Ruthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions in water and protic solvents

Article abstract of DOI:10.1002/ejoc.200390155

Cross-coupling between 3-buten-2-ol (2) and aldehyde in the presence of a catalytic amount of [RuCl₂(PPh₃)₃] has been developed, through a tandem olefin migration/aldol reaction in a water/toluene mixture. The presence of

Full text of DOI:10.1002/ejoc.200390155

FULL PAPER
Ruthenium-Catalyzed Tandem Olefin Migration/Aldol and Mannich-Type
Reactions in Water and Protic Solvents
Mingwen Wang,[a] Xiao-Fan Yang,[a] and Chao-Jun Li*[a]
Keywords: Alcohols / Aldehydes / CϪC coupling / Cross-coupling / Ruthenium
Cross-coupling between 3-buten-2-ol (2) and aldehyde in the
presence of a catalytic amount of [RuCl2(PPh3)3] has been
developed, through a tandem olefin migration/aldol reaction
in a water/toluene mixture. The presence of In(OAc)3 pro-
moted the aldol reaction with α-vinylbenzyl alcohol (4) and
aldehyde, while treatment of 3-buten-2-ol (2) with imines
generated Mannich-type reaction products; syn isomers were
formed as the major diastereomers for the aldol products
3a−3g and 5a−5e and the Mannich products 7a−7g.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
tions. In addition, aqueous Mannich-type reactions through
the use of silyl enol ethers or silyl ketene acetals have been
carried out by Kobayashi[16a] and Akiyama.[16b]
The aldol and Mannich-type reactions are among the
most important CϪC bond-forming reactions in organic
synthesis. Under classical aldol reaction conditions, how-
ever, dimerization, polymerization, and self-condensation
also occur.[1] The classical Mannich reaction also has lim-
itations.[2] An important modification of the classical aldol
and Mannich reactions is the Lewis acid catalyzed con-
densation of enol silyl ethers with carbonyl compounds
(Mukaiyama aldol reaction)[3] and imines.[4] More recently,
Trost has reported the highly efficient formation of aldol-
type products through vanadium-catalyzed coupling be-
tween propargyl alcohols and aldehydes.[5] Recent develop-
ments have also included hydrometalation/aldol[6] and α-
CϪH activation/aldol reactions of carbonyl compounds.[7]
Motherwell developed the Rh- and Ni-catalyzed isomeriz-
ation of allylic lithium alkoxides to lithium enolates that
Previously, during our studies of the development of air-
and water-tolerant catalysis, we reported that the functional
groups of homoallyl alcohols and allyl alcohols underwent
reshuffling in air and water in the presence of a catalytic
amount of [RuCl2(PPh3)3] (Figure 1, path a). A side prod-
uct of the isomerization is the formation of a ketone (Fig-
ure 1, path b).[17] The formation of this product was ex-
plained in terms of a competing process involving the cleav-
age of the allylic CϪH bond (rather than the CϪO bond)
to form a rutheniumϪenol complex, which was then hy-
drolyzed to give the ketone.[18] We postulated that, in the
presence of an aldehyde, such a rutheniumϪenol complex
might be captured,[19] and our initial work reported the suc-
cessful capture of the intermediate by aldehydes to afford
aldol-type products in water.[20] Subsequently, we found
that the [RuCl2(PPh3)3]-catalyzed tandem olefin migration/
aldol reaction in water can be significantly improved with
the aid of the water-tolerant Lewis acid In(OAc)3. In addi-
tion, cross-couplings of imines with allyl alcohols efficiently
generated Mannich-type reaction products under similar
conditions in methanol. Here we wish to describe the results
of these studies.
then undergo further aldol reactions,[8] while Gree recently
´
reported the [Fe(CO)5]-catalyzed isomerization, under
photolytic conditions, of allyl alcohol to its enol, which
then reacted with aldehydes to give aldol products (together
with other by-products).[9a] These workers also found that
[RhCl(PPh3)3]/BuLi combinations are effective catalysts for
the coupling of allyl alcohols with aldehydes. However, no
reaction was observed without the lithium co-reagent.[9b]
There has recently been growing interest in the develop-
ment of organic reactions in aqueous media.[10] For aque-
ous aldol-type condensations, Chan has developed tin- and
zinc-mediated cross-couplings between halo ketones and al-
dehydes,[11] while Lubineau,[12] Kobayashi,[13] Loh,[14] and
others[15] have developed aqueous Mukaiyama-type reac-
[a]
Department of Chemistry, Tulane University,
New Orleans, Louisiana 70118, USA
E-mail: cjli@tulane.edu
Figure 1. Ruthenium-catalyzed olefin migration in water
998
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0306Ϫ0998 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 998Ϫ1003

Tandem Olefin Migration/Aldol and Mannich-Type Reactions
FULL PAPER
At the beginning of our study, benzaldehyde (1a) was in Table 2). Most of the α-vinylbenzyl alcohol (4) was con-
stirred in water at 110 °C (oil bath) for 5 h with 3-buten-2- verted into propiophenone, the result of olefin migration by
ol (2) and a catalytic amount of [RuCl2PPh3)3] (3 mol%),
but none of the desired product was obtained (Scheme 1).
