Iridium(I)-Catalyzed C-C and C-N Bond Formation Reactions via the Borrowing Hydrogen Strategy

Article abstract of DOI:10.1021/acs.joc.9b00632

Iridium(I) complexes having an imidazol-2-ylidene ligand with benzylic wingtips efficiently catalyzed the β-alkylation of secondary alcohols with primary alcohols and acceptorless dehydrogenative cyclization of 2-aminobenzyl alcohol with ketones through a borrowing hydrogen pathway. The β-alkylated alcohols, including cholesterol derivatives, and substituted quinolines were obtained in good yields by using a minute amount of the catalyst with a catalytic amount of NaOH or KOH under the air atmosphere, liberating water (and H₂ in the case of quinoline synthesis) as the sole byproduct. Notably, this system demonstrated turnover numbers of 940 000 (for β-alkylation of secondary alcohols with primary alcohols by using down to 0.0001 mol % = 1 ppm of the catalyst) and 9200 (acceptorless dehydrogenative cyclization of 2-aminobenzyl alcohol with ketones).

Full text of DOI:10.1021/acs.joc.9b00632

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Article
Iridium(I)-Catalyzed C#C and C#N Bond Formation
Reactions via Borrowing Hydrogen Strategy
Sertaç Genç, Burcu Arslan, Süleyman Gülcemal, Salih Günnaz, Bekir Cetinkaya, and Derya Gülcemal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00632 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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Iridium(I)-Catalyzed C‒C and C‒N Bond Formation
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Reactions via Borrowing Hydrogen Strategy
Sertaç Genç, Burcu Arslan, Süleyman Gülcemal*, Salih Günnaz, Bekir Çetinkaya, Derya
Gülcemal*
Ege University, Chemistry Department, 35100 Bornova, Izmir,
KEYWORDS: iridium, N-heterocyclic carbene, alcohols, quinolines, alkylation, borrowing
hydrogen
ABSTRACT
Iridium(I) complexes having an imidazol-2-ylidene ligand with benzylic wingtips efficiently
catalyzed the β-alkylation of secondary alcohols with primary alcohols and acceptorless
dehydrogenative cyclization of 2-aminobenzyl alcohol with ketones through a borrowing
hydrogen pathway. The β-alkylated alcohols, including cholesterol derivatives, and substituted
quinolines were obtained in good yields by using a minute amount of catalyst with a catalytic
amount of NaOH or KOH under air atmosphere liberating water (and H2 in the case of quinoline
synthesis) as the sole-byproduct. Notably, this system demonstrated TONs of 940000 (for β-
alkylation of secondary alcohols with primary alcohols by using down to 0.0001 mol% = 1 ppm
of catalyst) and 9200 (acceptorless dehydrogenative cyclization of 2-aminobenzyl alcohol with
ketones).
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INTRODUCTION
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The borrowing hydrogen (BH) or hydrogen autotransfer (HA) methodology has become an
important alternative to construct C‒C and C‒N bonds for the synthesis of more complicated
molecules in one-step in the presence of a transition metal (TM) catalyst.1 The BH approach is a
tandem process, where alcohols are dehydrogenated followed by base-mediated condensation of
the resulting carbonyls with an amine or carbon nucleophile and subsequently the unsaturated
intermediate product is reduced. As a result of increasing interests for environmentally friendly
chemical processes, the direct substitution of alcohols through a BH strategy has recently
received significant attention and is considered one of the key green chemistry research areas by
the pharmaceutical manufacturers.2 The use of easily handled, renewable and inexpensive
alcohols as alkylating agents, offers increased step efficiency and atom economy over the
conventional stoichiometric activation and displacement method, and avoids the use of
mutagenic alkyl halides and sulfonate esters as alkylating agents, resulting in water as the sole
by-product.1
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β-Alkylation of alcohols, which can be realized by means of BH strategy is one of the most
fundamental C‒C bond formation reactions for the synthesis of long chain and branched
alcohols. Notably, until now, application of ruthenium,3 rhodium,4 iridium,5 palladium6 and other
first row TM catalysts7 or under TM-free conditions8 has been known for β-alkylation of
alcohols through a BH strategy. Despite significant advancements, these catalytic systems still
have many drawbacks, such as in most cases they require expensive or high amount of bases and
high catalyst loading so the final turnover numbers (TONs) for these reactions are still low and
far from any practical application. There are only a few reports by Kundu et. al. on cross-
coupling of alcohols to give β-alkylated alcohols in the presence of low catalyst loadings.3b-e
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Very recently, they disclosed TONs of 288000 for the coupling of primary and secondary
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3c
alcohols to give β-alkylated alcohols by using an (NHC)‒RuII‒NN complex.
The main
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limitation of this system is that it requires 40 mol% of expensive NaOiPr as a base and inert
reaction conditions for these high activities. Therefore, the development of more efficient
catalytic systems would be highly desirable to construct a new C‒C bond by employing alcohols
as alkylating agents by using a minute amount of catalyst and a low amount of common base
under operationally simple conditions.
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Another reaction based on the BH methodology is acceptorless dehydrogenative cyclization of
2-aminobenzyl alcohols with secondary alcohols or ketones to give substituted quinolines.1c,d,f,i,9
Heterocyclic aromatic organic compounds bearing quinoline scaffolds are very important class in
organic synthesis, because quinoline moiety is found in a broad range of pharmacologically
active compounds and natural products.10 Although quinolines can be prepared from 2-
aminobenzaldehyde and various ketones by following the classical Friendländer reaction, there
are several limitations for its applicability, including the low stability of 2-aminobenzaldehyde,
the requirement of harsh reaction conditions, numerous steps, lower stereoselectivity and low
total yields.11 Recently, remarkable effort has been dedicated for the development of the
modified Friendländer quinoline synthesis catalyzed by various TM complexes including
ruthenium,12 rhodium,13 iridium,14 palladium,15 manganese,16 iron,17 cobalt,18 nickel,19 and
copper,20 or TM-free conditions21. However, most of these methods require a stoichiometric
amount of strong bases, high catalyst loadings, excess of ketones as a coupling partner, or a
sacrificial hydrogen acceptor, which might cause environmental problems.
Our group is mainly focused on the application of NHC−IrI and NHC−IrIII complexes as
catalysts for transfer hydrogenation22 and dehydrogenation23 reactions. Recently, we have
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synthesized a series of [IrCl(COD)(NHC)] (COD = 1,5-cyclooctadiene) complexes (1) and
reported a remarkably active catalytic system with the highest turnover frequencies (TOFs)
reported for the reaction of primary alcohols with secondary alcohols and also with ketones to
give α‒alkylated ketones (4') by using 5-10 mol% KOH under air (Scheme 1).24 Our mechanistic
studies revealed that in the presence of 0.5 mol% 1d as catalyst the reaction of primary and
secondary alcohols results with a mixture of β-alkylated alcohol 4 and α‒alkylated ketone 4ʹ
then, 4 gradually dehydrogenates to give α-alkylated ketones (4ʹ) selectively.24 The alkylation of
secondary alcohols with primary alcohols often results with a mixture of the β-alkylated alcohols
(4) along with the corresponding α-alkylated ketones (4ʹ) and this selectivity issue is crucial for
the reaction. Encouraged by our previous findings, we envisioned that we could improve the
selectivity of the reaction to the β-alkylated alcohols (4) if the final dehydrogenation of 4 to 4ʹ
might be prevented. Herein, we disclose the selective formation of β-alkylated alcohols (4) by
cross-coupling of secondary alcohols with primary alcohols in the presence of 1-10 ppm
NHC‒IrI complex (1d) as catalyst and 20 mol% of NaOH under air (Scheme 1) along withup to
940000 TON. Notably, when combined with our previous results, a single catalyst has allowed
the selective synthesis of both β-alkylated alcohols (4) and α-alkylated ketones (4ʹ) with slightly
modified reaction conditions (Scheme 1). In addition, this catalytic system has also showed
promising catalytic activity (up to 9200 TON) for the reaction of 2-aminobenzyl alcohol with
ketones to give substituted quinolines (Scheme 1).
