Ring-opening reactions of cyclopropanes. Part 7.1 Selenenylation and cyanoselenenylation of ethyl 2,2-dimethoxycyclopropanecarboxylates

Article abstract of DOI:10.1039/b109480g

The uncatalyzed reaction of C3-substituted cyclopropanes 1b-d with benzeneselenenyl chloride 3 leads to 1-ethyl 4-methyl 2-(phenylseleno)butanedioates 5b-d while the unsubstituted 1a gives the 3-phenylseleno derivative 6a. Formation of 5b-d occurs regio-

Full text of DOI:10.1039/b109480g

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Ring-opening reactions of cyclopropanes. Part 7.1
Selenenylation and cyanoselenenylation of ethyl
2,2-dimethoxycyclopropanecarboxylates
1
M. Liliana Graziano,* M. Rosaria Iesce, Flavio Cermola, Giovanni Caputo and
Fulvio De Lorenzo
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II,
Complesso Universitario di Monte S. Angelo, via Cinthia, Napoli, I-80126, Italy
Received (in Cambridge, UK) 17th October 2001, Accepted 7th January 2002
First published as an Advance Article on the web 1st February 2002
The uncatalyzed reaction of C3-substituted cyclopropanes 1b–d with benzeneselenenyl chloride 3 leads to 1-ethyl
4-methyl 2-(phenylseleno)butanedioates 5b–d while the unsubstituted 1a gives the 3-phenylseleno derivative 6a.
Formation of 5b–d occurs regio- and stereoselectively via electrophilic ring-opening of 1 while 6a results from the
selenenylation of the alkene 2a formed via isomerization of 1a. The presence of TiCl4 influences the stereochemistry
of the reaction with chloride 3 while it is essential for reaction of the less reactive PhSeCN 4. With this electrophile
the reactions lead to α,α-dimethoxycarbonitriles 13a–d while only 1a and 1b give also the expected cyanoselenenyl
derivatives 12a and 12b. Moreover, from 1b compound syn- 5b is obtained, and 1a gives, via the alkene 2a, esters 14a
and 6a. A mechanistic interpretation suggests the intermediacy of well-stabilized dipolar species 9 which should be
formed by coordination of the Lewis acid to the carbonyl oxygen of 1 and subsequent ring opening.
Both benzeneselenenyl chloride 3 and phenyl selenocyanate 4
Introduction
add to alkenes giving rise to interesting compounds.9 However,
Vicinally donor–acceptor-substituted cyclopropanes are
while the halide 3 reacts easily, the presence of a Lewis acid
versatile building blocks in organic synthesis.2 In particular, due
catalyst is necessary in the reactions of cyanate 4,10 with the
to the push–pull combination of the gem-dialkoxy and alkoxy-
carbonyl groups, alkyl 2,2-dialkoxycyclopropanecarboxylates,
e.g. 1 (Fig. 1) undergo easy regioselective ring-opening at the
exception of strongly nucleophilic alkenes such as enamines11
or ketene acetals.12 While no examples of cyanoselenenylation
in cyclopropane derivatives have been hitherto reported, the
addition of benzeneselenenyl chloride 38,13 or analogues14 has
been found to occur in cyclopropane rings that form part of
highly strained molecular frameworks. Moreover, selenenyl-
ation by chloride 3 has been also described for various
2-(trimethylsiloxy)cyclopropanecarboxylates but it occurs
easily only if promoted by TiCl4.7
Results and discussion
The reaction of the cyclopropanes 1a–d with the halide 3 was
performed under strictly anhydrous conditions at room tem-
perature using CCl4 as solvent and an equimolecular amount of
3. The reaction was complete within 15 min for 1a–c and within
24 h for 1d (disappearance of the red colour of 3). As shown
in Scheme 1 and Table 1, cyclopropanes 1b–d led to 1-ethyl
4-methyl 2-(phenylseleno)butanedioates 5b–d; in particular,
cyclopropanes 1b,c which are of trans-configuration gave syn-
5b,c preferentially. The only reaction product obtained from 1a
was the 3-phenylseleno derivative 6a, and control experiments
showed that it is formed through selenenylation of the alkene
2a deriving from the isomerization of 1a. In addition to the
products 5b–d and 6a, NMR analysis showed the presence of
MeCl in all the reaction mixtures, but it could not be quantified
owing to its high volatility.