The benzaldehyde (1a) was found to have been partially ox-
idized into benzoic acid. No reaction was observed when
the solvent was changed to toluene, THF, DMSO, CHCl3,
or CH2Cl2 at their reflux temperatures. When the reaction
was performed in a 1:4 (v/v) mixture of water and toluene,
no reaction occurred at 70 °C. However, when the reaction
temperature was increased to 110 °C, the desired aldol
product 3a was obtained (in a syn/anti ratio of 70:30) in
50% isolated yield (Entry 1 in Table 1). A change of the
solvent ration to 4:1 (water/toluene) further increased the
yield (76%) and also produced a slight increase in the syn/
anti ratio (73:27) of the aldol product 3a (Entry 2 in
Table 1). The use of a water/ethanol (4:1) mixture decreased
both the yield (40%) and the diastereoselectivity (syn/anti ϭ
60:40, Entry 3 in Table 1). Subsequently, a variety of aro-
matic aldehydes 1bϪ1g were examined under the same reac-
tion conditions. In most cases, the desired aldol products
3aϪ3g were obtained in good yields (Entries 4Ϫ10 in
Table 1). When 3-fluorobenzaldehyde (1b) was used, the use
of water alone as the solvent provided the desired product
3b in 76% isolated yield (Entry 4 in Table 1). The use of
aliphatic aldehydes provided complicated mixtures, and ef-
forts to improve the reactions with such aldehydes are cur-
rently underway.
path b as described in Figure 1. We speculated that, to de-
crease the production of propiophenone and increase the
yield of aldol product, a Lewis acid was needed to activate
the aldehyde. Through screening, In(OAc)3 was found to be
an excellent co-catalyst.[21,22c] With the [RuCl2(PPh3)3] (3
mol%) ϩ In(OAc)3 (8 mol%)] catalyst system, the yield of
aldol product 5a was dramatically increased from 10 to 80%
(Entries 1 vs. 2 in Table 2). However, no reaction occurred
between propiophenone and benzaldehyde under the same
conditions, which ruled out a mechanism involving a ketone
formation/aldol reaction. When aldehydes 1c, 1e, 1g, and
1h were used, the reactions gave the desired aldol-type
products 5bϪ5e in moderate to high yields (51Ϫ82%,
Entries 2Ϫ6 in Table 2).
Our success with the aldol-type reaction prompted us to
explore a related coupling between allyl alcohols and imines
to generate Mannich-type reaction products (Scheme 3,
Table 3), which had not been reported in the literature. In
our experiments, imines 6aϪ6g were generated in situ from
aldehydes and p-anisidine, and the reactions between imines
6aϪ6g and 3-buten-2-ol (2) were carried out at 110 °C (oil
bath temperature) with [RuCl2(PPh3)3] as a catalyst. The
results in Table 3 show that, when water was chosen as reac-
tion solvent, a complicated mixture of products including
imine adduct 7 and aldol product 3 was obtained. In H2O/
toluene (1:4), the reaction between 6a and 3-buten-2-ol (2)
proceeded smoothly to generate the desired imine adduct
7a in moderate yield (47%, syn/anti ϭ 76:24), together with
the aldol product 3a (27% yield; syn/anti ϭ 59:41, Entry 1
in Table 3). When the ratio of H2O/toluene was changed
from 1:4 to 4:1, only the aldol product 3a was obtained
(Entry 3 in Table 3). It was speculated that, in the H2O/
toluene system, competition exists between imine 6a being
hydrolyzed to aldehyde 1a and its coupling with the enol
intermediate, due to the poor electrophilicity of imine. In-
creasing the ratio of H2O/toluene did not favor the Man-
nich-type reaction. In H2O/toluene (1:4), the presence of
Scheme 1
The above method having been established, aldol reac-
tions between α-vinylbenzyl alcohol (4) and aromatic alde-
hydes were examined (Scheme 2 and Table 2). Under the
same conditions, however, treatment of benzaldehyde (1a)
with 4 gave the product 5a only in low yield (10%, Entry 1 Lewis acids such as Sc(OTf)3, Zn(OTf)3, ZnBr2, or ZnCl2
Table 1. [RuCl2(PPh3)3]-catalyzed aldol-type reactions between allyl alcohols 2 and aldehydes 1 in aqueous media; reaction conditions:
[RuCl2(PPh3)3] (3 mol%), 110 °C (oil bath temperature), 5 h
Entry
Substrate
1, Ar
Solvent
Product
3, Ar
Yield (%)[a]
syn/anti[b]
1
2
3
1a, Ph
H2O/toluene (1:4)
H2O/toluene (4:1)
H2O/EtOH (4:1)
H2O
3a, Ph
50
76
40
72
35
70
68
73
27
44
70:30
73:37
60:40
66:34
60:40
74:26
51:49
79:21
67:33
63:37
1a, Ph
3a, Ph
1a, Ph
3a, Ph
4[c]
5[c]
6
1b, m-FC6H4
1c, p-ClC6H4
1c, p-ClC6H4
1d, p-MeOC6H4
1e, p-BrC6H4
1f, p-PhC6H4
1g, 2-naphthyl
3b, m-FC6H4
3c, p-ClC6H4
3c, p-ClC6H4
3d, p-MeOC6H4
3e, p-BrC6H4
3f, p-PhC6H4
3g, 2-naphthyl
H2O
H2O/toluene (4:1)
H2O/toluene (4:1)
H2O/toluene (4:1)
H2O/toluene (4:1)
H2O/toluene (4:1)
7
8
9
10
[a]
[b]
1
Isolated yields were reported. syn/anti ratios were determined by the H NMR spectra of the product mixtures (by comparison of
[c]
doublet peaks from ϪCHOH of the isomers). Reaction time was 5.5 h.
