An unusual regiochemistry of reactions of a cyclohexenylphosphonate bearing a β-ethoxycarbonyl group with aldehydes

Article abstract of DOI:10.1016/j.tet.2011.01.016

Reactions of lithiated ethyl 6-(dimethoxyphosphoryl)cyclohex-1- enecarboxylate with aliphatic, aromatic, and unsaturated aldehydes were studied and determined to proceed with α or δ regioselectivity. Such an unusual regioselectivity results from the contr

Full text of DOI:10.1016/j.tet.2011.01.016

Tetrahedron 67 (2011) 1938e1947
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An unusual regiochemistry of reactions of a cyclohexenylphosphonate bearing
a
b-ethoxycarbonyl group with aldehydes
*
Ewa Krawczyk , Krzysztof Owsianik
ꢀ ꢀ
Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2010
Received in revised form 9 December 2010
Accepted 6 January 2011
Available online 13 January 2011
Reactions of lithiated ethyl 6-(dimethoxyphosphoryl)cyclohex-1-enecarboxylate with aliphatic, aro-
matic, and unsaturated aldehydes were studied and determined to proceed with
a or d regioselectivity.
Such an unusual regioselectivity results from the contribution of two allylic carbanions: one, stabilized
by the phosphonate moiety and the other stabilized by the carboethoxy group. The course of the reaction
depends mainly on the structure of the aldehyde and the reaction conditions. The products of Hor-
nereWadswortheEmmons reaction, including an analogue of some retinol metabolites, were formed
Keywords:
under kinetic conditions whereas the
d
-adducts were obtained as thermodynamic products.
Ó 2011 Elsevier Ltd. All rights reserved.
Phosphonate
HWE reaction
Regioselectivity
Allylic compounds
1. Introduction
formed in most cases.7 The regioselectivity of these reactions (
-addition) was studied and it was established that steric effects of
a- vs
g
The chemistry of allylic anions containing
a
-heteroatom sub-
the selected aldehydes exerted an influence on the regiochemical
outcome of these condensations.
stituents, such as SiR3, SR, OR, NR2, P(O)R2 has been intensively in-
vestigated over the years.1 Among these ambident anions, those
containing phosphoryl functionality occupy an important position
since their reaction with carbonyl compounds constitutes a very
usefulmethodinsyntheticorganicchemistry.2 Regiochemical control
inthesereactions iscrucial tothe application of thesemethods. Alk-2-
As a part of our research concerning the synthesis of multifunc-
tional cyclic compounds 1,8 we have recently elaborated the regio-
and stereo-selective synthesis of new cyclic allylic phosphonates 2,
3.9 Selected model phosphonates were prepared via stereoselective
reaction of trimethyl phosphite with cyclohexen-2-yl phosphates 1.
The latter are cyclic BayliseHillman adducts (Scheme 1).
The phosphonates 2, 3 activated by the carboethoxy group in the
enylphosphonic esters being versatile compounds offer their
carbon atom as the nucleophilic center.2 These phosphonates, acti-
vated in , or position by an electron withdrawing or donating
a or g
a,b
g
b position, could be potential substrates for the preparation of exo/
group, have found wide applications in the synthesis of olefins via the
HornereWadswortheEmmons (HWE) reaction.1,3,4 In this way (E,E)
or (E,Z) carboalkoxy- and cyano-substituted butadiene3b,5 and (E,E)-
endo unsaturated cyclic compounds by HWE reaction with various
aldehydes. Such an unsaturated moiety constitutes a structural part
of some metabolites of vitamin A.10,11 Further development in this
area may lead to easy access to biologically important molecules.11
Thus, we decided to investigate the reaction of a cyclic allylic
phosphonate anion derived from 3 with appropriate aldehydes as
a possible alternative route to relevant model compounds. We have
particularly concentrated on the mechanistic investigations bring-
ing a better understanding on the varied reactivity of multifunc-
tional phosphonate 3. In this paper, we describe these studies and
report the preliminary results.
a,b,g,d
unsaturated esters4d were prepared. On the other hand some
reactions of allylic phosphonates, proceeding with g-regioselectivity,
provide easy access to differently substituted cyclic compounds,2b
including heterocyclic phosphonolactones.3c
The synthesis of
b-carotenes from retinylphosphonate is an
example of utilization of HWE reactions between aldehydes and
the acyclic allylic phosphonates containing no additional stabilizing
groups.6 Gerber and Modro examined reactions of non-activated
cyclohexen-2-ylphosphonate with various aldehydes and found
that 1-[10-hydroxyalkyl(aryl)]cyclohexen-2-ylphosphonates were
2. Results and discussion
In the reaction of phosphonate 3 with carbonyl compounds,
with respect to the structure of 3, we could consider the following
possible pathways (Scheme 2).
* Corresponding author. E-mail address: ewakrsoj@bilbo.cbmm.lodz.pl (E. Krawczyk).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.016

E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
1939
O
H
OP(O)(OEt)2
C(O)OEt
H
P(O)(OMe)2
C(O)OEt
SP(O)(OEt)2
C(O)OEt
(MeO)3P
R
Δ
R
toluene,
70-80%
R
n
n
n
1
2a R = H; n = 1
2b R = 3-Me; n = 2
2c R = 5-Ph; n = 2
R = H; n = 1,2
R = 3-Ph, 5-Me; n = 2
3
R = H; n = 2
Scheme 1. General synthesis of b-carboethoxy cycloalkenyl phosphonates 2 and 3.
Scheme 2. Proposed mechanism for the reaction of b-carboethoxy cyclohexenyl phosphonate 3 with aldehydes.
Treatment of the phosphonate 3 with a base should afford the
cyclic phosphoryl-stabilized allylic carbanion 4a, that can react as
protonation of adduct 8 leads to the final (4-hydroxyalkyl)vinyl-
phosphonate 9.
an ambident species with aldehydes in
a
-C or
g
-C position to give
The presence of the carboethoxy group at the
compound 3 also allows deprotonation at the position to form an
appropriate anion 4b. In this case the addition of the aldehyde can
take place either at the - or at -carbon atom to afford the in-
b-carbon atom of
one of two possible intermediates, oxyanion 5 or 812 (Scheme 2,
path ‘a’). This addition is usually reversible and the corresponding
d
a
-adduct 5 is formed as a kinetic, and
g-adduct 8 as a thermody-
b
d
namic product. Adduct 5 can undergo HWE reaction to give the
corresponding diene 6 and phosphate anion or can be simply
quenched forming (2-hydroxyalkyl)phosphonate 7.13 Similarly the
termediateadducts10 and12 thatsubsequentlyformproducts 11 and
13, respectively (Scheme 2, path ‘b’). We have assumed that equilib-
riumbetween 4aand 4bcould occurbya protonationedeprotonation

1940
E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
sequence and carboanion 4bwould be formed as the thermodynamic
isomer.14 Taking into account the reversibility of the aldehyde addi-
tion step, that can proceed by path ‘a’ or ‘b’, this reaction can lead to
different products. Using different conditions, the reaction can be
underkinetic or thermodynamiccontrol. Thecomplex natureof these
processes led us to search for a suitable procedure to control their
regioselectivity.
the anion stabilizing polarization of the phosphonyl group.16 Such
a downfield shift w40 ppm in the 31P NMR spectrum of an anion,
compared with its parent compound, is in agreement with de-
localization of negative charge in a salt-like structure 4a.3c,16,17
The reactions of phosphonate 3 performed by formation of the
carbanion with LDA and addition of simple aliphatic aldehydes
proceeded smoothly under the given conditions to give the desired
products of the HWE olefinationdthe corresponding (E/Z)-ethyl
6-alkylidenecyclohex-1-enecarboxylate 6. Dienes 6a (R¼CH3) and
6b (R¼C2H5) were obtained in moderate yield and stereoselectivity
(Scheme 3, Table 1, entries 1 and 2). When the crude reaction
mixture was quenched with water at 0 ꢁC instead of room tem-
perature, the product of the initial addition of acetaldehyde to 4a,
namely compound 7a (R¼CH3), was isolated (Scheme 3, Table 1,
entry 3). The product of the olefination reaction with 2,4-hex-
adienal 6d [R¼CH3e(CH]CH)2] was isolated in only 30% yield. The
other components of this reaction mixture were the parent phos-
phonate 3 and unreacted aldehyde (Scheme 3, Table 1, entry 5). In
the reaction with acrolein, only the product of addition to 4a (7c,
R¼eCH2]CH) was found and isolated in low yield from the re-
action mixture at room temperature (Scheme 3, Table 1, entry 4).
2.1. The reaction of phosphonate 3 with aldehydes under
standard conditions
First, we examined the reaction of 3 with selected aliphatic,
aromatic, and unsaturated aldehydes, according to a general pro-
cedure described for acyclic 2-carboethoxy substituted allylphos-
phonate.5a The reaction was performed by addition of an
appropriate aldehyde to a THF solution of the lithium phosphonate
carbanion at ꢀ78 ꢁC. The reaction mixture was stirred at low
temperature for 2 h and at room temperature for 10 h and finally
quenched with aqueous ammonium chloride.13 Crude reaction
mixtures were analyzed by 1H and 31P NMR spectroscopy. The
detailed reaction conditions are given in Table 1.
