Efficient catalyst turnover in the phosphitylation of alcohols with phosphoramidites

Article abstract of DOI:10.1016/j.tetlet.2008.12.065

We report a method for catalytic phosphitylation utilizing phosphoramidites. Traditionally, this reaction is inefficient unless an excess of catalyst is present due to catalyst deactivation by an amine by-product. Isocyanate additives have been evaluated

Full text of DOI:10.1016/j.tetlet.2008.12.065

Tetrahedron Letters 50 (2009) 975–978
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Tetrahedron Letters
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Efficient catalyst turnover in the phosphitylation of alcohols
with phosphoramidites
*
Patrick B. Brady, Elizabeth M. Morris, Owen S. Fenton, Bianca R. Sculimbrene
College of the Holy Cross, Department of Chemistry, Worcester, MA 01610, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a method for catalytic phosphitylation utilizing phosphoramidites. Traditionally, this reaction
is inefficient unless an excess of catalyst is present due to catalyst deactivation by an amine by-product.
Isocyanate additives have been evaluated for scavenging the amine to facilitate catalyst turnover. A vari-
ety of alcohols and phosphoramidites were screened with 5 mol % catalyst. In the presence of additive,
83–97% conversion was achieved in contrast to 7–31% conversion without additive.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 November 2008
Accepted 9 December 2008
Available online 24 December 2008
The derivatization of alcohols to diverse functional groups is a
vibrant field in synthetic organic chemistry. One such transforma-
tion is the synthesis of phosphates. Phosphates are ubiquitous in
nature, and are found in large biopolymers such as DNA, RNA,
and proteins as well as in small molecule messengers such as ino-
sitol phosphates. Phosphates have also been seen to increase the
aqueous solubility of drug candidates.1 Due to the unique oxida-
tion states of phosphorous (P), synthesis of phosphorylated com-
pounds can be completed with either P(V) reagents (such as
chlorophosphates2 or pyrophosphates3) or P(III) reagents (such as
phosphoramidites,4 phosphites,5 or phosphorochloridites6) fol-
lowed by oxidation.7
N
N
N
H
O
P
N
OBn
OBn
+
+
N
N
OH
R2
tetrazole
NH
N
H
O
N
R1
R1
R2
OBn
OBn
N
P
H
N
N
H
phosphoramidite (1)
+
N
N
then [O]
N
Scheme 1. Phosphitylation with phosphoramidites.
Catalytic methods for the phosphorylation [P(V)] or phosphity-
lation [P(III)] of alcohols are beneficial because they can potentially
reduce waste and open the possibility to enantioselective synthe-
ses. The P(V) reagent, diphenylchlorophosphate, has been used in
the phosphorylation of alcohols with catalytic Lewis acids2a and
nucleophiles.2b To date, other phosphorous-protecting groups have
been unsuccessful in catalytic reactions.8 In order to develop an
efficient catalytic reaction that is amenable with a wide array of
phosphorous-protecting groups, we explored phosphitylation with
phosphoramidites and subsequent oxidation.
Phosphoramidites have witnessed great success in oligonucleo-
tide synthesis.9 Advantages to using phosphoramidites include ro-
bust reagents that are commercially available with a variety of
orthogonal phosphorous-protecting groups. A current limitation
is the need for excess catalyst, commonly tetrazole.10 Conse-
quently, attempts to run this reaction with 5 mol % tetrazole lead
to poor conversions (vide infra). A possible explanation for low cat-
alyst turnover is the equivalent of diisopropylamine generated
during the course of the reaction (Scheme 1). As the concentration
of amine increases, the concentration of tetrazole (pKa = 5)11
decreases. Scavenging the amine by-product should re-adjust the
equilibrium in favor of active catalyst.
