Palladium catalysts for the formylation of vinyl triflates to form α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200800994

(Chemical Equation Presented) What a gas! Synthesis gas is the formylating agent in the efficient one-step title transformation promoted by a palladium catalyst with the bidentate ligand 1,2-bis(di-1-adamantylphosphinomethyl)benzene (see scheme). This method enables the conversion of six-to eight-membered-ring triflates into α,β-unsaturated aldehydes and the introduction of a formyl group into derivatives of elaborate natural compounds. Tf = trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.200800994

Angewandte
Chemie
DOI: 10.1002/anie.200800994
Synthetic Methods
Palladium Catalysts for the Formylation of Vinyl Triflates To Form
a,b-Unsaturated Aldehydes**
Helfried Neumann, Alexey Sergeev, and Matthias Beller*
Dedicated to Professor G. Oehme on the occasion of his 70th birthday
An essential challenge for modern organic chemistry is the
efficient and direct synthesis of important functional groups
without the need for protection/deprotection steps, func-
tional-group interconversions, and harsh reaction conditions.
In this respect, a,b-unsaturated aldehydes constitute partic-
ularly interesting targets. On the one hand, they have found
numerous applications as building blocks for the synthesis of
various biologically active compounds,[1,2] polymers,[3] fra-
grances,[4] feed additives,[5] and other compounds. On the
other hand, there is a need for improved and generally
applicable synthetic routes to these important building
blocks.[6] a,b-Unsaturated aldehydes are typically prepared
by oxidation of the corresponding allylic alcohols,[7] Horner–
Wadsworth–Emmons[8] and Peterson[9] olefinations, aldol
condensation, and Mannich reaction.[6,10,11]
In recent years, the transformation of vinyl triflates into
a,b-unsaturated aldehydes has become an important reaction
that is widely used in the synthesis of various natural products.
In general, this transformation is carried out in three steps,
through palladium-catalyzed alkoxycarbonylation followed
by reduction with DIBAL-H or LiAlH4 and subsequent
oxidation of the resulting alcohol to the aldehyde
(Scheme 1).[1] A more straightforward and atom-economical
(CO/H2), is not known.[16] Previously described palladium-
catalyzed formylation reactions require relatively high cata-
lyst loadings (in general 10 mol%) and the use of an additive
(LiCl).
Herein, we describe the first palladium-catalyzed syn-
thesis of a,b-unsaturated aldehydes from vinyl triflates that
makes use of synthesis gas. Recently, we developed a novel
palladium-catalyzed reductive carbonylation of aryl and
heteroaryl halides with Pd(OAc)2/cataCXium A (di(1-ada-
mantyl)-n-butylphosphine) as the catalyst system.[17,18] This
method enabled the first hydroformylation of aryl halides to
be performed on an industrial scale (> 1000 kg). On the basis
of these studies, we extended the scope of the reductive
formylation with synthesis gas to vinyl bromides.[19] However,
from a synthetic point of view, vinyl triflates are more
convenient and versatile substrates, as they can be prepared
readily from a variety of ketones.[20] In this regard, the use of
vinyl triflates as substrates for formylation reactions is
appealing.
To find a suitable palladium catalyst and establish optimal
reaction conditions, we studied the reductive carbonylation of
cyclohex-1-en-1-yl triflate (1) as a model system. Initially,
different phosphine and carbene ligands were tested. Cata-
lytic experiments were carried out in the presence of Pd-
(OAc)2 (1.5 mol%) and the corresponding monodentate
ligand (4.5 mol%) or bidentate ligand (2.25 mol%) in DMF
at 60–1008C and 20 bar of CO/H2 (1:1). Selected results are
summarized in Table 1. Unfortunately, cataCXium A, which
is an excellent ligand for the reductive carbonylation of aryl
and vinyl halides, gave only a trace amount of the desired
product (Table 1, entry 1). Instead, cyclohex-1-ene-1-carbox-
ylic anhydride was formed as the major product.[21] All other
monodentate ligands tested in this reaction were equally
inefficient (Table 1, entries 2–4).