Table 1
Reaction of phosphonate 3 with aldehydes according to procedures A and Ba
Entry
Aldehyde R
Path ‘a’
Path ‘b’ addition
Yield (%)
Ratio of isomers
product at Cd
6 or 7 or 11
Addition
HWE product
product at Ca
1
2
3
4
5
6
7
8
9
CH3
d
d
7a
7c
d
d
d
d
d
6a
6b
d
d
6d
d
d
d
d
d
41b
45b
46e
35e
30b
71e
44e
49e
41e
3:1c
2:1
2:1
1:1
nd
C2H5
d
d
CH3
d
CH2]CH
CH3(CH]CH)2
C6H5
d
d
11e
11e
11f
11f
2:1e
1:1e
1.3:1e
1:1e
f
C6H5
(CH3)2CH
(CH3)2CHg
a
Procedure A: base: LDA; procedure B: base: BuLi; conditions: (i) base, THF, ꢀ78 ꢁC; (ii) RCHO, THF, ꢀ78 ꢁC, 2 h; (iii) rt, 10 h, then NH4Cl/H2O.
b
c
d
e
f
Yield of isomers mixture after isolation.
After 24 h at rt.
Conditions: (iii) 0 ꢁC, 2 h, then H2O.
By 31P NMR spectroscopy of crude mixture.
Conditions: (ii), RCHO rt 12 h, then H2O.
Procedure B.
g
H1'
R
rt
10 h
C(O)OEt
6a R = CH3
6 b R = C2H5
O
Li
(MeO)2(O)P
RCHO
R
6d R =
CH3
C(O)OEt
LDA
3
4a
-78 oC
-78 o
2 h
C
HO
R
H
1 h
(MeO)2(O)P
H
5a-d
C(O)OEt
7a R = CH3
7c R = CH=CH2
0 oC or
rt,10 h
Scheme 3. Preparation of dienes 6a,b,d and a-adducts 7a,c from phosphonate 3.
The complete formation of the phosphonate carbanion 4a from 3,
This mixture also contained starting 3 and probably polymerized
acrolein.3a,18
using lithium diisopropylamide in tetrahydrofuran, was achieved at
ꢀ78 ꢁC within 1 h. This was proved by quenching the reaction with
The structures of all products obtained were confirmed by 1H
and 31P NMR spectroscopy and mass spectrometry. The E/Z ratio of
D2SO4, leading to a fully a
-deuterated phosphonate 3-d1.15 Addi-
tionally the structure of lithiated phosphonate 4a was confirmed by
low temperature 31P NMR spectroscopic studies. The 31P NMR signal
of lithium phosphonate shifted downfield at ꢀ70 ꢁC and indicated
6a, b was determined by 1H NMR spectroscopy, which indicated
0
that the H1 proton signals of the E isomer are observed downfield
in comparison to the Z isomer.7,19 Compound 6d was most likely

E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
1941
formed as a single E isomer.3a The configuration of the newly
formed double bond was not determined due to the complexity of
its 1H NMR spectrum. Adducts 7a and 7c were obtained as a mix-
tures of two diastereoisomers formed in a ratio of 2:1 and 1:1, re-
spectively, as determined by 31P NMR spectroscopy.
unidentified compounds were the remaining components of the
crude reaction mixture (Table 1, entry 7).
2.2. Reaction of phosphonate 3 with aldehydes under
modified conditions
In contrast, the reactions of lithiated 3 with benzaldehyde and 2-
methylpropanal, using LDA or BuLi as a base, afforded d-addition
Considering the potential synthetic utility of the reactions
studied we searched for a method for controlling and improving
the regioselectivity. To this end, we extended our studies to ex-
amine these reactions under different reaction conditions. The re-
sults of these experiments are summarized in Table 2.
products 11e (R¼C6H5) and 11f (R¼CH(CH3)2), respectively, in good
to moderate yield (Scheme 4, Table 1, entries 6, 8, and 9). The adduct
11e was stable at room temperature and only partially decomposed
to phosphonate 3 and other unidentified compounds when treated
with BuLi at low or at ambient temperature (Experimental).
Inspection of Table 2 shows that increasing the time (to
10e12 h) at low and at ambient temperature of the reactions of
lithiated phosphonate 3 with aliphatic aldehydes like propanal,
cyclohexanecarbaldehyde or 2-methylpropanal gave none or only
traces of the olefination product (6f) (Scheme 5, Table 2, entry 2).
Products arising from the self-condensation of aldehydes20 were
the main components of these post-reaction mixtures together
with a small amount of phosphonate 3 and other unidentified
compounds. Shortening of the time to 4 h at low and room tem-
(MeO)2(O)P
RCHO
4b
H
(MeO)2(O)P
H
C(O)OEt
C(O)OEt
LDA
-78 oC
1 h
rt
4a
3
-78 o
C
10 h
H
2 h
H
R
R
O
10e,f
Li
HO
H
11e R = C6H5
11f R = CH(CH3)2
perature in the reaction with propanal, provided mainly the a-ad-
duct 7b in 54% yield (Scheme 5, Table 2, entry 1).
Scheme 4. Preparation of d-adducts 11e, 11f from phosphonate 3.
Table 2
Reaction of phosphonate 3 with selected aliphatic and
a,b-unsaturated aldehydes and benzaldehyde under modified conditions
Entry
Aldehyde (R)
Conditionsa
Addition product
at Ca or at Cd
HWE product
Yieldb (%)
Ratio of isomers
6, 7 or 11
1
2
3
4
5
C2H5
(CH3)2CH
C6H5
C6H5
CH3(CH]CH)2
Cc
C
C
7b
d
d
d
d
6f
6e
6e
6d
54
w5e
52
55
35
nd
nd
4:1
5:1
nd
D
Cd
11d
30
1.2:1
C(O)OEt
6
Cf
d
6g
78
w20:1
a
Conditions; C: (i) basedLDA, ꢀ78 ꢁC, 1 h; (ii) RCHO, ꢀ78 ꢁC, 10e12 h, (iii) rt 10e12 h; D: (i) NaH, ꢀ10e0 ꢁC, 1 h; (ii) RCHO, ꢀ40 to ꢀ10 ꢁC, 10 h; (iii) 20 ꢁC, 12 h.
Yield of isomers mixture after isolation.
b
c
d
e
f
Conditions: (ii) RCHO, ꢀ78 ꢁC, 4 h; (iii) rt 4 h.
Conditions: (ii) RCHO, ꢀ78 ꢁC, 4 h; (iii) rt 14 h.
Estimated by 1H NMR spectroscopy and GCeMS spectra.
Conditions: (ii) RCHO, ꢀ78 ꢁC, 20 h; (iii) rt 20 h.
HO
(MeO)2(O)P
R
The structures of the new adducts 11e and 11f were determined
on the basis of detailed spectroscopic analysis: 1H, 13C, 31P NMR,
and mass spectrometry. Moreover, double-resonance experiments
(COSY), including heteronuclear 2D spectra (HMQC) ultimately
confirmed the structure of these derivatives. The formation of
H
C(O)OEt
rt, 4 h
54%
7 b R = C2H5
ii
i
g
-addition (vinyl phosphonate) as well as of
b-addition adducts
4a
3
5b,f
was excluded based on 1H and 31P NMR spectroscopic data. The
d-
R
H
adducts 11e, f were obtained as mixtures of two diastereoisomers,
formed in comparable proportions, as determined by 31P NMR
spectroscopy. The diastereomeric mixture of 11e (R¼C6H5) was
separated to individual isomers.
It is evident that the latter reactions (Scheme 4, Table 1, entries
6, 8, and 9) proceed via carbanion 4b leading to compounds 11e, f. It
was of interest to characterize carbanion 4b by means of 31P NMR
spectroscopy. Lithium phosphonate was prepared according to the
general procedure at low temperature. Then, after 1 h, this sample
was warmed up to ambient temperature and its 31P NMR spectrum
was recorded. The 31P chemical shift (30.3 ppm) of this in-
termediate was close to that of the parent compound 3. Addition of
benzaldehyde to the solution of this anion at room temperature
C(O)OEt
+ [(CH3)2CHCHO]n
rt,10 h
~5%
+ 3
i: LDA, -78 o
C
ii: C2H5CHO, -78 oC, 4 h
6f R= (CH3)2CH-
3 with aliphatic aldehydes under modified
or (CH3)2CHCHO, -78 oC, 10 h
Scheme 5. Reaction of phosphonate
conditions.
In this case, prolongation of time under kinetically-controlled
conditions, causes a competition between formation of the in-
gave the product of
d-addition 11e in 44% of yield after 12 h of the
termediate
a-adduct 5 and self-condensation of enolizable alde-
reaction time. Traces of unreacted phosphonate 3 and some
hydes. The latter experiment revealed that HWE olefination

1942
E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
reaction needed more than a few hours at ambient temperature to
be complete (Table 2, entry 1 and Table 1, entry 2).
in high yield (78%) and stereoselectivity, as concluded on the basis
of the 1H NMR spectrum of the crude reaction mixture. In this
C6H5
H
C6H5CHO
(MeO)2(O)P
-78 oC, 12 h
M
LDA
C(O)OEt
-78 oC, 1 h
C(O)OEt
next rt 10-12 h
3
(or -40o to -10 o
10 h, next rt 10-12 h)
C
or NaH
-10 oC, 1 h
6e
E:Z = 4:1 (5:1)
4a M = Li or Na
Scheme 6. Synthesis of substituted benzylidene cyclohexene 6e.
Extension of the reaction time allowed successful HWE olefi-
nation reactions with less reactive benzaldehyde, using LDA or
sodium hydride as a base (Scheme 6, Table 2, entries 3 and 4).
