Syntheses of highly substituted furan and pyrrole derivatives via lithiated 3-aryl-1-methoxyallenes: Application to the synthesis of codonopsinine

Article abstract of DOI:10.1055/s-2006-949622

Lithiated 1-methoxy-3-phenylallenes were generated in situ from a phenyl-substituted propargylic ether. They smoothly combined with aldehydes, ketones, or imines to give allenyl adducts, which cyclized to highly substituted heterocycles either under basic

Full text of DOI:10.1055/s-2006-949622

LETTER
2383
Syntheses of Highly Substituted Furan and Pyrrole Derivatives via Lithiated
3-Aryl-1-methoxyallenes: Application to the Synthesis of Codonopsinine
S
ynthese
s
of Highly Su
o
bstituted
F
u
r
ra
n
and
s
yrrole
D
e
h
rivatives ed Alam Chowdhury, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 16 June 2006
(2) (Scheme 1). This intermediate smoothly added to var-
Abstract: Lithiated 1-methoxy-3-phenylallenes were generated in
situ from a phenyl-substituted propargylic ether. They smoothly
combined with aldehydes, ketones, or imines to give allenyl ad-
ducts, which cyclized to highly substituted heterocycles either un-
ious electrophiles 3 such as aldehydes, ketones, and imi-
nes.11 Reaction of 2 with aldehydes 3a or 3b or acetone 3c
followed by quenching with methanol furnished allenyl
der basic conditions or with silver nitrate assistance. Analogously, alcohols 4a–c. All these steps from alkyne 1 to alcohols
a dihydropyrrole derivative was obtained by the addition of anisyl-
4a–c were carried out in a one-pot fashion. Due to their
substituted lithiated methoxyallene derivative to an N-tosyl imine
moderate stability, crude primary adducts 4 were not pu-
and subsequent cyclization of the intermediate. The two diaste-
rified, however, they were sufficiently stable to carry out
reomers obtained were subsequently transformed into the alkaloid
the subsequent cyclizations. Reaction of 4a and 4b with
( )-codonopsinine and one of its epimers. The key steps of these
sequences are highly diastereoselective hydroborations of silyl enol
potassium tert-butoxide in dimethyl sulfoxide3b (Method
1) furnished cis/trans mixtures of 5a or 5b in 45% and
42% yields, respectively (Scheme 1). Similarly, 4c cy-
clized to give 3-methoxy-2,2-dimethyl-5-phenyl-2,5-di-
hydrofuran (5c) in 26% overall yield. The cyclization of
4a–c with silver nitrate in acetonitrile12 (Method 2) was
also attempted, but only complex product mixtures were
obtained in the case of allenyl alcohols 4a and 4c. Com-
pound 4b gave 5b in 32% yield (dr 15:85) under these
conditions.
ethers quantitatively leading to hydroxylated intermediates.
Key words: methoxyallene, organo lithium compounds, pyrroles,
hydroboration, alkaloids
Lithiated alkoxyallenes are versatile C-3 building blocks
in organic syntheses.1 Arens et al.2 generated the simplest
compound in this series for the first time by treating meth-
oxyallene with n-butyllithium in diethyl ether at –40 °C.
