Iridium(III)- benzoxazolyl and benzothiazolyl phosphine ligands catalyzed versatile alkylation reactions with alcohols and the synthesis of quinolines and indole

Article abstract of DOI:10.1016/j.jorganchem.2018.04.036

A series of benzoxazolyl and benzothiazolyl phosphine ligands 4a-4g were synthesized and characterized, which prepared from commercially available 2-aminophenol/2-aminobenzenethiol and 2-bromobenzaldehyde via cyclization and phosphination. The representative ligands 4c and 4e were determined by single-crystal X-ray diffraction. The corresponding iridium complexes could be generated in situ when [Cp*IrCl₂]₂ (Cp* = pentamethylcyclopentadienyl) encountered ligands. The molecular structures of complexes 5c and 5e were crystallographically characterized. The dihedral angles of N (1)-C (1)-C (8)-C (9) showed an increasing twist compared with the corresponding ligand. The iridium (III) catalysts were screened, [Cp*IrCl₂]₂/4a proved to be the optimal catalyst, which exhibited efficient catalytic activity toward versatile alkylations including ketones, secondary alcohols and amines with primary alcohols. Additionally, the synthesis of quinolines from ketones with 2-aminobenzyl alcohol by intermolecular cyclization and indole from 2-(2-aminophenyl)ethanol by intramolecular cyclization were achieved under the optimized conditions.

Full text of DOI:10.1016/j.jorganchem.2018.04.036

Accepted Manuscript
Iridium(III)- benzoxazolyl and benzothiazolyl phosphine ligands catalyzed versatile
alkylation reactions with alcohols and the synthesis of quinolines and indole
Shuang Huang, Si-Peng Wu, Quan Zhou, He-Zhen Cui, Xi Hong, Yue-Jian Lin, Xiu-
Feng Hou
PII:
S0022-328X(18)30289-4
10.1016/j.jorganchem.2018.04.036
JOM 20428
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 7 February 2018
Revised Date: 19 April 2018
Accepted Date: 30 April 2018
Please cite this article as: S. Huang, S.-P. Wu, Q. Zhou, H.-Z. Cui, X. Hong, Y.-J. Lin, X.-F. Hou,
Iridium(III)- benzoxazolyl and benzothiazolyl phosphine ligands catalyzed versatile alkylation reactions
with alcohols and the synthesis of quinolines and indole, Journal of Organometallic Chemistry (2018),
doi: 10.1016/j.jorganchem.2018.04.036.
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ACCEPTED MANUSCRIPT
Iridium(III)- Benzoxazolyl and Benzothiazolyl Phosphine Ligands
Catalyzed Versatile Alkylation Reactions with Alcohols and the Synthesis of
Quinolines and Indole
1
1
1
1
1
Shuang Huang , Si-Peng Wu , Quan Zhou , He-Zhen Cui , Xi Hong ,
1
1,2 *
Yue-Jian Lin , Xiu-Feng Hou
1
2
Department of Chemistry, Fudan University, Shanghai 200433, China
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi
32003, China
8
Keywords: Iridium; Benzoxazolyl or benzothiazolyl phosphine ligands; Alkylation; Quinolines
Abstract: A series of benzoxazolyl and benzothiazolyl phosphine ligands 4a-4g were synthesized
and characterized, which prepared from commercially available 2-aminophenol
/
2-aminobenzenethiol and 2-bromobenzaldehyde via cyclization and phosphination. The
representative ligands 4c and 4e were determined by single-crystal X-ray diffraction. The
corresponding iridium complexes could be generated in situ when [Cp*IrCl2]2 (Cp* =
pentamethylcyclopentadienyl) encountered ligands. The molecular structures of complexes 5c and 5e
were crystallographically characterized. The dihedral angles of N(1)-C(1)-C(8)-C(9) showed an
increasing twist compared with the corresponding ligand. The iridium(III) catalysts were screened,
[
Cp*IrCl ] / 4a proved to be the optimal catalyst, which exhibited efficient catalytic activity toward
2 2
versatile alkylations including ketones, secondary alcohols and amines with primary alcohols.
Additionally, the synthesis of quinolines from ketones with 2-aminobenzyl alcohol by intermolecular
cyclization and indole from 2-(2-aminophenyl)ethanol by intramolecular cyclization were achieved

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under the optimized conditions.
_
________________________________________________________________
*
Corresponding author. E-mail: xfhou@fudan.edu.cn (X.-F. Hou)
1
. Introduction
Alkylation is a fundamental method to construct C-C or C-N bond, and has been applied in
organic synthesis for decades [1]. Transition-metal-catalyzed alkylation with alcohols by borrowing
hydrogen strategy, compared to traditional methods, is green process with high atom efficiency,
which has attracted significant attention in recent years [2].
Over the past decade, great progress has been witnessed in the alkylation reactions with primary
alcohols. The α- or β-alkylation of ketones or secondary alcohols catalyzed by transition metals, such
as Rh [3], Pd [4], Ir [5] Co [6], or Mn [7] has been paid much attention. The N-alkylation of amines
using Ru [8], Pd [9], Ir [10], Co [11], Fe [12], Mn [13], or Ni [14] metals catalyst has also developed.
∧
∧
Among them, iridium cooperated with N-heterocyclic carbene ligands [15], N C N-coordinating
ligands [16] and several bidentate ligands have studies. Taking into account their easy access and
diversity, bidentate ligands received more attentions. For example, N, C-ligands [17], N, O ligands
[
10s], N, N-ligands [10t] and P, N-ligands [5c, 10c, 10e] were reported. With respect to the
established catalytic systems, ligands supported iridium complexes [18] catalyzed multi-alkylation
reactions are rarely reported and highly desirable.
Based on our previous works on the hydrogen transfer reactions using [Cp*Ir(III)] complexes as
catalyst [19], we made an attempt to design a series of new catalysts applying in versatile alkylations.
The catalyst consists of [Cp*IrCl ] and benzoxazolyl or benzothiazolyl phosphine ligands with
2
2

