Nucleophilic allylation of N,O-acetals with allylic alcohols promoted by Pd/Et3B and Pd/Et2Zn systems

Article abstract of DOI:10.1016/j.tetlet.2010.12.064

Pd/Et₃B and Pd/Et₂Zn systems promote the nucleophilic allylations of 2-aminotetrahydrofuran and 2-aminotetrahydropyran with allylic alcohols to provide ω-hydroxyhomoallylamines in high yields. The transformation is applicable to the

Full text of DOI:10.1016/j.tetlet.2010.12.064

Tetrahedron Letters 52 (2011) 913–915
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Tetrahedron Letters
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Nucleophilic allylation of N,O-acetals with allylic alcohols promoted by
Pd/Et3B and Pd/Et2Zn systems
Yumi Yamaguchi b, Mariko Hashimoto b, Katsumi Tohyama b, Masanari Kimura a,
⇑
a Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, Bunkyo-machi 1-14, Nagasaki 852-8521, Japan
b Graduate School of Material and Science, Nagasaki University, Bunkyo-machi 1-14, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd/Et3B and Pd/Et2Zn systems promote the nucleophilic allylations of 2-aminotetrahydrofuran and 2-
aminotetrahydropyran with allylic alcohols to provide -hydroxyhomoallylamines in high yields. The
transformation is applicable to the allylation of non-protective carbohydrates, such as ribose and
Received 9 November 2010
Revised 4 December 2010
Accepted 15 December 2010
Available online 21 December 2010
x
deoxyribose.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Allylation
Hemiacetal
Umpolung
Carbohydrate
Pd-catalyzed allylations are among the most efficient strategies
for C–C bond formation in organic synthesis.1 In particular, nucle-
ophilic allylations of aldimines have well been utilized extensively
for fundamental skeleton elongations of carbon chains of nitrogen-
containing physiologically active molecules. Although aldimines
are widely synthetically useful for valuable functionalizations, it
is highly problematic that they tend to be less reactive than alde-
hydes.2 Recently, we have demonstrated that a combination of a
Pd catalyst and Et3B nicely promotes aldimines prepared from aro-
matic aldehydes and primary aliphatic amines bearing enolizable
protons to provide homoallylamines in excellent yields (Scheme
1).3 In this case, it is necessary to activate the aldimines using
either amines or aldehydes with electron withdrawing groups.
N,O-Acetals are currently used as potent constituents of imino-
sugars for the development of glycosidase inhibitors in a wide
range of diseases, such as viral infections, inherited lysosomal
disorder, and diabetes.4 Although 2-hydroxytetrahydrofuran and
2-hydroxytetrahydropyran with primary amines readily lead to
2-aminotetrahydrofurans and 2-aminotetrahydropyrans, respec-
O
O
HO
NHR
OH
NR
RNH2
- H2O
n
n
n
n = 1 or 2
Scheme 2. Equilibrium between cyclic hemiaminal and
x
-hydroxyamine.
tautomers in equilibrium with the N,O-acetals often renders the at-
tack by nucleophiles more difficult.5 Herein, we report that the Pd/
Et3B and Pd/Et2Zn systems have been successfully extended to the
nucleophilic allylation of N,O-acetals prepared from 2-hydroxytet-
rahydrofuran and 2-hydroxytetrahydropyran with primary amines
in the presence of allylic alcohols, providing
x-hydroxy homoallyl-
amines in good to excellent yields in a one-pot synthesis. The reac-
tivity and regioselectivity associated with the unique nucleophilic
allylation of N,O-acetals from a wide variety of carbohydrates and
primary amines are also reported.
Table 1 summarizes the allylation of N,O-acetals prepared from
a wide variety of primary amines with 2-hydroxytetrahydropyran.
The reaction was conducted as follows: in situ formation of N,O-
acetals from various amines and 2-hydroxytetrahydropyran (30-
min reflux in 1 mL of THF solvent), azeotropic distillation of THF/
H2O two times, and exposure of a mixture of Pd(OAc)2 catalyst,
n-Bu3P, Et3B, and allyl alcohol dissolved in THF to the N,O-acetal
residue. The reaction mixture was stirred at 50 °C under nitrogen
atmosphere. p-Methoxy, p-methyl, and p-chloro substituted ani-
lines were useful for the allylation reaction, providing the corre-
sponding allylated d-hydroxyhomoallylamines 1a–1d in good
tively (Scheme 2), the low concentration of the
x
-hydroxyimine
Pd catalyst
NHR
Ph
RNH2
PhCHO
OH
Et3B
Scheme 1. Allylation of aldimine with allyl alcohol promoted by Pd/Et3B.
⇑
Corresponding author. Fax: +81 95 819 2677.
E-mail address: masanari@nagasaki-u.ac.jp (M. Kimura).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.064

