A novel one-pot cycloisomerization-Wittig sequence with yne-allyl alcohols

Article abstract of DOI:10.1055/s-2004-817768

Alkyne allyl alcohols 1 are cycloisomerized under Pd catalysis to give γ,δ-enals 2 in moderate to good yields. These mild reaction conditions are fully compatible with a subsequent Wittig olefination. Thus, the cycloisomerization-Wittig olefination sequen

Full text of DOI:10.1055/s-2004-817768

LETTER
655
A Novel One-Pot Cycloisomerization-Wittig Sequence with Yne-Allyl Alcohols
O
C
ne-Pot Cycloiso
h
merization-W
r
ittig Se
i
quence
s
with
Y
ne
t
-Allyl
o
A
lcohols ph J. Kressierer, Thomas J. J. Müller*
Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)546579; E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de
Received 1 December 2003
equivalents of formic acid in dichloroethane at room tem-
Abstract: Alkyne allyl alcohols 1 are cycloisomerized under Pd
perature gives rise to the formation of the cycloisomerized
catalysis to give g,d-enals 2 in moderate to good yields. These mild
g,d-enals 2 in moderate to good yields (Scheme 2,
reaction conditions are fully compatible with a subsequent Wittig
olefination. Thus, the cycloisomerization-Wittig olefination se-
quence of yne allyl alcohols 1 and stabilized phosphorus ylides 3
furnishes 2,3,6,7-bisunsaturated carbonyl compounds 4 in moderate
to good yields in a one-pot fashion.
Table 1).7
,8
Key words: alkynes, catalysis, domino reactions, ene reactions,
Wittig reactions
Sequential one-pot transformations are economically and
ecologically highly intriguing for developing efficient
new synthetic processes. Mastering unusual combinations
of elementary organic reactions under similar conditions
is the major conceptual challenge in engineering novel
types of sequences. Transition metal catalyzed reactions Scheme 1 Palladium catalyzed cycloisomerization as an entry to
g,d-enals.
with exceptionally mild reaction conditions are of a para-
mount benefit if they can be directed in a domino fashion
generating a suitable reactive functionality en route. In
1
particular, among numerous catalytic carbon-carbon
bond-forming processes the intramolecular transition
2
,3
metal catalyzed Alder–ene reaction, i.e. the cyclo-
isomerization of a 1,6-enyne to a 1,3-diene, represents an
intriguing starting point for the development of novel se-
quential one-pot transformation. As part of our program
directed to initiate new multicomponent reactions, one-
pot sequences and domino processes based upon transi-
Scheme 2 Palladium catalyzed cycloisomerization of yne allyl
alcohols 1 to g,d-enals 2.
4
tion metal catalyzed in situ activation of alkynes, here we
communicate first palladium catalyzed cycloisomeriza-
tions of yne allyl alcohol substrates to g,d-enals and their
subsequent Wittig olefinations to give a rapid access to
structurally complex carbo- and heterocyclic 2,6-diene
carbonyl compounds.
The structures of the cycloisomerization products 2 were
1
13
unambiguously supported by H, C and DEPT, COSY,
NOESY, HETCOR and HMBC NMR experiments, IR,
UV–Vis, mass spectrometry and/or combustion analyses.
Most characteristically for the furan and cyclopentane de-
rivatives 2 bearing a stereogenic center at C4, all methyl-
Although the palladium-catalyzed cycloisomerization of
enynes has been developed to a synthetically useful meth-
1
ene protons are diastereotopic and appear in the H spectra
2
a–c,5
odology with broad scope,
the transformation of yne
as well resolved discrete signals with the dominant gemi-
nal (J = 18 Hz) and vicinal coupling constants. Character-
istically, the aldehyde methine resonances can be found
between d 9.7 and 9.9 whereas the olefinic protons of the
exocyclic double bonds can be detected between d 5.3 and
allyl alcohols furnishing g,d-enals as a consequence of the
instantaneous enol-aldehyde tautomerism of the initially
formed 1,3-dienol has remained unexplored to date
(
Scheme 1).
Therefore, we first investigated the Pd-catalyzed domino 6.3, depending on the steric and electronic nature of the
cycloisoerization-tautomerism of alkyne allyl alcohol adjacent substituent. The Z-configuration can be unam-
6
substrates. The reaction of alkyne allyl alcohols 1 in the biguously deduced from the appearance of significant
presence of a catalytic amount of Pd dba complex and 2 cross-peaks (olefinic methine signals and the methylene
2
3
proton resonances in a-position to the aldehyde) in the
NOESY spectra. Accordingly, the suggested structures
are supported by 13C NMR and mass spectra and the
molecular composition is confirmed either by HRMS or
SYNLETT 2004, No. 4, pp 0655–0658
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817768; Art ID: G33803ST
Georg Thieme Verlag Stuttgart · New York
©

