Direct conversion of benzylic and allylic alcohols to phosphonates

Article abstract of DOI:10.1021/jo200137k

Benzyl phosphonate esters often serve as reagents in Horner-Wadsworth- Emmons reactions. In most cases, they can be prepared from benzylic alcohols via formation of the corresponding halide followed by an Arbuzov reaction. To identify a more direct synthesis of phosphonate esters, we have developed a one-flask procedure for conversion of benzylic and allylic alcohols to the corresponding phosphonates through treatment with triethyl phosphite and ZnI₂.

Full text of DOI:10.1021/jo200137k

NOTE
pubs.acs.org/joc
Direct Conversion of Benzylic and Allylic Alcohols to Phosphonates
Rocky J. Barney, Rebekah M. Richardson, and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States
S Supporting Information
b
ABSTRACT: Benzyl phosphonate esters often serve as reagents in Horner-
Wadsworth-Emmons reactions. In most cases, they can be prepared from
benzylic alcohols via formation of the corresponding halide followed by an
Arbuzov reaction. To identify a more direct synthesis of phosphonate esters, we
have developed a one-flask procedure for conversion of benzylic and allylic alcohols to the corresponding phosphonates through
treatment with triethyl phosphite and ZnI2.
n recent years, we have pursued the synthesis of a number of
natural products that contain a trans-stilbene moiety, including
I
the schweinfurthins1-6 (e.g., schweinfurthin A,1,6 1) and the
pawhuskins7-9 (e.g., pawhuskin C,7 2) (Figure 1). The Horner-
Wadsworth-Emmons condensation of a benzylic phosphonate
with an aromatic aldehyde has proven to be a reliable strategy for
formation of these trans-stilbenes. However, synthesis of the
requisite phosphonate from the corresponding benzylic alcohol
has relied upon a classic three-step protocol involving formation
of the mesylate, conversion to the corresponding halide and a
final Michaelis-Arbuzov reaction.10,11 In some cases, this se-
quence has proven problematic12 or difficult to scale. Given our
long-standing interest in carbon-phosphorus bond forming
reactions,13-15 we were prompted to explore shorter paths to
semistabilized phosphonates. We report here our results with a
one-flask protocol based on treatment of the alcohol with triethyl
phosphite in the presence of ZnI2.
Figure 1. Some isoprenylated trans-stilbene natural products.
Scheme 1. Conversion of Benzyl Alcohol to Phosphonate 4
It has been known for some time that alcohols which afford
relatively stable cationic species, e.g., benzylic, allylic, and tertiary
alcohols, can be activated with zinc halides. The resulting species
have been trapped through reactions with hydride,16 alcohols,17
thiols,18 and other nucleophiles.19 However, somewhat to our
surprise, phosphorus nucleophiles have not been studied exten-
sively in this type of reaction.20 Triethyl phosphite also is a good
nucleophile, and one might envision a parallel reaction that
would afford a phosphonate product.
As an initial test case, benzyl alcohol (3) was treated with ZnI2
under a variety of conditions, and the reaction progress was
assessed by inspection of the 31P NMR spectrum of the reaction
mixture. When the reaction was attempted at room temperature
in toluene or methylene chloride, little or no product was
detected. However, when the reaction was conducted at reflux in
toluene, or even heated at ∼80 °C, formation of the desired
phosphonate 421 was evident (Scheme 1). After removal of the
volatiles in vacuo, treatment of the residue with NaOH to remove
ZnO,22 and column chromatography, phosphonate 4 was iso-
lated in good yield (84%).
under parallel reaction conditions (Table 1). With 3-bromo- and
3,4-dimethylbenzyl alcohols (5 and 7), the reactions proceeded
smoothly and gave the expected phosphonates 623 and 824 in
similar yields. With 4-methoxybenzyl alcohol (9), the yields were
variable when the reaction was conducted in toluene, ranging
from 76% (trial 4) down to modest amounts, which may be due
to competitive demethylation.25 However, when this reaction
was conducted in THF at reflux (trial 5), the desired phospho-
nate 1026 was formed in good yield. Parallel results were obser-
ved with the nitro compound 11. The desired product 1227 could
not be detected by 31P NMR upon attempted reaction in toluene.