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Scheme 1. NHC‒IrI Catalyzed C‒C and C‒N Coupling Reactions.
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1d
(0.5 mol%)
10 mol% KOH
PhMe, 130 °C, 2 h
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O
F3C
our previous work
R2
R1
4'
Cl
Cl
N
N
OH
Ir
Cl
[Cat.]:
+
R2
OH
+
R1
OH
1d
R1
R2
F3C
4
1d
(0.001-0.0001 mol%)
20 mol% NaOH
PhMe, 135 °C, 8-24 h
this work
1d
(0.01 mol%)
R2
R1
O
5 mol% KOH
OH
+
R2
PhMe, 135°C,16 h
R1
NH2
N
RESULTS and DISCUSSION
Catalytic Studies on NHC‒IrI Catalyzed β-Alkylation of Alcohols. Initially, the reaction of
1-phenylethanol (2a) with benzyl alcohol (3a) was selected as the benchmark experiment to
probe the potential of previously prepared [IrCl(COD)(NHC)] complexes (1a-d)24 as catalyst in
β-alkylation of equimolar amount of secondary alcohols with primary alcohols. The progress of
1
the reaction was monitored by H NMR spectroscopy and the yields are based on 1,3,5-
trimethoxybenzene as internal standard (Table 1). The reaction was performed in the presence of
NHC‒IrI catalysts (1a-d) (0.01 mol%) and KOH (10 mol%) in toluene (0.5 mL) at 135 ºC oil
bath temperature under air for 12 h (entries 1‒4). Among all catalysts tested, the best conversion
was obtained with catalyst 1d (entry 4). It was observed that the catalytic activity of iridium
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complexes was enhanced by introducing electron withdrawing groups on the NHC ligand and in
all cases the reaction was mainly selective to alcohol product 4aa. These results encouraged us to
further decrease the amount of catalyst to 0.001 mol% (10 ppm: prepared from a stock solution
of catalysts in toluene via serial dilution and stable for at least six months) and after 12 h,
reaction resulted with a mixture of 4aa and 4'aa in 32% yield in the presence of 10 mol% KOH
(entry 5). Replacing the KOH with NaOH increased the yield of the reaction to 76% with 99:1
4aa:4'aa ratio (entry 6), and KOtBu was inactive under same conditions (entry 7). Using the
closed systems or inert reaction conditions did not improve the yield of the reaction significantly
and the rest of the reactions were performed open to air (entries 8 and 9). The reaction proceeded
faster when the amount of NaOH increased to 20 mol%. The desired product 4aa was obtained
in 99% yield within 8 h (entry 10). Almost full conversion was observed upon adding a drop of
mercury to the reaction mixture, indicating the homogeneous nature of the catalyst system (entry
11).25 We could reduce the catalyst loading down to 0.0001 mol% (1 ppm) and still obtained the
desired product 4aa in 65% (in the presence of 10 mol% NaOH) and 81% (in the presence of 20
mol% NaOH) yield within 16 h (entries 12 and 13). Without any iridium(I) complex the reaction
- resulted with only 12% yield, and no conversion to products was observed in the absence of a
base as expected (entries 14 and 15).
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Table 1. Optimization of the conditions for the β-alkylation reaction of alcohols.a
OH
OH
O
1a-d
, Base
+
+
Ph
OH
Ph
Ph
Ph
Ph
Ph
PhMe, 135 °C
2a
3a
4aa
4'aa
Yield (%)
(4aa + 4'aa)
Ratio (%)
Entry
Cat. (mol%)
Base (mol%)
Time (h)
(4aa : 4'aa)
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1
2
1a (0.01)
1b (0.01)
1c (0.01)
1d (0.01)
1d (0.001)
1d (0.001)
1d (0.001)
1d (0.001)
1d (0.001)
1d (0.001)
1d (0.001)
1d (0.0001)
1d (0.0001)
‒
KOH (10)
KOH (10)
KOH (10)
KOH (10)
KOH (10)
NaOH (10)
KOtBu (10)
NaOH (10)
NaOH (10)
NaOH (20)
NaOH (20)
NaOH (10)
NaOH (20)
NaOH (20)
‒
12
12
12
12
12
12
12
12
12
8
63
90
99:1
89:11
84:16
85:15
93:7
99:1
90:10
99:1
99:1
99:1
99:1
99:1
99:1
ND
3
35
4
>99
32
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5
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76
7
18
8b
9 c
10
11 d
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15
79
78
>99
97
8
16
16
16
16
65
81
12
1d (0.001)
0
ND
F3C
MeO
F3C
Cl
Cl
N
N
N
N
N
N
Ir
Ir
Ir
Ir
N
N
Cl
Cl
Cl
Cl
1a
1b
1c
1d
F3C
MeO
F3C
a
Reaction conditions: 1-Phenylethanol (1.0 mmol), benzyl alcohol (1.0 mmol), 1a-d (0.01-
0.0001 mol%), base (10-20 mol%), toluene (0.5 mL), 135 °C, under air. Yields and ratios were
determined by H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene
1
b
as an internal standard. ND = Not determined. Reaction was performed in a 20 mL closed
tube. c Reaction was performed under an argon atmosphere. d A drop of mercury was added.
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To evaluate the substrate scope of the β-alkylation of various secondary alcohols (2) with a
variety of primary alcohols (3) was conducted under the optimized reaction conditions (0.001
mol % 1d, 20 mol% NaOH, 0.5 mL toluene, 135 °C, 8h, under air) (Table 2). The reaction of
para-substituted 1-phenylethanols bearing electron donating ‒Me and ‒OMe substituents and
electron-withdrawing ‒Br, ‒Cl and ‒CF3 substituents with benzyl alcohols gave the desired
products 4aa-4fa 85-97% isolated yields. Additionally, 1-(2-naphthyl)ethanol (2g) and α‒tetralol
(2h) gave the corresponding alcohols 4ga and 4ha in 91% and 94% yields under similar
conditions. Next, we examined the scope of β‒alkylation reaction with respect to primary
alcohols (3). In this case, 1-phenylethanol (2a) reacted smoothly with a variety of primary
alcohols (3b–l) to give well to excellent isolated yields (78–97%) of desired alkylated alcohols
(4ab–4al).
