Purposeful regioselectivity control of the Birch reductive alkylation of biphenyl-4-carbonitrile

Article abstract of DOI:10.1016/j.tet.2017.12.046

Birch's reductive alkylation of biphenyl-4-carbonitrile (1) provides alkylated 1,4-dihydroderivatives of various structural types: 4-alkyl-4-phenylcyclohexa-2,5-dienone, 1,4-dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile (with the same or different alkyl fragments), and 4-(1-alkylcyclohexa-2,5-dienyl)benzonitrile. Each of these products become dominant depending on the nature of long-living anionic form generated from 1, namely, the stable product of two-electrons reduction – dianion (1^2?); 1-alkyl-4-cyano-1-phenylcyclohexa-2,5-dien-4-yl anion (1-Alk₁^–), originated due to the alkylation of dianion 1^2? at the position 1 of biphenyl moiety; or 1-(4-cyanophenyl)cyclohexa-2,5-dien-1-yl anion (1-H_4’^–), being the product of dianion 1^2? protonation at position 4′ by protonating reagent (MeOH or NH₄Cl). The orientation of alkyl fragment incorporation into biphenyl-4-carbonitrile scaffold is in agreement with calculated electronic structure of the anionic species under investigation. The dominating type of their reactivity towards alkyl halides proved to be nucleophilic (S_N2 mechanism).

Full text of DOI:10.1016/j.tet.2017.12.046

Accepted Manuscript
Purposeful regioselectivity control of the Birch reductive alkylation of biphenyl-4-
carbonitrile
Pavel A. Fedyushin, Roman Yu. Peshkov, Elena V. Panteleeva, Evgeny V. Tretyakov,
Irina V. Beregovaya, Yuri V. Gatilov, Vitalij D. Shteingarts
PII:
S0040-4020(17)31330-3
10.1016/j.tet.2017.12.046
TET 29202
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 November 2017
Revised Date: 20 December 2017
Accepted Date: 22 December 2017
Please cite this article as: Fedyushin PA, Peshkov RY, Panteleeva EV, Tretyakov EV, Beregovaya
IV, Gatilov YV, Shteingarts VD, Purposeful regioselectivity control of the Birch reductive alkylation of
biphenyl-4-carbonitrile, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.046.
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ACCEPTED MANUSCRIPT
4
2 M
M=Li,
Na, K) CN
-cyanobiphenyl
NC
Ph
Alk'
Alk
CN
CN
NH3
Alk'Hal
-Hal–
(
CN
+
AlkHal
Hal-
AlkHal
Hal–
[H ]
Alk
2-
-
O
-
Ph
Alk
[
O]
Ph
H
H
O
Ph
Alk
AlkHal=BuCl, BuBr, BuI, CyBr, Br(CH ) COOEt,
2
5
O
Br
Alk'Hal=BuBr, Br(CH ) CN, Br(CH ) Br, Br(CH ) COOEt, MeI, CyBr
2
5
2 5
2 5

ACCEPTED MANUSCRIPT
Purposeful Regioselectivity Control of the Birch Reductive
Alkylation of Biphenyl-4-carbonitrile
[a]
[a,b]
[a,b]
Pavel A. Fedyushin, Roman Yu. Peshkov,*
Elena V. Panteleeva,
Evgeny V.
[a,b]
[a]
[a,b]
[a],ᵻ
Tretyakov,
Irina V. Beregovaya, Yuri V. Gatilov
and Vitalij D. Shteingarts
[
a] N.N. Vorozhtsov Institute of Organic Chemistry of the Siberian Branch of the Russian
Academy of Sciences, Ac. Lavrentiev Avenue, 9, Novosibirsk, 630090, Russia
Fax: 8(383)330-68-59; E-mail: peshkov@nioch.nsc.ru
[
b] Novosibirsk State University, Pirogova Str., 2, Novosibirsk, 630090, Russia
Deceased
ᵻ
Abstract
Birch’s reductive alkylation of biphenyl-4-carbonitrile (1) provides alkylated 1,4-
dihydroderivatives of various structural types: 4-alkyl-4-phenylcyclohexa-2,5-dienone, 1,4-
dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile (with the same or different alkyl fragments),
and 4-(1-alkylcyclohexa-2,5-dienyl)benzonitrile. Each of these products become dominant
depending on the nature of long-living anionic form generated from 1, namely, the stable product
2–
of two-electrons reduction – dianion (1 ); 1-alkyl-4-cyano-1-phenylcyclohexa-2,5-dien-4-yl
–
2–
anion (1-Alk ), originated due to the alkylation of dianion 1 at the position 1 of biphenyl
1
–
’
moiety; or 1-(4-cyanophenyl)cyclohexa-2,5-dien-1-yl anion (1-H ), being the product of
4
2
–
dianion 1 protonation at position 4′ by protonating reagent (MeOH or NH Cl). The orientation
4
of alkyl fragment incorporation into biphenyl-4-carbonitrile scaffold is in agreement with
calculated electronic structure of the anionic species under investigation. The dominating type of
their reactivity towards alkyl halides proved to be nucleophilic (S 2 mechanism).
N
Keywords: Reductive Alkylation / Biphenyl-4-carbonitrile/ Dianion / Cyclohexadienyl Anions /
Nucleophilic Substitution
1

ACCEPTED MANUSCRIPT
Introduction
The shortest and most convenient approach to compounds with cyclohexa-1,4-dienylic
[
1]
structural motif, valuable in synthesis of natural, bioactive compounds and new materials, is
[2]
based on Birch’s reduction or reductive alkylation of aromatic compounds. Despite the fact
that most of the substrates studied in Birch’s reaction were unsubstituted arenes or ones bearing
electron donating groups, the electron-deficient substrates are particularly attractive for the
following reason. Their reduction by alkali metal in liquid ammonia provides quite stable anionic
forms (AFs), viz., radical anions (RAs), dianions (DAs) or (after subsequent protonation)
cyclohexadienyl anions (CHDAs). In turn, stability of these AFs opens the possibility of their
preparative generation and the investigation of their identity, electronic structure and reactivity
towards electrophilic reagents (S /ET-mechanism competition). The data thus obtained can serve
N
as the basis for construction of a general synthetic approach utilizing electron-deficient arene’s
[
3 ]
AFs as effective anionic synthons.
Unlike AFs of nitro- and carbonyl-bearing arenes
undergoing predominantly transformations of functional group, AFs of aromatic carboxylic acids
and their derivatives (esters, amides, nitriles) provide dihydroproducts of aromatic ring
[
2d,e,m,n,4,5,6] [7]
modification at positions ipso-and para- to functional group.
Our research interest concerns arenecarbonitrile AFs. It has been shown that AFs of benzo-
and tolunitriles, 1-naphthonitrile, 9-anthracenecarbonitrile, phthalo- and terephthalonitrile, 9,10-
anthracenedicarbonitrile react with alkyl halides exclusively at aromatic moiety and provide the
products – subsequent alkylated cyanoarenes and cyanoalkyl–1,4-dihydroarenes – in good to
[
]
[8]
high yields . The presence of the readily and variably modifiable cyano group in product’s
7
structure provides wide possibilities for further preparing practically important substances and
materials.
In this work, we concentrated on study of biphenyl-4-carbonitrile (1) as the most affordable
isomer among biphenylcarbonitriles, which reductive alkylation has not been explored until now.
According to literature data, a fairly stable radical anion and dianion can be generated from
[
9]
[10]
[11]
nitrile 1 under chemical , electrochemical , pulse radiolysis
reduction. These data together
with our previous results describing identity, electronic structure and reactivity of cyanoarene
[
, ]
AFs in liquid ammonia 3 7 allowed us to anticipate the formation of quite stable dianion or
cyclohexadienyl anion under the two-electron reduction of 1 by alkali metal in liquid ammonia
in preparative amounts. Subsequent interaction of these AFs with alkyl halides would lead to the
formation of alkylated products, comprising in their structure dihydrobiphenylic moiety and
cyano group, which makes them valuable structural blocks in organic synthesis. Preparation of
products with given alkyl fragment location in cyanobiphenyl scaffold requires the study of the
2

