Dephosphonylation of β-Keto phosphonates with LiAlH4

Full text of DOI:10.1021/jo951757p

J . Org. Chem. 1996, 61, 2199-2201
2199
Sch em e 1
Dep h osp h on yla tion of â-Keto P h osp h on a tes
w ith LiAlH4
J ong Eoun Hong, Won Suk Shin, Won Bum J ang, and
Dong Young Oh*
Department of Chemistry, Korea Advanced Institute of
Science and Technology, 373-1, Kusong-Dong, Yusong-gu,
Taejon, 305-701, Korea
sodium enolate with LiAlH4 in THF afforded the corre-
sponding ketone 2a in high yield as shown in Scheme
1.9
Received September 26, 1995 (Revised Manuscript Received
December 8, 1995)
This observation prompted us to elaborate a general
procedure for the preparation of regioselective R-alky-
lated ketones by the dephosphonylation of the substituted
â-keto phosphonates which can be prepared by commonly
used methods such as acylation of alkylphosphonate
anions9 and R- or γ-alkylation of â-keto phosphonates.10,11
The dephosphonylation reaction is rather general as
indicated in the Table 1.
â-Aryl-â-keto phosphonates 1a -d were completely con-
verted into the corresponding ketones without byproducts
(2a -d ). On the other hand, in the case of 1-monosubsti-
tuted-â-alkyl-â-keto phosphonates 1e-g the reaction gave
the corresponding ketones in high yields (2e-g) along
with a small amount of the corresponding alcohols
resulting from further reduction. Although complete
consumption of the starting materials was observed on
reaction of â-alkyl-â-keto phosphonates bearing no sub-
stituent at the R-carbon (1h -j), the reaction produced the
desired ketones 2h -j in lower yields than in the former
cases and side products which could not be identified.
Although the use of LiAlH4 in this process was successful,
further attempts to find mild and effective reductants for
compatibility of a variety of functional groups failed
under the same conditions as shown in Table 1 (LiBEt3H,
DIBAL-H, Li(t-BuO)3AlH).
In tr od u ction
â-Keto phosphonates1 involve a phosphonate group as
a regiocontrol element for the alkylation, such as â-keto
esters2 and â-keto sulfones3 which are useful synthetic
intermediates containing a temporary activating group
for preparation of regioselective R-alkylated ketones by
R-alkylation with subsequent defunctionalization. In
contrast to the significant number of applications of
â-keto esters and â-keto sulfones in this manner, the
method using â-keto phosphonates has not been studied
yet, due to the fact that dephosphonylation4 of â-keto
phosphonate is less known.
Although various methods or reagents5,6 have been
used to reduce a C-PV bond into a C-H bond, the known
chemical methods for C-PV cleavage are of limited
generality due to the unique substrate requirements.
Moreover, there is only one literature7 reference involving
about the C-P bond reduction of â-keto-1-phosphonato
esters analogous to â-keto phosphonates. Recently,
Denmark8 pointed out that there was no general method
for cleavage of the C-P bond in â-keto phosphonate.
Herein we report a new utility of â-keto phosphonates
as building blocks for synthesis of R-alkylated ketones
via dephosphonylation.
To gain insight about the reaction mechanism, we
carried out some experiments using â-keto phosphonates
as shown in Scheme 2.
When â-keto phosphonate 1a was treated with NaBH4
in ethanol, â-keto phosphonate 1a was smoothly con-
verted to the corresponding â-hydroxy phosphonate 3. In
the case of LiAlH4 in THF, the reaction afforded the
complicated mixture 4. On the other hand, the reaction
of â-keto phosphonate 5 involving no R-proton with
LiAlH4 gave cleanly the corresponding â-hydroxy phos-
phonate 6 without dephosphonylated product.
The results of these experiments suggested that de-
phosphonylation could occur via formation of the metal
enolate of â-keto phosphonate, and that the complicated
mixture 4 might be caused by the action of LiAlH4 as a
base as well as a reductant.
