A synthesis of 6-tributylstannyl-3,4-dihydro-2H-pyrans via coupling of enol triflates with (Bu3Sn)(Bu)Culi·liCN

Article abstract of DOI:10.1055/s-2002-20041

Enol triflates derived from 6- and 7-membered ring lactones (6 cases) react with (Bu₃Sn)(Bu)CuLi·LiCN in THF at -78 °C to give the corresponding α-tributylstannyl cyclic enol ethers in 54-85% yield.

Full text of DOI:10.1055/s-2002-20041

PAPER
393
A Synthesis of 6-Tributylstannyl-3,4-dihydro-2H-pyrans via Coupling of Enol
Triflates with (Bu3Sn)(Bu)CuLi LiCN
S
ynthesis of 6-T
a
ributylstan
n
nyl-3,4-dihy
y
dro-2
H
-pyra
a
ns Wildman,a Philip J. Kocienski,*a Robert Narquizian,a William G. Whittinghamb
a
Department of Chemistry, Leeds University, Leeds, LS2 9JT, UK
Fax +44(113)2336401; E-mail: p.kocienski@chemistry.leeds.ac.uk
b
Syngenta, Jealott’s Hill International Research Station, Bracknell, Berkshire RG42 6EY, UK
Received 2 January 2002
O
O
Abstract: Enol triflates derived from 6- and 7-membered ring lac-
tones (6 cases) react with (Bu3Sn)(Bu)CuLi LiCN in THF at –78 °C
to give the corresponding -tributylstannyl cyclic enol ethers in 54–
85% yield.
(a)
(b)
LHMDS, HMPA, THF
–78 °C, 2 h
PhN(SO2CF3)2, THF
–78 °C to rt, 2 h
SePh
KHMDS, PhN(SO2CF3)2
THF, –78 °C, 30 min
1
Key words: cyanocuprate, coupling, enol triflate, stannane, trans-
metallation, tin, dihydropyran
O
OTf
The -lithiated dihydropyran 4 was a key intermediate in
our syntheses of the antitumor agents pederin, theopederin
D and mycalamide B.1 A 3-step sequence to 4 began with
the conversion of the lactone 1 to the enol triflate 2 that
underwent a Pd(0)-catalysed Stille-type coupling with
hexamethylditin to give the -trimethylstannyl dihydro-
pyran 3.2 Transmetallation of the -trimethylstannyl dihy-
dropyran 3 with BuLi occurred at –78 °C in THF to give
the desired intermediate 4. The route depicted in
Scheme 1 was able to deliver 5 g quantities of -trimeth-
ylstannyl dihydropyran 3 in 70% overall yield but practi-
cal problems beset every step of the sequence. In the first
step, HMPA was required for the conversion of the lac-
tone to its lithium enolate using lithium hexamethyldisi-
lazide. In the second step, hexamethylditin was used in the
Stille coupling. Hexamethylditin is expensive, only one of
the trimethylstannyl groups is consumed in the reaction
and the remaining trimethystannyl group produces toxic
and volatile trimethyltin byproducts that require great care
during the workup. The third step, the transmetallation re-
action with BuLi, was capricious. Unfortunately, attempts
to reduce the cost and hazard of the Stille coupling and fa-
cilitate the transmetallation3 by synthesising the tributyl-
stannyl analogue 5 were thwarted by low yields (14%) in
the coupling step.
SePh
2
Me6Sn2, LiCl, Pd(PPh3)4
THF, , 14 h
(Bu3Sn)(Bu)CuLi•LiCN (1.2 equiv.)
THF, –78 °C, 15 min; then aq. NH4Cl
O
SnMe3
O
O
SnBu3
+
15:85
SePh
SePh
SePh
3
5
6
(70% from 1)
(85% from 1)
O
Li
BuLi
THF, –78 °C
BuLi
THF, –78 °C
SePh
4
Scheme 1
at –78 °C, conversion to the enol triflate was complete.
The combination of potassium hexamethyldisilazide as
the base and the simultaneous addition of the lactone and
the triflating agent to the base gave a faster and cleaner re-
action without the need for HMPA.
We now report a new method for the synthesis of -tribu-
tylstannyl dihydropyrans from -lactones that is more ef-
ficient, cheaper and less hazardous. To illustrate the
advantages of the new route, we synthesised the -tribu-
tylstannyl dihydropyran 5. The sequence began with the
dropwise addition of lactone 1 (1.0 equiv) and N-
phenyltrifluoromethanesulfonimide (1.2 equiv) in THF to
potassium hexamethyldisilazide (KHMDS, 1.4 equiv) in
THF at –78 °C over 30 minutes. After a further 10 min
The key step in the sequence was accomplished by the ad-
dition of the Lipshutz4 mixed cuprate, (Bu3Sn)(Bu)Cu-
Li LiCN (1.2 equiv) to the crude enol triflate at –78 °C.
