Synthesis of 1,2-Dihydropyrimidine-2-carboxylates via Regioselective Addition of Rhodium(II) Carbenoids to 2H-Azirine-2-carbaldimines

Article abstract of DOI:10.1021/acs.joc.7b02484

An efficient two-step procedure imine formation/azirine-carbenoid coupling has been developed for the preparation of 1,2-dihydropyrimidines from azirine-2-carbaldehydes, primary amines, and diazo carbonyl compounds under Rh(II) catalysis. The formation of 1,2-dihydropyrimidines involves 100% regioselective addition of the rhodium carbenoid to endocyclic nitrogen atom of the 2H-azirine-2-carbaldimine. According to the DFT calculations the reaction proceeds via dissociation of the metal-bound complex of the azirinium ylide to metal-free azirinium ylide, ring-opening of the latter to give a 1,5-diazahexa-1,3,5-triene, followed by 1,6-cyclization. The 1,2-dihydropyrimidines with two different electron-withdrawing substituents at the C² position can undergo in solution inversion of configuration of the stereogenic center at C² via the N¹-C² bond cleavage/rotation around the N-C single bond/1,6-cyclization sequence.

Full text of DOI:10.1021/acs.joc.7b02484

Subscriber access provided by READING UNIV
Article
Synthesis of 1,2-Dihydropyrimidine-2-carboxylates via Regioselective
Addition of Rhodium(II) Carbenoids to 2H-Azirine-2-carbaldimines
Mikhail Sergeevich Novikov, Nikolai V. Rostovskii, Alexander N. Koronatov, Kirill
V. Zavyalov, Grigory V. Zubakin, Alexander F. Khlebnikov, and Galina L. Starova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02484 • Publication Date (Web): 13 Nov 2017
Downloaded from http://pubs.acs.org on November 18, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
The Journal of Organic Chemistry
1
Synthesis of 1,2-Dihydropyrimidine-2-carboxylates via Regioselective
2
3
4
Addition of Rhodium(II) Carbenoids to 2H-Azirine-2-carbaldimines
5
6
7
Mikhail S. Novikov,* Nikolai V. Rostovskii, Alexander N. Koronatov, Kirill V. Zavyalov,
Grigory V. Zubakin, Alexander F. Khlebnikov, Galina L. Starova
8
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
St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg,
199034 Russia
Graphical abstract
CO2R5
N2
NO
R4
RhLn
CO2R5
R4
R3
N
R3
N
O
N
R2
R1
R3
R3NH2
N
R2
R1
LnRh
CO2R5
R4
R2
R1
R2
R1
CO2R5
R4
N
N
N
24 examples
yield up to 83%
YES
ABSTRACT: An efficient two-step procedure “imine formation/azirine−carbenoid coupling” has
been developed for the preparation of 1,2-dihydropyrimidines from azirine-2-carbaldehydes,
primary amines and diazo carbonyl compounds under Rh(II)-catalysis. The formation of 1,2-
dihydropyrimidines involves 100% regioselective addition of the rhodium carbenoid to
endocyclic nitrogen atom of the 2H-azirine-2-carbaldimine. According to the DFT calculations
the reaction proceeds via dissociation of the metal-bound complex of the azirinium ylide to
metal-free azirinium ylide, ring-opening of the latter to give a 1,5-diazahexa-1,3,5-triene,
followed by 1,6-cyclization. The 1,2-dihydropyrimidines with two different electron-
withdrawing substituents at the C2 position can undergo in solution inversion of configuration of
the stereogenic center at C2 via “the N1−C2 bond cleavage/rotation around the N−C single
bond/1,6-cyclization” sequence.
Introduction
The pyrimidine ring system has wide occurrence in natural, as well as in numerous synthetic
molecules exhibiting a wide range of pharmacological activities.1 Among the compounds
containing the dihydropyrimidine moiety, there are derivatives with vasodilative and
antihypertensive,2 kinesin spindle protein inhibitory,3 and anti-mycobacterial activity.4 The 3,4-
dihydropyrimidines, being more readily accessible, have been more studied. They are usually
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 22
1
2
3
4
5
6
7
8
synthesized by the condensation of α,β-unsaturated carbonyl compounds with amidines and
related compounds.2a,c,5 In contrast, the range of known 1,2-dihydropyrimidines are not so
extensive due to the lack of general methods for their preparation. Synthetic applications and
biological activity of these compounds have practically not been studied. De La Hoz and Pardo
reported the synthesis of a 1,2-dihydropyrimidine derivative, containing an ester group at the C2
atom, by ring expansion of an N-vinylpyrazolium salt (Scheme 1, reaction 1).6 Another approach
to 1,2-dihydropyrimidines involves the generation of the 1,5-diazahexatriene intermediate A and
its subsequent 1,6-cyclization (Scheme 1, reaction 2). Diazatriene A could be prepared by the
condensation of a 4-amino-substituted 1-azabuta-1,3-diene with a carbonyl compound7 or by
condensation of 2,2-dihydroperfluorocarbaldehydes with a carbonyl compound and ammonia.8
The use of this method is limited, however, by the availability of 1,2-dihydropyrimidines with
electron-donating substituents at the C2 position.9 In this work we have developed a new
approach to 1,5-diazahexatriene intermediates C, as precursors for C2-functionalized 1,2-
dihydropyrimidine derivatives, by means of a carbenoid-mediated ring-opening in azirine-2-
carbaldimines B (Scheme 1, reaction 3). The use of acceptor-acceptor and donor-acceptor
rhodium(II) carbenoids in this reaction, which could be generated from readily available diazo
compounds, would allow the introduction of CO2R, CONR2, CN, CF3 functional groups at the C2
position of the pyrimidine system. The formation of the 2-azabuta-1,3-diene fragment from the
azirine moiety in reactions of aryl, alkyl and halogeno-substituted azirines,10 and azirine-2-
carbaldehydes was previously reported.11 These reactions were assumed to occur via the
formation and ring-opening of azirinium ylides.12 The problem that could arise here is a change
of the reactive center in compound B from azirine nitrogen to the more nucleophilic imine
nitrogen atom which can bound with the carbenoid to give azomethine ylide13 and then
undesirable products of its transformation. In particular, an electrophile such as diphenylketene
reacts exclusively with the exo-imino group of 2H-azirine-2-carbaldimines to give 2H-azirin-2-
ylazetidin-2-ones.14 To our knowledge, the reactions of rhodium(II) carbenoids with substrates
containing two and more sp2 hybridized nitrogen atoms are unknown.
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
ACS Paragon Plus Environment

Page 3 of 22
The Journal of Organic Chemistry
1
2
Scheme 1. Synthesis of 1,2-Dihydropyrimidines
3
4
5
6
7
8
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
Herein, we report the reaction of azirine-2-carbaldimines with diazo carbonyl compounds
under Rh(II)-catalysis as a synthetic route to novel 1,2-dihydropyrimidines. Theoretical and
experimental evidence for “1,2-dihydropyrimidine − 1,5-diazahexa-1,3,5-triene” ring-chain
tautomerism in 2,2-diacceptor-substituted 1,2-dihydropyrimidines and the ways for their
formation from azirine-2-carbaldimines and rhodium(II) α-carbonyl carbenoids are presented in
the second and third part of the work.
Results and Discussion
We initiated our studies by investigating the reaction of azirine-2-carbaldimines 2a−q with diazo
compound 3a (Table 1) in the presence of catalytic amounts of Rh(II) carboxylates as the most
commonly used catalysts for the decomposition of α-diazo esters to generate metal-stabilized
carbenoids. Aldimines 2a−q were prepared by the condensation of equimolar amounts of
aldehydes 1a−e and primary amines in the presence of molecular sieves in anhydrous benzene at
room temperature. Aldimines 2a−q are sensitive to hydrolysis and they were used without
further purification. The completeness of the conversion of the aldehydes to aldimines was
1
checked by H and 13C NMR spectra (Supporting Information). The reactions of azirines 2a−q
with 1.2−1.3 equiv of diazo compound 3a were carried out in refluxing 1,2-dichloroethane
(DCE) in the presence of Rh2(esp)2 (1 mol %) and gave pyrimidines 4a−q (Table 1). The use of
Rh2(OAc)4, Rh2(Oct)4, and Rh2(Piv)4 is also possible but leads to a slight decrease in yield of
pyrimidines 4 (by 5−10%) and slight tarring of the reaction mixtures. The yields of compounds 4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 22
1
2
3
4
5
6
are generally good, with the exception of pyrimidines 4f,q, which are derived from sterically
hindered azirines 2f,q. Aryl, alkyl and sulfonyl substituents at the imine nitrogen of compounds
2 tolerate the reaction conditions.
7
8
9
Table 1. Scope of Azirines 2a
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
N2
R3
F3C
CO2Et
R3
R2
R1
R1
O
R2
N
3a
R3NH2
N
R1
CF3
R2
N
molecular
sieves
r.t.