Eur. J. Org. Chem. 2003, 998Ϫ1003
999

M. Wang, X.-F. Yang, C.-J. Li
FULL PAPER
Table 2. [RuCl2(PPh3)3]/[In(OAc)3]-catalyzed aldol-type reactions between allyl alcohols 4 and aldehydes 1 in aqueous media; reaction
conditions: solvent H2O/toluene (4:1), 110 °C (oil bath temperature), 7 h
Entry
Substrate
1, Ar
Catalyst
Product
5, Ar
Yield (%)[a]
syn/anti[b]
1
2
3
4
5
6
1a, Ph
RuCl2(PPh3)3(3 mol%)
5a, Ph
10
80
79
82
51
54
60:40
68:32
63:37
61:39
60:40
63:37
1a, Ph
RuCl2(PPh3)3 (3 mol%) ϩ In(OAc)3 (8 mol%)
RuCl2(PPh3)3 (3 mol%) ϩ In(OAc)3 (8 mol%)
RuCl2(PPh3)3 (3 mol%) ϩ In(OAc)3 (8 mol%)
RuCl2(PPh3)3 (3 mol%) ϩ In(OAc)3 (8 mol%)
RuCl2(PPh3)3 (3 mol%) ϩ In(OAc)3 (8 mol%)
5a, Ph
1c, p-ClC6H4
1e, p-BrC6H4
1g, 2-naphthyl
1h, p-MeC6H4
5b, p-ClC6H4
5c, p-BrC6H4
5d, 2-naphthyl
5e, p-MeC6H4
[a]
[b]
1
Isolated yields reported. syn/anti ratios were determined by the H NMR spectra of the product mixtures.
path b in Figure 1) over the Mannich-type reaction. Sub-
sequently, a variety of imines 6bϪ6g generated from aro-
matic aldehydes were examined under the same reaction
conditions (Entries 6Ϫ15 in Table 3). In methanol, imines
reacted effectively to generate the desired Mannich-type
products 7bϪ7g (yields 44Ϫ70%). In H2O/toluene (1:4),
both the Mannich-type products 7aϪe (35Ϫ45% yield) and
the aldol-type products 3bϪ3e (23Ϫ35%) were obtained.
The use of imines generated from aliphatic aldehydes gave
complicated mixtures of products both in methanol and
H2O/toluene.
Scheme 2
as co-catalysts did not increase the reactivity of the imine,
both 7a and 3a being generated in yields similar to those in
Entry 1. No reaction was observed when the reaction was
carried out in DMF or toluene, the imines being recovered
completely. When methanol was used as the solvent, a clean
reaction between 6a and 3-buten-2-ol (2) occurred to pro-
vide only the Mannich-type product 7a (54% yield), and no
aldol-type product 3a was observed (Entry 4 in Table 3).
Interestingly, either in H2O/toluene or in methanol, an in-
crease in the catalyst loading from 4 to 8 mol% reduced the
yields of both 7a and 3a (Entries 1 vs. 2 and 4 vs. 5 in
Scheme 3
A tentative mechanism for the product formation is de-
Table 3). This suggests that increasing the catalyst picted in Figure 2. The ruthenium complex isomerizes the
[RuCl2(PPh3)3] loading favored the ketone formation (by allyl alcohol 2 or 4 to an enol that is coordinated with the
Table 3. [RuCl2(PPh3)3]-catalyzed Mannich-type reaction between imines 6 and allyl alcohol 2 in aqueous or protic media; reaction
conditions: [RuCl2(PPh3)3] (4 mol%), 110 °C (oil bath temperature), 10 h; imines were generated in situ from aldehydes and p-anisidine
[b]
Entry
Substrate
6, R
Solvent[a]
Product
syn/anti
7 (3)
R
Yield (%)[c]
1
2[d]
3
6a, Ph
H2O/toluene (1:4)
H2O/toluene (1:4)
H2O/toluene (4:1)
MeOH
MeOH
MeOH
H2O/toluene (1:4)
MeOH
H2O/toluene (1:4)
MeOH
H2O/toluene (1:4)
MeOH
H2O/toluene (1:4)
MeOH
Ph
Ph
Ph
Ph
7a, 47 (3a, 27)
7a, 20 (3a, 20)
(3a, 43)
76:24 (59:41)
70:30 (59:41)
(64:36)
58:42
56:44
63:37
60:40 (65:35)
59:41
55:45 (55:45)
63:37
60:40 (55:45)
57:43
6a, Ph
6a, Ph
4
6a, Ph
7a, 54
5[d]
6
6a, Ph
Ph
7a, 45
7b, 70
7b, 45 (3b, 30)
7c, 68
7c, 38 (3c, 34)
7d, 61
7d, 35 (3e, 35)
7e, 60
7e, 40 (3d, 23)
7f, 44
7g, 60
6b, m-FC6H4
6b, m-FC6H4
6c, p-ClC6H4
6c, p-ClC6H4
6d, p-BrC6H4
6d, p-BrC6H4
6e, p-MeOC6H4
6e, p-MeOC6H4
6f, o-MeC6H4
6g, 2-naphthyl
m-FC6H4
m-FC6H4
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
p-MeOC6H4
p-MeOC6H4
o-MeC6H4
2-naphthyl
7
8
9
10
11
12
13
14
15
55:45 (60:40)
50:50
57:43
MeOH
[a] H2O/toluene ratio in v/v. [b] syn/anti ratios were determined by the 1H NMR spectra of the product mixtures (by comparison of doublet
[c]
[d]
peaks from ϪCHNϪ of the isomers). Isolated yield. 8 mol% of the catalyst was used.
