Pd-catalyzed nucleophilic alkylation of aliphatic aldehydes with allyl alcohols: Allyl, 2-tetrahydrofuryl, and 2-tetrahydropyranyl ethers as useful C3, C4, and C5 sources

Article abstract of DOI:10.1002/anie.200351182

A combination of Pd° and Et₂Zn generates an allyl anion species from allyl alcohols which can be used for the allylation of aliphatic aldehydes to provide homoallyl alcohols in good yields (see scheme). The reaction proceeds at room temperature in poor coordination solvents, such as a mixture of toluene and n-hexane.

Full text of DOI:10.1002/anie.200351182

Communications
Allylation of Aliphatic Aldehydes
Pd-Catalyzed Nucleophilic Alkylation of
Aliphatic Aldehydes with Allyl Alcohols: Allyl,
2-Tetrahydrofuryl, and 2-Tetrahydropyranyl
Ethers as Useful C3, C4, and C5 Sources**
Masanari Kimura, Masamichi Shimizu,
Kazufumi Shibata, Minoru Tazoe, and
Yoshinao Tamaru*
The allylation of aldehydes at both the carbonyl carbon atom
and at the carbon atom a to the carbonyl group is among the
most fundamental and useful methods for elaborating mol-
ecules. These reactions, in general, have been performed by
using the activated forms of allyl alcohols, such as carboxylic
acid esters and other organic and inorganic acid esters. A
possible reason why allyl halides have been used most widely
for alkylation is because of their ready conversion into a
variety of allylmetallic species (Metal = Mg, Li, Si, Sn, etc.).
Recently, we disclosed that nucleophilic alkylation of an
aromatic aldehyde can be successfully performed by using
allyl alcohol itself. This is possible by virtue of the ability of
palladium(0) species to catalytically activate allyl alcohol as
its p-allylpalladium species in the presence of Et3B through an
allyl–ethyl exchange reaction between the p-allylpalladium
and Et3B species (Scheme 1).[1]
Scheme 1. Pd-catalyzed alkylation of aliphatic aldehydes (EtnM=Et3B
or Et2Zn). For the reaction with Et2Zn, the hydrogen atom(s) in paren-
thesis should be either ignored or replaced with Znii arisingas a result
of the hydrolysis of Et2Zn.
Unfortunately, the reaction is not applicable to aliphatic
aldehydes; aliphatic aldehydes undergo competitive nucleo-
philic and electrophilic alkylations under similar conditions.
For example, the reaction of cyclohexanecarboxaldehyde
(1a) and cinnamyl alcohol (2a) provided a mixture of 3a and
4a in almost equal amounts [Eq. 1 and Table 1, entry 1]. The
nucleophilic alkylation giving rise to 3a could be obviated by
[*] Prof. Dr. Y. Tamaru, Dr. M. Kimura, M. Shimizu, Dr. K. Shibata,
M. Tazoe
Department of Applied Chemistry
Faculty of Engineering
Nagasaki University
1–14 Bunkyo, Nagasaki 852–8521 (Japan)
Fax: (+81)95-819-2677
E-mail: tamaru@net.nagasaki-u.ac.jp
[**] We thank the Ministry of Education, Science, Sports, and Culture of
the Japanese Government for financial support.
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DOI: 10.1002/anie.200351182
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Angewandte
Chemie
diastereoselectivity found for the reactions carried out with
cinnamyl alcohol is modest and seems to depend on the steric
bulk of the alkyl chain of the aldehydes and ranges from
syn:anti = 1:18 (cyclo-C6H11CHO) to 1:2 (n-C5H11CHO). It is
worth noting that, despite in situ
formation of zinc alkoxides, no
Table 1: Effects of organometallic compounds and ligands (1a=1.1 mmol, 2a=1.0 mmol) in the Pd-
catalyzed ambiphilic allylation of aliphatic aldehydes with allyl alcohols.
aldol-, Cannizzaro-, or Tisch-
chenko-type products were
RM[a]
(equiv)
Phosphane
(equiv)
Solvent
(mL)
Time
[h]
% isolated
detected at all in these reactions.
