Annelation reactions of pentafluorobenzonitrile

Article abstract of DOI:10.1016/j.tet.2010.01.104

Annelation reactions between pentafluorobenzonitrile and N,N-dimethylethylene diamine and 3-methyl picoline gave [6,6]-bicyclic and [6,5,6]-tricyclic ring-fused systems, respectively. Reaction of 4-morpholino tetrafluorobenzonitrile with hydrazine and phenyl hydrazine gave [5,6] ring-fused systems arising from a tandem S_NAr and cyclisation process involving annelation onto the pendant cyano group providing an indication of the synthetic possibilities for heterocycle formation using the pentafluorobenzonitrile scaffold.

Full text of DOI:10.1016/j.tet.2010.01.104

Tetrahedron 66 (2010) 2356–2362
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Annelation reactions of pentafluorobenzonitrile
,
b
b
Matthew R. Cargill a, Katharine E. Linton a, Graham Sandford a , Dmitrii S. Yufit , Judith A.K. Howard
*
a Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Annelation reactions between pentafluorobenzonitrile and N,N-dimethylethylene diamine and 3-methyl
picoline gave [6,6]-bicyclic and [6,5,6]-tricyclic ring-fused systems, respectively. Reaction of 4-morpholino
tetrafluorobenzonitrile with hydrazine and phenyl hydrazine gave [5,6] ring-fused systems arising from
a tandem SNAr and cyclisation process involving annelation onto the pendant cyano group providing an
indication of the synthetic possibilities for heterocycle formation using the pentafluorobenzonitrile
scaffold.
Received 22 October 2009
Received in revised form 21 December 2009
Accepted 27 January 2010
Available online 2 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reported in the literature1 and, in general, nucleophilic substitution of
fluorine located para to the cyano group provides access to various
The chemistry of perfluorinated aromatic systems has been
a developing field since synthetic routes that provided ready access
to hexafluorobenzene and related highly fluorinated aromatic
systems were reported.1,2 It was realised very rapidly that reactions
of highly fluorinated aromatic systems occur readily with nucleo-
philic species, rather than electrophiles, and consequently, all of the
problems of regioselectivity of nucleophilic aromatic substitution
reactions, rates of reaction, control and functionalisation processes
began to be addressed. Of course, the literature contains a great
deal of information describing familiar electrophilic substitution
reactions of hydrocarbon aromatic and heteroaromatic derivatives
but research into the chemistry of corresponding perfluorinated
aromatic systems has been effectively summarised in a single re-
view article,1 providing an indication of the vast chemistry of these
systems that remains to be explored.
In a developing research programme, we have been utilising
simple highly fluorinated aromatic and heteroaromatic ‘building
blocks’ as starting materials for the construction of a variety of
macrocycles,3 glycosyl donors,4 polyfunctional5 and ring-fused
systems6–8 and have discussed the application of per-
fluoroheteroaromatic scaffolds in the drug discovery arena.5
In this paper, we present methodology for the synthesis of various
ring-fused systems from pentafluorobenzonitrile 1, a potentially very
useful and reactive scaffold that bears multiple, complementary
functionality but whose chemistry is relatively unexplored. Only
a limited number of reactions involving pentafluorobenzonitrile and
several nitrogen9–11 and oxygen9 centred nucleophiles have been
4-substituted tetrafluorobenzonitrile systems.
Potentially, nucleophilic displacement of fluorine atoms and
reactions involving the transformation of the cyano group may al-
low the synthesis of a diverse range of polyfunctional ring-fused
heterocycles upon reaction with appropriate difunctional nucleo-
philes utilising the general strategy outlined in Scheme 1, given that
reaction of the first nucleophile may be expected to occur at the site
para to the cyano group, consistent with earlier findings.
H
N
R'
CN
N
R
( )
n
CN
F
F
F
F
NHR
F
F
F
F
R
N
( )n
R'
R
Nuc1
H2N
F
N
R'
H2N
R'
CN
( )
NR
n
( )
n
F
F
F
NHR
F
F
F
Nuc1
Nuc1
Scheme 1. General synthetic strategy for annelation reactions.
2. Results and discussion
Reaction of pentafluorobenzonitrile 1 with a range of repre-
sentative mono- and di-functional nitrogen centred nucleophiles
are shown in Scheme 2.
* Corresponding author. Tel.: þ44 (0)1913342039; fax: þ44 (0)1913844737.
E-mail address: graham.sandford@durham.ac.uk (G. Sandford).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.104

M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
2357
H
N
CN
CN
F
F
F
F
F
F
F
F
2
, 1 eq. DIPEA, THF
reflux, 60 h
O
2a, 87%
F
1
N
O
H
N
CN
CN
O
F
F
F
F
F
F
N
F
2
, 2 eq. DIPEA, THF
reflux, 60 h
O
2b, 75%
F
1
N
O
CN
N
F
F
F
CN
CN
F
F
F
F
F
F
F
HN
NH2
F
NH2
.HCl
, 2 eq. DIPEA, THF
base
NH
Ar
reflux, 24 h
N
F
1
2d
2c, 45%
CN
F
F
F
CN
CN
NH
F
HN
F
F
F
, 2 eq. DIPEA, MeCN
F
F
F
F
N
+
reflux, 3 h
N
N
N
F
1
F
F
F
F
2f, 12%
2e, 37%
CN
CN
F
F
F
CN
F
F
F
N
NH2, DIPEA, THF
reflux, 48 h
2g,
61%
N
N
F
F
1
Scheme 2. Reactions of pentafluorobenzonitrile 1 with nitrogen centred nucleophiles.
