Intramolecular addition of γ-chloro carbanions to electrophilic groups: Synthesis of tricyclic tetrahydrofurans, pyrrolidines, and cyclopentanes

Article abstract of DOI:10.1002/ejoc.200901131

Carbanions of 3-chloropropyl phenyl sulfones containing electrophilic groups such as carbonyl and imino groups in the ortho position of the phenyl ring add intramolecularly to these groups to give aldol-type anions. These anions undergo intramolecular 1,5

Full text of DOI:10.1002/ejoc.200901131

FULL PAPER
DOI: 10.1002/ejoc.200901131
Intramolecular Addition of γ-Chloro Carbanions to Electrophilic Groups:
Synthesis of Tricyclic Tetrahydrofurans, Pyrrolidines, and Cyclopentanes
Anna Wojtasiewicz,[a] Michał Barbasiewicz,[a] and Mieczysław Makosza*[a]
˛
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Keywords: Carbanions / Aldol reactions / Cyclization / Nucleophilic substitution / Polycycles
Carbanions of 3-chloropropyl phenyl sulfones containing
electrophilic groups such as carbonyl and imino groups in
the ortho position of the phenyl ring add intramolecularly to
these groups to give aldol-type anions. These anions undergo
intramolecular 1,5-substitution of chlorine to give tricyclic
derivatives of tetrahydrofuran, pyrrolidine, and cyclopen-
tane.
Introduction
γ-Halo carbanions are short-lived intermediates that un-
dergo rapid intramolecular substitution to afford cyclopro-
panes.[1–3] Due to the high rate of this reaction, often
termed γ-elimination, intermolecular reactions of γ-halo
carbanions are not highly recognized. We have found[4–11]
that γ-chloro carbanions can be intermolecularly trapped
when they are generated by deprotonation of appropriate
precursors in the presence of active electrophilic partners.[12]
For instance, treatment of a mixture of 3-chloropropyl
phenyl sulfone and benzaldehyde with tBuOK in THF at
low temperature results in the formation of 2-phenyl-3-
(phenylsulfonyl)tetrahydrofuran in excellent yield.[4] The re-
Scheme 1. Intra- and intermolecular reactions of γ-halo carban-
ions.
action proceeds through the fast and reversible addition of tility of this synthetic tool is the high rate of intramolecular
the γ-chloro carbanion to the aldehyde followed by intra- 1,3-substitution; thus, the synthesis of the above-mentioned
molecular 1,5-substitution of the intermediate aldol-type five-membered ring systems depends upon the competition
adduct (Scheme 1).
between 1,3-intramolecular substitution and intermolecular
In general, addition of γ-chloro carbanions that contain addition to electrophilic partners. Taking into account the
nucleophilic and electrophilic centers in one molecule in a reversibility of the addition, the overall success of the syn-
1,3 relation to the electron-deficient double bonds C=O, thesis of these compounds depends not only on the afore-
C=N, and C=C of aldehydes, imines, and Michael ac- mentioned competition, but also on the position of the
ceptors, respectively, generates intermediates with nucleo- equilibrium and the rates of intramolecular 1,5-substitution
philic and electrophilic centers in a 1,5 relation. Further in the intermediate anionic adducts. The reversibility of the
intramolecular substitution in these intermediates should addition and the rate of 1,5-substitution acting as impor-
give substituted tetrahydrofurans,[4,5] pyrrolidines,[5,7] and tant factors in the synthesis of tetrahydrofurans by the reac-
cyclopentanes.[5,6] Indeed, we have shown that proper selec- tion of γ-chloro carbanions with aldehydes were clearly
tion of the γ-chloro carbanion precursors and electrophilic demonstrated.[8] We have observed that the crucial competi-
partners opens interesting possibilities for the synthesis of tion can be controlled in a few ways: by changing the leav-
these five-membered heterocyclic and carbocyclic com- ing group[4,8,9] and nucleophilicity of the carboanionic cen-
pounds. The main problem that limits the scope and versa- ter,[4,6,7,10] by introducing substituents in the carbanion
chain,[11] by separating the leaving group and the car-
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
boanionic centers in the γ-chloro carbanions by introducing
C=C bonds, and by varying the solvents and counterions,
etc.
ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-632-66-81
E-mail: icho-s@icho.edu.pl
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when 1 was treated with NaH in DMF, apart from products
of decomposition, vinylcoumarin 1b was obtained in 14%
yield (Scheme 2).
Results and Discussion
Taking into account that intramolecular reactions are
usually faster than their intermolecular counterparts, pro-
vided there are no steric difficulties, we studied the reac-
tions of γ-chloro carbanions containing an additional carb-
onyl group or similar electrophilic fragments in a proper
position of the γ-chloro carbanion molecule. We expected
that in such systems 1,5- or 1,6-intramolecular additions of
the carbanion would be preferred over 1,3-intramolecular
substitution. As model precursors of such γ-chloro carban-
ions we chose benzene derivatives that contain electrophilic
groups in an ortho relation to the γ-chloro carbanion
moiety. The main goal of the study was to verify the pre-
sented hypothesis by synthesizing new heterocycles, whereas
mechanistic investigations were secondary and limited to
systems where clear conclusions could be outlined.
Next, we studied reactions of (3-chloropropane)sulfonate
derivative 2. Because esters of sulfonic acids are less suscep-
tible to nucleophilic attack on sulfur, we expected that the
desired 1,6-intramolecular addition of the γ-halo carbanion
should proceed to give tricyclic tetrahydrofuran derivative
2a. Indeed, when 2 was treated with tBuOK in THF at
–40 °C to room temperature expected compound 2a was
obtained in a moderate yield of 30%. A substantially better
yield (51%) of 2a was obtained when 2 was treated with
NaH in DMF. On the other hand, when the reaction was
carried out in ethanol, the main product was ethyl sulfonate
2b (62% yield). It seems that this product was formed by
base-inducted ethanolysis of 2a (Scheme 3).
The first, readily accessible compound of this type that
was tested was the 4-chlorobutyrate of salicylaldehyde 1.
We expected that the γ-chloro enolate generated by treat-
ment of this ester with a strong base would add to the alde-
hyde carbonyl group to produce an aldol-type anion that
should give, by intramolecular 1,5-substitution, a tricyclic
tetrahydrofuran derivative 1a (Scheme 2).
Scheme 3. Reaction of sulfonate precursor 2 gave tricyclic com-
pound 2a; in ethanol, transesterified product 2b was obtained.
Interesting model compounds for verification of our con-
cept appeared to be (3-chloropropyl)phenyl sulfones 6–17
containing carbonyl or other groups acting as an electro-
philic partner in the ortho position of the phenyl ring. Syn-
thesis of these compounds is presented in Scheme 4.
Treatment of sulfonyl aldehyde 6 with tBuOK in THF
gave expected tricyclic tetrahydrofuran derivative 6a, but in
moderate yield only, together with a cyclopropyl phenyl sul-
fone (Scheme 5). The initially generated carbanion of 6
adds to the carbonyl group to give an aldol-type intermedi-
ate as two diastereoisomers (cis and trans). We assume that
under these conditions only the cis isomer can enter the 1,5-
intramolecular substitution to give 6a.
Scheme 2. Instead of expected tricyclic lactone 1a, reaction of 1
with NaH in DMF yields coumarin derivative 1b in low yield.
However, reaction with tBuOK in THF leads to neighboring group
accelerated cleavage of the ester function and release of salicylalde-
hyde exclusively.
It appears that under these conditions, intramolecular
1,5-addition and 1,3-substitution proceed with comparable
rates. The cis isomer of the anionic adduct cyclizes to 6a,
whereas the trans isomer can epimerize. The cyclopropyl
Unfortunately, when 1 was treated with our standard sulfone produced by 1,3-substitution is subsequently de-
base tBuOK in THF the only products were salicylaldehyde formylated through the addition of tBuOK to the carbonyl
and 4-chlorobutyric acid, even without aqueous treatment group followed by splitting of the C–C bond in the hemi-
of the reaction mixture. Apparently, the initial process was acetal anion to produce cyclopropyl phenyl sulfone (6c) and
addition of the tBuO– anion to the aldehyde followed by tert-butyl formate. To confirm the last step, we prepared 2-
intramolecular addition of the produced hemiacetal anion formyldiphenyl sulfone (19) by lithiation of diphenyl sulf-
to the ester functionality and subsequent departure of the one (18) followed by reaction with dimethyl formamide.[14]
phenolic anion of salicylaldehyde.[13] On the other hand, This sulfone treated with potassium tert-butoxide in THF
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Intramolecular Addition of γ-Chloro Carbanions to Electrophilic Groups
Scheme 5. Product distribution in the reaction of 6 with tBuOK
depends on the solvent: reaction in THF gives a mixture of tetra-
hydrofuran (i.e., 6a) and cyclopropane (i.e., 6c) derivatives, whereas
in EtOH 6a is formed exclusively. The mechanism of the base-in-
duced deformylation to cyclopropane derivative 6c in THF was
established on the basis of the reactivity of model substrate 19 (see
text).
Scheme 4. Synthesis of compounds 3–16.
underwent complete deformylation to give quantitatively
diphenyl sulfone (18). To improve the yield of 6a the reac-
tion of 6 with tBuOK was carried out in ethanol. It was
observed earlier that this solvent favors aldol-type addition
in intermolecular reactions of γ-chloro enolates to alde-
hydes and ketones, perhaps due to solvation of the aldol-
type anion, which thus improves the overall yields of the
tetrahydrofurans.[10]
Indeed, the reaction of 6 and 7 with tBuOK in ethanol
(the acting base was actually potassium ethoxide) carried
out for a long time (18–22 h) gave 6a and 7a in 97 and 99%
yield, respectively. On the other hand, when the reactions
were stopped after a short time, besides 6a and 7a, the trans Scheme 6. Reaction of 6 and 7 with tBuOK in EtOH gives tricyclic
cis isomers 6a and 7a in excellent yields. When the reaction is
isomers of aldol-type adducts 6b and 7b were isolated
stopped after a short time only uncyclized trans adducts 6b and 7b
are observed (see the text).
