Visible Light Photocatalytic Radical-Radical Cross-Coupling Reactions of Amines and Carbonyls: A Route to 1,2-Amino Alcohols

Article abstract of DOI:10.1021/acs.joc.6b01217

An intermolecular radical-radical cross-coupling reaction of secondary and tertiary amines with aryl ketones and aldehydes has been developed using visible light photoredox catalysis. This reaction provides an efficient and straightforward approach to some useful 1,2-amino alcohols in moderate to good yields under mild conditions.

Full text of DOI:10.1021/acs.joc.6b01217

Subscriber access provided by the University of Exeter
Article
Visible Light Photocatalytic Radical-Radical Cross-Coupling
Reactions of Amines and Carbonyls: A Route to 1,2-Amino Alcohols
Wei Ding, Liang-Qiu Lu, Jing Liu, Dan Liu, Hai-Tao Song, and Wen-Jing Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01217 • Publication Date (Web): 06 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
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 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Visible Light Photocatalytic RadicalꢀRadical Crossꢀ
Coupling Reactions of Amines and Carbonyls: A Route
to 1,2ꢀAmino Alcohols
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
Wei Ding, LiangꢀQiu Lu, Jing Liu, Dan Liu, HaiꢀTao Song, and WenꢀJing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central
China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
Eꢀmail: wxiao@mail.ccnu.edu.cn
ABSTRACT: An intermolecular radicalꢀradical crossꢀcoupling reaction of secondary and tertiary
amines with aryl ketones and aldehydes has been developed using visible light photoredox catalysis.
This reaction provides an efficient and straightforward approach to some useful 1,2ꢀamino alcohols in
moderate to good yields under mild conditions.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 22
INTRODUCTION
1
2
3
4
5
6
7
8
9
1,2ꢀAmino alcohols are a type of structural motif found in a variety of bioactive natural products and
pharmaceutical agents.1 In addition, these compounds are important building scaffolds for the synthesis
of various chiral ligands, auxiliaries and bioactive compounds (Scheme 1).2 Considerable research
efforts have been devoted to search for new and more efficient synthetic methods of 1,2ꢀamino alcohols.
Traditionally, these scaffolds have been prepared by reduction of amino acids or their derivatives with
strong reductants3 or transition metalꢀcatalyzed aminohydroxylation of olefins.4ꢀ6 However, many of
these methods require harsh reaction conditions and result in low atom economy and/or unsatisfactory
regioselectivity. Therefore, the development of more efficient and straightforward protocols for the
construction of diverse 1,2ꢀamino alcohol products under mild conditions using readily available starting
materials is still highly desirable.7
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 1. Representative Chiral Ligands, Auxiliaries and Bioactive Compounds Containing 1,2-
Amino Alcohol Motifs
Over the past decade, photoredox catalysis driven by visible light has attracted increasing interest
from synthetic chemists due to its inherent green and sustainable features.8 This strategy has been
successfully applied to a wide range of transformations including radicalꢀradical coupling reactions to
construct valuable organic molecules.9 In 2011, MacMillan and coꢀworkers reported the first visibleꢀ
lightꢀinduced CꢀH arylation of various tertiary amines with cyanoaromatics via a radicalꢀradical crossꢀ
coupling process, which afforded an efficient method for the construction of benzylic amines.9a Then,
this synergistic strategy was successfully expanded to the βꢀhydroxyalkylation of cyclic ketones with
aryl ketones via a combination of photoredox catalysis and organocatalysis (Scheme 2a).9b Critical to
2
ACS Paragon Plus Environment

Page 3 of 22
The Journal of Organic Chemistry
these successes is the simultaneously activation of the two coupling partners in a single photoredox
catalytic cycle: oxidation of intermediate enamines to ꢀenaminyl radicals and reduction of aryl ketones
to ketyl radicals, followed by radicalꢀradical coupling reactions. In 2015, our group reported a novel
1
2
3
4
5
6
β
αꢀ
7
8
9
allylation of amines through a crossꢀcoupling reaction of
αꢀamino radical and allylic radical by
combining visible light photoredox catalysis and palladium catalysis (Scheme 2b).10 Therefore, 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
considered whether the αꢀamino radical and ketyl radical could be simultaneously generated in a single
photoredox catalytic cycle, and the subsequent radicalꢀradical crossꢀcoupling reaction could provide a
straightforward synthetic approach to 1,2ꢀamino alcohols. As part of our ongoing efforts to develop
novel photocatalytic reactions,11 we designed and implemented this general methodology for 1,2ꢀamino
alcohol construction (Scheme 2c).
Scheme 2. Visible Light Photocatalytic Radical-Radical Coupling Reactions
a) MacMillan (2013):
O
O
amine
catalyst
radical-radical
cross-coupling
N
O
+
Ar R1
OH
Ar R1
-hydroxyketone
fac-Ir(ppy)3
O
visible light
Ar R1
b) Our previous work (2014):
R1
R1
R1
N
R3
N
R3
R2
radical-radical
cross-coupling
R2
N
R3
R2
Pd(PPh3)4
+
Ir-photocatalyst
visible light
R4
X
R4
R4
R5
R5
R5
homoallylic amine
c) This work:
R1
R1
N
N
R3
R2
R3
R2
R1
X
radical-radical
cross-coupling
R4 Ar
fac-Ir(ppy)3
X = H, TMS
N
R2
+
O
OH
DMAP, LiBF4
THF, RT
R3
R4
Ar
1,2-amino alcohol
21 examples
up to 75% yield
visible light
Ar R4
O
Li
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 22
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
During the preparation of this manuscript, Meggers and coꢀworkers reported an elegant example of
visible light photocatalytic asymmetric radicalꢀradical coupling of amines and ketones in the presence of
a chiral iridium catalyst.12 In this case, only the tertiary aryl amine and quite electronꢀdeficient heteroaryl
trifluoromethyl ketones were suitable substrates for this transformation. Herein, we chose secondary
amines 1a as the model substrate for the reaction with benzophenone 2a to investigate the feasibility of
the proposed reaction. To our delight, the radicalꢀradical crossꢀcoupling reaction occurred smoothly in
the presence of facꢀIr(ppy)3 (2 mol%; ppy = 2ꢀphenylpyridine), 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO,
2.0 equiv.) and LiBF4 (1.0 equiv.) in THF under irradiation with 3W blue LEDs (Table 1, entry 1),13
which afforded the desired 1,2ꢀamino alcohol (3aa) in 34% yield. Encouraged by this result, we
continued to optimize the conditions by varying the reaction parameters to improve the reaction
efficiency. A series of other commercially available iridium, ruthenium, and organic dye photocatalysts
were evaluated (entries 2ꢀ4). We determined that an Ir complex photocatalyst (Ir(ppy)2(dtbbpy)PF6)
could also catalyze this transformation, albeit in lower yield (18% yield). In sharp contrast, no desired
coupling product was observed when Ru(bpy)3Cl2 and Eosin Y were employed. A survey of the reaction
media for this photoreaction indicated that the transformation was sensitive to the solvent and THF was
determined to be the best choice (entries 5ꢀ7). The substrate molar ratio on the reaction efficiency has
been investigated and it has been found that utilization of excess amine 1a substantially improved the
reaction efficiency (entry 8 and Table S2). Examination of a range of organic and inorganic bases (Table
S2) revealed that 4ꢀdimethylaminopyridine (DMAP), which acts as a base, was the most effective
(entries 8ꢀ12). Therefore, we defined the reaction of secondary amines 1a and benzophenone 2a in the
presence of facꢀIr(ppy)3 (2 mol%), DMAP (2.0 equiv.) and LiBF4 (1.0 equiv.)14 in THF under irradiation
with 3W blue LEDs at room temperature as the standard conditions (entry 9). Finally, control
experiments indicated that the photocatalyst, visible light, base and LiBF4 were all essential for this
photochemical transformation (entries 13ꢀ16). In this reaction, the 1,2ꢀdiamine byꢀproduct can be
observed, which was generated by radicalꢀradical homoꢀcoupling. We have performed the control
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
ACS Paragon Plus Environment

Page 5 of 22
The Journal of Organic Chemistry
experiments using only amine 1a or ketone 2a as substrate under the standard conditions. These
reactions did not give the 1,2ꢀdiamine or 1,2ꢀdiol compound, and the substrate can be recovered from
the reaction mixture (see Section 3 in the Supporting Information for details).