Morpholine and 1 gave product 2a arising from displacement of
fluorine at the site para to the cyano group and its structure was
confirmed by X-ray crystallography (Fig. 1).
fused products 2e and 2g, respectively, in good yield. The structures
of 2e and 2g follow from 19F NMR studies, in which three reso-
nances are observed as expected, and other spectroscopic tech-
niques are consistent with the structures proposed.
Reaction of 1 with 2 equiv of morpholine gave 2b where the
second substitution was found to be regioselective and occurs at
the site ortho to the electron withdrawing and, therefore, highly
activating, cyano group. The structure of 2b could be determined by
19F NMR spectroscopy, which showed three resonances at ꢀ134.4,
ꢀ135.7 and ꢀ151.0 ppm in a 1:1:1 ratio. A consideration of the 19F
NMR substituent chemical shifts from literature data12 and this
work, confirmed the structure of 2b.
After the model reactions described above confirmed that nu-
cleophilic substitution of nitrogen centred nucleophiles occurred at
the 4- then 2-positions regioselectively, reactions of 1 with nitro-
gen centred difunctional nucleophiles were studied. Benzamidine
gave 2c, as confirmed by X-ray crystallography (Fig. 1), but no
cyclised product 2d could be obtained upon reaction of 2c
with various strong bases. In contrast, stronger nucleophiles,
N,N0-dimethylethylene diamine and 2-amino-3-picoline gave ring-
Reaction of the 4-morpholino derivative 2a with benzamide
gave the [6,6]-ring-fused system 3a (Scheme 3) by reaction of the
nitrogen centred nucleophile firstly at the site ortho to the ring
cyano group, consistent with the regioselectivity of these processes
as discussed above, and subsequent reaction with the carbon atom
of the cyano group, reminiscent of reactions that we reported
earlier involving tetrafluoro-4-cyanopyridine (Scheme 4).13
By a similar process, reaction of phenyl hydrazine with 2a gave
[5,6]-fused system 3b while reaction of 2a with hydrazine allowed
the synthesis of the ring-fused system 3c whose structure was
confirmed by X-ray crystallography (Fig. 2).
Reaction of 2a with N,N0-dimethylethylene diamine gave the
[6,6]-ring-fused system 3d arising from annelation of the benzene
ring only, reflecting the ease of formation of a six-membered ring in
the annelation step rather than a seven-membered ring, which

2358
M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
Figure 1. Molecular structures of 2,3,5,6-tetrafluoro-4-morpholinobenzonitrile 2a (above, only one position of the disordered morpholine ring is shown) and (Z)-N0-(4-cyano-
2,3,5,6-tetrafluorophenyl)benzimidamide 2c (below).
H2N
F
N
CN
N
F
F
F
F
N
F
HN
NH2 .HCl, DIPEA, THF
reflux, 9 days
3a
, 37%
F
N
O
O
2a
B
H
CN
CN
H
CN
NH
Ph
NH
Ph
HN
N
F
F
F
F
F
F
-H+
NH2
Ph
F
F
F
F
F
F
HN
N
O
N
O
N
O
H
N
N
C
HN
H2N
F
N
Ph
N
Ph
H
Ph
N
F
F
F
N
F
F
F
N
F
H
F
N
O
N
O
N
O
Scheme 3. Formation of 3a.
would be formed upon corresponding cyclisation involving the
cyano substituent.
3. Experimental
3.1. General
In summary, we have demonstrated that pentafluorobenzonitrile
1 may be used very effectively for the synthesis of various [5,6]- and
[6,6]-ring-fused systems upon efficient reaction with appropriate
difunctional nucleophiles, further illustrating the synthetic possi-
bilities afforded by highly fluorinated heteroaromatic scaffolds for
heterocyclic synthesis.
All starting materials were obtained commercially (Sigma–
Aldrich) and all solvents were dried using standard laboratory pro-
cedures. NMR spectra were recorded in deuteriochloroform, unless
otherwise stated, on Varian VXR NMR spectrometers with

M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
2359
H2N
N
CN
N
F
F
F
F
N
F
F
PhNHNH2, n-BuLi, THF
3b
, 31%
-78οC - rt
F
N
O
O
2a
H2N
CN
N
N
F
F
F
F
F
H
NH2NH2, DIPEA, THF
reflux, 72 h
3c, 93%
F
F
N
N
O
2a
O
CN
CN
F
F
F
F
F
F
N
N
NH
, DIPEA, THF
HN
3d
, 28%
reflux, 24 h
N
N
O
O
2a
Scheme 4. Reactions of 4-morpholino derivative 2a with difunctional nucleophiles.
Figure 2. Molecular structure of 4,5,7-trifluoro-6-morpholino-1H-indazole-3-amine 3c.
tetramethylsilane and trichlorofluoromethane as internal standards.
Assignments were made with the aid of data collected by 1H–1H
COSY and 1H–13C HETCOR experiments and coupling constants are
given in hertz. Mass spectra were recorded on either a VG 7070E
spectrometer or a Fisons VG Trio 1000 spectrometer coupled with
a Hewlett Packard 5890 series II gas chromatograph. Elemental
analyses were obtained on either a Perkin–Elmer 240 or a Carlo Erba
Elemental Analyser. Melting points were recorded at atmospheric
pressure and are uncorrected. Column chromatography was carried
out on silica gel (Merck No. 1-09385, 230–400 mesh) and TLC
analysis was performed on silica gel TLC plates.
pentafluorobenzonitrile 1 (1.19 g, 6.1 mmol) and DIPEA (0.78 g,
6.0 mmol) in anhydrous acetonitrile (30 mL) under an atmosphere of
dry argon and the mixture was heated and stirred under reflux for
12 h. The mixture was allowed to cool to room temperature, poured
into water (100 mL) and extracted with DCM (3ꢁ40 mL). The com-
bined organic extracts were washed with water and dried (MgSO4).
