The preparation of 6-bromo-3,4-dihydro-2H-pyrans from tetrahydropyran-2-ones via a Ni(0)-catalysed coupling reaction and their halogen-metal exchange to 6-lithio-3,4-dihydro-2H-pyrans

Article abstract of DOI:10.1055/s-2002-22698

The enol triflate derivatives prepared from readily accessible tetrahydropyran-2-ones undergo Ni(0)-catalysed substitution with LiBr to give the corresponding 6-bromo-3,4-dihydro-2H-pyrans under mild conditions. The 6-bromo-3,4-dihydro-2H-pyrans undergo h

Full text of DOI:10.1055/s-2002-22698

LETTER
607
The Preparation of 6-Bromo-3,4-dihydro-2H-pyrans from Tetrahydropyran-
2-ones via a Ni(0)-catalysed Coupling Reaction and their Halogen-metal
Exchange to 6-Lithio-3,4-dihydro-2H-pyrans.
T
he Prepa
a
ration of 6-
c
Bromo-3,4
q
H
-
u
pyrans from
e
Tetrahydr
o
l
pyran-2
i
-onesne E. Milne, Krzysztof Jarowicki, Philip J. Kocienski*
Department of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
Fax +44(113)2336401; E-mail: p.kocienski@chemistry.leeds.ac.uk
Received 15 January 2002
vided a route to -lithiated enol ethers with -alkyl sub-
stituents. Unfortunately the Yu-Jin procedure cannot be
easily adapted to the cyclic series owing to the method
used to synthesise the -bromo vinyl ethers.
Abstract: The enol triflate derivatives prepared from readily acces-
sible tetrahydropyran-2-ones undergo Ni(0)-catalysed substitution
with LiBr to give the corresponding 6-bromo-3,4-dihydro-2H-pyr-
ans under mild conditions. The 6-bromo-3,4-dihydro-2H-pyrans
undergo halogen-metal exchange with tert-butyllithium to give the
corresponding 6-lithio-3,4-dihydro-2H-pyrans.
TMSBr
(a) t-BuLi, THF, –78 °C
MeOH
Key words: 6-bromo-3,4-dihydro-2H-pyrans, lactones, Ni(0), cou-
pling, halogen-metal exchange
(b) Me3SiCl
RO
Br
RO
SiMe3
–40 °C
OR
Scheme 2
6-Lithio-3,4-dihydro-2H-pyrans 2 are synthetically useful
acyl anion equivalents.1,2 Boeckman and Bruza reported
the first practical and direct synthesis of 2 by metallation
of the dihydropyran 1 (Scheme 1) with t-BuLi (1.0 equiv)
in THF at -20 °C to 0 °C.3 The metallation reaction is sen-
sitive to substitution. Quantitative conversion is often
only achieved with a large excess of t-BuLi in which case
heteroatom substituents - or the THF - may undergo com-
peting metallation.4 Even simple alkyl-substituted dihy-
dropyrans may require 4 equivalents of t-BuLi for
satisfactory conversion.5 In order to avoid the complica-
tions associated with the presence of excess t-BuLi, the 6-
lithio-3,4-dihydro-2H-pyran 2 can be converted to its sta-
ble and isolable 6-tributylstannyl-3,4-dihydro-2H-pyran 3
by reaction with Bu3SnCl and the lithium derivative re-
generated by the transmetallation of the stannane 3 with n-
BuLi in THF at –78 °C.6 The ease, generality and efficien-
cy of the tin-lithium transmetallation reaction stimulated
the development of several alternative syntheses of the
stannanes 3 from lactone7–12 sulfone13,14 or alkynol pre-
cursors.15–18
We now report a synthesis of 6-bromo-3,4-dihydro-2H-
pyrans from tetrahydropyran-2-ones 4a–d based on the
Ni(0)-catalysed coupling of enol triflates 5a–d with LiBr
(Scheme 3) and their halogen-metal exchange with t-BuLi
to the corresponding 6-lithio-3,4-dihydro-2H-pyrans
7a–d. In a typical procedure a mixture of N-phenyltriflu-
oromethanesulfonimide (1.2 equiv) and tetrahydropyran-
2-one 4a (1 equiv) in THF was added dropwise to a solu-
tion of KHMDS (1.4 equiv) in THF at –78 °C. Without
aqueous workup, the reaction mixture was concentrated in
vacuo and the residue filtered through an alumina plug us-
ing hexanes-ether to yield the enol triflate 5a. Care must
be taken to avoid the removal of all traces of solvent from
the enol triflate, otherwise decomposition takes place. The
crude enol triflate 5a was then immediately treated with
LiBr (12 equiv) and [Ph3P]2Ni(0) (10 mol%) prepared by
reaction of DIBALH with Ni(acac)2 according to the pro-
cedure of Mori and co-workers.20 After 12 h at room tem-
perature, the labile 6-bromo-3,4-dihydro-2H-pyran 6a
was isolated by a standard aqueous workup and purified
by column chromatography. The NMR spectra of 6a–d
revealed the presence of triphenylphosphine and other mi-
nor contaminants (up to 10%) but attempts to remove
them by further chromatography or distillation resulted in
products of worse quality with poor mass recovery.
