C-N Bond Formation from Allylic Alcohols via Cooperative Nickel and Titanium Catalysis

Article abstract of DOI:10.1021/acs.joc.8b01474

Amination of allylic alcohols is facilitated via cooperative catalysis. Catalytic Ti(O-i-Pr)₄ is shown to dramatically increase the rate of nickel-catalyzed allylic amination, and mechanistic experiments confirm activation of the allylic alcohol by titanium. Aminations of primary and secondary allylic alcohols are demonstrated with a variety of amine nucleophiles. Diene-containing substrates also cyclize onto the nickel allyl intermediate prior to amination, generating carbocyclic amine products. This tandem process is only achieved under our cooperative catalytic system.

Full text of DOI:10.1021/acs.joc.8b01474

Subscriber access provided by STEPHEN F AUSTIN STATE UNIV
Note
C–N Bond Formation from Allylic Alcohols
Via Cooperative Nickel and Titanium Catalysis
S. Hadi Nazari, Norma Tiempos-Flores, Kelton G. Forson, Jefferson E. Bourdeau, and David J. Michaelis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01474 • Publication Date (Web): 07 Aug 2018
Downloaded from http://pubs.acs.org on August 8, 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 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 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.
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 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
C–N Bond Formation from Allylic Alcohols Via Cooperative Nickel and
Titanium Catalysis
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. Hadi Nazari,1 Norma Tiempos-Flores,2 Kelton G. Forson,1 Jefferson E. Bourdeau,1 David J. Michae-
lis1*
1Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, United States
2 Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Pedro de Alba s/n, Ciudad Universitaria, 66451
San Nicolás de los Garza, Nuevo León, México.
Supporting Information Placeholder
ABSTRACT: Amination of allylic alcohols is facilitated via cooperative catalysis. Catalytic Ti(Oi-Pr)4 is shown to dramatically
increase the rate of nickel-catalyzed allylic amination and mechanistic experiments confirm activation of the allylic alcohol by tita-
nium. Aminations of primary and secondary allylic alcohols are demonstrated with a variety of amine nucleophiles. Diene-containing
substrates also cyclize onto the nickel allyl intermediate prior to amination, generating carbocyclic amine products. This tandem
process is only achieved under our cooperative catalytic system.
Cooperative catalysis is a strategy for reaction engineering
that involves the simultaneous use of multiple catalysts to im-
prove reaction efficiency or facilitate different reaction mecha-
nisms.1 This approach provides unique opportunities for sub-
strate activation that can enable catalysis under much milder
conditions and enable new selectivity not observed in single cat-
alyst systems. In addition, the catalytic activation of multiple
reacting partners2 can preclude the need for stoichiometric sub-
strate activation, which is a common strategy in single catalyst
systems. One application of cooperative catalysis is the in situ
activation of alcohol electrophiles by Lewis acids for cross cou-
pling reactions.3 This approach enables the use of readily avail-
able allylic alcohols as electrophilic partners for cross couplings
without the need for stoichiometric activation of the alcohol as
a carbonate, halide, or ester. Our group is interested in the dis-
covery and development of cooperative catalysis systems, in-
cluding those with heterobimetallic complexes.4,5 Our results
presented herein demonstrate that catalytic activation of the al-
lylic alcohol is a viable strategy for rapid allylic amination un-
der nickel catalysis and that this approach provides unique sub-
strate reactivity not observed in single catalyst systems.
using nickel catalysts and acetate additives (Figure 1a).10 Ki-
mura and Onodera11 also recently reported allylic aminations
with allylic alcohols under palladium catalysis with boronic es-
ter-containing phosphine ligands, which activate the allylic al-
cohol (Figure 1b). In this report, we show that the in situ acti-
vation of allylic alcohols with catalytic amounts of titanium
Lewis acids enables highly efficient nickel-catalyzed allylic
aminations with a broad range of primary and secondary allylic
alcohols and various primary and secondary amine nucleo-
philes. In addition, we demonstrate that diene-containing
a) Mashima:
0.5% [Ni(cod)2]
R1
R1
1% dppf
R
R
HN
R2
N
OH
+
R2
2.5% nBu4NOAc
MeCN, 60 ºC
b) Kimura and Onodera:
B
PPh2
R1
R1
Pd(OAc)2
/
R
R
HN
R2
N
OH
+
+
R2
c) This work:
R
Metal-catalyzed allylic functionalization reactions, including
allylic aminations, are widely employed in modern catalysis
due to the ability of these reactions to proceed with high product
selectivity.6 The use of unactivated allylic alcohols in this trans-
formation is attractive because it precludes the need for stoichi-
ometric activation of the alcohol, but the acidity of the OH bond
and the poor leaving group ability of alcohols makes this trans-
formation difficult to achieve.7 Our previous studies have
shown that bidentate NHC phosphine ligands enable selective
nickel-catalyzed Suzuki-Miyaura cross couplings with allylic
alcohols and boronic esters.8 Nickel-catalyzed allylic amination
reactions with unprotected alcohols have also previously been
demonstrated,9 including in work by Mashima and coworkers
0.5% [Ni(cod)2]
R1
R1
1% dppf
R
HN
R2
N
OH
R2
30% Ti(OiPr)4
MeCN, rt
Unprotected
Allylic Alcohol
Cooperative Ni/Ti catalysis
d)
R
5% [Ni(cod)2]
5% dppf
R1
R
R
R1
R2
N
HN
R
+
Ti(OiPr)4 (1 equiv)
rt, 12 h
R2
HO
(±)
Tandem Cyclization/Amination
Figure 1. Allylic amination under mild conditions via cooperative
Ni/Ti catalysis.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
substrates readily cyclize prior to amination only under our co- but not to the same degree as with titanium isopropoxide. We
1
2
3
4
5
6
7
8
operative catalysis conditions, generating carbocyclic allylic
amine products with good diastereoselectivity (Figure 1d).
also investigated the impact of phosphine ligand structure on
the rate of catalysis and found that various phosphines could be
employed, but dppf provided the highest yield in the reaction
(entries 9–13). Acetonitrile as solvent was also found to be im-
portant to obtaining good conversions (entries 14–17).
During the course of our studies in C–C bond forming Su-
zuki-Miyaura couplings with allylic alcohols,8 we wondered
whether the nickel allyl intermediate generated in the reaction
could be trapped with amine nucleophiles to generate the allyl
amine product. To begin our optimization studies, we found
that addition of Ni(cod)2 and bis-(diphenylphosphino)ferrocene
(dppf) to the reaction of morpholine with cinnamyl alcohol re-
sulted in very low yield of the amination product (Table 1, entry
1). However, the addition of a catalytic amount of titanium iso-
propoxide (30%) to the reaction dramatically improved the rate
of product formation, presumably via alcohol activation (entry
2). Similar Lewis acid effects have been observed in allylic ami-
nations with noble metal catalysts.12 Importantly, this allylic
amination occurs under very mild conditions at room tempera-
ture with inexpensive nickel catalysts. No conversion was ob-
served in the absence of nickel and in the presence of titanium
(entry 3) and lower amounts of titanium led to slower reactions
(entry 4). Under conditions previously reported for nickel-cata-
lyzed allylic aminations using tetrabutylammonium acetate
(TBAA) as additive,10 only 12% yield was observed under the
same conditions (Entry 5). Catalytic amounts of alternative
Lewis acids also accelerated the transformation (entries 6–8),
In order to further investigate the role of titanium, we also
conducted the reaction with 0.5 and 1.0 equivalents of the Lewis
acid and found that the rate increased as the amount of titanium
increased (Table 1, entries 18–19). This supports our hypothe-
sis that titanium activates the alcohol toward oxidative addition
by the nickel catalyst, presumably via formation of the Ti(O-
allyl)4 species. Indeed, when titanium isopropoxide is mixed
with cinnamyl alcohol in the presence or absence of morpho-
line, shifts in the 1H NMR spectrum indicate coordination of the
alcohol with the Lewis acid. However, when titanium iso-
propoxide was added to the preformed nickel dppf catalyst, no
change in the 1H NMR spectrum was observed (see supporting
information). This final result suggests that the titanium does
not impact the structure of the nickel catalyst.
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
Our next goal was to demonstrate that our catalytic system
performed well across a wide variety of substrates. To this end,
we screened a variety of allylic alcohol substrates and found
that the reaction tolerates various substitutions at the alkene and
alcohol carbons (Figure 2). For example, simple allyl alcohols
that are unsubstituted or monosubstituted on the alkene react in
high yield (2a–2c). Electron rich and electron poor cinnamyl
alcohols also provide high yield of the allyl amine product (2d–
2h). Secondary allylic alcohols are also well-tolerated and pro-
vide high yields of the secondary amine products (2i–2m). Sub-
strates containing the thiophene heterocycle also react in high
yield (2n). However, while trisubstituted alkenes do react (2o),
including Baylis-Hillman adducts (2p), they provide only mod-
est yield of the product. For the majority of substrates, catalytic
amounts of titanium are sufficient to obtain high yields. In cer-
tain cases much better yields were obtained with stoichiometric
titanium Lewis acid, such as with secondary allylic alcohols
(2i–k, 2m) and with other sensitive functional groups (2n–2p).
Table 1. Optimization of cooperative catalysis system.