As bidentate ligands have been employed successfully in
the past in palladium-catalyzed carbonylation reactions,[22,23]
we tested a number of chelating phosphines (Table 1,
entries 5–16). The use of bidentate ligands with diphenyl-
phosphino substituents led to an increase in the yield of the
cyclohexenecarbaldehyde to up to 21%. However, the best
results were observed when diphosphine ligands with bulky
alkyl substituents were used (Table 1, entries 13–16). To
explore more thoroughly the potential of bulky bidentate
phosphine ligands in the model reaction, we also synthesized
new chelating ligands with di-1-adamantylphosphino moieties
attached to various backbones (Scheme 2). There were two
reasons for our decision to use adamantyl substituents: First,
the adamantyl group is a very bulky substituent, even more
Scheme 1. Typical synthesis of an a,b-unsaturated aldehyde froma
vinyl triflate. Tf=trifluoromethanesulfonyl.
approach to a,b-unsaturated aldehydes is the one-step
reductive carbonylation of vinyl triflates. Although the use
of tin[12,13] and silyl[14,15] hydrides has been described, to the
best of our knowledge reductive formylation with the simplest
and most environmentally benign formyl source, synthesis gas
[*] Dr. H. Neumann, Dr. A. Sergeev, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V., Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
[**] This research was supported by the State of Mecklenburg-Vor-
pommern, the BMBF, the DFG (Leibniz Prize), and the Fonds der
Chemischen Industrie (FCI). We thank Dr. W. Baumann and S.
Giertz (LIKAT) for their excellent analytical and technical support.
Angew. Chem. Int. Ed. 2008, 47, 4887 –4891
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Communications
Table 1: Variation of ligands in the model reaction.[a]
Entry
Ligand[b]
T [8C]
Conversion [%][c]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
cataCXiumA
PPh3
IPr2·HCl
IMes·HCl
dppf
80
100
100
100
80
80
80
80
80
80
80
80
80
60
80
100
60
80
100
98
90
94
100
61
60
81
100
40
99
91
100
50
100
100
34
100
100
100
5
4
1
2
3
14
18
21
11
7
dppe
dppp
dppb
diop
binap
xantphos
dppx
5
0
12
74
29
73
65
27
85
67
0
Scheme 2. Synthesis of novel bidentate phosphines: a) nBuLi, TMEDA,
tBuONa, heptane, 658C, 1 h (for A, B); nBuLi, TMEDA, Et2O, room
temperature, 16 h (for C); b) (1-Ad)2PCl in THF, À308C, 20 min, then
roomtemperature, 12 h; c) (1-Ad) 2PH, EtOH, 808C, 30 min; e) Et3N,
roomtemperature, 16 h. Ad =adamantyl, TMEDA=N,N,N’,N’-tetra-
methylethylenediamine.
dtbpx[e]
josiphos
josiphos
josiphos
A
A
A
B
C
100
80
80
backbone, afforded the desired aldehyde in 85% yield
(Table 1, entry 18). Comparison of the efficiency of ligand
A with that of its known tert-butyl analogue dtbpx and
josiphos reveals a distinct advantage of ligand A (Table 1,
entries 13 and 18, 15 and 18, respectively). To further optimize
the reaction conditions, we also studied the effect of the
reaction temperature. Optimal yields were observed when the
reactions were carried out at 808C (Table 1, entries 14–19). At
a lower temperature, conversion was incomplete, and at
1008C the yields decreased, presumably as a result of
decomposition of the starting material. We studied the
effect of different bases on the reaction with a combination
of Pd(OAc)2 and ligand A as the precatalyst at 808C. Pyridine
was found to be the most efficient base, whereas the use of
TMEDA, NEt3, and NEtiPr2 led to lower yields, and the
inorganic base potassium carbonate was inactive.
