Synthesis of 8-substituted 1,5-diazabicyclo[3.2.1]octane derivatives via double aza-Michael addition of homopiperazine to 3-trifluoroacetyl-4H-chromenes

Article abstract of DOI:10.1016/j.jfluchem.2017.09.006

The reaction of homopiperazine with 2-trifluoroacetyl-1H-benzo[f]chromenes affords 2-(1,5-diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[f]chromen-3-ols, while 3-trifluoroacetyl-4H-chromenes give 2-[2-(1,5-diazabicyclo[3.2.1]octan

Full text of DOI:10.1016/j.jfluchem.2017.09.006

Accepted Manuscript
Title: Synthesis of 8-substituted 1,5-diazabicyclo[3.2.1]octane
derivatives via double aza-Michael addition of
homopiperazine to 3-trifluoroacetyl-4H-chromenes
Authors: Dmitry V. Osipov, Irina V. Melnikova, Vitaly A.
Osyanin, Anton V. Lukashenko, Yury N. Klimochkin
PII:
S0022-1139(17)30367-6
DOI:
Reference:
http://dx.doi.org/10.1016/j.jfluchem.2017.09.006
FLUOR 9048
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Received date:
Revised date:
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17-8-2017
8-9-2017
9-9-2017
Please cite this article as: Dmitry V.Osipov, Irina V.Melnikova, Vitaly
A.Osyanin, Anton V.Lukashenko, Yury N.Klimochkin, Synthesis of 8-substituted
1,5-diazabicyclo[3.2.1]octane derivatives via double aza-Michael addition
of homopiperazine to 3-trifluoroacetyl-4H-chromenes, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.09.006
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Synthesis of 8-substituted 1,5-diazabicyclo[3.2.1]octane derivatives via double aza-Michael
addition of homopiperazine to 3-trifluoroacetyl-4H-chromenes
Dmitry V. Osipov,a Irina V. Melnikova,a Vitaly A. Osyanin,*a,b Anton V. Lukashenko, a
Yury N. Klimochkina
a Department of Organic Chemistry, Chemical Technological Faculty, Samara State
Technical University, 244 Molodogvardeyskaya St., 443100 Samara, Russian Federation.
Fax: +7 846 332 2122; e-mail: vosyanin@mail.ru
b Organic Chemistry Department, Faculty of Science, RUDN University, 6 Miklukho-
Maklaya St., 117198 Moscow, Russian Federation.
Graphical abstract
Highlights
 Novel approach to 8-substituted 1,5-diazabicyclo[3.2.1]octane derivatives
has been developed
 First example of synthesis of 1,5-diazabicyclo[3.2.1]octane core via double
aza-Michael addition has been founded
 Unpredictable cleavage of CF3C(O) group in reaction of 3-trifluoroacetyl-
4H-chromenes and homopiperazine has been shown
The reaction of homopiperazine with 2-trifluoroacetyl-1H-benzo[f]chromenes affords 2-
(1,5-diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[f]chromen-3-
ols, while 3-trifluoroacetyl-4H-chromenes give 2-[2-(1,5-diazabicyclo[3.2.1]octan-8-
yl)ethyl]phenols. Both reactions are the first examples of synthesis of 1,5-

