Selective One-Pot Three-Step Cascade Reaction: From Aromatic Aldehydes to 2,2-Diphenylethanol Derivatives

Article abstract of DOI:10.1021/acs.oprd.6b00382

We report herein a green and scalable one-pot, three-step, pinacol-coupling-rearrangement-reduction cascade reaction useful for the formation of 2,2-diphenylethanol derivatives. The reaction is carried out in water in the presence of a commercially available and regenerable supported acid under moderate pressure. A dozen of aromatic aldehydes have been successfully submitted to the standard protocol giving the target 2,2-diarylethanol derivatives in good yield (70-85%).

Full text of DOI:10.1021/acs.oprd.6b00382

Full Paper
Selective One-Pot-Three-Steps Cascade Reaction: from
aromatic aldehydes to 2,2-diphenylethanol derivatives
Muriel Billamboz, Claire Imbs, Estelle Banaszak-Léonard, and Christophe Len
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 29 May 2017
Downloaded from http://pubs.acs.org on May 29, 2017
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Selective One-Pot-Three-Steps Cascade Reaction: from aromatic aldehydes to 2,2-
diphenylethanol derivatives
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Muriel Billamboz,a,b Claire Imbs,c Estelle BanaszakꢀLéonard,a and Christophe LEN *,c
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a
Ecole Supérieure de Chimie Organique et Minérale, 1 rue du Réseau JeanꢀMarie
Buckmaster, Fꢀ60200 Compiègne, France.
b Ecole des Hautes Etudes d’Ingénieur (HEI), Yncréa HautsꢀdeꢀFrance, UCLille, Laboratoire
de Pharmacochimie, 13 Rue de Toul, Fꢀ59046 Lille, France
c
Sorbonne Universités, Université de Technologie de Compiègne, Centre de Recherche
Royallieu, CS 60 319, Fꢀ60203 Compiègne cedex, France.
Fax: +33 (0)3 44 97 15 91; Tel: +33 (0)3 44 23 43 23; Eꢀmail: christophe.len@utc.fr
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ABSTRACT: We report herein a green and scalable oneꢀpotꢀthreeꢀsteps pinacolꢀcouplingꢀ
rearrangementꢀreduction cascade reaction useful for the formation of 2,2ꢀdiphenylethanol
derivatives. The reaction is carried out in water in presence of a commercially available and
regenerable supported acid under moderate pressure. A dozen of aromatic aldehydes have
been successfully submitted to the standard protocol giving the target 2,2ꢀdiarylethanol
derivatives in good yield (70ꢀ85%).
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Key words: Pinacol coupling / Rearrangement / Cascade reaction / Green chemistry /
microwave / Scaleꢀup
INTRODUCTION
2,2ꢀDiphenylethanol derivatives are often used for the formation of new biologically active
compounds1ꢀ6 or formulated in a wide range of applications.7ꢀ10 As a consequence,
methodologies to selectively obtain such compounds are of great interest.
From literature data, 2,2ꢀdiphenylethanol (6a) is mainly obtained by three synthetic routes,
coming from (i) the reduction of 2,2ꢀdiphenylethanal (4a); (ii) the direct reduction of the
corresponding carboxylic acid
7 into alcohol or (iii) the hydroboration/oxidation process of
1,1ꢀdiphenylethylene ( ) (Scheme 1).
8
Scheme 1. Literature data for the formation of 2,2-diphenylethanol (6a)
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O
4
5
6
OH
O
1a
7
[29]
7
[13-22]
8
9
OH
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[23-26]
O
[27]
[28]
OH
O
OH
6a
[11-12]
4a
1a
2a
8
Only two recent works described the conversion of 1,1ꢀdiphenylethylene (8) to 2,2ꢀ
diphenylethanol (6a) : the first has been reported by Horvath et al. using an immobilized
rhodium catalyst11 and the second reported a flow method for hydroboration/oxidation of
olefins 12
. The direct reduction of carboxylic acid to alcohol is much more studied and several
efficient reducing systems have been developed: H2 gas/transition metal,13 NaBH4ꢀadditive
protocol,14 borane reducing reagents such as (BH3)2,15 BH3ꢀSMe2,16 9ꢀ
borabicyclo[3.3.1]nonane (9ꢀBBN),17 strong aluminum hydrides such as AlH3,18 LiAlH4,19
DIBALꢀH,20
EtMe2SiH/rutheniumꢀbased
catalyst,21
1,1,3,3ꢀtetramethyldisiloxane
(TMDS)/Cu(OTf)2.22 In most of these cases, reactions are carried out under harsh conditions,
or generate stoichiometric amounts of inorganic salts. Successful protocols based on metalꢀ
induced reactions24 such as solventꢀless ironꢀcatalyzed hydrosilylation24a or ironꢀtetraphos
complex hydrogenation24b have been reported for the reduction of 2,2ꢀdiphenylethanal (4a) to
2,2ꢀdiphenylethanol (6a).23 Typically, metal hydrides as well as other stoichiometric reagents
are used for this transformation on a laboratory scale. Boron derivatives such as Nꢀ
heterocyclic carbene boranes are often described for this transformation.25 An innovative
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protocol also proposed the catalytic frustrated Lewis pair hydrogenation of 2,2ꢀ
diphenylethanal (4a) in moderate yield.26
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Collecting all these data, it appears than reported methodologies for the formation of 2,2ꢀ
diphenylethanol (6a) included at least one of the following statement: (i) the use of complex
metalꢀcatalyzed reactions; (ii) the use of sensitive reactant such as carbene borane,
borohydride or hydrogen; (iii) the use of organic solvents. As a consequence, simple protocol
to obtain 2,2ꢀdiphenylethanol (6a) in a green and recyclable medium is of particular interest.