The mixture was filtered, volatiles removed in vacuo and the residue
was purified by column chromatography on silica gel using DCM as
the eluent to afford 2,3,5,6-tetrafluoro-4-morpholinobenzonitrile 2a
(1.40 g, 87%) as a white solid, mp 78–79 ꢂC; Rf (DCM) 0.3; IR 2968,
2861, 2236, 1648, 1524 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 3.40–3.44
(4H, m, NCH2CH2O), 3.80–3.85 (4H, m, NCH2CH2O); 13C NMR
4
(126 MHz, CDCl3)
d
51.1 (t, JCF¼4.4 Hz, NCH2CH2O), 67.2 (s,
3.2. Reactions of pentafluorobenzonitrile 1
2
3
NCH2CH2O), 84.5 (tt, JCF¼8.8 Hz, JCF¼1.7 Hz, 1-C), 108.5 (t,
3JCF¼3.4 Hz, CN),135.6 (tt, 2JCF¼9.4 Hz, 3JCF¼2.9 Hz, 4-C),140.7 (dddd,
3.2.1. 2,3,5,6-Tetrafluoro-4-morpholinobenzonitrile 2a. Morpholine
1JCF¼245 Hz, JCF¼13.8 Hz, JCF¼6.3 Hz, JCF¼4.1 Hz, 3-C), 148.4
2
3
4
(0.56 g,
6.4 mmol)
was
added
to
a
solution
of

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M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
2
3
4
(dddd, 1JCF¼245 Hz, JCF¼14.5 Hz, JCF¼6.3 Hz, JCF¼3.8 Hz, 2-C); 19F
purified by column chromatography on silica gel using DCM and
hexane (9:1) as the eluent to afford 5,7,8-trifluoro-1,4-dimethyl-
1,2,3,4-tetrahydroquinoxaline-6-carbonitrile 2e (0.55 g, 37%) as an
NMR (658 MHz, CFCl3)
d
ꢀ134.4 (2F, m, 2-F), ꢀ149.8 (2F, m, 3-F); GC–
MS (probe) 70 eV m/z (rel int.): 260 [M]þ (38), 202 (100), 201 (80),
174 (18), 124 (22). Anal. Calcd for C11H8N2OF4: C, 50.78; H, 3.10; N,
10.77. Found C, 50.72; H, 3.14; N, 10.90%.
off-white solid, mp 112–113 ꢂC; Rf 0.6 (DCM/hexane, 9:1); IR
n
2221,
1640, 1529, 1494 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
2.75 (3H, br s,
3
5
CH3), 3.00 (2H, t, JHH¼4.8 Hz, CH2), 3.22 (3H, d, JHF¼4.9 Hz, CH3),
3
3.2.2. 2,3,5-Trifluoro-4,6-dimorpholinobenzonitrile 2b. Morpholine
(0.65 g, 7.4 mmol) was added to a solution of pentafluorocy-
anobenzene (0.57 g, 2.95 mmol) and DIPEA (0.92 g, 7.2 mmol) in
anhydrous acetonitrile (30 mL) under an atmosphere of dry argon.
The mixture was heated and stirred under reflux for 60 h. The
mixture was allowed to cool to room temperature, poured into water
(100 mL) and extracted with DCM (3ꢁ40 mL). The combined organic
extracts were washed with water and dried (MgSO4). The mixture
was filtered, volatiles evaporated and the residue purified by column
chromatography on silica gel using hexane and ethyl acetate (7:3) as
the eluent to afford 2,3,5-trifluoro-4,6-dimorpholinobenzonitrile 2b
(0.72 g, 75%) as a white solid, mp 125–126 ꢂC; Rf (hexane/ethyl ac-
etate, 7:3) 0.4; IR 2363, 1650, 1494 cmꢀ1; 1H NMR (700 MHz, CDCl3)
