Synthesis of α-Alkylated Ketones via Selective Epoxide Opening/Alkylation Reactions with Primary Alcohols

Alkylation Reactions with Primary Alcohols

Letter

Synthesis of α‑Alkylated Ketones via Selective Epoxide Opening/

Sertac ̧ Genc ,̧ S uleyman Gulcemal, Salih Gunnaz, Bekir C ̧etinkaya, and Derya Gulcemal*

̈ ̈ ̈ ̈

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sı Supporting Information

ABSTRACT: A new method for converting terminal epoxides and primary

alcohols into α-alkylated ketones under borrowing hydrogen conditions is

reported. The procedure involves a one-pot epoxide ring opening and alkylation

via primary alcohols in the presence of an N-heterocyclic carbene iridium(I)

catalyst, under aerobic conditions, with water as the side product.

etones are versatile key intermediates that are widely used

Scheme 1. Catalytic Methods for the Synthesis of α-

Alkylated Ketones and Selective Ring Opening of Epoxides

in the organic synthesis of valuable pharmaceutical

compounds, polymers, and natural products. Of the numerous

protocols for synthesizing α- or β-alkylated ketones, the

transition-metal (TM)-catalyzed alkylation of ketones or

secondary alcohols with alcohols through a borrowing

hydrogen (BH) methodology has recently attracted a great

deal of interest over conventional alkylation methods. The use

of readily available and inexpensive alcohols as both alkylating

agents and hydrogen sources in the BH strategy oﬀers a

greener and more sustainable alternative to conventional

alkylating methods, avoiding the use of mutagenic alkyl halides

or excessive amounts of a strong base. In this context,

alkylation of ketones or secondary alcohols with alcohols for

the synthesis of α- or β-alkylated ketones using various

−6

precious (Ru, Rh, Pd, and Ir) and nonprecious (Ti, Mn, Fe,

−12

Co, Ni, and Cu)

a).

Epoxides are useful intermediates that can be transformed

into various valuable organic molecules through ring opening

TM catalysts has been reported (Scheme

reactions. One of the well-known epoxide ring opening

reactions is their acid-catalyzed isomerization into aldehydes

and/or ketones, usually termed the Meinwald rearrangement

Scheme 1b). In the case of terminal epoxides, correspond-

ing aldehydes are formed as the major product.

tional methods for reductive ring opening of epoxides in the

presence of either a stoichiometric amount or an excess of

(

strong reducing reagents (MBH , where M = Li, Na, or K)

13e,14b,15

Inverse

result in the selective formation of secondary alcohols.

Heterogeneous Pd and Pt catalysts were also studied for

hydrogenation or transfer hydrogenation of epoxides, where

selectivity from the nucleophilic ring opening of terminal

epoxides into the corresponding methyl ketones has also been

reported in the presence of TM catalysts, Lewis acidic (LA)

metal catalysts, or the nucleophilic organic base DABCO.

Received: May 26, 2021

Published: June 18, 2021

Another important approach to the transformation of epoxides

is reductive ring opening reactions to produce industrially

valuable primary and/or secondary alcohols (Scheme 1c).

13a−d

The major challenge in this transformation is the control of

regioselectivity into anti-Markovnikov selective primary

alcohols or Markovnikov selective secondary alcohols. Tradi-

2021 American Chemical Society

229

Org. Lett. 2021, 23, 5229−5234

Organic Letters

Reaction conditions: 1a (0.6 −1 mmol), 2a (0.5 mmol), catalyst (1 −

Letter

primary alcohols are the major product from aryl epoxides and

secondary alcohols are the major product from alkyl epoxides.

Table 1. Optimization of the Reaction Conditions

Recently, homogeneous catalysis-enabled hydrogenation,

hydrosilylation, and hydroborylation of epoxides have

been reported for the selective formation of primary alcohols.

