In situ formation of allyl ketones via Hiyama-Nozaki reactions followed by a chromium-mediated Oppenauer oxidation

Article abstract of DOI:10.1021/jo001750u

In Hiyama-Nozaki reactions of allylchromium with aldehydes the expected products are homo-allylalcohols. However, oxidation products derived from these, predominantly allyl ketones, can be common side products. This can be explained by an Oppenauer-(Meerwein-Ponndorf-Verley)-type mechanism (OMPV-reaction). The amount of oxidation is strongly dependent on the substitution pattern of the reaction partners and the reaction conditions. An appropriate choice of these can lead to preferential formation of ketones instead of the alcohols. In addition to its synthetic usefulness, the oxidation-reduction equilibrium is of the utmost importance for the design of enantioselective Hiyama-Nozaki reactions because it is also a potential racemization pathway.

Full text of DOI:10.1021/jo001750u

VOLUME 67, NUMBER 7
APRIL 5, 2002
© Copyright 2002 by the American Chemical Society
Articles
In Situ F or m a tion of Allyl Keton es via Hiya m a -Noza k i Rea ction s
F ollow ed by a Ch r om iu m -Med ia ted Op p en a u er Oxid a tion
Henri S. Schrekker,† Martin W. G. de Bolster, Romano V. A. Orru, and
Ludger A. Wessjohann*,†
Faculty of Sciences, Chemistry Division, Department of Organic and Inorganic Chemistry,
Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
wessjohann@ipb-halle.de
Received December 15, 2000
In Hiyama-Nozaki reactions of allylchromium with aldehydes the expected products are homo-
allylalcohols. However, oxidation products derived from these, predominantly allyl ketones, can be
common side products. This can be explained by an Oppenauer-(Meerwein-Ponndorf-Verley)-
type mechanism (OMPV-reaction). The amount of oxidation is strongly dependent on the substitution
pattern of the reaction partners and the reaction conditions. An appropriate choice of these can
lead to preferential formation of ketones instead of the alcohols. In addition to its synthetic
usefulness, the oxidation-reduction equilibrium is of the utmost importance for the design of
enantioselective Hiyama-Nozaki reactions because it is also a potential racemization pathway.
In tr od u ction
Instead, the reactions of these vinylogous substrates
seem to proceed via a typical allylchromium Hiyama-
Nozaki pathway.1,8 The reaction of some allylic halides
with chromium(II) and benzaldehyde, especially that of
dimethylallyl bromide, resulted in considerable formation
of the corresponding allyl ketone instead of the expected
homoallyl alcohol (Scheme 1).8,9 Allyl ketone formation
was also observed by Mulzer10 as a byproduct. He
suggested that an Oppenauer-type oxidation of the chro-
mium(III) alkoxide intermediate was responsible for this
behavior. The simultaneous presence of an alkoxide, an
aldehyde, and a multivalent metal ion (as a potent Lewis
acid) together with the exclusion of oxygen suggests
optimal conditions for an Oppenauer-type oxidation
Chromium(II)-mediated reactions such as the Hiyama-
Nozaki, the Takai-Utimoto-Kishi, or the chromium-
Reformatsky reaction have become popular in total
syntheses of natural products due to the mild conditions,
excellent chemoselectivity, and predictable stereoselec-
tivity.1,2 During our studies on the chromium-Reformat-
sky reaction, we observed that especially 1-halo crotonate
esters do not react via the usual enolate intermediate.3-7
* Corresponding author.
† New address: Institute of Plant Biochemistry, Weinberg 3,
D-06120 Halle (Saale), Germany. Fax: ++49 (345) 5582-1309.
(1) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1-36.
(2) Fu¨rstner, A. Chem. Rev. 1999, 99, 991-1045.
(3) Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38, 1363-
1366.
(8) Wessjohann, L.; Mu¨hlbauer, A. In 24. GDCh-Hauptversammlung
Hamburg; GDCh, Ed.; VCH: Weinheim, 1993; p 502.
(9) Wessjohann, L. Habilitation Thesis, Ludwig-Maximilians-Uni-
versita¨t Mu¨nchen, Germany, 1998.
(10) Maguire, R. J .; Mulzer, J .; Bats, J . W. Tetrahedron Lett. 1996,
37, 5487-5490.
(4) Wessjohann, L.; Gabriel, T. J . Org. Chem. 1997, 62, 3772-3774.
(5) Wessjohann, L.; Wild, H. Synthesis 1997, 512-514.
(6) Wessjohann, L.; Wild, H. Synlett 1997, 731-733.
(7) Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38, 4387-
4388.
10.1021/jo001750u CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/13/2002

1976 J . Org. Chem., Vol. 67, No. 7, 2002
Schrekker et al.
Ta ble 1. Op tim iza tion of th e Hiya m a -Noza k i Rea ction
w ith Su bsequ en t (in Situ ) Op p en a u er Oxid a tion of
P r en ylbr om id e 1a (R1 ) CH3, R2 ) CH3, X ) Br ) w ith
Ben za ld eh yd e 2a (R3 ) H)f]
Sch em e 1
rel yield rel yield rel yield
ratio
LiI
t
ketone alcohol
ester
conv.
entry 1a :2a (mol %) (h) 3a (%)
4a (%) 5a (%)a (%)b
1
2
3
4
5
6
1.1:1.0
1.1:1.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:3.0
1.0:3.0
1.0e:3.0
0
25
0
10
0
10
0
0
3
3
3
3
6
6
3
3
3
37
34
82
81
81
79
83
67d
69e
37
49
13
15
14
13
8
0c
0c
5
4
5
8
9
10
12
78
65
78
79
78
66
85
95d
71e
7
8d
9e
23
19
0
a
The MS degradation pattern of 5a is in accordance with that
Sch em e 2
b
of other Tishchenko products such as 5j. Conversion to products
based on 2a (entries 1 and 2) or 1a (entries 3-8). The ratio of
oxidized products to benzyl alcohol [(3a + 5a ):6a ] was in all cases
(1.0-1.8):1.0. c Formation of small amounts of an unidentified
d
alcohol. Reaction at 55 °C, cooled to 0 °C, then quenched at 0
°C. e Dimethylallyl chloride 1b was used instead of dimethylallyl
bromide 1a . f T ) 55 °C, quenched at 55 °C [except entry 8,
quenched at 0 °C, and entry 9, 1b (R1 ) CH3, R2 ) CH3, X ) Cl)
instead of 1a .
formed stereocenter is scrambled through such a process,
and the development of asymmetric versions of the
Hiyama-Nozaki reaction would be severely hampered.
