Selective Pinacol-Coupling Reaction using a Continuous Flow System

Article abstract of DOI:10.1021/acs.joc.6b02069

The first continuous flow pinacol coupling reaction of carbonyl compounds was successfully achieved within only 2 min during a single pass through a cartridge filled with zinc(0). The optimized method allowed the efficient production of gram-scale value-added compounds with high productivity. The developed methodology is efficient for aromatic or α,β-unsaturated aldehydes but gives moderate results for more stable acetophenone derivatives. Moreover, the flow method displayed better results in terms of yield and selectivity in comparison to the corresponding batch methodology.

Full text of DOI:10.1021/acs.joc.6b02069

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Article
Selective Pinacol-Coupling Reaction Using a Continuous Flow System
Nicolas Sotto, Clément Cazorla, Carole Villette, Muriel Billamboz, and Christophe Len
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02069 • Publication Date (Web): 25 Oct 2016
Downloaded from http://pubs.acs.org on October 26, 2016
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Selective Pinacol-Coupling Reaction Using a Continuous Flow System
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†
Nicolas Sotto,† Clément Cazorla,† Carole Villette,‡ Muriel Billamboz,‡ and Christophe Len *,
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† Sorbonne Universités, Université de Technologie de Compiègne, Centre de Recherche
Royallieu, CS 60 319, F-60203 Compiègne cedex, France. Fax: +33 (0)3 44 97 15 91; Tel:
+33 (0)3 44 23 88 28; E-mail: christophe.len@utc.fr
‡ Ecole Supérieure de Chimie Organique et Minérale, 1 rue du Réseau Jean-Marie
Buckmaster, F-60200 Compiègne, France.
OH
OH
OH
OH
Cl
R3
R3
O
Zn (0)
(4 equiv)
[0.75 M]
R3 = CH3, C3H7, C6H5
Cl
R1 R2
OH Cl
Cl
AcOH (2 equiv)
ethanol
RT
R4
yield 9-92%
OH
OH
OH
OH
2 mL min-1
OH
R4
R4 = H, CH3, Br, Cl
ABSTRACT: The first continuous flow pinacol coupling reaction of carbonyl compounds
was successfully achieved within only 2 minutes during a single-pass through a cartridge
filled with zinc(0). The optimized method allowed the efficient production of gramm-scale
value-added compounds with high productivity. The developed methodology is efficient for
aromatic or α,β-unsaturated aldehydes but give moderate results for much stable
acetophenone derivatives. Moreover, the flow method displayed better results in terms of
yield and selectivity than the corresponding batch methodology.
INTRODUCTION
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Pinacol coupling of carbonyl compounds is of particular interest within all C-C coupling
methods because of the synthetic potential of pinacol derivatives.1 Following pioneer works
reported by Fitting,2 this reaction still finds many applications for constructing biologically
important products or useful synthetic intermediates.3 Many batch methodologies for pinacol
coupling reactions have been developed using low-valent metals in excess such as Zn-Cu
couple,4 Mg,5 Mn,6 Zn,7 In,8 Sm,9 Al,10 Ga11 and other metals.12 Ti-, V- or Zr- complexes
were also widely used to promote this reaction.13 In the frame of green chemistry, our
research group focused on this particular reaction and several batch sustainable methodologies
have been reported: (i) using micellar catalysis under sonication;14 (ii) based on commercially
available acidic resins15 or using sole acidic water.16 Following our interest and first
encouraging results, a continuous flow system for selective pinacol coupling reaction was
envisaged. In fact, in the past few years, the use of heterogeneous flow systems in synthetic
organic chemistry has been widely explored due to many expected advantages such as very
efficient heat transfer compared with batch methodologies, good monitoring of temperature
and enhanced mass transfer.17 This innovative approach also permits the integration of several
steps into one single streamlined process, thus shortening the time from research to pilot-scale
and production.18 Concerning the pinacol coupling reaction, our goal was to enhance the
selectivity for pinacol coupling versus side reactions thanks an intimate contact between the
metal and the substrates. In fact, from our experiments, the limiting step for pinacol coupling
relies on the meeting of ketyl radicals allowing the formation of the C-C bound. As a
consequence, the main observed side product came from direct reduction of the carbonyl
compound 1 to the corresponding alcohol 3 (Scheme 1). Our goal was to design efficient and
selective coupling reaction in flow system in green conditions.