1000
Eur. J. Org. Chem. 2003, 998Ϫ1003

Tandem Olefin Migration/Aldol and Mannich-Type Reactions
FULL PAPER
with brine, and dried with anhydrous Na2SO4. The mixture was
then concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: hexane/EtOAc) to
afford the Mannich-type products 7aϪ7g.
ruthenium catalyst, and in situ coupling between the
rutheniumϪenol complex with the aldehyde or imine gener-
ates the aldol or Mannich-type product. The formation of
primarily the syn isomer (Tables 1Ϫ3) is consistent with
previous studies on aldol- or Mannich-type reactions with
silyl enol ether.[16,22]
Characterization of the New Compounds
4-(3-Fluorophenyl)-4-hydroxy؊3-methylbutan-2-one (3b) (syn/
anti ؍ 66:34). 3b, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.24Ϫ7.31
(m, 1 H), 7.03Ϫ7.08 (m, 2 H), 6.90Ϫ6.96 (m, 1 H), 5.12 (d, J ϭ
3.6 Hz, 1 H), 3.20 (br. s, 1 H), 2.79 (dq, J ϭ 3.6, 8.0 Hz, 1 H), 2.17
(s, 3 H), 1.04 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 213.9, 164.3, 161.9, 144.6(2), 130.2(2), 121.6(2),
114.5, 114.3, 113.3, 113.1, 72.2(2), 53.0, 29.5, 10.0 ppm. IR (film):
ν˜ ϭ 3436, 2937, 1708, 1591, 1449, 1359, 1245, 1179, 1133, 1028
cmϪ1. 3b, anti: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.26Ϫ7.33 (m, 1
H), 7.02Ϫ7.09 (m, 2 H), 6.94Ϫ7.00 (m, 1 H), 4.73 (dd, J ϭ 3.6,
8.0 Hz, 1 H), 2.97 (d, J ϭ 3.6 Hz, 1 H), 2.83Ϫ2.92 (m, 1 H), 2.20
(s, 3 H), 0.95 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 213.5, 164.4, 161.9, 144.8(2), 130.3, 130.2, 122.5(2),
115.2, 115.0, 113.8, 113.6, 76.0, 53.6, 30.3, 14.3 ppm. IR (film): ν˜ ϭ
3426, 2924, 1708, 1591, 1451, 1359, 1246, 1170, 1023 cmϪ1. HRMS:
m/z calcd. for C11H13FO2: 219.0792 [M ϩ Na], 197.0972 [M ϩ H];
found 219.0793 [M ϩ Na], 197.0970 [M ϩ H].
4-Hydroxy-4-(4-methoxyphenyl)-3-methylbutan-2-one (3d) (syn/
anti ؍ 51:49). 3d, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.19Ϫ7.24
(m, 2 H), 6.83Ϫ6.87 (m, 2 H), 4.99 (d, J ϭ 4.0 Hz, 1 H), 3.77 (s, 3
H), 2.91 (br. s, 1 H), 2.79 (dq, J ϭ 4.0, 8.0 Hz, 1 H), 2.10 (s, 3 H),
1.08 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
213.9, 159.1, 134.1, 127.3, 113.9, 73.1, 55.5, 53.5, 29.8, 10.7 ppm.
IR (film): ν˜ ϭ 3435, 2936, 1707, 1611, 1513, 1357, 1248, 1176, 1031
cmϪ1. 3d, anti: 1H NMR (CDCl3, 400 MHz, ppm): δ ϭ 7.19Ϫ7.25
(m, 2 H), 6.83Ϫ6.88 (m, 2 H), 4.67 (d, J ϭ 8.4 Hz, 1 H), 3.78 (s, 3
H), 2.83Ϫ2.91 (m, 1 H), 2.75 (br. s, 1 H), 2.20 (s, 3 H), 0.88 (d,
J ϭ 8.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz, ppm): δ ϭ
213.8, 159.5, 134.3, 128.1, 114.1, 76.3, 55.5, 54.0, 30.2, 14.3 ppm.
