Discovery and Comparison of Homogeneous Catalysts in a Standardized HOT-CAT Screen with Microwave-Heating and qNMR Analysis: Exploring Catalytic Hydration of Alkynes

Accepted Article

Title: Discovery and Comparison of Homogeneous Catalysts in a

Standardized HOT-CAT Screen with Microwave-Heating and

qNMR Analysis: Exploring Catalytic Hydration of Alkynes

Authors: Matthias Schreyer, Tobias M. Milzarek, Marcus Wegmann,

Andreas Brunner, and Lukas Hintermann

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To be cited as: ChemCatChem 10.1002/cctc.201900456

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10.1002/cctc.201900456

ChemCatChem

FULL PAPER

Discovery and Comparison of Homogeneous Catalysts in a

Standardized HOT-CAT Screen with Microwave-Heating and

qNMR Analysis: Exploring Catalytic Hydration of Alkynes

Matthias Schreyer,^[a,b]Tobias M. Milzarek,^[a]Marcus Wegmann,^[a,b]Andreas Brunner^[a]and Lukas

Hintermann*^[a,b]

Abstract: A HOT-CAT (homogeneous thermal catalysis) screen

using microwave-heating and quantitative NMR (qNMR) analysis

has been developed for identification and comparison of catalyst

activity in homogeneous metal-based catalysis. The hydration of

terminal alkynes to ketones or aldehydes served as a model reaction

in this proof-of-concept study. Key aspects of the screen are the use

of a high-temperature setting (e.g., 160 °C) at a fixed, short reaction

time (e.g., 15 min) for all samples. Analysis of crude reaction

mixtures by a standardized, quantitative ¹H NMR protocol gives a

comprehensive picture of catalyst chemo- and regioselectivity, which

permits broad comparisons and the discovery of non-target reactivity.

For catalytic alkyne hydration, data for 105 runs involving 81 catalyst

systems with 15 different metals is presented. The activity of all

established catalyst systems was reproduced, and new catalyst

systems with Markovnikov hydration selectivity were discovered and

(ratios) define a catalyst system, whereas catalyst loading is

rather a reaction condition.^[4]Considering the large number of

independent variables and parameter settings, the de novo

search for a catalyzed reaction can be inherently complex, even

for a predefined target transformation.^[2a,5]

catalyst system

• metal-precursor

• ligand

O

H

• additive(s)

R

+

H

+ H₂O

H

R

H

O

• solvent

• time

• temperature

• pressure

• ratio

• concentration

• conversion

• selectivity

Output

• side-products

Reaction Conditions

applied to preparative runs, namely Cu₂O–CSA (CSA

=

camphorsulfonic acid), Co(OAc)₂–tetraphenylporphyrin–CSA and

[IrCl(COD)]–CSA.

Scheme 1. General scheme of a catalyzed transformation (alkyne hydration).

The reaction system is defined by setting parameters for general reaction

conditions (variables), and for the subset of variables that make up the catalyst

system. Each parameter setting affects the reaction output, measured as

product composition and expressed in derived quantities.

Introduction

Over the past years we have observed the development

process for homogeneous catalytic hydration of alkynes to

carbonyl compounds for application in organic synthesis.^[6,7]In

new research papers on alkyne hydration catalysts, there often

is a common structure:^[8](I) A potential new catalyst system is

proposed based on a mechanistic hypothesis or by analogy to

established catalysts. (II) A screening with a suitable assay is

performed, i.e. a suitable model reaction, whose product is

readily detected, is performed in the presence of the potential

catalyst. (III) Catalysis is confirmed through analysis or isolation

of a target product in quantities exceeding those found in blank

reactions. (IV) Key parameters of the single most promising

catalyst system are optimized in a focused screen, until the

model reaction reaches a satisfactory product yield. (V) The new

catalyst system is applied to a selection of diversely co-

functionalized substrates, with parameter settings optimized for

the model substrate, and product yields are recorded as

(exclusive) indicators of efficiency.

The identification of new catalysts for synthetic transformations

is important for progress in synthetic organic chemistry.^[1]Any

new catalytic system that displays unique activity and selectivity

patterns may help solving a specific synthetic problem. In

searching new catalysts for an organic transformation one is first

faced with choosing reaction conditions by defining relevant

parameters for variables like temperature, pressure, solvent,

reactant ratios, concentration and reaction time.^[2]Limiting the

discussion to homogeneous, metal-complex-catalyzed reactions,

one will subsequently generate a potential catalyst by combining

a metal precursor, steering ligand and various co-catalytic

additives.^[3]Such substance variables and their relative settings

[a]

[b]

Dr. M. Schreyer, T. M. Milzarek, Dr. M. Wegmann, Dr. A. Brunner,

Prof. Dr. L. Hintermann

Technische Universität München, Department Chemie,

Lichtenbergstr. 4, 85748 Garching bei München, Germany

Certain aspects of this operation mode seem unsatisfactory:

a) Restricting a study to a single type of catalyst system avoids

recognizing interdependencies between chemically different, but

related catalyst systems; b) optimizing a reaction to the maximal

yield of a model target, while disregarding the nature and

amount of side-products formed, ignores selectivity aspects and

limits the predictive value of optimization data; c) the common

Dr. M. Schreyer, Dr. M. Wegmann, Prof. Dr. L. Hintermann

TUM Catalysis Research Center, Ernst-Otto-Fischer-Str. 1, 85748

Garching bei München, Germany

E-mail: lukas.hintermann@tum.de

http://www.oca.ch.tum.de

Supporting information for this article is given via a link at the end of

the document

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FULL PAPER

approach to run a reaction to consumption of the starting

material (at variable reaction times), or the failure to quantify

unreacted starting material (at fixed reaction times), render

comparisons among catalyst systems difficult, because the

target yield intertwines activity and selectivity aspects (Figure 1).

Results

Definition of the screening procedure and conditions. The

reaction temperature in a comparative catalyst screening can be

set to the lowest value for achieving notable, yet incomplete

conversions. Relative catalyst activities are then derived by

comparing the yield of target product after a fixed reaction

time.^[14]If a highly active catalyst emerges from the screening,

the temperature setting may be lowered or the catalyst loading

reduced for further optimization.^[14,15]We have defined a different

HOT-CAT (homogeneous thermal catalysis) approach for

catalysis screening, where catalytic reactions are screened in a

microwave reactor at deliberately high temperature settings.^[16,17]

Reaction times are fixed at short duration (15–30 min) to allow

for serial experiments in a mono-mode reactor with auto-sampler.

A boundary condition of our screen is that the desired catalytic

activity will be scarce. Detecting the desired activity at all is a

priority, no matter if it is high or low. An inherent assumption of

our approach is that low activity catalysts will be easier to detect

at a very high temperature setting. More active catalysts tend to

show activity well above their usual temperature optimum and

will therefore also be detected in the screen. We propose that

the HOT-CAT approach is most suited to detect catalytic activity

with the least number of (e.g., a single) experiments. The

second key aspect of our approach is quantification of all

relevant reaction components to define catalyst selectivity. For

efficiency, analysis should be limited to a single measurement,

which places restrictions on the model reaction and suitable

analytical techniques.

a)

b)

100

80

60

40

20

0

SM

80

60

40

20

0

74%

SM

P

SP

0

1

2

3

4

5

0

1

2

3

4

5

time / h

Figure 1. Two hypothetical, catalyzed reactions of starting material (SM) to

product (P): a) Highly selective catalyst with low activity. b) More active, but

less selective catalyst, generating side-product(s) (SP). The two cases are in-

distinguishable by a single-point yield determination of P after 5 h.

We now present a case-study in catalyst-screening that aims

at collecting comprehensive information on catalyst activity and

selectivity for a specific model reaction. Widely differing catalyst

systems will be compared by activity and selectivity, based on a

standardized experimental procedure. The kind of information

we want to obtain is that usually found in a review article, where

it is normally compiled from various individual studies and where

direct comparisons are not possible, since all studies covered

tend to use different model reactions and reaction conditions.

The reaction in case is catalytic hydration of terminal alkynes

to aldehydes or ketones (Scheme 1).^[6]This transformation is of

synthetic interest, involves a fundamental selectivity (Markov-

nikov vs. anti-Markovnikov regioselectivity) and has already

been catalyzed by a number of metal- and other element-based

species. Our 2007 review listed catalytic activities for Brønsted

acids, enzymes, Hg, other metals (Ce, W; Fe; Ru, Rh, Ir, Pd, Pt,

Cu, Ag, Au, Zn, Cd, Tl) and a half-metal (Te). In total, hydration

activity was listed for catalysts based on ca. 17 elements.^[6]Over

the past 12 years, alkyne hydration activity has been reported

for additional elements (Ca,^[9]Co,^[10,11]Ga,^[8c]In,^[12]Tm,^[8d]Yb,^[8c]

Sc,^[8c]Bi,^[8a]Y,^[8a]Eu,^[8a]La,^[8a]Sn^[8e]) while one reported activity

has been refuted (W).^[13]Many more new catalyst systems have

been described for elements with previously established activity,

the frequency of reports following the order Au >> Cu, Ag > Pt,

Ru, Fe, Pd. We now wish to explore a generalized, systematic

activity screening that can be applied to any type of potential

alkyne hydration catalysts, and which will provide information on

the relative activity and selectivity of each catalyst. As a

secondary aim, we hope to find new and practically useful

catalyst systems for alkyne hydration with either Markovnikov or

anti-Markovnikov selectivity.

In short, we wish to perform a fast, efficient screening for

new catalytic reactivity under HOT-CAT conditions in

a

microwave-reactor, use a deliberately high reaction temperature

at a fixed, short reaction time and gain comparative information

on a large number of catalyst systems, their relative activity,

chemo- and stereoselectivity, through quantitative product

analysis. Questions to be answered are: is the HOT-CAT

approach viable for new catalyst discovery? Does it reproduce

known catalytic activity under screening conditions to validate

the approach? Can we detect new catalysts for a defined model

reaction? Will unexpected new catalytic activity towards

unpredicted products be found?

Screening System 1: Microwave heating–GC-MS analysis.

Our first approach to catalyst screening centered on the hydra-

tion of 1-heptyne in aqueous acetone. As secondary substrate,

1-octene was added to the test mixture with the intention to

concomitantly screen for catalytic alkene hydration.^[17,18]This

part of the project proved futile and will not be further discussed.

Screening experiments were run under the conditions defined in

Scheme 2. Di-n-butyl ether was added to the cooled reaction

mixture as internal standard for GC–MS analysis.^[19]Hydration

products 2-heptanone, 1-heptanal and remaining 1-heptyne

were quantified through calibration with reference samples.

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catalyst (5 mol%)

Me

catalyst

O

Me

HO-(CH₂)₈

O

C₄H₉

+

HO-(CH₂)₈

O

acetone–H₂O (5:1)

C₄H₉

O

HO-(CH₂)₈

solvent–H₂O

1-heptyne

(0.25 M)

180 °C (µW), 15 min

1

2

3

K

A

Off-target

products:

Markovnikov

product

anti-Markovnikov

product

OR'

+ nBu₂O (int. standard)

MeO OMe

HO-(CH₂)₈

OR'

Scheme 2. First reaction system for alkyne hydration catalyst screening.

Conditions: 2 mL of test solution (0.25 M in 1-heptyne and 0.0625 M in 1-

octene, see text).

5

4a (R' = Me); 4b (R' = iPr)

6

7a (n = 8)

7b (n = 7)

Me

HO-(CH₂)₈

HO-(CH₂)_n

8

This screening system detects catalytic hydration activity at a

threshold of ca. 1 mol% of either Markovnikov- (2-heptanone) or

anti-Markovnikov- (1-heptanal) product formation. The GC-MS-

analysis was performed directly from the reaction mixture. Dis-

advantages of this approach, besides the not overly high

sensitivity, were low substance recoveries, which implied that

unknown reaction products had escaped detection. The scree-

ning was performed on a total of ca 60 potential metallic cataly-

sts which were either tested as such, in combination with an am-

bifunctional pyridylphosphane ligand,^[20,21]and other additives

(CSA, AgOTf). The results from 159 runs thus performed are lis-

ted in the supporting information (Table S1) and will be referred

to in the ensuing text where adequate. Eventually the first scree-

ning system was abandoned because of the difficulty of obtai-

ning accurate quantitative data and satisfactory recoveries.

HO-(CH₂)_8-n

HO

(CH₂)₉

OH 10

9

(CH₂)_nCH₃

HO-(CH₂)₉

(CH₂)₉-OH

HO-(CH₂)₉

(CH₂)₉-OH

11a

11b

(CH₂)₉-OH

HO-(CH₂)₉

(CH₂)₉-OH

12a

12b

Scheme 3. On-target alkyne hydration of 1 to 2 and 3, and side-products 4–12

from off-target-reactions that were identified in the course of the screen.