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Scheme 1. Pinacol coupling reaction and reduction side reaction
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OH
R
R
OH
O
R
+
R
OH
1
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RESULTS AND DISCUSSION
In the present work, a continuous flow system was used. All reactants were dissolved in
ethanol and pumped into the system thanks to an HPLC pump (0.5−20 mL min−1) at room
temperature. The solution was then flowed into a cartridge filled with zinc(0) powder. The
cartridge possesses an internal diameter of 15 mm and a length of 100 mm. In our case, the
piston was placed to allow a fixed useful volume of 4 mL containing the immobilized catalyst
and potential additives (Figure 1).
Zn (0)
(2-8 equiv)
pinacol compound 2
carbonyl compound 1 [0.75 M]
acid (1-4 equiv)
ethanol
1-4 mL min-1
Figure 1. Experimental set-up of the flow system.
In a first time, in order to insure a good solubility of all reactants, ethanol was selected as
solvent for the continuous flow reaction and zinc Zn(0) was packed. Crotonaldehyde (1a) was
chosen as model substrate and diluted in ethanol [0.75 M] in presence of 2 equivalents of
acetic acid as activator. Acetic acid was selected thanks to previously reported works for its
high promoting ability at room temperature.16 The solution was pumped at a 2 mL min-1 flow
rate at room temperature and the resulting solution was collected and analyzed (Table 1, entry
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1). After a single pass, 83% of the substrate 1a is converted and 75% of the corresponding
pinacol 2a is obtained. Only 4% of alcohol 2a is observed in the resulting solution. In such
conditions, the reaction in flow is highly selective. As expected, in absence of zinc, the
reaction did not occur (Table 1, entry 2). Increasing the amount of zinc to 3 equivalents
allowed a weak improvement of conversion and yield in 2a with an excellent selectivity
(Table 2, entry 3). However, when more zinc was in contact of the solution, the conversion
increased but favored the alcohol formation (Table 2, entries 4-5). As a compromise, the
amount of zinc was fixed at 4 equivalents to reach a total conversion (96%) and other
parameters were screened to manage the selectivity of the reaction.
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Table 1. Screening of zinc amount a
AcOH (2 equiv)
Zn (0-8 equiv)
EtOH
OH
OH
O
+
RT
2 mL min-1
OH
1a
[0.75 M]
2a
3a
relative sel.b
dl/meso
for 2a
45/55
-
equiv conversion
2a
(%)
75
0
3a
(%)
4
global sel.c
entry
(%)
Zn
2
(%)
83
0
(%)
90
-
1
2
3
4
5
95
-
0
0
3
85
96
94
77
81
83
4
95
94
92
91
84
88
40/60
40/60
40/60
4
5
8
7
a
Reaction conditions: crotonaldehyde (1a, 6 mmol) and AcOH (2 equiv) were diluted in
ethanol (8 mL) and flowed through the cartridge filled with a variable amount of zinc dust at 2
b
mL min-1 at room temperature. Relative selectivity is defined as the ratio between 2a and
(2a+3a). c Global selectivity is defined as the ratio between 2a and conversion.
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In a second time, different acid sources and quantities were screened and compared. For
liquid acids, they were directly diluted in ethanol in presence of crotonaldehyde (1a). For
insoluble ones, they were packed in the cartridge in presence of Zn(0). Two systems were
attempted: (i) the first one consisted in grinding the supported acid with zinc and packed them
together; (ii) the second one consisted in placing supported acid before and after the layer of
zinc (Figure 2). All results were gathered in Table 2.
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Figure 2. Different packing of zinc Zn(0) (grey) and Amberlyst®H15 (orange).
Table
2.
Influence
of
acid
sources
and
quantitiesa
acid (1-4 equiv)
Zn (4 equiv)
EtOH
OH
OH
O
+
RT
2 mL min-1
OH
2a
1a
[0.75 M]
3a
dl/meso
for 2a
40/60
equiv of conversion 2a 3a
relative
sel.b (%)
94
global
sel.c (%)
84
56
entry
acid source
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58
59
acid
(%)
(%) (%)
81
1
AcOH
2
96
5
60
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AcOH
AcOH
1
4
80
98
95
96
30
15
64
4
94
90
31
73
73
73
80
89
31
73
73
73
45/55
40/60
40/60
45/55
40/60
40/60
40/60
87 10
30 65
70 26
H2SO4
2
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CH3SO3H
2
Amberlyst®H15
Amberlyst®H15
H2SO4@SiO2
(33wt%)
2d
1+1e
22
8
11
4
8
2d
35
20 15
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aReaction conditions: crotonaldehyde (1a, 6 mmol) and acid were diluted in ethanol (8 mL)
and flowed through the cartridge filled with zinc dust (4 equiv) at 2 mL min-1 at room
b
c
temperature. Relative selectivity is defined as the ratio between 2a and (2a+3a). Global
d
selectivity is defined as the ratio between 2a and conversion. The supported acid was
e
grinding with zinc and the resulting mixture was filled in the cartridge. Zinc was packed
between two layers of supported acid separated by porous frits.
