Tandem Regioselective Hydroformylation-Hydrogenation of Internal Alkynes Using a Supramolecular Catalyst

Article abstract of DOI:10.1002/anie.201809073

New supramolecular ligands containing an acyl guanidine function were designed based on the strategy of increasing the π-acceptor ability of phosphine ligands by introducing electron-withdrawing groups. By applying this novel catalytic system, a general protocol for the Rh-catalysed hydroformylation-hydrogenation of unsymmetrical internal alkynes, functionalized with a carboxylic acid, was found to furnish aliphatic aldehydes in high regio- and chemoselectivities. Control experiments confirm the enzyme-like supramolecular catalyst mode of action.

Full text of DOI:10.1002/anie.201809073

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Accepted Article
Title: Tandem Regioselective Hydroformylation-Hydrogenation of
Internal Alkynes employing a Supramolecular Catalyst
Authors: Bernhard Breit and Weiwei Fang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809073
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10.1002/anie.201809073
Angewandte Chemie International Edition
COMMUNICATION
Tandem Regioselective Hydroformylation-Hydrogenation of
Internal Alkynes employing a Supramolecular Catalyst
Weiwei Fang,[a] and Bernhard Breit*[a]
Abstract: New supramolecular ligands containing an acyl guanidine
function were designed based on the strategy of increasing the π-
acceptor ability of phosphine ligands by introducing electron-
withdrawing groups. By applying this novel catalytic system, a
poor phosphine ligands equipped with an acyl guanidine
functionality. Using this new supramolecular catalyst system,
tandem Rh-catalyzed HF-hydrogenation of unsymmetrical
internal alkynes functionalized with carboxylic acid was realized
in high regio- and chemoselectivity providing facile access to
aliphatic aldehydes (Scheme 1b).
general
protocol
for
the
Rh-catalyzed
hydroformylation-
hydrogenation of unsymmetrical internal alkynes functionalized with
a carboxylic acid was expounded furnishing aliphatic aldehydes in
high regio- and chemoselectivities. Control experiments are provided
that prove the enzyme-like supramolecular catalyst mode of action.
a previous work
O
O
[Rh]/Ligand
CO/H2
CHO
O
HO
HO
Ph2P
N
R
R
N
NH2
NH2
Natural enzymes efficiently combine molecular recognition and
catalysis in one functional assembly, which offers significantly
higher rate constants and selectivities than corresponding
bimolecular reactions due to the formation of enzyme-substrate
complexes resulting in a transition state stabilization.[1] Inspired
by this, supramolecular catalysis has been a long-term objective
for chemists, with the ultimate goal to construct catalytic systems
capable of mimicking natural enzymes.[2,3] Simple hydrogen
bonding interactions between the substrate and functional
groups of catalyst have shown to greatly improve the selectivity
of transition metal catalysis.[4-9] In this context we recently
R = H : regioselectivity: 23:1, conversion: 100%
R = Me : regioselectivity: 11:1, conversion: 80%
b this work
CF3
CHO
[Rh]/Ligand
R1
R2
O
R1
R2
F3C
P
N
N
NH2
NH2
R
1 = CH2COOH, R2 = alkyl, aryl.
Excellent chemo- and regioselectivity (up
to 25:1)
F3C
CF3
Scheme 1. Rh-catalyzed HF-hydrogenation of unsymmetrical internal alkynes
using a supramolecular ligand
reported on acyl guanidinium-functionalized phosphines[5,6]
,
We commenced our investigation by designing new
phosphine ligands with enhanced π-acceptor ability.[11g] We
reckoned that the introduction of additional electron-withdrawing
groups such as CF3 and F to the aryl substituents at the
phosphine scaffold could enhance the coordination ability of the
catalyst to alkynes while simultaneously facilitating CO
dissociation, resulting in higher catalytic activity (Scheme 2a).