Fig. 1
C1–C2 bond by various unsaturated electrophiles such as
heterocumulenes,3a alkenes,3b alkynes,3c carbonyl compounds,3d
diazenes3e or oxidants4 leading to interesting compounds. In
many cases, this electrophilic ring-opening competes with
the isomerization to 1,1-dialkoxyalkenes, e.g. 2, especially for
C3-unsubstituted derivatives.1,3a,5 Recently, we reported that
cyclopropanes 1 react smoothly also with saturated electro-
philes such as sulfenyl chlorides and afford 1-ethyl 4-methyl
2-sulfenylbutanedioates and/or their 3-sulfenyl analogues, the
latter deriving from the addition of the reagents to the alkenes
2.1 Continuing our investigation into the ring-opening of cyclo-
propanes 1 in order to identify new methods for compounds of
applicative or biological interest, we examined the reaction of
1a–d with benzeneselenenyl chloride 3 and phenyl seleno-
cyanate 4. It also appeared interesting to compare the data
for areneselenenylation with those previously reported for
arenesulfenylation since the reactivity of selenenyl compounds
is often compared with that of their sulfenyl analogues.6–8
The reaction of cyclopropanes 1a–d with halide 3 was also
performed in the presence of TiCl4 at Ϫ78 ЊC. As shown in
Table 1, the catalyst influenced the ratio of the syn and anti
isomers 5b,c and enhanced the yield of 5d while it had no effect
on the reaction of 1a.
The products were separated and purified chromatographic-
ally and satisfactory analytical and spectroscopic data were
664
J. Chem. Soc., Perkin Trans. 1, 2002, 664–668
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b109480g

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Table 1 Reactions of cyclopropanes 1a–d with benzeneselenenyl
chloride 3 in the absencea and in the presenceb of TiCl4
Product (Yield %)c
Cyclopropane
Reaction conditions
5 (syn/anti)
6
1a
1a
1b
1b
1c
1c
1d
1d
3
65d
60
3/TiCl4
3
60 (85/15)
50 (50/50)
57 (80/20)
55 (55/45)
15
3/TiCl4
3
3/TiCl4
3
3/TiCl4
45
a Equimolecular amounts of 1 and 3; dry CCl4; room temperature; 15
min (24 h for 1d). b Equimolecular amounts of 1, 3 and TiCl4; dry
CH2Cl2; Ϫ78 ЊC; 2 h. c Yield and isomeric ratio were evaluated by
chromatography. d Compound 6a can be obtained in 70% yield by treat-
ing 2a under the same conditions used for 1a.
Scheme 3
the two pathways is shown in Scheme 3 using trans-1b,c as sub-
strates in order to evidence the configurations of the reaction
products, too. The SE2-type corner attack, which occurs with
inversion of configuration at C1, should generate the well-
stabilized ionic syn intermediates 8b,c which, through an SN2
type displacement, should lead to syn-5b,c and MeCl. Instead,
the edge attack leads, with retention at the same carbon C1, to
anti-5b,c and MeCl (Scheme 3). The high syn diastereoselectiv-
ity observed is due to the preferred corner attack as previously
found in the sulfenylation.1 In the presence of TiCl4 we assume
that, as reported,3d,7 the Lewis acid promotes ring opening to
the dipolar species 9 which may be attacked at both sides as
shown by the obtaining of an almost equimolecular mixture of
the syn and anti-isomers 5b,c (Table 1, Scheme 4).
Scheme 1
obtained for all of them. Since the diastereomeric pairs 5b,c
exhibited the same value of the vicinal coupling constant for
both isomers, configuration was assigned on the basis of a
straightforward comparison of 1H NMR spectral data with
those of the corresponding thio analogues.1 For the pair 5b the
syn-isomer shows the doublet due to 3-CH3 (δ 1.43) at lower
field than that for the anti-isomer (δ 1.27) while the signal for
CO2Me (δ 3.64) is at higher field than that of the anti (δ 3.73).
For the pair 5c the syn-isomer shows signals due to the chain
methylene in the δ range 1.7–2.2 and the anti-counterpart in the
δ range 1.5–1.8.1 Configuration of pair 5b was also confirmed
chemically by stereoselective obtaining of the alkenes15 (Z)-7
or (E)-7 from syn- or anti-5b, respectively, via the well-known
oxidative selenoxide syn-elimination16 (Scheme 2).
Scheme 4
Unlike 1b–d, the C3-unsubstituted 1a never affords 5a but
only 6a, which is the adduct to the alkene 2a. This suggests that
in the presence of TiCl4 the intermediate 9a once formed
promptly isomerizes to 2a before adding the electrophile 3.18 In
the absence of TiCl4 it is necessary to assume that the formation
of 2a is induced by selenenyl halide acting as Lewis acid catalyst
since the uncatalyzed isomerization of 1a occurs at prolonged
times and high temperature.5
As expected, no reaction of 1a–d took place with the less
reactive PhSeCN 4 at both room temperature and at reflux in
the absence of a catalyst, and only unchanged cyclopropane or
its alteration product was observed (see Experimental section).