Rh2(esp)2 (1 mol%)
N
N
CO2Et
4a q
DCE, 84
C
1a e
2a q
Cl
Cl
N
Br
Ph
N
N
N
CF3
CF3
CO2Et
4b (72%)
CF3
CO2Et
4c (71%)
CF3
CO2Et
4d (63%)
Ph
N
Ph
N
Ph
N
Ph
N
CO2Et
4a (69%)
OMe
MeO
CF3
N
N
N
N
CF3
CF3
CF3
CO2Et
4g (59%)
Ph
N
Ph
Ph
N
CO2Et
CO2Et
4f (31%)
4e (66%)
Ph
Ph
N
N
N
CF3
N
CF3
CF3
CF3
N
Ph
Ph
N
Ph
N
CO2Et
CO2Et
CO2Et
Ph
N
CO2Et
4k (68%)
4j (68%)
4i (57%)
4h (72%)
Cl
Me
Cl
O
S
N
N
O
CF3
CO2Et
CF3
N
N
Ph
N
Cl
CO2Et
4n (83%)
CF3
CO2Et
Ph
N
Cl
Cl
4m (73%)
4l (81%)
Cl
Cl
Me
Ph
N
N
N
N
CF3
CF3
CF3
CO2Et
4q (56%)
N
N
CO2Et
4o (60%)
CO2Et
MeO
4p (63%)
a Yields of 4 are calculated on azirinecarbaldehyde 1.
Next, the substrate scope with respect to the diazo compound was evaluated (Table 2). The
reactions of azirine 2b with diazo esters 3b−f, diazo keto ester 3g and diazo ketone 3h were
performed, and the corresponding dihydropyrimidines 4r−x were isolated in good yields. A
slight decrease in product yield was observed in the reaction of diazo keto ester 3g, in which 3
ACS Paragon Plus Environment

Page 5 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
equiv of the diazo compound had to be used to achieve full conversion of the azirine. It is
known that the Rh(II)-catalyzed reaction of α-diazo keto esters and α-diazo ketones with aryl-
and alkyl-substituted 2H-azirines gives 2H-1,4-oxazines, the products of 1,6-cyclization of
oxazapolyene intermediates.10a,b It was found, however, that the reactions of diazo compounds 3g
and 3h with azirinecarbaldimine 2b do not provide 2H-1,4-oxazine derivatives: 1,6-cyclization
of oxadiazatetraene intermediates occurs exclusively across the C=N bond to give
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
1
dihydropyrimidine derivatives. The structures of dihydropyrimidines 4a−x were verified by H,
13C NMR and HRMS spectra, and the structure of pyrimidine 4r was confirmed by X-ray
analysis (Figure S-1, Supporting Information).15
Table 2. Scope of Diazo Compounds 3a
a Yields of 4 are calculated on azirinecarbaldehyde 1a.
The decrease in yield of pyrimidine 4w could be explained by its side reaction with the
rhodium carbenoid derived from 3g, but we failed to isolate products of these reactions from the
reaction mixture. However, when pure pyrimidine 4b was reacted under standard conditions with
diazo compound 3a in the presence of Rh2(esp)2 (1 mol%) a 1.3:1 mixture of cyclopropanes
endo,exo-5b and exo,exo-5b was isolated in 97% yield (Scheme 2). The relative configurations
of the stereogenic centers in both cyclopropapyrimidine isomers were established by X-ray
diffraction analysis (Figures S-2, S-3, Supporting Information).15 While studying the stability of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 22
1
2
3
4
5
6
7
8
these compounds we found that heating of pure cyclopropane exo,exo-5b in DCE for 11 h gave
pyrimidine 6b as a 1:1 mixture of diastereomers RS,RS-6b and RS,SR-6b in quantitative yield.
Under the same conditions the conversion of isomer endo,exo-5b to 6b was only 40%, but the
reaction was completed in toluene at 150 °C in 4 h. Interestingly, that when both cyclopropanes
endo,exo-5b and exo,exo-5b were still in the reaction mixture after their synthesis and were not
isolated, they isomerize to 6b much faster. Thus, conversion of mixture 5b to 6b occurred
completely in 3 h under reflux of the reaction mixture in DCE, the yield of pyrimidine 6b after
chromatographic purification being 96% (Scheme 2).
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
Scheme 2. Rh2(esp)2-Catalyzed Reaction of Pyrimidine 4b with Diazo Compound 3a
Compound 6b, containing two chiral centers, was used to study ring-chain tautomerism of
the 1,2-dihydropyrimidine system. Isomer RS,RS-6b was obtained in pure form from a
diastereomeric mixture of 6b by crystallization. The relative configuration of the chiral centers in
this compound was established by X-ray diffraction analysis (Figure S-4, Supporting
Information).15 It was found that dihydropyrimidine RS,RS-6b undergoes epimerization in CDCl3
solution to give an 1:1 mixture RS,RS-/RS,SR-6b in several minutes at room temperature. As the
compounds containing a 2-aryl/hetaryl-3,3,3-trifluoropropanoate chiral fragment are known to be
configurationally stable at room temperature16 we assumed that the observed epimerization of
RS,RS-6b involves the change of the configuration of the C2 atom of the dihydropyrimidine ring
and occurs via a “N1−C2 ring-opening to 1,5-diazahexatriene/rotation around the single C−N
bond /cyclization” sequence (Scheme 3). To verify this hypothesis, we performed quantum-
chemical calculations (DFT B3LYP/6-31+G(d,p), PCM for 1,2-dichloroethane) of the 1,2-
dihydropyrimidine ring-opening using pyrimidine R-4y as a model structure (Scheme 3).
According to the calculations the ring-opening of compound R-4y occurs non-torqueselectively:
ACS Paragon Plus Environment

Page 7 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
the barriers for ‘inward’ and ‘outward” rotation of the CF3 group are practically equal (ꢀꢀG≠ 0.4
kcal mol-1). Calculated parameters for enantiomerization of R-4y through E-diazahexatriene E-7
are presented in Scheme 3. The barrier for pyrimidine ring-opening of R-4y to diazahexatriene 7
(TS1) proved to be only 15.6 kcal mol-1. The ring-opening is the rate-determining stage since the
transition state energy for the rotation around the C4−N5 bond in diazahexatriene 7 (TS2) is lower
than that for TS1 by 7.4 kcal mol-1.
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
Thus, the experimental and calculation results reveal that 1,2-dihydropyrimidines having
two electron-withdrawing substituents at the C2 are configurationally labile systems in solution
at room temperature, existing in equilibrium with stereoisomeric dihydropyrimidines and less
stable open-chain 1,5-diazahexatriene forms. Such isomerization of 1,2-dihydropyrimidines was
observed for the first time, while the 2Н-1,3-oxazine ring-opening across the C2−O bond into 1-
oxa-5-aza-1,3,5-triene systems is a well-known process.11a
Scheme 3. Calculated Parameters for Enantiomerization of Model Dihydropyrimidine R-4y
(ꢀG≠, kcal mol-1)
Possible pathways for the formation of 1,2-dihydropyrimidine 4z in the model reaction of
azirinecarbaldimine 2r with methyl 2-diazo-3,3,3-trifluoropropanoate (3i) in the presence of
dirhodium tetraformate are presented in Scheme 4. When analyzing the reaction mechanism, we
tried to clarify two points: a) the reason for regioselective addition of the carbenoid to the azirine
nitrogen atom of compound 2 and b) the structure of the precursor of diazatriene 12, namely,
whether 12 is formed directly from the metal-bound ylide 9 or an additional step, the formation
of metal-free ylide 11, should be included in the reaction sequence.
Scheme 4. Calculated Parameters for Possible Pathways of Rh2(form)4-catalyzed Reaction
of Azirine 2r with Diazo Compound 3i (ꢀG≠, kcal mol-1)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 22
1
2
3
4
5
Rh2(form)4
-N2
CO2Me
N2
Rh2(form)4
F3C
F3C
CO2Me
3i
8
6
7
Ph
NMe
8
9
N
2r
-9
syn
-9
anti
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
Ph
Ph
NMe
CF3
NMe
Ph
Me
N
N
N
+
N
F3C
CO2Me
Rh2(form)4
F3C
CO2Me
MeO2C
Rh2(form)4
Rh2(form)4
syn-9
anti-9
10
0.21 nm
TS1Z
4.2
TS1E
TS3Z
6.9
62.1
TS3E
61.1
Rh2(form)4
Rh2(form)4
Rh2(form)4
4.6
8.6
Rh2(form)4
10
24.5
27.7
Rh2(form)4
Ph
TS2E
TS2Z
3.9
Ph
NMe
CO2Me
NMe
CF3
NMe
NMe
N
2.3
N
35.8
34.7
MeO2C
CF3
11
F3C
CO2Me
11
N
N
CF3
CO2Me
Ph
Ph
E-
Z-
12
E-
12
Z-
Me
N
CO2Me
Ph
N
CF3
4z
Figure 1. Energy Profiles (Gibbs Free Energies, B3LYP/6-31+G(d,p), kcal⋅mol-1, 357K,
1,2-Dichloroethane) for Transformations of Metal-bound Azirinium Ylides syn-9 and anti-9 to
Diazatrienes Z-12, E-12.