Its addition to aldehydes or ketones provided allenyl alco-
hols which were transformed into a variety of interesting
compounds.3 Trisubstituted pyrroles and trisubstituted
5,6-dihydropyridines were also synthesized by the reac-
tion of lithiated alkoxyallenes with 2-vinyloxyethyl
isothiocyanate.4 Recently, our group used lithiated
alkoxyallenes for the stereoselective preparation of syn-
thetically useful five- and six-membered heterocycles.5
As part of our continued interest in this field we generated
3-aryl-substituted lithiated 1-alkoxyallenes6 for an intend-
ed synthesis of higher substituted heterocycles. To the
best of our knowledge there are no reports on the reaction
of these allene derivatives with aldehydes, ketones, or
imines. This effort allowed us to introduce not only alkyl
groups but also aryl groups into the 5-position of pyrrole7
and furan derivatives.8 These heterocyclic compounds are
of particular interest because many biologically active
compounds contain these skeletons.9
1. n-BuLi
–78 °C, 1 h
OMe
H
OMe
Li
Ph
•
2. MeOH
3. n-BuLi
Ph
1
–78 °C, 0.5 h
2
R1
R2
–78 °C
Y
3
OMe
H
OMe
R1
R2
R1
R2
t-BuOK, DMSO
•
Ph
Y
50 °C, 1 h
Ph
HY
5
4
yield of 5 (%)
dr
Y
R1
R2
3–5
45
42
26
50 : 50
55 : 45
–
O
O
O
NPh
H
H
Me
H
Me
Ph
Me
Ph
a
b
c
d
55 (Method 2)
45 : 55
Scheme 1 Synthesis of dihydrofurans 5a–c and dihydropyrrole de-
rivative 5d starting from alkyne 1.
Treatment of methyl(3-phenylpropargyl) ether (1)10 with
one equivalent of n-butyllithium at –78 °C and addition of
one equivalent of methanol after one hour afforded 3-phe-
nyl methoxyallene. Addition of a second equivalent of n-
butyllithium, to this in situ prepared intermediate, subse-
quently afforded 1-lithiated 1-methoxy-3-phenylallene
Similarly, lithiated allene 2 added to imine 3d to furnish
the corresponding allenyl amine 4d as a mixture of diaste-
reomers. Cyclization of crude 4d using Method 2 gave
pyrrole derivative 5d in 55% yield as a mixture of diaste-
reomers (trans/cis 45:55). The two isomers were separat-
ed by fractional crystallization and (2,5-trans)-5d and
(2,5-cis)-5d were obtained in 25% and 28% yields, re-
spectively. The relative configurations of products 5 were
SYNLETT 2006, No. 15, pp 2383–2386
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-949622; Art ID: G20106ST
© Georg Thieme Verlag Stuttgart · New York

2384
M. A. Chowdhury, H.-U. Reissig
LETTER
confirmed by comparing their NMR data with those of re- 45:55).11 Fractional crystallization allowed isolation of
lated compounds (for 5d see ref. 7c).
pure (2,5-trans)-13 and (2,5-cis)-13 in 25% and 44%
yields, respectively. Subsequent reactions of these two
isomers were carried out separately. In general identical
reaction conditions were applied and the results were very
similar in both series (Schemes 3 and 4). Acid-promoted
hydrolysis of the enol ether moiety of 13 gave ketones 14
which were converted into silyl enol ethers 15 under stan-
dard conditions.
We subsequently tried the analogous reactions of electro-
philes 3 with lithiated methoxyallene derivative 6, which
bears an additional 3-methyl group. Addition of propar-
gylic ether 1 to one equivalent of n-butyllithium at –78 °C
followed by reaction with one equivalent of methyl iodide
afforded 1-methoxy-3-methyl-3-phenylallene which was
directly treated with another equivalent of n-butyllithium.
This one-pot protocol generated trisubstituted lithiated al-
lene 6, which smoothly added to benzaldehyde 3b or ace-
tone 3c to provide allenyl alcohols 7b (as a mixture of
diastereomers) or 7c (Scheme 2); these intermediates
were again cyclized without purification. Compound 7b
was transformed in 51% overall yield into 8b (diastereo-
meric mixture) by employing silver nitrate (Method 2).
Cyclization of 7c using either potassium tert-butoxide
(Method 1) or silver nitrate (Method 2) afforded pentasub-
stituted dihydrofuran derivative 8c in 74% or 84% overall
yields, respectively.
