Simple synthesis of 2-aminoaryliminophosphoranes from N -aryl-2-nitrosoanilines and their application in 2-aminobenzimidazole synthesis

Article abstract of DOI:10.1055/s-0033-1340055

Condensation of N-aryl-2-nitrosoanilines with triphenylphosphine leads efficiently to substituted aryliminophosphoranes which, in turn, react with alkyl isocyanates furnishing 2-alkylaminobenzimidazole derivatives in high yields. Georg Thieme Verlag Stutt

Full text of DOI:10.1055/s-0033-1340055

LETTER
▌217
lSetitemr ple Synthesis of 2-Aminoaryliminophosphoranes from N-Aryl-2-nitroso-
anilines and Their Application in 2-Aminobenzimidazole Synthesis
Synthesis of Aryliminophosphoranes and 2-Aminobenzimidazoles
Emilia Łukasik, Zbigniew Wróbel*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: zbigniew.wrobel@icho.edu.pl
Received: 13.09.2013; Accepted after revision: 01.10.2013
The reaction appears to be general with regard to substit-
Abstract: Condensation of N-aryl-2-nitrosoanilines with triphe-
uents para to the nitroso group as well as the aryl group in
nylphosphine leads efficiently to substituted aryliminophos-
the N-aryl-2-nitrosoanilines. Steric hindrance caused by
phoranes which, in turn, react with alkyl isocyanates furnishing
two ortho-methyl groups in the N-aryl ring (Table 1, entry
3) lowered the yield of the product only slightly. 2-Aryl-
amino triphenyliminophosphoranes 3 turned out to be sta-
ble, crystalline compounds which can be shelf-stored and
purified by chromatography without notable decomposi-
tion.11 When stirred in wet THF, 3g remained unchanged,
but after acidification slow hydrolysis/reduction to the
corresponding diamine was observed. The process was
much faster in refluxing ethanolic HCl;12 as a result 3g
was converted into 5-chloro-1-N-(4-chlorophenyl)ben-
zene-1,2-diamine, albeit in rather low yield.
2-alkylaminobenzimidazole derivatives in high yields.
Key words: cyclization, condensation, heterocycles, annulation
Aryliminophosphoranes were first reported 1919.1a Since
then several methods for their synthesis have been devel-
oped including the Staudinger reaction of aromatic azides
with phosphines,1,2 coupling of amines and phosphines
with the help of halogenating agents,3 oxidants such as al-
kyl azodicarboxylates4 or acetylenedicarboxylates.5 In
very few cases, they have been obtained from nitro
compounds6 or via elaborate rearrangements.5 Preparation
of aryliminophosphoranes from nitrosoarenes is, to our
knowledge, so far unknown.7
Table 1 Synthesis of Aryliminophosphoranes 3
Entry
X
Ar
Product 3 Yield (%)a
In 2007 we described a simple and efficient method for
the synthesis of N-aryl-2-nitrosoanilines from nitroarenes
and anilines in basic media.8 We proved the versatility of
these compounds especially for the synthesis of some
nitrogen-containing heterocyclic frameworks.8a,9
1
2
3
4
5
6
7
8
Cl
4-MeC6H4
4-MeC6H4
2,6-Me2C6H3
4-ClC6H4
3a
3b
3c
3d
3e
3f
98
96
85
93
94
89
90
97
OMe
Cl
F
Having numerous 2-nitrosoanilines 1 readily accessible,
we tried to access aryliminophosphoranes by the reaction
of 1 with triphenylphosphine (2). The procedure was very
simple and comprised portionwise addition of the solid
substrate to a suspension of an excess of triphenylphos-
phine in dry acetonitrile, without exclusion of air or mois-
ture, followed by stirring at room temperature until
Br
Cl
4-MeC6H4
2-MeC6H4
4-ClC6H4
Cl
3g
3h
Ph
4-MeC6H4
completion of reaction. The reaction proceeded smoothly a Isolated yield.
furnishing products 3 in almost quantitative yields (Table
1).10 In most cases the products precipitated from the re-
action mixture in a pure form. Additional column chroma-
O
PPh3
N
N
tography of the filtrate improved the isolated yield
marginally. Since nitroso compounds 1 are more accessi-
ble than the corresponding azides, this approach appears
to be a valuable alternative to the Staudinger method.
NHAr
NHAr
MeCN
r.t.