Therefore, the labile -bromo dihydropyrans were used
immediately in the next step.
R
R
R
Bu3SnCl
t-BuLi
n-BuLi
THF
–20 °C
O
H
O
Li
O
SnBu3
1
2
3
Scheme 1
The -bromo dihydropyrans 6a–d underwent halogen-
metal exchange on treatment with t-BuLi (2 equiv) at
–78 °C in Et2O to give the -lithiated dihydropyrans
7a–d. Quenching with D2O, gave the 6-deuterio deriva-
tives 8a–d in 49–61% overall yield from the lactones
4a–d. By the same protocol, the deuterated 4,5-dihy-
drobenzo[b]oxepine 10 was prepared in 62% overall yield
from the corresponding lactone 9. The sequence fails with
Recently Yu and Jin19 described the synthesis and subse-
quent lithium-halogen exchange of -bromo vinyl ethers
as shown in Scheme 2. Their method for the first time pro-
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0607,0609,ftx,en;D00102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

608
J. E. Milne et al.
LETTER
General Procedure for the Preparation of Enol Triflates 5a–d
To a solution of KHMDS (0.41 M in toluene, 1.4 equiv) in THF (1.7
mL) at –78 ºC was added a mixture of N-phenyltrifluoromethane-
sulfonimide (1.2 equiv) and the lactone 4a–d (1 equiv) in THF (3
mL) over a period of 1 h. The reaction mixture was allowed to stir
for 15 min at –78 °C and then concentrated in vacuo to about one
quarter of its original volume and the residue was flushed through
an alumina plug (deactivated with 5% water) using hexanes–Et2O
(0.5% Et3N) to yield the enol triflate. The eluent was concentrated
in vacuo to a volume of 2 mL and used immediately in the next step.
If all of the solvent is removed, the enol triflates decompose rapidly.
For the purposes of calculating quantities of reagents in the next
step, we assumed a yield of 100%.
KHMDS
PhN(Tf)2
[Ph3P]2Ni(0)
LiBr
THF
R
O
O
R
O
OTf
R
O
6a-d
Br
THF
4a-d
5a-d
t-BuLi (2 equiv.)
%8 from 4
R
a
b
c
d
n-C7H15
Ph(CH2)3
61
54
D2O
R
O
Li
R
O
D
t-BuPh2SiOCH2 51
3-MeOC6H4 49
7a-d
8a-d
General Procedure for the Preparation of -Bromo Dihydropy-
rans 6a–d
(a) KHMDS, PhN(Tf)2
(b) [Ph3P]2Ni(0), LiBr
A solution of DIBALH (1.5 M in toluene, 0.2 mmol) was added
dropwise to a mixture of Ni(acac)2 (0.1 mmol) and PPh3 (0.2 mmol)
in THF (25 mL), at 0 °C. The dark red-brown mixture was stirred at
r.t. for 15 min, then cooled to –78 °C. To the mixture was added
LiBr (12 mmol) and THF (9.2 mL) and enol triflate (1 mmol) in
THF (3 mL/1 mmol) at –78 °C. The dark red-brown mixture was al-
lowed to warm gradually to r.t. overnight. Saturated aqueous
NaHCO3 (20 mL) was added and the mixture filtered through celite
and the layers separated. The aqueous layer extracted with Et2O (3
100 mL) and the combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The residue was rapidly flushed through
an alumina plug (deactivated with 5% water) using hexanes–Et2O
(0.5% of Et3N). The polarity of the eluent was adjusted according to
the polarity of the product. NMR spectroscopic analysis of the crude
product revealed up to 10% contamination by triphenylphosphine
and other minor impurities. Attempts to remove the impurities by
chromatography resulted in substantial loss of material and product
degradation; therefore, the crude -bromo dihydropyrans were used
immediately in the next step. For the purposes of calculating quan-
tities of reagents in the next step, we assumed a yield of 100%.
