Fragmentation of trifluoromethylated alkenes and acetylenes by N, N -binucleophiles. Synthesis of imidazolines or imidazolidines (Oxazolidines) controlled by substituent

Article abstract of DOI:10.1021/jo101107t

The reaction of β-halogeno-β-polyfluoromethylstyrenes with N,N- or N,O-binucleophiles leads to unexpected fragmentation products (imidazolines) or to heterocyclization giving CF₃-substituted imidazolidines (N,N-) and oxazolidines (N,O-) depending on aryl substituent. The scope and the reaction mechanism are discussed.

Full text of DOI:10.1021/jo101107t

pubs.acs.org/joc
Fragmentation of Trifluoromethylated Alkenes and Acetylenes by
N,N-Binucleophiles. Synthesis of Imidazolines or Imidazolidines
(Oxazolidines) Controlled by Substituent
Valentine G. Nenajdenko,*,† Vasiliy M. Muzalevskiy,† Aleksey V. Shastin,*,‡
Elizabeth S. Balenkova,† Evgeniy V. Kondrashov,§ Igor A. Ushakov,§ and
Alexander Yu. Rulev*,§
†Department of Chemistry, Moscow State University, Leninskie Gory, Moscow 119992, Russia,
‡Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia, and
§A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
Favorsky Str., Irkutsk 664033, Russia
nen@acylium.chem.msu.ru; shastin@icp.ac.ru; rulev@irioch.irk.ru
Received June 8, 2010
The reaction of β-halogeno-β-polyfluoromethylstyrenes with N,N- or N,O-binucleophiles leads to
unexpected fragmentation products (imidazolines) or to heterocyclization giving CF3-substituted
imidazolidines (N,N-) and oxazolidines (N,O-) depending on aryl substituent. The scope and the
reaction mechanism are discussed.
Introduction
ultimate cost of the products. Because of their polyfunction-
ality, trifluoromethylated halogenoalkenes could be very
valuable starting materials for the preparation of complex
fluorinated targets. We have recently studied the unusual
reaction of CF3-styrenes 1 with secondary3 and primary
amines4 leading to either the expected aminoalkenes or
vinylogous guanidinium salts depending on the nature of
aromatic substituent. Encouraged by these results and acc-
umulated knowledge of the chemistry of captodative tri-
fluoromethylated halo- and aminoalkenes,5 we recognized
the signitificant synthetic potential of the styrenes 1 as
useful precursors for trifluoromethylated heterocycles via
reaction with binucleophiles. Trifluoromethylated and
CF2Cl-substituted alkenes6 are easily available using the
new catalytic olefination reaction, a novel general method
Although trifluoromethyl substituted heterocycles are
target compounds for chemical, medicinal, and agricultural
research, their synthesis is not always trivial.1,2 Therefore,
development of new efficient methodologies for the prepara-
tion of fluorinated heterocycles is strongly required and
continues to provide challenges for modern organic chem-
istry. One of the most attractive methods for the construction
of these heterocyclic compounds is based on the use of easily
available fluorine-containing building blocks. This approach
minimizes quantities of the reagents, reaction times, and the
(1) For reviews see: (a) Muzalevskiy, V. M.; Shastin, A. V.; Balenkova,
E. S.; Haufe, G.; Nenajdenko, V. G. Synthesis 2009, 3905–3929. (b) Schlosser,
M. Angew. Chem., Int. Ed. 2006, 45, 5432–5446. (c) Furin, G. Adv. Hetero-
cycl. Chem. 2006, 90, 239–310. (d) Pace, A.; Pibiri, I.; Buscemi, S.; Vivona, N.
Heterocycles 2004, 63, 2627–2648. (e) Zhu, S. Z.; Wang, Y. L.; Peng, W. M.;
Song, L. P.; Jin, G. F. Curr. Org. Chem. 2002, 6, 1057–1096. (f) Erian, A. W.
J. Heterocycl. Chem. 2001, 38, 793–808.
(2) For the latest monographs see: (a) Fluorinated Heterocycles; Gakh,
A. A., Kirk, K. L., Eds.; ACS Symposium Series 1043; Oxford University
Press: New York, 2009. (b) Fluorinated Heterocyclic Compounds. Synthesis,
Chemistry and Aplications; Petrov, V., Ed.; John Wiley & Sons: New York,
2009.
(3) Muzalevskiy, V. M.; Nenajdenko, V. G.; Rulev, A. Yu.; Ushakov,
I. A.; Romanenko, G. V.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.
Tetrahedron 2009, 65, 6991–7000.
(4) Rulev, A. Yu.; Muzalevskiy, V. M.; Kondrashov, E. V.; Ushakov,
I. A.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G. Eur. J.
Org. Chem. 2010, 300–310.
(5) Rulev, A. Yu. Russ. Chem. Rev. 2002, 71, 195–221.
DOI: 10.1021/jo101107t
r
Published on Web 07/29/2010
J. Org. Chem. 2010, 75, 5679–5688 5679
2010 American Chemical Society

Nenajdenko et al.
JOCArticle
SCHEME 1. Proposed Pathway to Fluorinated Piperazines 5
and/or Imidazolidines 6 via Reactions of CF2X-Substituted
Styrenes (1) with Binucleophiles
SCHEME 2. Reactions of β-Halogeno-β-trifluoromethyl- and
β-(Chlorodifluoromethyl)styrenes 1 with Ethylenediamines 2
room temperature. Imidazolidine 6a is formed only as a
minor product, and formation of piperazine derivative 5 is
not observed at all. As a rule the known oxidations of the
double bonds are carried out in the more harsh conditions, in
acidic media with strong oxidants such as KMnO4 or
K2Cr2O7.11
for olefination of carbonyl compounds developed by our
group.7 We expected the possibility of formation of such
relatively rare CF2X-substituted heterocycles as piperazines8
5 or imidazolidines9 6, known to exhibit highly specific activ-
ity against Trypanosome rhodesiense. We expected this reac-
tion to lead to target five- or six-membered heterocycles
through nucleophilic halogen substitution followed by an
intramolecular cyclization via attack by the secondary nucle-
ophilic center at the double bond (Scheme 1). Earlier, capto-
dative carbonyl-bearing halo- or aminoalkenes have been
successfully transformed into oxazoline, morpholine, or
piperazine derivatives by a one-pot procedure.10
To study the scope and the mechanism of this unusual
reaction, we investigated the influence of substrate structure
(variations of substituents in aromatic ring, the nature of the
halogen at the double bond (F, Cl, Br) and in the CHal3
moiety, correspondingly CF3 and CF2Cl derivatives) and
binucleophile structure to the reaction path. The possibility
to control the reaction by solvent and temperature were
studied as well.
We found that cleavage of the double bond is the major
reaction path for the styrenes 1 bearing electron-donating
substituents on the aromatic ring. The treatment of com-
pounds 1a-j with ethylenediamine gave a mixture of non-
fluorinated imidazolines 7a-f and fluorinated imidazo-
lidines 6a-g. The high total yield of these heterocycles let
us to conclude that no other types of transformations of
initial styrenes occur. Compounds 7a-f (Table 1) are formed
preferentially in most cases. Moreover styrenes 1k,l gave
imidazolines 7g,h as the only products.
Solvent and temperature effects were studied to optimize
the reaction conditions. The reaction of a model styrene 1a
proceeded smoothly at room temperature in solvent-free
conditions, but rather prolonged reaction time (about 1 day)
was required (entry 1). In refluxing THF, ethanol or toluene
the complete conversion of the substrate 1a occurred in 6-7 h
to increase the total yield of the products up to 96%. Altho-
ugh the content of 6a in product mixture declined 2-fold, one
cannot say that the solvent has a principal influence on the
reaction.
The reaction is quite general. For example, treatment of
styrenes 1h,k with N-methyl ethylenediamine led analo-
gously to N-methyl imidazolines 7i,j. Similar behavior was
also observed for alkenes activated with a CF2Cl group. No
significant difference was observed in the case of CF2Cl-
substituted alkene 1b, which gave 6b and 7a in almost the
same ratio compared to its trifluoromethylated analogue 1a.
Next, we studied the influence of the olefinic halogen atom
(F, Cl, Br) on the reaction path. It is known that the SNV
reaction (nucleophilic vinylic substitution) may proceed by a
variety of mechanisms depending on the substrate structure,
nucleophile, leaving group, and solvent. The most common
one is the two-step addition-elimination or elimination-
addition sequence. However, other variants including radi-
cals and cation species are also known.12
Results and Discussion
To our surprise, the model reaction of bromide 1a with
ethylenediamine gave compound 7a as a major product,
which was a result of cleavage of the C-C double bond
(Scheme 2). It should be noted that the oxidation state of the
arylmethyne carbon atom is increased in the course of the
reaction because the product 7a is a derivative of benzoic
acid. Formally an oxidative cleavage of double bond in
nucleophilic conditions takes place. It is remarkable that
the transformation occurs under solvent-free conditions at
(6) (a) Nenajdenko, V. G.; Shastin, A. V.; Korotchenko, V. N.; Varseev,
G. N.; Balenkova, E. S. Eur. J. Org. Chem. 2003, 302–308. (b) Korotchenko,
V. N.; Shastin, A. V.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2001,
57, 7519–7527. (c) Nenajdenko, V. G.; Varseev, G. N.; Korotchenko, V. N.;
Shastin, A. V.; Balenkova, E. S. J. Fluorine Chem. 2003, 124, 115–118.
(d) Nenajdenko, V. G.; Varseev, G. N.; Korotchenko, V. N.; Shastin, A. V.;
Balenkova, E. S. J. Fluorine Chem. 2004, 125, 1339–1345. (e) Nenajdenko,
V. G.; Varseev, G. N.; Shastin, A. V.; Balenkova, E. S. J. Fluorine Chem.
2005, 126, 907–913. (f) Shastin, A. V.; Muzalevsky, V. M.; Balenkova, E. S.;
Nenajdenko, V. G. Mendeleev Commun. 2006, 16, 179–180.
(7) (a) Shastin, A. V.; Korotchenko, V. N.; Nenajdenko, V. G.; Balenko-
va, E. S. Tetrahedron 2000, 56, 6557–6563. (b) Korotchenko, V. N.; Shastin,
A. V.; Nenajdenko, V. G.; Balenkova, E. S. Synthesis 2001, 2081–2084.
(c) Korotchenko, V. N.; Shastin, A. V.; Nenajdenko, V. G.; Balenkova, E. S.