0.5% [Ni(cod)2]
1% ligand
HN
Ph
N
+
Ph
OH
O
O
30% additive
solvent, rt
conv.b
(yield)
time
(h)
entrya
ligand
additive
-
solvent
MeCN
1
2
dppf
dppf
-
24
12
20
20
12
12
12
12
12
12
12
12
12
12
12
12
12
4
3
90(85)
-
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
3
4c
dppf
dppf
dppf
dppf
dppf
PPh3
dppe
dppp
dppb
BINAP
dppf
dppf
dppf
dppf
dppf
dppf
36
14
22
45
65
46
21
41
86
67
9
0.5% [Ni(cod)2]
1% dppf
R1
R1
R
R
5
TBAA
TiCl4
BF3
MeCN
MeCN
MeCN
MeCN
HN
R2
N
OH
+
R2
30% Ti(OiPr)4
MeCN, rt
Bn
6
Bn
Bn
N
7
N
N
Bn
Bn
Bn
8
AlCl3
97% (2a)
92% (2b)
90% (2c)
9
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 toluene
R
Yield
10
11
12
13
14
15
16
17
18d
19e
H
OMe
Me
Cl
CF3
86% (2d)
97% (2e)
98% (2f)
N
O
R
83% (2g)a
94% (2h)
O
N
Bn
Me
Bn
O
N
O
HN
N
N
Ti(Oi-Pr)4
Ti(Oi-Pr)4 dioxane
Ti(Oi-Pr)4 DMF
THF
6
Ph
Me Ph
Ph
6
94% (2i)b 98% (2j)b 57% (2k)b
97% (2l)
82% (2m)b
1
Ph
CO2Me
Ph
O
Ti(Oi-Pr)4 MeCN
Ti(Oi-Pr)4 MeCN
96
99 (96)
Ph
N
N
N
S
O
2
O
87% (2n)b
30% (2o)b
30% (2p)b
a) Reaction run with 1.6 mmol alcohol, 2.4 mmol amine (1.5
equiv) in solvent (4 M). b) Conversion measured by 1H NMR anal-
ysis of the crude reaction. c) With 10% Ti(Oi-Pr)4. d) With 50%
Ti(Oi-Pr)4. e) With 100% Ti(Oi-Pr)4
Figure 2. Amination of various primary and secondary alcohol
substrates. a) Reaction run with 2 mol% Ni and 0.5 equiv Ti(Oi-
Pr)4. b) Reaction run with 5 mol% Ni and 1 equiv Ti(Oi-Pr)4.
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
E
E
Our attention next turned to exploring the substrate scope
with respect to the amine nucleophile (Figure 3). Secondary
amines are excellent substrates for the allylic amination (3a–3i),
including cyclic amines (3g–3i) and heterocyclic amine 3i. Pri-
mary amines are also acceptable substrates and give mono-al-
lylated products (3j–3k), but slightly reduced yields are ob-
served due to the formation of overalkylated products. Alpha-
branched primary amines, however, provide high yields with
primary alcohols (3l), and monosubstituted primary amines pro-
vide higher yields with secondary allylic alcohols (3m). In these
last cases, steric hindrance around the amine product is essential
for obtaining high yield of the mono-alkylated product. Very
sterically hindered amines, on the other hand (3n), only provide
modest yield in the reaction.
E
5% [Ni(cod)2]
10% dppf
E
1
+
NHR2
R
2
3
4
5
6
7
8
9
100% Ti(OiPr)4
MeCN, rt, 20 hrs
N
R
OH
(±)
E = CO2Et
E
E
E
E
Ni
Ni
E
E
E
E
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
E
E
Ph
Bn
N
Me
HN
N
Bn
Bn
0.5% [Ni(cod)2]
R1
1% dppf
R2
78% (4a)
(4.7:1 dr)
88% (4b)
(8.8:1 dr)
91% (4c)
(3.5:1 dr)
HN
R2
Ph
N
+
OH
Ph
30 or 100% Ti(OiPr)4
R1
E
E
MeCN, rt
E
E
Ph
Ph
i-Pr
Bn
Et
N
N
N
N
N
N
N
Et
Me
Ph
i-Pr
Bn
90% (3a)a
99% (3b)a
96% (3c)a
89% (3d)b
77% (3e)b
88% (4d)
(6:1 dr)
60% (4e)
(4.8:1 dr)
Bn
N
Ph
N
N
N
E
E
N
H
E
NMe
Me
E
MeN
96% (3f)b
93% (3g)b
88% (3h)b
95% (3i)b
O
76% (3j)
N
N
C10H21
Me
HN
C10H21
N
N
H
N
H
Ph
46% (4f)
(4:1 dr)
96% (4g)
(5.8:1 dr)
Ph
Me
40% (3k)
96% (3l)
75% (3m)
30% (3n)
Figure 4. Tandem cyclization/amination of diene-containing
substrates.
Figure 3. Substrate scope for the amine nucleophile. a) reaction run
with 2 mol% nickel and 100% Ti(Oi-Pr)4. b) reaction run with
100% Ti(Oi-Pr)4.
tional group. These results provide access to synthetically val-
uable allylic amine products in high yield as potential building
blocks for alkaloid synthesis.
Tandem processes are attractive synthetically because they
enable the formation of multiple bonds in the same transfor-
mation, leading to rapid construction of complex molecules. In
this vein, we investigated the tandem oxidative addition, cy-
clization, and amination reaction shown in Figure 4. When our
cooperative catalysis system was employed, the cyclized prod-
ucts (4) were observed as the major product and in good yield
when 5% nickel catalyst and 100% titanium isopropoxide were
used. In contrast, under the catalytic conditions developed by
Mashima (see Figure 1a),10 only amination was observed and
no cyclization. To the best of our knowledge, this is the first
example of an insertion of a nickel allyl intermediate into a pen-
dant diene to generate a cyclized amination product. This new
transformation generates a multifunctional cyclopentane prod-
uct containing two stereocenters with moderate to good dia-
stereoselectivity. The reaction proceeds in moderate to high
yield with a variety of amine nucleophiles, including acyclic
(4a, 4b, 4c), cyclic (4d, 4e), and heterocyclic amines (4f, 4g).
These new amine products could be valuable intermediates in
the synthesis of complex alkaloids due to the dense arrangement
of reactive functional groups.
Experimental Section
General Information: All reactions were carried out under an
atmosphere of nitrogen or argon in oven-dried glassware with
magnetic stirring, unless otherwise indicated. Solvents were
dried by J. C. Meyer’s Solvent Purification System. The sub-
strates were prepared by literature procedures or as described
below. All other reagents were used as obtained unless other-
wise noted. Flash chromatogaphy was performed with EM Sci-
ence silica gel (0.040-0.063µm grade). Analytical thin-layer
chromatography was performed with 0.25 mm coated commer-
cial silica gel plates (E. Merck, DC-Plastikfolien, kieselgel 60
F254). Proton nuclear magnetic resonance (1H-NMR) data were
acquired on an Inova 300 MHz, an Inova 500 MHz, or an NMR-
S 500 MHz spectrometer. Chemical shifts are reported in delta
(δ) units relative to the 2H signal of the CDCl3 solvent. Signals
are reported as follows: s (singlet), d (doublet), t (triplet), q
(quartet), dd (doublet of doublets), qd (quartet of doublets), bs
(broad singlet), m (multiplet), rot (rotamers). Coupling con-
stants are reported in hertz (Hz). Carbon-13 nuclear magnetic
resonance (13C-NMR) data were acquired on an Inova at 75
MHz or Inova or NMR-S spectrometer at 125 MHz. Chemical
shifts are reported in ppm. All NMR spectra were collected at
298 K. Mass spectral data were obtained using ESI techniques
(Agilent, 6210 TOF). Infrared (IR) data were recorded as films
on sodium chloride plates on a Thermo Scientific Nicolet IR100
FT-IR spectrometer. Absorbance frequencies are reported in re-
ciprocal centimeters (cm-1).
In conclusion, we have developed a cooperative catalytic sys-
tem for the amination of unactivated allylic alcohols under mild
conditions. These conditions rely on the Ti-mediated activation
of the allylic alcohol to facilitate efficient catalysis. A broad
range of amines and alcohol substrates react in high yield in this
transformation. In addition, this catalytic system enables tan-
dem cyclization amination reactions for the first time via inser-
tion of the nickel allyl intermediate into a pendent diene func
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 10
Substrates 2i-2k were synthesized according to previously re-
ported procedures13.
using pure hexanes to 50% EtOAc/hexanes as eluent (369 mg,
92%). Spectral data is in accordance with the reported values15a
1
.
2
3
4
5
6
7
8
9
diethyl
2-((E)-4-hydroxybut-2-en-1-yl)-2-((E)-penta-2,4-
N,N-dibenzyl-2-methylprop-2-en-1-amine (2c): Prepared
following the general procedure using Ni(COD)2 (2.2 mg, 0.008
mmL, 0.005eq), dppf (9 mg, 0.016 mmol, 0.01 eq), 2-methyl-
2-propene-1-ol (115 mg, 1.6 mmol, 1 eq), dibenzylamine (473
mg, 2.4 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.1 mL, 0.3 eq, 4.879
M solution in toluene) in acetonitrile (300 µL). Product was pu-
rified on column using pure hexanes to 50% EtOAc/hexanes as
eluent (361 mg, 90%). Spectral data is in accordance with the
dien-1-yl)malonate (4): To a solution of diethyl (E)-2-(penta-
2,4-dien-1-yl)malonate14a (L1, 550 mg, 2.43 mmol, 1eq) in THF
was added sodium hydride (60% dispersion in mineral oil, 146
mg, 3.64 mmol, 1.5 eq) at 0 oC and stirred at room temperature
for 30 minutes. A solution of (E)-tert-butyl((4-chlorobut-2-en-
1-yl)oxy)dimethylsilane14b (L2, 642 mg, 2.91 mmol, 1.2 eq) in
DMSO (2mL) was added and the mixture stirred overnight. The
reaction mixture diluted with ethyl acetate and washed with Na-
HCO3 (aq), dried over magnesium sulfate, and concentrated in
vacuum. Purification on column using EtOAc/hexanes(1% to
2.5%) gave the product as a yellowish liquid (900 mg, 76%).1
1H NMR (500 MHz, CDCl3) δ 6.19-6.35 (m, 1H), 6.02-6.13 (m,
1H), 5.41-5.68 (m, 3H), 5.08 (d, J = 16.91 Hz, 1H), 5.0 (d, J =
10.55 Hz,1H), 4.17 (q, J = 14.23 Hz, 4H), 4.10 (d, J = 4.66 Hz,
2H), 2.63 (t, J = 7.82 Hz, 4H), 1.23 (t, J = 7.12 Hz, 6H), 0.9 (s,
9H), 0.055 (s, 6H) ; 13C NMR (75 MHz, CDCl3) δ 170.8,
136.7, 135.0, 134.1, 128.0, 123.9, 116.3, 63.6, 61.3, 57.7, 35.8,
35.5, 26.0, 14.2, -5.1; IR (film)νmax 2929, 2856, 1736, 1462,
1256, 1133; HRMS(ESI) calcd. for C30H29N3P, [M+H]+,
463.2172; found, 463.2175.
