Radical Anions of Aromatic Carbonitriles as Reagents for Arylation of Fluorinated Benzonitriles

Article abstract of DOI:10.1021/acs.joc.8b02904

The first example of phenylation of fluorobenzonitriles with the sodium salt of a benzonitrile radical anion in liquid ammonia is presented. The reaction regioselectivity corresponds to the ortho- and para-fluorine atom substitution in fluorobenzonitrile with the phenyl moiety of the benzonitrile radical anion and affords 2- and 4-cyanobiphenyls in 40-90% yields. 3-Methoxybenzonitrile as well as 1-cyanonaphthalene radical anions were also successfully subjected to this interaction forming 3′-methoxycyanobiphenyls and (1-naphthyl)benzonitriles, respectively. The radical anion acts as an ipso-C-nucleophile with consequent loss of the cyano group. The revealed new type of radical anion reactivity opens up the prospect of developing a general approach to fluorinated cyanobisarenes on the basis of an interaction of the cyanoarene radical anion with fluorinated substrates activated to aromatic nucleophilic substitution.

Full text of DOI:10.1021/acs.joc.8b02904

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Article
Radical Anions of Aromatic Carbonitriles as
Reagents for Arylation of Fluorinated Benzonitriles
Roman Yu. Peshkov, Chunyan Wang, Elena V. Panteleeva,
Tatyana V. Rybalova, and Evgeny V. Tretyakov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02904 • Publication Date (Web): 24 Dec 2018
Downloaded from http://pubs.acs.org on December 25, 2018
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Radical Anions of Aromatic Carbonitriles as Reagents for Arylation of
Fluorinated Benzonitriles
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Roman Yu. Peshkov,*†,‡ Chunyan Wang,‡, § Elena V. Panteleeva,†,‡ Tatyana V. Rybalova,†,‡
Evgeny V. Tretyakov†,‡
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†N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch of Russian
Academy of Sciences, 9 Ac. Lavrentiev Avenue, Novosibirsk 630090, Russia
‡ Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia
§Heilongjang University, Xuefu Road, 74, Harbin 150080, China
Corresponding author – Roman Yu. Peshkov, e-mail: peshkov@nioch.nsc.ru
Abstract
The first example of phenylation of fluorobenzonitriles with the sodium salt of a benzonitrile
radical anion in liquid ammonia is presented. The reaction regioselectivity corresponds to the
ortho- and para-fluorine atom substitution in fluorobenzonitrile with the phenyl moiety of the
benzonitrile radical anion and affords 2- and 4-cyanobiphenyls in 40–90% yields. 3-
Methoxybenzonitrile as well as 1-cyanonaphthalene radical anions were also successfully
subjected to this interaction forming 3′-methoxycyanobiphenyls and (1-naphthyl)benzonitriles,
respectively. The radical anion acts as an ipso-C-nucleophile with consequent loss of the cyano
group. The revealed new type of radical anion reactivity opens up the prospect of developing a
general approach to fluorinated cyanobisarenes on the basis of an interaction of the cyanoarene
radical anion with fluorinated substrates activated to aromatic nucleophilic substitution.
CN
CN
CN
Fn-1
F
CN
Na+
CN
Fn-1
F
CN
X=H, OMe
Fn=1-3
Y
Y
CN
CN
Na+
NH3 liq.
40-90%
F
F
CN
F
(18 examples)
Keywords: fluorinated cyanobiphenyls; cyanoarene radical anion; aromatic substitution of
fluorine
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Introduction
Cyanoarenes are known to yield long-living anionic species (radical anions, dianions, and
cyclohexadienyl anions) in preparative amounts via reduction by alkali metals in liquid
ammonia.1 A common feature of these anionic forms is the HOMO localization mostly on the
aromatic ring, not in the cyano group.2,3 That is why alkylation occurs at the ipso- or
unsubstituted (predominantly para-) position of the aromatic fragment thus producing
alkylarenes, alkylcyanoarenes, or dihydro derivatives in good-to-high yields.1 In addition to high
productivity of cyanoarenes in Birch reductive alkylation, we uncovered the possibility of
arylation of neutral aromatic substrates (benzonitrile,4 tolunitrile, methoxy- and
fluorobenzonitrile,5,6 or 2- and 3-cyanobiphenyl7) with terephthalonitrile dianion 12–. The
coupling of dianion 12– with neutral cyanoarenes proceded predominantly as a nucleophilic
substitution of the substrate para-hydrogen atom with the para-cyanophenyl moiety of dianion
(SNH) and/or one electron transfer followed by recombination of radical anions in a primary cage
(ET). Oxidation or alkylation of thus formed long-living dimeric anion 2– provided the
corresponding biphenyl- and terphenylcarbonitriles and their alkylated derivatives in a one-pot
manner (Scheme 1). Nevertheless, there was one example of a fluorine atom substitution (SNArf)
when dianion 12– reacted with 4-fluorobenzonitrile and formed 4,4′-dicyanobiphenyl5.
4
5
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Scheme 1. para-Cyanophenylation of cyanoarenes with terephthalonitrile dianion
X
CN
SNH / ET
CN
NC
CN
CN
CN
2-
[O]
X
X
2Na
NH3
RBr
-33oC
X
-CN-
-Br-
CN
1
CN
X = H; 2-,3-Me,
2-,3-OMe;
2-,3-Ph;
12-
-H+,-CN-
NC
R
CN
2-
CN
F
2-,3-,F
R = C4H9, (CH2)5Br,
(CH2)3CH=CH2, (CH2)5CO2Et,
(CH2)4CN,
-CN-,
-F-
SNArF
O
O
NC
CN
2
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Figure 1. A HOMO view of dianion 12– (left) and SOMO of radical anion 3•– (right) (DFT
(U)M06-2X/6-31G(d), US GAMESS).8
The development of the synthetic approach to bisarenes utilizing the anionic forms of
cyanarenes requires clarification of the possibility of involving an anionic form other than
dianion 12– in aromatic cross-coupling. Our attention was drawn to benzonitrile radical anion 3•–
for the following reasons: it closely resembles dianion 12– in terms of electronic structure (Figure
1); its reactivity toward alkyl halides has proved to be nucleophilic only and results in selective
ipso-alkylation of 3•–9–11 giving alkylbenzenes in high yields (Scheme 2, Alkylation). We
assumed the nucleophilic reactivity of 3•– to be a promising feature that could be responsible for
the fluorine atom substitution in fluorinated benzonitriles. These compounds are commonly used
as universal structural blocks activated to aromatic nucleophilic substitution with various
nucleophiles, thereby affording products that are prone to further modifications via substitution
of fluorine atoms as well as transformations in the cyano group.12–15 We chose mono-, di-, and
trifluorobenzonitriles 4a–n as neutral substrates for testing 3•– because substrates that are more
fluorinated cannot be used in a liquid ammonia medium owing to rapid aminodefluorination. In
case of success, the arylation of fluorobenzonitriles by the radical anion 3•– would lead to the
selective one-pot synthesis of fluorinated 2- (5) and 4-cyanobiphenyls (6) (Scheme 2, Arylation).