6
56
C. J. Kressierer, T. J. J. Müller
LETTER
Table 1 Palladium Catalyzed Cycloisomerization of Yne Allyl
Alcohols 1 to g,d-Enals 2
dichloroethane furnishes the 2,3,6,7-bisunsaturated car-
a
bonyl compounds 4 in moderate to good yields
,9
(
Scheme 3, Table 2).8
b
Entry Yne allyl alcohol 1
Time (h) g,d-Enal 2 (yield,%)
1
1
2
1a: X = O, R = CH
18
3
2
a (41)
1
1b: X = O, R =
0.5
CH OCH3
2
2
2
2
2
2
b (65)
c (65)
d (82)
e (79)
f (76)
1
3
4
5
6
7
1c: X = O, R = Ph
1.25
1
1d: X = O, R = SiMe 0.5
3
Scheme 3 A cycloisomerization-Wittig sequence of yne allyl alco-
hols 1 to 2,3,6,7-bisunsaturated carbonyl compounds 4.
The structures of the cycloisomerization-Wittig olefina-
1e: X = C(CO Me) ,
2
1
13
2
2
tion products 4 were unambiguously supported by H, C
and DEPT, COSY, NOESY, HETCOR and HMBC NMR
experiments, IR, UV–Vis, mass spectrometry and/or com-
bustion analyses. Most characteristically for the newly
formed double bond the E-configuration can be readily as-
1
R = SiMe3
1f: X = C(CO Me) ,
1.6
6
2
2
1
1
R = Ph
signed in the H spectra by the appearance of olefinic me-
thine resonances with dominant vicinal coupling
constants (J = 18 Hz). The Z-configuration of the exo dou-
ble bond is retained under the reaction conditions and can
be deduced from the appearance of significant cross-
peaks (olefinic methine signals and the allylic methylene
proton resonances) in the NOESY spectra. As indicated
before, all methylene protons are diastereotopic and ap-
1g: X = C(CO Me) ,
R = CH OCH
2
2
1
2
3
2
g (60)
1
pear in the H spectra as well resolved discrete signals
a
Reaction conditions: 1.0 equiv of the yne allyl alcohol 1, 2 equiv
of HCOOH, 0.04 equiv of Pd (dba) ·CHCl , (0.1 M in dichloro-
with the dominant geminal (J = 18 Hz) and vicinal cou-
2
3
3
13
pling constants. Additionally, the C NMR and mass
ethane).
b
spectra support the structures of the compounds 4 and
their molecular composition is confirmed either by
HRMS or elemental analysis.
Yields refer to isolated yields of compounds 2 after flash chroma-
tography on silica gel to be ≥ 95% pure as determined by NMR
spectroscopy and elemental analysis and/or HRMS.
In conclusion, starting from a palladium-catalyzed cyclo-
isomerization of yne allyl alcohols 1 to g,d-enals 2 we
have developed a novel one-pot cycloisomerization-
Wittig olefination sequence to carbo- and heterocyclic
elemental analysis. In the IR spectra the dominant carbo-
nyl valence vibration at 1720 cm is most characteristic
for aliphatic aldehydes.
–
1
2
,3,6,7-bisunsaturated carbonyl compounds 4. Studies
addressing the scope of this novel sequence and related
sequential transformations to enhance molecular diversity
in pharmaceutically interesting targets are currently
underway and will be reported in due course.
With this facile cycloisomerization of alkyne allyl alco-
hols to g,d-enals in hand the stage is set for sequential one-
pot transformations that are compatible with the mild re-
action conditions of the initial Pd-catalyzed process. The
newly formed aldehyde functionality is perfectly suited
for a subsequent Wittig olefination in a sequential one-pot Acknowledgment
reaction. Thus, the reaction of alkyne allyl alcohols 1 in
Financial support of the Deutsche Forschungsgemeinschaft (SFB
the presence of a catalytic amount of Pd dba complex and
2
3
623), the Fonds der Chemischen Industrie and the Dr. Otto-Röhm
2
equivalents of formic acid in dichloroethane at room Gedächtnisstiftung is gratefully acknowledged. We also cordially
temperature and, after subsequent addition, with stabil- thank Stefan Knecht and Anja Reinhart for experimental assistance
and BASF AG for the generous donation of chemicals.
ized phosphorus ylides 3 at room temperature or in boiling
Synlett 2004, No. 4, 655–658 © Thieme Stuttgart · New York

