Functionalization of 2-alkylidenetetrahydrofurans and 2- alkylidenepyrrolidines by palladium(0)-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-2004-830892

2-Alkylidenetetrahydrofurans and 2-alkylidenepyrrolidines were efficiently functionalized by bromination of the exocyclic double bond and subsequent palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1055/s-2004-830892

LETTER
2169
Functionalization of 2-Alkylidenetetrahydrofurans and 2-Alkylidene-
pyrrolidines by Palladium(0)-Catalyzed Cross-Coupling Reactions
F
unctionalizatio
s
n
of 2-Al
enahydrofurans and
2
-Alkylidenepyrr
e
olidines llur, Peter Langer*
Institut für Chemie und Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstrasse 16, 17487 Greifswald, Germany
E-mail: peter.langer@uni-greifswald.de
Received 23 February 2004
Cl
Abstract: 2-Alkylidenetetrahydrofurans and 2-alkylidenepyrrol-
idines were efficiently functionalized by bromination of the exo-
cyclic double bond and subsequent palladium-catalyzed cross-
coupling reactions.
Br
O
OLi
OLi
i
OR
OR
70–76%
O
Key words: bromination, cross-coupling, palladium, pyrrolidines,
tetrahydrofurans
1a–c
2a–c
ii
2-Alkylidenetetrahydrofurans1,2 and 2-alkylidenepyrroli-
dines3,4 represent important synthetic building blocks for
the synthesis of pharmacologically relevant natural prod-
ucts and natural product analogues. The exocyclic double
bond of 2-alkylidenetetrahydrofurans has been function-
alized by cycloaddition reactions,1a–1d nucleophilic addi-
tions,1e,f cyclopropanations1g or hydrogenations.1h,5h,i 2-
Alkylidenetetrahydrofurans are direct precursors of tet-
rahydrofuran natural products, such as methyl nonactate.5
In addition, they were successfully transformed into natu-
rally occurring spiroketals, such as chalcogran.6 Recently,
we have reported the functionalization of 2-alkylidenetet-
rahydrofurans by lithiation and subsequent alkylation.7
Herein, we wish to report palladium-catalyzed cross-cou-
pling reactions of 2-alkylidenetetrahydrofurans and 2-
alkylidenepyrrolidines. This methodology allows a con-
venient functionalization of the exocyclic double bond
and offers new synthetic vistas.
Br
Ar
O
O
Ar B(OH)2
iii
OR
OR
O
O
4a–g
3a–c
Scheme
1
Functionalization of 2-alkylidenetetrahydrofurans.
Reagents and conditions: i: THF, 78 °C to 20 °C, 14 h, then reflux, 12
h, 2a (R = t-Bu): 76%, 2b (R = Me): 72%, 2c (R = Et): 73%; ii: NBS
(1.3 equiv), CCl4, 3 h, 3a (R = t-Bu): 73%, 3b (R = Me): 84%, 3c
(R = Et): 84%; iii: Pd(PPh3)4 (3 mol%), K3PO4 (1.5 equiv), dioxane,
reflux, 6 h.
Table 1 Suzuki Reactions of 2-Alkylidenetetrahydrofurans
4
a
b
c
d
e
f
R
Ar
Yield (%)a
Our starting point was the development of a method for
the bromination of the exocyclic double bond of 2-alkyl-
idenetetrahydrofurans.8 The required starting materials,
tetrahydrofurans 2a–c, were prepared by the recently
reported cyclization of 1-bromo-2-chloroethane with the
dianions of tert-butyl, methyl and ethyl acetoacetate
(Scheme 1).9
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Ph
87
88
77
87
81
92
62
4-MeC6H4
4-(MeO)C6H4
4-ClC6H4
2-Thienyl
4-ClC6H4
2-Thienyl
The reaction of 2a–c with NBS (1.3 equiv) resulted in
selective bromination of the double bond and formation of
the desired products 3a–c. Bromination of both the double
bond and carbon C-3 was observed in the reaction of 2c
with an excess of NBS (3.0 equiv); the dibrominated prod-
uct was isolated in 93% yield (E-isomer: 70%, Z-isomer:
23%). The employment of other bromination reagents
(e.g. Br2) was unsuccessful. During the optimization, the
reaction time (3 h), temperature (reflux) and solvent
(CCl4) proved to be important parameters.10
g
Me
a Yields of isolated products, E:Z >98:2
Palladium-catalyzed cross coupling reactions of 3a,b
were studied (Scheme 1, Table 1). Stille reactions of 3a
with Me3SnPh or Bu3SnPh proved unsuccessful under a
variety of conditions. In contrast, the Suzuki reaction of
3a with PhB(OH)2 in the presence of Pd(PPh3)4 (3 mol%)
afforded the desired 2-alkylidenetetrahydrofuran 4a. The
best yields (up to 87%) were obtained when Pd(PPh3)4,
phenylboronic acid, K3PO4 and dioxane (reflux) were
SYNLETT 2004, No. 12, pp 2169–2171
0
1
.1
0
.2
0
0
4
Advanced online publication: 05.08.2004
DOI: 10.1055/s-2004-830892; Art ID: D04704ST
© Georg Thieme Verlag Stuttgart · New York

2170
E. Bellur, P. Langer
LETTER
used.11 The reaction of 3a with 4-tolyl-, 4-methoxyphe-
nyl-, 4-chlorophenyl and 2-thienylboronic acid afforded
the functionalized 2-alkylidenetetrahydrofurans 4b–e.