After 15 min at –78 °C, the reaction was quenched by the
addition of a solution composed of saturated aqueous am-
monium chloride and ammonia. A standard aqueous
workup followed by column chromatography on deacti-
vated neutral alumina (5% water) eluting with 0.5% Et3N
in hexanes gave the desired -tributylstannyldihydropyr-
an 5 in 85% yield. In order to obtain good yields, it is es-
sential that the temperature of the cuprate be maintained
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0393,0398,ftx,en;Z00402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

394
T. Wildman et al.
PAPER
at –50 °C during the addition. The Lipshutz mixed cu- The one blight on the sequence was the simultaneous for-
prate is easily prepared (Scheme 2). We saw no evidence mation of the dihydropyrans 17–20 and tetrahydroox-
for transfer of the butyl group.
epine 21 that required careful chromatographic separation
from the desired stannanes. The ratio of stannane to dihy-
dropyran was typically between 5:1 and 18:1 and varied
with the substrate but it also varied on repetition with the
same substrate. Formation of the dihydropyrans was not a
consequence of protodestannylation during workup be-
cause a pure sample of stannane 13 survived the workup
and chromatographic purification conditions intact. A re-
ductive mechanism could be ruled out too because use of
Bu3SnD in the generation of the Lipshutz cuprate failed to
incorporate deuterium into the product whereas quench-
ing the coupling reaction with D2O did lead to deuterium
incorporation. The latter experiment shows that the hydro-
gen did not come from a -hydride elimination of a butyl-
copper species and that deuteration of an -metallo
dihydropyran intermediate is the most likely source of
deuterium incorporation.
Bu
Bu
–H2
+
+
2 Bu3SnH
CuLi•LiCN
Bu4Sn
CuLi•LiCN
Bu
Bu3Sn
Scheme 2
In a study of the scope and limitations of the coupling re-
action we examined several enol triflates and cuprate re-
agents. (Bu3Sn)2CuLi, Bu3SnCu SMe2 (prepared by the
method of Piers5) and (Bu3Sn)2CuLi LiCN – which had
previously been used in the stannylation of enol triflates
derived from ketones6 – were inferior to the Lipshutz re-
agent in terms of economy, efficiency and ease of prepa-
ration.
A
further
4
tetrahydropyran-2-ones 7–10
(Scheme 2) were examined as substrates as well as a sin-
gle example of a 7-membered ring lactone 11. The corre-
sponding -tributylstannyl enol ethers 12–16 were
obtained in 54–72% yield overall from the three-step se-
quence (Figure).
In conclusion, we have devised a new route to -tributyl-
stannyl-3,4-dihydro-2H-pyrans from enol triflate deriva-
tives of 6- and 7-membered ring lactones that uses the
readily available Lipshutz mixed cuprate. The prime ben-
efits are: (a) an improved enol triflate synthesis that does
not require HMPA for efficient reaction; (b) lower hazard
associated with the use of tributylstannyl rather than trim-
ethylstannyl ligands; and (c) more efficient transmetalla-
tion to the corresponding lithium. The reaction cannot yet
be applied to 5-membered ring lactones because the req-
uisite enol triflates are formed in poor yield, if at all, by
the procedure described. Our method provides access to
6-lithio-3,4-dihydro-2H-pyrans by transmetallation of the
tin derivative in cases where direct deprotonation of the
corresponding 3,4-dihydro-2H-pyran is precluded or inef-
ficient. 7
O
O
O
O
SnBu3
O
7
17
18
12 (54%)
n-C7H15
O
n-C7H15
O
SnBu3
n-C7H15
O
13 (72%)
OMe
8
OMe
OMe
MeO
MeO
MeO
Unless otherwise stated, all NMR spectra were recorded in CDCl3
solutions and referenced to the residual CHCl3 signal (1H, = 7.27;
13C, = 77.2). NMR spectra were recorded on either a Bruker 300
or 400 MHz spectrometer. All 1H and 13C chemical shifts are given
in ppm. DEPT experiments give the number of hydrogens attached
O
O
O
SnBu3
O
19
to each carbon. These values are given in parenthesis after the 13
C
9
14 (65%)
chemical shifts. IR spectra were taken on either a Jasco FT/IR 410
or OMNIC ESP spectrometer. All experiments were carried out at
ambient temperature and under N2 unless otherwise stated. Solvents
were removed using a Büchi Rotavapor R-114.
O
O
O
O
SnBu3
OMe
10
OMe
20
(2R,3R,4S)-2,3-Dimethyl-4-phenylselanylmethyl-6-tributyl-
stannyl-3,4-dihydro-2H-pyran (5); Typical Procedure
OMe
15 (68%)
To a solution of KHMDS (4.5 mL, 2.2 mmol, 0.5 M in toluene) in
THF (4.5 mL) at –78 °C was added dropwise a solution of the lac-
tone 1 (508 mg, 1.7 mmol) and PhNTf2 (672 mg, 1.9 mmol) in THF
(4.5 mL) over 25 min. After addition was complete, the mixture was
stirred for a further 10 min to give the enol triflate 2 that was used
immediately in the next step. Meanwhile, to a suspension of CuCN
(200 mg, 2.2 mmol) in THF (5.6 mL) at –78 °C, was added drop-
wise BuLi (2.0 mL, 4.4 mmol, 2.3 M in hexane). The cooling bath
was temporarily removed (2 min) and the clear pale yellow solution
was then cooled again to –78 °C. After 5 min at –78 °C, Bu3SnH
(1.2 mL, 4.4 mmol) was added dropwise (H2 evolution) and the dark
yellow solution was then stirred at –78 °C for another 20 min.