3.26 (2H, t, JHH¼4.8 Hz, CH2); 13C NMR (126 MHz, CDCl3)
d 42.2
4
4
(d, JCF¼13.4 Hz, CH3), 43.5 (d, JCF¼5.6 Hz, CH3), 46.4 (s, CH2), 47.9
2
3
(s, CH2), 79.6 (ddd, JCF¼18.7, 17.1 Hz, JCF¼2.1 Hz, 6-C), 110.6
3
2
3
(d, JCF¼3.4 Hz, CN), 122.3 (ddd, JCF¼12.4 Hz, JCF¼3.5 Hz,
4JCF¼2.6 Hz, 4b-C), 135.9 (ddd, JCF¼7.2 Hz, JCF¼5.8 Hz, JCF¼3.8 Hz,
4a-C), 136.9 (ddd, 1JCF¼243 Hz, 2JCF¼14.3 Hz, 4JCF¼2.9 Hz, 8-C), 147.1
(ddd, 1JCF¼252 Hz, 2JCF¼15.0 Hz, 3JCF¼8.4 Hz, 7-C), 151.4
(ddd, 1JCF¼252 Hz, 3JCF¼6.2 Hz, 4JCF¼1.1 Hz, 5-C); 19F NMR (658 MHz,
2
3
4
CFCl3)
d
ꢀ123.5 (1F, dd, 4JFF¼4.6 Hz, 5JFF¼8.2 Hz, 5-F), ꢀ139.8 (1F, dd,
3JFF¼20.2 Hz, JFF¼4.6 Hz, 7-F), ꢀ155.9 (1F, ddq, JFF¼20.2 Hz,
5JHF¼4.9, 8.2 Hz, 8-F); GC–MS (probe) 70 eV m/z (rel int.): 241 [M]þ
(100), 226 (70), 211 (25),170 (57), 42 (20). Anal. Calcd for C11H10N3F3:
C, 54.77; H, 4.18; N, 17.42. Found: C, 54.59; H, 4.02; N, 17.47%; and
4,40-(ethane-1,2-diylbis(methylazanediyl))bis(2,3,5,6-tetrafluorobenzo
nitrile) 2f (0.33 g, 12%) as a white solid; mp 155–156 ꢂC; Rf 0.25
4
3
d
3.20–3.28 (4H, m, CH2), 3.28–3.36 (4H, m, CH2), 3.70–3.82 (8H, m,
CH2); 13C NMR (176 MHz, CDCl3)
d
51.3 (t, JCF¼3.6 Hz, NCH2CH2O),
4
4
52.1 (d, JCF¼4.4 Hz, NCH2CH2O), 67.5 (s, NCH2CH2O), 67.7
(s, NCH2CH2O), 91.9 (m, 1-C), 112.4 (m, CN), 134.9 (t, 2JCF¼11.0 Hz, 4-
C), 138.7 (d, 2JCF¼14.3 Hz, 6-C), 141.0 (ddd, 1JCF¼247 Hz, 2JCF¼13.3 Hz,
(DCM/hexane, 9:1); IR
(500 MHz, CDCl3)
13C NMR (126 MHz, CDCl3)
n
2236, 1640, 1520, 1494 cmꢀ1
;
1H NMR
5
d
3.07 (6H, t, JHF¼2.9 Hz, CH3), 3.58 (4H, s, CH2);
d
40.9 (t, 4JCF¼5.2 Hz, CH3), 52.8 (s, CH2),
3JCF¼6.7 Hz, 3-C), 148.4 (dm, JCF¼246 Hz, 5-C), 149.7 (dm,
84.0 (tt, JCF¼17.5 Hz, JCF¼1.3 Hz, 4-C), 108.1 (t, JCF¼3.5 Hz, CN),
1
2
3
3
1JCF¼247 Hz, 2-C); 19F NMR (658 MHz, CFCl3)
d
ꢀ134.4 (1F, dd,
135.5 (tt, JCF¼9.7 Hz, JCF¼2.8 Hz, 1-C), 140.3 (dddd, JCF¼245 Hz,
2JCF¼10.2 Hz, 3JCF¼5.7 Hz, 4JCF¼3.7 Hz, 3-C), 148.2 (dddd,
2
3
1
3JFF¼20.7 Hz, JFF¼9.8 Hz, 2-F), ꢀ135.7 (1F, br s, 5-F), ꢀ151.0 (1F, d,
3JFF¼20.7, 3-F); GC–MS (probe) 70 eV m/z (rel int.): 327 [M]þ (86),
269 (52), 211 (100), 184 (59), 157 (18). Anal. Calcd for C15H16N3O2F3:
C, 55.04; H, 4.93; N, 12.84. Found C, 55.10; H, 4.98; N, 12.77%.
5
1JCF¼259 Hz, JCF¼15.1 Hz, JCF¼7.0 Hz, JCF¼4.1 Hz, 2-C); 19F NMR
2
3
4
(658 MHz, CFCl3)
d
ꢀ134.0–134.2 (4F, m, Ar–F), ꢀ149.8–150.1 (4F, m,
Ar–F); GC–MS (probe) 70 eV m/z (rel int.): 434 [M]þ (1), 231 (15), 217
(100), 201 (20), 188 (10). Anal. Calcd for C18H10N4F8: C, 49.78; H, 2.32;
N, 12.90. Found: C, 49.66; H, 2.30; N, 12.96%.
