Ru-Catalyzed Cross-Dehydrogenative Coupling between Primary Alcohols to Guerbet Alcohol Derivatives: With Relevance for Fragrance Synthesis

Article abstract of DOI:10.1021/acs.joc.8b01558

A simple method has been developed for the cross dehydrogenative coupling between two different primary alcohols using readily available RuCl₂(PPh₃)₃ as a precatalyst through the borrowing-hydrogen approach. The present methodology is applicable to a large variety of alcohol derivatives including long chain aliphatic alcohols and heteroaryl alcohols. In addition, the methodology was applied in a straightforward protocol to synthesize commercially available fragrances such as Rosaphen and Cyclamenaldehyde in good yields.

Full text of DOI:10.1021/acs.joc.8b01558

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Article
Ru-Catalyzed Cross-Dehydrogenative Coupling between Primary Alcohols
to Guerbet Alcohol Derivatives - with Relevance for Fragrance Synthesis
Seetharaman Manojveer, Saleh Salahi, Ola F Wendt, and Magnus T Johnson
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Aug 2018
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Ru-Catalyzed Cross-Dehydrogenative Coupling between Primary Alcohols to Guerbet
Alcohol Derivatives - with Relevance for Fragrance Synthesis
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Seetharaman Manojveer*†, Saleh Salahi†‡, Ola F. Wendt† and Magnus T. Johnson*†
† Centre for Analysis and Synthesis, Department of Chemistry
Lund University, P.O. Box 124
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SEꢀ22100 Lund, Sweden
‡ School of Chemistry, College of Science, University of
Tehran, P.O. Box 14155 6455, Tehran, Iran
Eꢀmail: magnus.johnson@chem.lu.se
Table of content
Ru(PPh3)3Cl2 (2 mol%)
HO
KOtBu (1 equiv.)
n
R1
R2
OH
OH
n
R2
R1
Toluene, reflux
1
2
3
24 h
n = 1, 2, 3
R1 = Aryl, heteroaryl R2 = Aryl
alkyl heteroaryl
23 examples
56-87% yields
O
OH
H
Rosaphen
Cyclamenaldehyde
57% in two steps
56% in one step
ABSTRACT
A simple method has been developed for the cross dehydrogenative coupling between
two different primary alcohols using readily available RuCl2(PPh3)3 as a precatalyst through
the borrowingꢀhydrogen approach. The present methodology is applicable to a large variety
of alcohol derivatives including long chain aliphatic alcohols and heteroaryl alcohols. In
addition, the methodology was applied in a straightforward protocol to synthesize
commercially available fragrances such as Rosaphen and Cyclamenaldehyde in good yields.
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INTRODUCTION
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The conversion of readily available and highly abundant alcohol derivatives to value
added products under hydrogenꢀborrowing conditions has become an increasingly important
concept in transition metal catalysis.1 Classically, it is known as the Guerbet reaction which
involves the conversion of primary alcohols into the corresponding βꢀalkylated dimeric
alcohol with loss of water as the sole byproduct.2 A wide variety of catalytic methods has
been developed for the activation of alcohols using different transition metals in the last
decades involving catalytic hydrogen transfer. The vast majority have concerned the direct
alkylation of ketones1c and amines using alcohols as a coupling partner.1e The coupling
between secondary and primary alcohols is significantly less frequent, but attracting
increased interest.3 In addition, the acceptorless dehydrogenative coupling (ADC) between
alcohols to give esters is well known.4 Recently, we5 and the Obora6 group reported the
completely deoxygenative coupling of 2ꢀarylethanol derivatives using ruthenium and iridium
catalysts, respectively. Surprisingly, the selective cross coupling between two different
primary alcohols such as aryl ethanol and benzylic alcohol derivatives is relatively
underexplored. Beller,7 Obora8 and Xu9 have developed a method for alkylation of 2ꢀ
phenylethanol using methanol as a coupling partner.
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Scheme 1: Cross alkylation involving two primary alcohols.
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To the best of our knowledge, only two reports are available for the cross aldol
reaction between aryl ethanol and aryl methanol derivatives to produce Guerbet alcohols
through the borrowingꢀhydrogen strategy. Ramón and coꢀworkers developed a method for
cross alkylation of primary alcohols using recyclable impregnated iridium oxide on magnetite
as a catalyst under heterogeneous conditions (Scheme 1, eq. 1).10 The cross dehydrogenative
coupling between two different primary alcohols to α,βꢀunsaturated aldehydes through in situ
formation of enolates using a ruthenium catalyst, silicaꢀgrafted amine and crotononitrile as a
hydrogen acceptor was demonstrated by Porcheddu et al. under microwave conditions
(Scheme 1, eq. 2).11 Herein, we present a simple protocol for the heterocoupling between aryl
ethanol and benzyl alcohol derivatives using readily available RuCl2(PPh3)3 catalyst under
mild and convenient reaction conditions (Scheme 1, eq. 3). Linear, cyclic and heterocyclic
alcohols could be used in the present method to prepare a wide variety of Guerbet alcohol
derivatives. This eventually led us to develop an operationally simple method for the
synthesis of Rosaphen and Cyclamenaldehyde fragrances.