It should be noted that fluorinated cyanbiphenyls are valuable p-deficient building blocks on
both supramolecular chemistry16 and materials science17 as well as precursors of biologically
active substances,18,19 including agrochemicals.20
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Scheme 2. Benzonitrile radical anion alkylation products formation and anticipated
arylation products
5
6
7
8
9
Alkylation
Arylation
Anticipated products
Fn-1
CN
CN
R
CN
Fn=1-3
R CN
R CN
_
SN2
RX
-X-
Fn-1
10
11
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60
4a-n
3
NC
+
-CN
-F-, -CN-, -3
-3
3
75-90%
Br
RX = MeI, BuHlg (Hlg = Cl, Br, I), BuiBr, BusBr, CyBr, 5-HexenylBr,
PhCH2Br, m-MeOC6H4CH2Br, Br(CH2)4CN, Br(CH2)5CO2Et,
5
6
O
O
Br
Results and Discussion
We began with trifluorobenzonitriles 4a–e as the most reactive substrates. Radical anion 3•– was
generated by the reduction of benzonitrile 3 with sodium in liquid ammonia. Because of the
stoichiometry of the radical anionic transformations, half the amount of trifluorobenzonitrile 4a–
e was employed with respect to the salt of radical anion 3•–. The expected
difluorocyanobiphenyls 5a,e and 6b–e formed in all cases with good total yields (Entries 1–5,
Table 1).
Table 1: Interaction of radical anion 3•– sodium salt with fluorinated benzonitriles in liquid
ammonia at –33 ºCa
CN
CN
CN
CN
CN
Fn=1-3
Fn-1
+
F
Fn-1
+
4a-n
Na
NC
NH3
-
-
3
-F , -CN , -
-33oC
3
3
5
6
7
3
-
-
3
-F , -CN , -
6d 5e 6e
for
,
,
Entry
1
Fluorobenzonitrile
Products
Product
yieldb
CN
CN
F
F
F
50 (41)
F
4a
5a
F
4
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CN
CN
2
3
4
62 (56)
72 (68)
4b
4c
4d
F
F
F
F
F
F
6b
CN
10
11
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CN
F
F
F
F
F
6c
CN
CN
F
F
F
8 (7)
F
6d
56 (50)
CN
F
7d
CN
5
CN
1521
F
F
4e
5e
F
F
F
CN
F
F
21 (20)
30 (25)
6e
CN
CN
F
F
7e
5f
6b
37 (25)22
CN
F
F
4f
5
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CN
F
7
CN
223
F
4g
5g
F
8
9
CN
85 (65)24
F
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6g
CN
8
9
CN
1325
F
4h
F
F
5h
F
F
CN
CN
CN
69 (51)26
75 (60)
F
4i
5i
CN
10
4j
F
F
F
6j
CN
11
12
---
4k
F
F
CN
CN
CN
F
35
93
4l
5l
CN
13
14
4m
F
6m
CN
---
4n
F
a
Benzonitrile (4.0 mmol), sodium (3.0 mmol), fluorinated benzonitrile (1.5 mmol), liquid
ammonia ~40 mL, duration of the reaction: 1–2 h.
b
NMR yield, % (isolated yield, %) calculated as mean values from no fewer than two runs.
Deviation does not exceed 5%
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Utilization of benzonitriles 4d and 4e provided m-terphenyls [5′-fluoro- (7d) and 2′-fluoro-
[1,1′:3′,1′′-terphenyl]-4′-carbonitrile (7e), respectively] along with biphenyls 6d, 5e, and 6e
(Entries 4 and 5, Table 1). The formation of terphenyls 7d and 7e is obviously caused by the
involvement of initially formed biphenyls 6d and 5e, 6e into further arylation. According to this
notion, an increase in the molar ratio of 3•– to 4e from 2/1 to 8/1 led to an increase in the
terphenyl 7e yield from 30% to 58%, with the yield of para-cyanobiphenyl 6e being only 2%,
whereas the ortho-isomer 5e was almost absent. It should be mentioned that in addition to the
target products 5, 6, and 7, the reaction mixtures always contained some amount of starting
benzonitriles 3 and 4 (10–50% of the initial amount), as well as minor components whose
molecular weights corresponded to di- and tetrafluorodicyanobiphenyls (~5% in total),
aminofluorocyanobiphenyls (1–3%), and difluorinated 4-amino-2-phenylquinazolines (2–10%,
their formation is discussed below). All the synthesized difluorobiphenylcarbonitriles were
readily isolated from reaction mixtures via preparative TLC.
10
11
12
13
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The involvement of difluorobenzonitriles 4f–k in the interaction with 3•– was successful for
substrates containing ortho- and para-fluorine atoms, activated to substitution (Entries 6, 7, 9,
and 10 in Table 1). In the case of 2,5-difluorobenzonitrile 4h, cyanobiphenyl 5h formed in a low
yield, whereas phenylation of 3,5-difluorobenzonitrile 4k did not take place at all (Entries 8 and
11 in Table 1). Unlike transformations involving trifluorobenzonitriles 4d and 4e, reactions with
difluorobenzonitriles 4g and 4i did not lead to the formation of terphenylcarbonitriles. Probably,
monofluorinated cyanobiphenyls 6g and 5i are less activated to phenylation by 3•– than their
difluorinated analogs are. Data on 5-fluoro-2-cyanobiphenyl 5g23 and 4-fluoro-2-cyanobiphenyl
5h25 can be found in the literature (catalytic cross-coupling was conducted for their synthesis).
Because of their small content in the reaction mixtures, we did not isolate these products.
With respect to monofluorobenzonitriles 4l–n, only 4-fluorobenzonitrile 4m converted into
corresponding 4-cyanobiphenyl 6m almost completely (Entry 13, Table 1). 2-Fluorobenzonitrile
4l resulted in the formation of 2-cyanobiphenyl 5l with a significantly lower yield (Entry 12,
Table 1). In the case of 3-fluorobenzonitrile 4n, no phenylation occurred, and the reaction
mixture contained mainly benzonitriles 3 and 4n (46% and 31%), a small amount (~5%) of
benzamides, and phenylated 1,3,5-triazines, being products of starting nitriles alkaline hydrolysis
and trimerization, respectively.
The above results indicate well-pronounced productivity of radical anion 3•– as a reagent for
the phenylation of fluorobenzonitriles regardless of the number of fluorine atoms in substrates 4.
The substitution of fluorine occurs at positions ortho- and para- toward the cyano group of 4, in
agreement with the orientation observed in the reactions of these compounds with carbon-
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centered and heteroatomic nucleophiles proceeding via the SNAr mechanism12–14,27–30. Taking
these data into account, it could be assumed that radical anion 3•– has the properties of a
nucleophile rather than a one-electron donor toward fluorinated benzonitriles 4. At the same
time, the detection of fluorinated dicyanobiphenyls as minor byproducts does not allow us to
completely eliminate some ET-share of the 3•– reactivity. Dicyanobiphenyls can arise as a result
of the ET from 3•– to fluorobenzonitriles 4 affording radical anions prone to dimerization
followed by the departure of fluoride.31,32
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12
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59
60
Scheme 3 illustrates the reaction pathway proposed for the phenylation of fluorinated
benzonitriles 4 by radical anion 3•–, with trifluorobenzonitrile 4e. At the first stage, the
substitution of the ortho- and para-fluorine atom in benzonitrile 4e by the 3•– ipso-carbon atom
bearing the maximum electron density (see Figure 1) takes place, leading to the corresponding
biphenyl radicals 8ortho and 8para. Further reduction of these radicals with radical anion 3•– yields
anions 9ortho and 9para (containing a geminal cyano group), which rapidly undergo decyanation,
thus restoring aromaticity and providing cyanobiphenyls 5e and 6e.