Moreover, methodologies able to furnish 2,2ꢀdiphenylethanol derivatives from the
corresponding benzaldehyde derivatives in large scale is desirable.
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Following our continuous interest for the development of sustainable pinacol coupling
reactions,27 direct formation of 2,2ꢀdiphenylethanal (4a) from benzaldehyde (1a) has been
examined. 2,2ꢀDiphenylethanal (4a) can be obtained by pinacolic rearrangement of pinacol 2a
under acidic conditions (Lewis acid supported on silica gel,28a H2SO4 in AcOH28b, ionicꢀ
liquidꢀmediated rearrangement28c...).28 Moreover, two protocols using the combination of a
nobleꢀmetal catalyst and a promoter have been reported for the oneꢀpotꢀtwoꢀsteps formation
of 2,2ꢀdiphenylethanal (4a) from benzaldehyde (1a).29 The first one consisted in a
combination of a platinium complex and a polyoxometalate29a and led to 2ꢀ2ꢀ
diphenylacetaldehyde 4a in 72% yield with 86% global selectivity. The second protocol was
mediated by indium in THF in presence of trimethylsilylchloride in excess and gave the
targeted product 4a in 88% yield.29b
In order to improve the cost and sustainability of the process, a focus on the acid and metal
catalyzed oneꢀpotꢀthree steps pinacol couplingꢀrearrangementꢀreduction of aromatic
aldehydes to 2,2ꢀdiphenylethanol derivatives has been examined (Scheme 2). In the frame of
green chemistry principles, water was selected as solvent and particular attention was paid to
the selectivity, scalability and recyclability of the system. In fact, several sideꢀproducts such
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as the reduction product 3a (benzyl alcohol) and deoxybenzoin 5a are expected to be
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observed (Scheme 2).
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Scheme 2. Envisaged cascade reaction with all potential intermediates and side-products
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OH
OH
O
O
OH
6a
4a
1a
2a
+
+
O
OH
3a
5a
RESULTS AND DISCUSSION
At first, the cascade reaction was realized in sole water under microwave irradiation.
Combining literature data, the protocol was divided into two parts: (i) heating at 70°C during
1 hour to achieve the pinacol coupling reaction, then (ii) heating at 150°C during 1 additional
hour to realize the pinacol rearrangement of the preformed pinacol derivative and the
subsequent reduction of 2,2ꢀdiphenylacetaldedyde 4a to 2,2ꢀdiphenylethanol (6a). From
literature data, zinc was selected as electron supplier and Amberlyst®H15 was chosen as
supported acid (Table 1, entry 1). Starting aldehyde 1a was completely converted. Target 2,2ꢀ
diphenylethanol (6a) was obtained in an encouraging 55% yield. The selectivity for the
pinacolic rearrangement was high and very few deoxybenzoin 5a was recovered at the end of
the cascade reaction. However, a high amount of benzylic alcohol 3a, coming from the direct
reduction of benzaldehyde (1a) before pinacol coupling was observed (28% yield, Table 1,
entry 1). A small amount of pinacol derivative 2a was also obtained (5%) proving that the
pinacolic rearrangement was not complete.
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Table 1. One-Pot-3-Steps cascade reaction from benzaldehyde (1a) to 2,2-
diphenylethanol (6a) a
6
7
8
9
OH
OH
O
O
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OH
6a
4a
1a
2a
+
+
O
OH
3a
5a
equiv
equiv
Metal
4 (Zn)
4 (Mg)
4 (Al)
4 (Mn)
2
Conversion
Entry
2a (%)
3a (%)
4a (%)
5a (%)
6a (%)
SEL PC/Rb
SEL R/Dc
Amberlyst® H15
(%)
100
80
0
1
2
3
4
5
6
3
3
3
3
3
1
5
10
ꢀ
28
70
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
55
ꢀ
69:31
12:88
ꢀ
96:4
ꢀ
ꢀ
ꢀ
ꢀ
0
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
95
89
3
24
28
2
1
42
11
66:34
59:41
95:5
92:8
4
28
a Typical procedure: a 30 mL pyrex vessel adapted to microwave irradiation was charged with
benzaldehyde (1a, 1.5 mmol), Amberlyst®H15 and zinc. 5 mL of water were then added. The
mixture was stirred and heated at 70°C during 1 hour then at 150°C during 1 additional hour.
b SEL PC/R defined the selectivity between pinacol coupling reaction and direct reduction.
c
SEL R/D referred to the selectivity between pinacolic rearrangement and dehydration of
pinacol 2a
.
Based on these results, several experiments were carried out to limit the amount of reduced
compound 3a. As expected, changing the metal source did not allowed better selectivity nor
yield in 6a (Table 1, entries 2ꢀ4). Decreasing the amount of zinc to 2 equivalents allowed to
limit the amount of benzylic alcohol 3a to 24% yield but with a partial conversion (Table 1,
entry 5). With 1 equivalent of supported acid, the conversion decreased and the rate of
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pinacolic rearrangement was low (Table 1, entry 6). From these first partial results, we
concluded that the amount of Amberlyst®H15 or zinc did not have a high impact on the
amount of benzyl alcohol 3a but played a key role in selectivities and rates of the cascade
reaction. As a consequence, different sources of acid were screened to master the reduction
side reaction (Table 2).