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RESULTS AND DISCUSSION
The reaction between 2ꢀphenylethanol 1a and benzyl alcohol 2a under the previously
reported reaction conditions for [Ru]ꢀcatalysed fully deoxygenative coupling of arylethanols5
were chosen as a model reaction for optimization studies. We obtained both the heteroꢀ 3a
and homoꢀ 4a products in 45% and 32% yields respectively (table 1, entry 1). The yields of
products 3a and 4a respectively, were improved when the base was changed to KOtBu (entry
2). Selectivity towards the heterocoupled alcohol 3a was enhanced in the presence of a
stoichiometric amount of base (entry 3). For the more selective formation of the cross aldol
product, we turned our attention to increase both catalyst and benzyl alcohol amounts (entries
4ꢀ6). Selectivity towards the heterocoupled product was achieved when the reaction was
conducted in the presence of 2.0 mol% of Ru(PPh3)3Cl2, 3.0 equivalents of benzyl alcohol
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and 1.0 equivalents of KOtBu in toluene for 24 h refluxing at 120 °C (entry 6). As expected,
the selective crossꢀcoupling product was obtained, compared to when not using the benzyl
alcohols which produces the homoꢀcoupled net decarbonylative phenylethanol.5 Then, the
reaction was tested with other Ruꢀcatalysts (entries 7 and 8), and Wilkinson’s catalyst (entry
9). Different Feꢀsalts (entries 10ꢀ16) were also evaluated and the results were inferior to
RuCl2(PPh3)3 under otherwise identical reaction conditions.
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Table 1. Optimization study
S. No. Catalyst (mol%)
Base (equiv.)
2a (equiv.)
Yield (%)a
3a
4a
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17
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RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (1)
RuCl2(PPh3)3 (2)
RuHCl(CO)(PPh3)3 (2)
NaOtBu (0.6)
KOtBu (0.6)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
1.5
1.5
1.5
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
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59
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66
83
91 (84)
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[Ru(pꢀcyemene)Cl2]2 (2) KOtBu (1.0)
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RhCl(PPh3)3 (2)
FeCl3.6H2O (5)
FeCl2.4H2O (5)
Fe(acac)3 (5)
FeBr2 (5)
Fe(OTf)2 (5)
Fe(BF4)2 (5)
Ferrocene
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
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a. GC yield. Values in parentheses refers to isolated yield.
Having established the optimized reaction conditions in Table 1, entry 6, we decided
to investigate the substrate scope and results are shown in Figure 1. A wide variety of aryl
substituted ethanol derivatives 1 and benzyl alcohol derivatives 2 underwent selective cross
coupling reaction to afford the corresponding alcohol derivatives 3 in good yields. Steric
effects influence the outcome of the reaction. For instance, para substituted aryl ethanol (2ꢀ
(pꢀtolyl)ethanol) 1b gave the alcohol derivative (3b) with benzyl alcohol in 87% yield
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whereas ortho substituted aryl ethanol derivative (2ꢀ(oꢀtolyl)ethanol) (1d) furnished the
corresponding alcohol derivative (3d) in 72% yield. Methoxyꢀsubstituted alcohol derivatives
3e and 3f are obtained in 83% and 81% yields respectively under the standard reaction
conditions. Cl, Br and F substituted aryl ethanol derivatives gave the respective cross aldol
products (3gꢀ3k) in good yields. Based on the current results, there is no significant electronic
effect as the isolated yields remain within the 70ꢀ80% range when varying the substituents.
To our delight, the furan moiety tolerated the present reaction conditions and products 3l and
3m were obtained in 71% and 76% yields respectively. As expected, sulfur functional groups
appeared to act as a catalyst poisons, though product 3n was obtained in 55% yield,
indicating that the thiophene group was tolerated under these reaction conditions. In addition,
both thiopheneꢀ and furanꢀcontaining
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Figure
1.
Substrate Scope
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compounds as 3o could be prepared in 68% yield using the method. Interestingly, the
method is not restricted to 2ꢀaryl ethanol derivatives, as also aliphatic alcohol derivatives
such as 2ꢀcyclohexyl ethanol underwent selective cross aldol reaction with 2a to give 3p in
78% yield. Moreover, 80% of naphthyl substituted alcohol product 3q was obtained under the
optimized conditions. The reaction of 1a was carried out in 5.0 mmol scale and we obtained
the desired product 3a in 79% yield along with 7% of 4a under the present reaction
conditions.
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Unfortunately, the reaction of 1a with 2ꢀpyridinemethanol 2e did not work to get the
product 3r and we observed only trace amounts of 2e along with unreacted starting material
1a in GCꢀ and GCꢀMS analysis. It should be pointed out that the < 5% yield of the homoꢀ
coupled product was observed in GCꢀanalysis from the reaction of aryl ethanol derivatives.