The functionalized products 4f–g were prepared from 3b.
All Suzuki reactions proceeded in good to very good
yields (62–92%) and with very good E-diastereoselectiv-
ity.
O
OiPr
H
OLi
OLi
N
i,ii, iii
OiPr
8
1d
O
O
OiPr
iv
OiPr
H
H
B(OH)2
N
N
+
Br
Br
OMe
Br
O
OMe
OMe
O
Br
10 (19%)
i
OMe
9 (75%)
O
O
3b
5 (96%)
O
OiPr
H
v
ii, iii
N
O
+
O
O
Cl
B(OH)2
O
Cl
O
O
11 (87%)
Z-6 (35%)
E-6 (54%)
Scheme 4 Functionalization of 2-alkylidenepyrrolidine 8, Z:E = 3:1
for all products. Reagents and conditions: i: Br(CH2)2Cl, THF, 78 °C
to 0 °C; ii: NaN3, DMSO, 50 °C, 12 h; iii: PPh3, THF, reflux, 6 h; iv:
NBS (1.3 equiv), CCl4, reflux, 3 h; v: Pd(PPh3)4 (3 mol%), K3PO4 (1.5
equiv), dioxane, reflux, 6 h.
Scheme 2 Sequential Suzuki reaction and lactonization. Reagents
and conditions: i: Pd(PPh3)4 (3 mol%), K3PO4 (1.5 equiv), dioxane,
reflux, 6 h; ii: BBr3, CH2Cl2; iii: t-BuOK, H2O.
The application of our methodology to the synthesis of 2-
alkylidenetetrahydrofuran 6, a saturated analogue of the
natural product calycine,12,13 was studied next
(Scheme 2). The reaction of 3b with 2-methoxyphenyl-
boronic acid afforded 5. Sequential treatment of 5 with
BBr3 (CH2Cl2) and t-BuOK (H2O) afforded 6 as a separa-
ble mixture of E/Z-isomers.
10 (19%). The Suzuki reaction of 9 with 4-chloro-
phenylboronic acid afforded the desired Z-configured
pyrrolidine 11 in 87% yield (Scheme 4). All 2-alkyl-
idenepyrrolidines were formed with Z-selectivity, due to
the formation of a stable intramolecular hydrogen bond
NHO.
t
t
CO2 Bu
CO2 Bu
Acknowledgment
Br
O
O
We thank Dr. Ilia Freifeld for an experimental contribution.
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
i
OMe
OMe
O
O
7 (62%)
3b
References
Scheme 3 Heck reaction of 3b. Reagents and conditions: i:
(1) For cycloadditions, see: (a) Weichert, A.; Hoffmann, H. M.
R. J. Org. Chem. 1991, 56, 4098. (b) Tchelitcheff, P. Bull.
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Pd(PPh3)4 (3 mol%), Et3N, DMF, 100 °C, 25 h.
Alkenyl substituted 2-alkylidenetetrahydrofurans were
successfully prepared by Heck reactions. For example, the
reaction of 3b with tert-butyl acrylate afforded, under
standard conditions, the desired alkenyl substituted
tetrahydrofuran 7 (Scheme 3).
The known 2-alkylidenepyrrolidine 8 was prepared by re-
action of the dianion 1d with 1-bromo-2-chloroethane to
give isopropyl 6-chloro-1,3-dioxohexanoate, subsequent
displacement of the chloride by treatment with NaN3
(DMSO) and cyclization by treatment with PPh3–THF
(Staudinger–Aza–Wittig reaction).14 The reaction of 8
with NBS–CCl4 gave a separable mixture of 9 (75%) and
cyclopropanations, see: Kirmse, W.; Rode, K. Chem. Ber.