(c) t-BuLi (2 equiv.)
(d) D2O
O
O
O
D
9
10 (62%)
Scheme 3
5-membered ring lactones because the requisite enol tri-
flates cannot be formed.
The lactone 4a was converted to the corresponding chlo-
ro- and iodo-analogues 11 and 12 using LiCl and LiI re-
spectively. The chloro derivative 11 was more stable than
bromo derivative 6 but halogen metal exchange required
6 equivalents of t-BuLi and 12 equivalents of THF at
room temperature for complete conversion to the lithium
species. The iodo analogue 12 could only be handled in
dilute solution and was too unstable to be practical. Final-
ly, in order to demonstrate that nucleophiles other than
halogen participate in the Ni(0)-catalysed coupling, we
prepared the nitrile 13 in 59% yield as shown in
Scheme 4.
A sample of 6-bromo-2-heptyl-3,4-dihydro-2H-pyran (6a) (ca 95%
pure) gave the following spectroscopic data: IR (film): 1647 cm-1;
1H NMR (400 MHz, C6D6): = 4.97 (1 H, br dd, J = 4.6, 2.9 Hz,
C=CH), 3.78 (1 H, m, OCH), 1.80–1.27 (16 H, m), 1.02 (3 H, t, J =
8 Hz, CH3); 13C NMR (100 MHz, C6D6): = 132.8 (C), 101.9 (CH),
81.0 (CH), 35.4 (CH2), 32.5 (CH2), 30.2 (CH2), 29.9 (CH2), 27.4
(CH2), 25.8 (CH2), 23.4 (CH2), 23.0 (CH2), 14.7 (CH3); LRMS (EI
+ mode): m/z (%) = 260, 262 (M+, 20), 181 (20), 163 (25), 135 (17),
111 (20), 83 (62), 69 (60), 55 (100), 41 (50); HRMS (EI + mode):
Found, 79Br, 260.0776. C12H21BrO requires M, 260.0775.
n-C7H15
O
Cl
n-C7H15
O
I
11
12
[Ph3P]2Ni(0) (1.0 equiv.)
Bu4NCN (1.2 equiv.)
General Procedure for Halogen-metal Exchange Reactions
To a solution of the -bromo dihydropyrans 6a–d in anhydrous di-
ethyl ether was added t-BuLi (1.5 M solution in pentane, 2 equiv) at
–78 °C. The reaction mixture was stirred for about 30 min at –78 °C
whereupon the intermediate 6-lithio-3,4-dihydro-2H-pyrans 7a–d
were quenched with D2O. Standard aqueous workup returned the -
deuterated dihydropyrans 8a–d after column chromatography or
Kugelrohr distillation.
THF, –78 °C to r.t., 12 h
59% (1 mmol scale)
n-C7H15
O
OTf
n-C7H15
O
CN
5a
13
Scheme 4
In conclusion, we have devised a 3-step synthesis of cy-
clic -lithiated enol ethers from readily available lactone
precursors based on the Ni(0)-catalysed coupling of ha-
lide ions with enol triflates. The prime advantages are the
use of Ni(0) rather than Pd(0) in the crucial coupling step
and the avoidance of toxic and expensive tin intermedi-
2-Heptyl-3,4-dihydro-2H-pyran-6-d (8a): IR (film): 1632 cm-1;
1H NMR (300 MHz, C6D6): = 4.71 (1 H, m, CD=CH), 3.78 (1 H,
apparent tt, J = 7.8, 4.5 Hz, OCH), 1.90–1.15 (16 H, m), 1.01 (3 H,
t, J = 6.7 Hz, CH3); 13C NMR (75 MHz, C6D6): = 144.9 (CD),
100.2 (CH), 75.6 (CH), 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).