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hemilable coordinating sites [20]. The steric and electronic properties of the catalysts can be easily
tailored by the variation of the backbone of ligands as well as the substitution of benzoxazolyl and
benzothiazolyl and phosphine group [21].
Herein, we describe in situ generated iridium(III)- benzoxazolyl and benzothiazolyl phosphine
complexes catalyzed α-alkylation of ketones, β-alkylation of secondary alcohols and N-alkylation of
amines with primary alcohols as well as its application in the synthesis of quinolines and indole.
2
. Results and discussion
2.1. Synthesis and characterization of benzoxazolyl and benzothiazolyl
phosphine ligands
2-(2-Bromophenyl)-benzoxazoles or benzothiazoles 3 were prepared from 2-aminophenols /
2-aminobenzenethiols 1 and 2-bromobenzaldehyde 2 according to our previous report [22]. Starting
from the brominated ligand precursors 3, the benzoxazolyl and benzothiazolyl phosphine ligands
a-4g were afforded by lithiation with n-butyl lithium, then trapped with PR Cl (R = phenyl or
4
2
1
13
31
cyclohexyl) [21, 23] (Scheme 1). All ligands (4a-4g) were characterized by H, C, and P NMR
spectroscopy. It is worth noting that the substituents on the phosphorus atom and the type of
3
1
benzoxazolyl and benzothiazolyl moiety had a significant effect on the P NMR signal of 4a-4g. The
phosphorus signals of 4a / 4c (δ= -5.61 / -9.01 ppm) with phenyl group shifted to higher field in
comparison with that of 4b / 4d (δ= -4.62/ -4.56 ppm) with cyclohexyl on the phosphorus atom. For

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3
1
4
e-4g with the same phosphine moiety, the P NMR spectra of 4e with electron-donating methyl, 4f
with electron-withdrawing fluoro group, and 4g with large steric hindrance t-butyl group, appeared
as singlets at -5.62, -5.37 and -6.14 ppm, respectively. These indicated that different substituents on
the benzoxazolyl group had impact on the phosphorus signals. Therefore, phenyl or cyclohexyl on
the phosphorus atom as well as electron-donating methyl, electron-withdrawing fluoro or steric
hindrant t-butyl group on the benzoxazolyl moiety would probably affect the steric and electronic
properties of benzoxazolyl and benzothiazolyl phosphine ligands.
Crystals of compounds 4c and 4e suitable for X-ray crystallography were obtained from slow
evaporation of corresponding solution in n-hexane. The molecular structures of 4c and 4e (Fig. 1)
show that PR group is located in the N atom side of benzoxazolyl or benzothiazolyl group [24]. The
2
o
torsion angle of benzothiazolyl with phenyl in 4c (22.5 ) is slightly larger than the one of
o
benzoxazolyl with phenyl in 4e (9.8 ). Although there are torsion angles between benzoxazolyl or
benzothiazolyl and phenyl ring, the distance between N(1) and P(1) are appropriate (2.88 Å in 4c,
2.78 Å in 4e), supporting the possibility of chelating coordination of N and P with one metal centre.
The crystallographic data and the structure refinement details for 4c and 4e are summarized in Table
1.
Scheme 1. Synthetic pathway of the benzoxazolyl and benzothiazolyl phosphine ligands. (i)
o
o
o
3
-Butyl-1-methyl-1H-imidazolium iodide, K CO , m-xylene, 120 C; (ii) n-BuLi, THF, -78 C; R PCl, -78 C to r.t.
2 3 2

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Fig. 1. Molecular structures of 4c (a) and 4e (b). Ellipsoids at the 20% probability level. Hydrogen atoms and solvent
molecules have been omitted for clarity. Selected bond lengths (Å) and angles (deg) for molecule 4c [molecule 4e]:
P(1)-C(9) 1.840(2) [1.847(3)], N(1)-C(1) 1.287(3) [1.277(3)], C(8)-C(9) 1.403(3) [1.414(3)]; N(1)-C(1)-C(8) 123.19(19)
[
128.7(2)], C(8)-C(9)-P(1) 120.66(16) [121.49(18)]; N(1)-C(1)-C(8)-C(9) 22.53(32) [9.808(424)].
2.2. Synthesis and characterization of Ir(III) complexes
Benzoxazolyl and benzothiazolyl phosphine Ir(III) complex 5 was prepared from [Cp*IrCl2]2
o
with the corresponding ligand 4 in methanol at 55 C [25]. Then through an anion-exchange process
with KPF , the iridium complex 5 were isolated in quantitative yields (Scheme 2).
6
The representative complexes 5c and 5e were characterized by NMR spectroscopy and X-ray
1
diffraction. In the H NMR spectra, the singlets at 1.25 ppm for 5c and 1.33 ppm for 5e was assigned
3
1
to CH of Cp* group, indicating the formation of Cp*Ir complexes. The P NMR spectra of 5c and
3
-
5
e, the signals at -3.4, -3.3 ppm and around -144 ppm were attributed to PR and PF , in which the
2
6
signals of PR shifted to lower field in comparison with the free ligands [10h]. X-ray crystal
2
-
structures (Fig. 2) revealed that 5c and 5e are constituted by a cationic part and PF anion. A
6
six-membered ring is observed between P, N atoms of ligand and metal centre. The iridium(III)

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center is situated in a distorted octahedral environment with Cp* as a three-coordinated ligand,
which is the classic piano stool conformation [2m, 19a,19c]. Other three coordination sites occupy
by the N and P atoms of the ligand and a Cl atom. The lengths of Ir-N and Ir-P bond and bond angle
N-Ir-P are in the range of the reported iridium complexes [10c, 10h, 10y]. It is noteworthy that the
o
o
dihedral angles of N(1)-C(1)-C(8)-C(9) in 5c is 33.9 , and 26.5 for 5e, both show an increasing
twist compared with the corresponding ligand, which would benefit to match the coordination
geometry of Ir(III) [21b]. The crystallographic and refinement data for 5c and 5e are shown in Table
1.
Scheme 2. Synthesis of iridium complexes 5.
Fig. 2. Molecular structures of complexes (a) 5c and (b) 5e. Ellipsoids at the 20 % probability level. Hydrogen atoms and
-
noncoordinated PF anions omitted for clarity. Selected bond lengths (Å) and angles (deg) for molecule 5c [molecule 5e]:
6
Ir(1)-N(1) 2.131(7) [2.131(7)], Ir(1)-P(1) 2.309(3) [2.2932(11)], P(1)-C(9) 1.831(10)[ 1.841(4)], N(1)-C(1) 1.318(11)
[
1.306(6)], Ir(1)-Cl(1) 2.396(2)[2.4042(11)], P(1)-C(15) 1.820(8)[1.830(4)], P(1)-C(21) 1.819(9)[1.830(4)], S(1)-C(1)