Ph3P
+
2
X
1
X
3
The mechanism of the reaction probably involves the
Cadogan formation of nitrene 4,7a an active intermediate,
which condenses with an excess of 2 to form the final 4-
X-2-N-aryl-1-N-(triphenyl-λ5-phosphanylidene)benzene-
1,2-diamine 3 (Scheme 1).
••
N
NHAr
X
4
SYNLETT 2014, 25, 0217–0220
Advanced online publication: 12.11.2013
Scheme 1
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340055; Art ID: ST-2013-D0876-L
© Georg Thieme Verlag Stuttgart · New York

218
E. Łukasik, Z. Wróbel
LETTER
4-X-2-N-Aryl-1-N-(triphenyl-λ5-phosphanylidene)ben-
zene-1,2-diamines were then applied to the synthesis of 1-
aryl-2-aminobenzimidazoles. For this purpose we adopt-
ed the known reaction of iminophosphoranes with isocy-
anates, initially leading to carbodiimides, susceptible to
further conversions.13 In our case intramolecular addition
of the nucleophilic ortho-amine function to the carbodi-
imide would be expected to lead to the 2-aminobenzimid-
azole framework (Scheme 2).14 In fact, the reaction of 3
with alkyl isocyanates proceeded smoothly in dichloro-
methane solution at room temperature furnishing the ex-
pected products in good to excellent yields (Table 2).15,16
References and Notes
(1) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(b) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 436. (c) Gololobov, Y. G.; Kasukhin,
L. F. Tetrahedron 1992, 48, 1353.
(2) (a) Nie, Y.-B.; Duan, Z.; Ding, M.-W. Tetrahedron 2012,
68, 965. (b) Alajarin, M.; Bonillo, B.; Marin-Luna, M.;
Vidal, A. l.; Sanchez-Andrada, P.; Orenes, R.-A.
Tetrahedron 2012, 68, 4672. (c) Burns, C. T.; Shang, S.;
Thapa, R.; Mashuta, M. S. Tetrahedron Lett. 2012, 53, 4832.
(d) Foster, R. S.; Adams, H.; Harrity, J. P. A.; Jakobi, H.
J. Org. Chem. 2013, 78, 4049. (e) Alajarin, M.; Bonillo, B.;
Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A. Eur. J. Org.
Chem. 2011, 1896. (f) Casimiro, M.; Iglesias, M. J.; Lopez,
O. F.; Roces, L.; Garcia-Granda, S. Org. Lett. 2013, 15,
2378.
N
3
NHR
+
RNCO
(3) (a) Llamas-Saiz, A. L.; Foces-Foces, C.; Elguero, J.; Molina,
P.; Alajarin, M.; Vidal, A. J. Chem. Soc., Perkin Trans. 2
1991, 1667. (b) He, H.-F.; Wang, Z.-J.; Bao, W. Adv. Synth.
Catal. 2010, 352, 2905. (c) De Borger, R.; Collas, A.;
Dommisse, R.; Blockhuys, F. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 2010, 66, o–50. (d) Yun, J. C.; Han,
N. S.; Soo, Y. J.; Kim, J.; Dong, J. C.; Jae, Y. L.; Rhim, H.
Arch. Pharm. (Weinheim) 2008, 341, 661. (e) Zeng, F.;
Alper, H. Org. Lett. 2013, 12, 1188.
6
N
X
Ar
7
N
R
C
N
NHAr
– POPh3
(4) Adib, M.; Sheikhi, E.; Deljoush, A. Tetrahedron 2011, 67,
4137.
X
(5) Yavari, I.; Adib, M.; Hojabri, L. Tetrahedron 2002, 58,
7213.
8
Scheme 2
Table 2 Synthesis of 2-Aminobenzimidazoles from 3
(6) Duchek, J.; Vasella, A. Helv. Chim. Acta 2011, 94, 977.
(7) Reactions of the nitroso group with trivalent phosphorous
compounds found in the literature are more complex, rarely
leading to iminophosphorane-type products: (a) Cadogan, J.
I. G. Q. Rev. Chem. Soc. 1968, 22, 222. (b) Bunyan, P. J.;
Cadogan, J. I. G. J. Chem. Soc. 1963, 42. (c) Dyatkin, B. L.;
Mochalina, E. P.; Konstantinov, Y. S.; Sterlin, S. R.;
Knunyants, I. L. Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.) 1967, 2200. (d) Wang, H.; Xian, M. Angew.
Chem. Int. Ed. 2008, 47, 6598.