The reaction of lithium phosphonate 4a with 2,4-hexadienal,
performed under the conditions described in Table 1, gave the
desired olefination product. However, due to low conversion such
a procedure is not synthetically useful. Taking into account that
C(O)OEt
H1'
OHC
EtO(O)C
1) LDA, THF
-78oC, 20h
2) rt, 20h
+
H3'
H5
6g
H7'
P(O)(OMe)2
C(O)OEt
H2
C(O)OEt
NOE-3%
78%
3
products of the HWE reaction of phosphonate 3 with
a,b-un-
saturated aldehydes can constitute a building block for the synthesis
of polyene-structured natural products,21 it seemed important
searching for suitable conditions to improve the yield of the olefi-
nation reaction. Thus, using 2,4-hexadienal, the reaction time was
increased. This reaction, performed under the conditions given in
Table 2 (entry 5) gave diene 6d in slightly higher yield (35% after
Scheme 8. Synthesis of poliene 6g.
spectrum, mainly one isomer with traces of a second were detected
(Scheme 8; Table 2, entry 6).
Full spectroscopic analysis of 6g, including 1He1H double-res-
onance was carried out. The E geometry of the newly formed
isolation) together with the unexpected d-addition product 11d,
formed in 30% yield. Adduct 11d spontaneously converted into
P(O)(OMe)2
C(O)OEt
OHC
CH3
C(O)OEt
LDA, 1h
4a
+
3
4b
1) -78 oC, 4 h
2) rt 14 h
-78 oC
HO
H
P(O)(OMe)2
11d (30%)
6d (35%)
C(O)OEt
5 oC, 5d
11d
14
Scheme 7. Reaction of phosphonate 3 with 2,4-hexadienal.
conjugated derivative 14 after 5 days when stored at 5 ꢁC (Scheme 7,
Table 2, entry 5).
double bond was assigned from 1H NOE experiment. Irradiation of
the methylene protons (H5) of the cyclohexene ring gave an
0
In turn, utilization of an
a
,b
-unsaturated aldehyde containing
enhancement (w3%) of only one signal (vinyl proton H3 ). The
a
long polyethylene chain, namely (2,6-dimethyl-7-ethoxy-
MNDO calculation of both E and Z isomers of 6g confirmed the E
0
0
5
5
22
geometry (H3 eHax, H3 eHeq 3.4 A and 3.5 A, respectively). The
derivative 6g constitutes an analogue of some retinol metabolites
such as anhydroretinol (AR) or 14-hydroxy-4,14-retro-retinol (14-
HRR).10
ꢁ
ꢁ
carbonyl)-2,4,6-heptatrienal, under the same conditions, did not
yield any product. Only unreacted starting materials were found in
the crude post-reaction mixture.
It is clear that for condensation with a,b-unsaturated aldehydes,
much longer reaction time at low and at room temperature is
needed to obtain of HWE reaction product 6 in reasonable yield.
Therefore, in the next experiment with (2,6-dimethyl-7-ethoxy-
carbonyl)-2,4,6-heptatrienal, the adjusted reaction conditions were
applied. Prolongation of the reaction time up to 20 h at low and at
ambient temperature gave the desired HWE olefination product 6g
We have also tested the BonadieseScettri23 procedure, which
was earlier successfully adapted by Takacs and co-workers for the
synthesis of (E,E)-
promoted HWE reaction of 3 with both
a,b,g,d
unsaturated esters.4d From this LiOH-
a,b-unsaturated aldehydes,
that is, hexadienal and substituted hexatrienal, only starting ma-
terials were isolated.

E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
1943
Our investigations revealed that among the possible pathways
shown in Scheme 2, the addition of lithiated phosphonate 3 to
Variations of these procedures are given with the data of the in-
dividual product and in Tables 1 and 2.
aldehydes took place exclusively at the a-C and d-C with respect to
phosphorus. Such unusual regiochemistry results from the in-
volvement of two allylic carbanions: 4a, stabilized by the phos-
phonate moiety and 4b stabilized by the carboethoxy group.
4.2.1. Ethyl 6-deutero-6-(dimethoxyphosphoryl)cyclohex-1-enecarbox-
ylate (3-d1). To a stirred solution of diisopropylamine (30 mg,
0.3 mmol) in THF (1.5 mL) at ꢀ78 ꢁC was added butyllithium
(0.12 mL, 0.3 mmol, 2.5 M solution in hexane). The mixture was
allowed to warm to ꢀ20 ꢁC for 30 min, after which was cooled to
ꢀ78 ꢁC and phosphonate 3 (63 mg, 0.25 mmol) in THF (2 mL) was
added dropwise. The light brown solution was stirred at ꢀ78 ꢁC for
The formation of carbanion 4a after removal of the
a-proton
to phosphorus is kinetically determined. Subsequent reversible
reaction of carbanion 4a with the aldehyde proceeding under ki-
netic conditions gave the intermediate a-adduct 5, which collapses
to diene 6 and phosphate anion or transposes to 2-hydrox-
yphosphonate 7 after being quenched with a proton source.
The equilibration of carbanion 4a to 4b occurs by a proto-
nationedeprotonation sequence yielding 4b as the more thermo-
dynamically stable isomer. It is a dominant process at elevated
1 h and quenched by the addition of concentrated D2SO4 (25 mL,
0.5 mmol). The resulting colorless mixture was allowed to warm to
room temperature, diluted with CH2Cl2 (5 mL), washed with water
(5 mL), extracted with CH2Cl2 (2ꢂ3 mL), and dried (MgSO4). The
solvent was evaporated in vacuo to give the crude mixture (36 mg).
dP (81 MHz, CDCl3) 32.5 (10%), 31.8 (7%), 31.5 (83%). Purification of the
crude product by preparative chromatography (50% hexane/EtOAc)
gave the title compound 3-d1 (30 mg, 45%) as yellowish oil; Rf (45%
hexane/EtOAc) 0.2; dP (81 MHz, CDCl3) 31.5; dH (200 MHz CDCl3) 7.03
(1H, t, J 3.4 Hz, C]CH), 4.20 (2H, q, J 7.1 Hz, OCH2CH3), 3.71 (3H, t, J
10.6 Hz, OCH3) 3.70 (3H, t, J 10.6 Hz, OCH3), 2.30e1.79 (4H, m, CH2),
1.72e1.52 (2H, m, CH2), 1.28 (3H, t, J 7.1 Hz, OCH2CH3); dD (500 MHz,
CDCl3) 3.32 (1D, br s, C(D)-P(O)(OMe)2); m/z (CI, isobutane) 264 (100,
MHþ), 218 (16%).
temperature leading exclusively to the
d-substituted conjugated
derivatives 11. The -regioselectivity of the reaction with aldehydes
d
containing a bulky substituent could be influenced by steric factors.
A similar result was achieved when the phosphonate carbanion
was treated with iodomethane to give the product of d-alkylation’s
(2b) (Experimental).
3. Conclusion
To summarize, we have shown that the course of the reaction of
aldehydes with the cyclic allylic phosphonate carbanion, activated
4.3. Reactions of phosphonate 3 with aldehydes
in the b-position by a carboethoxy group, depends on the structure
of the aldehyde as well as on the reaction conditions. We have
established that these conversions are regioselective giving the
Procedure A. A solution of phosphonate 3 (262 mg, 1.0 mmol) in
THF (3 mL) was added dropwise at ꢀ78 ꢁC to THF solution of LDA
(1.25 mmol) [freshly prepared from diisopropylamine (0.175 mL,
1.25 mmol) and BuLi (0.78 mL,1.6 M solution in hexane,1.25 mmol)
in THF (5 mL) at the ꢀ20 ꢁC for 30 min]. The mixture was stirred at
ꢀ78 ꢁC for 1 h before addition of relevant aldehyde (1.0 mmol,
freshly distilled) in THF (2 mL). After 2 h, the reaction mixture was
allowed to warm to room temperature, stirred for further 10 h and
quenched by the addition of saturated aqueous ammonium chlo-
ride solution (5 mL), extracted with CHCl3 (3ꢂ5 mL), and dried
(MgSO4). The solvent was evaporated in vacuo and residue was
purified by flash chromatography on silica gel using gradient of
EtOAc/petroleum ether as eluent to give the compounds charac-
terized below.
products via a
a- or d-addition reaction. The unusual d regiose-
lectivity of some reactions was caused by the presence of the car-
boethoxy functionality that is responsible for the formation of the
appropriate allylic carbanion after removal of the acidic d hydrogen
atom. We have defined the proper HWE reaction conditions to
obtain the corresponding substituted polyene (6g), an analogue of
retinol metabolites.
4. Experimental
4.1. General
1H, 13C, and 31P NMR spectra were recorded on a Bruker AC 200
Spectrometer at 200.13, 50.32 and 81.02 MHz, respectively (using
CDCl3 as solvent) unless otherwise noted. When necessary, homo-
nuclear 1He1H correlation (COSY) and heteronuclear 1He13C cor-
relation (HMQC) spectra were obtained for structural assignments.