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Table 2. Screening of acid sourcesa
OH
OH
O
O
OH
6a
4a
1a
2a
+
+
O
OH
3a
5a
Entry
acid source
Amberlyst®H15 (3 equiv)
NH4Cl sat. (ꢀ)
Conversion (%)
2a (%)
3a (%)
28
4a (%)
5a (%)
6a (%)
SEL PC/Rb
69:31
SEL R/Dc
1
2
3
4
5
6
100
86
5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
55
ꢀ
96:4
5
50
10:90
ꢀ
AcOH (3 equiv)
100
100
100
100
15
24
37
38
73
ꢀ
ꢀ
17:83
ꢀ
CH3SO3H (3 equiv)
Al(CF3SO3)3 (1 equiv)
VCl3 (1 equiv)
40
1
ꢀ
28
ꢀ
57:43
96:4
56
40:60
ꢀ
ꢀ
32
ꢀ
ꢀ
54:46
®
Dowex 50WX8 (3 equiv)
7
8
100
92
13
2
23
11
ꢀ
ꢀ
2
1
39
15
70:30
62:38
95:5
94:6
®
Nafion NR50 (3 equiv)
Amberlite®
9
100
26
21
ꢀ
2
35
75:25
95:5
IR120 (3 equiv)
a Reaction conditions: benzaldehyde (1,5 mmol), zinc (4 eq.) and acid source in water (5 mL)
are stirred at 1200 rpm under microwave irradiation at 70°C during 1 hour then at 150°C
during 1 additional hour.
b SEL PC/R defined the selectivity between pinacol coupling reaction and direct reduction.
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c
SEL R/D referred to the selectivity between pinacolic rearrangement and dehydration of
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pinacol 2a
.
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Running the reaction in saturated ammonium chloride as acid source did not allow any
pinacolic rearrangement nor dehydration but a large amount of benzyl alcohol 3a was
observed at the end of the reaction (Table 2, entry 2). Acetic acid was reported as promoter
for the pinacol coupling reaction at room temperature.27a However, at 70°C, acetic acid
favored the direct reduction of the aldehyde 1a to the corresponding alcohol 3a in 73% yield.
Methanesulfonic acid, a strong homogeneous acid, allowed the cascade reaction but with a
low selectivity towards pinacol coupling (Table 2, entry 4). Lewis acids were also reported to
promote the pinacol coupling reaction.28a,30 Trifluoromethanesulfonic aluminium (III) at
stoechiometric amount was evaluated for the cascade reaction conducting to a total
conversion in favor of benzyl alcohol 3a (Table 2, entry 5). Vanadium chloride, previously
described31 as promoter for the pinacol coupling reaction gave pinacol product 2a at 38%
yield accompanied by 32% of undesired alcohol 3a and some minor undetermined side
products (Table 2, entry 6). As Lewis acids and homogeneous acids (NH4Cl, AcOH or
CH3SO3H) were not able to limit benzyl alcohol formation supported Brönsted acids were
investigated.
Dowex®50WX8 hydrogen form is a strongly acidic cation exchange resin which allowed
the pinacol coupling reaction and the pinacolic rearrangement. Indeed, 39% of target 2,2ꢀ
diphenylethanol (6a) was obtained starting from the aldehyde 1a accompanied by some
residual pinacol 3a (Table 2, entry 6). It is notable that a lower amount of undesired benzylic
alcohol 3a was formed compared with the use of Amberlyst®H15 (Table 2, entries 1 and 6).
Moreover, the selectivity for pinacolic rearrangement compared with dehydration is very
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high. Nafion®NR50, a hydroscopic super acidic ion exchange resin catalyst, promoted the
conversion of benzaldehyde (1a) but low target product 6a was observed at the end of the
reaction (15% yield). Moreover, the pellets swelled and it was difficult to recover all products
for analysis (Table 2, entry 7). As a consequence Nafion®NR50 was not selected for further
optimization. Amberlite®IR120, a strongly acidic gelꢀtype resin with sulfonic acid
functionality, allowed the total conversion of aldehyde 1a and gave 35% of target product 6a
with an excellent selectivity (Table 2, entry 8). Comparing these four supported acidic media
led to the conclusion that Amberlite®IR120 displayed the higher potential in terms of
selectivities and Amberlyst® H15 in terms of reaction rate. Consequently, these two supported
acids were selected for further optimization.