Scanning of potential energy surfaces (B3LYP/6-31+G(d,p)/Stuttgart RSC 1997 ECP) for
the formation of metal-bound ylides 9 and 10 from azirine 2r and carbenoid 8 along the forming
ACS Paragon Plus Environment

Page 9 of 22
The Journal of Organic Chemistry
1
2
bonds CRh−Nazirine or CRh−Nimine did not reveal any activation barriers. The calculations showed
3
4
that each of diastereomeric azirinium ylides
9
and
9′ can adopt two stable conformations around
5
6
the CRh−N bond: syn anti (Scheme 4) and syn
-
9
,
-
9
-9
′, anti ′ (Table S-1, Supporting
-9
7
8
9
information). In contrast, each of diastereomeric iminium ylides, 10 (Scheme 4) and 10′ (Table
S-1, Supporting information), can exist in a single conformation around the CRh−N bond. These
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
compounds are less stable than the most favorable conformation of azirinium ylide (anti-9) by
9.9 and 9.0 kcal mol-1, respectively. Spatial location of phenylazirinyl and methyl substituent at
azomethine fragment of ylides 10 and 10′ does not enable rotation around the CRh−N bond. Thus,
in contrast to azirinium ylides
9, 9′, the formation of iminium ylides 10, 10′ from compound 2r
and carbenoid could occur like a key slipping into a lock leading to the only possible
8
conformation around the CRh−N bond. As the result, the increased entropy contribution to the
activation Gibbs free energy for the formation of iminium ylides 10 and 10′ is likely the main
reason for the absence of the products resulting from an attack of the cabenoid onto the nitrogen
atom of azomethine group.
The structure of the intermediate species undergoing three-membered ring-opening in the
reactions of azirines with rhodium carbenoids is still debatable. Often, in describing the
mechanism, the authors confine themselves only to a mentioning of metal-bound azirinium ylide
without specifying the sequence of the Rh−C and azirine N−C bond cleavage while forming the
azapolyene.12b,c,17 However, in some work the participation of metal-free ylides was also
postulated.18 A good agreement between the calculated torqueselectivity for the ring-opening of
metal-free ylides and the experimental results on stereoselectivity of the 2-azabuta-1,3-dienes
formation, 10a,c,19 as well as the fact of the formation of 1,5-electrocyclization products10b that is
characteristic of metal-free 1,3-dipoles, gave reason for inclusion of metal-free azirinium ylides
in some published mechanistic schemes. Using DFT calculations we tried to discover the most
preferable transformation pathways from metal-bound ylide
calculations were performed for two complexes, syn and anti
other and provide diazatrienes 12 and 12 respectively. The calculation results are presented
in Scheme 4 and Figure 1. The barriers for dissociation of the Rh−C bond in both syn
to give metal-free ylides 11 and
diazatrienes 12 and
12 (TS3Z, TS3E). Further ring-opening in metal-free azirinium ylides
11 and
Thus, the transformation of metal-bound ylides
breaking of the Rh−C and the azirine N−C bond, i.e. via intermediate formation of metal-free
azirinium ylides 11
9
to diazatriene 12 (Scheme 4). The
-
9
-9
, which do not convert into each
Z-
E-
-
9
and anti
-
-
9
Z-
E-
11 (TS1Z, TS1E) are lower than those for ring-opening to
Z-
E-
Z
E-
11 occurs with very low barriers in both cases (ꢀG≠ 3.9 and 2.3 kcal mol-1 respectively).
to diazatrienes 12 occurs via sequential
9
.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 22
1
2
3
4
5
6
7
8
In conclusion, we have developed an effective two-step method for the preparation of 1,2-
dihydropyrimidines from azirine-2-carbaldehydes, primary amines and diazo carbonyl
compounds. Azirine-2-carbaldimines, formed in the first step, react with rhodium carbenoids,
generated from the diazo compounds under Rh2(esp)2 catalysis, by endocyclic nitrogen atom
exclusively. The reaction involves dissociation of a metal-bound azirinium ylide complex to
metal-free azirinium ylide, ring opening to 1,5-diazahexatriene followed by 1,6-cyclization. The
formed 1,2-dihydropyrimidines with two different acceptor substituents on the C2 atom undergo
inversion of the C2 stereogenic center via “the N1−C2 bond cleavage/ rotation around the N−C
single bond /1,6-cyclization” sequence in solution at room temperature. 1,2-Dihydropyrimidines
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
4
are less active toward Rh(II)-carbenoids than azirines 2, but can undergo cyclopropanation of
the C5=C6 bond under standard conditions to give 2,4-diazabicyclo[4.1.0]hept-4-ene derivatives.
The latter are isomerized to 5-substituted 1,2-dihydropyrimidines under heating.
EXPERIMENTAL SECTION
1
General Methods. Melting points were determined on a melting point apparatus. The H
NMR spectra were recorded at 400 MHz. The 13C NMR spectra were recorded at 100 MHz.
Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane in CDCl3.
High-resolution mass spectra were recorded on an HRMS-ESI-QTOF instrument, electrospray
ionization, positive mode. Thin-layer chromatography (TLC) was conducted on aluminum sheets
precoated with SiO2 ALUGRAM SIL G/UV254. Column chromatography was performed on
silica gel 60 M (0.04−0.063 mm). Benzene and toluene were distilled and stored over sodium
metal. 1,2-Dichloroethane was washed with concentrated H2SO4 and water, distilled from P2O5,
and stored over anhydrous K2CO3. The catalyst Rh2(esp)2,20 2
H-azirine-2-carbaldehydes 1a,b,
e21
and diazo compounds 3a 22 3b 23 f 24 3g 25 3h26 were prepared by the reported procedures.
,
,
3c
–
,
,
General procedure for the preparation of 2H-azirine-2-carbaldehydes 1c,d. The
solution of 3-aryl-3-chloroacrylaldehyde (10 mmol) in DMSO (50 mL) was added dropwise at
10–15 ºС to the stirred suspension of NaN3 (22.5 mmol) in DMSO (135 mL). After addition was
completed, the reaction mixture was stirred for 15 min at room temperature. Then the reaction
mixture was slowly poured into water (200 mL), maintaining the temperature of the mixture at
10–15 ºС. The product was extracted with benzene (3×150 mL), organic layer was washed with
water (3×150 mL) and dried (Na2SO4). The solution obtained after filtration was heated for 2.5 h
at 50−60 °С (oil bath temperature) and then the solvent was removed in vacuum. The residue
was purified by flash column chromatography on silica gel (eluent hexane−EtOAc 5:1) to give
azirinecarbaldehydes 1c,d.
ACS Paragon Plus Environment

Page 11 of 22
The Journal of Organic Chemistry
1
2
3-(4-Methoxyphenyl)-2H-azirine-2-carbaldehyde (1c): Obtained from 3-chloro-3-(4-
3
4
5
6
methoxyphenyl)acrylaldehyde27 according to the general procedure. Orange solid (670 mg, yield
1
38%). Mp: 61−63 °C; H NMR (400 MHz, CDCl3) δ 2.83 (d,
J
= 6.7 Hz, 1H), 3.93 (s, 3H),
7.05−7.15 (m, 2H), 7.80−7.91 (m, 2H), 8.93 (d,
J
= 6.7 Hz, 1H); 13С NMR (100 MHz, CDCl3) δ
7
8
9
39.0, 55.7, 114.9, 115.1, 132.7, 157.9, 164.5, 200.5; HRMS−ESI [M + Na]+ calcd for
+
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
C10H9NNaO2 198.0525; found 198.0532.
3-tert-Butyl-2H-azirine-2-carbaldehyde (1d): Obtained from 3-chloro-4,4-dimethylpent-2-
enal28 according to the general procedure. Pale yellow oil (300 mg, yield 24%). 1H NMR (400
MHz, CDCl3) δ 1.33 (s, 9H), 2.62 (d, J = 6.4 Hz, 1H), 8.88 (d, J
= 6.4 Hz, 1H); 13С NMR (100
MHz, CDCl3) δ 25.5, 33.2, 39.7, 168.1, 199.8; HRMS−ESI [M + Na]+ calcd for C7H11NNaO+
148.0733; found 148.0735.
General procedure for the preparation of 1,2-dihydropyrimidines 4a−x.
Azirinecarbaldimine synthesis (stage 1) 29
Azirinecarbaldehyde 1a−e (0.3 mmol, 1.0 equiv),
.
amine (0.3 mmol, 1.0 equiv), molecular sieves 4Å (350 mg, dried at 150 °C in vacuum 0.1 Torr),
and anhydrous benzene (2.0 mL) were placed into a round-bottom flask and stirred at room
1
temperature for 1−7 days (control by H NMR spectroscopy). The solid was decanted and
washed thoroughly with benzene (3 × 1 mL). The mixture was filtered off through a pad of
Celite and the solvent was removed in vacuum to give crude azirinecarbaldimine
2.
1,2-Dihydropyrimidine synthesis (stage 2). The solution of diazo compound 3a
−
h
(1.1−3.0 equiv) in 1,2-dichloroethane (DCE) (0.7 mL) was added to the above residue. The
solution was rapidly heated to reflux (oil bath temperature 115 °C) under stirring. Then Rh2(esp)2
(2.3 mg, 0.01 equiv) was added in one portion and refluxing was continued until nitrogen
evolution had ceased (about 1−20 min). Full consumption of reagents was controlled by TLC
(hexane−EtOAc). The solvent was removed in vacuum and the residue was purified by column
chromatography on silica gel (eluent hexane−EtOAc) unless otherwise stated to give 1,2-
dihydropyrimidine 4a
−x.
