Solvent selection in synthesis of 4-(1-arylfluoroethoxy)quinazolines and thienopyrimidines

Article abstract of DOI:10.1016/j.jfluchem.2013.05.011

The nucleophilic aromatic substitution of 4-chloroquinazoline and 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 1-aryl-2-fluoroethanols as nucleophilies has been studied focusing on the use of carbonate bases in combination of environmental acceptable solvents. The conversion rate depended on the solvent properties, the acidity of the nucleophile and the nature of the base. By using acetonitrile as reaction medium and K₂CO₃ as base, 2,2,2-trifluoro-, 2,2-difluoro-, and 2-fluoro-1-phenylethanol could efficiently be coupled to 4-chloropyrimidines. Alternatively, employing Cs ₂CO₃, allowed for shorter reaction time for these substrates, and also couplings of the non-fluorinated alcohols proceeded well. tert-Butanol was also found to be a suitable reaction medium in transformation of the fluoro alcohols. Testing of hydrolytic stability of the 4-alkoxypyrimidines revealed that the fluorinated and nonfluorinated derivatives were labile under acidic conditions, whereas in basic media the fluoroalkoxy derivatives were more stable than their non-fluorinated counterparts.

Full text of DOI:10.1016/j.jfluchem.2013.05.011

Journal of Fluorine Chemistry 153 (2013) 82–88
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Solvent selection in synthesis of 4-(1-arylfluoroethoxy)quinazolines
and thienopyrimidines
a,b
b
a,
Jin Han , Eirik Sundby , B a˚ rd Helge Hoff *
a
Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway
b
Sør-Trøndelag University College, E. C. Dahls Gate 2, 7004 Trondheim, Norway
A R T I C L E I N F O
A B S T R A C T
Article history:
The nucleophilic aromatic substitution of 4-chloroquinazoline and 6-bromo-4-chlorothieno[2,3-
d]pyrimidine with 1-aryl-2-fluoroethanols as nucleophilies has been studied focusing on the use of
carbonate bases in combination of environmental acceptable solvents. The conversion rate depended on
the solvent properties, the acidity of the nucleophile and the nature of the base. By using acetonitrile as
Received 21 March 2013
Received in revised form 8 May 2013
Accepted 9 May 2013
Available online 18 May 2013
reaction medium and K
2
CO
3
as base, 2,2,2-trifluoro-, 2,2-difluoro-, and 2-fluoro-1-phenylethanol could
CO , allowed for shorter
efficiently be coupled to 4-chloropyrimidines. Alternatively, employing Cs
2
3
Keywords:
reaction time for these substrates, and also couplings of the non-fluorinated alcohols proceeded well.
tert-Butanol was also found to be a suitable reaction medium in transformation of the fluoro alcohols.
Testing of hydrolytic stability of the 4-alkoxypyrimidines revealed that the fluorinated and non-
fluorinated derivatives were labile under acidic conditions, whereas in basic media the fluoroalkoxy
derivatives were more stable than their non-fluorinated counterparts.
Solvent selection
Quinazolines
Thienopyrimidines
1
-Aryl-2-fluoroethanols
Cs CO
-Alkoxypyrimidine
2
3
4
ß 2013 Elsevier B.V. All rights reserved.
1
. Introduction
catalysed ether formation [10], and microwave assisted reactions
[11,12], can also be envisioned. Various challenges can be
Fluorinated molecules are important for the pharmaceutical
encountered with these methods such as partial racemisation
[13–15], handling of hazardous chemicals, waste issues, the use of
strong and flammable bases, or the risk of contaminating the end
product with transition metals [16].
Herein, we have investigated the coupling of 1-aryl-2-
fluoroethanols in nucleophilic aromatic substitution reactions
with 4-chloroquinazoline and 6-bromo-4-chlorothieno[2,3-d]py-
rimidine [17], a potential building block for kinase inhibitors
[18,19]. As the acidity of the alcohol function increase upon
fluorination [20,21], we envisioned that more sustainable reaction
conditions than those mentioned above could be employed, and
wish to communicate our findings.
industry [1–3], but since the chemistry towards these molecules is
often hampered by difficult and hazardous process steps,
fluorinated pharmaceuticals could be argued not to comply with
the principals of sustainable chemistry. However, the improve-
ment in properties of the end product such as bioactivity,
bioavailability and metabolic stability, allowing for lower dosing
of the drug, might compensate for the lack of sustainability in the
fluorination step. Moreover, if the chemistry undertaken with
fluorinated precursor molecules can benefit from the electron
withdrawing properties of the fluoro atoms, the overall environ-
mental impact of the process could be reduced.