J. Chem. Soc., Perkin Trans. 1 2002, 883–887. (d) Shastin, A. V.; Nenajdenko,
V. G.; Korotchenko, V. N.; Balenkova, E. S. Russ. Chem. Bull. 2001, 50,
1401–1405. (e) Korotchenko, V. N.; Nenajdenko, V. G.; Shastin, A. V.;
Balenkova, E. S. Org. Biomol. Chem. 2003, 1906–1908. (f) Nenajdenko,
V. G.; Korotchenko, V. N.; Shastin, A. V.; Balenkova, E. S. Russ. Chem.
Bull. 2004, 53, 1034–1064.
(8) Jenneskens, L. W.; Mahy, J.; Berg, E. M. M.; Hoef, I.; Lugtenburg, J.
Recl. Trav. Chim. Pays-Bas 1995, 114, 97–102.
(9) (a) Szinai, S.; Crank, G.; Harding, D. J. Med. Chem. 1970, 13, 1215–
1217. (b) Slusarczuk, G. M. J.; Joullie, M. M. J. Org. Chem. 1971, 36, 37–43.
(c) Dondy, B.; Doussot, P.; Iznaden, M.; Muzard, M.; Portella, C. Tetra-
hedron Lett. 1994, 35, 4357–4360. (d) Funabiki, K.; Tamura, K.; Ishihara, T.;
Yamanaka, H. Bull. Chem. Soc. Jpn. 1994, 67, 3021–3029. (e) Sosnovskikh,
V. Ya.; Morozov, M. Yu. Chem. Heterocycl. Compd. 1998, 34, 743–744.
(f) Sosnovskikh, V. Ya.; Mel’nikov, M. Yu.; Kovaleva, I. A. Russ. Chem.
Bull. 1998, 47, 2234–2237.
It was shown that alkenes 1 bearing F, Cl, Br substituents
in R-position to a CF3 group gave the same products in all
cases independently of halogen nature.3,4,13 The 6a/7a ratio
(10) (a) Rulev, A. Yu.; Larina, L. I.; Chuvashev, Yu. A.; Novokshonov,
V. V. Mendeleev Commun. 2005, 128–130. (b) Rulev, A. Yu.; Maddaluno, J.
J. Phys. Org. Chem. 2002, 15, 590–598.
(11) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley & Sons: New York, 2009.
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JOCArticle
TABLE 1. Synthesis of Imidazolidines 6 and Imidazolines 7
yield, % b
entry
1
Ar
Hal
CF2X
R
conditions/time
Aa/1 d
THF, reflux, 7 h
EtOH, 78 °C, 7 h
toluene, 110 °C, 7 h
A/1 d
dioxane, 100 °C, 7 h
neat, 80 °C, 6 h
A/3 d
A/1 d
A/1d
A/4d
A/4d
A/4d
A/2d
A/5d
A/3d
A/1d
6
7
ratio 6:7
1
2
3
4
5
6
7
8
a
a
a
a
b
c
d
e
f
g
h
i
j
k
l
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
Br
Br
Br
Br
F
CF3
CF3
CF3
CF3
CF2Cl
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
6a (26)
6a (20)
6a (16)
6a (14)
6b (26)
6a (51)
6a (30)
6c (19)
6c (15)
6d (10)
6e (12)
6f (20)
6g (20)
7a (41)
7a (75)
7a (80)
7a (78)
7a (61)
7a (40)
7a (39)
7b (58)
7b (55)
7c (55)
7d (56)
7e (64)
7f (45)
7g (61)
7h (54)
7i (65)
7j (58)
39:61
21:79
17:83
15:85
30:70
56:44
43:57
25:75
21:79
15:85
18:82
24:76
31:69
0:100
0:100
0:100
0:100
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
F
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
9
Ph
4-FC6H4
10
11
12
13
14
15
16
17
4-MeC6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
4-MeC6H4
4-MeOC6H4
h
k
aA = neat, rt. bIsolated yield.
SCHEME 3. Reactions of CF3-Substituted Acetylenes 8a and
8b with Ethylenediamine
of reaction of 1a with ethylenediamine in methanol. The
reaction mixture (after 2 h at rt) contained 54% of starting
material 1a, 16% of the corresponding acetylene 8a, 7% of
6a, and 23% of 7a. (Relative values were obtained by inte-
gration of corresponding chromatographic peaks. The values
were calculated to give a sum equial 100%.) These observa-
tions confirmed beyond doubt that reaction may proceed
through the formation of acetylenes. Taking into account
this data, we proposed a plausible mechanism for the reac-
tion (Scheme 4). Two alternative transformations can be
postulated as an initial step of the cascade process. The first
one is dehydrohalogenation to form acetylene 8 (proceeds
preferentially for chlorides and bromides), and another one
is an addition of ethylenediamine to the double bond (for
fluorides).
Probably these directions are two competitive pathways of
the reaction depending on conditions and reagents. Regios-
electivity of acetylene hydroamination has a decisive role on
further transformations in both cases. When ethylenedia-
mine attacks β-position of styrene, enamine 3 is formed
followed by tautomerization into imine 4 and cyclization
into final imidazolidine 6. Much deeper and more complex
transformations are observed when ethylenediamine attacks
R-position of styrene and/or acetylene 8. In this case enamine
nitrogen activates fluorine (anchimeric like assistance) and
promotes an elimination of hydrogen fluoride from 10 giving
difluoroalkene 11. Probably the formation of a quite stable
HF molecule (enthalpy of formation -65 kcal/mol) is strong
compensation for the total energy consumption of double or
triple bond breaking. Addition of ethylenediamine to the
strongly activated double bond of difluoroalkene 11 gives
difluoride 12, which eliminates easily hydrogen fluoride form-
ing the highly conjugated system of intermediate 1-aza-1,3-
diene 13. Intramolecular addition of an amino group fol-
lowed by the extrusion of the last hydrogen fluoride molecule
results in formation of nonfluorinated imine 14. Compound
14 is cyclized to 15, which is the key intermediate of the whole
transformation. The finalizing step proceeds through the six-
membered ring transition state accompanyied by the break-
ing of C-C bond. As a result imidazolines 7 and 17 are
formed. Since twomolecules are formed from a single molecule
of 15, the total entropy of the system rises. The increasing of
for chloro-(1d) and bromoalkenes (1a) was found to be quite
similar (43:57 and 39:61, correspondingly). In contrast, in the
case of vinylfluoride 1c the product 6a was formed predo-
minantly and the 6a/7a ratio switched to 56:44. Therefore,
halogen substitution is not a crucial step for chlorides and
bromides, and reactions occur through the same intermedi-
ate. We assumed that an elimination-addition sequence
takes place in both cases to form acetylene as the first inter-
mediate. Fluoride is a relatively poor leaving group, and
therefore addition-elimination may also make noticeable
contribution to the transformation.
To confirm this hypothesis CF3-substituted acetylenes 8a
and 8b were prepared from the corresponding chloroalkenes
by treatment with lithium hexamethyldisylazide and then
used as substrates in the reaction with ethylenediamine
(Scheme 3).
To our delight the reactions of CF3-substituted acetylenes
8a and 8b with ethylenediamine provided compounds 6a, 7a,
and 7g with the same 6/7 ratio but in higher yields compared
to the corresponding parent alkenes. Additionally, the forma-
tion of acetylenes was confirmed by mass-spectral monitoring
(12) For reviews on the SNV mechanism see: (a) Rappoport, Z. Adv.
Phys. Org. Chem. 1969, 7, 1–114. (b) Modena, G. Acc. Chem. Res. 1971, 4,
73–80. (c) Miller, S. I. Tetrahedron 1977, 33, 1211–1218. (d) Rappoport, Z.
Acc. Chem. Res. 1981, 14, 7–15. (e) Rappoport, Z. Recl. Trav. Chim. Pays-
Bas 1985, 104, 309–349. (f) Shainyan, B. A. Russ. Chem. Rev. 1986, 55, 511–
530. (g) Okuyama, T.; Lodder, G. Adv. Phys. Org. Chem. 2002, 37, 1–56.
(h) Rulev, A. Yu. Russ. Chem. Rev. 1998, 67, 279–293. (i) Bernasconi, C. F.;
Rappoport, Z. Acc. Chem. Res. 2009, 42, 993–1003. (j) Galli, C; Rappoport,
Z. Acc. Chem. Res. 2003, 36, 580–587. (k) Rappoport, Z. Acc. Chem. Res.
1992, 25, 474–479.
(13) (a) Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Nenajdenko,
V. G. Russ. Chem. Bull. 2007, 56, 1526–1533. (b) Nenajdenko, V. G.;
Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. J. Fluorine
Chem. 2007, 128, 818–826. (c) Muzalevskiy, V. M.; Nenajdenko, V. G.;
Shastin, A. V.; Balenkova, E. S.; Haufe, G. Synthesis 2009, 2249–2259.
(d) Goldberg, A. A.; Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.;
Nenajdenko, V. G. J. Fluorine Chem. 2010, 131, 384–388.
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SCHEME 4. Plausible Mechanism for the Reaction of Styrenes 1 with Ethylenediamine
the reaction entropy might be an additional compensation
for such rare (unusual) bond cleavage. We undertake some
efforts to trap the second reaction component 17. The NMR
spectra of several crude reaction mixtures were measured.
Analyzing carefully reaction mixtures formed by alkenes 1a,
1k, and ethylenediamine, we observed the identical sets of the
signals, which are the same as those known from the litera-
ture for methyl imidazoline 17. The quantity of 17 found in
both reaction mixtures is equal to the corresponding amount
of imidazolines 7a and 7g, which is in agreement with pro-
posed mechanism.
Real time monitoring of the reaction of 1k with N-methy-
lethylenediamine was carried out by measuring both 1H and
19F spectra every 30 min during 24 h. This data set allowed
observation of the signals of postulated acetylene 8b, mix-
tures of Z/E-enamines 10a, and imines 9a. The content of
these compounds rose for some time accompanied by simul-
taneous shrinking of initial styrene share in the reaction
mixture. In the next 24 h all fluorine signals disappeared
with the exception of the fluoride anion signal. The major
product did not contain fluorine and was assigned as inter-
mediate 14a by the set of 1H-13C HMBC and 1H-13C
HSQC experiments. After 3 days of standing at room tem-
perature, compound 14a also disappeared. Therefore almost
all steps of the proposed reaction mechanism are perfectly
confirmed by spectral data.
SCHEME 5. Reaction of Ketoester 18a with Ethylenediamine
the mechanism of these transformations has never been
studied. We decided to confirm our proposal experimentally
to have additional mechanistic data. In our hands, reaction
of ethyl benzoylacetate with ethylenediamine led to forma-
tion of the same fragmentation products 7b and 17, observed
by mass and NMR spectra (scheme 5). So, reactions of keto-
esters and styrenes with ethylenediamines lead to the same
type of products and apparently have similar key intermedi-
ates. This is an additional reason to regard intermediate 15 as
key intermediate of styrene cleavage, because it has the same
oxidation level as ketoesters.