(Scheme 6). Obviously the initially formed trans adducts 6b
and 7b in protic media were epimerized to cis isomers of 6b
and 7b, which underwent intramolecular 1,5-substitution to
6a and 7a.
Imines are weaker electrophiles than aldehydes; however, case, 1,3-intramolecular substitution leading to cyclopro-
they still react with γ-chloro carbanions to give substituted pane was faster than 1,5-addition. Subsequent deproton-
pyrrolidines. Treatment of imines 8, 9, and 10 with tBuOK ation of the sulfonyl cyclopropane followed by addition of
in THF gave expected tricyclic pyrrolidine derivatives 8a, its carbanion to the imino group gives 11c. On the other
9a, and 10a in good yields. On the other hand, when the hand, when 11 was treated with tBuOK in toluene, 48%
reaction of 11 was carried out under the same conditions, of derivative of pyrrolidine 11a was obtained together with
spirocyclopropane derivative 11c was formed. Thus, in this cyclopropane 11c (24%, Scheme 7).
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ular 1,5-Michael addition was followed by intramolecular
1,5-nucleophilic substitution in the produced anionic ad-
duct.
Scheme 7. Reactions of imines 8–11 with tBuOK in THF and tolu-
ene.
We then have found that esters 12–14 and nitrile 15,
when treated with tBuOK, gave exclusively spirocyclopro-
pane derivatives 13c and 15c. Due to the rather low electro-
philic activity of the alkoxycarbonyl and cyano groups, 1,3-
intramolecular substitution producing sulfonyl cyclopro-
pane proceeds faster than 1,5-addition. Further deproton-
ation of the produced cyclopropane and addition of the
cyclopropyl carbanion gives 13c and 15c; variation of the
reaction conditions Ϫ solvents, counterions Ϫ does not
change the reaction course (Scheme 8). However, 13c and
15c may be alternatively formed by addition of the γ-halo
carbanion to the multiple bond, followed by proton transfer
from the acidic α position, and subsequent cyclization to
cyclopropane derivative, but the latter possibility seems to
be less feasible.
Scheme 9. Under basic conditions in THF, cinnamate 16 gives un-
cyclized adduct 16b,[16] whereas malonodinitrile derivative 17 cy-
clizes in ethanol to desired tricyclic compound 17a.
Conclusions
The results presented in this paper confirm our expecta-
tion that when γ-chloro carbanions contain additional elec-
trophilic fragments in a proper spatial position intramolec-
ular 1,5- or 1,6-addition of the carbanions to such frag-
ments proceeds faster than intramolecular 1,3-substitution,
which leads to the formation of cyclopropanes. Further 1,5-
substitution in the produced anionic adducts gives polycy-
clic tetrahydrofuran, pyrrolidine, and cyclopentane deriva-
tives. The investigated substrates required individual opti-
mization of the reaction conditions, but the methodology
has proved to be suitable and useful for the construction of
five- and six-membered rings.
Experimental Section
General: Reactions of carbanions were conducted in flame-dried
glassware under an atmosphere of argon. Column chromatography
was performed with Fisher Scientific Matrex Silica 60 (35–70 mi-
cron). Melting points were measured with a Griffin electrothermal
apparatus. IR spectra were recorded with a Perkin–Elmer Spectrum
1
One FTIR spectrometer. H and 13C NMR spectra were recorded
with Bruker DPX300 or DRX500 Fourier Transform spectrometers
by using an internal deuterium lock. Electrospray ionization (ESI)
was performed with either a Micromass LCT TOF spectrometer
or a Waters-Micromass ZMD spectrometer. High-resolution mass
spectrometry (HRMS) was obtained by peak matching with the
use of polyethylene glycol as a standard.
Scheme 8. Cyclization of sulfones 12–15 under basic conditions to
give cyclopropane derivatives 13c and 15c.[15]
Finally, we verified the possibility to synthesize tricyclic
cyclopentane derivatives through the reaction of chloropro-
pyl aryl sulfones containing Michael acceptor fragments 16
and 17 in the ortho position of the phenyl ring (Scheme 9).
Treatment of 16 with tBuOK in THF gave the Michael-type
adduct, which under the applied reaction conditions does
not cyclize. On the other hand, when 17 was treated with
tBuOK in EtOH the expected tricyclic cyclopentane deriva-
1: Triethylamine (10.30 g, 102 mmol) in Et2O (20 mL) was added
dropwise to a solution of salicylaldehyde (12.21 g, 100 mmol) and
4-chlorobutyryl chloride (14.10 g, 100 mmol) in Et2O (130 mL) at
–10 °C. After 5 min, the mixture was warmed to room temperature
and after 18 h water (300 mL) was added. The mixture was then
extracted with EtOAc (2ϫ100 mL). The combined organic phases
were washed with aqueous K2CO3 (2ϫ150 mL), water
tive was obtained in good yield. In this case, the intramolec- (2ϫ150 mL), and brine (100 mL) and then dried with MgSO4. The
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Intramolecular Addition of γ-Chloro Carbanions to Electrophilic Groups
solvent was evaporated, and the mixture was distilled to yield 1
was warmed to room temperature and after 30 min an aqueous
(16.6 g, 73%). Oil, b.p. 120–125 °C/4ϫ10–2 Torr. 1H NMR solution of NH4Cl was added. The mixture was then extracted with
(200 MHz, CDCl3, 25 °C): δ = 2.18–2.34 (m, 2 H, CH2CH2Cl), CH2Cl2 (2ϫ20 mL). The combined organic phases were washed
2.89 (t, JH,H = 7.1 Hz, 2 H, CH2CH2CH2Cl), 3.71 (t, JH,H = 6.3 Hz, with brine and dried with MgSO4. Column chromatography (hex-
1
2 H, CH2Cl), 7.18 (dd, JH,H = 8.0, 1.1 Hz, 1 H, Harom), 7.42 (ddd,
JH,H = 7.6, 7.6, 1.1 Hz, 1 H, Harom), 7.64 (ddd, JH,H = 8.0, 7.4,
1.8 Hz, 1 H, Harom), 7.87 (dd, JH,H = 7.7, 1.8 Hz, 1 H, Harom),
10.07 (s, 1 H, CHO) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ
= 27.3, 31.0, 43.9, 123.4, 126.5, 128.0, 131.9, 135.3, 151.0, 171.0,
ane/EtOAc) gave 2a (0.113 g, 51%). M.p. 153–154 °C (EtOH). H
NMR (500 MHz, CDCl3, 25 °C): δ = 2.54–2.68 (m, 2 H, 3-H),
3.91–3.97 (m, 1 H, 2-H), 4.02–4.07 (m, 1 H, 2-H), 4.17 (ddd, JH,H
= 9.3, 7.7, 6.2 Hz, 1 H, 4-H), 5.36 (d, JH,H = 7.7 Hz, 1 H, 5-H),
7.13 (dd, JH,H = 8.1, 1.0 Hz, 1 H, Harom), 7.30 (dt, JH,H = 8.1,
1.0 Hz, 1 H, Harom), 7.39 (dt, JH,H = 8.1, 1.6 Hz, 1 H, Harom), 7.52
(dd, JH,H = 8.1, 1.6 Hz, 1 H, Harom) ppm. 13C NMR (125 MHz,
188.8 ppm. IR (CH2Cl2 film): ν = 2965, 2862, 2754, 1764, 1699,
˜
1605, 1581, 1482, 1456, 1412, 1369, 1308, 1276, 1198, 1124, 929,
757, 649, 425 cm–1. MS (ESI, 70 eV): m/z (%) = 226 (2) [M+], 173 CDCl3, 25 °C): δ = 28.4, 58.9, 66.8, 77.7, 119.2, 122.8, 126.6, 130.3,
(2), 122 (59), 107 (31), 105 (100). C11H11ClO3 (226.66): calcd. C 130.7, 150.1 ppm. IR (CH2Cl2 film): ν = 2963, 2924, 2879, 1489,
˜
58.29, H 4.89, Cl 15.64; found C 58.62, H 4.89, Cl 15.16.
1457, 1372, 1186, 1162, 1152, 1109, 1093, 1050, 896, 786, 758,
546 cm–1. HRMS (ESI): calcd. for C10H10O4SNa 249.0192; found
249.0197. C10H10O4S (226.25): calcd. C 53.09, H 4.46, S 14.17;
found C 53.15, H 4.56, S 14.20.
Reaction of 1 with tBuOK in THF: tBuOK (224 g, 2 mmol) in THF
(2 mL) was added dropwise to a solution of 1 (226 mg, 1 mmol) in
THF (5 mL) at –70 °C under an atmosphere of argon. After
30 min, the mixture was warmed to room temperature and after
15 min an aqueous solution of NH4Cl was added. The mixture was
then extracted with CH2Cl2 (2ϫ20 mL). The combined organic
Reaction of 2 with tBuOK in EtOH: Solid tBuOK (0.224 g, 2 mmol)
was added to a solution of 2 (0.264 g, 1 mmol) in EtOH (5 mL) at
room temperature under an atmosphere of argon. After 1 h an
aqueous solution of NH4Cl was added, and the mixture was ex-
tracted with CH2Cl2 (2ϫ20 mL). The combined organic phases
were washed with brine and dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 2b (0.168 g, 62%). Oil. 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 1.13 (t, JH,H = 7.1 Hz, 3 H,
CH2CH3), 2.55–2.62 (m, 1 H, 4-H), 2.72–2.79 (m, 1 H, 4-H), 3.81
(dt, JH,H = 9.9, 7.1 Hz, 1 H, 3-H), 3.93–4.00 (m, 2 H, CH2CH3),
4.09 (ddd, JH,H = 9.2, 6.0, 3.5 Hz, 1 H, 5-H), 4.42 (dt, JH,H = 8.5,
5.7 Hz, 1 H, 5-H), 5.26 (d, JH,H = 6.0 Hz, 1 H, 2-H), 6.82 (dd, JH,H
= 8.1, 1.0 Hz, 1 H, Harom), 6.89 (dt, JH,H = 7.5, 1.0 Hz, 1 H, Harom),
7.08 (br. s, 1 H, OH), 7.16–7.20 (m, 1 H, Harom), 7.22–7.24 (m, 1
H, Harom) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 14.9,
28.3, 63.2, 65.6, 66.6, 81.1, 116.6, 119.7, 119.8, 128.2, 129.3,
1
phases were washed with brine and dried with MgSO4. H NMR
analysis showed the presence of salicylaldehyde only (as compared
with original sample).