Ru(PPh3)3Cl2 (2 mol%)
HO
OH
KOtBu (1 equiv.)
OH
Toluene, reflux
24 h
1m
2a
3s, 64%
Ru(PPh3)3Cl2 (2 mol%)
HO
KOtBu (1 equiv.)
OH
OH
OH
Toluene, reflux
24 h
3t, 61%
1n
2a
2a
Ru(PPh3)3Cl2 (2 mol%)
HO
KOtBu (1 equiv.)
OH
Toluene, reflux
24 h
3u, 75%
1o
HO
Ru(PPh3)3Cl2 (2 mol%)
OH
KOtBu (1 equiv.)
OH
Toluene, reflux
24 h
1p
3v, 69%
2a
Scheme 2: The crossꢀcoupling between propanol and butanol derivatives.
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The applicability of these reaction conditions can be extended to other primary
alcohols as shown in the Scheme 2. Aliphatic alcohols such as 1ꢀpropanol 1m and 1ꢀbutanol
1n underwent cross dehydrogenative coupling with benzyl alcohol 2a and afforded the
corresponding products 3s and 3t in 64% and 61% yields, respectively. Similarly, under the
optimized reaction conditions ωꢀphenyl substituted propanol 1o and butanol 1p reacted with
benzyl alcohol to give alcohol derivatives 3u and 3v in 75% and 69% yields respectively.
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In order to show the applicability of our methodology, the present reaction conditions
were used as a key step for the preparation of the commercially available fragrances
Rosaphen and Cyclamenaledehyde from highly stable and abundant alcohol derivatives in
good yields (Scheme 3). In general, the preparation method for these fragrances involves the
condensation of the corresponding aldehydes followed by hydrogenation.12, Rosaphen
(Symrise) has been used in body lotions, shampoos, detergents and soaps as rose blossom
odour.12 The coupling of 3ꢀphenylpropanꢀ1ꢀol 1o with excess amount of 1ꢀpropanol
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Scheme 3: Synthesis of Rosaphen and Cyclamenaldehyde fragrances.
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1m resulted in 56% yield of Rosaphen 3w in single step. Similarly, cyclamenaledehyde 5 can
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be synthesized in two steps. First the cross coupling between two alcohols such as 1ꢀ
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propanol 1m and 4ꢀisopropylbenzyl alcohol (Cumic alcohol) 2f was performed to produce
compound 3x in 71% yield under the present reaction conditions. Using DessꢀMartin
periodinane,14 compound 3x was oxidized to cyclamenaledehyde 5 in 81% yield.15 The
overall yield for the preparation of cyclamenaledehyde in two steps is 57%.
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Scheme 4: Plausible mechanism
A plausible mechanism for the cross coupling between two primary alcohols has been
shown in the scheme 4. Initially, alcohols 1 and 2 would undergo dehydrogenation in the
presence of Ru(PPh3)3Cl2 and base to give the respective aldehydes A and B. Base promoted
aldol condensation would take place between aldehydes A and B to afford an intermediate C
which subsequently undergoes hydrogenation reaction to give the final Guerbet alcohol
derivative 3 in the presence of Ruꢀcatalyst.
CONCLUSIONS
In summary, we have developed a simple method for the cross dehydrogenative
coupling between two different primary alcohol using readily available RuCl2(PPh3)3 catalyst
through the borrowingꢀhydrogen approach which leads to different fragrance analogues. The
present methodology is applicable to a large variety of alcohol derivatives including long
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chain aliphatic alcohols and heteroaryl alcohols. In addition, we have shown a
straightforward protocol to synthesize commercially available fragrances such as Rosaphen
and Cyclamenaldehyde in good yields. The development of corresponding asymmetric
version and further studies in this line are currently underway in our laboratory.
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EXPERIMENTAL SECTION:
General information: All experiments were carried out under an atmosphere of argon or
nitrogen using standard Schlenk or high vacuum line techniques unless otherwise noted.
Unless stated otherwise, commercially available reagents were purchased from Sigma
Aldrich or Acros Organics and used as received. NMRꢀspectra were recorded on Bruker
Avance 400 MHz spectrometers. Multiplicities are abbreviated as follows: (s) singlet, (d)
doublet, (t) triplet, (q) quartet, (m) multiplet, (b) broad. IR spectra were recorded on a Bruker
Alpha spectrometer, with diamond ATR–FT IR detection. Gas chromatographic analyses
(GC) were made using a Hewlettꢀ Packard 5890 II instrument with a flame ionization
detector (FID) and a capillary column (CPꢀSil 19CB 14% cyanopropylꢀphenyl/86%
dimethylpolysiloxane, 0.2 ꢁm, 0.2 mm, 25 m) with decane or dodecane as an internal
standard. The retention times of different compounds in the gas chromatogram were
identified using commercially available and synthesized pure compounds.
