α-Triethylsilyl-α-diazoacetone in double cross-aldolisation: Convenient acetone equivalent toward 5-hydroxy-1,3-diketones

Article abstract of DOI:10.1016/j.tet.2012.09.063

α-Triethylsilyl-α-diazoacetone underwent a sequential aldolisation-deprotection-aldolisation process to access the 2-diazo-3-oxo-1,5-dihydroxy skeleton with significant diversity. The diazo group could be efficiently removed by treatment with rhodium acetate to afford the corresponding 5-hydroxy-1,3-diketones.

Full text of DOI:10.1016/j.tet.2012.09.063

Tetrahedron 68 (2012) 9652e9657
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a-Triethylsilyl-
a
-diazoacetone in double cross-aldolisation: convenient acetone
equivalent toward 5-hydroxy-1,3-diketones
a
a
a
a
b
ꢀ
ꢀ ꢀ
Anthony Lancou , Heloua Haroun , Uday K. Kundu , Frederic Legros , Nicolas Zimmermann ,
b
b
a
a
ꢀ
Monique Mathe-Allainmat , Jacques Lebreton , Gilles Dujardin , Catherine Gaulon-Nourry ,
,
Pascal Gosselin a
*
a
ꢀ
ꢀ
ꢁ
ꢀ
IMMMdEquipe Methodologie et Synthese OrganiquedCNRS UMR 6283, Universite du Maine, Avenue Olivier Messiaen, 72085 Le Mans, France
CEISAMdEquipe SymbiosedCNRS UMR 6230, Universite de Nantes, 2 rue de la Houssiniere, BP 92208, 44322 Nantes, France
b
ꢀ
ꢀ
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Received in revised form 7 September 2012
Accepted 11 September 2012
Available online 18 September 2012
a
-Triethylsilyl-a-diazoacetone underwent a sequential aldolisationedeprotectionealdolisation process
to access the 2-diazo-3-oxo-1,5-dihydroxy skeleton with significant diversity. The diazo group could be
efficiently removed by treatment with rhodium acetate to afford the corresponding 5-hydroxy-1,3-
diketones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diazoacetone
Silyl-protected diazoacetone
Aldolisation
Dediazotation
Rhodium acetate
1. Introduction
of diazomethyl ketones has proven efficient with hindered and/or
sensitive aldehydic substrates, giving rise to several applications in
a-Diazocarbonyl compounds are useful synthetic intermediates.
total synthesis.9 The interest of diazoketones in synthesis was ex-
They can undergo a wide range of synthetic transformations,
mainly via their decomposition into Fischer-type metal carbenes by
transition metal complexes (insertions, cyclopropanations, 1,2-
migrations.).1 On the other hand, while generally unstable in
acidic media, the diazo functionality is stable under a variety of
basic conditions. This stability enables diazomethyl ketones A to
undergo base-promoted aldol additions with aldehydes or ketones
tended by Taber’s group, who reported that the potassium enolate
to generate a-diazo-b
-hydroxyketones B (Scheme 1(a)).2 The re-
action usually involves deprotonation of the most acidic azome-
thine hydrogen with KOH,3 NaOH,4 CH3MgBr5 or LDA.6 With
activated aldehydes, direct nucleophilic addition of the diazo car-
bon to the aldehyde has been reported, either in the presence of
a catalytic amount of DBU at room temperature,7,3c or even in
neutral conditions without solvent for reactive and base-sensitive
sugar-derived aldehydes.8 The
ing from this diazo-side aldol addition can be readily transformed
a-diazo-b-hydroxyketone B result-
into the corresponding versatile b-diketone C, via 1,2-hydride mi-
gration catalyzed by Rh2(OAc)4.6c The aldol addition methodology
* Corresponding author. Tel.: þ33 243 833 371; fax: þ33 243 833 902; e-mail
Scheme 1. Diazo-side and methyl-side aldol additions in the literature.
address: pascal.gosselin@univ-lemans.fr (P. Gosselin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.063

A. Lancou et al. / Tetrahedron 68 (2012) 9652e9657
9653
generated from an
a-diazo-methylketone added efficiently to var-
We investigated thus the reactivity of the lithium enolate of a-
ious conjugated aldehydes (Scheme 1(b)). This methyl-side aldol
addition constituted a key-step in the synthesis of isoprostanes.10
In the course of ongoing research, we have been involved in the
convergent elaboration of highly-functionalized 5-hydroxy-1,3-
diketones (D, Fig. 1). The commonly used strategy to access such
triethylsilyl-a-diazoacetone 1, generated using LDA according to an
inverse addition protocol (Scheme 4).14 Reaction with PMP-CHO led
to a separable mixture of C-silylated aldol 3a and C-desilylated aldol
4a. Conveniently, methanolysis of the crude product allowed re-
covering of the sole desilylated aldol 4a, still in a modest 45%
Desilylation and
Diazo-side
aldolisation
Methyl-side
aldolisation
Methyl-side
aldolisation
diazo-side
aldolisation
O
R1
O
OH
R2
2
1
2
O
O
1
R1CHO
R2CHO
R1CHO
R2CHO
R3Si
H
D
N2
pathway 2
N2
pathway 1
Fig. 1. New ‘diazo strategy’ to access 5-hydroxy-1,3-diketones.
functionalized skeletons consists of two successive nucleophilic
additions of the enolates of acetone to an acid chloride and to an
aldehyde.11 However, the sensitive acid chloride functionality may
be difficult to generate and to handle on elaborate substrates.
Considering the scope of the aldol-type chemistry of diazoketones,
we have envisioned an alternative approach involving diazo-
acetone as an acetone equivalent and two aldehydes. Initially, our
strategy involved the successive diazo-side then methyl-side aldol
additions of diazoacetone’s enolates to the aldehydes R1CHO and
R2CHO, respectively (Fig. 1, pathway 1), followed by the Rh(II)-
Scheme 3. Methyl-side aldolisation under Taber’s conditions.
catalyzed delivery of the corresponding
b-diketone D. However,
in our hands, diazo-ketol skeleton B (Scheme 1(a), R¼Me) proved
hardly compatible with the basic conditions used for the methyl-
side aldolisation (Scheme 1(b)). This prompted us to investigate
an original inverted approach, in which methyl-side aldolisation
would be carried out before the diazo-side aldolisation (Fig. 1,
pathway 2). The present work describes the feasibility of this
convergent diazo-strategy to access diversely substituted 5-
hydroxy-1,3-diketones.
