Ruthenium-catalyzed remote electronic activation of aromatic C-F bonds

Article abstract of DOI:10.1002/adsc.201200879

The tandem isomerization and nucleophilic aromatic substitution of allylic fluoro-substituted benzylic alcohols is described for the first time. In the presence of the ruthenium complex Ru(PPh₃)₃(CO)(H) ₂, 1-(4-fluorophenyl)prop-2-en-1-ol is converted into the corresponding para-amino ketone or para-phenolic substituted ketone. Copyright

Full text of DOI:10.1002/adsc.201200879

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DOI: 10.1002/adsc.201200879
Ruthenium-Catalyzed Remote Electronic Activation of Aromatic
À
C F Bonds
Andrew J. A. Watson,a Benjamin N. Atkinson,a Aoife C. Maxwell,b
and Jonathan M. J. Williamsa,*
a
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
E-mail: j.m.j.williams@bath.ac.uk
GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
b
Received: September 29, 2012; Revised: January 13, 2013; Published online: February 22, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200879.
Abstract: The tandem isomerization and nucleophilic ol is converted into the corresponding para-amino
aromatic substitution of allylic fluoro-substituted ketone or para-phenolic substituted ketone.
benzylic alcohols is described for the first time.
In the presence of the ruthenium complex Keywords: arenes; isomerization; nucleophilic substi-
RuACHTUNGTRENNUNG(PPh3)3(CO)(H)2, 1-(4-fluorophenyl)prop-2-en-1- tution; ruthenium
Introduction
Alcohols are widely accessible and more stable than
their aldehyde or ketone counterparts. However, the
range of chemistry applicable to alcohols is very limit-
ed when compared with the diversity offered by alde-
hydes and ketones. Therefore a technology capable of
harnessing the reactivity and breadth of chemistry ac-
cessible to carbonyl compounds, but from the alcohol
would be very powerful. Furthermore, it would avoid
oxidations whilst reducing the amount of waste by-
products and number of synthetic steps.
Hydrogen transfer reactions are one approach to
this idea.[1] The transfer of two hydrogen atoms from
the alcohol to an oxidant generates the aldehyde in
situ, which can then react further. We have previously
reported several examples of this approach
(Scheme 1) to access amides,[2] activated alkenes,[3]
heterocycles,[4] esters[5] and more recently substituted
aromatic ketones and alcohols.[6]
Scheme 1. Applications of hydrogen transfer chemistry.
Nucleophilic aromatic substitution proceeds well The latter can also be considered as an oxidation of
for electron-deficient arenes, however, it is unsuccess- the alcohol, followed by reduction of the alkene. Al-
À
ful for electron-rich arenes (Scheme 2). This provides ternative approaches to metal-catalyzed C F bond ac-
an opportunity to apply hydrogen transfer methodolo- tivation are reported in the literature.[7]
gy. By starting from the alcohol, which cannot under-
go substitution, and then converting into the ketone
which can undergo the nucleophilic aromatic substitu- Results and Discussion
tion, an activation/substitution tandem process could
be achieved. We chose to take two approaches to this Work began by looking at the nucleophilic aromatic
reaction; a direct oxidation of the alcohol (Scheme 3) substitution of 4-fluoroacetophenone with morpholine
and an isomerization of an allylic alcohol (Scheme 4). (Scheme 5) as this reaction dictates the conditions to
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Ruthenium-Catalyzed Remote Electronic Activation of Aromatic C F Bonds
Scheme 6. Hydrogen transfer reaction in DMSO.
used ruthenium precursors was conducted to establish
which were active for hydrogen transfer in DMSO
(Scheme 6 and Table 1).
Several likely catalysts proved to be inert in
DMSO, although two catalysts were active, Shvoꢁs
Scheme 2. SNAr reactions of fluoro-aromatics.
catalyst 1 (Table 1, entry 4) and RuACTHUNTGRNEG(UN PPh3)3(CO)(H)2 2
(Table 1, entry 5) returning 23% and 93% conversion,
respectively. Considering the success of 2, the related
catalyst RuACTHUNTRGNE(UNG PPh3)3(CO)(H)(Cl) 3 (Table 1, entry 6)
was also added to the screen, however, it was not as
active, returning only 28% conversion.
Optimization of the tandem oxidation/substitution
reaction (Scheme 3) began with an oxidant screen.
