MHz for
13C and 162 MHz for 31P) in CDCl3 unless stated. Phos-
phorous chemical shifts (δ) are reported relative to a
85% H3PO4 external standard. Analytical thin layer
chromatography (TLC) was carried out using silica gel
60 F254 precoated plates. Visualizations were accom-
plished with a UV lamp or 20% (V/V) H2SO4 in ethanol.
High resolution mass spectra (HRMS) were recorded on
a Bruker APEX II high-resolution mass spectrometer
with electrospray ionization (ESI).
General procedure for the synthesis of phosphate
esters
Alcohol (1.0 mmol) was added to a stirred solution
of B(C6F5)3 (0.1 mmol) in dry CH2Cl2 (5 mL).
Triethylamine (0.14 mL, 1.0mmol) was added, followed
by the addition of diphenyl chlorophosphate (0.20 mL,
1.0 mmol). After stirring at room temperature for 0.5 h,
the mixture was filtered through Celite, and concen-
trated. The residue was purified by silica gel chroma-
tography to provide the product.
(1,2,3,4-Di-O-isopropylidene-)-D-galactopyrano-
syl diphenyl phosphate (1a)[5c] Colorless oil; 1H
NMR (CDCl3) δ: 7.30—7.35 (m, 4H), 7.23—7.26 (m,
4H), 7.15—7.19 (m, 2H), 5.54 (d, J＝5.2 Hz, 1H),
*
E-mail: xuewh@lzu.edu.cn; Tel.: 0086-0931-8915686
Received March 21, 2012; accepted May 2, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200264 or from the author.
Chin. J. Chem. 2012, XX, 1—4
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Xue & Zhang
FULL PAPER
4.40—4.62 (m, 1H), 4.35—4.42 (m, 1H), 4.31—4.33
(m, 2H), 4.23 (d, J＝6.0 Hz, 1H), 4.11—4.14 (m, 1H),
1.47 (s, CH3, 3H), 1.43 (s, CH3, 3H), 1.32 (s, CH3, 3H),
1.31 (s, CH3, 3H); 13C NMR (CDCl3) δ: 150.51 (d, J＝
7.0 Hz), 129.64, 125.22, 120.10 (d, J＝5.0 Hz), 109.54,
108.78, 96.15, 70.53, 70.41, 70.39, 67.37, 66.69, 60.27,
25.89, 25.85, 24.88, 24.31; 31P NMR (CDCl3) δ:
－12.01. HRMS (ESI) calcd for C24H29O9PNa＋ [M＋
Na＋] 515.1447, found 515.1472.
phenyl phosphate (6f) Colorless oil; 1H NMR
(CDCl3) δ: 7.32—7.35 (m, 4H), 7.23—7.30 (m, 4H),
7.15—7.20 (m, 2H), 4.44 (dd, J＝4.4, 6.4 Hz, 1H), 2.24
(d, J＝12.0 Hz, 1H), 2.04 (d, J＝4.4 Hz, 1H), 1.67 (d,
J＝14.0 Hz, 2H), 1.24—1.43 (m, 2H), 1.21 (t, J＝3.6
Hz, 1H), 1.00—1.03 (m, 1H), 0.73—0.91 (m, 9H); 13C
NMR (CDCl3) δ: 150.68 (d, J＝8.0 Hz), 129.55, 125.04,
120.15 (d, J＝5.0 Hz), 120.05 (d, J＝5.0 Hz), 120.00,
81.48 (d, J＝7.0 Hz), 48.36 (d, J＝7.0 Hz), 42.36, 33.82,
31.45, 25.36, 22.73, 21.81, 20.74, 15.49; 31P NMR
(CDCl3) δ: － 12.40; HRMS (ESI) calcd for
C22H29O4PNa＋ [M＋Na＋] 411.1701, found411.1733.
(R)-Methyl 2-(2-chlorophenyl)-2-(diphenoxypho-
sphoryloxy) acetate (7g) Colorless oil; 1H NMR
(CDCl3) δ: 7.44—7.46 (m, 1H), 7.34—7.37 (m, 2H),
7.05—7.30 (m, 11H), 6.40 (d, J＝9.6 Hz, 1H), 3.70 (s,
3H); 13C NMR (CDCl3) δ: 167.87 (d, J＝6.0 Hz),
150.33 (d, J＝8.0 Hz), 149.99 (d, J＝7.0 Hz), 133.37,
132.36, 132.31, 130.59, 129.71, 129.54, 129.48, 129.37,
127.11, 125.33, 125.22, 120.13 (d, J＝5.0 Hz), 119.87
(d, J＝5.0 Hz), 74.83 (d, J＝5.0 Hz), 52.78; 31P NMR
(CDCl3) δ: －12.70; HRMS (ESI) calcd for C21H18Cl-
O6PNa＋ [M＋Na＋] 455.0427, found 455,0448.