In practice, the screening procedure consisted in combining a

potential catalyst with degassed solvent, water and 1 in a micro-

wave tube, followed by heating to 160 °C for 15 minutes. After

addition of internal standard and following a suitable workup-pro-

cedure, the sample was analyzed by quantitative ¹H NMR spec-

troscopy. Catalytic reactions were performed in one or several

solvents (A: iPrOH, B: acetone, C: methanol, D: NMP) with water

(4:1 (v/v)). Such comparatively water-rich, non-acidic media

were deliberately chosen to reduce unspecific Brønsted acid

catalysis as opposed to metal-specific reactivity.^[26]

Screening System 2: Microwave heating–qNMR analysis.

Undec-10-yn-1-ol (1) is commercially available as liquid alkyne

that is easily purified by vacuum distillation and can be dosed by

microliter syringe. The compound and its follow-up-products are

little volatile, have low water solubility and are readily recovered

by extractive workup. The hydration products ketone 2 (d 2.12, 3

H) and aldehyde 3 (d_H9.77, 1 H) display characteristic, isolated

peaks suitable for quantitative analysis by ¹H NMR spectroscopy.

Unreacted 1 is detected through its acetylenic C–H (d 1.94),

while the R-CH₂OH signal (d 3.64, 2 H) provides the total of

products derived from 1 with intact alcohol end-groups. Multiple

non-target products were also detected (Scheme 3; for qNMR

diagnostics, see Table S2): acetals (4, 5) result from

acetalization of 2/3 and alcoholic solvent (MeOH, iPrOH), or via

direct addition of the latter to alkyne. Allene 6 was an impurity in

commercial 1, but else was not significantly formed in the

catalytic runs. Through hydride transfer and isomerization

reactions, alkyne 1 is transformed into a hydrocarbon chain (7),

a terminal alkene (8), or into isomeric internal (9) alkenes.^[22]

Transfer-hydrogenation of aldehyde 3 to diol 10 as secondary

reaction was sometimes seen with iPrOH as solvent. Generation

of 10 raises [CH₂OH] above 100 mol% relative to initial 1, per-

mitting an approximate quantification.^[23]Alkyne trimerization^[24]

returns arenes 11a/b, whereas alkyne dimerization^[25]potentially

generates (E/Z)-stereoisomers of regioisomers 12a/b. Recovery

is the sum of all individually detected components 1–12 in mol%.

In case it amounts to less than [CH₂OH], there must be

undetected components derived from 1 in the sample (vide infra).

The difference is listed as unknown and serves as control for the

integrity of analysis.

Validation of the screening approach with established

alkyne hydration catalyst systems. Initial experiments focused

on established catalyst systems for anti-Markovnikov hydration

of terminal alkynes to check if their reported activities and selec-

tivity are reproduced under HOT-CAT screening conditions

(Table 1). Wakatsuki's catalyst CpRuCl(dppm)^[27](dppm = 1,2-

bis-diphenylphosphino-methane) gave close to 90% aldehyde 3

at a regioselectivity of >200:1 (entry 1). The conversion was

incomplete at lower catalyst loading, due to deactivation as con-

firmed by detection of 1-decanol, formed via R-CH₂-CH₂-CO-

[Ru].^[28]The reported activity ("reactions using 2–10 mol% of ca-

talyst in 2-propanol at 100 °C gave the desired aldehydes in

good to excellent yields after 12 h") is well mirrored by the 15

min HOT-CAT experiment. A combination of CpRu⁺-precursor

[29]

complex [CpRu(C₁₀H₈)]PF₆

with dppm presented comparably

high activity (entry 3), whereas the lower activity of a CpRu⁺–

dppe system (entry 4) mirrors Wakatsuki's findings with the latter

ligand.^[27]The choice of precursor is critical since CpRuCl(PPh₃)₂

with dppm is unreactive (entry 5); inactive [CpRu(h²-dppm)-

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(PPh₃)]⁺may have been formed (cf. Table S1, entry 93). The ca-

talyst system CpRuCl(PPh₃)₂–ISIPHOS (ISIPHOS = 2-(diphenyl-

use optimal solvent mixtures for the respective catalyst systems,

catalytic activity is also traced in a non-standard NMP–H₂O me-

dium (entry 7). In practice, if novel but low activity was observed

in one medium, we repeated the experiment in other media.

phosphino)-6-(2,4,6-triisopropylphenyl)pyridine)^[21,30]

performs

predictably well (entries 6, 7), with entry 6 mirroring our previ-

ously published HOT-CAT conditions.^[30]Although entries 1–6

Table 1. HOT-CAT screen with some established anti-Markovnikov- or Markovnikov hydration catalysts.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

1

Catalyst (mol%)^[b]

Solv.^[c]

1

2

3

4^[d]

6^[e]

0.5

0.7

0.0

0.6

0.8

0.0

0.6

0.0

0.5

0.8

0.0

0.8

0.9

7a/b^[f]

4.0

2.5

3.5

2.1

1.2

0.1

3.2

2.8

2.9

1.0

0.8

1.8

1.0

0.4

8

9

Rec.^[g]

96.1

95.2

96.0

100.2

98.1

96.4

97.0

99.0

98.1

93.9

99.9

97.7

99.6

100.0

[CH₂OH]^[h]

98.8

Unk.^[i]

2.7

4.3

4.4

0.7

1.5

1.7

3.4

0.0

0.4

2.9

-0.1

-0.5

0.3

0.5

CpRuCl(dppm) (4)

A

B

C

B

D

0.6

0.4

89.3

53.8

90.4

48.6

0.6

0.8^Pr

0.4^Pr

1.8^Pr

2.7^Pr

0.0

0.5

0.0

1.1

0.0

0.8

0.5

0.6

0.0

0.8

0.4

1.8

2.7

0.0

0.4

0.2

0.8

0.0

0.5

0.0

2

CpRuCl(dppm) (2)

37.5

0.0

0.3

99.5

3

[CpRu(C₁₀H₈)]PF₆–dppm (4)

[CpRu(C₁₀H₈)]PF₆–dppe (4)

CpRuCl(PPh₃)₂–dppm (4)

CpRuCl(PPh₃)₂–ISIPHOS (2)

[CpRu(MeCN)₃]PF₆–BTF-bipy (4)

NaAuCl₄(2)

0.3

100.4

100.9

99.6

4

44.6

95.4

0.0

0.5

5

0.1

6

0.2

96.1

13.2

94.4

91.9

0.5

0.0

98.1

7

79.2

0.0

100.4

99.0

8

0.9

0.0

9

0.0

2.0

0.0

98.5

10

11

12

13

14

38.0

56.1

0.0

52.8

41.3

95.0

33.5

0.4

0.8

96.8

AuCl(PPh₃) (2)

0.4

99.8

(SPhos)AuOTf (2)

0.4

0.5

97.2

AgOTf (2)

63.5

98.2

0.3

0.5

99.9

CSA (10)

0.0

0.14

100.5

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities in mol% by qNMR against internal standard. [b] Precatalyst

and ligand quantity (mol%) in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D =

MeOH–H₂O (4:1). [d] Methyl acetal 4a, or iPr-acetal 4b, if denoted by a superscript Pr. [e] Allene 6 was an impurity (0.8 mol%) in 1. [f] Sum of 7a/b; for Ru-

catalysts in particular, 7b can be formed by decarbonylation. [g] Recovery, sum of analytically detected components from 1 in mol%; 10–12 were not detected. [h]

Total hydroxymethylene (d_H3.64) in mol% of 1. [i] Unidentified products, calculated as [RCH₂OH] - [recovery], see text. BTF-bipy = 5,5'-bis-trifluoromethyl-2,2'-

bipyridine; dppm = CH₂(PPh₂)₂, dppe = Ph₂P(CH₂)₂PPh₂; SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; CSA = camphorsulfonic acid; Tf = SO₂CF₃;

C₁₀H₈= naphthalene.

The recent catalyst by Herzon combining CpRu⁺with 5,5'-bis-tri-

fluoromethyl-2,2'-bipyridine^[31]worked well under HOT-CAT

conditions, both in the original NMP–H₂O solvent (entry 8) or in

acetone–H₂O (entry 9). Some runs were also performed with

established Markovnikov hydration catalysts, including NaAuCl₄

in MeOH–H₂O (entry 10).^[32]The moderate conversion of 62%

might be caused by solvent-induced catalyst deactivation

(Au^I®Au⁰). The original reaction conditions involve reflux at

lower temperature (MeOH–H₂O 10:1; ca. 70 °C, 1 h).^[32]Com-

plex AuCl(PPh₃) is not regarded as an alkyne hydration catalyst,

but becomes active after ionization to (Ph₃P)Au⁺,^[33]which appa-

rently takes place under HOT-CAT conditions in aqueous sol-

vent, with no need for promotors (entry 11). Preformed cationic

Au(SPhos)OTf predictably shows higher activity (entry 12).^[34]

We did not cover classical Hg(II) catalysts in a microwave setup

due to toxicity.^[35]Recent reports describe the catalytic alkyne

hydration activity of simple silver salts with non-nucleophilic

counter-ions.^[36]This was supported by a positive screening re-

sult with AgOTf (entry 13). A blank experiment with camphorsul-

fonic acid (CSA)^[37]confirmed the absence of background acid

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catalysis in the hydration of 1 (entry 14). Complementary results

from the initial HOT-CAT/GC-MS screen with 1-heptyne and

either CSA or HOTf in acetone–H₂O at 180 °C (15 min) produc-

ed no more than 1 mol% of 2-heptanone (Table S1, entries 1, 2).

The results of Table 1 confide that alkyne hydration catalysts are

efficiently and reliably detected within a HOT-CAT-screen. The

stage was set for a broader screen of alkyne hydration activity

across the periodic table, emphasizing transition metal

complexes.

Group 1–6 metals and lanthanides. Reported alkyne hydration

activity among early transition metals (groups 3–5), the

lanthanides^[8,38]and main group metals^[12b]is limited to acidic

systems at low water content, conditions deliberately not

reflected by our screening conditions. The preliminary screen

(see Table S1, entries 3–17) indicated low activity for Ce(OTf)₃

(1% ketone), Ce(SO₄)₂·4 H₂O (1%), Al(OTf)₃(2%), Bi(OTf)₃

(≤1%), but none for La(OTf)₃, Eu(hfc)₃or Yb(OTf)₃. The

observed activities and ketone selectivity are consistent with

18–23). Neither would group VI complex K₂[Cr(oxalate)₃] (Table

S1, entries 24–26) or Mo(CO)₆(Table 2, entry 1); the latter

displayed minor activity for alkyne hydrogenation and

-

trimerization. We have recently disproven the earlier claimed

acetylene hydration activity of tungsten(IV) complex

(NEt₄)₂[WO(mnt)₂] (mnt

=

maleonitrile dithiolate).^[13,39]The

complex was also inactive in the HOT-CAT screen with 1 (Table

2, entry 2).

Group 7 metals. Alkyne hydration activity is not documented in

group 7, but analogies of Mn-vinylidenes^[40]to those of rutheni-

um incited a search for anti-Markovnikov hydration catalysts with

that element. Table 2 reveals that a focus screen with methyl-

cyclopentadienyl-manganese-tricarbonyl either alone (entries 3,

4), together with co-ligands (entries 5, 6), or additionally with

NMO as carbonyl-releasing reagent^[41](entry 6) induced no

catalytic activity. A combination of Mn(III), tetraphenylporphyrin

(TPP) and acid (cf. ref.^[10]) was inactive (entry 7). Rhenium

dodecacarbonyl showed little activity for Markovnikov hydration,

acid-induced hydration. A screen of group 4 complexes Cp₂TiCl₂, besides alkyne trimerization (entry 8).

(RO)₂TiCl₂and Cp₂ZrCl₂did not reveal activity (Table S1, entries

Table 2. HOT-CAT alkyne hydration screen with Mo, W, Mn, and Re compounds.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

Catalyst (mol%)^[b]

Solv.^[c]

1

2

3

4a

6^[d]

0.6

0.7

0.0

0.8

7

8

9

11^[e]

Rec.^[f]

91.6

[CH₂OH]^[g]

96.9

Unk.^[h]

5.3

1

2

3

4

5

6

7

8

Mo(CO)₆(4)

D

B

D

87.0

98.1

99.3

98.7

96.1

99.0

99.3

91.2

0.0

0.1

1.8

0.9

0.6

1.1

0.9

2.0

1.0

0.8

0.0

2.2

0.0

1.2

(NEt₄)₂[WO(mnt)₂] (20)

Cp'Mn(CO)₃(4)

0.16

0.0

1.1

0.15

0.0

0.2

100.0

99.9

100.5

101.2

100.8

100.9

101.0

101.3

97.4

0.5

1.3

Cp'Mn(CO)₃(4)

99.8

1.0

Cp'Mn(CO)₃–ISIPHOS (4)

Cp'Mn(CO)₃–dppe (4), NMO (114)

Mn(OAc)₃–TPP (4), CSA (10)

Re₂(CO)₁₀(2)

97.0

3.9

101.0

101.1

95.4

0.0

0.2

2.0

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Allene 6 was an impurity (0.8 mol%) in 1. [e] Quantities of 11 (arenes; Scheme 3) are expressed in mol% of 1 incorporated; 12 (enyne, Scheme 3)

was not reliably detected. [f] Recovery, sum of analytically detected components from 1 in mol%. [g] Total RCH₂OH (d_H3.64) in mol% of 1. [h] Unidentified

products, calculated as [CH₂OH] - [recovery], see text. Cp' = methyl-cyclopentadienyl; CSA = camphorsulfonic acid; mnt = maleonitrile-dithiolate; TPP =

tetraphenylporphyrine; NMO = N-methylmorpholine-N-oxide; ISIPHOS = 2-(diphenylphosphino)-6-(2,4,6-triisopropylphenyl)pyridine.