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Table 3. Optimization with Amberlyst®H15
OH
OH
O
O
OH
6a
4a
1a
2a
+
+
O
OH
3a
5a
equiv
equi
Solvent
Conversion
2a
(%)
5
3a
(%)
28
28
24
29
22
28
3
5a
(%)
2
6a
(%)
55
11
42
55
49
47
24
37
Entry
T1 (°C) t1 (min) T2 (°C) t2 (min)
rpm
acid
3
v Zn
4
(mL)
(%)
100
89
1 a
2 a
3 a
4 a
5 a
6 a
7 a
8 a
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (3)
H2O (8)
EtOH (5)
EtOH (5)
70
70
70
70
70
70
70
70
60
60
60
60
60
60
60
60
150
150
150
180
180
180
150
180
60
60
60
60
60
60
60
60
1200
1200
1200
1200
1200
1200
1200
1200
1
4
44
2
<1
2
3
2
95
3
4
100
99
1
4
3
4
ꢀ
4
3
4
92
ꢀ
4
3
4
78
ꢀ
4
3
4
75
ꢀ
2
5
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96%EtO
H (5)
9 a
3
3
4
4
70
70
60
60
150
150
60
60
1200
1200
60
75
10
31
9
5
4
12
20
EtOH (4)
H2O (1)
EtOH
10 a
18
11 a
3
4
(2,5)
70
60
150
60
1200
100
28
19
5
11
10
11
12
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15
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H2O (2,5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
12 b
13 b
14 b
15 b
16 b
17 c
3
3
3
3
3
3
4
4
4
4
4
4
70
50
70
50
30+30
10+50
30+30
10+50
180
180
60
60
600
600
600
600
600
600
100
100
68
ꢀ
6
27
27
21
17
23
27
4
4
3
0
3
3
64
55
6
20
15
8
50
0
150
180
60
60
95
50
64
100
ꢀ
a Reaction conditions: benzaldehyde (1.5 mmol), zinc and acid source in solvent (H2O/EtOH)
are stirred under microwave irradiation at 70°C during 1 hour then at T2 during 1 additional
hour.
b
Reaction conditions: benzaldehyde (1.5 mmol), zinc and acid source in water (5 mL) are
stirred under microwave irradiation. T1 [(x + y) min] is reached in x minutes then the reaction
medium is stirred at T1 during y minutes. After that, if needed, the mixture is heated as fast as
possible to T2 and stirred at T2 during 1 additional hour.
c
Reaction conditions: benzaldehyde (1.5 mmol), zinc and acid source in water (5 mL) are
heated and stirred at 180°C during 1 hour.
Using 1 equivalent of Amberlyst®H15 decreased the global conversion (89% vs 100%)
and hindered the pinacolic rearrangement step (Table 3, entries 1 and 2). Decreasing the
amount of zinc to 2 equivalents allowed to reach a very good conversion of aldehyde 1a
(95%) and 42% of target compound 6a was obtained. However, 24% of alcohol 3a still
remained in the medium (Table 3, entry 3).
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3
4
5
6
7
8
9
Increasing the temperature of the second step to 180°C or concentrated the reaction
medium did not help (Table 3, entries 1ꢀ5). Diluting the medium decreased the rate of reaction
and did not allow to limit the side reactions or increase the selectivity for pinacol coupling or
pinacolic rearrangement (Table 4, entry 6). As a consequence, the initial concentration at
0.3M was kept for further experiments.
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
25
26
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethanol, reported as able to limit the reduction side reaction, was evaluated (Table 3,
entries 7ꢀ11). In absolute ethanol, even if lower amounts of benzyl alcohol were observed,
conversions decreased and lot of unpreviously observed side products were obtained (Table 3,
entries 7 and 8). As a consequence, some experiments in a mixture of ethanol and water were
attempted (Table 3, entries 9ꢀ11) but with limited success. The more water was added in the
medium, the more benzyl alcohol was obtained (Table 3, entries 8ꢀ11). As a consequence, the
replacement of water by bioꢀsourced ethanol, even if it slowed the reduction side reaction,
was abandoned.
In order to limit the amount of benzyl alcohol 3a some experiments were carried out with
a monitored heating to the target temperature T1. It is noteworthy that decreasing the speed of
stirring to 600 rpm led to the production of 6a in 64% yield with total conversion of
benzaldehyde (1a) and pinacol 2a. However, 27% of benzyl alcohol 3a is still observed,
accompanied by a small amount of deoxybenzoin 5a (4%) (Table 3, entry 12). Conducting the
reaction at 50°C led to a total conversion but without improvement of the selectivity (Table 3,
entry 13). Comparing these two experiments, it was decided to stop the reaction after heating
at T1 (Table 3, entries 14 and 15). From these results, it seems that the majority of the reaction
is carried out at the higher temperature T2. As a consequence, the reaction was realized in a
sole step at the higher temperature and confirmed our hypothesis: 50% of target compound 6a
is obtained, with good conversions in benzaldehyde (1a) and pinacol 2a. 23% of benzyl
alcohol 1a is produced and a high selectivity for pinacolic rearrangement is observed (Table
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3, entry 16). Conducting the reaction at 180°C and 600 rpm led to total conversions with 64%
4
5
6
yield in 6a (Table 3, entry 12).
7
8
9
All these experiments in hand, Amberlite®IR120 was optimized as a potential supported
acid which would limit the reduction side reaction at 0.3M as defined for Amberlyst®H15. A
slow heating at 70°C and a second step at 180°C were then attempted (Table 4, entry 2). This
protocol did not allow the total conversion of aldehyde 1a but the profile of the reaction
remained the same. From literature, metal(III) chloride as additive could help the pinacol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
coupling reaction and decreased the amount of benzyl alcohol 3a 32
In our conditions, the
.
addition of iron (III) chloride boosted the formation of the reduced product 3a and inhibited
the pinacolic rearrangement step (Table 4, entry 3).
