Synthesis of substituted tetrahydropyrans via intermolecular reactions of δ-halocarbanions with aldehydes

Article abstract of DOI:10.1055/s-2007-965972

Intramolecular substitution in δ-halocarbanions leading to cyclobutanes is a relatively slow process, thus they readily add to carbonyl groups; the thus-produced anionic adducts cyclize to tetrahydropyran derivatives. A simple mechanistic discussion, opti

Full text of DOI:10.1055/s-2007-965972

PAPER
1209
Synthesis of Substituted Tetrahydropyrans via Intermolecular Reactions of
d-Halocarbanions with Aldehydes
S
ynthesis of Substitute
i
d
T
etra
c
hydropyran
h
s
ał Barbasiewicz, Aneta Brud, Mieczysław Mąkosza*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, P. O. Box 58, 01-224 Warsaw 42, Poland
Fax +48(22)6326681; E-mail: icho-s@icho.edu.pl
Received 4 January 2007
R
Abstract: Intramolecular substitution in d-halocarbanions leading
O
EWG
R
R
O
LG
base
to cyclobutanes is a relatively slow process, thus they readily add to
carbonyl groups; the thus-produced anionic adducts cyclize to tet-
rahydropyran derivatives. A simple mechanistic discussion, optimi-
zation of the reaction conditions, and scope of the reaction is
presented.
+
EWG
LG
O
EWG
1
2
3
EWG = electron-withdrawing group
LG = leaving group
Key words: aldol reactions, sulfones, halocarbanions, cyclizations,
tetrahydropyrans
Scheme 1
rans,11 Hassner and co-workers reported the synthesis of
substituted cyclohexanes via the reaction of 4-bromobutyl
phenyl sulfone carbanion with chiral a,b-unsaturated ox-
azolines.12 In a similar reaction 5-bromo-1-phenylpentan-
1-one reacted with highly electrophilic N-substituted isat-
ine giving spiro derivatives of tetrahydropyrans.13 On the
basis of these precedents and our generalized scheme de-
veloped for the reactions of g-halocarbanions, we com-
menced studies in the area of intermolecular reactions of
d-halocarbanions.14
In preliminary experiments,15 conducted under conditions
described by Fleming for the reactions of w-haloalkane-
nitriles (t-BuOK, THF, 0 °C, 3 h, then to r.t.) we observed,
that base-induced reaction of the model carbanion precur-
sor 4-chlorobutyl phenyl sulfone (1a) with benzaldehyde
gave 2-phenyl-3-(phenylsulfonyl)tetrahydro-2H-pyran
(3a) with yields not exceeding 50%, probably due to the
decomposition of this compound under the reaction con-
ditions. On the other hand at lower temperatures (–25 °C,
1 h) we observed only traces of 3a in the crude reaction
mixture (1H NMR), the uncyclized aldol-type adduct be-
ing the main product. To increase the rate of cyclization
via intramolecular substitution at low temperature we
changed the halogen and used 4-bromobutyl phenyl sul-
fone (1b). At –50 °C after a short reaction time (1 min)
and subsequent quenching of the reaction mixture with
aqueous ammonium chloride, we observed exclusive for-
mation of the intermediate aldol-type adduct 2a from the
addition of the carbanion to the aldehyde as a mixture of
two diastereomers (94%, ~2:1),16 but only traces of the fi-
nal cyclized tetrahydropyran derivative 3a were formed.
Extension of the reaction time to one hour and a slight in-
crease in the temperature to –40 °C led to the formation of
3a as single trans-diastereomer in high yield (89%)
(Scheme 2).
In our preceding papers we have shown that although g-
halocarbanions undergo fast intramolecular 1,3-substitu-
tion they can be trapped by suitable electrophilic reagents.
