LiAlH4-induced reductive dephosphonylation of αα-dialkyl triethyl β-phosphonyl esters: Mechanistic study and synthetic application

Article abstract of DOI:10.1055/s-0031-1290485

Treatment of αα-dialkyl triethyl β-phosphonyl esters with LiAlHin CHlTHF caused the one-pot dephosphonylation and reduction to yield the corresponding primary alcohols bearing a controllable β secondary carbon center. Mechanistic study has revealed that the LiAlHinduced dephosphonylation should occur first with the assistance of the carboxylate group, and the hydrogen source of the resultant new C-H bond is LiAlH. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0031-1290485

LETTER
▌863
letter
LiAlH4-Induced Reductive Dephosphonylation of α,α-Dialkyl Triethyl
β-Phosphonyl Esters: Mechanistic Study and Synthetic Application
Reductive Dephosphonylation of β-Phosphonyl Esters
Jia-Liang Zhu,* Jr-Sheng Bau, You-Cheng Shih
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan, R.O.C.
Fax +886(3)8633570; E-Mail: jlzhu@mail.ndhu.edu.tw
Received: 10.01.2012; Accepted after revision: 24.01.2012
nyl ester system. In this regard, we decided to carry out a
close examination on the reaction in Scheme 1 for explor-
ing a mechanistic rationale and a synthetic route to highly
substituted primary alcohols.
Abstract: Treatment of α,α-dialkyl triethyl β-phosphonyl esters
with LiAlH4 in CH2Cl2–THF caused the one-pot dephosphonylation
and reduction to yield the corresponding primary alcohols bearing a
controllable β secondary carbon center. Mechanistic study has re-
vealed that the LiAlH4-induced dephosphonylation should occur
first with the assistance of the carboxylate group, and the hydrogen
source of the resultant new C–H bond is LiAlH4.
LiAlH4 (6 equiv), THF, r.t., 4 h
PO(OEt)2
CO2Et
H
Key words: reductive dephosphonylation, β-phosphonyl esters,
C–P bond cleavage, lithium aluminum hydride, primary alcohols
31%
CH2OH
1
2
Scheme 1 Reaction of 1 with LiAlH4 in THF
The cleavage of a phosphonyl group is an important pro-
cess in synthetic chemistry.1 During the previous study on
the Diels–Alder reaction of 2-phosphono-2-alkenoates,2
we serendipitously discovered that treatment of phospho-
ryl ester 1 derived from the cycloaddition between triethyl
2-phosphonoacrylate and cyclopentadiene with lithium
aluminum hydride (LiAlH4) caused the one-pot dephos-
phonylation–reduction to afford endo-{bicyclo[2.2.1]hept-
5-en-2-yl}methanol (2)3,4 as an useful synthetic
intermediate5 (Scheme 1). This so far undisclosed result
attracted our attention because the reactions of phospho-
nates with LiAlH4 in ethereal solutions usually produce
the corresponding primary phosphines (RPH2).6 A litera-
ture search revealed that the reductive dephosphonylation
of the phosphonates bearing a β-carbonyl moiety is rare
and difficult to be achieved in practice.1,7 Among few doc-
umented methods, Oh’s group once reported a dephos-
phonylating operation on β-keto phosphonates, which
involved treating the metal enolates of these substrates
with LiAlH4 in THF followed by quenching the reaction
mixture with aqueous H2SO4 solution to yield dephospho-
nylated ketones.8 For this transformation, the results from
deuterium-labeled experiments suggest that the cleavage
of the P–C bond is not caused by the attack of a hydride
on the α- or γ-carbon atoms. However, the detailed mech-
anism of dephosphonylation has remained to be obscure.
Apart from this, Amedjkouh’s group reported a related
methodology for transferring the cyclic β-iminophospho-
nates into amines by LiAlH4, and the dephosphonylation
upon the reduction was proposed to occur via the rear-
rangement of a lithiated phosphonyl amide intermediate.9
To our knowledge, the LiAlH4-mediated reductive de-
phosphonylation has never been reported on β-phospho-
In THF, the reaction in Scheme 1 only produced 31% of 2
along with complex mixtures. For improving the yield, we
initially examined several other solvents. As outlined in
Table 1, the reactions performed in diethyl ether or 1,2-di-
methoxyethane afforded 2 in the comparable yields (29%
and 27%) as in THF (Table 1, entries 1 and 2), while a bet-
ter conversion (48%) was obtained by employing dichlo-
romethane (CH2Cl2) as a solvent (Table 1, entry 3).