Moreover, the installation of the acyl guanidinium group (as a
recognition unit for carboxylic acid) in the meta position with
respect to the phosphine unit would allow for two-point binding
and thus conformational orientation of the substrate via
hydrogen bonding interactions.[5a]
exhibiting excellent activities and regioselectivities in the Rh-
catalyzed hydroformylation (HF) of vinylacetic acid[5a] and its
analogues[5b], which furnished aliphatic aldehydes in good
regioselectivities (Scheme 1a). However, limitations of this
catalyst system became apparent when we attempted to use
internal alkenes. Hence, only a methyl-substituted Z-configured
substrate could be utilized which sets narrow synthetic
limitations. Since a Z-configured alkene is generally obtained
from an internal alkyne through cis-hydrogenation employing a
Lindlar-type catalyst, we envisioned whether we could employ
internal alkynes directly. With an appropriate supramolecular
catalyst,
a
corresponding tandem regioselective HF-
hydrogenation might furnish the same type of products with a
largely extended substrate scope.
1)
2)
3)
O
O
Ar2P
N
Ar2P
N
Br
N
Br
Ar2P
N
Br
OH
HN
NH2
NBoc
In the past decades, the HF of unsymmetrical internal
alkynes has been widely neglected to date and only very few
examples were reported with rather low regioselectivity.[10] In
2013, we introduced a Rh/self-assembling ligand system for
chemoselective HF of symmetrical and terminal alkynes with
excellent stereoselectivity.[11g] Therefore, the design of new
types of phosphine ligands for highly regioselective HF of
unsymmetrical internal alkynes is a great challenge in this area
at current stage.
A1-3
B1-3
C1-3
4)
O
N
Ar2P
N
L1: Ar = 3',5'-bis(trifluoromethyl) phenyl
L2: Ar = 3',5'-difluoro phenyl
NH2
L3: Ar = 4'-trifluoromethyl phenyl
NH2
Scheme 2. Ligand synthesis: 1) nBuLi, -78 oC, DCM; Ar2PCl. 2) nBuLi, -78 oC,
DCM; CO2. 3) Boc-guanidine, N-methyl morphine, BOP, DMF and 4) TFA, 1,3-
dimethoxybenzene; Na2CO3.
In continuation of our long-standing research interests in
developing supramolecular concepts for homogeneous catalysis
[5,6,11], we herein report on new appropriately designed electron-
The general synthetic protocol for accessing the respective
ligands L1-3 is depicted in Scheme 2. Compounds A1-3 were
easily formed by coupling of the corresponding chloro
diarylphosphines with mono-lithiated 2,6-dibromopyridine.
Bromine lithium exchange of A1-3 followed by quenching with
CO2 furnished the carboxylic acids B1-3. The coupling reaction
between B1-3 and mono-Boc-protected guanidine led to C1-3.
[a] W. Fang, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg,
Germany
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201809073
Angewandte Chemie International Edition
COMMUNICATION
Subsequent deprotection and neutralization furnished pure
ligands L1-3 as colorless solids.
Table 1. Reaction optimization[a]
To evaluate catalytic performances of the new ligands in
regioselective HF-hydrogenation of unsymmetrical internal
alkynes, 3-pentynoic acid S1 was selected as a model substrate
o
(Table 1). When the reaction was performed in toluene at 55 C
Yields/%
(1a/1b/1c/1d)
Entry
L
A
Select.
1c/%
Ratio
(γ/β)
Conv.