Cholesterolyl diphenyl phosphate (2b)[5c] White
1
solid; m.p. 234—237 ℃; H NMR (CDCl3) δ: 7.32—
7.37 (m, 4H), 7.22—7.27 (m, 4 H), 7.16—7.21 (m, 2 H),
5.37 (d, J ＝ 4.8 Hz, 1H), 4.43—4.47 (m, 1H),
2.42—2.44 (m, 2H), 0.68—2.03 (m, 41H); 13C NMR
(CDCl3) δ: 150.75 (d, J＝7.0 Hz), 139.10, 129.69,
125.16, 123.33, 120.15 (d, J＝5.0 Hz), 80.36 (d, J＝7.0
Hz), 56.66, 56.14, 49.97, 42.32, 39.80, 39.76, 39.70,
39.52, 36.87, 36.39, 36.18, 35.77, 31.88 (d, J＝6.0 Hz),
29.52, 29.52, 29.48, 28.20, 28.01, 24.26, 23.83; 31P
NMR (CDCl3) δ: －12.87; HRMS (ESI) calcd for
C39H55O4PNa＋ [M＋Na＋] 641.3736, found 641.3755.
Dioscinyl diphenyl phosphate (3c) White solid;
m.p. 292—296 ℃; 1H NMR (CDCl3) δ: 7.32—7.36 (m,
4H), 7.21 — 7.24 (m, 4H), 7.16—7.19 (m, 2H),
5.35—5.37 (d, J＝5.2 Hz, 1H), 4.0—4.20 (d, J＝7.2 Hz,
2H), 3.40—3.42 (m, 1H), 3.80—3.41 (m, 1H),
2.42—2.44 (m, 2H), 2.00 (m, 2H), 0.79—1.87 (m, 32H);
13C NMR (CDCl3) δ: 150.63 (d, J＝8.0 Hz), 139.03,
129.62, 125.10, 122.97, 120.06 (d, J＝5.0 Hz), 109.16,
80.68, 80.13 (d, J＝7.0 Hz), 66.75, 62.01, 56.31, 49.78,
41.53, 40.16, 39.68, 39.63, 39.59, 36.74, 36.43, 31.92,
31.75, 31.31, 31.27, 30.21, 29.40, 29.36, 28.73, 20.74;
31P NMR (CDCl3) δ: －12.82; HRMS (ESI) calcd for
C39H51O6PNa＋ [M＋Na＋] 669.3321, found 669.3346.
2-(2-(2-Chloroethoxy)ethoxy)ethyl diphenyl
Diphenyl 2-(thiophen-2-yl)ethyl phosphate (8h)
Colorless oil; 1H NMR (CDCl3) δ: 7.32—7.36 (m, 4 H),
7.16—7.24 (m, 4 H), 6.95 (m, 1H), 6.86—6.94 (m, 1H),
4.44—4.49 (m, 2H), 3.21—3.25 (m, 2H); 13C NMR
(CDCl3) δ: 150.28 (d, J＝7.0 Hz), 138.27, 129.58,
126.78, 125.84, 125.17, 124.06, 119.85 (d, J＝5.0 Hz),
68.80 (d, J＝6.0 Hz), 30.56 (d, J＝7.0 Hz); 31P NMR
(CDCl3) δ: －12.04; HRMS (ESI) calcd for C18H17O4P-
SNa＋ [M＋Na＋] 383.0483, found 383.0507.
Diphenyl prop-2-ynyl phosphate (9i)[5] Colorless
oil; 1H NMR (CDCl3) δ: 7.30—7.34 (m, 4H),
7.23—7.25 (m, 4H), 7.15—7.19 (m, 2H), 4.80—4.83
(dd, J＝2.4, 10.8 Hz, 2H), 2.61—2.62 (m, 1H); 13C
NMR (CDCl3) δ: 150.38 (d, J＝6.0 Hz), 129.86, 125.60,
125.59, 120.16 (d, J＝5.0 Hz), 76.88 (d, J＝7.0 Hz),
56.41, 56.36; 31P NMR (CDCl3) δ: －11.81; HRMS
(ESI) calcd for C15H13O4PNa＋ [M＋Na＋] 311.0449,
found 311.0461.