Figure 2. Tentative mechanism for the ruthenium-catalyzed Aldol-
type or Mannich-type reactions (R ϭ Me or Ph; X ϭ O or p-
MeOC6H4N; Y ϭ H)
In conclusion, ruthenium-catalyzed tandem olefin migra-
tion/aldol and Mannich-type reactions in aqueous media
or in methanol have been developed. The scope (such as
asymmetric synthesis), mechanisms, and synthetic applica-
tions of these novel reactions are under investigation.
IR (film): ν˜ ϭ 3428, 2934, 1706, 1611, 1513, 1249, 1176, 1032 cmϪ1
.
HRMS: m/z calcd. for C12H16O3: 208.1094, 231.0992 [M ϩ Na];
found 208.1095, 231.0991 [M ϩ Na].
Experimental Section
4-Hydroxy-3-methyl-4-(4-phenylphenyl)butan-2-one (3f) (syn/anti ؍
67:33). 3f, syn: H NMR (CDCl3, 400 MHz): δ ϭ 7.54Ϫ7.59 (m, 4
General: Commercially available chemicals were used directly as
received. Flash chromatography employed E. Merck silica gel (Kie-
selgel 60, 230Ϫ400 mesh) purchased from Scientific Adsorbents.
High-resolution mass spectrometry was performed at the Institute
of Chemistry, the Chinese Academy of Sciences.
1
H), 7.30Ϫ7.45 (m, 5 H), 5.15 (d, J ϭ 3.6 Hz, 1 H), 3.08 (br. s, 1
H), 2.86 (dq, J ϭ 3.6, 8.0 Hz, 1 H), 2.17 (s, 3 H), 1.11 (d, 3 H,
7.2 Hz) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 214.0, 141.0,
140.4, 129.0, 127.5, 127.3, 127.2, 126.6, 72.9, 53.3, 29.6, 10.4 ppm.
IR (film): ν˜ ϭ 3439, 2926, 1703, 1486, 1358, 1178, 1008 cmϪ1. 3f,
General Procedure for Tandem Olefin Migration/Aldol-Type Reac-
tion in Aqueous Media: A mixture of the aldehyde (0.5 mmol), allyl
alcohol (1.25 mmol), and [RuCl2(PPh3)3] (0.015 mmol, 3 mol%) in
H2O/toluene (4 mL/1 mL) was stirred in air at 110 °C (oil bath
temperature) for 5 h. The reaction mixture was then allowed to
cool to room temperature, diluted with diethyl ether, washed with
brine, and dried with anhydrous Na2SO4. The mixture was concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: hexane/EtOAc) to afford the
aldol-type products 3a,[23] 3b, 3c,[24] 3d, 3e,[24] 3f, 3g, 5a,[25] 5b,[26]
5c,[25] 5d,[27] and 5e.[28]
1
anti: H NMR (CDCl3, 400 MHz, ppm): δ ϭ 7.55Ϫ7.59 (m, 4 H),
7.31Ϫ7.45 (m, 5 H), 4.78 (d, J ϭ 8.0 Hz, 1 H), 2.91Ϫ3.00 (m, 1
H), 2.85 (br. s, 1 H), 2.85 (br. s, 1 H), 2.23 (s, 3 H), 0.97 (d, J ϭ
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz, ppm): δ ϭ 213.7,
141.1(2), 141.0, 129.0, 127.6, 127.5, 127.3(2), 76.5, 53.8, 30.3, 14.4
ppm. IR (film): ν˜ ϭ 3426, 2926, 1708, 1485, 1357, 1241, 1170, 1008
cmϪ1. HRMS: m/z calcd. for C17H18O2: 254.1301; found 254.1308.