This idea has been elegantly put into practice by Hayakawa
et al.12 They demonstrated that 5 mol % of the more reactive p-
nitrophenyltetrazole in the presence of 10 Å molecular sieves
(MS) was effective for the phosphoramidite coupling of oligonucle-
otides. The MS were present to sequester the amine by-product
over the larger oligonucleotide building blocks. While this work
demonstrated the ability of the catalyst to turnover, the method
is only amenable to substrates and catalysts that are larger than
diisopropylamine. We envisioned that an alternative method
would exploit the unique nucleophilic reactivity of amines. Isocy-
anates and isothiocyanates have been successfully employed as
amine scavengers as solid supported13 and fluorous tagged14 re-
agents. The resulting urea is no longer basic, allowing the active
protonated catalyst to circulate.
Our study began by examining the effect of additives in promot-
ing catalyst turnover (Table 1). Reactions were conducted with
5 mol % tetrazole and 1.2 equiv of phosphoramidite 1. When no
* Corresponding author. Tel.: +1 508 793 3425; fax: +1 508 793 3530.
E-mail address: bsculimb@holycross.edu (B.R. Sculimbrene).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.065

976
P. B. Brady et al. / Tetrahedron Letters 50 (2009) 975–978
Table 1
Table 2
Additives for promotion of catalytic phosphitylationa
Phosphitylation of primary and secondary alcoholsa
5 mol% tetrazole
OH P(OBn)2NiPr2 (1)
additive, CH2Cl2
additive:
OBn
OBn
5 mol% tetrazole,
P(OBn)2NiPr2 (1),
additive, CH2Cl2
O
P
O
PIC
O
C
N
P
O
OBn
OBn
OH
R2
O
then 30% H2O2/H2O
R1
R1
R2
Ph
then 30% H2O2/H2O
Entry
1
Additive
None
Conversionb (%)
Time (h)
13
Entry
Product
No additive
With PIC
Conversion (%)
17
Conversionb (isolated yield)
18
96
N
C O
2
3
4
5
13
13
13
16
Ph
O
P
1
2
3
4
83% (74%)
OBn
OBn
N
C
C
S
27
42
3
O
Me
O
OBn
OBn
N
S
P
O
26
18
14
94% (88%)
96% (85%)
86% (82%)
Ph
9
N
C O
OBn
O
O
P
OBn
N
C O
O
6
>98
16
O
P
OBn
OBn
O2N
a
Ph
Reactions performed with 1.2 equiv of P(OBn)2NiPr2 and 1.1 equiv of additive
followed by an oxidative workup with 30% H2O2/H2O.
O
P
b
Conversions obtained from integrations of 1H NMR of unpurified reactions. Data
OBn
OBn
reported are the average of two trials.
5
7
83%
O
Ph
Ph
additive was introduced, the phosphitylation of 2-adamantanol
proceeded with only 18% conversion (entry 1). To our delight, the
addition of 1.1 equiv of phenylisocyanate (PIC) generated 96% con-
version (entry 2). The less reactive thioisocyanates (entries 3 and 4)
provided only 27% and 42% conversion, respectively. Unfortu-
nately, extremely low conversion (3%) was obtained with ethyliso-
cyanate (entry 5). In this case, the additive must be inhibiting the
reaction. Encouragingly, 4-nitrophenylisocyanate also provided
high conversions with no detectable starting material by 1H NMR
(entry 6).
Different primary and secondary alcohols were then examined
in the presence and absence of PIC (Table 2). Aliphatic alcohols pro-
vided between 14% and 26% conversion without isocyanate and
83-96% conversion with PIC (entries 1–4).15 sec-Phenethyl alcohol
was also phosphitylated in 83% yield in the presence of PIC; how-
ever, purification of this substrate leads to decomposition16 (Table
2, entry 5). The higher reactivity of primary alcohols toward phos-
phitylation was witnessed by higher conversion (31%) in the ab-
sence of additive (Table 2, entry 6).17
To test the effectiveness of the methodology with multiple pro-
tecting groups, other phosphoramidites were examined (Table 3).