ACCEPTED MANUSCRIPT
dependence of alkylation orientation upon the type of AF generated from nitrile 1 and its
reactivity toward different alkyl halides, that was the subject of our present paper.
Results and Discussion
Reduction of nitrile 1 was performed by the action of alkali metal (Li, Na, K ~2.1 equiv. per
1
) in liquid ammonia. At first, we observed the formation of а dark green solution obviously
•−
pertinent to the RA 1 , which in 2−5 min turned into a dark-brown suspension of obviously
2
−
[12]
being DA 1 alkali salt (Scheme 1). Unfortunately, the low solubility of this salt in ammonia
prevented to get its NMR spectra that’s why the conclusion about the identity (DA or CHDA)
and stability of nitrile 1 two electron reduction product in liquid ammonia was made on the basis
of the following experimental data. Stirring of the obtained suspension for an hour in atmosphere
of evaporating ammonia with subsequent quenching by bringing into contact with air led to a
return of nitrile 1 (≥90%) and the appearance of a small amount (≤ 5%) of biphenyl. Also this
suspension remained unchanged in sealed NMR ampoule at room temperature during a week;
subsequent alkylation by the excess of butyl bromide led to the product mixture identical to the
one obtained by the alkylation of this AF just after generation (see Table 1, entry 6); the main
product was 1,4-dibutyl-4-phenylcyclohexa-2,5-dienecarbonitrile. These results in total allowed
us to suggest that two electron reduction of nitrile 1 in liquid ammonia provides the long living
2−
DA 1 , which is quite stable with the respect to fragmentation as well as to protonation by the
solvent.
2
−
Scheme 1. The routes of products formation proposed for DA 1 alkylation.
3

ACCEPTED MANUSCRIPT
2−
In order to reveal the reactivity and synthetic productivity of DA 1 , we used alkylating
reagents differing in alkyl fragment structure, the additional ω-functions, and on the nature of the
halogen atom (Scheme 1). The structure of the main alkylated product was found out to depend
substantially on the nature of alkylating regent. On the contrary, the nature of the alkali metal
used to reduce 1 had no significant effect on the results of reductive alkylation, sodium proved to
be the most convenient to handle the reactions (Table 1, Entries 6-8). Thus the interaction of DA
2−
1
sodium salt with butyl chloride provides 4-butyl-4-phenylcyclohexa-2,5-dienone (2a) as the
[
13]
main product, along with a small amount 4-butylbiphenyl (3a),
other components of the
reaction mixture were starting nitrile 1 and butyl halide (Table 1, Entry 1). The formation of
dienone 2 as the main reaction product allows us to propose the following pathway. At first, DA
2−
1
is alkylated predominantly at position 1 of biphenylic moiety with the formation of 1-butyl-4-
−
1
2−
cyano-1-phenylcyclohexa-2,5-dien-4-yl anion (1-Alk ), which is less reactive than DA 1 in
relation to the primary alkyl chloride under low experimental temperature (−40 ÷ −33 °C). Being
−
sufficiently stable under inert reaction conditions, anion 1-Alk is oxidized into dienone 2a by
1
oxygen while processing of the reaction mixture. As regards the minor alkylaromatic product 3a,
2
−
its formation is obviously due to DA 1 alkylation at position 4, followed by rapid decyanation
−
4
of thus formed unstable anion 1-Alk , thus restoring aromaticity and providing 4-butylbiphenyl.
2
–
[a]
Table 1. The interaction of DA 1 with alkylhalides
[b]
Product, NMR yield, trans-/cis-diastereomeric ratio
isolated yield %, trans-/cis-diastereomeric ratio)
Entry Metal, AlkHal, mmol
(
Na,
BuCl, 1.68
1
2a, 78 (55)
3a, 10
Na,
2
3
4
1) BuCl, 1.12;
2) MeI, 1.23
4ab, 82, 1.05/1
65, 1/1)
2a, 9
3
a, 5
a, 10
a, 14
(
Na,
1) BuCl, 1.12;
2
) Br(CH ) CN, 1.12
4ac, 79, 2.4/1
71, 4.1/1)
2
5
3
3
(
NC (CH2)5CO2Et
Na,
1) BuCl, 1.12;
Bu Ph
2
) Br(CH ) CO Et,
2
5
2
4ad, 66, 1.9/1
1.68
(
52, 1.8/1)
4

ACCEPTED MANUSCRIPT
Na,
5
1) BuCl, 1.12;
) Br(CH ) Br, 1.68
4
ae, 66, 2.7/1
54, 2.8/1)
trans-4ae, 30 , cis-4ae, 10)
2
2
5
(
3a, 6
(
Na,
BuBr, 2.24
6
7
8
4
aa, 67, 1.2/1
(60, 1.3/1)
3a, 10
5
5
2
a, 19
Li,
BuBr, 2.24
4
4
4
aa, 44, 1.3/1
aa, 50, 1.5/1
aa, 21, 1.3/1
3
a, 8
a, 11
a, 20
5a, 3
K,
BuBr, 2.24
3
3
a, 15
Na,
BuI, 2.24
[
c]
9
5a, 8
Na,
CyBr, 1.12
1
0
1
g, 55
36)
4gg, 4
3g, 11
3g, 9
(
Na,
1
1) CyBr, 1.12;
) BuBr, 1.34
2
4
ga, 39, 4.6/1
2
g, 9
(
trans-4ga, 31)
Na,
CyBr, 3.36
[d]
1
2
4
gg, 63
2g, 6
3g, 5
(
trans-4gg, 40)
[
a] 1.12 mmol of 1 and 2.29 mmol of alkali metal in 30 − 40 ml of liquid ammonia were used. The
performed values averaged over the results of at least two runs (deviation was at most 5%). [b] 1,4-
Dialkyl-1-phenylcyclohexa-2,5-dienecarbonitriles arise in form of two diastereoisomers. [c] Besides
5