Resu lts a n d Discu ssion
We first observed the dephosphonylation of â-keto
phosphonate 1a when the reaction of â-keto phosphonate
(1) Wadsworth, W. S.; Emmons, W. D. J . Am. Chem. Soc. 1961, 83,
1733. Horner, L.; Hoffmann, H.; Wippell, H. G.; Klahre, G. Chem. Ber.
1959, 92, 2499. Horner, L.; Hoffmann, H.; Klink, W.; Ertel, H.; Toscano,
V. G. Chem. Ber. 1962, 95, 581. Wadworth, W. S. Org. React. (N.Y.)
1977, 25, 73.
(2) Krapcho, A. P. Synthesis 1982, 893.
(3) (a) Kinoshita, H.; Hori, I.; Oishi, T.; Ban, Y. Chem. Lett. 1984,
1517. (b) Kurth, M. J .; O’brien, M. J . J . Org. Chem. 1985, 50, 3846. (c)
Fujii, M.; Nakamura, K.; Mekata, H.; Oka, S.; Ohno, A. Bull. Chem.
Soc. J pn. 1988, 61, 495.
In order to investigate further the dephosphonylation
reaction, we carried out the following reactions. When
reduction of sodium enolate of â-keto phosphonate 1c
with LiAlD4 was followed by quenching with dilute H2-
SO4, the reaction afforded the ketone 2c containing no
deuterium. In the case of using LiAlH4 and deuterated
acid, the reaction gave the ketone 2c′13 containing two
deuteriums as shown in Scheme 3.
(4) To distinguish between “dephosphorylation” and “dephosphon-
ylation”, we use the term “dephosphonylation” as a limited meaning
of P-C bond cleavage in compound containing phosphonate groups.
(5) (a) Bestmann, H. J .; Schultz, H. Chem. Ber. 1962, 95, 2921. (b)
Okamoto, Y.; Iwamoto, N.; Takamuku, S. J . Chem. Soc., Chem.
Commun 1986, 1516. (c) Bestmann, H. J .; Graf, G.; Kolewa, S.;
Vilsmeier, E. Chem. Ber. 1970, 103, 2794. (d) Kondo, K.; Negishi, A.;
Tunemoto, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 407.
(6) Recently we reported that enamine phosphonates bearing R-sta-
bilized groups such as phenyl or thiophenyl gave the corresponding
deoxybenzoin or â-keto sulfides during basic hydrolysis. Oh, D. Y.; Lee,
K. Bull. Kor. Chem. Soc. 1991, 12, 254.
(7) In this case, it was reported as a notable result that during
attempted reductions of 2-oxo-1-phosphonato ester to corresponding
2-hydroxy-1-phosphonato ester with various reductants, Li(t-BuO)3AlH
among them cleaved selectively C-P bond to give the corresponding
â-keto ester. However, its mechanism and applications have not been
reported. Durrant, G.; Sutherland, J . K. J . Chem. Soc., Perkin Trans.
1 1972, 2582.
(9) (a) Honda, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett.
1984, 25, 3857. (b) Mikolajczyk, M.; Balczewski, P. Synthesis 1984,
691.
(10) Clark, R. D.; Kozar, L. G.; Heathcock, C. H. Synthesis 1975,
635.
(11) Grieco, P. A.; Pogonowski, C. S. Synthesis 1973, 425.
(12) n-BuLi was used instead of NaH as a base because the reaction
with NaH failed to form the enolate of 1j.
(8) Denmark, S. E.; Marlin, J . E.; J . Org. Chem. 1991, 56, 1003
0022-3263/96/1961-2199$12.00/0 © 1996 American Chemical Society

2200 J . Org. Chem., Vol. 61, No. 6, 1996
Ta ble 1. Dep h osp h on yla tion of Su bstitu ted â-Keto P h osp h on a tesa
Notes
entry
(substrate)
time,
h
yield,b,c
R
R′
products
%
1 (1a )
2 (1b)
3 (1c)
4 (1d )
5 (1e)
6 (1f)
7 (1g)
8 (1h )
H
H
Me
allyl
Ph
CH2Ph
cinnamyl
H
H
H
Ph
4-Cl-Ph
Ph
4-Cl-Ph
Me
Et
<0.2
<0.2
<0.2
<0.2
0.5
0.5
0.5
1
2a
2b
2c
2d
2e
2f
2g
2h
2i
98
97
96
97
89
91
87
57
72
65
Et
CH2CH2Ph
CH(CH3)CH2CHdCHPh
C(CH3)2CH2CHdCHPh
9 (1i)
1
1
10 (1j12
)
2j
d
a
b
All reactions run in THF and quenched with 10 N sulfuric acid. Yield of isolated, purified products. c Solvent was evaporated below
d
0 °C. n-BuLi used instead of NaH.