To a solution of the product from above (1 g, 2.5 mmol, 1eq) in
THF was added tetrabutylammonium fluoride (1M in THF, 6
mL, 6 mmol, 2 eq) at 0oC. The reaction mixture warmed up and
stirred at room temperature overnight. The mixture was diluted
with EtOAc and washed with water. Organics were dried on so-
dium sulfate, concentrated, and purified on column chromatog-
raphy using hexanes/EtOAc (0 to 25%) gave the product as a
colorless liquid (600 mg, 82%). 1H NMR (500 MHz, CDCl3) δ
6.22-6.32 (m, 1H), 6.05-6.13 (m, 1H), 5.68-5.77 (m, 1H), 5.47-
5.59 (m, 2H), 5.12 (d, J = 17.34 Hz, 1H), 5.01 (d, J = 10.42 Hz,
1H), 4.18 (q, J = 14.31 Hz, 4H), 4.08 (t, J = 5.39 Hz, 2H), 2.64
(dd, J = 7.96,11.23 Hz, 4H), 1.24 (t, J = 7.18 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 170.7, 136.6, 135.1, 133.8, 127.9, 126.1,
116.5, 63.4, 61.4, 57.6, 35.8, 35.4, 14.2; IR (film) νmax 3465,
2980, 1732, 1456, 1202,; HRMS (ESI) calcd. for C30H29N3P,
[M+H]+, 463.2172; found, 463.2175.
reported values15b
.
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-cinnamylmorpholine (2d): Prepared following the general
procedure using Ni(COD)2 (2.2 mg, 0.008 mmL, 0.005 eq),
dppf (9 mg, 0.016 mmol, 0.01 eq), cinnamyl alcohol (214 mg,
1.6 mmol, 1 eq), morpholine (236 mg, 2.4 mmol, 1.5 eq), and
Ti(Oi-Pr)4 (0.1 mL, 0.3 eq, 4.879 M solution in toluene) in ace-
tonitrile (300 µL). Product was purified on column using pure
hexanes to 50% EtOAc/hexanes as eluent (277 mg, 86%). Spec-
tral data is in accordance with the reported values15b
.
(E)-4-(3-(4-methoxyphenyl)allyl)morpholine (2e): prepared
following the general procedure using Ni(COD)2 (1.1 mg, 0.004
mmol, 0.005 eq), dppf (9 mg, 0.008 mmol, 0.01 eq), (E)-3-(4-
methoxyphenyl)prop-2-en-1-ol (132mg, 0.8 mmol, 1 eq), mor-
pholine (140 mg, 1.2 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL,
0.3 eq, 4.879 M solution in toluene) in acetonitrile (100 µL).
Product was purified on column using pure hexanes to 50%
EtOAc/hexanes as eluent (90.5 mg, 97%). Spectral data is in
accordance with the reported values15b
.
(E)-4-(3-(p-Tolyl)allyl)morpholine (2f): Prepared following
the general procedure using Ni(COD)2 (1.1 mg, 0.008 mmol,
0.005 eq), dppf (9 mg, 0.008 mmol, 0.01 eq), (E)-3-(p-
tolyl)prop-2-en-1-ol (120 mg, 0.8 mmol, 1 eq), morpholine (140
mg, 1.2 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.3 eq, 4.879
M solution in toluene) in acetonitrile (100 µL). Product was pu-
rified on column using pure hexanes to 50% EtOAc/hexanes as
eluent (85 mg, 98%). Spectral data is in accordance with the
reported values15c
.
(E)-4-(3-(4-chlorophenyl)allyl)morpholine (2g): Prepared
following the general procedure using Ni(COD)2 (2.2 mg, 0.008
mmol, 0.02 eq), dppf (9 mg, 0.016 mmol, 0.04 eq), (E)-3-(4-
chlorophenyl)prop-2-en-1-ol (68 mg, 0.4 mmol, 1 eq), morpho-
line (70 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq,
4.879 M solution in toluene) in acetonitrile (100 µL). Product
was purified on column using pure hexanes to 50% EtOAc/hex-
General procedure for nickel-catalyzed cross coupling of al-
lylic alcohols with amines: Inside a glove box and in a 3 mL
dram vial were placed Ni(COD)2 (2.2 mg, 0.008 mmL, 0.005eq)
and dppf (9 mg, 0.016 mmol, 0.01eq) in acetonitrile (300 µL).
the mixture stirred for 5 minutes, and after addition of the allylic
alcohol (1.6 mmol, 1 eq), the amine (2.4 mmol, 1.5 eq), and
Ti(Oi-Pr)4 (0.1 mL, 0.3 eq, 4.879 M solution in toluene), the
vial was sealed and the reaction mixture stirred for 12 hours. All
the volatiles were removed on the rotovap, and the crude mix-
ture was purified on column using EtOAc/hexanes as eluent.
1
anes as eluent (79 mg, 83%). H NMR (500 MHz, CDCl3) δ
7.22-7.36 (m, 4H), 6.48 (d, J = 16.33 Hz, 1H), 6.16-6.28 (m,
1H), 3.73 (t, J = 4.62 Hz, 4H), 3.13 (dd, J = 1.38, 6.74 Hz, 2H),
2.49 (t, J = 4.64 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 132.1,
128.7, 127.5, 126.9, 67.0, 61.4, 53.7; IR (film) νmax 2856,
2464, 1492, 1452, 1119; HRMS (ESI) calcd. for C13H16ClNO,
[M+H]+, 239.0891; found, 239.0897.
N,N-dibenzylprop-2-en-1-amine (2a): Prepared following the
general procedure using Ni(COD)2 (2.2 mg, 0.008 mmL, 0.005
eq), dppf (9 mg, 0.016 mmol, 0.01eq), allyl alcohol (93 mg, 1.6
mmol, 1 eq), dibenzyl amine (473 mg, 2.4 mmol, 1.5 eq), and
Ti(Oi-Pr)4 (0.1 mL, 0.3 eq, 4.879 M solution in toluene) in ace-
tonitrile (300 µL). Product was purified on column using pure
hexanes to 50% EtOAc/hexanes as eluent (368 mg, 97%). Spec-
(E)-4-(3-(4-(trifluoromethyl)phenyl)allyl)morpholine (2h):
Prepared following the general procedure using Ni(COD)2 (2.2
mg, 0.008 mmol, 0.02 eq), dppf (9 mg, 0.016 mmol, 0.04 eq),
(E)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol (80 mg, 0.4
mmol, 1 eq), morpholine (70 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-
Pr)4 (0.05 mL, 0.5 eq, 4.879 M solution in toluene) in acetoni-
trile (100 µL). Product was purified on column using pure hex-
tral data is in accordance with the reported values15a
.
(E)-N,N-dibenzylbut-2-en-1-amine (2b): Prepared following
the general procedure using Ni(COD)2 (2.2 mg, 0.008 mmL,
0.005eq), dppf (9 mg, 0.016 mmol, 0.01 eq), (E)-2-butene-1-ol
(115 mg, 1.6 mmol, 1 eq), dibenzylamine (473 mg, 2.4 mmol,
1.5 eq), and Ti(Oi-Pr)4 (0.1 mL, 0.3 eq, 4.879 M solution in tol-
uene) in acetonitrile (300 µL). Product was purified on column
1
anes to 50% EtOAc/hexanes as eluent (101.5 mg, 94%). H
NMR (500 MHz, CDCl3) δ 7.38-7.63 (m, 4H), 6.57 (d, J = 15.68
Hz, 1H), 6.27-6.45 (m, 1H), 3.73 (t, J = 4.62 Hz, 4H), 3.13 (dd,
J = 1.38, 6.74 Hz, 2H), 2.49 (t, J = 4.64 Hz,4H); 13C NMR (75
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
MHz, CDCl3) δ 131.9, 129.1, 126.5, 125.6, 67.0, 61.3, 53.7; mmol, 0.05 eq), dppf (18mg, 0.04 mmol, 0.1 eq), (E)-3-(thio-
1
2
3
4
5
6
7
8
IR (film) νmax 2958, 2806, 1615, 1325, 1117; HRMS (ESI)
phen-2-yl)prop-2-en-1-ol (56 mg, 0.4mmol, 1 eq), morpholine
(64 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879
M solution in toluene) in acetonitrile (100 µL). Product was pu-
rified on column using pure hexanes to 50% EtOAc/hexanes as
eluent (73 mg, 87%). Spectral data is in accordance with the
calcd. for C14H16F3NO, [M+H]+, 272.1218; found, 272.1212.
N-benzylcyclohex-2-en-1-amine (2i): Prepared following the
general procedure using Ni(COD)2 (5.5 mg, 0.02 mmol, 0.05
eq), dppf (18 mg, 0.04 mmol, 0.1eq), cyclohex-2-en-1-ol (40
mg, 0.4 mmol, 1 eq), benzylamine (64 mg, 0.6 mmol, 1.5 eq),
and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879 M solution in toluene) in
acetonitrile (100 µL). Product was purified on column using
pure hexanes to 50% EtOAc/hexanes as eluent (101.5 mg,
reported values15g
.