We envisaged that the reaction
conditions that were successful for
the activation of allyl alcohols
should be applicable to the activa-
tion of allyl ethers because an ether
group is a much better leaving
Entry
3a[b]
4a
1
2
3
4
5
Et3B (2.4)
Et2Zn (3.6)
Et2Zn (3.6)
Et2Zn (3.6)
Et2Zn (3.6)
PPh3 (0.2)
PPh3 (0.2)
PBu3 (0.2)
PBu3 (0.2)
PBu3 (0.4)
THF (5.0)
THF (5.0)
THF (5.0)
tol[e] (0.5)
tol[e] (0.5)
4
30[d]
10
30
6
39
18
53
79
75
30[c]
0
0
0[c]
0
group than
a
hydroxy group.[4]
[a] A 1m solution of Et2Zn or Et3B in n-hexane was used. [b] syn:anti=1:14 to ca. 1:18. [c] 1,4-Diphenyl-
1,5-hexadiene was obtained in 20% (entry 1) and 3% yields (entry 3). [d] 45% Conversion. tol=toluene.
Indeed, allyl 2-tetrahydrofuryl
(THF) ethers 5 and allyl 2-tetrahy-
dropyranyl (THP) ethers 6[5] turned
using LiCl and Et3N as additives. This resulted in the selective
a-alkylation of aliphatic aldehydes to give 4a.[2]
Here we report that nucleophilic alkylation of aliphatic
aldehydes with allyl alcohols proceeds selectively just by
substituting Et3B for Et2Zn.[3]
out to readily effect nucleophilic allylation of w-formylalka-
nolates formed in situ to furnish 1,4-dihydroxy-6-heptenes 7
and 1,5-dihydroxy-7-octenes 8, respectively, in excellent
yields (Table 2).[6] Except for highly branched allylic sub-
strates, most of the reactions were completed within a few
hours at room temperature.
The regioselectivity is in accord with that displayed by
structurally fluctuant allylmetallic species of main-group
elements, which give rise exclusively to the most highly
branched isomers. In particular, the clean transformation of
6e to 8e and 6 f to 8 f is notable. These observations suggest
that allylzinc species are reactive intermediates in these
reactions. However, the poor stereoselectivity of 8d (Table 2,
entry 6) is quite different from that reported previously by us;
the allylation of aldehydes by umpolung of 1,3-dimethylallyl
benzoates provides Z-anti adducts exclusively.[7]
Our working hypothesis (Scheme 1)[2] suggested that
organometallic species of higher migratory aptitude might
promote the allyl–alkyl exchange process more readily and
hence facilitate generation of an allylmetal species. Accord-
ingly, we reexamined the reaction of 1a and 2a (Table 1)
using Et2Zn in place of Et3B. As was expected, 4a was not
produced at all; however, the reaction was very sluggish and
provided the expected 3a, albeit in low yield (Table 1,
entry 2). Application of nBu3P, in place of Ph3P, dramatically
increased the yield of 3a and the reaction rate (entry 3,
Table 1). Interestingly, nonpolar solvents seem to give the
best results (Table 1, entries 4 and 5). The solvent system in
these reactions is rather unique: it consists of toluene
(0.5 mL) and n-hexane (3.6 mL) for a 1 mmol scale reaction.
The amount of toluene is set to make the initial reaction
mixture homogeneous at 08C (Scheme 2, see also the
Experimental Section).
We thus examined the reaction of 6d in the presence of
three equivalents of benzaldehyde under otherwise identical
conditions and found that (Z)-anti-2-methyl-1-phenyl-3-pen-
tenol (3 f) was produced exclusively in excellent yield [Eq. 2].
The utility and generality of the present nucleophilic
alkylation of aliphatic aldehydes with allyl alcohols are
apparent from the results summarized in Scheme 2. The
This result clearly indicates that allylzinc species generated
from different sources (benzoate and 6d) are identical and
react with benzaldehyde via a transition state II (Scheme 3).