Table 4. Optimization with Amberlite®IR120
OH
OH
O
O
OH
6a
4a
1a
2a
+
+
O
OH
3a
5a
equiv
equiv
T1
(°C)
70
t1
T2
t2
(min)
60
Conversion
2a
(%)
26
16
35
15
5
3a
(%)
21
18
33
16
15
8
4a
5a
6a
(%)
35
39
1
Entry
rpm
acid
3
Zn
4
(min)
60
(°C)
150
180
180
160
180
180
180
(%)
100
79
(%)
(%)
2
1 a
2 b
3 b,c
4 d
1200
1200
1200
600
ꢀ
ꢀ
3
4
70
30+30
30+30
60
2
3
4
70
60
89
ꢀ
1
3
4
120
120
120
120
88
ꢀ
2
53
46
25
48
5 d
3
4
900
82
ꢀ
2
6 d
2
2
900
60
10
8
8
4
2
7 d
3
3
900
81
16
2
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2
3
4
5
6
7
8
9
8 d
9 e
4
4
4
5
5
3
3
3
3
2
180
160
180
160
160
120
900
600
600
600
600
83
100
94
ꢀ
12
4
8
2
ꢀ
53
72
62
80
47
90
90
90
90
60
60
60
60
10+50
10+50
10+50
10+50
19
19
16
18
10 e
11 e
12 e
10
ꢀ
ꢀ
100
85
ꢀ
18
a
Reaction conditions: benzaldehyde (1.5 mmol), zinc and Amberlite®IR120 in water (5 mL)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
are stirred at 1200 rpm under microwave irradiation at 70°C during 1 hour then at 150°C
during 1 additional hour.
b Reaction conditions: benzaldehyde (1,5 mmol), zinc and Amberlite
®IR120 in water (5 mL)
are stirred at 1200 rpm and gradually heated in 30 minutes to 70°C under microwave
irradiation. The mixture is maintained at 70°C during 30 additional minutes then at 180°C
during 1 additional hour.
c Reaction realized in presence of FeCl3 (1 eq).
d Reaction conditions: benzaldehyde (1.5 mmol), zinc and Amberlite
are heated at T2 during 2 hours under microwave irradiation.
®
IR120 in water (5 mL)
IR120 in water (5 mL)
e Reaction conditions: benzaldehyde (1.5 mmol), zinc and Amberlite
®
are heated at 90°C during 1 hour under microwave irradiation then gradually heated in 10
minutes to T2. The mixture is maintained at T2 during 50 additional minutes.
From the optimized protocol for Amberlyst®H15, fast heating at the higher temperature T2
was carried out (Table 4, entries 4ꢀ8). A first attempt at 160°C during 2 hours at 600 rpm led
to the target compound 6a in 53% yield with an excellent selectivity. Moreover, only 16% of
alcohol 3a was obtained, which was twice less than with Amberlyst®H15 in equivalent
conditions (Table 4, entry 4). Increasing the temperature and stirring speed slowed down the
reaction (Table 4, entry 5). As a consequence, the proportions between acid and zinc were
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screened to determine the best ratio (Table 4, entries 6ꢀ8). Decreasing the quantity of metallic
reductor impacted on the reduction of diphenylethanal 4a to diphenylethanol 6a as 4a was
observed in 4 to 8% yield at the end of the process (Table 4, entry 6). Increasing the quantity
of supported acid accelerated the pinacolic rearrangement (Table 4, entries 7 and 8).
However, for all experiments, independently of the reductor/acid ratio, aldehyde 1a was not
totally converted in two hours. As a consequence, a reaction step at 90°C was introduced to
allow the total conversion of benzaldehyde 1a (Table 4, entry 9). The reaction mixture was
heated under moderate stirring as fast as possible at 90°C and maintained at this temperature
during one hour. During that stirring, no overꢀpressure was monitored and reactants were on
the liquid phase. After one hour, the mixture was slowly heated for 10 minutes to 160°C and
maintained at that temperature for 50 minutes. As expected, this 2ꢀhour process led to a total
conversion of aldehyde 1a and 72% of target product 6a was obtained (Table 4, entry 9). 19%
of benzyl alcohol and only 1% of deoxybenzoin 5a were produced. Moreover 8% of residual
pinacol 2a could be converted to 6a to optimize the target yield. A second attempt was
realized using the same protocol and zinc/acid ratio but with 180°C as higher temperature.
This small difference had a dramatic impact on conversion and yield of 6a (Table 4, entry 10).
As a consequence, 160°C was kept for the last experiments and the amount of resin was
increased to 5 equivalents in order to reach 80% yield of 6a with an excellent selectivity. With
this amount of acid, 16% of benzyl alcohol 2a were observed and less than 1% of
deoxybenzoin 5a, resulting from a dehydration sideꢀreaction was monitored (Table 4, entry
11). Our last attempt was to decrease the amount of zinc to 2 equivalents but this led to lower
conversions and yields (Table 4, entry 12).
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To summarize, two optimized methodologies for the oneꢀpotꢀthreeꢀsteps cascade reaction
from aldehyde 1a to 2,2ꢀdiphenylethanol (6a) were realized in sole water under microwave
irradiation using commercially available supported acids (Table 5).
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Table 5. Optimized methodologies for the cascade reaction
3
4
5
6
7
8
Entry acid source
equiv
T1
t1
T2
t2
(min)
Conversion
(%)
3a
(%)
16
27
35
15
5a
(%)
1
6a
(%)
80
3
Zn
3
(°C)
90
(min)
60
(°C)
160
180
160
180
1 a
2 b
3 a
4 b
Amberlite®IR120 (5 equiv)
10+50
60
100
9
Amberlyst®H15 (3 equiv)
Amberlyst®H15 (5 equiv)
Amberlite®IR120 (3 equiv)
4
100
64
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
90
60
10+50
60
100
55
36
4
62
3
a
Reaction conditions: benzaldehyde (1.5 mmol), zinc and acid in water (5 mL) are stirred at
600 rpm under microwave irradiation at 90°C during 1 hour then at 160°C during 1 additional
hour.
b
Reaction conditions: benzaldehyde (1.5 mmol), zinc and acid in water (5 mL) are stirred at
600 rpm under microwave irradiation at 180°C during 1 hour.