O
O
O
O
SnBu3
OMe
11
OMe
16 (69%)
OMe
21
Figure The structures of compounds 7–21
Synthesis 2002, No. 3, 393–398 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Tributylstannyl-3,4-dihydro-2H-pyrans
395
The enol triflate solution was then quickly transferred using a large
cannula to the solution of (Bu3Sn)(Bu)CuLi LiCN and the reaction
mixture was then stirred at –78 °C for 5 min before being poured
onto a solution containing conc. aq NH3 (10 mL) and sat. aq NH4Cl
(90 mL). After addition of CH2Cl2 (10 mL) and strong shaking (5
min), the phases were separated and the blue aqueous layer was ex-
tracted with CH2Cl2 (3 30 mL). The combined extracts were dried
J = 2.5, 6.6, 11.1, 17.1 Hz, C3H), 1.96 (1 H, dddd, J = 2.9, 4.8, 5.9,
17.1 Hz, C3H), 1.84–1.74 (1 H, m, C4H), 1.62–1.25 (31 H, m, C4H,
15 CH2), 0.93–0.87 (12 H, m, 4 CH3).
13C NMR (75 MHz, CDCl3): = 162.5 (C6), 111.8 (C5H), 75.2
(C2H), 35.7 (CH2), 32.1 (CH2), 29.8 (CH2), 29.5 (CH2), 29.2 (3
CH2), 28.5 (CH2), 27.4 (3 CH2), 25.7 (CH2), 22.9 (CH2), 21.7
(CH2), 14.3 (CH3), 13.9 (3 CH3), 9.7 (3 CH2Sn).
1
(Na2SO4) and concentrated in vacuo. H NMR spectroscopy (400
LRMS (CI mode, isobutane): m/z (rel. Int., %) = 474 ([M + H]+, 60),
472 (50), 415 (100), 359 (10), 291 (35), 253 (5), 197 (12), 185 (10).
MHz, CDCl3) of the crude product showed a mixture of the desired
stannane 5 and dihydropyran 6 (85:15). The stannane 5 was purified
by column chromatography on alumina (500 g, deactivated with 5%
H2O), eluting with hexanes containing 1% Et3N. Pure stannane 5
(837 mg, 85%) was obtained as a colourless oil; [ ]D18 –7.4 (c = 1.1,
CHCl3).
Anal. Calcd for C24H48OSn: C, 61.16; H, 10.26. Found: C, 61.45; H,
10.00.
6-Heptyl-3,4-dihydro-2H-pyran (18)
IR (film): 1632 (s) cm–1.
IR (film): 2955, 2926, 2870, 2853, 1596, 1579, 1476, 1462, 1437,
1080, 734 cm–1.
1H NMR (300 MHz, C6D6): = 6.60 (1 H, d, J = 6.2 Hz, C6H), 4.71
(1 H, m, C5H), 3. 78 (1 H, apparent tt, J = 7.8, 4.5 Hz, C2H), 1.90–
1.15 (16 H, m), 1.01 (3 H, distorted t, J = 6.7 Hz, CH3).
13C NMR (75 MHz, C6D6): = 145.0 (C6H), 100.4 (C5H), 75.6
(C2H), 36.2 (CH2), 32.6 (CH2), 30.4 (CH2), 30.1 (CH2), 28.7 (CH2),
26.1 (CH2), 23.5 (CH2), 20.7 (CH2), 14.7 (CH3).
LRMS (EI+ mode): m/z (rel. int., %) = 182 (M+, 9), 151 (32), 138
(17), 126 (31), 121 (20), 111 (20), 97 (57), 83 (100), 70 (56), 57
(75), 41 (52).
1H NMR (400 MHz, CDCl3): = 7.43–7.35 (2 H, m), 7.20–7.13 (3
H, m), 4.35 (1 H, JH-Sn = 28.8 Hz, C5H), 3.84 (1 H, dq, J = 6.5, 1.4
Hz, C2H), 2.75 (2 H, d, J = 8.2 Hz, CH2Se), 2.67–2.60 (1 H, m,
C4H), 1.80–1.72 (1 H, m, C3H), 1.50–1.60 (6 H, m), 1.29–1.16 (6
H, m), 1.08 (3 H, d, J = 6.5 Hz, C2-CH3), 0.78–0.88 (6 H, m), 0.81
(9 H, t, J = 7.3 Hz, 3 CH2CH3), 0.69 (3 H, d, J = 6.8 Hz, C3-CH3).
13C NMR (100 MHz, CDCl3): = 162.6 (C6), 132.6 (2 CH), 130.5
(CH), 129.0 (2 CH), 126.7 (CH), 112.5 (t, JC-Sn = 30 Hz, C5H),
75.3 (t, JC-Sn = 10 Hz, C2H), 38.4 (t, JC-Sn = 16 Hz, C4H), 33.9
(C3H), 31.6 (CH2Se), 29.0 (3 CH2, t, JC-Sn = 10 Hz), 27.1 (3
CH2, JC-Sn = 26 Hz), 18.5 (C2-CH3), 13.7 (3 CH3), 9.6 (3 CH2Sn,
tt, JC-Sn = 170, 163 Hz), 5.3 (C3-CH3).