/%
with 1 mol% of [Rh(CO)2acac] and 5 mol% of L1 under 6 bar of
CO/H2 (1:1), low conversion (11%) was obtained and an α,β-
unsaturated aldehyde 1a was obtained as the main product in
excellent regioselectivity (γ/β >25) (Entry 1). In consideration of
complete protonation of the acyl guanidinium function to incease
the hydrogen bonding interaction between the ligand and
substrate[6a], 5 mol% TsOH was added. Gladly, the conversion of
S1 increased to 79% and the main product was changed to the
aliphatic aldehyde 1c, however the ratio of γ/β decreased (Table
S1). Other solvents such as DCE, CH2Cl2 and THF were
examined with DCE providing the most promising result (Entry
2). Furthermore, the addition of acid co-catalysts showed a
significant effect on the reaction results: stronger acids such as
TFA and CSA led to 1c in a higher yield with excellent
regioselectivity (Entries 4 and 5), and similar results to that of
TsOH were obtained when TfOH, MsOH and PhSO3H were
used. Conversely, using much weaker acids such as AcOH and
H3PO4 only resulted in very poor results (Table S3). For
operational simplicity, crystalline CSA was chosen for further
optimization of reaction conditions. Decreasing the amount of
CSA from 5 to 2.5 mol% resulted in a lower conversion and
chemoselectivity of 1c (96% vs. 26%), but the regioselectivity
remained unaffected (γ/β >25, Table S4, for reaction
temperature effect see Table S5). The reaction time could be
shortened to 12 h with similar results (Entries 5 and 7). As
expected, the electron withdrawing groups of ligands showed a
significant effect on the activity and selectivity of the
supramolecular catalyst systems. L1 with the strongest electron
withdrawing ability proved to be the best ligand, which clearly
confirmed our initial strategy used in the ligand design (Entries
7-13). The parent diphenylphosphine-substituted ligand L5 did
not show any catalytic activity at all (Entry 11).
1[b]
2
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
\
10/<1/0/0
1/<1/87/11
36/<1/46/1
0/0/96/3
0/0/96(90)/4
1/2/72/22
0/<1/95(92)/4
3/1/5/2
0
>25
7
11
TsOH
TfOH
TFA
CSA
MsOH
CSA
CSA
CSA
CSA
CSA
CSA
CSA
85
53
96
96
68
95
20
8
99
3
>25
28
25
3
94
4
100
100
96
5
6
7[c]
8[c]
9[c]
10[c]
11[c]
12[c]
13[c]
22
3
100
35
1/1/1/1
2
11
0/0/0/0
0
\
84
0/0/0/0
0
\
12
0/0/0/0
0
\
44
0/0/0/0
0
\
34
[a] [Rh(CO)2acac]/L/additive/S1 = 1:5:5:100, c(S1) = 0.5 M, DCE (2 mL),
CO/H2 (1:1, 6 bar), 55 oC, 20 h. Yield was determined by NMR spectroscopy
using 1,3,5-trimethoxybenzene (TMB) as the internal standard and isolated
yield was shown in parentheses. Selectivity (Select.), ratio of γ/β
[n(a+c)/n(b+d)] and conversion (conv.) were determined by analysis of the
reaction mixture by NMR spectroscopy. [b] Toluene was used. [c] 12 h. DCE =
1,2-dichloroethane,
trifluoromethanesulfonic acid, CSA
methanesulfonic acid. PhSO3H = benzenesulfonic acid. AcOH = acetic acid
TsOH
=
p-toluenesulfonic
acid,
TfOH
=
=
=
camphorsulfonic acid, MsOH
With the optimized conditions in hand, we sought to examine
the general scope of the supramolecular catalytic protocol. As
shown in Table 2, a variety of unsymmetrical internal alkynes
underwent efficient HF-hydrogenation processes, affording
corresponding aliphatic aldehydes in good to excellent yields
with outstanding chemo- and regioselectivity. The chain length
of the R group (1c-6c) hardly affected the efficiency and
selectivity, and the desired aldehydes were obtained in 90-94%
yields with regioselectivity up to 25:1. However, a bulkier
followed by a double bond isomerization forming the butenolide,
which is structural key element of multitude of
pharmaceuticals.[13]
a
a
Next, we turned our attention to the HF-hydrogenation of