The more selective was based on the reactivity of Amberlite®IR120 at 90°C then 160°C
during 2 hours (Table 5, entry 1). The protocol using Amberlyst®H15 was fast, with good
selectivity and total conversion after 1 hour at 180°C (Table 5, entry 2). Using
Amberlyst®H15 under the optimized conditions for Amberlite®IR120 led to bad results in
terms of selectivity with a high amount of alcohol 3a (Table 5, entry 3). As previously
observed, using Amberlite®IR120 at 180°C during 1 hour led to moderate conversion (Table
5, entry 4). As a consequence, Amberlite®IR120 was kept for further investigations on the
recycling of the system and the scope of the reaction.
One of the advantage of using supported media deals with the possibility of recycling the
support by simple filtration to separate the filtrate, zinc and Amberlite®IR120. In our case,
Amberlite®IR120 can be recycled twice before a dramatic decrease in activity, obviously
related to the loss of protons on the surface of Amberlite®IR120 (Figure 1). In our conditions,
the support showed no physical damages. A good activity was maintained for 10 runs without
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7
8
significant losses on selectivity after regeneration of the resin by an acidic washing (Figure 1).
Several aromatic aldehydes were then subjected to the optimized recyclable green reaction
conditions for the oneꢀpotꢀthree steps cascade reaction (Table 6).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90
80
70
60
50
Without regeneration
40
30
20
10
0
With regeneration
1
2
3
4
5
6
7
8
9
10
Figure 1. Recycling of Amberlite®IR120 with or without regeneration between each run.
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Table 6. Scope of the cascade reaction
3
4
5
6
7
8
9
OH
R
R
Amberlite IR120 (5eq)
Zinc (3eq)
R
OH
O
OH
+
R
+
R
+
R
R
O
Water
OH
90°C, 1h then 160°C, 1h
MW irradiation
6
5
3
2
1
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound
R
conversion
6 (%)
2 (%)
3 (%)
5 (%)
SEL PC/R a
SEL R/D
Entry
b
1
a
b
c
d
e
f
1
H
100
100
90
80
85
75
78
83
0
ꢀ
ꢀ
16
11
13
19
15
5
1
2
2
2
1
ꢀ
84/16
89/11
86/14
81/19
84/16
80/20
85/15
85/15
83/17
74/26
83/17
98/2
98/2
97/3
97/3
98/2
ND
2
4ꢀCH3
4ꢀF
3
ꢀ
4
4ꢀCl
100
100
25
ꢀ
5
4ꢀBr
4ꢀOMe
3ꢀCH3
2ꢀCH3
3ꢀCl
ꢀ
6
20
ꢀ
7
g
h
i
100
100
100
100
100
82
83
78
70
79
15
15
17
25
16
3
2
3
3
3
97/3
97/3
96/4
96/4
96/4
8
ꢀ
9
10
11
j
2ꢀCl
k
3ꢀBr
a SEL PC/R defined the selectivity between pinacol coupling reaction and direct reduction.
b
SEL R/D referred to the selectivity between pinacolic rearrangement and dehydration of
pinacol 2a.
It is notable than few differences were observed when derivatives of aldehyde 1a were
used as substrate except for 4ꢀmethoxybenzaldehyde (1f). In our conditions, the formation of
the ketyl radical seems to be the limiting step. As a consequence, the efficiency of the reaction
was directly correlated with the electrophily of the carbon atom of the carbonyl group.
Compared with benzaldehyde (1a), derivatives with a mesomeric donating group at para or
ortho position are expected to react slowly than those in meta position. As a consequence, 4ꢀ
methoxybenzaldehyde (1f), as expected, reacted very slowly to give only 25% conversion and
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20% of the corresponding pinacol 2f (Table 6, entry 6). Moreover, this donatingꢀgroup seems
to hinder the pinacolic/pinacolone rearrangement. Derivatives with moderate donating groups
either by mesomeric or inductive effects gave total conversions and good yields (Table 6,
entries 3ꢀ5 and entries 9ꢀ11). Derivatives with methyl groups exhibit the same reactivity,
independently of the substituent position on the aromatic ring (Table 6, entries 2, 7 and 8),
with total conversions and high yields and selectivities for 2,2ꢀdiphenylethanol derivatives 6b,
6g and 6h. It is notable than the choroꢀderivatives gave higher amounts of chlorobenzylic
alcohols 3d, 3i and 3j than the others halogenated substrates. This tendancy for direct
reduction was previously reported by our group.27 In a general manner, the selectivity for the
pinacol coupling reaction versus direct reduction to alcohol is good and the selectivity for
pinacolic rearrangement to 2,2ꢀdiphenylethanol 6 is excellent (SEL R/D >96%).
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As our main goal is to produce 2,2ꢀdiphenylethanol (6a) in large scale, efforts have then
been focused on the evaluation of the reaction in a larger scale. Considering that flow
microwave devices are less industrially used than autoclaves, some experiments in sealed
vessels have been carried out using the optimized protocol with Amberlite®IR120 (Table 7
and Figure 2).