This highlighted that previously successful oxidants
such as crotononitrile, ketones and levulinic acid de-
rivatives[10] were all unsuitable due to the occurrence
of side reactions. The use of unfunctionalized alkenes
was more successful, despite the low conversion (6–
34%).[9]
Scheme 3. Tandem oxidation/aromatic substitution.
Steric and electronic tuning of the catalyst by the
addition of alternative ligands (Table 2) improved the
conversion to 60%, however, further improvement
past this point was unsuccessful. The alternative ap-
proach (Scheme 4) using an allylic alcohol was then
considered, as this would not require an external oxi-
dant. Furthermore, tandem metal-catalyzed isomeri-
zations are well known[11] and have been used previ-
ously with other reactions such as reduction,[12] C H
À
activation[13] and fluorination.[14] Using the data al-
ready obtained, a ligand screen (Table 3) using 2 in
DMSO was conducted for the isomerization of the
model allylic alcohol (Scheme 7).
Scheme 4. Tandem isomerization/aromatic substitution.
From the results, two ligands clearly generated
more efficient catalysts, DPEphos (Table 3, entry 9)
Table 1. Catalyst screen.
Entry[a]
Catalyst
[Ru(p-cymene)Cl2]2
Conversion [%][b]
Scheme 5. Nucleophilic aromatic substitution reaction in
DMSO.
1
2
3
4
5
6
G
0
0
0
23
93
28
RuCl2A(PPh3)3
Ru3(CO)12
Shvoꢁs catalyst 1
Ru(PPh3)3(CO)(H)2 2
Ru(PPh3)3(CO)(H)(Cl) 3
C
[c]
be used for the oxidation, if it is to occur in situ as de-
sired. Despite many reports in the literature,[8] there
is very little detail on the limitations of this reaction.
A screen of solvents[9] showed that only DMSO gave
100% conversion to the product.
Having previously avoided DMSO as a solvent due
to its high boiling point, a screen of several widely
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Conditions: acetophenone (1 mmol), 1,4-butanediol
(1.5 mmol), [Ru] (5 mol%), DMSO (1 mL), 1158C, 24 h.
Conversion determined by H NMR.
[b]
[c]
1
6 mol% ruthenium.
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Table 2. Ligand screen for oxidation.
Entry[a]
Ligand
Conversion [%][b]
1
2
3
4
5
6
7
8
dppm
dppe
dppp
dppb
dpppent
dppbe
Xantphos
DPEphos
48
47
34
24
15
41
41
17
33
10
60
Scheme 8. Tandem isomerization/substitution test.
for further work due to its lower relative cost. With
the conversion at 50%, the reaction time was doubled
to 3 h, in order to drive the reaction to completion.
However, the reaction only proceeded to 71% conver-
sion (Table 3, entry 15). Further heating to 5 h
(Table 3, entry 16) also resulted in incomplete conver-
sion, but leaving the reaction for 24 h led to complete
conversion (Table 3, entry 17).
9
10
11
A
Triphos
dcpe
[a]
Conditions: 1-(4-fluorophenyl)ethanol (1 mmol), mor-
pholine (2.2 mmol), 1-octene (1.5 mmol), 2 (5 mol%),
DMSO (1 mL), 1158C, 24 h.
The isomerization and nucleophilic substitution
were then run together to test whether the combina-
tion would indeed give the desired result (Scheme 8).
1H NMR analysis of the reaction showed full conver-
sion. It was also possible to reduce the catalyst load-
Conv. ing slightly to 4 mol% without reducing overall con-
[b]
1
Conversion determined by H NMR.
Table 3. Isomerization ligand screen.
Entry[a]
Ligand
[%][b]
version.
With conditions optimized, the substrate scope was
1
2
3
4
5
6
7
8
no ligand
dppm
dppe
dppp
dppb
13
evaluated. Earlier work on the aromatic substitution
16
of 4-fluoroacetophenone had highlighted that only
19
35
20
13
16
12
50
27
27
58
15
17
71
81
>99
Table 4. Cyclic secondary amine scope.
dpppent
dppbe
Entry[a] Amine
Product
Isolated Yield
[%]
(+/À)-BINAP
9
DPEphos
10
11
12
13
14
15[c]
16[d]
17[e]
Xantphos
1,2-bis(dicyclohexylphosphino)ethane
1,4-bis(dicyclohexylphosphino)butane
Triphos
1
77
87
cis-1,2-bis(diphenylphosphino)ethylene
DPEphos
DPEphos
DPEphos
2
3
4
[a]
Conditions: 1-(4-fluorophenyl)prop-2-en-1-ol (1 mmol), 2
(5 mol%), DMSO (1 mL), 1158C, 90 min.