diazabicyclo[3.2.1]octane core via double Michael addition and include cascade Michael
addition/pyran ring opening/Michael addition.
Keywords: homopiperazine; cascade reactions; 3-trifluoroacetyl-4H-chromenes; 1,5-
diazabicyclo[3.2.1]octane; aza-Michael reaction
1. Introduction
One of the strategic reactions for the formation of C–N bond is the aza-Michael reaction, which
is widely used in the synthesis of agrochemicals, pharmaceuticals and fluorescent materials [1].
Using polyfunctional substrates, aza-Michael reaction may be the initial stage of the cascade
process and lead to a significant increase in the molecular complexity. Promising objects for
studying the processes of cyclization of Michael adducts are 3-trifluoroacetyl-4H-chromenes and
their benzo-fused analogues, which can be easily obtained via cascade reactions of ortho-
quinone methide precursors and 1,1,1-trifluoro-4-morpholinobut-3-en-2-one [2, 3a]. The
presence of an oxyvinyl moiety conjugated to the electron-withdrawing group makes 3-
trifluoroacetyl-4H-chromenes masked 1,3-binucleophiles; it should be noted that highly
electrophilic related β-ketoaldehydes are unstable compounds. At the same time, 3-acyl-4H-
chromenes are stable and retain a high reactivity. The push-pull character of the double bond in
the pyran ring opens up ample opportunities for obtaining a variety of heterocycles. In
continuation of our interest in the chemistry of 3-trifluoroacetyl-4H-chromenes [3], we have
studied their interaction with homopiperazine (1,4-diazepane) due to wide range of biological
effects of their derivatives. Among substituted homopiperazines novel inhibitors of the CCR2b
receptor [4a], gelatinase [4b], dipeptidyl peptidase IV [4c] and proteasomes [4d] were identified.
In addition, some of them possess anti-cancer [4e] and anti-tubercular activity [4f].
2. Results and discussion

We have shown that stirring a mixture of homopiperazine 1 and 2-trifluoroacetyl-1H-
benzo[f]chromenes 2a–c in the molar ratio 1:1 in methanol affords 2-(1,5-
diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[f]chromen-3-ols 3a–c
(Scheme 1).
13C NMR spectra of compounds 3a–c show the carbon atom of trifluoromethyl group and
1
the adjacent hemiacetal carbon atom as quartets at 122.9 ppm with JC–F = 288 Hz and at 96.5–
2
96.7 ppm with JC–F = 31.5 Hz, respectively. The carbon atoms connected with two nitrogen
atoms (C8') resonate at 88.0 ppm. The signals for the benzylic carbon atoms (C1) in the 13C NMR
spectra are found at 21.5–21.6 ppm. The proton of the hydroxyl group in 3a–c is strongly
deshielded (δ = 12.24–12.27 ppm in CDCl3 solution), which is due to the presence of a strong
intramolecular hydrogen bond with the nitrogen atom. Chemical non-equivalence of the carbon
atoms C4' and C2', C6' and C7' is also explained by the hydrogen bond. Characteristic signals in
1
the H NMR spectra corresponding to proton H2 are observed at 2.26–2.28 ppm as a doublet of
doublets with 3J = 10.8–11.0 and 3J = 6.3–6.4 Hz due to vicinal interaction with protons H8' and
H1, respectively. The protons H8' are displayed as a doublet at 3.99–4.03 ppm. The number of
13
protons that are directly linked to C atoms, inferred from DEPT spectra, is in accordance with
the presented structures. The H8' proton shows heteronuclear correlations with five methylene
carbon atoms, including the benzyl carbon atom C1 (in the HMBC spectrum of 3a, Figure 1),
which denies the structures of isomeric cyclic hemiaminals 4 and 5 (Scheme 2).
This cascade reaction includes the following main steps: aza-Michael addition of
homopiperazine to chromenes 2, opening of the dihydropyran ring in the intermediate A with
formation of the enaminone B, repeated aza-Michael addition and hemiketalization (Scheme 2).
Additionally, the cis-position of 1,5-diazabicyclo[3.2.1]octane fragment and hydroxyl
group in the structure of compound 3a was confirmed by X-ray diffraction analysis of
monocrystal (Figure 2). The unit cell contains two crystallographically independent molecules;