Ethyl 1,4-diphenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate
(4a):
Obtained according to the general procedure. Stage 1: from azirine 1a and aniline, 1 day. Stage
2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent for chromatography
hexane−EtOAc 12:1. Pale yellow solid (77 mg, yield 69%). Mp: 89−91 °C; 1H NMR (400 MHz,
CDCl3) δ 0.96 (t,
J = 7.1 Hz, 3H), 3.99–4.12 (m, 2H), 5.98 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 7.4
Hz, 1H), 7.28–7.55 (m, 8H), 7.89–8.02 (m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.3, 62.3, 82.9
(q,
J
= 27.8 Hz), 96.0, 123.6 (q,
J
= 292 Hz), 126.2, 127.2, 127.3, 128.3, 129.1, 130.7, 136.7,
+
142.6, 143.3, 163.9, 165.0; HRMS−ESI [M + H]+ calcd for C20H18F3N2O2 375.1315; found
375.1315.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 22
1
2
Ethyl
1-(4-chlorophenyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
3
4
5
6
carboxylate (4b): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
chloroaniline, 2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 12:1. Pale yellow solid (88 mg, yield 72%). Mp: 88−90 °C;
7
8
9
1H NMR (400 MHz, CDCl3) δ 1.03 (t,
Hz, 1H), 6.83 (d,
= 7.5 Hz, 1H), 7.31–7.41 (m, 4H), 7.43–7.54 (m, 3H), 7.88–7.99 (m, 2H); 13С
NMR (100 MHz, CDCl3) δ 13.4, 62.5, 82.8 (q, = 27.8 Hz), 96.4, 123.4 (q, = 291 Hz), 127.2,
J = 7.1 Hz, 3H), 4.10 (q, J = 7.1 Hz, 2H), 5.98 (d, J = 7.5
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
J
J
J
127.8, 128.4, 129.2, 130.8, 133.0, 136.5, 141.8, 142.3, 163.8, 165.0; HRMS−ESI [M + H]+ calcd
+
for C20H1735ClF3N2O2 409.0925; found 409.0924.
Ethyl
1-(2-chlorophenyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4c): Obtained according to the general procedure. Stage 1: from azirine 1a and 2-
chloroaniline, 2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 12:1. Pale yellow solid (87 mg, yield 71%), mixture of two
atropoisomers in 1 : 1.5 ratio. Mp: 81−83 °C; 1H NMR (400 MHz, CDCl3, –40 °С) δ 0.83 (t,
J
J
=
=
6.9 Hz, 1.3H), 1.34 (t, = 6.8 Hz, 2.1H), 3.87–4.03 (m, 0.8H), 4.28–4.49 (m, 1.3H), 6.08 (d,
J
7.2 Hz, 1H), 6.68–6.82 (m, 1H), 7.27–7.62 (m, 6.5H), 7.67–7.78 (m, 0.5H), 7.88–8.11 (m, 2.7H);
13C NMR (100 MHz, CDCl3) δ 12.9, 13.9, 62.6, 63.2, 81.7 (q,
= 27.3 Hz), 82.3 (q, = 28.3
Hz), 96.7, 97.1, 121.8 (q, = 286 Hz), 123.6 (q, = 295 Hz), 127.0, 127.28, 127.31, 127.4,
J
J
J
J
128.34, 128.38, 129.7, 130.08, 130.12, 130.58, 130.62, 130.8, 131.8 (2C), 134.8, 135.0, 136.4,
136.5, 138.1, 138.8, 143.3, 144.5, 163.73, 163.80, 164.6, 167.9; HRMS−ESI [M + H]+ calcd for
+
C20H1735ClF3N2O2 409.0925; found 409.0943.
Ethyl 1-(4-bromophenyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate
(4d): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-bromoaniline,
2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent for
chromatography hexane−EtOAc 12:1. Pale yellow solid (86 mg, yield 63%). Mp: 104−107 °C;
1H NMR (400 MHz, CDCl3) δ 1.03 (t,
Hz, 1H), 6.83 (d,
= 7.3 Hz, 1H), 7.20–7.35 (m, 2H), 7.37–7.63 (m, 5H), 7.81–8.05 (m, 2H); 13С
NMR (100 MHz, CDCl3) δ 13.4, 62.5, 82.8 (q, = 28.0 Hz), 96.4, 120.9, 123.4 (q, = 291 Hz),
J = 6.9 Hz, 3H), 4.10 (q, J = 6.9 Hz, 2H), 5.98 (d, J = 7.3
J
J
J
127.2, 128.0, 128.4, 130.8, 132.2, 136.5, 142.2, 142.3, 163.8, 164.9; HRMS−ESI [M + H]+ calcd
+
for C20H1779BrF3N2O2 453.0420; found 453.0428.
Ethyl
1-(4-methoxyphenyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4e): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
methoxyaniline, 2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 7:1. Pale yellow solid (80 mg, yield 66%). Mp: 74−76 °C;
1H NMR (400 MHz, CDCl3) δ 1.07 (t,
J = 7.1 Hz, 3H), 3.83 (s, 3H), 4.11 (q, J = 7.1 Hz, 2H),
ACS Paragon Plus Environment

Page 13 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
5.89 (d,
7.53 (m, 3H), 7.89–7.99 (m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.5, 55.4, 62.3, 83.1 (q,
27.6 Hz), 94.9, 114.1, 123.4 (q, = 291 Hz), 127.3, 128.3, 128.9, 130.6, 135.9, 137.0, 143.7,
158.9, 163.8, 165.4; HRMS−ESI [M + H]+ calcd for C21H20F3N2O3 405.1421; found 405.1421.
Ethyl 1-(2-methoxyphenyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.84–6.94 (m, 2H), 7.32–7.40 (m, 2H), 7.42–
J
=
J
+
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
carboxylate (4f): Obtained according to the general procedure. Stage 1: from azirine 1a and 2-
methoxyaniline, 9 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 7:1. Pale yellow solid (38 mg, yield 31%). Mp: 112−115 °C;
1H NMR (400 MHz, CDCl3) δ 1.16 (t,
5.81 (d, = 7.4 Hz, 1H), 6.69 (d, = 7.4 Hz, 1H), 6.92–7.00 (m, 2H), 7.30–7.37 (m, 1H), 7.41–
7.57 (m, 4H), 7.91–7.99 (m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.7, 55.8, 62.3, 82.9 (q,
J = 7.1 Hz, 3H), 3.81 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H),
J
J
J
=
27.6 Hz), 93.7, 112.1, 120.4, 123.1 (q,
J
= 291 Hz), 127.3, 128.3, 129.7, 129.9 (q,
J
= 2.3 Hz),
+
130.4, 131.2, 137.4, 145.5, 157.0, 163.8, 165.9; HRMS−ESI [M + H]+ calcd for C21H20F3N2O3
405.1421; found 405.1421.
Ethyl 4-phenyl-2-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]-1,2-dihydropyrimidine-2-
carboxylate (4g): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
(trifluoromethyl)aniline, 2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5
min, eluent for chromatography hexane−EtOAc 12:1. Pale yellow solid (78 mg, yield 59%). Mp:
1
90−92 °C (EtOAc); H NMR (400 MHz, CDCl3) δ 0.94 (t,
J
= 7.1 Hz, 3H), 4.01–4.14 (m, 2H),
= 7.6 Hz, 1H), 7.43–7.55 (m, 5H), 7.67 (d, = 8.5 Hz, 2H),
7.90–7.98 (m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.3, 62.6, 82.7 (q,
= 27.8 Hz), 97.6, 123.5
(q, = 292 Hz), 123.8 (q, = 272.0 Hz), 125.4 (q, = 2.3 Hz), 126.4 (q, = 3.7 Hz), 127.3,
128.5, 128.8 (q, = 1.2 Hz), 163.8, 164.6;
6.07 (d,
J
= 7.6 Hz, 1H), 6.90 (d,
J
J
J
J
J
J
J
J
= 33.0 Hz), 131.0, 136.4, 141.3, 146.4 (q, J
+
HRMS−ESI [M + H]+ calcd for C21H17F6N2O2 443.1189; found 443.1193.