In contrast to styrenes 1a-l, their analogues 1m-t bearing
an electron-withdrawing group at the benzene ring afforded
exclusively the target trifluoromethylated heterocycles 6 and
the fragmentation was not observed (Scheme 6, Table 2). In
the same way styrenes 1m,n having o-bromine gave only
imidazolidines 6 without an admixture of fragmentation pro-
ducts 7. Such results can be easily rationalized by the influe-
nce of electron and (or) sterical properties of substituent in
aryl ring. The strong negative mesomeric effect of the nitro
group as well as the bulkiness of the o-bromine direct the ethy-
lenediamine to attack the β-position of styrene. As a result
the reaction proceeds regioselectively resulting in formation
of imidazolidines 6 as the only reaction products. According
to our previous results such styrenes are more active in re-
actions with both secondary and primary amines.3,4 As a rule
the reaction of 2- or 4-nitrostyrenes 1 with ethylenediamine
proceeds smoothly at room temperature to give the target
derivatives in good to excellent yield. 3-Nitrostyrene 1q was
found also to be rather reactive (Table 2, entry 5). Other bin-
ucleophiles (both N,N- and N,O-types) gave similar imidazo-
lidines (oxazolidines in the case of aminoalcohols); however,
Deeper analysis of the fragmentation reflects some simila-
rities with retro-Claisen reaction. Indeed, both fragmenta-
tion products 7 and 17 are the carboxylic acids derivatives as
well as intermediates 14, 15 can be considered as ketoester
derivatives 18. In addition the trifluoromethylated alkenes 1,
acetylenes 8 and ketoesters have the same oxidation level. In
literature there are rare examples of similar destruction of
ketoesters. For example, the reaction of ketoesters with phe-
nylenediamines gives substituted benzimidazoles.14 However,
(14) (a) Eynde, J. J. V.; Mayence, A.; Lor, P.; Haverbeke, Y. V. Bull. Soc.
Chim. Belg. 1995, 104, 387–392. (b) Bougrin, K.; Soufiaoui, M. Tetrahedron
Lett. 1995, 36, 3683–3686. (c) Wang, Z.-X.; Qin, H.-L. J. Heterocycl. Chem.
2005, 42, 1001–1005. (d) Rostamizadeh, S.; Nojavan, M.; Heshmatpoor, F.
Heterocycl. Comm. 2007, 13, 305–310. (e) Raju, B. C.; Theja, N. D.; Kumar,
J. A. Synth. Commun. 2009, 39, 175–188.
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SCHEME 6. Reactions of Binucleophiles 2 with Styrenes 1 Bearing an Electron-Withdrawing Group in the Aromatic Ring
TABLE 2. Synthesis of Fluorinated Imidazolidines and Oxazolidines 6
entry
Ar
halogen
CF2X
conditions
yield, %a
Binucleophile = ethylenediamine R1 = R2 = R3 = R = H; Y = NH
1
2
3
4
5
6
7
m
n
o
p
q
r
2-BrC6H4
2-BrC6H4
F
Br
F
Cl
Cl
F
CF2Cl
CF3
CF3
CF3
CF3
A/2 d
A/1 h
A/1 d
A/1 d
A/1 d
A/1 d
A/1 d
6h (63)
6i (82)
6j (89)
6j (55)
6k (55)
6l (69)
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2-NO2C6H4
CF2Cl
CF3
s
Cl
6m (97)
Binucleophile = N-methylethylenediamine R1 = R2 = R3 = H; R = H; Y = NMe
8
9
10
p
q
t
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
Cl
Cl
Br
CF3
CF3
CF3
A/1 d
A/4 h
A/4 h
6n (91)
3a (52)b 6o (35)
6p (92)
Binucleophile = N,N0-dimethylethylenediamine R1 = R2 = R3 = H; R = Me; Y = NMe
11
12
13
p
q
t
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
Cl
Cl
Br
CF3
CF3
CF3
A/1 d
THF, reflux, 7 h
A/6 d
6q (89)
3b (32)c
6r (76)
Binucleophile = 1,2-diaminocyclohexane R1 = R = H; R2 = R3= -(CH2)4-; Y = NH
2-NO2C6H4 Cl CF3 A/1 d
14
s
6s (82)
Binucleophile = ethanolamine R1 = R2 = R3 = R = H; Y = O
15
16
p
s
4-NO2C6H4
2-NO2C6H4
Cl
Cl
CF3
CF3
dioxane, reflux, 7 h
THF, reflux, 7 h
6t (53)
3c þ 4a (66)d 6u (60)
Binucleophile = 2-aminobutanol R2 = R3 = R = H; R1 = Et; Y = O
4-NO2C6H4- Cl CF3
neat, 80 °C, 6 h
Binucleophile = 2-amino-2-methylpropanol R3 = R = H; R1 = R2 = Me; Y = O
2-NO2C6H4- Cl CF3 neat, reflux, 2 h
17
18
p
s
6v (88)
6w (64)e
aIsolated yield. bThe enamine 3a was cyclized into imidazolidine 6o during purification by column chromatography on silica gel. cInitial styrene 1q
(25%) was recovered after column chromatography. dInitial styrene 1s (10%) was recovered after column chromatography. The mixture (∼1:1) of 3c and
4a has been transformed almost completely into the heterocycle 6u after reflux in dioxane for 19 h (yield 60% (starting from initial styrene) after column
chromatography). eIn the presence of Et3N (1 equiv).
more prolonged reaction time and/or more severe experi-
mental conditions were required.
of the olefinic proton and the signals of double bond carbon
atoms, correspondingly) are accompanied by the character-
istic signals of its isomer 4a (singlet of methylene group and
the quadruplet of the azomethine carbon atom). The simple
heating of the mixture of enamine 3c and its tautomer 4a in
dioxane for 19 h has afforded oxazolidine 6u in high yield.
The stereochemistry of enamine derivatives was determined
unambiguously by 2D NMR spectroscopy and deserves
some comments related to the mechanism of the reaction
of alkenes bearing an EWG. Taking into account the same Z/
E ratio of the initial substrate 1q and enamine 3a (Z/E = 4:1),
we concluded that the substitution of the halostyrenes pro-
ceeds stereoselectively with the retention of configuration.
These results are in a good agreement with the postulated
addition-elimination sequence of transformations that in-
volves intermediate formation of the adduct where most
steric interactions are minimized (Scheme 7).
We succeeded in confirming also the intermediate forma-
tion of enamines in the reaction. Sometimes the cyclization
step for substituted diamines or aminoalcohols was rather
slow and only acyclic derivatives 3 were obtained (entries 9,
12, 16). In fact, when styrene 1q was treated with N-met-
hylethylenediamine, only enamine 3a was obtained in good
yield (Table 2, entry 9). The reaction of the same styrene 1q
with symmetric N,N0-dimethylethylenediamine proceeds slowly,
leading to the acyclic derivative 3b as a major product in mode-
rate yield even after a long refluxing in THF (Table 2, entry
12). The enamines 3a,b were quite stable: no changes oc-
curred when they were kept at ambient temperature even for
2 weeks in CDCl3 solution or in the pure state. Surprisingly,
in the attempt to purify by column chromatography on silica
gel, enamine 3a undergoes a transformation into its cyclic
isomer 6o. Consequently, both cyclic and acyclic derivatives
can be isolated in pure state depending on the experimental
conditions.
Next, we checked the influence of the distance between
two nucleophilic centers of the binucleophile on the reaction
direction. We studied a reaction of the model substrate 1a
with 1,3-propylenediamine, which is a 1,3-binucleophile
(Scheme 8). We observed again the generality of the reaction;
the cleavage of the double bond was observed leading to the
It should be noted that enamine 3c is formed in the mixture
with their imino-tautomer 4a. Thus, in the 1H and 13C spec-
tra the signals of the enamine moiety of compound 3c (singlet
J. Org. Chem. Vol. 75, No. 16, 2010 5683

Nenajdenko et al.
JOCArticle
SCHEME 7. Stereochemistry of Reaction of Binucleophiles
with Styrenes 1 Bearing an Electron-Withdrawing Group
SCHEME 10. Reaction Pathways Depending on Substituent in
β-Halogeno-β-trifluoromethylstyrenes
SCHEME 8. Reactions of β-Halogeno-β-trifluoromethylstyr-
enes 1 with 1,3-Diaminopropane
tation and formation of imidazolines 7 are observed if the
binucleophile attacks the R-position (neighboring to the aryl
ring) of styrene or acetylene. Otherwise the reaction products
are imidazolidines 6.
Conclusion
formation of amidine derivative 22a and competitive forma-
tion of 21a.
In summary, the reaction direction of β-halogeno-β-tri-
fluoromethyl styrenes with N,N- and N,O-binucleophiles is
controlled by electron and sterical factors. Alkenes bearing
an EWG at the aromatic ring give trifluoromethylated
imidazolidines in good to high yields. The unprecedented
fragmentation of styrenes having an EDG is observed. The
possible reaction mechanism is discussed.
Electron-poor nitrostyrene 1p gave exclusively trifluoro-
methylated compound 21b, whereas electron-rich methoxy-
styrene 1k provided only the fragmentation product 22b. It
should be noted that the fragmentation/nonfragmentation
product ratio is very similar to that observed for ethylenedia-
mine. This fact points out additionally the decisive role of sty-
rene electron nature on the reaction direction. Electron-donat-
ing substituents in the aryl ring direct the initial attack of the
nucleophile to the R-position of styrene, leading to unstable
enamine 23. The latter one undergoes a cascade of transforma-
tions giving intermediate 24, which forms fragmentation pro-
ducts 22 and 25. Heterocycle 25 was observed in both mass and
NMR spectra, although we could not isolate it in pure form.
Formation of compound 25 is an additional proof of the
proposed fragmentation mechanism (Scheme 9).