Entry 3
X
Ar
6
R
Product Yield
7
(%)a
1
2
3a
Cl
4-MeC6H4
6a
6a
n-Bu 7aa
n-Bu 7ba
n-Bu 7ca
n-Bu 7da
85
87
94
93
86
89
69
90
92
91
89
3b
3c
3d
3d
3d
3d
3c
3a
3e
3f
OMe 4-MeC6H4
(8) (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel,
Z.; Kwast, A. Synthesis 2010, 3865.
3
Cl
F
2,6-Me2C6H3 6a
(9) (a) Wróbel, Z.; Stachowska, K.; Grudzień, K.; Kwast, A.
Synlett 2011, 1439. (b) Kwast, A.; Stachowska, K.;
Trawczyński, A.; Wróbel, Z. Tetrahedron Lett. 2011, 6484.
(c) Wróbel, Z.; Stachowska, K.; Kwast, A.; Gościk, A.;
Królikiewicz, M.; Pawłowski, R.; Turska, I. Helv. Chim.
Acta 2013, 96, 956. (d) Wróbel, Z.; Stachowska, K.; Kwast,
A. Synthesis 2013, 45, 127. (e) Wróbel, Z.; Królikiewicz, M.
J. Heterocycl. Chem. 2013, in press. (f) Królikiewicz, M.;
Cmoch, P.; Wróbel, Z. Synlett 2013, 24, 973.
4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
6a
6b
6c
6d
5
F
Et
7db
6
F
t-Bu 7dc
7
F
Ph
Et
Et
Et
Et
7dd
7cb
7ab
7eb
7fb
8
Cl
Cl
Br
Cl
2,6-Me2C6H3 6b
9
4-MeC6H4
4-MeC6H4
2-MeC6H4
6b
6b
6b
(g) Królikiewicz, M.; Błaziak, K.; Danikiewicz, W.;
Wróbel, Z. Synlett 2013, 24, 1945.
10
11
(10) General Procedure for the Synthesis of 3
To a stirred suspension of Ph3P (3275 mg, 12.5 mmol) in dry
MeCN (25 mL) solid N-aryl-2-nitrosoaniline 1 (5 mmol)
was added portionwise over 30 min under external cooling
with cold water, and the mixture was stirred at r.t. overnight.
The precipitated solid was filtered off, and the filtrate was
concentrated under vacuum and chromatographed using
hexane–EtOAc gradient elution (8:1 to 2:1). An analytically
pure sample of the product was obtained by recrystallization
from EtOAc–hexane.
a Isolated yield.
Since variously substituted 2-aminobenzimidazoles show
biological activity17 this simple and efficient method for
their formation should provide a worthwhile approach
compared to the other known routes.
(11) Analytical Data for Novel Products 3
Compound 3a: pale yellow crystals; mp 164–167 °C. 1H
NMR (500 MHz, DMSO-d6): δ = 2.26 (s, 3 H), 6.22 (d, J =
8.2 Hz, 1 H), 6.32 (dd, J = 8.2, 2.5 Hz, 1 H), 6.95 (t, J = 2.6
Hz, 1 H), 7.12 (s, 4 H), 7.55–7.61 (m, 7 H), 7.62–7.66 (m, 3
Synlett 2014, 25, 217–220
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Aryliminophosphoranes and 2-Aminobenzimidazoles
219
H), 7.73–7.78 (m, 6 H). 13C NMR (125 MHz, DMSO-d6): δ
7.61–7.66 (m, 3 H), 7.71–7.76 (m, 6 H), 7.81 (s, 1 H). 13
C
= 20.3, 110.8, 117.5, 118.8, 119.2 (d, JCP = 10 Hz), 120.8,
129.0 (d, JCP = 12 Hz), 129.5 (d, JCP = 99 Hz), 129.6, 129.7,
132.1 (d, JCP = 10 Hz), 132.2 (d, JCP = 2 Hz), 137.5, 139.1 (d,
JCP = 20 Hz), 140.0. Ms (EI): m/z (%) = 495 (19), 494 950),
493 (50), 492 (100), 262 (44), 183 (45). HRMS (EI): m/z
calcd for C31H26N231P35Cl: 492.1522; found: 492.1529.