While very little has been reported on aromatic ether formation
using 2-fluoro- and 2,2-difluoro-1-arylethanols [4], the patent
literature have documented the use of 2,2,2-trifluoro-1-aryletha-
nol in such reactions. Strategies used include converting the
alcohol to a good leaving group such as triflate and reaction with a
phenol (Williams type) [5], Mitsunobu conditions [6,7], and the
coupling of aliphatic alcohols with aryl chlorides or fluorides in the
presence of a suitable base [8,9] (Scheme 1). Transition metal
2. Result and discussion
2.1. Investigation of the coupling chemistry
Quinazoline is an important scaffold in medicinal chemistry
[22,23], and 4-chloroquinazoline (1) was therefore selected as a
model substrate. Compound 1 reacted smoothly with 1-pheny-
lethanol (2a) and 2,2,2-trifluoro-1-phenylethanol (2d) as nucleo-
phile with sodium hydride as base giving the corresponding 4-
alkoxy quinazolines in good yield. However, we were interested in
identifying more safe and environmental sound processes, using
carbonate bases in combination with a suitable reaction solvent.
*
Corresponding author. Tel.: +47 73593973.
E-mail addresses: bard.helge.hoff@chem.ntnu.no, bard.hoff@online.no
(B.H. Hoff).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.05.011

J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
83
Scheme 1. Possible strategies to fluoro containing 4-alkoxypyrimidines.
N
N
O
N
OH
+
M2CO3
Solvent
N
N
HN
Ph
R
Cl
R
O
4
1
2
3a or 3d
Ph
R= CH3 (a), CF3 (d)
Scheme 2. Nucleophilic aromatic substitution on 4-chloroquinazoline (1).
Solvent selections do not only depend on solubility of the
reactants, but also on safety, effects on reaction rate, stability of
the reagent and product, ease of work-up, pricing and environ-
mental concerns [24,25]. However, solvent selection guidelines
have been developed to aid the chemist in these sometimes
difficult dilemmas [26]. Based on these guidelines we selected 2-
methyl tetrahydrofuran (2-MeTHF), THF, acetonitrile, tert-butanol
and water as interesting reaction media. In addition N,N-
Substitutions of
(2d) in the presence of K
1
with 2,2,2-trifluoro-1-phenylethanol
CO proceeded more readily also
2
3
in the less polar solvents THF and 2-MeTHF (entries 7–8).
Besides DMF also the use of acetonitrile and t-BuOH gave an
acceptable rate of reaction for 2d (entries 9–11). Given the
higher nucleophilicity of 2,2,2-trifluoro-1-phenylethanol (2d)
as compared to 2a, the main product in water was 3d. Overall,
2 3
in the presence of K CO the reaction rate depending on solvent
dimethylformamide (DMF) was included as
conditions usually employed [27].
a
reference to
followed the order DMF> acetonitrile> t-BuOH > >THF, 2-
MeTHF. Water was concluded unsuited as solvent since the
4
-Chloroquinazoline (1) was first reacted in these six solvents at
co-production of
process.
4 leads to a more difficult purification
a scale of 100 mg in 2 mL solvent with either 1-phenylethanol (2a)
or 2,2,2-trifluoro-1-phenylethanol (2d) as nucleophile and potas-
sium or caesium carbonate as bases (2.5 equiv.), see Scheme 2.
Reactions in water and DMF were performed at 90 8C, while for the
other solvents reflux conditions were employed.