Reaction of 1 with NaH in DMF: Solid NaH (0.027 g, 1.1 mmol)
was added to a solution of 1 (0.226 g, 1 mmol) in DMF (5 mL) at
–40 °C under an atmosphere of argon. After 30 min the mixture
was warmed to room temperature and after 20 h an aqueous solu-
tion of NH4Cl was added. The mixture was then extracted with
CH2Cl2 (2ϫ20 mL). The combined organic phases were washed
with brine and dried with MgSO4. Column chromatography (hex-
ane/EtOAc) gave 1b (0.024 g, 14%) and unreacted 1 (0.011 g, 5%).
Data for 1b: Oil. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 5.41 (dd,
JH,H = 11.3, 1.1 Hz, 1 H, =CHEHZ), 6.11 (dd, JH,H = 17.6, 1.1 Hz,
1 H, =CHEHZ), 6.66 (ddd, JH,H = 17.6, 11.3, 0.7 Hz, 1 H, CH=),
7.18–7.21 (m, 1 H, Harom), 7.22–7.26 (m, 1 H, Harom), 7.40–7.44
(m, 2 H, Harom), 7.63 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 116.4, 119.4, 119.5, 124.5, 125.1, 127.8, 130.5,
154.8 ppm. IR (CH2Cl2 film): ν = 3431, 2985, 2884, 1599, 1504,
˜
1495, 1459, 1344, 1166, 1062, 1000, 917, 757, 494 cm–1. HRMS
(ESI): calcd. for C12H16O5SNa 295.0611; found 295.0599.
3: Solid KOH (31.5 g, 0.56 mol) was slowly added to an intensively
stirred suspension of 2-mercaptobenzoic acid (30.83 g, 0.2 mol) and
1-bromo-3-chloropropane (47.66 g, 0.3 mol) in EtOH (300 mL).
The mixture was heated at reflux for 3.5 h, cooled to room tem-
perature, and poured to a mixture of water (1500 mL) and concen-
trated aqueous HCl (80 mL). After 18 h the solid was filtered,
washed with 30% solution of EtOH in water, and dried to give 3
(46 g, 88%). The crude product was used to the next reaction with-
out further purification. M.p. 126–128 °C (EtOH). 1H NMR
(200 MHz, [D6]DMSO, 25 °C): δ = 1.96–2.12 (m, 2 H, CH2CH2Cl),
3.04 (t, JH,H = 7.2 Hz, 2 H, CH2CH2CH2Cl), 3.76 (t, JH,H = 6.4 Hz,
2 H, CH2Cl), 7.15–7.27 (m, 1 H, Harom), 7.37–7.58 (m, 2 H, Harom),
7.86 (dd, JH,H = 7.8, 1.6 Hz, 1 H, Harom), 13.00 (br. s, 1 H, COOH)
ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 28.0, 30.8, 44.1,
131.3, 137.6, 153.1, 160.2 ppm. IR (CH Cl film): ν = 3040, 1760,
˜
2
2
1717, 1626, 1604, 1456, 1369, 1001, 950, 921, 751, 733, 643, 631,
454 cm–1. HRMS (FD): calcd. for C11H8O2 172.0524; found
172.0522.
2: To a solution of salicylaldehyde (1.83 g, 15 mmol) and (3-chloro-
propane)sulfonyl chloride (2.66 g, 15 mmol) in Et2O (20 mL) at
–10 °C Et3N was added dropwise (1.55 g, 15.3 mmol) in Et2O
(3 mL). After 5 min the mixture was warmed to room temperature
and after 20 h water (45 mL) was added. The mixture was then
extracted with EtOAc (2ϫ30 mL). The combined organic phases
were washed with aqueous K2CO3 (2ϫ30 mL), water (2ϫ30 mL),
and brine (30 mL) and then dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 2 (2.00 g, 65%). Oil. 1H
124.1, 125.6, 128.6, 131.0, 132.4, 140.0, 167.5 ppm. IR (KBr): ν =
˜
NMR (500 MHz, CDCl3, 25 °C):
δ = 2.47–2.55 (m, 2 H,
2970, 2644, 1677, 1561, 1463, 1411, 1319, 1277, 1251, 1150, 1060,
1047, 923, 741, 704, 554 cm–1. MS (ESI, 70 eV): m/z (%) = 232 (30)
[M+], 230 (82), 194 (8), 184 (6), 176 (8), 167 (34), 153 (41), 150
(49), 136 (100). C10H11ClO2S (230.72): calcd. C 52.06, H 4.81, Cl
15.37, S 13.87; found C 52.33, H 4.91, Cl 14.09, S 13.94.
CH2CH2Cl), 3.60–3.65 (m, 2 H, CH2CH2CH2Cl), 3.73–3.78 (m, 2
H, CH2Cl), 7.40–7.50 (m, 2 H, Harom), 7.62–7.70 (m, 1 H, Harom),
7.96–8.22 (m, 1 H, Harom), 10.29 (s, 1 H, CHO) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 26.70, 42.17, 48.90, 123.55, 127.78,
130.42, 132.90, 135.56, 149.35, 187.91 ppm. IR (CH Cl film): ν =
˜
2
2
2969, 1699, 1603, 1481, 1455, 1370, 1351, 1311, 1274, 1187, 1159,
1090, 878, 813, 779 cm–1. HRMS (FD): calcd. for C10H11ClNaO4S
284.9959; found 284.9951.
General Procedure of the Synthesis 12–14: Crude 3 (23.05 g,
100 mmol) was dissolved in acetic acid (200 mL). The mixture was
warmed to 90 °C and hydrogen peroxide (30%, 23.02 g, 203 mmol)
was added dropwise. The mixture was gently heated at reflux for
3 h, acetic acid was evaporated under vacuum, the residue was
treated with thionyl chloride (30.8 g, 259 mmol) and then warmed
Reaction of 2 with NaH in DMF: Solid NaH (0.027 g, 1.1 mmol)
was added to a solution of 2 (0.264 g, 1 mmol) in DMF (5 mL) at
–40 °C under an atmosphere of argon. After 30 min the mixture
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1889

A. Wojtasiewicz, M. Barbasiewicz, M. Makosza
˛
FULL PAPER
at 50 °C for 20 h. The mixture was evaporated, and the residue was
dissolved in a mixture of CH2Cl2 (100 mL) and alcohol (250 mmol)
at 0 °C. To this solution was slowly added pyridine (17.5 g,
221 mmol) in CH2Cl2 (100 mL) over 20 min. The mixture was left
at room temperature for 20 h, washed with dilute aqueous HCl
(2ϫ100 mL), NaHCO3 (2ϫ100 mL), and brine (2ϫ100 mL), and
dried with MgSO4. Column chromatography (hexane/EtOAc) gave
12–14.
(79), 105 (59). C10H13ClO3S (248.73): calcd. C 48.29, H 5.27, Cl
14.25, S 12.89; found C 48.36, H 5.40, Cl 14.27, S 12.93.
6: To an intensively stirred solution of 5 (4.60 g, 18.5 mmol) in
CH2Cl2 (100 mL) was added pyridinium chlorochromate (PCC,
4.01 g, 18.6 mmol) over 10 min. After 1 h, a second portion of PCC
(0.41 g, 1.9 mmol) was added, and the mixture was stirred for 5 h.
Then, the mixture was filtered through Celite, and the solvent was
evaporated. Column chromatography (hexane/EtOAc) gave
6
(3.38 g, 74%). M.p. 47–50 °C (EtOH). 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 2.20–2.36 (m, 2 H, CH2CH2Cl), 3.42–3.53 (m,
2 H, CH2CH2CH2Cl), 3.65 (t, JH,H = 6.1 Hz, 2 H, CH2Cl), 7.75–
7.89 (m, 2 H, Harom), 8.04–8.16 (m, 2 H, Harom), 10.75 (s, 1 H,
CHO) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 25.5, 42.5,
55.1, 130.5, 130.6, 133.8, 134.3, 134.9, 139.6, 189.5 ppm. IR (KBr):
1
12: Yield 65% (18.1 g), oil. H NMR (200 MHz, CDCl3, 25 °C): δ
=
2.23–2.37 (m, 2 H, CH2CH2Cl), 3.64–3.72 (m, 4 H,
CH2CH2CH2Cl), 3.98 (s, 3 H, OCH3), 7.62–7.74 (m, 3 H, Harom),
8.04–8.11 (m, 1 H, Harom) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = 25.7, 42.8, 53.3, 53.8, 129.8, 130.6, 131.1, 133.4, 133.7,
137.7, 167.4 ppm. IR (film): ν = 3003, 2955, 1735, 1434, 1295, 1262,
˜
1153, 1125, 1058, 957, 830, 787, 765, 739, 598, 569, 538 cm–1. MS
(ESI, 70 eV): m/z (%) = 276 (Ͻ1) [M+], 245 (29), 199 (58), 181 (62),
169 (58), 148 (73), 135 (83), 105 (100), 92 (50), 77 (57). HRMS (EI):
calcd. for C11H13ClO4S 276.0223; found 276.0230. C11H13ClO4S
(276.74): calcd. C 47.74, H 4.73, Cl 12.81, S 11.59; found C 47.80,
H 4.91, Cl 12.83, S 11.76.