General procedure for [Ru]-Catalysis: Substituted ethanol 1 (1.0 equiv.) and benzyl
alcohol 2 (3.0 equiv.) derivatives were charged into a solution of Ru(PPh3)3Cl2 (2.0 mol%)
and KOtBu (1.0 equiv.) in toluene (3 mL/mmol.) at room temperature. After refluxing the
reaction mixture for 24 h at 120 °C, water was added and the compound was extracted using
EtOAc. Then, the crude was purified by column chromatography (silica gel, hexanes/EtOAc)
to furnish the pure compound 3.
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2,3ꢀDiphenylpropanꢀ1ꢀol (3a):10 It was obtained as a yellow oil in 84% yield (137 mg). H
NMR (400 MHz, CDCl3): δ 7.35ꢀ7.31 (m, 2H), 7.27ꢀ7.21 (m, 5H), 7.19ꢀ7.17 (m, 1H), 7.12ꢀ
7.10 (m, 2H), 3.80ꢀ3.78 (m, 2H), 3.14ꢀ2.90 (m, 3H), 1.47 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 141.9, 139.9, 129.0, 128.6, 128.2, 128.0, 126.8, 126.0, 66.3, 50.1, 38.6.
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3ꢀPhenylꢀ2ꢀ(pꢀtolyl)propanꢀ1ꢀol (3b): It was obtained as a yellow oil in 87% yield (113 mg).
Rf = 0.3 (in 10% EtOAc/Hexanes); IR (neat): 3355, 3024, 2920, 2862, 1603, 1513, 1495,
1
1453, 1378, 1183, 1113, 1018, 650, 910, 811, 751, 721, 697, 594 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 7.40ꢀ7.36 (m, 2H), 7.33ꢀ7.24 (m, 7H), 3.94ꢀ3.86 (m, 2H), 3.25ꢀ3.02 (m, 3H), 2.48
(s, 3H), 1.56 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 140.0, 138.7, 136.3, 129.3, 129.0,
128.2, 127.9, 125.9, 66.4, 49.7, 38.7, 21.0. HRMS (ESIꢀTOF): [M+NH4]+ Calcd for
C16H22NO 244.1701; Found 244.1706.
3ꢀPhenylꢀ2ꢀ(mꢀtolyl)propanꢀ1ꢀol (3c): It was obtained as a yellow oil in 82% yield (133 mg).
IR (neat): 1H NMR (400 MHz, CDCl 3 ): δ 7.26ꢀ7.23 (m, 3H), 7.20ꢀ7.17 (m, 1H), 7.13ꢀ7.11
(m, 2H), 7.07ꢀ7.04 (m, 3H), 3.78ꢀ3.76 (m, 2H), 3.10ꢀ2.98, (m, 2H), 2.95ꢀ2.90 (m, 1H), 2.34
13
(s, 3H), 1.32 (br s, 1H); C NMR (100 MHz, CDCl 3 ): δ 141.8, 140.0, 138.2, 129.0, 128.8,
128.5, 128.2, 127.6, 126.0, 125.0, 66.3, 50.0, 38.7, 21.5. HRMS (ESIꢀTOF): [M+NH4]+ Calcd
for C16H22NO 244.1701; Found 244.1701.
3ꢀPhenylꢀ2ꢀ(oꢀtolyl)propanꢀ1ꢀol (3d): It was obtained as a yellow oil in 72% yield (110 mg).
Rf = 0.3 (in 10% EtOAc/Hexanes); IR (neat) 3324, 3027, 2921, 1494, 1453, 1380, 1206,
1014, 727, 695, 594 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 7.6 Hz, 1H), 7.25ꢀ7.21
(m, 2H), 7.19ꢀ7.17 (m, 1H), 7.14ꢀ7.12 (m, 2H), 7.09ꢀ7.07 (m, 2H), 3.81 (d, J = 6.4 Hz, 2H),
3.44 (quint, J = 7.2 Hz, 1H), 3.03 (dd, J = 13.2, 7.2 Hz, 1H), 2.86 (dd, J = 13.2, 7.2 Hz, 1H),
2.18 (s, 3H), 1.38 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 140.0, 137.0, 130.5, 129.0,
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128.2, 126.4, 126.3, 126.00, 125.97, 65.9, 44.8, 38.9, 19.7. HRMS (ESIꢀTOF): [M+NH4]+
Calcd for C16H22NO 244.1701; Found 244.1704.
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2ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3e):10 It was obtained as a yellow oil in 83%
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yield (162 mg). H NMR (400 MHz, CDCl3): δ 7.25ꢀ7.21 (m, 2H), 7.17 (d J = 7.6 Hz, 1H),
7.13 (d, J = 8.8 Hz, 2H), 7.10ꢀ7.08 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.77ꢀ3.71
(m, 2H), 3.070ꢀ2.98 (m, 2H), 2.90ꢀ2.85 (m, 1H), 1.42 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 158.4. 140.0. 133.7, 129.02, 128.97, 128.2, 125.9, 114.0, 66.4, 55.2, 49.3, 38.8.
3ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀphenylpropanꢀ1ꢀol (3f):10 It was obtained as a yellow oil in 81%
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yield (103 mg). H NMR (400 MHz, CDCl3): δ 7.34 (t, J = 6.8 Hz, 2H), 7.28ꢀ7.27 (m, 1H),
7.24ꢀ7.22 (m, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 3.81ꢀ3.79 (m, 2H), 3.79
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(s, 3H), 3.11ꢀ2.85 (m, 3H), 1.61 (br s, 1H); C NMR (100 MHz, CDCl3): δ 157.8, 142.0,
131.9, 129.9, 128.5, 128.0, 126.7, 113.6, 66.2, 55.1, 50.3, 37.7.
2ꢀ(4ꢀChlorophenyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3g):10 It was obtained as a yellow oil in 81% yield
(128 mg). 1H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.21 (m, 4H), 7.19ꢀ7.16 (m, 1H), 7.13 (d, J =
8.4 Hz, 2H), 7.08ꢀ7.06 (m, 2H), 3.80ꢀ8.74 (m, 2H), 3.12ꢀ3.01 (m, 2H), 2.88ꢀ2.83 (m, 1H),
1.34 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 140.4, 139.4, 132.5, 129.4, 129.0, 128.7,
126.1, 66.2, 49.6, 38.6.
2ꢀ(2ꢀChlorophenyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3h):10 It was obtained as a yellow oil in 61% yield
(101 mg). 1H NMR (400 MHz, CDCl3): δ 7.38 (dd, J = 8.0, 1.2 Hz, 1H), 7.34 (dd, J = 7.6, 1.6
Hz, 1H), 7.28ꢀ7.24 (m, 3H), 7.21ꢀ7.15 (m, 4H), 3.83ꢀ3.74 (m, 3H), 3.07 (dd, J = 14.0, 8.0 Hz,
1H), 2.97 (dd, J = 14.0, 6.8 Hz, 1H), 1.40 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 139.5,
139.4, 134.6, 129.8, 129.0, 128.3, 127.7, 126.9, 126.1, 64.5, 45.1, 37.6.
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3ꢀ(4ꢀChlorophenyl)ꢀ2ꢀphenylpropanꢀ1ꢀol (3i):10 It was obtained as a yellow oil in 63% yield
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(102 mg). H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.30 (m, 2H), 7.25ꢀ7.23 (m, 1H), 7.18ꢀ7.16
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(m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 3.79 (d, J = 6.0 Hz, 2H), 3.07ꢀ3.02 (m, 2H), 2.89ꢀ2.83 (m,
1H), 1.48 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 141.3, 138.3, 131.7, 130.4, 128.7,
128.3, 128.1, 127.0, 66.3, 50.1, 37.9.
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2ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3j):10 It was obtained as a yellow oil in 72% yield
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(83 mg). H NMR (400 MHz, CDCl3): δ H NMR (400 MHz, CDCl3): δ 7.42 (d J = 8.4 Hz,
2H), 7.25ꢀ7.21 (m, 2H), 7.18ꢀ7.16 (m, 1H), 7.08ꢀ7.05 (m, 4H), 3.82ꢀ3.74 (m, 2H), 3.10ꢀ300
(m, 2H), 2.89ꢀ2.83 (m, 1H), 1.35 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 140.9, 139.4,
131.6, 129.8, 129.0, 128.3, 126.1, 120.6, 66.1, 49.6, 38.5.
2ꢀ(4ꢀFluorophenyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3k): It was obtained as a yellow oil in 83% yield
(136 mg). Rf = 0.2 (in 10% EtOAc/Hexanes); IR (neat) 3358, 3027, 2924, 1603, 1508, 1453,
1301, 1221, 1065, 1028, 1014, 830, 753, 721, 691, 593 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ
7.26ꢀ7.21 (m, 2H), 7.19ꢀ7.14 (m, 3H), 7.08ꢀ7.06 (m, 2H), 6.99 (t, J = 8.4 Hz, 2H), 3.82ꢀ3.73
(m, 2H), 3.12ꢀ3.01 (m, 2H), 2.88ꢀ2.83 (m, 1H), 1.43 (br s, 1H); 13C NMR (100 MHz, CDCl3):
δ 161.7 (d, J = 243.0 Hz), 139.6, 137.5 (d, J = 4.0 Hz), 129.5, 129.4, 129.0, 128.2, 126.1,
115.3 (d, J = 21.0 Hz), 66.3, 49.4, 38.8. HRMS (ESIꢀTOF): [M+HCO2]ꢀ Calcd for C16H16FO3
275.1083; Found 275.1083.