Scheme 3. Phenylation of fluorobenzonitrile 4e with benzonitrile radical anion
SNArF
CN
CN
CN
CN
F
F
0.5
F
F
F
F
F
F
F
F
F
F
F
F
CN
ET
F
4e
+
CN
3
+
CN
CN
-CN-
+
3
-
NC
NC
NC
NC
-F-
3
8ortho
8para
9ortho
9para
5e
6e
Evaluating the synthetic productivity of the reaction under investigation, it should be noted
that all the product mixtures obtained in the reactions of ortho-fluorinated benzonitriles
contained corresponding 4-amino-2-phenylquinazolines (10) in substantial amounts along with
target cyanobiphenyls 5 and 6. The highest content (33%) was found for 4-amino-2-phenyl-8-
fluoroquinazoline (10f) formed in the reaction of 2,3-difluorobenzonitrile 4f. This new
quinazoline was isolated (yield 27%), and its structure was confirmed by X-ray analysis (Figure
1 in SI).
Probably, the formation of aminoquinazolines 10 is due to some processes initiated by the
amide anion and proceeding in parallel with the main reaction (the presence of the amide ion is
quite likely under the conditions employed). This assumption was confirmed by counter-
synthesis (alike33) involving the formation of amidine 11 sodium salt from benzonitrile 3 under
the action of sodium amide, and subsequent interaction with difluorobenzonitriles 4f or 4i
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accomplished by the cyclization into quinazolines 10f or 10i, respectively, with a yield of 40%
and 42% (Scheme 4). For 10i, a crystal suitable for XRD analysis was obtained (Figure 2 in SI).
5
6
Quinazolines are among privileged structures with a wide spectrum of biological activities34–37
;
7
8
9
therefore, the demonstrated simplicity and ease of preparation of fluorinated 4-amino-2-phenyl
derivatives 10 according to the proposed scheme in liquid ammonia has synthetic value, but
beyond the scope of the present work.
10
11
12
13
14
15
16
17
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19
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44
45
46
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48
49
50
51
52
53
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60
Scheme 4. The way assumed for 4-amino-2-quinazolines 10 formation
Base
CN
CN
F
F
Na
NH2
N
H2N
CN
N
4f
3
NH2
N
Na
NaNH2
NH3
-F-
FeCl3 cat.
N
NH3
-33oC, 1.5h
11
F
F
10f
Regarding the phenylation of fluorinated benzonitriles 4 by radical anion 3•–, we have every
reason to suppose that the revealed new type of reactivity could also be inherent in radical anions
of other cyanoarenes, characterized by a common type of electronic structure. To determine
whether the revealed reaction is of a general nature, radical anions of 3-methoxybenzonitrile
(12•–) and 1-cyanonaphthalene (13•–, Figure 2) were subjected to the interaction with fluorinated
benzonitriles 4a, 4c, 4j, and 4l.
Figure 2. A SOMO view of radical anions 3•– (left), 12•– (middle), and 13•– (right) (DFT UM06-
2X/6-31G(d), US GAMESS).
Generation of radical anions 12•– and 13•– and their reactions with fluorinated benzonitriles
were carried out under the conditions analogous to phenylation with radical anion 3•–. As
expected, target cyanobisaryls 14 and 15 were detected for both radical anions; 12•– proved to be
more productive (Table 2). Radical anion 13•– provided naphthylbenzonitriles 15 with the yields
decreasing markedly with the diminishing number of fluorine atoms in substrate 4.
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Table 2: Interaction of radical anion 12•– and 13•– sodium salts with fluorinated benzonitriles in
liquid ammonia at –33 ºCa
5
6
7
8
Entry
1
Radical anion
Fluorobenzonitrile
Product
Product yieldb
60 (38)
CN
CN
F
F
F
F
OMe
4a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14a
F
CN
CN
2
CN
85 (56)
4j
F
F
F
OMe
12
F
14j
OMe
CN
3
4
CN
83
OMe
4l
14l
CN
CN
F
F
43 (31)
4c
F
F
F
15c
CN
CN
CN
5
6
35 (28)
4j
4l
13
F
F
F
F
15j
CN
CN
traces
15l
a Nitrile 12 or 13 (4.0 mmol), sodium (3.0 mmol), fluorinated benzonitrile (1.5 mmol), and liquid
ammonia ~40 mL; duration of the reaction 1–2 h.
NMR yield, % (isolated yield, %) calculated as mean values of no fewer than two runs.
b
Deviation does not exceed 5%
The known 3′-methoxy-[1,1′-biphenyl]-2-carbonitrile 14l38 and 2-(naphthalen-1-
yl)benzonitrile 15l,39 which formed in the reactions of 12•– and 13•– with fluorobenzonitrile 4l,
were not isolated from the reaction mixtures. Fluorinated methoxycyanobiphenyls 14a and 14j as
well as naphthylbenzonitriles 15c and 15j are novel compounds, in addition to the spectral
characteristics, a single crystal was grown from products 14j and 15c for structural verification
by the X-ray diffraction analyses (Figures 3, 4 in SI, respectively).
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The localization of the methoxy group at the 3′-position of the biphenyl core in all the
products 14 indicated that radical anion 12•– behaved as the ipso-localized nucleophile. On the
contrary, the para-localization of the nucleophilic center should lead to the formation of 2′-
methoxylated isomers of 14, which were not observed. Thus, the experimental evidence has been
obtained in favor of validity of the reaction pathway suggested above, which involves formation
of the new bond between the ipso-atom of the cyanoarene radical anion and the fluorinated
carbon atom of the substrate activated to nucleophilic substitution (Scheme 3).
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Conclusion
For the first time, we propose a convenient one-pot synthesis of cyanobisarenes using the
benzo- and naphthonitrile radical anions in liquid ammonia as nucleophilic reagents effectively
substituting the aromatic fluorine atoms. We obtained 11 new fluorinated cyanoarenes with a
biphenylic, terphenylic, and phenylnaphthylic framework.
Recently, Zhang and collegues40 described the selective C-F bond arylation through
palladium-catalyzed cross-coupling of polyfluoroarenes with arylboronic acids. It is worth noting
that the authors link the high reaction regioselectivity with the significant nucleophilic character
of chosen electron-rich palladium complex (Pd(0)BrettPhos) which facilitates the oxidative
addition of the Pd center to the C−F bond.
As for the the synthetic utilization of the cross-coupling of radical anions with neutral
fluoroaromatic substrates, that is an almost unexplored area. The synthetically significant
reactions of the benzophenone radical anion with naphthalene41 and also with N-oxides of
azaheterocycles are known.42–44 In all these cases, the SNH reactions formed a new bond at the
benzophenone carbonyl carbon atom, and thus provided aryldiphenylcarbinols. The products of
the coupling between the reagent and substrate aromatic rings were not mentioned in the cited
articles. The ability of the monocyanoarene radical anion to arylate substrates activated to
aromatic fluorine substitution, as discovered in the present work, opens up the prospect of
developing a new general approach to the directed synthesis of functionalized cyanobisaryls,
which are widely used as valuable structural blocks for the synthesis of bioactive compounds and
new materials.18 Productivity of the proposed reaction is comparable to that of cross-coupling
catalyzed by transition metals that is currently utilizing as common approach to such
compounds.45-47 The advantages of the method proposed can be attributed primarily to the
absence of the need to use catalityc systems and pre-activated reagents.
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Experimental
General information: Liquid ammonia was purified just before use by dissolving metallic
sodium in it, followed by distillation into a reaction vessel cooled to ca. 80ºC. Metallic sodium
was freed from oxide film under dry hexane. Commercial benzonitrile was purified by
distillation over P2O5. Commercially available 3-methoxybenzonitrile, 1-cyanonaphthalene and
fluorinated benzonitriles 4a–n were used without further purification. Melting points of products
5–7, 10f, 14, 15 are uncorrected.