ν = 2931, 1685, 1588, 1413, 1295, 1262, 1193, 1146, 1111, 958, 825,
˜
750, 727, 606, 532 cm–1. MS (ESI, 70 eV): m/z (%) = 247 (1) [M+],
231 (11), 229 (31), 169 (100), 153 (12), 142 (26). C10H11ClO3S
(246.71): calcd. C 48.68, H 4.49, Cl 14.37, S 13.00; found C 48.50,
H 4.64, Cl 14.24, S 13.09.
Reaction of 6 with tBuOK in THF: tBuOK (0.112 g, 1 mmol) in
THF (2 mL) was added dropwise to a solution of 6 (123 mg,
0.5 mmol) in THF (5 mL) at –70 °C under an atmosphere of argon.
After 30 min the mixture was warmed to room temperature and
after 15 min an aqueous solution of NH4Cl was added. The mix-
ture was then extracted with CH2Cl2 (2ϫ20 mL). The combined
organic phases were washed with brine and dried with MgSO4.
Column chromatography (hexane/EtOAc) gave 6a (0.037 g, 34%)
and 6c[4] (0.035 g, 38%). Data for 6a: Oil. 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 2.34–2.43 (m, 1 H, 3-H), 2.65–2.72 (m, 1 H, 3-
H), 3.57–3.63 (m, 1 H, 2-H), 3.98 (ddd, JH,H = 9.0, 7.6, 3.3 Hz, 1
H, 2-H), 4.04 (ddd, JH,H = 9.9, 7.1, 2.9 Hz, 1 H, 4-H), 5.74 (d, JH,H
= 7.1 Hz, 1 H, 5-H), 7.59 (ddd, JH,H = 8.1, 7.2, 1.2 Hz, 1 H, Harom),
7.63 (d, JH,H = 7.0 Hz, 1 H, Harom), 7.67 (ddd, JH,H = 8.1, 7.2,
1.2 Hz, 1 H, Harom), 7.73 (d, JH,H = 7.8 Hz, 1 H, Harom) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 29.1, 63.2, 67.9, 79.8, 121.1,
1
13: Yield 59% (17.2 g), oil. H NMR (200 MHz, CDCl3, 25 °C): δ
= 1.41 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3), 2.21–2.36 (m, 2 H,
CH2CH2Cl), 3.62–3.73 (m, 4 H, CH2CH2CH2Cl), 4.44 (q, JH,H
7.2 Hz, 2 H, OCH2CH3), 7.60–7.74 (m, 3 H, Harom), 8.01–8.12 (m,
1 H, Harom) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 14.0,
25.7, 42.8, 53.9, 62.5, 129.8, 130.6, 131.0, 133.7, 133.8, 137.5,
=
167.0 ppm. IR (film): ν = 2983, 1732, 1441, 1368, 1293, 1261, 1153,
˜
1123, 1058, 740, 599, 538 cm–1. MS (ESI, 70 eV): m/z (%) = 290 (1)
[M+], 247 (14), 245 (38), 213 (11), 195 (8), 185 (37), 182 (16), 169
(60), 162 (16), 149 (16), 145 (31), 121 (22), 105 (100). C12H15ClO4S
(290.77): calcd. C 49.57, H 5.20, Cl 12.19, S 11.03; found C 49.62,
H 5.35, Cl 12.08, S 10.91.
1
14: Yield 60% (20.6 g), oil. H NMR (500 MHz, CDCl3, 25 °C): δ
=
2.27–2.34 (m, 2 H, CH2CH2Cl), 3.61–3.69 (m, 4 H,
CH2CH2CH2Cl), 4.74 (q, JH,H = 8.4 Hz, 2 H, CH2CF3), 7.72–7.78
127.6, 131.0, 134.1, 136.1, 139.8 ppm. IR (CH Cl film): ν = 3626,
˜
2
2
(m, 3 H, Harom), 8.09–8.13 (m, 1 H, Harom) ppm. 13C NMR
3061, 2985, 2872, 1956, 1584, 1470, 1452, 1299, 1260, 1205, 1173,
1146, 1120, 1049, 925, 888, 841, 757, 634, 592, 558, 536, 488,
427 cm–1. MS (ESI, 70 eV): m/z (%) = 210 (14) [M+], 167 (95), 163
(30), 147 (14), 137 (100), 115 (88). C10H10O3S (210.25): calcd. C
57.13, H 4.79, S 15.25; found C 57.03, H 4.72, S 15.21.
(125 MHz, CDCl3, 25 °C): δ = 25.6, 42.7, 53.9, 61.9 (q, JC,F
36.7 Hz), 121.7, 123.9, 130.1, 130.9, 131.5, 132.0, 133.9, 138.2,
165.3 ppm. IR (film): ν = 2972, 1755, 1574, 1441, 1415, 1303, 1250,
=
˜
1155, 1115, 1063, 964, 784, 764, 739, 663, 599, 569, 535 cm–1. MS
(ESI, 70 eV): m/z (%) = 267 (28), 203 (50), 181 (55), 145 (88), 120
(26), 105 (100), 91 (60), 41 (58). HRMS (ESI): calcd. for
C12H12ClF3O4NaS 366.9989; found 366.9987.
Synthesis of 19 was performed according to a procedure described
in the literature.[14]
Deformylation of 19: tBuOK (0.112 g, 1 mmol) in THF (2 mL) was
added dropwise to a solution of 19 (0.123 g, 0.5 mmol) in THF
(5 mL) at –70 °C under an atmosphere of argon. After 30 min the
mixture was warmed to room temperature and after 15 min an
aqueous solution of NH4Cl was added. The mixture was then ex-
tracted with CH2Cl2 (2ϫ20 mL). The combined organic phases
were washed with brine and dried with MgSO4. The residue was
recrystallized from EtOH to give 19 (0.103 g, 95%). M.p. 93–94 °C
5: DIBAL-H (13 mL, 13 mmol, 1  in toluene) was added dropwise
to a solution of 13 (1.79 g, 6.2 mmol) in toluene (35 mL) at 0 °C
under an atmosphere of argon. After 80 min, MeOH (10 mL), an
aqueous solution of NH4Cl (30 mL), and hydrochloric acid
(10 mL) were added, and the mixture was extracted with EtOAc
(3ϫ30 mL). The combined organic phases were washed with aque-
ous NaHCO3 (30 mL) and brine (30 mL) and then dried with
MgSO4. The solvent was evaporated, and crude product 5 was ob-
tained (1.43 g, 93% yield) and used in the next reaction without
1
(CCl4); ref.[14] 93 °C. H NMR spectroscopic data consistent with
the literature.[14]
1
further purification. Oil. H NMR (200 MHz, CDCl3, 25 °C): δ =
2.12–2.35 (m, 2 H, CH2CH2Cl), 3.10 (t, JH,H = 6.7 Hz, 1 H, OH),
Reaction of 6 with tBuOK in EtOH: tBuOK (0.241 g, 2.15 mmol)
3.35–3.46 (m, 2 H, CH2CH2CH2Cl), 3.64 (dd, JH,H = 6.2, 6.2 Hz, in EtOH (1 mL) was added dropwise to a solution of 6 (0.247 g,
2 H, CH2Cl), 4.93 (d, JH,H = 6.7 Hz, 2 H, CH2OH), 7.47–7.72 (m, 1 mmol) in EtOH (5 mL) at room temperature under an atmo-
3 H, Harom), 8.00 (dd, JH,H = 7.6, 1.0 Hz, 1 H, Harom) ppm. 13C
NMR (50 MHz, CDCl3, 25 °C): δ = 25.5, 42.7, 53.9, 63.0, 128.8,
sphere of argon. After 30 min an aqueous solution of NH4Cl was
added, and the mixture was extracted with CH2Cl2 (2ϫ20 mL).
The combined organic phases were washed with brine and dried
with MgSO4. Column chromatography (hexane/EtOAc) gave 6a
(0.162 g, 77%) and 6b (0.045 g, 18%). Data for 6b: Oil. H NMR
(500 MHz, CDCl3, 25 °C): δ = 2.34–2.44 (m, 1 H, CHHCH2Cl),
130.7, 131.7, 134.6, 136.9, 140.5 ppm. IR (film): ν = 3503, 2965,
˜
1442, 1299, 1192, 1150, 1120, 1023, 765, 605, 572, 537 cm–1. MS
(ESI, 70 eV): m/z (%) = 250 (1), 248 (3) [M+], 233 (7), 231 (19), 171
(11), 153 (100), 145 (12), 143 (34), 137 (22), 125 (29), 109 (43), 107
1
1890
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1885–1894

Intramolecular Addition of γ-Chloro Carbanions to Electrophilic Groups
2.57–2.65 (m, 1 H, CHHCH2Cl), 3.20 (d, JH,H = 8.3 Hz, 1 H, OH),
3.55–3.61 (m, 1 H, 2-H), 3.79–3.91 (m, 2 H, CH2Cl), 5.04 (dd, JH,H
C16H14O3S (286.35): calcd. C 67.11, H 4.93, S 11.20; found C 67.19,
H 4.94, S 11.35. Data for 7b: M.p. 124–125 °C (EtOH). H NMR
1
= 8.3, 7.4 Hz, 1 H, 3-H), 7.53–7.58 (m, 1 H, Harom), 7.64–7.74 (m, (200 MHz, CDCl3, 25 °C): δ = 1.81–2.09 (m, 2 H, CH2CH2Cl),
3 H, Harom) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 29.3,
41.5, 66.7, 72.6, 121.3, 125.5, 130.3, 134.1, 137.9, 139.6 ppm. IR
2.95 (br. s, 1 H, OH), 3.67 (dd, JH,H = 7.1, 5.8 Hz, 1 H, CH2Cl),
4.02 (dd, JH,H = 8.7, 5.8 Hz, 1 H, 2-H), 7.22–7.36 (m, 5 H, Harom),
7.41–7.47 (m, 1 H, Harom), 7.57–7.71 (m 2 H, Harom), 7.80–7.87 (m,
1 H, Harom) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 28.4,
(CH Cl film): ν = 3469, 2928, 1632, 1698, 1467, 1453, 1292, 1182,
˜
2
2
1151, 1122, 1085, 1048, 944, 915, 759, 705, 660, 593, 560, 511 cm–1.