4-Hydroxy-3-methyl-4-(2-naphthyl)butan-2-one (3g) (syn/anti
63:37). 3g, syn: H NMR (CDCl3, 400 MHz): δ ϭ 7.79Ϫ7.84 (m,
4 H), 7.42Ϫ7.50 (m, 2 H), 7.35Ϫ7.39 (m, 1 H), 5.26 (d, J ϭ 3.6 Hz,
؍
1
General Procedure for Tandem Olefin Migration/Mannich-Type Re- 1 H), 3.25 (br. s, 1 H), 2.92 (dq, J ϭ 3.6, 8.0 Hz, 1 H), 2.16 (s, 3
action in Methanol: A mixture of the aldehyde (0.5 mmol) and p- H), 1.09 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz):
anisidine (0.55 mmol) in methanol (5 mL) was heated at gentle re- δ ϭ 214.0, 139.3, 133.4, 133.0, 128.2, 127.9, 126.4, 126.1, 125.0,
flux (under air). After 2 h, allyl alcohol (1.25 mmol) and 124.1, 73.2, 53.2, 29.6, 10.3 ppm. IR (film): ν˜ ϭ 3429, 2980, 1709,
[RuCl2(PPh3)3] (0.02 mmol, 4 mmol%) were added, and the mixture 1413, 1358, 1177, 1022 cmϪ1. 3g, anti: 1H NMR (CDCl3, 400 MHz,
was stirred in air for 10 h. The reaction mixture was then allowed ppm): δ ϭ 7.79Ϫ7.85 (m, 3 H), 7.73Ϫ7.76 (m, 1 H), 7.44Ϫ7.50 (m,
to cool to room temperature, diluted with diethyl ether, washed 3 H), 4.90 (d, J ϭ 8.0 Hz, 1 H), 2.98Ϫ3.07 (m, 1 H), 2.95 (br. s, 1
Eur. J. Org. Chem. 2003, 998Ϫ1003
1001

M. Wang, X.-F. Yang, C.-J. Li
FULL PAPER
H), 2.22 (s, 3 H), 0.94 (d, J ϭ 7.2 Hz, 3 H). 13C NMR (CDCl3, 132.0, 129.0, 121.4, 115.5, 115.0, 59.3, 55.8, 53.6, 29.7, 11 ppm. IR
100 MHz, ppm): δ ϭ 213.7, 139.5, 133.4, 133.3, 128.7, 128.2, 127.9, (film): ν˜ ϭ 3393, 2932, 1707, 1512, 1358, 1243, 1177, 1036, 1009
126.5, 126.3, 126.1, 124.4, 53.7, 30.4, 14.4 ppm. IR (film): ν˜ ϭ
cmϪ1. 7d, anti: 1H NMR (CDCl3, 400 MHz, ppm): δ ϭ 7.33Ϫ7.39
3415, 2929, 1707, 1358, 1239, 1172, 1021 cmϪ1. HRMS: m/z calcd. (m, 2 H), 7.09Ϫ7.14 (m, 2 H), 6.57Ϫ6.64 (m, 2 H), 6.38Ϫ6.48 (m,
for C15H16O2: 228.1145, 251.1042 [M ϩ Na]; found 228.1144, 2 H), 4.30 (d, J ϭ 7.6 Hz, 1 H), 3.61 (s, 3 H), 2.85Ϫ3.00 (m, 1 H),
251.1039 [M ϩ Na].
2.01 (s, 3 H), 1.03 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 210.7, 152.4, 140.9, 140.8, 132.0, 129.1, 121.6,
115.0, 114.9, 61.2, 55.9, 53.3, 29.4, 15.3. IR (film): ν˜ ϭ 3364, 2931,
1705, 1512, 1357, 1239, 1176, 1036, 1009 cmϪ1. HRMS: m/z calcd.
for C18H20BrNO2: 362.0750 [M ϩ H]; found 362.0749.
4-(4-Methoxyphenylamino)-3-methyl-4-phenylbutan-2-one (7a) (syn/
anti ؍ 56:44). 7a, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.18Ϫ7.32
(m, 5 H), 6.62Ϫ6.67 (m, 2 H), 6.41Ϫ6.48 (m, 2 H), 4.65 (d, J ϭ
5.2 Hz, 1 H), 3.66 (s, 3 H), 2.95Ϫ3.07 (m, 1 H), 2.09 (s, 3 H), 1.06
(d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
211.0, 152.3, 141.6, 141.5, 128.8, 127.5, 127.2, 115.1, 114.9, 55.9,
53.2, 29.6, 15.5, 11.3 ppm. IR (film): ν˜ ϭ 3390, 2933, 1707, 1512,
4-(4-Methoxyphenyl)-4-(4-methoxyphenylamino)-3-methylbutan-2-
1
one (7e) (syn/anti ؍ 57:43). 7e, syn: H NMR (CDCl3, 400 MHz):
δ ϭ 7.17Ϫ7.21 (m, 2 H), 6.80Ϫ6.84 (m, 2 H), 6.62Ϫ6.67 (m, 2 H),
6.41Ϫ6.46 (m, 2 H), 4.58 (d, J ϭ 5.6 Hz, 1 H), 3.76 (s, 3 H), 3.66
(s, 3 H), 2.90Ϫ3.00 (m, 1 H), 2.06 (s, 3 H), 1.06 (d, J ϭ 6.8 Hz, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 211.3, 158.9, 152.3,
141.3, 133.3, 128.1, 115.0, 114.9, 114.2, 59.4, 55.4, 53.5, 29.9, 29.7,
11.4 ppm. IR (film): ν˜ ϭ 3383, 2929, 1707, 1607, 1511, 1247, 1177,
1031 cmϪ1. 7e, anti: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.09Ϫ7.15
(m, 2 H), 6.74Ϫ6.79 (m, 2 H), 6.56Ϫ6.62 (m, 2 H), 6.38Ϫ6.43 (m,
2 H), 4.28 (d, J ϭ 8.0 Hz, 1 H), 3.70 (s, 3 H), 3.61 (s, 3 H),
2.77Ϫ2.86 (m, 1 H), 1.97 (s, 3 H), 1.05 (d, J ϭ 6.8 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ ϭ 212.8, 159.0, 152.3, 141.1,
133.5, 128.1, 115.1, 114.9, 114.2, 61.1, 55.9, 54.2, 29.9, 29.1, 15.3
ppm. IR (film): ν˜ ϭ 3433, 2923, 1709, 1622, 1511, 1364, 1251, 1029
1453, 1243, 1178, 1037 cmϪ1
.