Compound 3b: pale yellow crystals; mp 188–190 °C. 1H
NMR (500 MHz, DMSO-d6): δ = 2.24 (s, 3 H), 3.55 (s, 3 H),
5.92–5.98 (m, 1 H), 6.18–6.25 (m, 1 H), 6.65–6.71 (m, 1 H),
NMR (125 MHz, DMSO-d6): δ = 113.8, 118.7, 119.3, 119.9
(d, JCP = 10 Hz), 120.5, 123.0, 128.9, 129.0 (d, JCP = 12 Hz),
129.5 (d, JCP = 99 Hz), 132.1 (d, JCP = 10 Hz), 132.2 (d, JCP
= 3 Hz), 137.5 (d, JCP = 20 Hz), 139.1, 142.2. MS (EI): m/z
(%) = 516 (20), 515 (32), 514 (74), 513 (51), 512 (100), 262
(63), 183 (64). HRMS (EI): m/z calcd for C30H23N231P35Cl2:
512.0976; found: 512.0974.
Compound 3h: yellow crystals; mp 185–186 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 2.25 (s, 3 H), 6.38 (d, J = 8.1 Hz,
1 H), 6,65 (dd, J = 8.1, 2.1 Hz, 1 H), 7.09–7.11 (m, 2 H),
7.19–7.20 (m, 3 H), 7.31–7.37 (m, 3 H), 7.44–7.46 (m, 2 H),
7.55–7.61 (m, 7 H), 7.64–7.67 (m, 3 H), 7.76–7.84 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 20.7, 117.4, 118.7, 125.8,
126.2 126.4, 127.1, 128.4, 128.5 (d, JCP = 12 Hz), 128.8 (d,
JCP = 11 Hz), 129.1 (d, JCP = 99 Hz), 129.7, 130.3, 131.8 (d,
JCP = 3 Hz), 132.1 (d, JCP = 10 Hz), 132.5–133.0 (br signal),
141.4; some carbons not observed. MS (EI): m/z (%)
= 535 (52), 534 (100), 262 (33), 183 (30). HRMS (EI): m/z
calcd for C37H31N231P: 534.2225; found: 524.2215.
(12) Kawazoe, Y.; Shimogawa, H.; Uesugi, M.; Sato, A. Angew.
Chem. Int. Ed. 2011, 50, 5478.
(13) (a) Jung, S. Y.; Lee, S. H.; Kang, H. B.; Park, H. A.; Chang,
S. K.; Kim, J.; Choo, D. J.; Lee, J. Y.; Oh, C. R.; Kim, Y. D.;
Seo, J. H.; Lee, K.-T. Bioorg. Med. Chem. Lett. 2010, 20,
6633. (b) Saito, T.; Shiotani, M.; Otani, T.; Hasaba, S.
Heterocycles 2003, 60, 1045. (c) Hirota, S.; Kato, R.;
Suzuki, M.; Soneta, Y.; Otani, T.; Saito, T. Eur. J. Org.
Chem. 2008, 2075. (d) Jonckers, T. H. M.; van Miert, S.;
Cimanga, K.; Bailly, C.; Colson, P.; Pauw-Gillet, M.-C. De.;
van den Heuvel, H.; Claeys, M.; Lemiere, F.; Esmans, E. L.;
Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.;
Lemière, G. L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem.
2002, 45, 3497. (e) Naganaboina, V. K.; Chandra, K. L.;
Desper, J.; Rayat, S. Org. Lett. 2011, 13, 3718.
7.08 (s, 4 H), 7.52–7.65 (m, 10 H), 7.71–7.80 (m, 6 H). 13
C
NMR (125 MHz, DMSO-d6): δ = 20.3, 54.9, 99.9, 102.3,
117.7, 118.5 (d, JCP = 9 Hz), 128.7, 128.9 (d, JCP = 12 Hz),
129.6, 130.4 (d, JCP = 99 Hz), 132.0, 132.1, 137.9 (d, JCP
=
20 Hz), 140.7, 151.5 (one C missing). MS (EI): m/z (%) =
490 (11), 489 (46), 488 (100), 262 (32), 183 (34). HRMS
(EI): calcd for C32H29N231PO35Cl: 488.2018; found:
488.2014.
Compound 3c: grey crystals; mp 183–185 °C. 1H NMR (500
MHz, DMSO-d6): δ = 2.17 (s, 6 H), 5.74 (s, 1 H), 6.18 (s, 2
H), 7.06–7.12 (m, 2 H), 7.15–7.18 (m, 2 H), 7.56–7.67 (m, 9
H), 7.77–7.83 (m, 6 H). 13C NMR (125 MHz, DMSO-d6): δ
= 17.9, 108.1, 115.7, 118.7 (d, JCP = 10 Hz), 121.2, 125.6,
128.2, 129.0 (d, JCP = 12 Hz), 129.9 (d, JCP = 99 Hz), 132.1
(d, JCP = 9 Hz), 132.2 (d, JCP = 3 Hz), 135.4, 136.3, 139.6,
142.1 (d, JCP = 20 Hz). MS (EI): m/z (%) = 509 (17), 508
(51), 507 (51), 506 (100), 262 (55), 183 (62). HRMS (EI):
m/z calcd for C32H28N231P35Cl: 506.1679; found: 506.1678.
