Novel three-component reactions based on a heck carbopalladation/ cyclization domino reaction

Article abstract of DOI:10.1002/anie.200461134

In one fell swoop: the reaction of alkynyl-allyl alcohols with aryl halides in the presence of [Pd(PPh₃)₂Cl₂] under Heck reaction conditions provides cyclic γ,δ-enals (see scheme). This reaction serves as the starting sequ

Full text of DOI:10.1002/anie.200461134

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One-Pot Syntheses
icals, catalysts, and even novel molecule-based materials.
Therefore, mastering unusual combinations of elementary
organic reactions is a major conceptual challenge in engineer-
ing novel types of sequences. As part of our program directed
toward developing new one-pot sequences and domino
processes based upon transition-metal-catalyzed in situ acti-
vation of alkynes by cross coupling[6] or cycloisomerization,[7]
we report herein on the first Heck carbopalladation/cycliza-
tion sequence of ynallyl alcohols and aryl halides to give g,d-
enals. Two novel consecutive three-component reactions
initiated by this new domino reaction serve as illustrations.
Although intramolecular Heck reactions[8] have a broad
range of applications culminating in domino sequences like
the impressive Negishi zipper reactions,[1a] and since the use of
enynes as relays for Heck carbopalladation/cyclization
sequences has been thoroughly studied,[9,10] the transforma-
tion of ynallyl alcohols that could furnish g,d-enals has
remained unexplored to date. However, the generation of an
aldehyde functionality en route could enormously enhance
the degree of molecular diversity possible in multicomponent
reactions.
Novel Three-Component Reactions Based on a
Heck Carbopalladation/Cyclization Domino
Reaction**
Christoph J. Kressierer and Thomas J. J. Müller*
Dedicated to Professor Armin de Meijere
on the occasion of his 65th birthday
Palladium-catalyzed domino reactions based on sequences of
insertions of organopalladium species into multiple bonds
(carbopalladation) have fundamentally revolutionized syn-
thetic concepts for the formation of carbo- and heterocyclic
systems.[1,2] These transformations proceed under exception-
ally mild reaction conditions and are highly compatible with
polar functional groups. Conceptually, multicomponent reac-
tions[3] initiated by palladium-catalyzed carbon–carbon bond-
forming reactions[2,4] address very fundamental principles of
synthetic efficiency and reaction design and, therefore, they
have recently attracted considerable and steadily increasing
academic, economic, and ecological interest. Besides, the
prospect of extending one-pot reactions for combinatorial
and solid-phase applications[3c,5] promises manifold opportu-
nities for developing novel lead structures for pharmaceut-
The reaction of alkynylallyl alcohols 1[11] and aryl halides 2
in the presence of 2 mol% of [Pd(PPh3)2Cl2] in boiling
triethylamine under Heck reaction conditions furnished the
cyclized g,d-enals 3 (the tetrahydrofuran derivatives 3a–i and
chromane derivatives 3k–m) in moderate to good yields
(Scheme 1, Table 1).[12]
Scheme 1. The palladium-catalyzed Heck carbopalladation/cyclization sequence for the conversion of ynallyl alcohols 1 into g,d-enals 3.
The structures of the ethylidenetetrahydrofuranyl and
ethylidenechromanyl acetaldehydes 3 were supported unam-
biguously by spectroscopic analyses (1H, 13C and DEPT,
COSY, NOESY, HETCOR, and HMBC NMR experiments,
IR, UV/Vis, mass spectrometry). The configuration of the
tetrasubstituted double bonds can be deduced unequivocally
from the appearance of significant cross peaks (between the
signals of the exocyclic trimethylsilyl, methyl, and methylene
substituents and endocyclic methylene proton resonances in
a-position to the ether bridge) in the NOESY spectra.
[*] Dipl.-Chem. C. J. Kressierer, Prof. Dr. T. J. J. Müller
Organisch-Chemisches Institut
Ruprecht-Karls-Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-546-579
E-mail: thomas_j.j.mueller@urz.uni-heidelberg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623), the Fonds der Chemischen Industrie, and the Dr.-Otto-
Röhm Gedächtnisstiftung is gratefully acknowledged. The authors
also cordially thank the BASF AG for the generous donation of
chemicals.