Nevertheless, it took much longer time for LiAlH4 to dis-
perse homogeneously in CH2Cl2 than in the tested ethereal
solvents, and consequently, a prolonged reaction time (8
h) was required for the reaction to complete. On this basis,
we further screened a few co-solvents of CH2Cl2 with
THF, diethyl ether, and 1,2-dimethoxyethane, respective-
ly, in different ratios (Table 1, entries 4–8), and found that
Table 1 Evaluation of Solvent Effect on the Formation of 2
LiAlH4 (6 equiv), solvent
2
1
r.t.
Yield (%)a
Entry Solvent
Time (h)
1
2
3
4
5
6
7
8
Et2O
4
4
8
2
2
2
2
2
29
27
48
75
53
63
54
70
1,2-dimethoxyethane
CH2Cl2
CH2Cl2–THF (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–1,2-dimethoxyethane (1:1)
CH2Cl2–THF (2:1)
CH2Cl2–THF (1:2)
SYNLETT 204012, 236, 0863–0866
a Yield is for isolated, chromatographically pure product.
Advanced online publication: 28.02.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290485; Art ID: ST-2012-W0021-L
© Georg Thieme Verlag Stuttgart · New York

864
J.-L. Zhu et al.
LETTER
all of these co-solvents resulted in higher yields (53–75%) has remarkably distinguished our protocol from the previ-
than each solvent used alone. Among which, the best re- ously reported dephosphonylation of β-keto phospho-
sult was received from CH2Cl2 and THF in a ratio 1:1 nates.8
(v/v), affording 2 in 75% isolated yield after two hours at
room temperature (Table 1, entry 4). Thus the reaction
conditions in entry 4 are tentatively considered to be our
choice to effect the formation of 2.
3
LiAlD4 (6 equiv), THF–CH2Cl2 (1:1), r.t., 2 h
1
2
D
1
64%
8
D
OH
We originally thought that the dephosphonylation might
be initiated by the reduction of the carboxylate group into
D
4
an alkoxide intermediate, and the subsequent addition of
the resulting oxide to the P=O bond could induce the
cleavage of C–P bond in a Horner–Emmons-like process.
To verify this, we treated 1 with one and two equivalents,
respectively, of LiAlH4 in CH2Cl2–THF. However, both
reactions did not provide any trace of hydroxyl phospho-
nate or phosphate resulting from the reduction of the ester
group, but rather produced the endo-norbornenyl ester 310
exclusively in 23% yield or together with 2 in 48% yield,
plus 65% and 5% of recovered 1 (Scheme 2). In contrast
to our original assumption, these results unambiguously
demonstrate that the dephosphonylation should take place
prior to the reduction of the ester group. Once formed, es-
ter 3 can be quickly reduced into 2 by excess of LiAlH4.
Scheme 3 Deuterium-labeled reaction with LiAlD4
Based on the aforementioned results, we propose a possi-
ble pathway for the dephosphonylation as depicted in
Scheme 4. Since one equivalent of LiAlH4 was not
enough to completely convert 1 into 3, it is possible that 1
would be first reduced into a phosphine oxide at the ex-
pense of the reducing agent. With the coordination by re-
leased aluminum hydride (AlH3), the P=O bond would
then experience a nucleophilic attack by the carbonyl ox-
ygen atom to furnish a transient four-membered cyclic in-
termediate. Subsequent cleavage of P–C bond would give
the formation of a phosphoenol-type complex. From
which, the delivery of a hydride from the aluminium com-
plex to the β-position from the less hindered exo side
would trigger consecutive double-bond migration and
elimination to furnish ester 3. This mechanism well ex-
plains the selective formation of 3 as the endo product as
well as the origin of the C-2 hydrogen, which, as we see,
would be hardly explained without considering the partic-
ipation of the ester group.