3.2.3. (Z)-N0-(4-Cyano-2,3,5,6-tetrafluorophenyl)benzimidamide
2c. Benzamidine hydrochloride (0.95 g, 6.1 mmol) was added to
a solution of pentafluorocyanobenzene (1.08 g, 5.6 mmol) and DIPEA
(1.49 g, 11.5 mmol) in anhydrous acetonitrile (30 mL) under an
atmosphere of dry argon. The mixture was heated and stirred under
reflux for 24 h. The mixture was allowed to cool to room temperature,
poured into water (100 mL) and extracted with DCM (3ꢁ40 mL). The
combined organic extracts were washed with water and dried
(MgSO4). The mixture was filtered, volatiles evaporated and the res-
idue purified by column chromatography on silica gel using hexane
and THF (7:3) as the eluent to afford (Z)-N0-(4-cyano-2,3,5,6-tetra-
fluorophenyl)benzimidamide 2c (0.73 g, 45%) as a white solid, mp 164–
165 ꢂC; Rf 0.3 (hexane/THF, 7:3); IR 3432, 2238, 1640, 1591,
3.2.5. 6,8,9-Trifluoro-4-methyl-benzo[4,5]imidazo[1,2-a]pyridine-7-
carbonitrile 2g. 2-Amino-3-picoline (0.45 g, 4.2 mmol) was added to
a solution of pentafluorocyanobenzene (0.85 g, 4.4 mmol) and DIPEA
(0.55 g, 4.26 mmol) in anhydrous acetonitrile (30 mL) under an at-
mosphere of dry argon. The mixture was heated and stirred under
reflux for 48 h. The mixturewas allowed to cool to room temperature,
poured into water (100 ml) and extracted with DCM (3ꢁ40 mL). The
combined organic extracts were washed with water and dried
(MgSO4). The mixture was filtered, volatiles evaporated and the
residue purified by column chromatography on silica gel using hex-
ane and ethyl acetate (1:1) as the eluent to afford 6,8,9-trifluoro-4-
1568 cmꢀ1; 1H NMR (700 MHz, d6-DMSO)
d
3
7.15 (1H, br s, NH), 7.47
methyl-benzo[4,5]imidazo[1,2-a]pyridine-7-carbonitrile 2g (0.66 g,
61%) as a yellow solid, mp 211–212 ꢂC; Rf 0.4 (hexane/ethyl acetate,
3
(2H, dd, JHH¼7.7, 7.7 Hz, 30-H), 7.54 (1H, t, JHH¼7.7 Hz, 40-H), 7.89,
(1H, br s, NH), 7.92 (2H, d, JHH¼7.7 Hz, 20-H); 13C NMR (176 MHz,
1:1); IR
n
2235, 1650, 1550 cmꢀ1
;
1H NMR (700 MHz, CDCl3)
d
2.70
3
2
3
DMSO-d6)
d
84.0 (t, JCF¼17.8 Hz, 4-C), 109.5 (s, CN), 128.0 (s, 20-C),
(3H, s, CH3), 6.95 (1H, t, JHH¼6.9 Hz, 2-H), 7.36–7.40 (1H, m, 3-H),
128.8 (s, 30-C),131.8 (s, 40-C), 134.1 (s, 10-C), 138.1 (t, 2JCF¼14.4 Hz,1-C),
140.2 (dm, 1JCF¼243 Hz, 3-C), 147.8 (dm, 1JCF¼255 Hz, 2-C), 159.1 (s,
8.54 (1H, d, JHH¼6.9 Hz, 1-H); 13C NMR (126 MHz, CDCl3)
d 17.7 (s,
3
CH3), 89.2 (t, 2JCF¼18.1 Hz, 7-C), 109.5 (d, 3JCF¼3.0 Hz, CN), 113.6 (s, 2-
NHCNH); 19F NMR (658 MHz, CFCl3)
d
ꢀ137.4 (m, Ar–F), ꢀ149.7 (m,
C), 123.0 (m, Ar–C), 125.2 (d, JCF¼6.7 Hz, 1-C), 129.3 (s, 4-C), 130.2
4
Ar–F); GC–MS (probe) 70 eV m/z (rel int.): 293 [M]þ (58), 274 (59), 216
(15),124 (20),104 (36), 77 (100), 51 (34). Anal. Calcd for C14H7N3F4: C,
57.35; H, 2.41; N, 14.33. Found C, 57.20; H, 2.42; N, 14.09%.
(s,
3-C), 130.7
(d,
2JCF¼17.7 Hz,
Ar–C), 135.9
(ddd,
1JCF¼252 Hz, 2JCF¼16.8 Hz,4JCF¼5.5 Hz, 9-C), 143.3 (ddd, 1JCF¼253 Hz,
2JCF¼14.0 Hz,3JCF¼3.6 Hz,
8-C),
151
(ddd,
1JCF¼269 Hz,
3JCF¼3.4 Hz, JCF¼3.4 Hz, 6-C), 151.4 (s, 4a-C); 19F NMR (658 MHz,
4
3
4
3.2.4. 5,7,8-Trifluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-
6-carbonitrile 2e and 4,40-(ethane-1,2-diylbis(methylazane-
diyl))bis(2,3,5,6-tetrafluorobenzonitrile) 2f. N,N0-Dimethylethylene
diamine (0.60 g, 6.8 mmol) was added to a solution of penta-
fluorocyanobenzene (1.19 g, 6.2 mmol) and DIPEA (2.02 g,
15.6 mmol) in anhydrous acetonitrile (30 mL) under an atmosphere
of dry argon. The mixture was heated and stirred under reflux for
3 h. The mixture was allowed to cool to room temperature, poured
into water (100 mL) and extracted with DCM (3ꢁ40 mL). The com-
bined organic extracts were washed with water and dried (MgSO4).
The mixture was filtered, volatiles evaporated and the residue
CFCl3)
d
ꢀ119.9 (1F, dd, JFF¼19.5 Hz, JFF¼6.2 Hz, Ar–F), ꢀ141.2
(1F, dd, 3JFF¼19.5 Hz, 4JFF¼6.2 Hz, Ar–F), ꢀ141.2 (1F, dd, 3JFF¼19.5 Hz,
5JFF¼19.5, 9-F); GC–MS (probe) 70 eV m/z (rel int.): 261 [M]þ (100),
208 (9),155 (11),105 (12), 51 (42). Anal. Calcd for C13H6N3F3: C, 59.78;
H, 2.32; N, 16.09. Found: C, 59.58; H, 2.36; N, 15.95%.