Scheme 4. Methyl-side aldolisation using LDA. Reagents and conditions: (a) (i) LDA
(1 equiv), ꢀ50 ꢁC, then 1 (1 equiv), THF, ꢀ50 ꢁC, 0.5 h, then PMP-CHO, ꢀ100 ꢁC, 1 h; (ii)
MeOH, 25 ꢁC, 24 h; 45%. (b) (i) LDA (2 equiv), ꢀ50 ꢁC, then 1 (1 equiv), THF, ꢀ50 ꢁC,
0.5 h, then PMP-CHO, ꢀ100 ꢁC, 1 h; (ii) MeOH, 25 ꢁC, 24 h; 68%.
2. Results and discussion
yield.15 However, yield of the latter was significantly increased to
68% by using a two-fold excess of LDA.
The last conditions were applied to a set of aryl-, alkyl- and
alkenyl- aldehydes (Table 1). In every case, high conversion of 1 into
Prior protection of the azomethine proton in diazoacetone was
required to implement this new strategy. Accordingly,
a-trie-
thylsilyl- -diazoacetone 1 was synthesized. The preparation of 1
a
was first reported using toxic mercury intermediates.12aec We
eventually preferred the convenient method using triethylsilyl
triflate as the silylating agent of diazoacetone.12d-g The latter was
safely prepared in two steps on a multigram scale via the diazo
transfer from an imidazolinium salt to pentane-2,4-dione13a fol-
lowed by rapid alkaline hydrolysis13b (Scheme 2).
Table 1
Methyl-side aldolisation on
a
-triethylsilyl-a-diazoacetone 1
R2
4
Isolated yield (%)
p-MeO(C6H4)
Ph
4-NO2(C6H4)
t-Bu
Cyclohexyl
iso-Butyl
4a
4b
4c
4d
4e
4f
68
55
47
43
51
42
Scheme 2. Preparation of diazoacetone and a-triethylsilyl-a-diazoacetone.
Methyl-side aldolisation of a-triethylsilyl-a-diazoacetone 1 was
first carried out under Taber’s conditions,10 consisting in the addi-
tion of an equimolar mixture of aldehyde/TESCl to the potassium
enolate of a diazoketone (Scheme 3). When applied to para-ani-
Ph
4g
48
4h
67
saldehyde (PMP-CHO) and
a-triethylsilyl-a-diazoacetone 1, the al-
dol addition produced O-silylated aldol 2a in low yield (Scheme 3).

9654
A. Lancou et al. / Tetrahedron 68 (2012) 9652e9657
aldol products 3/4 (as a separable mixture) was achieved. Depro-
tected ketols 4ae4h were obtained as sole aldol products after
methanolysis of thecrude mixture in onlymoderateyields (42e67%),
due to their limited stability during silica gel column chromatogra-
3. Conclusions
In conclusion, we reported here an interesting extension in
the field of the base-promoted chemistry of diazoketones. An
original and convergent approach to the versatile 5-hydroxy-1,3
diketone scaffold 6 was described, involving
diazoacetone as synthetic equivalent of acetone and two alde-
hydes. The readily prepared -triethylsilyl- -diazoacetone un-
phy purification. Interestingly, in the case of
hydes 4ge4h, no elimination side-reaction was observed.
The previous methyl-side aldolisation of -triethylsilyl-
oacetone 1 having allowed a quite general access to diazomethyl
a,b-unsaturated alde-
a-triethylsilyl-a-
a
a-diaz-
b
-
a
a
ketols (4ae4h), we investigated then the diazo-side aldolisation on
the latter compounds. Ketols 4a and 4h were chosen as represen-
tative substrates (Table 2). The reaction was carried out at ꢀ100 ꢁC
using the Barbier conditions commonly used for diazo-side aldo-
lisations in the literature.9 LDA (1.25 equiv) was added to a mixture
of diazoketol 4a or 4h and diversely substituted aldehydes R1CHO
(Table 2). The reaction proceeded rapidly at ꢀ100 ꢁC, producing 2-
diazo-3-oxo-1,5-diols 5ae5e, which were isolated in yield up to
65%, without noticeable presence of dehydration side-products.
Interestingly, the use of 2 equiv of base didn’t improve the yield
of the reaction, although conducted on the unprotected diazoketol.
Worthy of note, this diazo-side aldolisation proved to work well
with bulky aldehydes (R1¼t-Bu), as well as with enolizable (R1¼i-
Pr) or aromatic (R1¼Ph or p-MeO(C6H4)) ones. However, it was
found to proceed without 1,5-diastereoselectivity.
derwent two sequential aldolisations, first at the methyl-side
position, second at the diazo-side position after desilylation. The
second aldolisation was efficiently performed, without O-pro-
tection of the primary aldol on various aliphatic and aromatic
aldehydes. Bulky aldehydes proved reactive and enolizable al-
dehydes were well-tolerated. The resulting original 2-diazo-3-
oxo-1,5-diols 5 were readily dediazotated with Rh2(OAc)4 to
provide the expected 5-hydroxy-1,3-diketones 6. The asymmet-
ric extension of this methodology is currently under in-
vestigation in our laboratories.
4. Experimental
4.1. General
All experiments were carried out under argon surpressure un-
less otherwise stated, using oven-dried glassware. Solvents were
purified as followed: THF, CH2Cl2 and Et2O were dried on a GT S100
drying station (Glass Technology). LDA was prepared as a stock
solution (w1 M) and was titrated just before use.18 Commercial
chlorotriethylsilane, diisopropylamine and aldehydes were distilled
or sublimed before use. Acetonitrile was distilled from CaH2. Tol-
uene was dried with sodium prior distillation. Purification by flash
column chromatography was carried out using Merck Kieselgel 60
Table 2
Diazo-side aldolisation on diazoketols 4a and 4h
silica gel (particle size: 32e63
mm). Thin-layer chromatography
R2
R1
5
Isolated yield (%)
(TLC) was performed using Merck pre-coated silica gel 60 F-254
sheets.
p-MeO(C6H4) (4a)
t-Bu
i-Pr
p-MeO(C6H4)
t-Bu
5a
5b
5c
5d
65
62
1H and 13C NMR spectra were recorded on Bruker AC-400 and
Bruker DPX-200 spectrometers and are reported as follows:
50a
53
(4h)
chemical shift
d in parts per million (multiplicity, number of pro-
Ph
5e
64
tons, coupling constants J). Multiplicity is expressed as: s (singlet),
d (doublet), t (triplet), q (quartet), qt (quintuplet), h (heptuplet), m
(multiplet), bs (broad singlet) or combinations of these. For spectra
recorded in CDCl3, TMS (dH¼0 ppm) was used as internal standard.
The multiplicity of 13C signals was determined by DEPTQ experi-
ments. IR spectra were recorded using a Nicolet Avatar 370 DTGS
ATR-FTIR spectrometer. High-resolution mass spectra were de-
termined on a Waters Micromass GCT Premier spectrometer using
a
NMR yield.