3ꢀ(Furanꢀ2ꢀyl)ꢀ2ꢀphenylpropanꢀ1ꢀol (3l): It was obtained as a yellow oil in 71% yield (101
mg). Rf = 0.35 (in 10% EtOAc/Hexanes); IR (neat): 3362, 3028, 2924, 1599, 1505, 1494,
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1452, 1241, 1145, 1060, 1007, 884, 802, 731, 697, 598, 536. H NMR (400 MHz, CDCl3): δ
7.39ꢀ7.34 (m, 2H), 7.32 (dd, J = 2.0, 0.8 Hz, 1H), 7.31ꢀ7.25 (m, 3H), 6.27 (dd, J = 3.2, 2.0
Hz, 1H), 5.95 (dd, J = 3.2, 0.8 Hz, 1H), 3.87ꢀ3.79 (m, 2H), 3.25 (p, J = 6.8 Hz, 1H), 3.14ꢀ
2.97 (m, 2H), 1.56 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 153.7, 141.6, 141.0, 128.7,
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128.6, 128.3, 127.8, 126.9, 110.1, 106.3, 66.4, 47.2, 30.7. HRMS (ESIꢀTOF): [M+H]+ Calcd
for C13H15O2 203.1072; Found 203.1077.
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3ꢀ(Furanꢀ2ꢀyl)ꢀ2ꢀ(pꢀtolyl)propanꢀ1ꢀol (3m): It was obtained as a yellow oil in 61% yield (101
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mg). Rf = 0.3 (in 10% EtOAc/Hexanes); IR (neat) 3395, 2921, 1721, 1596, 1514, 1240, 1145,
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1059, 1006, 931, 812, 727, 598, 535 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.29 (dd, J = 2.0,
1.2 Hz, 1H), 7.15ꢀ7.10 (m, 4H), 6.23 (dd, J = 3.2, 2.0 Hz, 1H), 5.91 (dd, J = 3.2, 0.8 Hz, 1H),
3.81ꢀ3.73 (m, 2H), 3.18 (quint, J = 7.2 Hz, 1H), 3.05 (dd, J = 15.2, 7.6 Hz, 1H), 2.94 (dd, J =
15.6, 7.6 Hz, 1H), 2.33 (s, 3H), 1..46 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 153.9,
141.0, 138.4, 136.5, 129.3, 127.7, 110.1, 106.3, 66.5, 46.8, 30.8, 21.0. HRMS (ESIꢀTOF):
[M+H]+ Calcd for C14H17O2 217.1229; Found 217.1233.
3ꢀPhenylꢀ2ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀol (3n): It was obtained as a pale brown oil in 55% yield
(93 mg). Rf = 0.35 (in 10% EtOAc/Hexanes); IR (neat): 3331, 3027, 2925, 2872, 1495, 1453,
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1241, 1205, 1064, 1021, 911, 847, 740, 693, 594. H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.24
(m, 2H), 7.21ꢀ7.19 (m, 2H), 7.15ꢀ7.13 (m, 2H), 6.95 (dd, J = 5.2, 3.6 Hz, 1H), 6.84 (dq, J =
3.2, 0.8 Hz, 1H), 3.81ꢀ3.70 (m, 2H), 3.44ꢀ3.37 (m, 1H), 3.09ꢀ2.94 (m, 2H), 1.52 (br s, 1H);
13C NMR (100 MHz, CDCl3): δ 145.3, 139.4, 129.0, 128.3, 126.8, 126.2, 124.9, 123.8, 66.5,
45.6, 39.6. HRMS (ESIꢀTOF): [M+H]+ Calcd for C13H15SO 219.0844; Found 219.0850.
3ꢀ(Furanꢀ2ꢀyl)ꢀ2ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀol (3o): It was obtained as a yellow oil in 68%
yield (112 mg). Rf = 0.3 (in 10% EtOAc/Hexanes); IR (neat) 3419, 3010, 2926, 1596, 1506,
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1438, 1215, 1147, 1064, 1039, 1007, 827, 903, 747, 666, 598 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 7.31 (dd, J = 1.6, 0.8 Hz, 1H), 7.19 (dd, J = 5.2, 1.2 Hz, 1H), 6.96 (dd, J = 5.2, 3.6
Hz, 1H), 6.88 (dq, J = 6.0, 0.8 Hz, 1H), 6.26 (dd, J = 3.2, 2.0 Hz, 1H), 5.99 (dd, J = 3.2, 0.8
Hz, 1H), 3.82ꢀ3.72 (m, 2H), 3.52 (quint, J = 7.2 Hz, 1H), 3.13ꢀ2.98 (m, 2H), 1.73 (br s, 1H);
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13C NMR (100 MHz, CDCl3): δ 153.1, 144.8, 141.2, 126.8, 124.7, 123.8, 110.2, 106.7, 66.5,
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42.8, 31.8. HRMS (ESIꢀTOF): [M+H]+ Calcd for C11H13SO2 209.0636; Found 209.0641.