In this case, reduction of the nitro group by the triethyl phosphite
may be competitive at the high reaction temperature.28 When the
reaction was conducted in THF, the desired phosphonate 12 was
isolated in low yield (15%). While the low yield may be a result of
the electron-withdrawing effect of the nitro group, it is more
likely that nitrene formation is problematic even at the lower
reaction temperature. This later view is supported by the results
observed with the methoxycarbonyl compound 13. In this case,
To gauge the generality of this process, a number of benzylic
alcohols were treated with triethyl phosphite and zinc iodide
Received: September 1, 2010
Published: March 15, 2011
r
2011 American Chemical Society
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NOTE
Table 1. Conversion of Benzyl Alcohols to Diethyl Benzyl-
phosphonates in Zn-Mediated Reactions
Table 2. Conversion of Allylic Alcohols to Diethyl Phos-
phonates in Zinc-Mediated Reactions
a Conducted at reflux in toluene. b Conducted at reflux in THF.
The generally attractive yields available with the benzylic
alcohols summarized in Table 1, encouraged exploration of this
process with other alcohols that might afford relatively stable
cationic systems. Several isoprenoid phosphonates have been
studied as inhibitors of isoprenoid metabolism,32 and so the first
examples examined in this reaction were terpenoid allylic alco-
hols (Table 2). Geraniol (21) reacted smoothly under the stan-
dard reaction conditions to afford diethyl geranylphosphonate
(22).33 In contrast, the tertiary allylic alcohol linalool (23) gave a
complex mixture under the standard reaction conditions, although
the geranyl phosphonate 22 could be isolated from this reaction
in modest yield. Perillyl alcohol (24) and cinammyl alcohol (26)
also reacted smoothly under the standard reactions conditions,
and gave the expected phosphonates 2534 and 2735 in good
yields. This suggests that a free carbocation is not formed and/or
that steric factors dominate the site of C-P bond formation. In
either case, it is clear that attack of the phosphorus nucleophile is
consistently favored at the primary position over the secondary
or tertiary sites.
These results do not afford a complete mechanistic picture,
but some aspects of the reaction sequence are apparent. While a
process involving formation of an intermediate benzylic iodide
and a subsequent Arbuzov reaction would explain formation of
the phosphonate products, past work indicates that treatment of
an alcohol with ZnI2 is more likely to afford the corresponding
ether than the iodide.16,17,20a Furthermore, no evidence for an
intermediate iodide was found in this case. Addition of a sub-
stantial excess of ZnI2 was detrimental to isolated yields, contrary
to what one might expect if formation of an intermediate iodide
were required, and when substoichiometric amounts of ZnI2
were employed, it became the limiting reagent. Formation of a
zinc-phosphite complex may be more likely, a conclusion sup-
ported by a shift in the 31P NMR resonance when ZnI2 is added
to a solution of (EtO)3P (from 138.6 to 33.6 ppm). A similar
resonance was observed when the reaction mixture was analyzed
by 31P NMR.
a Conducted at reflux in toluene. b Conducted at reflux in THF.
despite the presence of an electron withdrawing group, treatment
with triethyl phosphite and zinc iodide under standard condi-
tions resulted in C-P bond formation. These conditions also
induced ester exchange to afford the ethyl ester 14.29
Because natural products like the schweinfurthins and the
pawhuskins often display phenols, application of this reaction
to protected phenols was of special interest. With the di-
MOM protected compound 15, the desired phosphonate 1630
was readily obtained, although the yield was modest. In a
similar sense, the di-TBS protected compound 17 could be
converted to phosphonate 18,31 although again the isolated
yield was diminished relative to the reaction with benzyl
alcohol itself (3). A more attractive yield was obtained with
the benzofuran 19, suggesting that systems with a single
protecting group may undergo this transformation more
smoothly than those that bear two.25 Attempted preparation
of phosphonate 20 via a traditional Arbuzov sequence led only
to decomposition.12
Finally, zinc bromide also has proven to be effective for
conversion of benzyl alcohol to phosphonate 4 (trial 11).
Although this yield was a bit lower than that observed with zinc
iodide (trial 1, Table 1) and a longer reaction time was employed,
this is still an efficient transformation.
Application of this protocol to (S)-1-phenylethanol gave
phosphonate that was essentially racemic by chiral HPLC anal-
ysis (∼3% ee), which suggests an SN1-like process. The tertiary
alcohol 2-phenyl-2-propanol failed to react under these conditions,
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NOTE
Scheme 2. Partial Mechanistic Rationale
A reaction sequence leading to phosphonate 31 might be
based on a Lewis acid mediated ester exchange between the
aliphatic alcohol and triethyl phosphite, followed by a more
traditional Arbuzov reaction. When alcohol 30 was treated
with ZnI2 in THF, phosphonate 31 was accompanied by ethyl
3-phenylpropyl phosphite (33) in a 1:1 ratio, which confirms that
ester exchange can occur under these reaction conditions.