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Table 2. Scope of the β-alkylation of secondary alcohols with primary alcohols.a
OH
1d
OH
(0.001 mol%)
+
R2
OH
R1
R1
R2
NaOH (20 mol%)
PhMe, 135°C
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OH
OH
OH
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7
MeO
8
9
4aa
: 97% yield
4ba
4ca
: 95% yield
8h,
8h,
8h,
: 88% yield
8h,
8h,
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OH
OH
OH
Cl
F3C
Br
4da
4ea
4fa
: 96% yield
8h,
: 85% yield
: 89% yield
OH
OH
4hab
8h,
: 94% yield
4ga
: 91% yield
8h,
OH
OH
OH
OMe
4ab
4ac
8h,
: 93% yield
8h,
: 91% yield
4ad
: 95% yield
8h,
OH
OH
OH
CF3
Br
Cl
4ae
4af
OH
8h,
: 91% yield
8h,
: 90% yield
4ag
24h,
: 97% yield
OH
OH
Cl
MeO
4ai
: 92% yield
4aj
24h,
OH
: 90% yield
4ah
8h,
: 78% yield
8h,
OH
OH
O
S
: 96% yield
4akc
4al
4amc
24h, : 54% yield
24h,
: 87% yield
24h,
a Reaction conditions: Secondary alcohol (2) (1.0 mmol), primary alcohol (3) (1.0 mmol), 1d
(0.001 mol% = 10 ppm), NaOH (20 mol%), toluene (0.5 mL), 135 °C, under air. Isolated yield.
bMixture of diastereoisomers (68:32). c1d (0.01 mol%)
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The reaction of 1-phenylethanol with para- and ortho-substituted benzyl alcohols bearing
electron donating 4‒Me, 4‒OMe, 4‒iPr and 2‒OMe, substituents and electron-withdrawing 4‒Br,
4‒Cl and 2‒Cl all resulted with high yields under optimized reaction conditions however,
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4‒trifluoromethylbenzyl
alcohol
(3g),
2,4,6‒trimethylbenzyl
alcohol
(3j)
and
2‒thiophenemethanol (3l) as primary alcohols longer reaction time (24 h) was required for high
yields. In the case of 2-furanmethanol (3k) and 1-octanol (3m) the amount of catalyst increased
to 0.01 mol% and the corresponding alcohols 4ak and 4am were isolated in 87% and 54% yield
respectively within 24 h.
Next, encouraged by these promising results, the substrate scope was extended to a cyclic
secondary alcohol 5α-cholestan-3β-ol (2i), a saturated derivative of cholesterol. For this purpose
2i was reacted with one equivalent benzyl alcohol (3a) under standard conditions and reaction
resulted with complete conversion of 2i along with β-alkylated cholesterol derivatives 4ia7a and
its diastereoisomer 4''ia with a ratio of 73:27 (calculated by NMR analysis) after 20 h (Scheme
2). Pleasingly, we have isolated both diastereoisomers 4ia7a (66% isolated yield) and 4''ia (19%
isolated yield). The structure of the minor diastereoisomer was assigned to be 4''ia by 2D NMR
studies (Supporting Information). The cholesterol derivative 2i was also reacted similarly with 4-
methoxybenzyl alcohol (3c) and corresponding diastereoisomers 4ic and 4''ic were isolated in
71% and 18% yield respectively (Scheme 2). Configrations of all diastereoisomers are specified
by using NOESY experiments and discussed in supporting information.
In addition, to make this process practically viable, gram scale reactions were also carried out
by using ppm amount of NHC‒IrI catalyst. Cross-coupling of 1-arylethanols (5 mmol) with
different benzyl alcohols (5 mmol) were resulted in 81-94% isolated yields for five examples in
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the presence of only 1 ppm (0.0001 mol%) of 1d as catalyst and 20 mol% NaOH after 24 h and
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this system disclosed up to 940000 TON(Table 3).
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Scheme 2. NHC‒IrI Catalyzed β-Alkylation of Cholestanol (aisolated yield).
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R
R
1d
(0.001 mol%)
H
H
H
NaOH (20 mol%)
OH
+
+
H
H
H
PhMe, 135 °C, 20 h
open air
H
H
H
R
HO
HO
HO
H
H
H
(1 equiv.)
3a
a
a
2i
4ia
4ic
4''ia
(R = H), 27% (19%)
(R = H), 73% (66%)
(R = OMe) 76% (71%)
(R = H)
Conv.: 100%
Conv.: 100%
a
a
3c
(R = OMe)
4''ic
(R = OMe) 24% (18%)
Table 3. Gram scale β-alkylation reaction of secondary alcohols with primary alcohols.a
1d
(1 ppm = 0.0001 mol%)
NaOH (20 mol%)
OH
OH
+
R2
OH
R1
R1
R2
PhMe (8 mL), 135°C, 24 h
5 mmol
5 mmol
2
3
4
OH
OH
OH
Cl
4aa
: 91% (0.95 g)
4ba
: 90% (1.02 g)
4ea
: 94% (1.16 g)
OH
OH
Cl
4ab
: 93% (1.05 g)
4af
: 81% (0.99 g)
a Reaction conditions: Secondary alcohol (2) (5.0 mmol), primary alcohol (3) (5.0 mmol), 1d
(0.0001 mol% = 1 ppm), NaOH (20 mol%), toluene (8 mL), 135 °C, under air. Isolated yield.
Brand-new glassware and stirring bar were used.
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Mechanistic Studies on NHC‒IrI Catalyzed β-Alkylation of Alcohols. A plausible
mechanism for this cross-coupling of secondary alcohols with primary alcohols, in view of
literature reports by us 24 and other groups 3b-f,5a,j,7b and also the experimental data, can be shown
in Scheme 3. The mechanism involves the dehydrogenation of alcohols (2 and 3) to give
corresponding carbonyls (2' and 3') along with in situ generated transient iridium–hydride.5a,24
These resulting carbonyl compounds may give the α,β‒unsaturated ketone (5) in the presence of
a base. This α,β‒unsaturated ketone can be reduced to give the 4ʹ and 4 by iridium–hydride. In a
very recent study we observed that, in the presence of 0.5 mol% 1d the reaction of 2 and 3 was
very fast and complete within 12.5 minutes along with a mixture of 4 and 4ʹ in a 51:49 ratio,
then, 4 gradually dehydrogenated to give α-alkylated ketones (4ʹ) selectively. 24 In the present
study, we aimed to exploit these observations to improve the selectivity of the reaction to favor
the β-alkylated alcohols (4) instead of α-alkylated ketones (4ʹ). In other words, the main idea of
the present study was to prevent the final dehydrogenation of 4 to 4ʹ by decreasing the amount of
catalyst used.
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Scheme 3. Plausible Reaction Mechanism for NHC‒IrI Catalyzed β-Alkylation of Alcohols
5
6
7
- H2
8
9
+ H2
OH
O
OH
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R
OH
+
+
2
R1
R2
R1
R2
R1
2
3
4
4'
[Ir]
- 2H2
+ 2H2
+ H2
[Ir]-H
O
O
base
- H2O
R
2
+
O
R1
R2
R1
2'
3'
5
To obtain more information regarding final dehydrogenation of the β-alkylated alcohol (4) to
α-alkylated ketone (4ʹ) a series of control experiments were executed. For this purpose,
dehydrogenation of 1,3-diphenylpropan-1-ol (4aa) was carried out in the presence of 1d (0.5 to
0.001 mol%) and NaOH (20 mol%) (Scheme 4). In the presence of 0.5 mol% catalyst the
reaction resulted in 92% conversion to 1,3-diphenylpropan-1-one (4ʹaa) within 2 h. Lowering the
catalyst loading to 0.1 mol% and 0.01 mol% resulted with 45% and 6% conversion to 4ʹaa
within 2 h respectively. As expected, lower conversion to the 4ʹaa was observed even after 24 h
of the reaction in the presence of 0.001 mol% 1d. It is clear that by decreasing the amount of
catalyst used, final dehydrogenation step (dehydrogenation of 4 to 4ʹ) of the reaction can be
prevented and this results with selective formation of β-alkylated alcohols (4).