1. n-BuLi
–78 °C, 1 h
OMe
H
OMe
Li
Ar
•
2. MeOH
3. n-BuLi
Ar
9
–78 °C, 0.5 h
4-MeOC H
Ar =
6
4
10
Me
–78 °C to –20 °C
1.5 h
N
11
Tos
OMe
Me
H
OMe
Me
Tos
K2CO3, AgNO3
MeCN, r.t., 16 h
•
Ar
N
Ar
Tos
HN
12
1. n-BuLi
–78 °C, 1 h
Me
Ph
OMe
Li
OMe
(2,5-trans)-13 (25%)
•
Ph
and (2,5-cis)-13 (44%)
2. MeI
3. n-BuLi
–78 °C, 0.5 h
1
H2SO4, THF
reflux, 1 h
6
R1
R2
–78 °C
O
OTBS
1. LDA, THF,
–78 °C to 0 °C, 0.5 h
Y
3
OMe
Me
Ph
OMe
Ar
Me
Ar
Me
AgNO3, MeCN
r.t., 4 h
R1
R2
2. TBSCl, DMPU
–78 °C, 45 min
r.t., 2.5 h
Me
Ph
N
N
•
R1
R2
Tos
Y
Tos
HY
(2,5-trans)-14 (83%)
and (2,5-cis)-14 (quant.)
8
(2,5-trans)-15 (70%)
and (2,5-cis)-15 (quant.)
7
R1
H
Me
H
R2
Ph
Me
Ph
yield of 8 (%)
dr
60 : 40
–
Y
O
O
NPh
3,7,8
Scheme 3 Preparation of diastereomeric dihydropyrrole derivatives
15 starting from alkyne 9.
51
84
78
b
c
d
45 : 55
Hydroboration of the silyl enol ether moiety of isomers
15 with borane in THF installed the second hydroxyl
group in 16 with perfect stereoselectivity5e for both dia-
stereomeric series (Scheme 4). After desilylation with
TBAF to give 17 and detosylation of the nitrogen with
sodium naphthalenide14 the tetrasubstituted pyrrolidine
derivatives 18 were obtained in very good yields. Finally,
N-methylation was smoothly achieved by stirring 18 with
methyl iodide in THF at room temperature to obtain the
expected (t-3,c-4,t-5)-19, ( )-codonopsinine, and in the
second series of experiments the epimer of this alkaloid
(t-3,c-4,c-5)-19. The spectroscopic data of both isomers
are in good agreement with data reported in the litera-
ture.13c
Scheme 2 Synthesis of dihydrofurans 8b and 8c and dihydropyrrole
derivative 8d starting from alkyne 1.
Similarly, imine 3d smoothly combined with in situ gen-
erated 6 to form allenyl amine 7d, which on cyclization
with silver nitrate afforded 8d (diastereomeric mixture) in
78% overall yield (trans/cis 45:55). The mixture was sub-
jected to column chromatography which gave pure trans-
8d and cis-8d in 35% and 36% yields, respectively.
We finally applied the developed straightforward method
for the generation of highly substituted dihydropyrrole de-
rivatives to the stereoselective preparation of the alkaloid
( )-codonopsinine.13 As depicted in Scheme 3, alkyne 9
was successfully transformed into lithiated allene 10 us-
ing the sequence of steps described for the generation of
2. Addition of N-tosyl imine 11 to in situ generated 10 fur-
nished allenyl adducts 12, which on cyclization with sil-
ver nitrate in acetonitrile in the presence of potassium
carbonate afforded 13 in 78% overall yield, after column
chromatography, as a mixture of diastereomers (trans/cis
In summary, we demonstrated that disubstituted and
trisubstituted lithiated allenes can easily be generated in
situ by an appropriate sequence of reactions with 3-aryl-
substituted propargylic ethers such as 1 as precursors. Ad-
dition of the generated lithiated species to electrophiles
such as carbonyl compounds or imines provided primary
adducts which can be cyclized to highly substituted furan
Synlett 2006, No. 15, 2383–2386 © Thieme Stuttgart · New York

LETTER
Syntheses of Highly Substituted Furan and Pyrrole Derivatives
2385
(5) Selected references: (a) Hormuth, S.; Reissig, H.-U. J. Org.
Chem. 1994, 59, 67. (b) Okala Amombo, M. G.; Hausherr,
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G.; Reissig, H.-U. Eur. J. Org. Chem. 2005, 1003.