PO(OEt)2
or
H
CH2OH
CH2OPO(OEt)2
LiAlH4, CH2Cl2–THF (1:1)
r.t., 3 h
1
H
+
2
+
recovered 1
AlH3
CO2Et
3
O
P
LiAlH4
AlH3
AlH3
O
P
_
1
H
H
H
H
LiAlH4 (1 equiv)
LiAlH4 (2 equiv)
23%
48%
65%
5%
19%
CO2Et
EtO
O
Scheme 2 Evaluation of effect of amount of LiAlH4
H
H
Al
H
Al
H
H
O
O
H
To investigate the mechanism in a more direct manner, we
further conducted an isotopic labeling experiment with
LiAlD4. Interestingly, the reaction furnished compound 4
incorporated by three deuterium atoms at C-2 and C-8 po-
sitions as the single endo isomer (Scheme 3). In compari-
– H2POAlH2
H
H
P
3
P
H
H
O
O
EtO
EtO
Scheme 4 Proposed mechanism for dephosphonylation
1
son of its H NMR spectrum with that of 2, the original
signals of the C-2 methine proton at δ = 2.34–2.25 ppm
and the C-8 methylene protons at δ = 3.40 and 3.26 ppm
disappeared, while the splitting pattern of the C-3 endo
proton at δ = 0.53 ppm changed from ddd (J = 11.6, 4.4,
2.6 Hz) into dd (J = 11.6, 2.6 Hz). On its 13C NMR spec-
trum, the C-2 and C-8 peaks at δ = 41.0 and 65.7 ppm
were, respectively, displayed as a triplet (J = 20.1 Hz) and
a quintet (J = 21.6 Hz) resulting from the splitting by the
deuterium nucleus. We also observed that the aqueous
workup of the reaction with LiAlH4 (1 equiv) by D2O did
not give any deuterium-labeled product but afforded 3 in
25% yield, plus 61% of recovered 1. These results demon-
strate that the hydrogen source of the resultant new C–H
bond comes from LiAlH4 instead of protic solution, which
In an attempt to further clarify the role of the carboxylate
moiety, we also synthesized norbornenyl phosphonate 511
through the cycloaddition of diethyl vinylphosphonate12
with cyclopentadiene and allowed it to react with LiAlH4
under the developed conditions. In the absence of the car-
boxylate group, the reaction merely followed the reduc-
tive pattern of normal phosphonates6 to give the formation
of phosphine 613 (Scheme 5), thus again validating the
crucial role that the carboxylate group played on the de-
phosphonylation. Furthermore, it is noteworthy that at
least six equivalents of LiAlH4 were required to ensure a
regular formation of 2, and the use of less amounts, for ex-
Synlett 2012, 23, 863–866
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Dephosphonylation of β-Phosphonyl Esters
865
ample, four or five equivalents, usually led to the incon- THF, v/v) (Table 2, entries 2 and 6).17 As such, both sol-
sistent yields.
vent systems (CH2Cl2–THF = 1:1 and 2:1) are suggested
to be practically attempted.
PO(OEt)2
Table 2 LiAlH4-Promoted Reductive Dephosphonylation of α,α-Di-
alkyl Triethyl β-Phosphonyl Esters
LiAlH4 (6 equiv)
CH2Cl2–THF (1:1)
toluene, reflux, 21 h
13%
+
1
H
H
r.t., 2 h
H
H
H
R2
LiAlH4 (6 equiv), CH2Cl2–THF, r.t.