Conversion determined by H NMR.
Reaction run for 3 h.
Reaction run for 5 h.
Reaction run for 24 h.
[b]
[c]
[d]
[e]
1
81
86
71
and 1,4-bis(dicyclohexylphosphino)butane (Table 3,
entry 12) returning 50% and 58% conversion, respec-
tively. Despite being less active, DPEphos was chosen
5
[a]
Conditions: 1-(4-fluorophenyl)prop-2-en-1-ol (3 mmol),
morpholine (6.6 mmol), 2 (4 mol%), DPEphos (4 mol%),
DMSO (3 mL), 1158C, 24 h.
Scheme 7. Model allylic alcohol isomerization.
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Ruthenium-Catalyzed Remote Electronic Activation of Aromatic C F Bonds
Table 5. Double bond substitution scope.
Table 6. Aromatic ring substitution.
Entry[a] Starting Material Product
Isolated
Yield [%]
Entry[a] Starting Mate- Product
rial
Isolated
Yield [%]
1
86
52
57
0[c]
37
85
1
2
3
51
2[b]
74
3[b]
67[b]
4
–
4
5
6
58
5[b]
6
61
[a]
Conditions: 1-(4-fluorophenyl)prop-2-en-1-ol (3 mmol),
morpholine (6.6 mmol), 2 (4 mol%), DPEphos (4 mol%),
DMSO (3 mL), 1158C, 24 h. R2N- is morpholino.
5 mol% catalyst and ligand used and the reaction run for
48 h.
41[c]
[b]
[c]
1
Determined by H NMR.
7
35[b]
cyclic secondary amines proceeded well, with acyclic
examples returning poor conversions and primary
amines showing no conversion at all. With this in
mind, a range of cyclic secondary amines was
screened under the reaction conditions (Table 4).
All the substrates used led to good isolated yields,
with 5-, 6- and 7-membered rings being tolerated for
the substitution reaction (Table 4, entries 1–3). Func-
tionalized amines were also well tolerated including
[a]
Conditions: 1-(4-fluorophenyl)prop-2-en-1-ol (3 mmol),
morpholine (6.6 mmol), 2 (4 mol%), DPEphos (4 mol%),
DMSO (3 mL), 1158C, 24 h.
5 mol% catalyst and ligand used.
5 mol% catalyst and ligand used for 48 h.
[b]
[c]
morpholine (Table 4, entry 4) and 1-methylpiperazine lyst loading and longer reaction times to achieve simi-
(Table 4, entry 5). lar conversions to the other substituted alkenes. The
Substitution around the alkene was considered next low isolated yield in this case is due to the difficulty
(Table 5), as this would have an effect on the rate of in isolating the product from the reaction mixture.
isomerization. As expected, these results were less
Finally, substitution on the aromatic ring was evalu-
successful, with only the homoallylic alcohol (Table 5, ated (Table 6). Introducing methyl groups into the
entry 6) performing as well as the allylic examples ortho and meta positions (Table 6, entries 1 and 2)
(Table 5, entry 1). Higher catalyst loadings and longer still allowed the isomerization to occur successfully.
reaction times were required for more substituted al- However, the aromatic substitution was severely ham-
kenes (Table 5, entries 2 and 3). However, the tetra- pered when the methyl substituent was ortho to the
substituted alkene (Table 5, entry 4) did not give the fluorine (Table 6, entry 2). Whilst in this case the iso-
desired product, even with the higher loading and merization was complete, analysis of the crude reac-
1
longer reaction time, instead returning the alternative tion mixture by H NMR showed only 6% conversion
isomer of the starting material. The use of a conjugat- for the aromatic substitution. Interestingly, alternative
ed alkene (Table 5, entry 5) also required higher cata- substituents located ortho to the fluoro group did not
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Andrew J. A. Watson et al.
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Scheme 9. Tandem isomerization/substitution phenol test.
prevent substitution (Table 6, entries 3–5). In particu-
lar, the trifluoromethyl derivative (Table 6, entry 5)
isomerized well and returned a good yield on the aro-
matic substitution. This suggests that the substitution
Scheme 10. Borrowing hydrogen methodology.
Table 7. Isomerization ligand screen.
Entry[a] Phenol
Product
Isolated
Yield [%]
process is sensitive to electronic effects as well as
steric effects.