In contrast, Markovnikov selective secondary alcohols were

yield (%)

obtained by Ru-catalyzed hydrogenation and Mg-catalyzed

catalyst

1a:2a

(mmol)

time

(h)

hydroboration of terminal epoxides.

entry

(mol %)

solvent

3a 3′a

Recently, the superior catalytic activities of [IrCl(cod)-

Ir-1 (1)

Ir-1 (2)

Ir-2 (2)

Ir-3 (2)

Ir-2 (2)

−

PhMe

dioxane

1:0.5

−

(

NHC)] (cod = 1,5-cyclooctadiene) complexes for the

6d 6d,e

selective α-alkylation of ketones, secondary alcohols,

t-AmOH

t -AmOH

25a

nitriles, and β-alkylation of secondary alcohols by primary

alcohols have been reported by our group. With this in mind,

we decided to explore whether these NHC−Ir catalysts would

enable the one-pot selective ring opening of terminal epoxides,

leading to either ketones or secondary alcohols, and alkylation

by primary alcohols for the synthesis of α-alkylated ketones

through a BH methodology. We report an eﬃcient NHC−Ir-

based catalytic system that enables selective ring opening and

alkylation of terminal epoxides with primary alcohols to the

corresponding ketones (Scheme 1d). This catalytic system uses

primary alcohols as both the hydrogen source and the

alkylating agent and liberates water as the only byproduct

under aerobic conditions.

−

1:0.5

0.75:0.5

0.6:0.5

Ir-2 (2)

−

Initially, the reaction of styrene oxide (1 mmol) with benzyl

alcohol (0.5 mmol) was selected as the benchmark experiment

to probe the potential of the previously prepared Ir-1 complex

as the catalyst, which is one of the most active NHC-based

catalysts for the transfer hydrogenation of carbonyl com-

mol %), Cs CO (10 mol %), solvent (1 mL), 140 °C (oil bath

pounds. The progress of the reaction was monitored by H

NMR spectroscopy, and the yields are based on 1,3,5-

trimethoxybenzene as an internal standard (Table 1). The

reaction was performed in the presence of the Ir-1 catalyst (1

mol %) and Cs CO (10 mol %) in diﬀerent solvents (1 mL)

temperature), open to air. NMR yields were determined from H

NMR analysis of the crude reaction mixture using 1,3,5-trimethox-

ybenzene as the internal standard. KOH (10 mol %) used as the

base. NaOH (10 mol %) used as the base. KO Bu (10 mol %) used

as the base. Without a base. The reaction was performed under an

argon atmosphere.

at 140 °C (maintained by an oil bath) for 20 h while open to

air (Table 1, entries 1−3). Using tert-amyl alcohol as the

solvent gave a better yield and exclusively resulted in ketone

product 3a in 57% NMR yield (entry 3). Increasing the

catalyst loading to 2 mol % (entry 4) resulted in a higher yield

of 3a (88%) along with a smaller amount of over-reduced

alcohol 3′a (5%). Replacing Cs CO with KOH, NaOH, or

ing ketones (3n−q) were isolated in moderate yields (38−

51%) when heteroaromatic or aliphatic primary alcohols were

tested. The reaction of 2.4 equiv of styrene oxide with 1,4-

phenylene dimethanol in the presence of 4 mol % catalyst and

20 mol % Cs CO gave corresponding diketone product 3r in a

60% yield. Finally, the reaction of styrene oxide with 2-

aminobenzyl alcohol provided 2-phenylquinoline (3s) in 27%

isolated yield.

KO Bu (entries 5−7) did not improve the activity.

Furthermore, decreasing the amount of styrene oxide (1a) to

either 0.75 or 0.6 mmol resulted in slightly lower yields (entry

or 9, respectively). Upon replacement of the NHC ligand in

the [IrCl(cod)(NHC)] complex with IMes (Ir-2) or IPr (Ir-3)

entry 10 or 11, respectively), better outcomes were achieved,

The reactions of benzyl alcohol with -Me-, -OMe-, -Cl-, -Br-,

(

or -CF -substituted styrene oxides and 2-(naphthalen-2-

with a 98% NMR yield (92% isolated yield) of product 3a

obtained with [IrCl(cod)(IMes)] (Ir-2) as the catalyst.