Anal. Calcd for C12H22O: C, 79.06; H, 12.16. Found: C, 78.95; H,
12.10.
4-(3,4-Dimethoxyphenyl)-6-tributylstannyl-3,4-dihydro-2H-
pyran (14)
The typical procedure was performed on a 1 mmol scale to give the
title compound (0.33 g, 65%) as a colourless oil after rapid column
chromatography of the crude product on deactivated alumina (5%
H2O) eluting with hexanes–Et2O (5:1) + Et3N (0.5%).
LRMS (CI mode): m/z = 573 (92), 571 [(M + H)+, 100%], 569 (76),
415 (25), 413 (18), 308 (7), 283 (20), 281 (10).
HRMS (EI mode): m/z Found 570.1587. C26H44OSeSn requires M,
570.1587.
The reaction was repeated on a 1 mmol scale on the lactones 7–11.
In each case the desired stannane was separated from the accompa-
nying dihydropyran and Bu4Sn by column chromatography on alu-
mina deactivated with 5% H2O, eluting with hexanes containing
0.5% Et3N (in the case of 12 and 13) or hexanes–Et2O containing
0.5% Et3N (in the case of 14, 15, and 16). Although silica gel gave
better separation, it was rarely used owing to substantial material
loss (approximately 10%) and protodestannylation of the stannanes.
IR (film): 1602 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 6.83 (3 H, apparent s), 4.79 (1 H,
d, J = 3.1 Hz, JSn-H 29.2 Hz, C5H), 3.93 (2 H, t, J = 5.2 Hz, C2H2),
3.88 (3 H, s, OCH3), 3.88 (3 H, s, OCH3), 3.44 (1 H, dt, J = 6.7, 3.2
Hz, C4H), 2.20–2.12 (1 H, m, C3H), 1.87–1.79 (1 H, m, C3H),
1.61–1.53 (6 H, m, 3 CH2CH2Sn), 1.35 (6 H, sextet, J = 7.3, 3
CH2CH3), 7.87 (6 H, t, J = 8.1 Hz, 3 CH2Sn), 0.91 (9 H, t, J = 7.3
Hz, 3 CH3).
13C NMR (75 MHz, CDCl3): = 163.5 (C6), 149.0 (C), 147.6 (C),
139.4 (C), 119.8 (CH), 115.5 (C5H), 111.2 (CH), 111.1 (CH), 64.3
(C2H2), 56.1 (OCH3), 55.9 (OCH3), 37.5 (C4H), 32.9 (C3H2), 29.2
(3 CH2CH2Sn), 27.4 (3 CH2CH3), 13.9 (3 CH3), 9.7 (3
CH2Sn).
4-Methyl-6-tributylstannyl-3,4-dihydro-2H-pyran (12)
Separation of the title compound from the SnBu4 by chromatogra-
phy on alumina was difficult and the yield of 54% of analytically
pure product was obtained after further chromatography of mixed
fractions on a short plug of silica gel eluting with hexanes contain-
ing Et3N (0.5%). Dihydropyran 12 gave identical 1H and 13C NMR
data to those reported.8 The 4-methyl-3,4-dihydro-2H-pyran (17)
was too volatile to isolate and characterise, and its presence was in-
ferred from 1H NMR spectroscopy of the crude reaction mixture.
LRMS (EI+ mode): m/z (rel. int., %) = 510 (M+, 7), 453(M+ + 2H –
2Bu, 100), 397 (53), 339 (28), 309 (26), 259 (10), 219 (20), 191
(32), 170 (40), 145 (17), 121 (16), 57 (8).
Anal. Calcd for C25H42O3Sn: C, 58.96; H, 8.31. Found: C, 58.70; H,
8.20.
Anal. Calcd for C18H36OSn: C, 55.84; H, 9.37. Found: C, 55.65; H,
9.30.
4-(3,4-Dimethoxyphenyl)-3,4-dihydro-2H-pyran (19)
2-Heptyl-6-tributylstannyl-3,4-dihydro-2H-pyran (13)
Separation of the title compound from the SnBu4 by chromatogra-
phy on alumina was difficult. An analytically pure sample of the ti-
tle compound gave the following spectroscopic data but the yield
(72%) of 13 was determined from pure material isolated together
with an NMR spectroscopic estimate of the mole fraction of 13 in
the mixed fractions.
IR (film): 1605 (w) cm–1.
1H NMR (300 MHz, CDCl3): = 4.70 (1 H, ddd, J = 1.2, 2.5, 3.9
Hz, JSn–H = 32 Hz, C5H), 3.67 (1 H, m, C2H), 2.11 (1 H, dddd,
IR: (film): 1644 (s) cm–1.