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Scheme 4. NHC‒IrI Catalyzed Dehydrogenation of 1,3-Diphenylpropan-1-ol (4aa) (1H NMR
5
6
conversions).
7
8
9
1d
(0.001-0.5 mol%)
OH
O
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NaOH (20 mol%)
PhMe, 135 °C
open air
 H2
4aa
4'aa
1d
1d
1d
1d
1d
4'aa
4'aa
4'aa
(0.5 mol%) / 2 h: 92 % conv. to
(0.1 mol%) / 2 h: 45 % conv. to
(0.01 mol%) / 2 h: 6 % conv. to
(0.001 mol%) / 2 h: <1 % conv. to
(0.001 mol%) / 24 h: 4 % conv. to
4'aa
4'aa
Then, we monitored the progress of the model reaction between 1-phenylethanol (2a) and
benzyl alcohol (3a) as a function of time with catalyst loadings ranging between 0.5–0.001 mol%
(Figure 1). The reaction of 2a and 3a is very fast and results in complete conversion to a mixture
of 4aa and 4ʹaa within 15, 30 and 120 min. in the presence of 0.5, 0.1 and 0.01 mol% 1d
respectively. Then, initially formed 4aa gradually undergoes dehydrogenation to form 4′aa
(Figure 1a-c). However, in the presence of 0.001 mol% 1d, the concentration of 4ʹaa was
minimal (< 1%) and did not altered significantly during the progress of the reaction (Figure 1d).
In addition, no accumulation of the α,β-unsaturated ketone (chalcone, 5aa), resultant from the
cross-condensation process, was observed during the whole course of the reaction, which
suggests that the reduction of intermediate product 5aa was very fast. From these observations, it
can be suggested that the dehydrogenation of the alcohol substrates 2 and 3 is most likely the
rate-limiting step.7b
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1d
(0.001 mol%)
NaOH (20 mol%)
OH
OH
O
+
+
Ph
OH
Ph
Ph
Ph
Ph
Ph
PhMe, 135 °C
7
2a
4aa
4'aa
8
3a
9
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a) 0.5 mol% 1d
Total conversion
4aa
4'aa
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h)
b) 0.1 mol% 1d
Total conversion
4aa
4'aa
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h)
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c) 0.01 mol% 1d
5
6
Total conversion
4aa
4'aa
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9
100
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10
0
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0
1
2
3
4
5
6
7
8
Time (h)
d) 0.001 mol% 1d
Total conversion
4aa
4'aa
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h)
Figure 1. Time course of the reaction of benzyl alcohol with 1-phenylethanol. Reaction
Conditions: 2a (1.0 mmol), 3a (1.0 mmol), 1d (0.5-0.001 mol%), NaOH (20 mol%), toluene (0.5
1
mL), 135 ºC, under air. Yields and ratios were determined by H NMR analysis of the
independent reaction mixtures using 1,3,5-trimethoxybenzene as an internal standard: (a) 0.5
mol% 1d; (b) 0.1 mol% 1d; (c) 0.01 mol% 1d; (d) 0.001 mol% 1d.
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There are some reports which supports the involvement of transition metal catalyst in cross-
aldol condensation step.3e,5b In order to confirm the possible involvement of the used catalyst in
this step, a reaction of 4-methylacetophenone (2ʹb) and p-tolualdehyde (3ʹb) was also performed
in the presence and absence of 1d using the standard catalytic conditions (Scheme 5). In the
presence of 1d (0.001 mol%) the reaction resulted with a mixture of products, containing 38% of
1,3-di-p-tolylprop-2-en-1-one (4,4'-dimethylchalcone, 5bb) and 10% of 1,3,5-tri-p-tolylpentane-
1,5-dione (5ʹbb), which was the product of the 1,4-addition of 4-methylacetophenone (2ʹb) on
4,4'-dimethylchalcone (5bb), after 4 h. The reaction also gave a similar mixture (36% of 5bb
and 9% of 5ʹbb) in the absence of catalyst and these results may indicate that the catalyst was not
involved in the cross-aldol condensation step of the present catalytic system. Interestingly, after
the 16 h reaction of 2ʹb and 3ʹb in the presence of 0.001 mol% 1d and 20 mol% NaOH unreacted
2ʹb was not detected as it was converted to a mixture of 5bb (33%) and 1,4-addition product
5ʹbb (30%) and more importantly, increasing the molar ratio of 2ʹb:3ʹb to 2:1 resulted with 91%
and 82% formation of 1,4-addition product 5ʹbb after 4 h in the presence of 0.001 mol% and
absence of catalyst 1d respectively. With Ni-based catalysts, similar results on the formation of
this 1,4-addition products have also reported very recently.26
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Scheme 5. Control Experiments on the Involvement of Catalyst in Cross-Aldol Condensation
Step of the β-Alkylation of Alcohols (1H NMR conversions).
7
8
9
1d
with / without
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O
O
O
NaOH (20 mol%)
+
+
O
O
PhMe, 135 °C
open air
2'b
3'b
5bb
5'bb
2'b
3'b
1d
(mol%)
Time
(h)
Yield
5bb
a
(mmol)
(mmol)
5'bb
/ %
(%
)
1
1
1
2
2
1
1
1
1
1
0.001

4
4
38 / 10
36 / 9
33 / 30
4 / 91
9 / 82
0.001
0.001

16
4
4
a 1H NMR yield, 1,3,5-trimethoxybenzene used as an internal standard.
Next, we investigated the reduction of α,β-unsaturated ketones (5) and α-alkylated ketones (4ʹ)
by using primary or secondary alcohols as hydrogen source. For this purpose, 4,4'-
dimethylchalcone (5bb) and 1,3-di-p-tolylpropan-1-one (4ʹbb) were used as the model substrate
(Scheme 6). Reduction of 5bb in the presence of benzyl alcohol (1 equiv.) by using optimized
reaction conditions afforded 74% of 1,3-di-p-tolylpropan-1-one (4ʹbb) and 12% of 1,3-di-p-
tolylpropan-1-ol (4bb) after 4 h (Eq. 1). Increasing the amount of benzyl alcohol (2 equiv.) under
similar conditions resulted with 62% 4ʹbb and 25% 4bb after 4 h (Eq. 2). Transfer
hydrogenation of 4ʹbb in the presence of benzyl alcohol (1 equiv.) under similar reaction
conditions were also carried out and 58% conversion to 4bb was observed after 4 h (Eq. 3). In
addition, 5bb can also be reduced by using 1 equiv. secondary alcohols (2). Irrespective from
their electronic nature, in the presence of all the tested secondary alcohols (2) 4,4'-
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dimethylchalcone (5bb) was reduced to give a mixture of 4ʹbb (58-60%) and 4bb (8-13%)
within 4 h. All these results further suggest that NHC‒IrI complex (1d) can efficiently catalyze
the transfer of hydrogen from the substrate alcohols (2 and 3) to the C=C and C=O bonds.
