Switchable Chemoselective Transfer Hydrogenations of Unsaturated Carbonyls Using Copper(I) N-Donor Thiolate Clusters

Article abstract of DOI:10.1021/acs.joc.7b02676

Unsaturated alcohols and saturated carbonyls are important chemical, pharmaceutical, and biochemical intermediates. We herein report an efficient transfer hydrogenation protocol in which conversion of unsaturated carbonyl compounds to either unsaturated alcohols or saturated carbonyls was catalyzed by Cu(I) N-donor thiolate clusters along with changing hydrogen source (isopropanol or butanol) and base (NaOH or K₂CO₃). Mechanistic studies supported by DFT transition state modeling indicate that such a chemoselectivity can be explained by the relative concentrations of Cu(I) monohydride and protonated Cu(I) hydride complexes in each catalytic system.

Full text of DOI:10.1021/acs.joc.7b02676

Subscriber access provided by READING UNIV
Article
Switchable Chemoselective Transfer Hydrogenations of
Unsaturated Carbonyls Using Copper(I) N-donor Thiolate Clusters
Meng-Juan Zhang, Da-Wei Tan, Hong-Xi Li, David James
Young, Hui-Fang Wang, Hai-Yan Li, and Jian-Ping Lang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02676 • Publication Date (Web): 09 Jan 2018
Downloaded from http://pubs.acs.org on January 10, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Switchable Chemoselective Transfer Hydrogenations of
Unsaturated Carbonyls Using Copper(I) N-donor Thiolate
Clusters
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
MengꢀJuan Zhang,† DaꢀWei Tan,† HongꢀXi Li,*,†,‡ David James Young,§ HuiꢀFang Wang,*,†
HaiꢀYan Li,† and JianꢀPing Lang*,†,‡
†College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, Jiangsu, People’s Republic of China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
§Faculty of Science and Engineering, University of the Sunshine Coast, Maroochydore DC,
Queensland, 4558 Australia
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
__________________________
† Soochow University
‡ Shanghai Institute of Organic Chemistry
§ University of the Sunshine Coast
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 44
1
2
3
4
______________________________________________________________________________
5
6
7
8
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
ABSTRACT: Unsaturated alcohols and saturated carbonyls are important chemical,
pharmaceutical and biochemical intermediates. We herein report an efficient transfer
hydrogenation protocol in which conversion of unsaturated carbonyl compounds to either
unsaturated alcohols or saturated carbonyls was catalyzed by Cu(I) Nꢀdonor thiolate clusters
along with changing hydrogen source (isopropanol or butanol) and base (NaOH or K2CO3).
Mechanistic studies supported by DFT transition state modeling indicate that such a
chemoselectivity can be explained by the relative concentrations of Cu(I) monohydride and
protonated Cu(I) hydride complexes in each catalytic system.
______________________________________________________________________________
INTRODUCTION
The chemoselective hydrogenation of unsaturated aldehydes and ketones to generate allylic
alcohols1ꢀ4 or saturated carbonyl compounds5ꢀ7 is an important transformation in organic
synthesis, pharmaceutical chemistry, and biochemistry.8ꢀ11 Considerable efforts have been
devoted to selective heterogeneous and homogeneous catalytic reductions using flammable
hydrogen gas,12ꢀ15 costly hydrosilanes,16ꢀ20 borohydrides,21ꢀ23 Hantzsch esters,24ꢀ26 etc,27ꢀ32 as
reducing agents. The selectivity of hydrogenation is influenced by the metal center, organic
2
ACS Paragon Plus Environment

Page 3 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ligand, the structure, texture and composition of the catalyst (particle size, shape, support, molar
ratio of components), reaction conditions (temperature, pressure and solvent) and substituents on
the substrates.33ꢀ43 Catalytic transfer hydrogenation using benign alcohols as hydride sources
represents an attractive alternative to these methods, in terms of atom economy and
environmental impact.44ꢀ53 Metal hydride species generated from molecular Pd,54ꢀ56 Ir,57ꢀ59
Ru,60,61 Ni62 complexes, preferentially transferꢀhydrogenate the C=C bond of unsaturated
carbonyls to saturated carbonyl compounds. By comparison, metalꢀligand bifunctional
H−M−NH catalysis, pioneered by Noyori’s group,63,64 provides an efficient chemoselective
transfer hydrogenation of C=O bonds in unsaturated carbonyl compounds.66ꢀ78 Chemoselective
access to both unsaturated alcohols and saturated carbonyls with a single catalyst has hitherto not
been achieved.
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
We have a longꢀstanding interest in the synthesis and catalytic properties of Cu(I) Nꢀ
heterocycle thiolate clusters.79,80 These complexes are attractive candidates for the
chemoselective transfer hydrogenation of unsaturated carbonyls to both allylic alcohols and
saturated carbonyls because (i) thiolate ligands can stabilize Cu(I) hydride catalysts,81,82 (ii) Cu(I)
thiolates display high catalytic activity,83 (iii) copper nanoparticles (CuNPs) are active for the
transfer hydrogenation of carbonyl compounds,84,85 but show poor chemoselectivity in the
presence of C=C, C=N and N=N bonds,85 and (iv) Nꢀdonor thiols such as pyrimidineꢀ2ꢀthiol are
relatively nonꢀtoxic ligands that bind metal ion as the neutral thione or anionic thiolate.79,80,83,86ꢀ91
This dual coordinating ability could potentially form dualꢀacting catalytic intermediates (Scheme
1). Can the two active species transfer hydrogenate unsaturated carbonyls with C=C bond54ꢀ63
reduction or C=O bond64ꢀ78 reduction? We herein report that indeed Cu(I) Nꢀheterocycle thiolate
clusters efficiently mediate the chemoselective transfer hydrogenation of unsaturated carbonyl
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 44
1
2
3
4
5
6
compounds to either unsaturated alcohols or saturated carbonyls by a simple manipulation of
reaction conditions.
7
8
9
Scheme 1. Structures of Cu(I) N-heterocycle Thiolate Complexes and Possible Dual Acting
Hydride Species for Hydrogenation of Unsaturated Carbonyl Compounds
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
O
N
N
R3
R3
R3
R1
R1
R2
R2
R2
S
S
H
S
Cu
S
S
n
O
N
N
monohydride complex
S
S
H
N
N
N
OH
R1
H
S
Cu
N
n
protonated Cu(I) hydride complex
RESULTS AND DISCUSSION
A series of Cu(I) Nꢀheterocycle thiolate complexes [Cu3(pymt)3]n (1a)87,88 and [Cu6(L)6] (L =
btt (1b),89 pyt (1c),90 dmpymt (1d),91 5ꢀphpymt (1e),80 mtpmt (1f),79 4ꢀphpymt (1g), 4,5ꢀ
diphpymt (1h) were prepared by reaction of CuI with excess pyrimidineꢀ2ꢀthiol (Hpymt), 2ꢀ
benzothiazolethiol (Hbtt), pyridineꢀ2ꢀthiol (Hpyt), 4,6ꢀdimethylpyrimidineꢀ2ꢀthiol (Hdmpymt),
5ꢀphenylpyrimidineꢀ2ꢀthiol (5ꢀHphpymt), 4ꢀphenylpyrimidineꢀ2ꢀthiol (4ꢀHphpymt), 5ꢀmethylꢀ4ꢀ
(pꢀtolyl)pyrimidineꢀ2ꢀthiol (Hmtpmt) or 4,5ꢀdiphenylpyrimidineꢀ2ꢀthiol (4,5ꢀHdiphpymt) in the
presence of Et3N. Solvothermal reaction of CuI with 4,6ꢀdiphenylꢀ5,6ꢀdihydropyrimidineꢀ2(1H)ꢀ
thione (4,6ꢀH3diphpymt) produced [Cu6(4,6ꢀdiphpymt)6] (1i, 4,6ꢀHdiphpymt
=
4,6ꢀ
diphenylpyrimidineꢀ2ꢀthiol). In this reaction, 4,6ꢀH3diphpymt was oxidized to the 4,6ꢀdiphpymtꢀ
ligand in situ (Scheme 2). The structures of 1gꢀ1i (Figures S1ꢀS3) resemble those of 1bꢀ1f.79,80,89ꢀ
91
Six Cu(I) atoms are connected by six 4ꢀphpymt, 4,5ꢀdiphpymt or 4,6ꢀdiphpymt ligands to
yield a hexanuclear structure.
4
ACS Paragon Plus Environment

