Journal of Fluorine Chemistry 189 (2016) 7–12

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Journal of Fluorine Chemistry

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Reactions of thebaine derivatives with trifluoroacetyl acetylenes: [4

+2]-addition solely
Irina V. Sandulenko, Daria V. Semenova, Maria V. Zelentsova, Sergey K. Moiseev* ,
Andrey B. Koldobskii, Alexandr S. Peregudov, Ivan S. Bushmarinov, Valery N. Kalinin
Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova, 28, V-334, Moscow 119991, Russia

A R T I C L E I N F O A B S T R A C T

Article history:
Received 10 May 2016 Trifluoroacetyl acetylenes, highly reactive dienophiles and electrophiles, were used as the probe for study
Received in revised form 20 July 2016 competitive [4+2] vs nucleophilic addition reactions in thebaine series. Unlike thebaine itself that reacts
Accepted 21 July 2016 with these electron deficient acetylenes giving rise to the adducts resulted from the nucleophilic attack of
Available online 30 July 2016 the nitrogen at the alkyne carbon, the reactions of N-acyl-N-northebaines with trifluoroacetyl acetylenes
furnished the [4+2]-adducts solely. The last ones readily rearranged to the corresponding 3H-furo[4,3,2-
Keywords: fg][3]benzazocine derivatives. So, the use of N-acyl-N-northebaines as the starting materials in the
Trifluoroacetyl acetylenes reactions with acetylenic dienophiles provides the general methodology to avoid a formation of the
Thebaine
undesirable “nucleophilic” adducts typical for the reactions of the natural alkaloid thebaine.
Diels-Alder cycloaddition
ã 2016 Elsevier B.V. All rights reserved.
Azocines

1. Introduction 2. Results and discussion

Unlike the numerous Diels-Alder adducts of natural alkaloid
thebaine (1) with ethylenic dienophiles, the [4+2]-adducts of 1
with acetylenes are relatively rare. The reason is an ambiguity of
reactions of 1 with acetylenic dienophiles. Depending on both on
the nature of the acetylenic compound and the reaction conditions
(mainly, the solvent), the reactions can produce either “normal” [4
+2]-adducts 2 (Scheme 1, route a) [1] or the products of a
nucleophilic attack of the nitrogen atom in 1 on the acetylenic
carbon (route b) [2,3]. The last process dominates in polar solvents
and obviously proceeds via a formation of zwitterionic intermedi-
ate 3 (that may be represented by formulas 3a or 3b) [2,4] finally
leading to products 4 [2,4]. Various transformations of zwitterionic
intermediate 3 have been described [4] (see also [3]). A mild acid
hydrolysis of enol ethers 4 furnished ketones 5 [2,3].
The use of monosubstituted acetylenes facilitates the nucleo-
philic attack of the nitrogen atom leading to a formation of
anomalous adducts 4 [2,5,6]. The use of disubstituted acetylenes
facilitates a formation of “normal” adducts 2 [1].
* Corresponding author.
E-mail address: skm@ineos.ac.ru (S.K. Moiseev).
Fluorinated acetylenic ketones RCRC

CO

CF3 (R = H (6),
Me3Sn (7)) have been reported and proved to be very active
dienophiles in [4+2]-cycloaddition reactions [7,8]. From the other
hand, compounds 6 and 7 are very electron deficient acetylenes
due to the presence of the strong electron withdrawing COCF3
group. So, they must be highly susceptible to the nucleophilic
attack. Therefore, we have anticipated that acetylenes 6 and 7
could be used as the convenient model compounds for studying of
[4+2]-addition vs nucleophilic processes among the dienes relative
to compound 1.
In addition, one can see that the fluorinated adducts of general
formulae 8 (Scheme 2) which allegedly have to be formed as a
result of the [4+2]-cycloaddition reactions of diene 1 or its N(17)-
substituted derivatives with ketones 6 or 7 are structurally related
to thevinone (9), the adduct of 1 with methyl vinyl ketone. It should
be specially stressed that ketone 9 is the key intermediate in the
syntheses of so called Bentley’s compounds (10), one of the main
types of opioid receptor ligands that have found applications both
in human medicine and veterinary as well as pharmacological tools
[9–11]. So, preparations of the C(21)-fluorinated compounds
structurally related to ketone 9 along with disclosing chemical
properties thereof would be very desirable [12] because fluorinat-
ed compounds have a remarkable record in medicinal chemistry
[13] due to both very similar steric impact of hydrogen and fluorine
[14] and the influence of hydrogen substitution for fluorine on