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1
.731(9), O(1)-C(1) 1.359(5), C(1)-C(8) 1.482(12)[1.454(6)], C(8)-C(9) 1.400(13)[1.412(6)]; N(1)-Ir(1)-P(1) 81.7(2)
[
82.11(9)], P(1)-Ir(1)-Cl(1) 89.00(9) [93.41(4)], C(8)-C(9)-P(1) 118.6(7) [115.0(3)], C(1)-N(1)-Ir(1) 122.8(6)[123.6(3)],
N(1)-C(1)-C(8) 127.7(8)[130.1(4)], C(1)-C(8)-C(9) 122.3(8)[123.3(4)] C(9)-P(1)-C(15) 106.2(4)[100.4(2)]
C(15)-P(1)-C(21) 100.7(4)[103.2(2)]; N(1)-C(1)-C(8)-C(9) 33.973(23) [26.529(816)].
Table 1. Crystal data and structure refinement parameters for ligands 4c, 4e and complexes 5c, 5e.
4
c
4e
5c
5e
Empirical formula
C
25
H18NPS
C
26
H20NOP
C
35
H
33ClF
6
IrNSP
2
36 6 2
C H35ClF IrNOP
Formula weight
Temperature, K
Wavelength, Å
Crystal system
Space group
a, Å
395.43
393.40
903.27
901.24
293(2)
293(2) K
0.71073
Monoclinic
173(2) K
0.71073
173(2) K
0.71073
0.71073
Monoclinic
Orthorhombic
Pca2
Monoclinic
P2 /c
P2
1
/c
P2
1
/c
1
1
9.039(6)
15.335(10)
15.174(10)
90
11.059(4)
9.699(4)
29.481(3)
10.8787(10)
21.0174(18)
90
10.5699(9)
11.0799(10)
29.220(3)
90
b, Å
c, Å
19.399(7)
90
α, deg
β, deg
106.823(9)
90
96.049(6)
90
90
98.1930(10)
90
γ, deg
90
3
Volume, Å
2013(2)
4
2069.3(14)
4
6740.5(10)
8
3387.2(5)
4
Z
3
Density (calculated), Mg/m
Absorption coefficient, mm
F(000)
1.305
1.263
1.780
1.767
-1
0.250
0.150
4.259
4.180
824
824
3552
1776
3
Crystal size, mm
0.500 x 0.400 x 0.400
1.931 to 25.998
-11<=h<=11,
0.700 x 0.700 x 0.350
1.852 to 26.998
-13<=h<=14,
-11<=k<=12,
-24<=l<=11
9922
0.420 x 0.190 x 0.180
1.381 to 27.458
-38<=h<=35,
-8<=k<=14,
0.360 x 0.150 x 0.120
1.408 to 27.482
-13<=h<=11,
-14<=k<=14,
-37<=l<=37
Theta range for data collection, deg
Index ranges
-
18<=k<=17,
15<=l<=18
-
-27<=l<=27
Reflections collected
9071
41355
23994
Independent reflections
Completeness to theta = 25.242°
Absorption correction
3936 [R(int) = 0.0348]
99.6 %
4453 [R(int) = 0.1023]
99.7 %
15286 [R(int) = 0.0588]
99.9 %
7699 [R(int) = 0.0393]
99.2 %
Semi-empirical from
equivalents
Semi-empirical from
equivalents
1.000 and 0.069
Semi-empirical from
equivalents
Semi-empirical from
equivalents
Max. and min. transmission
1.000 and 0.674
0.208 and 0.134
0.262 and 0.169

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Refinement method
Full-matrix least-squares
Full-matrix least-squares
Full-matrix least-squares
Full-matrix least-squares
2
2
2
2
on F
on F
on F
on F
Data / restraints / parameters
3936 / 0 / 253
1.003
4453 / 0 / 263
0.788
15286 / 1 / 857
0.925
7699 / 12 / 439
1.025
2
Goodness-of-fit on F
Final R indices [I>2sigma(I)]
R1 = 0.0444,
wR2 = 0.1141
R1 = 0.0632,
wR2 = 0.1238
n/a
R1 = 0.0597,
wR2 = 0.1286
R1 = 0.1036,
wR2 = 0.1356
n/a
R1 = 0.0373,
wR2 = 0.0668
R1 = 0.0570,
wR2 = 0.0731
0.032(5)
R1 = 0.0303,
wR2 = 0.0765
R1 = 0.0442,
wR2 = 0.0839
n/a
R indices (all data)
Extinction coefficient
-3
Largest diff. peak and hole, e.Å
0.409 and -0.185
0.386 and -0.355
1.391 and -0.922
1.212 and -0.852
2.3. Screening iridium catalysts by α-alkylation of acetophenone with benzyl
alcohol
We initiated our work with the screen appropriate iridium(III) catalysts. α-Alkylation of
acetophenone with benzyl alcohol to obtained 1,3-diphenylpropan-1-one (6a) was selected as a
model reaction to optimize the reaction conditions (Table 2).
Without ligand, taking [Cp*IrCl ] alone as precatalyst [10r], only moderate yield was observed
2
2
(entry 1). When added ligand 4, the reaction afforded up to 99 % yield (entries 2-8), indicating the
ligand could enhance the catalytic activity. Then screening of ligands 4a-4g was carried out. The
ligands (4a and 4c) with phenyl on the phosphorus atom (entries 2 and 4) gave better results than
those containing cyclohexyl substituent (entries 3 and 5). The ligands with benzoxazolyl group
(entries 2 and 3) also obtained higher yield than that of benzothiazolyl (entries 4 and 5). It was
worthy to note that electron-donating methyl on the phenyl ring of benzoxazolyl (entry 6) was better
than the electron-withdrawing fluoro and the large steric hindrance tert-butyl-substituent (entries 7
and 8). Therefore, ligand 4a and [Cp*IrCl ] were chosen as the optimal catalyst.
2
2
Subsequently, we adopted iridium(III) catalyst bearing ligand 4a and [Cp*IrCl ] to optimize
2
2