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Scheme 6. Control Experiments on Reduction of Intermediate Products with Primary and
Secondary Alcohols.
1d
(0.001 mol%)
OH
O
O
NaOH (20 mol%)
OH
+
+
+
+
+
(Eq. 1)
(Eq. 2)
(Eq. 3)
PhMe, 135 °C, 4 h
open air
5bb
3a
0.5 mmol
4'bb
4bb
0.5 mmol
74 %
12 %
1d
(0.001 mol%)
OH
O
O
NaOH (20 mol%)
OH
PhMe, 135 °C, 4 h
open air
5bb
3a
4'bb
4bb
0.5 mmol
1.0 mmol
62 %
25 %
1d
(0.001 mol%)
OH
O
NaOH (20 mol%)
OH
PhMe, 135 °C, 4 h
open air
4'bb
3a
4bb
58 %
0.5 mmol
0.5 mmol
1d
(0.001 mol%)
OH
O
OH
O
NaOH (20 mol%)
+
+
(Eq. 4)
PhMe, 135 °C, 4 h
open air
R
5bb
2
4'bb
60 %
4bb
R = H
0.5 mmol
0.5 mmol
13 %
R = OMe
R = CF3
58 %
59 %
11 %
8 %
Catalytic Studies on NHC‒IrI Catalyzed Acceptorless Cyclization of 2-Aminobenzyl
Alcohol with Ketones. Following the advantages of BH technique and high activity of NHC–IrI
complexes (1) in related reactions, we assumed that these complexes can catalyze acceptorless
dehydrogenative cyclization of 2-aminobenzyl alcohol (6) with ketones (2ʹ) to give substituted
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quinoline derivatives (7) in the presence of low amount of catalyst and strong base. Initially,
several experiments were carried out to optimize the reaction conditions for this transformation
(Supporting Information, Table S1). Reaction of equimolar amount of 2-aminobenzyl alcohol (6)
with a variety of ketone (2ʹ) in presence of complex 1d (0.01 mol%) and KOH (5 mol%) at 135
ºC in toluene for 16 h resulted with moderate to high isolated yields (55-92%) to desired
substituted quinoline derivatives (7a-j, (Table 4). To the best of our knowledge, one of the
highest TON (up to 9200) - reported for the reaction or 2-aminobenzyl alcohol with ketones to
give substituted quinolines.
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Table 4. Scope for the reaction of 2-aminobenzyl alcohol with ketones to give quinolines.a
R2
O
1d
(0.01 mol%)
OH
+
R2
KOH (5 mol%)
PhMe / 135°C
16h
R1
NH2
N
R1
6
2'
7
7a:
7b:
7c:
7d:
7e:
7f:
R = H; 82%
R = Me; 85%
R = OMe; 92%
R = Br; 83%
R = Cl; 85%
R = CF3; 55%
N
N
R
7g:
86%
N
N
N
7h:
7i:
7j:
62%
59%
91%
a
Reaction conditions: 2-Aminobenzyl alcohol (6) (1.0 mmol), ketone (2ʹ) (1.0 mmol), 1d
(0.01 mol%), KOH (5 mol%), toluene (1 mL), 135 °C,16 h, under air. Isolated yield.
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CONCLUSIONS
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In summary, we reported here a highly active catalytic system for the cross-coupling of
alcohols to give β-alkylated alcohols (up to 940000 TONs) and acceptorless dehydrogenative
cyclization of 2-aminobenzyl alcohol with ketones to synthesize substituted quinoline derivatives
(up to 9200 TON) following borrowing hydrogen strategy by using catalytic amount of NaOH or
KOH without using any inert reaction conditions. Varieties of β-alkylated alcohols, including
cholesterol derivatives, and substituted quinolines were obtained in good isolated yields by using
this efficient and operationally simple catalytic system. Furthermore, when combined with our
previous results, selectivity can be controlled by a single catalyst: both β-alkylated alcohols (4)
and α-alkylated ketones (4ʹ) can be obtained by the reaction of secondary and primary alcohols
with slightly modified reaction conditions.
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EXPERIMENTAL SECTION
General Information. Unless otherwise stated all reactions and work-up procedures were
carried out in open air, all reagents and solvents were obtained commercially and used without
further purification. [IrCl(COD)(NHC)] complexes 1a27 and 1b-d24 were synthesized according
to published procedure. The physical properties and spectroscopic features of known complexes
and isolated alcohols and quinolines are in good agreement with those reported in the literatures.
Due to small quantities of catalyst that were used in the reactions, different catalyst solutions
were prepared via serial dilution of prepared stock solutions and these solutions are stable for at
least six months. NMR spectra were recorded on Varian AS 400 Mercury NMR spectrometer at
1
13
19
400 MHz for H NMR, 100 MHz for C NMR and 376 MHz for F in CDCl3 and reported in
units of parts per million (ppm) relative to tetramethyl silane (δ = 0 ppm) or CDCl3 (δ = 7.26
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ppm for H and δ = 77.0 ppm for C NMR). Coupling constants (J) are reported in Hertz (Hz).
Melting points were determined on Gallenkamp electrothermal melting point apparatus without
correction. HRMS analyses were performed on an Agilent 6530 Accurate-Mass Q-TOF mass
spectrometer at Atatürk University East Anatolia High Technology Application and Research
Center.
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General Procedure for β-Alkylation of Secondary Alcohols with Primary Alcohols. Base
(0.1-0.2 mmol, 10-20 mol%), secondary alcohol (1.0 mmol), primary alcohol (1.0 mmol) and a
solution of complex 1 (0.0001-0.000001 mmol, 0.01-0.0001 mol%) in toluene (0.5 mL) were
added under air atmosphere to a 20 mL reaction tube (1 cm × 20 cm) with a reflux condenser.
The reaction mixture was vigorously stirred (1200 rpm) under reflux in a preheated oil bath at
135 ºC for required time. Then the reaction mixture was cooled to ambient temperature and in
the case of optimization studies, 1,3,5-trimethoxybenzene (0.25 mmol) were added into the
reaction mixture as an internal standard and the conversions and selectivity were calculated
1
through H NMR analysis. For the substrate scope experiments, all the crude products were
purified by silica gel column chromatography using hexane and ethyl acetate (9:1 v/v) mixture as
eluent to afford the desired alcohol.
1,3-diphenylpropan-1-ol (4aa)8b. Pale yellow oil; 97% yield (206 mg). H NMR (CDCl3, 400
1
MHz) δ (ppm): 7.38-7.20 (m, 10H), 4.72- 4.68 (m, 1H), 2.82-2.66 (m, 2H), 2.21-2.01 (m, 2H, bs,
1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 144.6, 141.8, 128.5, 128.5, 128.4, 127.6,
13
126.0, 125.9, 73.9, 40.5, 32.1.
3-phenyl-1-(p-tolyl)propan-1-ol (4ba)28. Colorless oil; 88% yield (199 mg). H NMR (CDCl3,
1
400 MHz) δ (ppm): 7,37-721 (m, 9H), 4,67 (dd, J1 = 7.4 Hz, J2 = 5.6 Hz, 1H), 2.83-2.67 (m, 2H),
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2.42 (s, 3H), 2.29 (bs, 1H, OH), 2.21-2.02 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm):
5
6
142.0, 141.7, 137.3, 129.2, 128.5, 128.4, 126.0, 125.9, 73.7, 40.4, 32.2, 21.2.