1H NMR (300 MHz, CDCl3): = 6.83 (2 H, s, ArH), 6.81 (1 H, d,
J = 1.4 Hz), 6.57 (1 H, d, J = 6.2 Hz, C6H), 4.77 (1 H, dd, J = 6.2,
3.4 Hz, C5H), 4.07–3.97 (2 H, m, C2H), 3.89 (3 H, s, OCH3), 3.88
(3 H, s, OCH3), 3.48–3.43 (1 H, m, C4H), 2.22–2.41 (1 H, m, C3H),
1.89–1.81 (1 H, m, C3H).
13C NMR (75 MHz, CDCl3): = 148.9 (C), 147.6 (C), 144.9 (C6H),
138.4 (C), 119.7 (CH), 111.1 (CH), 110.8 (CH), 103.9 (C5H), 63.9
(C2H2), 56.0 (3, OCH3), 55.9 (3, OCH3), 35.9 (C4H), 32.4 (C3H2).
Synthesis 2002, No. 3, 393–398 ISSN 0039-7881 © Thieme Stuttgart · New York

396
T. Wildman et al.
PAPER
LRMS (EI+ mode): m/z (rel. int. %) = 220 (M+, 100), 189 (82), 177
(40), 161 (63), 145 (14), 138 (19), 121 (16), 115 (12), 103 (14), 91
(22),77 (24), 51 (16), 39 (11).
27.8 (C4H2 or C5H2), 27.5 (3 CH2), 26.0 (C6H2), 13.9 (3 CH3),
10.0 (3 CH2Sn).
LRMS (EI+ mode): m/z (rel. int., %) = 493 ([M – H]+, 11), 437 (69),
381 (12), 323 (13), 251 (14), 235(26), 203(16), 175 ([M + H – OMe
– SnBu3]+,100), 147(14), 121 (89), 91 (18), 67 (32), 55 (20).
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.75; H,
7.30.
Anal. Calcd for C25H42O2Sn: C, 60.87; H, 8.58. Found: C, 61.10; H,
8.30.
2-(3-Methoxyphenyl)-6-tributylstannyl-2,3-dihydro-2H-pyran
(15)
The general procedure was performed on 1 mmol scale to give the
title compound (0.33 g, 68%) as a colourless oil after column chro-
matography of the crude product on deactivated alumina (5% H2O)
eluting with hexanes–Et2O (5:1) + Et3N (0.5%).
2-(3-Methoxyphenyl)-2,3,4,5-tetrahydrooxepine (21)
IR (film) 1650 cm–1.
1H NMR (300 MHz, CDCl3): = 7.28 (1 H, t, J = 8.1 Hz), 6.98–
6.92 (2 H, m), 6.83 (1 H, ddd, J = 8.3, 1.2, 1.2 Hz), 6.43 (1 H, dd,
6.8, 1.2 Hz, C7H), 4.90 (1 H, q, J = 5.9 Hz, C6H), 4.76 (1 H, dd,
J = 10.2, 2.6 Hz, C2H), 3.83 (3 H, s, OCH3), 2.42–2.26 (1 H, m,
C5H), 2.21–2.07 (2 H, m, C5H, C3H), 2.07–1.93 (2 H, m, C3H,
C4H), 1.69–1.54 (1 H, m, C4H).
13C NMR (75 MHz, CDCl3): = 159.8 (C), 147.5 (C7H), 145.0 (C),
129.5 (CH), 118.2 (CH), 113.2 (CH), 111.3 (CH), 110.4 (C6H),
84.5 (C2H), 55.4 (3, OCH3), 39.1 (C3H2), 26.0 (C4H2), 26.0
(C5H2).
IR (film): 1605 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 7.27 (1 H, t, J = 8.1 Hz), 6.96–
6.91 (2 H, m), 6.82 (1 H, dd, J = 8.2, 8.1 Hz), 4.83 (1 H, m, JSn–
H = 27.6 Hz, C5H), 4.76 (1 H, d, J = 9.2 Hz, C2H), 3.82 (3 H, s,
OCH3), 2.35–2.19 (1 H, m, C3H), 2.12–1.95 (2 H, m, C4H2), 1.95–
1.79 (1 H, m, C3H), 1.55 (6 H, sextet, J = 8.1 Hz, 3 CH2CH3),
1.35 (6 H, quintet, J = 7.4 Hz, 3 CH2CH2Sn), 0.96 (6 H, t, J = 8.2
Hz, 3 CH2Sn), 0.90 (9 H, t, J = 7.3 Hz, 3 CH3).
13C NMR (75 MHz, CDCl3): = 162.7 (C6), 159.7 (C), 145.2 (C),
129.3 (CH), 118.3 (CH), 112.8 (CH), 112.1 (C5H), 111.4 (CH),
76.8 (C2H) 55.3 (3, OCH3), 31.1 (C4H2), 29.1 (3 CH2), 27.4 (3
CH2), 22.0 (C3H2), 13.9 (3 CH3), 9.7 (3 CH2Sn).
LRMS (EI+ mode): m/z (rel. int., %) = 204 (M+, 14), 176 (100), 147
(44), 135 (48), 121 (51), 103 (27), 91 (56), 77 (29), 65 (22), 51 (19),
39 (39).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.40; H,
7.85.