intramolecular hydrogen bond lengths are 1.622 and 1.675 Å, corresponding O–H···N angles are
161.20 and 153.38º. The hexahydropyrimidine ring of 3a exists in chair conformation, the
chromene fragment is located in equatorial position.
It should be noted that all known 8-R-substituted 1,5-diazabicyclo[3.2.1]octanes, which are
still a very small class of bicyclic diamines, were obtained from aliphatic or aromatic aldehydes
and homopiperazine [5]. Therefore, this reaction appears to be the first example of the
preparation of 1,5-diazabicyclo[3.2.1]octanes based on the Michael cascade addition. Interest in
this type of compounds is due to both their antimalarial effect [6] and to the use as models for the
study of anomeric and homoanomeric effects [7].
It is interesting to note that the reaction of homopiperazine 1 with 6-nitro-3-trifluoroacetyl-
4H-chromene 2d or 6,8-dibromo-3-trifluoroacetyl-4H-chromene 2e in the molar ratio 2:1 in
methanol leads to products 6a,b with absence of a trifluoromethyl group. It can be explained the
less nucleophilicity of the oxygen atom of the phenolic hydroxyl group due to the effect of
acceptor substituents. As a result, not an intramolecular attack on the carbonyl carbon atom, but
an acid-type cleavage under the action of the second equivalent of homopiperazine occurs. At a
ratio of 1:1 homopiperazine and chromenes 2d-f, we did not observe the formation of any other
products and the reaction mixture contained unreacted chromenes 2d-f in addition to the
homopiperazine derivatives 6a,b. In the reaction of 2,2,3,3,3-pentafluoro-1-(6-nitro-4H-
chromen-3-yl)propan-1-one 2f with homopiperazine in methanol the same product 6a was
obtained in 70% yield (Scheme 3).
13
The C NMR spectra of products 6a,b show characteristic signals at 86.3–86.6 ppm
1
for aminal carbon atoms. In the H NMR spectra, protons attached to these atoms appear in the
region of 3.80–3.83 ppm as triplets.
Refluxing of the chromenol 3a in formic acid for 4 h leads to starting 2-
trifluoroacetyl-1H-benzo[f]chromene 2a in 57% yield (Scheme 4). The mechanism of this

transformation apparently includes initial protonation of nitrogen atom, opening of the
dihydropyran ring, cleavage of the 1,5-diazabicyclo[3.2.1]octane and elimination of
homopiperazine as a salt or N-formyl derivative.
3. Conclusions
In conclusion, we have developed a new method for the synthesis of 8-substituted 1,5-
diazabicyclo[3.2.1]octane derivatives from homopiperazine and trifluoroacetylchromenes. These
reactions are the first examples of synthesis of 1,5-diazabicyclo[3.2.1]octane core via double
aza-Michael addition.
4. Experimental
4.1 General
IR spectra were recorded on a Shimadzu IR Affinity-1 spectrometer with the Specac
1
13
19
Diamond ATR GS 10800-B attachment. H, C and F (400, 100 and 376 MHz, respectively)
as well as DEPT, HMBC, HMQC, NOESY NMR spectra were acquired on a JEOL JNM-
13
ECX400 spectrometer in CDCl3 or DMSO-d6, with residual solvent peaks (1H, C) and CFCl3
(19F) as internal standart. Elemental analysis was performed on a Euro Vector EA-3000
automatic CHNS-analyser. Known chromenes 2a–e were prepared according to the literature
procedures [3a, 8].
4.2. Synthetic procedures
4.2.1. 2,2,3,3,3-Pentafluoro-1-(6-nitro-4H-chromen-3-yl)propan-1-one (2f) [9].
Morpholine (6 g, 0.07 mol) was added with stirring to the solution of 1-ethoxy-4,4,5,5,5-
pentafluoropent-1-ene-3-one 7 (15 g, 0.07 mol) in 35 ml of cyclohexane. Immediately formed
pale-pink precipitate of 4,4,5,5,5-pentafluoro-1-morpholinopent-1-en-3-one 8 was rapidly
filtered off, washed with cyclohexane, dried and used without additional purification. Yield 17.1
g (96%), colorless crystals: mp 127-128 ºС. 1H NMR (CDCl3) δ: 3.38 (br. s, 2H, CH2), 3.51 (br.
s, 2H, CH2), 3.74 (br. s, 4H, 2CH2); 5.44 (d, 1H, CH–N, J = 12.4 Hz), 7.84 (d, 1H, CH–СО, J =