The degree of conversion and product distribution seen for the
couplings in the various solvents with potassium carbonate are
shown in Table 1. Using 2a as nucleophile only processes in DMF
gave a decent rate of reaction, and full conversion was reached in
The results for the same transformations performed with
CO as base are shown in Table 2. With 1-phenylethanol (2a) as
Cs
2
3
nucleophile in Me-THF (Table 2, entry 1), full conversion could be
obtained in 11 h, and even shorter reaction time was achieved with
the more polar solvents (entries 2–5).
2 3
The increase in reactivity as compared to the use of K CO , can
be accounted for by the higher solubility of the base, and the lower
degree of solvation of the Cs-alkoxide [28,29]. Reactions with
2,2,2-trifluoro-1-phenylethanol (2d) as nucleophile under the
same conditions proceeded with full conversion in less than one
hour (entries 7–11). The use of water again gave 4 as a by-product
5
h (Table 1, entry 4).
A mediocre degree of conversion was observed in acetonitrile
and t-BuOH (entries 3 and 5), while no product were detected by
GC when performing the substitution in 2-MeTHF or THF (entries
in comparable amounts to that observed when using K
Overall, with Cs CO as base the conversion rate depended less on
the solvent used.
2 3
CO .
1
–2). Reaction in water led to hydrolysis of the starting material
2
3
yielding 4-hydroxyquinazoline (4) as the main product.
Table 1
Reaction of 4-chloroquinazoline (1) with alcohol 2a and 2d using 2.5 equivalents of potassium carbonate as base, scale: 100 mg 1 in 2 mL solvent.
a
Entry
Substrate
R
Solvent
Temp. (8C)
Time (h)
Conv. (%)
Product(s)
Ratio 3/4
b
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2d
2d
2d
2d
2d
2d
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
2-MeTHF
THF
81
67
82
90
82
90
81
67
82
90
82
90
24
24
23
5
<1
<1
81
99
63
3a
–
b
3a
–
3
CH CN
3a
>100
>100
>100
11/89
>100
>100
>100
>100
>100
87/13
DMF
3a
t-BuOH
Water
2-MeTHF
THF
23
24
19
19
1.5
0.5
2
3a
c
95
3a + 4
3d
CF
CF
CF
CF
CF
CF
3
>99
>99
>99
>99
>99
>99
3
3d
3
3
3
3
3
CH CN
3d
1
1
1
0
1
2
DMF
3d
t-BuOH
Water
3d
5
3d + 4
a
b
c
Conversion was measured by gas chromatography.
No product was observed.
Compound 4 was the main product.

8
4
J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
Table 2
Reaction of 4-chloroquinazoline (1) with alcohol 2a and 2d using caesium carbonate (2.5 equiv.) as base in different solvents, scale: 100 mg 1 in 2 mL solvent.
a
Entry
Substrate
R
Solvent
Temp. (8C)
Time (h)
Conv. (%)
Product
Ratio 3/4
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2d
2d
2d
2d
2d
2d
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
Me-THF
THF
81
67
82
90
82
90
81
67
82
90
82
90
11
6
>99
99
3a
>100
>100
>100
>100
>100
13/87
>100
>100
>100
>100
>100
86/14
3a
3
CH CN
3.5
1
99
3a
DMF
99
3a
t-BuOH
Water
Me-THF
THF
6
>99
3a
b
24
1
95
3a + 4
3d
CF
CF
CF
CF
CF
CF
3
>99
>99
>99
>99
>99
>99
3
0.5
0.5
0.5
0.5
3
3d
3
3
3
3
3
CH CN
3d
1
1
1
0
1
2
DMF
3d
t-BuOH
Water
3d
3d + 4
a
Conversion was measured by gas chromatography.
Compound 4 was the main product.
b
As t-BuOH and acetonitrile are regarded as less toxic and more
reaching 99% conversion in 2 h, and 90% conversion in 24 h in the
presence of K CO . Isolated yields in acetonitrile with Cs CO as
base were in the range of 85–93%.