Other nucleophiles known to participate in SNAr
reactions were examined. However, replication of the
results of aromatic substitution with 4-fluoroacetophe-
none achieved with heterocycles[15] was unsuccessful
at 1158C. However, the use of phenols was successful
with a catalyst loading of 5 mol% (Scheme 9).
1
2
3
61
56
58
A range of phenols was then screened with the
higher catalyst loading. Except for 4-(trifluorome-
thyl)phenol (Table 7, entry 7), the yields were consis-
tent (55–65%). In this case only 9% conversion of the
aromatic substitution was observed. The same result
was obtained with aromatic substitution with 4-fluo-
roacetophenone, indicating that this phenol is not
a good nucleophile, presumably due to the electron-
withdrawing trifluoromethyl group. The introduction
of methyl groups in the meta, para or even the ortho
position had little effect on the amount of substitution
(Table 7, entries 2-4). Whilst the inclusion of other
substituents (Table 7, entries 5 and 6) also had little
effect. Both 1- and 2-substituted naphthols (Table 7,
entries 8 and 9) were also well tolerated.
Having applied nucleophilic aromatic substitution
to a tandem hydrogen transfer system, it was hoped
that it would also work under borrowing hydrogen[16]
conditions (Scheme 10). However, whilst the reaction
did work in both cases, it still requires a significant
amount of further work in order to achieve good con-
versions into product. We believe that reduction of
the intermediate substituted ketones is disfavoured
due to their stability arising from the electron-donat-
ing para-substituent.
4
5
59
55
6
65
7
8
–
9[b]
55
63
9
Conclusions
In summary, this report describes the application of
a ruthenium-catalyzed isomerization and tandem nu-
cleophilic aromatic substitution. The reaction pro-
ceeds well with a variety of substrates and with both
cyclic secondary amines and phenols. The effects of
[a]
Conditions: 1-(4-fluorophenyl)prop-2-en-1-ol (3 mmol),
phenol (3.3 mmol), K2CO3 (3.3 mmol), 2 (5 mol%), DPE-
phos (5 mol%), DMSO (3 mL), 1158C, 24 h.
[b]
1
Conversion determined by H NMR.
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Ruthenium-Catalyzed Remote Electronic Activation of Aromatic C F Bonds
gen-purged ampule. The alcohol (3 mmol) in anhydrous
substitution on both the alkene and aromatic ring
were investigated.
DMSO (3 mL) was then added before the vessel was sealed
with a Youngꢁs tap. The reaction mixture was then agitated
and heated to 1158C for 24 h. After 24 h, the mixture was
allowed to cool to room temperature before transferring it
to a separating funnel and washing with DMSO. H2O
(20 mL) and brine (5 mL) were added before the mixture
was extracted with Et2O (3ꢃ25 mL). The combined organic
layers were then concentrated under vacuum before purify-
ing by silica column chromatography (eluent: hexane/
EtOAc).
Experimental Section
General Information
1
The H and 13C NMR were recorded on a Bruker Avance
300 MHz spectrometer. The chemical shifts (d) are reported
in ppm and the coupling constants (J) in Hz. High resolution
mass spectra (HR-MS) were obtained on a Bruker Daltron-
ics micrOTOF (ESI-TOF). Column chromatography was
performed on 60 ꢂ silica gel and TLC was performed using
polythene-backed plates pre-coated with Macherey–Nagel
Sil G/UV254nm neutral silica gel.
All reactions were carried out under nitrogen in dried
glassware. All chemicals were used as received unless other-
wise stated and the solvents were all purchased as anhy-
drous and used as such.
Acknowledgements
We thank GlaxoSmithKline, Astra-Zeneca, Novartis, Pfizer
and the EPSRC for funding for a PhD studentship (for A. J.
A. Watson) through the Pharma-Synthesis Network. We are
grateful to Dr. J. P. Lowe for assistance with NMR spectros-
copy.
General Procedure I: Synthesis of Allyl Alcohol
Starting Materials
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quenching with NH4Cl (saturated solution, 50 mL) and H2O
(50 mL). The organic layer was then separated and the
aqueous layer extracted with EtOAc (2ꢃ100 mL). The com-
bined organic layers were then dried (MgSO4) and concen-
trated under vacuum before purifying by silica column chro-
matography (eluent: petroleum ether bp 40–608C/diethyl
ether).
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General Procedure III: Tandem Isomerization/Sub-
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