MS (ESI, 70 eV): m/z (%) = 248 (16), 246 (44) [M+], 231 (15), 229 41.3, 69.3, 80.2, 121.1, 125.8, 126.4, 128.4, 128.5, 130.7, 134.7,
(39), 197 (31), 169 (100), 154 (19), 153 (19), 142 (30), 137 (41).
C10H11ClO3S (246.71): calcd. C 48.68, H 4.49, Cl 14.37, S 13.00;
found C 48.71, H 4.70, Cl 14.87, S 13.22.
138.4, 139.5, 143.7 ppm. IR (CH Cl film): ν = 3460, 3061, 2923,
˜
2 2
1496, 1449, 1298, 1152, 1123, 1042, 763, 749, 702, 589, 562, 544,
506 cm–1. MS (ESI, 70 eV): m/z (%) = 322 (Ͻ1) [M+], 304 (19), 273
(10), 213 (100), 195 (56), 181 (14), 165 (9), 152 (14), 105 (20), 77
(22). HRMS (ESI): calcd. for C16H15ClNaO3S 345.0323; found
345.0307. C16H15ClO3S (322.81): calcd. C 59.53, H 4.68, Cl 10.98,
S 9.93; found C 59.51, H 4.85, Cl 10.82, S 9.88.
The same reaction carried out for 18 h gave 6a (0.203 g, 97%) as
the only product.
The stereochemistry of 6a and 6b was established on the basis of
NOE experiments.
The same reaction carried out for 22 h gave 4a (0.140 g, 99%) as
the only product.
General Procedure for the Synthesis of 8–11: A mixture of 6
(0.494 g, 2 mmol), amine (2 mmol), and anhydrous MgSO4
(0.962 g, 8 mmol) in toluene (10 mL) was stirred at room tempera-
ture for 24 h. The mixture was then was filtered, and the solvent
was evaporated. Crystalline products were recrystallized from
EtOH.
8: Yield quant., m.p. 88–90 °C (EtOH). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 2.19–2.26 (m, 2 H, CH2CH2Cl), 2.39 (s, 3 H,
CH3), 3.32–3.36 (m, 2 H, CH2CH2CH2Cl), 3.61 (t, JH,H = 6.2 Hz,
2 H, CH2Cl), 7.23 (m, 4 H, Harom), 7.65 (dt, JH,H = 7.8, 1.3 Hz, 1
H, Harom), 7.74–7.78 (m, 1 H, Harom), 8.08 (dd, JH,H = 7.9, 1.1 Hz,
1 H, Harom), 8.39 (dd, JH,H = 7.8, 1.1 Hz, 1 H, Harom), 9.40 (s, 1
H, N=CH) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 21.1,
25.6, 42.5, 54.7, 121.3, 129.5, 129.9, 130.1, 130.8, 134.1, 135.8,
7: Phenylmagnesium bromide (3.34 mL, 10 mmol, 3  in THF) was
added dropwise to a suspension of 4 (2.81 g, 10 mmol) and CuI
(1.91 g, 10 mmol) in THF (60 mL) at –5 °C. The mixture was
warmed to room temperature and after 2 h a 5% aqueous solution
of HCl (60 mL) and ammonia (60 mL) were added, and the mix-
ture was extracted with CH2Cl2 (2ϫ50 mL). The combined organic
phases were washed with brine and dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 7 (2.09 g, 65%). M.p. 99–
100 °C (EtOH). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 2.20–2.34
(m, 2 H, CH2CH2Cl), 3.54–3.69 (m, 4 H, CH2CH2CH2Cl), 7.39–
7.51 (m, 3 H, Harom), 7.57–7.66 (m, 1 H, Harom), 7.68–7.74 (m, 2
137.2, 137.9, 148.5, 155.3 ppm. IR (KBr): ν = 3064, 3023, 2970,
˜
2921, 1618, 1562, 1506, 1463, 1438, 1311, 1290, 1147, 1114, 1059,
1019, 962, 840, 819, 776, 750, 708, 635, 600, 541, 523, 496 cm–1.
MS (ESI, 70 eV): m/z (%) = 335 (65) [M+], 286 (21), 229 (61), 195
(72), 153 (97), 106 (100), 91 (57), 65 (56), 41 (43). HRMS (EI):
H, Harom), 7.76–7.84 (m, 2 H, Harom), 8.08–8.16 (m, 1 H, Harom
)
ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 25.7, 42.7, 55.2,
128.5, 130.0, 130.4, 130.6, 133.1, 133.9, 136.3, 137.9, 140.5, 144.4,
calcd.
for
C17H18ClNO2S
335.0747;
found
335.0734.
161.1 ppm. IR (KBr): ν = 3319, 3094, 2962, 1668, 1595, 1581, 1450,
˜
C17H18ClNO2S (335.86): calcd. C 60.80, H 5.40, Cl 10.56, N 4.17,
S 9.55; found C 60.76, H 5.46, Cl 10.51, N 4.01, S 9.62.
9: Yield quant., m.p. 80–82 °C (EtOH). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 2.21–2.27 (m, 2 H, CH2CH2Cl), 3.32–3.36 (m,
2 H, CH2CH2CH2Cl), 3.63 (t, JH,H = 6.1 Hz, 2 H, CH2Cl), 7.22–
1312, 1293, 1271, 1196, 1152, 1115, 936, 780, 771, 709, 634, 569,
537 cm–1. MS (ESI, 70 eV): m/z (%) = 245 (25), 240 (28), 213 (36),
182 (74), 169 (37), 152 (55), 105 (100), 77 (72). HRMS (ESI): calcd.
for C16H15ClNaO3S 345.0323; found 345.0327. C16H15ClO3S
(322.81): calcd. C 59.53, H 4.68, Cl 10.98, S 9.93; found C 59.37,
H 4.79, Cl 10.96, S 10.04.
7.26 (m, 2 H, Harom), 7.36–7.40 (m, 2 H, Harom), 7.68 (dt, JH,H
=
7.6, 1.2 Hz, 1 H, Harom), 7.77 (t, JH,H = 7.6 Hz, 1 H, Harom), 8.09
(dd, JH,H = 7.8, 1.2 Hz, 1 H, Harom), 8.39 (dd, JH,H = 7.8, 1.2 Hz, 1
H, Harom), 9.37 (s, 1 H, N=CH) ppm. 13C NMR (125 MHz, CDCl3,
25 °C): δ = 25.6, 42.5, 54.8, 122.6, 129.4, 129.6, 130.2, 131.2, 132.7,
Reaction of 7 with tBuOK in EtOH: tBuOK (0.112 g, 1 mmol) in
EtOH (2 mL) was added dropwise to a solution of 7 (0.161 g,
0.5 mmol) in EtOH (5 mL) at room temperature under an atmo-
sphere of argon. After 90 min an aqueous solution of NH4Cl was
added, and the mixture was extracted with CH2Cl2 (2ϫ20 mL).
The combined organic phases were washed with brine and dried
with MgSO4. Column chromatography (hexane/EtOAc) gave 7a
(0.085 mg, 60%) and 7b (0.061 g, 38%). Data for 7a: M.p. 118–
119 °C (EtOH). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 2.37–2.57
(m, 1 H, 3-H), 2.71–2.84 (m, 1 H, 3-H), 3.66–3.78 (m, 1 H, 2-H),
3.95 (dd, JH,H = 9.4, 2.4 Hz, 1 H, 4-H), 4.16–4.25 (m, 1 H, 2-H),
7.23–7.48 (m, 6 H, Harom), 7.53–7.65 (m, 2 H, Harom), 7.72–7.82
134.2, 135.3, 138.2, 149.5, 156.7 ppm. IR (KBr): ν = 3065, 2965,
˜
1616, 1561, 1486, 1312, 1290, 1262, 1188, 1147, 1113, 1091, 1059,
878, 832, 757, 722, 591, 570, 540, 520 cm–1. MS (ESI, 70 eV): m/z
(%) = 355 (5) [M+], 229 (52), 213 (50), 178 (45), 153 (72), 126 (51),
111 (41), 75 (53), 41 (100). HRMS (ESI): calcd. for
C16H15Cl2NNaO2S 378.0093; found 378.0100. C16H15Cl2NO2S
(356.27): calcd. C 53.94, H 4.24, Cl 19.90, N 3.93, S 9.00; found C
53.83, H 4.10, Cl 19.72, N 3.80, S 9.16.
(m, 1 H, Harom) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 10: Yield quant., oil. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.33
29.7, 68.1, 71.1, 90.9, 120.5, 125.4, 127.1, 128.1, 128.6, 130.7, 134.5, (t, JH,H = 7.3 Hz, 3 H, CH3), 2.18–2.24 (m, 2 H, CH2CH2Cl), 3.29–
139.5, 140.4, 141.9 ppm. IR (CH Cl film): ν = 3082, 2970, 2862, 3.33 (m, 2 H, CH2CH2CH2Cl), 3.63 (t, JH,H = 6.2 Hz, 2 H, CH2Cl),
˜
2
2
1449, 1297, 1175, 1144, 1121, 1055, 986, 767, 759, 748, 705, 560,
509, 495 cm–1. MS (ESI, 70 eV): m/z (%) = 286 (20) [M+], 239 (41),
213 (100), 178 (26), 165 (61), 136 (24), 115 (26), 105 (18), 77 (21).