Sch em e 2
In conclusion, we have described the first general
example of dephosphonylation of â-keto phosphonates
with respect to its simplicity and efficiency. Also these
results suggest that the use of â-keto phosphonates as
precursors to R-alkylated ketones would complement
existing methods used to synthesize alkylated ketones
which use â-keto esters and â-keto sulfones.
Further studies on the mechanism and dephosphon-
ylation of other â-carbonyl phosphonates are in progress.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under an
atmosphere of nitrogen in oven-dried glassware with magnetic
stirring. THF was distilled from Na/benzophenone ketyl. 1H-
NMR spectra were recorded at 200 or 300 MHz in CDCl3 using
TMS or residual CHCl3 as internal references. Starting materi-
als 1a -1i were synthesized as described in the literature with
minor modification.10-12
Sch em e 3
Gen er a l P r oced u r e for Dep h osp h on yla tion of â-Keto
P h osp h on a te 1a . A solution of â-keto phosphonate 1a (0.256
g, 1 mmol) in anhydrous THF was added via syringe to a stirred
suspension of NaH and rinsed with hexane (0.027 g, 1.1 mmol)
in anhydrous THF at room temperature. After being stirred for
1 h, the resulting enolate was transferred into a stirred solution
of LiAlH4 (0.114 g, 3 mmol) in THF at room temperature and
stirred for 10 min. The mixture is quenched by transferring it
to aqueous 10 N sulfuric acid (10 mL). The solution was
extracted with diethyl ether (30 mL x 2). The organic phase
was washed with 5% aqueous NaHCO3 and water and then dried
over anhydrous MgSO4; the drying agent was filtered off, and
the filtrate was evaporated under reduced pressure at below 0
°C. The residue was purified by flash chromatography with
ethyl acetate/hexane (10/90) as eluent to give acetophenone (2a ,
0.118 g, 98%). 1H NMR (200 MHz,CDCl3) δ 7.97-7.91 (m, 2Η),
7.56-7.39 (m, 3H), 2.58 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
197.9, 136.9, 132.9, 121.3, 128.1, 26.3.
4-Ch lor oa cetop h en on e 2b: obtained as a colorless liquid
(0.150 g, 97%) from â-keto phosphonate 1b (0.291 g, 1 mmol).
Reduction time; 10 min. Purification by flash chromatography
(ethyl acetate/hexane 10/90). 1H NMR (200 MHz, CDCl3) δ
7.93-7.84 (m, 2H), 7.46-7.39 (m, 2H), 2.58 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 196.6, 139.3, 135.2, 129,5 128.7, 26.3.
P r op iop h en on e 2c: obtained as a colorless liquid (0.129 g,
96%) from â-keto phosphonate 1c (0.291 g, 1 mmol). Reduction
time; 10 min. Purification by flash chromatography (ethyl
acetate/hexane 10/90). 1H NMR (200 MHz ,CDCl3) δ 8.00-7.92
(m, 2H), 7.59-7.38 (m, 3H), 2.99 (q, J ) 7.3 Hz, 2H), 1.22 (t, J
) 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 206.6, 136.7, 132.6,
128.3, 127.7, 31.5, 8.0.
These results suggest that during the cleavage of the
P-C bond, the hydride does not attack the carbon atom
linked with phosphorus atom, and that after cleavage of
the P-C bond, the intermediate might have dianion
character.