1
phosphate (4d) Colorless oil; H NMR (CDCl3) δ:
7.29—7.33 (m, 4H), 7.21—7.23 (m, 4H), 7.14—7.18
(m, 2H), 4.34—4.39 (m, 2H), 3.67—3.72 (m, 8H),
3.56—3.58 (m, 2H); 13C NMR (CDCl3) δ: 150.33 (d,
J＝7.0 Hz), 129.54, 125.13, 119.88 (d, J＝5.0 Hz),
71.11, 70.39 (d, J＝4.0 Hz), 69.64 (d, J＝7.0 Hz), 67.92,
67.85, 42.57; 31P NMR (CDCl3) δ: －11.84; HRMS
(ESI) calcd for C18H22 O6ClPNa＋ [M＋Na＋] 423.0740,
found 423.0764.
(1,2,4,6-Di-O-isopropylidene)-D-glucofranosyl
diphenyl phosphate (5e) [5b,5c] Colorless oil; 1H NMR
(CDCl3) δ: 7.16—7.35 (m, 10H), 5.78 (d, J＝4.4 Hz,
1H), 5.02—5.05 (dd, J＝3.6, 7.2 Hz, 1H), 4.63 (d, J＝
3.6, 1H), 4.21—4.23 (m, 1H), 4.18—4.20 (m, 1H),
4.05—3.95 (m, 2H), 1.47 (s, CH3), 1.38 (s, CH3), 1.24
(s, CH3), 1.23 (s, CH3); 13C NMR (CDCl3) δ: 150.40 (d,
J＝8.0 Hz), 129.70 (d, J＝5.0 Hz), 125.52 (d, J＝11.0
Hz), 125.41, 120.13 (d, J＝4.0 Hz), 120.01 (d, J＝5.0
Hz), 119.96, 112.31, 109.24, 83.12, 81.00, 80.94, 80.31
(d, J＝8.0 Hz), 71.81, 67.01, 26.69, 26.54, 26.02, 24.95;
31P NMR (CDCl3) δ: －12.88. HRMS (ESI) calcd for
C24H29O9PNa＋ [M＋Na＋] 515.1447, found 515.1460.
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl di-
tert-Butyl diphenyl phosphate (10j)[5c] Colorless
oil; 1H NMR (CDCl3) δ: 7.33—7.27 (m, 4H),
7.24—7.12 (m, 6H), 1.58 (s, 9H); 13C NMR (CDCl3) δ:
150.91 (d, J＝8.0 Hz), 124.86, 120.14 (d, J＝5.0 Hz),
85.80 (d, J＝8.0 Hz), 30.0 (d, J＝4.0 Hz); 31P NMR
(CDCl3) δ: － 12.30; HRMS (ESI) calcd for
C16H19O4PNa＋ [M＋Na＋] 329.0919, found 329.0930.
Results and Discussion
Initial study was carried out by treating 1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose as a model substrate
with diphenyl chlorophosphate (1 equiv.) and Et3N (1
equiv.) in the presence of the selected catalysts (10
mol%) in CH2Cl2 and the results are shown in Table 1.
The use of B(C6F5)3 as a catalyst afforded the expected
phosphorylated product in excellent yields after 30 min.
2
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—4

B(C6F5)3 as a Highly Effective Catalyst for the Phosphoryl Transfer Reaction
Then we observed that lowering the concentration of
B(C6F5)3 to 8 mol% and 5 mol% (Entries 6 and 7) re-
sulted in an apparent drop in yields, even further exten-
sion of reaction time did not lead to the increase of
amount of the product.
Table 2 Catalytic phosphorylation of alcohols by B(C6F5)3
B(C6F5)3 (10 mol%)
Et3N (1 equiv.), r.t.
O
P
O
P
ROH
+
PhO
OR
PhO
Cl
CH2Cl2
OPh
OPh
1a - 1j
2a - 2j
Table 1 Catalyst screening for the tested phosphorylation of
1,2:5,6-di-O-isopropylidene-α-D-glucofuranosea
Entry
Substrate
Product Yielda/%
O
OH
O
Entry
Catalyst
TMSOTf
BF3•(Et)2O
B(C6F5)3
LiOTf
Catalyst loading/mol% Isolated yield/%
1
2
3
4
5
6
7
10
10
10
10
10
8
40
none
94
O
1
2
99
2a
O
O
1a
15
HO
In (OTf) 3
B(C6F5)3
B(C6F5)3
26
73
95
2b
5
58
1b
a Reactions performed with of Et3N (1 equiv.) and (PhO)2P(O)Cl
(1 equiv.) in the presence of catalyst in CH2Cl2 at room tempera-
ture for 0.5 h.