3.3. Reactions of 2,3,5,6-tetrafluoro-4-
morpholinobenzonitrile 2a
3.3.1. 5,6,8-Trifluoro-7-morpholino-2-phenylquinazolin-4(3H)-imine
3a. Benzamidine hydrochloride (0.47 g, 3.0 mmol) was added to

M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
2361
a
solution of 2,3,5,6-tetrafluoro-4-morpholinobenzonitrile 2a
stirring, to reflux for a period of 72 h, after which time complete
conversion of starting materials was observed by 19F NMR spectros-
copy. The reaction mixture was allowed to cool to room temperature,
poured into water (100 ml) and extracted with DCM (3ꢁ40 mL). The
combined organic extracts were washed with water and dried
(MgSO4). The mixture was filtered, volatiles removed in vacuo and
purified by column chromatography on silica gel using hexane and
ethyl acetate (2:1) as the eluent to afford pure 4,5,7-trifluoro-6-mor-
pholino-1H-indazol-3-amine 3c (0.92 g, 93%) asawhite solid, mp 188–
(0.72 g, 2.8 mmol) and DIPEA (0.41 g, 3.2 mmol) in anhydrous
acetonitrile (30 mL) under an atmosphere of dry argon. The mix-
ture was heated and stirred under reflux for nine days. The mix-
ture was allowed to cool to room temperature, poured into water
(100 mL) and extracted with DCM (3ꢁ40 mL). The combined or-
ganic extracts were washed with water and dried (MgSO4). The
mixture was filtered, volatiles evaporated and the residue purified
by column chromatography on silica gel using hexane and ethyl
acetate (7:3) as the eluent to afford 5,6,8-trifluoro-7-morpholino-2-
phenylquinazolin-4(3H)-imine 3a (0.370 g, 37%) as a white solid,
189 ꢂC; Rf 0.35 (hexane/ethyl acetate, 2:1); IR
n
3434, 3260, 3201,
2920, 2362 cmꢀ1; 1H NMR (700 MHz, DMSO-d6)
d 3.20–3.38 (4H, m,
mp 227–228 ꢂC; Rf 0.4 (hexane/ethyl acetate, 7:3); IR
n
3515, 3311,
3.31
NCH2CH2O), 3.75 (4H, t, 3JHH¼4.6 Hz, NCH2CH2O), 5.35 (2H, br s, NH2),
3213, 2863, 1631, 1569 cmꢀ1; 1H NMR (700 MHz, DMSO-d6)
d
12.2 (1H, br s, NH); 13C NMR (176 MHz, DMSO-d6)
d 51.3 (s,
3
3
(4H, t, JHH¼4.2 Hz, NCH2CH2O), 3.70 (4H, t, JHH¼4.2 Hz,
NCH2CH2O), 7.30 (1H, br s, NH), 7.42–7.50 (3H, m, Ar–H), 8.07 (1H,
br s, NH), 8.38–8.42 (2H, m, Ar–H); 13C NMR (176 MHz, DMSO-d6)
NCH2CH2O), 66.7 (s, NCH2CH2O), 100.5 (m, 3a-C), 126.4 (t,
2JCF¼11.4 Hz, 6-C), 129.4–129.6 (m, 7a-C), 138.2 (dm, 1JCF¼246 Hz, F–
C), 138.5 (dm, 1JCF¼235 Hz, F–C), 139.6 (dm, 1JCF¼241 Hz, F–C), 148.1–
d
51.1 (s, NCH2CH2O), 67.1 (s, NCH2CH2O), 98.6 (d, 2JCF¼10.0 Hz, 4a-
148.3 (m, 3–C); 19F NMR (658 MHz, CFCl3)
d
5
ꢀ147.9 (1F, d,
3
C), 128.2 (s, Ar–C), 128.7 (s, Ar–C), 130.8 (s, Ar–C), 132.2 (t,
5JFF¼18.8 Hz, 7-F), ꢀ153.0 (1F, dd, JFF¼19.8 Hz, JFF¼18.8 Hz, 4-F),
ꢀ160.3 (1F, d, 3JFF¼19.8 Hz, 5-F); GC–MS (probe) 70 eV m/z (rel int.):
272 [M]þ (33), 214 (100), 185 (23), 28 (72). Anal. Calcd for
C11H11N4F3O: C, 48.53; H, 4.07; N, 20.58. Found: C, 48.23; H, 4.07; N,
20.24%.
2JCF¼11.3 Hz, 7-C), 138.1 (s, Ar–C), 138.6 (d, JCF¼12.0 Hz, 8a-C),
2
141.9 (ddd,1JCF¼246 Hz, 2JCF¼14.5 Hz, 3JCF¼6.9 Hz, F–C), 143.1 (ddd,
1JCF¼252 Hz, 2JCF¼14.1 Hz, 3JCF¼2.7 Hz, F–C), 146.2 (d, 1JCF¼248 Hz,
8-C), 159.2 (s, Ar–C), 160.7 (s, Ar–C); 19F NMR (658 MHz, CFCl3)