Aldol-type adducts from g-halocarbanions and aldehydes
undergo rapid intramolecular substitution reactions giving
2,3-disubstituted tetrahydrofurans.1,2 A similar reaction of
various g-halocarbanions with electron-deficient imines
and the Michael acceptors gave pyrrolidines3 and cyclo-
pentanes,4 respectively. On the other hand, intramolecular
1,4-substitution in d-halocarbanions, for enthalpic and en-
tropic reasons, is a relatively slow process.5,6 Such differ-
ences in the behavior of g- and d-halocarbanions can be,
for example, observed during the alkylation of methylenic
carbanions with 1,2- and 1,3-dihaloalkanes.7 Alkylation
of diethyl malonate, ethyl cyanoacetate, or phenylacetoni-
trile carbanions with 1,2-dibromoethane cannot be arrest-
ed at the 2-haloethyl derivative stage, because they
cyclize immediately giving substituted cyclopropanes,8
whereas in the reaction of these carbanions with 1,3-di-
bromopropane a number of products are formed; a 3-bro-
mopropyl-substituted derivative is the major product.9 We
could, therefore, expect that d-halocarbanions generated
from 4-bromobutyl phenyl sulfone, alkyl 5-bromopen-
tanoate, or 5-bromo-1-phenylpentan-1-one should form
reasonably long-lived species that could be trapped by al-
dehydes and ketones, intramolecular substitution in the
thus-produced intermediate aldol-type anions should give
substituted tetrahydropyrans (Scheme 1).
In the literature, only few specific examples of intermo-
lecular reactions of carbanions with leaving groups in the
d-position are reported.10 5-Chloropentanenitrile reacted
with nonenolizable aldehydes in the presence of potassi-
um tert-butoxide giving the expected cyanotetrahydropy-
SYNTHESIS 2007, No. 8, pp 1209–1213
x
x
.
x
x
.2
0
0
7
The discrepancy between the observed diastereoselectivi-
ty of the initial aldol addition process and the composition
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965972; Art ID: P00107SS
© Georg Thieme Verlag Stuttgart · New York

1210
M. Barbasiewicz et al.
PAPER
Ph
OH Br
EWG
R
RCHO
+
–50 °C
1 min
t-BuOK
THF, –40 °C
1h
PhSO2
O
2a
EWG
Br
PhSO2
Br
94%
PhCHO
(2:1 mixture of isomers)
Scheme 4
t-BuOK
THF
1b
PhSO2
–40 °C
1 h
The scope and limitations of this addition–alkylation se-
quence under optimized conditions19 (–40 °C, 1 h) were
determined for reactions d-halocarbanion precursors, 1b
and methyl 5-bromopentanoate (1c) with other nonenoliz-
able aldehydes (Scheme 4, Table 1).
Ph
O
3a
89%
(one isomer)
Scheme 2
Under these conditions, reactions of 1b and 1c with non-
of the product 3a prompted us to investigated this matter enolizable aldehydes proceeded cleanly and in high yield.
further. For this purpose we isolated samples of the pure By contrast, the reaction of 5-bromo-1-phenylpentan-1-
diastereomers of 2a and introduced them into cross exper- one (1d) with benzaldehyde under the same conditions
failed to give the expected product (Scheme 5).21
iments with 4-methoxybenzaldehyde under the standard
reaction conditions. Analysis of the crude reaction mix-
1
tures with H NMR showed that only minor amounts
t-BuOK
other products
(<5%)17 of the 4-methoxyphenyl-substituted tetrahydro-
pyran 3b were formed. It appears, therefore, that the ini-
tially formed aldol-type adducts do not dissociate under
these conditions, or they dissociate more slowly than they
cyclize to give 3a (Scheme 3).
THF, –40 °C
1 h
O
Br
Ph
O
1d
Ph
+
PhCHO
t-BuOK
Ph
OH Br
t-BuOK
Ph
O
EtOH, r.t.
overnight
PhSO2
PhSO2
Ph
3h, 80%
+
PhSO2
2a
THF, –40 °C
1 h
Scheme 5
4-MeO-C6H4
O
O
+
3a
3b
4-MeO-C6H4CHO
(1 equiv)
To overcome this problem, we successfully used a protic
solvent, ethanol; the procedure was described by us earlier
for reactions g-haloenolates of ketones.2 In all explored
cases, formation of pure trans-diastereomers was ob-
served (Schemes 4, 5).