0
[a] Reaction conditions: Vinyl triflate (0.5 mmol), pyridine (0.75 mmol),
diglyme (0.35 mmol; internal standard for GC), Pd(OAc)2 (1.5 mol%),
monodentate (4.5 mol%) or bidentate ligand (2.25 mol%), DMF
(2 mL), CO/H2 (1:1; 20 bar), 60–1008C, 16 h. [b] IPr2·HCl=1,3-diiso-
propyl-4,5-dihydroimidazolium chloride, IMes·HCl=1,3-bis(2,4,6-trime-
thylphenyl)imidazolium chloride, dppf=1,1’-bis(diphenylphosphino)fer-
rocene, dppe=1,2-bis(diphenylphosphino)ethane, dppp=1,3-bis(di-
phenylphosphino)propane, dppb=1,4-bis(diphenylphosphino)butane,
diop=O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)bu-
tane, binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, xantphos=
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, dppx=a,a’-bis(di-
phenylphosphino)-o-xylene, dtbpx=a,a’-bis(di-tert-butylphosphino)-o-
xylene, josiphos=1-[2-(diphenylphosphino)ferrocenyl]ethyldicyclohexyl-
phosphine. [c] Yield and conversion were determined by GC. DMF=
N,N-dimethylformamide.
Next, different vinyl triflates were formylated with syn-
thesis gas under the optimized conditions (Table 2). The
reaction was applied successfully to cycloalkenyl triflates with
six-, seven-, and eight-membered rings (Table 2, entries 1–3).
These nonfunctionalized triflates were converted smoothly
into the corresponding aldehydes in high yields (85–87%). In
contrast, the reaction of cyclopent-1-en-1-yl triflate gave the
desired product in low yield. An analogous five-membered-
ring triflate was also found to be a poor substrate for Bu3SnH-
mediated formylation.[13]
As the introduction of a formyl group into six-membered-
ring compounds is of considerable importance in organic
synthesis,[1,15] we focused our attention on the reactions of
cyclohexenyl triflates with substituents at various positions.
Derivatives of cyclohexenyl triflate with substituents at the 4-
position also underwent formylation readily to give the
corresponding aldehydes in high yields (Table 2, entries 4
and 5). However, the cis-3,5-disubstituted cyclohexenyl
triflate 6 is somewhat less reactive (Table 2, entry 6). The
sterically encumbered substrates 7–9 were also converted into
sterically hindered than the tert-butyl group, and second,
phosphines containing two adamantyl groups are air-stable
solids which can be handled conveniently and even exposed to
air for a short period of time.[24] The new ligands A–C were
prepared in a one-pot procedure that involved the a metala-
tion of a dimethylarene and subsequent treatment with
Ad2PCl.[25] The resulting phosphines precipitated directly
from the reaction mixture and were isolated readily by
filtration after quenching the reaction mixture with water. For
the synthesis of ligand D, Ad2PH was alkylated with a,a’-
dibromo-meta-xylene followed by treatment with a base.[26]
Interestingly, pronounced differences were observed in
the formylation reaction with the novel ligands, in terms of
both efficiency and selectivity. The use of the meta-xylene-
related ligands C and D resulted in very low conversion
(<5%), whereas complete conversion was observed with
ligand B; however, none of the desired aldehyde was
detected. In sharp contrast to the reactions with ligands B
and C, the reaction with ligand A, which has an ortho-xylene
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Chemie
Table 2: Scope and limitations of the formylation of vinyl triflates with synthesis gas.[a]
Entry
1
Vinyl triflate
T [8C] Conversion [%][b] Yield [%][b] Entry
Vinyl triflate
T [8C] Conversion [%][b] Yield [%][b]
1
2
3
80
80
80
100
100
100
85
87
85
8
8
9
80
80
100
92
63
2
3
9
63[c]
10
10 120
98
42[d]
4
4
80
100
87
11
11
80
100
69[e]
5
6
5
6
80
80
99
95
72
57
12
13
12
13
80
80
100
100
trace
51[c]
7
7
80
97
61
[a] Reaction conditions: Vinyl triflate (0.5 mmol), pyridine (0.75 mmol), diglyme (0.35 mmol; internal standard for GC), Pd(OAc)2 (1.5 mol%), ligand
A (2.25 mol%), DMF (2 mL), CO/H2 (1:1; 20 bar), 80 or 1208C, 16 h. [b] Yields and conversions were determined by GC. [c] The response factor of the
starting triflate was used to calculate the yield. [d] Reaction time: 8 h. [e] Yield of the isolated product.