5
3
d
ꢀ140.4 (1F, d, JFF¼15.0 Hz, 8-F), ꢀ142.2 (1F, dd, JFF¼20.8 Hz,
5JFF¼15.0 Hz, 5-F), ꢀ149.3 (1F, d, JFF¼20.8 Hz, 6-F); GC–MS
(probe) 70 eV m/z (rel int.): 360 [M]þ (85), 302 (100), 199 (18), 151
(30), 77 (24). Anal. Calcd for C18H15N4F3O: C, 60.00; H, 4.20; N,
15.55. Found: C, 59.70; H, 4.23; N, 15.48%.
3.3.4. 6,7-Difluoro-1,4-dimethyl-8-morpholino-1,2,3,4-tetrahy-
droquinoxaline-5-carbonitrile 3d. N,N0-Dimethylethylene diamine
(0.210 g, 2.38 mmol) was added to a solution of 2,3,5,6-tetrafluoro-
4-morpholinobenzonitrile (0.640 g, 2.46 mmol) and DIPEA (0.63 g,
4.90 mmol) in anhydrous THF (30 mL) under an atmosphere of dry
argon. The mixture was heated and stirred under reflux for 24 h,
after which time complete consumption of pentafluorocy-
anobenzene was observed by 19F NMR spectroscopy. The mixture
was allowed to cool to room temperature, poured into water
(100 mL) and extracted with DCM (3ꢁ40 mL). The combined or-
ganic extracts were washed with water and dried (MgSO4). The
mixture was filtered, volatiles removed in vacuo and purified by
column chromatography on silica gel using hexane and ethyl ace-
tate (1:1) as the eluent to afford 6,7-difluoro-1,4-dimethyl-8-mor-
pholino-1,2,3,4-tetrahydroquinoxaline-5-carbonitrile (0.210 g, 28%)
as a white solid, mp 132–133 ꢂC; Rf 0.5 (hexane/ethyl acetate, 9:1);
3
3.3.2. 4,5,7-Trifluoro-6-morpholino-2-phenyl-2H-indazol-3-amine
3b. Phenylhydrazine (0.30 g, 2.8 mmol) in anhydrous THF (10 mL)
was cooled to ꢀ78 ꢂC under an atmosphere of dry argon, which
was maintained throughout the experiment. To the cooled solu-
tion n-BuLi (0.15 g, 2.3 mmol, 1.6 M in hexanes) was added in
a dropwise manner with stirring, followed by the addition of
a
solution of 2,3,5,6-tetrafluoro-4-morpholinobenzonitrile
(0.50 g, 1.9 mmol) in anhydrous THF (20 mL). The reaction mixture
was allowed to warm to room temperature with stirring, poured
into water (100 mL) and extracted with DCM (3ꢁ40 mL). The
combined organic extracts were washed with water and dried
(MgSO4). The mixture was filtered, volatiles evaporated and the
residue purified by column chromatography on silica gel using
hexane and ethyl acetate (7:3) as the eluent to afford 4,5,7-tri-
fluoro-6-morpholino-2-phenyl-2H-indazol-3-amine 3b (0.21 g,
31%) as an off-white solid, mp 178–179 ꢂC; Rf 0.3 (hexane/ethyl
IR
CDCl3)
n ;
2851, 2961, 2219, 1600, 1450, 1109 cmꢀ1 1H NMR (700 MHz,
d
3
2.72 (3H, s, CH3), 2.92 (2H, t, 3JHH¼4.8 Hz, NCH2CH2N), 3.16
(2H, t, JHH¼4.8 Hz, NCH2CH2N), 3.19 (3H, s, CH3), 3.31 (4H, br s,
NCH2CH2O), 3.78 (4H, t, JHH¼4.5 Hz, NCH2CH2O); 13C NMR
3
(176 MHz, CDCl3)
d 41.7 (s, CH3), 44.0 (s, CH3), 45.4 (s, NCH2CH2N),
4
acetate, 7:3); IR
(700 MHz, CDCl3)
n
3330, 3226, 2362, 1646 cmꢀ1
;
1H NMR
46.7 (s, NCH2CH2N), 50.1 (d, JCF¼5.1 Hz, NCH2CH2O), 67.6 (s,
2
3
d
3.25 (4H, t, 3JHH¼4.6 Hz, NCH2CH2O), 3.80 (4H,
NCH2CH2O), 84.0 (d, JCF¼15.8 Hz, 5-C), 114.5 (d, JCF¼2.7 Hz, CN),
128.8 (s, 4a-C), 138.14 (dd, 2JCF¼7.5 Hz, 3JCF¼2.4 Hz, 8-C), 139.6 (dd,
3
t, JHH¼4.6 Hz, NCH2CH2O), 4.32 (2H, s, NH2), 7.31 (1H, tt,
3JHH¼7.2 Hz, JHH¼1.3 Hz, NCCHCHCH), 7.41–7.48 (4H, m, Ar–H);
1JCF¼250 Hz, JCF¼14.0 Hz, 7-C), 141.5 (d, JCF¼3.7 Hz, 4b-C), 149.3
4
2
3
13C NMR (176 MHz, CDCl3)
d
2
51.6 (t, 4JCF¼3.3 Hz, NCH2CH2O), 67.5
(dd, JCF¼250 Hz, JCF¼15.8 Hz, 6-C); 19F NMR (658 MHz, CFCl3)
1
2
3
4
(s, NCH2CH2O), 103.2 (ddd, JCF¼21.0 Hz, JCF¼6.1 Hz, JCF¼2.6 Hz,
3a-C), 124.3 (s, Ar–C), 126.8 (s, Ar–C), 127.2 (m, Ar–C), 128.7 (s, Ar–
C), 129.0 (t, 2JCF¼12.9 Hz, 6-C), 138.6 (dm, 1JCF¼241 Hz, F–C), 139.6
(dm, 1JCF¼252 Hz, F–C), 139.9 (dm, 1JCF¼250 Hz, F–C), 140.0 (s, Ar–
d
ꢀ137.3 (1F, br s, Ar–F), ꢀ158.1 (1F, m, Ar–F); GC–MS (probe) 70 eV
m/z (rel int.): 308 [M]þ (100), 234 (65), 220 (38), 208 (41). Anal.
Calcd for C15H18N4F2O: C, 58.43; H, 5.88; N, 18.17. Found: C, 58.23;
H, 5.89; N, 18.15%.