Page 5 of 44
The Journal of Organic Chemistry
1
2
3
4
Scheme 2. Structures of Complexes 1a-1i
5
6
7
8
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
With these asꢀprepared copper(I) Nꢀdonor thiolate clusters 1aꢀ1i in hands, we examined their
catalytic activity toward the transfer hydrogenation reduction of cinnamaldehyde (2aa) with
propanꢀ2ꢀol (iꢀPrOH) as both the hydrogen source and solvent (Table 1). The hydrogenation of
2aa could occur at C=O and/or C=C bonds to afford cinnamic alcohol (3aa), 3ꢀphenylpropanal
(4aa) and 3ꢀphenylpropanꢀ1ꢀol (5aa), respectively. We firstly carried out the reaction of 2aa (1.0
mmol) with 1a (5 mol% of Cu) and NaOH (20 mol%) in 4 mL iꢀPrOH at 100 ºC. After 10 hours,
the conversion of 2aa was achieved 90% and the selectivity for 3aa was 84% in the final product
distribution. As presented in Table 1, 1aꢀ1i selectively reduced the C=O bond prior to the
reduction of the C=C bond (entries 1ꢀ9). Among these catalysts, 1d displayed the highest activity
and selectivity, giving an almost quantitative conversion to 3aa with 98% selectivity (entry 4).
By comparison, [CuI(bpy)]2 (bpy = 2,2'ꢀbipyridine), [CuI(phen)]2 (phen = 1,10ꢀphenanthroline)
and CuI (entries 10ꢀ12) exhibited a much lower catalytic activity and chemoselectivity than these
Cu clusters. The blank reaction of using only NaOH without catalyst proceeded in 13%
conversion (entry 13), which was ascribed to the baseꢀcatalyzed MeerweinꢀPondorfꢀVerley
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 44
1
2
3
4
5
6
7
8
9
(MPVꢀO) reduction.92ꢀ94 These results indicated that Cu(I) Nꢀheterocycle thiolate complexes
were responsible for the hydrogen transfer reaction and the Nꢀdonor thiolate ligands exerted a
significant impact on their catalytic activity. Therefore 1d and 2aa were chosen as a model
system to optimize the reaction conditions such as base, solvent, and temperature. Base played a
critical role in catalytic hydrogenation and the product distribution (entries 14ꢀ22). NaOH proved
excellent conversion with superior selectivity (entry 4). The use of tꢀBuONa or tBuOK as a base
gave a complete conversion of 2aa, but with lower selectivity for 3aa than NaOH (entries 14 and
15). When KOH, LiOH, or Cs2CO3 was used as a base, the conversions of 2aa were 89ꢀ98%
with 92ꢀ53% selectivity of 3aa (entries 16ꢀ18). Surprisingly, weak bases such as K2CO3 and
K3PO4 (entries 19 and 20) exhibited reduced activity and lower selectivity while Na2CO3 was
almost inactive (entry 21). Cluster 1d did not work without the addition of base (entry 22). A
decreased proportion of NaOH (10 mol%) led to a lower catalysis performance (entry 23), but
beyond this amount (20 mol %), the selectivity of 3aa actually decreased to 90% and 85% for
stoichiometries of 50 mol% and 100 mol%, respectively (entries 24 and 25). At lower
temperatures (80 ºC), the reaction proceeded in a commensurately yield (entry 26). 1d also
showed high activity but with moderate selectivity for 3aa (45ꢀ59%) in MeOH, EtOH and 1ꢀ
butanol (nꢀBuOH) (entries 27ꢀ29). The selectivity of 5aa in MeOH and EtOH increased. The
yield of 4aa increased from 2% in iꢀPrOH to 42% in nꢀBuOH. The chemoselective transfer
hydrogenation could be best achieved in iꢀPrOH as a solvent and hydrogen agent using 1d (5 mol
% Cu) as a catalyst, 20 mol % of NaOH as a base, at 100 ºC within 10 h.
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
Table 1. Optimizing Reaction Conditions for the Transfer Hydrogenation Reduction of 2aa
CHO
CH2OH
CH2OH
CHO
Cat., Base
Solvent, 100 oC
+
+
2aa
3aa
4aa
5aa
6
ACS Paragon Plus Environment