ACCEPTED MANUSCRIPT
indicated compounds, the reaction mixture contained some unidentified di- and
tributyldihydrobiphenyles ~5−10% of each compound. [d] The reaction time was 3 h.
2
−
The sequential treating of DA 1 sodium salt with 1 equiv. of butyl chloride and, after about
an hour, 1 equiv. of more reactive reagent – methyl iodide – led mainly to isomeric (trans- and
cis-) 4-butyl-1-methyl-4-phenylcyclohexa-2,5-dienecarbonitrile (4ab), together with minor
amount of dienone 2a and butylbiphenyl 3a (Table 1, Entry 2). The utilization of Br(CH ) CN,
2
5
Br(CH ) CO Et or Br(CH ) Br (Entries 3-5) instead of methyl iodide provided corresponding 4-
2
5
2
2 5
butyl-1-(ω-X-alkyl)-1,4-dihydroderivatives 4ac–4ae as the main reaction products. In
2−
accordance with the obtained results, the addition of two equiv. of butyl bromide to DA 1
sodium salt (Table 1, Entry 6) led to the isomeric 1,4-dibutyl-4-phenylcyclohexa-2,5-
dienecarbonitriles (4aa) as the major product. In significantly fewer amounts the reaction
mixture contained butylbiphenyl 3a and a new type of dihydroderivative ‒ 4-(1-butylcyclohexa-
2
–
2
,5-dienyl)benzonitrile (5a). Lithium and potassium salts of DA 1 , when reacting with butyl
bromide, gave the same products in similar amounts (Table 1, Entries 7 and 8). The reaction
selectivity markedly lowered when butyl iodide was used instead of alkyl bromides: some di-
and tributyldihydrobiphenyls in amounts comparable to products 3a, 4aa and 5a were obtained
(Table 1, Entry 9). Typically, such decrease in selectivity of cyanoarene AF alkylation was
observed due to electron transfer (ET) mechanism in the cases when alkyl iodide as well as
[
7]
tertiary alkyl halide were used.
2−
The interaction of DA 1 sodium salt with 1 equiv. of secondary alkylating reagent ‒
cyclohexyl bromide ‒ provided 4-cyclohexyl-4-phenylcyclohexa-2,5-dienone (2g); 4-
[
14]
cyclohexylbiphenyl (3g) and 1,4-dicyclohexyl-4-phenylcyclohexa-2,5-dienecarbonitrile (4gg)
also formed in a much smaller amount (Table 1, Entry 10). The sequential treating of a
2
−
suspension of DA 1 sodium salt first with cyclohexyl bromide, and after an hour ‒ butyl
bromide, led to formation of the isomeric 4-butyl-1-cyclohexyl-4-phenylcyclohexa-2,5-
dienecarbonitriles (4ga) as the major products (Table 1, Entry 11). If 3 equiv. of cyclohexyl
bromide were used and the reaction time was increased from 1 to 4 hours, the major product
became 1,4-dicyclohexyldihydro derivative (4gg) (Table 1, Entry 12).
The structures of all new products were defined by NMR and IR spectroscopic analysis and
supported by mass-spectroscopy. In addition, we carried out X-ray single-crystal analysis for
trans-4ac, cis-4ae, 2g, and trans-4gg as representatives for typical products structure (Figure 1).
6

ACCEPTED MANUSCRIPT
2
g
4
gg
4
ae
4
ac
Figure 1. Molecular structure of compounds 2g, 4gg (trans-isomer), 4ac (trans-isomer), 4ae
cis-isomer), in crystals. Thermal ellipsoids were scaled to 30% and 50% (4gg) probability level.
(
Open bondtype for 4ac show the major parts of disordered groups. The 4ae molecule lies on a
mirror plane.
The X-ray diffraction studies revealed that in all studied compounds hexadienyl cycles are
planar (the highest atom deviation from the cycle plane is 0.043 A in 4ac).. In compound 2g,
bond lengths of the cyclohexadienone fragment are close to the same length in the 4,4-diphenyl-
[
15]
2
,5-cyclohexadienone. For derivatives 4ac, 4ae, 4gg bond lengths in 1-phenylcyclohexa-2,5-
dienyl fragment are close to the bond lengths of the same fragment in 1,1,2,2-tetramethyl-6-
[
16]
phenylspiro[2.5]octa-4,7-diene-6-carboxylic acid (see Table 2 in SI).
The orientation of the
phenyls depends on the second substituent of this position: in the case of cyclohexylenes, the
torsional angles are 7.9 C5-C4-C7-C8 (2g) and 13.2 C5-C4-C14-C15 (4gg), and in the case of
butyls - 40.9 C5-C4-C14-C15 (4ac) and 59.7 C3-C4-C11-C16 (4ae). Cyclohexyl substituents are
oriented in the same way ‒ the torsion angles of HC CC (= C) are close to 180º.
2
−
General observation of the obtained results show that alkylation of DA 1 gives
predominantly the products of two structural types - dienone 2 or isomeric 1,4-dialkyl-1,4-
2
−
dihydroderivative 4. Consequently, primary and secondary alkyl halides easily alkylate DA 1 at
position 1 mainly and, to much lesser extent, at position 4 with the formation of corresponding
7

ACCEPTED MANUSCRIPT
−
1
−
4
alkylcyclohexadienyl anions 1-Alk and 1-Alk (Scheme 1). The established orientation of DA
2−
1
alkylation is consistent with the orientation of the S 2-alkylation of unsubstituted biphenyl
N
[
17]
DA lithium salt in THF, studied in detail by A. Guijarro . Also similar transformations took
[
18]
[19]
place under alkylation of 9,10-dicyanoanthracene and 9-anthracenecarbonitrile DAs alkali
salts in liquid ammonia: the first reaction gave 10-alkylanthrone or 9,10-
dialkyldihydroderivatives, the second one provided exclusively dialkyldihydroproducts. Both
2−
reactions proceeded via S 2 mechanism. The revealed high regioselectivity of DA 1 alkylation
N
together with increased products yield when going from secondary to primary alkylating reagent
[
]
can be considered as an indication of S 2 reaction mechanism, rather than ET.
7
The last one,
probably, takes its share in the less selective DA 1 alkylation with butyl iodide (Entry 9, Table
).
N
2−
1
To rationalize the regularities observed experimentally, we performed quantum chemical
2
−
calculations of electronic structure of the DA 1 and possible ways of its alkylation. According
to the data obtained, the major density of the highest energy occupied molecular orbital (HOMO)
2
−
of DA 1 is located at the carbon atoms in positions 1 and 4 (Figure 2). Thus, the
regioselectivity of this DA alkylation (see Scheme 1) is consistent with the HOMO structure,
indicating the reaction is likely to have an early transition state (TS). Because there is noticeable
HOMO localization at the carbon atoms in positions 1’ and 4’, we are unable to rule out these
positions from our consideration. Figure 3 shows the electronic structure (HOMO view) and
relative stability of isomeric CHDAs formed by addition of a model alkyl fragment (methyl) to
–
N
position 1, 4, 1’ and 4’. Resulted model anions are denoted as 1-Me , where N is a position
number. These anions were considered to be free of the interaction with a cation (experimental
data show that the change of cation nature effected the reaction regioselectivity to a small degree,
[20]
see Table 1, Entries 6-8), and CPCM model was used to account the solvent effect of liquid
[21]
[22]
ammonia (solvent radius 1.9 Å , dielectric constant 21 ), thus ignoring any possible specific
solvation.
2
−
[23]
Figure 2. HOMO view of DA 1 (DFT B3LYP/6-31+G(d), GAMESS US ).
8

ACCEPTED MANUSCRIPT
–
N
Figure 3. Relative energies and HOMO view of anions 1-Me .(DFT B3LYP/6-31+G(d),
GAMESS US).
–
–
–
–
1’
The relative energy of the anions goes up in a row: 1-Me4’ ≤ 1-Me < 1-Me <<1-Me .
1
4
–
–
1
The most stable anions 1-Me4’ and 1-Me turned out to be very close in energy (within 1.7
kcal/mol). The observed relative stability of the anions is obviously related to the differences in
the possibilities of negative charge delocalization over two rings and the electron withdrawing
–
CN group. The significant energy increase (6.4 kcal/mol) in the case of anion 1-Me indicates
4
the greater effect of CN group compared to phenyl fragment on anions stability. The anion 1-
–
Me1’ has the smallest delocalization degree, its anionic moiety is isolated from conjugation both
with CN group and phenyl fragment, that undoubtedly provides the highest energy.
–
2–
The calculated relative stabilities of anions 1-MeN show the preference of DA 1 alkylation
at position 4’ than at positions 1 or 4. Evident discrepancy between the relative energy of
2
–
isomeric anions and experimental data on DA 1 alkylation may be one more evidence of the
reaction has an early TS. To support the above conclusion, we considered the reaction pathways
2
–
for DA 1 alkylation at positions 1, 4, and 4’ with CH Cl and CH Br in a model solvent with
3
3
electrostatic parameters of liquid ammonia. We did not calculate the cross section of the PES
along the reaction coordinate proceeding at the 1’ position, because this pathway was proved to
be significantly (ca. for a one third, ~20 kcal/mol) less exothermic in comparison to others; thus,
according to Hammond postulate, its TS should also be significantly higher in energy than others.
9