http://dx.doi.org/10.1016/j.jfluchem.2016.07.015
0022-1139/ã 2016 Elsevier B.V. All rights reserved.
8 I.V. Sandulenko et al. / Journal of Fluorine Chemistry 189 (2016) 7–12

CH3 CH3 R2 CH3 R2

N N N
R1 R1
1 2
R C CR
(b)
O O
H3CO OCH3 H3CO OCH3 O
1 H3CO OCH3
3a 3b

(a) R1C CR2

CH3 R2 CH3 R2
CH3
N N N
R2 R1 R1

R1
O O O
H3CO OCH3 H3CO OCH3 H3CO O
2 4 5

Scheme 1. Reactions of 1 with acetylenes: [4+2]-addition (a) vs nucleophilic attack (b).

Scheme 2. [4+2]-Fluorinated adducts (8) reported herein and their structural similarity to thevinone (9); 9 as the key precursor of Bentley’s compounds (10).

CH3 H CH3 H
N O N O

HC C-CO-CF3 (6) CF3 H CF3

THF
H3CO O OCH3 O
H3CO O
11 (16%) 12 (traces)
CH3
N

CH3 H CH3 H
N O N O
O
H3 CO OCH3 H
CF3 CF3
1

H3CO O OCH3 O
H3CO O
Me3Sn C C-CO-CF3 (7) 11 (36%) 12 (1.5%)
THF
CH3 CH3
N N
SnMe3 H
O O

CF3 CF3
O O
H3 CO OCH3 H3 CO OCH3
8a (2%) 8b (traces)

Scheme 3. Reactions of 1 with fluorinated acetylenes 6 and 7.

lipophilicity, metabolism, conformational and other properties of
the molecules [13,15].
First of all, we tried to clarify whether [4+2]-addition process in
the reactions of 1 with very reactive fluorinated dienophiles 6 or 7
can compete with the nucleophilic attack of the nitrogen atom on
the acetylenic carbon (Scheme 3).
The reaction of 1 with 6 in THF solution furnished fluorinated
ketone 11 (16%), a product of the nucleophilic attack. The
molecular structure of 11 (from MeOH) was elucidated by a
single-crystal X-ray study [16]. In addition to 11, the traces of
diketone 12 (see below for the details of its structure elucidation)
were detected in the reaction mixture (LC–MS).
 I.V. Sandulenko et al. / Journal of Fluorine Chemistry 189 (2016) 7–12
To hinder the nucleophilic attack of the nitrogen at the terminal
acetylenic carbon atom, fluorinated acetylene 7 bearing both the
bulky and electron donating Me3Sn group was used in the reaction
with 1. But the acidic workup of the reaction mixture for the
destannylation again afforded 11 (36%) as the main product
accompanied by minor amounts of not only ketone 12 but also [4
+2]-cycloaddition products 8a and 8b. The last three products were
separated by TLC with the exception of 8b that was isolated in
traces as the mixture with 8a (in a 8a: 8b = 2: 5 molar ratio
according to 1H and 19F NMR data). Compound 12 was also
obtained in 30% yield (Scheme 4) by a hydrolysis of 11 with 37% aq.
HCl in MeOH (1:17 vol ratio).
According to the LC–MS data, products 8a and 8b are the 1:1
adducts of 1 with 7, with 8b being free from the Me3Sn group (m/
z = 596 [M+1]+, 598 [;+1]+ for 8a indicative for the presence of Sn;
m/z = 434 [M+1]+ for 8b). 1H NMR spectra of the both compounds
exhibit the AB-system peaks (d about 5.5 and 6.4 ppm) character-
istic of the cis-etheno bridge indicating the presence of 6,14-endo-
ethenomorphinane core in the structures of both 8a and 8b. In
addition, both spectra were found to be very similar in the region of
4.5–7.0 ppm to that ones of compounds 8c and 8d (see below), the
“normal” Diels-Alder adducts of the N-substituted derivatives of 1
with 7, indicating the close similarity in the frameworks of
molecules 8a-d. Thus, compounds 8a and 8b were attributed with
the molecular structures as depicted.
As for 12, its structure was deduced as follows. Prepared by an
acid hydrolysis of 11, compound 12 has lack of one of the methyl
groups. This was proved by the difference in the masses of the
molecular ions derived from 11 (m/z = 434 [M+1]+) and 12 (m/
z = 420 [M+1]+) that corresponds to CH2 group. The molecular
structure of diketone 12 was elucidated by 1H, 13C and 19F NMR
spectra as well as the correlation spectroscopy data (COSY, HMQS,
HMBC). The 1H NMR spectrum of 12 exhibited signals for only one
OMe and one NMe groups, with the chemical shift for the residual
OMe group (d 3.89 ppm) being characteristic of the 3-OMe. 13C
NMR spectrum of 12 showed the presence of two C¼O group
signals (d 193.2 and 177.3 ppm), with the last one being quartet (2JC,
F = 32 Hz) indicating its CO