Summarizing the obtained results, we can conclude that
the direction of reaction of binucleophiles with β-halogeno-
β-trifluoromethylstyrenes is controlled strongly by substitu-
ents on the aromatic ring. We can speculate that the reaction
occurs in two different pathways (Scheme 10) depending on
the nature of substituents. In the case of an EWG such as a
nitro group or a bulky substituent as o-bromine, the mechan-
ism includes the formation of captodative enamine 3 via
initial attack of the binucleophile on the β-olefin carbon
atom of styrene 1 followed by base-mediated elimination of
HHal. The isolation of the intermediate 3in some cases (Table 2,
entries 9, 12, 16) as a precursor of heterocycles 6 supports stron-
gly this hypothesis. To the best of our knowledge, the successful
synthesis of heterocycles 6 is the first example of double
nucleophilic addition to the same carbon atom of the double
bond adjacent to a strong electron-withdrawing group of cap-
todative system. In the case of electron-donating groups the
intermediate formation of acetylene 8 is possible. The fragmen-
Experimental Section
General Remarks. 1H, 13C, 15N, and 19F NMR spectra were
recorded on 400 MHz spectrometers in CDCl3 or DMSO-d6.
Chemical shifts (δ) in ppm are reported using TMS or residual
signals of chloroform (7.25 for 1H and 77.20 for 13C) or DMSO
(2.50 for 1H and 39.50 for 13C) as internal references. The coup-
ling constants (J) are given in hertz (Hz). The concerted applica-
1
tion of H-1H 2D COSY and NOESY homonuclear experi-
ments as well as 1H-13C 2D HSQC and HMBC heteronuclear
experiments was used for the distinction of the carbon and
proton resonances in cases of 3a-c, 4a, and 6n-r,t,u,w. The
silica gel used for flash chromatography was 230-400 mesh. All
reagents were of reagent grade and were either used as such or
distilled prior to use. All solvents were dried by standard pro-
cedures and freshly distilled prior to use. The β-bromo-,6e β-
chloro-,6b and β-fluoro-β-(tri-13d or difluoromethyl6b)styrenes
1a-u were prepared as reported previously. NMR spectra of
compounds 7a,b,d,g,15 7c,16 7f,17 7h,18 8a,b,19 17,20 22b,21 and
2522 are in agreement with published data.
General Procedure for Synthesis of Acetylenes 8. A preheated
100-mL three-necked round-bottomed flask was charged with
dry THF (30 mL) and hexamethyldisilazane (6.86 mL, 33 mmol)
and cooled down to -50 °C in argon flow. n-BuLi (13.2 mL of
2.5 M solution in hexane, 33 mmol) was slowly added, main-
taining the temperature below -30 °C. The reaction mixture was
kept 20 min at this temperature and cooled down to -90 °C.
Next, corresponding styrene 1 (30 mmol, solution in 10 mL of
dry THF) was added at a temperature below -70 °C. The
reaction mixture obtained was allowed to warm slowly to room
SCHEME 9. Possible Mechanism for the Reaction of Styrenes 1 with 1,3-Diaminopropane
5684 J. Org. Chem. Vol. 75, No. 16, 2010

Nenajdenko et al.
JOCArticle
temperature and broken down by a saturated solution of
NH4Cl. The organic phase was separated, and the water phase
was extracted with ether (3 ꢀ 20 mL). The combined extracts
were washed with water (2 ꢀ 50 mL) and dried over Na2SO4.
Volatiles were removed in vacuo, and the residue was filtered
through a short silica gel pad using hexane.
(NO2), 1652 (CdC), 3387 (NH), 3554 (OH) cm-1; 1H NMR (400
MHz, CDCl3) Z -izomer δ 2.36 (br.s., 1 H, OH), 2.85 (m, 2 H,
NCH2), 3.54 (m, 2 H, OCH2), 4.02 (br.s, 1 H, NH), 6.16 (s, 1 H,
dCH), 7.35 (m, 1 H, 4-H), 7.55 (m, 1 H, 5-H), 7.63 (m, 1 H, 6-H),
7.96 (m, 1 H, 3-H); E-izomer δ 3.16 (m, 2 H, NCH2), 3.85 (m, 2 H,
OCH2), 4.28 (s, 1 H, NH), 5.82 (s, 1 H, dCH); 13C NMR (100.6
MHz, CDCl3) Z-izomer δ 48.3 (NCH2), 61.1 (OCH2), 100.7 (q,
J = 5.6 Hz, dCH), 121.80 (q, J = 275.4 Hz, CF3), 124.9 (C-3),
127.9 (C-4), 130.0 (C-1), 131.4 (C-6), 133.0 (C-5), 135.2 (q, J =
30.4 Hz, dC-NH), 148.1 (C-2); E-izomer δ 45.7 (NCH2), 60.1
(OCH2), 98.1 (q, J = 2 Hz, dCH), 148.4 (C-2); 15N NMR (40.6
MHz, CDCl3) Z-izomer δ -326.6 (NH), -7.0 (NO 2); E-izomer δ
-320.1 (NH).
General Procedure for Reactions of β-Halogeno-β-(tri- or
difluoromethyl)styrenes 1 and Acetylenes 8 with Binucleophiles
2. The appropriate compound (styrene 1 or acetylene 8, 1-1.5
mmol) and the binucleophile 2 (5-15 mmol), either in the
solvent (2-3 mL) given or without solvent, were maintained
at room temperature or reflux or were heated in a sealed glass
tube with a Young tap (for conditions used in each particular
case see Tables 1 and 2). Excessive amine and the solvent were
evaporated off at reduced pressure, and the residue was purified
by column chromatography on silica gel using the appropriate
eluent [the following mixtures were used: CH2Cl2/pentane (2:1),
Et2O/hexane (1:2), CHCl3, CH2Cl2/MeOH (30:1), CHCl3/
MeOH (9:1), CH2Cl2/MeOH/NEt3 (80:15:5)]. In the NMR
spectra of some mixtures of the (Z,E)-enamines 3 and the
azomethines 4 only the most characteristic signals are given
for minor components.
N-Methyl-N0-[2-(3-nitrophenyl)-1-(trifluoromethyl)ethenyl]-
ethane-1,2-diamine (3a) (mixture (3.7:1) of Z,E-isomers). Yield
52%; yellow oil; ATR/FT-IR ν = 1349, 1526 (NO2), 1631
(CdC), 3378 (NH) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.15
(br.s., 2H, NH), 2.73 (s, 3 H, CH3), 2.82 (t, J = 2.0 Hz, 6.2 H,
CH2), 2.94 (t, J = 6.2 Hz, 2 H, CH2), 6.43 (s, 1 H, CHd), 7.50
(m, 1 H, 5-H), 7.70 (m, 1 H, 6-H), 8.08 (m, 1 H, 4-H), 8.42 (s, 1 H,
2-H); 13C NMR (100.6 MHz, CDCl3) δ 40.1 (NHCH3), 40.7
(CH2), 57.8 (CH2), 116.4 (q, J = 4.8 Hz, CHd), 122.5 (C-4),
122.8 (q, J = 280.8 Hz, CF3), 123.9 (C-2), 129.3 (C-5), 135.2 (C-
6), 136.4 (C-1), 139.4 (q, J = 28.4 Hz, dC-CF3), 148.5 (C-3).
Anal. Calcd for C12H14F3N3O2: C 49.83; H 4.88; N 14.53.
Found: C 49.52; H 4.69; N 14.11.
(Z)-N,N0-Dimethyl-N-[2-(3-nitrophenyl)-1-(trifluoromethyl)-
ethenyl]ethane-1,2-diamine (3b). Yield 32%); brown oil; ATR/
FT-IR ν = 1349, 1527 (NO2), 1630 (CdC), 3335 (NH) cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.70 (br.s., 1H, NH), 2.35 (s, 3 H,
CH3), 2.69 (m, 5 H, CH3, NHCH2), 3.00 (t, J = 6.2 Hz, 2 H,
N(Me)CH2), 6.40 (s, 1 H, CHd), 7.47 (m, 1 H, 5-H), 7.68 (m,
1 H, 6-H), 8.05 (m, 1 H, 4-H), 8.40 (s, 1 H, 2-H); 13C NMR (100.6
MHz, CDCl3) δ 36.3 (NHCH3), 40.9 (NCH3), 49.6 (NHCH2),
53.9 (NCH2), 115.9 (q, J = 4.8 Hz, CHd), 122.4 (C-4), 122.7 (q,
J = 280.8 Hz, CF3), 123.8 (C-2), 129.2 (C-5), 135.2 (C-6), 136.3
(C-1), 139.1 (q, J = 28.4 Hz, dC-CF3), 148.4 (C-3); 19F NMR
(282 MHz, DMSO-d6) δ -63.7; 15N NMR (40.6 MHz, CDCl3) δ
-11.6 (NO2), -345.3 (NCH3), -360.7 (NHCH3). Anal. Calcd
for C13H16F3N3O2: C 51.48; H 5.32; N 13.86. Found: 51.07; H
5.25; N 13.52.
2-{2,2,2-Trifluoro-[1-(2-nitrobenzyl)ethylidene]amino}ethanol
(4a) (E:Z isomers 1:9). ATR/FT-IR ν = 1343, 1523 (NO2), 1681
(CdN), 3554 (OH) cm-1 1H NMR (400 MHz, CDCl3) Z-
;
izomer δ 2.80 (br.s., 1 H, OH), 3.55 (t, J = 4.8 Hz, 2 H,
N-CH2), 3.86 (t, J = 4.8 Hz, 2 H, OCH2), 4.14 (s, 2 H, ArCH2),
7.21 (m, 1 H, 6-H), 7.44 (m, 1 H, 4-H), 7.58 (m, 1 H, 5-H), 8.02
(m, 1 H, 3-H); E-izomer δ 4.20 (s, 2 H, ArCH2), 7.25 (m, 1 H,
6-H); 13C NMR (100.6 MHz, CDCl3) Z-izomer δ 31.6 (ArCH2),
54.0 (NCH2), 61.6 (OCH2), 119.5 (q, J = 279.1 Hz, CF3), 125.7
(C-3), 128.8 (C-4), 130.6 (C-1), 131.0 (C-6), 134.0 (C-5), 148.7
(C-2), 157.4 (q, J = 32.4 Hz, CdN); 15N NMR (40.6 MHz,
CDCl3) Z-izomer δ -39.9 (CdN), -7.7 (NO2); E-izomer δ
-50.2 (CdN). Anal. Calcd for C11H11F3N2O3: C 47.83; H 4.01;
N 10.14. Found: C 47.80; H 3.72; N 10.19 (for the mixture of 3c
and 4a).