So far, the development of asymmetric versions has
proven to be troublesome, and only a few examples have
been reported.1,15-17 On the other hand, OMPV equilibria
would provide evidence for significant ligand exchange,
which may occur either at Cr(III) or equally well at Cr-
(II) centers as was discussed previously and which is a
prerequisite for catalytic versions of Hiyama-Nozaki
reactions.1,2,18 In addition, the possible formation of the
ketone instead of the expected alcohol has consequences
for the strategic planning of complex total syntheses.
These considerations prompted us to look more closely
into the relationship between Hiyama-Nozaki reactions
and OMPV transformations. Here, we wish to report the
results of this study and discuss the merits of this
potentially useful reaction.
Resu lts a n d Discu ssion
To test if an OMPV equilibrium (Scheme 2a) is
responsible for the formation of allyl ketones in Hiyama-
Nozaki reactions, the reaction of dimethylallyl bromide
(prenylbromide) 1a with benzaldehyde 2a was studied
in more detail (Scheme 1). All reactions were performed
under similar conditions (55 °C, THF) using 2.5 equiv of
chromium(II) chloride. Only the relative amount of the
hydrogen acceptor, benzaldehyde 2a , and the reaction
time and lithium iodide as the modifier were varied. The
results are summarized in Table 1. They clearly show
the formation of up to 83% (relative) of allyl ketone 3a
and a minor amount of homoallyl ester 5a next to the
Hiyama-Nozaki product 4a . When the molar ratio of
allylbromide 1a to aldehyde 2a is decreased (entries 1
reaction, which is based on a hydride transfer from the
alkoxide ion to a carbonyl compound.11 The reaction is
reversible, and thus, depending on the conditions, the
backward reaction, the Meerwein-Ponndorf-Verley re-
duction, should also be possible (Scheme 2a).12 Indeed,
such a reduction of aldehydes and ketones to alcohols in
a similar chromium-mediated reaction, using sec-Bu-
CrCl2, was reported.13 This reduction was explained by
assuming a transition state quite similar to that accepted
for the Oppenauer-Meerwein-Ponndorf-Verley (OMPV)
equilibrium reaction.14
The implications of an OMPV oxidation-reduction
equilibrium of the chromium alcoholate formed in Hiya-
ma-Nozaki reactions are quite dramatic. The newly
(11) Hudlicky´, M. Oxidations in Organic Chemistry; American
Chemical Society: Washington, DC, 1990.
(12) de Graauw, C. F.; Peters, J . A.; van Bekkum, H.; Huskens, J .
Synthesis 1994, 1007-1017.
(13) Kauffmann, T.; Beirich, C.; Hamsen, A.; Mo¨ller, T.; Philipp, C.;
Wingbermu¨hle, D. Chem. Ber. 1992, 125, 157-162.
(14) A CH2-Cr(III) intermediate is present instead of an O-Cr(III)
intermediate; see ref 13.
(15) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Angew. Chem. 1999, 111, 3558-3561.
(16) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Angew. Chem.
2000, 112, 2417-2420.
(17) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1997,
62, 2322-2323.
(18) Parris, M.; Ashbrook, A. W. Can. J . Chem. 1979, 57, 1233-
1237.

In Situ Formation of Allyl Ketones
J . Org. Chem., Vol. 67, No. 7, 2002 1977
Ta ble 2. Op tim iza tion of th e Hiya m a -Noza k i Rea ction
of P r en ylbr om id e 1a (R1 ) CH3, R2 ) CH3, X ) Br ) w ith
Ben za ld eh yd e 2a (R3 ) H, 1a :2a ) 1.1:1.0) tow a r d a
Min im iza tion of Op p en a u er Oxid a tion P r od u cts
vs 3 and 7), more of the oxidized products, allyl ketone
3a and homoallyl ester 5a , relative to the homoallyl
alcohol 4a were formed. As expected from OMPV equi-
librium reactions, higher concentrations of the hydrogen
acceptor (aldehyde) give more of the oxidized products
(3a + 5a ), up to 92% (relative). The formation of homo-
allyl ester 5a as a byproduct can be explained by
assuming a Tishchenko reaction (Scheme 2b), known to
accompany Oppenauer oxidations.12
In most cases, a nearly 1:1 relationship of oxidized
products (3a + 5a ) to benzyl alcohol 6a was observed, as
expected from theory.19 The OMPV mechanism (Scheme
2a) nicely accounts for these observations. Finally, it
should be mentioned that extension of the reaction time
(3 f 6h) at 55 °C (entries 3-6) did not result in more of
the OMPV product 3a or the Tishchenko product 5a . On
the other hand, when the reaction was performed as
usual at 55 °C but cooled to 0 °C for quenching (entry 8
vs entry 7), significantly less oxidation product was
formed. These experiments demonstrate the temperature
dependence of the oxidation reaction and its reversibility,
and they also suggest that an equilibrium is reached
already within 3 h. All this is in accordance with the
suggested mechanisms of Scheme 2.
To direct the chemoselectivity of the chromium(II)-
mediated reaction toward either the OMPV product 3a
or the Hiyama-Nozaki product 4a , optimal conditions
for each case were explored. The oxidation processes
(Oppenauer and Tishchenko, Scheme 2) are highly
favored using excess benzaldehyde. In this way, more
than 90% of oxidized products (3a + 5a ; 83% of 3a ) could
be formed when 3 equiv of benzaldehyde 2a was em-
ployed (Table 1, entry 7). The addition of LiI, which
enhances the solubility of the chromium(II) complex and
increases the reaction rate in THF, showed no significant
effect on the chemoselectivity toward allyl ketone 3a
(Table 1, entries 2, 4, and 6).1,4,9 The use of the cheaper
allyl chloride 1b (Table 1, entry 9) instead of allyl bromide
1a resulted in a lower chemoselectivity toward allyl
ketone 3b (3b ) 3a ) and a lower conversion. Because
allylbromides suffer some bromine-chlorine exchange
with the chloride counterion of chromium(II), the amount
of OMPV oxidation can probably be increased further by
using chromium(II) bromide instead of chromium(II)
chloride.9
Because the Hiyama-Nozaki reaction is frequently
used for the diastereoselective synthesis of homoallyl
alcohols in total syntheses of complex products, it is
important to establish reliable conditions for a chemose-
lective reaction toward the expected homoallyl alcohol 4a .