Carbon multiplicities were assigned byDEPTexperiments. IR spectra
were measured on an Ati Mattson Infinity FT IR 60. GC spectra were
performed on a HewlettePackard 5890. MS spectra (EI, CI, and
HRMS) were recorded on a Finnigan MAT 95 spectrometer. All the
reactions were carried out using anhydrous conditions and in an
atmosphere of argon. Chromatographic purification was performed
on silica gel columns (Merck, Kieselgel 70e230 mesh) with in-
dicated eluent. Chemicals and solvents were obtained from com-
mercial sources and distilled or dried according to standard
4.3.1. (Z/E)-Ethyl 6-ethylidenecyclohex-1-enecarboxylate (6a). Color
less oil; 73 mg, 41%; Rf (45% EtOAc/hexane) 0.52; nmax (film) 3030,
2920, 2860, 2845, 1710, 1640, 900, 730 cmꢀ1
; dH (200 MHz, CDCl3)
two isomers E and Z (3:1) 6.90 (1H, dd, J 4.1, 4.1 Hz, C]CH, Z), 6.51
(1H, t, J 3.8 Hz, C]CH, E), 5.95 (1H, q, J 9.3 Hz, CH3CH], E), 5.36 (1H,
q, J 9.1 Hz, CH3CH], Z), 4.20 (4H, q, J 7.1 Hz, OCH2CH3), 2.64e2.53
(3H, m, CH2), 2.41e2.24 (5H, m, CH2), 2.18e1.87 (5H, m, CH2,
CH3CH], Z), 1.64 (3H, d, J 9.3 Hz, CH3CH], E), 1.59e1.52 (2H, m,
CH2), 1.31 (6H, br t, J 7.1 Hz, OCH2CH3); dC (50 MHz, CDCl3) 169.0,
166.1, 145.2, 137.8, 132.3, 128.2, 124.9, 122.3, 61.2, 31.5, 28.1, 27.7,
27.1, 24.2, 22.5, 14.8, 14.1, 13.6; m/z (EI) 180 (25, Mþ), 165 (62), 119
(100%); HRMS (EI): Mþ, found: 180.1153. C11H16O2 requires
180.1150.
methods.
2E,4E,6E-2,6-Dimethyl-7-ethoxycarbonyl-2,4,6-hepta-
trienal24, and phosphonate 39 were prepared as described.
4.3.2. (Z/E)-Ethyl 6-propylidenecyclohex-1-enecarboxylate (6b). Col
orless oil; 87 mg, 45%; Rf (45% EtOAc/hexane) 0.65; nmax (film) 3009,
4.2. Metalations of phosphonate 3
2890, 2860, 1715, 1646, 1008, 920 cmꢀ1
; dH (200 MHz, CDCl3) two
isomers E and Z (2:1) 7.05 (1H, t, J 4.0 Hz, HC]CCOOEt, Z), 6.88 (1H,
t, J 4.7 Hz, HC]CCOOEt, E), 6.32 (1H, br d, J 9.9 Hz, C]CHEt, E), 5.85
(1H, dt, J 2.2, 9.1 Hz, C]CHEt, Z), 4.17 (2H, q, J 7.2 Hz, OCH2CH3), 4.14
(2H, q, J 7.3 Hz, OCH2CH3), 2.25e2.15 (4H, m, CH2), 2.12e2.02 (4H,
m, CH2), 1.46 (2H, d, J 7.5 Hz, CH2), 1.42 (4H, dd, J 7.4, 2.2 Hz, CH2),
1.40e1.33 (2H, m, CH2), 1.25 (3H, t, J 7.2 Hz, OCH2CH3), 1.14 (3H, t, J
7.3 Hz, OCH2CH3), 0.97 (3H, t, J 7.5 Hz, ]CHCH2CH3, E), 0.95 (3H, t, J
In general, lithiations of phosphonate 3 with lithium diisopro-
pylamide was carried out according to procedure A and C; with
butyllithium according to procedure B. Metalation using sodium
hydride was performed according to procedure D. The typical
procedure A or C, was used in the sets of experiments and repre-
sented reactions on scale of 0.25e1 mmol of phosphonate 3.

1944
E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
7.6 Hz, ]CHCH2CH3, Z); dC (50 MHz, CDCl3) 168.8, 165.3, 150.4,
146.2, 141.3, 137.8, 134.3, 131.5, 128.2, 122.3, 60.6, 32.3, 25.9, 25.2,
24.6, 22.5, 21.7, 19.4, 14.5, 13.3, 12.8; m/z (EI) 194 (33, Mþ), 179 (55),
165 (30), 109 (100%); HRMS (EI): Mþ, found: 194.1311. C12H18O2
requires 194.1307.
124.9 (Ar), 74.1 (CHOH), 59.6 (OCH2CH3), 52.3, 51.8 (d, J 7.8 Hz,
POMe), 42.7 (CHCH(OH)), 30.3 (d, J 132.0 Hz, CHP), 22.4 (PCHCH2),
17.4 (CH2CHCH]), 13.2 (OCH2CH3); m/z (CI, isobutane) 369 (100,
MHþ), 351 (60), 262 (8), 155 (18%).
4.3.5.1. Reaction of 11e with butyllithium. Butyllithium (0.17 mL
of 1.6 M solution in hexane, 0.27 mmol) was added to a stirred
solution of the compound 11e (two diastereoisomers 1:1, 60 mg,
0.16 mmol) in THF (4 mL) at ꢀ78 ꢁC. The mixture was allowed to
warm to room temperature, stirred for 10 h and quenched by the
addition of saturated aqueous ammonium chloride solution (3 mL),
extracted with CHCl3 (3ꢂ3 mL), and dried (MgSO4). The solvent
was evaporated in vacuo to give the crude product (37 mg); m/z
(CI, isobutane) 387 (34), 369 (30, MHþ), 285 (56), 263 (82), 155
(100%).
4.3.3. Ethyl 6-((2E,4E)-hexa-2,4-dienylidene)cyclohex-1-enecarbox-
ylate (6d). Yellow oil; 69 mg, 30%; Rf (40% hexane/EtOAc) 0.59; nmax
(film) 2930, 2857, 1737, 1687, 1642, 1449, 1315, 1139 cmꢀ1
; dH
(200 MHz, CDCl3) 6.96 (1H, br d, J 14.3 Hz, ]CH), 6.37e5.93 (2H, m,
]CH), 5.83e5.62 (1H, m, ]CH), 5.53e5.48 (1H, m, ]CH.), 5.34 (1H,
br t, J 5.5 Hz, ]CH), 4.22 (2H, q, J 7.2 Hz, OCH2CH3), 2.48e2.14 (4H,
m, CH2), 1.78e1.64 (5H, m, CH2, CH3), 1.29 (3H, t, J 7.2 Hz, OCH2CH3);
dC (50 MHz, CDCl3) 166.8, 147.6, 144.7, 141.3, 139.4, 137.3, 134.3,
132.4, 128.3, 61.1, 28.6, 26.5, 24.9, 19.3, 14.1; m/z (CI, isobutane) 233
(20, MHþ), 147 (100), 129 (10%).
4.3.6. Ethyl 6-(dimethoxyphosphoryl)-6-(1-hydroxyethyl)cyclohex-1-
enecarboxylate (7a). Procedure A. To THF solution of LDA (0.18 mmol)
[freshly prepared from diisopropylamine (0.025 mL, 0.18 mmol) and
BuLi (0.078 mL, 2.3 M solution in hexane, 0.18 mmol) in THF (1.5 mL)
at the ꢀ20 ꢁC for 30 min] at ꢀ78 ꢁC was added dropwise a solution of
phosphonate 3 (44 mg, 0.17 mmol) in THF (1 mL). The mixture was
4.3.4. Ethyl 6-(dimethoxyphosphoryl)-6-(1-hydroxybut-3-enyl)cyclo-
hex-1-enecarboxylate (7c). Colorless oil; 110 mg, 35%; Rf (42% EtOAc/
hexane) 0.3; nmax (film) 3380, 2951, 2860, 1702, 1430, 1215, 1118,
1060, 870 cmꢀ1
; dP (81 MHz, CDCl3) 31.9, 30.1 two diastereoisomers
(1:1); dH (200 MHz, CDCl3) 7.04 (1H, t, J 3.6 Hz, C]CHCH2),
6.78e6.54 (3H, m, CH]CH2, CH]CH2, C]CHCH2), 6.42 (1H, d, J
17.2 Hz, CH]CH2), 6.12 (1H, dd, J 10.3, 17.2 Hz, CH]CH2), 5.83 (2H, d,
J 10.3 Hz, CH]CH2), 4.34e4.17 (6H, m, OCH2Me, CHOH), 3.77 (6H, d, J
10.8 Hz, OMe), 3.74 (6H, d, J 10.8 Hz, OMe), 2.38e2.17 (6H, m, CH2),
2.09e1.93 (2H, br s, CH2), 1.88e1.68 (4H, m, CH2), 1.30 (6H, t, J 7.0 Hz,
OCH2CH3); dC (50 MHz, CDCl3) 166.7, 165.3, 141.2, 136.4, 136.3, 128.5,
128.3, 115.5, 114.3, 75.5, 74.2, 60.7, 52.8, 52.6, 46.8 (d, J 133.6 Hz) 45.3
(d, J 131.2 Hz), 24.9, 23.2, 22.9, 20.1, 17.2, 13.6; m/z (CI, isobutane) 319
(10, MHþ), 303 (20), 279 (30), 263 (100%).
stirred at ꢀ78 ꢁC for 1 h before addition of acetaldehyde (9.5
mL,
0.17 mmol, freshly distilled) in THF (0.5 mL). After 2 h, the reaction
mixture was allowed to warm to 0 ꢁC, and quenched by the addition
of water (1 mL), extracted with CHCl3 (2ꢂ2.5 mL), and dried (MgSO4).