Figure 2. Devices used for scaleꢀup study
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Table 7. Scale-up study using sealed devices under conventional heating
3
4
5
6
7
8
OH
OH
O
O
9
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6a
4a
1a
2a
+
+
O
OH
3a
5a
Volume
(mL)
30
Masse
1a (g)
0.159
0.159
6a
(%)
80
2a
(%)
ꢀ
3a
4a
(%)
ꢀ
5a
(%)
1
Entry
Device
conversion
100
SEL PC/R a
84/16
SEL R/D b
98/2
(%)
16
1
2
MW glass vessel
Glass vessel
30
Trac
e
95
79
trace
10
6
89/11
99/1
3
Teflon reactor
Teflon reactor
Steel reactor
60
0.318
5
100
100
100
80
77
79
trace
16
11
13
<1
4
84/16
89/11
87/13
95/5
95/5
96/4
4 c
5 c
300
750
8
5
trace
trace
4
12
3
a SEL PC/R defined the selectivity between pinacol coupling reaction and direct reduction.
b
SEL R/D referred to the selectivity between pinacolic rearrangement and dehydration of
pinacol 2a. c Concentration was put at 100g.Lꢀ1
As expected, the reactivity in the 30 mL sealed pyrex vessel under conventional heating is
similar to those under microwave heating (Table 7, entries 1ꢀ2). No effect of microvaves has
been observed for the cascade reaction. Scalingꢀup in 60 mL then 300 mL Teflon reactors
allowed to obtain 2,2ꢀdiphenylethanol (6a) gave similar yields and selectivity (Table7, entries
3ꢀ4). Working on a 5 gramꢀscale did not significantly change the selectivity. In fact, 8% of
pinacol 2a was observed at the end of heating. As a consequence, increasing the time of
heating could help to totally convert pinacol 2a (Table 7, entry 4). Conducting the cascade
reaction on a 12 gramꢀscale in a steel reactor gave the expected results (Table 7, entry 5). A
good 79% yield in targeted 2,2ꢀdiphenylethanol (6a) is obtained, accompanied by small
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amounts of side products. The conversion of pinacol 2a is not complete and could led to an
4
5
6
increase in yield by a longer heating at 160°C.
7
8
9
CONCLUSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A simple, green and reusable medium has been optimized for the oneꢀpotꢀthreeꢀstep pinacolꢀ
couplingꢀrearrangementꢀreduction cascade reaction to give 2,2ꢀdiphenylethanol derivatives in
70ꢀ85% yields from aromatic aldehydes in water. The originality of this medium is the use of
Amberlite®IR120 as heterogeneous regenerable proton supplier and zinc as cheap electron
supplier. This supported acid proved to enhance the selectivities of the reaction. Due to its
high stability, regenerated Amberlite®IR120 can be reuse 10 times without degradation or
loss in activity, allowing limiting waste production. Moreover, scaleꢀup of the process can be
made using autoclaves without significant loss in reactivity nor selectivity.
EXPERIMENTAL SECTION
General. All commercially available products and solvents were used without further
purification. Reactions were monitored by TLC (Kieselgel 60F254 aluminum sheet) using a
cyclohexane/AcOEt eluent with detection by UV light or potassium permanganate acidic
solution. Column chromatography was performed on silica gel 40−60 ꢁm. Flash column
chromatography was performed on an automatic apparatus, using silica gel cartridges. 1H and
13C NMR spectra were recorded on a 400 MHz/54 mm ultralong hold. Chemical shifts (δ) are
quoted in parts per million (ppm) and are referenced to TMS as an internal standard. Coupling
constants (J) are quoted in hertz. Comparisons with known or reported compounds have been
used to confirm the NMR peak assignments.
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4
5
6
7
8
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General procedure. A 30 mL pyrex vessel adapted to microwave irradiation was charged
with the aldehyde (1) (1.5 mmol), Amberlite IR120 (1.75 g, 5.0 eq), zinc (294 mg, 3.0 eq) and
water (5 mL). The mixture was irradiated under stirring (rpm 600) at 90°C for 1 hour then
gradually heated to 160°C in 10 minutes. The resulting mixture was kept at 160°C during 50
additional minutes under stirring. At the end of the reaction, zinc and Amberlite IR120 are
filtered and the final product is extracted from the filtrate with EtOAc (3 × 10 mL). The
organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude
product was purified over a column of silica gel and eluted with a gradient of cyclohexane /
ethyl acetate.
10
11
12
13
14
15
16
17
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19
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21
22
23
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26
27
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29
30
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32
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39
40
41
42
43
44
45
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47
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Procedure for the 12g scale process. A 750 mL steel reactor was charged with
benzaldehyde (12 g, 120 mmol), Amberlite IR120 (140 g, 5 eq), zinc (23.5 g, 3 eq) and water
(400 mL). The mixture was heated at 90°C for 1 hour then gradually heated to 160°C in 10
minutes. The resulting mixture was kept at 160°C during 50 additional minutes under stirring.
At the end of the reaction, zinc and Amberlite IR120 are filtered and the final product is
extracted from the filtrate with EtOAc (3 × 300 mL). The organic phase was washed twice by
sole water (2*250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The
crude product was then recrystallized from ethanol to give 2,2ꢀdiphenylethanol 6a in 79%
yield.