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2ꢀCyclohexylꢀ3ꢀphenylpropanꢀ1ꢀol (3p): It was obtained as a yellow oil in 78% yield (131
mg). Rf = 0.35 (in 10% EtOAc/Hexanes); IR (neat) 3616, 2920, 1558, 1496, 1206, 1079,
1037, 1014, 975, 954, 799, 696, 639, 593, 573, 561, 543, 524, 510 cmꢀ1; 1H NMR (400 MHz,
CDCl3): δ 7.30ꢀ7.27 (m, 2H), 7.21ꢀ7.17 (m, 3H), 3.56 (d, J = 5.6 Hz, 2H), 2.75 (dd, J = 13.6,
5.2 Hz, 1H), 2.53 (dd, J = 13.6, 9.2 Hz, 1H), 1.78ꢀ1.63 (m, 6H), 1.55ꢀ1.47 (m, 1H), 1.32ꢀ1.08
(m, 6H); 13C NMR (100 MHz, CDCl3): δ 141.6, 129.0, 128.3, 125.7, 62.7, 48.4, 38.3, 34.7,
30.2, 30.1, 26.8, 26.73, 26.69. HRMS (ESIꢀTOF): [M+NH4]+ Calcd for C15H26NO 236.2014;
Found 236.2018.
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2ꢀ(Naphthalenꢀ2ꢀyl)ꢀ3ꢀphenylpropanꢀ1ꢀol (3q): It was obtained as a yellow oil in 80% yield
(92 mg). Rf = 0.25 (in 10% EtOAc/Hexanes); IR (neat) 3350, 3053, 3024, 2923, 1600, 1507,
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1495, 1264, 1179, 1028, 1018, 962, 946, 891, 815, 735, 697, 659, 622, 590, 563 cmꢀ1; H
NMR (400 MHz, CDCl3): δ 7.83ꢀ7.78 (m, 3H), 7.66 (s, 1H), 7.48ꢀ7.45 (m, 2H), 7.38 (dd, J =
8.8, 2.0 Hz, 1H), 7.24ꢀ7.20 (m, 2H), 7.17ꢀ7.12 (m, 3H), 3.88 (t, J = 5.6 Hz, 2H), 3.28 (quint,
J = 7.2 Hz, 1H), 3.16ꢀ3.01 (m, 2H), 1.36 (t, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
139.8, 139.3, 133.5, 132.5, 129.0, 128.35, 128.27, 127.64, 127.60, 126.9, 126.10, 126.06,
126.04, 125.6, 66.3, 50.3, 38.6. HRMS (ESIꢀTOF): [M+NH4]+ Calcd for C19H22NO
280.1701; Found 280.1705.
2ꢀMethylꢀ3ꢀphenylpropanꢀ1ꢀol (3s):9 It was obtained as a colorless oil in 63% yield (112 mg).
1H NMR (400 MHz, CDCl3): δ 7.31ꢀ7.28 (m, 2H), 7.22ꢀ7.18 (m, 3H), 3.56ꢀ3.46 (m, 2H),
2.77 (dd, J = 13.2, 6.0 Hz, 1H), 2.43 (dd, J = 13.2, 8.0 Hz, 1H), 2.00ꢀ1.91 (m, 1H), 1.60 (br s,
1H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 140.6, 129.1, 128.2, 125.8,
67.6, 39.7, 37.7, 16.4.
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2ꢀBenzylbutanꢀ1ꢀol (3t):10 It was obtained as a colorless oil in 61% yield (96 mg). H NMR
(400 MHz, CDCl3): δ 7.32ꢀ7.28 (m, 2H), 7.22ꢀ7.19 (m, 3H), 3.55 (d, J = 5.6 Hz, 2H), 2.70ꢀ
2.60 (m, 2H), 1.79ꢀ1.70 (m, 1H), 1.57 (br s, 1H), 1.47ꢀ1.34 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 140.8, 129.1, 128.2, 125.8, 64.4, 44.1, 37.2, 23.2, 11.2.
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2ꢀBenzylꢀ3ꢀphenylpropanꢀ1ꢀol (3u):16 It was obtained as a colorless oil in 75% yield (113
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mg). H NMR (400 MHz, CDCl3): δ 7.33ꢀ7.29 (m, 4H), 7.24ꢀ7.19 (m, 6H), 3.51 (d, J = 4.8
Hz, 2H), 2.75ꢀ2.65 (m, 4H), 2.17ꢀ2.13 (m, 1H), 1.39 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 140.5, 129.1, 128.3, 125.9, 63.9, 44.5, 37.4.
2ꢀBenzylꢀ4ꢀphenylbutanꢀ1ꢀol (3v):17 It was obtained as a colorless oil in 69% yield (110 mg).