HO
OTBS
Me
1. BH3·THF, THF
–30 °C to r.t., 3 h
(2,5-trans)-15
and (2,5-cis)-15
Ar
2. H2O2, NaOH
–10 °C to r.t.
overnight
N
Tos
(t-3,c-4,t-5)-16 (quant.)
and (t-3,c-4,c-5)-16 (quant.)
TBAF, THF
15 h
0 °C to r.t.
(6) For early attempts to generate this type of allene, see:
Leroux, Y.; Mantione, R. J. Organomet. Chem. 1971, 30,
295.
HO
OH
HO
OH
Na-naph, DME
–78 °C, 1.5 h
(7) For selected recent syntheses of 2,5-disubstituted
dihydropyrroles: (a) Jones, A. D.; Knight, D. W.; Redfern,
A. L.; Gilmore, J. Tetrahedron Lett. 1999, 40, 3267.
(b) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929.
(c) Kagoshima, A.; Akiyama, T. J. Am. Chem. Soc. 2000,
122, 11741. (d) Hausherr, A. Dissertation; Freie Universität
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Angew. Chem. Int. Ed. 2002, 41, 4737; Angew. Chem. 2002,
114, 4931. (f) Donohoe, T. J.; Headley, C. E.; Cousins, R. P.
C.; Cowley, A. Org. Lett. 2003, 5, 999. (g) Morita, N.;
Krause, N. Org. Lett. 2004, 6, 4121. (h) Zhu, X.-F.; Henry,
C. E.; Kwon, O. Tetrahedron 2005, 61, 6276. (i) Dieter, R.
K.; Chen, N.; Yu, H.; Nice, L. E.; Gore, V. K. J. Org. Chem.
2005, 70, 2109. (j) Ohno, H.; Kadoh, Y.; Fujii, N.; Tanaka,
T. Org. Lett. 2006, 8, 947.
Ar
Me
Ar
Me
N
N
H
Tos
(t-3,c-4,t-5)-17 (94%)
and (t-3,c-4,c-5)-17 (97%)
(t-3,c-4,t-5)-18 (63%)
and (t-3,c-4,c-5)-18 (70%)
MeI, THF
r.t., overnight
HO
OH
HO
OH
and
Me
Me
N
N
MeO
MeO
Me
Me
(±)-codonopsinine 19 (85%)
(t-3,c-4,c-5)-19 (75%)
(8) For selected recent syntheses of 2,5-disubstituted
dihydrofurans: (a) Hoffmann-Röder, A.; Krause, N. Org.
Lett. 2001, 3, 2537. (b) Chen, J.; Song, Q.; Li, P.; Guan, H.;
Jin, X.; Xi, Z. Org. Lett. 2002, 4, 2269. (c) Ma, S.; Gao, W.
J. Org. Chem. 2002, 67, 6104. (d) Schultz-Fademrecht, C.;
Zimmermann, M.; Fröhlich, R.; Hoppe, D. Synlett 2003,
1969. (e) Berry, C. R.; Hsung, R. P.; Antoline, J. E.;
Petersen, M. E.; Challeppan, R.; Nielson, J. A.
Scheme 4 Synthesis of codonopsinine and one of its epimers.
or pyrrole derivatives. Although the overall yields are
only moderate to low in several cases the simplicity of the
method should still be attractive. A first application of our
method for the generation of highly substituted pyrroli-
dine derivatives led to a stereoselective synthesis of the al-
kaloid ( )-codonopsinine and one of its epimers. Further
applications and preparation of enantiomerically pure
compounds will be reported in due course.
J. Org. Chem. 2005, 70, 4038. (f) Buzas, A.; Istrate, F.;
Gagosz, F. Org. Lett. 2006, 8, 1957.
(9) (a) Franck, B.; Gehrken, H.-P. Angew. Chem., Int. Ed. Engl.
1980, 19, 461; Angew. Chem. 1980, 92, 484. (b) Boivin, T.