Decreasing the amount of acetic acid (1 vs 2) slowed the reaction rate and only 80%
conversion was obtained (Table 2, entry 2). Moreover, 64% of pinacol 2a was recovered at
the end of the process, suggesting that some product could be retained on the metal and did
not elute in the collection sample. As the acid is known to break down the chelates at the end
of the reaction, a low acid concentration should be insufficient for recovering all formed
products. Increasing the quantity of acetic acid (4 vs 2) boosted the conversion and allowed a
better 87% yield in pinacol 2a (Table 2, entry 3). However, as previously described, it also
favored the formation of the alcohol 3a in 10% yield. It is notable than all formed products
are recovered in the collection sample (98% conversion for 97% recovered products), which
proved the importance of a sufficient quantity of acid to recover them from zinc. Using
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sulfuric acid at 2 equivalents boosted the reaction but in favor of the direct reduction product
3a (Table 2, entry 4). This strong acid allowed the recovery of all formed products at the end
of the reaction. Liquid methanesulfonic acid was also strongly active in the reaction but with a
high 25% amount of alcohol formed (Table 2, entry 5). In order to vary the nature of acid,
some supported acids were used. Amberlyst®H15, a strongly acidic resin stable at room
temperature was mixed with zinc and the resulting mixture was packed in the cartridge. To
our disappointment, the conversion of the reaction after a single pass was low (only 30%)
even if the selectivity was good (Table 2, entry 6). Using the triple layer system
(acid/zinc/acid) decreased the conversion of the overall process but maintained the same
selectivity (Table 2, entry 7). Using sulfuric acid supported on silica gel gave moderate
conversion and yield with low selectivity (Table 2, entry 8). As a consequence, zinc Zn(0) (4
equiv) and acetic acid (2 equiv) in a continuous flow process at room temperature were kept
as standard for further optimization.
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Table 3. Influence of flow rate variationa
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AcOH (2 equiv)
Zn (4 equiv)
EtOH
OH
OH
O
+
8
9
RT
1-4 mL min-1
OH
2a
1a
[0.75 M]
3a
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2a 3a relative sel.b
global
dl/meso
residence
conversion
entry
sel.c (%)
74
for 2a
time (min)
(%)
95
96
79
89
(%) (%)
70 15
(%)
82
94
94
94
1
2
3
4
4
2
40/60
45/55
40/60
40/60
81
64
76
5
4
5
84
1.33
1
81
85
aReaction conditions: crotonaldehyde (1a, 6 mmol) and AcOH (2 equiv) were diluted in
ethanol (8 mL) and flowed through the cartridge filled with zinc dust (4 equiv) at room
b
c
temperature. Relative selectivity is defined as the ratio between 2a and (2a+3a). Global
selectivity is defined as the ratio between 2a and conversion.
In a third time, the flow rate was varied between 1 and 4 mL min-1 for 4 equivalents of
packed zinc dust in presence of acetic acid (2 equiv). This modification impacted on the
residence time and also on the productivity in pinacol 2a (Table 3). Indeed, the faster is the
flow rate, the lower is the residence time but the higher is the productivity. With a continuous
flow of 2 mL min-1, 96% conversion were obtained with a good 84% selectivity for pinacol
product 2a (Table 3, entry 2). Only 5% of alcohol 3a was observed after a single pass. When
the residence time is doubled the conversion is still high but a large amount of alcohol 3a
(15%) is obtained (Table 3, entry 1). A long contact with zinc seems to favor the direct
reduction process. When the flow rate increased, the conversion decreased but the selectivity
remained the same as for a 2 mL min-1 rate. It is possible than the carbonyl compound did not
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have enough contact time with zinc to efficiently react. As a consequence, 2 mL min-1 flow
rate was chosen as compromise between conversion, yield and selectivity.
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Zn (0)
(3-4 equiv)
Zn (0)
(3-4 equiv)
pinacol compound 2a
crotonaldehyde (1a) [0.75 M]
AcOH (2 equiv)
ethanol
RT
2 mL min-1
Figure 3. Experimental set-up of the flow system using two cartridges.
As the reaction is not total at the end of the first run, the collected solution was re-injected
in a second cartridge filled with fresh zinc Zn(0) (4 equiv) (Figure 3). To insure the recovery
of all formed products at the end of the two passes, a solution of AcOH in ethanol was
flowed. As expected, the conversion after passage trough the two cartridges is total and a
good 85% yield in pinacol 2a is obtained (Table 4, entry 2). When the same system was used
with 3 equivalents of zinc, the conversion is still total and an excellent 91% yield in pinacol
2a is obtained (Table 4, entry 4). 5% of alcohol 3a is observed accompanied by some minor
side-products.