7
8
9
1-(4-methoxyphenyl)-3-phenylpropan-1-ol (4ca)3g. White solid; 95% yield (230 mg); m.p.: 52
°C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.31-7.26 (m, 4H), 7.21-7.17 (m, 3H), 6.89 (d, J = 8.8
Hz, 2H), 4.64 (t, J = 6.2 Hz, 1H), 3.81 (s, 3H), 2.77-2.61 (m, 2H), 2.19-1.97 (m, 2H), 1.88 (bs,
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1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 159.1, 141.8, 136.7, 128.4, 128.3, 127.2,
125.8, 113.9, 73.5, 55.3, 40.3, 32.1.
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1-(4-bromophenyl)-3-phenylpropan-1-ol (4da)5e. Colorless oil; 85% yield (248 mg). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.48 (d, J = 8.4 Hz, 2H), 7.33-7.29 (m, 2H), 7.24-7.19 (m, 5H), 4.63
(dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 2.77- 2.63 (m, 2H), 2.24 (bs, 1H, OH), 2.14-1.95 (m, 2H);
13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 143.6, 141.5, 131.6, 128.5, 128.4, 127.7, 126.0,
121.3, 73.2, 40.4, 31.9.
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1-(4-chlorophenyl)-3-phenylpropan-1-ol (4ea)7d,8b. Colorless oil; 89% yield (220 mg). H
NMR (CDCl3, 400 MHz) δ (ppm): 7.35-7.19 (m, 9H), 4.65 (t, J = 6.4 Hz, 1H), 2.77-2.63 (m,
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2H), 2.15-1.96 (m, 2H), 2.12 (bs, 1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 143.1,
141.5, 133.2, 128.6, 128.5, 128.4, 127.3, 125.9, 73.1, 40.5, 31.9.
3-phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-ol (4fa)7a,8b. Colorless oil; 96% yield (269
1
mg). H NMR (CDCl3, 400 MHz) δ (ppm): 7.63 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),
7.32 (t, J = 7.2 Hz, 2H), 7.25-7.20 (m, 3H), 4.74 (dd, J1 = 7.6 Hz, J2 = 5.2 Hz, 1H), 2.81-2.67 (m,
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2H), 2.31 (bs, 1H, OH), 2.17-1.99 (m, 2H); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 149.0,
148.5, 141.4, 129.8 (q, J(C,F) = 32.0 Hz), 128.5, 128.4, 128.2, 126.2, 126.1, 125.5 (q, J(C,F) =
3.8 Hz), 124.2 (q, J(C,F) = 271.6 Hz), 73.2, 40.5, 31.8.
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1-(naphthalen-2-yl)-3-phenylpropan-1-ol (4ga)3g,7a,8b. White solid; 91% yield (239 mg); m.p.:
65 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.86-7.82 (m, 3H), 7.79 (s, 1H), 7.53-7.47 (m, 3H),
7.33-7.28 (m, 2H), 7.22 (d, J = 7.6 Hz, 3H), 4.86 (dd, J1 = 6.8 Hz, J2 = 6.0 Hz, 1H), 2.83-2.68
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(m, 2H), 2.29-2.09 (m, 2H), 2.07 (bs, 1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm):
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141.9, 141.8, 133.3, 133.1, 128.5, 128.4, 128.3, 128.0, 127.7, 126.2, 126.0, 125.8, 124.7, 124.1,
74.0, 40.3, 32.1.
Trans-2-benzyl-1,2,3,4-tetrahydronaphthalen-1-ol (trans-4ha)3c,29. White solid; 64% yield
(153 mg); m.p.: 116 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.51 (d, J = 6.8 Hz, 1H) 7.33-7.18
(m, 7H), 7.09 (d, J = 6.8 Hz, 1H), 4.51 (t, J = 7.2 Hz, 1H), 3.08 (dd, J1 = 13.6 Hz, J2 = 5.2 Hz,
1H), 2.81-2.73 (m, 2H), 2.52 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 2.11-1.95 (m, 2H), 1.69 (d, J =
7.2 Hz, 1H), 1.54-1.46 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 140.4, 138.6, 136.8,
129.3, 128.7, 128.4, 128.3, 127.4, 126.3, 126.0, 73.0, 43.9, 38.4, 27.6, 24.5.
Cis-2-benzyl-1,2,3,4-tetrahydronaphthalen-1-ol (cis-4ha)3c,29. White solid; 30% yield (71);
m.p.: 78 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.38-7.15 (m, 9H), 4.55 (s, 1H), 3.00 (dd, J1 =
13.6 Hz, J2 = 7.6 Hz, 1H), 2.95-2.89 (m, 1H), 2.82-2.74 (m, 2H), 2.11-2.03 (m, 1H), 1.93-1.82
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(m, 1H), 1.78-1.71 (m, 1H), 1.66 (bs, 1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm):
140.8, 138.6, 136.9, 130.1, 129.3, 129.1, 128.4, 128.0, 126.2, 125.9, 69.4, 41.8, 38.2, 29.2, 22.6.
1-phenyl-3-(p-tolyl)propan-1-ol (4ab)3c,6,8b. White solid; 93% yield (211 mg); m.p.: 55 °C. H
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NMR (CDCl3, 400 MHz) δ (ppm): 7.40-7.37 (m, 4H), 7.33-7.28 (m, 1H), 7.14-7.08 (m, 4H),
4.69 (t, J = 5.8 Hz, 1H), 2.77-2.62 (m, 2H), 2.36 (s, 3H), 2.19-1.99 (m, 2H), 1.96 (bs, 1H, OH);
13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 144.7, 138.7, 135.3, 129.1, 128.5, 128.3, 127.6,
125.9, 73.9, 40.6, 31.6, 20.9.
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3-(4-methoxyphenyl)-1-phenylpropan-1-ol (4ac)6,8a,b. White solid; 91% yield (221 mg); m.p.:
64 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.39-7.34 (m, 4H), 7.32-7.27 (m, 1H), 7.12 (d, J =
8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.68 (dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 3.79 (s, 3H), 2.74-
2.59 (m, 2H), 2.16-1.96 (m, 2H, bs, 1H, OH); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 157.8,
144.7, 133.8, 129.3, 128.5, 127.6, 125.9, 113.9, 73.8, 55.3, 40.7, 31.1.
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3-(4-isopropylphenyl)-1-phenylpropan-1-ol (4ad)17. Colorless oil; 95% yield (242 mg). H
NMR (CDCl3, 400 MHz) δ (ppm): 7.39 (d, J = 4.4 Hz, 4H), 7.37-7.30 (m, 1H), 7.22-7.16 (m,
4H), ), 4.71 (dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 2.99-2.89 (m, 1H), 2.81- 2.64 (m, 2H), 2.22- 2.03
(m, 2H), 2.16 (bs, 1H, OH), 1.31 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm):
146.4, 144.7, 139.1, 128.5, 128.4, 127.6, 126.5, 126.0, 74.0, 40.5, 33.7, 31.7, 24.1.