Page 7 of 44
The Journal of Organic Chemistry
1
2
3
4
Entrya Cat.
Base
Solvent
Conversionb
Yieldb
5
6
3aa 4aa 5aa
7
8
9
1a
1b
1c
1d
1e
1f
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
90%
97%
88%
>99%
94%
89%
95%
93%
94%
32%
47%
51%
13%
>99%
>99%
98%
97%
89%
20%
15%
<1%
<1%
79%
>99%
>99%
79%
84% 7%
92% 6%
83% 9%
98% 2%
85% 8%
9%
2%
8%
trace
7%
1
2
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
4
5
79% 12% 9%
6
1g
1h
1i
87% 7%
81% 9%
83% 9%
6%
7
10%
8%
8
9
CuI
42% 28% 30%
38% 35% 27%
44% 32% 24%
45% 23% 32%
78% 22% trace
62% 17% 21%
72% 10% 18%
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
26f
[CuI(phen)]2 NaOH
[CuI(bpy)]2 NaOH
ꢀ
NaOH
tꢀBuONa
tꢀBuOK
KOH
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
LiOH
92% 2%
53% 6%
6%
Cs2CO3
K3PO4
K2CO3
Na2CO3
ꢀ
41%
52% 22% 26%
42% 21% 37%
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
NaOH
NaOH
NaOH
NaOH
94% 4%
90% 4%
85% 7%
95% 3%
2%
6%
8%
2%
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 44
1
2
3
4
5
6
7
8
9
1d
1d
1d
NaOH
NaOH
NaOH
MeOH
EtOH
96%
45% 17% 38%
59% 8% 33%
52% 42% 6%
27
28
29
97%
nꢀBuOH
>99%
aReaction conditions: 2aa (1.0 mmol), base (0.20 mmol), cat. (5 mol% of Cu), iꢀPrOH (4
mL) at 100 ºC (oil bath) for 10 h under a N2 atmosphere. Conversion and selectivity
determined by HPLC. 0.10 mmol NaOH. 0.50 mmol NaOH. 1.0 mmol NaOH. At 80
ºC.
b
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
c
d
e
f
With the optimized conditions established, we next investigated the substrate scope of
unsaturated carbonyl complexes (Table 2). The transfer hydrogenation reactions proceeded well
for all substrates examined, and the desired unsaturated alcohols were isolated in good to
excellent yields with high chemoselectivity. Aromatic α,βꢀunsaturated aldehydes (2aaꢀ2ae,
entries 1ꢀ5) typically exhibited higher activity than the corresponding aliphatic unsaturated
aldehydes 2ag and 2ah (entries 7ꢀ8). The reduction of heteroatomꢀcontaining α,βꢀunsaturated
aldehydes resulted in C=O bondꢀselective hydrogenation to 3af, 3aiꢀ3ak (entries 6, 9ꢀ11) in
moderate yields. Higher yields of 74ꢀ80% for these substrates could be achieved by prolonging
the reaction time to 36 h. Unsaturated ketones required longer time for the transfer
hydrogenation reactions to complete the conversions. Substrates 2alꢀ2ap (entries 12ꢀ16) afforded
excellent yields of the desired secondary alcohols 3alꢀ3ap with retention of the olefinic bond
(82ꢀ93% yields). The above results revealed that 1d easily catalyzed the chemoselective transfer
hydrogenation of the C=O bond of conjugated or unconjugated unsaturated carbonyls to
unsaturated alcohols. The hydrogenation of chalcones 2ba, 2bb, 2caꢀ2cc (entries 17ꢀ21) gave the
corresponding unsaturated alcohols 3ba, 3bb, 3caꢀ3cc in 87ꢀ93% isolated yields.
Table 2. Transfer Hydrogenation of Unsaturated Carbonyls to Allylic Alcohols
8
ACS Paragon Plus Environment

Page 9 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Entrya Unsaturated carbonyls
1
Time Product
10 h
Conv.b Yieldc
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
100%
100%
94%
96%
3aa
3ab
2
3
10 h
14 h
96%
90%
3ac
4
5
6
12 h
12 h
12 h
95%
93%
92%
92%
91%
88%
3ad
3ae
3af
7
8
14 h
14 h
91%
92%
87%
86%
3ag
3ah
9
36 h
36 h
84%
85%
75%
74%
3ai
3aj
10
11
12
36 h
18 h
87%
97%
80%
93%
3ak
3al
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 44
1
2
3
4
5
6
13
24 h
95%
93%
3am
7
8
9
14
15
16
24 h
24 h
24 h
90%
86%
87%
84%
82%
82%
3an
3ao
3ap
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
17
18
24 h
24 h
96%
92%
93%
90%
3ba
3bb
OH
19
20
24 h
92%
94%
88%
91%
3ca
3cb
24 h
24 h
21
90%
87%
3cc
aReaction conditions: unsaturated ketone or aldehyde (1.0 mmol), NaOH (0.2 mmol), 1d (5
b
mol% Cu), iꢀPrOH (4 mL) at 100 ºC (oil bath) under N2. Data determined by HPLC with
biphenyl as an internal standard. cIsolated yield.
10
ACS Paragon Plus Environment

Page 11 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The formation of a trace amount of saturated aldehyde 4aa in the reduction of 2aa inspired
us to further investigate the selective synthesis of saturated carbonyl compounds. Table 1 also
showed that base and solvent (or hydrogen agent) did exert a significant impact on the
chemoselectivity. The use of 1b (10 mol% Cu) as catalyst, equimolar K2CO3 as base, nꢀBuOH (2
mL) as hydride source and solvent (Table S1) produced saturated carbonyl compounds in
excellent yield and high selectivity (Table 3). Both electronꢀdonating and electronꢀwithdrawing
aromatic substituted chalcones were hydrogenated to cleanly provide the corresponding ketones
4baꢀ4be, 4caꢀ4ce (entries 1ꢀ5 and 9ꢀ13). The position of the substituent groups on the benzene
rings did not affect the yield significantly. The chalcones with substituents at the 2ꢀ or 3ꢀ
positions gave good yields of products 4bf, 4cf, 4cg (entries 6, 14ꢀ15). To our delight,
heterocyclic αꢀenones exhibited good activity and high selectivity (4bg, 4bh, 4ch, 4ci, entries 7ꢀ
8 and 16ꢀ17). Likewise, the transfer hydrogenation of alkyl substituted αꢀenones proceeded
smoothly (4cj and 4ck, entries 18ꢀ19). However, the good conversion and lower selectivity for
unsaturated aldehyde 2aa were observed. The saturated aldehyde 4aa was isolated in 51% yield
under the optimized conditions (entry 20).
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
Table 3. Transfer Hydrogenation of Unsaturated Carbonyls to Saturated Carbonyls
Entrya
1
Unsaturated carbonyls
Product
Conv.b Yieldc
97%
92%
4ba
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 44
1
2
3
4
5
6
7
8
2
3
94%
93%
92%
91%
4bb
4bc
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
4
96%
95%
4bd
5
6
7
98%
89%
90%
93%
82%
87%
4be
4bf
4bg
8
75%
94%
95%
93%
72%
91%
94%
90%
4bh
4ca
4cb
4cc
9
10
11
12
ACS Paragon Plus Environment

Page 13 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
12
13
98%
96%
93%
92%
4cd
4ce
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
14
84%
80%
4cf
15
16
86%
72%
83%
71%
4cg
4ch
17
18
80%
81%
78%
74%
4ci
4cj
O
O
19
83%
90%
81%
51%
4ck
4aa
20d
aReaction conditions: unsaturated carbonyl (0.5 mmol), K2CO3 (0.5 mmol), 1b (10 mol% Cu), nꢀ
BuOH (2 mL) at 120 ºC (oil bath) under N2 for 24 h. bData determined by HPLC with biphenyl
c
d
as an internal standard. Isolated yield. The hydrogenation of 2aa with 90% conversion gave
4aa in 51% yield, 3aa in 38% yield and a trace of 5aa.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 44
1
2
3
4
5
6
7
8
9
A previous investigation using copper nanoparticles to catalyze selective transfer
hydrogenation indicated that high yield with high selectivity is very challenging with this
inexpensive metal.85 Cu(I) Nꢀdonor thiolate complexes displayed excellent selectivity towards
unsaturated alcohols or saturated ketones under the different optimized conditions. For better
understanding of the reasons for this switch in selectivity with hydride source and base, we
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
1
acquired the H NMR spectrum of 1d in CDCl3 in the presence and absence of the relevant
reagents. The 1H NMR spectrum of 1d exhibited two sets of aromatic resonances (at δ 6.67, 6.30
ppm) in a 1 : 0.11 ratio and two sets of methyl resonances (at δ 2.52/2.39, 2.31 ppm) in a 1 : 0.24
ratio (Figure S4). Approximately 90% of dmpymt kept ꢁ3ꢀκ(N):κ2(S) coordination in CDCl3
while 10% of this ligand coordinated with Cu(I) in ꢁꢀκ2(S) fashion. When NaOH was added into
the CDCl3 solution of 1d at room temperature, no change in the 1H NMR spectrum was observed.
However, the proton resonances of dmpymt showed small upfield shifts to δ 6.64, 6.27,
2.47/2.34, 2.27 ppm, when iꢀPrOH was added into the CDCl3 solution of 1d. We attribute these
changes to hydrogenꢀbonding interactions of the pyrimidyl ring N atoms with iꢀPrOH
molecules.80 Subsequent addition of NaOH increased the ratio of monodentate dmpymt up to ca.
30%, which we suggest is caused by the coordination of iꢀPrOꢀ to the Cu(I) center. After the
catalytic reaction of cinnamaldehyde as substrate, the resulting mixture was dried under vacuum
and then washed with Et2O several times. The 1H NMR spectrum of the residue was very similar
to that of 1d. This residue could be reused and displayed high activity and selectivity for the
reduction of 2aa, giving 3aa in 91% yield.
We propose that the mechanism leading to each product outcome involves either the
sequential hydride transfer from a copper hydride intermediate (Cat I, Scheme 3) followed by
protonation, or concerted hydride/proton transfer from protonated Cu(I) hydride species Cat II.
14
ACS Paragon Plus Environment