2,2-Bis(4-fluorophenyl)ethanol (6c). A 30 mL pyrex vessel adapted to microwave
irradiation was charged with 4ꢀfluorobenzaldehyde (1c) (186 mg, 1.5 mmol), Amberlite
IR120 (1.75 g, 5.0 eq), zinc (294 mg, 3.0 eq) and water (5 mL). The mixture was irradiated
under stirring (rpm 600) at 90°C for 1 hour then gradually heated to 160°C in 10 minutes. The
resulting mixture was kept at 160°C during 50 additional minutes under stirring. At the end of
the reaction, zinc and Amberlite IR120 are filtered and the final product is extracted from the
filtrate with EtOAc (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate
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and concentrated in vacuo. The crude product was purified over a column of silica gel and
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eluted with a gradient of cyclohexane / ethyl acetate to give the product 6c (131 mg, 75%
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yield) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ = 1.47 (bs, 1H, OH),
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4.20ꢀ4.11 (m, 3H, CHꢀCH2ꢀOH), 7.04ꢀ6.99 (tapp, H1/1’, JHꢀH=3JHꢀF = 8.7 Hz, 4H), 7.20 (dd,
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H2/2’, 3JHꢀH = 8.5 Hz, 4JHꢀF = 5.4 Hz, 4H). C NMR (100 MHz, CDCl3):
δ = 52.0 (CH2), 66.1
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(CH), 115.6 (d, 2 C1/1’, JCꢀF = 21.2 Hz, 2 CHAr), 129.7 (d, 2 C2/2’, JCꢀF = 7.9 Hz, 2 CHAr),
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137.0 (d, JCꢀF = 3.0 Hz, 2 CIV, 2 C3/3’), 162.8 (d, JCꢀF = 245 Hz, 2 CIV, 2 C4/4’). HRMS:
235.0911 (100%), calculated 235.0934 [M + H]+ ; 257.0724 calculated 257.0754 [M + Na]+.
2,2-Di-meta-toluylethanol (6g). A 30 mL pyrex vessel adapted to microwave irradiation
was charged with 3ꢀmethylbenzaldehyde (1g) (180 mg, 1.5 mmol), Amberlite IR120 (1.75 g,
5.0 eq), zinc (294 mg, 3.0 eq) and water (5 mL). The mixture was irradiated under stirring
(rpm 600) at 90°C for 1 hour then gradually heated to 160°C in 10 minutes. The resulting
mixture was kept at 160°C during 50 additional minutes under stirring. At the end of the
reaction, zinc and Amberlite IR120 are filtered and the final product is extracted from the
filtrate with EtOAc (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate
and concentrated in vacuo. The crude product was purified over a column of silica gel and
eluted with a gradient of cyclohexane / ethyl acetate to give the product 6g (139 mg, 82%
1
yield) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ = 1.66 (bs, 1H, OH),
2.31 (bs, 6H, 2 CH3), 4.10 (bs, 3H, CHꢀCH2ꢀOH), 7.06ꢀ7.01 (m, 6H, CHAr), 7.19 (t, J = 8.0
Hz, 2H, HAr). 13C NMR (100 MHz, CDCl3):
δ
= 21.6 (2 CH3), 53.7 (CH2), 66.2 (CH), 125.3
(2 CHAr), 127.6 (2 CHAr), 128.6 (2 CHAr), 129.2 (2 CHAr), 138.3 (2 CIV), 141.5 (2 CIV).
HRMS: 227.1514 (100%), calculated 227.1436 [M + H]+ ; 249.1278 calculated 248.1255 [M
+ Na]+.
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2,2-Di-ortho-toluylethanol (6h). A 30 mL pyrex vessel adapted to microwave irradiation was
charged with 2ꢀmethylbenzaldehyde (1h) (180 mg, 1.5 mmol), Amberlite IR120 (1.75 g, 5.0
eq), zinc (294 mg, 3.0 eq) and water (5 mL). The mixture was irradiated under stirring (rpm
600) at 90°C for 1 hour then gradually heated to 160°C in 10 minutes. The resulting mixture
was kept at 160°C during 50 additional minutes under stirring. At the end of the reaction, zinc
and Amberlite IR120 are filtered and the final product is extracted from the filtrate with
EtOAc (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product was purified over a column of silica gel and eluted
with a gradient of cyclohexane / ethyl acetate to give the product 6h (141 mg, 83% yield) was
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isolated as a colorless oil. 1H NMR (400 MHz, CDCl3):
7.0 Hz, 2H, CH2ꢀOH), 4.54 (t, J = 7.0 Hz, 1H, CH), 7.17ꢀ7.15 (m, 8H, CHAr). 13C NMR (100
δ = 2.30 (bs, 6H, 2 CH3), 4.08 (d, J =
MHz, CDCl3):
δ = 19.5 (2 CH3), 45.7 (CH2), 64.9 (CH), 126.2 (2 CHAr), 126.6 (2 CHAr),
127.26 (2 CHAr), 130.8 (2 CHAr), 136.9 (2 CIV), 139.0 (2 CIV). HRMS: 227.1488 (100%),
calculated 227.1436 [M + H]+ ; 249.1185 calculated 248.1255 [M + Na]+.
AUTHOR INFORMATION
Corresponding author
christophe.len@utc.fr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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CI thanks ESCOM for its financial support. The authors are grateful to some 4th year ESCOM
students for their practical preliminary works.
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SUPPORTING INFORMATION
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Experimental part for known products. 1H and 13C NMR spectra for all compounds are
provided as supporting information.
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