For lab scale processes the combination of acetonitrile and
CO at reflux was considered as convenient conditions, enabling
both the synthetic transformation and the purification to be
completed in one working day. We went on to test the suitability of
this method on the more sophisticated building block 6-bromo-4-
chlorothieno[2,3-d]pyrimidine (5) [17], with intended use as
building block for kinase inhibitors. The thienopyrimidine 5 was
subjected to reactions with a series of 12 nucleophiles, six of which
were fluorinated, see Table 4. The reactions were sampled for 12 h
and then left overnight.
sustainable solvents than DMF, and since reactions in these media
also gave an acceptable rate of reactions, these two solvents were
selected for the further study of nucleophilic aromatic substitu-
tions using also the mono fluorinated and difluorinated alcohols 2b
and 2b. We also found that the amount of base in the couplings
could be reduced to 1.2 equiv. without major effect on rates. The
results are shown in Table 3.
The reactions using t-BuOH as solvent (Table 3 entries 1–4)
revealed a higher conversion rate upon increasing the number of
-fluoro atoms in the nucleophile, in line with the increase in
2
3
2
3
Cs
2
3
a
acidity of the alcohols. For reactions with caesium carbonate as
base the alcohols 2a–d could be coupled in 6 h, while substitutions
using K
2
CO
3
required longer reaction time. A graphical represen-
Differences in rate of reactions were seen depending on the
nature of the R-group, but less pronounced depending on the aryl
moiety. The primary alcohols 2e, 2j and 2l reached full conversion
in 3–5 h, while the more sterically demanding secondary alcohols
2a, 2f and 2k required refluxing overnight (24 h, entries 4–6). The
tation on how fluoro insertion affects degree of conversion is
shown in Fig. 1. As seen, modulating the alcohol with one fluoro
atom has a tremendous effect on reaction progress.
The conversion rates in acetonitrile were higher as compared to
in t-BuOH, and with Cs
or less. Prolonged reaction time was required using K
trifluoroalcohol 2d was fully converted to 3d in only 3.5 h at reflux.
2
CO
3
2a–d were reacted to product in 3.5 h
a
effect of the pK of the reacting alcohol was again evident, and the
2
CO , but the
3
six fluoro containing derivatives reached full conversion in 1.5 h or
less (entries 7–12). No by-products were detected in these
reactions, and the non-optimised yields ranged from 82–96%.
2 3
Compound 2d was also coupled at 20 8C (entry 9), using Cs CO
Table 3
Reaction of 4-chloroquinazoline (1) with the alcohols 2a-2d using 1.2 equivalents of carbonate as base in t-BuOH or acetonitrile. Except for entry 9, all reactions were
performed at reflux (82 8C). Scale: 100 mg 1 in 2 mL solvent.
Entry
Substrate
R
Solvent
Cs
2
CO
3
2 3
K CO
a
a
Time (h)
Conv. (%)
Yield (%)
Time (h)
Conv. (%)
c
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
2d
CH
CH
3
2
t-BuOH
t-BuOH
t-BuOH
t-BuOH
6
>99
>99
>99
>99
>99
>99
>99
>99
>99
–
24
24
24
10
24
24
24
3.5
24
30
96
c
F
4
–
c
CHF
CF
2
4
–
98
c
3
1
–
>99
38
CH
CH
3
2
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
3.5
2.5
2.5
1
85
91
93
89
95
F
>99
>99
>99
90
CHF
2
CF
CF
3
3
b
9
2
a
Conversion is by GC.
b
c
The reactions were performed at 20 8C.
No isolation of product was performed.

J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
85
100
80
60
40
20
0
R = CH3
R= CH2F
R= CHF2
R= CF3
0
5
10
15
20
25
Reaction time (h)
2 3
Fig. 1. Conversion of compound 2a–d to 3a–d using K CO as base in t-BuOH.
Table 4
Coupling of the alcohols 2a–l with the thienopyrimidine 5 using Cs
2
CO
3
3
(1.2 equiv.) in acetonitrile at reflux, scale 200 mg 5 in 2 mL CH CN.
a
b
Entry
Substrate
Ar
R
Time (h)
Conv. (%)
Yield (%)
Product
1
2
3
4
5
6
7
8
9
2e
2j
Ph
H
3
5
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
92
88
86
91
92
93
89
93
82
96
93
87
6e
6j
1-Napht.
2-Napht.
Ph
H
2l
H
6
6l
2a
2f
CH
CH
CH
CH
CH
3
3
3
24
24
24
1.5
1.5
1.5
1
6a
6f
1-Napht.