1
2
3
4
5
6
7
8
9
Table 1. Optimization of Reaction Conditionsa
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
entry
photocatalyst
base
solvent
yieldb
1
2
facꢀIr(ppy)3
Ir(ppy)2(dtbbpy)PF6
Ru(bpy)3Cl2
Eosin Y
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
DBU
THF
THF
34%
18%
0%
3
THF
4
THF
0%
5
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
none
DMF
DMSO
CH3CN
THF
30%
15%
4%
6
7
8c
9c
56%
61% (60%)d
5%
THF
10c
11c
12c
13c
14c,e
15c
16c,f
THF
K2HPO4
Na2CO3
DMAP
DMAP
none
THF
47%
16%
0%
THF
THF
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
THF
0%
THF
0%
DMAP
THF
18%
aUnless otherwise noted, reactions were performed with 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.),
photocatalyst (0.004 mmol, 2 mol%), base (0.4 mmol, 2.0 equiv.), LiBF4 (0.2 mmol, 1.0 equiv.) and
solvent (2.0 mL) under Ar. Determined by H NMR using 1,3,5ꢀtrimethoxybenzene as an internal
b
1
c
d
standard. 1a (0.6 mmol, 3.0 equiv.) and 2a (0.2 mmol) were used. Isolated yield in parentheses.
eReaction performed in the dark. fReaction performed without LiBF4.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 22
With the optimized conditions in hand, we investigated the substrate scope of this photocatalytic
radicalꢀradical coupling reaction. As summarized in Table 2, a wide range of amines 1 and carbonyls 2
were suitable for this reaction. For the arylglycine ester substrates, incorporation of either electronꢀ
donating groups (Me and MeO) or electronꢀwithdrawing groups (Br and Cl) on the benzene ring had no
obvious impact on the reaction and the corresponding products (3aa-3ea) were obtained in 53–65 %
yields. The substrate bearing the naphthyl group on the nitrogen also tolerated the current conditions,
and 1,2ꢀamino alcohol 3fa was obtained in moderate yield. Moreover, replacement of the ethyl ester
group with other functional groups (i.e., methyl ester, cyano group and cyclic amide) did not
significantly affect the reaction efficiency, and the reactions afforded desired products 3ga-3ja in 56ꢀ
68% yields. In addition to secondary amines, tertiary amine Nꢀphenyl tetrahydroisoquinoline was also
suitable for this transformation, with conversion into corresponding product 3ka in 49% yield. Next, the
scope of the carbonyl substrates was investigated for this transformation. A range of substituted
benzophenones and 9ꢀfluorenone can serve as efficient coupling partners under our optimized conditions,
and afforded the vicinal aminoalcohol products 3ab-3ad in good yields. Unfortunately, when arylꢀalkyl
ketones and dialkyl ketones were used in this coupling protocol, the desired products were not obtained.
To further expand the generality of this reaction, we tested more challenging aromatic aldehydes. As
highlighted in Table 2, these substrates successfully participated in this transformation and afforded
moderate yields of the corresponding products, albeit with low diastereoselectivities (3ae-3ag: 47ꢀ50%
yields, 1.1:1 dr).
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
6
ACS Paragon Plus Environment

Page 7 of 22
The Journal of Organic Chemistry
1
2
3
Table 2. Scope of the Visible Light-Induced Radical-Radical Cross-Coupling Reactiona
4
5
6
7
8
R1
R1
N
fac-Ir(ppy)3 (2 mol%)
R
Ar
O
N
+
R3
R2
OH
R2
Ar
R
DMAP, LiBF4, THF, RT
3W blue LEDs
R3
9
1
2
3
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
Ph
Ph
OH
CO2Et
H
Ph
3aa,
Ph
OH
R=Me, 12 h, 60% yield
H
N
Me
N
3ba, R=OMe, 17 h, 54% yield
3ca, R=Br, 24 h, 53% yield
3da,
CO2Et
R=Cl, 24 h, 64% yield
R
3ea, 14 h, 65% yield
Ph
Ph
Ph
Ph
H
Ph
H
Ph
H
N
N
N
OH
OH
OH
CO2Et
CN
CO2Me
Me
3ha,
3ga, 16 h, 56% yield
3fa, 36 h, 29% yield
18 h, 58% yield
Ar
OH
H
Ar
H
N
N
Ph
N
OH
Ph
Ph
CO2Et
Ph
N
R
O
Me
HO
Ph
3ab,
Ar=4-MeO-Ph, 24 h, 48% yield
3ac, Ar=4-F-Ph, 12 h, 53% yield
3ia,
R=Me, 16 h, 68% yield
3ja, R=PMB, 16 h, 65% yield
3ka, 36 h, 49% yield
Ar
H
Ph
H
N
OH
N
H
N
OH
CO2Et
Me
OH
CO2Et
Me
3ae,
CO2Et
3af, Ar=4-Me-Ph, 38 h, 47% yieldb
Me
b
48 h, 50% yield
b
3ag,
Ar=4-Cl-Ph, 24 h, 49% yield
3ad,
24 h, 63% yield
aReaction conditions: 1 (0.6 mmol, 3.0 equiv.), 2 (0.2 mmol), facꢀIr(ppy)3 (0.004 mmol, 2 mol%),
DMAP (0.4 mmol, 2.0 equiv.), LiBF4 (0.2 mmol, 1.0 equiv.), THF (2.0 mL) under Ar. Yields of
isolated products. bThe dr values were 1.1:1.