CF3 group affiliation. Hence, the peak
at d 193.2 corresponds to C(6) = O. In addition, the 1H NMR
spectrum of 12 exhibited seven signals for the hydrogens attached
to sp2 hybridized carbon atoms at d 5.06–7.78 ppm, one
characteristic signal at d 5.01 (br. s, H(5)), and six signals for the
aliphatic hydrogens. The last ones can obviously be attributed to
2H(15), 2H(16), and 2H(10). The presence of two hydrogens at C
(10) was deduced from the weak cross-peak in 1H,1H-COSY
spectrum between the signal at d 6.77 ppm (d, H(1)) and the
signal at d 3.59 ppm (H(10b)) which is appeared in the spectrum as
the broadened doublet with a great spin–spin coupling constant
value (2J10a,10b = 20.3 Hz) due to the presence of the heminal
hydrogen H(10a). Two of the seven hydrogen atoms at the sp2
hybridized carbons (d 6.77 and 6.72 ppm) are obviously the
aromatic ones (H(1) and H(2), respectively). Thus, the rest five
characteristic olefinic hydrogens can be localized only at C(7), C(8),
C(9), C(18), and C(19) (d 6.00, 7.26, 6.43, 7.79 and 5.24 ppm,
CH 3 H CH3 H
N O
CF3
H2 O
HCl, MeOH
O O
H 3CO OCH 3
11
Scheme 4. The acid hydrolysis of ketone 11 and an interconversion of the conformers of resulting diketone 12.
9
respectively, all dublets). The 3J18,19 value (12.3 Hz) indicates the H
(18) and H(19) hydrogens are trans.
It should be noted that the 19F NMR spectrum of 12 exhibited
only one signal for the fluorine atoms. Meanwhile, both the 1H and
13
C NMR spectra of 12 exhibited double sets of the signals with very
similar chemical shifts for every hydrogen and carbon atoms (in
2:1 ratio in the 1H NMR spectrum). We anticipated that this is due
to the existence of 12 in the solution as a mixture of two
conformers with the same shielding of fluorine nuclei of the EF3
groups in both conformers. Taking into account the rigid structure
of the partially hydrogenated epoxyphenanthrene scaffold in 12
along with the flexibility of the alkyl substituent at C(13), an
existence of the conformers may be only due to the hindered
rotation of the conjugated enone moiety around the C(19)–C(20)
single bond that can be depicted by structures 12a and 12b
(Scheme 4).
Specifically, as one can see from the 1H NMR spectrum of 12, it is
the H(19) atom that has the most difference in the chemical shifts
(0.17 ppm) of the respective hydrogens signals in the two
conformers. This finding counts in favor of the above assumption.
Indeed, the 1H,19F-HOESY spectrum of 12 shows the strong cross-
peak between the signals of the CF3 group and H(19) of the major
conformer, whereas the corresponding cross-peak for the minor
conformer is rather weak. So, it can be deduced that the structure
of the major conformer matches formulae 12a with the crowded
CF3 group and H(19), whereas the minor conformer matches
formulae 12b in which CF3 and H(19) are more remote from each
other.
Thus, the above results showed that neither high dienophlic
activity of acetylenes 6 and 7 nor both bulkiness and electron
donating effect of the Me3Sn group in 7 could effectively prevent
the nitrogen in 1 from the nucleophilic attack on the fluorinated
acetylenes 6, 7. So, we changed the approach to a preparation of the
desirable [4+2]-adducts by decreasing a nucleophilicity of the
nitrogen in 1. Therefore, N-acyl derivatives of diene 1 were used for
further reactions with acetylenes 6 and 7.
N-cyclopropylcarbonyl substituted diene 13 [17] smoothly
reacts with 6 in PhCl or THF solutions under mild conditions
(Scheme 5). The exothermic reactions took only a few minutes at
5  C. Evaporation of PhCl at reduced pressure followed by keeping
of the residue at 100  C for 1 h gave raise to trifluoroacetylaryl
substituted 3H-furo[4,3,2-fg][3]benzazocine derivative 14 in 75%
yield. If THF was used as the solvent, evaporation of the reaction
mixture to dryness at the temperature below 40  C followed by
stirring of the oily residue in MeOH led to a formation of colorless
crystals of pure [4+2]-adduct 8e (11%). In a separate experiment,
the methanol solution of the above-mentioned residue obtained
after evaporation of THF was refluxed for 1 h. Cooling the solution
down to 5  C caused a precipitation of 8-methoxy substituted 7,8-
saturated [4+2]-adduct 15 (15%).
Benzazocine derivative 14 is a product of the intramolecular
rearrangement of “normal” [4+2]-adduct 8e (Scheme 6). It is
known that the “normal” Diels-Alder adducts of 1 with acetylenic
dienophiles are prone to the thermal rearrangement to the
18
CH3 H
N O CF3
N
19
20 21
H CF3 H
O
H3 CO O O
H3 CO O
12a 12b
10 I.V. Sandulenko et al. / Journal of Fluorine Chemistry 189 (2016) 7–12

