Tandem Cross Coupling Reaction of Alcohols for Sustainable Synthesis of β-Alkylated Secondary Alcohols and Flavan Derivatives

Article abstract of DOI:10.1002/adsc.201700722

A Ru(II) NHC complex (loading down to 0.001 mol%) catalyzed cross coupling of a broad range of aromatic, aliphatic and heterocyclic alcohols is reported. This protocol also functioned efficiently under solvent-free conditions. Remarkably, this catalytic system disclosed so far the highest TON of 288000 for the cross coupling of alcohols. Notably, this methodology was successfully applied for the one-pot synthesis of a range of flavan derivatives. A detailed DFT studies and kinetic experiments were performed to understand the reaction mechanism as well as the high reactivity of this catalytic system. (Figure presented.).

Full text of DOI:10.1002/adsc.201700722

Title: Tandem Cross Coupling Reaction of Alcohols for Sustainable
Synthesis of β-Alkylated Secondary Alcohols and Flavan
Derivatives
Authors: Sujan Shee, Bhaskar Paul, Dibyajyoti Panja, Bivas Chandra
Roy, Kaushik Chakrabarti, Kasturi Ganguli, Ayan Das, Gourab
Kanti Das, and Sabuj Kundu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700722
Link to VoR: http://dx.doi.org/10.1002/adsc.201700722

10.1002/adsc.201700722
Advanced Synthesis & Catalysis
COMMUNICATION
Tandem Cross Coupling Reaction of Alcohols for Sustainable
Synthesis of β-Alkylated Secondary Alcohols and Flavan
Derivatives
Sujan Shee,† Bhaskar Paul,† Dibyajyoti Panja,† Bivas Chandra Roy,† Kaushik Chakrabarti,† Kasturi
Ganguli,† Ayan Das,† Gourab Kanti Das,§ and Sabuj Kundu*†
Abstract: A Ru(II) NHC complex (loading down to 0.001 mol%)
catalyzed cross coupling of a broad range of aromatic, aliphatic and
heterocyclic alcohols is reported. This protocol also functioned
efficiently under solvent-free conditions. Remarkably, this catalytic
system disclosed so far the highest TON of 288000 for the cross
coupling of alcohols. Notably, this methodology was successfully
applied for the one-pot synthesis of a range of flavan derivatives. A
detailed DFT studies and kinetic experiments were performed to
understand the reaction mechanism as well as the high reactivity of
this catalytic system.
base catalyzed systems were also been explored.[11]
Unfortunately, poor selectivity, higher catalyst loading and
requirements of excess of one of the coupling partners made
these systems less effective.
Recently, some efforts have been devoted for the
improvement of these catalytic systems however, so far these
protocols allowed to reduce the catalyst loadings only up to 0.1-
1.0 mol% for the expensive Ir or Ru metal based complexes.
This is the biggest hurdle for any practical application and to
utilize this methodology in fine chemical industry. Therefore, to
construct a new C-C bond by employing alcohols as an
alkylating agents, more efficient catalytic system is undoubtedly
indispensable.
Transition metal catalyzed construction of C-C and C-N bond is
one of the most vital reaction in organic synthesis.[1] Among the
numerous protocols, to form these bonds, metal mediated
utilization of alcohols as electrophiles or alkylating agents has
recently received significant attention.[2] This methodology is
more viable and greener over the traditional multistep
transformations which generate stoichiometric amount of toxic
salt waste.[3]
Cho group first reported Ru catalyzed tandem β-alkylation
of secondary alcohols in 2003 in presence of excess hydrogen
acceptors.[4] Later on, several reports were emerged employing
Ir, Rh, Ru and Pd based complexes for the same reaction
following the hydrogen auto-transfer or hydrogen borrowing
methodology.[5] Compare with the previously reported literatures,
synthetically more effective C-C bond formation using alcohols
was reported by Crabtree group by using tridentate NNN pincer
Ir(III) and Ru(II) complexes.[6] Recently, Ru(III) catalyzed similar
transformation was demonstrated by Yu group.[7] Iridium
complexes bearing 6,6ʹ-dihydroxy-2,2ʹ-bipyridine and N-
heterocyclic carbene (NHC) were also effective for the formation
of C-C bond as depicted by Li and Perez-Torrente groups
respectively.[8] Ru(NHC)2 catalyzed α-alkylation of ketones
following the borrowing hydrogen strategy was lately conveyed
by Glorius groups though, the catalyst loading was high (2
mol%).[9] Bifunctional Ru(II) complex catalyzed synthesis of β-
alkylated secondary alcohols was recently reported by our group
which displayed the highest reactivity compared to all the
reported transition metal complexes.[10] Substituting these noble
metals based catalysts with Fe, Ni and Cu and as well as only
Scheme 1. Strategies for the synthesis of β-alkylated secondary alcohols
following hydrogen borrowing methodology.