To further expand the substrate scope of this reaction, a range of aꢀsilylamines were used as sources
of aꢀamino radicals.15 As disclosed in Table 3, the N,Nꢀdiaryl aꢀsilylamine proved to be suitable
substrates for this transformation, affording the corresponding aminoalcohol product 3la and 3ma in
high yields. The reaction of NꢀmethylꢀNꢀtrimethylsilylmethylaniline and NꢀbenzylꢀNꢀ
trimethylsilylmethylaniline also proceeded smoothly to give the desired products in 65% and 67% yield,
respectively.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 22
1
2
3
4
Table 3. Scope of the a-Silylamines for the Radical-Radical Cross-Coupling Reactiona
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
aReaction conditions: 1 (0.6 mmol, 3.0 equiv.), 2a (0.2 mmol), facꢀIr(ppy)3 (0.004 mmol, 2 mol%),
DMAP (0.4 mmol, 2.0 equiv.), LiBF4 (0.2 mmol, 1.0 equiv.), THF (2.0 mL) under Ar. Yields of
isolated products.
To demonstrate the synthetic utility of this method, a reaction of substrates 1a and 2a has been
performed on a gramꢀscale under the optimal conditions. This photocatalytic radicalꢀradical crossingꢀ
coupling reaction could proceed well to afford the desired product 3aa (1.06 g) without loss of the
reaction efficiency (Scheme 3a, 57% yield). Additionally, this reaction proceeded well by directly
applying sunlight as the light source, delivering the 1,2ꢀamino alcohol product 3aa in a shorter reaction
time and comparable yield (Scheme 3b, 8 h, 58% yield). Perhaps more importantly, a continuousꢀflow
reactor could improved significantly the reaction efficiency, achieving the coupling reaction in 40 min
(Scheme 3c).
8
ACS Paragon Plus Environment

Page 9 of 22
The Journal of Organic Chemistry
1
2
3
Scheme 3. Demonstration of Synthetic Utility and Control Experiments
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
To gain additional insight into the reaction mechanism, radicalꢀtrapping experiments were performed
under the standard reaction conditions by adding 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and
butylated hydroxytoluene (BHT) as radical scavengers (Scheme 3dꢀe). No desired product was observed
from the reaction mixture, which indicated that the current reaction may occur through a radical pathway.
In addition, we performed fluorescence quenching experiments with the facꢀIr(ppy)3 as photocatalyst
(Figure 1). As expected, the results of a series of Stern−Volmer quenching studies revealed that
benzophenone 2a efficiently quenched the excited state of fac-Ir(ppy)3 but amine 1a did not.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 22
4
3
2
1
0
benzophenone
amine 1a
1
2
3
4
5
6
7
8
0
5
10
15
20
25
30
Quencher concentration (mM)
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
Figure 1. fac-Ir (ppy)3 emission quenching with amine 1a and benzophenone 2a.
Based on these experimental results and related literature precedents,9,12,16 a plausible reaction
mechanism has been proposed for this transformation as shown in Scheme 4. Initially, irradiation of the
Ir(III) photocatalyst with visible light leads to the formation of photoexcited state Ir(III)*, which serves
as an efficient reductant to reduce Lewis acidꢀactivated carbonyl A by a single electron transfer (SET)
process to afford corresponding ketyl radical B along with the oxidized Ir(IV) species. Subsequently,
amine substrate 1 is oxidized by the Ir(IV) species to regenerate groundꢀstate Ir(III) with the formation
of
process.
1,2ꢀamino alcohol product 3 is released by the protonation step. Other reaction pathways involving
addition of ꢀamino radical to the Lewis acidꢀactivated carbonyl species or coordination of ꢀamino
αꢀamino radical D through a single electron transfer process and a baseꢀpromoted deprotonation
αꢀAmino radical D then readily couples with ketyl radical B to form intermediate E. Finally,
α
α
radical and ketyl radical by Li+ might be possible and could not be ruled out at the current stage (see
Section 5 in the Supporting Information for details).
10
ACS Paragon Plus Environment

Page 11 of 22
The Journal of Organic Chemistry
1
2
3
Scheme 4. Plausible Reaction Mechanism
4
5
6
7
8
9
Li+
Li+
O
R1
N
O
R3
Ar
R4
R2
Ar
R4
A
2
1
Ir(IV)
R1
N
R4 Ar
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
R2
Photoredox
Catalysis
+e
-e
R3
R1
N
3
R3
Ir(III)*
Li+
H+
Ir(III)
R2
C
visible light
base
base-H+
R1
N
Li
R4 Ar
radical-radical
cross-coupling
R1
N
O
R3
R2
O Li
R2
Ar
R4
R3
D
B
E
CONCLUSIONS
In summary, we have developed a visibleꢀlightꢀinduced photocatalytic radicalꢀradical crossingꢀ
coupling reaction of amines and carbonyls. This protocol provides a rapid and efficient access to
synthetically useful 1,2ꢀamino alcohols. This novel method features a broad substrate scope, mild
condition and simple operation.
Experimental Section
General Information. Unless otherwise noted, the materials were purchased from commercial
suppliers and used without further purification. All of the amine substrates were prepared according to
the literature procedures17 and determined by H NMR analysis. All of the solvents were treated
1
according to general methods. Flash column chromatography was performed using 200ꢀ300 mesh silica
1
gel. The H NMR spectra were recorded on 400/600 MHz spectrophotometers. The chemical shifts (δ)
are reported in ppm using the solvent resonance as the internal standard (CDCl3: 7.26 ppm). The data
are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q= quartet, dd =
doublet of doublets, m = multiplet), coupling constants (Hz) and integration. The 13C NMR spectra were
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 22
recorded on 400 (100 MHz) with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm).
Highꢀresolution mass spectra (HRMS) were equipped with an ESI source and a TOF detector. The IR
spectra were recorded on an IR spectrophotometer. The melting points were measured with digital
melting point detector.
1
2
3
4
5
6
7
8
9
General Procedure for the radical-radical coupling reaction of amines with carbonyls. To an ovenꢀ
dried 10 mL Schleck flask equipped with a magnetic stir bar, substrate amines 1 (0.6 mmol), carbonyls 2
(0.2 mmol), facꢀIr(ppy)3 (2 mol%, 0.004 mmol), DMAP (0.4 mmol, 48.9 mg), LiBF4 (0.2 mmol, 18.8
mg) and THF (2 mL) were added. The resulting mixture was degassed using a freezeꢀpumpꢀthaw
procedure (3 times). Then, the solution was stirred under argon and irradiated with 3W blue LEDs (400ꢀ
500 nm) (distance app. 5 cm) at room temperature. After the reaction was completed (monitored by TLC
analysis), the solvent was removed under reduced pressure and then the residue was purified by flash
column chromatography (petroleum ether/ acetone) to afford desired product 3.
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
Ethyl 3-hydroxy-3,3-diphenyl-2-(p-tolylamino)propanoate (3aa). Purification by chromatography
o
(petroleum ether/acetone = 40:1) afforded 3aa (45.2 mg, 60% yield) as a white solid. MP 163ꢀ164 C;
1H NMR (400 MHz, CDCl3) δ 7.53–7.49 (m, 2H), 7.46 (dd, J = 7.5, 1.8 Hz, 2H), 7.30 (t, J = 7.6 Hz,
2H), 7.25–7.20 (m, 3H), 7.16 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.59 (d, J = 8.3 Hz, 2H), 4.96
(d, J = 8.6 Hz, 1H, NꢀH), 4.64 (d, J = 8.6 Hz, 1H), 4.53 (s, 1H, OꢀH), 3.89 (q, J = 7.2 Hz, 2H), 2.21 (s,
13
3H), 0.89 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3) δ 174.2, 144.2, 143.8, 142.6, 129.7, 128.3,
128.2, 127.5, 127.4, 127.2, 125.8, 125.4, 113.5, 79.3, 62.0, 61.2, 20.4, 13.7; IR (in KBr): 3531, 3469,
3405, 3027, 2983, 1718, 1618, 1522, 1448, 1371, 1309, 1215, 1150, 1022, 812, 756, 697, 529 cmꢀ1;
HRMS (ESI) m/z calcd for C24H26NO3 [M+H+] 376.1907; found 376.1897.