When TiCl4 was used, the best procedure was to add one
equivalent of the acid to a precooled solution of equimolecular
amounts of 1 and 4 at Ϫ78 ЊC. As shown in Scheme 5 and Table
2, all of the cyclopropanes 1a–d gave the carbonitriles 13a–d
while only 1a and 1b led to 2-phenylseleno-4-cyanobutanoates
Scheme 2
The results given in Table 1 for 1b–d may be explained in
terms of the two classical competitive corner and edge attacks
of an electrophile at a cyclopropane ring.17 A representation of
J. Chem. Soc., Perkin Trans. 1, 2002, 664–668
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Table 2 Product distribution in the reactions of cyclopropanes 1a–d
with phenyl selenocyanate 4a
TiCl4 generates the primary complexes 10 which, at least in
the cases of the more reactive1 1a,b, are partly attacked by the
selenocyanate through the preferred SE2 mode and lead to the
adducts 12a and syn-12b via intermediates 11a,b. Substitution
at C3 should stabilize the positive charge of the intermediate
11b so that an SN2 type of displacement by cyanide can com-
pete and give syn-5b and MeCN. For all cyclopropanes 1a–d the
primary complexes 10a–d collapse to the dipolar species 9a–d
which lead to carbonitriles 13a–d by the nucleophilic trapping
of cyanide at the positive site and the subsequent hydrolytic
work-up. As suggested above, the intermediate 9a can partly
isomerize to alkene 2a, which adds the electrophile 4 leading to
14a or, via an SN2 nucleophilic displacement of the cyanide, to
6a and MeCN.
Yields (%)b
Cyclopropane
5
6
12
13
14
1a
1b
1c
1d
10
20
20
20
35
30
6
15c
22c
a Equimolecular amounts of 1, 4 and TiCl4; dry CH2Cl2; Ϫ78 ЊC; 2 h.
b Yield by chromatography. c syn-Isomer.
Conclusions
This work confirms the role of donor–acceptor-substituted
cyclopropanes 1 as building blocks for compounds of synthetic
and applicative interest. They react with electrophilic selenenyl
reagents such as 3 and 4 leading to selenobutanedioates or
selenobutanoates via regioselective ring-opening at C1–C2
bond. Moreover, with selenocyanate 4 the functionalized
α,α-dimethoxycarbonitriles 12–14 are formed in which the
carbonyl group is protected as a ketal from nucleophilic attack
and, hence, they would be especially suited to undergo selective
nucleophilic reactions at the cyano carbon.
It is interesting to note that the results appear to indicate a
higher reactivity, towards cyclopropanes 1, of benzeneselenenyl
chloride 3 than that of its thio analogue. Indeed, 3 is able to add
without a catalyst even to disubstituted 1d. For unsubstituted
1a, however, isomerization is still faster than ring addition, as is
also observed in the sulfenylation.1
Experimental
IR spectra were recorded on a Perkin-Elmer 1760/X-FT
1
spectrophotometer using CHCl3 as solvent. H and 13C NMR
Scheme 5
spectra were recorded with a Varian Gemini-300 spectrometer
using CDCl3 as solvent and Me4Si as internal standard.
J-Values are given in Hz. DEPT techniques were employed to
determine the multiplicity in the 13C NMR spectra. Elemental
analyses were performed using a Carlo Erba EA 1108-
Elemental analyzer. Low-resolution electron-impact mass
spectra were obtained operating at 70 eV on a GCMS-
QP5050A (Shimadzu). HPLC was performed on a Shimadzu
LC-9A instrument equipped with an LCA-Shimadzu UV
detector using a Merck Lichrosorb Si-60 (10 µm) column with
3 cm3 minϪ1 flow rate of elution. CCl4, and CH2Cl2 used in
the reactions were anhydrous. Silica gel [0.063–0.20 mm
(Macherey-Nagel)] and light petroleum (boiling range 40–60
ЊC) were used for column chromatography. TLC was performed
on silica gel layers (Whatman PK6F). Cyclopropanes 1a,5 trans-
1b,5 trans-1c,20 1d5 and alkene 2a5 were prepared according to
literature methods. Benzeneselenenyl chloride 3 was purchased
from Fluka and used without purification while phenyl seleno-
cyanate 4 was prepared from 3 and trimethylsilyl cyanate as
reported.21
12a and syn-12b which derive from the addition of the reagent 4
to the C1–C2 ring bond. Moreover, the cyclopropane 1b also
gave syn-5b, and 1a led to 6a and the 3-phenylseleno-4-
cyanobutanoate 14a, both of which are formed via the alkene
2a, as confirmed by control experiments. All of the products
were isolated and fully characterized. Stereochemistry of
syn-12b was assigned by converting it, according to the above
procedure, to the Z-alkene 15 (Scheme 6), whose configuration
Scheme 6
was determined on the basis of an NOESY experiment This
showed NOE effects between Me and H as well as between
OCH2 and OMe.
Control experiments showed that: i) prolonged reaction times
did not affect product distribution; ii) compounds 5b, 6a, 12a,b,
13a–d, 14a were stable under the reaction conditions.
The peculiar results obtained by using selenocyanate 4 as
electrophile can be explained by taking into account the
experimental procedure used (the addition of TiCl4 to the mix-
ture of 1 and 4), the lower reactivity of 4 than that of selenenyl
chloride 3, and the higher nucleophilicity of CN than the Cl
moiety. Scheme 5 shows a reasonable mechanistic hypothesis.