12 or 7 h
HO
PO(OEt)2
PH2
5
6
7a–g
R1
8a–g
Scheme 5 Preparation and reduction of phosphonate 5 by LiAlH4
Entrya
1b
Yield (%)d
Substrate
Product 8
8a R1 = R2 = 4-pentenyl
After completing the mechanistic study, we then turned
our attention to exploring the synthetic utility of the new
protocol. The generation of compounds with the con-
trolled creation of an alkylated carbon center is of consid-
erable use in synthetic chemistry with numerous
approaches having been developed to attend this goal.14
For example, the synthetic sequence involving the regi-
oselective alkylation of β-keto esters followed by the hy-
drolysis and decarboxylation has been realized as a useful
strategy for preparing the alkylated ketones in a regiocon-
trolled manner.14b In light of the efficient formation of 2,
we envisioned that the combination of the selective alkyl-
ation of a phosphonoacetate with the reductive dephos-
phonylation would provide a convenient entry into
primary alcohols bearing a controllable β secondary car-
bon center. To demonstrate this, we first carried out the al-
kylation on triethyl phosphonoacetate with a range of
selected alkylating agents including 5-bromo-1-pentene,
1,5-dibromopentane,15 1,6-dibromohexane, 1-iodopro-
pane, allyl bromide, 4-bromo-1-butene, iodoethane,16
benzyl bromide, iodomethane, 2-(bromomethyl)naphtha-
lene, and iodocyclohexane to synthesize substrates 7a–h
(Scheme 6). The good anion-stabilizing capability of the
phosphonyl moiety1 allowed the alkyl groups to be conve-
niently introduced either in a single step to afford 7a–c, or
in a stepwise manner to give the unsymmetrically substi-
tuted precursors 7d–h. Upon the treatment with LiAlH4 in
CH2Cl2–THF in a 1:1 ratio, most of the substrates (7a, c–
e,g,h) were smoothly converted into the expected alcohols
(8a,c–e,g,h) in synthetically useful yields (52–77%,
Table 2, entries 1, 3–5, 7, and 8) except for 7b and 7f, and
from which, the desired products 8b and 8f were only pro-
duced in 31% and 26% yield, respectively. Nevertheless,
the better conversions (60% and 41%) were obtained with
changing the ratio of the co-solvent into 2:1 (CH2Cl2–
7a
7b
7c
7d
7e
7f
52
60
2c
8b R1 = R2 = (CH2)n, n = 5
8c R1 = R2 = (CH2)n, n = 6
8d R1 = n-Pr, R2 = All
3b
67
70
60
41
69
77
4b
5b
8e R1 = n-Pr, R2 = 3-butenyl
8f R1 = Et, R2 = Bn
6c
7b
8g R1 = 2-naphthyl, R2 = Me
8h R1 = Et, R2 = cyclohexyl
7g
7h
8b
a Reactions of 7a,c–h were conducted for 12 h, whereas reaction of
7b was performed for 7 h at r.t.
b CH2Cl2–THF in a ratio of 1:1 (v/v) was used.
c CH2Cl2–THF in a ratio of 2:1 (v/v) was used.
d Isolated yield.
As compared with 1, we also noted that much longer times
(7–12 h) were required for these precursors, especially for
the acyclic phosphonates, to attend the completion of the
reactions. In accordance with our proposed mechanism
(Scheme 4), we postulate that the rigid bicyclic skeleton
of 1 can force the carbonyl and the phosphonyl groups to
inherently stay in a co-plane during the transition state, to
therefore facilitate the formation of the proposed cyclic
intermediate. For the acyclic precursors, however, only
the eclipsed intermediary conformer (Figure 1) can
achieve the co-planarity to form the cyclic oxaphosphet-
ane intermediate. We think that the higher energy level as-
sociated with this conformation should account for longer
reaction times observed for these substrates.
R1
H
H
R2
P
RX, t-BuOK, DMSO
EtO2C
R1
PO(OEt)2
R2
CO Et
O
2
EtO2CCH2PO(OEt)2
or RX, NaH, THF
Figure 1 Eclipsed intermediary conformer required for reaching the
cyclic intermediate
7a R1 = R2 = 4-pentenyl, 81%
7b R1 = R2 = -(CH2)n-, n = 5, 70%
7c R1 = R2 = -(CH2)n-, n = 6, 23%
7d R1 = n-Pr, R2 = allyl, 84%
7e R1 = n-Pr, R2 = 3-butenyl, 88%
7f R1 = Et, R2 = Bn, 95%
In summary, we have disclosed a novel LiAlH4-promoted
reductive dephosphonylation operation18 on β-phospho-
nyl esters. Substantive evidences have been provided to
support that the dephosphonylation should occur first with
the assistance of the carboxylate group and LiAlH4 is the
hydrogen source of the resultant new C–H bond, which
7g R1 = 2-naphthyl, R2 = Me, 83%
7h R1 = Et, R2 = cyclohexyl, 31%
Scheme 6 Preparation of α,α-dialkyl triethyl β-phosphonyl esters
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 863–866

866
J.-L. Zhu et al.
LETTER
(10) For characterization of 3, see: Fringuelli, F.; Girotti, R.;
Pizzo, F.; Vaccaro, L. Org. Lett. 2006, 8, 2487.
(11) The endo stereochemistry of 5 was assigned on the basis of
2D NOESY experiments as well as the coupling constant of
the C-1 signal on the 13C NMR spectrum (δ = 43.6 ppm,
3JP–C = 0 Hz), see: Defacqz, N.; Touillaux, R.; Tinant, B.;
Declercq, J.-P.; Peeters, D.; Marchand-Brynaert, J. J. Chem.