(13) Analysis of 1H NMR and 13C NMR spectra indicated dideuter-
ated ketone as the major product along with
a small amount of
monodeuterated ketone (ca. mono:di ) 1:9). To investigate the pos-
sibility of H-D exchange reaction between D3O+ and ketone, the
following procedure was carried out.
1-(4-Ch lor op h en yl)-4-p en ten -1-on e (2d ): obtained as a
colorless liquid (0.189 g, 97%) from â-keto phosphonate 1d (0.331
g, 1 mmol). Reduction time; 10 min. Purification by flash
No deuterized ketone was observed. See supporting information.

Notes
J . Org. Chem., Vol. 61, No. 6, 1996 2201
chromatography (ethyl acetate/hexane 10/90). 1H NMR (200
MHz, CDCl3) δ 7.89 (d, J ) 8.4 Hz, 2H), 7.42 (d, J ) 8.4 Hz,
2H), 5.97-5.81 (m, 1H), 5.13-4.98 (m, 2H), 3.04 (t, J ) 7.3 Hz,
2H), 2.53-2.43 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 198.0 139.2,
136.9, 135.1, 129.3, 128.7, 128.4, 127.9, 115.3, 37.5, 29.5, 27.9;
EIMS m/ e 194 (M+, 2.1), 141 (41), 139 (100), 113 (10), 111 (24),
75 (7).
1-P h en yl-2-p r op a n on e (2e): obtained as a colorless liquid
(0.132 g, 89%) from â-keto phosphonate 1e (0.284 g, 1 mmol).
Reduction time; 30 min. Purification by flash chromatography
(ethyl acetate/hexane 10/90). 1H NMR (300 MHz, CDCl3) δ
7.31-7.17 (m, 5H), 3.66 (s, 2H), 2.10 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 205.9, 134.0, 129.0, 128.3, 126.6, 50.5, 28.6; EIMS m/ e
134 (M+, 7), 121 (4), 111 (5), 107 (6), 106 (10), 105 (100), 91 (8),
77 (22), 43 (5).
1-P h en yl-3-p en ta n on e (2f): obtained as a colorless liquid
(0.147 g, 91%) from â-keto phosphonate 1f (0.298 g, 1 mmol).
Reduction time; 40 min. Purification by flash chromatography
(ethyl acetate/hexane 10/90). 1H NMR (200 MHz, CDCl3) δ
7.23-7.12 (m, 5H), 2.91-2.82 (m, 2H), 2.72-2.63 (m, 2H) 2.35
(q, J ) 7.3 Hz, 2H), 1.01 (t, J ) 7.3 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 210.1, 140.9, 128.1, 128.0, 125.7, 43.5, 35.7, 29.5, 7.4;
EIMS m/ e 162(M+, 59), 141 (12), 139 (25), 133 (45), 106 (10),
105 (100), 91 (60), 79 (10), 77 (16).
1-P h en yl-1-h ep ten -5-on e (2g): obtained as a colorless liquid
(0.164 g, 87%) from â-keto phosphonate 1g (0.324 g, 1 mmol).
Reduction time; 35 min. Purification by flash chromatography
(ethyl acetate/hexane 10/90). 1H NMR (200 MHz,CDCl3) δ 7.34-
7.17 (m, 5H), 6.39 (d, J ) 15.9 Hz, 1H), 6.17 (dt, J ) 15.8, 6.3
Hz 1H), 2.60-2.37 (m, 6H), 1.05 (t, J ) 7.3 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 210.5, 137.3, 130.5, 128.9, 128.3, 126.9, 125.8,
41.7, 35.9, 27.0, 7.6; EIMS m/ e 188 (M+, 69), 159 (30), 131 (57),
130 (14), 129 (39), 128 (26), 117 (100), 104 (21), 91 (72), 57 (21).
1-P h en yl-3-bu ta n on e (2h ): obtained as a colorless liquid
(0.084 g, 57%) from â-keto phosphonate 1h (0.284 g, 1 mmol).