Although the scope of this reaction with primary aliphatic alco-
hols has not yet been established, formation of phosphonate 31
does indicate the importance of a benzylic or allylic system for
direct conversion of an alcohol to the corresponding phospho-
nate in the ZnI2 mediated reactions.
In summary, we have demonstrated that benzylic and allylic
alcohols can be converted to the corresponding phospho-
nates through reactions with triethyl phosphite mediated by zinc
iodide. This procedure provides a convenient alternative to the
traditional Arbuzov reaction in these systems. Furthermore,
because benzylic systems conjugated to electron-withdrawing
substituents undergo this transformation in at least modest yields
under these conditions, the reaction may be of broader utility.
Studies designed to explore and extend the scope of this reaction
will be reported in due course.
Scheme 3. Synthesis of Phosphonates 31 and 32
’ EXPERIMENTAL SECTION
General Experimental Procedure. To a stirred solution of ZnI2
(1.5 equiv) in anhydrous toluene or freshly distilled THF was added
P(OEt)3 (1.5-3 equiv) followed by the alcohol. The reaction mixture
was allowed to stir at reflux overnight (approximately 12 h). After it had
cooled to room temperature, the reaction mixture was immediately
placed on a vacuum line to remove volatiles. The residue then was
washed with 2 N NaOH until the solids dissolved, extracted with ether,
dried (MgSO4), and concentrated in vacuo. The resulting oil was
purified via flash column chromatography on silica gel to afford the
desired diethyl phosphonate.
which may reflect the importance of steric effects as noted above
with the allylic systems. Taken together, these factors lead to the
partial mechanistic picture offered in Scheme 2. If formation of
a tetracoordinate zinc species36 such as the complex 28 were
followed by formation of a C-P bond through a process with
SN1 character, the loss of stereochemistry could be explained.
Formation of such a complex might be sensitive to steric factors
in the original alcohol, which would be consistent with the lack of
product from the tertiary alcohol. Finally, the last Arbuzov-like
step on an intermediate such as 29 might be assisted by the
presence of zinc halide serving as a Lewis acid,37 which would
explain why a slight excess (1.1-1.5 equiv) of the ZnI2 is beneficial.
While there is clear literature precedent16-19 for conversion of
benzylic and allylic alcohols to other functionality through zinc
halide mediated reactions, the common assumption is that such
transformations are facile only in systems that afford stabilized
cationic species. Nevertheless, the simplicity of these reaction
conditions and the attractive yields observed with many allylic
and benzylic systems encouraged examination of a simple
primary alcohol. Treatment of alcohol 30 with ZnI2 in toluene
(Scheme 3) did afford a phosphonate product of the desired
Diethyl (4-(tert-Butyldimethylsilyloxy)benzo-furan-6-yl)
methylphosphonate (20). Treatment of alcohol 19 (60 mg, 0.22 mmol)
under standard conditions in toluene at reflux gave phosphonate 20 (55 mg,
64%) as a colorless oil after purification by column chromatography (33%
EtOAc in hexane): 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 2.3, JHP
=
1.0 Hz, 1H), 7.09-7.08 (m, 1H), 6.74 (dd, J = 2.2, JHP = 0.8 Hz, 1H), 6.64
(d,JHP = 2.25 Hz, 1H), 4.04-3.99 (m, 4H), 3.20 (d, JHP = 21.5 Hz, 2H), 1.25
(t, J= 7.2 Hz, 6H), 1.04 (s, 9H), 0.24 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 156.5 (d, JCP = 2.8 Hz), 148.9 (d, JCP = 3.0 Hz), 143.6 (d, JCP = 1.4 Hz),