When ortho-xylyl phosphoramidite 2 was used in the presence of
1.1 equiv of 4-nitrophenylisocyanate, >97% conversion (79% iso-
lated yield) of 3 was obtained. The structurally defined ortho-xylyl
group may help to pre-organize the transition state for phospho-
rous transfer, which may be beneficial in future work involving
selectivity.18 Orthogonal-protecting groups were also examined
to facilitate the synthesis of complex phosphorylated products.
The isomerization-labile allyl phosphoramidite 4 was used to suc-
cessfully synthesize diallyl 519 in 80% yield. Lastly, the photo-labile
o-nitrobenzyl phosphoramidite 6 was synthesized in one step,20
and was screened in the phosphitylation of 2-dodecanol. Photo-la-
bile-protecting groups have been studied extensively in biological
settings for their spatial and temporal release of active phosphor-
ylated targets.21 While this phosphorylating agent did not provide
high conversions (w/o PIC: 10% of 7, with PIC: 38% of 7, Table 3), it
did demonstrate a preliminary result for future optimization.
OBn
OBn
O
4
P
O
6
31
>99% (84%)
a
Reactions performed with 1.2 equiv of P(OBn)2NiPr2 and 1.1 equiv of additive
followed by an oxidative workup with 30% H2O2/H2O.
Conversions obtained from integrations of 1H NMR of unpurified reactions.
b
To test the limitations of our method, tertiary alcohols were
examined. This substrate class is known to be problematic due to
lower reactivity and potential elimination of the products during
oxidation.22 The study began with n-butylcyclohexanol, which did
not generate any desired product under our standard conditions
(Table 4, entry 1). To minimize the congestion of the carbonol center,
2-methyl-3-butyn-2-ol was chosen. The reaction progressed to a
single product; however, allene 8 was formed instead of the ex-
pected phosphate (Table 4, entry 2). Rearrangements of alkynyl
phosphites to allenyl phosphonates have been observed before in
phosphitylation with phosphorochloridites, but have not yet been
reported with phosphoramidites.23 Allenyl phosphonates have been
successfully employed as versatile starting materials for cross cou-
pling reactions24 and selective hydrogenations.25 The synthesis of
this substrate class utilizing phosphoramidites will be examined.
To continue our pursuit of the synthesis of phosphates derived
from tertiary alcohols, a less sterically demanding phosphorami-
dite was examined. While N,N-diisopropylamidites are the most
common phosphitylating agents due to their higher stability,
N,N-diethylphosphoramidites are also commercially available and
offer reduced sterics around the phosphorous atom. When diben-
zyl N,N-diethylphosphoramidite was used in the phosphitylation
of n-butylcyclohexanol with 5 mol % tetrazole and 1.1 equiv of
PIC, the desired phosphate product 9 was isolated in 68% yield
(Table 4, entry 3). This result reinforced the hypothesis that sterics
control the lower reactivity of tertiary alcohols, which can be mit-
igated by managing the sterics of reagents.
In conclusion, we have demonstrated that the introduction of
additives to scavenge the amine by-product in the phosphitylation

P. B. Brady et al. / Tetrahedron Letters 50 (2009) 975–978
977
Table 3
nate as additives, and with a variety of phosphoramidites. Efforts
will now be focused on determining the mechanistic implications
of the additive and on generating chiral catalysts to facilitate a cat-
alytic enantioselective phosphitylation with phosphoramidites.
Phosphoramidite screena
O
P
5 mol% tetrazole, PIC
OR
OR
OH
phosphoramidite, CH2Cl2
O
R1
R2
then 30% H2O2/H2O
R1
R2
Acknowledgments
Phosphoramidite
Product
Conv. w/o
isocyanateb (%)
Yield
(conv.)
This work was supported by the Camille and Henry Dreyfus
Foundation (New Faculty Award to BRS and a Jean Dreyfus Boisse-
vain Summer Undergraduate Fellowship to OSF). PBB thanks the
Simon Fortin Research Fund for a summer undergraduate fellow-
ship. E.M.M. thanks the Pfizer Prepare Grant for a summer under-
graduate fellowship.