Group 8 metals. The known alkyne hydration activity of group 8

metals is focused on ruthenium.^[6]In contrast, the reported

activities of iron seem to fall into the category of Lewis-acid

assisted Brønsted acid catalyses.^[8f,42]Since such activation

pathways are suppressed in water-rich reaction media and are

less successful with aliphatic alkynes, the low Markovnikov

hydration activity of Fe(OTf)₃, comparable to that of Brønsted

acids, is expected (Table 3, entry 1; Table S1, entries 34, 35).

The initial screen with Fe(acac)₃, Fe(dbm)₃, FeCl₂(dppe),

[{CpFe(CO)₂}₂] and CpFeI(CO)₂failed to show iron-specific

10.1002/cctc.201900456

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FULL PAPER

activity (Table S1, entries 36–47). Combining the CpFe-fragment

with ambifunctional ligand via (attempted) oxidant-induced CO li-

gand release gave no hydration catalyst (entry 2). The low alky-

ne hydration activity seen with a water-soluble Fe–porphyrin

complex^[10]did not transform into a conclusive activity for the

Fe–TPP–CSA system (entry 3), reflecting the blank experiment

with CSA (Table 1, entry 14). Numerous ruthenium complexes

were tested in the first screen (Scheme 1; Table S1, entries 48–

98). Notable activity in the order of 5–10 mol% was found for

RuO₂–ISIPHOS–CSA (8% K, 4% A; cf. Scheme 2), RuCl₂(COD)

(9% K), (arene)RuCl₂(8–15% K), [(h³,h³)-(2,7-dimethylocta-

dienediyl)RuCl₂]^[43](13% K, 5% A) and Cp*RuCl₂–ISIPHOS–2

AgOTf (7% A); the latter example is notable since Cp*Ru-frag-

ments had shown a lack of activity, e.g. in the complex

[Cp*RuCl(tBuPyPHOS)₂].^[44]These ruthenium catalysts are not

very chemoselective, with ≤20 mol% alkyne hydration products

at ≥90% conversion. The first screen confirmed high anti-

Markovnikov hydration activity of CpRuCl(dppm) in acetone

besides iPrOH (72% A; cf. Table 1),^[27]and for in situ catalyst

[CpRu(C₁₀H₈)]PF₆–ISIPHOS (84% A).^[29]Additional runs with

ruthenium were included in the qNMR-screen (Table 3).

Table 3. HOT-CAT alkyne hydration screen of iron, ruthenium and osmium-compounds.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

Catalyst (mol%)^[b]

Fe(OTf)₃(10)

Solv.^[

1

2

3

4a

6^[d]

7a/

b^[e]

8

9

11/12^[f]

Rec.^[g]

[CH₂O

H]^[h]

Unk.^[i]

c]

1

2

B

D

97.0

1.4

0.0

0.1

1.0

0.7

1.5

0.3

0.0

n.d.

100.8

99.0

101.0

99.0

0.2

0.0

CpFe(CO)₂I–ISIPHOS (4),

CSA (10), NMO (116)

97.9

0.0/0.0

3

4

5

6

FeCl(TPP) (2), CSA (10)

CpRuCl(PPh₃)₂(4)

D

A

B

98.6

82.7

67.1

74.2

0.7

0.6

4.5

0.2

0.0

0.1

–

0.8

0.3

4.0

0.2

0.7

5.1

3.4

1.9

0.0

1.4

0.0

0.8

0.0

1.2

0.0

0.0/0.0

0.7/0.0

100.9

98.9^[i]

99.2

100.3

98.9

-0.6

0.0

1.7

1.1

2.6

[CpRu(C₁₀H₈)]PF₆–bipy (2)

20.2

20.6

0

100.9

100.1

[CpRu(C₁₀H₈)]PF₆–

Ph₂PyBOX (2),

0.4

99.0

7

CpRuCl(COD)–Ph₂PyBOX (2)

13–ISIPHOS (2)

13–dppm (2)

D

B

A

B

C

D

83.3

87.4

93.8

85.2

95.8

0.0

1.0

0.0

6.2

9.6

4.9

13.1

2.2

0.8

0.4

0.9

0.4

1.1

1.0

2.1

0.4

2.0

0.0

–

0.4

0.6

0.5

0.8

0.0

0.1

0.0

2.5

2.1

1.3

1.8

1.2

5.9

4.1

5.9

0.0

0.3/0.0

0.0/1.0

0.0/1.6

0.0/0.8

0.0/0.6

2.5/0.0

1.8/0.0

1.7/0.0

3.1/0.4

91.7

94.1

98.3

92.3

99.1

84.3

93.1

88.6

79.1

94.7

3.0

7.8

2.9

8.6

1.5

14.9

4.5

8.4

15.6

8

1.3

1.2

101.9

101.2

100.9

100.6

99.2

9

0.3

0.2

10

11

12

13

14

15

14–ISIPHOS (2)

14–dppm (2)

1.5

0.1

0.2

(NH₄)₂[OsCl₆] (5)

39.2

23.7

13.5

12.5

29.4

17.3

12.7

10.2

35.6

47.7

32.6

0.0

0.9

97.6

96.9

94.8

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parentheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Allene 6 was an impurity (0.8 mol%) in 1. [e] Sum of 7a/b; for Ru-catalysts in particular, 7b can be formed by decarbonylation. [f] Quantities of 11/12

(arenes/enynes, cf. Scheme 3) are expressed in mol% of 1 incorporated. [g] Recovery, sum of analytically detected components from 1 in mol%. [h] Total

hydroxymethylene (d_H3.64) in mol% of 1. [i] Unidentified products, calculated as [RCH₂OH] - [recovery], see text. [j] Includes 5.0 mol% 10. bipy = 2,2'-bipyridine;

Ph₂PyBOX = 2,6-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine.

10.1002/cctc.201900456

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The lack of catalytic activity for CpRuCl(PPh₃)₂(entry 4), in spite

of its similarity to Wakatsuki's catalyst, was confirmed.^[27,44,45]

The side-product pattern confirms catalyst deactivation by

hydro-de-carbonylation to L_nRu(CO) with release of decanol

7b.^[28,46]Even before Herzon's fluorinated bipyridines (Table 1,

entries 8, 9), Wakatsuki had noted the anti-Markovnikov

hydration activity of diimine complexes [CpRuCl(N–N)] or

potential cyanide scavenger (Table S1, entries 106, 107; Table 4,

entries 1–4). An in situ Co–porphyrin catalyst from cobalt(II)

acetate and TPP (tetraphenylporphyrin) under argon displayed

Markovnikov hydration activity after addition of CSA (entry 6);

higher conversions were obtained in air (entry 7) and even more

so with excess acid (entry 8). The active species in this system

is likely similar to the Co(III)-porphyrin of Naka,^[10]but is based

on the accessible ligand TPP,^[50]and thus was selected for

preparative evaluation (vide infra). No activity was observed with

Co(II)salen complexes – at least in the absence of Brønsted acid

(entries 9, 10). Cobalt cyclobutadiene sandwich complex,

[(C₄Me₄)Co(C₆H₆)]BF₄(15)^[49c](Figure 2) was inactive either

alone or with ambifunctional steering ligands (entries 11–13).

Catalytic alkyne hydration has been reported for aqueous Rh(III)

(RhCl₃–HCl,^[51a]RhCl₄^–[51b]), albeit with low chemoselectivity. Our

initial screen with neutral RhCl₃and Rh₂(OAc)₄failed to show

hydration products (Table S1, 108–111). Considering its well

established vinylidene complex chemistry,^[52]Rh(I) is a suitable

candidate in the search for new anti-Markovnikov hydration

catalysts. The first screen revealed some anti-Markovnikov

hydration activity for ligandless [RhCl(COD)]₂(4% A) or the

generation of both regioisomers (7% A, 4% K) with ISIPHOS

and CSA present, albeit at low chemoselectivity (Table S1,

entries 112–115). The qNMR-screen confirms the anti-

Markovnikov hydration selectivity of the ligandless system in

acetone (Table 4, entry 14) and reveals important side-reactions

including alkyne trimerization, transfer hydrogenation and alkene

isomerization, which cause low chemoselectivity.

[CpRu(N–N)(NCMe)]PF₆with (N–N)

=

bipyridine (bipy),

phenanthrolin (phen), and iPr₂PyBOX (PyBOX = pyridine-2,6-

bis-oxazoline) in a patent, although activity was lower than with

CpRuCl(dppm).^[47]Combining a CpRu⁺-precursor with bipy or

Ph₂PyBOX in the screen induced predominant anti-Markovnikov

hydration at conversions of 25–30%. The regioselectivity was

high with the more chemoselective PyBOX-system (entries 5, 6).

The presence of chloride suppressed this activity (entry 7).

The CpRu(II)⁺-fragment is to date retained in all anti-Markovni-

kov hydration catalyst systems, while Cp*Ru and h³-indenylru-

thenium(II) were proven ineffective.^[44,48]To evaluate further

organometallic fragments, (tetramethyl-oxymethylene-cyclopen-

tadienyl)ruthenium(II) complexes with naphthalene 13 and 14

(Figure 2) were obtained by courtesy of D. Perekalin^[49]and com-

bined with ISIPHOS or dppm as steering ligands in the screen

(entries 8–11). Traces of aldehyde 3 were detected, but catalytic

turnover for hydration was not realized.

For the first time, catalytic activity was detected with osmium

complexes (entries 12–15).^[6]Hydration with hexachloroosma-

te(IV) is Markovnikov-selective, and most notable in methanol

(entry 15). The overall low chemoselectivity is due to a preferen-

ce of transfer hydrogenation and alkene isomerization reactions

of this catalyst. The large proportion of "unknowns" points to

alkyne polymerization as other side-reaction (vide infra).

In methanol, the extent of hydration is even lower (entry 15–17).

Ambifunctional steering ligands earlier used with the CpRu(II)

fragment do not induce the anti-Markovnikov reaction mode with

Rh(I) (entries 16, 17). Experiments with Rh(I) in MeOH display

low analytical recoveries (50–66%) and [CH₂OH] values (74–

81%, entries 15–17). Some reaction components evidently

escape analytical detection altogether, while others having the

hydroxymethylene group remain unassigned for lack of

diagnostic NMR signals ("unknowns"). The discrepancies are

likely caused by alkyne oligomerizations, as known with Rh(I)-

BF₄

PF₆

O

Me

OEt

Me

OMe

Me

Ru

Co

phosphane complexes (vide infra).^[53,54]Complex (TRI-

[55]

13

14

15

PHOS)RhCl₃

revealed preference for Markovnikov hydration

(4 turnovers; entry 18). Overall, rhodium shows alkyne hydration

activity with a tendency for the anti-Markovnikov mode, but at

low chemoselectivity due to alkyne oligomerization or

polymerization.

Figure 2. Precursor complexes 13 (for Cp*^ARu⁺), 14 (for Cp*^BRu⁺) and 15 (for

(C₄Me₄)Co⁺= (TMB)Co⁺) used in the screening.

For iridium,

a

Markovnikov hydration catalyst system

Group 9 metals. Naka found catalytic activity of water-soluble,

sulfonated cobalt(III)porphyrins for Markovnikov hydration of

terminal alkynes under relatively mild conditions (MeOH–H₂O,

80 °C, 6–16 h; neutral or slightly acidic).^[10]Cationic

cobalt(III)salen complexes were also found to hydrate aryl-

alkynes in acidic media, but less so aliphatic alkynes.^[11]The

simple salts CoCl₂and Co(OAc)₂were inactive in the 1-heptyne

screen (Table S1, entries 101–105). Cyanocobalamin (vitamin

B₁₂) was included in both screens, but showed no catalytic

activity, neither in presence of acid nor with iron(III)triflate as

[Ir(COD)₂]BF₄–P(OiPr)₃–ZrCl₄(70 °C, 15 h) was reported by

Ishii^[56]Our screen indicated notable hydration activity of

[Ir(COD)Cl]₂in various solvents (entries 19–22). The highest

Markovnikov regioselectivity in MeOH–H₂O was 2:3 = 26:1,

although this ratio disregards the co-formation of methyl acetal.

The chemoselectivity for hydration is higher than with rhodium,

but generation of alkanol, alkenes and arenes is still notable.