Table 2 summarizes some experiments toward this goal,
which proved to be less straightforward than the rather
automatic formation of ketone 3a . However, with a slight
excess of dimethylallyl bromide 1a , a reduced reaction
temperature (0 °C, entries 9-14), and reaction time (30
min, entries 13-14), more than 95% (relative) of the
products comprised homoallyl alcohol 4a (entry 13).
Unfortunately, this chemoselectivity could only be achieved
at the expense of a rather low conversion level of 36% of
2a (entry 13). Fortunately, under these conditions, the
addition of a catalytic amount of lithium iodide resulted
in the desired effect and gave some 90% (relative) of the
rel yield rel yield rel yield
LiI
(mol %)
t
T
ketone alcohol
ester
conv.
entry
(h) (°C) 3a (%)
4a (%) 5a (%)a (%)b
1
0
25
CrCl3/
3
3
2
55
55
22
37
34
4
37
49
84
0c
0c
0c
78
65
86
2
3d
d
LiAlH4
4d,e CrCl3/
LiAlH4
5
6
7
8
9
10
11
12
13
14
2
22
78e
16e
6
99
d,e
0
25
0
25
0
10
0
10
0
10
1.5 22
1.5 22
0.5 22
0.5 22
3
3
1.5
1.5
0.5
0.5
23
9
20
9
16
9
9
9
1
5
71
85
78
89
79
89
85
84
97
90
2c
0c
2
78
80
79
91
74
80
49
76
36
70
0c
5
0
0
0
0
0
0
2
6
5c
2
0c
a
The MS degradation pattern of 5a is in accordance with that
b
of other Tishchenko products such as 5j. Conversion based on
2a . Conversion of 1a is quantitative. The ratio of oxidized products
to benzyl alcohol [(3 + 5):6] was in all cases (1.0-2.2):1.0 except
for entry 3 (1:5). c Formation of traces of an unidentified alcohol.
d
No LiI addition. CrCl2 substituted by CrCl3/LiAlH4 (2:1) accord-
ing to ref 21. e Preincubation with benzaldehyde (4 equiv) to
remove residual active aluminum hydride, followed by dimethyl-
allyl bromide after 15 min.
Hiyama-Nozaki product 4a at an improved conversion
of 70% (entry 14). In general, addition of lithium iodide
(entries 2, 6, 8, 10, 12, and 14) resulted in higher
conversion levels and improved chemoselectivities toward
homoallyl alcohols when the reaction was run for a
shorter time and at a lower temperature.
At this point, it is important to note that the original
Hiyama-Nozaki procedure employs chromium(III) chlo-
ride and lithium aluminum hydride (LAH) in a 2:1 ratio
to generate, in situ, the low-valent chromium reagent.20,21
This reagent should behave similar to commercially
available pure chromium(II) chloride. But when the
reagent was applied, oxidation products were almost
completely absent (<5% of 3a + 5a , entry 3). Because
CrCl3 and LAH were used in a 2:1 molar ratio instead of
the stoichiometric 4:1 ratio, active aluminum hydride
species should still be present as a reductant in the
reaction mixture. This was also indicated by the low ratio
of oxidation products (3a + 5a ) to benzyl alcohol 6a of
approximately 1:5. Thus, the “in situ”-generated Cr(II)
species was allowed to stir first with a 4-fold excess of
benzaldehyde 2a for 15 min in order to destroy excess
active hydride, before the coupling partner 1a was added.
This resulted in a complete switch in chemoselectivity
(entry 4) compared to the reaction without prior elimina-
tion of reductive residues. Now, the oxidation products
were formed preferentially and the OMPV pathway
dominates again. These observations nicely demonstrate
that the OMPV equilibria in the original Hiyama-Nozaki
reactions were masked by the only partially reduced
LAH, which either removed excess benzaldehyde as an
oxidant directly or indirectly re-reduced the OMPV
product 3a to 4a . Another explanation for the reduction
(20) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J . Am. Chem.
Soc. 1977, 99, 3179-3181.
(21) Hiyama, T.; Okude, Y.; Kimura, K.; Nozaki, H. Bull. Chem. Soc.
J pn. 1982, 55, 561-568.
(19) Ratios of oxidized product to benzyl alcohols were typically
between (1.0-1.8):1.0. The higher ratios are probably due to the
volatility and loss of benzyl alcohol 6a during workup.

1978 J . Org. Chem., Vol. 67, No. 7, 2002
Schrekker et al.
Sch em e 3
Ta ble 3. In flu en ce of Su bstitu en ts R1 a n d R2 of th e
Allylic Br om id e 1 on th e Exten t of Allyl Keton e
F or m a tion (R3 ) H, 1:2a ) 1.0:3.0, T ) 55 °C, t ) 3 h )
may also be the presence of excess or re-formed reductive
Cr(II) complexes.22
After studying the easily modifiable physical param-
eters and the influence of additives that guide the
reaction toward alcohol or ketone products, it seemed
useful to explore the steric and electronic effects of
substituents and reagents.
rel yield rel yield rel yield
substrate
ketone alcohol
ester
conv.
(%) b
entry
1
3 (%)
4 (%)
5 (%) a
1
2
3
c: R1 ) H, R2 ) H
d : R1 ) CH3, R2 ) H
a : R1 ) CH3,
<2
74
83
>98
24c
8
<2
2
9
quant.
85
85
First, the influence of substituents at the γ-position
(R1 and R2, 1a and 1c-e) of allylic bromide upon the
chromium(II)-mediated coupling with benzaldehyde 2a ,
was studied (Scheme 3, Table 3). All reactions were
performed under similar conditions (55 °C, THF, 3 h)
using allyl bromides 1 and benzaldehyde 2a in a molar
ratio of 1:3 and 2.5 equiv of chromium(II) chloride. The
results are summarized in Table 3. Only traces of
oxidation products 3c and 5c, compared to Hiyama-
Nozaki product 4c, were detected when unsubstituted
allylbromide 1c (R1 ) R2 ) H, entry 1) was used. Reaction
of the crotylbromide 1d (R1 ) H, R2 ) CH3, entry 2)
resulted in a dramatic increase in oxidation toward allyl
ketone 3d relative to the Hiyama-Nozaki product 4d .