Compound 3d: dark green solid; mp 131–133 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 6.18–6.26 (m, 2 H), 6.89 (dt, J =
10.8, 2.7 Hz, 1 H), 7.18–7.22 (m, 2 H), 7.27–7.30 (m, 2 H),
7.54–7.59 (m, 6 H), 7.61–7.66 (m, 3 H), 7.71–7.77 (m, 6 H),
7.85 (s, 1 H). 13C NMR (125 MHz, DMSO-d6): δ = 101.1 (d,
JCF = 26 Hz), 104.9 (d, JCF = 21 Hz), 118.6, 118.7 (d, JCP
19 Hz), 123.0, 129.0 (d, JCP = 12 Hz), 130.5 (d, JCP = 99 Hz),
132.1 (d, JCP = 10 Hz), 135.9 (d, JCP = 2 Hz), 136.9 (d, JCF
=
=
(14) Molina, P.; Lidon, J.; Tarraga, A. Tetrahedron 1994, 50,
10029.
(15) General Procedure for the Synthesis of 7
10 Hz), 137.0 (d, JCF = 11 Hz), 142.0, 154.6 (d, JCF = 232).
MS (EI): m/z (%) = 499 (13), 498 (44), 497 (43), 496 (100),
262 (58), 183 (55). HRMS (EI): m/z calcd for
The requisite 3 (1 mmol) was dissolved in dry CH2Cl2 (10
mL), and isocyanate 6 (1.1 mmol) was added in one portion.
The reaction flask was stoppered and stirred overnight. After
completion (TLC control) the solvent was evaporated, and
the residue was subjected to column chromatography (SiO2,
hexane–EtOAc, 1:1). Analytically pure samples of solid
products were obtained by recrystallization from hexane–
EtOAc.
C30H23N231P35ClF: 496.1271; found: 496.1270.
Compound 3e: grey crystals; mp 191–193 °C. 1H NMR (500
MHz, DMSO-d6): δ = 2.26 (s, 3 H), 6.18 (d, J = 8.2 Hz, 1 H),
6.43 (dd, J = 8.2, 2.5 Hz, 1 H), 7.06 (br s, 1 H), 7.09–7.15
(m, 4 H), 7.54–7.61 (m, 7 H), 7.63–7.66 (m, 3 H), 7.72–7.79
(m, 6 H). 13C NMR (125 MHz, DMSO-d6): δ = 20.3, 108.4,
135.5, 118.8, 119.8 (d, JCP = 10 Hz), 120.4, 129.0 (d, JCP
11 Hz), 129.5 (d, JCP = 96 Hz), 129.7, 129.8, 132.1 (d, JCP
=
=
(16) Analytical Data for Novel Products 7
8 Hz), 132.2 (d, JCP = 2 Hz), 138.0, 139.5 (d, JCP = 21 Hz),
140.0. MS (EI): m/z (%) = 539 (39), 538 (100), 537 (49), 536
(98), 262 (61), 183 (58). HRMS (EI): m/z calcd for
Compound 7aa: brown oil 1H NMR (500 MHz, DMSO-d6):
δ = 0.87 (t, J = 7.4 Hz, 3 H), 1.26–1.35 (m, 2 H), 1.52–1.59
(m, 2 H), 2.42 (s, 3 H), 3.29–3.34 (m, 2 H), 6.34 (t, J = 5.6
Hz, 1 H), 6.71 (d, J = 2.0 Hz, 1 H), 7.00 (dd, J = 8.3, 2.0 Hz,
1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.32–7.35 (m, 2 H), 7.41–7.45
(m, 2 H). 13C NMR (125 MHz, DMSO-d6): δ = 13.7, 19.5,
20.7, 31.1, 42.1, 107.1, 115.9, 120.7, 122.6, 126.8, 130.7,
131.4, 136.4, 138.2, 141.9, 155.1. MS (EI): m/z (%) = 315
(31), 314 (22), 313 (88), 286 (4), 285 (4), 284 (14), 273 (18),
272 (28), 271 (59), 270 (61), 259 (35), 258 (35), 257 (100),
256 (58). HRMS (EI): m/z calcd for C18H20N335Cl: 313.1346;
found: 313.1351.