914
Y. Yamaguchi et al. / Tetrahedron Letters 52 (2011) 913–915
Table 1
Table 2
Palladium-catalyzed allylation of aldimines prepared from 2-hydroxytetrahydropy-
Pd-catalyzed allylation of aldimines prepared from 2-hydroxytetrahydropyran and
ran and aminesa
PMPNH2 (PMP = p-MeOC6H4) with substituted allylic alcoholsa
R
Pd catalyst
O
OH
cat. Pd
O
OH
HO
HO
NHR
PMPNH2
RNH2
OH
Et3B or Et2Zn
OH
Et3B or Et2Zn
1
°
50 C
R
°
50 C
R
HO
NHPMP
HO
NHPMP
NR
4
3
2
Entry
Allylic alcohol
Time (h)
Yield% (syn:anti)
Entry
RNH2
R
Time (h)
Yield (%)
Et2Zn
Et3B/Et2Zn
24/5
Et3B
Et2Zn
Et3B/Et2Zn
Et3B
OH
OH
1
2
3
3a:55 (1.3:1)
3a:68 (3.2:1)
3b:68 (6.5:1)
3a:48 (3:1)
3a:42 (3:1)
1
2
3
4
5
6
7
p-OMeC6H4
p-MeC6H4
Ph
p-ClC6H4
c-C6H11
Bn
24/5
1a:74
1b:72
1c:69
1d:66
1eb
1a:53, 2a:10
1b:45, 2b:12
1c:45, 2c:12
1d:53, 2d:10
1e:76, 2e:8
1f:53, 2f:10
1g:49, 2g:7
24/24
24/24
24/24
24/5
24/5
24/5
24/5
Ph
OH
24/5
3b:16 (syn)
4b:37 (E)
1fb
1g:50
OH
OH
n-C6H13
4
5
24/6
24/5
3b:70 (syn)
3c:65
3b:21 (syn)
a
Ph
An aldimine, prepared in situ from 2-hydroxytetrahydropyran (1 mmol) and
4b:48 (E)
3c:17
amine (1.05 mmol), allyl alcohol (1.2 mmol), Pd(OAc)2 (10 mol %), n-Bu3P
(20 mol %), and Et3B (3.6 mmol) or Et2Zn (4.8 mmol) at 50 °C for the periods of time
indicated.
b
Intractable mixture of products.
a
An aldimine, prepared in situ from 2-hydroxytetrahydropyran (1 mmol) and
PMPNH2 (1.05 mmol), allyl alcohol (1.2 mmol), Pd(OAc)2 (10 mol %), n-Bu3P
(20 mol %), and Et3B (3.6 mmol) or Et2Zn (4.8 mmol) at 50 °C for the periods of time
indicated.
yields (Table 1, entries 1–4). Although the reaction of cyclohexyl-
amine and benzylamine resulted in formation of intractable mix-
tures of allylation products in the presence of Et3B, the desired
products 1e and 1f were produced in reasonable yields that were
promoted by Et2Zn along with the N-allylated homoallylamines 2
(Table 1, entries 5 and 6). The combination of Pd(0) and Et2Zn
tends to accelerate not only nucleophilic allylation at the imine
carbon atom but also the electrophilic allylation on the nitrogen
atom of d-hydroxyhomoallylamine to form N-allylated homoallyl-
amines 2.3a n-Hexylamine showed marginal success in the forma-
tion of 1g, irrespective of the promoters, Et3B or Et2Zn (Table 1,
entry 7).
entry 2). 3,4-O-Isopropylidene-2-hydroxytetrahydrofuran under-
went similar nucleophilic allylation providing a mixture of syn
and anti isomers 1j in a 1:5 ratio (Table 3, entry 3).
Et3B was insufficient for similar allylation of carbohydrates,
such as, deoxyribose and ribose, whereas an excess amount of
Et2Zn successfully promoted the reaction, giving rise to the desired
allylation products 1k and 1l, respectively (Table 3, entries 4 and
5).8 A spirocyclic acetal was also an adequate substrate and the
corresponding allylated product 1m was obtained in a reasonable
yield (Table 3, entry 6).
It has been reported that nucleophilic allylation of carbonyls
and imines with
a- and c-substituted allylmetal species in the
presence of a Pd catalyst tends to take place with high regioselec-
tivity, providing more substituted allylated products via six-mem-
bered ring transition states.6 However, in the present study, the
selectivities are unexpected. Some results using substituted allylic
alcohols are summarized in Table 2. trans-2-Buten-1-ol and 1-
methyl-2-propen-1-ol show marginal success in the formation of
a mixture of syn and anti methyl substituted homoallylamine 3a
(Table 2, entries 1 and 2). Phenyl substituted allyl alcohols dis-
played better stereoselectivity than those with a methyl group.
Cinnamyl alcohol provided the desired syn- and anti-3b in a
6.5:1 ratio by treatment with Et3B (Table 2, entry 3). Under similar
6-Vinyl-2-hydroxytetrahydropyran displayed similar reactivity
by treatment with Et3B to provide homoallylamine 1n in a 4:1 ratio
(Table 3, entry 7). A seven-membered cyclic hemiacetal underwent
similar allylation with Et3B to provide hydroxyhomoallylamine 1o,
while Et2Zn gave the allylated products 1o and 2o in modest yield
(Table 3, entry 8).
Although it is premature to rationalize the regio- and stereose-
lectivities for the present reaction, some plausible reaction mecha-
nisms are shown in Schemes 3 and 4. Based on the results of Table
2, an allyl metal species generated from methyl substituted allylic
alcohols might react with the hydroxyimine via transition state II
to avoid steric repulsion between the methyl group and the substi-
tuent on the nitrogen atom (transition state I), resulting in selec-
tive formation of the syn-3a isomer as depicted in Scheme 3. As
for the formation of anti-3a, the alternative structural feature asso-
ciated with the six-membered boat-like transition state III would
conditions, a-phenylallyl alcohol provided syn-3b as the sole prod-
uct (Table 2, entry 4). In contrast to the results of Et3B, Et2Zn shows
alternative regioselectivity giving rise to the linear product (E)-4b
predominantly along with the branched isomer 3b as a minor iso-
mer (entries 3 and 4).
Next, we examined the Pd-catalyzed allylation of N,O-acetals
prepared from various lactols with p-anisidine. The results using
Et3B and Et2Zn are summarized in Table 3. 2-Hydroxytetrahydrofu-
ran provided 1h in modest yield by means of Et3B, whereas Et2Zn
induced nucleophilic allylation and further electrophilic allylation
on the nitrogen atom to give the N-allylated homoallylamine 2h
selectively (Table 3, entry 1).3a,7 5-(2-Naphthyl)-2-hydroxytetrahy-
drofuran afforded 1i as a mixture of syn and anti isomers in a 1:1
ratio irrespective of employment of Et3B or Et2Zn (Table 3,
be probable. Regarding the selectivity of a-phenyl allyl alcohol
and cinnamyl alcohol, Et3B provided the branched isomer syn-3b
exclusively, whereas Et2Zn promoted the selective formation of
thermodynamically more stable isomer (E)-4b along with syn-3b
shown in Scheme 4. It is intriguing that Et2Zn would render a qua-
si-equatorial conformation of the phenyl group to minimize the
steric repulsion against the ligand on Zn (M = Zn), which is entirely
in contrast to the result of the steric repulsion between the ethyl
group of Et3B (M = BEt) and the phenyl substituent in Scheme 4.