Page 15 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cat I is formed by the βꢀelimination of acetone from Cu isopropoxide intermediate (I) and Cat
II by protonation of Cat I with alcohol. A Cat I like Cu(I) hydride species has been reported
previously.87 Hydrogenation at the C=O or C=C bonds of 2aa with Cat I resulted in the
formation of 3ꢀphenylpropꢀ2ꢀenꢀ1ꢀolate and 1ꢀoxoꢀ3ꢀphenylpropanꢀ2ꢀide anions, respectively.
They then were protonated by iꢀPrOH to produce 3ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (3aa) or 3ꢀ
phenylpropanal (4aa), respectively. To isolate the factors responsible for the switching reduction
pathways, we carried out the reaction of 2aa with iꢀPrONa as a hydride source and base, but in
the absence of a proton source in toluene at 90 ºC. Hydrogenation of the C=C bond under these
conditions was highly preferred over reduction of the C=O bond (Table 4), presumably via the
intermediacy of Cat I.
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
If we invoke a metalꢀligand bifunctional mechanism,64ꢀ78 the proton from propanꢀ2ꢀol is
delivered to the dmpymt ligand, yielding a hydride/proton complex (Cat II) and there exists
three possible hydrogenation products of 2aa (3aa, 4aa and 3ꢀphenylpropꢀ1ꢀenꢀ1ꢀol) (Scheme 3).
Compound 3ꢀphenylpropꢀ1ꢀenꢀ1ꢀol is the tautomer of saturated aldehyde 4aa. To investigate the
role of the NH or SH group, we modified Hdmpymt by methylation and phenylation to obtain
two new ligands 4,6ꢀdimethylꢀ2ꢀ(methylthio)pyrimidine (dmmtpym) and 4,6ꢀdimethylꢀ1ꢀ
phenylpyrimidineꢀ2(1H)ꢀthione (dmphpymt), both of which do not have a basic nitrogen for
protonation. The resulting two Cu(I) complexes [CuI(L)] (L = dmmtpym, dmphpymt), and
[Cu(SPh)] exhibited reduced activity and selectivity (Table 4). All of these results support the
idea of an NH (or SH) proton transfer concomitant with carbonyl reduction by CuꢀH.
Scheme 3. Possible Routes for the Hydrogenation of 2aa Using 1d
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 44
1
2
3
4
5
6
7
8
9
O
H
N
N
S
N
N
N
O
N
S
S
S
S
N
N
S
S
S
N
N
N
N
NaOH
S
(I)
S
N
i-PrOH
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
S
N
N
N
N
N
N
S
N
N
N
N
N
O
OH
O
O
+
+
H
N
N
N
S
H
N
H
N
N
N
N
S
OH-
H2O
S
S
N
N
N
N
S
S
S
N
S
N
i-PrO-
N
i-PrOH
N
N
S
N
S
N
S
S
N
N
N
N
N
(Cat II)
(Cat I)
C=O reduction
C=C reduction
1,2-addition
3,4-addition
1,4-addition
(3aa) Ph
OH
O
Ph
O
i-PrOH
(4aa)
Ph
Ph
Ph
O
(3aa)
(4aa)
Ph
Ph
OH
tautomerization
Ph
(2aa)
O
OH
i-PrOH
hydrogenation
3aa or 4aa
(5aa)
OH
Ph
O
Table 4. Transfer Hydrogenation of 2aa Under the Different Reaction Conditions
CHO
CH2OH
CH2OH
CHO
Cat., Base
Solvent, 100 oC
+
+
2aa
3aa
4aa
5aa
Yield
Entry
Cat.
Base
Solvent
Time
3aa
4aa
5aa
1a
2a
1d
1d
iꢀPrONa
iꢀPrONa
toluene
toluene
6 h
ꢀ
ꢀ
12%
20%
trace
trace
12 h
16
ACS Paragon Plus Environment