ACCEPTED MANUSCRIPT
2
–
The data for DA 1 alkylation with CH Cl are depicted in Figure 4 (the results obtained for
3
CH Br are similar and given in Supplementary file; the PES is less expressed, obviously, due to
3
[
24]
higher C–Cl bond energy compared to C–Br). The interaction starts with the formation of pre-
[25]
reaction complexes (PC), as it takes place in classic gas phase S 2 reactions. PCs preceding
N
methylation at positions 4 and 4’ have slightly lower energy comparing to starting reagents (R),
thus causing the reaction barriers to increase: they are 3.5 and 4.1 kcal/mol, respectively. In the
case of alkylation at position 1 corresponding PC is slightly higher than starting reagents, thus
decreasing the barrier to 2.5 kcal/mol. Finally, transformation of TS into products causes a
drastic decrease in energy, obviously, due to separation of 2 anions and thus decreasing the
2
–
Coulomb repulsion, inherent in DA 1 . The calculated characteristics indicate the preference of
2
–
DA 1 methylation at position 1, then at position 4, and position 4’ was found to be the less
favourable in this sequence. It is important that the structure of TSs was found to be close to the
–
N
2–
structure of PCs, rather than model monoanions 1-Me , thus indicating that alkylation of DA 1
has early TS.
Figure 4. Schematic reaction paths and geometries of pre-reaction complexes (below) and
2
–
transition states (above) of DA 1 alkylation with CH Cl. A – alkylation at position 4; B –
3
2
–
position 1; C – position 4’. Legend: R – reagents (DA 1 + CH Cl), PC – pre-reaction complex,
3
–
–
TS – transition state, P – products (1-MeN + Cl . Note: relative energy of P is calculated as a
–
N
–
sum of independent 1-Me and Cl ).
1
0

ACCEPTED MANUSCRIPT
2
−
To sum up, the experimental and calculated data show that the possibility of DA 1 “one-
pot” transformation into different alkylated products is based on the predominant formation of
−
1
anion 1-Alk . This anion hardly reacts with alkyl chloride and considerably slower is alkylated
2
−
by secondary bromide compared to DA 1 in the reaction conditions. The revealed reactivity
features make it possible to successfully generate long-lived anion, which further transformation
−
1
involves three possibilities. The first one is the oxidation of 1-Alk during the reaction mixture
contact with air under work up, that provides alkyldienone 2. The second possibility is the use of
excess of primary alkyl bromide, or less reactive secondary alkyl bromide but with prolonged
−
1
time, for selective 1-Alk alkylation at position 4 bearing maximum electron density, that leads
to 1,4-dialkyldihydroderivatives with similar alkyl fragments, like 4aa and 4gg. The third
−
possibility is the alkylation of long-living 1-Alk1 with another alkyl bromide, providing
products with different alkyl fragments (including functionalized ones, for example, 4ac, 4ad
and 4ae).
2
–
−
4
As mentioned above, DA 1 alkylation gave a minor anion 1-Alk along with the dominant
−
−
1
-Alk . However, the life time of 1-Alk containing a good leaving CN group in geminal
1 4
position is quite short. This anion quickly aromatizes by decyanation, forming alkylbiphenyl 3,
[
7,26]
such processes are well known for AFs of cyanoarenes.
2
−
Another group of minor products reproducibly formed (yields ~ 15%) in DA 1 interaction
with primary alkyl bromides were 4-(1-alkylcyclohexa-2,5-dienyl)benzonitriles 5. A priori, these
2
–
products could arise due to initial alkylation of DA 1 at position 1’, but the calculated
–
comparative stability of anions 1-MeN does not agree with this pathway. Another possibility
2
–
combines consecutive protonation of DA 1
at position 4’ providing the 1-(4-
−
’
cyanophenyl)cyclohexa-2,5-dien-1-yl anion (1-H ) and its further alkylation at position 1’. We
4
2
–
consider the latter way to take place because of DA 1 high basicity; alkyl halides as well as
2
–
their ammonolysis products could serve as protonating agents towards DA 1 . Our previous
studies showed that protonation of the cyanoarene DAs took place at position para- to cyano
−
’
[12]
group, thus forming CHDAs structurally resembling supposed 1-H . Also, the formation of
4
products structurally similar to 5 is described for Birch reductive alkylation of biphenyl and
some its derivatives in liquid ammonia; the first stage of these reaction was the protonation of
[1b,2j,k]
respective biphenyl dianion at position 4.
1
1

ACCEPTED MANUSCRIPT
–
–
1
Scheme 2. Alkylation of anions 1-H4’ and 1-H .
2−
[a]
Table 2. Alkylation of DA 1 in presence of protonating reagent.
Protonating reagent,
AlkHal mmol
Product, NMR yield
(isolated yield) %
Entry
MeOH,
BuBr 2.24
1
3
a, 10
5
a, 50 (36)
d, 38 (20)
[b]
NH Cl,
4
2
3
Br(CH ) CO Et 3.36
2
5
2
3
d, 8
5
CN
O
MeOH,
O
2.60
3f, 5
5f, 52 (35)
[
a] 2.24 mmol of 1, 4.59 mmol of metallic sodium in 40–50 ml of liquid ammonia were used, the
reaction time was ~1h. The performed values averaged over the results of at least two runs (deviation was
at most 5%). [b] NH Cl was used instead of MeOH in order to avoid transesterification that provided 4-
4
(
1-(6-methoxy-6-oxohexyl)cyclohexa-2,5-dienyl)benzonitrile in addition to ethyl ester 5d.
To support our idea of products 5 formation as well as to create a concise synthetic approach
−
to these compounds, we decided to generate anion 1-H4’ in situ and to examine the products of
its alkylation. Indeed, the addition of one equiv. of protonating agent (methanol or ammonium
2
–
chloride) to a suspension of DA 1 disodium salt in liquid ammonia followed by alkylation with
primary alkyl bromide provided the desired 4’-alkyldihydroderivatives 5 in moderate yields
(Table 2, Scheme 2). In addition to products 5, the reaction mixtures always contained 4-
alkylbiphenyls 3, starting nitrile 1 (both 5-10%) and small amounts (<5% in all cases) of
1
2