12.4 Hz). 13C NMR (CDCl3) δ: 46.4 (CH2), 53.9 (CH2), 65.6 (CH2), 66.8 (CH2), 88.4 (CH),
108.4 (tq, CF3, 1JCF = 263.2, 2JCF = 37.2 Hz); 118.6 (qt, CF2, 1JCF = 285.1, 2JCF = 36.2 Hz); 155.1
(CH); 179.1 (t, C=O, 2JCF = 23.8 Hz). 19F NMR (CDCl3) δ: -123.4 (2F, CF2), -82.4 (3F, CF3). IR
(ν/cm–1): 1651 (C=O), 1562, 1443, 1389, 1331, 1269, 1211, 1188, 1146, 1103, 1069, 999, 984,
872, 764, 714. Found (%): C, 41.79; H, 3.82; N, 5.31. Calc. for C9H10F5NO2 (%): C, 41.71; H,
3.89; N, 5.40.
Mixture of 4,4,5,5,5-pentafluoro-1-morpholinopent-1-en-3-one 8 (1.5 g, 5.79 mmol) and 2-
(chloromethyl)-4-nitrophenol 9 (1.2 g, 6.4 mmol) was refluxed in 13 ml of acetic acid and then
cooled. Formed yellow crystals were filtered off, washed with acetic acid and dried. Yield 1.15 g
1
(61%), yellow crystals: 181-183 ºС. H NMR (CDCl3) δ: 3.69 (s, 2H), 7.15-7.17 (m, 2H), 7.91
(s, 1H), 8.09-8.12 (m, 2H). 13C NMR (CDCl3) δ: 22.0 (CH2), 108.5 (tq, CF3, 1JCF = 266.0, 2JCF =
1
2
38.1 Hz), 111.8 (C), 117.8 (CH), 117.9 (qt, CF2, JCF = 286.0, JCF = 34.3 Hz), 120.7 (C), 124.2
4
2
(CH), 125.5 (CH), 145.2 (C), 153.1 (C), 155.6 (t, JCF = 10.0 Hz, CH), 181.1 (t, JCF = 26.7 Hz,
19
C=O). F NMR (CDCl3) δ: -115.1 (2F, CF2), -81.7 (3F, CF3). IR (ν/cm–1): 3119, 1678, 1638,
1578, 1524 (NO2), 1479, 1366, 1344 (NO2), 1315, 1217, 1194, 1165, 1152, 1126, 1088, 1059,
910, 845, 748, 735, 673, 629. Found (%): C, 44.69; H, 1.82; N, 4.26. Calc. for C12H6F5NO4 (%):
C, 44.60; H, 1.87; N, 4.33.
4.2.2.
2-(1,5-Diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-dihydro-1H-
benzo[f]chromen-3-ol (3a).
A mixture of chromene 2a (0.38 g, 1.4 mmol) and homopiperazine (0.14 g, 1.4 mmol) in
methanol (4 ml) was stored at room temperature for 2 days. The precipitate that formed was
filtered off, washed with ice-cold methanol and recrystallized from CH3OH–CH2Cl2 (2:1). Yield
0.31 g (60%), colorless crystals: mp 163–164 ºС. 1H NMR (CDCl3) δ: 1.06–1.11 (m, 1H, Heq3'),
1.79–1.92 (m, 1H, Hax3'), 2.28 (dd, 1H, H2, J = 11.0, 6.3 Hz), 2.79–2.82 (m, 2H, H2'), 2.90 (dd,
1H, H4', J = 13.8, 6.2 Hz), 3.02–3.20 (m, 6H, H1, H4', H6', H7'), 3.65 (d, 1H, H1, J = 17.4 Hz),
4.03 (d, 1H, H8', J = 11.0 Hz), 7.20 (d, 1H, H5, J = 9.0 Hz), 7.34–7.40 (m, 1H, H8), 7.46–7.52 (m,