Finally, in order to validate the whole sequence leading to 5-
hydroxy-1,3-diketones, 2-diazo-3-oxo-1,5-diols 5ae5e were sub-
jected to catalytic amounts of rhodium acetate (Scheme 5).16,6c
Dediazotation occurred with concomitant hydride migration,
affording the expected b-diketones 6ae6e in high yield, mainly as
ketoeenols (Table 3).17
€
either FI/FD or CI sources. Melting point was determined on a Buchi
B-540 apparatus and is uncorrected.
4.2. Preparation of
a
-triethylsilyl-
a
-diazoacetone (1)
4.2.1. Diazoacetone.13 To
a
solution of 3-diazopentane-2,4-
dione13a (2.98 g, 23.6 mmol, 1.0 equiv) in diethyl ether (118 mL)
was added an aqueous NaOH solution (1 M, 113 mL) and the re-
action mixture was stirred at rt for 2 h. H2O (50 mL) was added and
the aqueous phase was extracted with dichloromethane
(4ꢂ10 mL). The combined organic layer was dried over Na2SO4,
filtered, and the filtrate was concentrated under reduced pressure
(T¼20 ꢁC, Pꢃ250 mbars) to afford diazoacetone as a volatile yellow
Scheme 5. Dediazotation step.
Table 3
Dediazotation: preparation of 5-hydroxy-1,3-diketones 6ae6e
oil (1.77 g, 90% yield). 1H NMR (200 MHz, CDCl3):
3H), 5.26 (bs, 1H).
d
(ppm) 2.1 (s,
R1
R2
6
Isolated yield (%)
p-MeO(C6H4)
t-Bu
i-Pr
p-MeO(C6H4)
t-Bu
6a
6b
6c
6d
6e
86
81
77
88
70
4.2.2. 1-Diazo-1-(triethylsilyl)propan-2-one (1).12deg To
a stirred
solution of diazoacetone (840 mg, 10 mmol) in anhydrous Et2O
(60 mL) at 0 ꢁC was added DIPEA (3.4 mL, 20 mmol) and TESOTf
(3 mL, 14 mmol). After 30 min stirring, the mixture was allowed to
Ph

A. Lancou et al. / Tetrahedron 68 (2012) 9652e9657
9655
warm to rt, stirred for a further 90 min and quenched by the ad-
dition of saturated aqueous NaHCO3 (10 mL). The organic layer was
washed with saturated aqueous NH4Cl (2ꢂ50 mL) and brine
(100 mL), dried over Na2SO4, filtered, and the filtrate was concen-
trated under reduced pressure. The oily residue was chromato-
graphed (silica gel; petroleum ether/diethyl ether: 9:1) to afford 1
as an orange oil (1.94 g, 94% yield). Rf (petroleum ether/diethyl
2.74e2.59 (m, 2H). 13C NMR (100.6 MHz, CDCl3):
d
(ppm) 194.3 (s,
C]O), 159.2 (s), 135.2 (s), 127.0 (d), 114.0 (d), 70.4 (d), 55.9 (d, CH]
N2), 55.4 (q), 49.2 (t). HRMS m/z calcd for C11H12N2O3 [M]þ
:
ꢄ
220.0848, found: 220.0843.
4.4.2. 1-Diazo-4-hydroxy-4-phenylbutan-2-one (4b). Prepared from
-triethylsilyl- -diazoacetone 1 and benzaldehyde according to the
a
a
ether: 7:3)¼0.56. IR (neat): nmax (cmꢀ1
)
2954, 2876, 2060
general procedure. The product 4b was obtained after column
chromatography (cyclohexane/ethyl acetate: 8:2 to 6:4) as an or-
ange oil (55% yield). Rf (cyclohexane/ethyl acetate: 7:3)¼0.10. IR
(neat): nmax (cmꢀ1) 3412, 2920, 2104 (naC]N]N), 1756, 1617, 1365,
(
naC]N]N), 1637 (
nC]O), 1463, 1414, 1358, 1267, 1240, 1199, 1005,
964, 721. 1H NMR (400 MHz, CDCl3):
d (ppm) 2.26 (s, 3H), 0.98 (t,
9H, J¼7.7 Hz), 0.77 (q, 6H, J¼7.7 Hz). 13C NMR (100.6 MHz, CDCl3):
d
(ppm) 196.1, 53.5, 26.9, 6.8, 3.2. HRMS m/z calcd for C9H19N2OSi
1140, 1051. 1H NMR (200 MHz, CDCl3):
d (ppm) 7.39e7.26 (m, 5H),
[MþH]þ: 199.1267, found: 199.1275.
5.29 (bs, 1H), 5.16 (dd, 1H, J¼8.3, 4.3 Hz), 2.80e2.61 (m, 2H). 13C
NMR (50.3 MHz, CDCl3): d (ppm) 194.3 (s, C]O), 142.9 (s), 128.7 (d),
4.3. Methyl-side aldolisation of
(1) using KHMDS/TESCl
a
-triethylsilyl-
a
-diazoacetone
127.9 (d), 125.8 (d), 70.8 (d), 56.1 (d, CH]N2), 49.1 (t). HRMS m/z
calcd for C10H11N2O2 [MþH]þ: 191.0821, found: 191.0829.
4.3.1. 1-Diazo-4-(4-methoxyphenyl)-1-(triethylsilyl)-4-(triethyl sily-
loxy) butan-2-one (2a). To a stirred solution of -triethylsilyl-
4.4.3. 1-Diazo-4-hydroxy-4-(4-nitrophenyl)butan-2-one
(4c). Prepared from a-triethylsilyl-a-diazoacetone 1 and p-nitro-
a
a
-
diazoacetone 1 (100 mg, 0.51 mmol) in anhydrous toluene (5 mL) at
ꢀ78 ꢁC was added a 0.5 M solution of KHMDS (1.05 mL, 0.52 mmol).