ACCEPTED MANUSCRIPT
1
-alkyl-1-(4-cyanophenyl)cyclohexa-2,5-dien-4-ones 7. The latter arises obviously from initially
formed products 5 via oxidation by oxygen while processing of the reaction mixtures. Ease of
[27]
oxidation for structures similar to 5 is known. Furthermore, after long contact to air, diene 5a
was almost fully converted into corresponding dienone 7a, which was purified by TLC (see
−
Experimental Part). Alkylbiphenyls 3 could form by the competitive alkylation of anion 1-H4’ at
the carbon atom bearing the CN group and subsequent aromatization through dehydrocyanation
2
–
−
in basic reaction media. Another possibility means that DA 1 protonation provides anion 1-H
1
−
’
−
1
together with 1-H . In this case product 3 could form within the alkylation of anion 1-H at
4
position ipso to cyano group with subsequent dehydrocyanation of 4-alkyldihydroproduct 6,
which being, probably, more acidic than 5, undergoes aromatization into 4-alkylbiphenyl 3.
–
N
Figure 5. Relative energies and HOMO view of CHDAs 1-H (DFT B3LYP/6-31+G(d)).
–
N
2–
We calculated the relative energy of CHDAs (1-H ), derived by DA 1 protonation at
–
–
4’
positions 1, 4, 1’ and 4’ (Figure 5). The most favourable are anions 1-H and 1-H , that are
1
very close in energy (within 2.0 kcal/mol), both stabilized by the conjugation with CN group.
–
The HOMO localization in 1-H4’ is responsible for its alkylation at position 1’ leading to
–
1
dihydroproduct 5. The electronic structure of 1-H predetermines its alkylation at position 4.
–
–
4’
Hence, the calculated data agree with the possibility of both anions 1-H and 1-H formation,
1
and with the orientation of these anions alkylation. Predominance of dihydroproducts 5
–
–
alkylation is possibly due to anion 1-H4’ higher activity compared to 1-H .
1
1
3

ACCEPTED MANUSCRIPT
Conclusion
We suggested a simple and universal method for the directed synthesis of alkylated
dihydroproducts 2, 4 and 5, based on two-electron activation of biphenyl-4-carbonitrile 1. Two-
2−
electron reduction of nitrile 1 by alkali metal in liquid ammonia provides long-lived DA 1 .
Alkylation of this DA by n-, s-alkyl halide occurs within S 2 mechanism with early TS and
N
predominantly at position 1 of biphenyl scaffold, leading to corresponding alkylcyclohexadienyl
−
1
−
1
anion 1-Alk . Subsequent alkylation of 1-Alk takes place at position ipso to cyano group, thus
forming diastereomeric 1,4-dialkyl-4-phenylcyclohexa-2,5-dienecarbonitriles 4 with same or
different alkyl fragments depending on the alkyl halides applied. When exposed to air, anion
−
2−
1
-Alk is oxidized to 4-alkyl-4-phenylcyclohexa-2,5-dienone 2. Protonation of DA 1 occurs at
1
–
–
4’
positions 1 and 4’, leading to subsequent anions 1-H1 and 1-H . 4-(1-Alkylcyclohexa-2,5-
2−
dienyl)benzonitrile 5 is formed mainly when DA 1 is alkylated in presence of protonating
−
reagent, that corresponds to predominant alkylation of anion 1-H4’ at position 1’. Dienones like
[
4b, 28]
[1,2]
2
and alkylcyanodihydroderivatives like 4 and 5
are potentially valuable as structural
blocks for natural and bioactive compounds synthesis.
Experimental Section
General methods:
Liquid ammonia was purified just before use by dissolving metallic sodium in it, followed
by distillation into a reaction vessel cooled to between –80 and –70 °C. Metallic potassium,
sodium and lithium were freed from oxide film under dry hexane. Biphenyl-4-carbonitrile (1)
was synthesized from commercial biphenyl-4-carboxylic acid by sequential conversion into acyl
chloride under the action of SOCl , then to amide under the action of aqueous NH , finally to
2
3
carbonitrile under the action of SOCl and purified by crystallization, its spectral characteristics
2
[
29]
and melting point agree with literature.
1
1
The H NMR spectra were recorded with a Bruker Avance-300 (300.13 MHz for H),
1
13
1
Avance-400 (400.13 MHz for H and 100.62 MHz for C) and DRX-500 (500.13 MHz for H,
1
3
1
25.76 MHz for C) spectrometers. CDCl was used as solvent, with residual CHCl (δ = 7.26
3 3 H
1
3
ppm) or CDCl (δ = 77.0 ppm) serving as internal standards. C NMR spectra were registered
3
C
with C–H spin decoupling. The IR spectra were registered on a Vector-22 instrument for samples
pelleted with KBr (0.25%) or as thin films.
The reaction mixtures were analysed by GCMS on a Hewlett-Packard G1081A instrument
consisting of an HP-5890 Series II gas chromatograph and HP-5971 mass-selective detector (IE,
1
4

ACCEPTED MANUSCRIPT
–
1
7
0 eV) with an HP5 capillary column (30000×0.25) mm×0.25 ꢀm. A He flow (1 mL min ) was
used as carrier gas. The following temperature regime program was applied: 2 min at 50 °C,
–
1
5
0 °C to 280 °C at a rate of 10°C·min , 5 min at 280 °C. The evaporator temperature was
80 °C and the ion source temperature 173 °C. The scanning velocity was 1.2 scans per second
2
in the mass interval 30–650 amu. The precise molecular ion weights were determined on a DFS
instrument.
Single-crystal X-ray diffraction analysis data were collected at room temperature with a
Bruker KAPPA Apex II diffractometer by using graphite-monochromated Mo-Kα radiation (λ =
0
.71073 Å). The structures were solved by direct methods (SHELXS-97) and refined with full-
matrix least-squares technique (SHELXL-97). The hydrogen atoms were calculated and refined
as riding atoms.
[
23]
Quantum-chemical calculations were performed using the GAMESS package.
HOMO
structures and energies of the anionic species were calculated by DFT B3LYP/6-31+G(d)
[20]
method. Solvent effect was accounted for by the CPCM technique using the model solvent
[
21]
with electrostatic parameters of liquid ammonia (solvent radius 1.9 Å , dielectric constant
[
22]
2
1
). Types of stationary points (minima and transition states) were determined via the analysis
of normal vibrations.
Synthetic procedures
2−
−
’
Generation of dianion 1 and monoanion 1-H . The alkali metal (ca 2.05÷2 equiv., see
4
Tables 1 and 2) was added to a stirred suspension of carbonitrile 1 in liquid ammonia at −33 °C
under evaporating ammonia atmosphere. The obtained mixture was stirred for 5 min under the
2−
same conditions resulting in dark-brown suspension of the DA 1 salt. In order to generate
−
2−
monoanion 1-H4’ the DA 1 salt was quenched by equiv. amount of MeOH or NH Cl (Table
4
−
2
), giving dark-red solution of anion 1-H4’ salt.
2
−
4
-Alkyl-4-phenylcyclohexa-2,5-dienone (2). To a suspension of the of the DA 1 sodium
salt, n-butyl chloride or cyclohexyl bromide (1−1.1 equiv.) was added dropwise with stirring at
–
–
40°C. The reaction mixture was stirred for 1 h under evaporating ammonia atmosphere at
33 °C, then it was brought into contact with atmosphere, Et O (20 mL) was added and stirring
2
was continued until NH evaporated completely and r.t. reached. Afterwards H O (30 mL) was
3
2
added to the residue and products were extracted with Et O (3×20 mL). The combined organic
2
extracts were washed with H O (3×20 mL) and dried (MgSO ). Here and below the composition
2
4
1
of the reaction mixtures obtained after Et O evaporation was determined based on H NMR
2
spectroscopy and GCMS data. Individual products were separated by TLC on plates with a fixed
1
5