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Table 4. HOT-CAT alkyne hydration screen of cobalt, rhodium and iridium compounds.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entr

y

Catalyst (mol%)^[b]

Solv.^[

c]

1

2

3

4/5^[d]

6^[e]

7

8

9

11/12^[f]

Rec.^[g]

[CH₂O

H]^[h]

Unk.^[i]

1^[j]

2^[j]

3^[j]

4^[j]

vitamin B₁₂(2)

B

D

95.4

98.4

94.9

95.9

0.0

0.4

0.0

0.2

0.7

0.9

0.7

0.6

0.8

1.5

0.0

0.0/0.0

96.8

99.7

96.4

98.9

98.6

101.2

98.0

99.7

1.8

1.5

1.6

0.8

vitamin B₁₂(2)

vitamin B₁₂(2)–CSA (2)

vitamin B₁₂(2)–Fe(OTf)₃

(10)

5^[j]

6

Co(OAc)₂(4)

D

98.2

77.0

0.0

0.1

0.0

0.2

0.8

0.9

1.6

1.2

0.0

0.0/0.0

100.7

97.6

100.8

98.1

0.1

0.5

Co(OAc)₂–TPP (4)–CSA

(10)

18.3

7^[j]

8^[j]

Co(OAc)₂–TPP (4)–CSA

(10)

D

58.8

0.0

37.3

89.6

0.2

0.7

0.6/0.1

0.8

1.1

1.4

1.6

0.0

0.0/0.0

99.2

95.4

99.9

97.1

0.7

1.7

Co(OAc)₂–TPP (4)–CSA

(25)

2.2/0.14

9^[j]

Co(salen) (4)

Co(salen-J) (2)

15 (4)

D

B

D

98.6

98.4

90.4

78.9

90.5

55.1

41.4

25.9

0.0

1.4

1.9

0.0

0.3

5.8

1.3

0.3

0.0

1.2

0.0

0.8

0.1

0.4

0.5

0.0

0.6

1.0

1.6

1.2

0.4

2.6

2.0

0.9

0.0

0.6

0.4

0.6

4.3

1.3

2.5

0.0

0.2

0.0

3.5

0.0

0.0/0.0

2.2/0.0

4.0/0.0

3.5/0.0

13.2/2.0

5.2/3.4

3.1/17.7

100.0

100.2

95.4

85.3

95.8

87.9

57.7

50.4

101.1

100.8

100.5

100.2

101.1

100.0

76.5

1.1

10^[j]

11^[j]

12^[j]

13^[j]

14

0.6

5.1

15–ISIPHOS (4)

15–dppm (4)

[RhCl(COD)]₂(2)

14.9

5.3

12.1

18.8

23.4

15

16

[RhCl(COD)]₂–ISIPHOS

(2)

73.8

17

18

19

20

21

22

[RhCl(COD)]₂–dppm (2)

(TRIPHOS)RhCl₃(2)

[IrCl(COD)]₂(2)

D

A

B

C

D

56.8

61.1

0.0

1.9

0.1

1.0

5.8

7.1

3.6

1.7

0.2

0.0

1.0

0.9

1.4

3.5

3.8

6.4

4.0

0.0

1.8

1.9

2.7

2.1

2.6/2.8

2.7/2.0

3.9/1.8

3.2/3.0

3.9/3.6

3.4/3.4

66.3

78.1

78.2

81.4

71.8^[k]

72.8

81.0

87.7

97.7

96.3

93.2

95.4

14.7

9.6

8.1

0.6

1.2

44.0

41.7

16.6

44.3

0.3^Pr

0.0

17.2

18.1

7.6

19.5

14.9

21.4

22.6

[IrCl(COD)]₂(2)

2.6

[IrCl(COD)]₂(2)

27.1

0.0

[IrCl(COD)]₂(2)

2.9/0.14

10.8

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities in mol% determined by qNMR against internal standard. [b]

Precatalyst and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D

= MeOH–H₂O (4:1). [d] Methyl acetal 4a, or iPr-acetal 4b, if denoted by a superscript Pr. If ketal 5 was detected, the quantity is given after a "/" separator. [e]

Allene 6 was an impurity (0.8 mol%) of 1. [f] Quantities of 11/12 (arenes/enynes, cf. Scheme 3) are expressed in mol% of 1 incorporated. [g] Recovery, sum of

analytically detected components from 1 in mol%. [h] Total R-CH₂OH (d_H3.64) in mol% of 1. [i] Unidentified products, calculated as [CH₂OH] - [recovery], see

text. [j] Reaction performed in air. [k] Includes 0.25% unknown acetalic product. TRIPHOS = MeC(CH₂PPh₂)₃; COD

bis(salicylidene)ethylenediamine; sal-J = Jacobsen's salen ligand;^[57]TMB = tetramethyl-cyclobutadiene.

= 1,5-cyclooctadiene; salen =

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Component recoveries of 72–81 mol% at near complete

[CH₂OH] recoveries mean that 15–23 mol% "unknowns" are

present in the reaction mixtures. To identify those components,

we performed an [IrCl(COD)]₂-catalyzed hydration of 1-octyne

(0.6 M) under else identical conditions of Table 4, entry 22. The

composition of crude product mirrored that obtained with 1.

Distillation of volatiles gave 2-octanone, some 1,1-dimethoxy-

octane and 1,5-cyclooctadiene. The distillation residue consisted

of poly-1-octyne (16), which was accompanied by 1,2,4- and

1,3,5-tri-n-hexylbenzene (17a/b) (Figure 3).

The ¹H and ¹³C NMR spectra displayed broadened alkyl- (d_H

0.7–3, d_C14–35) and olefinic signals (d_H5–6.5, d_C127 and 138)

which fit reference data for poly-1-hexyne.^[58]Cyclotrimerized

arenes are common side-products in alkyne polymerization, and

organorhodium- and -iridium compounds are established alkyne

polymerization catalysts.^{[59 ]}Oligomerization and polymerization

satisfactorily explain unassigned materials listed in the column

"unknown". Generation of insoluble polymers may also be

responsible in case of low recoveries of the [CH₂OH] integral.

Group 10 (Ni, Pd, Pt). Nickel-based alkyne hydration catalysts

are unknown.^[6]The first screen covering Ni(acac)₂, NiCl₂(PPh₃)₂,

NiCl₂(BINAP), and NiCl₂(PCy₃)₂did not find hydration activity

(Table S1, entries 128–135). Simple palladium salts only hydrate

substrates that profit from anchimeric assistance.^[6,60]

Pd(PPh₃)₄–HCl hydrates aryl acetylenes with uneven results,^[61]

while PdCl₂(BOX) brings about hydration via hydroalkoxylation

and in situ hydrolysis.^[62]Our 1-heptyne screen of several

palladium complexes (Table S1, entries 136–154) revealed

notable Markovnikov hydration activity for PdCl₂(COD) (20% K)

and PdCl₂(11% K). For the former, Markovnikov hydration

activity at low chemoselectivity was confirmed in the qNMR

screen (Table 5, entry 1). Transfer hydrogenation and olefin

isomerization are competing, but the high level of "unknowns"

points to alkyne polymerization as major side-reaction. This was

even more pronounced for an in situ cationic catalyst with a

secondary phosphine oxide ligand^[63](Table 5, entry 2). The

results clarify that palladium-catalyzed alkyne hydration without

anchimeric assistance cannot usually compete with alkyne

polymerization.

ArH

(1,3,5)

Polymer

ArH

Polymer

(1,2,4)

Polymer

4.1

2

6.0

1.0

17.1

ppm

6

5

4

3

1

ArH

Pol

ArH

Pol

ArH

Pol

ppm

140

130

30

20

10

Figure 3. Analysis of the distillation residue of an iridium-catalyzed 1-octyne

hydration reaction mixture, showing presence of arene trimerization products

(ArH; 1,2,4- and 1,3,5-17) and poly-1-octyne ("Pol"; 16) signals. Top: ¹H NMR

spectrum (500 MHz, CDCl₃). Bottom: ¹³C NMR spectrum (126 MHz, CDCl₃).

Table 5. HOT-CAT alkyne hydration screen of Ni, Pd and Pt compounds.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

R

Me

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

Catalyst (mol%)^[b]

PdCl₂(COD) (2)

Solv.^[c]

1

2

3

4a

6^[d]

0.0

0.5

0.6

7

8

9

11/12^[e]

2.1/–

3.5/–

2.6/3.2

0/0

Rec.^[f]

36.7

12.1

71.7

98.9

84.6

[CH₂OH]^[g]

99.8

Unk.^[h]

63.1

73.6

22.7

2.1

1

2

3

4

5

D

B

D

30.6

0.0

3.1

0.2

0.4

0.6

0.0

0.3

0.1

0.0

0.8

0.4

0.3

0.5

0.0

1.8

0.6

1.0

1.5

2.8

2.1

1.1

1.0

0.6

2.6

0.3

0.0

0.3

Pd(OAc)₂(4)–Men₂POH (8)–CSA (8)

PtCl₂(2)

2.8

85.7

41.8

84.2

62.6

18.5

12.1

18.5

94.4

(dppe)Pt(C₆F₅)₂(2)–CSA (10)

(BINAP)PtCl(C₆F₅)–AgOTf (2)

101.0

98.0

0/0

13.4

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Allene 6 was an impurity (0.8 mol%) in 1. [e] Quantities of 11 (arenes, cf. Scheme 3) are expressed in mol% of 1 incorporated; 12 (enynes, cf.

Scheme 3) was not reliably detected. [f] Recovery, sum of analytically detected components from 1 in mol%. [g] Total hydroxymethylene (d_H3.64) in mol% of 1. [h]

Unidentified products calculated as [CH₂OH] - [recovery], see text. Men₂POH = dimenthylphosphine-P-oxide;^[63]BINAP = (rac)-2,2'-bis(diphenylphosphino)-1,1'-

binaphthalene.

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Catalytic Markovnikov hydration with PtCl₂is established.^[6,64]

HOT-CAT screens confirm the activity (Table S1, entries 155–

157), but the qNMR screen implies that polymerization may

have been overlooked in earlier work (Table 4, entry 3).^[64]In situ

generated [(P–P)Pt(C₆F₅)]⁺-cations^[65]show comparable Markov-

nikov hydration activity, but higher chemoselectivity with less

polymerization (Table 5, entries 4, 5).

Table 6. HOT-CAT alkyne hydration screen of copper, silver and gold compounds.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

Me

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

Catalyst (mol%)^[b]

Solv.^[c]

1

2

3

4a/5^[d]

6^[e]

0.8

0.9

0.8

0.9

0.7

0.8

7

8

9

Rec.^[f]

99.9

95.0

97.8

99.6

100.7

88.8

95.1

98.6

[CH₂OH]^[g]

100.6

97.5

Unk.^[h]

1

2

3

4

5

6

7

8

[Cu(MeCN)₄]PF₆(4)

Cu-chlorophyllin (4)

B

D

94.9

3.1

0.3

0.4

0.1

0.4

0.6

0.2

0.0

0.8

2.1

1.6

0.7

1.0

1.4

1.2

n.d.^[i]

0.0

0.7

2.5

0.8

0.0

-0.1

-0.2

1.0

1.1

75.4

95.1

97.5

88.8

46.6

0.0

15.8

0.0

0.4/0.02

0.2

98.6

[Cu(salen)] (4)

0.5

0.0

99.6

Cu(OAc)₂–TPP (4)–CSA (10)

AuCl(tBuPyPPh₂) (2)

AuCl(tBuPyPPh₂)–AgOTf (2)

AuCl(THT)–Men₂POH (4)

9.6

0.3

100.6

88.6

39.3

91.6

39.5

0.4

1.0

96.1

57.0

0.9/0.1

99.7

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Methyl acetal 4a. If methyl ketal 5 was detected, its content is given after a "/" separator. [e] Allene 6 was an impurity (0.8 mol%) in 1. [f] Recovery,

sum of analytically detected components from 1 in mol%. [g] Total hydroxymethylene (d_H3.64) in mol% of 1. [h] Unidentified products, calculated as [RCH₂OH] -

[recovery], see text. [i] Not detected due to signal overlap. Arenes (11) or enynes (12; cf. Scheme 3) were not detected in any of the reactions from this table.

tBuPyPPh₂= 2-(tert-butyl)-6-(diphenylphosphino)pyridine;^[21]THT = tetrahydrothiophene.

ref.^[36a]). Table

6 adds examples for Au(I)-complexes of

Group 11 transition metals. The initial screen failed to show

hydration with Cu(acac)₂, Cu(BH₄)(PPh₃)₂, CuCl(PPh₃)₃, [CuCl-

(phen)(PPh₃)], Cu(salen), CuI(PtBu₃), Cu(OC₆H₄CHC=NiPr)₂,

Cu(salen-J) or Cu(SC₆H₄Me), if applied as such or in combina-

tion with ISIPHOS, CSA and sometimes AgOTf (Table S1,

entries 163–185). A little hydration (3% K) was seen with

Cu(salen)–CSA, and considerable activity with CuOTf·(C₆H₆)_0.5

(46% K; Table S1, entries 160–162). Cationic complex

[Cu(MeCN)₄]PF₆was then screened by qNMR, where it dis-

played promising activity in MeOH (Table 6, entries 1, 2).