HRMS (ESI): calcd. for C16H14NaO3S 309.0556; found 309.0560.
3.75 (dq, JH,H = 7.3, 1.5 Hz, 2 H, CH2CH3), 7.59 (dt, JH,H = 7.9,
1.4 Hz, 1 H, Harom), 7.69 (dt, JH,H = 7.7, 1.0 Hz, 1 H, Harom), 8.03
(dd, JH,H = 7.9, 1.3 Hz, 1 H, Harom), 8.11 (dd, JH,H = 7.7, 1.3 Hz, 1
H, Harom), 9.14 (s, 1 H, N=CH) ppm. 13C NMR (125 MHz, CDCl3,
Eur. J. Org. Chem. 2010, 1885–1894
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1891

A. Wojtasiewicz, M. Barbasiewicz, M. Makosza
˛
FULL PAPER
25 °C): δ = 16.0, 25.6, 42.6, 54.5, 56.2, 129.5, 129.8, 130.3, 134.1,
129 (33), 115 (54), 103 (18), 75 (25). HRMS (EI): calcd. for
136.1, 137.3, 157.3 ppm. IR (CH Cl film): ν = 2971, 2933, 1636, C16H14ClNO2S 319.0434; found 319.0432.
˜
2
2
1442, 1309, 1150, 1119, 767, 598, 570, 540 cm–1. MS (ESI, 70 eV):
m/z (%) = 273 (Ͻ1) [M+], 196 (100), 152 (55), 131 (23), 103 (74), 77
(13), 44 (54). HRMS (ESI): calcd. for C12H16ClNNaO2S 296.0483;
found 296.0496. C12H16ClNO2S (273.78): calcd. C 52.65, H 5.89,
Cl 12.95, N 5.12, S 11.71; found C 52.53, H 5.81, Cl 12.71, N 4.87,
S 11.78.
10a: Yield 52%, m.p. 70–71 °C (EtOH). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 1.07 (t, JH,H = 7.1 Hz, 3 H, CH2CH3), 1.16
(ddd, JH,H = 9.7, 7.5, 5.3 Hz, 1 H, 3-H), 1.37–1.43 (m, 1 H, 3-H),
1.56 (ddd, JH,H = 10.7, 7.5, 5.7 Hz, 2 H, 2-H and 4-H), 1.68 (ddd,
JH,H = 10.7, 7.5, 5.3 Hz, 1 H, 2-H), 2.52 (dq, JH,H = 11.3, 7.1 Hz,
1 H, CH2CH3), 2.73 (dq, JH,H = 11.3, 7.1 Hz, 1 H, CH2CH3), 4.26
(s, 1 H, 5-H), 7.51–7.58 (m, 2 H, Harom), 7.60–7.64 (m, 1 H, Harom),
7.80 (d, JH,H = 7.7 Hz, 1 H, Harom) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 9.1, 13.8, 15.5, 40.4, 45.4, 60.3, 121.3, 126.6,
11: Yield quant., oil. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 2.13–
2.19 (m, 2 H, CH2CH2Cl), 3.22–3.27 (m, 2 H, CH2CH2CH2Cl),
3.56 (t, JH,H = 6.2 Hz, 2 H, CH2Cl), 4.90 (d, JH,H = 1.2 Hz, 2 H,
CH2N=), 7.26–7.31 (m, 1 H, Harom), 7.36 (d, JH,H = 4.4 Hz, 4 H,
129.6, 133.0, 139.3, 140.1 ppm. IR (CH Cl film): ν = 3341, 2968,
˜
2
2
2869, 1466, 1453, 1289, 1152, 1115, 1062, 1034, 969, 760, 724,
574 cm–1. MS (ESI, 70 eV): m/z (%) = 237 (8) [M+], 222 (21), 193
(100), 151 (59), 144 (28), 132 (88), 118 (24), 91 (21), 44 (75). HRMS
(EI): calcd. for C12H15NO2S 237.0824; found 237.0814.
C12H15NO2S (237.32): calcd. C 60.73, H 6.37, N 5.90, S 13.51;
found C 60.65, H 6.28, N 5.82, S 13.68.
H
arom), 7.60 (dt, JH,H = 7.6, 1.2 Hz, 1 H, Harom), 7.69 (dt, JH,H =
7.6, 1.0 Hz, 1 H, Harom), 8.03 (dd, JH,H = 7.8, 1.0 Hz, 1 H, Harom),
8.16 (dd, JH,H = 7.7, 1.2 Hz, 1 H, Harom), 9.24 (s, 1 H, N=CH)
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 25.5, 42.5, 54.5,
65.5, 127.3, 128.2, 128.6, 129.6, 129.8, 130.5, 134.1, 135.8, 137.5,
138.5, 158.7 ppm. IR (CH2Cl2 film): ν = 3064, 3029, 2923, 1634,
˜
11c: Yield 48%, oil. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.11–
1.17 (m, 1 H, CHHCH2), 1.45–1.51 (m, 1 H, CHHCH2), 1.59–1.64
(m, 1 H, CH2CHH), 1.66–1.72 (m, 1 H, CH2CHH), 1.83 (s, 1 H,
1495, 1453, 1309, 1149, 1119, 1062, 1027, 754, 700, 597, 569, 539,
510 cm–1. MS (ESI, 70 eV): m/z (%) = 335 (3) [M+], 258 (7), 194
(14), 150 (9), 118 (8), 106 (8), 91 (100), 65 (16), 41 (13). HRMS
(EI): calcd. for C17H18ClNO2S 335.0747; found 335.0758.
C17H18ClNO2S (335.86): calcd. C 60.80, H 5.40, Cl 10.56, N 4.17,
S 9.55; found C 60.66, H 5.35, Cl 10.37, N 4.02, S 9.61.
NH), 3.68 (d, JH,H = 13.2 Hz, 1 H, CHHNH), 3.89 (d, JH,H
=
13.2 Hz, 1 H, CHHNH), 4.30 (s, 1 H, 3-H), 7.23–7.28 (m, 1 H,
Harom), 7.30–7.33 (m, 4 H, Harom), 7.53–7.60 (m, 2 H, Harom), 7.62–
7.66 (m, 1 H, Harom), 7.79–7.82 (m, 1 H, Harom) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 9.2, 13.9, 45.5, 49.9, 59.6, 121.4,
126.6, 127.3, 128.0, 128.5, 129.7, 133.1, 139.4, 139.5, 139.9 ppm.
General Procedure for Reactions of 8–11 with tBuOK in THF:
tBuOK (0.112 g, 1 mmol) in THF (2 mL) was added dropwise to a
solution of imine (0.5 mmol) in THF (5 mL) at –70 °C under an
atmosphere of argon. After 30 min the mixture was warmed to
room temperature and after 15 min an aqueous solution of NH4Cl
was added. The mixture was then extracted with CH2Cl2
(2ϫ20 mL). The combined organic phases were washed with brine
and dried with MgSO4. The products were isolated and purified by
column chromatography (hexane/EtOAc).
IR (CH2Cl2 film): ν = 3342, 3063, 3029, 1495, 1453, 1290, 1152,
˜
1115, 1062, 1031, 966, 760, 700, 573 cm–1. HRMS (ESI): calcd. for
C17H17NNaO2S 322.0872; found 322.0885.
Reaction of 11 with tBuOK in Toluene: Solid tBuOK (0.112 g,
1 mmol) was added to a solution of 11 (0.168 g, 0.5 mmol) in tolu-
ene (5 mL) at –70 °C under an atmosphere of argon. After 30 min
the mixture was warmed to room temperature and after 15 min
an aqueous solution of NH4Cl was added. The mixture was then
extracted with CH2Cl2 (2ϫ20 mL). The combined organic phases
were washed with brine and dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 11a (48%, 0.068 g) and 11c
8a: Yield 83%, m.p. 234–236 °C (EtOH). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 2.32 (s, 3 H, CH3), 2.40 (dq, JH,H = 13.6,
8.8 Hz, 1 H, 3-H), 2.51–2.59 (m, 1 H, 3-H), 3.41 (dt, JH,H = 8.8,
7.0 Hz, 1 H, 2-H), 3.52 (ddd, JH,H = 9.3, 8.8, 3.7 Hz, 1 H, 2-H),
4.09 (dt, JH,H = 8.8, 7.1 Hz, 1 H, 4-H), 5.63 (d, JH,H = 7.1 Hz, 1
H, 5-H), 6.76–6.80 (m, 2 H, Harom), 7.12–7.16 (m, 2 H, Harom),
7.50–7.54 (m, 3 H, Harom), 7.72–7.76 (m, 1 H, Harom) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 20.3, 26.7, 48.7, 61.9, 63.0,
113.0, 121.8, 127.0, 127.7, 130.0, 130.1, 133.9, 137.5, 140.1,
1
(24%, 0.034 g). Data for 11a: M.p. 105–107 °C (EtOH). H NMR
(500 MHz, CDCl3, 25 °C): δ = 2.34–2.43 (m, 1 H, 3-H), 2.50–2.57
(m, 1 H, 3-H), 2.73–2.79 (m, 1 H, 2-H), 2.83–2.90 (m, 1 H, 2-H),
3.70 (d, JH,H = 13.0 Hz, 1 H, CHHN), 3.96 (d, JH,H = 13.0 Hz, 1
H, CHHN), 4.00–4.05 (m, 1 H, 4-H), 4.63 (d, JH,H = 7.1 Hz, 1 H,
5-H), 7.26–7.30 (m, 1 H, Harom), 7.31–7.39 (m, 4 H, Harom), 7.44
(d, JH,H = 7.6 Hz, 1 H, Harom), 7.51 (t, JH,H = 7.3 Hz, 1 H, Harom),
7.57 (t, JH,H = 7.3 Hz, 1 H, Harom), 7.72 (d, JH,H = 7.6 Hz, 1 H,
Harom) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 25.7, 53.1,
58.7, 63.3, 67.9, 121.5, 127.3, 127.5, 128.5, 128.8, 130.1, 133.5,
145.2 ppm. IR (KBr): ν = 3031, 2921, 2842, 1618, 1516, 1478, 1358,
˜
1327, 1292, 1256, 1184, 1143, 1114, 835, 801, 763, 594, 570, 533,
506 cm–1. MS (ESI, 70 eV): m/z (%) = 299 (100) [M+], 234 (50),
208 (33), 133 (42), 118 (72), 91 (46), 65 (20). HRMS (EI): calcd.
for C17H17NO2S 299.0980; found 299.0986. C17H17NO2S (299.39):
calcd. C 68.20, H 5.72, N 4.68, S 10.71; found C 68.21, H 5.73, N
4.60, S 10.72.