Ethyl
1-(naphthalen-1-yl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4h): Obtained according to the general procedure. Stage 1: from azirine 1a and 1-
naphthylamine, 2 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 12:1. Pale yellow viscous oil (92 mg, yield 72%), mixture of
two atropoisomers in 1 : 1.3 ratio. 1H NMR (400 MHz, CDCl3) δ 0.36 (t,
(t, = 7.1 Hz, 1.8H), 3.52–3.72 (m, 0.9H), 4.32–4.45 (m, 1.2H), 6.05 (d,
J
= 7.1 Hz, 1.4H), 1.34
= 7.3 Hz, 0.55H),
J
J
6.07 (d,
7.81 (d,
J
= 7.3 Hz, 0.45H), 6.78–6.89 (m, 1H), 7.44–7.60 (m, 6H), 7.75 (d,
= 7.4 Hz, 0.5H), 7.85–7.97 (m, 2H), 8.00–8.08 (m, 2.5H), 8.10 (d,
J
= 8.0 Hz, 0.6H),
= 7.4 Hz, 0.6H);
J
J
13C NMR (100 MHz, CDCl3) δ 12.5, 13.9, 62.0, 62.8, 82.7 (q,
J
= 27.3 Hz), 83.3 (q,
J = 28.4
Hz), 95.6, 95.9, 122.4 (q, = 284.3 Hz), 123.1 (br s), 124.0, 124.1 (q,
J
J
= 292.8 Hz), 125.0,
125.1, 126.31, 126.35, 126.8, 127.1, 127.38, 127.41, 127.5, 127.8 (br s), 128.0, 128.1, 128.38,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 22
1
2
128.41, 129.2, 129.3, 130.6, 130.7, 132.4, 132.7, 134.4, 134.5, 136.8, 137.0, 138.0, 138.4, 144.8,
3
4
+
146.0, 163.7, 164.3 (2C), 167.7; HRMS−ESI [M + H]+ calcd for C24H20F3N2O2 425.1471; found
5
6
425.1488.
Ethyl 1-benzyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (4i):
Obtained according to the general procedure. Stage 1: from azirine 1a and benzylamine, 2 h.
Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent for chromatography
hexane−EtOAc 16:1. Pale yellow solid (66 mg, yield 57%). Mp: 62–64 °С; 1H NMR (400 MHz,
7
8
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
CDCl3) δ 1.32 (t,
1H), 6.59 (d,
= 7.6 Hz, 1H), 7.32–7.51 (m, 8H), 7.81–7.93 (m, 2H); 13С NMR (100 MHz,
CDCl3) δ 13.9, 54.2 (q, = 2.0 Hz), 62.7, 83.0 (q, = 27.5 Hz), 91.7, 123.8 (q, = 293 Hz),
J = 7.1 Hz, 3H), 4.22–4.39 (m, 2H), 4.40–4.49 (m, 2H), 5.54 (d, J = 7.6 Hz,
J
J
J
J
127.1, 128.1, 128.3, 128.5, 128.9, 130.5, 135.7, 137.2, 144.0, 164.1, 165.9; HRMS−ESI [M +
+
H]+ calcd for C21H20F3N2O2 389.1471; found 389.1471.
Ethyl 1-phenethyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (4j):
Obtained according to the general procedure. Stage 1: from azirine 1a and phenethylamine, 1
day. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent for chromatography
1
hexane−EtOAc−NEt3 180:15:1. Yellow semisolid (82 mg, yield 68%). H NMR (400 MHz,
CDCl3) δ 1.37 (t,
5.53 (d, = 7.5 Hz, 1H), 6.67 (d,
NMR (100 MHz, CDCl3) δ 14.0, 36.3, 52.8, 62.7, 82.9 (q,
J
= 7.1 Hz, 3H), 2.94–3.08 (m, 2H), 3.39–3.52 (m, 2H), 4.31–4.45 (m, 2H),
= 7.5 Hz, 1H), 7.20–7.49 (m, 8H), 7.83–7.88 (m, 2H); 13С
= 27.8 Hz), 91.3, 123.5 (q, = 292
J
J
J
J
Hz), 126.8, 127.1, 128.3, 128.75, 128.84, 130.5, 137.2, 137.8, 144.4, 164.0, 166.1; HRMS−ESI
+
[M + H]+ calcd for C22H22F3N2O2 403.1628; found 403.1638.
Ethyl 1-tert-butyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (4k):
Obtained according to the general procedure. Stage 1: from azirine 1a and tert-butylamine, 3
days. Stage 2: from diazo compound 3a (0.36 mmol, 1.2 equiv), 5 min, eluent for
1
chromatography hexane−EtOAc 17:1. Pale yellow oil (81 mg, yield 76%). H NMR (400 MHz,
CDCl3) δ 1.39 (t,
(d,
= 7.9 Hz, 1H), 7.36–7.47 (m, 3H), 7.80–7.88 (m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.8,
29.8, 59.8, 62.3, 81.2 (q,
J = 7.2 Hz, 3H), 1.44 (s, 9H), 4.28–4.44 (m, 2H), 5.58 (d, J = 7.9 Hz, 1H), 7.02
J
J
= 27.0 Hz), 91.0, 124.0 (q,
J
= 295 Hz), 127.0, 128.2, 130.4, 137.0,
+
143.2, 162.7, 167.0. HRMS−ESI [M + H]+ calcd for C18H22F3N2O2 355.1628; found 355.1618.
Ethyl 1-[bis(4-chlorophenyl)methyl]-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4l): Obtained according to the general procedure. Stage 1: from azirine 1a and
bis(4-chlorophenyl)methanamine, 3 days. Stage 2: from diazo compound 3a (0.39 mmol, 1.3
equiv), 4 min, eluent for chromatography hexane−EtOAc 17:1. Pale yellow solid (129 mg, yield
1
81%). Mp: 124–126 °С (hexane−Et2O). H NMR (400 MHz, CDCl3) δ 1.07 (t,
J
= 7.1 Hz, 3H),
3.56 (dq,
J
= 10.8, 7.2 Hz, 1H), 4.05 (dq,
J
= 10.8, 7.2 Hz, 1H), 5.60 (d,
J
= 7.8 Hz, 1H), 5.99 (s,
ACS Paragon Plus Environment

Page 15 of 22
The Journal of Organic Chemistry
1
2
3
4
1H), 6.67 (d,
J
= 7.8 Hz, 1H), 7.10 (d,
J
= 8.4 Hz, 2H), 7.24 (d,
J
= 8.4 Hz, 2H), 7.31–7.52 (m,
= 27.3 Hz),
13
7H), 7.82–7.95 (m, 2H); C NMR (100 MHz, CDCl3) δ 13.4, 62.5, 64.5, 82.1 (q,
J
5
6
7
91.8, 123.7 (q,
J = 293 Hz), 127.0, 128.3, 128.8, 129.0, 129.5, 130.2, 130.7, 134.1, 134.4, 136.9,
137.5, 137.6, 141.5, 163.5, 165.3; HRMS−ESI [M + H]+ calcd for C27H2235Cl2F3N2O2
+
8
9
533.1005; found 533.1022.
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
Ethyl
1-(4-methylphenylsulfonyl)-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4m): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
methylbenzenesulfonamide, 7 days. Stage 2: from diazo compound 3a (0.36 mmol, 1.2 equiv),
11 min, eluent for chromatography hexane−EtOAc 20:1. Pale yellow semisolid (99 mg, yield
1
73%). H NMR (400 MHz, CDCl3) δ 1.42 (t,
J
= 7.1 Hz, 3H), 2.47 (s, 3H), 4.39–4.54 (m, 2H),
= 8.2 Hz, 1H), 7.36–7.45 (m, 4H), 7.47–7.53 (m, 1H), 7.79–
= 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.7, 21.6, 63.3, 80.3 (q,
= 29.3 Hz), 98.3, 122.7 (q, = 291 Hz), 127.2, 128.2, 128.5, 129.9, 131.6, 135.4, 135.5 (2C),
5.95 (d,
J = 8.2 Hz, 1H), 7.08 (d, J
7.86 (m, 2H), 7.92 (d,
J
J
J
145.4, 161.8, 164.5; HRMS−ESI [M + Na]+ calcd for C21H19F3N2NaO4S+ 475.0910; found
475.0924.
Ethyl
1,4-bis(4-chlorophenyl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate
(4n): Obtained according to the general procedure. Stage 1: from azirine 1b and 4-chloroaniline,
3 days. Stage 2: from diazo compound 3a (0.36 mmol, 1.2 equiv), 4 min, eluent for
chromatography hexane−EtOAc 15:1. Pale yellow solid (100 mg, yield 75%). Mp:.107−109 °C
1
(CHCl3). H NMR (400 MHz, CDCl3) δ 1.04 (t,
J
= 7.1 Hz, 3H), 4.11 (q,
= 7.5 Hz, 1H), 7.31–7.39 (m, 4H), 7.40–7.46 (m, 2H), 7.81–7.90
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.5, 62.7, 82.8 (q,
= 27.7 Hz), 95.8, 123.3 (q, = 291
J = 7.1 Hz, 2H), 5.91
(d,
J = 7.5 Hz, 1H), 6.82 (d, J
J
J
Hz), 128.0 (q,
J
= 1.8 Hz), 128.6, 128.7, 129.3, 133.4, 135.0, 137.1, 141.6, 142.8, 162.8, 165.0;
HRMS−ESI [M + H]+ calcd for C20H1635Cl2F3N2O2 443.0535; found 443.0529.