The reaction mixture was stirred for 10 min then a solution of p-
methoxybenzaldehyde (57 mg, 0.42 mmol) and chlorotriethylsilane
(76 mg, 0.51 mmol) in anhydrous toluene (2 mL) was added at
ꢀ78 ꢁC. After an additional 3 h, the reaction mixture was quenched
with saturated aqueous NH4Cl at ꢀ78 ꢁC and the temperature was
allowed to warm to rt. The aqueous layer was extracted with ethyl
acetate (3ꢂ) and the combined organic layer was washed with
water and brine before drying (Na2SO4) and concentration under
reduced pressure. The oily residue was chromatographed (silica
gel; cyclohexane/ethyl acetate 8:2) to afford 2a as a yellow oil
(73 mg, 32% yield). Rf (cyclohexane/ethyl acetate: 7:3)¼0.64. 1H
benzaldehyde according to the general procedure. The product 4c
was obtained after column chromatography (cyclohexane/ethyl
acetate: 8:2 to 6:4) as an orange oil (47% yield). Rf (cyclohexane/
ethyl acetate: 7:3)¼0.11. IR (neat): nmax (cmꢀ1) 3396, 2954, 2104
(
naC]N]N), 1762, 1605, 1518, 1344. 1H NMR (400 MHz, CDCl3):
d
(ppm) 8.20 (d, 2H, J¼8.8 Hz), 7.55 (d, 2H, J¼8.8 Hz), 5.32 (bs, 1H),
5.27 (dd,1H, J¼7.7, 4.6 Hz), 2.75e2.66 (m, 2H). 13C NMR (100.6 MHz,
CDCl3):
d (ppm) 193.6 (s, C]O), 150.3 (s), 147.6 (s), 126.6 (d), 123.9
(d), 70.0 (d), 56.4 (d, CH]N2), 48.3 (t). HRMS m/z calcd for
C10H10N3O4 [MþH]þ: 236.0671, found: 236.0684.
4.4.4. 1-Diazo-4-hydroxy-5,5-dimethylhexan-2-one (4d). Prepared
from a-triethylsilyl-a-diazoacetone 1 and pivalaldehyde according
NMR (200 MHz, CDCl3):
d
(ppm) 7.26 (d, 2H, J¼8.7 Hz), 6.83 (d, 2H,
to the general procedure. The product 4d was obtained after col-
umn chromatography (cyclohexane/ethyl acetate: 8:2 to 6:4) as an
orange oil (43% yield). Rf (cyclohexane/ethyl acetate: 7:3)¼0.15. IR
(neat): nmax (cmꢀ1) 3390, 2953, 2106 (naC]N]N), 1591, 1378, 1121.
J¼8.7 Hz), 5.14 (dd, 1H, J¼8.2, 5.0 Hz), 3.80 (s, 3H), 2.97 (dd, 1H,
J¼13.8, 8.2 Hz), 2.60 (dd, 1H, J¼13.8, 5.0 Hz), 1.00e0.72 (m, 24H),
0.60e0.42 (m, 6H).
1H NMR (200 MHz, CDCl3):
d (ppm) 5.34 (bs, 1H), 3.74 (dd, 1H,
4.4. Methyl-side aldolisation of
a
-triethylsilyl-
a
-diazoacetone
J¼10.0, 2.1 Hz), 3.20 (bs, 1H), 2.55e2.28 (m, 2H), 0.92 (s, 9H). 13C
(1) using LDA: general procedure
NMR (50.3 MHz, CDCl3):
d (ppm) 195.9 (s, C]O), 76.1 (d), 55.8 (d,
CH]N2), 42.4 (t), 34.8 (s), 25.9 (q). HRMS m/z calcd for C8H15N2O2
To a stirred solution of LDA (freshly titrated,18 2 equiv) in an-
[MþH]þ: 171.1134, found: 171.1134.
hydrous THF (2 mL/mmol of LDA) at ꢀ50 ꢁC was added a solution of
a
-triethylsilyl-
a
-diazoacetone 1 (1 equiv) in anhydrous THF (4 mL/
4.4.5. 4-Cyclohexyl-1-diazo-4-hydroxybutan-2-one (4e). Prepared
mmol of 1). After 30 min stirring at the same temperature, the
reaction mixture was cooled to ꢀ100 ꢁC and a solution of aldehyde
(1 equiv) in anhydrous THF (4 mL/mmol of aldehyde) was added
dropwise. After an additional 1.5 h stirring at ꢀ100 ꢁC, the reaction
mixture was quenched with saturated aqueous NH4Cl and slowly
warmed to rt. The aqueous layer was extracted with Et2O (ꢂ3). The
combined organic extract was washed with brine, dried (Na2SO4),
filtered and the filtrate was concentrated under reduced pressure.
To the crude material was added methanol (10 mL) and the solution
was stirred for 24 h at rt. After this time, the mixture was con-
centrated under reduced pressure and purified by column chro-
matography (silica gel; cyclohexane/ethyl acetate) to afford the
corresponding diazoketol 4ae4h.
from a-triethylsilyl-a-diazoacetone 1 and cyclohexanecarbox
aldehyde according to the general procedure. The product 4e was
obtained after column chromatography (cyclohexane/ethyl acetate:
8:2 to 6:4) as an orange oil (51% yield). Rf (cyclohexane/ethyl ace-
tate: 7:3)¼0.12. IR (neat): nmax (cmꢀ1) 3500, 2922, 2103 (naC]N]N),
1760, 1159, 1065. 1H NMR (200 MHz, CDCl3):
d (ppm) 5.34 (bs, 1H),
3.84e3.79 (m, 1H), 3.16 (bs, 1H), 2.54e2.28 (m, 2H), 1.83e1.57 (m,
6H), 1.39e0.76 (m, 5H). 13C NMR (50.3 MHz, CDCl3):
d
(ppm) 195.7
(s, C]O), 72.9 (d), 55.6 (d, CH]N2), 44.3 (t), 43.5 (d), 29.2 (t), 28.4
(t), 26.6 (t), 26.4 (t), 26.2 (t). HRMS m/z calcd for C10H17N2O2
[MþH]þ: 197.1290, found: 197.1284.
4.4.6. 1-Diazo-4-hydroxy-6-methylheptan-2-one (4f). Prepared
from
a-triethylsilyl-a-diazoacetone 1 and isovaleraldehyde
4.4.1. 1-Diazo-4-hydroxy-4-(4-methoxyphenyl)butan-2-one
according to the general procedure. The product 4f was obtained
after column chromatography (cyclohexane/ethyl acetate: 8:2 to
6:4) as an orange oil (42% yield). Rf (cyclohexane/ethyl acetate:
(4a). Prepared from
a-triethylsilyl-a-diazoacetone 1 and p-
methoxybenzaldehyde according to the general procedure. Diazo-
ketol 4a was obtained after column chromatography (cyclohexane/
ethyl acetate: 8:2 to 6:4) as a yellow oil (68% yield). Rf (cyclohexane/
ethyl acetate: 7:3)¼0.11. IR (neat): nmax (cmꢀ1) 3417, 2955, 2103
7:3)¼0.10. IR (neat): nmax (cmꢀ1
) 3441, 2956, 2927, 2102
(
naC]N]N), 1760, 1626, 1367, 1096. 1H NMR (400 MHz, CDCl3):
d
(ppm) 5.32 (bs, 1H), 4.20e4.10 (m, 1H), 2.53e2.36 (m, 2H), 1.80
(
naC]N]N), 1757, 1599, 1511, 1245, 1171, 1028. 1H NMR (400 MHz,
(m, 1H), 1.42 (ddd, 1H, J¼13.8, 8.9, 5.5 Hz), 1.11e1.02 (m, 1H), 0.85
CDCl3):
d
(ppm) 7.26 (d, 2H, J¼8.1 Hz), 6.86 (d, 2H, J¼8.1 Hz), 5.29
(d, 6H, J¼6.6 Hz). 13C NMR (100.6 MHz, CDCl3):
d (ppm) 195.2 (s,
C]O), 66.8 (d), 55.7 (d, CH]N2), 47.6 (t), 46.0 (t), 24.6 (d), 23.5
(bs, 1H), 5.08 (dd, 1H, J¼9.0, 2.7 Hz), 3.78 (s, 3H), 3.70 (bs, 1H),

9656
A. Lancou et al. / Tetrahedron 68 (2012) 9652e9657
(q), 22.2 (q). HRMS m/z calcd for C8H15N2O2 [MþH]þ: 171.1134,
1H), 1.03 (d, 3H, J¼6.5 Hz), 0.89 (d, 3H, J¼6.5 Hz). 13C NMR
found: 171.1133.