Neither Cu-chlorophyllin or Cu(salen) displayed notable activity,

although the latter would probably have benefitted from an acid

additive (Table 6, entries 3, 4). Distinct, if low activity was seen

with Cu(II)–TPP–CSA (entry 5; cf. ref.^[10]).

tBuPyPPh₂(2-tert-butyl-6-diphenylphosphino-pyridine),^[21]whose

activities are comparable to those of AuCl(PPh₃) or

Au(SPhos)OTf for the chloro and triflate forms, respectively

(entries 6, 7; cf. Table 1, entries 11, 12). The ambifunctional

ligand does not appear to play a specific role. An in situ gold(I)–

SPO (secondary phosphine oxide)^[66]catalyst was no more

active than other AuCl-based complexes (Table 6, entry 8 vs 6

vs Table 1, entry 11).^[67]

Group 12 transition metals. Alkyne hydration with zinc is

characterized by high reaction temperatures and conditions

point to an acid-induced mechanism, which render that element

unattractive for our study.^[6]We did not wish to reinvestigate the

already well-known hydration activity of mercury.^[6,35,68]

Considering the toxicity of the latter and that of cadmium, group

12 was passed over in the present study.

The Markovnikov hydration activity of silver and gold is well

established and was not investigated much further (cf. Table 1,

entries 10–13). The 1-heptyne screen found activity for AgOTf

(18% K) and inactivity for AgOBz (Table S1, entries186–189; cf.

Focus screening with cationic Cu(I). The promising screening

results with CuOTf(PhH)_0.5and [Cu(MeCN)₄]PF₆pointed our

attention to cationic copper(I). Copper-catalyzed alkyne

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hydration has recently seen renewed^[6]interest.^[8a,69]Some

catalyst systems used Cu(OTf)₂in "dry" media (1–2 equiv. of

H₂O),^[8a,69c]i.e., under conditions that favor hidden Brønsted acid

catalysis^[70,71]and which may not be specific to copper.^[72]A less

acidic copper catalyst (Cu(OAc)₂) used trifluoroacetic acid as

reaction medium and was limited to haloalkyne substrates.^[69d]

Still other systems with CuCl/CuBr included aniline as co-

catalyst for hydroamination–hydrolysis of internal alkynes,^[69a]or

require irradiation with blue LED's over 12 h, and were limited to

aryl-alkynes.^[69b]Our focus screen centered on Cu₂O as cheap

and easy to handle metal precursor. Combinations with nitrogen

ligands like bipyridine, picolinic acid or nicotinic acid presented

little or no activity (Table 7, entries 1–3). A binary combination

with CSA gave Markovnikov hydration product with preference

for methanol as cosolvent (entry 4 vs 5). The activity of this

system was boosted by excess co-catalytic acid (entry 6). An

increase of catalyst loading led to full conversion of starting

material under screening conditions (entries 7, 8). The excess

acidity (formally 5 mol%, since 10 mol% of Cu₂O will neutralize

20 mol% of CSA) is lower than in the blank experiment (Table 1,

entry 14), excluding significant background activity of Brønsted-

acid. The major side-product is dimethyl acetal 4b, which could

either arise via addition of MeOH across the alkyne, or by

equilibrium acetalization of 3. Preferential acetalization of 3 to 4b

might feign an overly high addition regioselectivity (2/3 = 70:1).

Table 7. HOT-CAT alkyne hydration focus screen of Cu₂O derived catalyst systems.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

Me

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Catalyst (mol%)^[b]

Cu₂O (4)–bipy (10)

Entry

Solv.^[c]

1

2

3

4a/5^[d]

0.0

6^[e]

7

8

9

Rec.^[f]

99.9

[CH₂OH]^[g]

99.9

Unk.^[h]

1

2

3

4

5

6

7

8

D

B

D

97.6

95.9

92.3

65.4

91.2

26.8

37.3

0.0

0.1

0.3

0.2

0.5

0.2

0.8

1.2

0.8

0.9

0.8

0.3

0.7

0.9

0.8

1.4

2.2

1.6

1.4

1.8

2.5

1.5

1.6

0.0

0.5

0.0

0.2

0.0

-0.1

-0.4

1.4

1.6

0.0

1.1

5.1

Cu₂O (4)–Hpic (10)

Cu₂O (4)–Hnic (10)

Cu₂O (4)–CSA (4)

Cu₂O (4)–CSA (10)

Cu₂O (10)–CSA (10)

Cu₂O (10)–CSA (25)

1.5

0.2

101.0

100.4

96.4

100.9

100.0

97.8

5.3

0.2

28.1

4.1

0.7/0.04

0.0

98.0

99.6

65.7

53.8

85.4

2.2

98.9

1.5

95.8

96.9

2.9/0.1

92.8

97.9

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Methyl acetal 4a; if 5 was observed, its quantity is given after a "/". [e] Allene 6 was an impurity (0.8 mol%) in 1. [f] Recovery, sum of analytically

detected components from 1 in mol%. [g] Total hydroxymethylene (d_H3.64) in mol% of 1. [h] Unidentified products, calculated as [RCH₂OH] - [recovery], see text.

Hnic = nicotinic acid; Hpic = picolinic acid.

Iridium focus screen. Another focus screen explored ligand

effects on complex [IrCl(COD)]₂, which had shown a fair level of

hydration catalyst,^[56]but the system performed similar to

[IrCl(COD)]₂alone (entry 1), except showing higher levels of

activity in MeOH, albeit at low chemoselectivity (Table 8, entry 1). acetal 4a. A PyBOX ligand suppressed most catalytic activity

The ligand dppm (entries 2, 3) or ambifunctional AZARYPHOS

ligands^[21](entries 4, 5) did not accelerate hydration or invert

regioselectivity. The level of polymerization remained high (cf.

row "unknowns"). Chelating diphosphanes (entries 6, 7) or PPh₃

(entry 8) gave less active and selective hydration catalysts.

Tributylphosphane induced high activity for alkyne (transfer)

hydrogenation, alkene isomerization and alkyne polymerization,

but not hydration (entry 9). Triisopropylphosphite (entries 10, 11)

was supposed to give an approximation of Ishii's alkyne

except polymerization (entry 12), whereas bipyridines restored

the Markovnikov hydration and stimulated transfer

hydrogenation (entries 13–14). Fluorinated bipyridine with silver

triflate activation slightly increases Markovnikov hydration (entry

15). Brønsted acid activation of [IrCl(COD)]₂also increased the

hydration activity (entries 16–20), with the strong acid CSA and

a high acid-to-metal ratio giving the best result (entry 18). The

similarity of entries 18 and 20 indicate that iridium does not

complex with TPP under reaction conditions.

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Table 8. HOT-CAT alkyne hydration focus screen of iridium-COD catalyst systems.^[a]

Me

catalyst

Me

R

OR'

R

O

MeO OMe

R

R¹

R

R²

solvent–H₂O

O

OR'

R

1

160 °C, 15 min

2

3

4a (R' = Me)

4b (R' = iPr)

5

6

7a

7b

8a

8b

9

R = HO-(CH₂)₈

Entry

1

Catalyst (mol%)^[b]

Solv.^[c]

D

1

2

3

4/5^[d]

7

8

9

11/12^[e]

3.4/3.4

3.9/4.6

2.8/5.2

3.2/6.0

0/–

Rec.^[f]

72.8

69.9

58.5

55.6

29.3

60.2

61.0

40.4

47.6

67.9

68.3

63.7

72.8

74.5

80.0

94.6

75.1

78.3

70.2

72.1

81.9

60.5

65.8

56.5

63.3

[CH₂OH]^[g]

95.4

89.6

87.4

89.5

83.4

93.0

90.2

81.6

95.6

94.8

94.5

92.8

92.7

96.9

106.4^[i]

96.2

96.5

97.4

91.3

96.1

95.4

90.9

88.4

86.4

86.6

Unk.^[h]

29.6

28.3

36.9

33.9

54.1

32.8

29.2

41.2

48.0

26.9

26.2

29.1

19.9

22.4

26.4

1.6

[IrCl(COD)]₂(2)

0.0

1.5

44.3

38.2

7.6

1.7

2.5

1.6

2.9

0.7

2.1

1.2

0.6

2.5

2.8

1.7

1.6

1.7

1.5

1.8

1.0

0.8

0.6

1.6

1.0

1.7

1.9

1.8

0.5

2.9/0.14

2.5/0.1

1.6

10.8

9.9

4.0

4.8

4.0

6.5

7.3

3.0

2.8

7.7

13.9

0.5

1.5

4.8

5.1

12.2

4.6

4.0

3.7

3.1

2.1

3.5

3.2

6.8

6.6

6.7

5.9

2.1

1.9

4.7

2.3

6.0

5.0

3.2

3.8

13.3

13.0

5.8

2.3

2.0

5.2

2.1

2.3

2.4

2.2

1.1

4.3

2.0

3.8

3.6

3.2

2

[IrCl(COD)]₂(2)–dppm (2)

[IrCl(COD)]₂(2)–dppm (4)

[IrCl(COD)]₂(2)–ISIPHOS (2)

[IrCl(COD)]₂(2)–tAmPyPPh₂(8)

[IrCl(COD)]₂(2)–dppe (4)

[IrCl(COD)]₂(2) DPEPhos (4)

[IrCl(COD)]₂(2)– PPh₃(8)

[IrCl(COD)]₂(2)–PBu₃(8)

[IrCl(COD)]₂(2)–P(OiPr)₃(8)

D

3

D

26.2

1.6

4.8

4

D

22.8

2.4

2.6/0.05

0.2

7.6

5

D

9.9

2.9

6

D

34.0

37.9

20.0

0.0

3.1

1.1/0.1

0.5

3.5

2.0/6.3

5.4/–

7

D

7.4

2.7

8

D

3.0

0.2

2.7

2.5/–

9

D

0.0

0.6

17.2

5.8

0/–

10

11

12

13

14

15

16

17

18

19^[j]

20

21

22

23

24

25

D

0.0

32.0

38.5

6.4

6.5/0.14

4.3/0.1

0.5

4.2/2.9

4.6/2.6

4.0/3.0

1.0/2.3

3.2/2.8

3.6/3.2

3.1/3.4

3.1/3.2

2.3/2.0

2.0/2.6

5.1/2.7

2.3/2.0

4.8/2.0

4.4/1.8

4.8/3.1

3.5/3.3

[IrCl(COD)]₂(2)–P(OiPr)₃(2)–AgOTf (2)

[IrCl(COD)]₂(2)–Ph₂PyBOX (4)

[IrCl(COD)]₂(2)–bipy (4)

D

0.0

9.2

D

38.1

0.0

2.8

D

21.8

23.0

48.9

44.8

46.9

52.0

26.4

35.7

53.2

16.3

13.8

6.7

1.7/0.1

2.5/0.1

3.3/0.14

2.9/0.15

3.4/0.14

3.0/0.13

1.7/0.1

4.7/0.1

2.9/0.12

0.0

37.2

22.3

12.7

32.3

11.4

12.7

2.9

[IrCl(COD)]₂(2)–BTF-bipy (4)

[IrCl(COD)]₂(2)–BTF-bipy (2), AgOTf (2)

[IrCl(COD)]₂(2)–PivOH (10)

[IrCl(COD)]₂(2)–TFA (10)

D

1.6

D

0.0

D

0.0

D

0.0

21.5

19.1

21.1

24.0

13.5

30.4

22.6

29.9

23.3

[IrCl(COD)]₂(2)–CSA (10)

D

0.0

[IrCl(COD)]₂(2)–CSA (10)

D

30.8

0.0

[IrCl(COD)]₂(4)–CSA (10)

D

14.4

15.2

6.5

[IrCl(COD)]₂(2)–TPP (4)–CSA (10)

[Ir(OMe)(COD)]₂(2)–CSA (10)

D

0.0

A

18.7

28.7

26.9

8.1

B

0.0

5.0

C

0.0

3.1

D

30.5

1.4/0.1

6.8

[a] Conditions: 1 (50 µL, 0.26 mmol, 0.1 M), microwave heating (160 °C, 15 min). Product quantities by qNMR against internal standard in mol%. [b] Precatalyst

and ligand quantity in parantheses. [c] Solvent systems and volume ratios: A = 2-propanol–H₂O (10:3), B = acetone–H₂O (4:1); C = NMP–H₂O (4:1); D = MeOH–

H₂O (4:1). [d] Methyl acetal 4a and Ketal 5, if present. [e] Quantities of 11 (arenes) and 12 (enynes; cf. Scheme 3) are expressed in mol% of 1 incorporated. [f]

Recovery, sum of analytically detected components from 1 in mol%. [g] Total hydroxymethylene (d_H3.64) in mol% of 1. [h] Unknowns, calculated as [CH₂OH] -

[recovery], see text. [i] A high (>100%) recovery of [CH₂OH] points to generation of diol 10. [j] Reaction with oil bath heating for 15 h at 60 °C. BTF-bipy = 5,5'-bis-

trifluoromethyl-2,2'-bipyridine.

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Halide-free reaction systems from [Ir(OMe)(COD)]₂and CSA

showed incomplete conversion and low hydration selectivity,

irrespective of the solvent (entries 22–25). Generally, the focus

screen revealed that [IrCl(COD)]₂-based catalyst systems sli-

ghtly profit from co-catalytic Brønsted acid, while phosphane

ligands have little or negative effects. Hydration activity levels

remained limited (≤55%), since alkyne polymerization, hydrogen-

ation and alkene isomerization remain important side-reactions.