Angew. Chem. Int. Ed. 2004, 43, 5997 –6000
DOI: 10.1002/anie.200461134
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5997

Communications
Table 1: Palladium-catalyzed Heck carbopalladation/cyclization of ynallyl alcohols 1 to give g,d-enals 3.[a]
Entry
Ynallyl alcohol 1
Aryl halide 2
t [h]
g,d-Enal 3
Yield [%][b]
1
5
65
2
1a
1a
1a
1a
1a
2.5
5
85
86
76
66
85
3
4
2
5
15
6[c]
0.5
7
2c
2c
4.5
47
29
8[d]
24
9[d]
2c
2a
28
26
58
10
6
11
12
1e
1e
2b
2c
5
6
60
65
For footnotes, see next page.
8
8
8

Angewandte
Chemie
This new palladium-catalyzed domino reaction has prece-
dence in its elementary steps, such as intramolecular insertion
of tethered alkynes and alkenes,[1a] and the Heck reaction of
allyl alcohols to furnish 3-arylpropanals,[13] and can therefore
be rationalized as follows (Scheme 1): After the oxidative
addition of the aryl halide 2 to the in situ generated Pd0
species, the arylpalladium halide 4 coordinates and the triple
bond of the ynallyl alcohol 1 is inserted by means of a syn
carbopalladation to furnish the vinylpalladium species 5 in a
stereospecific fashion. Coordination and cyclizing insertion of
the allyl alcohol fragment generates the alkylpalladium
species 6 which then undergoes a b-hydride elimination to
give the dienol 7. Instantaneously tautomerization of 7 gives
the enal product 3, and the hydridopalladium halide species 8,
which reductively eliminates hydrogen halide with base
assistance to regenerate the Pd0 species. After the oxidative
addition of 2 the catalytic cycle starts again. Interestingly, the
reaction with the trimethylsilyl-substituted alkynylallyl alco-
hol 1a gives considerably higher yields (Table 1, entries 1–6
and entries 7–9). The rigidified phenylene-bridged ynallyl
alcohol 1e readily participates in the sequence furnishing
chromanylacetaldehyde derivatives in reasonable yields
(entries 10–12). Since the Heck carbopalladation/cyclization
sequence is considerably hampered with electron-deficient
aryl halides—as reflected by either the longer reaction times
or, alternatively, microwave irradiation to achieve complete
conversion (entries 5 and 6)—the arylpalladium species
exerts a strong electronic effect in the carbopalladation step.
This new Heck carbopalladation/cyclization domino
sequence of alkynylallyl alcohols to give g,d-enals forms the
basis for sequential one-pot three-component reactions that
are compatible with the mild reaction conditions of the initial
Pd-catalyzed process. The newly formed aldehyde function-
ality is perfectly suited for a subsequent Wittig olefination.
Thus, the reaction of alkynylallyl alcohols 1a and 1e with the
aryl halides 2 in the presence of a catalytic amount of
[Pd(PPh3)2Cl2] in boiling triethylamine followed by addition
of a stabilized phosphorus ylide of type 9 at room temperature
furnishes the 2,3,6,7-diene esters 10 in moderate to good
yields (Scheme 2).[12]
Scheme 2. The palladium-catalyzed Heck carbopalladation/cyclization/
Wittig sequence giving 2,3,6,7-diene carbonyl compounds 10.
Scheme 3. The palladium-catalyzed Heck carbopalladation/cyclization/
reductive amination sequence yielding b-ethylaminobenzylidene tetra-
hydrofurans 12.
process was readily elaborated into two consecutive one-pot
three-component sequences in which a Heck carbopallada-
tion/cyclization/Wittig sequence and a Heck carbopallada-
tion/cyclization/reductive amination sequence give rise to
heterocyclic 2,3,6,7-diene esters and b-aminoethylalkylidene-
tetrahydrofurans, respectively. Studies addressing the scope
of these novel sequences and related sequential transforma-
tions to enhance molecular diversity in pharmaceutically
interesting targets are currently under investigation.