> 95:5
(according to 1H NMR)
Scheme 3
1H NMR analysis of crude reaction mixtures when these
experiments were halted before complete conversion (–40
°C, 10 min) showed also, that the diastereomers of 2a do
not interconvert via epimerization of their C–H acidic
centers. Thus, we can conclude that the exclusive forma-
tion of the pure trans-isomer of 3a is of thermodynamic
nature, due to the epimerization of the initially formed
mixture of cis- and trans-tetrahydropyran derivatives.18
Finally, we investigated the reaction of 1b with cyclohex-
anone. To avoid contact of the electrophile with the base,
we generated the lithium salt of carbanion of 1b with lith-
ium diisopropylamide before addition of cyclohexanone
to promote the addition–alkylation sequence.
Reaction of 1b with cyclohexanone gave the aldol-type
adduct 2i as the only isolable product (Scheme 6). Under
Table 1 Reactions of d-Halocarbanion Precursors with Nonenolizable Aldehydes
Entry
d-Halocarbanion precursor EWG
R
Product
3a
Isolated Yield (%)
1
2
3
4
5
6
7
1b
1b
1b
1b
1b
1c
1c
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
CO2Me
CO2Me
Ph
89
78
80
58
83
89a
81a
4-MeOC6H4
4-ClC6H4
2-furyl
t-Bu
3b
3c
3d
3e
Ph
3f
4-BrC6H4
3g
a Reaction was performed at –25 °C.20
Synthesis 2007, No. 8, 1209–1213 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Tetrahydropyrans
1211
tion (hexanes–EtOAc, 6:1 to 3:1) gave 3a as white crystals; yield:
PhSO2
269 mg (89%); mp 134–135 °C.
cyclohexanone
1b recovery
O
IR (KBr): 2945, 2868, 1586, 1456, 1446, 1380, 1303, 1285, 1143,
1087, 1023, 947, 760, 720, 696, 684, 606, 550, 538, 519 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.32–7.44 (m, 3 H), 7.02–7.26 (m,
7 H), 4.55 (d, J = 9.7 Hz, 1 H), 3.99–4.11 (m, 1 H), 3.55–3.66 (m, 1
H), 3.43–3.55 (m, 1 H), 2.46–2.61 (m, 1 H), 2.06 (dd, J = 12, 4.7
Hz, 1 H), 1.70–2.00 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 139.2, 137.7, 132.6, 128.7, 128.5,
128.3, 128.2, 127.8, 80.7, 68.2, 64.6, 25.5, 23.7.
MS (ESI): m/z [M + Na]+ calcd for C17H18NaO3S: 325.1; found:
t-BuOK
THF, –40 °C
1 h
not formed
1b
1) LDA, THF
–75 °C, 1 min
2) cyclohexanone
–70 °C, 1 h
OH
PhSO2
Br
3) –70 °C to r.t.
10 min
2i, 70%
325.1.
Scheme 6
Anal. Calcd for C17H18O3S: C, 67.52; H, 6.00; S, 10.60. Found: C,
67.54; H, 6.28; S, 10.30.
several conditions tested, we were unable to force the sub-
sequent cyclization process, leading to tetrahydropyran
derivatives.
Similar conditions were applied to the experiments depicted in
Schemes 3 and 4 and Table 1.
erythro-5-Bromo-1-phenyl-2-(phenylsulfonyl)pentan-1-ol
(erythro-2a)
Oil.
In conclusion, we have shown, that d-halocarbanions re-
act with nonenolizable aldehydes with the formation of
2,3-disubstituted tetrahydropyrans in the course of a two-
step addition–alkylation sequence.1 This route represents
simple, efficient, and general approach for the synthesis of
cyclic compounds, but requires optimization of the reac-
tion conditions in some cases.
IR (neat): 3516, 3064, 2963, 1968, 1816, 1603, 1585, 1495, 1448,
1401, 1304, 1148, 1084, 853, 759, 729, 689, 629, 585, 539 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.96–8.05 (m, 2 H), 7.58–7.79 (m,
3 H), 7.18–7.38 (m, 5 H), 5.38–5.43 (br s, 1 H), 3.38 (d, J = 2 Hz, 1
H), 3.10–3.17 (m, 1 H), 3.06 (t, J = 6.5 Hz, 2 H), 1.96–2.08 (m, 2
H), 1.22–1.55 (m, 1 H), 1.55–1.79 (m, 1 H).
All reagents were used as obtained from the commercial sources.