None of the steering ligands boosted alkyne hydration or

affected its regioselectivity notably.

Markovnikov regioselectivity of the iridium catalysts. The

preparative run with 1 closely reproduced the screening result,

and the yield of chromatographically purified 2 was close to the

analytical value. Aryl acetylene 18 was hydrated with low

chemoselectivity, and the yield was mediocre (Table 9, entry 2).

Alkyne polymerization is the major side-reaction. Another

catalyst system is Co(OAc)₂–TPP–CSA in air, which is easy to

set up and had shown favorable results in the screen (Table 4,

entry 8). This was confirmed by the high isolated yields of 2 and

19, both of which approached the analytical yields (Table 9,

entries 3, 4). The third new catalyst tested is the simple Cu₂O–

CSA system. It performed equally effective in the hydration of 1

Preparative runs with new catalyst systems. The utility of

reaction conditions found in HOT-CAT screens was validated by

applying three promising catalyst systems in preparative

hydration runs with each an aliphatic (1) and an aryl-substituted

(4-tert-butylphenylacetylene; 18) acetylene as substrate. The

reaction conditions were as in the screening, except for working

at higher concentration. The system [IrCl(COD)]₂–CSA (cf. Table

8, entry 18) had shown complete conversion and highest

and 18, giving methyl ketones

2 and 19 in high yield.

Chromatographic purification of the latter was complicated by

the presence of methyl-acetal, thus 19 was isolated as

crystalline dinitrophenylhydrazone (20).

Table 9. Preparative hydration with three selected new catalyst systems.^[a]

catalyst–ligand–additive

O

R

MeOH–H₂O (4:1)

R

Me

160 °C, 15 min

Entry

1

Catalyst system (mol%)^[b]

[IrCl(COD)]₂(2) – CSA (10)

Solvent

Substrate

Product

Yield (spectr.)^[c]

57

Yield (isol.)^[d]

54

MeOH–H₂O (4:1)

Me

HO

7

1

O

2

MeOH–H₂O (4:1)

2

[IrCl(COD)]₂(2) – CSA (10)

38

35

O

tBu

Me

18

19

2

MeOH–H₂O (4:1)

1

18

1

3

4

5

6

Co(OAc)₂(4) – TPP (4) – CSA (25)

Cu₂O (10) – CSA (25)

83

98

85

82

19

2

95

85

72^[e]

18

19

Cu₂O (10) – CSA (25)

[a] Conditions: 1 (200 µL, 1.04 mmol, 0.20 M); 18 (200 µL, 1.11 mmol, 0.21 M), MeOH (4.0 mL), H₂O (1.0 mL), microwave heating for 15 min at 160 °C. [b]

Precatalyst and ligand quantity in parentheses. [c] qNMR yield in mol% of substrate, determined against internal standard. [d] Isolated yields. [e] Yield of 2,4-

dinitrophenylhydrazone after precipitation and recrystallization from EtOAc.

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hydration (for stoichiometric precedence, see ref.^[75]). Transfer

hydrogenation, isomerization and polymerization were major

side-reactions. Further development is necessary to test if ligand

effects can steer this activity further towards hydration.

A glimpse of anti-Markovnikov hydration activity was seen with

[RhCl(COD)]₂(5.8% A, 1.4% K; Table 4, entry 14), but only in

acetone, and at low activity and chemoselectivity. anti-

Markovnikov selectivity was also observed for Cp*RuCl₂–

ISIPHOS in the 1-heptyne screen (Table S1, entries 68, 69),

where the active species may have been related to known

catalyst [CpRu(ISIPHOS)₂]⁺.^[30,44]Albeit low, it is the first

demonstration of such activity for a Cp*Ru system.

Discussion

Newly detected catalyst systems from screening results. All

of the established Markovnikov- and anti-Markovnikov-selective

alkyne hydration catalysts tested in the HOT-CAT screen

returned a positive result (Table 1; Table 2 for Ru; Table 5 for Pt;

Table 6 for Au). This provides a benchmark by proving that the

screen positively identifies active catalysts. The high reaction

temperature and short reaction time did not prevent observation

of catalytic activity with heat-sensitive systems (e.g., Ag(I),

Au(I/III)) whose thermal deactivation is reflected by lower

conversions.

Chemoselectivity was an issue with the moderately active

systems RhCl₃(TRIPHOS) (8% K; Table 4, entry 18),

PdCl₂(COD) (up to 20% K, Table S1, 144) and PdCl₂(11% K,

Table S1, 136 or 3% K, Table 5, entry 1). For the palladium-

catalysts, alkyne polymerization is the major side-reaction, which

explains the requirement for anchimeric assistance in successful

Pd-catalyzed alkyne hydrations.^[6]

The screens revealed many new findings, which can be divided

into sub-categories based on activity and novelty, if compared to

previously established catalyst systems:

1) Highly active catalysts with close analogy to established

systems: High activity was detected for Co-TPP-CSA (90% K;

highly chemoselective; Table 4, entry 8; also cf. Table 9, entries

3 and 4), [IrCl(COD)]₂(44% K; low chemoselectivity; Table 8,

entry 1) and Au(tBuPyPPh₂)OTf (92% K; Table 6, entry 7).

Those are more or less obvious variations of reported catalyst

systems (Co^[10], Ir,^[56]Au^[34]). Yet there are novel aspects, such

as the use of the simple TPP ligand with cobalt, as opposed to

its water-soluble sulfonated version. The relatively high catalytic

activity of [IrCl(COD)]₂with acid (e.g., Table 8, entry 18), or of

the complex alone (Table 8, entry 1), had not specifically been

reported, although Ishii had devised the optimized system

[IrCl(COD)]₂–P(OiPr)₃–ZrCl₄in MeOH as highly selective alkyne

hydration catalyst.^[56]Their screening data infer that both

P(OiPr)₃and ZrCl₄must be present to achieve high chemoselec-

tivity.

Catalytic activity besides the target hydration. All reaction

products are analyzed in our HOT-CAT screen, rather than

focusing on a specific target. Ideally, this provides information

about all important side-reactions. New or unexpected reactions

may be found, and knowledge of side-reactions can give hints

towards optimizing the target reaction. Our first screen with 1-

heptyne and using GC-MS analysis was unsatisfactory in this

regard, since the identification of "off-target" products in the

complex hydrocarbon mixture (containing heptene isomers,

heptyne dimers, -trimers, arenes etc.) was insecure, and

quantification of each compound would have required reference

samples. Consequently, the recoveries in that screen were often

low. This situation was amended by the new HOT-CAT screen

with alkyne 1 in combination with qNMR analysis. NMR signals

provide structural information, and new compounds could be

assigned based on literature data. Groups of similar compounds

(e.g., 7a/b, 8a/b, 9, total hydroxymethylene [CH₂OH]) are

captured by area integration. Recoveries were typically in the

95–102% range (79 out of 105 runs), and outliers could be

ascribed to polymer generation. Alkyne polymerization was the

single most important side-reaction, most prominent for (%

referring to mol% of 1): Pd(OAc)₂–Men₂POH–CSA (74%),^[76]

PdCl₂(COD) (63%), [IrCl(COD)]₂–PR₃(28–54%), PtCl₂(23%),

[IrCl(COD)]₂(15–23%), [RhCl(COD)]₂(19%, 23% with ISIPHOS,

15% with dppm).^[54,77]Even though alkyne dimerization is a very

common metal-catalyzed reaction of alkynes,^[25]it was

conspicuously absent from our screens, where dimers were

found to notable extent only with [RhCl(COD)]₂–ISIPHOS (18%)

and [IrCl(COD)]₂–(P–P) (4–6%; P–P = chelating diphosphine).

Presumably, dimers formed in other reactions underwent

polymerization under HOT-CAT reaction conditions.^[78]

2) Notable activity, moderate analogy to known systems: The

activities of CuOTf·(PhH)_0.5(Table S1, 160; 46% K) or

[Cu(MeCN)₄]PF₆(Table 6, entry 2; 16% K) from the screen were

regarded as very promising, since simple cationic Cu(I) had not

previously been reported for alkyne hydration. A focus screen

identified the co-catalytic effect of Cu(I) and H⁺in the practical

Cu₂O–CSA catalyst (Table 7; 85% K). The system is active in

aqueous methanol at low acidity and is thus different from

recently published Cu(OTf)₂-based systems, which work in

acidic media with a preference for aryl-alkynes.^[8c,69]An earlier

Cu(II)-system of Meier and Marsella in alcoholic solution^[60]may

well have contained a similar active component formed by

reaction of Cu(II) with alcohol.^[71]

The complex cations [(P–P)Pt(C₆F₅)⁺] (18.5%

K at 37%

conversion with BINAP, 12% K at 16% conversion with dppe;

Table 5, entries 4, 5) are chemically distinct from older platinum-

systems based on PtCl₂alone, or chloro complexes with alkene

and phosphane steering ligands.^[6,73]Those fluoroarylplatinum(II)

cations were studied for alkene epoxidation catalysis by

Strukul,^[65,74]but now also appear as development candidates for

catalytic alkyne hydration.

3) Low activity, at various degrees of analogy to existing

systems: Significant alkyne hydration activity, although not at

useful levels because of low chemoselectivity and turnover, was

detected with (NH₄)₂[OsCl₆] (13% K, 67% conversion; Table 3,

entry 15) as novel type of central metal in catalytic alkyne

Alkyne trimerization to arenes was seen with [RhCl(COD)]₂(13%

in acetone), and generally with Rh- and Ir- complexes at levels

up to 5% (referring to mol% of

1 incorporated). Some

trimerization also occurred with [(C₆H₆)Co(TMB)]⁺(4%).

Transfer-hydrogenation, alkene isomerization. A family of

metal-hydride induced reactions converts alkyne 1 to either

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terminal alkene 8a and/or alkane 7a by transfer-hydrogenation,

presumably involving solvent as hydride-donor. Once the alkene

stage is reached, double-bond isomerization to internal alkenes

9 may occur. Alkyne-semihydrogenation/alkene isomerization

activity was distinctive with (NH₄)₂OsCl₆, where such pathways

(including alkene hydrogenation) accounted for a remarkable

75% in the solvent iPrOH (Table 3, entry 12).^[79]Complex

[IrCl(COD)]₂apparently favors alkene hydrogenation of 1 to 7a

(Table 4), but since this was found alike in iPrOH (entry 19) and

acetone (entry 20), an alternative explanation that 7a was

formed through a chain-walking redox-isomerization involving

the –CH₂OH unit may be considered.^[80]

(entries 4–8). The final catalyst system was suitable for

preparative applications (Table 9).

Conclusions

We have proposed the HOT-CAT (homogeneous thermal

catalysis; i.e. homogeneous catalysis at unusually high

temperatures) screening approach as a tool to discover new

catalysts systems for a predefined organic transformation. A

peculiarity of this approach is that all test runs are performed at

the same set of reaction parameters at a deliberately high

temperature for a short reaction time. By fixing many reaction

variables to constant values (temperature, time, concentration),

and others to only few predefined settings (solvent type A–D,

acid additive (yes/no)), the number of experiments in the

screening of a variety of chemically distinct catalyst systems

remains small. Concurrently, the short reaction time and

standardized workup/analysis render the procedure efficient.

The bottlenecks are sample preparation and -analysis which

require a skilled operator.

Utility and limitations of the HOT-CAT screening approach.

The HOT-CAT approach has proven suitable for broad-band

screening across a large part of the periodic table. In spite of the

elevated reaction temperature, there is neither extensive

background reaction (e.g. by Brønsted acid) nor loss of starting

material by non-productive decomposition. The screen is

specific for catalytic activity by metal complexes and provides a

wealth of information about the target reaction, accompanying

side-reactions and about the catalyst systems tested. The

number of side-reactions and side-products which were

identified and analyzed for all individual catalyst systems in this

study exceeds that which has been presented in published

focused optimization studies for singular catalyst systems. Such

data ensures comparability between diverse catalyst systems

and will provide useful as reference in future searches for alkyne

hydration catalysts.

At least two new promising catalyst systems of relevance for

preparative application have emerged from the current work,

namely Cu₂O–CSA and Co(OAc)₂–TPP–CSA in MeOH–H₂O

(4:1), which both were run under the same microwave conditions

(160 °C, 15 min) of the screening and provided 72–95% isolated

yield of product in 4 runs with an aliphatic and an aryl acetylene.

One of the motivations behind the screen was the search for

new (non CpRu⁺-) types of anti-Markovnikov hydration catalysts.

Notwithstanding indications of (low) anti-Markvonikov hydration

activity with [RhCl(COD)]₂(Table 4, entry 14), this search has

not yet proven successful. The approach to invert

regioselectivity by systematically combining ambifunctional

pyridylphosphane ligands with metal precursor complexes was

so far not effective.