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the reaction conditions. KOH (entries 2, and 9-12) and toluene (entries 2, and 13-16) were proved to
be the best base and solvent, repectively. The polarity of solvent has no benefit for the reaction.
Control experiments showed that desired product 6a was barely detected without base (entry 17),
further demonstrating the necessity of the base to the catalytic activity of precatalyst [Cp*IrCl ] / 4a.
2
2
Increasing or reducing the amount of base had no positive effect on the yield of 6a compared with 10
mol% KOH (entries 18-19 vs. entry 2). When the loading of catalyst decreased to 0.5 mol%, the
yield of 6a reduced (entry 20). Same yield could be achieved when well-defined complexes 5c and
5
e from [Cp*IrCl ] with 4c and 4e as precatalyst (entry 21 and entry 22), indicating that Ir complex
2 2
generated in situ could be applied in the reaction of acetophenone with benzyl alcohol. Hence, the
optimum reaction conditions were as follows: catalyst loading with 1 mol% of [Cp*IrCl ] / 4a (1/2),
2
2
10 mol% of KOH, and toluene (5 mL) at 110 °C for 24 h.
a
Table 2. Optimization study of α-alkylation of acetophenone with benzyl alcohol
b
Entry
Ligand
-
Base
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
THF
Yield (%)
c
1
55
d
2
3
4
5
6
7
8
9
4a
4b
4c
99 (95)
97
89
72
75
66
34
96
65
50
47
75
87
< 2
< 2
4d
4e
4f
4g
4a
4a
4a
4a
4a
4a
4a
4a
t
KO Bu
1
0
1
K CO3
2
1
K PO4
3
1
1
1
1
1
2
3
4
5
6
KHCO3
KOH
KOH
KOH
KOH
DMF
CH CN
3

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e
f
1
7
4a
4a
4a
4a
-
-
toluene
toluene
toluene
toluene
toluene
toluene
< 2
61
22
87
90
76
1
8
KOH
KOH
KOH
KOH
KOH
g
h
i
1
2
9
0
2
2
1
2
j
-
a
Reaction conditions: acetophenone (1.0 mmol), benzyl alcohol (1.1 mmol), [Ir] loading (1
o
mol %), [Cp*IrCl ] / ligand = 1/2, base (10 mol %), solvent (5 mL), 110 C, 24 h
2
2
b
c
d
e
f
Yield determined by NMR analysis with 1,3,5-trimethoxybenzene as the internal standard
[
Cp*IrCl ] as catalyst without ligand
2 2
Isolated yield
Without base
KOH (100 mol %)
KOH (5 mol %)
g
h
i
[
5
5
Ir] loading (0.5 mol %)
c as catalyst
j
e as catalyst
2.4. α-Alkylation of ketones with primary alcohols
Under the optimized conditions, a wide range of substrates were screened (Table 3). The
reactions of ketones with benzyl alcohol proceeded smoothly (6a-6l). 4-Methylacetophenone
provided good yield (82 %). Acetophenones with halogen atoms such as fluoro, chloro and bromo on
the phenyl ring afforded good to excellent yields (6c-6e). 4-Acetylbenzonitrile with cyano of strong
electron-withdrawing group reacted smoothly with benzyl alcohol to afford 6f in 87 % yield.

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Heterocyclic ketones substituted with furyl and thienyl moieties could be alkylated in good yields
(6g, 6h). Interestingly, acetylferrocene also forged the 6i in 89 %. Other aromatic acetyl system, such
as 2-acetylnaphthalene, 1-tetralone, and 4-acetylbiphenyl, were also examined (6j-6l). These
reactions showed good tolerance for benzyl alcohols with amino (6m), trifluoromethyl (6n) or
methyl (6o) groups. Reactions with 2-naphthalenemethanol and 2-thiophenemethanol gave 93 % and
75 % yields to produce alkylated products 6p and 6q. More importantly, the aliphatic substrates such
as 1-pentanol and 1-hexanol also proceeded well with increasing the amount of alcohols and
elongated time, led to 6r and 6s in 65 % and 69 % yields, respectively.
a,b
Table 3. α-Alkylation of ketones with alcohols
6
a, 95%
6b, 82 %
6c, 84 %
c
6
d, 97 %
g, 89 %
6e, 91 %
6h, 96 %
6k, 87 %
6f, 87 %
6i, 89 %
6l, 72 %
6o, 89 %
6
6
j, 87 %
O
NH2
c
6
m, 95 %
6n, 73 %
d
6
p, 93 %
6q, 75 %
6r, 65 %

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d
6
s, 69 %
a
Reaction conditions: ketones (1.0 mmol), alcohols (1.1 mmol), [Ir] loading (1 mol %),
o
[
Cp*IrCl ] / 4a= 1/2, KOH (10 mol %), toluene (5 mL), 110 C, 24 h
2
2
b
Isolated yield
c
3
6 h
d
Alcohol (2 mol), 36 h
2.5. β-Alkylation of secondary alcohols with primary alcohols
β-Alkylation of secondary alcohols with primary alcohols, due to dehydrogenation of secondary
alcohols to carbonyl compounds, was more challenging than α-alkylation of ketones [26]. We
attempted the reactions under the optimized conditions (Table 4). Delightedly,
3
-phenylpropiophenone (6a) was obtained to yield 90 % from phenylethanol and benzyl alcohol.
Phenylethanol bearing methyl group or chlorinated substituent, were also subjected to this reaction
6b, 6d). Benzyl alcohols containing amino, trifluoromethyl and methyl were compatible with this
(
transformation (6m, 6n and 6o). Furthermore, 2-naphthalenemethanol reacted smoothly with
phenylethanol to provide the desired product 6p in 82 % yield. Satisfyingly, aliphatic alcohols such
as 1-pentanol and 1-hexanol also furnished to this reaction in moderate yields (6r, 6s).
a,b
Table 4. β-Alkylation of secondary alcohols with primary alcohols
6
d, 92 %