All reactions were carried out under an atmosphere of argon in dried
glassware using standard Schlenk techniques. THF was distilled
from K/benzophenone ketyl and anhydrous grade EtOH was used.
13C NMR (50 MHz, CDCl3): d = 139.4, 137.4, 134.3, 129.6, 128.7,
128.6, 127.8, 125.3, 69.7, 69.4, 32.5, 31.3, 20.4.
MS (ESI): m/z [M(81Br) + Na]+ calcd for C17H1981BrO3SNa: 407.0;
found: 407.0.
1
Melting points are uncorrected. H NMR and 13C NMR spectra
were recorded with CDCl3 as standard (d = 7.26 and 77.0 ppm) on
a Varian 200 spectrometer. IR data were recorded on an FT-IR Per-
kin-Elmer Spectrum 2000 using a film (for oils) or in KBr pellets
(for solids). MS data were obtained by electron ionization on an
AMD 604 GmbH spectrometer in EI mode or on a Mariner spec-
trometer in ESI mode. Microanalyses were performed at the Insti-
tute of Organic Chemistry, Polish Academy of Sciences.
Anal. Calcd for C17H19BrO3S: C, 53.27; H, 5.00; Br, 20.85; S, 8.37.
Found: C, 53.09; H, 5.35; Br, 20.69; S, 8.98.
threo-5-Bromo-1-phenyl-2-(phenylsulfonyl)pentan-1-ol (threo-
2a)
Mp 70–71 °C.
IR (KBr): 3483, 2930, 1446, 1280, 1136, 1079, 1052, 1023, 760,
731, 697, 644, 569, 537 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.98–8.06 (m, 2 H), 7.62–7.82 (m,
3 H), 7.34–7.43 (m, 5 H), 5.10 (dd, J = 8.9, 2.4 Hz, 1 H), 4.44 (d,
J = 2.4 Hz, 1 H), 3.33–3.44 (m, 1 H), 2.96–3.15 (m, 2 H), 1.67–1.94
(m, 1 H), 1.30–1.60 (m, 3 H).
Compounds 1a and 1b were obtained by the reaction of sodium ben-
zenesulfinate with 1,4-dichlorobutane and 1,4-dibromobutane, re-
spectively, according to the typical procedure. Compound 1c was
commercially available (Aldrich). Compound 1d was obtained by
the Friedel–Crafts reaction of benzene and 5-bromopentanoyl chlo-
ride according to the procedure described in literature.22
13C NMR (50 MHz, CDCl3): d = 139.2, 137.8, 134.1, 129.3, 128.8,
128.7, 127.2, 73.4, 69.9, 32.5, 29.8, 25.5.
4-Bromobutyl Phenyl Sulfone (1b); Typical Procedure
MS (ESI): m/z [M(81Br) + Na]+ calcd for C17H1981BrNaO3S: 407.0;
found: 407.0.
A suspension of sodium benzenesulfinate (24.63 g, 0.15 mol, Fluka)
and 1,4-dibromobutane (64.87 g, 0.30 mol) in polyethylene glycol
(PEG-400, Merck, 80 mL) was stirred overnight at 80 °C. The mix-
ture was poured into H2O (500 mL), extracted with EtOAc (5 × 100
mL), washed with H2O (3 × 100 mL), brine (500 mL), and dried
(MgSO4). The mixture was separated on a large chromatographic
column (hexanes–EtOAc, 3:1 to 1:1) to give 4-bromobutyl phenyl
sulfone (1b) (24.25 g, 58%) as a pale yellowish solidifying oil; mp
56–57 °C (Lit.23 58–59 °C) and 1,4-bis(phenylsulfonyl)butane (4.92
g, 19%) as white crystals; mp 120 °C (Lit.24 122–123 °C).
Anal. Calcd for C17H19BrO3S: C, 53.27; H, 5.00; Br, 20.85; S, 8.37.
Found: C, 53.20; H, 5.19; Br, 21.08; S, 8.55.
2-(4-Methoxyphenyl)-3-(phenylsulfonyl)tetrahydro-2H-pyran
(3b)
Oil.
IR (neat): 2959, 1613, 1515, 1446, 1307, 1247, 1145, 1084, 1071,
1021, 824, 753, 719, 690, 605, 547 cm–1.