unsymmetrical internal aryl alkynes. For these substrates a
higher pressure of syngas (10 bar) was necessary to achieve
high yields and chemoselectivity. 4-Phenyl-3-butynoic acid S10
furnished the desired aldehyde 10c in 79% yield with good
chemo- and regioselectivity (95%, γ/β up to 25:1). For
substituted aryls, the relative position of the substituent on the
phenyl ring affected the chemoselectivity (11c vs. 12c and 13c),
but excellent regioselectivity was maintained throughout all
substitution patterns (γ/β up to 25:1). Substrates with electron
secondary
alkyl
substituent
decreased
chemo-
and
regioselectivity (2c vs. 7c) but still favored the formation of the γ-
product with a quite remarkable selectivity of 7:1. Substrates
with functional groups such as PMB ethers and even
unprotected hydroxyl groups were well tolerated and products
with good regioselectivity were observed, but in slightly lower
yield (8c and 9). Unexpectedly, when 6-hydroxy-3-hexynoic acid
S9 was used, the butenolide 9a’ was formed, which has shown
to have interesting hepatoprotective properties.[12] Its formation
might involve attack of the free hydroxyl group at the rhodium-
acyl intermediate
withdrawing groups (such
F
and CF3) revealed higher
chemoselectivity rather than those having an electron donating
group (OMe) (96% and 95% vs. 90%, 15c and 16c vs. 14c) and
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10.1002/anie.201809073
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COMMUNICATION
all displayed high γ-regioselectivity. Polyaromatic- and
heterocyclic substituents were also well tolerated (17c and 18c).
hardly affected the outcome of the reactions using ligand L8,
further indicating that CSA serves to protonate the guanidine
function.[6a] Similar to the result of L5, no formation of any
aldehydes was observed when using triphenylphospine (Table
S12). As expected, very inferior results were obtained when
MeOH was used as the solvent, because its presence would
disturb hydrogen bonding interaction of the ligand and substrate.
Under the same reaction condition, the L1-derived catalyst
showed no activity towards a terminal alkyne, 3-butynoic acid
S19 and similar results were also obtained using L8 (Table S12).
Lower activity and worse selectivity were found when 4-hexynoic
acid S20 and 5-heptynoic acid S21 were involved, which
indicated that the distance between the carboxylic acid
functionality and the reactive alkyne group has a dramatic
impact. Further evidence came from the fact that methyl ester
S22, lacking the complementary functionality, reacted slowly and
with low selectivity. Similar results were observed for the internal
aryl substrate S10 and its methyl ester S23 (Table S12), and it
provided a solid support that the substrate preorientation via the
hydrogen bonding interactions elegantly controlled the selectivity
and enhanced the activity of catalysts.
Table 2. Substrate scope.[a]
O
γ
O
R
β
Rh(CO)2acac, L1, CSA
R
HO
HO
H2/CO (1:1 6 bar or 10 bar)
DCE, 55 oC, 20 h
CHO
c
S
O
O
O
Me
CHO
nPr
Et
HO
HO
HO
CHO
CHO
1c
3c
2c
Conv. >99%
Yield: 90%
Select.: 96%
γ/β: >25:1
Conv. >99%
Yield: 90%
Select.: 95%
γ/β: 19:1
Conv. >99%
Yield: 94%
Select.: 99%
γ/β: >25:1
O
O
O
nPent
nHex
CHO
nBu
CHO
HO
HO
HO
CHO
4c
5c
6c
Conv. >99%
Yield: 92%
Select.: 94%
γ/β: 22:1
Conv. >99%
Yield: 90%
Select.: 97%
γ/β: >25:1
Conv. >99%
Yield: 90%
Select.: 94%
γ/β: >25:1
O
O
O
iPr
CHO
OPMB
HO
HO
HO
Table 3. Control experiments[a]
CHO
O
O
7c
8c
9a'
Conv. >99%
Yield: 65%
Select.: 85%
γ/β: 7:1
Conv. >99%
Yield: 77%
Select.: 93%
γ/β: 15:1
Conv. 100%
Yield: 65%
9a'/9c': 3:1
γ/β: >25:1
O
Yields/%
(a/b/c/d)
Select.
c/%
Ratio
(γ/β)
Conv.