O
O
O
P
O
P
N
N
O
21
79%c
(>97%)
O
9
2
O
O
3
O
O
Supplementary data
P
O
O
NAd
80%
P
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.065.
5
4
O2N
O2N
O
References and notes
O
P
O
O
NO2
NO2
10
23%
(38%)
O
N
P
1. (a) Baker, W. R.; Cai, S.; Dimitroff, M.; Fang, L.; Huh, K. K.; Ryckman, D. R.;
Shang, X.; Shawar, R. M.; Therrien, J. H. J. Med. Chem. 2004, 47, 4693; (b)
Saulnier, M. G.; Langley, D. R.; Kadow, J. F.; Senter, P. D.; O Knipe, J.; Tun, M. M.;
Vyas, D. M.; Doyle, T. W. Bioorg. Med. Chem. Lett. 1994, 4, 2567.
2. (a) Jones, S.; Selitsianos, D. Org. Lett. 2002, 4, 3671; (b) Sculimbrene, B. R.;
Miller, S. J. J. Am. Chem. Soc. 2001, 123, 10125; (c) Deutsch, A.; Ferno, O. Nature
1945, 156, 604; (d) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc.
1945, 382.
O
9
6
7
a
Reactions performed with 1.2 equiv of phosphoramidite and 1.1 equiv of addi-
tive for 14 h followed by an oxidative workup with 30% H2O2/H2O.
Conversions obtained from integrations of 1H NMR of unpurified reactions.
b
3. (a) Nelson, T. D.; Rosen, J. D.; Bhupathy, M.; McNamara, J.; Sowa, M. J.; Rush, C.;
Crocker, L. S. Org. Synth. 2003, 80, 219; (b) Dudek, G. O.; Westheimer, F. H. J.
Chem Soc. 1959, 2641.
c
4-Nitrophenylisocyanate was used as the additive for ease of purification.
Conversion could not be obtained due to overlap of NMR resonances.
d
4. Nifantiev, E. E.; Grachev, M. K.; Burmistrov, S. Y. Chem. Rev. 2000, 100, 3755.
and references therein.
5. Watanabe, Y.; Maehara, S.; Ozaki, S. J. Chem Soc., Perkin Trans. 1 1992, 1879.
6. (a) Martin, S. F.; Josey, J. A. Tetrahedron Lett. 1988, 29, 3631; (b) Hayakawa, Y.;
Hyodo, M.; Kimura, K.; Kataoka, M. Chem. Commun. 2003, 1704.
7. I2/H2O: (a) Letsinger, R. L.; Lunsford, W. B. J. Am. Chem. Soc. 1976, 98, 3655;
mCPBA: (b) Ogilvie, K. K.; Nemer, M. J. Tetrahedron Lett. 1981, 22, 2531;
Dioxiranes: (c) Kataoka, M.; Hattori, A.; Okino, S.; Hyodo, M.; Asano, M.; Kawai,
R.; Hayakawa, Y. Org. Lett. 2001, 6, 815 and references therein; Singlet oxygen:
(d) Boldue, P. R.; Goe, G. L. J. Org. Chem. 1974, 21, 3178; Alkyl peroxides: (e)
Hayakawa, Y.; Uchiyama, M.; Noyori, R. Tetrahedron Lett. 1986, 27, 4191.
8. This is due to nucleophilic attack on carbon instead of phosphorous, see: (a)
Modro, T. A.; Moorhoff, C. M. J. Phys. Org. Chem. 1989, 2, 263; (b) Zervas, L.;
Dilaris, I. J. Chem. Soc. 1954, 77, 5354.
Table 4
Phosphitylation of tertiary alcoholsa
O
5 mol% tetrazole,
OBn
P
OH
R3
P(OBn)2N(R)2,
PIC, CH2Cl2
O
OBn
R1
R1
R3
R2
then 30% H2O2/H2O
R2
9. Beaucage, S. L.; Iyer, R. P. Tetrahedron 1992, 48, 2223.
Entry
1
R
Tertiary alcohol
OH
Product
Yield (%)
NA
10. For other catalysts see: (a) Hayakawa, Y.; Iwase, T.; Nurminen, E. J.; Tsukamoto,
M.; Kataoka, M. Tetrahedron Lett. 2005, 61, 2203; (b) Hayakawa, Y.; Kawai, R.;
Hirata, A.; Sugimoto, J.; Kataoka, M.; Sakakura, A.; Hirose, M.; Noyori, R. J. Am.