7a, anti: 1H NMR (CDCl3,
400 MHz): δ ϭ 7.17Ϫ7.33 (m, 5 H), 6.61Ϫ6.66 (m, 2 H), 6.40Ϫ6.47
(m, 2 H), 4.38 (d, J ϭ 8.0 Hz, 1 H), 3.65 (s, 3 H), 2.87Ϫ2.95 (m, 1
H), 2.01 (s, 3 H), 1.07 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 212.8, 152.3, 141.4, 141.3, 128.9, 127.8, 127.3,
115.0, 114.9, 59.8, 55.9, 54.0, 29.2, 15.3 ppm. IR (film): ν˜ ϭ 3390.0,
2931.4, 1707.2, 1623.9, 1506.8, 1453.4, 1288.6, 1246.3, 1191.1,
1034.1 cmϪ1. HRMS: m/z calcd. for C18H21NO2: 284.1645 [M ϩ
H]; found 284.1647.
4-(3-Fluorophenyl)-4-(4-methoxyphenylamino)-3-methylbutan-2-one
(7b) (syn/anti ؍ 63:37). 7b, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ
7.25Ϫ7.30 (m, 1 H), 6.99Ϫ7.10 (m, 2 H), 6.87Ϫ6.94 (m, 1 H),
6.63Ϫ6.69 (m, 2 H), 6.38Ϫ6.46 (m, 2 H), 4.64 (d, J ϭ 5.2 Hz, 1
H), 3.67 (s, 3 H), 2.93Ϫ3.01 (m, 1 H), 2.11 (s, 3 H), 1.06 (d, J ϭ
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 210.6, 164.6,
162.1, 152.5, 144.6, 140.9, 130.4, 130.3, 122.8, 122.7, 115.0, 114.9,
114.6, 114.4, 114.2, 113.9, 59.4, 55.9, 53.0, 29.6, 11.0 ppm. IR
cmϪ1
. HRMS: m/z calcd. for C19H23NO3: 313.1672; found
313.1671.
4-[(4-Methoxyphenyl)amino]-3-methyl-4-(2-methylphenyl)butan-2-
1
one (7f) (syn/anti ؍ 51:49). 7f, syn: H NMR (CDCl3, 400 MHz):
δ ϭ 7.28Ϫ7.32 (m, 1 H), 7.08Ϫ7.18 (m, 3 H), 6.61Ϫ6.66 (m, 2 H),
6.34Ϫ6.38 (m, 2 H), 4.88 (d, J ϭ 4.4 Hz, 1 H), 3.65 (s, 3 H),
2.92Ϫ3.01 (m, 1 H), 2.47 (s, 3 H), 2.17 (s, 3 H), 1.04 (d, J ϭ 7.2 Hz,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 210.7, 152.4, 141.4,
139.1, 134.6, 131.2, 127.3, 126.8, 126.5, 114.9, 114.8, 55.9, 55.7,
50.7, 29.4, 19.4, 10.4. IR (film): ν˜ ϭ 3396, 2930, 1708, 1512, 1463,
(film): ν˜ ϭ 3387, 2932, 1708, 1590, 1513, 1446, 1241, 1038 cmϪ1
.
7b, anti: 1H NMR (CDCl3, 400 MHz: δ ϭ 7.22Ϫ7.29 (m, 1 H),
7.03Ϫ7.07 (m, 1 H), 6.95Ϫ7.00 (m, 1 H), 6.87Ϫ6.93 (m, 1 H),
6.63Ϫ6.68 (m, 2 H), 6.42Ϫ6.47 (m, 2 H), 4.38 (d, J ϭ 7.6 Hz, 1
H), 3.66 (s, 3 H), 2.86Ϫ2.94 (m, 1 H), 2.02 (s, 3 H), 1.09 (d, J ϭ
6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 212.2, 164.6,
152.4, 144.7, 140.8, 130.4 (2), 122.8 (2), 115.0 (2), 114.7, 114.5,
114.0, 113.8, 61.3, 55.9, 53.6, 29.4, 15.3 ppm. IR (film): ν˜ ϭ 3360,
2931, 1707, 1590, 1513, 1449, 1241, 1037 cmϪ1. HRMS: m/z calcd.
for C18H20FNO2: 301.1472; found 301.1472.
1357, 1243, 1179, 1037 cmϪ1
. 7f, anti: 1H NMR (CDCl3,
400 MHz): δ ϭ 7.18Ϫ7.23 (m, 1 H), 7.07Ϫ7.15 (m, 3 H), 6.61Ϫ6.66
(m, 2 H), 6.37Ϫ6.43 (m, 2 H), 4.63 (d, J ϭ 7.2 Hz, 1 H), 3.65 (s, 3
H), 2.93Ϫ3.01 (m, 1 H), 2.43 (s, 3 H), 1.97 (s, 3 H), 1.10 (d, J ϭ
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 213.1, 152.3,
141.3, 139.1, 135.4, 130.9, 127.3, 126.8, 125.9, 115.2, 114.9, 57.9,
55.9, 52.5, 30.3, 29.9, 19.7, 15.1 ppm. IR (film): ν˜ ϭ 3405, 2926,
1708, 1620, 1506, 1461, 1244, 1035 cmϪ1. HRMS: m/z calcd. for
C19H23NO2: calcd. 297.1723; found 297.1722.