Ethyl 3-hydroxy-2-((4-methoxyphenyl)amino)-3,3-diphenylpropanoate (3ba). Purification by
chromatography (petroleum ether/acetone = 30:1) afforded 3ba (42.2 mg, 54% yield) as a white solid.
MP 135ꢀ136 oC; 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.34–
7.27 (m, 3H), 7.25–7.14 (m, 3H), 6.74 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 4.91 (s, 1H, NꢀH),
4.53 (s, 1H, OꢀH), 4.50 (s, 1H), 3.90 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR
12
ACS Paragon Plus Environment

Page 13 of 22
The Journal of Organic Chemistry
(100 MHz, CDCl3) δ 174.3, 152.6, 144.2, 142.6, 140.3, 128.3, 128.2, 127.4, 127.2, 125.8, 125.4, 115.0,
114.7, 79.2, 62.9, 61.2, 55.7, 13.7; IR (in KBr): 3526, 3458, 3405, 2992, 2834, 1712, 1516, 1452, 1374,
1224, 1030, 821, 756, 696, 523 cmꢀ1; HRMS (ESI) m/z calcd for C24H26NO4 [M+H+] 392.1856; found
392.1856.
1
2
3
4
5
6
7
8
9
Ethyl 2-((4-bromophenyl)amino)-3-hydroxy-3,3-diphenylpropanoate (3ca). Purification by
chromatography (petroleum ether/acetone = 40:1) afforded 3ca (46.9 mg, 53% yield) as a white solid.
MP 172ꢀ173 oC; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.36–
7.26 (m, 3H), 7.25–7.14 (m, 5H), 6.56 (d, J = 8.4 Hz, 2H), 4.93 (d, J = 8.7 Hz, 1H, NꢀH), 4.81 (d, J =
8.7 Hz, 1H), 4.52 (s, 1H, OꢀH), 3.93 (q, J = 7.1 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 173.7, 145.2, 143.9, 142.3, 131.9, 128.4, 128.3, 127.6, 127.3, 125.6, 125.3, 115.0, 110.0, 79.2,
61.6, 61.5, 13.7; IR (in KBr): 3524, 3453, 3417, 3027, 2980, 1713, 1595, 1499, 1373, 1314, 1213, 1147,
1066, 1019, 815, 755, 697, 505 cmꢀ1; HRMS (ESI) m/z calcd for C23H23BrNO3 [M+H+] 440.0856;
found 440.0861.
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
Ethyl 2-((4-chlorophenyl)amino)-3-hydroxy-3,3-diphenylpropanoate (3da). Purification by
chromatography (petroleum ether/acetone = 40:1) afforded 3da (50.9 mg, 64% yield) as a white solid.
MP 181ꢀ182 oC; 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.36–
7.26 (m, 3H), 7.25–7.14 (m, 3H), 7.09 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 4.94 (d, J = 8.7 Hz,
1H, NꢀH), 4.79 (d, J = 8.7 Hz, 1H), 4.52 (s, 1H, OꢀH), 3.93 (q, J = 7.1 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 173.7, 144.9, 144.0, 142.4, 129.1, 128.4, 128.3, 127.6, 127.3, 125.6,
125.3, 123.0, 114.6, 79.3, 62.0, 61.5, 13.7; IR (in KBr): 3527, 3457, 3415, 3028, 2980, 1714, 1599,
1501, 1447, 1373, 1313, 1211, 1147, 1018, 817, 756, 696, 506 cmꢀ1; HRMS (ESI) m/z calcd for
C23H23ClNO3 [M+H+] 396.1361; found 396.1353.
Ethyl 3-hydroxy-3,3-diphenyl-2-(m-tolylamino)propanoate (3ea). Purification by chromatography
o
(petroleum ether/acetone = 40:1) afforded 3ea (48.8 mg, 65% yield) as a white solid. MP 157ꢀ158 C;
1H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.36–7.26 (m, 3H),
7.25–7.14 (m, 3H), 7.04 (t, J = 7.7 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.50 (d, J = 7.4 Hz, 2H), 5.00 (d, J
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 22
= 8.7 Hz, 1H, NꢀH), 4.73 (d, J = 8.7 Hz, 1H), 4.53 (s, 1H, OꢀH), 3.91 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H),
0.91 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.1, 146.2, 144.3, 142.6, 139.0, 129.1, 128.3,
128.2, 127.4, 127.2, 125.8, 125.5, 119.3, 114.3, 110.5, 79.3, 61.8, 61.3, 21.5, 13.7; IR (in KBr): 3526,
3479, 3419, 2984, 1712, 1599, 1494, 1447, 1367, 1326, 1214, 1186, 763, 694, 515 cmꢀ1; HRMS (ESI)
m/z calcd for C24H26NO3 [M+H+] 376.1907; found: 376.1916.
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
Ethyl 3-hydroxy-2-(naphthalen-1-ylamino)-3,3-diphenylpropanoate (3fa). Purification by
chromatography (petroleum ether/acetone = 30:1) afforded 3fa (23.8 mg, 29% yield) as a white solid.
MP 181ꢀ182 oC; 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58
(d, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.39–7.30 (m, 4H), 7.26–7.21 (m,
4H), 7.14 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.59 (d, J = 7.3 Hz, 1H, NꢀH), 5.17 (d, J = 7.3
13
Hz, 1H), 4.61 (s, 1H, OꢀH), 3.93 (q, J = 7.1 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 174.0, 144.1, 142.6, 141.5, 134.3, 132.4, 130.0, 128.4, 128.32, 128.27, 127.6, 127.3, 126.2,
125.5, 124.9, 123.4, 120.1, 118.3, 105.2, 79.5, 61.8, 61.4, 13.7; IR (in KBr): 3527, 3480, 3418, 3060,
2986, 1719, 1582, 1525, 1477, 1409, 1369, 1218, 1146, 1019, 761, 698, 554 cmꢀ1; HRMS (ESI) m/z
calcd for C27H26NO3 [M+H+] 412.1907; found 412.1910.
Methyl 3-hydroxy-3,3-diphenyl-2-(phenylamino)propanoate (3ga). Purification by chromatography
o
(petroleum ether/acetone = 40:1) afforded 3ga (38.6 mg, 56% yield) as a white solid. MP 157ꢀ159 C;
1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.32 (t, J = 7.6 Hz,
2H), 7.26–7.20 (m, 3H), 7.20–7.11 (m, 3H), 6.73 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 5.01 (d, J
= 8.5 Hz, 1H, NꢀH), 4.77 (d, J = 8.5 Hz, 1H), 4.49 (s, 1H, OꢀH), 3.45 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 174.5, 146.0, 144.1, 142.3, 129.3, 128.4, 128.3, 127.5, 127.3, 125.7, 125.2, 118.3, 113.3, 79.2,
61.6, 52.2; IR (in KBr): 3523, 3394, 3058, 2956, 1719, 1600, 1503, 1441, 1357, 1312, 1216, 805, 756,
697, 537 cmꢀ1; HRMS (ESI) m/z calcd for C22H22NO3 [M+H+] 348.1594; found 348.1597.