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6
a, 90 %
6b, 87 %
c
6
n, 81 %
6o, 84 %
6
m, 80 %
c
c
6
p, 82 %
6r, 53 %
6s, 45 %
a
Reaction conditions: secondary alcohols (1.0 mmol), primary alcohols (1.1 mmol), [Ir]
o
loading (1 mol %), [Cp*IrCl ] / 4a= 1/2, KOH (10 mol %), toluene (5 mL), 110 C, 24 h
2
2
b
c
Isolated yield
Alcohols (2 mol), 36 h
2.6. N-Alkylation of amines with primary alcohols
Encouraged by the above results, we checked the applicability to N-alkylation of amines with
alcohols (Table 5). Initially, aniline was chosen to react with benzyl alcohol, 89 % isolated yield of
a was obtained. Either anilines with electron-donating methoxyl or electron-withdrawing
7
substituents such as fluoro and chloro, could gave the desired compounds in good yields (7b-7e).
The heterocyclic amines like 2-aminopyridine and 2-aminopyrimidine exhibited extremely high
reactivity, affording products (7f, 7g), in 99 % and 98 % yields. Benzamide was also alkylated,
giving 7h as the only product (82 % yield). p-Toluenesulfonamide was proved to be suitable to react
with benzyl alcohol, a moderate yield obtained (7i). Then we investigated the reactions of aniline
with substituted benzyl alcohols. 2-Thiophenemethanol and 2-naphthalenemethanol were appropriate
substrates for the reaction, smoothly delivering the products 7j-7k in 84-85 % yields. While

ACCEPTED MANUSCRIPT
electron-withdrawing substituent fluoro on the benzyl alcohol worked very well to provided the
desired secondary amine product 7l. More importantly, aliphatic alcohols such as 1-pentanol and
1-hexanol could still work as good coupling fragments (7m-7n), indicating the broad substrate
compatibility of the N-alkylation reactions.
For the mechanism of α-, β and N-alkylation reactions with alcohols, based on previous reports
[
16, 17c, 17d, 18], it proceeded via the hydrogen-borrowing strategy. Initially, iridium(III) complex
could be generated in situ when [Cp*IrCl ] encountered ligand 4a. Hydrogen autotransfer from
2
2
primary alcohol to iridium would lead to the formation of aldehyde and the iridium-hydride
intermediate. Subsequent base-mediated condensation of the producing aldehydes with ketones,
alcohols, or amines to form α, β- unsaturated carbonyl compounds or imines, which would undergo a
hydrogenation reaction in the presence of metal-hydride to give the α-, β and N -alkylated products
and the catalyst Ir complex regenerated.
a,b
Table 5. N-Alkylation of amines with alcohols.
7
a, 89 %
7b, 83 %
7e, 87 %
7h, 82 %
7c, 80 %
7f, 99 %
7i, 56 %
c
7
d, 81 %
7
g, 98 %
CF3
H
N

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c
7
j, 85 %
7k, 84 %
7l, 71 %
d
d
7
m, 64 %
7n, 72 %
a
Reaction conditions: amines (1.0 mmol), alcohols (1.1 mmol), [Ir] loading (1 mol %),
o
[
Cp*IrCl ] / 4a= 1/2, KOH (10 mol %), toluene (5 mL), 110 C, 24 h
2
2
b
Isolated yield
c
3
6 h
d
Alcohol (3 mmol), 36 h
2.7. Synthesis of quinolines and indole
Quinolines exhibited a wide variety of biological and pharmacological activities [27] and
applied in various polymers and nano materials [28]. The synthesis via hydrogen-borrowing concept
is highly efficient and has less byproducts [6, 10y, 29].
With the optimal conditions, we were pleased to apply the catalytic system into the synthesis of
quinolines from aromatic acetophenones and 2-aminobenzyl alcohol (Table 6). Substrates with p-Me,
p-F, and p-OMe were amenable to this transformation, afforded the desired quinolines 8a-8c in good
yields. Furthermore, heterocyclic ketones such as thiophene acetone and 1-tetralone were extended to
deliver 8d (82 %) and 8e (80 %). 3-Phenylpropiophenone was also compatible with the current
system, leading to the formation of 8f in 89 % yield.
a,b
Table 6. Formation of quinolines from ketones with 2-aminobenzyl alcohol

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8
a, 81 %
d, 82 %
8b, 79 %
8e, 80 %
8c, 86 %
8
8
f, 89 %
a
Reaction conditions: ketones (1.0 mmol), 2-aminobenzyl alcohol (1.1 mmol), [Ir]
o
loading (1 mol %), [Cp*IrCl ] / 4a= 1/2, KOH (10 mol %), toluene (5 mL), 110 C, 24 h
2
2
b
Isolated yield
Indole skeleton widely presents in natural products, raw organic materials, fine chemical
products [30]. Our protocol also allowed for 2-(2-aminophenyl)ethanol by intramolecular cyclization
leading to indole in 90% yield under the same conditions. The results further demonstrated the wide
applicability of the catalytic system of iridium(III)-benzoxazolyl phosphine ligand. (Scheme 3)
Scheme 3. Alternative synthesis route for indole.
3
. Conclusions
In summary, we have successfully prepared and characterized a series of new benzoxazolyl and
benzothiazolyl phosphine ligands. The molecular structures of representative ligands 4c, 4e showed
that the PR group was located in the N atom side of benzoxazolyl or benzothiazolyl group. The
2
corresponding iridium complexes could be generated in situ with [Cp*IrCl ] and ligands. The
2
2
representative complexes 5c, 5e were characterized by single-crystal X-ray study. The molecular