HO CF3
O O H3CO H
N N
OCH3
O O N

CF3 CF3
O O
H3CO OCH3 H3CO OCH3
8e (11%) 15 (15%)
H3 CO O
17 (31%)
6, THF, < 40°C
1) 6, THF,< 40°C
LiAlH4
2) CH3OH, reflux, 1 h
THF, 2 h
O O
O H3CO CF3
N
N
6, PhCl, 100°C O
O
N
O CF3
H3 CO OCH3 O OCH3
1b H3 CO
14 (75%)
7, a) PhCl, 90°C O
EtOOC b) THF, reflux H3 CO
COOEt
CH3 CN, 50-55°C O O

O N N
SnMe3
N O O
COOEt
CF3 CF3
COOEt O OCH3 O
H3 CO H3CO OCH3
O 14 8d
H3CO OCH3 a) (61%) a) (6%)
16 (77%) b) (91%) b) (4%)

Scheme 5. Reactions of N-cyclopropylcarbonyl substituted diene 13 with highly electron deficient acetylenes.

dienophiles that lack the cyclohexadienyl ring [18] (see also

1
R R
N N
O O
CF3
O O
H3 CO OCH 3 H 3 CO
Scheme 6. The intramolecular rearrangement of acetylenic [4+2]-adducts to
azocine derivatives.
corresponding 3H-furo[4,3,2-fg][3]benzazocines [1,6]. The rear-
rangement is the retro Diels-Alder reaction motivated by an
aromatization of the cyclohexadienyl moiety in [4+2]-adducts
derived from the reactions of 1 with acetylenic dienophiles. So, it
hardly proceeds with the adducts derived from ethylenic
1 [19,20]). The temperature at which the rearrangement begins to
contribute notably to the products make-up depends on the nature
of the acetylenic dienophile. For example, the adducts of 1 with
dimethyl acetylene dicarboxylate or ethyl propiolate smoothly
CF3 rearranged at 140  C [1]. A formation of the corresponding
OCH 3 benzazocines suggested strongly that the “normal” Diels-Alder
products were initially formed in the reactions of 1 with methyl
propiolate [5] or 1,2-bis(trifluoromethyl)acetylene [6], but the
adducts rearranged on prolonged heating at lower temperatures
than reported by Rapoport et al. [1]. A reason for the easy
rearrangement of [4+2]-adduct 8e to benzazocine derivative 14 is
the strong electron withdrawing effect of the COCF3 group. For
comparison, a reaction of 13 with diethyl acetylene dicarboxylate
(MeCN, 50–55 E, 3 h) furnished [4+2]-adduct 16 in 77% yield

O O O
O O
O N N
N
7, a) PhCl, 70°C SnMe3
b) THF, reflux O
O
CF3
CF3
O O H3 CO O OCH3
H3CO OCH3 H3CO OCH3 19
18 8c
a) (14%) a) (72%)
b) (20%) b) (74%)
6, THF, 5-20°C O
O
O O N
SnMe3
O O O
N N

O O CF3
O OCH3
H3 CO
CF3 CF3
O 20 (traces)
H3CO OCH3 H3 CO O OCH3
8f (47%) 19

Scheme 7. Reactions of N-Boc-substituted diene 18 with acetylenes 6,7.