The solvent was evaporated in vacuo to give the crude product. Pu-
rification by preparative chromatography (50% EtOAc/petroleum
ether) gave the title compound 7a (24 mg, 46%) as a colorless oil; Rf
(50% hexane/EtOAc) 0.07; nmax (film) 3015, 2929, 2850, 2845, 1708,
1640, 1290, 1285, 1109, 770 cmꢀ1
; dP (81 MHz, CDCl3) 31.2, 30.6 two
diastereoisomers (2:1); dH (200 MHz, CDCl3) 7.03 (2H, br q, J 4.1 Hz,
C]CH), 4.24 (2H, q, J 7.0 Hz, OCH2CH3), 4.23 (2H, q, J 7.0 Hz,
OCH2CH3), 4.17 (1H, br q, J 4.4 Hz, CHOH), 4.00 (1H, m, CHOH), 3.88
(6H, d, J 10.6 Hz, OMe), 3.76 (6H, d, J 10.7 Hz, OMe), 2.61e2.45 (3H, m,
CH2), 2.41e2.20 (4H, m, CH2), 2.11e2.00 (3H, m, CH2), 1.81e1.58 (2H,
m, CH2), 1.37 (3H, d, J 5.5 Hz, MeCHOH), 1.30 (6H, t, J 7.0 Hz,
OCH2CH3), 1.14 (3H, d, J 4.4 Hz, MeCHOH); dC (50 MHz, CDCl3) 167.3,
166.8, 135.5,133.7, 123.5, 120.8, 71.1, 70.5 (d, J 8.6 Hz), 53.0, 62.3, 52.8,
52.5, 43.2 (d, J 134.6 Hz), 40.8 (d, J 133.2 Hz), 29.4, 25.2, 22.2, 18.9,
14.2, 13.4; m/z (CI, isobutane) 307 (100, MHþ), 292 (20), 279 (40), 263
(20%); HRMS (EI): Mþ, found: 306.1233. C12H18O2 requires 306.1232.
4.3.5. Ethyl 6-(dimethoxyphosphoryl)-3-(hydroxy(phenyl)methyl)-cy
clohex-1-enecarboxylate (11e) [two diastereoisomers (2:1)]. Major
isomer separated from the crude mixture by flash chromatog-
raphy (10% hexane/EtOAc) (170 mg, 46%) as a yellow oil; Rf (50%
hexane/EtOAc) 0.19; nmax (film) 3425, 2962, 2871, 1712, 1611,
1606, 1453, 1365, 1261, 1099, 1083, 866, 799; dP (81 MHz, CDCl3)
31.4; dH (500 MHz, CDCl3) 7.41e7.28 (5H, m, Ph), 7.13 (1H, d, J 3.4,
Hz, C]CH), 4.71 (1H, d, J 5.4 Hz, HC(OH)Ph), 4.23 (2H, q, J 7.1 Hz,
OCH2CH3), 3.69 (3H, d, J 10.8 Hz, OMe), 3.68 (3H, d, J 10.8 Hz,
OMe), 3.32 (1H, dd, J 24.0, 5.2 Hz, HCP), 2.72 (1H, br s, CHCH(OH)
Ph), 2.22e2.15 (1H, m, CHaHbCH2CHCH]), 2.02 (1H, q, J 4.4 Hz,
CH2CHaHbCHCH]), 1.73e1.67 (1H, m, CHaHbCH2CHCH]),
4.3.7. Ethyl 6-(dimethoxyphosphoryl)-3-(1-hydroxy-2-methylpropyl)
cyclohex-1-enecarboxylate (11f). Procedure A. Yellow oil; 153 mg,
46%; Rf (40% hexane/EtOAc) 0.17; nmax (film) 2959, 2924, 2851, 1718,
1.64e1.53 (1H, m, CH2CHaHbCHCH]), 1.29 (3H, t,
J 7.1 Hz,
OCH2CH3); dC (125 MHz, CDCl3) 163.9 (COOEt), 142.8 (C-ipso-Ar),
144.4 (C]CH), 128.0 (Ar), 127.3 (C]CH), 126.9 (Ar), 125.7 (Ar),
75.1 (CHOH), 60.5 (OCH2CH3), 53.2, 53.0 (d, J 7.8 Hz, POMe), 43.1
1463, 1260, 1156, 1074, 801 cmꢀ1
; dP (81 MHz, CDCl3) 31.5, 31.2 two
diastereoisomers (1.3:1); dH (500 MHz, CDCl3) 7.04 (1H, br s, ]CH),
6.88e6.85 (1H, m, ]CH), 4.23 (2ꢂ2H, q, J 7.1 Hz, OCH2CH3), 4.09
(1H, m, CHCHOH), 3.79 (1H, br s, CHCHOH), 3.75 (6H, d, J 10.7 Hz,
OMe), 3.69 (6H, d, J 10.7 Hz, OMe), 3.48 (1H, br d, J 21.2, HCP), 3.33
(1H, br d, J 21.2 Hz, HCP), 2.96e2.52 (4H, m, Me2CH, CH2), 2.46 (1H,
t, J 6.5 Hz, CH2CHCHOH), 2.26e2.01 (3H, m, CH2, CH2CHCHOH),
1.82e1.38 (4H, m, CH2), 1.30 (3H, t, J 7.1 Hz, OCH2CH3), 1.20 (3H, t,
J 7.1 Hz, OCH2CH3), 0.97 (3H, d, J 7.1 Hz, MeCH), 0.93 (3H, d, J 6.8 Hz,
MeCH), 0.92 (3H, d, J 7.1 Hz, MeCH), 0.87 (3H, d, J 6.8 Hz, MeCH); dC
(50 MHz, CDCl3) 165.0, 164.1, 145.3, 142.2, 128.5, 128.3, 127.3, 80.0,
78.8, 60.7, 53.8, 53.6, 32.3 (d, J 137.0 Hz), 30.8 (d, J 132.0 Hz), 30.3,
29.9, 24.9, 23.2, 21.9, 21.5, 20.1, 19.4, 16.6; m/z (EI) 334 (18, Mþ), 263
(100%); HRMS (CI, isobutane): MHþ, found: 335.1550. C15H29O6P
requires 335.1545.
(CHCH(OH)), 31.3 (d,
J 137.6 Hz, CHP), 23.2 (PCHCH2), 18.4
(CH2CHCH]), 14.1 (OCH2CH3); m/z (CI, isobutane) 369 (100,
MHþ), 351 (76), 305 (8), 262 (10%); HRMS (CI, isobutane): MHþ,
found: 369.1470. C18H26O6P requires 369.1467.
Minor isomer separated from the crude mixture by flash chro-
matography (10% hexane/EtOAc) (92 mg, 25%) as a yellow oil; Rf
(50% hexane/EtOAc) 0.17; nmax (film) 3418, 2925, 2851, 1712, 1598,
1560,1445,1366, 1259,1137,1092,1075, 966, 697 cmꢀ1
; dP (81 MHz,
CDCl3) 31.6; dH (500 MHz, CDCl3) 7.41e7.28 (5H, m, Ph), 7.19 (1H, d, J
3.6 Hz, ]CH), 5.04 (1H, d, J 3.9 Hz, HC(OH)Ph), 4.22 (2H, q, J 7.1 Hz,
OCH2CH3), 3.77 (3H, d, J 10.8 Hz, OMe), 3.70 (3H, d, J 10.8 Hz, OMe),
3.32 (1H, dd, J 24.0, 5.1 Hz, HCP), 2.90 (1H, br s, CHCH(OH)Ph),
2.23e2.17 (1H, m, CHaHbCH2CHCH]), 2.04 (1H, t, J 10.0 Hz,
CH2CHaHbCHCH]), 1.73e1.67 (1H, m, CHaHbCH2CHCH]),
Procedure B. A BuLi (0.26 mL of 1.6 M solution in hexane,
0.42 mmol) was added to a stirred solution of the phosphonate 3
(72 mg, 0.27 mmol) inTHF (4 mL) at ꢀ78 ꢁC. The mixturewas stirred
at ꢀ78 ꢁC for 1 h before addition of 2-methylpropanal (20 mg,
1.46e1.41 (1H, m, CH2CHaHbCHCH]), 1.29 (3H, t,
J 7.1 Hz,
OCH2CH3); dC (125 MHz, CDCl3) 164.8 (COOEt), 143.7 (C]CH), 141.9
(ipso-Ar), 128.0 (Ar), 127.8 (Ar), 127.3 (C]CH), 126.5 (Ar), 125.2 (Ar),

E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
1945
0.27 mmol, freshly distilled) in THF (1 mL). After 2 h, the reaction
mixture was allowed to warm to room temperature, stirred for
further 10 h, and quenched by the addition of saturated aqueous
ammonium chloride solution (3 mL), extracted with CHCl3
(3ꢂ3 mL), and dried (MgSO4). The solvent was evaporated in vacuo
to give the crude product, which was purified by flash chromatog-
raphy (20% petroleum ether/EtOAc) to give the title compound 11f
(37 mg, 41%) as a yellowoil; Rf (50% hexane/EtOAc) 0.09; dP (81 MHz,
CDCl3) 32.0, 31.2 two isomers (1:1); dH (200 MHz, CDCl3) 7.10e6.70
(2H, m, ]CH), 4.21 (4H, q, J 7.1 Hz, OCH2CH3), 4.30e4.10 (2H, m,
CHCHOH), 3.80 (6H, d, J 10.1 Hz, OMe), 3.70 (6H, d, J 10.1 Hz, OMe),
3.42e3.38 (2H, m, HCP), 2.70e2.60 (3H, m, CHCHOH, Me2CH),
2.50e2.20 (4H, m, CH2, CHCHOH),1.90e1.30 (5H, m, CH2),1.24 (6H, t,
J 7.1 Hz, OCH2CH3), 0.93 (3H, d, J 7.1 Hz, MeCH), 0.91 (3H, d, J 6.3 Hz,
MeCH), 0.88 (3H, d, J 6.3 Hz, MeCH), 0.87 (3H, d, J 7.1 Hz, MeCH); m/z
(CI, isobutane) 335 (8, Mþ), 275 (15), 263 (100%).