2-Napht.
Ph
2k
2b
2g
2c
2h
2d
2i
6k
6b
6g
6c
6h
6d
6i
2
F
1-Napht.
Ph
2
F
CHF
CHF
2
1
1
1
0
1
2
1-Napht.
Ph
2
CF
CF
3
3
0.5
0.5
1-Napht.
a
Conversion is by GC.
b
Isolated, not optimised yield after silica-gel column chromatography.
2.2. Stability of the fluorinated alcohols and their products
Scheme 3. Trace amounts of some unidentified products were also
As shown from the investigation above, the target products
Table 5
could be obtained under different conditions (base/solvent/
temperature). This allows for flexibility in the choice of conditions
depending on if rate of reaction, price of reagent or environmental
issues are of main concern. A possible challenge could be that the
substrate alcohols decompose when exposed to the reaction
conditions for a prolonged period of time. Therefore, we subjected
the fluoro alcohols 2b–d to stability testing in THF containing 5%
Hydrolytic stability of the 4-alkoxyquinazolines 3a–d in the presence of acid and
base in THF.
a
Entry
Comp.
R
Conditions
Temp. (8C)
Conv.
Conv.
b
b
3 h (%)
24 h (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3d
3a
3b
3c
3d
3a
3b
3c
3d
CH
3
2.8 M HCl
2.8 M HCl
2.8 M HCl
2.8 M HCl
0.05 M HCl
0.05 M HCl
0.05 M HCl
0.05 M HCl
0.05 M HCl
2.8 M KOH
2.8 M KOH
2.8 M KOH
2.8 M KOH
82
82
82
82
82
20
20
20
20
82
82
82
82
100
100
100
100
100
31
24
20
37
55
2
–
–
CH2F
CHF
2
–
CF
CF
3
–
KOH and DMF containing Cs
fluoro-1-phenylethanol (2b) in the presence of KOH and Cs
2
CO
3
for 24 h. This revealed that 2-
CO
3
–
2
3
CH
CH
3
69
64
62
69
82
21
22
29
reacted to give 34% and 20% of styrene oxide (7), respectively,
2
F
CHF
CF
2
3
1
1
1
1
0
1
2
3
CH
CH
3
2
F
CHF
CF
2
1
3
5
a
3a–d (0.08 mmol) in THF (15 mL) and HCl/KOH (1.5 mL). Hexadecane was used
Scheme 3. By-product observed when treating 2b with potassium hydroxide or
as internal standard.
b
Cs
2
CO
3
.
Conversion determined by GC.

8
6
J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
Scheme 4. Hydrolytic stability of the 4-alkoxyquinazolines 3a–d.
seen in the DMF/Cs
2
CO
3
reaction. The difluoroalcohol 2c and the
possibly indicating a complex counter balance between steric
hindrances, electrophilicity at C-4, and leaving group ability.
It was expected that hydrolysis proceeded by attack at C-4. To
trifluoroalcohol 2d appeared stable under the same conditions.
Thus, for coupling of monofluorinated alcohols under basic
conditions, extended reaction times should be avoided, since
yield losses might occur due to decomposition of the starting
material.
Pyrimidines substituted with alkoxy groups are known to be
labile towards both acidic [30,31] and basic conditions [32]. For
work-up and further synthetic transformations it is important to
have some guidelines regarding the stability also for the new
fluoroalkoxy pyrimidines. To compare their stability the quinazo-
line based products 3a–d were subjected to basic and acidic
conditions (Table 5; Scheme 4).
0
rule out the possibility of a partial nucleophilic attack at C-1 , (R)-
3a and (S)-3d were subjected to hydrolysis in the presence of KOH.
Analysis using GC equipped with a CP-Chirasil-Dex CB column
revealed the enantiomeric excess and the stereochemistry of 2a
and 2d to be unaffected by the treatment, confirming that
hydrolysis exclusively occurs by attack at C-4.