2-Phenyl-3-(phenylsulfonyl)tetrahydro-2H-pyran (3a); Typical
Procedure
To a stirred soln of 1b (277 mg, 1 mmol) and benzaldehyde (133
mg, 1.25 mmol) in THF (4 mL) at –40 °C under argon was added 1
M t-BuOK in THF (2.1 mL). After 1 h, aq NH4Cl was added with
vigorous stirring and the mixture was extracted with EtOAc,
washed with brine, and dried (MgSO4). Chromatographic separa-
1H NMR (200 MHz, CDCl3): d = 7.40–7.54 (m, 3 H), 7.24–7.35 (m,
2 H), 7.07–7.16 (m, 2 H), 6.61–6.70 (m, 2 H), 4.56 (d, J = 9.7 Hz, 1
H), 4.05–4.17 (m, 1 H), 3.80 (s, 3 H), 3.48–3.71 (m, 2 H), 2.55–2.69
(m, 1 H), 2.12 (dd, J = 12.3, 4.7 Hz, 1 H), 1.78–2.04 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 159.7, 139.4, 132.4, 130.0, 129.3,
128.4, 127.8, 113.6, 80.1, 68.2, 64.9, 55.2, 25.5, 23.7.
Synthesis 2007, No. 8, 1209–1213 © Thieme Stuttgart · New York

1212
M. Barbasiewicz et al.
PAPER
MS (ESI): m/z [M + Na]+ calcd for C18H20NaO4S: 355.1; found:
MS (ESI): m/z [M + Na]+ calcd for C13H16NaO3: 243.1; found:
355.1.
243.1.
Anal. Calcd for C18H20O4S: C, 65.04; H, 6.06; S, 9.65. Found: C,
64.93; H, 6.08; S, 9.44.
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.58; H,
7.22.
2-(4-Chlorophenyl)-3-(phenylsulfonyl)tetrahydro-2H-pyran
(3c)
Methyl 2-(4-Bromophenyl)tetrahydro-2H-pyran-3-carboxy-
late (3g)
Mp 123–124 °C.
Oil.
IR (KBr): 2921, 2865, 1600, 1494, 1446, 1306, 1285, 1143, 1089,
1025, 952, 817, 745, 721, 682, 606, 552, 526 cm–1.
IR (neat): 2950, 2851, 1734, 1593, 1490, 1435, 1365, 1317, 1258,
1162, 1096, 1012, 956, 815, 539 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.40–7.59 (m, 3 H), 7.28–7.39 (m,
2 H), 7.07–7.20 (m, 4 H), 4.60 (d, J = 9.6 Hz, 1 H), 4.07–4.18 (m, 1
H), 3.44–3.73 (m, 2 H), 2.52–2.66 (m, 1 H), 2.13 (dd, J = 12.7, 4.8
Hz, 1 H), 1.77–2.06 (m, 2 H).
1H NMR (200 MHz, CDCl3): d = 7.45–7.53 (m, 2 H), 7.16–7.24 (m,
2 H), 4.41 (d, J = 10.1 Hz, 1 H), 4.06–4.17 (m, 1 H), 3.54–3.69 (m,
1 H), 3.46 (s, 3 H), 2.53–2.67 (m, 1 H), 2.08–2.21 (m, 1 H), 1.64–
2.00 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 139.1, 136.3, 134.5, 132.7, 129.6,
128.6, 128.4, 127.8, 79.9, 68.3, 65.0, 25.4, 23.7.
13C NMR (50 MHz, CDCl3): d = 173.5, 139.4, 131.4, 128.6, 121.9,
80.6, 68.5, 51.5, 49.7, 27.7, 24.6.
MS (ESI): m/z [M(35Cl) + Na]+ calcd for C17H1735ClNaO3S: 359.0;
MS (EI): m/z (%) = 300 (30), 298 (31), 240 (58), 238 (60), 185 (50),
found: 359.0.
183 (50), 114 (100).
Anal. Calcd for C17H17ClO3S: C, 60.62; H, 5.09; Cl, 10.53; S, 9.52.
Found: C, 60.66; H, 5.09; Cl, 9.92; S, 9.81.