LRMS (EI+ mode): m/z (rel. int., %) = 480 (M+, 5), 423 (26), 367,
(10), 177 (39), 121 (20), 91 (8), 55 (100).
Anal. Calcd for C24H40O2Sn: C, 60.14; H, 8.41. Found: C, 60.30; H,
8.65.
Preparation of Lactones (Scheme 3)
OMe
OMe
OMe
2-(3-Methoxyphenyl)-2,3-dihydro-2H-pyran (20)
MeO
MeO
CH3C(OEt)3
MeO
IR (film): 1650 (s), 782 (s) cm–1.
1H NMR (300 MHz, C6D6): = 7.22 (1 H, t, J = 7.9 Hz), 7.16 (1 H,
t, J = 1.9 Hz), 7.02 (1 H, d, J = 7.7 Hz), 6.85 (1 H, ddd, J = 8.2, 2.6,
0.8 Hz), 6.67 (1 H, dt, J = 6.1, 1.5 Hz, C6H), 4.81 (1 H, dd, J = 7.2,
5.1 Hz, C2H), 4.70–4.76 (1 H, m, C5H), 3.47 (3 H, s, OCH3), 2.11–
1.77 (4 H, m, C3H2, C4H2).
(a) 9-BBN
(b) NaOH, H2O2
47%
74%
CO2Et
OH
O
O
22
23
9
13C NMR (75 MHz, C6D6): = 160.7 (C), 144.9 (C6H), 144.7 (C),
129.9 (CH), 118.7 (CH), 113.6 (CH), 112.2 (CH), 100.7 (C5H),
77.4 (C2H), 55.0 (3, OCH3), 31.2 (C3H2), 20.8 (C4H2).
mCPBA, NaHCO3
O
O
LRMS (EI+ mode): m/z = 191 (M + H, 18), 161 (13),147 (15), 134
(100), 121 (7), 104 (11), 91 (13), 78 (11), 65 (9), 51 (6), 39 (6).
HRMS (ES+ mode): m/z Found: (M + H)+, 190.1161. C12H14O2 re-
O
CH2Cl2, r.t.
52%
OMe
OMe
quires M, 190.1150.
10
24
7-(3-Methoxyphenyl)-2-tributylstannyl-4,5,6,7-tetrahydro-
oxepin (16)
The general procedure was performed on 1 mmol scale to give the
title compound (0.34 g, 0.7 mmol, 69%) as a colourless oil after col-
umn chromatography of the crude product on deactivated alumina
(5% H2O) eluting with hexanes–Et2O (5:1) + Et3N (0.5%).
mCPBA, NaHCO3
O
O
O
CH2Cl2, r.t.
57%
OMe
OMe
IR: 1603 (m) cm–1.
25
11
1H NMR (300 MHz, CDCl3): = 7.23 (1 H, t, J = 7.9 Hz), 6.91 (2
H, m), 6.78 (1 H, dd, J = 2.2, 8.1 Hz), 5.07 (1 H, JSn–H = 28.8 Hz,
C4H), 4.65 (1 H, dd, J = 2.3, 11.0 Hz, C7H), 3.53 (3 H, s, OCH3),
2.39–2.07 (4 H, m, C4H2, C5H2), 2.05–1.84 (2 H, m, C6H2), 1.63–
1.35 (6 H, m, 3 CH2CH2Sn), 1.25 (6 H, sextet, J = 7.3 Hz, 3
CH2CH3), 0.99–0.75 (6 H, dt, J = 8.1 Hz, JSn–H = 25.2 Hz, 3
CH2Sn), 0.83 (9 H, t, J = 7.3 Hz, 3 CH3).
Scheme 3
3-Methyltetrahydropyran-2-one (7)9,10
The title compound, prepared in 47% yield (40 mmol scale) by the
NaBH4 reduction of 3-methylglutaric anhydride, gave H and 13C
1
NMR data consistent with the literature.10
13C NMR (75 MHz, CDCl3): = 168.6 (C2), 159.6 (C), 146.0 (C),
129.1 (CH), 124.3 (C3H), 118.1 (CH), 112.7 (CH), 111.0 (CH),
83.3 (C7H), 55.3 (3, OCH3), 39.7 (C4H2 or C5H2), 29.2 (3 CH2),
6-Heptyltetrahydropyran-2-one (8)
The title compound was obtained from Aldrich.
Synthesis 2002, No. 3, 393–398 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Tributylstannyl-3,4-dihydro-2H-pyrans
397
Ethyl-3-(3,4-dimethoxyphenyl)pent-4-enoate (23)
6-(3-Methoxyphenyl)tetrahydropyran-2-one (10)
A solution of 3,4-dimethoxycinnamyl alcohol (22;11,12 0.12 g, 0.6
mmol, 1 equiv), triethyl orthoacetate (0.4 mL, 0.36 g, 2.2 mmol, 3.5
equiv) and propionic acid (2.4 L, 2.4 mg, 0.03 mmol, 5 mol%) in
xylenes (10 mL) was refluxed (with a short path distillation appara-
tus to remove EtOH) for 9 h. The temperature was increased enough
to distil off most of the solvent, and the mixture was allowed to cool
before the remaining solvent was removed in vacuo. The residue
was purified by column chromatography eluting with hexanes–Et2O
(2:1 to 1:1) to give 23 (0.13 g, 74%) as a pale yellow oil.