ACCEPTED MANUSCRIPT
structures showed the typical piano-stool arrangement. The ligand was bound to the iridium(III)
center via P, N atoms to form a six-membered ring. The dihedral angles of N(1)-C(1)-C(8)-C(9) in 5c
and 5e, showed an increasing twist compared with the corresponding ligand. Subsequently,
[
Cp*IrCl ] and 4a were demonstrated as highly efficient catalysts for the alkylations of ketones,
2 2
secondary alcohols and amines with primary alcohols. This catalytic protocol is advantageous for not
only the effectiveness for versatile alkylation reactions from broad range of ketones, alcohols and
amines, but also atom-economic syntheses of quinolines and indole. This catalytic system is of great
interest for iridium(III) catalysts in synthetic chemistry regarding the formation of C-C and C-N
bonds. Further studies towards more applications of the iridium(III) catalytic system are under way
in our laboratory.
4
. Experimental section
All alkylation reactions were carried out under standard Schlenk techniques. Reaction
temperatures were the temperature of the bath surrounding the vessel. Chemical reagents were
1
13
obtained from commercial sources and used without further purification. H and C NMR spectra
were recorded by Bruker Avance III 400 MHz NMR Spectrometer. Spectra were collected at 295 K
in CDCl or DMSO-d . HRMS(ESI) analyses were proceeded by the EPSRC UK National Mass
3
6
Spectrometry Facility (NMSF), Swansea. GC-MS analysis was reported at a HP 5973 GCD system
using a HP5MS column (30 m × 0.25 mm). Fourier transform infrared (FT-IR) spectra were
-1
performed on a Nicolet AVATAR-360 IR using KBr discs in the range of 4000-400 cm .

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4.1. Preparation of ligands 4a-4g
Benzoxazolyl and benzothiazolyl phosphine ligands 4a-4g were synthesized following by two
steps:
Step 1, the brominated products (3a-3e) were prepared according to our published procedure
22]. The characterization data was listed in Supporting Information.
Step 2 [21]: 3a-3e (5 mmol) was dissolved in dry THF (30 mL) under N . After the solution was
[
2
cooled to -78 °C, n-butyl lithium (n-BuLi) 2.3 mL (5.5 mmol, 2.4 M, 1.1 equ.) was added dropwisely
via syringe during 15 min. The reaction mixture was stirred at -78 °C for 0.5 h. Then
diphenylphosphine / dicyclohexylphosphine chloride (5.5 mmol) was added. The reaction mixture
was allowed to warm to room temperature and stirred overnight. Added water and ethyl acetate to the
mixture. The organic phase was extracted and concentrated. Then dried over anhydrous Na SO .
2
4
Finally, it was purified by silica gel column chromatography to obtain the corresponding products
4a-4g).
(
2-(2-(Diphenylphosphanyl)phenyl)benzo[d]oxazole (4a)
1
5
8% Isolated yield (light yellow solid): H NMR (400 MHz, CDCl ) δ 8.31- 8.20 (m, 1H, Ph),
3
1
3
7
.74-7.67 (m, 1H, Ph), 7.50 (m, 1H, Ph), 7.47 - 7.23 (m, 15H, Ph), 7.08 (m, 1H, Ph) ppm; C NMR
(
101 MHz, CDCl ) δ 162.49, 150.37, 141.73, 139.22 (d, J = 26.9 Hz), 137.42, 134.48, 134.11 (d, J =
3
20.6 Hz), 131.20, 131.00, 130.64, 130.17(d, J = 3.3 Hz), 128.68, 128.44, 125.00, 124.25, 120.33,
3
1
1
10.43 ppm; P NMR (162 MHz, CDCl ) δ -5.61 (s) ppm. HRMS(ESI) calcd for C H NOP
3
25 19
(380.1204) (M+H), found: 380.1199.
2-(2-(Dicyclohexylphosphanyl)phenyl)benzo[d]oxazole (4b)

ACCEPTED MANUSCRIPT
1
6
2% Isolated yield (light yellow solid): H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 6.8 Hz, 1H,
3
Ph), 7.83 (m, 1H, Ph), 7.69 (d, J = 7.3 Hz, 1H, Ph), 7.60 (m, 1H, Ph), 7.51 (m, 2H, Ph), 7.37 (m, 2H,
1
3
Ph), 1.96 (d, J = 37.8 Hz, 4H, Cy-H), 1.72 (m, 8H, Cy-H), 1.38 - 1.10 (m, 10H, Cy-H) ppm. C
NMR (101 MHz, CDCl ) δ 164.06, 150.87, 141.89, 137.71 (d, J = 28.6 Hz), 135.06 (d, J = 27.6 Hz),
3
133.08 (d, J = 2.2 Hz), 130.84 (d, J = 5.7 Hz), 129.72, 128.37, 124.91, 124.23, 120.37, 110.68, 34.49
31
(
d, J = 14.4 Hz), 29.84, 29.86(d, J = 27.8 Hz), 27.32 (d, J = 2.0 Hz), 27.22, 26.39 ppm. P NMR
(
162 MHz, CDCl ) δ -4.62 (s) ppm. HRMS (ESI) calcd for C H NOP (392.2143) (M+H), found:
3
25 31
3
2
92.2138.
-(2-(Diphenylphosphanyl)phenyl)benzo[d]thiazole (4c)
1
6
0 % Isolated yield (yellowish solid solid): H NMR (400 MHz, CDCl ) δ 7.94 - 7.89 (m, 2H),
3
1
3
7
.84 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.39 - 7.29 (m, 12H), 7.12 (m, 1H) ppm; C NMR (101
MHz, CDCl ) δ 166.61, 153.21, 134.87, 134.07, 133.87, 130.56 (d, J = 3.8 Hz), 129.80, 128.70,
3
31
1
28.49, 128.43, 128.36, 128.01, 127.88, 125.95, 125.14, 123.43, 121.31 ppm; P NMR (162 MHz,
CDCl ) δ -9.01 (s) ppm. HRMS(ESI) calcd for C H NPS (396.0965) (M+H), found: 396.0964.
3
25 19
2-(2-(Dicyclohexylphosphanyl)phenyl)benzo[d]thiazole (4d)
1
5
4 % Isolated yield (yellow solid solid): H NMR (400 MHz, CDCl ) δ 7.96 - 7.88 (m, 1H, Ph),
3
7
1
1
1
.72-7.56 (m, 2H, Ph), 7.55 - 7.42 (m, 4H, Ph), 7.16 (d, J = 8.0 Hz, 1H, Ph), 1.96 (m, 4H, Cy-H),
1
3
.71 (m, 8H, Cy-H), 1.23 (m, 10H, Cy-H) ppm; C NMR (101 MHz, CDCl ) δ 164.06, 150.87,
3
41.89, 137.86, 137.57, 135.20, 134.92, 133.08 (d, J = 2.2 Hz), 130.84 (d, J = 5.7 Hz), 129.72,
28.37, 124.91, 124.23, 120.37, 110.68, 34.49 (d, J = 14.4 Hz), 29.86 (d, J = 27.9 Hz), 29.72, 27.32
31
(
d, J = 2.0 Hz), 27.22, 26.39 ppm; P NMR (162 MHz, CDCl ) δ -4.56 (s) ppm. HRMS (ESI) calcd
3
for C H NPS (408.1924) (M+H), found: 408.1928.
2
5
31