the corresponding aldehydes (Table 2, entries 7–9). The same
Experimental Section
Triflates[28] and di(1-adamantyl)chlorophosphine[29] were prepared
according to literature procedures.
was true for the bulky spiro compound 10, although in this
case a higher temperature (1208C) was required for full
conversion (Table 2, entry 10). The formylation procedure
can be applied to even more complex substrates, such as
cholest-3-en-3-yl triflate (11; Table 2, entry 11). The triflate 11
reacted under standard conditions to afford the correspond-
ing unsaturated aldehyde in 69% yield. As the application of
heterocyclic triflates as coupling partners in palladium-
catalyzed reactions is scarcely described in literature,[27] we
also tested the two heterocyclic triflates 12 and 13 in the
formylation reaction. Whereas the reaction of the nitrogen-
containing substrate 12 gave only a trace amount of the
desired aldehyde, that of the corresponding dihydropyranyl
substrate 13 afforded the product in 51% yield (Table 2,
entries 12and 13).
In summary, we have described the palladium-catalyzed
formylation of cyclic vinyl triflates with synthesis gas. A novel
catalytic system comprising the bidentate ligand A enables
the efficient transformation of various six-, seven-, and eight-
membered-ring triflates into the corresponding a,b-unsatu-
rated aldehydes. This method can be used to introduce a
formyl group into derivatives of elaborate natural com-
pounds, as illustrated by the formylation of (+)-cholest-3-en-
3-yl triflate. The novel bidentate ligands should also be useful
for a variety of other coupling reactions.
Synthesis of A: tBuONa (575 mg, 6 mmol) and a magnetic stir bar
were placed in a 50 mL Schlenk flask, which was then sealed with a
septum cap, evacuated, and filled with argon. Heptane (6 mL),
TMEDA (0.91 mL, 747 mg, 6.4 mmol), and ortho-xylene (245 mL,
212 mg, 2 mmol) were added to the flask with syringes. A solution of
nBuLi (2.5m in hexanes; 2.4 mL, 6 mmol) was then added dropwise
with stirring, and the reaction mixture was heated at 658C for 1 h and
then cooled to room temperature. A red precipitate was filtered,
washed with heptane (3 ” 3 mL), and suspended in heptane (11 mL).
The reaction flask was cooled to À308C, and a solution of di(1-
adamantyl)chlorophosphine (1.42g, 4.2mmol) in THF (8 mL) was
added dropwise over 10 min. The reaction mixture was then allowed
to warm to room temperature and was stirred overnight. The mixture
was quenched with degassed distilled water (10 mL), and the resulting
precipitate was filtered and washed with water (2” 6 mL) and
methanol (3 ” 8 mL) to give crude A (1.05 g, 74%) as an off-white
solid. The crude compound was of high purity according to NMR
spectroscopy, but contained a tiny amount of an insoluble material. It
was purified by precipitation with methanol from a saturated solution
in dichloromethane to give A (0.93 g, 65%) as white crystals. M.p.:
229–2308C; 1H NMR (300 MHz, CDCl3, 2 48C): d = 7.62–7.49 (m, 2H,
2
À
À
CAr H), 7.10–6.98 (m, 2H, CAr H), 3.00 (d, JP, H = 3.3 Hz, 4H, CH2),
2.03–1.61 ppm (m, 60H, 1-Ad); 13C{1H} NMR (75 MHz, CDCl3,
248C): d = 139.3 (dd, JP, C = 3.0, 10.9 Hz, Cquat), 130.9 (d, JP, C
16.4 Hz, CH), 124.9 (d, JP, C = 1.9 Hz, CH), 41.0 (d, JP, C = 10.5 Hz,
CH2), 37.0 (CH2), 36.8 (d, JP, C = 23.3 Hz, Cquat), 28.7 (d, JP, C = 7.8 Hz,
=
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Communications
CH), 21.8 ppm (dd, JP, C = 3.8, 22.9 Hz, CH2); 31P{1H} NMR (121 MHz,
CDCl3, 2 48C): d = 26.2 ppm; HRMS (EI): m/z calcd for C48H68P2:
706.47908 [M+]; found: 706.476976; elemental analysis: calcd (%) for
C48H68P2: C 81.54, H 9.69; found: C 81.09, H 9.55.