Anal. Calcd for C13H15BrO3: C, 52.19; H, 5.05; Br, 26.71. Found:
C, 52.05; H, 5.31; Br, 26.86.
2-(2-Furyl)-3-(phenylsulfonyl)tetrahydro-2H-pyran (3d)
Mp 126–128 °C.
3-Benzoyl-2-phenyltetrahydro-2H-pyran (3h)
To a stirred soln of 1d (241 mg, 1 mmol) and benzaldehyde (265
mg, 2.5 mmol) in EtOH (3 mL) at r.t. under argon was added a soln
of t-BuOK (238 mg, 2.1 mmol) in EtOH (2 mL). The mixture was
left overnight, then aq NH4Cl was added with vigorous stirring and
the product 3h was isolated according to the typical procedure; mp
76–80 °C.
IR (KBr): 3145, 2971, 2882, 1585, 1503, 1448, 1346, 1305, 1284,
1142, 1075, 1025, 941, 919, 878, 850, 817, 758, 749, 721, 687, 605,
550 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.63 (m, 5 H), 6.93 (d,
J = 1.9 Hz, 1 H), 6.29 (dd, J = 3.3, 0.6 Hz, 1 H), 6.11 (dd, J = 3.3,
1.9 Hz, 1 H), 4.64 (d, J = 9.7 Hz, 1 H), 3.96–4.08 (m, 1 H), 3.67–
3.82 (m, 1 H), 3.46–3.61 (m, 1 H), 2.43–2.58 (m, 1 H), 1.67–2.13
(m, 3 H).
IR (KBr): 3062, 3033, 2947, 2850, 1674, 1596, 1449, 1365, 1299,
1260, 1197, 1088, 1033, 952, 928, 831, 756, 699, 665, 551 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.62–7.72 (m, 2 H), 7.06–7.50 (m,
8 H), 4.71 (d, J = 9.7 Hz, 1 H), 4.14–4.26 (m, 1 H), 3.65–3.81 (m, 2
H), 1.67–2.22 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 202.1, 140.6, 136.6, 132.9, 128.4,
128.2, 127.9, 127.8, 126.9, 81.8, 68.5, 50.8, 28.7, 25.2.
13C NMR (50 MHz, CDCl3): d = 149.8, 142.8, 138.5, 132.9, 128.8,
128.1, 110.3, 71.9, 67.9, 62.1, 24.8, 23.2.
MS (EI): m/z (%) = 292 (1), 169 (2), 150 (100), 125 (22), 122 (19).
Anal. Calcd for C15H16O4S: C, 61.63; H, 5.52; S, 10.97. Found: C,
61.37; H, 5.66; S, 11.26.
MS (EI): m/z (%) = 266 (37), 160 (66), 146 (23), 131 (7), 117 (5),
115 (4), 105 (100), 91 (8), 77 (42).
2-tert-Butyl-3-(phenylsulfonyl)tetrahydro-2H-pyran (3e)
Oil.
Anal. Calcd for C18H18O2: C, 81.17; H, 6.81. Found: C, 80.86; H,
6.75.
IR (neat): 2961, 2878, 1585, 1478, 1445, 1299, 1282, 1212, 1144,
1079, 930, 763, 738, 688, 589, 445 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.86–7.95 (m, 2 H), 7.52–7.71 (m,
3 H), 3.67–3.99 (m, 2 H), 3.83 (d, J = 3.3 Hz, 1 H), 3.16–3.24 (m, 1
H), 1.65–2.04 (m, 4 H), 0.86 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 138.6, 133.7, 129.2, 128.7, 78.7,
62.5, 60.5, 35.8, 25.6, 18.6, 17.9.
1-[4-Bromo-1-(phenylsulfonyl)butyl]cyclohexan-1-ol (2i)
To a stirred soln of 1b (277 mg, 1 mmol) in THF (2 mL) at –75 °C
under argon, 2.0 M LDA in THF–heptane–ethylbenzene (0.5 mL,
Fluka) was added dropwise. After 1 min, a soln of cyclohexanone
(122 mg, 1.25 mmol) in THF (2 mL) was added dropwise and the
mixture was kept at –70 °C for 1 h. Then the flask was warmed to
0 °C (~10 min), aq NH4Cl was added with vigorous stirring and the
product 2i was isolated as an oil according to the typical procedure.