/%
O
Entry
L
S
O
HO
HO
Me
HO
CHOMe
CHO
12c
CHO
1
L8
L8
L1
L1
L1
L1
L1
S1
4/11/0/0
10/10/1/1
3/2/0/0
0
<1
1
1
\
23
28
16
27
40
10
43
11c
10c
Conv. >99%
Yield: 63%
11a/11c: 1:2
γ/β: >25:1
Conv. >99%
Yield: 75%
Select.: 98%
γ/β: >25:1
Conv. >99%
Yield: 79%
Select.: 95%
γ/β: >25:1
2[b]
3[c]
4[d]
5[e]
6[f]
7
4
S1
S1
0
F
Me
HO
OMe
HO
O
O
O
S19
S20
S21
S22
0/0/0/0
0
HO
CHO
15c
Conv. >99%
Yield: 75%
Select.: 96%
γ/β: >25:1
CHO
CHO
14c
Conv. >99%
Yield: 68%
Select.: 90%
γ/β: 21:1
21/5/15/0
3/3/2/0
34
20
32
4
1
2
13c
Conv. >99%
Yield: 73%
Select.: 94%
γ/β: >25:1
<1/1/<1/0
CF3
O
O
O
[a] [Rh(CO)2acac]/L/CSA/S = 1:5:5:100, c(S) = 0.5 M, DCE (2 mL), CO/H2
(1:1, 6 bar), 55 oC, 12 h. Yield was determined by NMR spectroscopy
using TMB as the internal standard. Selectivity (Select.), ratio of γ/β
[n(a+c)/n(b+d)] and conversion (conv.) were determined by analysis of
the reaction mixture by NMR spectroscopy. [b] Without of CSA. [c] MeOH
was used. [d] TsOH was used. [e] ratio (δ/γ). [f] ratio (ε/δ).
S
HO
HO
HO
CHO
CHO
16c
Conv. >99%
Yield: 68%
Select.: 95%
γ/β:>25:1
CHO
18cb
17c
Conv. >99%
Yield: 51%
Select.: 91%
γ/β: >25:1
Conv. >99%
Yield: 77%
Select.: 96%
γ/β: >25:1
F3C
δ
O
O
Me
HO
ε
O
Me
γ
O
Me
MeO
δ
P
HO
HO
[a] [Rh(CO)2acac]/L1/CSA/S = 1:5:5:100, c(S) = 0.5 M. Isolated yield.
Selectivity (Select.), ratio of γ/β [n(a+c)/n(b+d)] and conversion (conv.)
were determined by analysis of the reaction mixture by NMR spectroscopy.
[b] CO/H2 (1:1, 16 bar) and the yield was determined by NMR spectroscopy
using TMB as the internal standard. PMB = 4-methoxybenzyl.
2
3
F3C
L8
S19
S20
S22
S21
3
To clarify the role of ligand L1 in the course of this HF-
hydrogenation reaction, control experiments were undertaken as
depicted in Table 3. Using a rhodium catalyst derived from a
monodentate ligand, L8, gave no product 1c and only a mixture
of unsaturated aldehydes 1a and 1b was observed in very low
yields with rather poor regioselectivity, and the presence of CSA
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10.1002/anie.201809073
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COMMUNICATION
O
O
Me
[Rh], L1, CSA
CHO
HO
HO
CO/H2 (1:1, 6 bar), DCE
Me
S1
1c
a)
X
O
H2
Ar2P
LnRh
N
H
NH
HN
Hydrogenation
H
b)
d)
A
NH2
X
X
O
O
Ar2P
LnRh
N
H
Ar2P
N
H
+
+
N
H
NH2
N
H
NH2
LnRh
H
H
H
H
Me
O
O
NH
NH
1a + A
OHC
c)
CO/H2
Hydroformylation
O
H
O
H
Figure 1. Rh-catalyzed HF-hydrogenation of S1 as a function of reaction time.
