Ruthenium-catalysed oxidative synthesis of heterocycles from alcohols

Article abstract of DOI:10.1039/c1ob06516e

Ruthenium-catalysed hydrogen transfer has been successfully used for the conversion of alcohols into either 2,3-dihydroquinazolines or quinazolines. The choice of reaction conditions allows for the selective formation of either heterocycle and the methodology can also be applied to the sulfonamide analogue.

Full text of DOI:10.1039/c1ob06516e

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Ruthenium-catalysed oxidative synthesis of heterocycles from alcohols†
Andrew J. A. Watson,*a Aoife C. Maxwellb and Jonathan M. J. Williamsa
Received 3rd September 2011, Accepted 26th September 2011
DOI: 10.1039/c1ob06516e
Ruthenium-catalysed hydrogen transfer has been success-
fully used for the conversion of alcohols into either 2,3-
dihydroquinazolines or quinazolines. The choice of reaction
conditions allows for the selective formation of either het-
erocycle and the methodology can also be applied to the
sulfonamide analogue.
Ruthenium-catalysed oxidation of alcohols to their corresponding
carbonyl compounds is well reported in the literature.1 The
applications of this methodology in tandem processes have led to
a wide variety of different oxidation reactions of alcohols for the
synthesis of esters,2 amides,3 functionalised alkenes,4 heterocycles,5
C–H activation products6 and acetals.7
Scheme 2 Pharmaceuticals containing 2,3-dihydroquinazolines.
Our previous experience in this area (Scheme 1) has been
successful and we wanted to continue to expand the variety
of reactions available. As such, we wanted to use alcohols in
the synthesis of 2,3-dihydroquinazolinones‡ due to their use in
pharmaceuticals (Scheme 2).
Scheme 3 Initial reaction conditions.
use of ammonium chloride9 as a useful reagent in increasing the
rate of formation, therefore it was included over other previously
used salts such as piperidinium acetate. Initial results illustrated
that as well as forming the desired 2,3-dihydroquinazoline, over
oxidation to the quinazolinone was also occurring (Scheme 3),
and optimisation of the reaction conditions would be required
Scheme 1 Examples of ruthenium-catalysed tandem oxidative reactions
of alcohols.
(Table 1)
Our initial conditions (Scheme 3) were based on our successful
Varying the amount of NH4Cl below 20 mol% (Entries 2–4,
conversion of alcohols into methyl esters,2d while the addition of
Table 1) led to a decrease in conversion and selectivity for 2
a salt has proven to be important in previous work.4a,8 A review
of current syntheses of 2,3-dihydroquinazolines highlighted the
over 3. Swapping the NH4Cl for p-toluenesulfonic acid (Entry 6,
Table 1) led to reduced selectivity (2 : 1 rather than 10 : 1). Whilst
extended heating in the absence of an additive (Entry 5, Table 1)
led to 8 : 1 selectivity for 3 over 2, allowing access to both 2,3-
dihydroquinazolines and quinazolines. Reducing the amount of
oxidant from 2.5 equivalents to 1.5 (Entries 7–8, Table 1) again led
to reduced conversions and interestingly, reduced selectivity. The
exact role of the ammonium chloride is unclear, however, further
aDepartment of Chemistry, University of Bath, Claverton Down, Bath, UK,
BA2 7AY. E-mail: ajaw20@bath.ac.uk
bGlaxoSmithKline Research and Development, Gunnels Wood Road, Steve-
nage, UK, SG1 2NY
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06516e
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Table 1 Optimisation of reaction conditionsa
Table 2 2,3-Dihydroquinazoline resultsa
Entry
1
Alcohol
Isolated yield (%)
78
Conversionb
2
3
69
72
Entry
Ligand
Additive
1
2
3
1
2
3
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
dppm
NH4Cl
NH4Clc
NH4Cld
—
0
15
32
23
12
0
0
9
100
98
98
95
0
91
50
17
15
10
66
78
72
0
2
2
5
92
79
9
35
51
62
78
34
22
19
0
0
0
0
8
4
5e
6
—
4
5
6
71
69
63
PTSAd
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
7f
8g
9
10
11
12
13
14
dppe
dppp
dppb
( )-BINAP
DPEphos
17
4
a Reaction conditions: 2-aminobenzamide (1 mmol), benzyl alcohol
(1 mmol), crotononitrile (2.5 mmol), Ru(PPh3)3(CO)(H)2 (5 mol%), ligand
(5 mol%), additive (20 mol%), toluene (1 mL), 115 ◦C, 14 h. b Conversion
determined by 1H NMR. c 10 mol% additive. d 5 mol% additive. e Reaction
run for 24 h. f 2.0 eq. of crotononitrile. g 1.5 eq. of crotononitrile.
7
8
62
43b
investigations are ongoing. Finally, a screen of ligands (Entries
9–14, Table 1) highlighted that ( )-BINAP (Entry 13, Table 1)
was a marginally better ligand, however, due to the increased cost,
Xantphos was chosen as the ligand for further work.
a Reaction conditions: 2-aminobenzamide (1 mmol), alcohol (1 mmol),
crotononitrile (2.5 mmol), Ru(PPh3)3(CO)(H)2 (5 mol%), Xantphos
(5 mol%), NH4Cl (20 mol%), toluene (1 mL), 115 ◦C, 14 h. b Conversion
determined by 1H NMR.
A series of benzyl alcohols was then submitted to the reaction
conditions and the products isolated (Table 2). We were pleased to