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1H, 13C{1H} and 19F NMR spectra of all compounds were acquired with a Bruker Avance
III 500 instrument at 500.03, 125.76 and 470.50 MHz, respectively, in [D6]acetone (except 14a
acquired in [D6]DMSO); chemical shifts (δ) of 1H and 13C{1H} are given in ppm relative to TMS
using the solvent signals as the internal standard (δH = 2.05 ppm, δC = 29.8 and 206.3 ppm), the
internal standard for 19F spectra was C6F6 (δ= –162.9 ppm). Signal assignment and structure
justification were carried out based on the HSQC and HMBC data and on analysis of the C–F
spin–spin coupling constants.
IR spectra were recorded with a Vector-22 instrument for samples pelleted with KBr
(0.25 %).
GC–MS analysis was performed with a Hewlett–Packard G1081A instrument consisting
of an HP-5890 Series II gas chromatograph and an HP-5971 mass-selective detector (IE, 70 eV)
with an HP5 capillary column.
High resolution mass-spectra and exact masses were obtained using Thermo Fischer
Scientific Double Focusing System (DFS) magnetic sector high resolution mass-spectrometer
(Bremen, Germany). Samples were introduced into mass-spectrometer by direct inlet. The mass
spectrometer used electron ionization with 70 eV ionization energy. Measurements of the exact
masses of the ions were performed with respect to the standard lines of perfluorokerosene (PFK).
XRD data were obtained at room temperature on a Bruker Kappa Apex II CCD
diffractometer using φ, ω scans of narrow (0.5°) frames with Mo Kα radiation (λ = 0.71073 Å)
and a graphite monochromator. Absorption corrections were applied empirically using SADABS
programs.48 The structures were solved by direct methods and refined by full-matrix least-
squares method against all F2 in anisotropic approximation (beside the atoms H) using the
SHELX-97 programs set49. The H atoms positions were calculated with the riding model except
for the hydrogens of amino group in 10f refined independently. The asymmetric part of 10i
includes two independent molecules. The crystallographic data of 10f, 10i, 14j and 15c are listed
in SI. CCDC 1875478-1875481 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi, or
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from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
5
6
7
8
Quantum-chemical calculations were performed using the GAMESS8 package within
(U)MP2/6-31+G(d) level of theory. All stationary points were proved to be minima via analysis
of normal vibrations (no imaginary frequencies found). HOMO (SOMO) views were obtained
with MOLDEN50,51 utility.
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General Procedure: Metallic sodium (0.070 g, 3.0 mmol) and aromatic carbonitrile 3, 12 or 13
(4.0 mmol) were successively added to liquid NH3 (30-40 mL) under an atmosphere of
evaporating NH3 at -33÷-45 ºC. To thus obtained sodium salt of radical anion 3•–, 12•– or 13•–
fluorinated benzonitrile 4a-n (1.5 mmol) was added. The reaction mixture was stirred under an
atmosphere of evaporating NH3 at -33ºC for 1÷1.5 h. The reaction mixture was brought into
contact with air, Et2O (25 mL) was added and stirring continued until the NH3 completely
evaporated. H2O (25 ml) was added to the residue, the organic products were extracted with Et2O
(3 × 30 mL). The combined ether extract was successively washed with H2O, a saturated NaCl
solution, dried with MgSO4. The composition of the reaction mixtures obtained after distillation
1
of the Et2O was analyzed by H, 19F NMR and GC-MS. The products 5÷7, 14 and 15 were
separated by TLC on plates with a fixed layer of silica gel (Silica gel 60 PF254 containing
gypsum, Merck) and n-hexane/Et2O mixture (10/1 v/v ratio) as eluent, and recrystallized from
hexane. Yields refer to analytically pure samples.
4
3,6-Difluoro-[1,1'-biphenyl]-2-carbonitrile (5a): Yield: 132 mg (41%),
F
5
3
2
light fine needles, mp 89.6‒90.1 °C (hexane). 1H NMR (500.03 MHz, (CD3)2CO,
6
F
CN
1
δ): 7.68 (td, J = 9.2, 9.2, 4.7 Hz, H5, 1H), 7.58-7.52 (m, H2',3',4',5',6', 5H), 7.50 (ddd,
1`
6`
5`
2`
3`
13
J = 9.3, 8.4, 3.9 Hz, H4, 1H). C{1H} NMR (125.73 MHz, (CD3)2CO, δ): 161.0
(dd, J = 253, 2.8 Hz, C3, 1C), 156.4 (dd, J = 244, 2.6 Hz, C6, 1C), 134.7 (d, J =
4`
20.8 Hz, C1, 1C), 132.0 (d, J = 1.5 Hz, C1', 1C), 130.6 (d, J = 1.8 Hz, C2',6', 2C), 130.5 (s, C4', 1C),
129.6 (s, C3',5', 2C), 123.5 (dd, J = 26.1, 9.3 Hz, C5, 1C), 117.7 (dd, J = 22.7, 9.0 Hz, C4, 1C),
113.0 (d, J = 3.4 Hz, CCN, 1C), 103.7 (d, J = 17.7, 5.0 Hz, C2, 1C). 19F NMR (470.50 MHz,
(CD3)2CO, rel. C6F6, δ): 51.3 (ddd, J = 16.8, 8.3, 4.4 Hz, F3 or 6, 1F), 44.4 (ddd, J = 16.8, 9.0, 3.9
Hz, F6 or 3, 1F). IR (KBr) ṽmax: 2237 (C≡N) cm-1. EIMS (70 eV) m/z: 216 (15.1), 215 (100.0) [M+],
214 (11.0), 213 (5.0), 195 (13.3), 188 (14.8), 187 (5.6), 168 (6.2). HRMS: calcd. for C13H7F2N
[M+] 215.0541; found 215.0544.
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CN
2,6-Difluoro-[1,1'-biphenyl]-4-carbonitrile (6b): Yield: 181 mg (56%),
4
5
3
1
white powder, mp 135.6‒137.2°C (hexane). H NMR (500.03 MHz, (CD3)2CO,
2
6
F
F
1
δ): 7.71-7.64 (m, H3,5, 2H), 7.57-7.49 (m, H1',2',3',4',5', 5H). 13C{1H} (125.73
1`
6`
5`
2`
3`
MHz, (CD3)2CO δ): 160.8 (dd, J = 7.9, 250 Hz, C2,6, 2C), 131 (t, J = 1.9 Hz, C2',6'
2C), 130.2 (s, C4', 1C), 129.5 (s, C3',5', 2C), 128.4 (s, C1', 1C), 124.8 (t, J = 19.2
,
4`
10
11
12
13
14
15
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18
19
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Hz, C1, 1C), 117.3 (t, J = 3.5 Hz, CCN, 1C), 117.1 (dd, J = 22.7, 9.0 Hz, C3,5, 2C), 113.6 (t, J =
12.5 Hz, C4, 1C). 19F NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ): 52.3 (d, J = 6.5 Hz, F2.6, 2F).
IR (KBr) ṽmax: 2239 (C≡N) cm-1. EIMS (70 eV) m/z: 216 (14.8), 215 (100.0) [M+], 214 (11.4),
195 (7.4), 189 (5.4), 176 (6.2), 163 (6.6). HRMS: calcd. for C13H7F2N [M+] 215.0541; found
215.0544. Anal. calcd for C13H7F2N (215.054): C,72.56; H, 3.28; F, 17.66; N, 6.51; found:
C,72.77; H, 3.59; F, 17.53; N, 6.41.