+
Ethyl 1-(4-chlorophenyl)-4-(4-methoxyphenyl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4o): Obtained according to the general procedure. Stage 1: from azirine 1c and 4-
chloroaniline, 2 days. Stage 2: from diazo compound 3a (0.36 mmol, 1.2 equiv), 5 min, eluent
for chromatography hexane−EtOAc 15:1. Pale yellow solid (79 mg, yield 60%). Mp:.94−95 °C
1
(EtOAc). H NMR (400 MHz, CDCl3) δ 1.02 (t,
J
= 7.1 Hz, 3H), 3.88 (s, 3H), 4.03–4.14 (m,
= 7.5 Hz, 1H), 6.92–7.01 (m, 2H), 7.30–7.39 (m, 4H),
= 27.7 Hz), 96.2,
2H), 5.95 (d,
J
= 7.5 Hz, 1H), 6.79 (d, J
13
7.85–7.94 (m, 2H); С NMR (100 MHz, CDCl3) δ 13.5, 55.4, 62.5, 82.8 (q,
J
113.7, 123.5 (q,
J
= 292 Hz), 127.7 (q,
J
= 2.1 Hz), 129.0, 129.1, 129.2, 132.9, 141.99, 142.01,
162.0, 162.8, 165.2; HRMS−ESI [M + H]+ calcd for C21H1935ClF3N2O3 439.1031; found
+
439.1025.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 22
1
2
Ethyl
4-tert-butyl-1-(4-chlorophenyl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
3
4
5
6
carboxylate (4p): Obtained according to the general procedure. Stage 1: from azirine 1d and 4-
chloroaniline, 2 days. Stage 2: from diazo compound 3a (0.45 mmol, 1.5 equiv), 5 min, eluent
for chromatography hexane−EtOAc 20:1. Colorless solid (73 mg, yield 63%). Mp: 46−49 °C; 1H
7
8
9
NMR (400 MHz, CDCl3) δ 1.02 (t,
7.6 Hz, 1H), 6.60 (d,
= 7.6 Hz, 1H), 7.20–7.27 (m, 2H), 7.29–7.36 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 13.5, 27.8, 37.7, 62.1, 82.5 (q, = 27.2 Hz), 95.6, 123.4 (q, = 291.4 Hz), 127.3
(q,
= 2.1 Hz), 129.1, 132.5, 140.8, 142.2, 165.0, 174.6; HRMS−ESI [M + H]+ calcd for
J = 7.1 Hz, 3H), 1.19 (s, 9H), 3.97–4.12 (m, 2H), 5.51 (d, J =
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
J
J
J
J
+
C18H2135ClF3N2O2 389.1238; found 389.1243.
Ethyl 1-(4-chlorophenyl)-5-methyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-
carboxylate (4q): Obtained according to the general procedure. Stage 1: from azirine 1e and 4-
chloroaniline, 1 week. Stage 2: from diazo compound 3a (0.39 mmol, 1.3 equiv), 5 min, eluent
for chromatography hexane−EtOAc 15:1. Pale yellow solid (71 mg, yield 56%). Mp:.105−107
1
°C (EtOAc). H NMR (400 MHz, CDCl3) δ 1.00 (t,
J
= 7.1 Hz, 3H), 1.83 (d,
= 1.1 Hz, 1H), 7.31–7.38 (m, 4H), 7.41–7.47 (m, 3H), 7.50–7.55
(m, 2H); 13С NMR (100 MHz, CDCl3) δ 13.4, 16.0, 62.6, 82.6 (q,
= 27.6 Hz), 106.4, 123.3 (q,
J = 1.1 Hz, 3H),
4.00–4.13 (m, 2H), 6.55 (q,
J
J
J
= 292 Hz), 127.4 (q,
J
= 2.1 Hz), 128.2 (2C), 129.1, 129.3, 132.5, 137.8, 139.0, 141.8, 165.2,
+
169.1; HRMS−ESI [M + H]+ calcd for C21H1935ClF3N2O2 423.1082; found 423.1096.
Dimethyl 1-(4-chlorophenyl)-4-phenylpyrimidine-2,2(1H)-dicarboxylate (4r): Obtained
according to the general procedure. Stage 1: from azirine 1a and 4-chloroaniline, 2 days. Stage 2:
from diazo compound 3b (0.39 mmol, 1.3 equiv), 20 min, product was purified by washing with
hexane–Et2O (0.5 mL), filtration and drying instead of column chromatography. Pale yellow
solid (69 mg, yield 60%). Mp: 171−174 °C (EtOAc); 1H NMR (400 MHz, CDCl3) δ 3.70 (s, 6H),
6.02 (d,
J = 7.3 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 7.30–7.37 (m, 4H), 7.40–7.50 (m, 3H), 7.88–
7.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 53.3, 84.4, 97.5, 125.8, 127.4, 128.3, 129.1, 130.5,
+
132.2, 136.7, 141.2, 141.7, 162.5, 169.1; HRMS−ESI [M + H]+ calcd for C20H1835ClN2O4
385.0950; found 385.0964.
Methyl
1-(4-chlorophenyl)-2,4-diphenyl-1,2-dihydropyrimidine-2-carboxylate
(4s):
Obtained according to the general procedure. Stage 1: from azirine 1a and 4-chloroaniline, 2
days. Stage 2: from diazo compound 3c (0.33 mmol, 1.1 equiv), 1 min, eluent for
1
chromatography hexane−EtOAc 20:1. Pale yellow foam (85 mg, yield 70%). H NMR (400
MHz, CDCl3) δ 3.72 (s, 3H), 6.01 (d,
J = 7.3 Hz, 1H), 7.01–7.06 (m, 2H), 7.08 (d, J = 7.3 Hz,
1H), 7.12–7.17 (m, 2H), 7.26–7.32 (m, 3H), 7.42–7.53 (m, 5H), 7.96–8.02 (m, 2H); 13С NMR
(100 MHz, CDCl3) δ 52.7, 84.1, 96.7, 127.2, 127.7 (2C), 128.2, 128.4, 128.6 (2C), 130.1, 131.6,
ACS Paragon Plus Environment

Page 17 of 22
The Journal of Organic Chemistry
1
2
+
137.4, 138.5, 142.2, 142.6, 162.0, 172.6; HRMS−ESI [M + H]+ calcd for C24H2035ClN2O2
3
4
403.1208; found 403.1224.
5
Methyl
1,2-bis(4-chlorophenyl)-4-phenyl-1,2-dihydropyrimidine-2-carboxylate
(4t):
6
7
8
9
Obtained according to the general procedure. Stage 1: from azirine 1a and 4-chloroaniline, 2
days. Stage 2: from diazo compound 3d (0.33 mmol, 1.1 equiv), 1 min, eluent for
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
chromatography hexane−EtOAc 20:1. Pale yellow solid (77 mg, yield 59%). Mp:.140−142 °C
1
(EtOAc); H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 6.00 (d,
J
= 7.3 Hz, 1H), 6.98–7.06 (m,
2H), 7.07 (d,
J = 7.3 Hz, 1H), 7.14–7.22 (m, 2H), 7.23–7.33 (m, 2H), 7.37–7.53 (m, 5H), 7.88–
8.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 52.9, 83.6, 97.0, 127.2, 127.4, 128.0, 128.3, 128.9,
130.0, 130.3, 132.0, 134.5, 137.1, 137.3, 142.1, 142.5, 162.0, 172.3; HRMS−ESI [M + H]+ calcd
+
for C24H1935Cl2N2O2 437.0818; found 437.0811.
Methyl
1-(4-chlorophenyl)-2-(4-methoxyphenyl)-4-phenyl-1,2-dihydropyrimidine-2-
carboxylate (4u): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
chloroaniline, 2 days. Stage 2: from diazo compound 3e (0.33 mmol, 1.1 equiv), 1 min, eluent
1
for chromatography hexane−EtOAc 10:1. Pale yellow oil (87 mg, yield 67%). H NMR (400
MHz, CDCl3) δ 3.70 (s, 3H), 3.79 (s, 3H), 6.00 (d,
J = 7.3 Hz, 1H), 6.74–6.87 (m, 2H), 6.96–
7.06 (m, 2H), 7.07 (d, = 7.3 Hz, 1H), 7.10–7.20 (m, 2H), 7.35–7.54 (m, 5H), 7.90–8.07 (m,
J
2H); 13C NMR (100 MHz, CDCl3) δ 52.7, 55.2, 83.6, 96.6, 113.2, 127.2, 127.9, 128.2, 128.6,
129.9, 130.1, 130.7, 131.6, 137.5, 142.3, 142.8, 159.5, 162.0, 173.0; HRMS−ESI [M + H]+ calcd
+
for C25H2235ClN2O3 433.1313; found 433.1331.
Methyl
1-(4-chlorophenyl)-2-(4-nitrophenyl)-4-phenyl-1,2-dihydropyrimidine-2-
carboxylate (4v): Obtained according to the general procedure. Stage 1: from azirine 1a and 4-
chloroaniline, 2 days. Stage 2: from diazo compound 3f (0.33 mmol, 1.1 equiv), 1 min, eluent for
1
chromatography hexane−EtOAc 6:1. Pale yellow oil (87 mg, yield 65%). H NMR (400 MHz,
CDCl3) δ 3.67 (s, 3H), 6.03 (d,
J = 7.3 Hz, 1H), 7.02–7.07 (m, 2H), 7.11 (d, J = 7.3 Hz, 1H),
7.19–7.24 (m, 2H), 7.40–7.51 (m, 3H), 7.72–7.77 (m, 2H), 7.89–7.96 (m, 2H), 8.14–8.20 (m,
2H); 13С NMR (100 MHz, CDCl3) δ 53.1, 83.7, 97.3, 122.8, 126.5, 127.1, 128.3, 129.1, 129.5,
130.4, 132.0, 136.8, 141.7, 141.9, 145.5, 147.6, 161.8, 171.2; HRMS−ESI [M + H]+ calcd for
+
C24H1935ClN3O4 448.1059; found 448.1071.