Additionally, upon reducing the amount of triethylamine
to only two equivalents, the new Heck carbopalladation/
cyclization sequence can serve as an entry for a subsequent
reductive amination under Leuckart–Wallach conditions[14] in
a sequential one-pot reaction. Thus, the reaction of alkynyl-
allyl alcohol 1a in the presence of a catalytic amount of
[Pd(PPh3)2Cl2] and 2 equivof triethylamine in boiling 1,2-
dichloroethane followed by addition of various secondary
amines 11 and formic acid at 608C results in the formation of
b-aminoethylalkylidenetetrahydrofurans 12 in moderate to
excellent yields (Scheme 3).[12]
Experimental Section
Heck carbopalladation/cyclization sequence (3b): In a 50-mL screw-
top pressure vessel [Pd(PPh3)2Cl2] (15 mg, 0.02 mmol) was dissolved
in degassed triethylamine (10 mL). Then, 1a (198 mg, 1.00 mmol) and
2b (240 mg, 1.10 mmol) were added successively to the solution. The
In conclusion, we have developed a Heck carbopallada-
tion/cyclization domino reaction starting from ynallyl alco-
hols 1 and aryl halides to give g,d-enals 3. This new domino
Table 1: [a] Reaction conditions: 1.0 equiv ynallyl alcohol 1, 1.1 equiv aryl halide 2 (0.1m in triethylamine), and 0.02 equiv [Pd(PPh3)2Cl2] were heated at
reflux for 2–28 h. [b] Yields refer to yields of isolated compounds 3 after flash chromatography on silica gel; purity was estimated to be ꢀ95% by NMR
spectroscopy and elemental analysis and/or HRMS. [c] The reaction was performed in a microwave oven (0.50 mmol 1a, 0.55 mmol 2 f, 2 mol%
[Pd(PPh3)2Cl2]; heating rate: 160 s with 300 W to 1508C, 30 min of reaction time at 1508C, cooling rate: 240 s to 458C). [d] [Pd(PPh3)4] as a catalyst.
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reaction mixture was heated at reflux for 2.5 h then allowed to cool to
329.2167; Elemental analysis calcd for C20H31NOSi (329.56): C 72.89,
H 9.48, N 4.25; found: C 73.36, H 9.71, N 3.91.
room temperature before diethyl ether (150 mL) was added, and the
resulting precipitate was filtered. The solvents were removed from the
filtrate in vacuo, and the residue was flash chromatographed on silica
gel to give analytically pure 3b (239 mg, 85% yield) as a pale yellow
oil, Rf = 0.59 (hexane/diethyl ether 1:1). 1H NMR (CDCl3, 500 MHz):
d = À0.17 (s, 9H), 2.34 (s, 3H), 2.50–2.55 (m, 1H), 2.76–2.81 (m, 1H),
2.93 (ddd, J = 1.6, 9.7, 17.8 Hz, 1H), 3.68–3.72 (m, 1H), 3.81 (dd, J =
1.6, 11.3 Hz, 1H), 4.08 (d, J = 17.1 Hz, 1H), 4.20 (dd, J = 2.3, 17.2 Hz,
1H), 6.97–7.01 (m, 2H), 7.10–7.14 (m, 2H), 9.86–9.87 ppm (m, 1H);
13C NMR (CDCl3, 125.8 MHz): d = 0.2 (CH3), 21.1 (CH3), 31.2 (CH),
46.8 (CH2), 67.3 (CH2), 70.6 (CH2), 128.5 (CH), 128.7 (CH), 133.8
(Cquat.), 137.2 (Cquat.), 137.4 (Cquat.), 149.5 (Cquat.), 201.5 ppm (CH);
HRMS calcd for C17H24O2Si: 288.1546, found: 288.1543; Elemental
analysis calcd for C17H24O2Si (288.5): C 70.78, H 8.39; found: C 70.61,
H 8.43.