To finish, the recyclability of the zinc cartridge was evaluated. 8 initial equivalents of zinc
dust were packed in the cartridge and some freshly prepared solutions of crotonaldehyde (1a)
in AcOH/ethanol were flowed through the catalyst bed (Figure 4).
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Table 4. Effect of a double pass on the reactiona
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6
7
AcOH (2 equiv)
Zn (3-8 equiv)
EtOH
OH
OH
O
+
8
9
RT
2 mL min-1
OH
2a
1a
[0.75 M]
3a
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dl/meso
number of equiv
conversion
(%)
2a
global sel.b
entry
for 2a
cartridge
Zn
4
(%)
81
85
77
91
(%)
84
85
91
91
1
2
3
4
0
1
0
1
96
40/60
45/55
40/60
40/60
4 + 4
3
100
85
3 + 3
100
aReaction conditions: crotonaldehyde (1a, 6 mmol) and AcOH (2 equiv) were diluted in
ethanol (8 mL) and flowed through the cartridge filled with zinc dust Zn(0) at 2 mL min-1 at
room temperature. At the end of the process, a mixture of AcOH/ethanol was flowed to
b
recover all formed products. Global selectivity is defined as the ratio between 2a and
conversion.
100
80
Pinacol 2a
60
40
20
0
Conversion
1
2
3
4
5
6
7
8
9
10 11 12
Figure 4. Recycling of the packed catalyst over time for 12 consecutive runs.
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Until the 10th run, conversions are high and yields in 2a are good and comprised between
70 and 85% with an average value of 75%. After the 10th run, conversion begun to decrease
dramatically and lower amounts of pinacol 2a were observed. This decrease in yield and
conversion is accompanied by the physical disappearance of zinc dust in the cartridge. In fact,
after 10 runs, a lot of zinc dust has reacted and was converted to white zinc salts poorly
soluble in ethanol. Under these flow conditions, the pinacol coupling reaction is realized with
less than 1 equivalent of zinc per run which is a good result compared with all reported batch
methods.
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The optimized conditions: carbonyl compound (6 mmol) diluted in ethanol (8 mL) in
presence of AcOH (2 equiv) flowed through a packed zinc bed (4 equiv) at a flow rate of 2
mL min-1 at room temperature were then applied to some various carbonyl compounds in a
single pass (Table 5). The first scope was realized on α,β unsaturated compounds with a long
linear chain ((E)-hex-2-enal (1b)) and branched chain ((E)-2-methylpent-2-enal (1c)) (Table
5, entries 2-4). The pinacol coupling of aldehyde 1b afforded the desired product in a 70%
yield and 80% conversion. The selectivity for coupling is very good and only 9% of alcohol
3b is obtained (Table 5, entry 2). These results are slightly above those obtained for
crotonaldehyde (1a) in a single pass, probably due to the steric hindrance of the aliphatic
chain. As previously shown, a second pass through another zinc bed has been realized and, as
expected, the conversion is total and led to pinacol 2b in 88% yield with high selectivity
(Table 5, entry 3). Much hindered substrate 1c reacted with a moderate 50% conversion but
with a high selectivity for pinacol coupling 2c (Table 3, entry 4). Aromatic α,β unsaturated
aldehyde 1d reacted well in flow conditions and gave 85% yield in pinacol product 2d
accompanied with only 6% of cinnamyl alcohol 3d. Some aromatic aldehydes 1d-k, well
known for their reactivity in reductive coupling, were then submitted to the optimized flow
conditions. It is notable, than benzaldehyde (1e) was totally converted to 68% of pinacol 2e
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and 32% of benzyl alcohol (3e) (Table 5, entry 6). 4-Bromobenzaldehyde (1f) was then
successfully submitted to the continuous flow process, with an excellent 92% yield in pinacol
2f (Table 5, entry 7). The same result was observed for 4-tolualdehyde (1g), with excellent
yield and selectivity (Table 5, entry 8). Aromatic aldehydes bearing chlorine groups displayed
a moderate reactivity in favour of the direct reduction products 3h and 3i (Table 5, entries 9
and 10). It is noteworthy that the use of aldehydes 1f and 1h having respectively a bromine
and chlorine atom necessited to dilute the solution. Acetophenone (1j) reacted slowly under
such flow conditions, giving only 9% of the desired pinacol product 2j. This result can be
attributed to the steric hindrance and the lower reactivity of aromatic ketones compared with
aldehydes (Table 5, entry 11). As envisioned, much more hindered benzophenone (1k) or
aliphatic aldehyde 1l did not react in such conditions (Table 5, entries 12-13).