1987, 120, 847. (h) For hydrogenations, see: Ohta, T.;
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(3) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668; and
references cited therein.
Synlett 2004, No. 12, 2169–2171 © Thieme Stuttgart · New York

LETTER
Functionalization of 2-Alkylidenetetrahydrofurans and 2-Alkylidenepyrrolidines
2171
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190 (92), 162 (4) cm–1. The exact molecular mass m/z =
262.0205 2 mD [M+] for C10H15O3Br was confirmed by
HRMS (EI, 70 eV). Anal. Calcd for C10H15O3Br (263.131):
C, 45.65; H, 5.75. Found: C, 45.38; H, 6.03. All products
gave satisfactory spectroscopic and analytical and/or high-
resolution mass data.
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(11) Typical Experimental Procedure for 4a:
Tetrakis(triphenylphosphine)palladium (0.20 g, 0.017
mmol) was added to a 1,4-dioxane solution (5 mL) of 3a
(0.150 g, 0.57 mmol), K3PO4 (0.726 g, 3.42 mmol) and
phenylboronic acid (0.209 g, 1.71 mmol) at r.t. The reaction
mixture was stirred under reflux for 6 h. The solution was
allowed to cool to r.t. and a sat. solution of NH4Cl (20 mL)
was added. The solution was extracted with Et2O (4 × 30
mL). The combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, n-
hexane–EtOAc = 100:1 to 25:1) to give 4a as a slightly
yellow solid (0.128 g, 87%). 1H NMR (300 MHz, CDCl3):
d = 1.44 (s, 9 H, Ot-Bu), 2.11 (quint, J = 7.2 Hz, 2 H, CH2),
3.21 (t, J = 7.8 Hz, 2 H, CH2), 4.17 (t, J = 6.9 Hz, 2 H,
OCH2), 7.20–7.34 (m, 5 H, Ph). 13C NMR (75 MHz, CDCl3):
d = 24.36 (CH2), 28.46 (CH3), 31.74 (CH2), 71.92 (C-5),
79.83 (C), 106.37 (C=C-O), 126.35, 127.60, 130.60 (CH,
Ph), 136.18 (C, Ph), 167.92 (O=C-O), 170.73 (O-C=O). IR
(neat): n = 3079 (w), 2974 (m), 2921 (w), 2907 (w, C-H),
1687 (s, C=C-O), 1608 (s, C=C-C=O), 1492 (m), 1474 (m),
1452 (m), 1420 (w), 1384 (m), 1368 (m), 1321 (m), 1301
(m), 1269 (m), 1251 (m), 1231 (m), 1157 (s), 1113 (m), 1063
(s), 1038 (s), 956 (m), 930 (m), 880 (w), 839 (m), 812 (m),
778 (m), 756 (m), 697 (m), 654 (w), 508 (w) cm–1. MS (EI,
70 eV): m/z (%) = 260 (23) [M+], 203 (100), 186 (79), 169
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(10) Typical Experimental Procedure for 3a: N-Bromo-
succinimide (0.879 g, 4.9 mmol) was added to a CCl4
solution (40 mL) of 2a (0.700 g, 3.8 mmol) at r.t. The
reaction mixture was stirred under reflux for 3 h. The
reaction mixture was allowed to cool to r.t. and Et2O (20 mL)
was added. The solution was filtered and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane–EtOAc, 100:1 to 1:1)
to give 3a as a colorless solid (0.732 g, 73%). 1H NMR (300
MHz, CDCl3): d = 1.51 (s, 9 H, Ot-Bu), 2.21 (quint, J = 7.2
Hz, 2 H, CH2), 3.13 (t, J = 7.8 Hz, 2 H, CH2), 4.37 (t, J = 7.2
Hz, 2 H, OCH2). 13C NMR (150 MHz, CDCl3): d = 25.10
(CH2), 28.46 (CH3), 32.54 (CH2), 72.83 (C-5), 81.65 (C),
85.80 (Br-C=C), 163.38 (O=C-O), 170.80 (O-C=C). IR
(KBr): n = 2975 (w, C-H), 1694 (s, C=C-O), 1613 (s, C=C-
C=O), 1370 (m), 1295 (s), 1250 (w), 1243 (w), 1210 (m),
1170 (s), 1067 (s), 1039 (w), 1023 (w), 955 (w), 934 (w), 864
(4), 157 (1). The exact molecular mass m/z = 260.1412
mD [M+] for C16H20O3 was confirmed by HRMS (EI, 70
eV).
2
(12) Akermark, B. Acta Chem. Scand. 1961, 15, 1695.
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Synlett 2004, No. 12, 2169–2171 © Thieme Stuttgart · New York