According to literature reports,19 it is likely that the addition of
Selenenylation of cyclopropanes 1a–d
To a 0.2 mol dmϪ3 solution of 1 (1 mmol) in dry CCl4 an equi-
molecular amount of benzeneselenenyl chloride 3 was added
and the resulting mixture was kept under strictly anhydrous
conditions5,20 at room temperature until complete disappear-
ance of the red colour of the selenenyl halide (15 min for 1a–c,
24 h for 1d). The completion of the reaction was confirmed by
1H NMR analysis of a sample of the tetrachloride solution,
recorded in CDCl3, which also showed the presence of MeCl in
all the reaction mixtures. The solvent was then removed under
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J. Chem. Soc., Perkin Trans. 1, 2002, 664–668

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reduced pressure and the residue chromatographed on silica gel.
For the residues obtained starting from cyclopropanes 1a and
1d elution with light petroleum–Et2O (9 : 1 v/v) gave the esters
6a (204 mg, 65%) and 5d, respectively. From cyclopropanes 1b,c
column chromatography as above led to a mixture of syn- and
anti-5b,c which were separated by HPLC eluting with hexane–
tert-butyl methyl ether (17 : 3 v/v). The new compound 6a was
identified by comparison with an authentic sample synthesized
independently (see below).
7.23–7.65 (5 H, m, C6H5); δC 13.7 (q), 36.7 (t ϩ d), 51.9 (q), 60.5
(t), 126.3 (s), 128.7 (two overlapping d), 135.9 (d), 170.5 (s),
172.1(s); m/z (EI) 316 (Mϩ, 80Se), 314 (Mϩ, 78Se). Found: C,
49.5; H, 5.2. C13H16O4Se requires C, 49.53; H, 5.12%.
Selenenylation in the presence of TiCl4
To a 0.2 mol dmϪ3 solution of a cyclopropane 1 (1 mmol) in dry
CH2Cl2, kept at Ϫ78 ЊC, was added an equimolecular amount
of TiCl4 under nitrogen and the mixture was stirred. After 30
min, to the red solution, maintained at Ϫ78 ЊC, was added one
equivalent of PhSeCl 3 in CH2Cl2 (4 cm3) and stirring was con-
tinued for 2 hours. After addition of THF–water (1 : 1; 1 cm3),
the mixture was warmed to room temperature and then
extracted with CH2Cl2 (3 × 5 cm3). The combined extracts were
dried (MgSO4) and, finally, evaporated. Chromatography of the
residues carried out as above gave the ester 6a starting from 1a
and the esters 5b–d starting from 1b–d with the yields reported
in Table 1.
1-Ethyl 4-methyl 3-methyl-2-(phenylseleno)butanedioate (syn-
5b). Oil (164 mg, 50%); tR = 9.9 min; νmax/cmϪ1 1729; δH 1.18
(3 H, t, J 7.0, OCH2CH3), 1.43 (3 H, d, J 7.0, 3-CH3), 2.85 (1 H,
m, J 10.3 and 7.0, 3-H), 3.64 (3 H, s, OCH3), 3.71 (1 H, d,
J 10.3, 2-H), 4.09 (2 H, m, J 7.0, OCH2), 7.26–7.65 (5 H, m,
C6H5); δC 13.9 (q), 16.3 (q), 40.9 (d), 46.4 (d), 51.9 (q), 61.0 (t),
128.8 (d), 129.1 (d), 129.6 (s), 135.8 (d), 172.2 (s), 174.9 (s); m/z
(EI) 330 (Mϩ, 80Se), 328 (Mϩ, 78Se). Found: C, 51.1; H, 5.4.
C14H18O4Se requires C, 51.07; H, 5.51%.
Cyanoselenenylation of cyclopropanes 1
1-Ethyl 4-methyl 3-methyl-2-(phenylseleno)butanedioate (anti-
5b). Oil (32 mg, 10%); tR = 7.6 min; νmax/cmϪ1 1729; δH 1.19 (3 H,
t, J 7.0, OCH2CH3), 1.27 (3 H, d, J 6.9, 3-CH3), 3.01 (1 H, m,
J 10.2 and 6.9, 3-H), 3.73 (3 H, s, OCH3), 3.76 (1 H, d, J 10.2,
2-H), 4.10 (2 H, m, J 7.0, OCH2), 7.25–7.65 (5 H, m, C6H5);
δC 14.0 (q), 16.6 (q), 42.2 (d), 45.9 (d), 52.0 (q), 61.1 (t), 127.9
(s), 128.7 (d), 129.0 (d), 135.9 (d), 171.2 (s), 174.3 (s); m/z
(EI) 330 (Mϩ, 80Se), 328 (Mϩ, 78Se). Found: C, 51.0; H, 5.5.
C14H18O4Se requires C, 51.07; H, 5.51%.