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Table 5. Scope of the continuous flow process in a single passa
AcOH (2 equiv)
Zn (4 equiv)
EtOH
HO
O
R1
R2
OH
R1
R2
+
R1 R2
R1 R2
RT
2 mL min-1
OH
1
[0.75 M]
2
3
substrate
relative
conv.
2
3
global
dl/meso
entry cpd
sel.c (%)
(%)
96
(%) (%) sel.b (%)
for 2
40/60
35/65
35/65
0/100
60/40
R1
R2
H
H
H
H
H
1
2
a
b
b
c
d
(E) CH3-CH=CH-
(E) C3H7-CH=CH-
(E) C3H7-CH=CH-
(E) C2H5-CH=C(CH3)-
(E) C6H4-CH=CH-
81
70
88
40
85
5
9
84
87
88
80
89
94
89
88
-
80
3d
4
100
50
11
nde
6
5
95
93
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e
f
C6H5
4-Br-C6H4
4-CH3-C6H4
4-Cl-C6H4
2,3-(Cl)2-C6H4
C6H5
H
H
100
100
100
55
48
10
0
68
92
92
20
15
9
32
2
68
92
92
36
31
90
-
68
98
30/70
25/75
50/50
25/75
15/85
55/45
-
7f
8
9
8
g
h
i
H
<5
33
28
1
>95
38
10
9g
11
12
H
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11
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13
H
31
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j
CH3
C6H4
H
90
k
l
C6H5
0
0
-
-
CH3-CH2-CH2-
0
0
0
-
-
aReaction conditions: aldehyde or ketone (1, 6 mmol) and AcOH (2 equiv) were diluted in
ethanol (8 mL) and flowed through the cartridge filled with zinc dust (4 equiv) at 2 mL min-1
b
at room temperature. Global selectivity is defined as the ratio between 2a and conversion.
cRelative selectivity is defined as the ratio between 2 and (2+3). The collection sample was
d
e
f
re-injected in a second zinc cartridge (Zn(0) 4 equiv). nd = not determined. The reaction
medium was diluted to 24 mL of EtOH. gThe reaction medium was diluted to 32 mL of EtOH.
In terms of comparison, the batch reaction was carried out with some relevant examples
(Table 6). Crotonaldehyde (1a), which is highly reactive and possesses a short aliphatic chain,
reacted with an excellent selectivity for pinacol coupling (Table 6, entry 1). (E)-hex-2-enal
(1b) showed a dramatic decrease in results in batch conditions compared with the flow ones,
with a majority of alcohol 3b formed at the end of the process (Table 6, entry 2). The same
tendency was observed when cinnamaldehyde (1d), benzaldehyde (1e) or 4-tolualdehyde (1g)
were used as substrate, with lower selectivities in batch conditions than in continuous flow
process (Table 6, entries 3-5). These results confirmed that, in our conditions, continuous flow
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process favoured the pinacol coupling of the substrates, probably due to an intimate contact
between zinc and formed ketyl radicals.
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Table 6. Comparison with batch conditions using AcOH/EtOHa
5
6
7
8
AcOH (2 equiv)
Zn (4 equiv)
EtOH
HO
O
R1
R2
OH
R1
R2
+
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R1 R2
RT
20 min
1200 rpm
OH
9
1
[0.75 M]
2
3
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11
12
13
14
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global sel.b
relative sel.c
Substrate
R1
conv.
2
3
entry cpd
R2
H
H
H
H
H
(%)
100
60
(%) (%)
(%)
99
33
50
13
18
(%)
99
39
50
14
21
1
2
3
4
5
a
b
d
e
g
(E) CH3-CH=CH-
(E) C3H7-CH=CH-
(E) C6H4-CH=CH-
C6H5
99
20
42
8
1
31
42
49
27
90
60
4-CH3-C6H4
38
7
aReaction conditions: carbonyl compound (1, 6 mmol) and AcOH (2 equiv) in presence of
zinc Zn(0) (4 equiv) were diluted in ethanol (8 mL) and stirred (1200 rpm) at room
b
temperature for 20 minutes. Global selectivity is defined as the ratio between 2a and
conversion. cRelative selectivity is defined as the ratio between 2 and (2+3).
CONCLUSION
The first highly selective continuous flow pinacol coupling reaction in acidic medium has
been developed using an HPLC-type pump and a cartridge filled with the adequate reductor.