To a solution of the ketone 2413 (0.90 g, 4.8 mmol) in CH2Cl2 (20
mL) was added solid m-CPBA (ca. 50%, 1.23 g, 7.14 mmol) and
NaHCO3 (2 g). The mixture was stirred at r.t. for 16 h, diluted with
CH2Cl2 (20 mL) and an additional amount of m-CPBA (1.0 g) was
added. The mixture was stirred for a further 4 h, quenched with sat.
Na2S2O3 (50 mL), and the aqueous layer was extracted with EtOAc
(4 20 mL). The combined organic layers were dried (Na2SO4), fil-
tered and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel eluting with hexanes–Et2O (1:4)
to give 10 (0.51 g, 52%) as a colourless oil.
IR (film): 1734 (s), 1637 (s) cm–1.
IR (film): 1734 (s) cm–1.
1H NMR (300 MHz, CDCl3): = 6.84–6.73 (3 H, m), 5.98, (1 H,
ddd, J = 7.0, 10.2, 17.3 Hz, C4H), 5.08 (1 H, dd, J = 1.5, 16.0 Hz,
C5H), 5.08 (1 H, dd, J = 1.2, 11.4 Hz, C5H), 4.09 (2 H, q, J = 7.1
Hz, CH2CH3), 3.88 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 3.91–3.80
(1 H, m, C3H), 2.74 (1 H, dd, J = 8.0, 15.0 Hz, C2HAHB), 2.67 (1
H, dd, J = 7.5, 21.1 Hz, C2HAHB), 1.20 (3 H, t, J = 7.1 Hz,
CH2CH3).
13C NMR (75 MHz, CDCl3): = 172.1 (C=O), 149.0 (C),147.9 (C),
140.6 (C4H), 135.2 (C), 119.5 (CH), 114.8 (C5H2), 111.4 (CH),
111.1 (CH), 60.6 (CH2CH3), 56.1 (OCH3), 56.0 (OCH3), 45.4
(C3H), 40.6 (C2H2), 14.4 (CH2CH3).
1H NMR (300 MHz, CDCl3): = 7.29 (1 H, t, J = 7.9 Hz), 6.95–
6.84 (3 H, m), 5.34 (1 H, dd, J = 10.2, 3.3 Hz, C6H), 3.86 (3 H, s,
OCH3), 2.71 (1 H, dt, J = 17.9, 6.5 Hz, C3HAHB), 2.57 (1 H, dt,
J = 17.7, 7.7 Hz, C3HAHB) 2.23–2.13 (1 H, m, C5HAHB), 2.04–1.79
(3 H, m, C4H2, C5HAHB).
13C NMR (75 MHz, CDCl3): = 171.6 (C=O), 159.9 (C), 141.6
(C), 129.8 (CH), 118.0 (CH), 113.8 (CH), 111.4 (CH), 81.6 (C6H),
55.5 (OCH3), 30.6 (C5H2), 29.6 (C3H2), 18.7 (C4H2).
LRMS (EI+ mode): m/z (rel. int., %) = 206 (M+, 83), 134 (86), 108
(23), 92 (15), 70 (46), 63 (16), 42 (100).
LRMS (EI+ mode): m/z (rel. int., %) = 264 (M+, 82), 190 (20), 177
(100), 159 (20), 146 (46), 131 (12), 115 (13), 103 (12), 91 (17), 77
(11).
HRMS (ES+ mode): m/z calcd for C12H14O3Na (M
+
Na)+ = 229.0841. Found = 229.0845
Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 67.90; H,
7.50.
7-(3-Methoxyphenyl)oxepan-2-one (11)
To a solution of the ketone 2514 (0.56 g, 2.7 mmol) in CH2Cl2 (15
mL) was added solid m-CPBA (ca. 50%, 1.42 g, 5.5 mmol, 2 equiv).
The mixture was stirred at r.t. for 16 h, diluted with Et2O (20 mL)
and the Et2O layer was washed with sat. aq. NaHCO3–Na2S2O3 so-
lution (1:1, 5 20 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel eluting with hexanes–
Et2O (2:1) to give the title compound (0.35 g, 57%) as a colourless
oil.
4-(3,4-Dimethoxyphenyl)tetrahydropyran-2-one (9)
To a solution of 9-BBN (1.44 g, 5.9 mmol, 2 equiv) in THF (15 mL)
was added a solution of 23 (0.78 g, 3.0 mmol) in THF (20 mL). The
mixture was stirred at r.t. for 19 h, cooled to 0 °C in an ice/salt bath,
and NaOH (1 M, 5.9 mL, 2 equiv) was added dropwise. The mixture
was stirred for 20 min and H2O2 (30% w/v, 2.4 mL, 0.73 g, 21
mmol, 7.2 equiv) was added dropwise. The ice bath was removed
and the reaction mixture stirred at r.t. for 1 h before NaOH (2 M, 15
mL, 10 equiv) and MeOH (30 mL) were added and the mixture
stirred at r.t. overnight. The solvent was replaced with EtOAc and
the mixture acidified with HCl (2 M, 22 mL). The organic and aque-
ous layers were separated and the latter extracted with the EtOAc (4
100 mL). The combined organic extracts were dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel eluting first with Et2O, then
EtOAc and finally with MeOH–CH2Cl2 (1:1) to give the title com-
pound (0.33 g, 47%) as a white solid. Recrystallisation from
EtOAc–hexanes gave an analytical sample, mp 93–95 °C.