As racemisation was only anticipated for the trifluoro contain-
0
ing alkoxy pyrimidines, due to the acidity of the proton at C-1 [20],
also compound (R)-6d was made from (R)-2d. HPLC analysis using
a chiral column verified that the enantiomeric excess was retained
The hydrolysis of these molecules is expected to proceed via an
addition elimination mechanism, and under acidic conditions the
pyrimidine unit might be further activated by protonation of the
ring nitrogen. GC analysis showed that 3a–d all readily hydrolysed
upon refluxing in the presence of acid (Table 5, entries 1–5). Under
less harsh conditions (entries 6–9) the hydrolysis proceeded more
slowly and reached 62–69% conversion in 24 h. The conversion rate
seemed to be independent of the presence of fluoro atoms. Higher
stability was observed under basic conditions, and a clear
difference in degree of hydrolysis was seen as the non-fluorinated
molecules 3a reacted faster than the fluorinated derivatives 3b–d.
No clear difference in conversion rate was observed for 3b–d,
2 3
in the product upon synthesis (Cs CO /acetonitrile/reflux). Fur-
ther, the trifluoroethoxy derivative (R)-6d was stirred in the
presence of sodium hydride for 24 h, followed by work up. Also
under these conditions the enantiomeric excess of (R)-6d was
unaffected. Thus, the risk of racemisation appears to be low during
normal synthetic operations.
To verify the utility of such molecules, although their somewhat
labile nature, Suzuki couplings of the thienopyrimidines 6a and 6d
with ortho-, meta- and para-hydroxy phenylboronic acids, were
performed see Scheme 5.
Even though rather harsh conditions were used, the Suzuki
coupling products 8–10 were isolated in 82–97% yield. The
OH
R1
B
R1
N
O
HO
N
O
N
O
S
R
S
S
Br
Br
N
N
HN
Dioxane:H2O (1/1)
Pd(PPh3)4
R
Ph
6
K2CO3
Ph 8-10
11
o
90 C
Yield 82-97%
R = CH3 (a), CF3 (d)
R1 = o-OH (8), m-OH (9), p-OH (10)
Scheme 5. Suzuki coupling of 6a and 6d to the products 8–10.
Table 6
Selected NMR spectroscopic shifts (ppm) of 3a–d, 6a–d and 6f–i in CDCl
3
.
1
9
0
0
a
Comp.
R
Ar
F (
d
)
C-2 (
d
)
C-1 (
d
)
C-4 (
d
)
D C-4
3
3
3
3
6
6
6
6
6
6
6
6
a
b
c
d
a
b
c
d
f
CH
CH
3
2
Ph
–
22.5
84.6
74.5
76.4
75.5
73.8
74.6
76.4
75.5
73.7
72.0
74.0
72.6
70.3
166.0
166.0
165.2
164.6
161.7
161.5
160.7
160.0
161.8
161.5
160.7
160.1
0
F
Ph
ꢀ221.2
0
CHF
CF
2
Ph
ꢀ131.6/ꢀ129.4
ꢀ78.9
114.1
123.5
22.5
ꢀ0.8
ꢀ1.5
0
3
Ph
CH
CH
3
2
Ph
–
F
Ph
ꢀ224.7
ꢀ131.4/ꢀ129.4
ꢀ79.0
84.5
ꢀ0.2
ꢀ1.0
ꢀ1.7
0
CHF
CF
2
Ph
114.0
123.3
22.0
3
Ph
CH
CH
3
2
1-Napht.
1-Napht.
1-Napht.
1-Napht.
–
g
h
i
F
ꢀ221.9
ꢀ130.5–127.5
ꢀ78.1
84.2
ꢀ0.3
ꢀ1.1
ꢀ1.7
CHF
CF
2
114.3
123.9
3
a
Change in shift value at C-4 depending on degree of fluorination relative to the corresponding hydrogen analogues 3a, 6a and 6f.

J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
87
Table 7
1
9
F NMR couplings to proton and carbon in Hz.
1
2
2
3
Comp.
R
Ar
J
CF
J
CF
J
FH
J
FH
3
b
b
g
c
CH
CH
CH
2
2
2
F
F
F
Ph
179.3
19.8
47.3
16.6
16.1
15.7
6
6
3
6
6
3
6
6
Ph
179.4
19.8
47.6
1-Napht.