138.1, 138.4, 139.4 ppm. IR (KBr): ν = 3024, 2965, 2932, 2808,
˜
1451, 1304, 1210, 1153, 1124, 1057, 859, 760, 734, 703, 558, 537,
496 cm–1. HRMS (ESI): calcd. for C17H17NNaO2S 322.0872; found
322.0866. C17H17NO2S (299.39): calcd. C 68.20, H 5.72, N 4.68, S
10.71; found C 68.23, H 5.71, N 4.62, S 10.78.
9a: Yield 70%, m.p. 243–245 °C (EtOH). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 2.41 (dq, JH,H = 13.7, 8.8 Hz, 1 H, 3-H), 2.54–
2.61 (m, 1 H, 3-H), 3.42 (dt, JH,H = 8.8, 7.1 Hz, 1 H, 2-H), 3.52
(ddd, JH,H = 8.8, 8.4, 3.7 Hz, 1 H, 2-H), 4.11 (dt, JH,H = 8.8, Reaction of 13 with tBuOK in THF: tBuOK (0.112 g, 1 mmol) in
7.1 Hz, 1 H, 4-H), 5.63 (d, JH,H = 7.1 Hz, 1 H, 5-H), 6.76–6.80 (m, THF (2 mL) was added dropwise to a solution of 13 (0.145 g,
2 H, Harom), 7.25–7.29 (m, 2 H, Harom), 7.47–7.51 (m, 1 H, Harom),
7.52–7.56 (m, 2 H, Harom), 7.73–7.77 (m, 1 H, Harom) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 26.6, 48.6, 61.7, 63.0, 114.0,
122.0, 123.3, 126.8, 129.5, 130.3, 134.1, 137.6, 139.5, 145.7 ppm.
0.5 mmol) in THF (5 mL) at –70 °C under an atmosphere of argon.
After 30 min the mixture was warmed to room temperature and
after 15 min an aqueous solution of NH4Cl was added. The mix-
ture was then extracted with CH2Cl2 (2ϫ20 mL). The combined
organic phases were washed with brine and dried with MgSO4.
IR (KBr): ν = 2858, 1597, 1494, 1476, 1360, 1296, 1258, 1188, 1144,
˜
1115, 1096, 835, 807, 769, 705, 584, 533 cm–1. MS (ESI, 70 eV):
Recrystallization from EtOH gave 13c (0.064 g, 62%). M.p. 88–
m/z (%) = 319 (100) [M+], 254 (54), 228 (26), 153 (50), 138 (79), 90 °C (EtOH). H NMR (500 MHz, CDCl3, 25 °C): δ = 1.88–1.92
1
1892
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1885–1894

Intramolecular Addition of γ-Chloro Carbanions to Electrophilic Groups
(m, 2 H, CHHCHH), 2.01–2.04 (m, 2 H, CHHCHH), 7.82 (dt,
16: A suspension of ethyl (dimethoxyphosphoryl)acetate (0.392 g,
JH,H = 7.6, 1.0 Hz, 1 H, Harom), 7.94 (dt, JH,H = 7.6, 1.2 Hz, 1 H, 2 mmol), 6 (0.494 g, 2 mmol), and solid K2CO3 (0.828 g, 8 mmol)
Harom), 8.02–8.07 (m, 2 H, Harom) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 19.5, 47.1, 121.7, 124.0, 132.5, 133.8, 136.3,
in THF (10 mL) was stirred for 24 h at room temperature. The
solid was filtered off, water (30 mL) was added, and the residue
was extracted with CH2Cl2 (3ϫ25 mL). The combined organic
phases were washed with brine and dried with MgSO4. The product
146.4, 189.3 ppm. IR (KBr): ν = 3089, 1720, 1587, 1455, 1310,
˜
1294, 1207, 1149, 988, 786, 751, 684, 602, 568 cm–1. MS (ESI,
70 eV): m/z (%) = 208 (92) [M+], 178 (23), 169 (20), 152 (40), 115 was purified by column chromatography (hexane/EtOAc) to give
(22), 104 (100), 76 (43), 50 (18). HRMS (EI): calcd. for C10H8O3S 16 (0.53 g, 84%). A minor amount of the E isomer (yield 4%) was
1
208.0194; found 208.0193. C10H8O3S (208.24): calcd. C 57.68, H
3.87, S 15.40; found C 57.53, H 4.03, S 15.18.
also isolated. Oil. H NMR (500 MHz, CDCl3, 25 °C): δ = 1.14 (t,
JH,H = 7.1 Hz, 3 H, CH2CH3), 2.09–2.15 (m, 2 H, CH2CH2Cl),
3.24–3.29 (m, 2 H, CH2CH2 CH2Cl), 3.57 (t, JH,H = 6.3 Hz, 2 H,
Under the same conditions, 12 and 14 gave 13c as the only product
(crude reaction mixtures were analyzed by NMR spectroscopy;
products were not isolated).
CH2Cl), 4.06 (q, JH,H = 7.1 Hz, 2 H, CH2CH3), 6.20 (d, JH,H
=
11.9 Hz, 1 H, CH=CHCO2), 7.35 (d, JH,H = 7.5 Hz, 1 H, Harom),
7.54 (t, JH,H = 7.8 Hz, 1 H, Harom), 7.61 (dt, JH,H = 7.5, 1.1 Hz, 1
H, Harom), 7.68 (d, JH,H = 11.9 Hz, 1 H, CH=CHCO2), 8.02 (dd,
JH,H = 7.8, 1.1 Hz, 1 H, Harom) ppm. 13C NMR (125 MHz, CDCl3,
25 °C): δ = 14.0, 25.7, 42.8, 52.8, 60.6, 123.2, 128.7, 129.5, 130.7,
15: Crude 3 (6.65 g, 24 mmol) in CH2Cl2 (30 mL) was added drop-
wise to an aqueous solution of ammonia (30 mL, 25%) at 0 °C.
After 10 min the mixture was warmed to room temperature and
after 24 h the mixture was extracted with CH2Cl2 (3ϫ50 mL). The
combined organic phases were washed with brine and dried with
MgSO4. The mixture was filtered, evaporated, dissolved in DMF
(15 mL) and 2,4,6-trichloro-[1,3,5]triazine (1.29 g, 7 mmol) in tert-
butyl methyl ether (38 mL) was added dropwise. After 24 h at room
temperature, water (50 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (3ϫ50 mL). The combined organic phases
were washed with brine and dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 15 (4.56 g, 79%). M.p. 70–
133.5, 135.7, 136.9, 142.0, 165.5 ppm. IR (CH Cl film): ν = 2982,
˜
2
2
1716, 1469, 1404, 1384, 1306, 1203, 1152, 1120, 1027, 803, 768,
601, 570, 524 cm–1. MS (ESI, 70 eV): m/z (%) = 175 (53), 147 (100),
131 (14), 103 (16), 91 (8), 77 (8), 41 (10). HRMS (ESI): calcd. for
C14H17ClNaO4S 339.0428; found 339.0422. C14H17ClO4S (316.81):
calcd. C 53.08, H 5.41, Cl 11.19, S 10.12; found C 53.06, H 5.30,
Cl 11.13, S 10.25.
Reaction of 16 with tBuOK in THF: tBuOK (0.095 g, 0.85 mmol)
dissolved in THF (1 mL) was added dropwise to a solution of 16
(0.135 g, 0.43 mmol) in THF (5 mL) at –70 °C under an atmo-
sphere of argon. After 1 h the mixture was warmed to room tem-
perature and after 15 min an aqueous solution of NH4Cl was
added. The mixture was then extracted with CH2Cl2 (2ϫ20 mL).
The combined organic phases were washed with brine and dried
with MgSO4. Column chromatography (hexane/EtOAc) gave 16b
1
71 °C (EtOH). H NMR (500 MHz, CDCl3, 25 °C): δ = 2.26–2.32
(m, 2 H, CH2CH2Cl), 3.52–3.56 (m, 2 H, CH2CH2CH2Cl), 3.67 (t,
JH,H = 6.2 Hz, 2 H, CH2Cl), 7.81 (dt, JH,H = 7.4, 1.5 Hz, 1 H,
Harom), 7.86 (dt, JH,H = 7.7, 1.5 Hz, 1 H, Harom), 7.95 (dd, JH,H
7.4, 1.5 Hz, 1 H, Harom), 8.19 (dd, JH,H = 7.7, 1.5 Hz, 1 H, Harom
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 25.5, 42.4, 52.6,
=
)
111.5, 115.4, 130.5, 133.4, 134.0, 135.6, 141.3 ppm. IR (KBr): ν =
˜
1
(yield 74%). Oil. H NMR (500 MHz, CDCl3, 25 °C): δ = 1.27 (t,
3089, 2918, 2230, 1315, 1261, 1197, 1155, 1125, 1066, 774, 761,
568, 548 cm–1. MS (ESI, 70 eV): m/z (%) = 151 (11), 144 (53), 117
(15), 103 (100), 76 (25), 51 (13), 41 (73), 39 (30). HRMS (ESI):
calcd. for C10H10ClNNaO2S 266.0013; found 266.0004.