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3-(4-bromophenyl)-1-phenylpropan-1-ol (4ae)3c,7a,8b. Colorless oil; 91% yield (265 mg). H
NMR (CDCl3, 400 MHz) δ (ppm): 7.42-7.28 (m, 7H), 7.06 (d, J = 8.4 Hz, 2H), 4.65 (dd, J1 = 7.6
Hz, J2 = 5.6 Hz, 1H), 2.74-2.59 (m, 2H), 2.15-1.94 (m, 2H, bs, 1H, OH); 13C{1H} NMR (CDCl3,
100 MHz) δ (ppm): 144.4, 140.8, 131.4, 130.2, 128.6, 127.7, 125.9, 119.6, 73.7, 40.2, 31.4.
3-(4-chlorophenyl)-1-phenylpropan-1-ol (4af)3c,5j,8b. White solid; 90% yield (222 mg); m.p.:
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73 °C. H NMR (CDCl3, 400 MHz) δ (ppm): 7.39-7.28 (m, 5H), 7.26 (d, J = 8.4 Hz, 2H), 7.12
(d, J = 8.4 Hz, 2H), 4.65 (t, J = 5.2 Hz, 1H), 2.76-2.60 (m, 2H), 2.17 (bs, 1H, OH), 2.15-1.95 (m,
2H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 144.4, 140.3, 131.6, 129.8, 128.6, 128.5, 127.7,
125.9, 73.7, 40.3, 31.4.
1-phenyl-3-(4-(trifluoromethyl)phenyl)propan-1-ol (4ag)5j. Colorless oil; 97% yield (272 mg).
1H NMR (CDCl3, 400 MHz) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.39-7.28 (m, 7H), 4.71-4.66 (m,
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1H), 2.86-2.70 (m, 2H), 2.19-1.98 (m, 2H), 1.92 (bs, 1H, OH); C{1H} NMR (CDCl3, 100
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MHz) δ (ppm): 146.0, 144.3, 128.7, 128.5, 128.1 (q, J(C,F) = 32.0 Hz), 127.8, 125.9, (t, J(C,F) =
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272.6 Hz), 125.3 (q, J(C,F) = 3.8 Hz), 73.7, 40.1, 31.9.
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3-(2-chlorophenyl)-1-phenylpropan-1-ol (4ah)3c,7a,8a. Colorless oil; 78% yield (192 mg). H
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NMR (CDCl3, 400 MHz) δ (ppm): 7.39-7.35 (m, 5H), 7.33-7.28 (m, 1H), 7.25-7.13 (m, 3H),
4.72 (dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 2.95-2.76 (m, 2H), 2.21 (bs, 1H, OH), 2.16-2.02 (m, 2H);
13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 144.4, 139.5, 134.0, 130.4, 129.5, 128.5, 127.7,
127.4, 126.8, 125.9, 74.0, 38.7, 30.1.
3-(2-methoxyphenyl)-1-phenylpropan-1-ol (4ai)3c. Colorless oil; 92% yield (223 mg). 1H NMR
(CDCl3, 400 MHz) δ (ppm): 7.41-7.19 (m, 7H), 6.93 (td, J1 = 7.4 Hz, J2 = 1.2 Hz, 1H), 6.89 (d, J
= 8.0 Hz, 1H), 4.66 (t, J = 5.8 Hz, 1H), 3.85 (s, 3H), 2.79 (t, J = 7.6 Hz, 2H), 2.49 (bs, 1H, OH),
2.15-1.99 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 157.5, 144.9, 130.3, 130.2, 128.4,
127.4, 127.3, 126.1, 120.7, 110.5, 73.7, 55.4, 39.4, 26.6.
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3-mesityl-1-phenylpropan-1-ol (4aj). White solid; 90%yield (229 mg); m.p.: 76 °C. H NMR
(CDCl3, 400 MHz) δ (ppm): 7.43-7.30 (m, 5H), 6.85 (s, 2H), 4.81-4.77 (m, 1H), 2.81-2.74 (m,
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1H), 2.60-2.53 (m, 1H), 2.27 (s, 3H), 2.25 (s, 6H), 2.02-1.84 (m, 2H, bs, 1H, OH); C{1H}
NMR (CDCl3, 100 MHz) δ (ppm): 144.5, 135.9, 135.6, 135.0, 129.0, 128.5, 127.7, 125.9, 74.8,
38.2, 25.5, 20.8, 19.6. HRMS (APCI) m/z [M] calcd for C18H22O 254.1671; found 254.1672.
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3-(furan-3-yl)-1-phenylpropan-1-ol (4ak)3c,8b. Pale yellow oil; 87% yield (176 mg). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.34-7.27 (m, 6H), 6.29 (dd, J1 = 3.2 Hz, J2 = 2.0 Hz, 1H), 6.01 (dd,
J1 = 3.2 Hz, J2 = 0.8 Hz, 1H), 4.70 (dd, J1 = 7.8 Hz, J2 = 5.2 Hz, 1H), 2.79-2.67 (m, 2H), 2.18-
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2.02 (m, 2H, bs, 1H, OH); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 155.6, 144.3, 140.9,
128.5, 127.7, 125.9, 110.1, 105.0, 73.7, 37.2, 24.4.
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1-phenyl-3-(thiophen-3-yl)propan-1-ol (4al)3c. Colorless oil; 96% yield (210 mg). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.41-7.29 (m, 5H), 7.15 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H), 6.96 (dd,
J1 = 5.2 Hz, J2 = 3.2 Hz, 1H), 6.86-6.82 (m, 1H), 4.72 (t, J = 6.4 Hz, 1H), 3.02-2.89 (m, 2H),
2.27 (bs, 1H, OH), 2.25-2.06 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 144.7, 144.4,
128.6, 127.7, 126.8, 125.9, 124.3,123.1, 73.5, 40.7, 26.2.
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1-phenyldecan-1-ol (4am)6. Colorless oil; 54% yield (127 mg). 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.35-7.25 (m, 5H), 4.66 (dd, J1 = 7.2 Hz, J2 = 6.0 Hz, 1H), 1.89 (bs, 1H, OH), 1.85-1.63
(m, 2H), 1.45-1.25 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H); C{1H} NMR (CDCl3, 100 MHz) δ
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(ppm): 144.9, 128.4, 127.4, 125.9, 74.7, 39.1, 31.9, 29.6, 29.5, 29.3, 25.8, 22.7, 14.1.
(2R,3R,5S,8R,9S,10S,13R,14S,17R)-2-benzyl-10,13-dimethyl-17-((R)-6-methylheptan-2-
yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (4ia)7a. White solid; 66% yield (316 mg);
m.p.: 116 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.29-7.16 (m, 5H), 3.29 (td, J1 = 10.4 Hz, J2
= 4.8 Hz, 1H), 3.08 (dd, J1 = 13.6 Hz, J2 = 4.0 Hz, 1H), 2.37 (dd, J1 = 13.4 Hz, J2 = 8.8 Hz, 1H),
1.91 (dt, J1 = 12.0 Hz, J2 = 2.8 Hz, 1H), 1.82-1.69 (m, 2H), 1.64-0.93 (m, 27H), 0.88 (s, 3H),
0.86 (d, J = 0,8 Hz, 3H), 0.85 (d, J = 1.6 Hz, 3H), 0.73 (s, 3H), 0.60 (s, 3H), 0.59 (m, 1H);
13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 140.7, 129.3, 128.2, 125.7, 74.9, 56.5, 56.3, 54.4,
44.9, 42.8, 42.6, 42.3, 40.0, 39.5, 39.4, 38.3, 36.2, 36.1, 35.8, 35.3, 32.0, 28.4, 28.3, 28.0, 24.2,
23.9, 22.8, 22.6, 21.2, 18.7, 12.9, 12.1.