The relative yield of allyl ketone 3 could be further
improved by the use of the sterically even more demand-
ing allylbromides 1a (R1 ) R2 ) CH3, prenylbromide,
entry 3) and 1e (geranylbromide, entry 5), but the effect
of the second substituent was less dramatic. Thus, it is
likely that steric bulk is required, either at the γ-position
as shown here or at the â-position as observed by
Mulzer,10 to promote oxidation to allyl ketones 3. On a
R2 ) CH3
4
e: geranyl bromide
89
11
0
72
a
The MS degradation pattern is in accordance with that of other
b
Tishchenko products such as 5j. Conversion to products based
on 1a . The ratio of oxidized products to benzyl alcohol [(3 + 5):6]
was in all cases (1.0-1.1): 1.0. c Exclusive formation of the anti-
diastereomer (anti-4d ).
speculative basis, two explanations can be given for this
steric effect. First, the coordination strength of the
alcoholate to chromium(III) might be important and
reduced due to steric strain, thus allowing a faster ligand
exchange for the OMPV reaction to proceed. Second,
stabilization of transition state 8 (Scheme 2a, with a
developing π-orbital at the homoallylic position) might
play a role, either through hyperconjugative effects or
by Cr chelation of the vinyl group, brought into the right
position through a Thorpe-Ingold effect of the substit-
uents R1 and R2 (i.e., CH3, CH3 in 8a ). With 1-phenyl-
ethynylbromide as a substrate that is lacking the vinyl
group altogether, no ketone formation was observed.
These results are not only important for the scope of
the Hiyama-OMPV reaction but also give a better
insight into the development of enantioselective Hiyama-
Nozaki reactions. Interestingly, enantioselective transfer
(22) Gyarmati, J .; Hajdu, C.; Dinya, Z.; Micskei, K.; Zucchi, C.; Palyi,
G. J . Organomet. Chem. 1999, 586, 106-109.

In Situ Formation of Allyl Ketones
J . Org. Chem., Vol. 67, No. 7, 2002 1979
Ta ble 4. R3-Su bstitu en t Effects of th e Ben za ld eh yd e
Rea cta n t a n d Oxid a n t 2 on th e Exten t of Allyl Keton e
F or m a tion (R1 ) CH3, R2 ) CH3, X ) Br , 1a :2 ) 1.0:3.0,
T ) 55 °C, t ) 3 h )
extent. The effect is so small that it can be concluded
that both steric and electronic effects of substituents at
the para position of benzaldehyde have only a minor,
almost negligible, destabilizing effect on the required
transition states (Oppenauer oxidation, transition state
8, Scheme 2a).
rel yield rel yield rel yield
substrate
ketone
3 (%)
alcohol
4 (%)
ester
conv.
(%)b
entry
2
5 (%)a
On the other hand, treatment of 2a (H) and ortho-
substituted aldehydes 2f (o-OCH3) and 2i (o-CF3) (entries
1, 2, and 6, respectively) in a similar fashion gave a 230:
6:1 ratio of oxidation ratios [i.e., of (3 + 5):4], respectively.
Both types of ortho-substituents R3 now have a strong
negative effect on the oxidation processes. The effect is
slightly less pronounced for o-OCH3 compared to o-CF3.
Because the electronic effects of para and ortho substit-
uents should be similar, the decrease in oxidation prod-
ucts in favor of Hiyama-Nozaki product must be attrib-
uted to steric destabilization of the required transition
states for oxidation.
1
2
3c
4
5
6
7
8
a : R3 ) H
83
22
47c
58
80
5
8
78
53
37
19
95
21
22
9
0
0
5
1
0
36
24
85
f: R3 ) o-OCH3
f: R3 ) o-OCH3
g: R3 ) m-OCH3
h : R3 ) p-OCH3
i: R3 ) o-CF3
94
n.d.d
90
73
95
93
78
j: R3 ) m-CF3
k : R3 ) p-CF3
43
54
a
The MS degradation pattern is in accordance with that of other
b
Tishchenko products such as 5j. Conversion based on 1a . The
ratio of oxidized products to benzyl alcohol [(3 + 5):6] was in all
cases (1.0-1.5):1.0. c One equivalent of 2f added, followed by three
d
equivalents of benzaldehyde after 30 min. Not determined.
Finally, the reactions of 2a (H), 2g (m-OCH3), and 2j
(m-CF3) (entries 1, 4, and 7, respectively) resulted in a
7:1:2 ratio of oxidation ratios [of (3 + 5): 4], respectively.
As before, both substituents (OCH3 and CF3) disfavor the
oxidative process compared to the Hiyama-Nozaki pro-
cess somewhat similar to the para-substitution effect. In
this case, the negative effect on oxidation of a meta-
electron-donating substituent seems to be more pro-
nounced than that of a meta-electron-withdrawing sub-
stituent. A complex interplay between steric and electronic
factors must account for this observation.
from chromium allyl was only possible with the unsub-
stituted allyl when chiral Cr(II) alkoxides were used as
catalysts.17 When the substituted substrates were used,
the enantiomeric excesses of the easily oxidizable products
were negligible. A potential reason may have been the
OMPV scrambling of stereochemistry in the substituted
substrates or, alternatively, induction in the unsubsti-
tuted case may have resulted from OMPV equilibria
mediated by the asymmetric alkoxide catalyst, with the
equilibrium being at the homoallylic alcohols side only
in the unsubstituted case.
These results showed that with respect to electronic
influences, no really significant advantage toward or
against oxidation could be observed with either donor
methoxy or acceptor trifluoromethyl substituents. The
latter, however, exhibited an interesting effect on the
distribution of the oxidized products 3 and 5 (entries 7
and 8) shifting the reaction path more towards the
Tishchenko product 5. The reason for this is likely the
increased carbonyl activity in 2i-k shifting the equilib-
rium toward the hemiacetal intermediate of the Tish-
chenko pathway (Scheme 2b, cf. formation of 10).