2-(3-Phenylpropyl)-3,4-dihydro-2H-pyran-6-d (8b): IR (film):
1630 cm-1; 1H NMR (300 MHz, C6D6): = 7.12–6.94 (5 H, m, Ph),
4.68 (1 H, ddd, J = 4.6, 2.3, 0.8 Hz, CD=CH), 3.71 (1 H, apparent
tt, J = 8.2, 4.8 Hz, OCH), 2.38 (2 H, apparent t, J = 7.4 Hz, CH2Ph),
1.90–1.20 (8 H, m); 13C NMR (75 MHz, C6D6): = 144.9 (CD),
ates. However, the instability of the enol triflate and
-
bromo dihydropyran intermediates limits the scale of the
sequence.
Synlett 2002, No. 4, 607–609 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Preparation of 6-Bromo-3,4-dihydro-2H-pyrans from Tetrahydropyran-2-ones
609
143.1 (C), 129.1 (2 CH), 129.0 (2 CH), 126.5 (CH), 100.2 (CH),
75.6 (CH), 36.5 (CH2), 35.6 (CH2), 28.6 (CH2), 27.9 (CH2), 20.6
(CH2).
1.03 (3 H, t, J = 7 Hz, CH3); 13C NMR (100 MHz, C6D6): = 130.5
(C), 116.0 (CH), 115.7 (CN), 77.4 (CH), 35.3 (CH2), 32.5 (CH2),
30.2 (CH2), 29.9 (CH2), 26.6 (CH2), 25.6 (CH2), 23.4 (CH2), 21.1
(CH2), 14.7 (CH3).
2-[(tert-Butyldiphenylsilyloxy)methyl]-3,4-dihydro-2H-pyran-
6-d (8c): IR (film): 1651 cm-1; 1H NMR (300 MHz, C6D6): = 7.93–
7.87 (4 H, m, ArH), 7.35–7.31 (6 H, m, ArH), 4.64 (1 H, dd, J = 4.4,
2.6 Hz, CD=CH), 4.01–3.80 (3 H, m, OCH and CH2OSi), 1.85-1.71
(4 H, m), 1.28 (9 H, s, t-Bu); 13C NMR (75 MHz, C6D6): = 142.9
(CD), 134.7 (4 CH), 132.9 (2 C), 128.6 (4 CH), 124.4 (2 CH), 98.6
(CH), 74.3 (CH), 65.2 (CH2), 25.7 (3 CH3), 23.2 (CH2), 18.2 (C),
18.2 (CH2).
Acknowledgement
We thank the EPSRC, Pfizer Central Research, Merck Sharp and
Dohme and AstraZeneca Pharmaceuticals for support. We also
thank the Carnegie Foundation and Syngenta for scholarships (J. E.
M.) and Mr Tony Ritchie (Glasgow University) for mass spectra.
2-(3-Methoxyphenyl)-3,4-dihydro-2H-pyran-6-d (8d): IR (film):
1650, 782 cm-1; 1H NMR (300 MHz, C6D6): = 7.22 (1 H, apparent
t, J = 7.9 Hz), 7.16 (1 H, br s with fine splitting), 7.02 (1 H, d, J =
7.7 Hz), 6.85 (1 H, apparent ddd, J = 8.2, 2.6, 0.8 Hz), 4.81 (1 H, dd,
J = 7.2, 5.1 Hz, C2H), 4.70–4.76 (1 H, m), 3.47 (3 H, s, OCH3),
2.11–1.77 (4 H, m); 13C NMR (75 MHz, C6D6): = 160.7 (C), 144.9
(CD), 144.7 (C), 129.9, 118.7, 113.6, 112.2, 100.7, 77.4 (all CH),
55.0 (CH3), 31.2 (CH2), 20.8 (CH2).
References
(1) Braun, M. Angew. Chem. Int. Ed. 1998, 37, 430.
(2) Friesen, R. W. J. Chem. Soc., Perkin Trans. 1 2001, 1969.