2-(4-Chlorobenzyl)-2-(trifluoromethyl)imidazolidine (6a). Yield
26%; colorless solid; mp 108-109 °C; 1H NMR (400 MHz,
CDCl3) δ 1.94 (br s, 2H, 2NH), 2.67-2.70 (m, 2H, CH2),
2.98-3.01 (m, 2H, CH2), 3.02 (s, 2H, CH2), 7.26 (d, J = 8.3
Hz, 2H, Ar), 7.35 (d, J = 8.3 Hz, 2H, Ar); 13C NMR (100 MHz,
CDCl3) δ 38.0 (CH2), 46.5 (2(-NH-CH2)), 80.5 (q, J = 27.0 Hz,
C-CF3), 126.9 (q, J = 286.7 Hz, CF3); 128.8 (CH), 132.2 (CH),
132.4, 133.6 (Ar). ESI-MS (m/z) calcd for C11H12ClF3N2H [Mþ]
265.0719, found 265.0726.
2-(4-Chlorobenzyl)-2-(chlorodifluoromethyl)imidazolidine (6b).
Yield 26%; colorless solid; mp 113-114 °C; 1H NMR (400 MHz,
CDCl3) δ 2.02 (br s, 2H, 2NH), 2.58-2.63 (m, 2H, CH2),
2.97-3.02 (m, 2H, CH2), 3.06 (s, 2H, CH2), 7.25 (d, J = 8.2
Hz, 2H, Ar), 7.31 (d, J = 8.2 Hz, 2H, Ar); 13C NMR (100 MHz,
CDCl3) δ 38.9 (CH2), 46.5 (2(-NH-CH2)), 84.4 (t, J = 22.5 Hz,
C-CF2Cl), 132.9 (t, J = 303.0 Hz, CF2Cl); 128.6 (CH), 132.1
(CH), 132.8, 133.5 (Ar). Anal. Calcd for C11H12Cl2F2N2: C
47.00; H 4.30; N 15.27. Found: C 47.17; H 4.43.
2-Benzyl-2-(trifluoromethyl)imidazolidine (6c). Yield 15%;
pale yellow solid; mp 43-44 °C; 1H NMR (400 MHz, CDCl3)
δ 2.02 (br s, 2H, 2NH), 2.62-2.66 (m, 2H, CH2), 2.94-2.98 (m,
2H, CH2), 3.07 (s, 2H, CH2), 7.27-7.30 (m, 2H, Ar), 7.34-7.41
(m, 3H, Ar); 13C NMR (100 MHz, CDCl3) δ 38.1 (CH2), 46.7
(2(-NH-CH2)), 80.6 (q, J = 27.8 Hz, C-CF3), 126.7 (q, J =
285.8 Hz, CF3); 127.6 (CH), 128.8 (CH), 130.7 (CH), 133.6 (Ar).
Anal. Calcd for C11H13F3N2: C 57.39; H 5.56. Found: C 57.56;
H 5.44.
Mixture (1.2:1) of (E,Z)-Azometine (3c) and (E,Z)-Enamine
(4a). Yellow oil; yield (66%).
2-{[2-(2-Nitrophenyl)-1-(trifluoromethyl)ethenyl]amino}ethanol
(3c) (mixture (3.8:1) of Z,E-isomers). ATR/FT-IR ν = 1343, 1523
2-(4-Fluorobenzyl)-2-(trifluoromethyl)imidazolidine (6d). Yield
10%; colorless solid; mp 65-67 °C; 1H NMR (400 MHz,
(15) Sun, M.; Wei, H.-T.; Li, D.; Zheng, Y.-G.; Cai, J.; Ji, M. Synth.
Commun. 2008, 38, 3151–3158.
(16) Salgado-Zamora, H.; Campos, E.; Jimenez, R.; Cervantes, H. Het-
erocycles 1998, 47, 1043–1050.
(17) Parik, P.; Senauerova, S.; Liskova, V.; Handlir, K.; Ludwig, M.
J. Heterocycl. Chem. 2006, 43, 835–841.
(18) Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006, 47, 79–82.
(19) Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova,
E. S.; Haufe, G. Synthesis 2009, 2249–2259.
(20) Levesque, G.; Gressier, J.-C.; Proust, M. Synthesis 1981, 963–965.
(21) Mizuhara, T.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Chem.
Commun. 2009, 3413–3415.
(22) Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu,
G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller,
J. L. J. Org. Chem. 1987, 52, 1017–1021.
CDCl3)
δ 1.98 (br s, 2H, 2NH), 2.67-2.70 (m, 2H,
CH2), 2.97-3.02 (m, 2H, CH2), 3.03 (s, 2H, CH2), 7.06 (t,
J = 8.5 Hz, 2H, Ar), 7.26-7.31 (m, 2H, Ar); 13C NMR
(100 MHz, CDCl3) δ 37.6 (CH2), 46.6 (2(-NH-CH2)), 80.5
(q, J = 29.5 Hz, C-CF3), 126.6 (q, J = 287.5 Hz, CF3); 115.6
(d, J = 21.1 Hz, CH), 129.5, 132.3 (d, J = 8.4 Hz, CH), 162.3
(d, J = 247.0 Hz) (Ar). Anal. Calcd for C11H12F4N2: C 53.23; H
4.87. Found: C 53.41; H 4.77.
2-(4-Methylbenzyl)-2-(trifluoromethyl)imidazolidine (6e). Yield
12%; colorless solid; mp 59-60 °C; 1H NMR (400 MHz, CDCl3)
δ 2.07 (br s, 2H, 2NH), 2.37 (s, 3H, Me), 2.64-2.69 (m, 2H, CH2),
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Nenajdenko et al.
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2.94-2.99 (m, 2H, CH2), 3.04 (s, 2H, CH2), 7.14-7.21 (m, 4H,
Ar); 13C NMR (100 MHz, CDCl3) δ 21.1 (Me), 37.5 (CH2), 46.7
(2(-NH-CH2)), 80.6 (q, J = 26.1 Hz, C-CF3), 125.6 (q, J =
288.3 Hz, CF3); 128.1, 129.6 (CH), 130.5 (CH), 137.5 (Ar). ESI-
MS (m/z) calcd for C12H15F3N2H [Mþ] 245.1266, found 245.1271.
2-(3-Methoxylbenzyl)-2-(trifluoromethyl)imidazolidine (6f). Yield
20%; colorless solid; mp 48-49 °C; 1H NMR (400 MHz, CDCl3) δ
2.06 (br s, 2H, 2NH), 2.66-2.72 (m, 2H, CH2), 2.95-2.99 (m, 2H,
CH2), 3.04 (s, 2H, CH2), 3.83 (s, 3H, MeO), 6.82-6.91 (m, 2H, Ar),
7.29 (t, J = 7.8 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) δ 38.0
(CH2), 46.7 (2(-NH-CH2)), 55.3 (MeO), 80.6 (q, J = 27.0 Hz, C-
CF3), 126.8 (q, J = 285.8 Hz, CF3); 112.8 (CH), 116.6 (CH), 123.0
(CH), 129.9 (CH), 135.1, 159.9 (Ar). Anal. Calcd for C12H15F3N2O:
C 55.38; H 5.81. Found: C 55.42; H 5.94.
2-(2-Methoxylbenzyl)-2-(trifluoromethyl)imidazolidine (6g).
Yield 20%; colorless solid; mp 67-68 °C; 1H NMR (400 MHz,
CDCl3) δ 2.49-2.62 (m, 4H, CH2, 2NH), 2.88-2.91 (m, 2H,
CH2), 3.15 (s, 2H, CH2), 3.87 (s, 3H, MeO), 6.95 (d, J = 7.7 Hz,
1H, Ar), 6.98 (td, J = 7.7 Hz, J = 0.9 Hz, 1H, Ar), 7.16 (dd, J =
7.7 Hz, J = 1.7 Hz, 1H, Ar), 7.30 (td, J = 7.7 Hz, J = 1.7 Hz,
1H, Ar); 13C NMR (100 MHz, CDCl3) δ 32.2 (CH2), 47.0
(2(-NH-CH2)), 55.6 (MeO), 81.4 (q, J = 29.5 Hz, C-CF3),
126.6 (q, J = 285.8 Hz, CF3); 111.2 (CH), 121.3 (CH), 122.3,
129.2 (CH), 133.0 (CH), 157.7 (Ar). Anal. Calcd for C12H15-
F3N2O: C 55.38; H 5.81. Found: C 55.50; H 5.92.
CDCl3) δ 2.07 (br s, 2H, 2NH), 2.45-2.49 (m, 2H, CH2),
2.92-2.98 (m, 2H, CH2), 3.51 (s, 2H, CH2), 7.42-7.46 (m,
2H, Ar), 7.55 (t, J = 7.6 Hz, 1H, Ar), 7.87 (d, J = 7.6 Hz,
1H, Ar); 19F NMR (282 MHz, CDCl3) δ -80.30; 13C NMR (100
MHz, CDCl3) δ 36.3 (CH2), 45.8 (2(-NH-CH2)), 84.3 (t, J =
22.8 Hz, C-CF2Cl), 132.8 (t, J = 303.9 Hz, CF2Cl); 124.8 (CH),
128.2 (CH), 129.5, 132.2 (CH), 134.1 (CH), 151.6 (Ar). Anal.
Calcd for C11H12ClF2N3O2: C 45.30; H 4.15. Found: C 45.47; H
4.23.
2-(2-Nitrobenzyl)-2-(trifluoromethyl)imidazolidine (6m). Yield
1
97%; pale yellow solid; mp 53-55 °C; H NMR (300 MHz,
CDCl3) δ 1.96 (br s, 2H, CH2), 2.51-2.57 (m, 2H, CH2), 2.92-
2.97 (m, 2H, CH2), 3.47 (s, 2H, CH2), 7.43 (dd, J = 7.6 Hz, J =
1.4 Hz, 1H, Ar), 7.47 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H, Ar), 7.56
(td, J =7.6Hz, J =1.4 Hz, 1H, Ar), 7.90(dd, J =7.6Hz, J = 1.6
Hz, 1H, Ar); 19F NMR (282 MHz, CDCl3) δ -81.5; 13C NMR
(75 MHz, CDCl3) δ 35.5, 45.8, 80.2 (q, J = 27.4 Hz, C-CF3),
126.5 (q, J = 288.4 Hz, CF3); 124.9 (CH), 128.3 (CH), 129.1,
132.2 (CH), 134.0 (CH), 151.5 (Ar). ESI-MS (m/z) calcd for
C11H12F3N3O2H [Mþ] 276.0960, found 276.0954. Anal. Calcd
for C11H12F3N3O2: C 48.00; H 4.39; N 15.27. Found: C 47.97; H
4.53; N 15.08.
1-Methyl-2-(4-nitrobenzyl)-2-(trifluoromethyl)imidazolidine (6n).
Yield 91%; light yellow solid; mp 112 °C; IR (KBr) ν = 1130,
1154, 1345, 1513, 1604, 3376 cm-1; MS (EI) m/z (relative inten-
1
2-(2-Bromobenzyl)-2-(chlorodifluoromethyl)imidazolidine (6h).