The optimized conditions allowed the formation of pinacol products for α,β unsaturated and
aromatic aldehydes with a residence time of 2 minutes. The cartridge is filled with cheap zinc
metal Zn(0) which can be used at less than 1 equivalent per substrate for high conversion and
productivity.
EXPERIMENTAL SECTION
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General information. All commercially available products and solvents were used without
further purification. Reactions were monitored by TLC (Kieselgel 60F254 aluminum sheet)
with detection by UV light or potassium permanganate acidic solution. Column
chromatography was performed on silica gel 40−60 µm. Flash column chromatography was
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performed on an automatic apparatus, using silica gel cartridges. H and C 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 and 2D methods
(HMBC and HSQC experiments) have been used to confirm the NMR peak assignments.
General procedure for the synthesis of pinacol products 2. The desired carbonyl
compound (1, 6 mmol) is dissolved in ethanol (8 mL) in presence of acetic acid (2 equiv, 685
mg). The resulting solution is pumped at room temperature by an HPLC-type pump and
flowed through a packed zinc dust (4 equiv) cartridge (intern diameter 15 mm, length 100
mm, useful volume 4 mL) at 2 mL min-1 flow rate. At the end of the process, 8 mL of pure
ethanol is flowed through the system. Ethanol is then evaporated and the crude product was
purified over a column of silica gel and eluted with a gradient of cyclohexane / ethyl acetate
to give the pinacol products 2.
(2E,6E)-Octa-2,6-diene-4,5-diol (dl and meso) (2a).19, 15, 16 Table 5, entry 1, colorless oil
1
(346 mg, 81% yield): H NMR (400 MHz, CDCl3) δ ppm: 1.65 (t, J = 6,5 Hz, 6H, CH3),
2.55-2.47 (bs, 2H, OH), 3.84 (d, J = 4.7 Hz, 2H, CH-OH, dl form), 3.99 (d, J = 6.2 Hz, 2H,
CH-OH, meso form), 5.45-5.36 (m, 2H, CH=CH), 5.73-5.66 (m, 2H, CH=CH). 13C{1H}NMR
(100 MHz, CDCl3) δ ppm: 17.9 (2xCH3), 75.6 (CH), 75.8 (CH), 128.9 (CH=CH), 129.1
(CH=CH), 129.4 (CH=CH), 129.8 (CH=CH). MS (ESI): 143.10 [M + H]+, 165.11 [M + Na]+.
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(4E,8E)-Dodeca-4,8-diene-6,7-diol (dl and meso) (2b).20, 15,16 Table 5, entry 2, colorless oil
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9
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(417 mg, 70% yield): H NMR (400 MHz, CDCl3) δ ppm: 0.85-0.79 (m, 6H, 2 CH3), 1.36-
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1.30 (m, 4H, 2 CH2), 1.99-1.93 (m, 4H, 2 CH2), 2.82 (brs, 2H, OH), 3.81 (d, J = 8.4 Hz, 2H,
CH-OH dl form), 4.00 (d, J = 8.4 Hz, 2H, CH-OH meso form), 5.42-5.32 (m, 2H, CH=CH),
13
5.68-5.61 (m, 2H, CH=CH). dl-2b: C{1H}NMR (100 MHz, CDCl3) δ ppm: 13.6 (CH3),
22.2 (CH2), 34.4 (CH2), 76.1 (CH), 128.8 (CH=CH), 134.2 (CH=CH). meso-2b:
13C{1H}NMR (100 MHz, CDCl3) δ ppm: 13.6 (CH3), 22.2 (CH2), 34.4 (CH2), 75.6 (CH),
128.0 (CH=CH), 134.5 (CH=CH). MS (ESI): 199.16 [M + H]+, 221.17 [M + Na]+.
(3E,7E)-4,7-Dimethyldeca-3,7-diene-5,6-diol (meso) (2c).16 Table 5, entry 4, colorless oil
(238 mg, 40% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 0.92 (t, 6H, 2 CH3), 1.59 (s, 6H, 2
CH3), 2.00 (quint, J = 7.6 Hz, 4H, 2 CH2), 2.36 (bs, 2H, 2 OH), 3.97 (s, 2H, 2 CH-OH), 5.41
(td, 2H, 2 CH=C). 13C NMR (100 MHz, CDCl3) δ ppm: 11.8 (CH3), 13.9 (CH3), 20.8 (CH2),
78.8 (CH), 130.7 (CH=C), 133.0 (CH=C). HRMS (ESI): found 221.1508; calculated
221.1517 for C12H22O2Na.