Further evidence for the dominating steric ortho-effect
was obtained by experiments, in which 1 equiv of
anisaldehyde 2f was used and, after 30 min, 3 equiv of
benzaldehyde (R3 ) H) was added. Significantly increased
oxidation ratios of [(3 + 5):4] were obtained for o-
anisaldehyde (47% 3f + 5f, 53% 4f, Table 4, entry 2),23
m-anisaldehyde (69% 3g + 5g, 31% 4g),23,24 and p-
anisaldehyde (85% 3h + 5h , 15% 4h ).23,24 OMPV oxida-
tion was increased, as expected most notably in the ortho-
substituted derivative, because the negative steric effect
in the oxidant was compensated. Oxidation was still
lower than with benzaldehyde products (4a ) as the
substrate, probably because of the remaining steric effect
of the Hiyama-Nozaki intermediates 4f-h . On the other
hand, when ketones 12l and 12m (Scheme 3)24 were used
as oxidants instead of benzaldehyde, only very small
amounts of oxidation products were detected. Ketones are
inefficient as hydrogen acceptors, probably because co-
ordination at the sterically crowded chromium(III) center
does not take place easily.13
Finally, the effect of a substituent R3 on the aromatic
ring of aldehydes 2 was studied (Table 4, cf. Scheme 3).
Again, all reactions were performed under similar condi-
tions (55 °C, THF, 3 h) using dimethylallyl bromide 1a
and aldehydes 2 in a molar ratio of 1:3 and 2.5 equiv of
chromium(II) chloride. Although this substitution alters
two parameters at the same time, as the aldehydes are
a Hiyama reaction component, and simultaneously can
serve as an OMPV oxidant, the cross effects to a great
part can be eliminated by a multivariant analysis.
In general, with substituted benzaldehydes 2f-k the
products resulting from an oxidative process (3 + 5,
OMPV + Tishchenko) became less important relative to
the Hiyama-Nozaki product 4 (entries 2-8 vs 1). More-
over, for both electron-rich aldehydes (R3 ) OCH3) and
electron-poor aldehydes (R3 ) CF3), the substituent
position was the crucial factor for the product distribu-
tion. A dramatic decrease in the ratio of oxidized products
(allyl ketone 3 + homoallyl ester 5) to homoallyl alcohol
4 was observed, following the order of para > meta .
ortho for the substituent position effect on the oxidation
ratio ) (3 + 5):4. The reactions of para-substituted
aldehydes 2h (p-OCH3) and 2k (p-CF3) (entries 5 and 8,
respectively) resulted in an approximately 4:1 oxidation
ratio in both cases; i.e., oxidation is favorable, but a little
less compared to the benzaldehyde standard 2a (R3 ) H,
entry 1) with its ∼12:1 oxidation ratio.
For the evaluation of the relative effect of oxidation
propensity compared to the benzaldehyde standard, the
ratio of oxidation ratios [i.e., of (3 + 5):4] of benzaldehyde
to donor-aldehyde and to acceptor-aldehyde can be used.
This is 3:1:1 for 2a (H, oxidation ratio ) 12:1) over 2h
(p-OCH3, oxidation ratio ) 4:1) and 2k (p-OCF3, oxidation
ratio ) 4:1), respectively. Thus, both an electron-donating
as well as an electron-withdrawing substituent in the
para position retard the oxidation processes to a similar
Con clu sion
In conclusion, formation of allyl ketones 3 during
Hiyama-Nozaki reactions can be explained by an Op-
(23) Less than 1% of compound 5.
(24) These results are not additionally shown in the table.

1980 J . Org. Chem., Vol. 67, No. 7, 2002
Schrekker et al.
Gen er a l P r oced u r e for th e Hiya m a OMP V Rea ction s.
To chromium(II) chloride (2.5 equiv, 200 mg, 1.63 mmol) was
added THF (2.5 mL) under vigorous stirring. After a few
minutes, the aldehyde (3.0 equiv, 2.16 mmol) and the allyl
halide (1.0 equiv, 0.72 mmol) were added in this order. The
resulting mixture was stirred for 3 h at 55 °C, and the reaction
was quenched with a saturated aqueous NaCl solution. The
water layer was extracted three times with diethyl ether, and
the combined organic fractions were washed twice with a
saturated aqueous NaCl solution. The organic layer was dried
with MgSO4 and concentrated in vacuo. The residue was
filtered over a short silica column with diethyl ether and
penauer-type oxidation (Scheme 1). The following factors,
in a rough order of decreasing importance, favor the
subsequent formation of allyl ketones 3: alkyl substitu-
tion at the allylic γ- and â-position, excess aldehyde,
higher temperatures, aldehydes with electron-donating
substituents, unsubstituted benzaldehyde as the oxidant,
and allyl bromides instead of allyl chlorides. If a chemo-
selective reaction toward homoallyl alcohols 4 is required,
catalytic amounts of LiI are important at lower temper-
atures in order to achieve sufficient conversions. With
the CrCl3/LAH procedure (in situ generation of CrCl2),
the OMPV oxidations may be masked by reduction of the
aldehyde substrate 2 or reduction of the formed allyl
ketone 3 by the only partially reduced LAH (or from
excess or re-formed CrCl2). Thus, reaction conditions
should be chosen very carefully, especially when the
Hiyama-Nozaki method is applied in total synthesis or
when a chemo- and stereoselective reaction is required.
Efficient OMPV equilibria suggest themselves as a
reason for thwarted enantioselective catalyses in Hiyama-
Nozaki reactions.
1
concentrated in vacuo. Conversions were determined from H
NMR spectra of the crude product. Purification was done by
column chromatography on silica or by preparative GC.
Data of New Compounds:
2,6-Dim eth yl-1-ph en yl-2-vin yl-h ept-5-en -1-on e (3e). Con-
version of 64% based on geranyl bromide 1e: Rf ) 0.64
1
(hexane:ethyl acetate ) 98:2); colorless oil; H NMR δ 7.84-
7.82 (m, 1H), 7.46-7.43 (m, 1H), 7.38-7.34 (m, 2H), 6.16 (dd,
J ) 17.6, 10.8, 1H), 5.23 (d, J ) 10.8, 1H), 5.20 (d, J ) 17.6,
1H), 5.01 (m, 1H), 1.96-1.72 (m, 4H), 1.62 (s, 3H), 1.44 (s, 3H),
1.37 (s, 3H); 13C NMR δ 204.7 (CdO), 143.2 (CH), 137.8 (quart.