C), 147.9 (s, 3-C); 19F NMR (658 MHz, CFCl3)
d
ꢀ139.1 (1F, d,
5JFF¼18.4 Hz, 7-F), ꢀ152.6 (1F, dd, 3JFF¼20.6 Hz, 5JFF¼18.4 Hz, 4-F),
ꢀ156.0 (1F, d, 3JFF¼20.4, 5-F); GC–MS (probe) 70 eV m/z (rel int.):
348 [M]þ (88), 290 (91), 213 (13), 185 (19), 77 (100). Anal. Calcd for
C17H15N4F3O: C, 58.62; H, 4.34; N, 16.08. Found: C, 58.35; H, 4.44;
N, 16.15%.
3.4. X-ray structures
Single crystal X-ray data were collected on Bruker SMART 6000
(2a and 3d) and Rigaku Spider IP (2c) diffractometers equipped
with Cryostream (Oxford Cryosystems) nitrogen coolers at 120 K
3.3.3. 4,5,7-Trifluoro-6-morpholino-1H-indazol-3-amine
3c. Hydrazine monohydrate (0.340 g, 6.79 mmol) was added to
a solution of 2,3,5,6-tetrafluoro-4-morpholinobenzonitrile (0.950 g,
3.65 mmol) and DIPEA (0.64 g, 4.95 mmol) in anhydrous acetonitrile
(30 mL) under an atmosphere of dry argon, which was maintained
throughout the experiment. The reaction mixture heated, with
using graphite monochromated MoK
a
radiation (
l
¼0.71073 Å,
u
-scan). All structures were solved by direct methods and refined
by full-matrix least squares on F2 for all data using Olex2 software.
All non-disordered non-hydrogen atoms were refined with aniso-
tropic displacement parameters, non-disordered H-atoms were
located on the difference map and refined isotropically.

2362
M.R. Cargill et al. / Tetrahedron 66 (2010) 2356–2362
Crystallographic data for structures 2a, 2c and 3c have been
Acknowledgements
deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC 751884–751886.
We thank the Durham University M.Chem. Undergraduate
Degree programme for funding.
3.4.1. Crystal data for 2a. C11H8F4N2O, M¼260.19, orthorhombic,
space group Pna21, a¼16.0178(4), b¼7.5162(2), c¼9.0124(2) Å,
U¼1085.03(5) Å3, F(000)¼528, Z¼4, Dc¼1.593 mg mꢀ3
,
m¼0.151
References and notes
mmꢀ1. 11,904 reflections yielded 1322 unique data (Rmerg¼0.0624).
1. Brooke, G. M. J. Fluorine Chem. 1997, 86, 1–76.
2. Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004.
3. Sandford, G. Chem.dEur. J. 2003, 9, 1464–1469.
4. Hargreaves, C. A.; Sandford, G.; Davis, B. G. In Current Fluoroorganic Chemistry;
Soloshonok, V. A., Ed.; ACS Symposium Series 949; ACS: Washington, DC, 2007;
pp 323–336.
5. Armstrong, D.; Cartwright, M. W.; Parks, E. L.; Pattison, G.; Sandford, G.; Slater,
R.; Wilson, I.; Christopher, J.; Miller, D. D.; Smith, P. W.; Vong, A. In Fluorine in
Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; John Wiley and Sons:
New York, NY, 2009; pp p291–312.
6. Sandford, G.; Hargreaves, C. A.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A.
Tetrahedron 2007, 63, 5204–5211.
7. Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org. Chem. 2005,
70, 7208–7216.
8. Baron, A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org.
Chem. 2005, 70, 9377–9381.
9. Birchall, J. M.; Haszeldine, R. N.; Jones, M. E. J. Chem. Soc. 1971, 1343–1347.
10. Booth, B. L.; Haszeldine, R. N.; Taylor, M. B. J. Organomet. Chem. 1966, 6,
570–575.
Final wR2(F2)¼0.1629 for all data (157 refined parameters), conven-
tional R1(F)¼0.0525 for 950 reflections with I>2 , GOF¼1.039.
s
3.4.2. Crystal data for 2c. C11H8F4N2O, M¼293.23, monoclinic, space
group
P21/c,
a¼12.8354(4),
b¼8.9702(3),
c¼10.6272(4) Å,
b
¼91.05(1)ꢂ, U¼1223.37(7) Å3, F(000)¼592, Z¼4, Dc¼1.592 mg mꢀ3
,
m
¼0.141 mmꢀ1
. 22,102 reflections yielded 3572 unique data
(Rmerg¼0.0521). Final wR2(F2)¼0.1215 for all data (218 refined
parameters), conventional R1(F)¼0.0423 for 3261 reflections with
I>2s, GOF¼1.095.
3.4.3. Crystal data for 3c. C11H11F3N4O, M¼272.24, monoclinic,
space group P21/n, a¼4.2181(2), b¼16.4277(7), c¼15.3824(7) Å,
b
¼90.78(2)ꢂ, U¼1135.09(9) Å3, F(000)¼560, Z¼4, Dc¼1.593 mg mꢀ3
,
¼0.141 mmꢀ1
. 1178 reflections yielded 2756 unique data
11. Miller, A. O.; Furin, G. G. J. Fluorine Chem. 1987, 36, 247–272.
12. Berger, S.; Braun, S.; Kalinowski, H. O. NMR Spectroscopy of the Non-metallic
Elements; John Wiley and Sons: New York, NY, 1997.
13. Cartwright, M. W.; Sandford, G.; Bousbaa, J.; Yufit, D. S.; Howard, J. A. K.;
Christopher, J. A.; Miller, D. D. Tetrahedron 2007, 63, 7027–7035.
m
(Rmerg¼0.0710). Final wR2(F2)¼0.1315 for all data (216 refined
parameters), conventional R1(F)¼0.0507 for 1748 reflections with
I>2
s, GOF¼1.059.