C10H10ClNO2S (243.71): calcd. C 49.28, H 4.14, Cl 14.55, N 5.75,
S 13.16; found C 49.17, H 4.20, Cl 14.56, N 5.76, S 12.94.
JH,H = 7.2 Hz, 3 H, CH2CH3), 2.07–2.15 (m, 1 H, CHHCH2Cl),
2.56–2.64 (m, 1 H, CHHCH2Cl), 2.82 (dd, JH,H = 16.9, 5.5 Hz, 1
H, CHHCO2), 2.95 (dd, JH,H = 16.9, 7.7 Hz, 1 H, CHHCO2), 3.56–
3.66 (m, 2 H, 2-H and 3-H), 3.79–3.88 (m, 2 H, CH2Cl), 4.20 (q,
JH,H = 7.2 Hz, 2 H, CH2CH3), 7.40 (dq, JH,H = 7.7, 0.8 Hz, 1 H,
Harom), 7.51 (tt, JH,H = 7.6, 0.8 Hz, 1 H, Harom), 7.61 (dt, JH,H
=
Reaction of 15 with tBuOK in THF was performed according to
the same procedure as that used for 12–14, yield 90% (as a mixture
of geometric isomers observed by NMR spectroscopy).
7.6, 1.2 Hz, 1 H, Harom), 7.75 (dt, JH,H = 7.7, 0.6 Hz, 1 H, Harom
)
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 14.1, 32.3, 38.7,
40.8, 41.5, 61.3, 62.9, 122.0, 126.2, 129.5, 133.9, 138.0, 138.9,
170.9 ppm. IR (CH2Cl2 film): ν = 2982, 1731, 1296, 1190, 1155,
˜
Data for 15c: M.p. 148–149 °C (EtOH). Mixture of isomers (ca.
1:1). H NMR (500 MHz, [D6]DMSO, 25 °C): δ = 1.73–1.76 (m, 4
1127, 761, 576, 542 cm–1. MS (ESI, 70 eV): m/z (%) = 316 (3) [M+],
271 (19), 229 (16), 142 (89), 128 (100), 115 (45), 103 (22), 88 (27),
77 (19). HRMS (EI): calcd. for C14H17ClO4S 316.0536; found
316.0545. C14H17ClO4S (316.81): calcd. C 53.08, H 5.41, Cl 11.19,
S 10.12; found C 52.88, H 5.51, Cl 11.10, S 10.14.
1
H, CHHCHH), 1.80–1.90 (m, 4 H, CHHCHH), 7.88–7.96 (m, 4
H, Harom), 8.11–8.16 (m, 2 H, Harom), 8.17–8.20 (m, 1 H, Harom),
8.36–8.41 (m, 1 H, Harom), 10.65 (s, 1 H, NH=), 11.29 (s, 1 H,
NH=) ppm. 13C NMR (125 MHz, [D6]DMSO, 25 °C): δ = 16.6,
17.2, 44.5, 44.5, 121.0, 121.4, 122.7, 123.5, 130.5, 133.9, 133.9,
17: To a solution of 6 (0.988 g, 4 mmol) and malonodinitrile
(0.276 g, 4.16 mmol) in EtOH (8 mL) was added a few drops of
piperidine. The reaction mixture was heated at reflux for 20 h, then
the solvent was evaporated, water (10 mL) was added, and the mix-
ture was extracted with CH2Cl2 (3ϫ15 mL). The combined organic
phases were washed with brine and dried with MgSO4. Column
chromatography (hexane/EtOAc) gave 17 (0.823 g, 70%). Oil. 1H
134.0, 134.1, 141.1, 141.6, 165.3, 165.7 ppm. IR (KBr): ν = 3210,
˜
3087, 1638, 1355, 1305, 1152, 1120, 1051, 964, 770, 655, 595, 565,
532, 503 cm–1. MS (ESI, 70 eV): m/z (%) = 207 (90) [M+], 151 (37),
142 (36), 115 (46), 103 (100), 76 (48), 39 (30). HRMS (EI): calcd.
for C10H9NO2S 207.0354; found 207.0348. C10H9NO2S (207.25):
calcd. C 57.95, H 4.38, N 6.76, S 15.47; found C 58.00, H 4.28, N
6.85, S 15.45.
NMR (500 MHz, CDCl3, 25 °C):
δ = 2.20–2.27 (m, 2 H,
The same experiment was repeated, and the crude reaction mixture
was quenched with 10% aqueous HCl (10 mL), heated at reflux for
30 min, evaporated, and extracted with CH2Cl2 (3ϫ50 mL). The
combined organic phases were washed with brine and dried with
MgSO4. The solvent was removed, and the residue was recrys-
tallized from EtOH to give 13c (yield 90%).
CH2CH2Cl), 3.24–3.28 (m, 2 H, CH2CH2CH2Cl), 3.65 (t, JH,H
=
6.1 Hz, 2 H, CH2Cl), 7.80–7.88 (m, 2 H, Harom), 7.97–7.99 (m, 1
H, Harom), 8.15–8.18 (m, 1 H, Harom), 8.87 [s, 1 H, CH=C(CN)2]
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 25.4, 42.3, 54.2,
89.2, 111.2, 112.2, 130.2, 130.5, 131.1, 133.4, 134.7, 137.9,
157.8 ppm. IR (CH2Cl2 film): ν = 3065, 2926, 2235, 1699, 1598,
˜
Eur. J. Org. Chem. 2010, 1885–1894
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1893

A. Wojtasiewicz, M. Barbasiewicz, M. Makosza
˛
FULL PAPER
[7] M. Ma˛kosza, M. Judka, Helv. Chim. Acta 2005, 88, 1676–1681.
[8] M. Ma˛kosza, M. Barbasiewicz, D. Krajewski, Org. Lett. 2005,
7, 2945–2948.
1563, 1466, 1441, 1308, 1211, 1151, 1119, 1064, 960, 851, 792, 764,
619, 595, 568, 540, 517 cm–1.
[9] M. Ma˛kosza, A. Wojtasiewicz, Phosphorus Sulfur Silicon Relat.
Elem. 2009, 184, 857–864.
Reaction of 17 with tBuOK in EtOH: To a solution of 17 (0.147 g,
0.5 mmol) in EtOH (5 mL) was dropwise added tBuOK (0.112 g,
1 mmol) in EtOH (2 mL) at room temperature. After 48 h an aque-
ous solution of NH4Cl (10 mL) was added. The mixture was ex-
tracted with CH2Cl2 (2ϫ20 mL), The combined organic phases
were washed with brine (20 mL) and dried with MgSO4. Column
chromatography (hexanes/EtOAc) gave 17a (0.067 g, 52%). Oil. 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 2.35–2.44 (m, 1 H, 3-H),
2.68–2.73 (m, 1 H, 3-H), 3.62 (dt, JH,H = 9.1, 6.1 Hz, 1 H, 2-H),
[10] M. Barbasiewicz, M. Ma˛kosza, Synthesis 2006, 1190–1194.
´
[11] A. Brandt, M. Sniezek, A. Wojtasiewicz, M. Ma˛kosza, Tetrahe-
˙
dron, accepted.
[12] For other developments in the field, see: a) N. Baricordi, S.
Benetti, G. Biondini, C. De Risi, G. P. Pollini, Tetrahedron Lett.
2004, 45, 1373–1375; b) F. F. Fleming, V. Gudipati, O. W. Stew-
ard, J. Org. Chem. 2003, 68, 3943–3946; c) M. Smet, C.
van Oosterwijck, K. van Hecke, L. van Meervelt, A. Vandend-
riessche, W. Dehaen, Synlett 2004, 2388–2390; d) A. Hassner,
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4.00 (ddd, JH,H = 9.1, 7.6, 3.3 Hz, 1 H, 2-H), 4.04 (ddd, JH,H
=
9.9, 7.1, 2.8 Hz, 1 H, 4-H), 5.76 (d, JH,H = 7.1 Hz, 1 H, 5-H), 7.57–
7.65 (m, 2 H, Harom), 6.67–7.71 (m, 1 H, Harom), 7.72–7.76 (m, 1
H, Harom) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 29.1,
63.3, 67.9, 79.8, 121.1, 127.6, 131.1, 134.2, 136.1, 139.8 ppm. IR
(CH Cl film): ν = 2984, 2873, 1721, 1452, 1304, 1175, 1149, 1123,
˜
2
2
1052, 761, 559, 537, 489 cm–1.
The stereochemistry of 17a was established by comparison of the
1
corresponding H NMR signals (coupling constants) to 6a. 17a δ
= 5.76 (d, JH,H = 7.1 Hz, 1 H, 5-H); 6a δ = 5.74 (d, JH,H = 7.1 Hz,
1 H, 5-H) ppm.
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[15] When the reaction of 15 was quenched with 10% aqueous HCl
and heated at reflux for 30 min, 13c (90%) was isolated.
[16] The reaction of 16 conducted in EtOH was very unselective;
thus, only limited mechanistic conclusions are available in this
case.
[4] M. Ma˛kosza, M. Judka, Chem. Eur. J. 2002, 8, 4234–4240.
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Received: October 6, 2009
Published Online: February 23, 2010
[6] M. Ma˛kosza, M. Judka, Synlett 2004, 4, 717–719.
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