(1E,5E)-1,6-Diphenylhexa-1,5-diene-3,4-diol (dl and meso) (2d).14, 21a Table 5 entry 5,
1
white solid (679 mg, 85% yield): mp= 112-114°C [litt. 106-155°C]. H NMR (400 MHz,
CDCl3) δ ppm: 2.63 (bs, 2H, OH), 4.29 (dd, J = 11.4, 5.4 Hz, 2H, CH-OH dl form), 4.46 (dd,
J = 9.4, 3.8 Hz, 2H, CH-OH meso form), 6.35-6.26 (m, 2H, CH=CH), 6.76-6.70 (m, 2H,
13
CH=CH), 7.43-7.22 (m, 10H, CHAr). C{1H}NMR (100 MHz, CDCl3) δ ppm: 75.8 (CH
meso form), 75.9 (CH dl form), 126.6 (CH), 126.7 (CH), 127.1 (CH), 127.8 (CH), 127.9
(CH), 128.0 (CH), 128.6 (2 CH), 132.7 (CH), 133.0 (CH), 136.4 (CIV), 136.5 (CIV). MS (ESI):
267.13 [M + H]+, 289.12 [M + Na]+.
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1,2-Diphenylethane-1,2-diol (dl and meso) (2e).21a-c Table 5, entry 6, white solid (594 mg,
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1
68% yield): mp= 120-122°C [litt. 119-159°C]. dl-2e: H NMR (400 MHz, CDCl3) δ ppm:
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2.32 (bs, 2H, OH), 4.61 (s, 2H, CH-OH), 7.23-7.02 (m, 10H, CHAr). C{1H}NMR (100
MHz, CDCl3) δ ppm: 79.0 (CH-OH), 126.9 (2 CHAr), 127.9 (CHAr), 128.1 (2 CHAr), 139.8
1
(CIV). meso-2e: H NMR (400 MHz, CDCl3) δ ppm: 2.32 (bs, 2H, OH), 4.74 (s, 2H, CH-
OH), 7.23-7.02 (m, 10H, CHAr). C{1H}NMR (100 MHz, CDCl3) δ ppm: 78.0 (CH-OH),
13
127.1 (2 CHAr), 128.1 (CHAr), 128.2 (2 CHAr), 139.7 (CIV). MS (ESI): 215.10 [M + H]+,
237.11 [M + Na]+.
1,2-Bis(4-bromophenyl)-ethane-1,2-diol (dl and meso) (2f).21 Table 5, entry 7, white solid
(1.026 g, 92% yield): mp= 159-161°C. dl-2f: 1H NMR (400 MHz, CDCl3) δ ppm: 2.02-1.97
(bs, 2H, OH), 4.53 (s, 2H, CH-OH), 6.90 (d, J = 8.4 Hz, 4H, CHAr), 7.30 (d, J = 8.4 Hz, 4H,
CHAr). C{1H}NMR (100 MHz, CDCl3) δ ppm: 79.1 (CH), 128.1 (CIV), 127.1 (2 CHAr),
13
1
128.1 (CIV), 128.2 (2 CHAr), 139.7 (CIV). meso-2f: H NMR (400 MHz, CDCl3) δ ppm:
2.02-1.97 (bs, 2H, OH), 4.75 (s, 2H, CH-OH), 6.99 (d, J = 8.4 Hz, 4H, CHAr), 7.34 (d, J =
8.4 Hz, 4H, CHAr). C{1H}NMR (100 MHz, CDCl3) δ ppm: 78.0 (CH), 126.9 (2 CHAr),
13
127.9 (CIV), 128.1 (2 CHAr), 139.8 (CIV). MS (ESI): 370.92 (50%) [M + H]+, 372.92 (100%),
374.92 (50%).
1,2-Bis(4-methylphenyl)-ethane-1,2-diol (dl and meso) (2g).21a-c Table 6 entry 8, beige solid
(669 mg, 92% yield): mp= 165-166°C [litt 161-180°C]. 1H NMR (400 MHz, CDCl3) δ ppm:
2.22 (s, 6H, 2 CH3), 2.26 (s, 6H, 2 CH3), 4.57 (s, 2H, CH-OH dl form), 4.65 (s, 2H, CH-OH
meso form), 7.10-6.93 (m, 8H, CHAr). C{1H}NMR (100 MHz, CDCl3) δ ppm: 21.2 (4
13
CH3), 78.1 (CH-OH meso form), 78.8 (CH-OH dl form), 126.9 (2 CHAr), 127.1 (2 CHAr),
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128.8 (2 CHAr), 129.0 (2 CHAr), 137.0 (2 CIV), 137.5 (CIV), 137.8 (CIV). MS (ESI): 243.13
[M + H]+, 267.12 [M + Na]+.