Me
B
C
Scheme 3. Proposed reaction mechanism.
This new method involves two catalytic reactions: HF and
hydrogenation. The formation of the main product of 9a’,
containing the α,β-unsaturated γ-lactone moiety, indicated that
the HF could be the first step, then followed by hydrogenation.
So control experiments for detecting the possible intermediate in
the reaction of S1 at different reaction times were carried out.
The α,β-unsaturated aldehyde 1a was produced in 18% yield
after 1 h, and in line with the increasing reaction time, its amount
initially increased, reaching its maximum percentage at 40%
before levelling off to zero (Figure 1). At the same time, the
amount of 1c as well as its chemoselectivity were always
increasing during the process, and a yield of 95% was achieved
after 12 h. Notably, the regioselectivity was well maintained at a
high level (γ/β up to 22:1, Table S9). Based on these studies, it
can be reasoned that the HF of alkynes occurs first, forming the
enal 1a, which was further subsequently hydrogenated under
the reaction conditions, releasing the final saturated aldehyde 1c.
Based on our previous report[5a], (Z)-pent-3-enoic acid (Z-S24)
which would be the product in case an alkyne hydrogenation
occurs first and which could also possibly be transferred into 1c
using the catalyst derived from ligand L5. However, no traces of
Z-S24 could be detected during the course of this new tandem
reaction. Furthermore, reaction results with low activity and
selectivity were obtained when Z- and E-S24 were studied in this
new catalytic system (Table S12).
To conclude, we have designed and synthesized a series of
new supramolecular ligands, containing a functional guanidine
group with increasing π-acceptor ability of the phosphine donor
ligands. A protocol for a tandem Rh-catalyzed HF-hydrogenation
of unsymmetrical internal alkynes functionalized with carboxylic
acid in highly regio- and chemoselectivity was successfully
established, which yielded aliphatic aldehydes as desired
products. This study further highlighted the unique advantages
of supramolecular catalysis mimicking natural enzymes and an
investigation of corresponding rationally designed chiral ligands
are being undertaken in our lab.
Acknowledgements
We thank the Alexander von Humboldt Foundation (W.F.) for a
postdoctoral fellowship.
Conflict of interest
The authors declare no conflict of interest.
On the basis of the above results and the generally accepted
mechanism of HF catalyzed by Rh-triarylphosphine complexes,
we propose a mechanism consisting of four consecutive steps,
which is reminiscent of the working mode of enzymes.[14] a) The
presence of CSA would protonate the functional guanidine group
of ligand L1, forming an intermediate A with a guanidinium salt.
b) A could efficiently bind the substrate via hydrogen bonding
interaction in a way that the substrate is well preoriented closely
to the Rh center and activated by forming an intermediate B. c)
γ-Selective HF within the supramolecular substrate-catalyst B
occurred resulting in a complex C, consisted of α,β-unsaturated
aldehyde 1a and catalyst. d) Further hydrogenation within
Keywords: alkynes • enzyme mimics • ligand design •
regioselective hydroformylation • supramolecular catalysis
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COMMUNICATION
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10.1002/anie.201809073
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Weiwei Fang, Bernhard Breit*
Page No. – Page No.
Tandem Regioselective
Hydroformylation-Hydrogenation of
Internal Alkynes employing a
Supramolecular Catalyst
A new supramolecular catalyst enables a tandem Rh-catalyzed hydroformylation-
hydrogenation of unsymmetrical internal alkynes functionalized with carboxylic
acids in β-position gave access to aliphatic aldehydes in high regio- and
chemoselectivity. Control experiments prove enzyme-like catalyst behavior.
This article is protected by copyright. All rights reserved.