To a 0.2 mol dmϪ3 solution of a cyclopropane 1 (1 mmol) in dry
CH2Cl2, kept at Ϫ78 ЊC, were added an equimolecular amount
of PhSeCN 4 in the same solvent (4 cm3) and TiCl4 (1 mmol) in
succession under nitrogen and the resulting mixture was stirred
for 2 hours. Then, tetrahydrofuran–water (1 : 1; 1 cm3) was
added and the mixture was warmed to room temperature
and extracted with CH2Cl2 (3 × 5 cm3). The combined extracts
were dried (MgSO4) and evaporated. Silica gel chromatography
of the residue of 1a and elution with light petroleum–Et2O
(9 : 1 v/v) followed by HPLC (hexane–tert-butyl methyl ether,
9 : 1 v/v) gave 12a (71 mg, 20%), 14a (22 mg, 6%), 6a (32 mg,
10%) and 13a (40 mg, 20%), successively. Column chrom-
atography (light petroleum–Et2O, 9 : 1 v/v) of the mixture from
1b followed by HPLC (hexane–tert-butyl methyl ether, 17 : 3
v/v) gave the ester 13b (43 mg, 20%), syn-5b (49 mg, 15%) and
syn-12b (81 mg, 22%), successively. For the residues starting
from 1c and 1d column chromatography (light petroleum–Et2O,
9 : 1 v/v) gave 13c (80 mg, 35%) and 13d (68 mg, 30%), respect-
ively. Compound 14a was identified by comparison with an
authentic sample (see below).
1-Ethyl 4-methyl 3-ethyl-2-(phenylseleno)butanedioate (syn-
5c). Oil (157 mg, 46%); tR = 9.7 min; νmax/cmϪ1 1728; δH 0.88
(3 H, t, J 7.3, CH2CH3), 1.17 (3 H, t, J 7.3, OCH2CH3), 1.74–
2.20 (2 H, m, CH2), 2.75 (1 H, m, 3-H), 3.64 (3 H, s, OCH3),
3.77 (1 H, d, J 11.2, 2-H), 4.08 (2 H, q, J 7.3, OCH2), 7.25–7.64
(5 H, m, C6H5); δC 10.3 (q), 13.8 (q), 23.3 (t), 44.5 (d), 47.0 (d),
51.8 (q), 60.9 (t), 127.1 (s), 128.8 (d), 129.0 (d), 135.9 (d), 172.3
(s), 174.2 (s); m/z (EI) 344 (Mϩ, 80Se), 342 (Mϩ, 78Se). Found: C,
52.4; H, 5.9. C15H20O4Se requires C, 52.48; H, 5.87%.
1-Ethyl 4-methyl 3-ethyl-2-(phenylseleno)butanedioate (anti-
5c). Oil (38 mg, 11%); tR = 6.4 min; νmax/cmϪ1 1728; δH 0.90 (3 H,
t, J 7.1, CH2CH3), 1.18 (3 H, t, J 7.0, OCH2CH3), 1.55–1.77
(2 H, m, CH2), 2.88 (1 H, m, 3-H), 3.72 (d, J 11.2) and 3.74 (s)
(together 4 H, 2-H and OCH3), 4.10 (2 H, m, OCH2), 7.25–7.65
(5 H, m, C6H5); δC 11.7 (q), 13.9 (q), 25.2 (t), 45.0 (d), 49.3 (d),
51.7 (q), 61.1 (t), 127.9 (s), 128.8 (d), 129.0 (d), 135.9 (d), 171.3
(s), 173.8 (s); m/z (EI) 344 (Mϩ, 80Se), 342 (Mϩ, 78Se). Found: C,
52.6; H, 5.8. C15H20O4Se requires C, 52.48; H, 5.87%.
Ethyl
4-cyano-4,4-dimethoxy-2-(phenylseleno)butanoate
(12a). Oil; tR = 13.5 min; νmax/cmϪ1 1730, 2237; δH 1.17 (3 H, t,
J 7.3, CH3), 2.30 (1 H, dd, J 14.3 and 2.7) and 2.77 (1 H, dd,
J 14.3 and 10.7) (CH2), 3.35 and 3.36 (6 H, 2 s, 2 × OCH3), 3.85
(1 H, dd, J 10.7 and 2.7, 2-H), 4.08 (2 H, m, J 7.3, OCH2), 7.25–
7.74 (5 H, m, C6H5); δC 13.9 (q), 36.4 (d), 38.8 (t), 52.0 (q), 52.2
(q), 61.3 (t), 99.2 (s), 114.8 (s), 127.1 (s), 129.0 (d), 129.2 (d),
135.9 (d), 171.9 (s); m/z (EI) 357 (Mϩ, 80Se), 355 (Mϩ, 78Se).
Found: C, 50.6; H, 5.4; N, 3.8. C15H19NO4Se requires C, 50.57;
H, 5.38; N, 3.93%.