Ethyl 2-acetyl-1-(4-chlorophenyl)-4-phenyl-1,2-dihydropyrimidine-2-carboxylate (4w):
Obtained according to the general procedure. Stage 1: from azirine 1a and 4-chloroaniline, 2
days. Stage 2: from diazo compound 3g (0.9 mmol, 3.0 equiv), 5 min, eluent for chromatography
1
hexane−EtOAc 6:1. Pale yellow solid (49 mg, yield 43%). Mp: 82–84 °C (hexane–Et2O); H
NMR (400 MHz, CDCl3) δ 1.02 (t,
J
= 7.1 Hz, 3H), 2.33 (s, 3Н), 4.05–4.22 (m, 2Н), 5.92 (d,
J =
7.3 Hz, 1Н), 6.95 (d, = 7.3 Hz, 1Н), 7.22 (d,
J
J
= 8.8 Hz, 2H), 7.32 (d, = 8.8 Hz, 2H), 7.41–
J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 22
1
2
7.53 (m, 3H), 7.87–7.98 (m, 2Н). 13С NMR (100 MHz, CDCl3) δ 13.6, 26.3, 62.3, 87.8, 96.6,
3
4
5
6
125.3, 127.3, 128.4, 129.2, 130.6, 132.0, 136.8, 141.9, 142.0, 162.0, 168.7, 202.9. HRMS−ESI
+
[M + H]+ calcd for C21H2035ClN2O3 383.1157; found 383.1161.
1-[1-(4-Chlorophenyl)-2,4-diphenyl-1,2-dihydropyrimidin-2-yl]ethanone (4x): Obtained
according to the general procedure. Stage 1: from azirine 1a and 4-chloroaniline, 2 days. Stage 2:
from diazo compound 3h (0.36 mmol, 1.2 equiv), 2 min, product was purified by
recrystallization from Et2O (2 mL) and hexane–Et2O mixture (1:1, 4 mL) instead of column
7
8
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
1
chromatography. Orange solid (71 mg, yield 61%). Mp: 129–132 °C (hexane–Et2O); H NMR
(400 MHz, CDCl3) δ 2.14 (s, 3H), 5.92 (d,
J = 7.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2Н), 7.07 (d, J =
7.2 Hz, 1H), 7.11 (d, = 8.5 Hz, 2Н), 7.23–7.33 (m, 3H), 7.37–7.54 (m, 5H), 7.96–8.08 (m, 2H);
J
13С NMR (100 MHz, CDCl3) δ 26.2, 87.2, 95.3, 127.0, 127.8, 128.35, 128.41, 128.6, 129.05,
129.06, 130.2, 131.9, 137.57, 137.60, 142.4, 144.1, 162.3, 205.5. HRMS−ESI [M + H]+ calcd for
C24H2035ClN2O + 387.1259; found 387.1264.
Diethyl
rel-(1R,3R,6R,7R)-2-(4-chlorophenyl)-5-phenyl-3,7-bis(trifluoromethyl)-2,4-
diazabicyclo[4.1.0]hept-4-ene-3,7-dicarboxylate (exo,exo-5b) and diethyl rel-(1R,3S,6R,7R)-2-
(4-chlorophenyl)-5-phenyl-3,7-bis(trifluoromethyl)-2,4-diazabicyclo[4.1.0]hept-4-ene-3,7-
dicarboxylate (endo,exo-5b): Pyrimidine 4b (88 mg, 0.215 mmol), diazo compound 3a (98 mg,
0.54 mmol, 2.5 equiv) and 1,2-dichloroethane (1.0 mL) were placed to a round bottom flask and
the solution was rapidly heated to reflux (oil bath temperature 115 °C) under stirring. Then
Rh2(esp)2 (1.7 mg, 0.01 equiv) was added in one portion and refluxing was continued until the
nitrogen evolution had stopped (about 2 min). The solvent was removed in vacuum and the
residue was purified by column chromatography on silica gel (eluent hexane−EtOAc 12:1) to
give a 1.3:1 mixture of compounds endo,exo-5b and exo,exo-5b as a pale colorless solid (117
mg, yield 97%). Pure samples of each cyclopropane were obtained by column chromatography
on silica gel (eluent hexane−Et2O 10:1). Compound endo,exo-5b (major isomer). Mp: 105−107
1
°C (CHCl3); H NMR (400 MHz, CDCl3) δ 0.95 (t,
J
= 7.1 Hz, 3Н), 1.36 (t,
= 8.6 Hz, 1Н), 4.00–4.20 (m, 2Н), 4.32–4.45 (m, 2Н), 7.21–
7.27 (m, 2Н), 7.33–7.40 (m, 2Н), 7.47–7.60 (m, 3Н), 8.02–8.12 (m, 2Н); 13С NMR (100 MHz,
CDCl3) δ 12.9, 14.0, 21.0 (q, = 2.6 Hz), 44.0 (q, = 3.1 Hz), 45.1 (q, = 31.7 Hz), 62.5, 63.0,
81.0 (q, = 27.4 Hz), 122.5 (q, = 286 Hz), 122.7 (q, = 277 Hz), 127.2, 128.5, 129.3 br, 129.7,
= 1.2 Hz), 163.4, 166.2. HRMS−ESI [M + Na]+ calcd for
J = 7.1 Hz, 3Н),
2.92 (d,
J = 8.6 Hz, 1Н), 3.76 (d, J
J
J
J
J
J
J
131.8, 133.3, 136.5, 143.9, 162.0 (q,
J
+
C25H2135ClF6N2NaO4 585.0986; found 585.1009. Compound exo,exo-5b (minor isomer).
Mp:.112−114 °C (CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.87 (t,
J = 7.1 Hz, 3Н), 1.12 (t, J = 7.1
Hz, 3Н), 3.05 (d, = 7.1 Hz, 1Н), 3.70 (d, = 7.1 Hz, 1Н), 3.89–3.99 (m, 1Н), 4.01–4.11 (m,
J
J
1Н), 4.14–4.28 (m, 2Н), 7.15–7.22 (m, 2H), 7.26–7.31 (m, 2H), 7.48–7.60 (m, 3Н), 8.01–8.07
ACS Paragon Plus Environment

Page 19 of 22
The Journal of Organic Chemistry
1
2
(m, 2Н); 13С NMR (100 MHz, CDCl3) δ 13.1, 13.6, 21.6, 39.0, 42.8 (q,
J
= 30.9 Hz), 62.5, 62.9,
3
4
5
6
78.0 (q, J = 26.6 Hz), 118.3 (q, J = 2.2 Hz), 122.9 (q, J = 277 Hz), 123.9 (q, J = 293 Hz), 127.29,
127.31, 128.6, 128.7, 132.1, 135.9, 142.5, 161.0, 163.2, 164.8. HRMS−ESI [M + Na]+ calcd for
+
C25H2135ClF6N2NaO4 585.0986; found 585.0995.
7
8
9
Ethyl
(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (6b). Synthesis from pyrimidine 4b.
The above reaction mixture containing compounds endo exo-5b and exo exo-5b before
1-(4-chlorophenyl)-5-(3-ethoxy-1,1,1-trifluoro-3-oxopropan-2-yl)-4-phenyl-2-
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
,
,
chromatographic purification was refluxed for 3 h. The solvent was removed in vacuum and the
residue was purified by column chromatography on silica gel (eluent hexane−EtOAc from 6:1 to
4:1) to give compound 6b (116 mg, yield 96%) as a mixture of two diastereomers in 1 : 1 ratio.
Synthesis from cyclopropane exo,exo-5b. A solution of exo,exo-5b (10 mg, 0.018 mmol)
in DCE (0.5 mL) was placed in a screw-cap ampule and heated at 100 °C (oil bath temperature)
for 11 h. Evaporation of the solvent under reduced pressure affords compound 6b quantitatively.