(100), 279 (60), 275 (95), 205 (32%); HRMS (EI): Mþ, found: 320.1389.
C14H25O6P requires 320.1390.
4.4.3. Ethyl 6-(dimethoxyphosphoryl)-3-((2E,4E)-1-hydroxyhexa-2,4-
dienyl)cyclohex-1-enecarboxylate (11d). A solution of phosphonate 3
(112 mg, 0.43 mmol) in THF (4 mL) was added dropwise at ꢀ78 ꢁC to
THF solution of LDA (0.54 mmol) [freshly prepared from diisopro-
pylamine (0.075 mL, 0.54 mmol) and BuLi (0.23 mL, 2.3 M solution in
hexane, 0.54 mmol) in THF (4 mL) at the ꢀ20 ꢁC for 30 min]. The
mixture was stirred at ꢀ78 ꢁC for 1 h before addition of 2,4-hex-
adienal (40 mg, 0.41 mmol, freshly distilled) in THF (2 mL). After 4 h
the reaction mixture was allowed to warm to room temperature,
stirred for further 14 h and quenched by the addition of water (3 mL),
extracted with CHCl3 (3ꢂ5 mL), and dried (MgSO4). The solvent was
evaporated in vacuo and crude mixture was chromatographed (silica
gel, 50% petroleum ether/EtOAc, EtOAc) to give products: 6d (33 mg,
35%) as yellowish oil; Rf (40% hexane/EtOAc) 0.59, and the titled
compound 11d (44 mg, 30%)asyellowoil; Rf (40%hexane/EtOAc)0.07;
nmax (film) 3409, 2957, 2871, 1714, 1678, 1646, 1450, 1252, 1186,
4.4. Reaction of phosphonate 3 with aldehydes
Procedure C. A solution of phosphonate 3 (65 mg, 0.25 mmol) in
THF (1 mL) was added dropwise at ꢀ78 ꢁC to THF solution of LDA
(0.3 mmol) [freshly prepared from diisopropylamine (0.042 mL,
0.3 mmol) and BuLi (0.13 mL, 2.3 M solution in hexane, 0.3 mmol)
in THF (2 mL) at the ꢀ20 ꢁC for 30 min]. The mixture was stirred at
ꢀ78 ꢁC for 1 h before addition of relevant aldehyde (0.25 mmol,
freshly distilled) in THF (1 mL). After 10 h of the stirring at ꢀ78 ꢁC,
the reaction mixture was allowed to warm to room temperature,
stirred for further 10 h, and quenched by the addition of saturated
aqueous ammonium chloride solution (2 mL), extracted with CHCl3
(3ꢂ2 mL), and dried (MgSO4). The solvent was evaporated in vacuo.
The crude mixture was chromatographed (silica gel, hexane/EtOAc)
to give following products.
1054 cmꢀ1
; dP (81 MHz CDCl3) 30.6, 30.9, (two diastereoisomers,
1.2:1); dH (500 MHz, CDCl3) 7.05 (1H, d, J 3.8 Hz, CHCCOOEt,), 7.02 (1H,
dd, J 4.2, 4.2 Hz, CHCCOOEt), 6.30 (2H, dd, J 10.0, 15.1 Hz, MeCH]
CHCH]), 6.04 (2H, brt, J 10.0 Hz, MeCH]CHCH]), 5.79e5.65(3H, m,
2ꢂMeCH]CH, MeCH]CHCH]CH), 5.54 (1H, dd, J 6.3, 15.1 Hz,
MeCH]CHCH]CH), 4.36 (1H, t, J 6.3 Hz, CHOH), 4.21 (4H, q, J 7.1 Hz,
OCH2CH3), 4.13(1H, t, J7.1 Hz, CHOH), 3.78(3H, d,J10.8 Hz, OMe), 3.76
(3H, d, J 11.1 Hz, OMe), 3.74 (3H, d, J 10.8 Hz, OMe), 3.71 (3H, d, J
11.1 Hz, OMe), 3.32 (2H, br d, J 20.1 Hz, HCP), 2.62e2.48 (1H, m,
CHCHOH), 2.38e2.18 (5H, m, CHCH2CH2, PCHCH2CH2, CHCHOH),
2.09e1.85 (2H, m, CHCHaHbCH2, PCHCHaHbCH2), 1.74 (2ꢂ3H, d, J
6.2 Hz, MeCH]), 1.80e1.50 (2H, m, PCHCHaHbCH2, CHCHaHbCH2),
1.29 (6H, t, J 7.1 Hz, OCH2CH3); dC (50 MHz, CDCl3) 168.2, 143.0 (d, J
15.9 Hz), 141.9 (d, J 11.3 Hz), 139.4, 137.6, 137.3, 133.4, 132.9, 132.2,
124.2,78.7, 78.1, 61.2, 61.0, 52.8(d, J 7.0 Hz), 52.9 (d, J7.0 Hz), 46.4, 45.7,
34.0 (d, J 133.5 Hz), 31.6 (d, J 138.3 Hz), 22.6, 17.9, 17.2, 14.0, 13.6; m/z
(CI, isobutane) 359 (10, MHþ), 341 (100%).
4.4.1. (Z/E)-Ethyl 6-(2-methylpropylidene)cyclohex-1-enecarboxylate
(6f). Yellow oil; 2.6 mg, 5%; Rf (50% hexane/EtOAc) 0.76; dH
(200 MHz, CDCl3) 7.09 (1H, t, J 6.6 Hz, ]CHCOOEt), 5.89 (1H, d, J
6.6 Hz, ]CHCHMe2), 4.22 (2H, q, J 7.2 Hz, OCH2CH3), 2.58 (1H,
septet, J 6.6 Hz, Me2CH), 2.28e2.23 (2H, m, CH2), 2.02 (2H, dd, J 3.0,
3.9 Hz, CH2), 1.40 (2H, m, CH2), 1.34 (3H, t, J 7.2 Hz, OCH2CH3), 0.93
(6H, d, J 6.6 Hz, MeCH); m/z (CI, isobutane) 209 (4, MHþ) 208 (10),
206 (25), 205 (100), 183 (30), 159 (45%) [GCeMS; column: DB-1,
30 m, 50 (3)-10/mine250 (10), mass peak: retention time 1603200,
relative abundance: 50%].
4.4.4. Ethyl 6-(dimethoxyphosphoryl)-3-((2E,4E)-hexa-2,4-dienylidene)
cyclohex-1-enecarboxylate (14). Yellow oil; 27 mg, 20%; Rf (40% hex-
ane/EtOAc) 0.09; nmax (film) 2952, 2791, 1722, 1688, 1642, 1480, 1371,
1242, 1186, 1045 cmꢀ1
; dP (81 MHz, CDCl3) 28.6; dH (200 MHz, CDCl3)
6.74 (1H, s, CH), 6.29 (1H, dd, J 10.6, 15.1 Hz, CH), 6.07e6.00 (1H, m,
CH), 5.98e5.68 (2H, m, CH), 5.55 (1H, dd, J 15.1, 6.0 Hz, CHMe), 4.21
(2H, q, J 7.1 Hz, OCH2CH3), 3.77 (3H, d, J 10.8 Hz, OMe), 3.73 (3H, d, J
10.8 Hz, OMe), 3.36 (1H, dd, J 4.5, 25.3 Hz, HCP), 2.88e2.78 (1H, br s,
CH2), 2.58e2.51 (1H, m, CH2), 2.09e1.85 (1H, m, CH2), 1.74 (3H, d, J
6.0 Hz, CH3CH),1.58e1.38 (1H, m, CH2),1.29 (3H, t, J 7.0 Hz, OCH2CH3);
dC (51 MHz, CDCl3) 166.8, 144.7, 141.9 (d, J 11.5 Hz), 136.4, 133.4, 132.9,
132.2, 128.3, 61.4, 52.8 (d, J 11.0 Hz), 52.5 (d, J 11.0 Hz), 38.5 (d, J
141.4 Hz), 29.7, 28.5, 24.9, 23.8, 14.2; m/z (CI, isobutane) 341 (100,
MHþ), 679 (18%, 2ꢂ(MꢀH)); HRMS (CI, isobutane): MHþ, found:
341.1512. C17H26O5P requires 341.1518.
4.4.2. Ethyl 6-(dimethoxyphosphoryl)-6-(1-hydroxypropyl)cyclohex-1-
enecarboxylate(7b). A solution of phosphonate 3 (42 mg, 0.16 mmol)
in THF (1 mL) was added dropwise at ꢀ78 ꢁC to THF solution of LDA
(0.2 mmol) [freshly prepared from diisopropylamine (0.028 mL,
0.2 mmol) and BuLi (0.09 mL, 2.3 M solution in hexane, 0.2 mmol) in
THF (1 mL) at the ꢀ20 ꢁC for 30 min]. The mixture was stirred at
ꢀ78 ꢁC for 1 h before addition of propionaldehyde (10 mg,
0.17 mmol, freshly distilled) in THF (0.3 mL). After 4 h the reaction
mixture was allowed to warm to room temperature, stirred for fur-
ther 4 h and quenched by the addition of water (1 mL), extracted
with Et2O (3ꢂ1 mL), and dried (MgSO4). The solvent was evaporated
in vacuo to give the crude product, which was purified by preparative
chromatography (40% petroleum ether/EtOAc) to give the titled
compound 7b as colorless oil (28 mg, 54%); Rf (50% hexane/EtOAc)
4.4.5. (E)-ethyl 6-((2E,4E,6E)-8-ethoxy-2,6-dimethyl-8-oxoocta-2,4,6-
trienylidene)cyclohex-1-enecarboxylate (6g). A solution of phos-
phonate 3 (61 mg, 0.23 mmol) in THF (4 mL) was added dropwise at
ꢀ78 ꢁC to THF solution of LDA (0.28 mmol) [freshly prepared from
diisopropylamine (0.040 mL, 0.28 mmol) and BuLi (0.12 mL, 2.3 M
solution in hexane, 0.28 mmol) in THF (4 mL) at the ꢀ20 ꢁC for
30 min]. The mixture was stirred at ꢀ78 ꢁC for 1 h before addition
of (2,6-dimethyl-7-ethoxycarbonyl)-2,4,6-heptatrienal (42 mg,
0.2 mmol) in THF (2 mL). After 20 h at ꢀ78 ꢁC the reaction mixture
was allowed to warm to room temperature, stirred for further 20 h
and quenched by the addition of water (3 mL), extracted with CHCl3
(3ꢂ5 mL), and dried (MgSO4). The solvent was evaporated in vacuo
and crude mixture was chromatographed (silica gel, 10% EtOAc/
0.08; nmax 3315, 2940, 2755, 1706, 1648, 1257, 1118, 1080, 945 cmꢀ1
;
dP (81 MHz, CDCl3) 31.5; dH (200 MHz, CDCl3) 7.05 (1H, t, J 3.1 Hz, C]
CH), 4.24 (2H, q, J 7.1 Hz, OCH2CH3), 4.17e3.91 (1H, m, CHOH), 3.76
(3H, d, J 10.7 Hz, OMe), 3.73 (3H, d, J 10.7 Hz, OMe), 2.54e2.02 (4H. m,
CH2), 1.80e1.38 (4H, m, CH2, CH3CH2CH]), 1.32 (3H, t, J 7.1 Hz,
OCH2CH3), 1.12 (3H, t, J 7.2 Hz, CH3CH2CH); dC (50 MHz, CDCl3) 167.1,
134.1, 121.8, 72.1 (d, J 9.0 Hz), 62.4, 53.0, 51.8, 42.8 (d, J 133.4 Hz), 27.8,
24.5, 22.8, 18.9, 13.8, 12.1; m/z (CI, isobutane) 321 (18, MHþ), 291

1946
E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
petroleum ether) to give the titled compound 6g (53.6 mg, 78%) as
a yellow semisolid; Rf (50% hexane/EtOAc) 0.66; nmax (Nujol) 2956,
isobutane) 243 (44, MHþ), 227 (20), 91 (100%); HRMS (EI): Mþ,
found: 242.1302. C16H18O2 requires 242.1307.
2910, 2788, 1728, 1638, 1448, 1280, 1191, 1032 cmꢀ1
; dH (500 MHz,
CDCl3) 6.90 (1H, dd, J 11.4, 15.0 Hz, CH]CHCH]), 6.64 (1H, t, J
3.9 Hz, HC]CCOOEt), 6.41 (1H, s, C]CHCMe), 6.25 (1H, d, J 15.0 Hz,
]CMeCH]CHeCH), 6.13 (1H, d, J 11.4 Hz, HC]CMe), 5.77 (1H, s, C
(Me)]CHCOOEt), 4.25 (2H, q, J 7.1 Hz, OCH2CH3), 4.17 (2H, q, J
7.0 Hz, OCH2CH3), 2.60 (2H, t, J 5.6 Hz, HC]CCH2), 2.34 (3H, s, C
(Me)]CHCOOEt), 2.30e2.26 (2H, m, C]CHCH2), 1.99 (3H, s, HC]
CMe), 1.74e1.67 (2H, m, CH2CH2C]), 1.33 (3H, t, J 7.1 Hz, OCH2CH3),
1.28 (3H, t, J 7.0 Hz, OCH2CH3); dC (50 MHz, CDCl3) 167.9, 167.2
(2ꢂCOOEt), 152.6, 138.6 (2ꢂHC]C), 138.0, 135.3 (2ꢂHC]C), 133.7,
132.3 (2ꢂHC]C), 131.1, 130.7, 130.3, 118.8 (4ꢂHC]C), 60.7, 59.7
(2ꢂOCH2CH3), 27.5, 25.9, 22.1, (3ꢂCH2), 18.1, 13.8 (2ꢂCH3), 14.3,14.2
(2ꢂOCH2CH3); m/z (CI, isobutane) 345 (44, MHþ), 299 (100), 253
(40%); HRMS (CI, isobutane): MHþ, found: 345.2049. C21H29O4 re-
quires: 345.2065.
4.6. Ethyl 6-(dimethoxyphosphoryl)-3-methylcyclohex-1-
enecarboxylate (2b)9
A solution of phosphonate 3 (38 mg, 0.14 mmol) in THF (2 mL)
was added dropwise at ꢀ78 ꢁC to THF solution of LDA (0.18 mmol)
[freshly prepared from diisopropylamine (0.025 mL, 0.18 mmol)
and BuLi (0.11 mL, 1.6 M solution in hexane, 0.18 mmol) in THF
(3 mL) at the ꢀ20 ꢁC for 30 min]. The mixture was stirred at
ꢀ78 ꢁC for 1 h before the addition of methyl iodide (0.2 mL,
0.3 mmol, freshly distilled). After 0.5 h at ꢀ78 ꢁC the reaction
mixture was warmed to room temperature and stirred for further
1 h, quenched by the addition of saturated aqueous ammonium
chloride solution (3 mL), extracted with CHCl3 (3ꢂ2 mL), and dried
(MgSO4). The solvent was evaporated in vacuo and the crude
product was purified by column chromatography (silica gel, 70%
EtOAc/petroleum ether) to give the titled compound 2b (19 mg,
50%) as a yellow oil; Rf (50% hexane/EtOAc) 0.17; dP (81 MHz,
CDCl3) 32.6; dH (200 MHz, CDCl3) 7.04 (1H, br s, ]CH), 4.23 (2H, q,
J 7.1 Hz, OCH2CH3), 3.75 (3H, d, J 10.7 Hz, OMe), 3.69 (3H, d, J
10.7 Hz, OMe), 3.33 (1H, br d, J 24.6, HCP), 2.43e2.31 (1H, m,
MeCH), 2.21e2.06 (2H, m, CH2), 1.82e1.55 (2H, m, CH2), 1.30 (3H, t,
J 7.1 Hz, OCH2CH3), 1.07 (3H, d, J 6.6 Hz, MeCH); m/z (EI) 276 (15,
Mþ), 233 (15), 127 (100%).
4.4.6. (E/Z)-Ethyl 6-benzylidenecyclohex-1-enecarboxylate (6e). To
solution of carbanion 4a (0.16 mmol) in THF (0.5 mL) [freshly pre-
pared from phosphonate 3 (43 mg, 0.16 mmol) and LDA (0.24 mmol)
31
at ꢀ78 ꢁC and measured by P NMR at ꢀ70 ꢁC (subchapter 4.7.)]
benzaldehyde (13 mg, 0.12 mmol) in THF (0.5 mL) was added at
ꢀ78 ꢁC via cannula, under argon atmosphere. After 12 h at ꢀ78 ꢁ
C
and 10 h at room temperature, the reaction mixture was quenched
with water (0.5 mL), extracted with CHCl3 (2ꢂ0.5 mL), dried
(MgSO4), and evaporated in vacuo to give crude product, which was
purified by flash chromatography (30% EtOAc/hexane) to give 6e
(15 mg, 52%) as yellow semisolid; Rf (50% hexane/EtOAc) 0.6; dH
(200 MHz, CDCl3) two isomers E and Z (4:1), 7.36e7.29 (10H, m, Ph),
7.16 (1H, br s, C]CH, Z), 7.10 (1H, d, J 4.1 Hz, C]CH, E), 6.70 (1H, brs, H
(Ph)C]C, E), 6.55 (1H, d, J 5.6 Hz, H(Ph)C]C, Z), 4.36 (2H, q, J 6.9 Hz,
OCH2CH3, E), 4.22 (2H, q, J 6.8 Hz, OCH2CH3, Z), 2.98 (1H, br s, CH2, E),
2.86 (1H, t, J 7.8 Hz, CH2, Z), 2.83e2.73 (4H, m, CH2, E, and Z),
2.54e2.31 (4H, m, CH2, E, and Z), 2.26e1.82 (2H, m, CH2, Z),1.32 (3H, t,
J 6.9 Hz, OCH2CH3, E), 1.22 (3H, t, J 6.9 Hz, OCH2CH3, Z); m/z (EI) 242
(14, Mþ), 213 (74), 101 (100%).
4.7. Low-temperature 31P NMR measurements
31P NMR spectra were recorded on a Bruker DRX 500 Spec-
trometer at 202.45 MHz. There were obtained with proton decou-
pling and referenced to the external H3PO4. In experiments 5 mm
NMR tubes were used sealed with rubber septa. LDA was directly
prepared in NMR tube under argon at ꢀ70 ꢁC (acetone/dry ice) and
phosphonate 3 was added by a syringe. The spectra of phosphonate
carbanion were measured at low temperatures (ꢀ70 ꢁC) or in in-
dependent experiment at room temperature.