Nevertheless, the HOT-CAT screen has allowed us to realize an

unprecedentedly broad comparative overview of catalytic alkyne

hydration and its accompanying reactions. We propose that as

analytical tools progress, such generalized screens may be

planned and performed as multi-reaction screens, in which the

focus is no longer on a single target reaction, but as many

Reaction development experience gained in the HOT-CAT

screen. The HOT-CAT screen keeps many reaction variables at

fixed parameters and potentially deviates strongly from optimal

or even satisfactory conditions. The development history of the

practically applied catalyst systems (Table 9) provides critical

case-studies: A first screen with cobalt was carried out in

2011,^[81]prior to the report on water-soluble Co-porphyrin-

catalyst systems by Naka.^[10]Seven runs (CoCl₂, Co(OAc)₂,

vitamin B₁₂; each alone and with ISIPHOS; Co(OAc)₂

additionally with ISIPHOS–CSA (Table S1, entries 101–107)

displayed ≤10% conversion and no hydration product. The aim

of the study at the time was to explore new alkyne hydration

activity by harnessing potential accelerating effects of ambi-

functional ligands, and the outcome for cobalt was negative. In

this instance, the HOT-CAT screen failed to uncover a new type

of activity, because a specific ligand (porphyrin type) was not

considered for testing. More recently, and aware of Naka's

results, we performed another screen (Table 4, entries 1–8) with

cobalt. Vitamin B₁₂displayed no activity with co-catalytic acid or

iron(III)triflate. The switch to Co(OAc)₂–TPP proved partially

successful (Table 4, entry 6). The positive effects of oxygen and

co-catalytic acid were then recognized in two additional

experiments, providing the final catalyst system (Table 9).

With iridium, considerable activity was found with the simple

metal precursor complex [IrCl(COD)]₂in iPrOH–H₂O (Table 4,

entry 19). Solvents were then varied (entries 20–22), and MeOH

identified as best choice. The strategy to improve the low

chemoselectivity through steering ligand effects in a focus

screen failed (Table 8). Oligo- and polymerization were key

distractors of this catalysis. The best conditions combine

[IrCl(COD)]₂with Brønsted acid, and this system was applied in

two preparative runs, which still suffered from limited chemose-

lectivity (Table 9).

The catalytic activity of cationic copper(I) was obvious in the ini-

tial screen with CuOTf (46% K; Table S1, entry 160). Lowering

the catalyst loading and temperature with [Cu(MeCN)₄]PF₆

reduced the yield to 3%, whereas a solvent change to methanol

increased it once again to 16%. In spite of the low yield, the

chemoselectivity was high, which was taken as a hint to

"intensify" the reaction conditions (e.g., increase reaction

temperature, -time or acidity level). A Cu(I) focus screen with

Cu₂O is a simple precursor for cationic Cu(I) with acids was

performed (Cu₂O + 2 HX = 2 Cu⁺+ 2 X^–+ H₂O; Table 7). The

standard Brønsted acid additive of our screen, CSA^[37]proved

suitable, and, revealed a co-catalytic effect when used in excess

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Ir-catalyzed hydration of 1-octyne with product fractioning

reactions as analytical tools allow (cf. the concept of an

undirected screen, ref.^[5]) In that sense, rather than screening for

specific new catalyst systems, one will screen for reaction

systems and optimize established reactions while searching for

new ones.

[IrCl(COD)]₂-catalyzed hydration of 1-octyne: A 10 mL microwave vial

with a PTFE stirring bar was loaded in air with [IrCl(COD)]₂(40.9 mg,

60.7 µmol, 0.02 eq.). The vessel was placed under argon (3 cycles of

evacuation and argon flooding). In an argon counter-stream, water (1.0

mL, 55.5 mmol, 18.2 eq.), degassed MeOH (4.0 mL) and 1-octyne (450

µL, 336 mg, 3.05 mmol, 1 eq.) were added. The vial was capped and

placed into a microwave reactor for heating at 160 °C for 15 min (holding

time at target temperature). The cooled reaction solution was diluted with

Et₂O (10 mL) and completely transferred into a separatory funnel, the

vessel being washed with additional Et₂O (2 × 5 mL). The organic phase

was washed with H₂O (3 × 15 mL) and sat. aq. NaCl (10 mL). The

combined aq. phase was washed with Et₂O (10 mL). The combined

organic phases were dried (MgSO₄), filtered and evaporated (at 850

mbar, then shortly at 650 mbar). After addition of 1,1,2,2-

tetrachloroethane (100 µL, 159 mg, 947 µmol), a sample (0.1 mL) was

removed into an NMR tube and diluted with CDCl₃(0.5 mL) for qNMR

analysis. Composition of the crude (mol%): 1-octyne (0.0%), octanal

(0.6%), 2-octanone (42.3%), heptane (n.d.), 1-octene (2.2%), int. alkenes

(2.5%), 1,1-dimethoxyoctane (2.5%), tri-n-hexylbenzene isomers (7.5%,

in molar units of 1-octyne), enynes (ca. 2.6%, dito); component recovery:

60.2%; area integral for methyl end groups RCH₃: 89.6%; the difference

89.6–60.2 = 29.4% will approximately reflect poly-1-octyne.

Experimental Section

Unless otherwise specified, all reagents and solvents were obtained from

commercial suppliers and used without further purification. Solvents used

in catalytic reactions were purified by passing through a column of Al₂O₃

and kept under an argon atmosphere. Column chromatography (CC) was

performed on silica gel 60 (35–70 µm particle size), usually as a flash

chromatography with 0.2 bar positive air pressure. Thin layer

chromatography was performed on glass plates coated with silica gel 60

F₂₅₄and visualized with UV light (254 nm) or Mostain (molybdenum stain

with Ce(SO₄)₂catalyst in H₂SO₄aq). NMR spectra were recorded at

ambient temperature (19–24 °C). ¹H NMR spectra were internally

referenced to tetramethylsilane (TMS, d 0.00) or residual solvent peaks

(CDCl₃d 7.26; (D₆)-DMSO d 2.50). Measurements for qNMR analysis

used 16 scans and a pulse relaxation delay d1 of 20 seconds. ¹³C NMR

spectra were referenced to TMS (d 0.00) or solvent peaks (CDCl₃

77.16; (D₆)-DMSO d 39.52).

d

Product fractioning: After combining the NMR sample with the crude

product, solvent was removed and the residue was vacuum-distilled

using a short-path distillation unit, initially up to 120 °C/35 mbar (fractions

1 and 2). The receiving vessels were changed and the distillation

continued up to 140 °C/0.6 mbar (fraction 3, fraction 4 = residue). The

fractions were analyzed by ¹H NMR spectroscopy: fraction 1 (volatile,

receiving vessel cooled), 274 mg, contains 2-octanone, 1,1-dimethoxy-

octane, little 2,2-dimethoxyoctane, octanal, 1-octene; also contains

General microwave–qNMR screening procedure with alkyne 1

Sample preparation: To a microwave glass vial containing a magnetic

stirring bar, the metal precursor or -complex, the ligand, and/or any other

additive were added. The glass vial was placed into a Schlenk vessel (29

mm diameter opening) and placed under argon by evacuating and filling

with argon thrice. Solvent (2.0 mL), water (0.5 mL; 0.6 mL in case of

solvent combination A with iPrOH) and 10-undecyn-1-ol (1; 50 µL, 0.26

mmol) were added to the vial in an argon counter-stream. The glass vial

was closed with a corresponding standard cap and placed into the

microwave reactor, where it was heated to 160 °C with a holding time of

15 minutes. The cooled reaction solution was transferred into a 10 mL

headspace glass vial (for GC analysis), which contained the internal

standard for qNMR analysis (e.g., 20–25 mg of 1,3-dinitrobenzene). Ethyl

ether (3 x 2 mL) was used to complete the transfer. The content of the

capped headspace vial was homogenized by intense shaking. A quantity

of 0.5 mL of the resulting solution was removed into a 5 mL headspace

vial, where it was diluted with ethyl ether (2 mL) and washed with water

(2 x 2 mL) [5 drops of sat. aq. NaCl were added to speed up phase

separation] and sat. aq. NaCl (2 x 2 mL) by intense shaking and removal

of the lower water phase by a Pasteur pipette after phase separation.

The organic phase was transferred into a 5 mL headspace vial (with

stirring) containing MgSO₄(300 mg) and a magnetic stirring bar. The vial

was closed with a butyl rubber septum and sealed with an aluminum cap.

The suspension was magnetically stirred (1200 rpm) while vacuum was

applied by placing a hypodermic needle connected to a water aspiration

pump into the septum. A low vacuum (ca 500 mbar, weak water flow in

the pump) was initially applied to remove the majority of Et₂O, after which

the solid contents of the vial showed a dry, powdery appearance. A

stronger vacuum (full water flow, ca. 20 mbar) was then applied for

another 2 minutes. The solid residue was extracted with CDCl₃(0.6–0.8

mL) by magnetically stirring for 5 minutes, and the suspension was

filtered through a cotton plug into an NMR tube for analysis.

1,1,2,2-tetrachloroethane and 1,5-cyclooctadiene; fraction

2 (volatile,

receiving vessel not cooled), 86.7 mg, composition similar to fraction 1,

but contains more 1,1-dimethoxy-octane; fraction 3 (distillate): 19.2 mg,

aldol condensation products, alkyne dimers; fraction

4 (distillation

residue): 151 mg, cyclotrimerization products (1,2,4- and 1,3,5-isomers),

broad signals for poly-1-octyne.

NMR-Analysis of the distillation residue: ¹H NMR (500 MHz, CDCl₃):

poly-1-octyne: d 0.73–1.04 (m, CH₃), 1.07–1.75 (m, CH₂), 1.86–2.72 (m,

CH₂), 4.94–6.45 (m, C=CH); 1,3,5-tri-n-hexylbenzene: d 6.80 (s, 3 H,

ArH); 1,2,4-tri-n-hexylbenzene: d 6.91–6.97 (m, 2 H, ArH), 7.04 (d, J =

7.6 Hz, 1 H, ArH). ¹³C{¹H} NMR (126 MHz, CDCl₃): poly-1-octyne;^[58]

14.1 (br, CH₃), 22.7 (br, CH₂), 29.3 (br, CH₂), 31.8 (br, CH₂), 126.5–127.5

(C=CH), 138.7–139.3 (C=CH); 1,3,5- and 1,2,4-tri-n-hexylbenzene;^[59]

d

14.2, 22.8, 29.3, 29.6, 31.5, 31.7, 31.7, 31.9, 32.5, 32.9, 35.7, 36.1,

125.8, 125.9, 129.0, 129.3, 137.8, 140.2, 140.4, 142.8.

Preparative hydration of alkynes with [IrCl(COD)]₂–CSA

11-Hydroxyundecan-2-one (2): A 10 mL microwave vial with a stirring

bar was loaded in air with [IrCl(COD)]₂(14.0 mg, 20.8 µmol, 0.02 eq.)

and camphorsulfonic acid (24.2 mg, 104 µmol, 0.1 eq.). The vessel was

evacuated and flooded with argon thrice. In an argon counter-stream,

degassed H₂O (1.0 mL, 55.5 mmol, 52.9 eq.), degassed methanol (4.0

mL) and 10-undecyn-1-ol (1; 200 µL, 176 mg, 1.05 mmol, 1 eq.) were

added to the contents. The vial was capped and placed into the

microwave unit, where it was heated to 160 °C for 15 min (holding time at

target temperature). The cooled reaction mixture was transferred into a

separatory funnel and the vial washed with Et₂O (4 × 5 mL). The organic

phase was washed with water (3 × 15 mL) and sat. aq. NaCl (10 mL),

and the aq. phase was extracted with Et₂O (10 mL). The combined

Data analysis. ¹H NMR spectra were recorded with 16 scans using a

relaxation delay (d1) of 20 seconds. After phase- and baseline-correction,

the relevant signal integrals as detailed in Figure S1 and Table S3 were

collected for evaluation.

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organic phase was dried (MgSO₄), filtered and evaporated under

reduced pressure. To the residue, 1,3-dinitrobenzene was added (41.2

mg, 245 µmol) and the materials were homogeneously dissolved in

CDCl₃(0.7 mL). An aliquot (0.2 mL) was removed and placed into an

NMR tube with additional CDCl₃(0.3 mL) for qNMR analysis.

Composition (mol%): starting material (0.0%), aldehyde (0.7%), ketone

(56.9%), allene (0.0%), n-alkanols (9.1%), terminal alkene (2.3%),

internal alkenes (2.1%), dimethyl acetal (2.3%), component recovery

(73.4%), recovery of [CH₂OH] (98.9%). The NMR sample was combined

with the remainder material and the solvent removed in vacuum.

Purification by CC (SiO₂, EtOAc–hexanes 1:5→1:2) gave 11-

hydroxyundecan-2-one (2; 104 mg, 54%) as colorless solid after drying in

HV. R_f0.40 (EtOAc–hexanes 1:1, Mostain). M.p. 42.1–42.3 °C. ¹H NMR

(400 MHz, CDCl₃): d 1.24–1.46 (m, 10 H, 5×CH₂), 1.43 (br s., 1 OH),

1.52–1.61 (m, 4 H, 2×CH₂), 2.13 (s, 3 H, CH₃), 2.42 (t, J = 7.5 Hz, 2 H,

COCH₂), 3.64 (t, J = 6.6 Hz, 2 H, CH₂OH). ¹³C{¹H} NMR (101 MHz,

CDCl₃: d 23.83, 25.70, 29.13, 29.29, 29.33, 29.38, 29.84, 32.77, 43.79,

63.02, 209.36. Known compound, CAS-No. 35345-72-3.