CN
4
2,5-Difluoro-[1,1'-biphenyl]-4-carbonitrile (6c): Yield: 219 mg (68%),
5
F
3
1
white powder, mp. 56.5‒59.2°C (hexane). H NMR (500.03 MHz, (CD3)2CO, δ):
2
6
7.82 (dd, J = 9.7, 5.4 Hz, H3, 1H), 7.67-7.64 (m, H2',6', 2H), 7.62 (dd, J = 9.7, 6.1
F
1
1`
6`
5`
2`
3`
13
Hz, H6, 1H), 7.56-7.49 (m, H3',4',5', 3H). C{1H} NMR (125.73 MHz, (CD3)2CO
δ): 160.3 (dd, J = 253, 2.7 Hz, C5, 1C), 156.2 (dd, J = 244, 2.6 Hz, C2, 1C), 137.3
4`
(dd, J = 15.9, 8.4 Hz, C1, 1C), 134.0 (t, J = 1.7 Hz, C1', 1C), 130.4 (s, C4', 1C), 129.9 (d, J = 3.5
Hz, C2',6', 2C), 129.8 (s, C3',5', 2C), 121.7 (dd, J = 29.6, 1.3 Hz, C3, 1C), 119.2 (dd, J = 22.9, 4.1
19
Hz, C6, 1C), 113.5 (d, J = 2.2 Hz, CCN, 1C), 101.4 (dd, J = 18.3, 10.4 Hz, C4, 1C). F NMR
(470.50 MHz, (CD3)2CO, rel. C6F6, δ): 50.0 (ddd, J = 16.3, 9.6, 5.7 Hz, F5 or 2, 1F), 42.8 (ddd, J =
16.2, 8.9, 6.6 Hz, F2 or 5, 1F). IR (KBr) ṽmax: 2237 (C≡N) cm-1. EIMS (70 eV) m/z: 216 (15.1),
215 (100.0) [M+], 214 (14.8), 213 (6.8), 195 (8.4), 194 (6.1), 189 (8.7), 188 (5.1), 187 (5.9), 176
(6.0). HRMS: calcd. for C13H7F2N [M+] 215.0541; found 215.0543.
3,5-Difluoro-[1,1'-biphenyl]-4-carbonitrile (6d): Yield: 23 mg (7%),
CN
4
1
F
F
white powder, mp. 88.8‒92.6°C (hexane). H NMR (500.03 MHz, (CD3)2CO, δ):
5
3
2
7.83-7.79 (m, H2',6', 2H), 7.64 (d, J = 9.3 Hz, H2,6, 2H), 7.57-7.49 (m, H3',4',5', 3H).
13C{1H} NMR (125.73 MHz, (CD3)2CO δ): 164.2 (dd, J = 5.5, 257 Hz, C3,5, 2C),
150.4 (t, J = 10.1 Hz, C1, 1C), 137.7 (t, J = 2.4 Hz, C1', 1C), 130.8 (s, C4', 1C),
130.2 (s, C3',5', 2C), 128.2 (s, C2',6', 2C), 111.4 (dd, J = 3.4, 20.8 Hz, C2,6, 2C), 110
6
1
1`
6`
5`
2`
3`
4`
(s, CCN, 1C), 90.9 (t, J = 19.8 Hz, C4, 1C). 19F NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ): 57.9
(d, J = 9.7 Hz, F3,5, 2F). IR (KBr) ṽmax: 2237 (C≡N) cm-1. EIMS (70 eV) m/z: 216 (15.3), 215
(100.0) [M+], 214 (15.6), 213 (8.4), 195 (6.7), 194 (5.4), 189 (6.5), 187 (5.6). HRMS: calcd. for
C13H7F2N [M+] 215.0541; found 215.0544.
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5'-Fluoro-[1,1':3',1''-terphenyl]-4'-carbonitrile (7d): Yield: 205
3''
6''
1
mg (50%), white small needles, mp. 107.4‒108.1°C (hexane). H NMR
4''
5''
2''
1''
CN
4'
5
6
7
8
(500.03 MHz, (CD3)2CO, δ): 7.87-7.83 (m, H2,6, 2H), 7.75-7.70 (m,
H2',6',(3'',5'') or (2'',6''), 4H), 7.60-7.47 (m, H3,4,5,(3'',5'') or (2'',6''), 4'', 6H). 13C{1H}
NMR (125.73 MHz, (CD3)2CO δ): 165.3 (d, J = 251 Hz, C5', 1C), 148.7 (d,
J = 9.1 Hz, C1', 1C), 148.3 (d, J = 0.9 Hz, C3', 1C), 138.8 (d, J = 2.5 Hz, C1,
1C), 138.3 (d, J = 2.5 Hz, C1'', 1C), 130.3 (s, C4, 1C), 130.1 (s, C3,5,4'', 3C),
F
5'
6'
3'
2'
1'
1
9
6
5
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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4
129.8 (s, C(2'',6'') or (3'',5''), 2C), 129.7 (s, C(3'',5'') or (2'',6''), 2C), 128.3 (s, C2,6, 2C), 125.2 (d, J = 2.7 Hz,
C2', 1C), 114.2 (s, CCN, 1C), 113.8 (d, J = 21.3 Hz, C6', 1C), 99.7 (d, J = 16 Hz, C4', 1C). 19F NMR
(470.50 MHz, (CD3)2CO, rel. C6F6, δ): 56.4 (d, J = 11 Hz, F5', 1C). IR (KBr) ṽmax: 2231 (C≡N)
cm-1. EIMS (70 eV) m/z: 274 (21.2), 273 (100.0), 272 (28.0), 271 (7.7), 251 (6.9), 245 (5.1), 244
(6.8). HRMS: calcd. for C19H12FN [M+] 273.0948; found 273.0944.
2,3-Difluoro-[1,1'-biphenyl]-4-carbonitrile (6e): Yield: 64 mg (20%),
CN
4
F
F
1
5
6
small yellowish crystals, mp. 91.4‒93.3 °C (hexane). H NMR (500.03 MHz,
3
2
(CD3)2CO, δ): 7.73 (ddd, J = 8.2, 5.9, 1.9 Hz, H5, 1H), 7.66-7.64 (m, H2',6', 2H),
7.58-7.50 (m, H6,3',4',5', 4H). 13C{1H} NMR (125.73 MHz, (CD3)2CO δ): 152.0
(dd, J = 258, 15.9 Hz, C3, 1C), 147.6 (dd, J = 251, 11.7 Hz, C2, 1C), 136.5 (dd, J =
10.3, 1.0 Hz, C1, 1C), 133.0 (dd, J = 2.6, 1.3 Hz, C1', 1C), 129.4 (s, C4', 1C),
1
1`
6`
5`
2`
3`
4`
128.9(3) (d, J = 3.2 Hz, C2',6', 2C), 128.9(0) (s, C3',5', 2C), 128.3 (d, J = 4.7 Hz, C5, 1C), 126.5 (dd,
J = 4.0, 2.8 Hz, C6, 1C), 112.6 (d, J = 3.8 Hz, CCN, 1C), 101.5 (dd, J = 12.3, 1.5 Hz, C4, 1C). 19F
NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ): 30.8 (dd, J = 19.8, 5.7 Hz, F3 or 2, 1F), 22.4 (dd, J =
19.7, 6.7 Hz, F2 or 3, 1F). IR (KBr) ṽmax: 2237 (C≡N) cm-1. EIMS (70 eV) m/z: 216 (14.7), 215
(100.0), 214 (13.7), 213 (6.4), 195 (7.0), 189 (5.8), 188 (5.2), 187 (5.6). HRMS: calcd. for
C13H7F2N [M+] 215.0541; found 215.0543.