Heck carbopalladation/cyclization/Wittig sequence (10b): In a
50-mL screw-top pressure vessel [Pd(PPh3)2Cl2] (14 mg, 0.02 mmol)
was dissolved in degassed triethylamine (10 mL). Then, 1a (198 mg,
1.00 mmol) and 2b (241 mg, 1.10 mmol) were added successively to
the solution. The reaction mixture was heated at reflux for 2.5 h then
allowed to cool to room temperature before THF (5 mL) and 9
(523 mg, 1.50 mmol) were added successively, and the reaction
mixture was stirred at room temperature for 18 h. The precipitates
were removed by filtration, the solvents were removed from the
filtrate in vacuo, and the residue was flash chromatographed on silica
gel to give the analytically pure 10b (301 mg, 86%) as a yellow oil,
Rf = 0.72 (hexane/diethyl ether 1:1). 1H NMR (CDCl3, 250 MHz): d =
À0.16 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H), 2.23–2.61 (m, 6H), 3.58–3.66
(m, 1H), 3.81 (dd, J = 1.9, 11.2 Hz, 1H), 4.02–4.26 (m, 4H), 5.92 (dt,
J = 1.4, 15.6 Hz, 1H), 6.91–7.15 ppm (m, 5H); 13C NMR (CDCl3,
75.5 MHz): d = 0.4 (CH3), 14.2 (CH3), 21.1 (CH3), 35.2 (CH2), 36.0
(CH), 60.1 (CH2), 66.0 (CH2), 70.5 (CH2), 122.8 (CH), 128.6 (CH),
128.7 (CH), 134.5 (Cquat.), 137.1 (Cquat.), 137.6 (Cquat.), 147.1 (CH),
149.2 (Cquat.), 166.4 ppm (Cquat.); HRMS calcd for C21H30O3Si:
358.1964, found: 358.1950; Elemental analysis calcd for C21H30O3Si
(358.6): C 70.35, H 8.43; found: C 70.31, H 8.42.
Heck carbopalladation/cyclization/reductive amination sequence
(12b): In a 50-mL screw-top pressure vessel [Pd(PPh3)2Cl2] (28 mg,
0.04 mmol) was dissolved in a mixture of degassed 1,2-dichloroethane
(10 mL) and triethylamine (202 mg, 2.00 mmol). Then, 1a (198 mg,
1.00 mmol) and 2c (240 mg, 1.10 mmol) were added successively to
the solution. The reaction mixture was heated at reflux for 3 h then
allowed to cool to room temperature before formic acid (552 mg,
12.0 mmol) and pyrrolidine (11b) (356 mg, 5.00 mmol) were added
successively, and the reaction mixture was heated to 608C for 12 h.
The reaction mixture was allowed to cool to room temperature,
diethyl ether (150 mL) and anhydrous potassium carbonate were
added, and the precipitates were removed by filtration. The solvents
were removed from the filtrate in vacuo, and the residue was flash
chromatographed on basic alumina (Brockmann activity IV) to give
the analytically pure 12b (261 mg, 79%) as a yellow-red oil, Rf = 0.31
(hexane/diethyl ether 1:2). 1H NMR (CDCl3, 500 MHz): d = À0.22 (s,
9H), 1.67–1.85 (m, 6H), 2.09–2.18 (m, 1H), 2.42–2.60 (m, 6H), 3.60–
3.67 (m, 1H), 3.83 (dd, J = 2.2, 11.0 Hz, 1H), 4.04 (d, J = 16.9 Hz, 1H),
4.20 (dd, J = 2.2, 16.9 Hz, 1H), 7.04–7.11 (m, 2H), 7.20–7.30 ppm (m,
3H); 13C NMR (CDCl3, 125.8 MHz): d = 0.4 (CH3), 23.4 (CH2), 31.5
(CH2), 35.3 (CH), 54.3 (CH2), 54.9 (CH2), 66.8 (CH2), 70.4 (CH2),
127.2 (CH), 127.9 (CH), 128.8 (CH), 135.8 (Cquat.), 141.0 (Cquat.),
148.2 ppm (Cquat.); HRMS calcd for C20H31NOSi: 329.2175, found:
Received: June 30, 2004
À
Keywords: amination · C C coupling · domino reactions ·
multicomponent reactions · olefination
.
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6000 ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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