Recently, we synthesized various 1,10•phenanthroline based
NNN and NNC Ru(II) complexes and found that phenanthroline
supported Ru(II)-NHC complexes were more active compare to
phenanthroline-pyridine containing Ru(II) complexes in transfer
hydrogenation of ketones and nitroarenes.[12] Inspired by the
work from Glorius and Perez-Torrente groups using Ru(NHC)2
and Ir(NHC) complexes respectively in cross coupling reaction
of alcohols, we envisioned that our Ru(II)-NHC complexes may
also have the potential to catalyze the β-alkylation of secondary
alcohols. As a part of our continuous effort in transforming
alcohols to alkylating agents herein, we report highly active Ru-
NHC catalyzed (catalyst loading down to 0.001 mol%) cross
coupling reaction of various alcohols in toluene and also under
solvent-free conditions. Notably, this methodology can be
successfully applied for the one-pot synthesis of bioactive flavan
based natural products.
[†]
S. Shee, B. Paul, D. Panja, B. C. Roy, K. Chakrabarti, K. Ganguli, A.
Das, Dr. S. Kundu
At first, 1-phenylethanol and benzyl alcohol were selected
as benchmark substrates to screen the tandem β-alkylation
reaction using 0.01 mol% catalyst, 0.4 equiv. NaOiPr in toluene
under reflux condition (SI S5-A). Common Ru(II) precursors
such as RuCl2(PPh3)3 and RuHCl(CO)(PPh3)3 showed poor
Department of Chemistry
Indian Institute of Technology Kanpur
Kanpur 208016, India
E-mail: sabuj@iitk.ac.in
[§]
Dr. G. K. Das
yields of 1,3-diphenylpropanol (3aa). Next,
a series of
Department of Chemistry
Visva Bharati University
Santiniketan, West Bengal 731235, India
phenanthroline based NHC and pyridine containing NNC and
NNN pincer Ru(II) complexes were tested for this reaction which
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10.1002/adsc.201700722
Advanced Synthesis & Catalysis
COMMUNICATION
furnished significant improvement of the desired product.
Interestingly, both NNC and NNN Ru(II) complexes bearing
hexafluorophosphate as counter anion exhibited superior results
over their chloride analog. Among them, complex A containing a
optimized condition, 1-tetralinol, 1-(naphthalen-2-yl)ethanol and
1-(1,3-benzodioxol-5-yl)ethanol were successfully converted to
the corresponding β-alkylated products in 85-96% yields with
high selectivity. Challenging substrates such as aliphatic
branched or long chain secondary alcohols, 3-pyridylethanol and
1-cyclopropylethanol were also effectively coupled with benzyl
alcohol by using 0.05 mol% catalyst within 4-6 h (3m-pa).
Subsequently, this methodology was successfully employed in
tandem double alkylation of cyclopentanol by using 0.1 mol% of
complex A. Different substituted bis-alkylated products (3qa-k)
were obtained in good to excellent yields. Remarkably, β-
alkylation of various secondary alcohols were successfully
carried out within 12 h using 0.001 mol% complex A (SI S5-D).
mesityl group as
a
wingtip substituent demonstrated
exceptionally high catalytic activity for this reaction, yielded 3aa
quantitatively. Without any Ru(II) complex conversion of 1-
phenylethanol was only 6% (SI S5-A, entry 16). To optimize the
reaction, several bases were screened and NaOiPr displayed
the best result (SI S5-B).
Scheme 2. β-Alkylation of 1-phenylethanol with various primary alcohols. 1H
NMR yields (isolated yields). [a] Cat 0.1 mol%; [b] 6 h; [c] Cat. 0.02 mol%, 6 h;
[d] Cat. 0.001 mol%, 12 h.
Next, β-alkylation of 1-phenylethanol with variety of
different primary alcohols were carried out to expand the
applicability of this methodology (Scheme 2). Para- and meta-
substituted benzyl alcohols smoothly delivered the expected
coupled alcohols in excellent yields (3ab-f, 3ai) however, for
ortho- substituted benzyl alcohols either higher catalyst loading
or longer reaction time was required probably due to steric factor
(3ag, 3ah). Moreover, 1-naphthylmethanol and 3,4-
(methylenedioxy)benzyl alcohol could also be converted to the
alkylated alcohols in good yields. Heteroaromatic 2-
furanmethanol and 2-thiophenemethanol also effectively
afforded the corresponding alcohols (3al, 3am) in 71-81% yields.