LETTER
One-Pot Cycloisomerization-Wittig Sequence with Yne-Allyl Alcohols
657
Table 2 Cycloisomerization–Wittig Sequence of Yne Allyl Alco-
hols 1 and Phosphorus Ylides 3 to 2,3,6,7-Bisunsaturated Carbonyl
Compounds 4
References
a
(1) For recent excellent reviews on transition metal-assisted
sequential transformations and domino processes, see e.g.:
(a) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org.
Chem. 2003, 4101. (b) Battistuzzi, G.; Cacchi, S.; Fabrizi,
G. Eur. J. Org. Chem. 2002, 2671. (c) Negishi, E.-I.;
Copéret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996,
En-
try
Yne allyl Ylide 3
alcohol 1
Time 2,3,6,7-Bisunsaturated
(h)
carbonyl compound
b
4
(yield,%)
1
1a
3a:
R = OEt
18
96, 365. (d) Tietze, L. F. Chem. Rev. 1996, 96, 115.
2
(
2) For representative transition metal catalyzed Alder-ene
reactions, see e.g.: (a) Pd: Trost, B. M. Acc. Chem. Res.
1
990, 23, 34. (b) Pd: Trost, B. M. Janssen Chim. Acta 1991,
4
a (41)
9, 3. (c) Pd: Trost, B. M.; Krische, M. J. Synlett 1998, 1.
2
1b
3a
0.5
(
d) Ru: Trost, B. M. Chem. Ber. 1996, 129, 1313. (e) Ru:
Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739.
f) Rh: Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc.
000, 122, 6490. (g) Rh: Cao, P.; Zhang, X. Angew. Chem.
(
2
Int. Ed. 2000, 22, 4104. (h) Rh: Lei, A.; He, M.; Zhang, X.
J. Am. Chem. Soc. 2002, 124, 8198. (i) Ir: Chatani, N.;
Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J. Org. Chem.
4
4
4
4
b (51)
c (44)
d (69)
e (80)
3
4
5
6
1c
1d
1f
3a
3a
3a
1.25
0.5
2
2001, 66, 4433. (j) Ti: Sturla, S. J.; Kablaoui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976.
3) For leading reviews on Pd catalyzed cycloisomerizations,
see, e.g.: (a) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003,
(
215. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev.
2002, 102, 813.
(
4) (a) Karpov, A. S.; Rominger, F.; Müller, T. J. J. J. Org.
Chem. 2003, 68, 1503. (b) Yehia, N. A. M.; Polborn, K.;
Müller, T. J. J. Tetrahedron Lett. 2002, 43, 6907. (c)Braun,
R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297.
(
d) Müller, T. J. J.; Robert, J. P.; Schmälzlin, E.; Bräuchle,
C.; Meerholz, K. Org. Lett. 2000, 2, 2419. (e) Müller, T. J.
J.; Ansorge, M.; Aktah, D. Angew. Chem. Int. Ed. 2000, 39,
1
253.
5) (a) Trost, B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625.
b) Yamada, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
997, 38, 3027.
2
1f
3b: R =
Me
1.6
(
(
(
1
6) (a) The synthesis of yne allyl alcohol substrates were
4
4
f (67)
g (71)
performed according to: Sajiki, H.; Hirota, K. Tetrahedron
7
1g
3a
6
1998, 54, 13981. (b) The detailed protocols will be
described elsewhere.
(
7) Typical Procedure (2e, entry 5): To a solution of Pd2
(
dba) ·CHCl (31 mg, 0.03 mmol) in dichloroethane (10 mL)
3 3
were added 1e (0.312 g, 1.00 mmol) and HCOOH (92 mg,
.0 mmol). The reaction mixture was stirred at r.t. for 2 h and
2
a
Reaction conditions: 1.0 equiv of the yne allyl alcohol 1, 2 equiv
of HCOOH, 0.04 equiv of Pd (dba) ·CHCl , 1.3–1.8 equiv of ylide
then diluted with of Et O (150 mL). After filtration the
2
2
3
3
solvents were evaporated in vacuo and the residue was
chromatographed on silica gel to give 0.246 g (79%) of 2e as
a yellow oil. IR (neat): 2954 (s), 2897 (w), 2844 (w), 2724
3
(0.1 M in dichloroethane).
b
Yields refer to isolated yields of compounds 4 after flash chroma-
tography on silica gel to be ≥ 95% pure as determined by NMR
spectroscopy and elemental analysis and/or HRMS.
(
w), 1736 (s), 1626 (m), 1436 (s), 1251 (s), 1201 (s), 1165
(
7
s), 1122 (m), 1077 (m), 1026 (w), 961 (w), 866 (s), 841 (s),
–
1 1
48 (w), 693 (w) cm . H NMR (CDCl , 300 MHz): d = 0.11
3
(
s, 9 H), 1.85 (dd, J = 10.5, 13.0 Hz, 1 H), 2.48 (ddd, J = 2.0,
.2, 17.3 Hz, 1 H), 2.62–2.82 (m, 2 H), 2.91 (dt, J = 3.2, 17.0
Hz, 1 H), 2.96–3.05 (m, 1 H), 3.10 (d, J = 17.0 Hz, 1 H), 3.73
8
(
s, 3 H), 3.75 (s, 3 H), 5.30 (q, J = 2.3 Hz, 1 H), 9.79 (t, J =
1
3
1
3
5
.6 Hz, 1 H). C NMR (CDCl , 125.8 MHz): d = –0.6 (CH ),
3
3
8.9 (CH), 39.0 (CH ), 40.2 (CH ), 48.2 (CH ), 52.7 (CH ),
2
2
2
3
2.8 (CH ), 58.6 (Cquat.), 120.6 (CH), 158.7 (Cquat.), 171.7
3
(
(
Cquat.), 171.8 (C ), 201.2 (CH). EI–MS (70 eV): m/z
quat.
+
+
%) = 312 (6) [M ], 297 (9) [M – CH ], 281 (17), 270 (27),
3
2
1
5
3
52 (29), 237 (15), 225 (10), 209 (10), 193 (14), 163 (43),
+
49 (18), 137 (17), 120 (22), 89 (66), 73 (100) [Si(CH ) ],
3
3
9 (30). HRMS: m/z calcd for C H O Si: 312.1393; found:
1
5
24
5
12.1397.
Synlett 2004, No. 4, 655–658 © Thieme Stuttgart · New York