3-Hydroxy-3,3-diphenyl-2-(p-tolylamino)propanenitrile (3ha). Purification by chromatography
o
(petroleum ether/acetone = 30:1) afforded 3ha (37.8 mg, 58% yield) as a white solid. MP 173ꢀ174 C;
1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 2H), 7.49–7.38 (m, 4H), 7.38–7.30 (m, 3H), 7.30–
14
ACS Paragon Plus Environment

Page 15 of 22
The Journal of Organic Chemistry
7.25 (m, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 8.1 Hz, 2H), 4.99 (d, J = 10.8 Hz, 1H, NꢀH), 4.04 (d,
1
2
3
13
J = 10.8 Hz, 1H), 3.32 (s, 1H, OꢀH), 2.26 (s, 3H). C NMR (100 MHz, CDCl3) δ 142.3, 141.9, 141.3,
4
5
6
7
8
130.1, 130.0, 128.9, 128.5, 128.5, 128.2, 126.3, 126.0, 118.0, 115.1, 79.1, 56.1, 20.5; IR (in KBr): 3524,
3377, 3021, 2924, 1607, 1520, 1449, 1387, 1310, 1183, 1054, 872, 805, 751, 697, 507 cmꢀ1; HRMS
(ESI) m/z calcd for C22H21N2O [M+H+] 329.1648; found 329.1651.
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
3-(Hydroxydiphenylmethyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (3ia). Purification by
chromatography (petroleum ether/acetone = 20:1) afforded 3ia (46.9 mg, 68% yield) as a white solid.
MP 143ꢀ145 oC; 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 6.5 Hz, 2H), 7.41–7.34 (m, 4H), 7.30–7.27
(m, 3H), 7.19–7.16 (m, 1H), 6.87 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 7.9 Hz, 1H),
13
5.74 (s, 1H, NꢀH), 4.67 (s, 1H), 3.67 (s, 1H, OꢀH), 3.27 (s, 3H). C NMR (100 MHz, CDCl3) δ 167.9,
143.7, 142.9, 133.5, 128.5, 128.4, 128.0, 127.9, 127.5, 127.34, 127.27, 124.1, 119.2, 114.6, 113.7, 79.5,
64.1, 28.7; IR (in KBr): 3368, 3060, 1655, 1599, 1511, 1448, 1416, 1376, 1304, 1135, 1040, 745, 705,
641 cmꢀ1; HRMS (ESI) m/z calcd for C22H20N2NaO2 [M+Na+] 367.1417; found 367.1412.
3-(Hydroxydiphenylmethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinoxalin-2(1H)-one
(3ja).
Purification by chromatography (petroleum ether/acetone = 20:1) afforded 3ja (58.7 mg, 65% yield) as a
white solid. MP 145ꢀ147 oC; 1H NMR (400 MHz, CDCl3) δ 7.92–7.83 (m, 2H), 7.45–7.30 (m, 8H), 6.92
(d, J = 8.0 Hz, 2H), 6.85–6.73 (m, 4H), 6.64 (t, J = 7.7 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 5.87 (s, 1H, Nꢀ
H), 5.22 (d, J = 15.8 Hz, 1H), 4.85 (s, 1H), 4.79 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 1H, OꢀH).
13C NMR (100 MHz, CDCl3) δ 167.7, 158.7, 143.5, 142.6, 133.4, 128.5, 128.1, 128.0, 127.9, 127.8,
127.7, 127.5, 127.4, 125.7, 124.2, 119.0, 115.5, 114.1, 113.7, 79.8, 64.4, 55.2, 44.7; IR (in KBr): 3444,
3363, 3063, 1655, 1601, 1511, 1447, 1400, 1304, 1251, 1171, 1034, 817, 753, 701, 634, 587 cmꢀ1;
HRMS (ESI) m/z calcd for C29H26N2NaO3 [M+Na+] 473.1836; found 473.1825.
Diphenyl(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol
(3ka).
Purification
by
chromatography (petroleum ether/acetone = 40:1) afforded 3ka (38.3 mg, 49% yield) as a white solid.
MP 158ꢀ159 oC; 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 7.4 Hz, 2H), 7.36–7.31 (m, 2H), 7.31–7.27
(m, 1H), 7.27–7.21 (m, 5H), 7.21–7.17 (m, 2H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 7.02
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 22
(d, J = 7.6 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.21 (d, J = 7.8 Hz, 1H), 5.44 (s,
1H), 4.68 (s, 1H, OꢀH), 3.36–3.28 (m, 1H), 2.99–2.92 (m, 1H), 2.87–2.87 (m, 1H), 2.30–2.24 (m, 1H).
13C NMR (150 MHz, CDCl3) δ 151.6, 144.7, 143.4, 136.0, 133.2, 129.3, 129.1, 128.2, 128.0, 127.8,
127.7, 127.6, 127.4, 127.2, 126.9, 125.4, 120.8, 118.7, 80.4, 70.7, 42.9, 24.6; IR (in KBr): 3524,
3443,3352, 3054, 2967, 2911, 1591, 1493, 1336, 1268, 1206, 1140, 1036, 942, 758, 700, 571 cmꢀ1;
HRMS (ESI) m/z calcd for C28H26NO [M+H+] 392.2009; found 392.2018.
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
Ethyl 3-hydroxy-3,3-bis(4-methoxyphenyl)-2-(p-tolylamino)propanoate (3ab). Purification by
chromatography (petroleum ether/acetone = 30:1) afforded 3ab (41.7 mg, 48% yield) as a white solid.
MP 154ꢀ155 oC; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H), 6.97
(d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 4.87 (s,
1H), 4.40 (s, 1H, OꢀH), 3.92 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 2.22 (s, 3H), 0.94 (t, J = 7.1
13
Hz, 3H). C NMR (100 MHz, CDCl3) δ 174.2, 158.7, 158.5, 143.8, 136.7, 135.2, 132.2, 129.7, 127.5,
127.1, 126.6, 119.6, 113.5, 78.7, 62.2, 61.2, 55.2, 55.1, 20.4, 13.8; IR (in KBr): 3466, 3410, 2835, 1716,
1613, 1517, 1463, 1367, 1300, 1253, 1188, 1030, 818, 534 cmꢀ1; HRMS (ESI) m/z calcd for C26H30NO5
[M+H+] 436.2118; found 436.2109.