1Н, H9), 7.68 (d, 1Н, H6, J = 8.9 Hz), 7.78 (d, 1H, H7, J = 8.0 Hz), 7.86 (d, 1Н, H10, J = 8.5 Hz),
13
12.27 (br. s, 1Н, ОН). C NMR (CDCl3) δ: 18.1 (C3'), 21.6 (C1), 30.1 (C2), 49.1 and 50.6 (C6',
2
C7'), 54.6 and 56.1 (C2',C4'), 88.0 (C8'), 96.5 (q, C3, JCF = 31.5 Hz), 110.8 (C10b), 118.6 (C5),
122.5 (C10), 122.9 (q, CF3, 1JCF = 288.0 Hz), 123.9 (C8), 126.6 (C9), 128.3 (C6), 128.5 (C7), 129.6
19
(C6a), 132.6 (C10a), 150.5 (C4a). F NMR (CDCl3) δ: -82.9 (3F, CF3). IR (ν/cm–1): 3200–2400
(OH), 1626, 1597, 1514, 1466, 1398, 1346, 1263, 1219, 1177, 1146, 1099, 1074, 1051, 1020,
1007, 961, 905, 881, 812, 785, 768, 748, 733, 664. Found (%): C, 63.55; H, 5.50; N, 7.29. Calc.
for C20H21F3N2O2 (%): C, 63.48; H, 5.59; N, 7.40.
4.2.3. 8-(Adamantan-1-yl)-2-(1,5-diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-
dihydro-1H-benzo[f]chromen-3-ol (3b).
A mixture of chromene 2b (0.13 g, 0.32 mmol) and homopiperazine (32 mg, 0.32 mmol) in
methanol (4 ml) was refluxed for 1 min. After that the mixture was stored at room temperature
for 1 h. The precipitate formed was then filtered, washed ice-cold methanol. Yield 0.13 g (82%),
colorless crystals: mp 177–178 ºС. 1H NMR (CDCl3) δ: 1.08–1.13 (m, 1H, Heq3'), 1.79–1.95 (m,
7H, Hax3', CH2 Ad), 2.00 (br. s, 6Н, CH2 Ad), 2.13 (br. s, 3H, CHAd), 2.27 (dd, 1H, H2, J = 10.8, 6.4
Hz), 2.80–2.83 (m, 2H, H2'), 2.90 (dd, 1H, H4', J = 14.0, 6.3 Hz), 3.01–3.21 (m, 6H, H1, H4', H6',
H7'), 3.63 (d, 1H, H1, J = 17.4 Hz), 4.03 (d, 1H, H8', J = 10.8 Hz), 7.16 (d, 1H, H5, J = 8.9 Hz),
7.59 (dd, 1H, H9, J = 8.9, 1.8 Hz), 7.65 (d, 1H, Ar, J = 8.9 Hz), 7.67 (d, 1H, H7, J = 1.8 Hz), 7.82
13
(d, 1H, Ar, J = 8.9 Hz), 12.24 (br. s, 1Н, ОН). C NMR (CDCl3) δ: 18.1 (C3'), 21.6 (C1), 29.0
(3CHAd), 30.2 (C2), 36.2 (CAd), 36.9 (3CH2 Ad), 43.2 (3CH2 Ad), 49.1 and 50.6 (C6', C7'), 54.6 and
2
56.1 (C2', C4'), 88.0 (C8'), 96.5 (q, C3, JCF = 31.5 Hz), 110.5 (C10b), 118.4 (C5), 122.3 (C10),
1
122.9 (q, CF3, JCF = 287.9 Hz), 123.6 (C7), 124.7 (C9), 128.4 (C6), 129.6 (C6a), 130.7 (C10a),
19
146.9 (C8), 150.1 (C4a). F NMR (CDCl3) δ: -82.8 (3F, CF3). IR (ν/cm–1): 2908, 2847 (CHAd),
1605, 1508, 1470, 1453, 1394, 1289, 1237, 1218, 1174, 1159, 1146, 1133, 1100, 1087, 1072,
1010, 963, 929, 903, 882, 805, 786, 726. Found (%): C, 70.38; H, 6.71; N, 5.38. Calc. for
C30H35F3N2O2 (%): C, 70.29; H, 6.88; N, 5.46.