1-Ethyl 4-methyl 3,3-dimethyl-2-(phenylseleno)butanedioate
(5d). Oil (52 mg, 15%); νmax/cmϪ1 1723; δH 1.19 (3 H, t, J 7.1,
OCH2CH3), 1.43 and 1.46 (6 H, 2 s, 2 × 3-Me), 3.65 (3 H, s,
OCH3), 3.82 (1 H, s, 2-H), 4.12 (2 H, m, OCH2), 7.23–7.70 (5 H,
m, C6H5); δC 13.9 (q), 23.7 (q), 23.9 (q), 45.0 (s), 52.0 (q), 53.8
(d), 60.8 (t), 128.1 (d), 129.1 (d), 130.1 (s), 134.7 (d), 172.2 (s),
176.0 (s); m/z (EI) 344 (Mϩ, 80Se), 342 (Mϩ, 78Se). Found: C,
52.5; H, 5.9. C15H20O4Se requires C, 52.48; H, 5.87%.
Ethyl
4-cyano-4,4-dimethoxy-3-methyl-2-(phenylseleno)-
butanoate (syn-12b). Oil; tR = 12.1 min; νmax/cmϪ1 1729, 2237;
δH 1.09 (3 H, t, J 7.0, OCH2CH3), 1.34 (3 H, d, J 6.8, 3-CH3),
2.83 (1 H, m, J 6.8 and 10.2, 3-H), 3.32 and 3.37 (6 H,
2 s, 2 × OCH3), 3.80 (1 H, d, J 10.2, 2-H), 3.96 (2 H, m, J 12.4
and 7.0, OCH2), 7.23–7.68 (5 H, m, C6H5); δC 13.8 (q),
14.4 (q), 39.4 (d), 46.4 (d), 50.9 (q), 52.7 (q), 60.7 (t), 103.4 (s),
114.1 (s), 128.0 (s), 128.5 (d), 129.0 (d), 135.5 (d), 172.3
(s); m/z (EI) 371 (Mϩ, 80Se), 369 (Mϩ, 78Se). Found: C, 52.0;
H, 5.8; N, 3.9. C16H21NO4Se requires C, 51.89; H, 5.72; N,
3.78%.
Selenenylation of alkene 2a with selenenyl chloride 3
A 0.2 mol dmϪ3 solution of alkene 2a (1 mmol) in dry CCl4 was
treated with halide 3 as reported above for 1a. Then, the solvent
was removed and chromatography of the residue on silica gel
and elution with light petroleum–Et2O (9 : 1 v/v) gave 1-ethyl 4-
methyl 3-(phenylseleno)butanedioate 6a (220 mg, 70%) as an
oil; tR = 15.7 min (hexane–tert-butyl methyl ether, 9 : 1);
νmax/cmϪ1 1734; δH 1.21 (3 H, t, J 7.0, CH3), 2.70 (1 H, dd, J 17.4
and 5.9) and 2.89 (1 H, dd, J 17.4 and 9.9) (together CH2), 3.68
(3 H, s, OCH3), 4.01 (1 H, m, 3-H), 4.04 (2 H, q, J 7.0, OCH2),
Ethyl 4-cyano-4,4-dimethoxybutanoate (13a). Oil; tR = 16.7
min; νmax/cmϪ1 1730, 2235; δH 1.27 (3 H, t, J 7.0, CH3), 2.20–
2.32 (2 H, m, CH2), 2.48–2.60 (2 H, m, CH2), 3.41 (6 H, s,
2 × OCH3), 4.15 (2 H, q, J 7.0, OCH2); δC 14.0 (q), 28.4 (t), 31.1
(t), 51.2 (q), 60.7 (t), 99.4 (s), 115.2 (s), 172.5 (s); m/z (EI) 201
J. Chem. Soc., Perkin Trans. 1, 2002, 664–668
667

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(Mϩ). Found: C, 53.6; H, 7.5; N, 6.8. C9H15NO4 requires C,
53.72; H, 7.51; N, 6.96%.
(16 mg, 65%) by TLC using light petroleum–Et2O (8 : 2 v/v) as
eluent and identified by comparing its 1H NMR spectrum with
that reported.15
Ethyl 4-cyano-4,4-dimethoxy-3-methylbutanoate (13b). Oil;
tR = 9.0 min; νmax/cmϪ1 1729, 2237; δH 1.10 (3 H, d, J 7.0,
3-CH3), 1.27 (3 H, t, J 7.3, OCH2CH3), 2.16–2.30 (1 H, m,
J 16.6 and 10.2) and 2.55–2.71 (2 H, m) (CHCH2), 3.38 and
3.41 (6 H, 2 s, 2 × OCH3), 4.15 (2 H, q, J 7.3, OCH2); δC 14.1
(q), 14.4 (q), 35.0 (d), 36.1 (t), 51.0 (q), 51.8 (q), 60.5 (t), 102.9
(s), 114.3 (s), 171.8 (s); m/z (EI) 215 (Mϩ). Found: C, 55.7; H,
7.9; N, 6.4. C10H17NO4 requires C, 55.80; H, 7.96; N, 6.51%.