L. B. Tetrahedron 1987, 43, 3309. (c) Koert, U.; Stein, M.;
Wagner, H. Chem. Eur. J. 1997, 3, 1170. (d) Dondoni, A.;
Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002, 67,
7203. (e) Trost, B. M.; Dudash, J. Jr.; Dirat, O. Chem. Eur.
J. 2002, 8, 259. (f) Cren, S.; Gurcha, S. S.; Blake, A. J.;
Besra, G. S.; Thomas, N. R. Org. Biomol. Chem. 2004, 2,
2418. (g) Basler, B.; Brandes, S.; Spiegel, A.; Bach, T. Top.
Curr. Chem. 2005, 243, 1.
(10) Compounds such as 1 are easily prepared by Sonogashira
reactions of the corresponding propargylic ethers: Roesch,
S. K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
(11) Conversion of 9 into 13; Typical Procedure
To a solution of 1-methoxy-4-(3-methoxy-1-propynyl)ben-
zene (9; 1.20 g, 6.82 mmol) in Et2O (15 mL) n-BuLi (2.5 M
in hexane, 2.73 mL, 6.82 mmol) was added at –78 °C and
stirred for 1 h. MeOH (276 mL, 6.82 mmol) was added
slowly to the mixture and the resulting solution was warmed
with stirring to r.t. (0.5 h). The mixture was cooled again to
–78 °C and n-BuLi (2.73 mL, 6.82 mmol) was added slowly
and the resulting solution was stirred for 0.5 h. Imine 11
(1.34 g, 6.82 mmol) dissolved in Et2O (15 mL) was slowly
transferred to the reaction flask by syringe. After stirring for
1.5 h at –78 °C to –20 °C, the mixture was quenched with
H2O and the aqueous phase was extracted with Et2O (3 × 25
mL). The combined organic phases were washed with brine
(25 mL) and dried with MgSO4. Filtration and evaporation
of solvents in vacuo at r.t. afforded allenyl amine 12 (3.17 g,
Acknowledgment
Support of this work by the Alexander von Humboldt Foundation
(Research Fellowship to M. A. C.), Fonds der Chemischen Indu-
strie, and Schering AG is most gratefully acknowledged. We thank
Prof. F. A. Khan for discussions and Dr. R. Zimmer for help during
preparation of this manuscript.
References and Notes
(1) Reviews: (a) Zimmer, R.; Reissig, H.-U. Donor-Substituted
Allenes, In Modern Allene Chemistry, Vol. 1; Krause, N.;
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004, 425–
492. (b) Zimmer, R. Synthesis 1993, 165. (c) Zimmer, R.;
Khan, F. A. J. Prakt. Chem. 1996, 338, 92.
(2) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-
Bas 1968, 87, 916.
(3) (a) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1968, 87, 1179. (b) Hoff, S.; Brandsma, L.; Arens,
J. F. Recl. Trav. Chim. Pays-Bas 1969, 88, 609.
(4) Nedolya, N. A.; Brandsma, L.; Zinovéva, V. P.; Trofimov,
B. A. Russ. J. Org. Chem. 1997, 33, 80.
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2386
M. A. Chowdhury, H.-U. Reissig
LETTER
dr ca. 50:50), which was used for the subsequent cyclization
without purification. The crude product was dissolved in
anhyd MeCN (45 mL); K2CO3 (2.35 g, 17.0 mmol) followed
by AgNO3 (289 mg, 1.70 mmol) were added to the solution.
The resulting mixture was stirred for 16 h in the dark under
argon, then filtered through a pad of celite, washed with
EtOAc, and the filtrate was concentrated in vacuo at r.t. The
resulting product was purified by column chromatography
on silica gel (hexane–EtOAc, 4:1) to give 13 (1.98 g, 78%
from 9) as a mixture of diastereomers (trans/cis 45:55).
Isomers (2,5-trans)-13 (650 mg, 25%) and (2,5-cis)-13 (1.12
g, 44%) were separated by fractional crystallization.