2'-Fluoro-[1,1':3',1''-terphenyl]-4'-carbonitrile (7e): Yield: 102 mg
3''
4''
2''
CN
4'
1
(25%), white powder, mp. 95.7 °C with decomposition (hexane). H NMR
5''
1''
(500.03 MHz, (CD3)2CO, δ): 7.81 (d, J = 8.0, 0.9 Hz, H5', 1H), 7.73 (d, J =
8.0, 7.3 Hz, H6', 1H), 7.68-7.64 (m, 2H), 7.62-7.59 (m, 2H), 7.58-7.54 (m,
2H), 7.54-7.51 (m, 3H), 7.70-7.44 (m, 1H). 13C{1H} NMR (125.73 MHz,
(CD3)2CO δ): 157.2 (d, J = 249 Hz, C2', 1C), 135.2(2) (d, J = 15.2 Hz, 1C),
5'
6'
6''
3'
2'
F
1'
1
6
5
2
3
4
135.2(0) (d, J = 1.2 Hz, 1C), 134.5 (d, J = 20.4 Hz, 1C), 133.1 (s, C6', 1C), 131.7 (d, J = 4.3 Hz,
1C), 130.8 (d, J = 1.7 Hz, 2C), 130.3 (d, J = 4.6 Hz, C5', 1C), 130.0(3) (s, 2C), 130.0(1) (s, 1C),
129.8 (s, 1C), 129.6 (s, 2C), 129.4 (s, 2C), 117.8 (d, J = 3.9 Hz, CCN, 1C), 113.9 (d, J = 4.5 Hz,
C4', 1C). 19F NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ): 45.4 (d, J = 6.7 Hz, F2, 1F). IR (KBr)
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ṽmax: 2231 (C≡N) cm-1. EIMS (70 eV) m/z: 274 (21.1), 273 (100.0), 272 (18.3), 271 (5.8), 251
(7.4), 244 (6.1). HRMS: calcd. for C19H12FN [M+] 273.0948; found 273.0950.
6-Fluoro-[1,1'-biphenyl]-2-carbonitrile (5f)22: Yield: 74 mg (25%), yellowish powder,
mp. 107.4‒110.5°C (TLC).
9
3-Fluoro-[1,1'-biphenyl]-4-carbonitrile (6g)24: Yield: 192 mg (65%), colorless needles,
mp. 78.7‒79.0°C (hexane).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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3-Fluoro-[1,1'-biphenyl]-2-carbonitrile (5i)26: Yield: 151 mg (51%),
4
F
5
3
2
1
yellowish powder, mp. 78.2‒78.9°C (TLC). H NMR (500.03 MHz, (CD3)2CO,
6
CN
1
δ): 7.83 (ddd, J = 8.4, 7.8, 6.0 Hz, H5, 1H), 7.65-7.62 (m, H2',6', 2H), 7.58-7.50 (m,
H3',4',5', 3H), 7.47 (ddd, J = 7.8, 1.0, 0.4 Hz, H6, 1H), 7.43 (ddd, J = 9.3, 8.5, 1.0
Hz, H4, 1H). 13C{1H} NMR (125.73 MHz, (CD3)2CO δ): 164.9 (d, J = 256 Hz, C3,
1`
6`
5`
2`
3`
4`
1C), 148.1 (s, C1, 1C), 138.2 (d, J = 2.2 Hz, C1', 1C), 136.0 (d, J = 9.5 Hz, C5, 1C), 130.0 (s, C4',
1C), 129.6(9) (s, C2',6', 2C), 129.6(6) (s, C3',5', 2C), 126.9 (d, J = 3.2 Hz, C6, 1C), 115.7 (d, J =
20.2 Hz, C4, 1C), 114.0 (d, J = 1 Hz, CCN, 1C), 101.3 (d, J = 15.6 Hz, C2, 1C). 19F NMR (470.50
MHz, (CD3)2CO, rel. C6F6, δ): 56.2 (dd, J = 9.2, 6.0 Hz, F3, 1F). IR (KBr) ṽmax: 2231 (C≡N) cm-1.
EIMS (70 eV) m/z: 198 (14.7), 197 (100.0) [M+], 196 (19.7), 195 (7.4), 177 (9.1), 171 (5.7), 170
(13.6), 169 (10.2), 85 (6.7). HRMS: calcd. for C13H8FN [M+] 197.0635; found 197.0634.
2-Fluoro-[1,1'-biphenyl]-4-carbonitrile (6j): Yield: 178 mg (60%),
4CN
5
6
3
2
colorless layered crystals, mp. 78.1°C with decomposition (TLC). 1H NMR (500.03
MHz, (CD3)2CO, δ):7.76-7.70 (m, H3,5,6, 3H), 7.64-7.61 (m, H2',6', 2H), 7.55-7.51
F
1
1`
13
(m, H3',5', 2H), 7.49-7.46 (m, H4', 1H). C{1H} NMR (125.73 MHz, (CD3)2CO δ):
6`
5`
2`
3`
160.1 (d, J = 250 Hz, C2, 1C), 135.0 (d, J = 13.5 Hz, C1, 1C), 134.9 (d, J = 1.3 Hz,
C1', 1C), 133.0 (d, J = 4 Hz, C6, 1C), 129.9 (d, J = 3.2 Hz, C2',6', 1C), 129.8 (s, C4',
4`
2C), 129.7 (s, C3',5', 2C), 129.6 (d, J = 4 Hz, C5, 1C), 120.8 (d, J = 27 Hz, C3, 1C), 118.2 (d, J =
2.8 Hz, CCN, 1C), 113.4 (d, J = 9.8 Hz, C4, 1C). 19F NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ):
48.1 (t, J = 8.5 Hz, F2, 1F). IR (KBr) ṽmax: 2241 (C≡N) cm-1. EIMS (70 eV) m/z: 198 (15.1), 197
(100.0) [M+], 196 (21.2), 195 (8.2), 171 (7.1), 170 (7.4), 169 (11.1), 85 (6.7). HRMS: calcd. for
C13H8FN [M+] 197.0635; found 197.0637.