see that the results were generally good (60–80% isolated yields)
except for furfuryl alcohol (Entry 8, Table 1). Both electron rich
(Entries 2–4, Table 2) and electron poor (Entry 5, Table 2) gave
good yields. The reaction also tolerated both pyridyl (Entry 6,
Table 2) and thienyl (Entry 7, Table 2) with no difficulty.
When aliphatic alcohols were submitted to the reaction con-
ditions no 2,3-dihydroquinazoline was formed, instead only the
quinazoline was detected. As mentioned above, quinazolines
had been previously observed; however, their formation was
disfavoured under the reaction conditions chosen. This result
prompted us to reconsider the role of the ammonium chloride. It
was assumed that the over oxidation of the 2,3-dihydroquinazoline
was disfavoured due to steric reasons, the increased bulk blocking
the catalyst. In order to learn more, we ran two competition
experiments to compare the over oxidation reaction with and
without the ammonium chloride (Scheme 4).
Scheme 4 Oxidation contest.
71% conversion, a two fold increase in rate. This shows that
the ammonium chloride has an important role in retarding the
second oxidation of 4 to 5 but does not hinder the formation of
the aldehyde necessary for the formation of 4. Considering that
the formation of quinazolines was indeed possible, and that it
was faster without the presence of ammonium chloride, we chose
to screen a series of alcohols under a new set of conditions to
favour quinazoline formation (Table 3). We were also pleased to
The results showed that when the ammonium chloride was
present, the oxidation of 4 to 5 went to 36% conversion after
14 h, whilst the reaction without ammonium chloride went to
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Table 4 2H-1,2,4-Benzothiadiazine-1,1-dioxide resultsa
Table 3 Quinazoline resultsa
Entry
1
Alcohol
Isolated yield (%)
81
Entry
1
Alcohol
Isolated yield (%)
72
2
78
2
3
4
47
72
70
3
4
82
87
5
6
65
69
5
6
67
85
7
8
83
82
7
72
8
9
79
84
9
56
10
40b
10
11
52
35
a Reaction conditions: 2-aminobenzamide (1 mmol), alcohol (1 mmol),
crotononitrile (2.5 mmol), toluene (1 mL), Ru(PPh3)3(CO)(H)2 (5 mol%),
Xantphos (5 mol%), 115 ◦C, 24 h. b Conversion determined by 1H NMR.
a Reaction conditions: 2-aminobenzenesulfonamide (1 mmol), alcohol
(1 mmol), crotononitrile (2.5 mmol), toluene (1 mL), Ru(PPh3)3(CO)(H)2
(5 mol%), Xantphos (5 mol%), 115 ◦C, 24 h.
see that the products could be purified by recrystallization from
the reaction mixture with no need for column chromatography.
The results were generally good (55–85% isolated yields) except
for furfuryl alcohol (Entry 10, Table 3). The range of benzylic
alcohols with both electron donating (Entries 3–4, Table 3) and
electron withdrawing groups (Entry 5, Table 3) gave good results,
except for 4-methylbenzyl alcohol (Entry 2, Table 3). In this
case the alcohol was completely consumed and it is believed
the poor solubility of the 2,3-dihydroquinazoline intermediate is
responsible for the poor result. Both phenethyl (Entry 6, Table 3)
and aliphatic alcohols (Entries 6–9, Table 3) were tolerated well
returning excellent yields of 82–85%. Finally, the pyridyl (Entry 9,
Table 3) structure was also successful in reasonable yield.
been successful at N-alkylation of sulfonamides using Borrowing
Hydrogen methodology10 both thermally11 and under solvent free
microwave conditions.12 This led us to conclude that sulfonamides
may be tolerated under our reactions conditions allowing access to
2H-1,2,4-benzothiadiazine-1,1-dioxide structures. Indeed, by re-
placing the 2-aminobenzamide with 2-aminobenzenesulfonamide
we were able to isolate these heterocycles in good yield (Table 4)
without an increase in temperature.
Once again a range of benzylic alcohols was tolerated with both
electron donating (Entries 2–4, Table 4) and electron withdrawing
(Entries 5–6, Table 4) returning good yields. Phenethyl (Entry
Having seen success with these heterocyclic scaffolds, we wished
to expand the scope of this reaction further. Our group has
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7, Table 4) and aliphatic (Entries 8–9, Table 4) again gave good
results. Heterocycles were also tolerated with the pyridyl (Entry 10,
Table 4) and thienyl (Entry 11, Table 4) returning 52% and 35%
respectively. The latter result was disappointing, however, when
compared with the previous results of furfuryl alcohol (Entry 9,
Table 2 and Entry 10, Table 3) it can be seen that the reaction is
not as good with electron rich heteroaromatic structures.
To conclude, we have developed a ruthenium-catalysed synthesis
of three different heterocyclic scaffolds from alcohols using similar
conditions. Furthermore, no chromatography is required to access
the products in good yields.
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Notes and references
‡ During the preparation of this manuscript Zhou and Fang published a
related iridium-catalysed synthesis of quinazolines.13
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