Ph
180.6
20.2
47.0
CHF
CHF
CHF
2
2
2
246.6
25.7
55.4/55.0
12.5/10.3
11.8/10.6
11.5/9.3
6.8
c
Ph
246.3
26.2
55.3/55.1
h
d
d
i
1-Napht.
Ph
248.1/245.8
281.0
27.1/24.8
33.1
55.3/54.8
CF
3
CF
3
CF
3
–
–
–
Ph
280.8
33.4
6.8
1-Napht.
281.5
33.7
6.3
hydrolytic by-product 11 was not observed. Differences in yield
were judged to be caused by purification issues related to
impurities in the aryl boronic acids and cross coupling of the aryl
boronic acids, but also that 8a and 10a had a low solubility making
chromatographic separation more difficult.
increased. Interestingly, such ‘‘reversed’’ electronic effects have
been observed in other chemical systems and have been explained
by the so-called p-polarisation mechanism [33–35], where
localised dipoles are set up resulting in a change in electron
density at the specific sites [36,37].
The coupling constants data in Table 7 are arranged in
accordance with increasing number of inserted fluoro atoms.
As seen the size of the coupling constants are highly dependent
on the number of fluoro atoms, but within each series of mono, di
2
.3. NMR spectroscopy
The quinazolines 3a–d and thienopyrimidines 6a–i were
1
13
19
characterised by NMR spectroscopy ( H, C, F, HMBC and
HSQC). The most interesting NMR spectroscopic shifts of the fluoro
containing molecules 3b–d, 6b–d and 6g–i are shown in Table 6,
while relevant coupling constants are compiled in Table 7. The
numbering system and spin systems referred to are shown in Fig. 2.
Generally, the shift values were similarly affected by the
number of fluoro atoms in the two heteroaromatic systems.
and trifluorinated compounds, only minor variations were seen.
1
The H NMR spectroscopic spectrum of the FCH
2
CH fragments
of 3b, 6b and 6g, makes up a complicated ABMX-system, giving
total of 8 theoretical splitting (ddd) for each proton. Some
overlapping signals are usually observed in the AB-part, but aided
1
9
by F NMR, the coupling data for the systems could be enveloped.
2
The JAB couplings were in the range of 10.3–10.5 Hz. Although, the
0
1
In the normal way carbon C-2 connected to the fluoro atom
methylene protons are magnetically different as shown by H NMR
1
9
experience increasing deshielding as more fluoro atoms are
inserted. On the other hand, C-1 , had the highest deshielding
for the monofluoro derivatives, and the highest shielding for the
spectroscopy, the
doublets.
F NMR spectrum appears as a triplet of
0
1
9
The F NMR non decoupled spectra of the difluoro compounds
3c, 6c and 6h appeared as ABMX spin systems, where the two
fluoro atoms (A and B) couple to each other (288.4–288.6 Hz), but
also to the proton at C-2 (X, Fig. 2) with a coupling of 54.8–55.4 Hz,
and to the proton at C-1 with a smaller coupling of 9.3–12.5 Hz.
2 2 3 3
trifluoro compounds, giving the order – CH F < CHF < CH < CF
13
in terms of deshielding. The C NMR spectroscopic shift at C-4
could be used as a diagnostic tool for reactivity. In contrast to that
intuitively expected, the C NMR shift-values at C-4 resided at
lower ppm (more shielded) as the number of fluoro atoms is
0
13
0
1
9
The F NMR spectrum of 3c is shown in Fig. 3.
Fig. 2. Carbon numbering system used and NMR spin coupling systems observed.
1
9
Fig. 3. F NMR spectrum of compound 3c.

8
8
J. Han et al. / Journal of Fluorine Chemistry 153 (2013) 82–88
1
3
The C NMR spectra where mostly as expected giving doublet,
Appendix A. Supplementary data
0
0
triplets and quartets for carbons C-1 and C-2 , depending on the
number of inserted fluoro atoms. However, the C NMR spectrum
of compound 6 h, instead of showing triplet signals for C-1 and C-
, these appeared as doublets of doublets due to coupling to both
13
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.05.011.
0
0
2
fluoro atoms.
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Acknowledgment
The group is thankful to the Anders Jahres Foundation for
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