1H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.27 (m, 4H), 7.23ꢀ7.16 (m, 6H), 3.62ꢀ3.54 (m, 2H),
2.71 (d, J = 7.2 Hz, 2H), 2.69ꢀ2.61 (m, 2H), 1.90ꢀ1.84 (m, 1H), 1.76ꢀ1.62 (m, 2H), 1.36 (br s,
1H); 13C NMR (100 MHz, CDCl3): δ 142.3, 140.5, 129.1, 128.32, 128.30, 125.9, 125.7, 64.7,
42.0, 37.5, 33.2.
2ꢀMethylꢀ5ꢀphenylpentanꢀ1ꢀol (3w):18 It was obtained as a colorless oil in 56% yield (66 mg).
1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.28 (m, 2H), 7.19ꢀ7.17 (m, 3H), 3.50 (dd, J = 10.4, 6.0
Hz, 1H), 3.42 (dd, J = 10.4, 6.4 Hz, 1H), 2.63ꢀ2.58 (m, 2H), 1.68ꢀ1.62 (m ,3H), 1.49ꢀ1.42 (m,
3H), 1.25 (br s, 1H), 1.21ꢀ1.16 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 142.6, 128.4, 128.3, 125.7, 68.3, 36.2, 35.7, 32.8, 28.9, 16.5.
3ꢀ(4ꢀIsopropylphenyl)ꢀ2ꢀmethylpropanꢀ1ꢀol (3x):15 It was obtained as a colorless oil in 71%
yield (160 mg). 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz,
2H), 3.54 (dd, J = 10.8, 6.0 Hz, 1H), 3.47 (dd, J = 10.8, 6.0 Hz, 1H), 2.88 (quin, J = 7.2 Hz,
1H), 2.71 (dd, J = 13.6, 6.8 Hz, 1H), 2.41 (dd, J = 13.2, 7.6 Hz, 1H), 1.98 ꢀ1.90 (m, 1H), 1.24
(d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 146.4, 137.8,
129.0, 126.3, 67.7, 39.3, 37.8, 33.7, 24.0, 16.6.
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3ꢀ(4ꢀIsopropylphenyl)ꢀ2ꢀmethylpropanal (5):15 It was obtained as a colorless oil in 81% yield
(44 mg) by oxidation of 3x using DessꢀMartin reagent.14 1H NMR (400 MHz, CDCl3): δ 9.72
(d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.06 (dd, J = 13.6, 5.6
Hz, 1H), 2.88 (quin, J = 6.8 Hz, 1H), 2.69ꢀ2.24 (m, 1H), 2.58 (dd, J = 1.32, 8.0 Hz, 1H), 1.24
(d, J = 6.8 Hz, 6H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 204.6, 146.9,
136.0, 128.9, 126.5, 48.0, 36.2, 33.7, 24.0, 13.2.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
containing GCꢀFID calibration curves and 1Hꢀ and 13CꢀNMR spectra..
AUTHOR INFORMATION
Corresponding Author
* Email: magnus.johnson@chem.lu.se
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support by the Olle Engkvist Byggmästare foundation, the Royal Swedish
Academy of Forestry and Agriculture, the Magnus Bergvall Foundation and the Royal
Physiographic Society in Lund and the Science and Engineering Research Board (DST),
India, SB/OS/PDFꢀ004/2015ꢀ16 (SM) is gratefully acknowledged.
REFERENCES
1. Selected recent reviews on borrowingꢀhydrogen method, see: (a) Corma, A.; Navas,
J.; Sabater, M. J. Advances in OneꢀPot Synthesis through Borrowing Hydrogen
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Catalysis. Chem. Rev. 2018, 118, 1410ꢀ1459 and references cited therein. (b)
Chelucci, G. Ruthenium and Osmium Complexes in CꢀC bondꢀforming Reactions by
Borrowing Hydrogen Catalysis. Coord. Chem. Rev. 2017, 331, 1ꢀ36. (c) Huang, F.;
Liu, Z. Q.; Yu, Z. K. CꢀAlkylation of Ketones and Related Compounds by Alcohols:
TransitionꢀMetalꢀCatalyzed Dehydrogenation. Angew. Chem. Int. Ed. 2016, 55, 862ꢀ
875. (d) Gunanathan, C.; Milstein, D. Applications of Acceptorless Dehydrogenation
and Related Transformations in Chemical Synthesis. Science 2013, 341, 1229712. (e)
Bähn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller, M. The Catalytic
Amination of Alcohols. ChemCatChem 2011, 3, 1853ꢀ1864.
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2. (a) Matsuꢀura, T.; Sakaguchi, S.; Obora, Y.; Ishi, Y. Guerbet Reaction of Primary
Alcohols Leading to βꢀAlkylated Dimer Alcohols Catalyzed by Iridium Complexes. J.
Org. Chem. 2006, 71, 8306ꢀ8308. (b) Gregorio, G.; Pregaglia, G. F.; Ugo, R.
Condensation of Alcohols Catalysed by Tertiary Phosphine Transition Metal
Complexes. J. Organometal. Chem. 1972, 37, 385ꢀ387. (c) Veibel, S.; Nielsen, J. I.
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