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1,2-Bis(4-chlorophenyl)-1,2-ethanediol (dl and meso) (2h)14, 15, 16, 21c Table 5, entry 9, white
solid (mg, % yield): mp= 146-149°C. dl-2h: 1H NMR (400 MHz, CDCl3) δ ppm: 4.62 (s, 2H,
1
CH-OH), 7.02 (d, J = 8.4 Hz, 4H, 2 CHAr), 7.21 (d, J = 8.4 Hz, 4H, 2 CHAr). meso-2h: H
NMR (400 MHz, CDCl3) δ ppm: 4.84 (s, 2H, CH-OH), 7.113 (dd, J = 8.4, 1.6 Hz, 4H, 2
CHAr), 7.23 (m, 4H, CHAr). 13C{1H}NMR (100 MHz, CDCl3) δ ppm: 77.2 (CH meso
form), 78.6 (CH dl form), 128.4 (CHAr), 128.4 (CHAr), 128.4 (CHAr), 128.9 (CHAr), 131.6
(CIV), 133.9 (CIV), 137.8 (CIV), 137.9 (CIV). MS (ESI): 283.02 (100%), 285.02 (64%) [M +
H]+.
1,2-Bis(2,3-dichlorophenyl)-ethan-1,2-diol (dl and meso) (2i).14, 6a, 21, 22 Table 5 entry 9,
white solid (158 mg, 15% yield): mp= 178-180°C. dl-2i: 1H NMR (400 MHz, CDCl3) δ ppm:
2.19 (bs, 2H, OH), 5.38 (s, 2H, CH-OH), 7.26 (t, J = 8.0 Hz, 2H, CHAr), 7.43 (dd, J = 8.0, 1.6
13
Hz, 2H, CHAr), 7.62 (dd, J = 8.0, 1.6 Hz, 2H, CHAr). C{1H}NMR (100 MHz, CDCl3)
δ ppm: 73.0 (CH), 127.2 (CHAr), 127.3 (CHAr), 130.1 (CHAr), 131.5 (CIV), 133.2 (CIV),
1
139.7 (CIV). meso-2i: H NMR (400 MHz, CDCl3) δ ppm: 2.19 (bs, 2H, OH), 5.64 (s, 2H,
CH-OH), 7.11 (t, J = 8.0 Hz, 2H, CHAr), 7.18 (dd, J = 7.9, 1.7 Hz, 2H, CHAr), 7.35 (dd, J =
8.0, 1.6 Hz, 2H, CHAr). 13C{1H}NMR (100 MHz, CDCl3) δ ppm: 72.3 (CH), 126.9 (2
CHAr), 129.8 (CHAr), 129.8 (CIV), 132.5 (CIV), 138.5 (CIV). MS (ESI): 352.94 (100%),
350.94 (78%), 354.94 (48%) [M + H]+.
2,3-diphenylbutane-2,3-diol (dl and meso) (2j).14,16, 21b, 23 Table 5 entry 10, white solid (66
1
mg, 9% yield): mp= 128-129°C. H NMR (400 MHz, CDCl3) δ ppm: 1.50 (s, 6H, CH3 dl
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form), 1.58 (s, 6H, CH3 meso form), 2.49 (bs, 2H, OH dl and meso forms), 7.26-7.20 (m,
5
6
13
10H, CHAr dl and meso forms). C{1H}NMR (100 MHz, CDCl3) δ ppm: 24.9 (CH3 dl
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form), 25.0 (CH3 meso form), 78.6 (CIV meso form), 78.8 (CIV dl form), 126.8 (CHAr), 126.9
(2 CHAr), 127.0 (CHAr), 127.1 (2 CHAr), 127.2 (2 CHAr), 127.3 (2 CHAr), 143.3 (CIV),
143.7 (CIV). MS (ESI): 243.13 [M + H]+, 267.12 [M + Na]+.
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ASSOCIATED CONTENT
Supporting Information
1H and 13C experiments spectra are provided.
AUTHOR INFORMATION
Corresponding Author
*Fax: +33 (0)3 44 97 15 91. Tel: +33 (0)3 44 23 88 28. E-mail: christophe.len@utc.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was performed, in partnership with the SAS PIVERT, within the frame of the
French Institute for the Energy Transition (Institut pour la Transition Energétique (ITE)
P.I.V.E.R.T. (www.institut-pivert.com) selected as an Investment for the Future
(“Investissements d’Avenir”). This work was supported, as part of the Investments for the
Future, by the French Government under the reference ANR-001-01.
REFERENCES
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