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berg, M. Beller, Chem. Asian J. 2007, 2, 720 – 733.
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Chemicals, Wiley-Interscience, Hoboken, 2004, pp. 167 – 254.
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Flavor Materials, Wiley-VCH, Weinheim, 2001, pp. 11 – 39; b) C.
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Synthesis of (+)-cholest-3-en-3-carbaldehyde: The reaction was
carried out in a Parr Instruments 4560 series 300 mL autoclave
containing an alloy plate with wells for four 4 mL glass vials. Ligand A
(7.95 mg, 1.12” 10 À2 mmol, 2.25 mol%), 11 (259.4 mg, 0.5 mmol), and
a magnetic stir bar were placed in each of the vials, which were then
capped with a septum equipped with an inlet needle and flushed with
argon. A stock solution (2.1 mL) prepared from Pd(OAc)2 (10.2mg,
1.5 mol%), pyridine (362 mL, 4.5 mmol), and DMF (12mL) was
added to each vial with a syringe. The vials were placed in an alloy
plate, which was then placed in the autoclave. Once sealed, the
autoclave was purged several times with synthesis gas, then pressur-
ized to 20 bar at room temperature and heated at 808C for 16 h. It was
then cooled to room temperature and vented to discharge the excess
synthesis gas. The contents of the vials were combined, water (40 mL)
was added, and the product was extracted with diethyl ether (3 ”
30 mL). The extracts in diethyl ether were washed with brine, dried
over Na2SO4, and evaporated with adsorption onto silica gel. The
crude product was purified by column chromatography (eluent:
heptane) to give the title compound (550 mg, 69%) as a white solid.
M.p.: 788C; 1H NMR (300 MHz, CDCl3, 2 48C): d = 9.41 (s, 1H,
[7] G. Tojo, M. Fernµndes in Oxidation of Alcohols to Aldehydes
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=
CHO), 6.41–6.45 (m, 1H, C CH), 2.45–0.80 (m, 40H), 0.72 (s, 3H,
CH3), 0.67 ppm (s, 3H, CH3); 13C{1H} NMR (75 MHz, CDCl3, 2 48C):
[10] For an overview of synthetic methods for the synthesis of a,b-
=
=
=
d = 194.4 (C O), 155.6 (CH ),139.7 (C ), 56.4, 56.3, 53.3, 47.6, 35.8,
35.5, 28.1, 22.9, 22.6, 18.7, 12.5, 12.2 (12CH and CH3), 40.0, 39.6, 36.2,
33.1, 32.1, 28.3, 26.8, 24.2, 23.9, 21.3, 19.5 (11CH2), 42.7, 35.8 ppm
(2Cquat); IR (attenuated total reflection, neat): n˜ = 2942 (m), 1686 (vs,
=
unsaturated aldehydes through C C bond formation, see: R. C.
Larock, Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, Wiley-VCH, Weinheim, 1999,
pp. 317 – 340, and references therein.
=
C O), 1644 (w), 1462(w), 1383 (w), 1190 (w), 1069 (w), 992(w), 958
(w), 931 (w), 907 (w), 869 (w), 784 (w), 717 cmÀ1 (w); MS (70 eV): m/z
(%): 398 (100) [M+], 383 (48) [MÀCH3]+, 369 (26) [MÀCHO]+, 355
(9), 328 (15), 315 (15), 285 (33), 272 (34); elemental analysis: calcd
(%) for C28H46O: C 84.36, H 11.63; found: C 84.42, H 11.46.
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Received: February 29, 2008
Published online: May 21, 2008
Keywords: aldehydes · formylation · P ligands · palladium ·
.
vinyl triflates
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4890 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
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[25] Note added in proof: During the publication process we were
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derivatives have been patented by Lucite International WO
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