HO
We next examined the generality of this reaction us-
ing various alcohols. The results obtained for the
B(C6F5)3-catalyzed phosphorylation of alcohols were
summarized in Table 2. In most cases, the correspond-
ing phosphate esters were obtained in an average yield
of around 90% after workup, all the phosphorylation of
1°, 2° and 3° alcohols was complete in only 30 min and
only one new spot could be detected on TLC which was
identified to be the phosphorylated product exclusively.
Interestingly, sterically hindered tert-butyl alcohol can
be also smoothly efficiently phosphorylated. Moreover,
the reaction conditions were fairly mild so that some
functional groups remained intact, including the triple
bond in 9i, the ketal moiety in 1a and 5e, and the ole-
finic bond in 8h.
3
4
5
97
98
94
2c
2d
2e
O
O
1c
Cl
O
O
OH
1d
O
O
O
O
O
HO
1e
A plausible mechanism for the reaction is outlined in
Scheme 1. The reaction is presumed to proceed by ini-
tial formation of a high reactive intermediate borate es-
ter that then coordinates with the chlorophosphate, fol-
lowed by intramolecular transesterification to give the
phosphate products.
6
7
89
95
2f
OH
1f
O
Scheme 1 Proposed mechanism for the B(C6F5)3-catalyzed
phosphorylation of alcohols
H3CO
2g
OH Cl
B(C6F5)3
1g
ROH
OH
O
P
C6HF5
8
9
97
99
83
2h
2i
S
OPh
OPh
1h
Cl
O
P
RO B(C6F5)2
OPh
OPh
Et3NHCl +
RO
OH
OH
1i
+ ROH
RO B(C6F5)2
Et3N
10
2j
O
1j
OPh
P
a Isolated yields.
Cl
OPh
Chin. J. Chem. 2012, XX, 1—4
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Xue & Zhang
FULL PAPER
Garcia, G.; Fleisher, D. Int. J. Pharm. 2003, 261, 81; (b) Dewk, R. A.
Chem. Rev. 1996, 96, 683.
Conclusions
In summary, we have achieved the highly efficient
synthesis of phosphate esters through B(C6F5)3-cata-
lyzed reactions of diphenyl chlorophosphate with di-
verse alcohols. B(C6F5)3 offers distinct advantages over
the previously reported Lewis acids in terms of catalytic
activity, stability, and ease of handling.
[3] (a) Perich, J. W.; Johns, R. B. Tetrahedron Lett. 1987, 28, 101; (b)
Nifantiev, E. E.; Grachev, M. K.; Burmistrov, S. Y. Chem. Rev.
2000, 100, 3755.
[4] (a) Mora, N.; Lacombe, J. M. Tetrahedron Lett. 1993, 34, 2461; (b)
Schlimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
10125; (c) Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169.
[5] (a) Jones, S. Org. Lett. 2002, 4, 3671; (b) Jones, S.; Selitsianos, D.;
Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003, 68, 5211; (c) Liu,
C.-Y.; Pawer, V. D.; Chen, C.-T. Adv. Synth. Catal. 2010, 352, 188.
[6] (a) Isihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1993, 577; (b) Isi-
hara, K.; Hanaki, N.; Yamamoto, H. Synlett 1994, 963.
Acknowledgement
The work was supported by the Fundamental Re-
search Funds for the Lanzhou University (No. lzu-
jbky-2011-136) and the Natural Science Foundation for
Young Scientists in Gansu Province, China (No.
1107RJYA038).
[7] (a) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440; (b)
Rubin, M.; Gevorgyan, V. Org. Lett. 2001, 3, 2705; (c)
Chandrasekhar, S.; Raji Reddy, C. H.; Nagendra Babu, B.; Sekhar,
G. C. Tetrahedron Lett. 2002, 43, 3801; (d) Chandrasekhar, S.; Raji
Reddy, C. H.; Nagendra Babu, B. J. Org. Chem. 2002, 67, 9080; (e)
Chandrasekhar, S.; Rao, Y. S.; Reddy, N. R. Synlett 2005, 1471; (f)
Kim, Y.-J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.; Der-
ryberry, J.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 11906.
(Lu, Y.)
References
[1] Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315.
[2] (a) Heimbach, T.; Oh, D.-M.; Li, L. Y.; Rodriguez-Hornedo, N.;
4
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—4