(100.6 MHz, CDCl3): d (ppm) 193.4 (s, C]O), 159.5 (s), 135.0 (s),
127.0 (d), 114.2 (d), 72.4 (s, C]N2), 71.4 (d), 70.5 (d), 55.5 (q), 47.0
(t), 32.8 (d), 18.8 (q), 18.5 (q). HRMS m/z calcd for C15H20N2O4 [M]þ
:
ꢄ
4.4.7. (E)-1-Diazo-4-hydroxy-6-phenylhex-5-en-2-one
(4g). Prepared from
a-triethylsilyl-
a-diazoacetone 1 and (E)-cin-
292.1423, found: 292.1439.
namaldehyde according to the general procedure. The product 4g
was obtained after column chromatography (cyclohexane/ethyl
acetate: 8:2 to 6:4) as an orange oil (48% yield). Rf (cyclohexane/
4.5.3. 2-Diazo-1,5-dihydroxy-1,5-bis(4-methoxyphenyl)-pentan-3-
one (5c). Prepared from diazoketone 4a and p-anisaldehyde
according to the general procedure. The product 5c was obtained
after column chromatography (cyclohexane/ethyl acetate: 9:1 to
6:4) as an orange oil (50% NMR yield). Rf (ethyl acetate/cyclohex-
ethyl acetate: 7:3)¼0.13. IR (neat): nmax (cmꢀ1
) 3373, 2104
(
naC]N]N), 1759, 1599, 1373, 1132, 1103, 1071. 1H NMR (400 MHz,
CDCl3):
d
(ppm) 7.38e7.21 (m, 5H), 6.65 (d, 1H, J¼15.8 Hz), 6.21 (dd,
1H, J¼15.8, 5.8 Hz), 5.33 (bs, 1H), 4.76 (m, 1H), 2.66e2.58 (m, 2H).
ane: 3:7)¼0.17. 1H NMR (400 MHz, CDCl3):
d (ppm) 7.29 (d, 2H,
13C NMR (100.6 MHz, CDCl3):
d
(ppm) 194.1 (s, C]O), 136.6 (d),
J¼8.5 Hz), 7.28 (d, 2H, J¼8.5 Hz), 6.89 (d, 2H, J¼8.5 Hz), 6.87 (d, 2H,
J¼8.5 Hz), 5.99 (s, 1H), 5.17 (dd, 1H, J¼9.0, 2.8 Hz), 3.80 (s, 3H), 3.79
(s, 3H), 2.90 (dd,1H, J¼15.5, 9.0 Hz), 2.74 (d,1H, J¼15.5 Hz). 13C NMR
130.8 (d), 130.3 (d), 128.8 (d), 128.0 (d), 126.7 (d), 69.5 (d), 56.0 (d,
CH]N2), 42.7 (t). HRMS m/z calcd for C12H12N2O2 [M]þꢄ: 216.0899,
found: 216.0915.
(100.6 MHz, CDCl3):
d (ppm) 192.9 (s, C]O), 159.8 (s), 159.5 (s),
135.0 (s),130.8 (s),127.2 (d),127.1 (d),114.4 (d),114.2 (d), 75.6 (s, C]
N2), 70.6 (d), 67.7 (d), 55.5 (q, 2C), 47.3 (t). HRMS m/z calcd for
C19H20N2O5 [M]þꢄ: 356.1372, found: 356.1398.
4.4.8. (E)-1-Diazo-4-hydroxy-5-methyloct-5-en-2-one
(4h). Prepared from
a-triethylsilyl-a-diazoacetone 1 and (E)-2-
methyl-2-pentenal according to the general procedure. The prod-
uct 4h was obtained after column chromatography (cyclohexane/
ethyl acetate 8:2 to 6:4) as an orange oil (67% yield). Rf (cyclohex-
ane/ethyl acetate: 7:3)¼0.12. IR (neat): nmax (cmꢀ1) 3425, 2964,
2923, 2100 (naC]N]N), 1759, 1621, 1360, 1139, 1044, 860, 531. 1H
4.5.4. (E)-4-Diazo-3,7-dihydroxy-2,2,8-trimethylundec-8-en-5-one
(5d). Prepared from diazoketol 4h and pivalaldehyde according to
the general procedure. The product 5d was obtained after column
chromatography (cyclohexane/ethyl acetate: 9:1 to 6:4) as a pale
yellow oil (53% yield). Rf (petroleum ether/diethyl ether: 9:1)¼0.16.
NMR (400 MHz, CDCl3):
d
(ppm) 5.46 (t, 1H, J¼7.5 Hz), 5.38 (bs, 1H),
4.43 (dd, 1H, J¼9.3, 2.7 Hz), 3.26 (bs, 1H), 2.59e2.45 (m, 2H), 2.03
1H NMR (400 MHz, CDCl3):
d
(ppm) 5.48 (t, 1H, J¼7.3 Hz), 4.48 (dd,
(qt, 2H, J¼7.5 Hz), 1.62 (s, 3H), 0.96 (t, 3H, J¼7.5 Hz). 13C NMR
1H, J¼9.2, 2.9 Hz), 4.38 (d, 1H, J¼4.8 Hz), 3.20 (d, 1H, J¼4.8 Hz), 3.02
(bs, 1H), 2.74 (dd, 1H, J¼15.2, 9.2 Hz), 2.58 (dd, 1H, J¼15.2, 2.9 Hz),
2.03 (qt, 2H, J¼7.3 Hz), 1.64 (s, 3H), 0.97 (t, 3H, J¼7.3 Hz), 0.96 (s,
(100.6 MHz, CDCl3): d (ppm) 194.8 (s, C]O),135.0 (s),128.6 (d), 73.8
(d), 55.7 (d, CH]N2), 46.1 (t), 20.9 (t), 14.0 (q), 11.9 (q). HRMS m/z
calcd for C9H14N2O2 [M]þꢄ: 182.1055, found: 182.1067.