Ethyl 3,3-bis(4-fluorophenyl)-3-hydroxy-2-(p-tolylamino)propanoate (3ac). Purification by
chromatography (petroleum ether/acetone = 40:1) afforded 3ac (43.6 mg, 53% yield) as a white solid.
o
1
MP 142ꢀ144 C; H NMR (400 MHz, CDCl3) δ 7.64–7.44 (m, 2H), 7.44–7.31 (m, 2H), 7.25–7.18 (m,
1H), 7.02–6.85 (m, 5H), 6.58 (d, J = 8.4 Hz, 2H), 4.88 (s, 1H), 4.60 (s, 2H), 3.94 (q, J = 7.1 Hz, 2H),
2.22 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.9, 161.9 (d, J = 240 Hz),
143.7, 139.7, 139.4 (d, J = 170 Hz), 130.3 (d, J = 8 Hz), 129.8, 127.7 (d, J = 8 Hz), 127.4 (d, J = 8 Hz),
115.3 (d, J = 12 Hz), 115.0 (d, J = 12 Hz), 114.3 (d, J = 22 Hz), 113.8, 78.7, 62.4, 61.5, 20.4, 13.8; IR
(in KBr): 3534, 3479, 3409, 2970, 1717, 1606, 1513, 1409, 1372, 1302, 1236, 1160, 1015, 834, 597,
530, cmꢀ1; HRMS (ESI) m/z calcd for C24H24F2NO3 [M+H+] 412.1719; found 412.1719.
Ethyl 2-(9-hydroxy-9H-fluoren-9-yl)-2-(p-tolylamino)acetate (3ad). Purification by chromatography
o
(petroleum ether/acetone = 40:1) afforded 3ad (46.9 mg, 63% yield) as a white solid. MP 111ꢀ113 C;
16
ACS Paragon Plus Environment

Page 17 of 22
The Journal of Organic Chemistry
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz,
1H), 7.43–7.28 (m, 4H), 7.03 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.49 (s, 1H), 3.76 (q, J = 7.1
Hz, 2H), 2.25 (s, 3H), 0.79 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.1, 145.5, 144.9,
140.2, 140.0, 129.8, 129.5, 129.4, 129.1, 127.9, 127.8, 124.6, 123.7, 120.1, 119.8, 119.6, 115.6, 81.8,
66.3, 61.2, 20.5, 13.5; IR (in KBr): 3530, 3393, 2983, 2905, 1738, 1611, 1521, 1446, 1306, 1191, 1148,
1042, 819, 745, 616, 550, 488 cmꢀ1; HRMS (ESI) m/z calcd for C24H24NO3 [M+H+] 374.1751; found
374.1748.
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
Ethyl 3-hydroxy-3-phenyl-2-(p-tolylamino)propanoate (3ae). Purification by chromatography
(petroleum ether/acetone = 10:1) afforded 3ae (29.8 mg, 50% yield) as a white solid (1.1:1 dr). MP 102ꢀ
o
1
104 C; H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 2H, Major+Minor), 7.38–7.28 (m, 8H,
Major+Minor), 7.00 (d, J = 7.9 Hz, 2H, Minor), 6.96 (d, J = 7.9 Hz, 2H, Major), 6.65 (d, J = 7.9 Hz, 2H,
Minor), 6.54 (d, J = 7.9 Hz, 2H, Major), 5.16 (d, J = 4.6 Hz, 1H, Minor), 4.94 (d, J = 4.3 Hz, 1H,
Major), 4.38 (d, J = 4.6 Hz, 1H, Minor), 4.15 (d, J = 4.3 Hz, 1H, Major), 4.07–3.98 (m, 4H,
Major+Minor, NꢀH+OꢀH), 3.23 (s, 4H, Major+Minor), 2.24 (s, 3H, Minor), 2.22 (s, 3H, Major), 1.12–
13
0.99 (m, 6H, Major+Minor). C NMR (100 MHz, CDCl3) δ 172.2, 171.8, 144.3, 144.2, 139.7, 139.6,
129.8, 129.7, 128.8, 128.6, 128.39, 128.37, 128.2, 128.1, 126.4, 125.8, 114.8, 114.6, 74.6, 73.8, 64.8,
63.3, 61.4, 61.2, 20.5, 20.4, 14.0, 13.9; IR (in KBr): 3467, 3400, 2983, 2914, 1699, 1614, 1521, 1450,
1303, 1262, 1194, 1025, 814, 752, 702, 572, 503 cmꢀ1; HRMS (ESI) m/z calcd for C18H22NO3 [M+H+]
300.1594; found 300.1598.
Ethyl 3-hydroxy-3-(p-tolyl)-2-(p-tolylamino)propanoate (3af). Purification by chromatography
(petroleum ether/acetone = 10:1) afforded 3af (29.6 mg, 47% yield) as a white solid (1.1:1 dr). MP 109ꢀ
110 oC; 1H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H, Major), 7.21 (d, J = 7.9 Hz, 2H, Minor),
7.19–7.11 (m, 4H, Major+Minor), 6.99 (d, J = 8.0 Hz, 2H, Minor), 6.96 (d, J = 8.0 Hz, 2H, Major), 6.65
(d, J = 8.4 Hz, 2H, Minor), 6.55 (d, J = 8.4 Hz, 2H, Major), 5.12 (d, J = 4.6 Hz, 1H, Minor), 4.91 (d, J =
5.7 Hz, 1H, Major), 4.36 (d, J = 4.6 Hz, 1H, Minor), 4.13 (d, J = 5.7 Hz, 1H, Major), 4.10–3.99 (m, 4H,
Major+Minor), 3.14 (s, 2H, Major+Minor, OꢀH), 2.34 (s, 6H, Major+Minor), 2.24 (s, 3H, Minor), 2.22
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 22
13
(s, 3H, Major), 1.16–1.00 (m, 6H, Major+Minor). C NMR (100 MHz, CDCl3) δ 172.3, 171.9, 144.4,
144.3, 137.9, 137.8, 136.61, 136.60, 129.8, 129.7, 129.1, 129.0, 128.7, 128.5, 126.3, 125.7, 114.8,
114.7, 74.4, 73.7, 64.7, 63.3, 61.3, 61.2, 21.14, 21.13, 20.5, 20.4, 14.0, 13.9; IR (in KBr): 3323, 2980,
2917, 1735, 1690, 1616, 1519, 1308, 1264, 1195, 1069, 1023, 812, 508 cmꢀ1; HRMS (ESI) m/z calcd for
C19H24NO3 [M+H+] 314.1751; found 314.1755.
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
Ethyl
3-(4-chlorophenyl)-3-hydroxy-2-(p-tolylamino)propanoate
(3ag).