Page 17 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3a
4b
5b
6b
toluene
1d
iꢀPrONa
24 h
ꢀ
38%
9%
5%
8%
8%
12%
[CuI(dmmtpym)] NaOH
[CuI(dmphpymt)] NaOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
24 h
24 h
24 h
52%
56%
30%
8%
[Cu(SPh)]
NaOH
13%
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
aReaction conditions: 2aa (1.0 mmol), iꢀPrONa (1.0 mmol), 1d (10 mol% Cu), toluene (4 mL)
at 90 ºC (oil bath) under N2, and HPLC yield. Reaction conditions: 2aa (1.0 mmol), NaOH
(0.2 mmol), cat. (10 mol% Cu), iꢀPrOH (4 mL) at 100 ºC (oil bath) under N2, and HPLC
yield.
b
Density functional theory (DFT) calculations modeling the hydrogenation of 2aa with a
simplified “Cu(dmpymt)” unit were in agreement with our experimental observations
(Supporting information). The B3LYP hybrid functional was used in our calculations. The
LANL2DZ basis set, in conjunction with the LANL2DZ pseudo potential, was employed for
copper while the 6ꢀ311++G(d,p) basis set was used for other atoms. Frequency analyses were
performed on all optimized structures to verify local minima or transition states. All calculated
results were based on Gibbs free energies. We first examined the hydrogenation of
cinnamaldehyde through the interaction of the CuꢀH of “(dmpymt)CuꢀH” with the C=O bond or
C=C bond (Figure S5). The C=O and C=C hydrogenations have barriers of 16.9 and 16.1 kcal
molꢀ1, respectively. This energy barrier difference increased to 3.6 kcal molꢀ1 when the
LANL2TZ basis set was used for the Cu atom. This calculation supports our hypothesis that
monohydride Cu(I) complex Cat I preferentially hydrogenates the C=C bond of unsaturated
aldehydes or ketones.
There are two hydrogenation routes (1,2ꢀ, and 1,4ꢀaddition) for the reaction of 2aa with
protonated Cu(I) hydride species “(Hdmpymt)CuꢀH”. The calculated free energy diagram
indicates that the 1,2ꢀaddition pathway involves two transition states (TS1, TS2) (Figure S6)
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 44
1
2
3
4
5
6
7
8
9
with the higher energy barrier of 10.6 kcal molꢀ1 (TS1). The 1,4ꢀaddition pathway involves the
insertion of CuꢀH into the C=C bond via three consecutive transition states (TS3, TS4 and TS5)
(Figure S7). The highest energy barrier (TS4) is calculated to be 15.3 kcal molꢀ1. The calculated
energy difference between TS4 and TS1 is 1.06 kcal molꢀ1 when chalcone 2ba is used as a
substrate. These findings are in agreement with the experimentally observed formation of
unsaturated alcohol using 20 mol% NaOH as a base in iꢀPrOH.
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
The distribution of products derived from the hydrogenation of 2aa with 5 mol% 1d in iꢀ
PrOH and 20 mol% NaOH as base was monitored over time using HPLC (Figure 1(a)) and
revealed the initial generation of unsaturated alcohol 3aa over 3 hours. A small amount of 3ꢀ
phenylpropanꢀ1ꢀol (5aa) was also formed and then replaced by 3ꢀphenylpropanal (4aa, about 2%
HPLC yield). This observation of the clean, firstꢀorder generation of allylic alcohol with no
observable intermediates or significant other products is consistent with our proposed outerꢀ
sphere hydrogen transfer mechanism catalyzed by protonated Cu(I) hydride Cat II (Scheme 3
and 4). In this catalytic process, the concentration of unprotonated monohydride Cu(I) complex
Cat I is relatively low due to the catalytic (20%) amount of base. The conversion of 2aa had a
turnover number (TON) of 19.6 and a turnover frequency (TOF) as high as 2.86 h−1, while the
selectivity was 98% for the production of 3aa. The catalytic activity of complex 1d is higher
than that of [(Ph3P)CuH]6/PhP(CH2)4 (TON = 17.6, TOF = 0.98 hꢀ1), but lower than that of
[(Ph3P)CuH]6/PhPMe2 (TON = 18.6, TOF = 4.6 hꢀ1) (using 500 psi H2 as hydrogen agent).1 As
discussed above, 1d showed lower selectivity (Table 1, entries 27ꢀ29) in ROH (R = Me, Et, nꢀBu)
than in iꢀPrOH, which may be due to the fact that the smaller size of R in ROH favors Cat I to
hydrogenate the C=C bond.
18
ACS Paragon Plus Environment

Page 19 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
(a)
(b)
Figure 1. Timeꢀcourse monitoring of the transfer hydrogenation of 2aa in iꢀPrOH (a), 2ba in nꢀ
BuOH (b).
The selective transfer hydrogenation of α,βꢀunsaturated ketone 2ba to saturated ketone 4ba
was also monitored over time using HPLC shown in Figure 1(b). Unsaturated alcohol 3ba was
formed initially, concomitant with a sharp decrease in the concentration of 2ba, and then
replaced by the saturated alcohol 5ba. The increasing of base raised the concentration of
monohydride species Cat I, which resulted in the C=C hydrogenation of 3ba to give 5ba.
Compound 5ba was subsequently oxidized into 4ba. In a separate experiment, the reaction of
3ba for 5h under the same conditions resulted in the formation of 4ba in 48% yield, coupled with
saturated alcohol 5ba in 21% yield (Scheme 5, Eq. 1). Compared with NaOH and KOH, K2CO3
and K3PO4 as bases displayed higher chemoselectivity for saturated carbonyls (Table S1). These
bases could increase the concentration of Cat I in catalytic system without the formation of H2O,
which can hydrogenꢀinteract with N atom in Cat I. The reaction of 5ba under standard
conditions could not yield 4ba (Eq. 2). The addition of nꢀbutanal into the reaction system
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 44
1
2
3
4
5
6
7
8
9
increased the yield of 4ba to 81% (Eq. 3). Thus the transformations from unsaturated carbonyls
into saturated carbonyls proceeded through a oneꢀpot sequence of the hydrogenation of C=O
bond, the hydrogenation of C=C bond and transfer hydrogen of saturated alcohol with nꢀbutanal
(Schemes 3 and 4).
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
Scheme 4. Proposed Mechanism for the Transfer Hydrogenation of Unsaturated Carbonyls
to Unsaturated Alcohols or Saturated Carbonyls.
Scheme 5. The Reaction of 3ba or 5ba Catalyzed by 1b in n-BuOH
20
ACS Paragon Plus Environment

Page 21 of 44
The Journal of Organic Chemistry
1
2
3
4
CONCLUSIONS
5
6
7
8
9
In summary, we have developed an efficient and chemoselective transfer hydrogenation
protocol for converting unsaturated carbonyl compounds to either unsaturated alcohols or
saturated carbonyls catalyzed by Cu(I) Nꢀdonor thiolate clusters using either iꢀPrOH as the
hydrogen source and 20 mol% NaOH as base or nꢀBuOH and equimolar K2CO3. This
chemoselectivity can be explained by the relative concentrations of Cu(I) monohydride and
protonated Cu(I) hydride complexes in each catalytic system. These clusters may also effectively
mediate the αꢀalkylation of acetophenones with primary alcohols and these studies are currently
under way in our laboratory.
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
EXPERIMENTAL SECTION
General Information. [Cu3(pymt)3]n (1a)87,88 and [Cu6(L)6] (L = btt (1b),89 pyt (1c),90
dmpymt (1d),91 5ꢀphpymt (1e),80 mtpmt (1f),79 were prepared according to literature methods.
All reagents were obtained from commercial sources and used directly without further
purification. All solvents were obtained from commercial sources and were purified according to
1
standard procedures. Column chromatography was performed on silica gel. H and 13C NMR
spectra were recorded at 400 and 151 MHz in CDCl3 or DMSOꢀd6 using a BRUKER AVANCE
1
III HD spectrometer. H and 13C chemical shifts are reported in parts per million relative to
Me4Si using the residual solvent signal as an internal reference. Powder Xꢀray diffraction
(PXRD) patterns were recorded on an X’Pert PRO SUPERA rotation anode Xꢀray diffractometer
with Niꢀfiltered CuꢀKa radiation (λ = 1.5418 Å). Elemental analyses (C, H, and N) were
performed on a CarloꢀErbo CHNOꢀS microanalyzer. IR spectra (KBr disc) were recorded on a
Nicolet MagNaꢀIR550 FTꢀIR spectrometer (4000–400 cm−1). High resolution mass spectra
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 44
1
2
3
4
5
6
(HRMS) were obtained with a GCT Premier (Micromass UK Limited) chemical ionization timeꢀ
ofꢀflight mass spectrometer (CIꢀTOF).
7
8
9
Experimental Procedures. Synthesis of 1g. To a MeCN (10 mL) solution of 4ꢀphpymtH
(30.2 mg, 0.16 mmol) and Et3N (400 mg, 4.0 mmol) was added a MeCN (10 mL) solution of CuI
(14.3 mg, 0.075 mmol). The mixture was stirred for about one hour at ambient temperature to
form a yellow precipitate. After filtration, the solid was washed with MeCN and diethyl ether,
and dried in air. Yield: 18 mg (90%). Anal. Calcd for C64H48Cu6N14S6: C 48.44, H 3.05, N 12.36.
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
1
Found: C 48.64, H 3.21, N 11.67 %. IR: ν(C=N, C=C) 1629, 1578 cm−1. H NMR (400 MHz,
CDCl3, ppm) δ 8.03 (d, J = 7.3 Hz, 2H), 7.51–7.38 (m, 5H).
Synthesis of 1h. Orange solid of 1h was isolated in a similar manner to that used for the
isolation of 1g, using CuI (9.5 mg, 0.05 mmol) and 4,5ꢀdiphpymtH (26.4 mg, 0.10 mmol) as
starting materials. Yield: 15.8 mg (92%). Anal. Calcd for C100H78Cu6N14S6: C 58.61, H 3.84, N
1
9.57. Found: C 58.86, H 3.75, N 9.35 %. IR: ν(C=N, C=C) 1629, 1556 cm−1. H NMR (400
MHz, CDCl3, ppm) δ 8.59 (s, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 2.9 Hz, 4H), 7.22 (d, J =
7.5 Hz, 2H), 7.17 (d, J = 3.7 Hz, 2H).
Synthesis of 1i. To a Pyrex glass tube (15 cm in length, 7 mm inner diameter) was loaded
with CuI (9.5 mg, 0.05 mmol), 4,6ꢀdiphenylꢀ5,6ꢀdihydropyrimidineꢀ2(1H)ꢀthione (13.2 mg, 0.05
mmol), 2 mL of MeCN and 0.1 mL of DMF. The tube was sealed and heated in an oven to 120
ºC for 48 h, and then cooled to ambient temperature at a rate of 5 ºC per 60 min to give yellow
crystals, which were collected by filtration, washed with MeCN and Et2O, and dried in vacuo.
Yield: 15.5 mg (90%). Anal. Calcd for C100H78Cu6N14S6: C 58.61, H 3.84, N 9.57. Found: C
22
ACS Paragon Plus Environment