IR (film): 1732 (s) cm–1.
1H NMR (300 MHz, CDCl3): = 7.27 (1 H, t, J = 8.1 Hz), 6.95 (2
H, t, J = 2.4 Hz), 6.84 (1 H, dd, 7.9, 1.7 Hz), 5.27 (1 H, d, J = 9.2
Hz, C7H), 3.81 (3 H, s, OCH3), 2.81–2.69 (2 H, m, C6H2), 2.17–
1.92 (4 H, m, C3H2, C4HAHB, C5HAHB), 1.86–1.61 (2 H, m,
C4HAHB, C5HAHB).
13C NMR (75 MHz, CDCl3): = 175.1 (C=O), 159.8 (C), 142.4 (C),
129.7 (CH), 118.2 (CH), 113.8 (CH), 111.4 (CH), 82.1 (C7H), 55.4
(OCH3), 37.6 (C3H2), 35.1 (C6H2), 28.7 (C5H2), 22.9 (C4H2).
LRMS (EI+ mode): m/z (rel.int., %) = 220 (M+, 60), 147 (12), 136
(100), 121 (15), 91 (19), 77 (22), 65 (17), 55 (40), 41 (25).
IR (KBr): 1733 (s) cm–1.
1H NMR (300 MHz, CDCl3): = 6.84 (1 H, d, J = 8.2 Hz), 6.75 (1
H, dd, J = 8.2, 1.8 Hz), 6.71 (1 H, d, J = 1.8 Hz), 4.49 (1 H, dt,
J = 11.3, 4.4 Hz, C6HAHB), 4.37 (1 H, dt, J = 10.9, 3.7 Hz,
C6HAHB), 3.88 (3 H, s, OCH3), 3.86 (3H, s, OCH3), 3.19 (1 H, ddt,
Anal. Calcd. for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.65; H,
7.25.
J = 4.9, 5.5, 10.4 Hz, C4H), 2.90 (1 H, dd, J = 17.6, 5.9 H, Acknowledgement
C3HAHB), 2.61 (1 H, dd, J = 17.6, 10.5, C3HAHB), 2.19–2.14 (1 H,
m, C5HAHB), 2.05–1.95 (1 H, m, C5HAHB).
We thank Syngenta for a CASE studentship.
13C NMR (75 MHz, CDCl3): = 170.8 (C=O), 149.4 (C), 148.3
(C), 135.6 (C), 118.4 (CH), 111.6 (CH), 110.6 (CH), 68.7 (C6H2),
56.1 (OCH3), 56.1 (OCH3), 37.8 (C3H2), 37.2 (C4H), 30.6 (C5H2).
LRMS (EI+ mode): m/z (rel. int., %) = 236 (M+, 100), 177 (90), 164
(51), 149 (32), 138 (14), 131(7), 121 (18), 103 (16), 91 (47), 77 (26),
65 (13), 51 (14).
References
(1) Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C.;
Farrugia, L. J.; Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin
Trans. 1 2000, 2357.
(2) Barber, C.; Jarowicki, K.; Kocienski, P. Synlett 1991, 197.
(3) Chong, J. M.; Nielsen, N. Tetrahedron Lett. 1998, 39, 9617.
(4) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D.
C. Tetrahedron Lett. 1989, 30, 2065.
Anal. Calcd. for C13H16O4: C, 66.09; H, 6.83. Found: C, 66.05; H,
6.80.
Synthesis 2002, No. 3, 393–398 ISSN 0039-7881 © Thieme Stuttgart · New York

398
T. Wildman et al.
PAPER
(11) Freudenberg, K.; Schuhmacher, G. Chem. Ber. 1954, 87,
(5) Piers, E.; Morton, H. E.; Chong, J. M. Can. J. Chem. 1987,
65, 78.
1882.
(6) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D.
Tetrahedron Lett. 1988, 29, 4795.
(7) Boeckman, R. K.; Bruza, K. J. Tetrahedron 1981, 37, 3997.
(8) Genicot, C.; Ley, S. V. Synthesis 1994, 1275.
(9) Bailey, D. M.; Johnson, R. E. J. Org. Chem. 1970, 35, 3574.
(10) Tokoroyama, T.; Kusaka, H. Can. J. Chem. 1996, 74, 2487.
(12) Stevenson, R.; Block, E. J. Org. Chem. 1971, 36, 3453.
(13) Noguchi, K.; Takeda, M.; Nurimoto, S. Chem. Pharm. Bull.
1977, 25, 890.
(14) Caubere, P.; Guillaumet, G.; Mourad, M. S. Tetrahedron
1972, 28, 95.
Synthesis 2002, No. 3, 393–398 ISSN 0039-7881 © Thieme Stuttgart · New York