Additionally, when the reaction time was decreased to 16 h

yl)oxirane were robust, and the corresponding ketones 3t−y

were isolated with moderate to good yields (30−88%).

However, under similar conditions, when aliphatic 1,2-

epoxydodecane was reacted with benzyl alcohol, the formation

of a corresponding product 3z was detected in the reaction

(

entry 12), the activity was maintained. Control experiments

entries 13 and 14) demonstrated that both the catalyst and

the base are essential to the reaction. Finally, using inert

conditions did not improve the yield of the reaction (entry 15).

We next examined the scope of the reaction (Scheme 2).

First, styrene oxide (1a) was reacted with various primary

alcohols (2) under the optimized reaction conditions (Table 1,

entry 12). The reaction of 1a with a variety of electron-

mixture with a 32% yield determined by H NMR analysis

together with a number of other undesired side products. This

was probably due to more than one reactive α-carbon existing

in the molecule. Unfortunately, we failed to isolate 3z from the

complex reaction mixture.

The one-pot sequential epoxide opening/alkylation reaction

for the selective synthesis of β-alkylated alcohol product 3′a

upon addition of 2-propanol as an external hydrogen source at

a speciﬁed point during the reaction (Scheme 3) resulted in a

94% yield of the desired product. Similarly, dialkylated ketone

product 4a was also obtained in 48% yield upon addition of 1

donating and electron-withdrawing para- or ortho-substituted

benzyl alcohols having -Me, -OMe, - Pr, -Cl, -Br, -CF , or

NMe₂groups, 2-naphthalene methanol, and ferrocene

methanol aﬀorded a range of ketone products (3b−m) with

good to excellent isolated yields (52−96%). The correspond-

230

Org. Lett. 2021, 23, 5229−5234

Organic Letters

Letter

Scheme 2. Scope of the NHC−Ir-Catalyzed Regioselective

equiv of benzyl alcohol and 0.5 equiv of KOH, together with 1

mL of toluene, to the reaction mixture under the standard

conditions.

Ring Opening and Alkylation of Terminal Epoxides

We investigated the time proﬁle of the reaction between

styrene oxide and 4-methoxybenzyl alcohol (2c) under the

optimized conditions by performing individual experiments

over diﬀerent reaction times to understand the mechanism of

the reaction (Figure S1). The results showed that an induction

period is required in the early stages of the reaction (4%

conversion to 3c after 1 h) most probably due to

decoordination of Cl from [IrCl(cod)(IMes)] in the presence

of the base to generate the transient [Ir(cod)(IMes)]

intermediate and formation of iridium alkoxo species with

c. Subsequently, the complete conversion of the starting

materials to 3c (89% yield) and over-reduced alcohol 3′c (4%

yield) was observed over a period of 16 h in total. No

accumulation of the intermediate chalcone was observed

during the course of the reaction, suggesting the rapid

hydrogenation of chalcone. In addition, acetophenone, 1-

phenylethanol, and 4-methoxybenzaldehyde were detected

during the reaction; however, their individual abundances

never exceeded 5%.

Several control experiments were performed to gain insight

into the mechanism (Scheme 4). As noted previously, the

Scheme 4. Control Experiments

Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), Ir-2 (2 mol %),

Cs CO (0.05 mmol, 10 mol %), t-AmOH (1 mL), 140 °C (oil bath

temperature), 16 h, open to air. Isolated yields. 1 (1.2 mmol), Ir-2 (4

mol %), and Cs CO (0.1 mmol, 20 mol %) were used. The yield

was determined from H NMR analysis of the crude reaction mixture

using 1,3,5-trimethoxybenzene as the internal standard.