MS (ESI): m/z [M + Na]+ calcd for C15H22NaO3S: 305.1; found:
305.1.
IR (neat): 3516, 3063, 2922, 2858, 1585, 1447, 1286, 1137, 1082,
973, 854, 729, 690, 652, 576 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.85–7.98 (m, 2 H), 7.50–7.72 (m,
3 H), 3.80 (s br, 1 H), 3.12 (t, J = 6.3 Hz, 2 H), 3.04 (t, J = 4.5 Hz,
1 H), 1.07–2.17 (m, 14 H).
13C NMR (50 MHz, CDCl3): d = 140.2, 133.8, 129.3, 128.2, 75.1,
73.2, 36.3, 33.7, 32.4, 32.3, 25.3, 25.2, 21.3.
Anal. Calcd for C15H22O3S: C, 63.80; H, 7.85; S, 11.35. Found: C,
63.95; H, 8.06; S, 11.25.
Methyl 2-Phenyltetrahydro-2H-pyran-3-carboxylate (3f)
Oil.
IR (neat): 2950, 2852, 1733, 1495, 1454, 1436, 1368, 1317, 1261,
1162, 1094, 1028, 954, 759, 699, 537 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–7.45 (m, 5 H), 4.52 (d,
J = 10.1 Hz, 1 H), 4.15–4.26 (m, 1 H), 3.65–3.79 (m, 1 H), 3.51 (s,
3 H), 2.69–2.84 (m, 1 H), 2.16–2.30 (m, 1 H), 1.8–2.16 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.6, 140.2, 128.3, 128.0, 126.8,
81.4, 68.5, 51.3, 49.7, 27.7, 24.7.
MS (EI): m/z (%) = 376 (1), 374 (1), 278 (24), 276 (23), 235 (76),
233 (79), 217 (50), 215 (51), 197 (11), 169 (64), 165 (18), 163 (19),
137 (30), 135 (32), 99 (100).
HRMS (EI): m/z [M(79Br)]+ calcd for C16H2379BrO3S: 374.05513;
found: 374.05434.
Synthesis 2007, No. 8, 1209–1213 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Tetrahydropyrans
1213
Anal. Calcd for C16H23BrO3S: C, 51.20; H, 6.18; S, 8.54, Br, 21.29.
Found: C, 51.19; H, 6.44; S, 8.11; Br, 20.62.
NMR). This observation may lead to the conclusion, that
erythro-isomer cyclizes relatively rapidly, while this process
is slower for the threo-isomer and competitive retro-aldol
reaction gives cross product 3b. The conformational
preference for the cyclization of diastereomers of analogous
aldol-type adducts 2a on the basis of their 1H–1H coupling
constants and reactivity pattern were discussed in:
(a) Mąkosza, M.; Barbasiewicz, M.; Krajewski, D. Org. Lett.
2005, 7, 2945. (b) Hassner, A.; Usak, D.; Kumareswaran,
R.; Friedman, O. Eur. J. Org. Chem. 2004, 2421.
Acknowledgment
This work was supported by National Scientific Council (KBN),
Grant 4T09A 05 625. We thank Ms. Anna Jałmużna for technical
assistance.
(18) In an independent experiment we performed the reaction of
PhCHO (1 mmol), 4-MeOC6H4CHO (1 mmol), and 1b (1
mmol) under standard conditions to evaluate the effect of the
relative electrophilicity of aldehydes. This experiment gave
an approximately 1: 1 mixture of 3a and 3b (according to 1H
NMR of the crude reaction mixture), leading to the
conclusion that complete equilibration of adduct 2a with 4-
MeOC6H4CHO in the aldol dissociation–addition sequence
should lead to an equimolar mixture of 3a and 3b.
(19) During the optimization process, we observed that excess
benzaldehyde (>1.25 equiv) inhibits the second step of the
reaction(cyclization), which causes contamination of
product 3a with aldol-type adducts 2a and decreases the
reaction yield. We assume that this effect is based on
interaction of the O-anion of 2a with the carbonyl group of
excess aldehyde and formation of a hemiacetal-type adduct.