 I.V. Sandulenko et al. / Journal of Fluorine Chemistry 189 (2016) 7–12
(Scheme 5); no the rearrangement product was detected in the
reaction mixture.
A formation of 15 is a result of the Michael addition of MeOH to
the conjugated enone moiety in 8e. The molecular structure of 15
was elucidated by a single-crystal X-ray study [16] and proved to be
rather unusual. The MeO group at C(8) was found to occupy the a
position while the CF3CO group at C(8) is b oriented. Unlike the
thermally unstable Diels-Alder adduct 8e, compound 15 has single
C(7)-C(8) bond. A lack of the cyclohexa-1,4-diene moiety in its
structure prevents 15 from the further rearrangement to the
benzazocine derivative. Therefore, the reaction of 8e with MeOH
demonstrates that nucleophiles can be used to prevent the
rearrangement of the Diels-Alder adducts of the general formulae
8 to the corresponding benzazocine derivatives.
Amide 14 was reduced with LiAlH4 in THF (Scheme 5). We
succeeded in isolating only amine 17 (31%) from the reaction
mixture. The structure of 17 was confirmed by X-ray method [16].
The configuration of the chiral center at C(6) in 17 relates to that
one at C(9) in natural 1 and, therefore, is R. So, the configuration of
a new chiral center aroused in the side chain of the aryl ring was
found to be R.
The reactions of 13 with 7 proceed slower and under more
severe conditions than those with 6. The reaction in chlorobenzene
(90 E, 24 h) furnished benzazocine derivative 14 (61% yield) along
with adduct 8d (6%) (Scheme 5). The same products were obtained
from the reaction in THF (24 h, reflux) in 91% and 4% yields,
respectively. Product 14 was found to exist in a chloroform solution
as the mixture of two conformers in about 2:1 ratio (1= and 19F
NMR).
The reactions of 18 [21] with 7 in PhCl (4 h, 65–75  C) or THF
solutions (6.5 h, reflux) gave rise to the mixture of [4+2]-adduct 8c
(in 14% and 20% yields, respectively) and Me3Sn-free benzofur-
oazocine 19 (72% and 74% yields, respectively) (Scheme 7). The
products were separated by TLC on silica gel. The structure of 8c
was refined with 1H, 13C and 19F, NMR-spectroscopy, along with
1 1
H, H-COSY, HMQS, HMBS, NOESY experiments and finally
elucidated by a single-crystal X-ray study [16]. According to the
1
H and 19F NMR data, compound 19 exists in the CDCl3 solution as
the mixture (10: 11) of two conformers due to a presence of the
amide function.
Likewise 14, compound 19 is a product of the intramolecular
rearrangement of the initially formed [4+2]-adduct of 18 with 7
(Scheme 6). It should be stressed that we found out the traces of
stannylated benzazocine 20 in the reaction mixture formed at the
earlier stage of the reaction of 18 with 7. Small quantities of 20
were isolated by TLC on silica gel as the inseparable mixture with
8c. In addition to the signals of 8c, the 1H NMR spectrum of the
mixture exhibits another peak set very similar to that one of 19
excepting the lack of the downfield peak for H(8) along with the
presence of the characteristic peak for Me3Sn group. In addition,