Soc., Perkin Trans. 2 1977, 1965.
(12) Krawczyk, H.; Albrecht, L. Synthesis 2005, 2887.
(13) Compound 6 was found to be extremely air-sensitive and
decomposed quickly upon usual workup and purification.
Only the IR, 31P (δ = –115.4 ppm) and 1H NMR spectra of
the crude products were obtained. For the instability of
similar type of phosphines, see: Lasne, M. C.; Ripoll, J. L.;
Thuillier, A. J. Chem. Soc., Perkin Trans. 1 1988, 99.
(14) (a) House, H. O. In Modern Synthetic Reaction, 2nd ed.;
W. A. Benjamin, Inc: New York, 1972, 492–628. (b) Carey,
F. A.; Sundberg, R. J. In Advanced Organic Chemistry, 4th
ed., Part B; Plenum Press: New York, 2000, 13–15.
(15) Nasser, J.; About-Jaudet, E.; Collignon, N. Phosphorus,
Sulfur Silicon Relat. Elem. 1990, 171.
make our procedure to be unique to previously reported
dephosphonylation methods. Moreover, the convenient
preparation of a variety of primary alcohols from readily
accessed α,α-dialkyl β-phosphonyl esters in a controllable
fashion has further underscored the value of the protocol.
Acknowledgment
Financial support from NSC in Taiwan (ROC) are greatly acknowl-
edged.
References and Notes
(1) Savignac, P.; Iorga, B. In Modern Phosphonate Chemistry;
CPR Press: London, 2003, 217-375.
(2) Liao, C. C.; Zhu, J. L. J. Org. Chem. 2009, 74, 7873.
(3) For characterization of 2, see: Driver, T. G.; Franz, A. K.;
Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 6524.
(4) We previously observed that treatment of 1 with DIBAL-H
in toluene or Li(t-BuO)3AlH in THF did not cause the
dephosphonylation but only afforded the phosphono
aldehyde.
(16) Stritzke, K.; Schulz, S.; Nishida, R. Eur. J. Org. Chem. 2002,
3884.
(17) Such solvent effect was not observed for other substrates.
(18) Formation of 2 (Table 1, Entry 4) as a Typical Procedure
for the LiAlH4-Mediated Reductive Dephosphonylation
To a stirred suspension of LiAlH4 (95%, 169 mg, 4.23
mmol) in dry CH2Cl2 (5 mL) and THF (5 mL) precooled at
0 °C in an ice bath, a solution of 1 (213 mg, 0.705 mmol) in
CH2Cl2–THF (5 mL, v/v = 1:1) was added dropwise in 2 min
via a syringe under a nitrogen atmosphere. The ice bath was
then removed and stirring was continued for an additional 2
h at r.t. The reaction mixture was recooled in an ice bath and
cautiously quenched with 5% NaOH aq solution (2 mL). The
resulting pale grey suspension was diluted with CH2Cl2 (30
mL) and successively washed with H2O (2 × 8 mL) and brine
(10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was purified by flash
chromatography on silica gel (hexane–EtOAc = 5:1) to
afford 66 mg (75%) of 2 with the NMR spectral data
agreeing well with the literature.3 1H NMR (400 MHz,
CDCl3): δ = 6.15 (dd, J = 5.7, 3.0 Hz, 1 H), 5.96 (dd, J = 5.7,
2.9 Hz, 1 H), 3.40 (dd, J = 10.4, 6.5 Hz, 1 H), 3.26 (dd,
J = 10.4, 8.9 Hz, 1 H), 2.93 (br s, 1 H), 2.81(br s, 1 H), 2.34–
2.25 (m, 1 H), 1.82 (ddd, J = 11.6, 9.2, 3.9 Hz, 1 H), 1.45
(dm, J = 8.2 Hz, 1 H), 1.27 (br d, J = 8.6 Hz, 2 H), 0.53 (ddd,
J = 11.6, 4.4, 2.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 137.5, 132.1, 66.5, 49.5, 43.6, 42.2, 41.7, 28.8.
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(6) (a) Cabioch, J. L.; Pellerin, B.; Denis, J. M. Phosphorus,
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Synlett 2012, 23, 863–866
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