Purification
by
chromatography (petroleum ether/acetone = 10:1) afforded 3ag (32.5 mg, 49% yield) as a white solid
o
1
(1.1:1 dr). MP 89ꢀ91 C; H NMR (600 MHz, CDCl3) δ 7.38–7.31 (m, 6H, Major+Minor), 7.29 (d, J =
8.3 Hz, 2H, Minor), 7.01 (d, J = 8.0 Hz, 2H, Minor), 6.97 (d, J = 8.1 Hz, 2H, Major), 6.65 (d, J = 8.1
Hz, 2H, Minor), 6.55 (d, J = 8.1 Hz, 2H, Major), 5.14 (s, 1H, Minor), 4.92 (d, J = 5.6 Hz, 1H, Major),
4.35 (d, J = 4.6 Hz, 1H, Minor), 4.10 (d, J = 5.6 Hz, 1H, Major), 4.09–3.97 (m, 4H, Major+Minor), 3.23
(d, J = 26.3 Hz, 2H, Major+Minor, OꢀH), 2.24 (s, 3H, Minor), 2.23 (s, 3H, Major), 1.14–1.05 (m, 6H,
13
Major+Minor). C NMR (100 MHz, CDCl3) δ 172.0, 171.4, 144.0, 143.8, 138.3, 138.2, 134.0, 133.8,
129.9, 129.8, 129.1, 129.0, 128.53, 128.50, 127.9, 127.3, 114.9, 114.8, 73.9, 73.1, 64.6, 63.4, 61.5, 61.4,
20.5, 20.4, 14.1, 14.0; IR (in KBr): 3525, 3441, 3391, 3318, 2981, 1736, 1687, 1597, 1520, 1406, 1262,
1193, 1018, 813, 506 cmꢀ1; HRMS (ESI) m/z calcd for C18H21ClNO3 [M+H+] 334.1204; found
334.1206.
2-(Diphenylamino)-1,1-diphenylethanol (3la). Purification by chromatography (petroleum ether/
o
diethyl ether = 50:1) afforded 3la (54.8 mg, 75% yield) as a white solid. MP 138ꢀ139 C; 1H NMR (400
MHz, CDCl3) δ 7.41–7.32 (m, 4H), 7.19–7.07 (m, 10H), 6.88 (t, J = 7.3 Hz, 2H), 6.76 (d, J = 8.0 Hz,
13
4H), 4.63 (s, 2H), 3.26 (s, 1H, OꢀH). C NMR (100 MHz, CDCl3) δ 149.6, 145.0, 129.2, 128.0, 126.8,
126.1, 122.2, 122.0, 78.5, 64.0; IR (in KBr): 3472, 3026, 2946, 1591, 1492, 1448, 1331, 1234, 1178,
1062, 1021, 835, 775, 748, 696, 579 cmꢀ1; HRMS (ESI) m/z calcd for C26H24NO [M+H+] 366.1852;
found 366.1857. This compound is known.18
1,1-Diphenyl-2-(phenyl(p-tolyl)amino)ethanol (3ma). Purification by chromatography (petroleum
o
1
ether/ diethyl ether = 50:1) afforded 3ma (53.1 mg, 70% yield) as a white solid. MP 145ꢀ146 C; H
18
ACS Paragon Plus Environment

Page 19 of 22
The Journal of Organic Chemistry
NMR (400 MHz, CDCl3) δ 7.43–7.28 (m, 4H), 7.21–7.04 (m, 8H), 6.91 (d, J = 8.0 Hz, 2H), 6.81 (t, J =
7.3 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 8.3 Hz, 2H), 4.59 (s, 2H), 3.28 (s, 1H, OꢀH), 2.24 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 150.1, 146.4, 145.0, 132.7, 129.7, 128.8, 127.8, 126.6, 126.0,
124.0, 120.8, 119.8, 78.5, 64.1, 20.8; IR (in KBr): 3649, 3323, 2922, 2852, 1689, 1594, 1494, 1447,
1259, 1184, 750, 698, 591 cmꢀ1; HRMS (ESI) m/z calcd for C27H26NO [M+H+] 380.2009; found
380.2002.
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
2-(Methyl(phenyl)amino)-1,1-diphenylethanol (3na). Purification by chromatography (petroleum
o
ether/ diethyl ether = 50:1) afforded 3na (39.4 mg, 65% yield) as a white solid. MP 82ꢀ83 C; 1H NMR
(400 MHz, CDCl3) δ 7.53–7.49 (m, 3H), 7.34–7.26 (m, 4H), 7.24–7.16 (m, 4H), 7.15–7.11 (m, 2H),
6.90 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 7.3 Hz, 1H), 4.13 (s, 2H), 3.62 (s, 1H, OꢀH), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 128.9, 128.4, 128.1, 127.1, 126.8, 125.7, 118.6, 114.3, 76.6, 66.2, 39.6; IR (in
KBr): 3484, 3058, 3025, 2814, 1600, 1503, 1446, 1362, 1263, 1179, 1060, 1027, 952, 751, 699, 648,
604 cmꢀ1; HRMS (ESI) m/z calcd for C21H22NO [M+H+] 304.1696; found 304.1700. This compound is
known.18
2-(Benzyl(phenyl)amino)-1,1-diphenylethanol (3oa). Purification by chromatography (petroleum
o
1
ether/ diethyl ether = 50:1) afforded 3oa (50.9 mg, 67% yield) as a white solid. MP 101ꢀ102 C; H
NMR (400 MHz, CDCl3) δ 7.49–7.46 (m, 3H), 7.30–7.25 (m, 5H), 7.21–7.17 (m, 3H), 7.16–7.10 (m,
5H), 6.90 (d, J = 7.9 Hz, 3H), 6.73 (t, J = 7.2 Hz, 1H), 4.31 (s, 2H), 4.09 (s, 2H), 3.41 (s, 1H, OꢀH). 13C
NMR (100 MHz, CDCl3) δ 128.9, 128.4, 128.3, 128.1, 127.1, 126.9, 126.8, 126.7, 126.5, 125.7, 118.2,
114.4, 77.4, 62.2, 53.7; IR (in KBr): 3564, 3059, 3027, 2926, 1598, 1498, 1448, 1197, 1160, 1027, 749,
699, 651, 605 cmꢀ1; HRMS (ESI) m/z calcd for C27H26NO [M+H+] 380.2009; found 380.2010.
ASSOCIATED CONTENT
Supporting Information
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 22
Details for conditions optimization, luminescence quenching experiments, quantum yield mensuration
and copies of 1H NMR and 13C NMR spectra of products 3. This material is available free of charge on
the ACS Publications website at DOI: http://pubs.acs.org.
1
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Authors
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
*Eꢀmail for W.ꢀJ. X.: wxiao@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (No. 21232003, 21472057 and
21572074) for support of this research.
REFERENCES
(1) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835. (b) Bergmeier, S. C.
Tetrahedron 2000, 56, 2561. (c) Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2012, 10,
4311.
(2) (a) Lin, G. Q.; Xu, M. H.; Zhong, Y. W.; Sun, X. W. Acc. Chem. Res. 2008, 41, 831. (b) Burchak,
O. N.; Py, S. Tetrahedron 2009, 65, 7333.
(3) Bailey, P. D.; Collier, I. D.; Hollinshead, S. P.; Moore, M. H.; Morgan, K. M.; Smith, D. I.;
Vernon, J. M. J. Chem. Soc. Perkin Trans. 1, 1997, 1209.
(4) For reviews on metalꢀcatalyzed aminooxygenation, see: (a) Cardona, F.; Goti, A. Nat. Chem.
2009, 1, 269. (b) Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009. (c) Donohoe, T. J.; Callens, C. K.
A.; Flores, A.; Lacy, A. R.; Rathi, A. H. Chem. Eur. J. 2011, 17, 58. (d) Williamson, K. S.; Michaelis, D.
J.; Yoon, T. P. Chem. Rev. 2014, 114, 8016.
(5) For selected reports on aminooxygenation, see : (a) Noack, M.; Göttlich, R. Chem. Commun.