3-Methoxy-5-(4-methoxyphenyl)-2-methyl-1-tosyl-2,5-
dihydro-1H-pyrrole (2,5-trans)-13. Colorless crystals; mp
138–140 °C. IR (KBr): 3100–3000 (=CH), 3000–2840
(CH), 1670 (C=C), 1610 (CN), 1340, 1160 (RSO2N) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.63 (d, J = 6.3 Hz, 3 H,
Me), 2.31 (s, 3 H, Ts-Me), 3.62, 3.77 (2 s, 3 H each, OMe),
4.40–4.52 (m, 2 H, 2-H, 5-H), 5.50 (dd, J = 1.9, 4.7 Hz, 1 H,
4-H), 6.55–6.65, 6.90–7.00, 7.00–7.10 (3 m, 2 H, 4 H, 2 H,
Ar). 13C NMR (126 MHz): d = 20.9, 21.4 (2 q, Me), 55.4,
57.1 (2 q, OMe), 60.2 (d, C-2), 67.5 (d, C-5), 94.6 (d, C-4),
113.3, 126.7, 128.8, 129.9 (4 d, Ar), 132.1, 138.4, 141.9,
159.4 (4 s, Ar), 157.8 (s, C-3). MS (EI, 80 eV, 30 °C):
m/z (%) = 373 (30) [M]+, 358 (13) [M – CH3]+, 266 (26)
[M – C7H7O]+, 218 (100) [M – C7H7SO2]+, 155 (40)
[C7H7SO2]+. HRMS (EI, 80 eV, 30 °C): m/z calcd for
C20H23NO4S: 373.13478; found: 373.13450. Anal. Calcd for
C20H23NO4S (373.5): C, 64.32; H, 6.21; N, 3.75. Found: C,
64.29; H, 6.32; N, 3.69.
(RSO2N) cm–1. 1H NMR (500 MHz, CDCl3): d = 1.50 (d,
J = 6.3 Hz, 3 H, Me), 2.39 (s, 3 H, Ts-Me), 3.54, 3.78 (2 s, 3
H each, OMe), 4.30–4.42 (m, 2 H, 2-H, 5-H), 5.35 (m, 1 H,
4-H), 6.80–6.90, 7.20–7.35, 7.60–7.65 (3 m, 2 H, 4 H, 2 H,
Ar). 13C NMR (126 MHz): d = 21.6, 21.8 (2 q, Me), 55.4,
57.3 (2 q, OMe), 60.3 (d, C-2), 67.2 (d, C-5), 94.0 (d, C-4),
113.8, 127.7, 128.4, 129.6 (4 d, each, Ar), 134.9, 135.5,
143.4, 159.2 (4 s, Ar), 157.3 (s, C-3). MS (EI, 80 eV, 30 °C):
m/z (%) = 373 (8) [M]+, 358 (2) [M – CH3]+, 266 (11) [M –
C7H7O]+, 218 (48) [M – C7H7SO2]+, 217 (100), 155 (9)
[C7H7SO2]+. HRMS (EI, 80 eV, 30 °C): m/z calcd for
C20H23NO4S: 373.13478; found: 373.13432.
(12) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743.
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2797.
(13) Isolation and structural determination: (a) Matkhalikova, S.
F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin.
1969, 5, 606. (b) Matkhalikova, S. F.; Malikov, V. M.;
Yunusov, S. Y. Khim. Prir. Soedin. 1969, 5, 30. Previous
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Kibayashi, C. J. Org. Chem. 1987, 52, 1956. (d) Severino,
E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039. (e) Goti,
A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.;
Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235. (f) Toyao,
A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35.
(g) Haddad, M.; Larchevêque, M. Synlett 2003, 274.
(h) Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J.
Tetrahedron Lett. 2005, 46, 3127.
(14) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org.
Chem. 1989, 54, 1548.
(2,5-cis)-13. Brownish liquid. IR (KBr): 3100–3000 (=CH),
3000–2840 (CH), 1665 (C=C), 1610 (CN), 1350, 1160
Synlett 2006, No. 15, 2383–2386 © Thieme Stuttgart · New York