Especially, this protocol was successfully applied in β-alkylation
of 1-phenylethanol with challenging substrates such as
cyclohexylmethanol (2n) and long chain primary alcohols (2o,
2p) which selectively afforded the corresponding alcohols by
using 0.02 mol% catalyst after 6 h. To make this process
practically viable, the loading of the complex A was reduced to
0.001 mol% which remarkably resulted the formation of 3aa in
99% yield after 12 h (SI S5-A, entry 11). Subsequently, many of
these β-alkylation of 1-phenylethanol reactions were screened
by using 0.001 mol% of complex A which afforded the desired
products in good to excellent yields within 12 h (SI S5-D).
Scheme 3. β-Alkylation of various secondary alcohols with benzyl alcohol. 1H
NMR yields (isolated yields). [a] Cat. 0.05 mol%, 6 h; [b] Cat. 0.05 mol%, 4 h;
[c] Cat. 0.001 mol%, 12 h. For cyclopentanol Cat. (0.1 mol%), primary alcohol
(1.05 mmol), cyclopentanol (0.5 mmol), NaOiPr (0.5 mmol), 12 h, isolated
yields.
Additionally, following this protocol preparative scale reactions
also proceeded smoothly (Scheme 4). To our delight, for the
cross coupling of 1-phenylethanol with benzyl alcohol, this
system disclosed extraordinarily high TON of 288000 after 24 h
by using 0.00016 mol% complex A (SI S2). To best of our
knowledge, this is the highest TON reported so far in literature
for the cross coupling of alcohols.
Afterward, complex A catalyzed cross coupling of benzyl
alcohol and a number of secondary alcohols was carried out
(Scheme 3). 1-Phenylethanol bearing both the electron
withdrawing and donating groups in the para- and meta-
positions were selectively delivered the corresponding β-
benzylated alcohols in excellent yields (3b-ga). Under the
Scheme 4. Preparative scale reaction. Cat. (0.001 mol%), primary alcohol (20
mmol), secondary alcohol (20 mmol), NaOiPr (8 mmol), 12 h, isolated yields.
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10.1002/adsc.201700722
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COMMUNICATION
Solvent-free reactions have substantial environmental and
of various alcohols under solvent-free conditions were also
industrial relevance. Hence, complex A catalyzed cross coupling
Scheme 6. Calculated Gibbs free energies and enthalpies (kcal/mol) for the–alkylation of 1-phenylethanol with benzyl alcohol.
explored and it also selectively produced the corresponding β-
alkylated secondary alcohols efficiently even with 0.001 mol%
catalyst (SI S5-E, F).
functionalized flavans using combination of Pd and Cu
catalysts.[16] However, multistep synthesis, longer reaction time,
poor yields and harsh reaction conditions made these protocols
less attractive. Hence, we were motivated to develop efficient
greener route for the synthesis of flavan derivatives (Scheme 5).
Notably, a variety of flavan derivatives (4a-4h) were synthesized
from commercially available alcohols in one-pot fashion using
complex A and CuI/2,2'-bipyridine.[17] Under the optimized
reaction conditions, they were isolated in moderate to excellent
yields (68-90%). Among them 4h is a naturally occurring
compound found in Ageratum conyzoides plants.[18]
Based on the experimental studies (SI S7) and previous
literature reports [5c, 5j] we proposed a plausible catalytic cycle (SI
S8 - Scheme 2) for the β-alkylation of secondary alcohol which
was further supported by DFT calculations (Scheme 6). Initially,
the Ru complex (A) was converted to the alkoxo complex (I1)
through base assisted ligand substitution, from which
dissociation of acetonitrile generated the corresponding
pentacoordinated intermediate I2. Next, β-hydrogen elimination
via TS1 afforded the ruthenium hydride species (I3) and the
corresponding carbonyl compound. Subsequently, aldol
condensation between the resulting aldehydes and ketones
produced the α,β-unsaturated ketones. Notably, in comparison
to the other reported systems, energy barrier for the β-hydrogen
elimination in this process was significantly lower.[8a] Afterward,
there were two functional groups for the hydrogenation either,
the C=C or the C=O bond of the aldol product. Alkene bound
intermediate (I4) was found to be 8.16 kcal/mol higher in energy
compare to the ketone coordinated complex (I4ʹ). However, the
Scheme 5. One-pot synthesis of flavan derivatives. Isolated product yields.