128.5 (d, JCP = 9.2 Hz), 119.5 (d, JCP = 3.0 Hz), 114.3 (d, JCP = 6.1 Hz),
106.4 (d, JCP = 7.6 Hz), 104.1 (d, JCP = 1.6 Hz), 62.1 (d, JCP = 6.8 Hz, 2C),
33.9 (d, JCP = 138.6 Hz), 25.6 (3C), 18.2, 16.4 (d, JCP = 5.9 Hz, 2C), -4.4
(2C);31PNMR(CDCl3) δ26.3. Anal. Calcd for C19H31O5PSi: C, 57.26; H,
7.84. Found: C, 56.96; H, 8.02.
(S)-(p-Menth-1,8-dien-7-yl)phosphonic Acid, Diethyl Es-
ter (25). Treatment of alcohol 24 (0.50 g, 3.28 mmol) under standard
conditions in toluene at reflux gave phosphonate 25 (0.70 g, 78%) as a
colorless oil after purification by column chromatography (30% to 50%
1
molecular weight, but the H and 13C NMR spectra of this
material were not consistent with those expected for phospho-
nate 32. An authentic sample of phosphonate 3238 was prepared
in quantitative yield through catalytic hydrogenation of phos-
phonate 27 and was clearly a different compound. The structure
of the ZnI2 mediated product was assigned as compound 31,
based upon its spectral data. While the methylene groups of the
two esters overlap in the 1H NMR spectrum, the corresponding
carbon resonances are distinct, which indicates the absence of
symmetry around the central phosphorus. Furthermore, the
presence of a methylene group directly bonded to phosphorus
was apparent in a 13C resonance at 18.3 ppm (JCP = 142 Hz).
1
EtOAc in hexane): H NMR (300 MHz, CDCl3) δ 5.63 (br s, 1H),
4.73-4.70 (m, 2H), 4.15-4.05 (m, 4H), 2.52 (d, JHP = 21.8 Hz, 2H),
2.21-2.09 (m, 4H), 2.03-1.92 (m, 1H), 1.87-1.78 (m, 1H), 1.73 (s,
3H), 1.55-1.42 (m, 1H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 149.5, 127.9 (d, JCP = 11.0 Hz), 125.8 (d, JCP = 12.5 Hz),
108.5, 61.6 (d, JCP = 1.8 Hz), 61.5 (d, JCP = 1.9 Hz), 40.3, 34.8 (d, JCP
=
137.7 Hz), 30.7 (d, JCP = 2.8 Hz), 29.7 (d, JCP = 2.8 Hz), 27.6, 20.6, 16.3
(d, JCP = 6.1 Hz, 2C); 31P NMR (CDCl3) δ 27.9; HRMS (EIþ, m/z)
calcd for C14H25O3P (Mþ) 272.1541, found 272.1535. Anal. Calcd for
C14H25O3P H2O: C, 57.92; H, 9.37. Found: C, 57.89; H, 9.19.
3
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NOTE
Ethyl (3-Phenyl)propyl Ethylphosphonate (31). Treatment
of alcohol 30 (0.50 g, 3.68 mmol) under standard conditions in toluene
at reflux gave phosphonate 31 (469 mg, 50%) as a colorless oil after
purification by chromatography with EtOAc in hexane: 1H NMR (300
MHz) δ 7.30-7.23 (m, 2H), 7.19-7.16 (m, 3H), 4.14-4.00 (m, 4H),
2.71 (t, J = 7.2 Hz, 2H), 2.03-1.92 (m, 2H), 1.81-1.66 (m, 2H), 1.31 (t,
J = 6.6 Hz, 3H), 1.16 (dt, JHP = 19.8, J = 7.8 Hz, 3H); 13C NMR
(75 MHz) δ 140.7, 128.1 (4C), 125.6, 64.1 (d, JCP = 6.5 Hz), 61.1 (d,
JCP = 6.6 Hz), 31.8 (d, JCP = 6.2 Hz), 31.4, 18.3 (d, JCP = 141.5 Hz), 16.1 (d,
JCP = 5.9 Hz), 6.3 (d, JCP = 6.8 Hz); 31P NMR (CDCl3) δ 33.7; HRMS
(EIþ, m/z) calcd for C13H21O3P (Mþ) 256.1229, found 256.1220.
Ethyl 3-Phenylpropyl Phosphite (33). Treatment of alcohol 30
(1.0 g, 7.35 mmol) under standard conditions in THF at reflux gave
phosphonate 31 (530 mg, 28%) and phosphite 33 (478 mg, 27%) as a
colorless oil after purification by column chromatography (25% to 50%
EtOAc in hexane). For compound 33: 1H NMR (300, MHz) δ 7.16 (d,
J = 6.9 Hz, 2H), 7.09-7.03 (m, 3H), 6.69 (d, JHP = 693 Hz, 1H), 4.08-
3.91 (m, 4H), 2.61 (t, J = 7.5 Hz, 2H), 1.94-1.84 (m, 2H), 1.24 (t, J =
6.9 Hz, 3H); 13C NMR (75, MHz) δ 140.3, 128.0 (2C), 127.9 (2C),
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: david-wiemer@uiowa.edu.
’ ACKNOWLEDGMENT
Financial support in the form of a University of Iowa Presi-
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