6
58
C. J. Kressierer, T. J. J. Müller
LETTER
(
8) All compounds have been fully characterized
spectroscopically and by correct elemental analysis or
HRMS.
(dd, J = 10.6, 12.9 Hz, 1 H), 2.16–2.30 (m, 1 H), 2.46–2.66
(m, 2 H), 2.77–2.93 (m, 1 H), 3.07–3.18 (m, 1 H), 3.29 (d,
J = 17.7 Hz, 1 H), 3.61 (s, 3 H), 3.64 (s, 3 H), 4.10 (q, J = 7.2
Hz, 2 H), 5.83 (d, J = 15.4 Hz, 1 H), 6.19–6.25 (m, 1 H), 6.89
(dt, J = 7.1, 15.5 Hz, 1 H), 7.07–7.16 (m, 1 H), 7.16–7.30
(9) Typical Procedure (4e, entry 5): To a solution of Pd2
dba) ·CHCl (41 mg, 0.04 mmol) dichloroethane (10 mL)
(
3
3
1
3
were added 1f (0.316 g, 1.00 mmol) and HCOOH (92 mg,
.0 mmol). The reaction mixture was stirred at r.t. for 2 h and
(m, 4 H). C NMR (CDCl , 75.5 MHz): d = 14.4 (CH ), 36.7
3
3
2
(CH ), 38.6 (CH ), 38.9 (CH ), 42.8 (CH), 52.7 (CH ), 52.8
2 2 2 3
then 3a (0.627 g, 1.80 mmol) was added. Then, the reaction
(CH ), 58.9 (C ), 60.1 (CH ), 122.8 (CH), 123.0 (CH),
3 quat. 2
mixture was stirred at r.t. for 24 h before it was diluted with
126.4 (CH), 128.2 (CH), 128.3 (CH), 137.7 (Cquat.), 143.3
(Cquat.), 146.1 (CH), 166.1 (Cquat.), 171.7 (Cquat.). UV–Vis
Et O (150 mL). After filtration the solvents were evaporated
2
in vacuo and the residue was chromatographed on silica gel
to give 0.308 g (80%) of 4e as a yellow oil. IR (Film): 2955
(CH Cl ):
(e) = 258 (18846), 286 (1135) nm. EI–MS (70
2
2
max
+
+
eV): m/z (%) = 386 (44) [M] , 355 (6) [M – H – 2CH ] , 340
(17) [M – H – 3CH ] , 280 (22), 273 (20), 241 (19), 213
(100), 181 (10), 153 (48), 91 (18). HRMS: m/z calcd for
3
+
(
(
m), 1735 (s), 1653 (m), 1492 (w), 1435 (m), 1368 (w), 1265
s), 1203 (s), 1171 (s), 1044 (m), 752 (m), 697 (m) cm . H
3
–
1 1
NMR (CDCl , 300 MHz): d = 1.20 (t, J = 7.2 Hz, 3 H), 1.76
C H O : 386.1729; found: 386.1735.
3
22 26
6
Synlett 2004, No. 4, 655–658 © Thieme Stuttgart · New York