C), 131.9 (quart. C), 131.4 (CH), 129.0 (CH), 127.9 (CH), 124.0
(CH), 113.2 (CH2), 53.6 (quart. C), 39.0 (CH2), 25.6 (CH3), 23.0
(CH2 + CH3), 17.4 (CH3); IR (neat) 3082 (w), 3059 (w), 3021
(w), 2969 (m), 2928 (m), 2882 (m), 2859 (m), 1678 (s), 719 (m),
Exp er im en ta l Section
696 (m) cm-1; HRMS-EI (70 eV) m/z calcd for C24H28O2 (M+
C6H11) 159.0809, found 159.0800.
-
Gen er a l Meth od s. All reactions were carried out under an
argon atmosphere in flame-dried glassware using standard
syringe and septa techniques. The commercial reagents 1a -
e, 2f-k , 12l-m , and chromium(II) chloride (99.9% from Strem
Chemicals) were used as purchased. Tetrahydrofuran was
distilled from potassium/benzophenone. Benzaldehydes (2a -
e,l,m ) were distilled from potassium hydride. Spectral data
of the known compounds (3a ,b ,l,m ),25 3c,26 3d ,27 3g,28
(4a ,b,l,m ),29 4c,26 4d -e,30 4h ,31 6f,32 6g,33 6h ,33 and 6j34 were
in accordance with the literature data. The known compounds
(6a -e,l,m ), 6i, and 6k were characterized by comparison to
commercially available samples. Thin-layer chromatography
was carried out on Merck silica 60/F-254 aluminum-backed
plates. Flash chromatography was performed using Merck
silica gel 60 (40-60 µm). NMR spectra were recorded in CDCl3.
Chemical shifts δ are quoted in parts per million (ppm), and
coupling constants J are given in Hertz (Hz).
Gen er a l P r oced u r e for th e Hiya m a -Noza k i Rea c-
tion s. To chromium(II) chloride (2.5 equiv, 200 mg, 1.63 mmol)
and lithium iodide (0.1 equiv, 8.7 mg, 65 µmol) was added THF
(2.5 mL) under vigorous stirring. After a few minutes, the
aldehyde (1.0 equiv, 0.65 mmol) and the allyl halide (1.1 equiv,
0.72 mmol) were added in this order. The resulting mixture
was stirred for 30 min at 0 °C, and the reaction was quenched
with a saturated aqueous NaCl solution. The water layer was
extracted three times with diethyl ether, and the combined
organic fractions were washed twice with a saturated aqueous
NaCl solution. The organic layer was dried with MgSO4 and
concentrated in vacuo. The residue was filtered over a short
silica column with diethyl ether and concentrated in vacuo.
Conversions were determined from 1H NMR spectra of the
crude product. Purification was done by column chromatog-
raphy on silica or by preparative GC.
1-(2-Meth oxy-p h en yl)-2,2-d im eth yl-bu t-3-en -1-on e (3f).
Conversion of 21% based on dimethylallyl bromide: Rf ) 0.23
(hexane:ethyl acetate ) 9:1); colorless oil; 1H NMR δ 7.25 (m,
1H), 6.97 (dd, J ) 7.4, 1.7, 1H), 6.86-6.81 (m, 2H), 5.94 (dd,
J ) 17.4, 10.7, 1H), 5.05-5.00 (m, 2H), 3.71 (s, 3H), 1.24 (s,
6H); 13C NMR δ 210.7 (CdO), 155.8 (quart. C), 143.0 (CH),
131.2 (quart. C), 130.5 (CH), 127.2 (CH), 120.4 (CH), 114.0
(CH2), 111.3 (CH), 55.7 (CH3), 51.7 (quart. C), 24.4 (CH3); IR
(neat) 3086 (w), 2974 (m), 2934 (m), 2874 (w), 2837 (w), 1697
(s), 754 (s) cm-1; HRMS-EI (70 eV) m/z calcd for C13H16O2
204.1150, found 204.1163.
1-(4-Meth oxy-p h en yl)-2,2-dim eth yl-bu t-3-en -1-on e (3h ).
Conversion of 52% based on dimethylallyl bromide: Rf ) 0.66
1
(hexane:ethyl acetate ) 4:1); colorless oil; H NMR δ 7.88 (d,
J ) 9.0, 2H), 6.78 (d, J ) 9.0, 2H), 6.12 (dd, J ) 17.6, 10.6,
1H), 5.14 (dd, J ) 17.6, 0.66, 1H), 5.10 (dd, J ) 10.6, 0.66,
1H), 3.75 (s, 3H), 1.31 (s, 6H); 13C NMR δ 202.8 (CdO), 162.8
(quart. C), 144.8 (CH), 132.4 (CH), 129.6 (quart. C), 114.0
(CH2), 113.5 (CH), 55.7 (CH3), 50.2 (quart. C), 26.7 (CH3); IR
(neat) 3082 (w), 2974 (m), 2934 (m), 2874 (w), 2839 (w), 1670
(s), 843 (m); HRMS-EI (70 eV) m/z calcd for C13H16O2 204.1150,
found 204.1156. Anal. Calcd for C13H16O2: C, 76.44; H, 7.90.
Found: C, 76.32; H, 7.96.
2,2-Dim eth yl-1-(3-tr iflu or om eth yl-p h en yl)-bu t-3-en -1-
on e (3j). Conversion of 40% based on dimethylallyl bromide:
Rf ) 0.27 (hexane:ethyl acetate ) 95:5); colorless oil; 1H NMR
δ 8.08 (s, 1H), 7.98 (d, J ) 7.8, 1H), 7.64 (d, J ) 7.8, 1H), 7.44
(dd, J ) 7.8, 7.8, 1H), 6.10, (dd, J ) 17.6, 10.6, 1H), 5.19 (d,
J ) 17.6, 1H), 5.19 (d, J ) 10.6, 1H), 1.33 (s, 6H); 13C NMR δ
203.5 (CdO), 143.7 (CH), 138.0 (quart. C), 132.8 (CH), 131.0
(q, J ) 50.1, quart. C), 128.5 (CH), 128.4 (CH), 126.5 (CH),
124.1 (q, J ) 272, quart. C), 115.2 (CH2), 50.6 (quart. C), 26.2
(CH3); IR (neat) 3084 (w), 2982 (m), 2934 (m), 2884 (w), 1686
(s), 1333 (s), 1246 (m), 1169 (s), 1076 (m), 814 (m) cm-1; HRMS-
EI (70 eV) m/z calcd for C13H13F3O 242.0918, found 242.0937.