Yield 63%; brownish solid; mp 50-52 °C; 1H NMR (400 MHz,
CDCl3) δ 2.32 (br s, 2H, 2NH), 2.52-2.57 (m, 2H, CH2), 2.93-
2.99 (m, 2H, CH2), 3.34 (s, 2H, CH2), 7.17 (t, J = 7.6 Hz, 1H,
Ar), 7.30 (t, J = 7.6 Hz, 1H, Ar), 7.41 (d, J = 7.6 Hz, 1H, Ar),
7.59 (d, J = 7.6 Hz, 1H, Ar); 13C NMR (100MHz, CDCl3) δ 38.6
(CH2), 46.4 (2(-NH-CH2)), 84.9 (t, J = 23.2 Hz, C-CF2Cl),
133.0 (t, J = 302.7 Hz, CF2Cl); 125.7, 127.5 (CH), 129.1 (CH),
133.2 (CH), 133.3 (CH), 134.5 (Ar). Anal. Calcd for C11H12-
BrClF2N2: C 40.58; H 3.71. Found: C 40.39; H 3.80.
sity) 289 (Mþ, <1), 220 (24), 174 (22), 153 (100), 110 (40); H
NMR (400 MHz, CDCl3) δ 1.78 (s, 1 H, NH), 2.46 (m, 1 H), 2.65
(q, J = 1.6 Hz, 3 H), 2.89 (A-part of the AB-system, J = 14.1 Hz,
1 H), 2.90 (m, 3 H), 3.14 (B-part of the AB-system, J = 14.1 Hz,
1 H), 7.41 (d, J = 8.4 Hz, 2 H), 8.08 (d, J = 8.4 Hz, 2 H). 13
C
NMR (100.6 MHz, CDCl3) δ 34.0 (NCH3), 35.8 (ArCH2), 43.3
(HNCH2), 52.9 (NCH2), 80.1 (q, J = 25.1 Hz, N-C-N), 123.1
(C-3,5), 126.9 (q, J = 296.3 Hz, CF3), 132.0 (C-2,6), 142.6 (C-1),
147.3 (C-4). Anal. Calcd for C12H14F3N3O2: C 49.83; H 4.88; N
14.53. Found: C 49.85; H 5.03; N 14.87.
2-(2-Bromobenzyl)-2-(trifluoromethyl)imidazolidine (6i). Yield
82%; white solid; mp 42-43 °C; 1H NMR (400 MHz, CDCl3) δ
2.23 (br s, 2H, 2NH), 2.59-2.65 (m, 2H, CH2), 2.93-2.99 (m, 2H,
CH2), 3.30 (s, 2H, CH2), 7.19 (t, J = 7.6 Hz, 1H, Ar), 7.32 (t, J =
7.6 Hz, 1H, Ar), 7.40 (d, J = 7.6 Hz, 1H, Ar), 7.61 (d, J = 7.6 Hz,
1H, Ar); 13C NMR (100 MHz, CDCl3) δ 37.5 (CH2), 46.4
(2(-NH-CH2)), 80.9 (q, J = 27.0 Hz, C-CF3), 126.6 (q, J =
286.6 Hz, CF3); 125.7, 127.6 (CH), 129.3 (CH), 133.2 (CH), 133.4
(CH), 134.0 (Ar). Anal. Calcd for C11H12BrF3N2: C 42.74; H
3.91. Found: C 42.88; H 3.99.
2-(4-Nitrobenzyl)-2-(trifluoromethyl)imidazolidine (6j). Yield
27%; pale purple crystals; mp 108-109 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.57-2.67 (m, 2H, CH2), 2.73-2.84 (m, 2H, CH2),
2.98-3.09 (br s, 2H, CH2), 3.11 (s, 2H, CH2), 7.74 (d, J = 8.8
Hz, 2H, Ar), 8.16 (d, J = 8.8 Hz, 2H, Ar); 19F NMR (282 MHz,
DMSO-d6) δ -79.3; 13C NMR (75 MHz, DMSO-d6) δ 38.7,
45.7, 79.8 (q, J = 26.8 Hz, C-CF3), 126.6 (q, J = 287.7 Hz, CF3);
122.6 (CH), 132.1 (CH), 143.1, 146.5 (Ar). ESI-MS (m/z) calcd
for C11H12F3N3O2H [Mþ] 276.0960, found 276.0954. Anal.
Calcd for C11H12F3N3O2: C 48.00; H 4.39; N 15.27. Found: C
48.06; H 4.46; N 15.09.
1-Methyl-2-(3-nitrobenzyl)-2-(trifluoromethyl)imidazolidine
(6o). Yield 67%; orange-red solid; mp 51-52 °C; ATR/FT-IR
ν = 1350, 1523 (NO2), 3374 (NH) cm-1. MS (EI) m/z (relative
intensity) 289 (Mþ, <1), 220 (7), 174 (7), 153 (100), 110 (13), 90
(8), 69 (7); 1H NMR (400 MHz, CDCl3) δ 1.79 (s, 1 H, NH), 2.47
(m, 1 H), 2.69 (q, J = 2.0 Hz, 3 H, CH3), 2.90 (m, 4 H, CH3,
A-part of the AB-system), 3.18 (B-part of the AB-system, J =
13.8 Hz, 1 H), 7.48 (m, 1 H, 5-H), 7.59 (m, 1 H, 6-H), 8.14 (m,
2 H, 4-H, 2-H). 13C NMR (100.6 MHz, CDCl3) δ 34.1 (NCH3),
35.5 (ArCH2), 43.4 (NH-CH2), 52.9 (N-CH2), 80.1 (q, J =
24.6 Hz, N-C-N), 122.3 (C-4), 126.0 (C-2), 127.0 (q, J = 296.3
Hz, CF3), 128.9 (C-5), 136.8 (C-1), 137.3 (C-6), 148.1 (C-3).
Anal. Calcd for C12H14F3N3O2: C 49.83; H 4.88; N 14.53.
Found: C 50.06; H 4.86; N 14.26.
1-Methyl-2-(2-nitrobenzyl)-2-(trifluoromethyl)imidazolidine
(6p). Yield 92%; solid; mp 87 °C; IR (KBr) ν = 1153, 1361, 1526,
3395 cm-1; MS (EI) m/z (relative intensity) 289 (Mþ, <1), 220
(15), 173 (7), 153 (100), 110 (42); 1H NMR (400 MHz, CDCl3) δ
1.87 (s, 1 H, NH), 2.04 (m, 1 H), 2.49 (q, J = 2.1 Hz, 3 H), 2.77
(m, 3 H), 2.98 (A-part of the AB-system, J = 13.8 Hz, 1 H), 3.63
(B-part of the AB-system, J = 13.8 Hz, 1 H), 7.27-7.35 (m, 1 H,
6-H), 7.35-7.40 (m, 1 H, 4-H), 7.45-7.52 (m, 1 H, 5-H), 7.70-
7.75 (m, 1 H, 3-H). 13C NMR (100.6 MHz, CDCl3) δ 32.9
(N-CH3), 33.3 (q, J = 1.5 Hz, ArCH2), 43.3 (NH-CH2), 52.6
(N-CH2), 79.9 (q, J = 25.1 Hz, N-C-N), 124.4 (C-3), 126.7 (q,
J = 295.6 Hz, CF3), 128.1 (C-3), 129.2 (C-1), 131.8 (C-5), 134.3
(C-6), 152.1 (C-2); 19F NMR (376.5 MHz, CDCl3) δ -75.94.
Anal. Calcd for C12H14F3N3O2: C 49.83; H 4.88; F 19.70.
Found: C 49.80; H 5.10; F 19.72.
2-(3-Nitrobenzyl)-2-(trifluoromethyl)imidazolidine (6k). Yield
1
55%; pale yellow solid; mp 65-67 °C; H NMR (400 MHz,
CDCl3) δ 1.97 (br s, 2H, 2NH), 2.66-2.73 (m, 2H, CH2), 2.98-
3.02 (m, 2H, CH2), 3.10 (s, 2H, CH2), 7.51 (t, J = 7.9 Hz, 1H,
Ar), 7.69 (d, J = 7.9 Hz, 1H, Ar), 8.14 (dd, J = 7.9 Hz, J = 1.3
Hz, 1H, Ar), 8.24 (s, 1H, Ar); 13C NMR (100 MHz, CDCl3) δ
38.9 (CH2), 46.3 (2(-NH-CH2)), 80.2 (q, J = 27.0 Hz, C-CF3),
126.5 (q, J = 288.3 Hz, CF3); 122.4 (CH), 125.8 (CH), 129.1
(CH), 136.4, 137.2 (CH), 148.1 (Ar). Calcd for C11H12F3N3O2:
C 48.00; H 4.39. Found: C 47.87; H 4.49.
1,3-Dimethyl-2-(4-nitrobenzyl)-2-(trifluoromethyl)imidazolidine
(6q). Yield: 89%; yellow solid; mp 43-44 °C; MS (EI) m/z
(relative intensity) 303 (Mþ, <1), 234 (62), 188 (50), 167 (100),
2-(Chlorodifluoromethyl)-2-(2-nitrobenzyl)imidazolidine (6l).
Yield 69%; pale yellow solid; mp 98-100 °C; 1H NMR (400 MHz,
110 (45); H NMR (400 MHz, CDCl3) δ 2.50 (q, J = 1.7 Hz,
1
5686 J. Org. Chem. Vol. 75, No. 16, 2010

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JOCArticle
6 H), 2.77 (m, 2 H), 2.90 (m, 2 H), 3.06 (s, 2 H), 7.51 (d, J = 8.7
Hz, 2 H), 8.08 (d, J = 8.7 Hz, 2 H). 13C NMR (100.6 MHz,
CDCl3) δ 33.9 (N-CH3), 35.4 (ArCH2), 51.4 (N-CH2), 81.4 (q,
J = 23.6 Hz, N-C-N), 122.8 (C-3,5), 127.0 (q, J = 301.9 Hz,
CF3), 132.0 (C-2,6), 144.4 (C-1), 146.9 (C-4). IR (KBr) ν = 1132,
. Anal. Calcd for
C13H16F3N3O2: C 51.48; H 5.32; N 13.86. Found: C 51.75; H
5.45; N 13.48.