Scheme 3. Synthesis of β-Alkylated Alcohols and α,α-

Dialkylated Ketones

Standard conditions: Ir-2 (2 mol %), Cs CO (0.05 mmol, 10 mol

), t-AmOH (1 mL), 140 °C (oil bath temperature), 16 h, open to

air. H NMR yields based on 1,3,5-trimethoxybenzene as the internal

standard. GC conversion. NMR conversion.

selective ring opening of epoxides can result in the formation

of either ketones (5) or secondary alcohols (5′) (Scheme 1b,c)

and NHC−Ir-catalyzed alkylation of these species with

primary alcohols will allow the synthesis of α-alkylated ketones

(Scheme 1a). To prove that 5 and 5′ are indeed the reaction

intermediates, control experiments were conducted using 1b as

the starting material under standard conditions (eq 1a) and in

the presence of an additional hydrogen source (0.5 mL of 2-

propanol, eq 1b). In the absence of a hydrogen source,

Reaction conditions: (a) (1) standard conditions (Table 1, entry 12)

and then (2) IPA (0.5 mL), 6 h (isolated yield); (b) (1) standard

conditions (Table 1, entry 12) and then (2) 2a (0.5 mmol), KOH

(0.25 mmol), PhMe (1 mL), 16 h (isolated yield).

231

Org. Lett. 2021, 23, 5229−5234

Organic Letters

5100 Bornova, Izmir, Turkey; orcid.org/0000-0002-

Letter

Experimental details and traces of H and ¹³C NMR

spectra (PDF)

isomerization product 5b was obtained in only 17% (eq 1a),

while under transfer hydrogenation conditions, the corre-

sponding hydrogenation product 5′b was obtained in 79%

yield (eq 1b). This result demonstrates the importance of the

hydrogen source (primary alcohol in the case of the current

protocol) in the selective epoxide ring opening step.

Dehydrogenation of possible intermediates 5′a and 3′a was

also conﬁrmed by independent control experiments under the

standard conditions, wherein these secondary alcohols were

dehydrogenated to their corresponding ketones, 5a (86%) and

AUTHOR INFORMATION

Corresponding Author

■

Derya Gu

lcemal − Ege University, Chemistry Department,

565-5508 ; Email: derya.gulcemal@ege.edu.tr

Authors

3a (62%), respectively (eqs 2 and 3). In addition, the reaction

Sertaç Genç − Ege University, Chemistry Department, 35100

of acetophenone with benzyl alcohol gave the desired product

Bornova, Izmir, Turkey; orcid.org/0000-0003-1856-

075

leyman Gu

5100 Bornova, Izmir, Turkey; orcid.org/0000-0003-

2738-3219

Salih Gunnaz − Ege University, Chemistry Department, 35100

Bornova, Izmir, Turkey; orcid.org/0000-0002-7422-

593

Bekir C

a in 98% yield after just 4 h (eq 5). Similarly, the reaction of

-phenylethanol with benzaldehyde under optimized con-

lcemal − Ege University, Chemistry Department,

ditions provided alkylated product 3a in 84% yield (eq 6).

On the basis of the experimental evidence presented herein,

and our previous report, a catalytic cycle for the reaction is

proposed in Scheme 5. The mechanism involves the Ir-

Scheme 5. Proposed Mechanism

etinkaya − Ege University, Chemistry Department,

5100 Bornova, Izmir, Turkey; orcid.org/0000-0002-

551-8650

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01765

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

This work was supported by TUBITAK (120Z818) and Ege

University Scientiﬁc Research Projects Coordination (FDK-

■

021-22946). B.Ç. acknowledges the Turkish Academy of

Science (TUBA) for the ﬁnancial support. The authors also

thank the Ege University Directorate of Library and

Documentation, EGE-PIK, and Enago for providing editing

services.

catalyzed dehydrogenation of a primary alcohol (2) to an

aldehyde (6) and isomerization/transfer hydrogenation of a

terminal epoxide to a ketone (5) or secondary alcohol (5′)

[

which can also undergo dehydrogenation to form the ketone

5)]. The low conversion of the epoxide to the isomerization

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ASSOCIATED CONTENT

■

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