9H). 13C NMR (100.6 MHz, CDCl3):
d (ppm) 193.3 (s, C]O), 134.9 (s),
128.9 (d), 74.1 (d), 72.7 (d), 72.3 (s, C]N2), 43.6 (t), 38.3 (s), 25.8 (q,
3C), 21.0 (t), 14.1 (q), 12.0 (q). IR (neat): 3365, 2965, 2873, 2090,
1539, 1576, 1456, 1375, 1319, 1233, 1150, 1013, 933, 897, 876, 724.
HRMS m/z calcd for C14H25N2O3 [MþH]þ: 269.1866, found:
269.1865.
4.5. Diazo-side aldolisation of diazoketols 4a and 4h: general
procedure
To a stirred solution of diazoketol 4h or 4h (1 equiv) and alde-
hyde (1 equiv) in anhydrous THF (1.5 mL/mmol) was slowly added
LDA (1.25 equiv) at ꢀ100 ꢁC. After 1.5 h stirring at ꢀ100 ꢁC, a solu-
4.5.5. 2-Diazo-1,5-dihydroxy-6-methyl-1-phenylnon-6-en-3-one
(5e). Prepared from diazoketol 4h and benzaldehyde according to
the general procedure. The product 5e was obtained after column
chromatography (cyclohexane/ethyl acetate: 9:1 to 6:4) as an or-
ange oil (64% yield). Rf (ethyl acetate/cyclohexane: 3:7)¼0.13. 1H
tion of acetic acid (1.5 equiv) in Et2O (500 mL) was added slowly and
the mixture was allowed to warm to rt. A mixture of water/Et2O (1.5
mL/3 mL) was added and the aqueous layer was extracted with
Et2O (ꢂ3). The combined organic extract was washed with satu-
rated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated
under reduced pressure. The oily residue was chromatographed
(silica gel; cyclohexane/ethyl acetate) to afford products 5ae5e.
NMR (400 MHz, CDCl3):
d (ppm) 7.47e7.29 (m, 5H), 6.04 (bs, 1H),
5.55e5.46 (m, 1H), 4.51 (dd, 1H, J¼9.5, 2.7 Hz), 2.76e2.60 (m, 2H),
2.05e2.01 (m, 2H), 1.62 (s, 3H), 0.96 (t, 3H, J¼7.5 Hz). 13C NMR
(100.6 MHz, CDCl3):
d (ppm) 193.5 (s, C]O), 138.7 (s), 134.9 (s),
4.5.1. 4-Diazo-1,5-dihydroxy-1-(4-methoxyphenyl)-6,6-
dimethylheptan-3-one (5a). Prepared from diazoketol 4a and piv-
alaldehyde according to the general procedure. The product 5a was
obtained after column chromatography (cyclohexane/ethyl acetate:
9:1 to 6:4) as an orange oil (65% yield). Rf (ethyl acetate/cyclohex-
129.0 (d), 128.7 (d), 128.6 (d), 125.9 (d), 75.1 (s, C]N2), 73.8 (d), 68.1
(d), 43.8 (t), 21.0 (t), 14.1 (q), 12.0 (q). HRMS m/z calcd for
C16H20N2O3 [M]þꢄ: 288.1474, found: 288.1494.
4.6. Dediazotation using Rh2(OAc)4: general procedure
ane: 3:7)¼0.16. 1H NMR (400 MHz, CDCl3):
d (ppm) 7.29 (d, 2H,
J¼8.7 Hz), 6.88 (d, 2H, J¼8.7 Hz), 5.13 (dd, 1H, J¼9.0, 2.7 Hz), 4.40 (s,
1H), 3.80 (s, 3H), 2.89 (dd, 1H, J¼15.4, 9.0 Hz), 2.76 (dd, 1H, J¼15.4,
To a stirred solution of 2-diazo-3-oxo-1,5-diol 5ae5e in anhy-
drous DCM (10 mL/mmol) at rt was added anhydrous rhodium
acetate (2 mol %). After 3 h stirring, the green mixture was filtered
on CeliteÒ. The filtrate was concentrated under reduced pressure.
The residue was dissolved in Et2O and washed with water. The
organic layer was dried (Na2SO4) and concentrated under reduced
pressure. The oily residue was chromatographed (silica gel; petro-
leum ether/diethyl ether) to afford the corresponding 5-hydroxy-
1,3-diketone 6ae6e.
2.7 Hz), 0.93 (s, 9H). 13C NMR (100.6 MHz, CDCl3):
d (ppm) 193.1 (s,
C]O),159.5 (s), 135.1 (s),127.1 (d),114.2 (d), 73.0 (d), 71.7 (s, C]N2),
70.5 (d), 55.5 (q), 46.8 (t), 38.5 (s), 25.8 (q). HRMS m/z calcd for
C16H22N2O4 [M]þꢄ: 306.1580, found: 306.1581.
4.5.2. 4-Diazo-1,5-dihydroxy-1-(4-methoxyphenyl)-6-
methylheptan-3-one (5b). Prepared from diazoketol 4a and iso-
valeraldehyde according to the general procedure. The product 5b
was obtained after column chromatography (cyclohexane/ethyl
acetate: 9:1 to 6:4) as an orange oil (62% yield). Rf (ethyl acetate/
4.6.1. (Z)-1,5-Dihydroxy-1-(4-methoxyphenyl)-6,6-dimethyl-hept-4-
en-3-one (6a). Prepared from diazoketone 5a according to the
general procedure. The product 6a was obtained after column
chromatography (petroleum ether/diethyl ether: 8:2) as a pale
yellow oil (86% yield). Rf (petroleum ether/diethyl ether: 7:3)¼0.13.