CHNH), 3.41 (d, J = 13.9 Hz, 1H, CH2-Ar), 4.01 (t, J =
7.1 Hz, 1H, CH2O), 7.53 (d, J = 8.7 Hz, 2H, Ar), 8.24 (d, J =
8.7 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3) δ -82.1; 13C
NMR (75 MHz, CDCl3) δ 10.5, 25.7, 37.1, 59.5, 73.0, 95.3 (q,
J = 29.7 Hz, C-CF3), 124.6 (q, J = 288.2 Hz, CF3); 123.5 (CH),
132.0 (CH), 141.1, 147.5 (Ar); minor isomer: 1H NMR (300
MHz, CDCl3) δ 2.52 (t, J = 8.0 Hz, 1H, CH2O), 3.93 (t, J = 7.1
Hz, 1H, CH2O); 19F NMR (282 MHz, CDCl3) δ -82.2; 13C
NMR (75 MHz, CDCl3) δ 10.8, 26.2, 38.8, 73.1; 123.2 (CH),
131.9 (CH), 141.7, 147.3 (Ar). ESI-MS (m/z) calcd for
C13H15F3N2O3Na [Mþ] 327.0932, found 327.0931. Anal. Calcd
for C13H15F3N2O3: C 51.32; H 4.97; N 9.21. Found: C 51.63; H
5.06; N 9.11.
1160, 1262, 1347, 1515, 1604 cm-1
1,3-Dimethyl-2-(2-nitrobenzyl)-2-(trifluoromethyl)imidazolidine
(6r). Yield 76%; yellow solid; mp 46-48 °C; IR (KBr) ν = 1134,
1160, 1265, 1358, 1529 cm-1; MS (EI) m/z (relative intensity) 303
(Mþ, <1), 234 (17), 187 (5), 167 (100), 110 (21); 1H NMR (400
MHz, CDCl3) δ 2.21 (q, J = 1.1 Hz, 6 H), 2.61 (m, 2 H), 2.76 (m,
2 H), 3.37 (s, 2 H), 7.35 (m, 1 H, 6-H), 7.43-7.50 (m, 2 H, 4-H,
5-H), 7.72 (m, 1 H, 3-H). 13C NMR (100.6 MHz, CDCl3) δ 31.4
(N-CH3), 35.6 (ArCH2), 51.7 (N-CH2), 80.8 (q, J = 24.3 Hz,
N-C-N), 124.3 (C-3), 126.8 (q, J = 297.8 Hz, CF3), 127.6 (C-
1), 130.4 (C-4), 131.2 (C-5), 134.4 (C-6), 152.5 (C-2). Anal. Calcd
for C13H16F3N3O2: C 51.48; H 5.32; N 13.86. Found: C 51.62; H
5.39; N 14.04.
2-(2-Nitrobenzyl)-2-(trifluoromethyl)-octahydro-1H-benzo[d]-
imidazole (6s). Yield 82%; white solid; mp 127-129 °C; 1H
NMR (400 MHz, CDCl3) δ 0.84-1.00 (m, 2H, CH2), 1.04-1.21
(m, 2H, CH2), 1.32-1.40 (m, 1H, CH2), 1.56-1.65 (m, 2H,
CH2), 1.66-1.73 (m, 1H, CH2), 1.80-1.88 (m, 1H, CH2), 1.96
(br s, 2H, 2NH), 2.52-2.60 (m, 1H, CH2), 3.24 (d, J = 13.7 Hz,
1H, CH2-Ar), 3.67 (d, J = 13.7 Hz, 1H, CH2-Ar), 7.47 (t, J =
7.6 Hz, 2H, Ar), 7.57 (td, J = 7.6 Hz, J = 0.8 Hz, 1H, Ar), 7.90
(d, J = 7.6 Hz, Ar); 13C NMR (100 MHz, CDCl3) δ 24.0 (CH2),
24.2 (CH2), 29.9 (CH2), 30.1 (CH2), 36.7 (CH2-Ar), 62.2 (CH-
NH), 62.5 (CH-NH), 78.6 (q, J = 27.8 Hz, C-CF3), 126.4 (q, J =
289.4 Hz, CF3); 124.8 (CH), 128.2 (CH), 129.4, 132.0 (CH),
134.1 (CH), 151.8 (Ar). Anal. Calcd for C15H18F3N3O2: C 54.71;
H 5.51. Found: C 54.92; H 5.62.
4,4-Dimethyl-2-(2-nitrobenzyl)-2-(trifluoromethyl)-1,3-oxazo-
lidine (6w). Yield 64%; white solid; mp 59 °C; IR ν = 1357, 1530
(NO2), 3383 (NH) cm-1; MS (EI) m/z (relative intensity) 305
(Mþ þ 1, <1), 168 (58), 55 (100); 1H NMR (400 MHz, CDCl3) δ
0.41 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 2.25 (s, 1 H, NH), 3.34 (d,
J = 7.8 Hz, 1 H, CH2N), 3.37 (A-part of AB-system, J = 14.2
Hz, 1 H, ArCH2), 3.53 (B-part of AB-system, J = 14.2 Hz, 1 H,
ArCH2), 3.67 (d, J = 7.8 Hz, 1 H, CH2N), 7.40-7.50 (m, 2 H,
4,5-H), 7.50-7.60 (m, 1 H, 6-H), 7.80-7.90 (m, 1 H, 3-H); 13
C
NMR (100.6 MHz, CDCl3) δ 27.8, 28.5 (CH3), 34.5 (ArCH2),
59.1 (NCMe2), 79.7 (OCH2), 96.0 (q, J = 29.5 Hz, CCF3), 124.8
(C-3), 124.9 (q, J = 289.9 Hz, CF3), 128.5 (C-1), 128.7 (C-4),
132.4 (C-5), 135.1 (C-6), 151.8 (C-2); 19F NMR (376.5 MHz,
CDCl3) δ -81.87; 15N NMR (40.6 MHz, CDCl3) δ -307.9
(NH), -4.5 (NO2). Anal. Calcd for C13H15F3N2O3: C 51.32; H
4.97; N 9.21. Found: C 51.35; H 5.13; N 9.30.
2-(4-Chlorophenyl)-4,5-dihydro-1H-imidazole (7a). Yield 41%;
white powder; mp 186-187 °C(lit.23 186-187 °C). 1H NMR (400
MHz, CDCl3) δ 3.80 (s, 4H, CH2), 4.41 (br s, 1H, NH), 7.38 (d,
J = 8.6 Hz, 2H, Ar), 7.74 (d, J = 8.6 Hz, 2H, Ar). ESI-MS (m/z)
calcd for C9H9ClN2H [Mþ] 181.0533, found 181.0527.
2-(4-Nitrobenzyl)-2-(trifluoromethyl)-1,3-oxazolidine(6t). Yield
53%; yellow-orange solid; mp 113-114 °C; IR (KBr) ν = 1350,
1520 (NO2), 1606, 3323 (NH) cm-1; MS (EI) m/z (relative
intensity) 276 (Mþ, <1), 257 (2), 245 (2), 229 (2), 207 (8), 177
2-Phenyl-4,5-dihydro-1H-imidazole (7b). Yield 55%; white
1
powder; mp 102-103 °C (lit.23 101-102 °C); H NMR (400
MHz, DMSO-d6) δ 3.60 (s, 4H, CH2), 7.40-7.47 (m, 3H, Ar),
7.82 (d, J = 7.8 Hz, 2H, Ar). ESI-MS (m/z) calcd for C9H10N2H
[Mþ] 147.0922, found 147.0917.
1
(2), 161 (5), 140 (100), 136 (5), 89 (25), 69 (25); H NMR (400
MHz, CDCl3) δ 2.05 (br.s, J = 7.5 Hz 1 H, NH), 2.89 (m, 1 H),
3.05 (A-part of the AB-system, J = 14.1 Hz, 1 H), 3.34 (B-part of
the AB-system, J = 14.1 Hz, 1 H), 3.90 (m, 1 H), 7.48 (d, J = 8.2
Hz, 2 H), 8.15 (d, J = 8.2 Hz, 2 H); 13C NMR (100.6 MHz,
CDCl3) δ 37.4 (ArCH2), 46.3 (NCH2), 68.2 (OCH2), 95.3 (q, J =
29.5 Hz, N-C-N), 123.8 (C-3,5), 124.9 (q, J = 288.2 Hz, CF3),
132.1 (C-2,6), 141.2 (C-1), 147.8 (C-4). Anal. Calcd for
C11H11F3N2O3: C 47.83; H 4.01; N 10.14. Found: C 47.85; H
3.98; N 10.04.
2-(2-Nitrobenzyl)-2-(trifluoromethyl)-1,3-oxazolidine (6u). Yield
60%; white solid; mp 99 °C; IR (KBr) ν = 1368, 1529 (NO2), 3324
(NH) cm-1; MS (EI) m/z (relative intensity) 276 (Mþ, <1), 259
(3), 214 (5), 198 (6), 169 (5), 140 (100), 120 (8), 92 (17), 77 (18), 69
(33); 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 1 H, NH), 2.77 (m, 1
H), 3.04 (m, 1 H), 3.30 (m, 1 H), 3.40 (A-part of the AB-system,
J = 14.2 Hz, 1 H), 3.64 (B-part of the AB-system, J = 14.2 Hz,
1 H), 3.86 (m, 1 H), 7.42-7.48 (m, 2 H, 4-H, 5-H), 7.55 (m, 1 H,
6-H), 7.85 (m, 1 H, 3-H). 13C NMR (100.6 MHz, CDCl3) δ 34.1
(ArCH2), 45.9 (NCH2), 68.2 (OCH2), 95.2 (q, J = 29.9 Hz,
O-C-N), 124.8 (q, J = 288.2 Hz, CF3), 125.0 (C-3), 128.0 (C-
1), 128.8 (C-4), 132.6 (C-5), 134.5 (C-6), 151.5 (C-2). Anal. Calcd
for C11H11F3N2O3: C 47.83; H 4.01; N 10.14. Found: C 47.80; H
3.82; N 10.15.
2-(4-Fluorophenyl)-4,5-dihydro-1H-imidazole (7c). Yield 55%;
white powder; mp149-150 °C (lit.16 147-148 °C); 1H NMR(400
MHz, CDCl3) δ 3.78 (s, 4H, CH2), 5.59 (br s, 1H, NH), 7.06 (t,
J = 8.6 Hz, 2H, Ar), 7.78-7.83 (m, 2H, Ar).
2-(4-Methylphenyl)-4,5-dihydro-1H-imidazole(7d). Yield 56%;
white powder; mp180-181 °C (lit.23 178-179 °C); 1H NMR(400
MHz, CDCl3) δ2.39(s,3H, Me), 3.78 (s, 4H, CH2), 5.03 (br s, 1H,
NH), 7.21 (d, J = 8.1 Hz, 2H, Ar), 7.70 (d, J = 8.1 Hz, 2H, Ar).