The same procedure was carried out starting from anti-5a
(46 mg, 0.14 mmol) and led to the alkene E-7 (18 mg, 73%)
which was identified by comparing its 1H NMR spectrum with
that reported.15
Ethyl (Z )-4-cyano-4,4-dimethoxy-3-methylbut-2-enoate (15)
The same oxidative procedure as for syn-5b was carried out
starting from syn-12b (74 mg, 0.2 mmol) and led, after purifi-
cation by TLC (light petroleum–Et2O, 17 : 3 v/v), to the alkene
Z-15 (25 mg, 60%) as an oil; νmax/cmϪ1 2236, 1724, 1650; δH 1.31
(3 H, t, J 7.0, CH3), 1.92 (3 H, d, J 1.7, 3-CH3), 3.35 (6 H, s,
2 × OCH3), 4.21 (2 H, q, J 7.0, OCH2), 6.02 (1 H, q, J 1.7, 2-H);
m/z (EI) 213 (Mϩ). Found: C, 56.4; H, 7.1; N, 6.3. C10H15NO4
requires C, 56.32; H, 7.09; N, 6.57%.
Ethyl 4-cyano-3-ethyl-4,4-dimethoxybutanoate (13c). Oil;
νmax/cmϪ1 1729, 2244; δH 0.97 (3 H, t, J 7.1, CH2CH3), 1.27 (t,
J 6.9), 1.30–1.45 (m) and 1.65–1.85 (m) (together 5 H,
OCH2CH3 and CH2CH3), 2.26–2.60 (3 H, m, CHCH2), 3.39
(6 H, s, 2 × OCH3), 4.14 (2 H, q, J 6.9, OCH2); δC 11.4 (q), 14.0
(q), 22.8 (t) 34.0 (t), 41.3 (d), 51.3 (q), 51.6 (q), 60.5 (t), 103.0 (s),
114.6 (s), 172.4 (s); m/z (EI) 229 (Mϩ). Found: C, 57.6; H, 8.4;
N, 6.1. C11H19NO4 requires C, 57.62; H, 8.35; N, 6.11%.
Acknowledgements
We thank CNR for financial support and MURST (L488/92)
for the purchase of the GCMS-QP5050A (Shimadzu) used in
this work. NMR spectra were run at the Centro di Metodologie
Chimico-fisiche, Università di Napoli Federico II.
Ethyl 4-cyano-4,4-dimethoxy-3,3-dimethylbutanoate (13d).
Oil; νmax/cmϪ1 1724, 2234; δH 1.23 (6 H, s, 2 × 3-CH3), 1.29 (3 H,
t, J 7.0, OCH2CH3 ), 2.46 (2 H, s, CH2), 3.65 (6 H, s, 2 × OCH3),
4.15 (2 H, q, J 7.0, OCH2); δC 14.2 (q), 21.7 (two overlapping q),
40.4 (t), 43.8 (s), 56.2 (q), 60.2 (t), 106.4 (s), 113.3 (s), 171.5 (s);
m/z (EI) 229 (Mϩ). Found: C, 57.7; H, 8.4; N, 6.1. C11H19NO4
requires C, 57.62; H, 8.35; N, 6.11%.
When the reaction mixture was stirred for 6 h and worked as
described, the results were very similar. When an equimolecular
solution of 1 and 4 in CH2Cl2 was kept in the absence of TiCl4
at room temperature under anhydrous conditions for 12 h, the
1H NMR spectrum showed only the presence of the starting
material 1 and no trace of the above products. At higher tem-
perature, after 6 h, the results were similar except for the pres-
ence of polymeric material and for 1a a little of the alkene 2a,
too.
References
1 Part 6: M. L. Graziano, M. R. Iesce and F. Cermola, Synthesis,
1999, 1944.
2 Review H.-U. Reissig, Top. Curr. Chem., 1988, 144, 73. For more
recent work, see:; P. K. Patra and H.-U. Reissig, Synlett, 2001, 33;
R. Zimmer, A. Ziemer, M. Gruner, I. Brudgam, H. Hartl and
H.-U. Reissig, Synthesis, 2001, 1649.
3 (a) M. L. Graziano and G. Cimminiello, J. Chem. Res., (S),
1989, 42; (M), 0446; (b) S. Shimada, K. Saigo, Y. Hashimoto,
Y. Maekawa, T. Yamashita, T. Yamamoto and M. Hasegawa, Chem.
Lett., 1991, 1475; M. L. Graziano and S. Chiosi, J. Chem. Res., (S),
1989, 44; (c) M. L. Graziano, M. R. Iesce, F. Cermola and
G. Cimminiello, J. Chem. Res., (S), 1992, 4; (M), 0157;
(d ) S. Shimada, Y. Hashimoto, T. Nagashima, M. Hasegawa and
K. Saigo, Tetrahedron, 1993, 49, 1589; (e) M. L. Graziano, M. R.
Iesce and F. Cermola, J. Chem. Res. (S), 1996, 82; (M), 0622.
4 V. Piccialli and M. L. Graziano, Tetrahedron Lett., 2001, 42, 93 and
references therein.