3,6-Difluoro-3'-methoxy-[1,1'-biphenyl]-2-carbonitrile
(14a):
'
4
OCH3
'
3
5'
6'
Yield: 140 mg (38%), white powder, mp. 103.1‒103.5°C (hexane). 1H NMR
(500.03 MHz, (CD3)2SO, δ): 7.80 (td, J = 9.2, 9.2, 4.7 Hz, H5, 1H), 7.65
(ddd, J = 9.2, 8.7, 4.0 Hz, H4, 1H), 7.48 (ddd, J = 8.2, 7.6, 0.6 Hz, H5', 1H),
7.14-7.08 (m, H2',4',6', 3H), 3.81 (s, OCH3, 3H). 13C{1H} NMR (125.73 MHz,
(CD3)2SO δ): 159.4 (dd, J = 253, 2.6 Hz, C3, 1C), 159.1 (s, C3', 1C), 154.8
'
2
1'
1
F
NC
F
2
6
3
5
4
(dd, J = 243, 2.5 Hz, C6, 1C), 132.8 (d, J = 21.0 Hz, C1, 1C), 131.6 (d, J = 1.5 Hz, C1', 1C), 129.8
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(s, C5', 1C), 123.0 (dd, J = 25.9, 9.5 Hz, C5, 1C), 121.7 (d, J = 1.7 Hz, C6', 1C), 117.1 (dd, J =
22.5, 9.1 Hz, C4, 1C), 115.2 (d, J = 1.6 Hz, C2', 1C), 115.1 (s, C4', 1C), 112.4 (d, J = 3.4 Hz, CCN,
1C), 101.9 (dd, J = 17.5, 5.1 Hz, C2, 1C), 55.2 (s, COCH3, 1C). 19F NMR (470.50 MHz, (CD3)2SO,
rel. C6F6, δ): 50.6 (ddd, J = 16.8, 8.5, 4.6 Hz, F3 or 6, 1F), 43.8 (ddd, J = 16.6, 9.2, 3.9 Hz, F6 or 3
,
7
8
9
1F). IR (KBr) ṽmax: 2231 (C≡N), 1248, 1043 (C–O–C) cm-1. EIMS (70 eV) m/z: 246 (16.0), 245
(100.0), 217 (24.6), 216 (24.5), 215 (24.6), 202 (46.0), 188 (18.0), 176 (33.7), 175 (16.9), 39
(19.7). HRMS: calcd. for C14H9F2NO [M+] 245.0647; found 245.0645.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Fluoro-3'-methoxy-[1,1'-biphenyl]-4-carbonitrile (14j): Yield: 190
CN
4
3
1
5
6
mg (56%), white crystalls, mp. 88.3°C with decomposition°C (hexane). H
NMR (500.03 MHz, (CD3)2CO, δ): 7.76 (ddd, J = 8.1, 7.6, 0.9 Hz, H6, 1H),
7.74-7.71 (m, H3, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, H5, 1H), 7.43 (ddd, J = 8.2,
7.5, 0.5 Hz, H5', 1H), 7.20-7.15 (m, H2',6', 2H), 7.05 (ddd, J = 8.3, 2.6, 0.9 Hz,
H4', 1H), 3.87 (s, OCH3, 3H). 13C{1H} NMR (125.73 MHz, (CD3)2CO δ): 161.0
2
F
1
1'
6'
5'
2'
3'
OCH3
4'
(s, C3', 1C), 160.1 (d, J = 250 Hz, C2, 1C), 136.2 (d, J = 1.4 Hz, C1', 1C), 134.9 (d, J = 13.4 Hz,
C1, 1C), 133.0 (d, J = 4.0 Hz, C6, 1C), 130.7 (s, C5', 1C), 129.6 (d, J = 4.0 Hz, C5, 1C), 122.1 (d, J
= 3.2 Hz, C6', 1C), 120.8 (d, J = 27.0 Hz, C3, 1C), 118.2 (d, J = 2.8 Hz, CCN, 1C), 115.5 (d, J = 3.1
19
Hz, C2', 1C), 115.4 (s, C4', 1C), 113.4 (d, J = 9.9 Hz, C4, 1C), 55.6 (s, COCH3, 1C). F NMR
(470.50 MHz, (CD3)2CO, rel. C6F6, δ): 48.6 (t, J = 8.8 Hz, F2, 1F). IR (KBr) ṽmax: 2233 (C≡N),
1217, 1022 (C–O–C) cm-1. EIMS (70 eV) m/z: 228 (16.3), 227 (100.0), 198 (8.5), 197 (29.0),
196 (12.4), 184 (29.5), 182 (5.3), 158 (23.1), 157 (5.2). HRMS: calcd. for C14H10FNO [M+]
227.0741; found 227.0743.
2,5-Difluoro-4-(naphthalen-1-yl)benzonitrile (15c): Yield: 123 mg
CN
1
1
2
F
(31%), white crystalls, mp. 107.9°C with decomposition°C (hexane). H
6
5
NMR (500.03 MHz, (CD3)2CO, δ): 8.07 (dm, J = 8.3 Hz, H8', 1H), 8.03 (dm,
J = 8.1 Hz, H5', 1H), 7.90 (ddd, J = 8.5, 5.4, 0.4 Hz, H3, 1H), 7.64(4) (dm, J =
8.3 Hz, H4', 1H), 7.64(2) (dd, J = 8.3, 7.0 Hz, H3', 1H), 7.59 (ddd, J = 8.1,
6.8, 1.4 Hz, H7', 1H), 7.58 (ddd, J = 9.1, 5.7, 0.4 Hz, H6, 1H), 7.55 (dm, J =
3
F
4
8'
1'
8'a
2'
3'
7'
6'
4'a
4'
5'
7.0 Hz, H2', 1H), 7.54 (ddd, J = 8.3, 6.8, 1.5 Hz, H6', 1H). 13C{1H} NMR (125.73 MHz,
(CD3)2CO δ): 160.2 (dd, J = 254, 2.8 Hz, C2 or 5, 1C), 156.7 (dd, J = 243, 2.6 Hz, C5 or 2, 1C),
136.7 (dd, J = 19.5, 8.5 Hz, C4, 1C), 134.6 (s, C4'a, 1C), 132.1 (d, J = 1.3 Hz, C1', 1C), 131.9 (d, J
= 0.8 Hz, C8'a, 1C), 130.6 (s, C8', 1C), 129.4 (s, C5', 1C), 128.7 (d, J = 1.1 Hz, C2', 1C), 127.9 (s,
C6', 1C), 127.3 (s, C7', 1C), 126.2 (s, C3', 1C), 125.8 (d, J = 1.6 Hz, C4', 1C), 121.2 (dd, J = 29.0,
1.3 Hz, C3, 1C), 121.0 (dd, J = 22.4, 4.0 Hz, C6, 1C), 113.6 (d, J = 2.2 Hz, CCN, 1C), 102.2 (dd, J
19
= 18.1, 10.1 Hz, C1, 1C). F NMR (470.50 MHz, (CD3)2CO, rel. C6F6, δ): 49.8 (ddd, J = 16.5,
9.2, 5.4 Hz, F2 or 5, 1F), 49.6 (ddd, J = 15.3, 6.2, 2.3 Hz, F5 or 2, 1F). IR (KBr) ṽmax: 2237 (C≡N)
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2
3
4
cm-1. EIMS (70 eV) m/z: 266 (18.0), 265 (100.0), 264 (62.1), 263 (28.2), 246 (11.3), 245 (20.7),
244 (12.0), 119 (13.4). HRMS: calcd. for C17H9F2N [M+] 265.0700; found 265.0702.