Reduction time; 1 h. Purification by flash chromatography (ethyl
acetate/hexane 10/90). 1H NMR (200 MHz, CDCl3) δ 7.30-7.17
(m, 5H), 2.93-2.69 (m, 4H), 2.11 (s, 3H);13C NMR (50 MHz,
CDCl3) δ 207.7, 140.9, 128.4, 128.1, 126.0, 45.0, 29.9, 29.6; EIMS
m/ e 148 (M+, 100), 133 (22), 115 (11), 105 (88), 91 (58), 77 (18),
65 (6), 51 (5).
CDCl3) δ 7.34-7.17 (m, 5H), 6.39 (d, J ) 15.8 Hz, 1H), 6.09 (dt,
J ) 15.7, 7.0 Hz, 1H), 2.68-2.45 (m, 2H), 2.29-215 (m, 1H),
2.12 (s, 3H), 1.11 (d, J ) 6.8, 3H); 13C NMR (50 MHz, CDCl3) δ
211.5, 137.1, 131.8, 128.3, 127.1, 127.0, 125.8, 46.8, 35.9, 28.2,
15.8; EIMS m/ e 188 (M+, 26), 173 (6), 145 (28), 129 (17), 117
(100), 104 (22), 97 (17), 91 (46), 43 (9).
5,5-Dim eth yl-1-p h en yl-1-h exen -5-on e (2j): obtained as a
colorless liquid (0.132 g, 72%) from â-keto phosphonate 1j (0.338
g, 1 mmol). n-BuLi (0.7 mL, 1.6 N solution, 1.1 mmol) was used
to form enolate instead of NaH. Reduction time; 1 h. Purifica-
tion by flash chromatography (ethyl acetate/hexane 10/90). 1H
NMR (200 MHz, CDCl3) δ 7.34-7.14 (m, 5H), 6.38 (d, 1H), 6.06
(dt, 1H), 2.39 (dd, J ) 7.4, 1 Hz, 2H), 2.14 (s, 3H), 1.15 (s, 6H);
13C NMR (50 MHz, CDCl3) δ 213.3, 137.2, 133.0, 128.4, 127.1,
126.1, 125.7, 48.1, 43.0, 25.3, 24.2.; EIMS m/ e 202 (M+, 9), 188
(5), 117 (100), 105 (6), 91(21), 77(3).
Red u ction w ith LiAlD4 in Sch em e 3. According to the
general procedure described above, the corresponding enolate
of â-keto phosphonate 1c (1 mmol) was transferred into a stirred
solution of LiAlD4 (0.126 g, 3 mmol) in THF at room temperature
and stirred for 10 min. Normal workup was followed. The
resulting ketone is identical with 2c (0.124 g, 92%).
Qu en ch in g w ith Deu ter a ted Acid in Sch em e 3. Accord-
ing to general procedure described above, the corresponding
enolate of â-keto phosphonate 1c (1 mmol) was transferred into
a stirred solution of LiAlH4 (0.114 g, 3 mmol) in THF at room
temperature and stirred for 10 min. The mixture is quenched
by transferring it to 30% AcOD in D2O (20 mL). Normal workup
gave R,R-d2-Propiophenone 2c′ (0.095 g, ca. mono:di ) 1:9, 70%).
1H NMR (200 MHz, CDCl3) δ 7.97-7.93 (m, 2H), 7.54-7.44 (m,
3H), 1.20 (br s, 3H); 13C NMR (50 MHz, CDCl3) δ 200.8, 136.8,
132.7, 128.4, 127.8, 30.9 (quintet, J C-D ) 19.0 Hz).
Ack n ow led gm en t. This research was supported by
Korea Science and Engineering Foundation (KOSEF).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds in Table 1 and Scheme 3 (21
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of
the journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
5-Meth yl-1-p h en yl-1-h exen -5-on e (2i): obtained as a color-
less liquid (0.136 g, 72%) from â-keto phosphonate 1I (0.324 g,
1 mmol). Reduction time; 1 h. Purification by flash chroma-
tography (ethyl acetate/hexane 10/90). 1H NMR (200 MHz,
J O951757P