4-(3,3-diphenylallyl)morpholine (2o): Prepared following the
general procedure using Ni(COD)2 (5.5 mg, 0.02 mmol, 0.05
eq), dppf (18mg, 0.04 mmol, 0.1eq), 3,3-diphenylprop-2-en-1-
ol (84 mg, 0.4mmol, 1 eq), morpholine (64 mg, 0.6 mmol, 1.5
eq), and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879 M solution in toluene)
in acetonitrile (100 µL). Product was purified on column using
pure hexanes to 50% EtOAc/hexanes as eluent (33 mg, 30%).
9
94%). Spectral data is in accordance with the reported values15c
.
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
N-benzyl-N-methylcyclohex-2-en-1-amine (2j): Prepared fol-
lowing the general procedure using Ni(COD)2 (5 mg, 0.016
mmol, 0.04 eq), dppf (18 mg, 0.320 mmol, 0.08 eq), cyclohex-
2en-1-ol (100 mg, 1 mmol, 1 eq), N-methylbenzylamine (250
mg, 2 mmol, 2 eq), and Ti(Oi-Pr)4 (284 mg, 1 mmol, 1 eq) in
acetonitrile (500 µL). Product was purified on column using
pure hexanes to 10% ethylacetate/hexanes as eluent (197 mg,
98%). 1H NMR (500 MHz, CDCl3) δ 7.18-7.33 (m, 5H), 5.79-
5.85 (m, 1H), 5.70-5.74 (m, 1H), 3.62-3.66 (d, J = 13.5 Hz, 1H),
3.43-3.47 (d, J=13.5 Hz, 1H), 3.32-3.37 (m, 1H), 2.20 (s, 3H),
1.94-1.99 (m, 2H), 1.76-1.85 (m, 2H), 1.50-1.56 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 140.4, 130.5, 129.9, 128.8,
128.3, 126.8, 59.5, 57.4, 37.9, 25.4, 22.9, 21.8; IR (film) νmax
2911, 2931, 2859, 2836, 2787, 1494, 1452, 1043; HRMS (ESI)
calcd. for C14H19N [M+H]+, 202.1596; found, [M+H]+,
202.1590.
Spectral data is in accordance with the reported values15f
.
Methyl (E)-2-(morpholinomethyl)-3-phenylacrylate (2p):
Prepared following the general procedure using Ni(COD)2 (5.5
mg, 0.02 mmol, 0.05 eq), dppf (18 mg, 0.04 mmol, 0.1eq), me-
thyl 2-(hydroxy(phenyl)methyl)acrylate (77 mg, 0.4mmol, 1
eq), morpholine (64 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.08
mL, 1 eq, 4.879 M solution in toluene) in acetonitrile (100 µL).
Product was purified on column using pure hexanes to 50%
EtOAc/hexanes as eluent (23mg, 30%). Spectral data is in ac-
cordance with the reported values15h
.
(E)-N,N-dibenzyl-3-phenylprop-2-en-1-amine (3a): prepared
following the general procedure using Ni(COD)2 (2.2 mg, 0.008
mmol, 0.02 eq), dppf (9 mg, 0.016 mmol, 0.04eq), cinnamyl al-
cohol (54 mg, 0.4 mmol, 1 eq), dibenzylamine (118 mg, 0.6
mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879 M solution
in toluene) in acetonitrile (100 µL). Product was purified on col-
umn using pure hexanes to 50% EtOAc/hexanes as eluent
(112.5 mg, 90%). Spectral data is in accordance with the re-
4-(cyclohex-2-en-1-yl)morpholine (2k): Prepared following
the general procedure using Ni(COD)2 (5 mg, 0.016 mmol, 0.04
eq), dppf (18 mg, 0.320 mmol, 0.08 eq), cyclohex-2en-1-ol (100
mg, 1 mmol, 1 eq), morpholine (300 mg, 3 mmol, 3eq), and
Ti(Oi-Pr)4 (284 mg, 1 mmol, 1 eq) in acetonitrile (500 µL).
Product was purified on column using pure pentane to 20%
ether/pentane as eluent (96 mg, 57%). 1H NMR (500 MHz,
CDCl3) δ 5.82-5.85 (m, 1H), 5.65-5.67 (m, 1H), 3.71-3.73 (m,
4H), 3.15-3.17 (m, 1H), 2.54-2.6 (m, 4H), 1.98-1.99 (m, 2H),
1.78-1.81 (m, 2H), 1.53-1.57 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 133.5, 133.3, 130.4, 128.8, 128., 128.1, 69.9, 67.5,
60.4, 25.3, 23.1, 21.4; IR (film) νmax 2911, 2930.26, 2853.28,
1450.28, 1249.41, 1117.06; HRMS (ESI) calcd. for C10H17NO,
[M+H]+, 168.1388; found, [M+H]+, 168.1382
ported values16a
.
N-cinnamyl-N-methylaniline (3b): Prepared following the
general procedure using Ni(COD)2 (2.2 mg, 0.008 mmol, 0.02
eq), dppf (9 mg, 0.016 mmol, 0.04 eq), cinnamyl alcohol (54
mg, 0.4 mmol, 1 eq), N-methyl aniline (64 mg, 0.6 mmol, 1.5
eq), and Ti(Oi-Pr)4 (0.08 mL, 1eq, 4.879 M solution in toluene)
in acetonitrile (100 µL). Product was purified on column using
pure hexanes to 50% EtOAc/hexanes as eluent (88.5 mg, 99%).
Spectral data is in accordance with the reported values16b
.
(E)-4-(4-phenylbut-3-en-2-yl)morpholine (2l): Prepared fol-
lowing the general procedure using Ni(COD)2 (2.2 mg, 0.008
mmol, 0.02eq), dppf (9 mg, 0.016 mmol, 0.04 eq), (E)-4-phe-
nylbut-3-en-2-ol (60 mg, 0.4 mmol, 1 eq), morpholine (64 mg,
0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq, 4.879 M
solution in toluene) in acetonitrile (100 µL). Product was puri-
fied on column using pure hexanes to 50% EtOAc/hexanes as
eluent (84.2 mg, 97%). Spectral data is in accordance with the
N-cinnamyl-N-phenylaniline (3c): Prepared following the
general procedure using Ni(COD)2 (2.2 mg, 0.008 mmol,
0.02eq), dppf (9 mg, 0.016 mmol, 0.04 eq), cinnamyl alcohol
(54 mg, 0.4 mmol, 1 eq), diphenyl amine (100 mg, 0.6 mmol,
1.5 eq), and Ti(Oi-Pr)4 (0.08 mL, 1eq, 4.879 M solution in tol-
uene) in acetonitrile (100 µL). Product was purified on column
using pure hexanes to 50% EtOAc/hexanes as eluent (109 mg,
96%). Spectral data is in accordance with the reported values16c
.
reported values15d
.
(E)-N,N-diethyl-3-phenylprop-2-en-1-amine (3d): Prepared
following the general procedure using Ni(COD)2 (1.1 mg, 0.008
mmol, 0.005eq), dppf (9 mg, 0.008 mmol, 0.01eq), cinnamyl
alcohol (54 mg, 0.4 mmol, 1 eq), diethylamine (44mg, 0.6
mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq, 4.879 M solu-
tion in toluene) in acetonitrile (100 µL). Product was purified
on column using pure hexanes to 50% EtOAc/Hexanes as elu-
ent (67 mg, 89%). Spectral data is in accordance with the re-
(E)-4-(1,3-diphenylallyl)morpholine (2m): Prepared follow-
ing the general procedure using Ni(COD)2 (5.5mg, 0.02 mmol,
0.05eq), dppf (18 mg, 0.04 mmol, 0.1 eq), (E)-1,3-diphe-
nylprop-2-en-1-ol (84 mg, 0.4 mmol, 1 eq), morpholine (64 mg,
0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879 M so-
lution in toluene) in acetonitrile (100 µL). Product was purified
on column using pure hexanes to 50% EtOAc/hexanes as eluent
(91 mg, 82%). Spectral data is in accordance with the reported
ported values16d
.
values15e
.
(E)-N,N-diisopropyl-3-phenylprop-2-en-1-amine (3e): Pre-
pared following the general procedure using Ni(COD)2 (2.2 mg,
0.008 mmol, 0.02eq), dppf (9 mg, 0.016 mmol, 0.04 eq), cin-
namyl alcohol (54 mg, 0.4 mmol, 1 eq), diisopropylamine (60
(E)-4-(3-(thiophen-2-yl)allyl)morpholine (2n): Prepared fol-
lowing the general procedure using Ni(COD)2 (5.5 mg, 0.02
ACS Paragon Plus Environment

The Journal of Organic Chemistry
mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq, 4.879 (E)-3-phenyl-N-(1-phenylethyl)prop-2-en-1-amine
Page 6 of 10
(3l):
1
2
3
4
5
6
7
8
M solution in toluene) in acetonitrile (100 µL). Product was pu-
rified on column using pure hexanes to 50% EtOAc/hexanes as
eluent (67 mg, 77%). Spectral data is in accordance with the
Prepared following the general procedure using Ni(COD)2 (1.1
mg, 0.008 mmol, 0.005 eq), dppf (9 mg, 0.008 mmol, 0.01eq),
cinnamyl alcohol (54 mg, 0.4 mmol, 1 eq), 1-phenylethan-1-
amine (73 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5
eq, 4.879 M solution in toluene) in acetonitrile (100 µL). Prod-
uct was purified on column using pure hexanes to 50%
EtOAc/hexanes as eluent (91 mg, 96%). Spectral data is in ac-
reported values16e
.