ACCEPTED MANUSCRIPT
layer of silica gel (Silica gel 60 PF2 containing gypsum) and a hexane/Et O mixture (from 9/1
54
2
to 8:1 v/v ratio) as eluent.
4
-Butyl-4-phenylcyclohexa-2,5-dienone (2a): Colorless oil. Yield 140 mg (0.62 mmol,
1
5
5%). H NMR (400.13 MHz, CDCl ): δ = 0.87 (t, J=7.2 Hz, 3 H), 1.17-1.25 (m, 2H), 1.29-1.39
3
(m, 2 H), 2.06-2.10 (m, 2 H), 6.33 (d, J=10.4 Hz, 2 H), 6.89 (d, J=10.4 Hz, 2 H), 7.23-7.36 (m, 5
1
3
H) ppm. C NMR (75.48 MHz, CDCl ): δ = 13.8, 23.0, 26.6, 37.1, 49.0, 126.5, 127.4, 128.4,
3
−
1
1
28.9, 140.1, 154.4, 186.2 ppm. IR (neat) ṽmax, cm : 1666 (CO). HRMS: calcd. for C H O
16 18
+
[
M ] 226.1352; found 226.1356.
4
-Cyclohexyl-4-phenylcyclohexa-2,5-dienone (2g): Transparent crystals. Yield 108 mg (0.43
1
mmol, 38%), mp 124−126 °C. H NMR (400.13 MHz, CDCl): δ = 0.90-1.08 (m, 5 H), 1.08-1.26
(
m, 4 H) 1.50-1.67 (m, 5 H), 1.67-1.83 (m, 6 H), 1.87 (tt, J =12.2 Hz, J =2.4 Hz, 1 H), 5.73 (d,
1 2
13
J=10.2 Hz, 2 H), 6.03 (d, J=10.2 Hz, 2 H), 7.14-7.25 (m, 3 H), 7.29 (t, J=7.5 Hz 2 H) ppm. C
NMR (75.47 MHz, CDCl ): δ = 26.23, 26.72, 27.90, 126.7, 45.86, 52.51, 126.68, 127.12, 128.95,
3
−
1
1
29.33, 140.53, 153.31, 186.10 ppm. IR (KBr) ṽmax, cm : 1664 (CO). HRMS: calcd. for
+
C H O [M ] 252.1509; found 252.1510.
18
20
1
,4-Dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile with the same alkyl fragments. To a
2
−
suspension of the DA 1 salt, an alkylbromide (2−2.1 equiv.) was added dropwise with stirring
at –40 °C. Then the reaction mixture was treated as described above for dienone 2.
1
,4-Dibutyl-4-phenylcyclohexa-2,5-dienecarbonitrile (4aa): Colorless oil. Yield 205 mg
1
(
two diastereoisomers, (E)/(Z) = 1.3/1, 0.7 mmol, 60%,). H NMR (400.13 MHz, CDCl ): δ =
3
0
.88-0.96 (m, 6 H), 1.17-1.52 (m, 8 H), 1.73-1.82 (m, 2 H), 1.84-1.89 (m, 2 H), 5.74 (d, J=10.0
Hz, 2 H of (Z)-isomer), 5.76 (d, J=10.0 Hz, 2 H of (E)-isomer), 5.82 (d, J=10.0 Hz, 2 H of (Z)-
13
isomer), 5.88 (d, J=10.0 Hz, 2 H of (E)-isomer), 7.18-7.25 (m, 1 H), 7.25-7.37 (m, 4 H) ppm. C
NMR (75 MHz, CDCl ): δ = 13.87, 13.95, 14.05, 14.09, 22.64, 22.73, 23.16, 23.22, 26.67, 26.74,
3
2
6.95, 27.60, 36.81, 37.06, 38.42, 39.36, 40.44, 40.51, 44.57, 121.47, 123.12, 123.38, 126.46,
26.53, 126.70, 126.74, 128.57, 128.63, 135.54, 135.85, 144.98, 145.74 ppm. IR (neat) ṽmax
1
,
−
1
+
cm : 2229 (CN). HRMS: calcd. for C H N [M ] 293.2138; found 293.2135.
2
1
27
trans-1,4-Dicyclohexyl-4-phenylcyclohexa-2,5-dienecarbonitrile (trans-4gg). Transparent
1
crystals. Yield 55 mg (0.16 mmol, 40%). H NMR (400.13 MHz, CDCl ): δ = 0.88-1.25 (m, 10
3
H), 1.52-1.66 (m, 5H), 1.67-1.82 (m, 6 H), 1.87 (tt, J =12.2 Hz, J =3.0 Hz, 1 H), 5.73 (d, J=10.4
1
2
1
3
Hz, 2H), 6.04 (d, J=10.4 Hz, 2 H), 7.29 (tm, J=7.5 Hz, 2 H) ppm. C NMR (75.47 MHz,
CDCl ): δ = 25.86, 26.13, 26.39, 26.77, 27.66, 27.72, 41.60, 46.23, 46.57, 47.93, 120.84, 122.77,
3
−
1
1
25.96, 126.41, 128.38, 134.94, 145.07 ppm. IR (KBr) ṽmax, cm : 2227 (CN). HRMS: calcd. for
+
C H N [M - C H ] 262.1590; found 262.1591. The compound decomposes at HRMS, losing
19
20
6
11
one cyclohexyl fragment.
1
6

ACCEPTED MANUSCRIPT
1
,4-Dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile with the different alkyl fragments. To a
2
-
suspension of the DA 1 sodium salt, butyl chloride or cyclohexyl bromide (1 equiv.) was added
dropwise at –40 °C and the reaction mixture was kept at the same conditions for 40÷60 min.
Afterwards required alkyl bromide (1.1÷1.4 equiv.) was added (Table 1, entries 2÷5) and
reaction mixture was treated as described above for dienone 2.
4
-Butyl-1-methyl-4-phenylcyclohexa-2,5-dienecarbonitrile (4ab): Colorless oil. Yield 183
1
mg (two diastereoisomers, (E)/(Z) = 1/1, 0.73 mmol, 65%). H NMR (300.13 MHz, CDCl ): δ =
3
0
.87-0.92 (m, 3 H), 1.09-1.5 (m, 1 H), 1.26-1.38 (m, 3 H), 1.53 (s, 3 H, CH of one isomer), 1.54
3
(
s, 3 H, CH of another isomer), 1.81-1.89 (m, 2 H), 5.76 (bs, 4 H of (Z)-isomer), 5.78 (d, J=10.5
3
1
3
Hz, 2 H, of (E)-isomer), 5.79 (d, J=10.5 Hz, 2 H, of (E)-isomer), 7.18-7.33 (m, 5 H) ppm. C
NMR (75.48 MHz, CDCl ): δ = 13.9, 23.0, 26.8, 27.3, 27.9, 28.0, 32.4, 32.6, 37.9, 38.8, 44.29,
3
4
4.32, 121.8, 124.0, 124.2, 126.3, 126.4, 126.6 128.5, 134.6, 134.7, 144.9, 145.4 ppm. IR (neat)
−
1
+
ṽmax, cm : 2222 (CN). HRMS: calcd. for C H N [M ] 251.1669; found 251.1668.
18
21
4
-Butyl-1-(5-cyanopentyl)-4-phenylcyclohexa-2,5-dienecarbonitrile (4ac): Transparent
1
crystals. 263 mg (two diastereoisomers, (E)/(Z) = 4.1/1, 0.79 mmol, 71%). H NMR (300.13
MHz, CDCL ): δ = 0.88 (t, J=7.2 Hz, 3 H), 1.08-1.18 (m, 1H), 1.18-1.35 (m, 5 H), 1.49-1.55 (m,
3
2
H), 1.57-1.62 (m, 2H), 1.71-1.78 (m, 2 H), 1.81-1.87 (m, 2 H), 2.26 (t, J=6.9 Hz, 2 H of (E)-
isomer), 2.35 (t, J=6.9 Hz, 2 H of (Z)-isomer), 5.67 (m, 2 H), 5.84 (d, J=10.2 Hz, 2 H of (Z)-
13
isomer),), 5.92 (d, J=10.2 Hz, 2H of (E)-isomer), 7.18-7.32 (m, 5 H) ppm. C NMR (75 MHz,
CDCl ): δ = 13.88, 13.97, 16.87, 17.00, 22.99, 23.04, 23.69, 23.82, 25.03, 25.11, 26.82 27.46,
3
2
1
8.27, 28.41, 36.57, 36.83, 38.29, 39.54, 30.07, 40.25, 44.41, 44.45, 119.38, 121.03, 121.22,
22.58, 122.91, 126.82, 127.46, 128.27, 128.41, 135.80, 136.10, 144.63, 145.53 ppm. IR (KBr)
−
1
+
ṽmax, cm : 2243 (CN), 2231 (CN). HRMS: calcd. for C H N [M ] 332.2247; found 332.2249.
23
28
2
4
-Butyl-1-(6-ethoxy-6-oxohexyl)-4-phenylcyclohexa-2,5-dienecarbonitrile (4ad): yellow oil.
1
2
20 mg (two diastereoisomers, (E)/(Z) = 1.8/1, 0.58 mmol, 52%): NMR H (500.13 MHz,
CDCl ): δ = 0.87 (t, J=7.5 Hz, 3 H of (Z)-isomer), 0.88 (t, J=7.5 Hz, 3 H of (E)-isomer), 1.10-
3
1
.68 (m, 10 H), 1.23 (t, J=7.5 Hz, 3H of (E)-isomer), 1.24 (t, J=7.5 Hz, 3 H of (Z)-isomer), 1.72-
.79 (m, 2 H), 1.77-1.85 (m, 2 H), 2.24 (t, J=7.5 Hz, 2 H of (E)-isomer), 2.29 (t, J=7.5 Hz, 3 H
1
of (Z)-isomer), 4.08-4.14 (m, 2H), 5.71 (d, J=10.0 Hz, 2 H of (Z)-isomer), 5.73 (d, J=10.0 Hz, 2
H of (E)-isomer), 5.81 (d, J=10.0 Hz, 2 H of (Z)-isomer), 5.87 (d, J=10.0 Hz, 2 H of (E)-isomer),
13
7
.19 (t, J=7.5Hz, 1 H), 7.25 (d, J=7.5 Hz, 2 H), 7.32 (t, J=7.5 Hz, 2 H) ppm. NMR C (125.77
MHz, CDCl ): δ = 13.88, 13.82, 14.02, 22.87, 22.93, 23.98, 24.08, 24.40, 24.48, 26.68, 27.31,
3
2
8.63, 28.73, 33.84, 33.89, 36.47, 36.72, 38.13, 39.15, 40.15, 40.23, 44.28, 60.04, 60.06, 121.07,
21.13, 122.65, 122.91, 126.15, 126.28, 126.42, 126.47, 128.32, 128.37, 135.43, 135.75, 144.61,
1
1
7