2,2-Dim eth yl-1-(4-tr iflu or om eth yl-p h en yl)-bu t-3-en -1-
on e (3k ). Conversion of 42% based on dimethylallyl bromide:
Rf ) 0.34 (hexane:ethyl acetate ) 95:5); colorless oil, containing
a minor impurity of a 2k derivative (∼4%, probably hydrated
aldehyde), which could not be removed by preparative GC; 1H
NMR δ 7.87 (dd, J ) 8.2, 0.68, 2H), 7.56 (dd, J ) 8.2, 0.68,
2H), 6.08 (dd, J ) 17.6, 10.6, 1H), 5.18 (dd, J ) 10.6, 0.54,
1H), 5.17 (dd, J ) 17.6, 0.54, 1H), 1.32 (s, 6H); 13C NMR δ
204.4 (CdO), 143.5 (CH), 140.7 (quart. C), 133.5 (q, J ) 37.6,
quart. C), 129.7 (CH), 125.4 (CH), 122.7 (q, J ) 308, quart.
C), 115.2 (CH2), 50.7 (quart. C), 26.1 (CH3); IR (neat) 3086 (w),
(25) Katritzky, A. R.; Wu, H.; Xie, L. J . Org. Chem. 1996, 61, 4035-
4039.
(26) J ones, P.; Knochel, P. J . Org. Chem. 1999, 64, 186-195.
(27) Reetz, M. T.; Wenderoth, B.; Urz, R. Chem. Ber. 1985, 118, 348-
353.
(28) Marceau, P.; Gautreau, L.; Beguin, F. J . Organomet. Chem.
1991, 403, 21-27.
(29) J ubert, C.; Knochel, P. J . Org. Chem. 1992, 57, 5425-5431.
(30) Kobayashi, S.; Nishio, K. J . Org. Chem. 1994, 59, 6620-6628.
(31) Ahn, Y.; Doubleday, W. W.; Cohen, T. Synth. Commun. 1995,
25, 33-41.
(32) Yates, P.; Macas, T. S. Can. J . Chem. 1988, 66, 1-10.
(33) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J . Org. Chem. 1982,
47, 4702-4708.
(34) Blanco, F. E.; Harris, F. L. J . Org. Chem. 1977, 42, 868-871.

In Situ Formation of Allyl Ketones
J . Org. Chem., Vol. 67, No. 7, 2002 1981
1
2980 (m), 2936 (m), 2876 (w), 1686 (s), 1327 (s), 1169 (s), 1131
(s), 1069 (s), 853 (m) cm-1; HRMS-EI (70 eV) m/z calcd for
C13H13F3O 242.0918, found 242.0912.
Rf ) 0.32 (hexane:chloroform ) 1:1); colorless oil; H NMR δ
7.48-7.32 (m, 4H), 5.80 (dd, J ) 17.5, 10.8, 1H), 5.09 (dd, J )
10.8, 0.9, 1H), 5.00 (dd, J ) 17.5, 0.9, 1H), 4.39 (d, J ) 2.68,
1H), 2.09 (d, J ) 2.68, 1H), 0.93 (s, 3H), 0.87 (s, 3H); 13C NMR
δ 144.8 (CH), 142.1 (quart. C), 131.5 (CH), 130.3 (q, J ) 38.3,
quart. C), 128.2 (CH), 124.9 (CH), 124.6 (CH), 124.6 (q, J )
274, quart. C), 80.4 (CH), 42.7 (quart. C), 24.6 (CH), 21.2 (CH);
IR (neat) 3485 (m, br), 3086 (w), 2974 (m), 2934 (m), 2899 (m),
1329 (s), 1165 (s), 1128 (s), 1074 (s), 806 (m) cm-1; HRMS-EI
(70 eV) m/z calcd for C13H15F3O (M+ - C5H9) 175.0371, found
175.0360.
1-(2-Meth oxy-p h en yl)-2,2-d im eth yl-bu t-3-en -1-ol (4f).
Conversion of 73% based on dimethylallyl bromide: Rf ) 0.74
(hexane:ethyl acetate ) 2:1); colorless oil; 1H NMR δ 7.22-
7.13 (m, 2H), 6.86 (m, 1H), 6.78 (d, J ) 8.3, 1H), 5.88 (dd, J )
17.5, 10.8, 1H), 4.99 (dd, J ) 10.8, 1.4, 1H), 4.94 (dd, J ) 17.5,
1.4, 1H), 4.77 (d, J ) 5.64, 1H), 3.72 (s, 3H), 2.52 (d, J ) 5.64,
1H), 0.96 (s, 3H), 0.90 (s, 3H); 13C NMR δ 157.4 (quart. C),
145.9 (CH), 129.6 (CH), 129.6 (quart. C), 128.6 (CH), 120.5
(CH), 113.2 (CH2), 110.9 (CH), 76.0 (CH), 55.5 (CH3), 43.4
(quart. C), 24.5 (CH3), 22.2 (CH3); IR (neat) 3478 (m, br), 3081
2,2-Dim eth yl-1-(4-tr iflu or om eth yl-p h en yl)-bu t-3-en -1-
ol (4k ). Conversion of 17% based on dimethylallyl bromide:
1
(w), 2967 (m), 2934 (m), 2874 (w), 2837 (w), 754 (s) cm-1
;
Rf ) 0.29 (hexane:chloroform ) 1:1); colorless oil; H NMR δ
HRMS-EI (70 eV) m/z calcd for C13H18O2 (M+ - C5H9)
137.0603, found 137.0601. Anal. Calcd for C13H16O2: C, 75.69;
H, 8.80. Found: C, 75.43; H, 8.88.