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2-(2-(Diphenylphosphanyl)phenyl)-5 methylbenzo[d]oxazole (4e)
1
5
8 % Isolated yield (lightly yellow solid): H NMR (400 MHz, CDCl ) δ 8.26 (m, 1H, Ph), 7.49
3
(
m, 2H, Ph), 7.39 (m, 5H, Ph), 7.33 (m, 7H, Ph), 7.13 - 7.04 (m, 2H, Ph), 2.45 (s, 3H, Ph-CH ) ppm;
3
1
3
C NMR (101 MHz, CDCl ) δ 162.55, 148.65, 141.94, 139.08 (d, J = 26.9 Hz), 137.56 (d, J = 10.6
3
Hz), 134.46, 134.19, 133.99, 131.31 (d, J = 21.1 Hz), 130.49, 130.06 (d, J = 2.9 Hz), 128.53(d, J =
31
2
1.5 Hz), 128.40(d, J = 6.9 Hz), 126.11, 120.21, 109.75, 21.42 ppm; P NMR (162 MHz, CDCl ) δ
3
-
5.62 (s) ppm. HRMS (ESI) calcd for C H NOP (394.1361) (M+H), found: 394.1350.
26 21
2-(2-(Diphenylphosphanyl)phenyl)-5 fluorobenzo[d]oxazole (4f)
1
6
1 % Isolated yield (lightly white solid): H NMR (400 MHz, CDCl ) δ 8.22 (m, 1H, Ph), 7.49
3
1
3
(
m, 1H, Ph), 7.45 - 7.28 (m, 13H, Ph), 7.09 - 6.97 (m, 2H, Ph) ppm. C NMR (101 MHz, CDCl ) δ
3
1
1
61.11, 139.55, 137.22 (d, J = 10.1 Hz), 134.51, 134.18, 133.98, 130.90, 130.19 (d, J = 3.2 Hz),
19
28.75, 128.47, 128.46(d, J = 7.3 Hz), 112.80, 112.53, 110.72, 110.62, 106.73, 106.48 ppm; F
3
1
NMR (376 MHz, CDCl ) δ -117.42 (td, J = 8.8, 4.3 Hz) ppm; P NMR (162 MHz, CDCl ) δ -5.47 (s)
3
3
ppm. HRMS (ESI) calcd for C H FNOP (398.1110) (M+H), found: 398.1092.
2
5
18
5-(tert-Butyl)-2-(2-(diphenylphosphanyl)phenyl)benzo[d]oxazole (4g)
1
7
5 % Isolated yield (light green solid): H NMR (400 MHz, CDCl ) δ 8.24 (m, 1H, Ph), 7.71 (s,
3
1H, Ph), 7.49 (t, J = 7.5 Hz, 1H, Ph), 7.41 - 7.29 (m, 14H, Ph), 7.06 (m, 1H, Ph), 1.37 (s, 9H,
1
3
Ph-C(CH ) ) ppm. C NMR (101 MHz, CDCl ) δ 162.56, 148.41, 147.70, 141.67, 139.06, 138.80,
3
3
3
137.57 (d, J = 10.5 Hz), 134.55, 134.07 (d, J = 20.5 Hz), 131.55, 131.34, 130.74, 130.47, 130.03 (d,
31
J = 3.0 Hz), 128.48(d, J = 23.3.0 Hz), 128.43, 122.75, 116.86, 109.50, 34.85, 31.73 ppm; P NMR
(
162 MHz, CDCl ) δ -6.14 (s) ppm. HRMS (ESI) calcd for C H NOP (436.1830) (M+H), found:
3 29 27
436.1812.

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4.2 Preparation of Ir(III) complexes 5c and 5e
According to previous report [25], 4c or 4e (0.1 mmol) with [Cp*IrCl ] (40 mg, 0.05 mmol)
2
2
were added to a 25 mL Schlenk flask. Added into 2 mL of anhydrous methanol. The reaction mixture
was warmed to 55 °C for 14 h. Then potassium hexafluorophosphate (KPF ) (55 mg, 0.3 mmol) was
6
added. By centrifugal separation, the corresponding product was obtained.
5
c, light yellow solid (76.7mg, 85 %). C H ClF IrNP S (903.1031): FT-IR (KBr) 3061 (w),
35 33 6 2
3
8
1
000 (w), 2923 (w), 1509 (w), 1457(m), 1436 (w), 1411 (m), 1227 (w), 1090(w), 1028(w), 991(w),
-1 1
42 (s), 756 (w), 713 (m), 556 (m), 535 (m), 508 (m) cm . H NMR (400 MHz, DMSO) δ 8.39 (m,
H, Ph), 8.30 (m, 1H, Ph), 8.25 (m, 1H, Ph), 8.16 - 8.05 (m, 1H, Ph), 8.03 (m, 1H, Ph), 7.90 (m, 3H,
Ph), 7.80 - 7.66 (m, 4H, Ph), 7.67 - 7.57 (m, 1H, Ph), 7.34 - 7.22 (m, 2H, Ph), 7.09 (m, 1H, Ph), 7.00
1
3
(
m, 2H, Ph), 1.25 (s, 16H, Cp*-CH ) ppm; C NMR (101 MHz, CDCl ) δ 174.64, 174.58, 155.49,
3
3
1
1
1
7
40.30, 140.18, 139.86 (d, J = 7.3 Hz), 138.30, 138.22, 138.13, 137.97, 137.87, 137.76, 136.39,
35.83, 135.73, 134.77 (d, J = 11.6 Hz), 133.65, 133.48, 133.09 (d, J = 11.3 Hz), 132.71, 129.59,
31
28.98, 128.66, 128.41, 99.88, 13.09 ppm; P NMR (162 MHz, DMSO) δ -3.43, -144.18 (hept, J =
19
11.4 Hz) ppm; F NMR (376 MHz, DMSO) δ -70.12 (d, J = 711.4 Hz). HRMS (ESI) calcd for
C H ClF IrNP S (904.1109) (M+H), found: 904.1112.
35
34
6
2
5
e, light yellow solid (80.2 mg, 89 %). C H ClF IrNOP (901.1416): FT-IR (KBr) 3058 (w),
36 35 6 2
2
8
994 (w), 2925 (w), 1530 (w), 1481(m), 1446 (w), 1434 (m), 1280 (w), 1191(w), 1108(w), 1031(w),
-1 1
42 (s), 756 (w), 704 (m), 557 (m), 528 (m), 518 (m) cm . H NMR (400 MHz, DMSO) δ 8.48 (d, J
=
3.3 Hz, 1H, Ph), 8.19 - 8.02 (m, 2H, Ph), 8.01- 7.93 (m, 1H, Ph), 7.87 (d, J = 7.9 Hz, 3H, Ph), 7.75