This type of equilibrium operates, for example, in the
reaction of the anion of 2-chloroethanol with aldehydes:
Barbasiewicz, M.; Mąkosza, M. Org. Lett. 2006, 8, 3745.
(20) Reaction of 1c with benzaldehyde (–40 °C, 1 h) led to a
mixture of the expected product 3f and uncyclized aldol-type
adduct 2f (according to 1H NMR analysis of the crude
reaction mixture). To force the cyclization process the
temperature was increased to –25 °C. Similar behavior was
observed for analogous reactions of g-halocarbanions: an
aldol-type adduct of 3-chloropropyl phenyl sulfone
carbanion and benzaldehyde cyclizes much faster to the
tetrahydrofuran derivative than its ester or cyano congeners:
Barbasiewicz M., Mąkosza M., unpublished results.
(21) Probably due to the less favorable equilibrium of addition of
stabilized enolate of ketone to the carbonyl group under
these conditions, as compared to other less stabilized
carbanions, see ref. 2 for details. The only isolable
compound was the product of reaction of the expected
tetrahydropyran derivative with the second molecule of
aldehyde and/or its subsequent transformations (yield
~20%).
References
(1) (a) Mąkosza, M.; Przyborowski, J.; Klajn, K.; Kwast, A.
Synlett 2000, 773. (b) Mąkosza, M.; Judka, M. Chem. Eur.
J. 2002, 4234. (c) Barbasiewicz, M.; Judka, M.; Mąkosza,
M. Russ. Chem. Bull. 2004, 53, 1771.
(2) Barbasiewicz, M.; Mąkosza, M. Synthesis 2006, 1190.
(3) Mąkosza, M.; Judka, M. Helv. Chim. Acta 2005, 88, 1676.
(4) Mąkosza, M.; Judka, M. Synlett 2004, 717.
(5) Winnik, M. A. Chem. Rev. 1981, 81, 491.
(6) Eliel, E. L.; Whilen, S. H. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York, 1994.
(7) Barbasiewicz, M.; Marciniak, K.; Fedoryński, M.
Tetrahedron Lett. 2006, 47, 3871.
(8) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(9) Fedoryński M., manuscript in preparation.
(10) For example of reactions of nonstabilized d-halocarbanion
equivalents, see: Mudryk, B.; Cohen, T. J. Am. Chem. Soc.
1991, 113, 1866.
(11) Fleming, F. F.; Gudipati, V.; Steward, O. W. J. Org. Chem.
2003, 68, 3943.
(12) Basil, L. F.; Meyers, A. I.; Hassner, A. Tetrahedron 2002,
58, 207.
(13) Smet, M.; van Oosterwijck, C.; van Hecke, K.; van
Meervelt, L.; Vandendriessche, A.; Dehaen, W. Synlett
2004, 2388.
(14) Our attempts to synthesize a substituted dihydropyran in
reactions from 4-chlorobut-2-enyl phenyl sulfone with
benzaldehyde under a plethora of conditions were
unsuccessful. For similar attempts using an imine, see:
Balasubramanian, T.; Hassner, A. Tetrahedron: Asymmetry
1998, 9, 2201.
(15) The behavior of 1a and 1b without an electrophile under
basic conditions [t-BuOK (2 equiv), THF, –50 °C or 0 °C, 1
h] revealed that, in contrast to g-halocarbanions,
intramolecular substitution in d-halocarbanions leading to
cyclobutanes is a slow process disturbed by competitive
elimination and oligomerization reactions.
(22) Yu, J.-W.; Huang, S. K. Org. Prep. Proced. Int. 1997, 29,
214.
(23) Decesare, M. J.; Corbel, B.; Durst, T.; Blount, J. F. Can. J.
Chem. 1981, 59, 1415.
(16) The ratio of the diastereomers of 2a remains almost constant,
in the range 1:0.55–1:0.70 (erythro/threo, according to 1H
NMR), during the course of the reaction.
(17) The erythro-isomer gave product 3a exclusively, while the
(24) Shinriki, N.; Nambara, T. Chem. Pharm. Bull. 1963, 11, 178.
threo-isomer gave a mixture of 3a/3b (9:1, according to 1H
Synthesis 2007, No. 8, 1209–1213 © Thieme Stuttgart · New York