ESI-MS (m/z) calcd for C10H12N2H [Mþ] 161.1079, found
161.1075.
2-(3-Methoxyphenyl)-4,5-dihydro-1H-imidazole (7e). Yield 64%;
white powder; mp 96-97 °C(lit.23 98-99 °C); 1HNMR(400MHz,
CDCl3) δ 3.72 and 3.73 (both s, 7H, MeO and 2CH2), 6.94 (dd, J =
8.0 Hz, J = 2.1 Hz, 1H, Ar), 7.20 (t, J = 8.0 Hz, 1H, Ar), 7.39 (d,
J = 8.0 Hz, 1H, Ar), 7.44 (d, J = 2.1 Hz, 1H, Ar), 7.91 (br s, 1H,
NH).
2-(2-Methoxyphenyl)-4,5-dihydro-1H-imidazole (7f). Yield
1
45%; white solid; mp 60-62 °C (lit.17 60-64 °C); H NMR
(400 MHz, CDCl3) δ 3.64 (s, 4H, 2CH2), 3.89 (s, 3H, MeO),
5.70 (br s, 1H, NH), 7.00 (t, J = 7.8 Hz, 1H, Ar), 7.06 (d, J =
7.8 Hz, 1H, Ar), 7.43 (td, J = 7.8 Hz, J = 1.8 Hz, 1H, Ar), 8.01
(dd, J = 7.8 Hz, J = 1.8 Hz, 1H, Ar).
2-(4-Methoxyphenyl)-4,5-dihydro-1H-imidazoleHydrobromide
(7g). Yield 61%; white powder; mp 218-220 °C (lit.23 218-
219 °C); 1H NMR (400 MHz, CD3CN) δ 3.90 (s, 3H, MeO), 3.96
2-(4-Nitrobenzyl)-4-ethyl-2-(trifluoromethyl)oxazolidine (6v).
mixture of isomers (93:7); yield 88%; white crystals; mp 72-
75 °C; major isomer: 1H NMR (300 MHz, CDCl3) δ 0.75 (t, J =
7.4 Hz, 3H, Me), 0.94-1.11 (m, 1H, CH2-CH3), 1.19-1.35 (m,
1H, CH2-CH3), 1.74 (br s, 1H, NH), 2.80 (t, J = 8.0 Hz, 1H,
CH2O), 3.08 (d, J = 13.9 Hz, 1H, CH2-Ar), 3.29-3.44 (m, 1H,
(23) Piskov, V. B.; Kasperovich, V. P.; Yakovleva, L. M. Chem. Hetero-
cycl. Compd. 1976, 12, 917–923.
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(s, 4H, CH2), 7.11 (d, J = 8.8 Hz, 2H, Ar), 8.26 (d, J = 8.8 Hz,
2H, Ar).
3.06-3.16 (m, 2H, NHCH2), 7.26 (d, J = 8.5 Hz, 2H, Ar), 7.31
(d, J = 8.5 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3) δ 25.2
(CH2), 40.5 (2(-NH-CH2)), 40.8 (CH2Ar), 70.0 (t, J = 25.1
Hz, C-CF3), 127.3 (t, J = 293.5 Hz, CF3); 128.4 (CH), 132.6
(CH), 133.4 (2 -C=, (Ar). Anal. Calcd for C12H14ClF3N2: C
51.71; H 5.06. Found: C 51.92; H 5.17.
2-(4-Nitrobenzyl)-2-(trifluoromethyl)-hexahydropyrimidine
(21b). Yield 62%; colorless crystals; mp 143-145 °C; 1H NMR
(400 MHz, CDCl3) δ 1.28-1.40 (m, 1H, CH2), 1.42-1.50 (m,
1H, CH2), 1.57 (br s, 2H, 2NH), 2.90-2.98 (m, 2H, NHCH2),
2.99 (s, 2H, CH2Ar), 3.07-3.13 (m, 2H, NHCH2), 7.51 (d, J =
8.6 Hz, 2H, Ar), 8.16 (d, J = 8.6 Hz, 2H, Ar); 13C NMR (100
MHz, CDCl3) δ 25.0 (CH2), 40.4 (2(-NH-CH2)), 41.2
(CH2Ar), 70.4 (t, J = 25.4 Hz, C-CF3), 127.1 (t, J = 294.2
Hz, CF3); 123.2 (CH), 132.2 (CH), 142.2, 147.3 (Ar). Anal.
Calcd for C12H14F3N3O2: C 49.83; H 4.88. Found: C 49.73; H
4.97.
2-(4-Chlorophenyl)-1,4,5,6-tetrahydropyrimidine (22a). Yield
51%; white powder; mp 127-130 °C; 1H NMR (400 MHz,
CDCl3) δ 1.64 (quintet, J = 5.7 Hz, 2H, CH2), 3.24 (t, J = 5.7
Hz, 4H, 2N-CH2), 6.23 (br s, 1H, NH), 7.13 (d, J = 8.5 Hz, 2H,
Ar), 7.42 (d, J = 8.5 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
δ 20.2 (CH2), 41.5 (2(-NH-CH2)) 154.8 (CdN); 127.8 (CH),
128.2 (CH), 134.5, 135.7 (Ar). Anal. Calcd for C10H11ClN2: C
61.70; H 5.70. Found: C 61.50; H 5.84.
2-(4-Methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (22b). Yield
42%; white solid; mp 132-135 °C (lit.21 132-134 °C); 1H NMR
(400 MHz, CDCl3) δ 1.71 (quintet, J = 5.8 Hz, 2H, CH2), 3.34 (t,
J = 5.8 Hz, 4H, 2N-CH2), 3.70 (s, 3H, MeO), 4.48 (br s, 1H,
NH), 6.75 (d, J = 8.8 Hz, 2H, Ar), 7.51 (d, J = 8.8 Hz, 2H, Ar).
2-Methyl-1,4,5,6-tetrahydropyrimidine (25). 1H NMR (400
MHz, DMSO-d6) δ 1.72 (quintet, J = 5.8 Hz, 2H, CH2), 2.04
(s, 3H, CH3), 3.25 (t, J = 5.8 Hz, 4H, 2N-CH2).
2-(3,4-Dimethoxyphenyl)-4,5-dihydro-1H-imidazole (7h). Yield
54%; white powder; mp 152-154 °C (lit.24 153-154 °C); 1H
NMR (400 MHz, DMSO-d6) δ 3.61 (s, 4H, 2CH2), 3.78 and 3.80
(both s, 3H, MeO), 6.99 (d, J = 8.5 Hz, 1H, Ar), 7.38 (dd, J = 8.5
Hz, J = 1.8 Hz, 1H, Ar), 7.44 (d, J= 1.8 Hz, 1H, Ar). ESI-MS(m/
z) calcd for C11H14N2O2H [Mþ] 207.1134, found 207.1127.
1-Methyl-2-(4-methylphenyl)-4,5-dihydroimidazole Hydrobro-
mide (7i). Yield 65%; yellow solid; mp 148-150 °C; MS (EI)
m/z (relative intensity) 174 (29, Mþ), 131 (100), 116 (17), 91 (23),
65 (28); 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3 H, Me), 3.17 (s,
3 H, NCH3), 3.95 (m, 2 H, NCH2), 4.13 (m, 2 H, dNCH2), 7.28
(d, J = 8.0 Hz, 2 H, 3,5-H), 7.61 (d, J = 8.0 Hz, 2 H, 2,6-H),
9.50-10.50 (br s, 1 H, HBr). 13C NMR (100.6 MHz, CDCl3) δ
21.8 (Me), 35.1(NMe), 42.8 (CH2N), 52.7 (CH2N=), 118.9 (C-
1), 129.3 (C-3,5), 130.0 (C-2,6), 144.8 (C-4), 166.3 (N-CdN).
Anal. Calcd for C11H15BrN2 H2O: C 48.36; H 6.27; N 10.25.
Found: C 48.28; H 5.91; N 10.00.
2-(4-Methoxyphenyl)-1-methyl-4,5-dihydroimidazole Hydrobro-
1
mide (7j). Yield 58%, yellow solid; mp 143-144 °C; H NMR
(400 MHz, CDCl3) δ 3.08 (s, 3 H, CH3), 3.68 (s, 3 H, CH3), 3.80
(m, 2 H, CH2), 4.00 (m, 2 H, CH2), 6.84 (d, J = 8.7 Hz, 2 H, 3,5-
H), 7.58 (d, J = 8.7 Hz, 2 H, 2,6-H); 13C NMR (100.6 MHz,
CDCl3) δ 35.1 (NMe), 42.3 (CH2-N), 52.6 (CH2-N=), 55.5
(OMe), 113.3 (C-1), 114.6 (C-3,5), 131.3 (C-2,6), 163.5 (C-4),
165.6 (N-CdN). Anal. Calcd for C11H15BrN2O 0.5 H2O: C
47.16; H 5.76; N 10.00. Found: C 47.21; H 5.67; N 9.86.
1-Chloro-4-(3,3,3-trifluoroprop-1-ynyl)benzene (8a). Yield 77%;
colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.6
Hz, 2H, Ar), 7.49 (d, J = 8.6 Hz, 2H, Ar).
1-Methoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene (8b). Yield
1
85%; colorless liquid; H NMR (400 MHz, CDCl3) δ 3.83 (s,
3H, OCH3), 6.89 (d, J = 8.9 Hz, 2H, Ar), 7.49 (d, J = 8.9 Hz,
2H, Ar).
Acknowledgment. This research was supported by the
Russian Foundation for Basic Research (grants no. 08-03-
00067-a, 08-03-00736-a, and 10-03-00897-a) and Federal
Special Program (grant P962).
2-Methyl-4,5-dihydro-1H-imidazole (17). 1H NMR (400
MHz, DMSO-d6) δ 1.79 (s, 3H, CH3), 3.40 (s, 4H, 2CH2).
2-(4-Chlorobenzyl)-2-(trifluoromethyl)-hexahydropyrimidine
1
(21a). Yield 30%; viscous oil; H NMR (400 MHz, CDCl3) δ
1.25-1.36 (m, 1H, CH2), 1.39-1.47 (m, 1H, CH2), 1.55 (br s,
2H, 2NH), 2.86 (s, 2H, CH2Ar), 2.89-2.97 (m, 2H, NHCH2),
Supporting Information Available: 1H and 13C NMR spec-
tra of all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Shi, Z.; Gu, H. Synth. Commun. 1997, 27, 2701–2709.
5688 J. Org. Chem. Vol. 75, No. 16, 2010