An aliquot (0.2 mL) was removed and placed into an NMR tube with

additional CDCl₃(0.3 mL) for qNMR analysis. Composition (mol%):

starting material (9.4%), aldehyde (0.3%), ketone (83.2%), allene (0.7%),

n-alkanols (0.0%), terminal alkene (0.2%), internal alkenes (0.0%),

dimethyl acetal (0.8%), component recovery (94.6%); the quantities were

referenced to the [CH₂OH]-signal (d_H3.60, 2 H) at 200%. The NMR

sample was combined with the remaining material and the solvent

removed in vacuum. The residue was distilled in vacuum (0.6 mbar/up to

120 °C) to give 180 mg of colorless solid, which was further purified by

CC (SiO₂, EtOAc–hexanes 1:10→1:4) to give 11-hydroxyundecan-2-on

(2; 160 mg, 82%) as colorless solid. See above for characterization data.

4-tert-Butylacetophenone (19): A 10 mL microwave vial with a stirring

bar was loaded in air with Co(OAc)₂(11.0 mg, 44.2 µmol, 0.04 eq.),

tetraphenylporphyrin (27.3 mg, 44.4 µmol, 0.04 eq) and camphorsulfonic

acid (64.4 mg, 277 µmol, 0.25 eq.). H₂O (1.0 mL, 55.5 mmol, 50 eq.),

methanol (4.0 mL) and 4-tert-butylphenylacetylene (18; 200 µL, 176 mg,

1.11 mmol, 1 eq.) were added to the contents in air. The vial was capped

and placed into the microwave unit, where it was heated to 160 °C for 15

min (holding time at target temperature). The cooled reaction mixture

was transferred into a separatory funnel and the vial washed with Et₂O (4

× 5 mL). The organic phase was washed with water (3 × 15 mL) and sat.

aq. NaCl (10 mL), and the combined aq. phase was extracted with Et₂O

(10 mL). The combined organic phase was dried (MgSO₄), filtered and

evaporated under reduced pressure. To the residue, 1,3-dinitrobenzene

was added (40.2 mg, 239 µmol) and everything was dissolved in CDCl₃

(0.7 mL). An aliquot (0.2 mL) was removed and placed into an NMR tube

with additional CDCl₃(0.3 mL) for qNMR analysis. Composition (mol%):

starting material (0.0%), aldehyde (0.0%), ketone (98.4%), dimethyl

acetal (0.0%), component recovery (98.4%). The NMR sample was com-

bined with the remainder of material and the solvent removed in vacuum.

Shortpath-distillation (up to 90 °C/0.7 mbar) removed the catalyst resi-

dues to give 221 mg of colorless oil, which was further purified by CC

(SiO₂, EtOAc–hexanes 1:20) to give 4-tert-butylacetophenone (19; 187

mg, 95%) as colorless oil. See above for analytical data.

4-tert-Butylacetophenone (19). A 10 mL microwave vial with a stirring

bar was loaded in air with [IrCl(COD)]₂(14.9 mg, 22.2 µmol, 0.02 eq.)

and camphorsulfonic acid (25.7 mg, 111 µmol, 0.1 eq.). The vessel was

evacuated and flooded with argon thrice. In an argon counter-stream,

degassed H₂O (1.0 mL, 55.5 mmol, 50 eq.), degassed methanol (4.0 mL)

and 4-tert-butylphenylacetylene (18; 200 µL, 176 mg, 1.11 mmol, 1 eq.)

were added to the contents. The vial was capped and placed into the

microwave unit, where it was heated to 160 °C for 15 min (holding time at

target temperature). The cooled reaction mixture was transferred into a

separatory funnel and the vial washed with Et₂O (4 × 5 mL). The organic

phase was washed with water (3 × 15 mL) and sat. aq. NaCl (10 mL),

and the combined aq. phase was extracted with Et₂O (10 mL). The com-

bined organic phase was dried (MgSO₄), filtered and evaporated under

reduced pressure. To the residue, 1,3-dinitrobenzene was added (41.1

mg, 245 µmol) and the materials were dissolved homogeneously in

CDCl₃(0.7 mL). An aliquot (0.2 mL) was removed and placed into an

NMR tube with additional CDCl₃(0.3 mL) for qNMR analysis.

Composition (mol%): starting material (0.0%), aldehyde (0.3%), ketone

(38.0%), dimethyl acetal (1.0%), component recovery (39.3%). Broad

signals (d_H6.5–7.5) indicate the presence of polymeric material. The

NMR sample was combined with the remainder of material and the sol-

vent was removed in vacuum. Purification by CC (SiO₂, EtOAc–hexanes

1:50→1:20) gave 92.6 mg of a yellowish oil. Shortpath-distillation (up to

75 °C/0.7 mbar) gave 4-tert-butylacetophenone (19; 68.9 mg, 35%) as

colorless oil. R_f0.63 (EtOAc–hexanes 1:5, UV). ¹H NMR (300 MHz,

CDCl₃): d 1.34 (s, 9 H, CMe₃), 2.58 (s, 3 H, COMe), 7.43–7.52 (m, 2 H,

Ar-H), 7.86–7.94 (m, 2 H, Ar-H). ¹³C{¹H} NMR (75 MHz, CDCl₃): d 26.55,

31.09, 35.10, 125.49, 128.28, 134.62, 156.81, 197.84. Known compound,

CAS-No. 943-27-1, data consistent with ref.^[82]

Preparative hydration of alkynes using the Cu₂O–CSA system

Hydration of 10-undecyn-1-ol (1) to 11-hydroxyundecan-2-one (2): A

10 mL microwave vial with a stirring bar was loaded in air with Cu₂O

(14.9 mg, 104 µmol, 0.1 eq., 20 mol% [Cu]) and camphorsulfonic acid

(60.4 mg, 260 µmol, 0.25 eq.). The vessel was evacuated and flooded

with argon thrice. In a counter-stream of argon, water (1.0 mL, 55.5 mmol,

53 eq.), methanol (4.0 mL) and 10-undecyn-1-ol (1; 200 µL, 176 mg, 1.05

mmol, 1 eq.) were added to the contents. The vial was capped and

placed into the microwave unit, where it was heated to 160 °C for 15 min

(holding time at target temperature). The cooled reaction mixture was

transferred into a separatory funnel and the vial washed with Et₂O (4 × 5

mL). The organic phase was washed with water (3 × 15 mL) and sat. aq.

NaCl (15 mL), and the combined aq. washing phase was reextracted with

Et₂O (10 mL). The combined organic phase was dried (MgSO₄), filtered

and evaporated under reduced pressure. Purification by CC (SiO₂,

EtOAc–hexanes 1:10→1:4) gave 11-hydroxyundecan-2-one (2; 166 mg,

85%) as colorless solid after drying in HV. Analytical data coincided with

previous samples, see above.

Preparative hydration of alkynes with Co(OAc)₂–TPP–CSA

11-Hydroxyundecan-2-one (2): A 10 mL microwave vial with a stirring

bar was loaded in air with Co(OAc)₂(10.4 mg, 41.8 µmol, 0.04 eq.),

tetraphenylporphyrin (25.6 mg, 41.6 µmol, 0.04 eq.) and camphorsulfonic

acid (60.5 mg, 260 µmol, 0.25 eq.). H₂O (1.0 mL, 55.5 mmol, 53 eq.),

methanol (4.0 mL) and 10-undecyn-1-ol (1; 200 µL, 175 mg, 1.04 mmol,

1 eq.) were added to the contents in air. The vial was capped and placed

into the microwave unit, where it was heated to 160 °C for 15 min

(holding time at target temperature). The cooled reaction mixture was

transferred into a separatory funnel and the vial washed with Et₂O (4 × 5

mL). The organic phase was washed with water (3 × 15 mL) and sat. aq.

NaCl (10 mL), and the aq. phase was extracted with Et₂O (10 mL). The

combined organic phase was dried (MgSO₄), filtered and evaporated

under reduced pressure. The residue was dissolved in CDCl₃(0.7 mL).

4-tert-Butylacetophenone 2,4-dinitrophenylhydrazone (20): A 10 mL

microwave vial with a stirring bar was loaded in air with Cu₂O (15.9 mg,

111 µmol, 0.1 eq., 20 mol% [Cu]) and camphorsulfonic acid (64.4 mg,

277 µmol, 0.25 eq.). The vessel was evacuated and flooded with argon

thrice. In a counter-stream of argon, H₂O (1.0 mL, 55.5 mmol, 50 eq.),

methanol (4.0 mL) and 4-tert-butylphenylacetylene (18; 200 µL, 176 mg,

1.11 mmol, 1 eq.) were added to the contents. The vial was capped and

placed into the microwave unit, where it was heated to 160 °C for 15 min

10.1002/cctc.201900456

ChemCatChem

FULL PAPER

(holding time at target temperature). The cooled reaction mixture was

transferred into a separatory funnel and the vial washed with Et₂O (4 × 5

mL). The organic phase was washed with water (3 × 15 mL) and sat. aq.

NaCl (15 mL), and the combined aq. phase was reextracted with Et₂O

(10 mL). The combined organic phase was dried (MgSO₄), filtered and

evaporated under reduced pressure. To the residue, 1,3-dinitrobenzene

was added (40.4 mg, 240 µmol) and everything was dissolved

homogeneously in CDCl₃(0.7 mL). An aliquot (0.2 mL) was removed and

placed into an NMR tube with additional CDCl₃(0.3 mL) for qNMR

analysis. Composition (mol%): starting material (0.8%), aldehyde (1.8%),

ketone (83.8%), dimethyl acetal (5.7%), component recovery (92.1%).

The NMR sample was combined with the remainder of the material and

the solvent was removed in vacuum. The residue was purified by CC

(SiO₂, EtOAc–hexanes 1:20) to give crude product (165 mg, purity 93

mol%), which contained dimethylacetal (6 mol%) and aldehyde (1 mol%)

as impurity. For purification, the material was derivatized by dissolving in

MeOH (2.0 mL) and adding with stirring to a dinitrophenylhydrazine

solution^[83](from 0.5 g of 2,4-dinitrophenylhydrazine {50% with water}, 2.5

mL of H₂SO₄conc., 3.3 mL of H₂O and 12 mL of MeOH). After a short

time, the precipitate formed was filtered through a glass filter and washed

with water (2 x 20 mL) and 5% NaHCO₃aq (2 x 20 mL). The solid was

dried in high vacuum (337 mg, 84%) and recrystallized from EtOAc to

give microcrystalline yellow solid (20; 286 mg, 72%). Data for 1-(1-(4-

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¹H

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NMR (400 MHz, CDCl₃): d 1.36 (s, 9 H, CMe₃), 2.46 (s, 3 H, MeC=N),

7.46–7.51 (m, 2 H, Ar-H), 7.78–7.83 (m, 2 H, ArH), 8.13 (d, J = 9.6 Hz, 1

H, Ar-H), 8.35 (ddd, J = 9.6, 2.5, 0.6 Hz, 1 H, Ar-H), 9.16 (d, J = 2.5 Hz, 1

H, Ar-H), 11.36 (br. s, 1 H, NH). ¹³C{¹H} NMR (101 MHz, CDCl₃): d 13.64,

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material is no longer detected) of substrate can be compared, although

this is theoretically less sound (the starting material might never be fully

consumed), requires repeated monitoring and is subject to a large error

margin.

Acknowledgements

Funding of the microwave reactor was provided through

Deutsche Forschungsgemeinschaft. We thank Dr. Li Xiao for the

synthesis of gold(I) complexes.

[15] Comments on choices of typical reaction times: J. Yoshida, Flash

Chemistry: Fast Organic Synthesis in Microsystems, John Wiley &

Sons, 2008, p. 1.

Keywords: alkyne hydration • homogeneous catalysis •

microwave reactions • transition metals • screening

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10.1002/cctc.201900456

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Entry for the Table of Contents

FULL PAPER

Using alkyne hydration as example,

the work suggests an efficient

screening procedure to find

Matthias Schreyer, Tobias M. Milzarek,

Marcus Wegmann, Andreas Brunner,

Lukas Hintermann*

homogeneous catalytic activity

covering a vast field of diverse

potential catalysts, using a low

number of experiments. The key idea

is combining homogeneous thermal

conditions (HOT-CAT) in a

Page No. – Page No.

Discovery and Comparison of

Homogeneous Catalysts in a

Standardized HOT-CAT Screen with

Microwave-Heating and qNMR

Analysis: Exploring Catalytic

Hydration of Alkynes

microwave-unit with accurate

quantitative NMR analysis.

Article Doi

Discovery and Comparison of Homogeneous Catalysts in a Standardized HOT-CAT Screen with Microwave-Heating and qNMR Analysis: Exploring Catalytic Hydration of Alkynes

DOI: 10.1002/cctc.201900456

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Article abstract of DOI:10.1002/cctc.201900456

Full text of DOI:10.1002/cctc.201900456

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