Chem. Soc. 2001, 123, 8165.
11. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2003.
12. Hayakawa, Y.; Kataoka, M. J. Am. Chem. Soc. 1997, 119, 11758.
13. (a) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882; (b) Cho, J. K.;
White, P. D.; Klute, W.; Dean, T. W.; Bradley, M. Chem. Commun. 2004, 502.
14. Linclau, B.; Sing, A. K.; Curran, D. P. J. Org. Chem. 1999, 64, 2835.
15. Typical procedure for phosphitylation: The alcohol (1.20 mmol) was dissolved in
12 mL of CH2Cl2. An aliquot of 0.45 M tetrazole solution in acetonitrile was
iPr
iPr
No reaction
O
BnO
OH
P
BnO
2
40
68
C
H
8
O
added (134
diisopropylphosphoramidite (475
containing the additive, phenylisocyanate (143
l
L, 0.060 mmol, 5 mol %) followed by dibenzyl N,N-
L, 1.41 mmol, 1.2 equiv). For reactions
L, 1.32 mmol, 1.1 equiv) was
OH
P
OBn
OBn
O
l
3
Ethyl
l
then introduced. After 14 h, the reaction was cooled to 0 °C followed by
addition of 3 mL of 30% H2O2/H2O. After 1 h, the solution was quenched slowly
with 25 mL of saturated sodium sulfite, while the temperature was maintained
at 0 °C. The mixture was then washed with 2 Â 25 mL of CH2Cl2. The combined
organic layers were dried with MgSO4 and were concentrated under reduced
pressure. Crude NMRs were obtained for conversion data. The crude product
was then purified by silica gel chromatography with a gradient of 20% ether/
petroleum ether to 50% ether/petroleum ether. Cyclohexyl dibenzyl phosphate.
1H NMR (CDCl3, 400 MHz) d 7.36–7.31 (m, 10H), 5.03 (m, 4H), 4.36 (m, 1H),
1.88 (m, 2H), 1.71 (m, 2H), 1.54–1.43 (m, 3H), 1.33–1.20 (m, 3H); 13C NMR
(CDCl3, 100 MHz) d 136.3 (d, J = 6.8 Hz), 128.8, 128.6, 128.1, 77.9 (d, J = 6.0 Hz),
69.2 (d, J = 6.1 Hz), 33.5 (d, J = 4.6 Hz), 25.3, 23.7; 31P NMR (CDCl3, 162 MHz) d
À0.6; IR (film, cmÀ1) 2937, 2859, 1497, 1455, 1259, 1214; TLC Rf 0.31 (30%
ethyl acetate/hexanes); Exact mass calcd for [C20H25O4P+H]+ requires m/z
361.1569. Found 361.1536 (FAB).
9
a
Reactions performed with 1.2 equiv of phosphoramidite and 1.1 equiv of PIC for
14 h followed by an oxidative workup with 30% H2O2/H2O.
of alcohols with phosphoramidites can successfully re-engage the
catalyst for further rounds in the catalytic cycle. We postulate that
the additive is reacting with the amine by-product, forming a urea
that is no longer basic and, therefore, does not deactivate the cat-
alyst. This methodology was validated by examining different alco-
hols, additives, and phosphoramidites to survey the generality of
this process. Encouraging results were found with primary, sec-
ondary, and tertiary alcohols, with PIC and 4-nitrophenylisocya-
16. From NMR analysis, product decomposed slowly on the column to styrene and
dibenzylphosphate.

978
P. B. Brady et al. / Tetrahedron Letters 50 (2009) 975–978
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K. C. K. J. Org. Chem. 2006, 71, 9128.
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