(E)-N-benzyl-N-methyl-3-phenylprop-2-en-1-amine
(3f):
Prepared following the general procedure using Ni(COD)2 (2.2
mg, 0.008 mmol, 0.02eq), dppf (9 mg, 0.016 mmol, 0.04 eq),
cinnamyl alcohol (54 mg, 0.4 mmol, 1 eq), N-methyl-1-phenyl-
methanamine (73 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05
mL, 0.5 eq, 4.879 M solution in toluene) in acetonitrile (100
µL). Product was purified on column using pure hexanes to
50% EtOAc/hexanes as eluent (91 mg, 96%). Spectral data is in
cordance with the reported values16m
.
(E)-N-(4-phenylbut-3-en-2-yl)decan-1-amine (3m): Prepared
following the general procedure using Ni(COD)2 (2.2 mg, 0.008
mmol, 0.02eq), dppf (9 mg, 0.016 mmol, 0.04eq), (E)-4-phenyl-
but-3-en-2-ol (60 mg, 0.4mmol, 1 eq), decylamine (94 mg, 0.6
mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05 ml, 0.5 eq, 4.879 M solution
in toluene) in acetonitrile (100 µl). Product was purified on a
column of silica gel using 20% methanol/EtOAc as eluent
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
accordance with the reported values16f
.
1-cinnamylpyrrolidine (3g): Prepared following the general
procedure using Ni(COD)2 (2.2 mg, 0.008 mmol, 0.02eq), dppf
(9 mg, 0.016 mmol, 0.04 eq), cinnamyl alcohol (54 mg, 0.4
mmol, 1 eq), pyrrolidine (43 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-
Pr)4 (0.05 mL, 0.5 eq, 4.879 M solution in toluene) in acetoni-
trile (100 µL). Product was purified on column using pure hex-
anes to 50% EtOAc/hexanes as eluent (69.6 mg, 93%). Spectral
1
(86mg, 75%). H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 3.7
Hz, 2H), 7.31 (t, J = 7.64 Hz, 2H), 7.20-7.25 (m, 1H), 6.47 (d,
J = 7.96 Hz, 1H), 6.09 (q, J = 7.89 Hz, 1H), 3.36 (quin, J = 6.68,
1H), 2.61-2.68 (m, 1H), 2.53-2.60 (m, 1H), 1.45-1.55 (m, 2H),
1.23-1.34 (m, 18H), 0.89 (t, J = 6.68 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 137.2, 134.6, 129.7, 128.5, 127.3, 136.3, 56.4,
47.7, 31.9, 30.4, 29.6, 29.6, 29.3, 27.5, 22.7, 22.1, 14.1; IR
(film) νmax 2924, 2359, 1465, 1136, 964; HRMS (ESI) calcd.
for C20H33N, [M+H]+, 288.2691; found, 288.2698.
data is in accordance with the reported values16g
.
1-cinnamylpiperidine (3h): Prepared following the general
procedure using Ni(COD)2 (2.2 mg, 0.008 mmol, 0.02eq), dppf
(9 mg, 0.016 mmol, 0.04eq), cinnamyl alcohol (54 mg, 0.4
mmol, 1 eq), piperidine (51 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-
Pr)4 (0.05 mL, 0.5 eq, 4.879 M solution in toluene) in acetoni-
trile (100 µL). Product was purified on column using pure hex-
anes to 50% EtOAc/hexanes as eluent (70.4 mg, 88%). Spectral
1-cinnamyl-2,2,6,6-tetramethylpiperidine (3n): prepared fol-
lowing the general procedure using Ni(COD)2 (5.5mg, 0.02
mmol, 0.05 eq), dppf (18mg, 0.04 mmol, 0.1eq), cinnamyl al-
cohol (54 mg, 0.4 mmol, 1 eq), 2,2,6,6-tetramethylpiperidine
(85 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.08 mL, 1 eq, 4.879
M solution in toluene) in acetonitrile (100 µL). Product was pu-
rified on column using pure hexanes to 50% EtOAc/hexanes as
eluent (31 mg, 30%). Spectral data is in accordance with the
data is in accordance with the reported values16h
.
1-cinnamyl-4-methylpiperazine (3i): Prepared following the
general procedure using Ni(COD)2 (2.2 mg, 0.008 mmol, 0.02
eq), dppf (9 mg, 0.016 mmol, 0.04eq), cinnamyl alcohol (54 mg,
0.4 mmol, 1 eq), N-methyl piperazine (60 mg, 0.6 mmol, 1.5
eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq, 4.879 M solution in tolu-
ene) in acetonitrile (100 µL). Product was purified on column
using pure hexanes to 50% EtOAc/hexanes as eluent (82 mg,
95%). Spectral data is in accordance with the reported values16i.
reported values16n
.
diethyl (E)-3-(3-(dibenzylamino)prop-1-en-1-yl)-4-vinylcy-
clopentane-1,1-dicarboxylate (4a): Prepared following the
general procedure using Ni(COD)2 (1.5 mg, 0.005 mmol,
0.05eq), dppf (5.5 mg, 0.01 mmol, 0.1 eq), diethyl 2-((E)-4-hy-
droxybut-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)malonate (30
mg, 0.1 mmol, 1 eq), dibenzylamine (24 mg, 0.12 mmol, 1.2
eq), and Ti(Oi-Pr)4 (0.03 mL, 1 eq, 4.879 M solution in toluene)
in acetonitrile (50 µL). The product was obtained as an unsepa-
rable mixture of two diastereomers (4.7:1) after purification on
column using pure hexanes to 70% EtOAc/hexanes as eluent
N-cinnamylaniline (3j): Prepared following the general proce-
dure using Ni(COD)2 (2.2 mg, 0.008 mmol, 0.02eq), dppf (9
mg, 0.016 mmol, 0.04 eq), cinnamyl alcohol (54 mg, 0.4 mmol,
1 eq), aniline (56 mg, 0.6 mmol, 1.5 eq), and Ti(Oi-Pr)4 (0.05
mL, 0.5 eq, 4.879 M solution in toluene) in acetonitrile (100
µL). Product was purified on column using pure hexanes to
50% EtOAc/hexanes as eluent (63 mg, 76%). Spectral data is in
accordance with the reported values16j.
1
(37 mg, 78%). H NMR (500 MHz, CDCl3) δ 7.21-7.39 (m,
10H) 5.62-5.78 (m, 1H), 5.48-5.58 (m, 2H), 4.94-5.03 (m, 2H),
4.16-4.24 (m, 4H), 3.56 (s, 4H), 3.01 (2,2H), 2.74-2.84 (m, 2H),
2.44-2.58 (m, 2H), 2.14-2.26 (m, 2H), 1.20-1.31 (m, 6H); 13
C
(E)-N-(4-phenylbut-3-en-2-yl)decan-1-amine (3k): Prepared
following the general procedure using Ni(COD)2 (1.1 mg, 0.008
mmol, 0.005eq), dppf (9 mg, 0.008 mmol, 0.01 eq), cinnamyl
alcohol (54 mg, 0.4 mmol, 1 eq), decylamine (94 mg, 0.6 mmol,
1.5 eq), and Ti(Oi-Pr)4 (0.05 mL, 0.5 eq, 4.879 M solution in
toluene) in acetonitrile (100 µL). Product was purified on col-
umn using pure hexanes to 20% Methanol/EtOAc as eluent (46
mg, 40%). 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 4.04 Hz,
2H), 7.31 (t, J =7.45 Hz, 2H), 7.20-7.25 (m, 1H), 6.52 (d, J =
7.45 Hz, 1H), 6.26-6.35 (m, 1H), 3.29 (d, J = 3.19, 2H), 2.51 (t,
J = 7.55 Hz, 1H), 1.48-1.57 (m,1H), 1.19-1.33 (m, 8H), 0.85-
0.95 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 137.2, 134.6,
129.7, 128.5, 127.3, 136.2, 56.4, 47.7, 31.9, 30.4, 29.6, 29.6,
29.3, 27.5, 22.7, 22.1, 14.1; IR (film) νmax 2924, 2359, 1733,
1456, 1273; HRMS (ESI) calcd. for C19H31N, [M+H]+,
274.2535; found, 274.2530.
NMR (75 MHz, CDCl3) δ 172.7, 139.8, 138.7, 133.5, 128.8,
128.3, 128.2, 126.8, 115.2, 61.6, 61.5, 59.1, 57.6, 55.3, 50.1,
48.8, 47.3, 46.1, 39.2, 38.7, 14.1; IR (film) νmax 2979, 2793,
1729, 1254, 1104; HRMS (ESI) calcd. for C30H37NO4,
476.2756; found, [M+H]+, 476.2753.
diethyl (E)-3-(3-(benzyl(methyl)amino)prop-1-en-1-yl)-4-
vinylcyclopentane-1,1-dicarboxylate (4b): Prepared follow-
ing the general procedure using Ni(COD)2 (1.5 mg, 0.005
mmol, 0.05 eq), dppf (5.5 mg, 0.01 mmol, 0.1 eq), diethyl 2-
((E)-4-hydroxybut-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)ma-
lonate (30 mg, 0.1 mmol, 1 eq), N-methyl-1-phenylmethana-
mine (15mg, 0.12 mmol, 1.2 eq), and Ti(Oi-Pr)4 (0.03 mL, 1 eq,
4.879 M solution in toluene) in acetonitrile (50 µL). The prod-
uct was obtained as an unseparable mixture of two diastere-
omers (8.8:1) after purification on column using pure hexanes
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
to 70% EtOAc/hexanes as eluent (35 mg, 88%). 1H NMR (500
(q, J = 7.10 Hz, 2H), 2.14-2.24 (m, 2H), 1.78-1.83 (m, 4H),
1.21-1.28 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 172.4,
138.5, 115.2, 61.6, 59.1, 58.0, 53.7, 47.2, 46.0, 39.1, 38.7, 23.4,
14.0; IR (film) νmax 2925, 2359, 1729, 1255, 1178; HRMS
(ESI) calcd. for C20H31NO4, 350.2287; found, [M+H]+,
350.2281.