4.5. Reaction of phosphonate 3 with benzaldehyde
4.7.1. Reaction of phosphonate carbanion 4b with benzaldehyde. To
solution of carbanion 4b (0.16 mmol) in THF (0.5 mL) [freshly pre-
4.5.1. (E/Z)-Ethyl 6-benzylidenecyclohex-1-enecarboxylate (6e). Proce
dure D. To a mixture of sodium hydride (14 mg, 0.57 mmol, 60%
dispersion in oil, freshly washed with dry hexane) in THF (10 mL) at
ꢀ10 ꢁC was added a solution of phosphonate 3 (59 mg, 0.23 mmol)
in THF (5 mL). The mixture was stirred at ꢀ5 ꢁC to 0 ꢁC for 1 h before
addition of benzaldehyde (22 mg, 0.21 mmol, freshly distilled) at
ꢀ40 ꢁC. The mixture was stirred at ꢀ40 ꢁC to ꢀ10 ꢁC for 10 h and
was allowed to warm to room temperature, stirred for further 12 h
and quenched by the adsorption on silica gel (10 mL). Elution with
hexane (100 mL), 50% hexane/EtOAc (150 mL) and evaporation of
the solvent gave the brown oil. Purification of the crude product by
preparative chromatography gave the titled compound 6e (26 mg,
52%) as a yellow semisolid; Rf (50% hexane/EtOAc) 0.66; nmax (Nujol)
pared from phosphonate
3 (30 mg, 0.11 mmol) and LDA
(0.15 mmol) at ꢀ78 ꢁC for 1 h, slowly warmed to room temperature
and measured by 31P NMR at 20 ꢁC], benzaldehyde (9.6 mg,
0.10 mmol) in THF (0.2 mL) was added, via cannula, under argon
atmosphere. After 10 h at room temperature, the reaction mixture
was quenched by the addition of water (0.5 mL), extracted with
CHCl3 (2ꢂ0.5 mL), dried (MgSO4), and evaporated in vacuo to give
crude product, which was purified by preparative chromatography
(50% EtOAc/hexane) to give 11e (15 mg; 42%), Rf (50% hexane/
EtOAc) 0.17; dP (200 MHz, CDCl3) 30.3, 30.1; m/z (CI, isobutane) 369
(64, MHþ), 351 (56), 305 (50), 263 (42%).
2952, 2850, 1710, 1606, 1560, 1445, 1236, 1137, 1093, 732, 697 cmꢀ1
;
Acknowledgements
dH (500 MHz, CDCl3) two isomers E and Z (5:1), 7.42e7.28 (10H, m,
Ph), 7.23 (1H, br s, CH]CCOOEt, E), 7.20e7.18 (1H, m, CH]CCOOEt,
Z), 6.68 (1H, br s, H(Ph)C]C, E), 6.58 (1H, br s, H(Ph)C]C, Z), 4.32
(2H, q, J 7.0 Hz, OCH2CH3, E), 4.28 (2H, q, J 7.1 Hz, OCH2CH3, Z), 2.95
(1H, m, CHaHbC]C, E), 2.84 (2H, dd, J 5.8, 6.8 Hz, ]CHCH2, Z), 2.73
(3H, br d, J 4.1 Hz, CH2C]C, ]CHCH2, E), 2.55 (1H, t, J 6.5 Hz,
CHaHbC]C, Z), 2.50 (1H, m, CHaHbC]C, Z), 1.86e1.56 (4H, m,
CH2CH2CH2, E, and Z) 1.39 (3H, t, J 7.0 Hz, OCH2CH3, E), 1.32 (3H, t, J
7.1 Hz, OCH2CH3, Z); dC (50 MHz, CDCl3) 167.9, 167.1, 142.4, 139.8,
137.7, 136.7, 136.1, 133.7, 133.4, 129.3, 128.3, 128.1, 127.5, 127.3, 126.7,
126.6, 60.9, 60.8, 35.1, 31.6, 29.2, 27.2, 26.5, 26.3, 14.3, 14.2; m/z (CI,
Financial support by the Ministry of Science and Higher Edu-
cation of Poland (Grant No 3 T09A 083 29; 2005e2008) is gratefully
acknowledged.
The authors thank Dr. W.H. Midura for helpful discussion.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.01.016.

E. Krawczyk, K. Owsianik / Tetrahedron 67 (2011) 1938e1947
1947
R.; Labia, R.; Potier, P. Eur. J. Org. Chem. 2003, 2250; (c) Spino, C.; Hill, B.; Dube,
P.; Gingras, S. Can. J. Chem. 2003, 81, 81 and Ref. 10b.
References and notes
12. Muller, E. L.; Modro, T. A. Bull. Soc. Chim. Fr. 1993, 130, 668.
13. Muller, E. L.; Modro, T. Heteroat. Chem. 1994, 5, 287.
14. (a) Kempf, D. J.; Wilson, K. D.; Beak, P. J. Org. Chem. 1982, 47, 1610; (b) Beak, P.;
Kempf, D. J.; Wilson, K. D. J. Am. Chem. Soc. 1985, 107, 4745.
15. Shortening of the lithiation reaction time to 30 min at ꢀ78 ꢁC gave the partially
deuterated phosphonate.
1. (a) Fetles, K.; Mc Quire, L.; Murray, A. W. J. Chem. Soc., Perkin Trans. 1 1995, 2123;
(b) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 701; (c) Seebach, D.; Geiss,
K.-H. J. Organomet. Chem. 1976, 1, 1; (d) Gschwend, H. W.; Rodriguez, H. R. Org.
React. 1979, 26, 1; (e) Krief, A. Tetrahedron 1980, 36, 2531.
2. (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863; (b) Philips, A. M. M. M.;
Modro, T. A. J. Chem. Soc., Perkin Trans. 1 1991, 1875; (c) Pienaar, A.; Modro, T. A.
Heteroatom Chem. 1996, 7, 443.
3. (a) Janecki, T. Synth. Commun. 1993, 23, 641; (b) Muthiah, C.; Kumar, K. S.; Vittal,
J. J.; Kumara Swamy, K. C. Synlett 2002, 1787; (c) Al-Badri, H.; About-Jandet, E.;
Collignon, N. J. Chem. Soc., Perkin Trans. 1 1996, 931.
4. (a) Al-Badri, H.; About-Jandet, E.; Collignon, N.; Combret, J.-C. Synthesis 1995,
1401; (b) Muller, E. L.; Modro, T. A. J. Chem. Soc., Perkin Trans. 1 1996, 931; (c)
Muller, E. L.; Modro, T. A. Tetrahedron Lett. 1995, 36, 393; (d) Takacs, J. M.; Jaber,
M. R.; Clement, F.; Walters, C. J. Org. Chem. 1998, 63, 6757.
16. (a) Denmark, S. E.; Swiss, K. A.; Miller, P. C.; Wilson, S. R. Heteroat. Chem. 1998, 9,
209; (b) Denmark, S. E.; Swiss, K. A. J. Am. Chem. Soc. 1993, 115, 12195; (c)
Denmark, S. E.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 864; (d) Yuan, C.; Yao, J.;
Li, S.; Ma, Y.; Zhong, X. Phosphorus, Sulfur and Silicon 1989, 46, 25; (e) Bottin-
Strzalko, T. T.; Seyden-Penne, J.; Pouet, M.-J.; Simonnin, M.-P. J. Org. Chem. 1978,
43, 4346.
17. The signal in 31P NMR spectrum at
d 40 ppm is split into two peaks, which may
correspond to more than one complex of phosphonate 3 and lithium base.
18. The polyene derivatives 6d and 7c like other polyenes are unstable at room
temperature and decompose even stored in refrigerator, see Ref. 3a
19. Doering, W. E.; Roth, W. R.; Bauer, F.; Boenke, M.; Breuckmann, R.; Ruhkamp, J.;
Wortmann, O. Chem. Ber. 1991, 124, 1461.
20. (a) Schetter, B.; Ziemer, B.; Schnakenburg, G.; Mahrwald, R. J. Org. Chem. 2008,
73, 813; (b) Hon, Y.-S.; Lee, C.-F. Tetrahedron 2001, 57, 6181.
21. Lee, S. Y.; Lee, B. S.; Lee, C.-W.; Oh, D. Y. J. Org. Chem. 2000, 65, 256.
22. MNDO calculation of compound 6g for both isomers E and Z were carried out
using HyperChem package (Release 6.03 for Windows, Molecular Modeling
System).
5. (a) Janecki, T.; Bodalski, R. Synthesis 1989, 506; (b) Janecki, T. Synthesis 1991, 167.
6. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559.
7. (a) Gerber, J. P.; Modro, T. A. Phosphorus, Sulfur and Silicon 1994, 88, 99; (b)
Gerber, K. P.; Modro, T. A.; Muller, E. L.; Philips, A. M. Phosphorus, Sulfur and
Silicon 1993, 75, 19.
ꢀ
8. Krawczyk, E.; Owsianik, K.; Skowronska, A.; Wieczorek, M.; Majzner, W. New J.
Chem. 2002, 26, 1753.
9. Krawczyk, E.; Owsianik, K.; Skowronska, A. Tetrahedron 2005, 61, 1449.
ꢀ
10. (a) Derguini, F.; Nakanishi, K.; Buck, J.; Hammerling, U.; Grun, F. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1837; (b) Derguini, F.; Nakanishi, K.; Hammerling, U.
Biochemistry 1994, 33, 623.
11. Some examples of the synthetic approach to anhydroretinol (AR) and (14R)-14-
hydroxy-4,14-retro-retinol (14-HRR): (a) Alvarez, R.; Iglesias, B.; Lopez, S.; de
Lera, A. R. Tetrahedron Lett. 1998, 39, 5659; (b) Cartier, D.; Valla, A.; Le Guillous,
23. Bonadies, F.; Cardilli, A.; Lattanazi, A.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1995,
36, 1449.
24. Lambertin, F.; Wende, M.; Quirin, M. J.; Taran, M.; Delmond, B. Eur. J. Org. Chem.
1999, 1489.