A practical application of this methodology was further validated
by one-pot synthesis of several flavan derivatives from simple
alcohols. The flavan structural core are widely present in various
flavonoid natural products which exhibited numerous biological
and pharmacological activities.[13] There are several routes to
synthesize the flavan derivatives.[14] Among them Chen group
reported tosylhydrazine mediated transformation of 2-hydroxyl
chalcones to 2-arylchromans.[15] Satyanarayana group
developed
a
three-step strategy for the synthesis of
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10.1002/adsc.201700722
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COMMUNICATION
was evaporated under reduced pressure. Under argon
atmosphere, 2-bromo substituted primary alcohol (0.5 mmol),
secondary alcohol (0.5 mmol) and NaOH (10 mg, 0.25 mmol)
and 1.5 mL toluene were added in the tube. The reaction
calculated activation energy barrier for the C=C bond
hydrogenation was much lower (2.38 kcal/mol; TS2) than the
C=O bond (20.43 kcal/mol, TS2ʹ). Based on these data, we
could conclude that the alkene insertion into the Ru-H (I3) was
more favored. Lower barrier for the C=O bond hydrogenation
(4.70 kcal/mol, TS3) improvised the greater selectivity for the
alcohol product which was consistent with the experimental
results. Briefly, the lower activation energy barriers for the
dehydrogenation of alcohols as well as hydrogenation of the α,β-
unsaturated ketones signified the higher efficiency and
selectivity of this catalytic system.
In summary, we demonstrated a highly active Ru(II)-NHC
catalyzed β-alkylation of secondary alcohols and double
alkylation of cyclopentanol with different primary alcohols
following the hydrogen borrowing methodology. A large variety
of aromatic, aliphatic and heterocyclic alcohols were cross
coupled efficiently using significantly lower catalyst loading
(down to 0.001 mol%). This efficient, atom economical and
greener strategy enables straightforward access to a variety of
β-alkylated secondary alcohols with high selectivity using solvent
as well as under neat conditions. Importantly, this catalytic
system revealed exceptionally high TON of 288000 which is the
highest among all the reported transition metal complexes in
cross coupling of alcohols. Notably, utilizing this sustainable
protocol biologically active flavan derivatives were synthesized
in one-pot manner in good to excellent yields. Furthermore the
proposed mechanism was supported by detailed DFT
calculations and kinetic experiments.
°
mixture was heated at 125 C for 6 h. Then the reaction mixture
was cooled under argon atmosphere. After that, CuI (20 mol%),
2,2ʹ-bipyridine (20 mol%), NaOH (60 mg, 1.5 mmol) and another
1 mL toluene were added to the same tube and heated further
°
for 24 h (oil bath temperature: 125 C). Then tube was cooled
and reaction mixture was quenched with aqueous NH4Cl
solution. Next, dichloromethane was added to the reaction
mixture and the organic layer was separated. This process was
repeated three times (3×12 mL) and the combined organic
phase was dried over anhydrous Na2SO4. Then the solvent was
removed under reduced pressure. The corresponding flavan
derivatives were isolated through silica gel column
chromatography using hexane/ethyl acetate as eluent. The final
products were authenticated by NMR, GC-MS and ESI-MS
analysis.
Acknowledgements
We are grateful to Science and Engineering Research Board
(SERB), India and Council of Scientific & Industrial Research
(CSIR) and DST-INSPIRE for financial support. S.S., B.C.R.
thank CSIR India, B.P., K.C. thank UGC India, D.P., K.G. thank
IITK for fellowship.
Keywords: alkylation • ruthenium • sustainable synthesis •
tandem process
Experimental Section
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General Procedure for β-Alkylation of Secondary
Alcohols with Primary Alcohols
A catalytic stock solution was prepared by dissolving complex A
(6 mg, 8.24×10-3 mmol) in 4 mL acetonitrile. Then required
amount of the stock solution (0.01 mol%) was taken in a Schlenk
tube, equipped with a magnetic stir bar and acetonitrile was
evaporated under reduced pressure. Next, secondary alcohol
(0.5 mmol), primary alcohol (0.5 mmol; for double alkylation of
cyclopentanol, 1.05 mmol), NaOiPr (0.20 mmol and 0.5 mmol for
cyclopentanol) and 1.5 mL toluene were taken in the tube under
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°
argon atmosphere. After that, the tube was heated at 125 C (oil
bath temperature) for 3 h (12 h for double alkylation of
cyclopentanol). After immediate cooling, 10 µL solution was
syringed out for GC analysis (mesitylene was used as internal
standard). 0.25 mL reaction mixture was concentrated under
reduced pressure and the crude residue was subjected for 1H
NMR. The conversion and product selectivity were calculated
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COMMUNICATION
A Ru catalyzed cross coupling of
alcohols is reported with highest TON
288000. Proposed mechanism is
supported by DFT calculations and
kinetic experiments.
Sujan Shee,† Bhaskar Paul,† Dibyajyoti
Panja,† Bivas Chandra Roy,† Kaushik
Chakrabarti,† Kasturi Ganguli,† Ayan
Das,† Gourab Kanti Das,§ and Sabuj
Kundu*†
Page No. – Page No.
Tandem Cross Coupling Reaction of
Alcohols for Sustainable Synthesis of
β-Alkylated Secondary Alcohols and
Flavan Derivatives
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