the LC–MS data also indicate the presence of the Me3Sn group in 20
(MS (ESI): m/z = 626 and 628 [M-(C(CH3)3)]+). The presence of 20 in
the reaction mixture indicates that adduct 8c rearranges to the
benzazocine derivative, at least partly, with a retention of the
Me3Sn group via the intermediate formation of 20 followed by the
destannylation of the last one yielding 19. From the other hand, we
have no proof that the rearrangement 8c ! 19 proceeds via the
intermediate formation of destannylated adduct 8f.
Alkyne 6 reacts with 18 in THF notably easier than does 7
(Scheme 7). The reaction proceeds at 5–20  C for a few minutes.
Evaporation of the solvent at room temperature resulted in the
solid comprised the mixture (1H and 19F NMR) of adduct 8f and
rearranged adduct 19 in 11:3 ratio (19F NMR). The solid was stirred
with MeOH leading to a precipitation of pure product 8f in 47%
yield. 1H and 19F NMR spectra disclosed that 8f exists in the CDCl3
solution as the 3:5 mixture of two conformers.
11
Unlike stannylated adducts 8c,d, Me3Sn-free adducts 8e,f were
found to be insufficiently stable and slowly rearrange to azocines
14, 19 even in a solid state. Storage of both 8e and 8f at room
temperature for a few months led to pure 14 or 19, respectively (1H
NMR).
So, N-acyl substituted derivatives of N-northebaine 13 and 18
react with trifluoroacetyl acetylenes giving rise to the “normal” [4
+2]-adducts which undergo the intramolecular rearrangement
furnishing 3-(trifluoroacetyl)aryl substituted 3H-furo[4,3,2-fg][3]
benzazocines. To the purpose, the method for preparation of
trifluoroacetyl substituted azocine derivatives by the intramolec-
ular rearrangement of the [4+2]-adducts of 1,3-dienes with
trifluoroacetyl acetylenes have been reported [22]. The non-
fluorinated 3H-furo[4,3,2-fg][3]benzazocines prepared from the [4
+2]-adduct of 1 with an ethylenic dienophile [23] have been found
to exhibit antidepressant and analgesic activities [24].
3. Conclusion
In conclusion, unlike thebaine (1) which reacts with electron
deficient acetylenes giving rise to the adducts resulted from the
nucleophilic attack of the nitrogen at the alkyne carbon, use of the
N-acylated derivatives of N-northebaine (13, 18) directs the
reactions with the acetylenic dienophiles to a formation of the
“normal” Diels-Alder type adducts solely. However, the [4+2]-
adducts of the trifluoroacetyl acetylenes were proved to be rather
labile and rearrange to (R)-4,5,6,7-tetrahydro-6-(3-trifluoroacetyl-
4-methoxyphenyl)-10-methoxy-3H-furo[4,3,2-fg][3]benzazo-
cines.
Acknowledgments
Authors acknowledge Dr. V. I. Kadentsev and MSc D. B. Eremin
(Institute of Organic Chemistry, Russian Academy of Sciences,
Moscow) for registration and discussion of the HRMS spectra and
Dr. A. F. Smol’yakov (Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow) for X-ray study of
compound 11.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
jfluchem.2016.07.015.
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