Page 23 of 44
The Journal of Organic Chemistry
1
2
3
4
5
59.06, H 3.63, N 9.39 %. IR: ν(C=N, C=C) 1638, 1566 cm−1. 1H NMR (400 MHz, CDCl3, ppm)
δ 8.08 (d, J = 6.9 Hz, 2H), 7.68 (d, J = 7.1 Hz, 2H), 7.52 (dd, J = 14.7, 7.3 Hz, 6H), 7.22 (s, 1H).
6
7
8
9
Xꢀray crystallography. Each single crystal (1g·2DMF·Et2O, 1h·4CHCl3 and 1i) was
mounted on a glass fiber with grease and cooled in a liquid nitrogen stream at 193 K
(1g·2DMF·Et2O), 173 K (1h·4CHCl3), or 293 K (1i). Crystallographic measurements were made
on a Rigaku Saturn (1g·2DMF·Et2O and 1i) or a Bruker APEXꢀII CCD (1h·4CHCl3),
diffractometer by using a graphiteꢀmonochromated MoꢀKα (λ = 0.71070 Å) radiation. The
crystal structures of 1g·2DMF·Et2O, 1h·4CHCl3 and 1i were solved by direct methods and
refined on F2 by fullꢀmatrix leastꢀsquares techniques with SHELXTLꢀ97 program.95,96 Crystal
structural data for 1g·2DMF·Et2O, 1h·4CHCl3 and 1i (CCDC 1522340ꢀ1522342) are contained
in the respective CIFs.
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
Computational details. Geometry optimizations were performed at a mixed basis set
(LANL2DZ for copper atom and 6ꢀ311++G(d,p) for other atoms) using the B3LYP functional97
in Gaussian 09.98 Transition states were optimized with the Berny algorithm using GEDIIS in
redundant internal algorithm. Analytical frequencies were calculated at the same theoretical level
to obtain Gibbs free energies and to verify a local minimum or a transition state.
Transfer hydrogenation of unsaturated carbonyls to unsaturated alcohols. In a typical
procedure, a test tube equipped with a magnetic stirring bar was charged with unsaturated
carbonyl (1.0 mmol), NaOH (0.20 mmol), 1d (5 mol % Cu) and iꢀPrOH (4 mL) and then was
sealed. The reaction mixture was stirred at 100 ºC. After cooling to room temperature, the
mixture was partitioned between water and ethyl acetate. The organic layer was separated, and
the aqueous layer was extracted with ethylacetate (3 × 15 mL). The combined organic layer was
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 44
1
2
3
4
5
6
washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography.
7
8
9
Cinnamic alcohol (3aa).15 Yield: 126 mg (94%). 1H NMR (400 MHz, CDCl3, ppm): δ 7.38
(d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.24 (dd, J = 8.8, 5.2 Hz, 1H), 6.61 (d, J = 15.9 Hz,
1H), 6.36 (dt, J = 15.8, 5.7 Hz, 1H), 4.31 (d, J = 5.5 Hz, 2H), 1.75 (d, J = 7.9 Hz, 1H). 13C NMR
(151 MHz, CDCl3, ppm): δ 136.6, 131.1, 128.6, 128.5, 127.7, 126.4, 63.7. HRMS m/z calcd for
C9H10O [M + H]+ 135.0810, found 135.0811.
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
1
4ꢀMethoxycinnamic alcohol (3ab).77 Yield: 157 mg (96%). H NMR (400 MHz, DMSOꢀd6,
ppm): δ 7.35 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.21 (dt, J =
15.8, 5.1 Hz, 1H), 4.80 (t, J = 5.3 Hz, 1H), 4.09 (t, J = 4.8 Hz, 2H), 3.74 (s, 3H). 13C NMR (151
MHz, DMSOꢀd6, ppm): δ 158.6, 129.5, 128.3, 128.2, 127.3, 114.0, 61.6, 55.0. HRMS m/z calcd
for C10H13O2 [M + H]+ 165.0916, found 165.0918.
1
4ꢀNitrocinnamic alcohol (3ac).77 Yield: 161 mg (90%). H NMR (400 MHz, CDCl3, ppm):
δ 8.19 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 16.0 Hz, 1H), 6.54 (dt, J = 15.9,
4.9 Hz, 1H), 4.41 (d, J = 4.4 Hz, 2H). 13C NMR (151 MHz, CDCl3, ppm): δ 146.9, 143.2, 133.5,
128.3, 126.9, 124.0, 63.1. HRMS m/z calcd for C9H9NO3 [M + H]+ 180.0661, found 180.0662.
1
αꢀMethylcinnamic alcohol (3ad).15 Yield: 136 mg (92%). H NMR (600 MHz, CDCl3,
ppm): δ 7.32 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 7.22 (dd, J = 14.4, 7.1 Hz, 1H), 6.52
(s, 1H), 4.17 (s, 2H), 1.89 (s, 3H). 13C NMR (151 MHz, CDCl3, ppm): δ 137.7, 137.8, 129.0,
128.2, 126.5, 125.1, 69.0, 15.4. HRMS m/z calcd for C10H12O [M + H]+ 149.0966, found
149.0966.
24
ACS Paragon Plus Environment