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 5.63-5.78 (m, 1H), 5.45-5.55 (m, 2H), 4.94-
5.00 (m, 2H), 4.19 (dq, J = 7.15, 7.03 Hz, 4H), 3.46 (d, J = 2.85
Hz, 2H), 2.94-2.97 (m, 2H), 2.72-2.84 (m, 2H), 2.47 (dd, J =
13.89, 13.89 2H), 2.16-2.24 (m, 2H), 2.15 (s, 3H), 1.20-1.28 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 172.7, 172.4, 139.1,
138.6, 133.7, 129.1, 128.2, 126.9, 115.2, 61.5, 61.5, 59.5, 59.1,
47.3, 46.1, 42.0, 39.2, 38.7, 29.7, 14.1; IR (film) νmax 2925,
2359, 1730, 1453, 1254,; HRMS (ESI) calcd. for C24H33NO4,
[M+H]+, 400.2443; found, 400.2447.
diethyl (E)-3-(3-morpholinoprop-1-en-1-yl)-4-vinylcyclo-
pentane-1,1-dicarboxylate (4f): Prepared following the gen-
eral procedure using Ni(COD)2 (3 mg, 0.01 mmol, 0.05 eq),
dppf (11 mg, 0.02 mmol, 0.1 eq), diethyl 2-((E)-4-hydroxybut-
2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)malonate (60 mg, 0.2
mmol, 1 eq), morpholine (30 mg, 0.3 mmol, 1.5 eq), and Ti(Oi-
Pr)4 (0.05 mL, 1 eq, 4.879 M solution in toluene) in acetonitrile
(50 µL). The product was obtained as an unseparable mixture
of two diastereomers (4:1) after purification on column using
pure hexanes to 70% EtOAc/hexanes as eluent (33 mg, 46%).
1H NMR (500 MHz, CDCl3) δ 5.60-5.74 (m, 1H), 5.40-5.55 (m,
2H), 4.93-5.08 (m, 2H), 4.19 (q, J = 7.13 Hz, 4H), 3.70 (t, J=
4.64 Hz, 4H), 2.88-3.02 (m, 2H), 2.71-2.83 (m, 2H), 2.43-2.50
(m,2H), 2.33-2.54 (m, 6H), 2.11-2.24 (m, 2H), 1.19-1.29 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 172.6, 172.3, 139.3,
138.5, 134.6, 126.8, 115.5, 115.2, 67.0, 61.6, 59.1, 53.7, 53.5,
49.9, 48.5, 47.2, 46.0, 40.2, 39.9, 39.1, 38.7, 29.7, 14.0; IR
(film) νmax 2926, 2806, 1729, 1453, 1257, 1118; HRMS (ESI)
calcd. for C20H31NO5, [M+H]+, 366.2236; found, 366.2231. Di-
9
diethyl (E)-3-(3-((1-phenylethyl)amino)prop-1-en-1-yl)-4-
vinylcyclopentane-1,1-dicarboxylate (4c): Prepared follow-
ing the general procedure using Ni(COD)2 (1.5 mg, 0.005
mmol, 0.05 eq), dppf (5.5 mg, 0.01 mmol, 0.1 eq), diethyl 2-
((E)-4-hydroxybut-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)ma-
lonate (30 mg, 0.1 mmol, 1 eq), 1-phenylethan-1-amine (15 mg,
0.12 mmol, 1.2 eq), and Ti(Oi-Pr)4 (0.03 mL, 1 eq, 4.879 M
solution in toluene) in acetonitrile (50 µL). The product was ob-
tained as an unseparable mixture of two diastereomers (3.5:1)
after purification on column using pure hexanes to 70%
EtOAc/hexanes as eluent (36.3 mg, 91%). 1H NMR (500 MHz,
CDCl3) δ 7.20-7.36 (m, 5H), 5.59-5.75 (m, 1H), 5.29-5.55 (m,
2H), 4.92-5.08 (m, 2H), 4.12-4.23 (m, 4H), 3.78 (q, J = 6.24
Hz,1H), 2.97-3.09 (m, 2H), 2.70-2.79 (m, 2H), 2.37-2.56
(m,2H), 2.10-2.23(m, 2H), 1.34 (d, J = 6.44, 3H), 1.24 (q, J =
6.85, 6H); 13C NMR (75 MHz, CDCl3) δ 172.7, 172.4, 145.5,
138.6, 138.5, 132.1, 129.5, 129.4, 128.4, 126.9, 126.7, 126.6,
115.3, 61.5, 59.1, 57.2, 49.8, 49.3, 48.4, 47.2, 45.9, 40.3, 40.0,
39.1, 39.0, 38.7, 24.2, 21.8, 21.5, 14.0; IR (film) νmax 2924,
1728, 1254, 1178; HRMS (ESI) calcd. for C24H33NO4, [M+H]+,
400.2443; found, 400.2448.
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-((E)-4-morpholinobut-2-en-1-yl)-2-((E)-4-morpho-
linopent-2-en-1-yl)malonate (4h) was isolated as the main by-
product of the reaction as a brown liquid (30 mg, 40%) using
Methanol/EtOAc as eluent. 1H NMR (500 MHz, CDCl3) δ 5.52-
5.65 (m, 1H), 5.41-5.52 (m, 2H), 5.29-5.41 (m, 2H), 4.16 (q, J
= 7.18 Hz, 4H), 3.70 (s, 8H), 2.93 (d, J = 6.33, 2H), 2.75-2.85
(m, 2H) 2.53-2.65 (m, 4H), 2.30-2.52 (m, 8H), 1.20-1.30 (m,
6H), 1.12 (d, J = 6.47, 4H); 13C NMR (75 MHz, CDCl3) δ
170.7, 170.7, 136.9, 131.0, 127.9, 125.5, 67.1, 66.9, 62.7, 61.3,
61.1, 57.6, 53.5, 50.6, 35.4, 17.9, 14.1; IR (film) νmax 2958,
2807, 1731, 1453, 1265, 1200; HRMS (EI) calcd. for
C30H29N3P, [M+H]+, 463.2172; found, 463.2175.
diethyl (E)-3-(3-(piperidin-1-yl)prop-1-en-1-yl)-4-vinylcy-
clopentane-1,1-dicarboxylate (4d): Prepared following the
general procedure using Ni(COD)2 (1.5 mg, 0.005 mmol, 0.05
eq), dppf (5.5 mg, 0.01 mmol, 0.1eq), diethyl 2-((E)-4-hydroxy-
but-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)malonate (30 mg, 0.1
mmol, 1 eq), piperidine (11 mg, 0.12 mmol, 1.2 eq), and Ti(Oi-
Pr)4 (0.03 mL, 1 eq, 4.879 M solution in toluene) in acetonitrile
(50 µL). The product was obtained as an unseparable mixture
of two diastereomers (6:1) after purification on column using
pure hexanes to 70% EtOAc/hexanes as eluent (35 mg, 88%).
1H NMR (500 MHz, CDCl3) δ 5.65-5.76 (m, 1H), 5.43-5.54 (m,
2H), 4.93-5.03 (m, 2H), 4.19 (q, J = 8.02, 4H), 2.89-2.93 (m,
2H), 2.71-2.83 (m, 2H), 2.46 (q, J = 7.14 Hz, 2H), 2.27-2.40 (s,
4H), 2.13-2.24(m, 2H), 1.58 (t, J=5.28, 4H), 1.42 (s, 2H), 1.24
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 172.7, 172.4, 138.6,
133.8, 127.6, 115.1, 114.4, 67.5, 61.5, 59.1, 54.3, 47.7, 47.2,
46.0 48.4, 47.2, 45.9, 39.0, 38.7, 24.2, 21.5, 14.0; IR (film)
νmax 2933, 2795, 1730, 1443, 1254,; HRMS (ESI) calcd. for
C21H33NO4, [M+H]+, 364.2443; found, 364.2449.
diethyl (E)-3-(3-(4-methylpiperazin-1-yl)prop-1-en-1-yl)-4-
vinylcyclopentane-1,1-dicarboxylate (4g): Prepared follow-
ing the general procedure using Ni(COD)2 (1.5 mg, 0.005
mmol, 0.05 eq), dppf (5.5 mg, 0.01 mmol, 0.1 eq), diethyl 2-
((E)-4-hydroxybut-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)ma-
lonate (30 mg, 0.1 mmol, 1 eq), N-methylpiperazine (15 mg,
0.12 mmol, 1.2 eq), and Ti(Oi-Pr)4 (0.03 mL, 1 eq, 4.879 M so-
lution in toluene) in acetonitrile (50 µL). The product was ob-
tained as an unseparable mixture of two diastereomers (5.8:1)
after purification on column using 10% MeOH/EtOAC as elu-
ent (36.5 mg, 96.5%). 1H NMR (500 MHz, CDCl3) δ 5.60-5.78
(m, 1H), 5.46-5.55 (m, 2H), 4.90-5.06 (m, 2H), 4.19 (q, J = 7.10
Hz, 4H), 2.91-2.98 (m, 2H), 2.71-2.85 (m, 2H), 2.37-2.59 (m,
10H), 2.29 (s, 3H), 2.15-2.24 (m, 2H), 1.19-1.30 (m, 6H); 13
C
diethyl (E)-3-(3-(pyrrolidin-1-yl)prop-1-en-1-yl)-4-vinylcy-
clopentane-1,1-dicarboxylate (4e): Prepared following the
general procedure using Ni(COD)2 (1.5 mg, 0.005 mmol, 0.05
eq), dppf (5.5 mg, 0.01 mmol, 0.1 eq), diethyl 2-((E)-4-hy-
droxybut-2-en-1-yl)-2-((E)-penta-2,4-dien-1-yl)malonate (30
mg, 0.1mmol, 1 eq), pyrrolidine (11 mg, 0.12 mmol, 1.2 eq),
and Ti(Oi-Pr)4 (0.03 mL, 1 eq, 4.879 M solution in toluene) in
acetonitrile (50 µL). The product was obtained as an unsepara-
ble mixture of two diastereomers (4.8:1) after purification on
column using pure hexanes to 70% EtOAc/hexanes as eluent
NMR (300 MHz, CDCl3) δ 172.4, 138.6, 134.3, 127.3, 115.2,
61.6, 61.5, 60.1, 59.1, 55.1, 53.2, 52.9, 47.2, 46.1, 39.1, 38.7,
14.1; IR (film) νmax 2934, 2794, 2359, 1730, 1456, 1256, 1178;
HRMS (ESI) calcd. for C21H34N2O4, 379.2553; found, [M+H]+,
379.2557.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Spectral images for all compounds (PDF)
1
(21 mg, 60%). H NMR (500 MHz, CDCl3) δ 5.63-5.76 (m,
1H), 5.47-5.60 (m, 2H), 4.94-5.07 (m, 2H), 4.19 (q, J = 7.19 Hz,
4H), 3.06-3.15 (m, 2H), 2.71-2.82 (m, 2H), 2.44 (s, 4H), 2.47
Corresponding Author
* dmichaelis@chem.byu.edu
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
S. L.; Michaelis, D. Allylic Aminations with Hindered Secondary
Amine Nucleophiles Catalyzed by Heterobimetallic Pd−Ti Complexes.