4.2.4. 8-Bromo-2-(1,5-diazabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)-2,3-dihydro-1H-
benzo[f]chromen-3-ol (3c).
Title compound was prepared similarly to compound 3a from chromene 2c (0.2 g, 0.56
mmol) and homopiperazine (56 mg, 0.56 mmol) in methanol (4 ml). Yield 174 mg (68%).
Colorless crystals: mp 120–122 ºС (МеОН). 1H NMR (CDCl3) δ: 1.08–1.14 (m, 1H, Heq3'), 1.80–
1.94 (m, 1H, Hax3'), 2.26 (dd, 1H, H2, J = 10.8, 6.4 Hz), 2.78–2.82 (m, 2H, H2'), 2.91 (dd, 1H, H4',
J = 13.5, 6.4 Hz), 3.00–3.20 (m, 6H, H1, H4', H6', H7'), 3.60 (d, 1H, H1, J = 17.4 Hz), 3.99 (d, 1H,
H8', J = 11.0 Hz), 7.20 (d, 1H, H5, J = 8.9 Hz), 7.55 (dd, 1H, H9, J = 8.9, 1.8 Hz), 7.58 (d, 1H,
Ar, J = 8.9 Hz), 7.72 (d, 1H, Ar, J = 9.2 Hz), 7.92 (d, 1H, H7, J = 1.8 Hz), 12.24 (br. s, 1Н, ОН).
13C NMR (CDCl3) δ: 18.1 (C3'), 21.5 (C1), 30.0 (C2), 49.1 and 50.5 (C6', C7'), 54.6 and 56.1 (C2',
C4'), 87.9 (C8'), 96.7 (q, C3, 2JCF = 31.5 Hz), 111.1 (C10b), 117.7 (C8), 119.7 (CH), 122.9 (q, CF3,
1JCF 287.9 Hz), 124.3 (CH), 127.4 (CH), 129.8 (CH), 130.4 (CH), 130.8 (C), 131.1 (C), 150.8
19
(C4a). F NMR (CDCl3) δ: -82.8 (3F, CF3). IR (ν/cm–1): 2954, 2893, 1624, 1591, 1497, 1464,
1390, 1358, 1296, 1238, 1215, 1192, 1157, 1134, 1103, 1095, 1072, 1008, 974, 962, 902, 879,
804, 785, 721, 657. Found (%): C, 52.61; H, 4.49; N, 5.98. Calc. for C20H20BrF3N2O2 (%): C,
52.53; H, 4.41; N, 6.13.
4.2.5. 2-[2-(1,5-Diazabicyclo[3.2.1]octan-8-yl)ethyl]-4-nitrophenol (6a).
Method 1. A solution of chromene 2d (0.2 g, 0.73 mmol) and homopiperazine (0.15 g, 1.5
mmol) in methanol (3 ml) was kept at room temperature for 2 days. The solvent was removed
under reduced pressure, the residue was extracted with hot benzene (3 ml). The benzene was
evaporated in vacuo to give the crude product, which was recrystallized from benzene (1 ml),
filtered, washed with cyclohexane (2 ml) and dried in air. Yield 144 mg (71%), yellow crystals:
1
mp 158–160 ºС. H NMR (CDCl3) δ: 1.24 (tt, 1H, CH2, J = 14.5, 4.7 Hz), 1.74–1.79 (m, 2H,
CH2), 1.86–1.99 (m, 1H, CH2), 2.63–2.67 (m, 2H, CH2), 2.95–3.11 (m, 8H, CH2), 3.83 (t, 1H,
CHN, J = 8.1 Hz), 6.88 (d, 1H, H2, J = 8.2 Hz), 7.80–8.03 (m, 2H, H3, H5), 10.76 (br. s, 1Н,
ОН). 13C NMR (CDCl3) δ: 17.4 (CH2), 26.1 (CH2), 31.9 (CH2), 49.4 (2CH2), 55.2 (2CH2), 86.6