The methyl group a to the Zn atom occupies a quasi-axial
position in this six-membered chairlike transition state so as
to minimize the steric repulsion with the two ligands on the
Znii center. Thus, a quasi-equatorial conformation of the
methyl group g to the Znii center is rendered the most likely
one.[8]
The poor stereoselectivity of 8d may be attributed to the
formation of a cyclic zinc w-formylalkanolate species through
coordination of the aldehyde oxygen atom to the Znii center,
which makes approach of the aldehyde with its substituent in
Scheme 2. Nucleophilic allylation of aliphatic aldehydes undertaken
usingconditions A (Table 1, entry 3) and/or B (Table 1, entry 5).
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Table 2: Pd-catalyzed, Et2Zn-promoted alkylation of hemiacetals generated from allyl 2-THF 5 and allyl 2-
tetrahydropyran (THP) ethers 6.[a]
provide unsaturated diols 7 and 8,
which are of significant importance
as synthetic intermediates.
Entry Allyl ether
Reaction time [h]
Product
Yield (diastereomer ratio)
In conclusion, we have shown
that allyl alcohols and their 2-THF
and 2-THP ether derivatives are
good substrates for performing the
nucleophilic allylation of aliphatic
aldehydes. The reaction proceeds at
room temperature in the presence
of a catalytic amount of a Pd0 spe-
cies and a stoichiometric amount of
Et2Zn. The reaction contrasts the
electrophilic allylation at the a-
position of aliphatic aldehydes,
which proceeds in the presence of
a catalytic amount of a Pd0 species
and a stoichiometric amount of
Et3B together with Et3N and LiCl.[2]
Further studies to demonstrate
the utility of the present umpolung
methodology are in progress, for
example, modification of carbohy-
drates that possess five- and six-
membered hemiacetal structures
such as 5 and 6 as a common
structural motif.
1
1
87
2
3
4
1
88 (syn/anti=1:3)
91
2
0.5
97 (syn/anti=1:2)
5
17
78 (1:2)[b]
6
7
27
9
89 (Z:E:E=2:1.5:1)[b]
73
8
1
92
[a] Reaction conditions: 5 or 6 (1 mmol), Pd(OAc)2 (0.1 mmol), P(nBu)3 (0.4 mmol), and Et2Zn
(3.6 mmol, 1m n-hexane) in toluene (0.5 mL) at room temperature under N2. [b] The stereochemistry
(syn or anti) is unknown.
Experimental Section
General procedure (Table 2, entry 3):
Diethylzinc (3.2 mmol, 1.0m n-hexane
solution) and 6a (142.2 mg, 1.0 mmol)
were added successively by syringe to a homogeneous solution of
Pd(OAc)2 (22.6 mg, 0.1 mmol) and nBu3P (80.9 mg, 0.4 mmol) in
toluene (0.5 mL, dried over Na/benzophenone ketyl) at 08C under N2.
After completion of the addition, the mixture was allowed to warm to
room temperature and stirred for an additional 2 h, during which time
a copious amount of a white precipitate appeared and the reaction
mixture became sludgy. The mixture was diluted with EtOAc and
washed with HCl (0.2m), sat. NaHCO3, and brine and then the
organic phase was dried (MgSO4) and concentrated in vacuo to give a
yellow oil, which was purified by column chromatography over silica
gel (AcOEt/hexane, 1/4 v/v) to give 8a (230.6 mg, 91%, Rf = 0.48;
AcOEt/hexane, 1/4 v/v). 8a: IR (neat) n˜ = 3331 (s), 3076 (m), 1641
1
(m), 1435 (m), 1340 (m), 914 (m) cmÀ1; H NMR (400 MHz, CDCl3,
tetramethylsilane (TMS)) d = 1.40–1.64 (m, 6H), 2.17 (dt, J = 14.1,
7.3 Hz, 1H), 2.29 (brdt, J = 14.1, 7.3 Hz, 1H), 2.55 (brs, 2H), 3.64 (m,
1H), 3.63 (t, J = 6.2 Hz, 2H), 5.11 (d, J = 11.7 Hz, 1H), 5.12 (dm, J =
15.8 Hz, 1H), 5.83 ppm (ddt, J = 15.8, 11.7, 7.7 Hz 1H); 13C NMR
(100 MHz, CDCl3, tetramethylsilane) d = 21.8, 32.4, 36.3, 42.0, 62.3,
70.7, 117.6, 135.0 ppm; HRMScalcd for C 8H16O2: 144.1150; found
m/z (relative intensity): 144.1098 (1), 126 (4), 116 (2), 71(100).