Cyanoselenenylation of 2a
A 0.2 mol dmϪ3 solution of 2a (1 mmol) in dry CH2Cl2 was
treated with cyanate 4 as reported above for 1a. Chromato-
graphy of the residue on silica gel (light petroleum–Et2O, 9 : 1)
followed by HPLC (hexane–tert-butyl methyl ether, 9 : 1 v/v) led
to the esters 14a (32 mg, 9%), 6a (72 mg, 23%) and 13a (36 mg,
18%), successively.
5 M. L. Graziano and R. Scarpati, J. Chem. Soc., Perkin Trans. 1,
1985, 289.
6 K. A. Jensen and A. Kjær, in The Chemistry of Organic Selenium and
Tellurium Compounds, ed. S. Patai and Z. Rappoport, Wiley,
New York, 1986, vol. 1, p. 1.
7 H.-U. Reissig and I. Reichelt, Tetrahedron Lett., 1984, 25, 5879.
8 P. L. Beaulieu, V. M. Morisset and D. G. Garratt, Can. J. Chem.,
1980, 58, 1005.
9 E. Block and A. L. Schwan, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, p. 329.
10 S. Tomoda, Y. Takeuchi and Y. Nomura, J. Chem. Soc., Chem.
Commun., 1982, 871.
Ethyl
4-cyano-4,4-dimethoxy-3-(phenylseleno)butanoate
(14a). Oil; tR = 14.4 min; νmax/cmϪ1 2238, 1726; δH 1.22 (3 H, t,
J 7.2, Me), 2.67 and 3.00 (2 H, 2 dd, J 13.7, 9.8, 4.2, CH2), 3.36
and 3.42 (6 H, 2 s, 2 × OMe), 3.90 (1 H, dd, J 9.8 and 4.2, 3-H),
4.10 (2 H, q, J 7.2, OCH2), 7.20–7.75 (5 H, m, C6H5); δC 14.0
(q), 35.9 (t), 44.0 (d), 52.7 (q), 52.9 (q), 61.0 (t), 103.1 (s), 114.2
(s), 127.5 (s), 128.5 (d), 129.1 (d), 135.8 (d), 170.8 (s); m/z (EI)
357 (Mϩ, 80Se), 355 (Mϩ, 78Se). Found: C, 50.7; H, 5.4; N, 3.9.
C15H19NO4Se requires C, 50.57; H, 5.38; N, 3.93%.
11 S. Tomoda, Y. Takeuchi and Y. Nomura, Tetrahedron Lett., 1982, 23,
1361.
12 S. Tomoda, Y. Takeuchi and Y. Nomura, Chem. Lett., 1982, 1733.
13 H. Finch, R. M. Highcock, S. M. Roberts, K. M. Short and V. Sik,
J. Chem. Soc., Chem. Commun., 1989, 670.
14 Y. Gaoni, Tetrahedron, 1989, 45, 2819.
15 D. Bornstein, A. Weisz and A. Mandelbaum, Org. Mass Spectrom.,
1986, 21, 225.
16 J. H. Byers and G. C. Lane, J. Org. Chem., 1993, 58, 3355.
17 J. B. Lambert, E. C. Chelius, W. J. Schulz, Jr. and N. E. Carpenter,
J. Am. Chem. Soc., 1990, 112, 3156; J. M. Coxon, P. J. Steel and
B. I. Wittington, J. Org. Chem., 1990, 55, 4136.
18 Methyl 2-(trimethylsiloxy)cyclopropanecarboxylates not dialkylated
at C3 rearrange to the corresponding silyl enol ethers via Lewis acid-
coordinated ring-opened species: H.-U. Reissig and J. Böhm,
Tetrahedron Lett., 1983, 24, 715.
19 H.-U. Reissig, H. Holzinger and G. Glomsda, Tetrahedron, 1989, 45,
3139; S. Shimada, Y. Hashimoto, A. Sudo, M. Hasegawa and
K. Saigo, J. Org. Chem., 1992, 57, 7126.
20 M. L. Graziano and M. R. Iesce, Synthesis, 1985, 762.
21 S. Tomoda, Y. Takeuchi and Y. Nomura, Chem. Lett., 1981, 1069.
When the reaction was carried out in the absence of the
Lewis acid at Ϫ78 ЊC for 2 h and at room temperature for 24 h,
after work-up only ethyl methyl butanedioate5 was recovered,
derived from hydrolysis of 2a.†
1-Ethyl 4-methyl (E )- and (Z )-3-methylbutenedioates (7)
Oxidation was carried out as reported,16 by adding three drops
of 30% H2O2 to a solution of syn-5b (46 mg, 0.14 mmol) in
THF (5 cm3) kept at 0 ЊC. NMR analysis of the mixture after 30
min showed the presence of only Z-alkene 7, which was isolated
† The ketene ketals which have been reported to undergo uncatalyzed
cyanoselenenylation are 1,1-diethoxyethene, which is well known to be
highly reactive, and ketene alkyl silyl ketals.12
668
J. Chem. Soc., Perkin Trans. 1, 2002, 664–668