ACCEPTED MANUSCRIPT
−
1
+
1
3
45.41, 172.25 ppm. IR (KBr) ṽmax, cm : HRMS: calcd. for C H O N [M ] 379.2506; found
25 33 2
79.2502.
trans-4-Butyl-1-(5-bromopentyl)-4-phenylcyclohexa-2,5-dienecarbonitrile
(trans-4ae):
1
Transparent crystals. 131 mg, (0.34 mmol, 30%). NMR H (400.13 MHz, CDCl ): δ = 0.89 (t,
3
J=7.2 Hz, 3 H), 1.20-1.35 (m, 4 H), 1.35-1.50 (m, 4 H), 1.70-1.78 (m, 2 H), 1.78-1.87 (m 4 H),
3
7
2
1
.34 (t, J=6.8 Hz, 2 H), 5.74 (d, J=10 Hz, 2 H), 5.90 (d, J=10 Hz, 2 H), 7.20 (t, J=7.2 Hz, 1 H),
1
3
.25 (d, J=7.2 Hz, 2 H), 7.31 (t, J=7.2 Hz, 2 H) ppm. NMR C (125.77 MHz, CDCl ): δ = 13.85,
3
2.95, 23.59, 26.76, 27.77, 32.24, 33.34, 36.82, 39.36, 40.20, 44.36, 121.15, 122.95, 126.21,
−
1
26.41, 128.42, 135.63, 145.49 ppm. IR (KBr) ṽmax, cm : 2224 (CN). HRMS: calcd. for
+
C H BrN [M ] 385.1400; found 385.1395.
22
28
cis-4-Butyl-1-(5-bromopentyl)-4-phenylcyclohexa-2,5-dienecarbonitrile
(cis-4ae):
1
Transparent crystals. 44 mg (0.11 mmol, 10%). NMR H (400.13 MHz, CDCl ): δ = 0.88 (t,
3
J=7.2 Hz, 3 H), 1.13-1.21 (m, 2 H), 1.31-1.40 (m, 2 H), 1.50-1.53 (m, 4 H), 1.79-1.94 (m 6 H),
3
.40 (t, J=6.8 Hz, 2 H), 5.72 (d, J=10 Hz, 2 H), 5.82 (d, J=10 Hz, 2 H), 7.15-7.26 (m, 1 H), 7.31
13
(
bs, 2 H), 7.32 (s, 2 H) ppm. NMR C (125.77 MHz, CDCl ): δ = 13.95, 23.03, 23.69, 27.44,
3
2
7.90, 32.33, 33.38, 36.58, 38.25, 40.36, 44.41, 121.11, 122.68, 126.56, 128.44, 128.50, 135.97,
−
1
+
1
44.67 ppm. IR (KBr) ṽmax, cm : 2225 (CN). HRMS: calcd. for C H BrN [M ] 385.1400;
22 28
found 385.1395.
trans-1-Butyl-4-cyclohexyl-4-phenylcyclohexa-2,5-dienecarbonitrile (trans-4ga): Colorless
1
oil. 110 mg (0.34 mmol, 31%). H NMR (400.13 MHz, CDCl ): δ = 0.84 (t, J=7.0 Hz, 2 H, 3H),
3
0
1
2
.91-1.00 (m, 2 H), 1.09 (tt, J =12.2 Hz, J =3.0 Hz, 1 H), 1.18 (tt, J =12.2 Hz, J =3.0 Hz, 2 H),
1 2 1 2
.25-1.37 (m, 4 H), 1.55-1.79 (m, 7 H), 1.90 (tt, J =12.2 Hz, J =3.0 Hz, 1 H), 5.77 (d, J=10.0 Hz,
1
2
H), 5.99 (d, J=10.0 Hz 2 H), 7.19 (tm, J=7.2 Hz, 1 H), 7.23 (dm, J=8.0 Hz, 2 H), 7.31 (tm, J=8
1
3
Hz, 2 H) ppm. C NMR (75.47 MHz, CDCl ): δ = 13.62, 22.41, 26.36, 26.38, 26.74, 27.69,
3
3
7.23, 39.97, 46.22, 47.86, 121.31, 124.00, 126.05, 126.41, 128.45, 134.16, 145.02 ppm. IR
−
1
(
KBr) ṽmax, cm : 2230 (CN). HRMS: calcd. for C H N [M+] 319.2295; found 319.2290.
23 29
−
4
-(1-Alkylcyclohexa-2,5-dienyl)benzonitrile (5). To a solution of anion 1-H sodium salt in
4’
liquid ammonia alkyl bromide (1÷1.5 equiv., Table 2) was added dropwise at –33 °C, then the
reaction mixture was treated as described above for dienone 2.
4
-(1-Butylcyclohexa-2,5-dienyl)benzonitrile (5a): Colorless oil. 190 mg (0.80 mmol, 36%).
1
H NMR (400 MHz, CDCl ): δ = 0.90 (t, J=7.2 Hz, 3 H), 1.18-1.28 (m, 2 H), 1.28-1.38 (m, 2 H),
3
1
.75-1.79 (m, 2 H) 2.67-2.70 (m, 2 H), 5.56 (dt, J =10.4 Hz, J =2 Hz, 2 H), 5.88 (dt, J=10.4 Hz,
1 2
1
3
J=3.6 Hz, 2 H), 7.46 (d, J=8.8 Hz, 2 H), 7.58 (d, J=8.8 Hz, 2 H) ppm. C NMR (75 MHz,
CDCl ): δ = 13.92, 23.04, 25.89, 26.95, 39.59, 44.26, 109.38, 118.93, 124.28, 127.40 131.38,
3
1
8