(3) Boeckman, R. K.; Bruza, K. J. Tetrahedron 1981, 37, 3997.
(4) Friesen, R. W.; Sturino, C. F.; Daljeet, A. K.; Kolaczewska,
A. J. Org. Chem. 1991, 56, 1944.
1
(5) Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989, 45, 107.
(6) Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc., Chem.
Commun. 1986, 926.
4,5-Dihydrobenzo[b]oxepine-2-d (10): IR (film): 1640 cm-1; H
NMR (300 MHz, C6D6): = 7.18 (1 H, d, J = 7.9 Hz, ArH), 7.08–
7.00 (1 H, m, ArH), 6.95 (2 H, m), 4.61 (1 H, t, J = 3.97 Hz,
CH=CD), 2.87 (2 H, t, J = 5.8 Hz, ArCH2), 2.11 (2 H, dt, J = 7.2,
4.6 Hz, CD=CHCH2); 13C NMR (75 MHz, C6D6): = 159.3 (CO),
144.0 (CD), 134.1 (C), 130.5, 127.8, 124.4, 121.0, 108.4 (all CH),
33.2 (CH2), 28.0 (CH2).
(7) Genicot, C.; Ley, S. V. Synthesis 1994, 1275.
(8) Barber, C.; Jarowicki, K.; Kocienski, P. Synlett 1991, 197.
(9) Hareau-Vittini, G.; Kocienski, P.; Reid, G. Synthesis 1995,
1007.
(10) Kocienski, P.; Jarowicki, K.; Marczak, S. Synthesis 1991,
1191.
(11) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Gaertner, P.;
Yang, Z. J. Am. Chem. Soc. 1997, 119, 5467.
(12) Nicolaou, K. C.; McGarry, D. G.; Sommers, P. K. J. Am.
Chem. Soc. 1990, 112, 3696.
(13) Lesimple, P.; Beau, J. M.; Jaurand, G.; Sinaÿ, P.
Tetrahedron Lett. 1986, 27, 6201.
(14) Gunn, A.; Jarowicki, K.; Kocienski, P.; Lockhart, S.
Synthesis 2001, 331.
(15) McDonald, F. E.; Bowman, J. L. Tetrahedron Lett. 1996, 37,
4675.
(16) McDonald, F. E.; Zhu, Y. H. Tetrahedron 1997, 53, 11061.
(17) McDonald, F. E. Chem.–Eur. J. 1999, 5, 3103.
(18) Schmidt, B.; Kocienski, P.; Reid, G. Tetrahedron 1996, 52,
1617.
(19) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840.
(20) Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000,
122, 1624.
6-Heptyl-5,6-dihydro-4H-pyran-2-carbonitrile (13): A solution
of DIBALH (1.3 mL, 2 mmol, 1.5 M in toluene, 200 mol%) was
added dropwise to a mixture of Ni(acac)2 (0.257 g, 1 mmol, 100
mol%) and PPh3 (0.524 g, 2 mmol, 200 mol%) in toluene (2.3 mL),
at 0 °C. The dark red-brown mixture was stirred at r.t. for 15 min.,
then cooled to –78 °C. To the reaction mixture was added THF (4
mL) followed by a solution of tetrabutylammonium cyanide (0.331
g, 1.2 mmol, 1.2 equiv) and enol triflate 5a (approximately 1 mmol)
in THF (5 mL) over a period of 1.5 h at –78 °C. The dark red-brown
mixture was allowed to warm gradually to r.t. overnight. The reac-
tion mixture was hydrolysed with saturated aqueous NaHCO3
(20 mL) and extracted with Et2O (3 100 mL). Filtration through
Celite was necessary to separate the layers. The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by column chromatography on alumina deactivated
with 5% water, eluting with hexanes containing 0.5% of Et3N, to
give the nitrile 13 (0.122 g, 59% over 2 steps): IR (film): 2231, 1643
cm-1; 1H NMR (400 MHz, C6D6): = 5.11 (1 H, ddd, J = 4.8, 3.5,
1.0 Hz, C=CH), 3.42–3.34 (1 H, m, OCH), 1.54–1.05 (16 H, m),
Synlett 2002, No. 4, 607–609 ISSN 0936-5214 © Thieme Stuttgart · New York