Scheme 3. Transition states II and III leadingto Z-anti isomers in the
reactions of benzaldehydes and w-formylalkanolates, respectively, with
1,3-dimethylallylzinc.
a quasi-equatorial position impossible. For example, transi-
tion state III, which leads to a Z-anti isomer, apparently
suffers from 1,3-diaxial Me···Me repulsion and is unfavorable.
The allyl,[9] 2-tetrahydrofuryl, and 2-tetrahydropyranyl
groups have been recognized as useful protecting groups of
hydroxy groups.[10] They can be easily introduced and
removed selectively under a wide variety of mild conditions,
under which other functional groups remain intact. In
contrast, the results in Table 2 indicate that these protecting
groups could be utilized as useful C3, C4, and C5 sources and
Received: February 13, 2003 [Z51182]
Keywords: aliphatic aldehydes · allyl alcohols · allylation ·
.
palladium · zinc
[1] M. Kimura, T. Tomizawa, Y. Horino, S. Tanaka, Y. Tamaru,
Tetrahedron Lett. 2000, 41, 3627.
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Angew. Chem. Int. Ed. 2003, 42, 3392 – 3395

Angewandte
Chemie
[2] M. Kimura, Y. Horino, S. Mukai, S. Tanaka, Y. Tamaru, J. Am.
Chem. Soc. 2001, 123, 10401.
[3] For the use of allyl alcohols as nucleophiles, see a) Y. Masuyama
in Advances in Metal-Organic Chemistry, JAI, Vol. 3, 1994, pp.
255–303; b) S. Araki, T. Kamei, T. Hirashita, H. Yamamura, M.
Kawai, Org. Lett. 2000, 2, 847.
[4] We have already shown with one example that an allyl ether is
capable of effecting the nucleophilic allylation of benzaldehyde,
albeit in modest yields, when being exposed to a Pd–Et3B
catalytic system: M. Kimura, I. Kiyama, T. Tomizawa, Y. Horino,
S. Tanaka, Y. Tamaru, Tetrahedron Lett. 1999, 40, 6795.
[5] The ethers 5 and 6 were obtained in quantitative yield according
to a standard procedure (acid-catalyzed addition of allyl alcohols
to dihydrofuran and dihydropyran, respectively). All reagents
were commercially available and used as received.
[6] For the nucleophilic activation of allyl ethers by Mn, see a) T.
Nishikawa, T. Nakamura, H. Kakiya, H. Yorimitsu, H. Shino-
kubo, K. Oshima, Tetrahedron Lett. 1999, 40, 6613; by Zr, see
b) Y. Hanzawa, K. Kiyono, N. Tanaka, T. Taguchi, Tetrahedron
Lett. 1997, 38, 4615, and references therein.
[7] Y. Tamaru, A. Tanaka, K. Yasui, S. Goto, S. Tanaka, Angew.
Chem. 1995, 107, 862; Angew. Chem. Int. Ed. Engl. 1995, 34, 787.
[8] The diastereomeric structures and the ratios of 7b and 8b were
determined unequivocally by 400 MHz 1H NMR spectroscopy
on the basis of the coupling constants between the C5-H and C6-
H protons of 5,6-disubstituted 2,2-dimethyl-1,3-dioxanes derived
from 7b and 8b by: a) benzoylation of the primary alcohol,
b) ozonolysis, followed by reduction with NaBH4, and c) aceto-
nization with excess 2,2-dimethoxypropane/cat. TsOH.
[9] T. Taniguchi, K. Ogasawara, Angew. Chem. 1998, 110, 1137;
Angew. Chem. Int. Ed. 1998, 37, 1136.
[10] T. W. Green, P. G. M. Wuts in Protective Groups in Organic
Synthesis, Wiley, 1999.
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