7.48 (d, J ) 8.0, 2H), 7.33 (d, J ) 8.0, 2H), 5.80 (dd, J ) 17.5,
10.8, 1H), 5.09 (dd, J ) 10.8, 1.2, 1H), 5.00 (dd, J ) 17.5, 1.2,
1H), 4.39 (d, J ) 2.8, 1H), 2.08 (d, J ) 2.8, 1H), 0.93 (s, 3H),
0.87 (s, 3H); 13C NMR δ 145.1 (quart. C), 144.9 (CH), 130.0 (q,
J ) 53.8, quart. C), 128.5 (CH), 124.8 (CH), 124.6 (q, J ) 272,
quart. C), 114.9 (CH2), 80.4 (CH), 42.7 (quart. C), 24.7 (CH3),
21.3 (CH3); IR (neat) 3458 (m, br), 3086 (w), 2974 (m), 2933
(m), 2876 (m), 1327 (s), 1165 (s), 1127 (s), 1069 (s), 851 (m)
cm-1; HRMS-EI (70 eV) m/z calcd for C13H15F3O (M+ - F)
225.1091, found 225.1098.
1-(3-Meth oxy-p h en yl)-2,2-d im eth yl-bu t-3-en -1-ol (4g).
Conversion of 33% based on dimethylallyl bromide: Rf ) 0.17
(hexane:ethyl acetate ) 95:5); colorless oil; 1H NMR δ 7.15 (m,
1H), 6.80-6.72 (m, 3H), 5.84 (dd, J ) 17.5, 10.8, 1H), 5.06 (dd,
J ) 10.8, 1.24, 1H), 5.00 (dd, J ) 17.5, 1.24, 1H), 4.33 (s, 1H),
3.72 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H); 13C NMR δ 159.4 (quart.
C), 145.5 (CH), 142.9 (quart. C), 128.8 (CH), 120.8 (CH), 114.2
(CH), 114.0 (CH2), 113.2 (CH), 81.0 (CH), 53.6 (CH3), 42.6
(quart. C), 24.9 (CH3), 21.6 (CH3); IR (neat) 3538 (s, br), 3084
3-Tr iflu or om eth yl-ben zoic Acid 2,2-Dim eth yl-1-(3-tr i-
flu or om eth yl-p h en yl)-bu t-3-en yl Ester (5j). Conversion of
34% based on dimethylallyl bromide: Rf ) 0.22 (hexane:ethyl
(w), 2967 (m), 2934 (m), 2874 (w), 2836 (w), 789 (m) cm-1
;
1
HRMS-EI (70 eV) m/z calcd for C13H18O2 206.1307, found
206.2808. Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found:
C, 75.50; H, 8.77.
acetate ) 95:5); colorless oil; H NMR δ 8.31 (s, 1H), 8.25 (d,
J ) 7.8, 1H), 7.84 (m, 1H), 7.62 (dd, J ) 7.8, 7.8, 1H), 7.57-
7.53 (m, 3H), 5.93 (dd, J ) 17.5, 10.8, 1H), 5.83 (s, 1H), 5.12
(dd, J ) 10.8, 1.0, 1H), 5.02 (dd, J ) 17.5, 1.0, 1H), 1.14 (s,
3H), 1.11 (s, 3H); 13C NMR δ 164.6 (CdO), 143.2 (CH), 138.5
(quart. C), 132.7 (CH), 131.4 (q, J ) 36.1, quart. C), 131.1 (CH),
130.9 (quart. C), 130.2 (q, J ) 38.9, quart. C), 129.6 (CH), 129.6
(CH), 128.3 (CH), 126.5 (CH), 124.5 (CH), 124.5 (CH), 124.1
(q, J ) 284, quart. C), 123.6 (q, J ) 269, quart. C), 114.3 (CH2),
82.4 CH), 41.35 (quart. C), 23.96 (CH3), 22.85 (CH3); IR (neat)
3090 (w), 2974 (m), 2934 (m), 2878 (w), 1730 (s), 1331 (s), 1252
(s), 1169 (s), 1131 (s), 756 (m) cm-1; HRMS-EI (70 eV) m/z calcd
for C21H18F5O2 (M+ - F) 397.1227, found 397.1235. Anal. Calcd
for C21H18F6O2: C, 60.58; H, 4.36. Found: C, 60.80; H, 4.17.
2,2-Dim eth yl-1-(2-tr iflu or om eth yl-p h en yl)-bu t-3-en -1-
ol (4i). Conversion of 91% based on dimethylallyl bromide:
1
Rf ) 0.30 (hexane:chloroform ) 1:1); colorless oil; H NMR δ
7.65 (d, J ) 8.0, 1H), 7.55 (d, J ) 7.8, 1H), 7.44 (dd, J ) 8.0,
7.6, 1H), 7.29 (dd, J ) 7.8, 7.6, 1H), 6.02 (dd, J ) 17.6, 10.8,
1H), 5.08 (dd, J ) 10.8, 1.3, 1H), 4.97 (dd, J ) 17.6, 1.3, 1H),
4.85 (s, 1H), 1.99 (bs, 1H), 1.02 (s, 3H), 0.87 (s, 3H); 13C NMR
δ 144.8 (CH), 140.9 (quart. C), 131.6 (CH), 130.0 (CH), 128.9
(q, J ) 48.3, quart. C), 128.0 (CH), 126.0 (q, J ) 274, quart.
C), 125.9 (CH), 114.3 (CH2), 75.2 (CH), 42.9 (quart. C), 26.2
(CH3), 22.3 (CH3); IR (neat) 3442 (m, br), 3084 (w), 3011 (w),
2972 (m), 2934 (m), 2876 (w), 1310 (s), 1161 (s), 1123 (s), 768
(m) cm-1; HRMS-EI (70 eV) m/z calcd for C13H15F3O (M+
C5H9) 175.0371, found 175.0378. Anal. Calcd for C13H15F3O:
C, 63.93; H, 6.19. Found: C, 64.16; H, 5.96.
-
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
3e, 3f, 3j, 3k , 4j, and 4k . This material is available free of
charge via the Internet at http://pubs.acs.org.
2,2-Dim eth yl-1-(3-tr iflu or om eth yl-p h en yl)-bu t-3-en -1-
ol (4j). Conversion of 19% based on dimethylallyl bromide:
J O001750U