Synthesis from cyclopropane endo,exo-5b. A solution of endo,exo-5b (10 mg, 0.018
mmol) in toluene (0.5 mL) was placed in a screw-cap ampule and heated at 150 °C (oil bath
temperature) for 4 h. Evaporation of the solvent under a vacuum affords compound 6b
quantitatively. Pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.91 (t,
= 7.1 Hz, 3Н), 1.30 (t, = 7.1 Hz, 3Н), 1.37 (t, = 7.1 Hz, 3Н), 3.93–4.37 (m, 10Н), 7.22 (s,
1Н), 7.28–7.33 (m, 3Н), 7.37–7.43 (m, 4Н), 7.46–7.51 (m, 10Н), 7.52–7.56 (m, 2Н). 13С NMR
(100 MHz, CDCl3) δ 13.2, 13.6, 13.8, 14.0, 48.1 (q, = 29.2 Hz), 48.2 (q, = 29.7 Hz), 62.2,
62.3, 62.9, 63.2, 76.0 (q, = 33.1 Hz), 82.0 (q, = 27.7 Hz), 100.8 (2С), 122.2 (q, = 287 Hz),
123.3 (q, = 280 Hz), 123.6 (q, = 279 Hz), 126.1 (d, = 293 Hz), 126.9 (q, = 2.3 Hz), 128.2,
128.5, 128.7 (2С), 129.4, 129.5, 129.8 (q, = 1.4 Hz), 129.99, 130.03, 133.5, 134.7, 135.9,
J = 7.1 Hz, 3Н), 1.22 (t, J
J
J
J
J
J
J
J
J
J
J
J
J
136.0, 140.4, 141.2, 143.6, 145.3, 163.8, 166.0 (2C), 166.2 (q,
J = 2.8 Hz), 167.1, 167.8.
+
HRMS−ESI [M + H]+ calcd for C25H2235ClF6N2O4 563.1167; found 563.1191. Pure sample of
(RS,RS)-isomer was obtained by crystallization from hexane. Mp: 129–132 °C (hexane).
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
…..
Tables S-1, S-2, S-3, 1H and 13C NMR spectra for all new compounds, X-ray crystallography
data for compounds 4r, endo,exo-5b, exo,exo-5b, and RS,RS-6b, computation details with
energies of the reactants, transition states, their Cartesian coordinates, and tube representation of
the calculated molecules (PDF)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 22
1
2
AUTHOR INFORMATION
3
4
Corresponding Author
5
6
*E-mail: m.novikov@spbu.ru.
7
8
9
ORCID
Mikhail S. Novikov: 0000-0001-5106-4723
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
Nikolai V. Rostovskii 0000-0002-8925-794X
Alexander F. Khlebnikov: 0000-0002-6100-0309
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support of the Russian Science Foundation (Grant No.
17-13-01078). This research used resources of ‘Magnetic Resonance Research Centre’,
‘Chemical Analysis and Materials Research Centre’, ‘Computing Centre’, ‘Centre for X-ray
Diffraction Studies’ and ‘Chemistry Educational Centre’ of the Research Park of St. Petersburg
State University.
REFERENCES
(1) Lagoja, I. M. Chem. Biodiv. 2005, 2, 1.
(2) (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.; Takeuchi, Y.;
Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.; Funahashi, K.;
Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem
S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.;
Malley, M. F. J. Med. Chem 1992 35, 3254. (c) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.;
Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.;
Malley, M. F. J. Med. Chem 1990 33, 2629.
. 1989, 32, 2399. (b) Rovnyak, G. C.; Atwal, K.
.
,
.
,
(3) (a) Cox, C. D.; Breslin, M. J.; Mariano, B. J.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.;
Hamilton, K.; Huber, H. E.; Kohl, N. E.; Torrent, M.; Yan, Y.; Kuo, L. C.; Hartman, G. D.
Bioorg. Med. Chem. Lett. 2005
2008 , 698.
(4) Ali, M. A.; Manogaran, E.; Govindasamy, J.; Sellappan, V.; Pandian, S. J. Enzyme Inhib.
Med. Chem. 2011 26, 149.
(5) (a) Kappe, C. O.; Stadler, A. Org. React 2004, 63, 1. (b) Cho, H.; Nishimura, Y.; Yasui, Y.;
, 15, 2041. (b) Zhang, Y.; Xu, W. Anticancer Agents Med. Chem.
,
8
,
.
Kobayashi, S.; Yoshida, S.; Kwon, E.; Yamaguchi, M. Tetrahedron 2011, 67, 2661 and
references cited therein.
ACS Paragon Plus Environment

Page 21 of 22
The Journal of Organic Chemistry
1
2
(6) De la Hoz, A.; Pardo, C. Tetrahedron Lett. 1985, 26, 3869.
3
4
5
6
7
8
9
(7) (a) Barluenga, J.; Tomás, M.; Fustero, S.; Gotor, V. Synthesis 1979, 346. (b) Gómez Aranda,
V.; Barluenga, J.; Gotor, V.; Fustero, S. Synthesis 1974, 720. (c) Teuber, H.-J.; Schütz, G.;
Kern, W. Chem. Ber
(8) Yang, X.-J.; Zhang, L.-S.; Liu, J.-T. Tetrahedron 2007, 63, 5643.
(9) Goerdeler, J.; Lindner, C.; Zander F. Chem. Ber 1981 114, 536.
. 1975, 108, 383.
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
.
,
(10) (a) Rostovskii, N. V.; Novikov, M. S.; Khlebnikov, A. F.; Khlebnikov, V. A.; Korneev, S.
M. Tetrahedron 2013, 69, 4292. (b) Rostovskii, N. V.; Novikov, M. S.; Khlebnikov, A. F.;
Starova, G. L.; Avdontseva, M. S. Beilstein J. Org. Chem. 2015
Khlebnikov, A. F.; Rostovskii, N. V.; Tcyrulnikov, S.; Suhanova, A. A.; Zavyalov, K. V.; Yufit,
D. S. J. Org. Chem. 2015 80, 18. (d) Smetanin, I. A.; Novikov, M. S.; Agafonova, A. V.;
Rostovskii, N. V.; Khlebnikov, A. F.; Kudryavtsev, I. V.; Terpilowski, M. A.; Serebriakova, M.
K.; Trulioff, A. S.; Goncharov N. V. Org. Biomol Chem 2016 14, 4479; (e) Khlebnikov, A. F.;
Novikov, M. S.; Gorbunova, Y. G.; Galenko, E. E.; Mikhailov, K. I.; Pakalnis, V. V.;
Avdontseva, M. S. Beilstein J. Org. Chem. 2014 10, 1896.
(11) (a) Zavyalov, K. V.; Novikov, M. S.; Khlebnikov, A. F.; Pakalnis V. V. Tetrahedron 2014
70, 3377. (b) Zavyalov, K. V.; Novikov, M. S.; Khlebnikov, A. F.; Yufit, D. S. Tetrahedron
2013 69, 4546.
(12) (a) Rostovskii, N. V.; Ruvinskaya, J. O.; Novikov, M. S.; Khlebnikov, A. F.; Smetanin, I.
A.; Agafonova, A. V. J. Org. Chem 2017 82, 256. (b) Ryu, T.; Baek, Y.; Lee, P. H. J. Org.
Chem. 2015, 80, 2376. (c) Wang, Y.; Lei, X.; Tang, Y. Chem. Commun 2015, 51, 4507. (d)
Zhao, Y.-Z.; Yang, H.-B.; Tang, X.-Y.; Shi, M. Chem. - Eur. J 2015 21, 3562. (e) Ding, H.;
Hong, S.; Zhang, N. Tetrahedron Lett 2015 56, 507.
(13) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ. Chem. Rev. 2005
(14) Nunes Júnior, J.; Kascheres, A. J. Heterocyclic Chem. 1997 34, 341.
(15) CCDC 1558072 (4q), CCDC 1554714 (exo,exo 5b), CCDC 1554692 (endo,exo
CCDC 1554701 (RS,RS 6b) contain the supplementary crystallographic data for this paper. The
, 11, 302. (c) Novikov, M. S.;
,
.
,
,
,
,
.
,
.
.
,
.
,
,
74, 171.
,
-
-5b) and
-
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(16) Iagafarova, I. E.; Vorobyeva, D. V.; Loginov, D. A.; Peregudov, A. S.; Osipov, S. N. Eur. J.
Org. Chem. 2017, 840.
(17) Loy, N. S. Y.; Singh, A.; Xu, X.; Park, C.-M. Angew. Chem., Int. Ed
(18) Loy, N. S. Y.; Kim, S.; Park C.-M. Org. Lett 2015 17, 395.
(19) Smetanin, I. A.; Novikov, M. S., Rostovskii, N. V.; Khlebnikov, A. F.; Starova, G. L; Yufit,
D. S. Tetrahedro 2015 71, 4616.
. 2013, 52, 2212.
.
,
n
,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 22
1
2
(20) Kornecki, K. P.; Berry, J. F. Eur. J. Inorg. Chem. 2012, 562.
3
4
5
6
(21) Brahma, S.; Ray, J. K. J. Heterocycl. Chem. 2008
(22) Shi, G.; Xu, Y. J. Org. Chem. 1990 55, 3383.
, 45, 311.
,
(23) Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125,
7
8
9
4478.
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
(24) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010
(25) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004 60, 3967.
(26) Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.-M. Chem. Commun. 2012
(27) Prim, D.; Fuss, A.; Kirsch, G.; Silva, A. M. S. J. Chem. Soc., Perkin Trans. 2 1999, 1175.
(28) Shaffer, A. R.; Schmidt, J. A. R. Chem. Eur. J. 2009 15, 2662.
, 12, 604.
,
,
48, 3133.
,
(29) Alper, H.; Prickett, J. E.; Wollowitz, S. J. Am. Chem. Soc. 1977, 99, 4330.
ACS Paragon Plus Environment