5
6
7
8
3-Fluoro-4-(naphthalen-1-yl)benzonitrile (15j). Yield: 103 mg
CN
1
1
(28%), white solid (TLC). H NMR (500.03 MHz, (CD3)2CO, δ): 8.05 (d, J =
6
2
3
9
8.3 Hz, H, 1H), 8.02 (d, J = 8.2 Hz, H, 1H), 7.82 (dd, J = 9.5, 1.5 Hz, H, 1H),
7.80 (dd, J = 7.7, 1.6 Hz, H, 1H), 7.68 (dd, J = 7.8, 7.3 Hz, H, 1H), 7.63 (dd, J
5
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
1'
8'a
8'
2'
3'
7'
6'
13
= 8.2, 7.1 Hz, H, 1H), 7.60-7.55 (m, H, 2H), 7.54-7.50 (m, H, 2H). C{1H}
4'a
4'
NMR (125.73 MHz, (CD3)2CO δ): 160.6 (d, J = 249 Hz, C3, 1C), 134.6(2) (s,
5'
C, 1C), 134.6(0) (d, J = 4.1 Hz, C5, 1C), 134.3 (d, J = 16.7 Hz, C4, 1C), 133.0 (s, C, 1C), 132.1
(s, C, 1C), 130.2 (s, C, 1C), 129.5 (d, J = 3.9 Hz, C6, 1C), 129.4 (s, C, 1C), 128.6 (d, J = 1.1 Hz,
C, 1C), 127.7 (s, C, 1C), 127.2 (s, C, 1C), 126.3 (s, C, 1C), 125.9 (d, J = 1.5 Hz, C, 1C), 120.4
(d, J = 26.4 Hz, C2, 1C), 118.0 (d, J = 2.9 Hz, CCN, 1C), 114.1 (d, J = 9.6 Hz, C1, 1C). 19F NMR
(470.50 MHz, (CD3)2CO, rel. C6F6, δ): 52.4 (ddd, J = 9.4, 6.8, 2.7 Hz, F3, 1F). IR (KBr) ṽmax
:
2237 (C≡N) cm-1. EIMS (70 eV) m/z: 248 (18.5), 247 (100.0), 246 (64.8), 245 (31.9), 227 (11.1),
226 (8.1), 219 (7.7), 110 (10.7). HRMS: calcd. for C17H10FN [M+] 247.0792; found 247.0794.
4-Amino-2-phenyl-8-fluoroquinazoline (10f). Metallic sodium
NH2
5
4
4a
(33 mg, 1.4 mmol) was dissolved in liquid ammonia (30-40 ml). FeCl3
6
N
6'
7
1'
(a drop) was put into metal-ammonia solution, benzonitrile 3 (1.3
mmol) was added after the formation of NaNH2, and the resulting
mixture was maintained under an atmosphere of evaporating NH3 at -
5'
4'
2
8a
N
8
F
2'
3'
33ºC for ca. 0.5 h. 2,3-Difluorobenzonitrile 4f (1.4 mmol) was added to the thus obtained
suspension of the amidine 11 sodium salt and stirring was continued for 1.5 h. The reaction
mixture was brought into contact with air, Et2O (25 mL) was added and stirring continued until
NH3 was completely evaporated. To the residue H2O (25 ml) was added, the organic products
were extracted with Et2O (3 × 25 mL). The combined ether extract was successively washed
with H2O, a saturated NaCl solution, dried with MgSO4. The composition of the reaction mixture
1
19
obtained after distillation of the Et2O was analyzed by H, F NMR and GC-MS. Quinazoline
10f was isolated by crystallization of the reaction mixture from acetone. Yield: 124 mg (40%),
white crystals, mp 179.4-179.6°C. H NMR (500.03 MHz, (CD3)2CO, δ): 8.61-8.57 (m, H2',6'
,
1
2H), 8.02 (ddd, J = 8.3, 1.1, 0.9 Hz, H5, 1H), 7.55 (ddd, J = 10.6, 7.8, 1.2 Hz, H7, 1H), 7.51-7.46
(m, H3',4',5', 3H), 7.44 (ddd, J = 8.2, 7.9, 4.9 Hz, H6, 1H), 7.35-7.22 (br.s, NH2, 2H). 13C{1H}
NMR (125.73 MHz, (CD3)2CO δ): 162.9 (d, J = 3.7 Hz, C4, 1C), 161.4 (d, J = 1.1 Hz, C2, 1C),
158.6 (d, J = 254 Hz, C8, 1C), 142.4 (d, J = 12.4 Hz, C8a, 1C), 139.7 (s, C1', 1C), 131.0 (s, C4',
1C), 129.2 (s, C2',6', 2C), 128.9 (s, C3',5', 2C), 125.6 (d, J = 7.8 Hz, C6, 1C), 119.6 (d, J = 4.7 Hz,
C5, 1C), 118.0 (d, J = 18.7 Hz, C7, 1C), 116.0 (d, J = 3.5 Hz, C4a, 1C). F NMR (470.50 MHz,
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6
(CD3)2CO, rel. C6F6, δ): 55.3 (dd, J = 10.6, 4.9 Hz, F8, 1F). IR (KBr) ṽmax: 3475, 3311, 3174
(NH2) cm-1. EIMS (70 eV) m/z: 239 (100.0), 223 (39.6), 136 (58.0), 108 (34.2), 104 (24.6), 94
(31.2), 77 (85.9). HRMS: calcd. for C14H10FN3 [M+] 239.0853; found 239.0854.
7
8
9
4-Amino-2-phenyl-5-fluoroquinazoline (10i). Yield: 130 mg
F
NH2
4
5
1
4a
8a
(42%), white crystals, mp 158.7-159.8°C. H NMR (500.03 MHz,
6
7
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6'
(CD3)2CO, δ): 8.57-8.53 (m, H2',6', 2H), 7.75 (ddd, J = 8.4, 8.0, 6.2 Hz,
H7, 1H), 7.65 (dd, J = 8.4, 1.0 Hz, H8, 1H), 7.48-7.46 (m, H3',4',5', 3H),
7.19 (ddd, J = 11.9, 7.9, 1.1 Hz, H6, 1H), 7.32-7.86 (br.s, NH2, 2H).
5'
4'
1'
2
N
8
2'
3'
13C{1H} NMR (125.73 MHz, (CD3)2CO δ): 162.1 (d, J = 1.7 Hz, C2, 1C), 160.1 (d, J = 252.0 Hz,
C5, 1C), 161.0 (d, J = 4.1 Hz, C4, 1C), 154.5 (s, C8a, 1C), 139.3 (s, C1', 1C), 133.8 (d, J = 11.1 Hz,
C7, 1C), 131.1 (s, C3',5', 2C), 129.2 (s, C2',6', 2C), 128.9 (s, C4', 1C), 125.3 (d, J = 3.9 Hz, C8, 1C),
111.0 (d, J = 22.9 Hz, C6, 1C), 104.52 (d, J = 11.2 Hz, C4a, 1C). 19F NMR (470.50 MHz,
(CD3)2CO, rel. C6F6, δ): 51.8-51.5 (m, F5, 1F). IR (KBr) ṽmax: 3523, 3300, 3196 (NH2) cm-1.
EIMS (70 eV) m/z: 240 (16.6), 239 (100.0), 238 (21.8), 223 (25.1), 136 (22.1), 120 (8.2), 108
(7.0), 104 (10.9), 94 (6.8), 77 (20.4). HRMS: calcd. for C14H10FN3 [M+] 239.0853; found
239.0854.
Associated content
Supporting Information includes:
13
19
1H, C{1H} and F spectra of synthesized compounds, XRay data, Cartesian coordinates and
total energies of calculated structures (PDF).
X-ray crystallographic data of compounds 10i, 10f, 14j and 15c (CIF).
Acknowledgements
The authors thank the Multi-Access Chemical Service Center SB RAS for spectral and analytical
measurements. Authors are grateful to Dr. Ilia V. Eltsov (Novosibirsk State University) for the
help in performing NMR measurements. The present work was supported by grant of RFBR
№18-33-00132.
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References
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Vasilieva, N. V.; Shteingarts, V. D. Synthesis of 2-X-, 3-X-4,4′-Dicyanobiphenyls (X = CH3,
OCH3, F) by Cross-Coupling of the Terephthalonitrile Dianion with Substituted Benzonitriles.
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65 (10), 2430–2436. DOI: 10.1007/s11172-016-1602-x
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