(2S,3R,5S,8R,9S,10S,13R,14S,17R)-2-benzyl-10,13-dimethyl-17-((R)-6-methylheptan-2-
yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (4''ia). White solid;19% yield (91 mg);
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m.p.: 122 °C. H NMR (CDCl3, 400 MHz) δ (ppm): 7.30-7.17 (m, 5H), 3.70 (s, 1H), 2.68 (dd, J1
= 13.6 Hz, J2 = 8.8 Hz, 1H), 2.52 (dd, J1 = 13.2 Hz, J2 = 6.4 Hz, 1H), 1.96 (dt, J1 = 12.0 Hz, J2 =
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3.2 Hz, 1H), 1.86-1.76 (m, 2H), 1.69-1.62 (m, 1H), 1.60-0.94 (m, 26H), 0.90 (d, J = 6.8 Hz, 3H),
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0.88 (d, J = 2.0 Hz, 3H), 0.86 (d, J = 1.6 Hz, 3H), 0.76 (s, 3H), 0.64 (s, 3H); C{1H} NMR
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(CDCl3, 100 MHz) δ (ppm): 140.9, 129.0, 128.2, 125.7, 67.7, 56.5, 56.2, 54.4, 42.6, 40.0, 39.5,
39.3, 39.2, 39.2, 39.1, 36.7, 36.4, 36.1, 35.8, 35.4, 32.0, 28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 20.8,
18.7, 12.2, 12.1. HRMS (APCI) m/z [M] calcd for C34H54O 478.4175; found 478.4217.
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(2R,3R,5S,8R,9S,10S,13R,14S,17R)-2-(4-methoxybenzyl)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (4ic). White solid; 71%
yield (361); m.p.: 104 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.08 (d, J = 8.4 Hz, 2H), 6.81
(d, J = 8.4 Hz, 2H) 3.79 (s, 3H), 3.28 (td, J1 = 10.4 Hz, J2 = 5.2 Hz, 1H), 2.99 (dd, J1 = 13.6 Hz,
J2 = 4.0 Hz, 1H), 2.33 (dd, J1 = 13.4 Hz, J2 = 8.0 Hz, 1H), 1.92 (d, J = 12.0 Hz, 1H), 1.84-1.73
(m, 1H), 1.72-0.92 (m, 28H), 0.89 (s, 3H), 0.87 (d, J = 2.0 Hz, 3H), 0.85 (d, J = 2.0 Hz, 3H),
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0.72 (s, 3H), 0.61 (s, 3H), 0.57 (m, 1H); C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 157.7,
132.6, 130.2, 113.6, 74.9, 56.5, 56.3, 55.2, 54.4, 44.9, 42.8, 42.6, 42.4, 40.0, 39.5, 38.5, 38.2,
36.2, 36.1, 35.8, 35.3, 32.0, 28.3, 28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 21.3, 18.6, 12.9, 12.0. HRMS
(APCI) m/z [M] calcd for C35H56O2 508.4280; found 508.4304.
(2S,3R,5S,8R,9S,10S,13R,14S,17R)-2-(4-methoxybenzyl)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (4''ic). White solid; 18%
yield (92 mg); m.p.: 114 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.11 (d, J = 8.8 Hz, 2H),
6.82 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 3.70 (s, 1H), 2.62 (dd, J1 = 13.4 Hz, J2 = 8.8 Hz, 1H), 2.45
(dd, J1 = 13.4 Hz, J2 = 6.8 Hz, 1H), 1.94 (dt, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H), 1.84-1.72 (m, 2H),
1.65 (dd, J1 = 12.8 Hz, J2 = 3.2 Hz, 1H) 1.55-0.95 (m, 26H), 0.89 (d, J = 6.8 Hz, 3H), 0.87 (d, J
= 2.0 Hz, 3H), 0.86 (d, J = 1.6 Hz, 3H), 0.75 (s, 3H), 0.73 (m, 1H), 0.64 (s, 3H); 13C{1H} NMR
(CDCl3, 100 MHz) δ (ppm): 157.7, 132.9, 129.9, 113.6, 67.7, 56.5, 56.2, 55.2, 54.4, 42.6, 40.0,
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39.5, 39.3, 39.2, 39.1, 38.4, 36.7, 36.3, 36.2, 35.8, 35.4, 32.0, 28.2, 27.9, 24.2, 23.8, 22.8, 22.6,
20.8, 18.6, 12.2, 12.1. HRMS (APCI) m/z [M] calcd for C35H56O2 508.4280; found 508.4328.
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Gram Scale β-Alkylation of Secondary Alcohols with Primary Alcohols. Base (1.0 mmol,
20 mol%), secondary alcohol (5.0 mmol), primary alcohol (5.0 mmol) and a solution of complex
1 (0.000001 mmol, 0.0001 mol%) in toluene (8 mL) were added under air atmosphere to a 50
mL reaction tube with a reflux condenser. The reaction mixture was vigorously stirred (1200
rpm) under reflux in a preheated oil bath at 135 ºC for 24 h. Then the reaction mixture was
cooled to ambient temperature. The crude products were purified by silica gel column
chromatography using hexane and ethyl acetate (9:1 v/v) mixture as eluent to afford the desired
alcohols; 4aa: 91% yield (0.95 g); 4ba: 90% yield (1.02 g); 4ea: 94% yield (1.16 g); 4ab: 93%
yield (1.05 g); 4af: 81% yield (0.99 g).
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(E)-1,3-di-p-tolylprop-2-en-1-one (5bb)30. Pale green solid; m.p.: 132 °C. H NMR (CDCl3,
400 MHz) δ (ppm): 7.32-7.17 (m, 6H), 7.11 (s, 2H), 4.66 (dd, J1 = 7.4 Hz, J2 = 5.6 Hz, 1H),
2.80-2.59 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H).
1
1,3,5-triphenylpentane-1,5-dione. (5'bb)31. White solid; m.p.: 101 °C. H NMR (CDCl3, 400
MHz) δ (ppm): 7.48 (d, J = 8.0 Hz, 4H), 7.33 (d, J = 8.0 Hz, 4H), 7.16 (d, J = 8.0 Hz, 2H), 7.07
(d, J = 8.0 Hz, 2H), 4.04-3.97 (m, 1H), 3.43 (dd, J1 = 16.4 Hz, J2 = 6.8 Hz, 2H), 3.28 (dd, J1 =
16.4 Hz, J2 = 6.8 Hz, 2H), 2.39 (s, 6H), 2.28 (s, 3H).
1
1,3-di-p-tolylpropan-1-ol (4bb)7d. White solid; m.p.: 70 °C. H NMR (CDCl3, 400 MHz) δ
(ppm): 7.32-7.17 (m, 6H), 7.11 (s, 2H), 4.66 (dd, J1 = 7.4 Hz, J2 = 5.6 Hz, 1H), 2.80-2.59 (m,
13
2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21-1.97 (m, 2H), 1.91 (bs, 1H, OH); C{1H} NMR (CDCl3,
ACS Paragon Plus Environment
29