Page 25 of 44
The Journal of Organic Chemistry
1
2
3
4
1
αꢀAmylcinnamic alcohol (3ae).15 Yield: 186 mg (91%). H NMR (600 MHz, CDCl3, ppm):
5
6
δ 7.32 (t, J = 7.6 Hz, 2H), 7.25–7.20 (m, 3H), 6.52 (s, 1H), 4.22 (s, 2H), 2.30–2.27 (m, 2H), 1.62
7
8
13
(s, 1H), 1.52–1.47 (m, 2H), 1.31–1.26 (m, 4H), 0.87 (t, J = 6.6 Hz, 3H). C NMR (151 MHz,
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
CDCl3, ppm): δ 142.5, 137.7, 128.8, 128.3, 126.6, 125.4, 67.2, 32.2, 28.9, 28.2, 22.6, 14.2.
HRMS m/z calcd for C14H20O [M + H]+ 205.1592, found 205.1594.
1
3ꢀ(Furanꢀ2ꢀyl)propꢀ2ꢀenꢀ1ꢀol (3af).15 Yield: 109 mg (88%). H NMR (600 MHz, CDCl3,
ppm): δ 7.33 (s, 1H), 6.42 (d, J = 15.9 Hz, 1H), 6.37–6.34 (m, 1H), 6.27 (dt, J = 15.8, 5.6 Hz,
13
1H), 6.22 (d, J = 3.0 Hz, 1H), 4.26 (d, J = 5.5 Hz, 2H). C NMR (151 MHz, CDCl3, ppm): δ
152.5, 142.1, 127.3, 119.3, 111.4, 108.0, 63.2. HRMS m/z calcd for C7H8O2 [M + H]+ 125.0603,
found 125.0604.
1
Heptꢀ2ꢀenꢀ1ꢀol (3ag).15 Yield: 99 mg (87%). H NMR (600 MHz, CDCl3, ppm): δ 5.71–
5.64 (m, 1H), 5.64–5.58 (m, 1H), 4.06 (d, J = 4.9 Hz, 2H), 2.03 (q, J = 6.7 Hz, 2H), 1.36–1.28
(m, 4H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3, ppm): δ 133.6, 128.9, 63.9, 32.0,
31.4, 22.3, 14.0. HRMS m/z calcd for C7H14O [M + H]+ 115.1123, found 115.1126.
1
2ꢀMethylpentꢀ2ꢀenꢀ1ꢀol (3ah).15 Yield: 86 mg (86%). H NMR (600 MHz, CDCl3, ppm): δ
5.39 (t, J = 6.7 Hz, 1H), 3.98 (s, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.65 (s, 3H), 0.96 (t, J = 7.5 Hz,
3H). 13C NMR (151 MHz, CDCl3, ppm): δ 134.2, 128.3, 69.1, 21.0, 14.1, 13.6. HRMS m/z calcd
for C6H12O [M + H]+ 101.0966, found 101.0967.
1
2ꢀFurfurylalcohol (3ai).77 Yield: 74 mg (75%). H NMR (400 MHz, CDCl3, ppm): δ 7.38
13
(s, 1H), 6.33 (s, 1H), 6.27 (s, 1H), 4.55 (s, 2H), 2.75–2.66 (m, 1H). C NMR (151 MHz, CDCl3,
ppm): δ 154.0, 142.4, 110.3, 107.7, 57.2. HRMS m/z calcd for C5H6O2 [M + H]+ 99.0446, found
99.0448.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 44
1
2
3
4
1
Thiophenꢀ2ꢀylmethanol (3aj).77 Yield: 84 mg (74%). H NMR (400 MHz, CDCl3, ppm): δ
5
6
7
8
7.23 (s, 1H), 6.94 (s, 2H), 4.71 (s, 2H), 3.05–2.78 (m, 1H). 13C NMR (151 MHz, CDCl3, ppm): δ
144.0, 126.8, 125.5, 125.4, 59.7. HRMS m/z calcd for C5H6OS [M + H]+ 115.0217, found
115.0221.
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
1
3ꢀPyridylmethanol (3ak).77 Yield: 87 mg (80%). H NMR (400 MHz, CDCl3, ppm): δ 8.40
13
(s, 1H), 8.33 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.24–7.19 (m, 1H), 5.16 (s, 1H), 4.63 (s, 2H). C
NMR (151 MHz, CDCl3, ppm): δ 147.9, 147.8, 137.2, 135.2, 123.6, 61.8. HRMS m/z calcd for
C6H7NO [M + H]+ 110.0606, found 110.0610.
4ꢀPhenylbutꢀ3ꢀenꢀ2ꢀol (3al).2 Yield: 138 mg (93%). H NMR (400 MHz, CDCl3, ppm): δ
1
7.39 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1H), 6.57 (d, J = 16.0 Hz,
1H), 6.28 (dd, J = 15.9, 6.3 Hz, 1H), 4.53–4.46 (m, 1H), 2.30–2.16 (m, 1H), 1.39 (d, J = 6.4 Hz,
3H). 13C NMR (151 MHz, CDCl3, ppm): δ 136.7, 133.6, 129.3, 128.6, 127.6, 126.4, 68.8, 23.4.
HRMS m/z calcd for C10H12O [M + H]+ 149.0966, found 149.0967.
1ꢀ(4ꢀStyrylphenyl)ethanꢀ1ꢀol (3am).99 Yield: 208 mg (93%). H NMR (400 MHz, DMSOꢀ
1
d6, ppm): δ 7.59 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.36 (dd, J = 15.7, 7.8 Hz, 4H),
7.30–7.20 (m, 3H), 5.16 (d, J = 4.1 Hz, 1H), 4.73 (dd, J = 10.8, 5.6 Hz, 1H), 1.32 (d, J = 6.4 Hz,
3H). 13C NMR (151 MHz, DMSOꢀd6, ppm): δ 147.4, 137.5, 135.8, 129.1, 128.7, 128.1, 127.9,
126.8, 126.6, 126.1, 68.3, 26.3. HRMS m/z calcd for C16H16O [M + H]+ 225.1279, found
225.1281.
1ꢀPentenꢀ3ꢀol (3an).47 Yield: 72 mg (84%). 1H NMR (400 MHz, CDCl3, ppm): δ 5.85 (ddd,
J = 16.8, 10.2, 6.3 Hz, 1H), 5.22 (d, J = 17.2 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.02 (d, J = 5.8
Hz, 1H), 2.34–2.19 (m, 1H), 1.56 (dd, J = 8.1, 5.0 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR
26
ACS Paragon Plus Environment