ACCEPTED MANUSCRIPT
−
1
+
1
2
31.88, 153.71 ppm. IR (KBr) ṽ , cm : 2225 (CN). HRMS: calcd. for C H N [M ]
max 17 19
37.1512; found 237.1510.
4
-(1-(6-ethoxy-6-oxohexyl)cyclohexa-2,5-dienyl)benzonitrile (5d). Pale yellow oil. 144 mg
1
(
0.36 mmol, 20%). H NMR (500.143 MHz, CDCl ): δ = 1.24 (t, J=7.0 Hz, 3 H), 1.24-1.31 (m, 2
3
H), 1.33-1.39 (m, 2 H), 1.59-1.65 (m, 2 H), 1.75-1.78 (m, 2 H), 2.27 (t, J=7.5 Hz, 2 H), 2.65-
.68 (bs 2 H), 4.11 (q J=7.0 Hz, 2 H), 5.54 (dm, J=10.5, 2 H), 5.89 (dt, J =10.5 Hz, J =3 Hz, 2
2
1
2
1
3
H), 7.44 (d, J=8.5 Hz, 2 H), 7.57 (d, J=8.5 Hz, 2 H) ppm. C NMR (125.76 MHz, CDCl ): δ =
3
1
1
4.12, 24.47, 24.75, 25.90, 29.45, 34.03, 3416, 39.59, 44.31, 60.05, 109.47, 118.94, 124.52,
−
1
27.47, 131.27, 131.94, 153.70, 173.67 ppm. IR (KBr) ṽmax, cm : 2228 (CN), 1732 (C=O).
+
HRMS: calcd. for C H N [M - C H ] 180.0808; found 180.0805. The compound decomposes
1
3
10
8
15
at HRMS, losing one 6-ethoxy-6-oxohexyl fragment.
4
-(1-(2-(1,3-Dioxolan-2-yl)ethyl)cyclohexa-2,5-dienyl)benzonitrile (5f): Colorless oil. 222
1
mg (0.79 mmol, 35%). H NMR (500.14 MHz, CDCl ): δ = 1.63-1.67 (m, 2 H), 1.87-1.90 (m, 2
3
H), 2.66 (bs, 2 H), 3.80-3.89 (m, 2 H), 3.89-3.98 (m, 2 H), 4.87 (t, J=5.0 Hz, 1 H), 5.50 (dm,
J=10.5, 2 H), 5.89 (dt, J =10.5 Hz, J =3 Hz, 2 H), 7.45 (d, J=8.5 Hz, 2 H), 7.56 (d, J=8.5 Hz, 2
1
2
1
3
H) ppm. NMR C (125.75 MHz, CDCl ): δ = 25.81, 29.42, 33.15, 43.82, 64.74, 104.29, 109.50,
3
−
1
1
18.89, 124.89, 127.39, 130.70, 131.91, 153.18 ppm. IR (KBr) ṽmax, cm : 2228 (CN). HRMS:
+
calcd. for C H NO [M - C H ] 251. 0946; found 251.0945. The compound decomposes with
1
6
13
2
2
6
the loss of mass equal to ethane.
-(1-Butyl-4-oxocyclohexa-2,5-dienyl)benzonitrile (7a): Yellow oil. 60 mg. H NMR (13
MHz, CDCl ): δ = 0.85 (t, 3 H), 1.12-1.25 (m, 2 H), 1.25-1.40 (m, 2 H), 2.01-2.10 (m, 2 H), 6.35
1
4
3
(d, J=10.1 Hz, 2 H), 6.82 (d, J=10.1 Hz, 2 H), 7.40 (d, J=8.5 Hz, 2 H), 7.60 (d, J=8.5 Hz, 2 H)
1
3
ppm. NMR C (125.75 MHz, CDCl ): δ = 13.65, 22.77, 26.35, 36.86, 48.88, 111.29, 118.16,
3
−
1
1
27.32, 129.12, 132.54, 145.53, 152.58, 185.44 ppm. IR (KBr) ṽmax, cm : 2228 (CN), 1666
+
(
CO). HRMS: calcd. for C H NO [M ] 251.1305; found 251.1304.
17
17
X-ray Diffraction Data:
Compound 2g: monoclinic, space group P2 /c, a = 15.4210(6), b = 8.3456(3), c =
1
3
–3
–1
1
1.4327(4) Å, β = 99.703(2)°, V = 1450.31(9) Å , ρ = 1.156 g cm , ꢀ = 0.069 mm , Z = 4,
calc
θmax = 26.0°, 2846 independent (R = 0.0335) and 2365 observed reflections [I >2σ(I)], R =
int
0
.0472, wR = 0.1597 (all data), S = 1.054.
2
Compound (E)-4gg: monoclinic, space group P2 /n, a = 11.8640(14), b = 9.3641(9), c =
1
3
–3
–1
1
9.265(2) Å, β = 105.658(4)°, V = 2060.9(4) Å , ρ = 1.114 g cm , ꢀ = 0.063 mm , Z = 4, θ
calc
max
=
25.1°, 3641 independent (R = 0.0775) and 2237 observed reflections [I >2σ(I)], R = 0.0468,
int
wR = 0.1566 (all data), S = 1.049.
2
1
9

ACCEPTED MANUSCRIPT
Compound (E)-4ac: orthorhombic, space group P2 2 2 , a = 8.3298(7), b = 9.4558(6), c =
1
1 1
3
–3
–1
2
6.372(2) Å, V = 2077.2(3) Å , ρ = 1.063 g cm , ꢀ = 0.062 mm , Z = 4, θ = 25.1°, 3625
calc max
independent (R = 0.0484) and 2461 observed reflections [I >2σ(I)], R = 0.0553, wR = 0.1838
int
2
(all data), S = 0.979. Parts of the cyanopentyl and butyl groups are disordered over two positions
with 62:38 and 75:25 ratio.
Compound (Z)-4ae: orthorhombic, space group Pnma, a = 18.6978(16), b = 7.4208(6), c =
3
–3
–1
1
5.1760(13) Å, V = 2105.7(3) Å , ρ = 1.219 g cm , ꢀ = 1.955 mm , Z = 4, θ = 25.1°, 1988
calc max
independent (R = 0.0384) and 980 observed reflections [I >2σ(I)], R = 0.0434, wR = 0.1851
int
2
(all data), S = 0.947.
Supporting Information (see footnote on the first page of this article): NMR spectra; X-ray
crystal data for compounds 2g, 4gg, 4ac and 4ae. CCDC-1453032 (for 2g), -1453033 (for 4gg), -
1
453034 (for 4ac) and -1453035 (for 4ae) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Authors would like to acknowledge the Multi-Access Chemical Service Center SB RAS for
spectral and analytical measurements and the Supercomputing Center of the Novosibirsk State
University (http://nusc.nsu.ru) for provided computational resources. Current work is a part of
CP SB RAS projects V.44.1.13 and V.44.5.8.
Declarations of interest
None.
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