ACCEPTED MANUSCRIPT
(s, 3H, Ph), 7.65 (s, 1H, Ph), 7.43 (d, J = 8.0 Hz, 1H, Ph), 7.25 - 6.87 (m, 5H, Ph), 2.47 (d, J = 14.1
13
Hz, 3H, Ph-CH ), 1.33 (s, 15H, Cp*-CH ) ppm; C NMR (101 MHz, DMSO) δ 161.04, 160.97,
3
3
1
48.94, 137.95, 136.77, 135.49 (d, J = 12.7 Hz), 134.37, 133.63, 133.26 (d, J = 9.1 Hz), 133.10,
32.69, 131.62, 131.02, 130.09 (d, J = 11.6 Hz), 129.79, 129.55, 129.26, 129.05, 128.46 (d, J = 10.4
1
3
1
Hz), 128.05, 127.95, 124.41, 123.84, 119.75, 112.46, 95.26, 21.73, 8.49 ppm; P NMR (162 MHz,
1
9
DMSO) δ -3.34 (s, 1P, ligand 4e), -144.19 (hept, J = 711.6 Hz, 1P, PF ) ppm. F NMR (376 MHz,
6
DMSO) -70.14 (d, J = 711.4 Hz, PF ) ppm. HRMS (ESI) calcd for C H ClF IrNOP (902.1494)
6
36 36
6
2
(M+H), found: 902.1488.
4.3 General procedure for alkylation reactions
[
Cp*IrCl ] (1 mol %, 0.01mmol, 8.0 mg), 4a (2 mol %, 0.02 mmol, 7.6 mg), KOH (10 mol %,
2 2
0
.1 mmol, 5.6 mg), and toluene (5 mL) were added to a 25 mL Schlenk tube with stirring under N at
2
room temperature. Then ketones/ secondary alcohols/ amines (1 mmol), primary alcohols (1.1 mmol,)
were added by syringe. The reaction mixture was heated to 110 °C under reflux in an oil bath for 24
h. It was cooled to ambient temperature. Then it was concentrated in vacuo, and purified by flash
column chromatography with petroleum ether/ ethyl acetate to afford the corresponding alkylated
product.
4.4 General procedure for preparation of quinolines and indole
In a 25 mL Schlenk tube, ketones (1 mmol) and 2-aminobenzyl alcohol (1.1 mmol) (for

ACCEPTED MANUSCRIPT
quinolines), or 2-(2-aminophenyl)ethanol (1 mmol) (for indole), [Cp*IrCl ] (1 mol %, 0.01mmol,
2
2
7.96 mg), 4a (2 mol %, 0.02 mmol, 7.60 mg), KOH (10 mol %, 0.1 mmol, 5.6 mg), and toluene (5
mL) were placed under N . The reaction mixture was heated under reflux for 24 h. The reaction
2
mixture was cooled to ambient temperature, concentrated in vacuo, and purified by flash column
chromatography with petroleum ether/ ethyl acetate to afford the corresponding quinolines and
indole.
4.5 X-ray crystallography
Suitable single crystals for X-ray diffraction analysis were obtained from slow evaporation of
corresponding solution, 4c,4e in n-hexane and 5c, 5e in MeOH. Intensity data for the compounds
were collected on Bruke Smart APEX (at 293 K) and Bruker APEX DUO diffract meters (at 173 K).
Both are equipped with 2.4 kW sealed tube X-ray source (Mo-Kα radiation, λ = 0.71073 Å)
operating at 50 kV and 30 mA. A hemisphere of intensity data was collected at room temperature
with a scan width of 0.60° in ω. Empirical absorption corrections were based on SADABS program
[
31]. The structures were solved by direct methods and refined by full-matrix least squares
refinement using the SHELXTL-97 program [32]. The positions of all non-hydrogen atoms were
refined with anisotropic displacement factors. The hydrogen atoms were generated theoretically onto
the specific atoms and refined. Crystal structure and refinement data can be found in Table 1. CCDC
1821599 (4c), 1821600 (4e), 1821601(5c), and 1821602 (5e) contain the supplementary of
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements
Financial support by the National Science Foundation of China (grant nos. 21271047, 21701028)
and ShanXi Science and Technology Department, China (project no. MH2014-07) is gratefully
acknowledged.
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Highlights
•
•
A series of new benzoxazolyl and benzothiazolyl phosphine ligands were
prepared.
Iridium(III) complexes could be generated in situ when [Cp*IrCl ] encountered
2
2
ligands.
Versatile alkylation reactions were efficiently catalyzed by [Cp*IrCl ] /ligand.
•
•
2
2
Quinolines and indole were synthesized using the same catalyst.