4-(4-Chlorophenyl)-4-(4-methoxyphenylamino)-3-methylbutan-2-one
(7c) (syn/anti ؍ 59:41). 7c, syn: H NMR (CDCl3, 400 MHz): δ ϭ
1
7.12Ϫ7.23 (m, 5 H), 6.56Ϫ6.63 (m, 2 H), 6.32Ϫ6.40 (m, 2 H), 4.56
(d, J ϭ 5.6 Hz, 1 H), 3.61 (s, 3 H), 2.85Ϫ2.93 (m, 1 H), 2.04 (s, 3
H), 1.00 (d, 3 H, J ϭ 7.2) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
209.5, 151.3, 139.7, 139.1, 131.8, 127.8, 127.2, 113.8, 113.7, 58.0,
54.6, 52.4, 28.1, 14.1 ppm. IR (film): ν˜ ϭ 3396, 2932, 1709, 1622,
1510, 1245, 1178, 1091, 1035 cmϪ1. 7c, anti: 1H NMR (CDCl3,
400 MHz): δ ϭ 7.13Ϫ7.24 (m, 5 H), 6.55Ϫ6.62 (m, 2 H), 6.31Ϫ6.40
(m, 2 H), 4.32 (d, J ϭ 7.6 Hz, 1 H), 3.61 (s, 3 H), 2.84Ϫ2.94 (m, 1
H), 2.00 (s, 3 H), 1.03 (d, J ϭ 7.2 Hz, 3 H ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 211.0, 151.2, 139.6, 138.8, 132.0, 127.8, 127.3,
113.8, 113.7, 59.8, 51.8, 28.4, 9.9 ppm. IR (film): ν˜ ϭ 3423, 2931,
1709, 1621, 1507, 1253, 1093, 1032 cmϪ1. HRMS: m/z calcd. for
C18H20ClNO2: 317.1177; found 317.1178.
4-(4-Methoxyphenylamino)-3-methyl-4-(2-naphthyl)butan-2-one (7g)
(syn/anti ؍ 57:43). 7g, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ
7.74Ϫ7.82 (m, 4 H), 7.41Ϫ7.47 (m, 3 H), 6.60Ϫ6.66 (m, 2 H),
6.44Ϫ6.49 (m, 2 H), 4.82 (d, J ϭ 5.2 Hz, 1 H), 3.64 (s, 3 H),
3.05Ϫ3.14 (m, 1 H), 2.12 (s, 3 H), 1.09 (d, J ϭ 7.2 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ ϭ 211.0, 152.4, 141.3, 139.0,
133.6, 133.0, 128.7, 128.1, 127.9, 126.4, 126.1, 126.0, 125.0, 115.1,
114.9, 60.0, 55.9, 53.2, 29.6, 11.1 ppm. IR (film): ν˜ ϭ 3396, 2932,
1709, 1511, 1359, 1243, 1178, 1036 cmϪ1. 7g, anti: 1H NMR
(CDCl3, 400 MHz): δ ϭ 7.71Ϫ7.81 (m, 4 H), 7.38Ϫ7.47 (m, 3 H),
6.59Ϫ6.65 (m, 2 H), 6.47Ϫ6.52 (m, 2 H), 4.54 (d, J ϭ 7.6 Hz, 1
H), 3.63 (s, 3 H), 2.98Ϫ3.06 (m, 1 H), 2.03 (s, 3 H), 1.10 (d, J ϭ
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 212.6, 152.4,
4-(4-Bromophenyl)-4-(4-methoxyphenylamino)3-methylbutan-2-one
(7d) (syn/anti ؍ 63:37). 7d, syn: 1H NMR (CDCl3, 400 MHz): δ ϭ
7.32Ϫ7.39 (m, 2 H), 7.10Ϫ7.15 (m, 2 H), 6.58Ϫ6.64 (m, 2 H), 141.1, 139.1, 128.9, 128.1, 127.9, 126.4, 126.3, 126.1, 124.7, 115.2,
6.39Ϫ6.47 (m, 2 H), 4.60 (d, J ϭ 5.6 Hz, 1 H), 3.66 (s, 3 H), 114.9, 62.0, 55.9, 53.8, 29.3, 15.4 ppm. IR (film): ν˜ ϭ 2390, 2935,
2.90Ϫ2.99 (m, 1 H), 2.10 (s, 3 H), 1.05 (d, 3 H, J ϭ 7.2Hz) ppm.
2832, 1697, 1613, 1504, 1453, 1350, 1228, 1170, 1029 cmϪ1. HRMS:
13C NMR (CDCl3, 100 MHz): δ ϭ 212.3, 152.5, 140.9, 140.6, m/z calcd. for C22H23NO2: 334.1801 [M ϩ H]; found 334.1799.
1002
Eur. J. Org. Chem. 2003, 998Ϫ1003

Tandem Olefin Migration/Aldol and Mannich-Type Reactions
FULL PAPER
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Received September 23, 2002
[O02526]
Eur. J. Org. Chem. 2003, 998Ϫ1003
1003