2002, 536. (b) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690. (c) Desai, L.
V.; Sanford, M. S. Angew. Chem. Int. Ed. 2007, 46 , 5737. (d) Fuller, P. H.; Kim, J.ꢀW.; Chemler, S. R.
20
ACS Paragon Plus Environment

Page 21 of 22
The Journal of Organic Chemistry
J. Am. Chem. Soc. 2008, 130, 17638. (e) Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132,
4570. (f) Haro,T. de; Nevado, C. Angew. Chem. Int. Ed. 2011, 50, 906. (g) Williamson, K. S.; Yoon, T.
P. J. Am. Chem. Soc. 2012, 134, 12370. (h) Lu, D.ꢀF.; Zhu, C.ꢀL.; Jia, Z.ꢀX.; Xu, H. J. Am. Chem. Soc.
2014, 136, 13186.
1
2
3
4
5
6
7
8
9
(6) For selected reports on Sharpless aminooxygenation, see : (a) Sharpless, K. B.; Chong, A. O.;
Oshima, K. J. Org. Chem. 1976, 41, 177. (b) Li, G.; Chang, H.ꢀT.; Sharpless, K. B. Angew. Chem. Int.
Ed. 1996, 35, 451. (c) Reiser, O. Angew. Chem. Int. Ed. 1996, 35, 1308. (d) O’Brien, P. Angew. Chem.
Int. Ed. 1999, 38,326.
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
(7) (a) Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Knowles, R. R., J. Am. Chem. Soc.
2013, 135, 17735. (b) Miyazawa, K.; Koike, T.; Akita, M. Chem. Eur. J. 2015, 21, 11677.
(8) (a) Inagaki, A.; Akita, M. Coord. Chem. Rev. 2010, 254, 1220. (b) Narayanam, J. M.;
Stephenson, C. R. Chem. Soc. Rev. 2011, 40, 102. (c) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687.
(d) Xuan, J.; Xiao, W. J. Angew. Chem. Int. Ed. 2012, 51, 6828. (e) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (f) Xi, Y.; Yi, H.; Lei, A. Org. Biomol. Chem. 2013,
11 2387. (g) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 985. (h) Nicewicz, D. A.; Nguyen, T. M.
ACS Catalysis 2014, 4, 355. (i) Hu, C.; Chen, Y. Tetrahedron Lett. 2015, 56, 884.
(9) (a) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114. (b) Petronijevic, F.
R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 18323. (c) Pirnot, M. T.; Rankic, D.
A.; Martin, D. B.; MacMillan, D. W. C. Science 2013, 339, 1593. (d) Qvortrup, K.; Rankic, D. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 626. (e) Cuthbertson, J. D.; MacMillan, D. W. C.
Nature 2015, 519, 74. (f) Nakajima, M.; Fava, E.; Loescher, S.; Jiang, Z.; Rueping, M. Angew. Chem.
Int. Ed. 2015, 54, 8828. (g) Uraguchi, D.; Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem. Soc. 2015, 137,
13768. (h) Li, W.; Duan, Y.; Zhang, M.; Cheng, J.; Zhu, C. Chem. Commun. 2016, 52, 7596. (i) Fava, E.;
Millet, A.; Nakajima, M.; Loescher, S.; Rueping, M. Angew. Chem. Int. Ed. 2016, 55, 6776.
(10) (a) Lang, S. B.; O’Nele, K. M.; Tunge, J. A. J. Am. Chem. Soc. 2014, 136, 13606. (b) Xuan, J.;
Zeng, T.ꢀT.; Feng, Z.ꢀJ.; Deng, Q.ꢀH.; Chen, J.ꢀR.; Lu, L.ꢀQ.; Xiao, W.ꢀJ.; Alper, H. Angew. Chem. Int.
Ed. 2015, 54, 1625.
(11)(a) Ding, W.; Zhou, Q.ꢀQ.; Xuan, J.; Li, T.ꢀR.; Lu, L.ꢀQ.; Xiao, W.ꢀJ. Tetrahedron Lett. 2014, 55,
4648. (b) Hu, X.ꢀQ.; Chen, J.ꢀR.; Wei, Q.; Liu, F.ꢀL.; Deng, Q.ꢀH.; Beauchemin, A. M.; Xiao, W.ꢀJ.
Angew. Chem. Int. Ed. 2014, 53, 12163. (c) Xuan, J.; Xia, X.ꢀD.; Zeng, T.ꢀT.; Feng, Z.ꢀJ.; Chen, J.ꢀR.;
Lu, L.ꢀQ.; Xiao, W.ꢀJ. Angew. Chem. Int. Ed. 2014, 53, 5653. (d) Guo, W.; Lu, L.ꢀQ.; Wang, Y.; Wang,
Y.ꢀN.; Chen, J.ꢀR.; Xiao, W.ꢀJ. Angew. Chem. Int. Ed. 2015, 54, 2265. (e) Zhou, Q.ꢀQ.; Guo, W.; Ding,
W.; Wu, X.; Chen, Xi.; Lu, L.ꢀQ.; Xiao, W.ꢀJ. Angew. Chem. Int. Ed. 2015, 54, 11196.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 22
(12) Wang, C.; Qin, J.; Shen, X.; Riedel, R.; Harms, K.; Meggers, E. Angew. Chem. Int. Ed. 2016, 55,
685.
1
2
3
(13) The homocoupling compound of the secondary amines 1a was afforded as a byꢀproduct in the
model reaction.
4
5
6
7
8
9
(14) (a) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886. (b)
Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 14604.
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
(15) (a) Miyake, Y.; Ashida, Y.; Nakajima, K.; Nishibayashi, Y. Chem. Commun. 2012, 48, 6966. (b)
Miyake, Y.; Ashida, Y.; Nakajima, K.; Nishibayashi, Y. Chem. Eur. J. 2014, 20, 6120. (c) Ruiz Espelt,
L.; McPherson, I. S.; Wiensch, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2015, 137, 2452.
(16) (a) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O. Org. Lett. 2012, 14, 672. (b) Miyake, Y.;
Nakajima, K.; Nishibayashi, Y. Chem. Eur. J. 2012, 18, 16473. (c) Zhou, H.; Lu, P.; Gu, X.; Li, P. Org.
Lett. 2013, 15, 5646.
(17) (a) Rossi, S.; Pirola, O.; Selva, F. Tetrahedron 1968, 24, 6395. (b) Anderson, W. K.;
Bhattacharjee, D.; Houston, D. M. J. Med. Chem. 1989, 32, 119. (c) Alagiri, K.; Devadig, P.; Prabhu, K.
R. Tetrahedron Lett. 2012, 53, 1456. (d) Deng, Q. H.; Zou, Y. Q.; Lu, L. Q.; Tang, Z. L.; Chen, J. R.;
Xiao, W. J. Chem. Asian J. 2014, 9, 2432. (e) Wei, X.ꢀH.; Wu, Q.ꢀX.; Yang, S.ꢀD. Synlett 2015, 26,
1417. (f) Ruiz Espelt, L.; McPherson, I. S.; Wiensch, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2015, 137,
2452.
(18) Davidson, R. S. Chem. Commun. 1966, 575.
22
ACS Paragon Plus Environment