Org. Lett. 2015, 17, 752–755.
6. a) Tsuji, J. Transition Metal Reagents and Catalysis, Wiley-VCH,
Weinheim, 2000. b) Trost, B. M.; Lee, C., in Catalytic Asymmetric Syn-
thesis (Ed.: Ojima, I.), 2nd ed., Wiley-VCH, Weinheim, 2000. c) Trost,
B. M.; Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic
Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103,
2921–2944.
ACKNOWLEDGMENT
1
2
3
4
5
6
Acknowledgment is made to the donors of the American Chemical
Society Petroleum Research Fund for support of this research (PRF
No. 56371-DNI1). Financial support was also provided by the Na-
tional Science Foundation (CHE-1665015).
REFERENCES
7
8
9
1. a) Allen, A. E.; MacMillan, D. W. C. Synergistic catalysis: A
powerful synthetic strategy for new reaction Development. Chem. Sci.
2012, 3, 633–658. b) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Enan-
tioselective cooperative catalysis. Org. Biomol. Chem. 2015, 13, 8116–
8162. c) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual catalysis, strate-
gies in photochemical synthesis. Chem. Rev. 2016, 116, 10035–10074.
2. For leading references, see: a) Trost, B. M.; Luan, X. Contempo-
raneous Dual Catalysis by Coupling Highly Transient Nucleophilic and
Electrophilic Intermediates Generated in Situ. J. Am. Chem. Soc.
2011,133, 1706–1709. b) Krautwald, S.; Schafroth, M. A.; Sarlah, D.;
Carreira, E. M. Stereodivergent α-Allylation of Linear Aldehydes with
Dual Iridium and Amine Catalysis. J. Am. Chem. Soc. 2014, 136, 3020–
3023. c) Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D.
J. Diastereodivergent organocatalytic asymmetric vinylogous Michael
reactions. Nat. Comm. 2014, 5, 4479. d) Huo, X.; Zhang, J.; Fu, J.; He,
R.; Zhang, W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent
Access to α,α-Disubstituted α-Amino Acids Bearing Vicinal Stereo-
centers. J. Am. Chem. Soc. 2018, 140, 2080–2084. e) Jiang, X.; Boehm,
P.; Hartwig, J. F. Stereodivergent Allylation of Azaaryl Acetamides
and Acetates by Synergistic Iridium and Copper Catalysis. J. Am.
Chem. Soc. 2018, 140, 1239–1242. f) Wei, L.; Xu, S.-M.; Zhu, O.; Che,
C.; Wang, C.-J. Synergistic Cu/Pd Catalysis for Enantioselective Al-
lylic Alkylation of Aldimine Esters: Access to a,a-Disubstituted a-
Amino Acids. Angew. Chem. Int. Ed. 2017, 56, 12312–12316. g) Lin,
L.; Feng, X. Catalytic Strategies for Diastereo divergent Synthesis.
Chem. Eur. J. 2017, 23, 6464–6482.
3. For reviews see: a) Tamaru, Y.; Kimura, M. Palladium-catalyzed
selective activation of allyl alcohols as allyl cations, allyl anions, and
zwitterionic trimethylenemethanes. Pure Appl. Chem. 2008, 80, 979–
991. b) Kimura, M.; Tamaru, Y. Amphiphilic Allylic Alkylation with
Allyl Alcohols Promoted by Pd-Catalyst and Triethylborane. Mini-Rev.
in Org. Chem. 2009, 6, 392–397. For selected examples, see: c) Ki-
mura, M.; Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. Strikingly
Simple Direct a-Allylation of Aldehydes. J. Am. Chem. Soc. 2001, 123,
10401–10402. d) Mukai, R.; Horino, Y.; Tanaka, S.; Tamaru, Y.; Ki-
mura, M. Pd(0)-Catalyzed Amphiphilic Activation of Bis-allyl Alcohol
and Ether. J. Am. Chem. Soc. 2004, 126, 11138–11139. e) Kimura, M.;
Futamata, M.; Mukai, R.; Tamaru, Y. Pd-Catalyzed C3-Selective Al-
lylation of Indoles with Allyl Alcohols Promoted by Triethylborane. J.
Am. Chem. Soc. 2005, 127, 4592–4593. f) Trost, B. M.; Quancard, J.
Palladium-Catalyzed Enantioselective C-3 Allylation of 3-Substituted-
1H-Indoles Using Trialkylboranes. J. Am. Chem. Soc. 2006, 128,
6314–6315. g) Olsson, V. J.; Sebelius, S.; Selander, N.; Szabo´, K. J.
Direct Boronation of Allyl Alcohols with Diboronic Acid Using Palla-
dium Pincer-Complex Catalysis. A Remarkably Facile Allylic Dis-
placement of the Hydroxy Group under Mild Reaction Conditions. J.
Am. Chem. Soc. 2006, 128, 4588–4589. h) Larsson, J. M.; Szabo´, K.
J. Mechanistic Investigation of the Palladium-Catalyzed Synthesis of
Allylic Silanes and Boronates from Allylic Alcohols. J. Am. Chem. Soc.
2013, 135, 443–455. i) Jia, X.-G.; Guo, P.; Duan, J.; Shu, X.-Z. Dual
nickel and Lewis acid catalysis for cross electrophile coupling: the al-
lylation of aryl halides with allylic alcohols. Chem. Sci. 2018, 9, 640–
645.
7. For reviews, see: a) Tamaru, Y. Activation of Allyl Alcohols as
Allyl Cations, Allyl Anions, and Amphiphilic Allylic Species by Pal-
ladium. Eur. J. Org. Chem. 2005, 2647-2656. b) Sundararaju, B.;
Achard, M.; Bruneau, C. Transition metal catalyzed nucleophilic al-
lylic substitution: activation of allylic alcohols via p-allylic species.
Chem. Soc. Rev. 2012, 41, 4467-4483. c) Muzart J. Procedures for and
Possible Mechanisms of Pd-Catalyzed Allylations of Primary and Sec-
ondary Amines with Allylic Alcohols. Eur. J. Org. Chem. 2007, 3077-
3089. d) Muzart, J. Palladium-catalysed reactions of alcohols. Part B:
Formation of C–C and C–N bonds from unsaturated alcohols. Tetrahe-
dron 2005, 61, 4179-4212. e) Butt, N. A.; Zhang, W. Transition metal-
catalyzed allylic substitution reactions with unactivated allylic sub-
strates. Chem. Soc. Rev. 2015, 44, 7929-7967. f) Bandini, M. Allylic
Alcohols: Sustainable Sources for Catalytic Enantioselective Alkyla-
tion Reactions. Angew. Chem., Int. Ed. 2011, 50, 994−995.
8. Nazari, S. H.; Bourdeau, J. E.; Talley, M. R.; Valdivia-Berroeta,
G. A.; Smith, S. J.; Michaelis, D. J. Nickel-Catalyzed Suzuki Cross
Couplings with Unprotected Allylic Alcohols Enabled by Bidentate
N-Heterocyclic Carbene (NHC)/Phosphine Ligands. ACS Catal. 2018,
8, 86–89.
9. a) Furukawa, J.; Kiji, J.; Yamamoto, K.; Tojo, T. Nickel-cata-
lyzed allyl-transfer reactions. Tetrahedron, 1973, 29, 3149–3151. b)
Bricout, H.; Carpentier, J. F.; Mortreux, A. Nickel vs. palladium cata-
lysts for coupling reactions of allyl alcohol with soft nucleophiles: ac-
tivities and deactivation processes. J. Mol. Cat. A-Chem. 1998, 136,
243–251.
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
10. Kita, Y.; Sakaguchi, H.; Hoshimoto, Y.; Nakauchi, D.; Naka-
hara, Y.; Carpentier, J.-F.; Ogoshi, S.; Mashima, K. Pentacoordinated
Carboxylate π-Allyl Nickel as key intermediates for direct amination
of allylic alcohols. Chem. Eur. J. 2015, 21, 14571–14578.
11. Hirata, G.; Satomura, H.; Kumagae, H.; Shimizu, A.; Onodera,
G.; Kimura, M. Direct Allylic Amination of Allylic Alcohol Catalyzed
by Palladium Complex Bearing Phosphine−Borane Ligand. Org. Lett,
2017, 19, 6148–6151.