Page 27 of 44
The Journal of Organic Chemistry
1
2
3
4
(151 MHz, CDCl3, ppm): δ 140.9, 114.6, 74.4, 29.8, 9.5. HRMS m/z calcd for C5H10O [M + H]+
5
6
87.0810 found 87.0814.
7
8
9
Hexꢀ5ꢀenꢀ2ꢀol (3ao).66 Yield: 82 mg (82%). 1H NMR (600 MHz, CDCl3, ppm): δ 5.83 (ddt,
J = 16.9, 10.2, 6.7 Hz, 1H), 5.04 (ddd, J = 17.1, 3.4, 1.7 Hz, 1H), 4.96 (ddd, J = 10.1, 3.0, 1.2
Hz, 1H), 4.76 (s, 2H), 3.80 (dt, J = 12.4, 6.2 Hz, 1H), 2.53 (s, 1H), 2.18–2.09 (m, 2H), 1.19 (d, J
= 6.2 Hz, 3H). 13C NMR (151 MHz, CDCl3, ppm): δ 138.4, 114.6, 67.4, 38.2, 30.0, 23.3. HRMS
m/z calcd for C6H12O [M + H]+ 101.0966, found 101.0969.
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
6ꢀMethylheptꢀ5ꢀenꢀ2ꢀol (3ap).75 Yield: 105 mg (82%). 1H NMR (400 MHz, CDCl3, ppm): δ
5.13 (t, J = 6.6 Hz, 1H), 3.81 (dt, J = 12.3, 6.1 Hz, 1H), 2.07 (dt, J = 14.0, 6.8 Hz, 2H), 1.82 (s,
1H), 1.69 (s, 3H), 1.62 (s, 3H), 1.53–1.44 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H). 13C NMR (151
MHz, CDCl3, ppm): δ 132.1, 124.2, 68.0, 39.3, 25.8, 24.6, 23.5, 17.7. HRMS m/z calcd for
C8H16O [M + H]+ 129.1279, found 129.1281.
1
1,3ꢀDiphenylpropꢀ2ꢀenꢀ1ꢀol (3ba).2 Yield: 195 mg (93%). H NMR (400 MHz, DMSOꢀd6,
ppm): δ 7.43 (d, J = 4.8 Hz, 4H), 7.37–7.24 (m, 6H), 6.67 (d, J = 15.8 Hz, 1H), 6.42 (dd, J =
15.9, 6.3 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 5.31–5.27 (m, 1H). 13C NMR (151 MHz, DMSOꢀd6,
ppm): δ 144.9, 137.1, 134.1, 129.0, 128.6, 128.5, 127.8, 127.3, 126.7, 126.6, 73.6. HRMS m/z
calcd for C15H14O [M + H]+ 211.1123, found 211.1125.
1
3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (3bb).2 Yield: 220 mg (90%). H NMR (600
MHz, DMSOꢀd6, ppm): δ 7.45 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 7.4 Hz, 2H), 7.37–7.32 (m, 4H),
7.24 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 6.45 (dd, J = 15.9, 6.2 Hz, 1H), 5.70 (d, J =
13
4.2 Hz, 1H), 5.29–5.26 (m, 1H). C NMR (151 MHz, DMSOꢀd6, ppm): δ 144.2, 135.6, 134.6,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 44
1
2
3
4
131.7, 128.5, 128.2, 128.0, 126.9, 126.8, 126.2, 73.1. HRMS m/z calcd for C15H13ClO [M + H]+
5
6
245.0733, found 245.0735.
7
8
9
1
1ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (3ca).78 Yield: 229 mg (88%). H NMR (600
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
MHz, DMSOꢀd6, ppm): δ 7.93–7.87 (m, 4H), 7.55 (dd, J = 8.5, 1.4 Hz, 1H), 7.51–7.46 (m, 2H),
7.44 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 6.70 (d, J = 15.9 Hz,
1H), 6.48 (dd, J = 15.9, 6.3 Hz, 1H), 5.77 (d, J = 4.2 Hz, 1H), 5.44–5.41 (m, 1H). 13C NMR (151
MHz, DMSOꢀd6, ppm): δ 136.6, 133.4, 132.9, 132.2, 128.6, 128.3, 127.7, 127.7, 127.5, 129.4,
126.3, 126.0, 125.6, 125.0, 124.2, 73.2. HRMS m/z calcd for C19H16O [M + H]+ 261.1279, found
261.1282.
1
3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (3cb).2 Yield: 222 mg (91%). H NMR (400
MHz, DMSOꢀd6, ppm): δ 7.47–7.38 (m, 6H), 7.31 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H),
6.66 (d, J = 15.8 Hz, 1H), 6.39 (dd, J = 15.8, 6.3 Hz, 1H), 5.79 (d, J = 4.0 Hz, 1H), 5.33–5.26
(m, 1H). 13C NMR (151 MHz, DMSOꢀd6, ppm): δ 143.8, 136.9, 133.6, 131.8, 129.0, 129.0,
128.5, 128.5, 127.9, 126.8, 72.9. HRMS m/z calcd for C15H13ClO [M + H]+ 245.0733, found
245.0731.
1
3ꢀ(4ꢀNitrophenyl)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (3cc).100 Yield: 222 mg (87%). H NMR (600
MHz, CDCl3, ppm): δ 8.05 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 7.5 Hz,
2H), 7.25 (t, J = 7.5 Hz, 2H), 7.20 (dd, J = 9.3, 5.1 Hz, 1H), 6.63 (d, J = 15.8 Hz, 1H), 6.24 (dd, J
= 15.8, 7.1 Hz, 1H), 5.40 (d, J = 7.0 Hz, 1H). 13C NMR (151 MHz, CDCl3, ppm): δ 150.0, 146.9,
135.8, 131.8, 130.0, 128.5, 128.1, 126.8, 126.5, 123.5, 74.0. HRMS m/z calcd for C15H13NO3 [M
+ H]+ 256.0974, found 256.0978.
28
ACS Paragon Plus Environment

Page 29 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Transfer hydrogenation of unsaturated carbonyls to saturated carbonyls. In a typical
procedure, a test tube equipped with a magnetic stirring bar was charged with unsaturated
carbonyl (0.5 mmol), K2CO3 (0.5 mmol), 1b (10 mol % Cu) and nꢀBuOH (2 mL). The reaction
mixture was stirred at 120 ºC for 24 h. After cooling to room temperature, the mixture was
partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous
layer was extracted with ethylacetate (3 × 15 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product
was purified by flash column chromatography.
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
1
1,3ꢀDiphenylpropanꢀ1ꢀone (4ba).55 Yield: 193 mg (92%). H NMR (400 MHz, CDCl3,
ppm): δ 7.95 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.28 (dt, J =
15.3, 7.6 Hz, 4H), 7.20 (t, J = 7.0 Hz, 1H), 3.30 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H). 13C
NMR (151 MHz, CDCl3, ppm): δ 199.2, 141.3, 136.8, 133.0, 128.6, 128.5, 128.4, 128.0, 126.1,
40.4, 30.1. HRMS m/z calcd for C15H15O [M + H]+ 211.1123, found 211.1124.
1
3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀphenylpropanꢀ1ꢀone(4bb).55 Yield: 244 mg (92%). H NMR (400
MHz, CDCl3, ppm): δ 7.88 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H),
7.26–7.20 (m, 3H), 3.26 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H). 13C NMR (151 MHz,
CDCl3, ppm): δ 197.8, 141.0, 139.5, 135.2, 129.4, 128.9, 128.6, 128.4, 126.2, 40.4, 30.0. HRMS
m/z calcd for C15H14OCl [M + H]+ 245.0733, found 245.0728.
1
3ꢀ(4ꢀBromophenyl)ꢀ1ꢀphenylpropanꢀ1ꢀone (4bc).55 Yield: 262 mg (91%). H NMR (400
MHz, CDCl3, ppm): δ 7.80 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H),
7.25–7.19 (m, 3H), 3.25 (t, J = 7.6 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H). 13C NMR (151 MHz,
29
ACS Paragon Plus Environment