(CHN), 118.5 (CH), 124.5 (CH), 126.8 (CH), 128.9 (C), 140.3 (C), 163.7 (C–O). IR (ν/cm–1):
2940, 1589, 1477 (NO2), 1443, 1327 (NO2), 1296, 1285, 1207, 1163, 1136, 1126, 1086, 1034,
1005, 961, 939, 912, 903, 881, 876, 835, 785, 760, 743, 725, 681, 644. Found (%): C, 60.53; H,
6.82; N, 15.02. Calc. for C14H19N3O3 (%): C, 60.63; H, 6.91; N, 15.15.
Method 2. The same compound was prepared like in method 1 from chromene 2f (0.2 g,
0.62 mmol) and homopiperazine (0.12 g, 1.2 mmol) in methanol (3 ml). Yield 120 mg (70%).
4.2.6. 2-[2-(1,5-Diazabicyclo[3.2.1]octan-8-yl)ethyl]-4,6-dibromophenol (6b)
Was obtained analogously to 6a from chromene 2e (0.2 g, 0.52 mmol) and homopiperazine
(0.1 g, 1.04 mmol) in methanol (4 ml). After evaporation of the solvent, the residue was purified
by recrystallization from aqueous methanol. Yield 0.17 g (85%). Colorless crystals: mp 89–90 ºС
(МеОН–Н2О, 10:1). 1H NMR (DMSO-d6) δ: 1.06 (tt, 1H, CH2, J = 14.6, 4.7 Hz), 1.52–1.58 (m,
2H, CH2), 1.77–1.90 (m, 1H, CH2), 2.46–2.51 (m, 2H, CH2), 2.74–2.83 (m, 4H, CH2), 2.88–2.95
(m, 4H, CH2), 3.80 (t, 1H, CHN, J = 7.8 Hz), 4.42 (br. s, single averaged peak with residual
water, ОН), 7.22 (d, 1H, H Ar, J = 2.0 Hz), 7.43 (d, 1H, H Ar, J = 2.0 Hz). 13C NMR (DMSO-
d6) δ: 17.3 (CH2), 26.6 (CH2), 32.0 (CH2), 49.0 (2CH2), 54.6 (2CH2), 86.3 (CHN), 109.1 (C),
114.0 (C), 132.5 (CH), 132.6 (CH), 133.4 (C), 154.6 (C–O). IR (ν/cm–1): 3400–2700 (ОН),
1654, 1566, 1533, 1490, 1463, 1450, 1431, 1396, 1276, 1251, 1222, 1057, 1039, 1012, 985, 954,
931, 912, 879, 850, 833, 779, 688. Found (%): C, 43.20; H, 4.62; N, 7.09. Calc. for
C14H18Br2N2O (%): C, 43.10; H, 4.65; N, 7.18.
4.2.7. 1-(1H-Benzo[f]chromen-2-yl)-2,2,2-trifluoroethan-1-one (2a). A solution of
chromenol 3a (0.1 g, 0.26 mmol) in formic acid (2 ml) was refluxed for 4 h. The mixture was
kept at 10 °C for 3 h, the precipitated solid was filtered off and recrystallized from methanol.
Yield 42 mg (57%). Colorless crystals; mp 112–114 °C. Product was identical in spectral
characteristics to a sample prepared previously [3a].
4.3. Crystallographic data for 3a

Crystals of C20H21F3N2O2 (M = 378.39) are monoclinic, space group P2(1)/c, at 293 K: a =
14.675(5), b = 9.808(5) and c = 25.532(7) Å, β = 98.73(3)º, Z = 8, V 3632(2) Å3, dcalc = 1.384 g
cm–3, μ (CuKα) = 0.756 mm–1, F(000) = 1584. Total of 38084 reflections were measured and
6150 independent reflections (Rint = 0.0602) were used in a further refinement. The refinement
converged to wR2 = 0.1088 and GOF = 1.005 for all independent reflections [R1 = 0.0440 was
calculated against F for 4078 observed reflections with I > 2σ(I)].
The measurements were made on a AgilentSuperNova diffractometer with CuKα radiation
(λ = 1.54184 Å). The structure was solved by direct methods, and non-hydrogen atoms were
located from the trial structure and then refined anisotropically with SHELXL using a full-matrix
least-squares procedure on F2. The H atoms were determined from a difference Fourier
synthesis.
CCDC 1540987 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk.
Acknowledgement
This publication was supported by the Ministry of Education and Science of the Russian
Federation (the Agreement number 02.a03.21.0008) and by RFBR according to the research
project № 17-03-01158 a). The authors also express their thanks to Dr. Marat R. Baymuratov for
carrying out the NMR spectra.
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Figures
Figure 1 Selected HMBC 1H–13C correlations of compound 3a

Figure 2 An ORTEP diagram of compound 3a with 50% probability ellipsoid displacement.
Scheme 1

Scheme 2
Scheme 3
Scheme 4