Y. Yamaguchi et al. / Tetrahedron Letters 52 (2011) 913–915
915
Table 3
Pd-catalyzed allylation of aldimines prepared from lactols and PMPNH2 (PMP =
p-MeOC6H4)
O
M
N
O
O
M
N
a
Ph
M
N
Ph
Ph
Entry
1
Lactol
Time (h)
Yield% (syn:anti)
H
H
PMP
PMP
H
H
PMP
VI
Et3B/Et2Zn
Et3B
Et2Zn
V
O
OH
48/24
24/24
1h:38
1h:15
2h:61
HO
Ph
NH
HO
NH
Ph
O
2
3
1i:66 (1:1)
1j:83 (1:5)
1i:48 (1:1)
OH
H
H
H
PMP
(E)-4b
PMP
syn-3b
O
OH
Scheme 4. A plausible reaction mechanism for the formation of a mixture of syn-3b
and (E)-4b from phenyl substituted allyl alcohols.
24/24
1j:75 (1:5)
O
O
Acknowledgments
OH
O
OH
OH
4
5
24/24
24/24
1kb
1k:58 (1.6:1)
1l:54 (1.3:1)
1m:69
Financial support from the Ministry of Education, Culture,
Sports, Science and Technology, Japanese Government (Grant-in
Aid for Scientific Research (B) 21350055) is gratefully acknowl-
edged. This work was supported by the Tokuyama Science
Foundation.
HO
OH
O
1lb
HO
O
OH
OH
References and notes
6
7
27/24
27/24
1m:75
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(3.6 mmol) or Et2Zn (4.8 mmol) at 50 °C for the periods of time indicated.
b
Intractable mixture of products.
O
M
N
O
M
N
syn-3a
syn-3a
anti-3a
anti-3a
H
Me
Me PMP
H
PMP
II
I
O
H
O
Me
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M
N
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H
PMP
PMP
III
IV
Scheme 3. Reaction mechanism for the formation of a mixture of syn- and anti-3a
from methyl substituted allyl alcohols.
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7. Pd/Et2Zn system promotes allyl alcohols to undergo nucleophilic allylation of a
wide range of carbonyl compounds and aldimines. The modest yields by Pd/Et3B
system might be due to the formation of by-products encompassing the
In conclusion, the combination of Pd catalyst with Et3B or Et2Zn
promotes 2-aminotetrahydrofuran or 2-aminotetrahydropyran,
prepared from tetrahydrofuran or tetrahydropyran with a primary
amine in situ, to undergo nucleophilic allylation with allylic alco-
hols to provide c- and d-hydroxyhomoallylamines in high yields.
electrophilic
a-allylation of enolizable aldimines or intractable mixture of
The reaction is compatible with non-protected carbohydrates, such
as deoxyribose and ribose, to afford polyhydroxyhomoallylamines
in reasonable yields. These reaction protocols might be of great
interest to organometallic chemistry as well as to the transforma-
tion of biologically active molecules such as carbohydrates and
aminocarbohydrates.
boronic acid esters.
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