cyclohexane: 3:7)¼0.14. 1H NMR (400 MHz, CDCl3):
d (ppm) 7.28 (d,
2H, J¼8.4 Hz), 6.88 (d, 2H, J¼8.4 Hz), 5.13 (dd, 1H, J¼3.2, 9.4 Hz),
4.41 (d, 1H, J¼7.5 Hz), 3.80 (s, 3H), 2.75e2.92 (m, 2H), 1.80e1.89 (m,

A. Lancou et al. / Tetrahedron 68 (2012) 9652e9657
9657
IR (neat): nmax (cmꢀ1) 3436, 2927,1722, 1602, 1586, 1512,1246, 1173,
1033, 830. 1H NMR (400 MHz, CDCl3):
(ppm) 7.30 (d, 2H,
(400 MHz, CDCl3):
d
(ppm) 7.88e7.86 (m, 2H), 7.54e7.43 (m, 3H),
d
6.21 (s, 1H), 5.50 (t, 1H, J¼7.1 Hz), 4.51 (dd, 1H, J¼8.9, 3.8 Hz), 2.70
(dd, 1H, J¼15.0, 8.9 Hz), 2.62 (dd, 1H, J¼15.0, 3.8 Hz), 2.04 (q, 2H,
J¼7.4 Hz), 1.67 (s, 3H), 0.96 (t, 3H, J¼7.4 Hz). 13C NMR (100.6 MHz,
J¼8.7 Hz), 6.88 (d, 2H, J¼8.7 Hz), 5.57 (s, 1H), 5.11 (dd, 1H, J¼8.9,
3.8 Hz), 3.80 (s, 3H), 2.78 (dd, 1H, J¼15.5, 8.9 Hz), 2.69 (dd, 1H,
J¼15.5, 3.8 Hz), 1.16 (s, 9H). 13C NMR (100.6 MHz, CDCl3):
d
(ppm)
CDCl3): d (ppm) 196.6 (s), 182.4 (s), 135.2 (s), 134.6 (s), 132.6 (d),
198.7 (s), 195.8 (s), 159.4 (s), 135.5 (s), 127.2 (d), 114.1 (d), 96.5 (d),
70.9 (d), 55.5 (q), 48.5 (t), 38.8 (s), 27.5 (q, 3C). HRMS m/z calcd for
C16H22O4 [M]þꢄ: 278.1518, found: 278.1512.
129.0 (d), 128.8 (d), 127.2 (d), 97.4 (d), 74.5 (d), 45.5 (t), 21.0 (t), 14.1
(q), 11.9 (q). HRMS m/z calcd for C16H20O3 [M]þꢄ: 260.1412, found:
260.1428.
4.6.2. (Z)-1,5-Dihydroxy-1-(4-methoxyphenyl)-6-methylhept-4-en-
3-one (6b). Prepared from diazoketone 5b according to the general
procedure. The product 6b was obtained after column chroma-
tography (petroleum ether/diethyl ether: 8:2) as a pale yellow oil
(81% yield). Rf (petroleum ether/diethyl ether: 7:3)¼0.15. IR (neat):
nmax (cmꢀ1) 3527, 2963, 1738, 1611, 1587, 1514, 1247, 1218, 1172,
References and notes
1. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York, NY, 1998; (b) Zhang, Z.;
Wang, J. Tetrahedron 2008, 64, 6577e6605.
2. (a) Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350e5361; (b) Zhao, Y.; Wang, J.
Synlett 2005, 2886e2892.
3. (a) Burkoth, T. L. Tetrahedron Lett. 1969, 5049e5052; (b) Wenkert, E.;
McPhersen, A. J. Am. Chem. Soc. 1972, 94, 8084e8090; (c) Tsvetkov, N. P.; Bayir,
A.; Schneider, S.; Brewer, M. Org. Lett. 2012, 14, 264e267.
1026, 833. 1H NMR (400 MHz, CDCl3):
d (ppm) 7.29 (d, 2H,
J¼8.7 Hz), 6.88 (d, 2H, J¼8.7 Hz), 5.50 (s, 1H), 5.11 (dd, 1H, J¼3.6,
9.0 Hz), 3.80 (s, 3H), 2.75 (dd, 1H, J¼15.5, 9.0 Hz), 2.66 (dd, 1H,
J¼15.5, 3.6 Hz), 2.45 (h,1H, J¼6.9 Hz),1.14 (d, 6H, J¼6.9 Hz). 13C NMR
4. (a) Woolsey, N. F.; Khalil, M. H. J. Org. Chem. 1972, 37, 2405e2408; (b) Woolsey,
N. F.; Khalil, M. H. J. Org. Chem. 1973, 38, 4216; (c) Woolsey, N. F.; Khalil, M. H. J.
Org. Chem. 1975, 40, 3521e3528.
(100.6 MHz, CDCl3):
d (ppm) 196.9 (s), 195.1 (s), 159.4 (s), 135.5 (s),
~
5. Cuevas-Yanez, E.; Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron Lett. 2004,
127.1 (d), 114.1 (d), 98.4 (d), 70.8 (d), 55.5 (q), 48.2 (t), 36.2 (d), 19.6
(q), 19.5 (q). HRMS m/z calcd for C15H20O4 [M]þꢄ: 264.1362, found:
264.1382.
45, 2417e2419.
€
ꢀ
6. (a) Schollkopf, U.; Banhidai, B.; Frasnelli, H.; Meyer, R.; Beckhaus, H. Justus
Liebigs Ann. Chem. 1974, 1767e1783; (b) Pellicciari, R.; Castagnino, E.; Corsano,
S. J. Chem. Res., Synop. 1979, 76e77; (c) Pellicciari, R.; Fringuelli, R.; Sisani, E.;
Curini, M. J. Chem. Soc., Perkin Trans. 1 1981, 2566e2569; (d) Collins, J. C.;
Dilworth, B. M.; Garvey, N. T.; Kennedy, M.; McKervey, M. A.; O’Sullivan, M. B. J.
Chem. Soc., Chem. Commun. 1990, 362e364; (e) McKervey, M. A.; Ye, T. Tetra-
hedron 1992, 48, 8007e8022.
4.6.3. (Z)-1,5-Dihydroxy-1,5-bis(4-methoxyphenyl)pent-1-en-3-one
(6c). Prepared from diazoketone 5c according to the general pro-
cedure. The product 6c was obtained after column chromatography
(petroleum ether/diethyl ether: 8:2) as a pale yellow oil (77% yield).
7. (a) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285e1287; (b) Smith, J. A. I.;
Wang, J.; Nguyen-Mau, S.-M.; Lee, V.; Sintim, H. O. Chem. Commun. 2009,
7033e7035.
Rf (petroleum ether/diethyl ether: 7:3)¼0.18. IR (neat): nmax (cmꢀ1
)
3388, 2924, 1715, 1599, 1510, 1250, 1172, 1028, 824. 1H NMR
ꢀ
8. (a) Lopez-Herrera, F. J.; Sarabia-García, F. Tetrahedron Lett. 1993, 34, 3467e3470;
ꢀ
ꢀ
ꢀ
(b) Sarabia-García, F.; Pedraza-Cebrian, G. M.; Heras-Lopez, A.; Lopez-Herrera,
F. J. Tetrahedron 1998, 54, 6867e6896.
9. (a) Pellicciari, R.; Castagnino, E.; Fringuelli, R.; Corsano, S. Tetrahedron Lett. 1979,
20, 481e484; (b) Pellicciari, R.; Sisani, E.; Fringuelli, R. Tetrahedron Lett. 1980, 21,
4039e4042; (c) Cooksey, J. P.; Kocienski, P. J.; Li, Y.-F.; Schunk, S.; Snaddon, T. N.