12. a) Yoshiro, M.; Masaaki, K.; Yasuhiko, K. Palladium-Catalyzed
Allylic Amination of Allyl Alcohols with Tin(II) Chloride and Tri-
ethylamine. Chem. Lett. 1995, 24, 1121–1122. b) Yang, S.C.; Hung,
C.W. Palladium-Catalyzed Amination of Allylic Alcohols Using Ani-
lines. J. Org. Chem. 1999, 64, 5000–5001. c) Shue, Y.-J.; Yang, S.C.;
Lai, H.C. Direct palladium(0)-catalyzed amination of allylic alcohols
with aminonaphthalenes. Tetrahedron Lett. 2003, 44, 1481–1485. d)
Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F.; Iridium-Catalyzed,
Asymmetric Amination of Allylic Alcohols Activated by Lewis Acids
J. Am. Chem. Soc. 2007, 129, 7508–7509.
13. a) Henderson, D. A.; Fuchter, M. J. Lanthanide replacement
in organic synthesis: Luche-type reduction of α,β-unsaturated ketones
in the presence of calcium triflate. Green Chem. 2012, 14, 2129 –
2132. b) Bigler, R.; Huber, R.; Mezzetti, A. Highly Enantioselective
Transfer Hydrogenation of Ketones with Chiral (NH)2P2 Macrocyclic
Iron(II) Complexes. Angew. Chem. Int. Ed. 2014, 54, 17, 5171–5174.
c) Stoner, E. J.; Cothron, D. A.; Balmer, M. K.; Roden, B. A. Ben-
zylation via Tandem Grignard reaction—iodotrimethylsilane
(TMSI) mediated reduction. Tetrahedron, 1995, 51, 11043–11062.
14. a) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. Nickel-Cat-
alyzed Addition of Dimethylzinc to Aldehydes across Alkynes and 1,3-
Butadiene:ꢀ An Efficient Four-Component Connection Reaction. J. Am.
Chem. Soc. 2005 , 127, 201–209. b) Takacs, M.; Myoung, Y.
C.; Anderson, L. G.; Catalytic Iron-Mediated Triene Carbocycliza-
tions: Stereoselective Five-Membered Ring Forming Carbocycli-
zations, J. Org. Chem. 1994, 59, 6928–6942.
4. Chaudhary, A.; Singh, A.; Kamboj, R. C. Heterobimetallic Com-
plexes as Promising Catalysts. Chem. Sci. Rev. Lett. 2016, 5, 170–192.
5. a) Talley, M. R.; Stokes, R. W.; Walker, W. K.; Michaelis, D. J.
Electrophilic activation of alkynes for enynecycloisomerization reac-
tions with in situ generated early/late heterobimetallic Pt–Ti Catalysts.
Dalton Trans. 2016, 45, 9770–9773. b) Walker, W. K.; Kay, B. M.;
Michaelis, S. A.; Anderson, D. L.; Smith, S. J.; Ess, D. H.; Michaelis,
D. J. Origin of Fast Catalysis in Allylic Amination Reactions Catalyzed
by Pd−Ti Heterobimetallic Complexes. J. Am. Chem. Soc. 2015, 137,
7371–7378. c) Walker, W. K.; Anderson, D. L.; Stokes, R. W.; Smith,
15. a) Cazorla, C.; Billamboz, M.; Bricout, H.; Monflier,
E.; Len, C. Green and Scalable Palladium-on-Carbon-Catalyzed
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
Tsuji–Trost Coupling Reaction Using an Efficient and Continuous
Flow System. Eur. J. Org. Chem. 2017, 1078–1085. b) Hirata,
G.; Satomura, H.; Kumagae, H.; Shimizu, A.; Onodera, G.; Ki-
mura, M. Direct Allylic Amination of Allylic Alcohol Catalyzed by
Palladium Complex Bearing Phosphine–Borane Ligand. Org.
Lett. 2017, 19, 6148–6151. c) Kita, Y.; Sakaguchi, H.; Hoshimoto,
Y.; Nakauchi, D.; Nakahara, Y.; Carpentier, J. F.; Ogoshi,
S.; Mashima, K. Pentacoordinated Carboxylate π-Allyl Nickel Com-
plexes as Key Intermediates for the Ni-Catalyzed Direct Amination of
Allylic Alcohols. Chem. Eur. J. 2015, 21, 14571–4578. d) Park,
K.; Lee, S. Additive-Free Decarboxylative Coupling of Cinnamic
Acid Derivatives in Water: Synthesis of Allyl Amines, Org.
Lett. 2015, 17, 1300–1303. e) Nishina, N.; Yamamoto, Y. ; Gold-
Catalyzed Intermolecular Hydroamination of Allenes: First Exam-
ple of the Use of an Aliphatic Amine in Hydroamination. Syn-
lett 2007, 11, 1767–1770. f) Goldfogel, M. J.; Roberts, C.
C.; Meek, S. J. Intermolecular Hydroamination of 1,3-Dienes Cat-
alyzed by Bis(phosphine)carbodicarbene–Rhodium Complexes. J.
Am. Chem. Soc. 2014, 136 , 6227–6230. g) Xie, Y.; Hu, J.; Wang,
Y.; Xia, C.; Huang, H. Palladium-Catalyzed Vinylation of Ami-
nals with Simple Alkenes: A New Strategy To Construct Allyla-
mines. J. Am. Chem. Soc. 2012, 134, 20613–20616. h) Beck, J.
F.; Samblanet, D. C.; Schmidt, J. A. R. Palladium catalyzed inter-
molecular hydroamination of 1-substituted allenes: an atom-economi-
cal method for the synthesis of N-allylamines. RSC Adv. 2013, 3,
20708–20718.
16. a) Wang, M.; Xie, Y.; Li, J.; Huang, H. Palladium-Cata-
lyzed Direct Amination of Allylic Alcohols at Room Temperature.
Synlett 2014, 25, 2781–2786. b) Hirata, G.; Satomura,
H.; Kumagae, H.; Shimizu, A.; Onodera, G.; Kimura, M. Direct
Allylic Amination of Allylic Alcohol Catalyzed by Palladium
Complex Bearing Phosphine–Borane Ligand. Org. Lett. 2017, 19,
6148–6151. c) Shimizu, Y.; Obora, Y.; Lshii, Y. Intermolecular
Aerobic Oxidative Allylic Amination of Simple Alkenes with Dia-
rylamines Catalyzed by the Pd(OCOCF3)2/NPMoV/O2 System.
Org. Lett. 2010, 12, 1372–1374. d) Chardon, A.; Mohy El Dine,
T.; Legay, R.; De Paolis, M.; Rouden, J.; Blanchet, J. Borinic Acid
Catalysed Reduction of Tertiary Amides with Hydrosilanes: A Mild
and Chemoselective Synthesis of Amine. Chem. Eur. J. 2017, 23,
2005–2009. e) Kita, Y.; Sakaguchi, H.; Hoshimoto, Y.; Nakauchi,
D.; Nakahara, Y.; Carpentier, J.; Ogoshi, S.; Mashima, K.; Penta-
coordinated Carboxylate π-Allyl Nickel Complexes as Key Intermedi-
ates for the Ni-Catalyzed Direct Amination of Allylic Alcohols. Chem.
Eur. J. 2015, 21, 14571–14578. f) Jing, J.; Huo, X.; Shen, J.; Fu,
J.; Meng, Q.; Zhang, W. Direct use of allylic alcohols and allylic
amines in palladium-catalyzed allylic amination. Chem. Comm. 2017,
53, 5151 – 5154. g) Hirata, G.; S.; Kumagae, H.; Shimizu, A.; On-
odera, G.; Kimura, M. Direct Allylic Amination of Allylic Alcohol
Catalyzed by Palladium Complex Bearing Phosphine–Borane Lig-
and. Org. Lett. 2017, 19, 6148–6151. h) Horn, P. A.; Braun, R.
K.; Isoppo, V. G.; Costa, J. S.; Lüdtke, D. S.; Moro, A. V. Combin-
ing Copper-Catalyzed Hydroboration with Palladium-Catalyzed Su-
zuki Coupling for the One-pot Synthesis of Arylallylamines under Mi-
cellar Conditions. Adv. Synth. Cat. 2017, 359, 2322–2328. i) Yu,
H.; Gao, B.; Hu, B.; Huang, H. Org. Lett. 2017, 19, 3520–3523. j)
Takale, B. S.; Tao, S.; Yu, X. Q.; Feng, X.; Jin, T.; Bao, M.; Yama-
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
moto,
Y.
Org.
Lett. 2014,
16,
2558–2561.
k)Takeuchi; U.; Tanabe; Y.; Shiga. Iridium Complex-Catalyzed
Allylic Amination of Allylic Esters. J. Am. Chem. Soc. 2001, 123,
9525–9534. l) Wang, Y.; Li, M.; Ma, X.; Liu, C.; Gu, Y.; Tian, S.
Deammoniative Condensation of Primary Allylic Amines with Nonal-
lylic Amines. Ch. J. Chem. 2014, 32, 741–751. m) Walker, W.
K.; Anderson, D. L.; Stokes, R. W.; Smith, S. J.; Michaelis, D. J. ;
Allylic Aminations with Hindered Secondary Amine Nucleophiles
Catalyzed by Heterobimetallic Pd–Ti Complexes. Org. Lett. 2015,
17, 752–755.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
1
2
3
4
5
6
Abstract Graphic:
7
8
9
R
Ni catalyst
Ti co-catalyst
R1
R
R
R1
R2
N
HN
R
+
rt, 12 h
R2
HO
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
(±)
●
●
●
Cooperative Catalysis
Mild Reaction Conditions
Tandem Cyclization/Amination
Unprotected
Allylic Alcohol
ACS Paragon Plus Environment