Org. Biomol. Chem. 2006, 4, 3325e3336.
10. (a) Taber, D. F.; Herr, R. J.; Gleave, D. M. J. Org. Chem. 1997, 62, 194e198; (b)
Taber, D. F.; Kanai, K. Tetrahedron 1998, 54, 11767e11782; (c) Taber, D. F.; Kanai,
K. J. Org. Chem 1999, 64, 7983e7987; (d) Taber, D. F.; Jiang, Q. J. Org. Chem 2001,
66, 1876e1884; (e) Taber, D. F.; Teng, D. J. Org. Chem. 2002, 67, 1607e1612; (f)
Taber, D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121e13126; (g)
Taber, D. F.; Hoerrner, R. S.; Herr, R. J.; Gleave, D. M.; Kanai, K.; Pina, R.; Jiang, Q.;
Xu, M. Chem. Phys. Lipids 2004, 128, 57e67.
11. (a) Andrews, P. C.; Junk, P. C.; Krautscheid, H. Org. Biomol. Chem. 2010, 8,
698e705; (b) Wender, P. A.; Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5,
4549e4552.
12. (a) Kruglaya, O. A.; Fedot’eva, I. B.; Fedot’ev, B. V.; Kalikhman, I. D.; Brodskaya,
E. I.; Vyazankin, N. S. Izv. Akad. Nauk, Ser. Khim. 1976, 1887e1889; (b) Kruglaya,
O. A.; Fedot’eva, I. B.; Fedot’ev, B. V.; Kalikhman, I. D.; Brodskaya, E. I.;
Vyazankin, N. S. J. Organomet. Chem. 1977, 142, 155e164; (c) Fedot’eva, I. B.;
Kruglaya, O. A.; Kalikhman, I. D.; Vyazankin, N. S. Izv. Akad. Nauk SSSR, Ser. Khim.
1979, 2365e2366; (d) Brueckmann, R.; Maas, G. Chem. Ber. 1987, 120, 635e641;
(e) Brueckmann, R.; Schneider, K.; Maas, G. Tetrahedron 1989, 45, 5517e5530;
(f) Marsden, S. P.; Ducept, P. C. Beilstein J. Org. Chem. 2005, 1, 5, http://dx.doi.org/
10.1186/1860-5397-1-5; (g) Bucher, S M.; Brueckmann, R.; Maas, G. Eur. J. Org.
Chem. 2008, 4426e4433.
(400 MHz, CDCl3):
d
(ppm) 7.84 (d, 2H, J¼8.9 Hz), 7.33 (d, 2H,
J¼8.9 Hz), 6.94 (d, 2H, J¼8.9 Hz), 6.89 (d, 2H, J¼8.9 Hz), 6.10 (s, 1H),
5.16 (dd, 1H, J¼9.0, 3.7 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 2.86 (dd, 1H,
J¼15.3, 9.0 Hz), 2.77 (dd, 1H, J¼15.3, 3.7 Hz). 13C NMR (100.6 MHz,
CDCl3):
d (ppm) 194.5 (s), 182.9 (s), 163.5 (s), 159.4 (s), 135.5 (s),
129.4 (d), 127.2 (d), 127.0 (s), 114.2 (d), 114.1 (d), 96.5 (d), 71.1 (d),
55.7 (q), 55.5 (q), 48.5 (t). HRMS m/z calcd for C19H20O5 [M]þ
:
ꢄ
328.1311, found: 328.1333.
4.6.4. (3Z,8E)-3,7-Dihydroxy-2,2,8-trimethylundeca-3,8-dien-5-one
(6d). Prepared from diazoketone 5d according to the general pro-
cedure. The product 6d was obtained after column chromatography
(petroleum ether/diethyl ether: 8:2) as a pale yellow oil (88% yield).
Rf (petroleum ether/diethyl ether: 9:1)¼0.19. IR (neat): nmax (cmꢀ1
)
3444, 2964, 2933, 2871, 1595, 1459, 1363, 1284, 1219, 1135, 1010,
894, 860, 784, 732. 1H NMR (400 MHz, CDCl3):
d (ppm) 5.62 (s, 1H),
5.47 (t, 1H, J¼7.2 Hz), 5.44 (dd, 1H, J¼8.8, 3.8 Hz), 2.58 (dd, 1H,
J¼15.1, 8.8 Hz), 2.51 (dd, 1H, J¼15.1, 3.8 Hz), 2.03 (qt, 2H, J¼7.2 Hz),
1.64 (s, 3H), 1.17 (s, 9H), 0.96 (t, 3H, J¼7.2 Hz). 13C NMR (100.6 MHz,
CDCl3): d (ppm) 197.1 (s), 193.8 (s), 133.2 (s), 126.8 (d), 94.5 (d), 72.3
13. (a) Kitamura, M.; Tashiro, N.; Okauchi, T. Synlett 2009, 2943e2944; (b)
Hendrickson, J. B.; Wolf, W. A. J. Org. Chem. 1968, 33, 3610e3618.
14. The potential risk of self-condensation of TES-diazoacetone was prevented by
following an inverse addition protocol according to which a THF solution of
TES-diazoacetone 1a was slowly added to a stirred THF solution of LDA cooled
at ꢀ50 ꢁC.
(d), 43.1 (t), 36.9 (s), 25.5 (q, 3C), 19.0 (t), 12.1 (q), 9.9 (q). HRMS m/z
calcd for C14H25O3 [MþH]þ: 241.1804, found: 241.1804.
4.6.5. (1Z,6E)-1,5-Dihydroxy-6-methyl-1-phenylnona-1,6-dien-3-
one (6e). Prepared from diazoketone 5e according to the general
procedure. The product 6e was obtained after column chromatog-
raphy (petroleum ether/diethyl ether: 8:2) as a pale yellow oil (70%
yield). Rf (petroleum ether/diethyl ether: 7:3)¼0.15. IR (neat): nmax
(cmꢀ1) 3426, 2927, 1716, 1599, 1568, 1269, 1176, 1026, 765. 1H NMR
15. Maas, G.; Brueckmann, R. J. Org. Chem. 1985, 50, 2801e2802.
16. Padwa, A.; Sa, M. M. J. Braz. Chem. Soc. 1999, 10, 231e236.
17. The ketoeenol tautomer depicted in Scheme 5 for 6ae6e was shown to be
the most stable one at the EDF2/6-31G(d) level (Spartan’10 Wavefunction, Ir-
vine, CA)
18. Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188e196.