C31H26N231P79Br: 536.1017; found: 536.1016.
Compound 3f: pale green crystals; mp 172–173 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 2.24 (s, 3 H), 6.24 (d, J = 8.3 Hz,
1 H), 6.34 (dd, J = 8.3, 2.4 Hz, 1 H), 6.88–6.92 (m, 2 H),
7.18–7.26 (m, 2 H), 7.34–7.37 (m, 1 H), 7.54 (s, 1 H), 7.56–
7.61 (m, 6 H), 7.64–7.68 (m, 3 H), 7.73–7.80 (m, 6 H). 13
C
NMR (125 MHz, DMSO-d6): δ = 17.6, 110.6, 117.4, 117.6,
119.1 (d, JCP = 10 Hz), 120.9, 121.2, 126.7, 127.6, 129.0 (d,
J
CP = 13 Hz), 129.9 (d, JCP = 99 Hz), 130.0, 132.0 (d, JCP =
10 Hz), 132.3 (d, JCP = 3 Hz), 137.5, 138.9 (d, JCP = 20 Hz),
140.6. MS (EI): m/z (%) = 494 (46), 493 (46), 492 (100), 262
(51), 183 (58). HRMS (EI): m/z calcd for C31H26N231P35Cl:
492.1522; found: 492.1513.
Compound 7ba: orange solid; mp 183–184 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 0.88 (t, J = 7.4 Hz, 3 H), 1.26–
1.35 (m, 2 H), 1.52–1.58 (m, 2 H), 2.41 (s, 3 H), 3.29–3.30
(m, 2 H), 3.64 (s, 3 H), 5.95 (t, J = 5.6 Hz, 1 H), 6.36 (d, J =
2.3 Hz, 1 H), 6.61 (dd, J = 8.4, 2.3 Hz, 1 H), 7.14 (d, J = 8.4
Hz, 1 H), 7.30–7.34 (m, 2 H), 7.41–7.44 (m, 2 H). 13C NMR
(125 MHz, DMSO-d6): δ = 13.7, 19.5, 20.7, 31.1, 42.2, 55.5,
93.4, 107.8, 115.3, 126.7, 130.6, 132.0, 135.8, 136.9, 137.7,
Compound 3g: pale yellow crystals; mp 150–151 °C. 1H
NMR (500 MHz, DMSO-d6): δ = 6.26 (dd, J = 8.3, 1.0 Hz,
1 H), 6.43 (dd, J = 8.3, 2.5 Hz, 1 H), 7.04 (t, J = 2.7 Hz, 1 H),
7.16–7.19 (m, 2 H), 7.27–7.30 (m, 2 H), 7.54–7.59 (m, 6 H),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 217–220

220
E. Łukasik, Z. Wróbel
LETTER
153.5, 153.9. MS (EI): m/z (%) = 310 (43), 309 (100), 294
(18), 280 (10), 267 (28), 266 (36), 253 (47), 252 (20). HRMS
(EI): m/z calcd for C19H23O: 309.1841; found: 309.1834.
Compound 7ca: brown crystals; mp 91–93 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 0.85 (t, J = 7.4 Hz, 3 H), 1.25–
1.36 (m, 2 H), 1.50–1.57 (m, 2 H), 1.90 (s, 3 H), 3.28–3.34
(m, 2 H), 6.31 (t, J = 5.7 Hz, 1 H), 6.40 (d, J = 2.1 Hz, 1 H),
6.99 (dd, J = 8.3, 2.1 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.31
(d, J = 7.5 Hz, 2 H), 7.39 (t, J = 7.5 Hz, 1 H). 13C NMR (125
MHz, DMSO-d6): δ = 13.7, 17.1, 19.4, 31.2, 41.9, 106.5,
115.9, 120.6, 122.6, 128.8, 129.4, 131.3, 135.1, 137.0,
142.2, 154.8. MS (EI): m/z (%) = 329 (44), 328 (34), 327
(100), 300 (7), 299 (5), 298 (20), 287 (13), 286 (19), 285
(39), 284 (41), 257 (22), 256 (22), 255 (60), 254 (10). HRMS
(EI): m/z calcd for C19H22N335Cl: 327.1502; found:
327.1503.
157.7 (d, JCF = 234 Hz). MS (EI): m/z (%) = 339 (43), 338
(47), 337 (100), 336 (64), 323 (18), 322 (12), 321 (51).
HRMS (EI): m/z calcd for C19H13N335ClF: 337.0782; found:
337.0786.
Compound 7cb: colorless crystals; mp 148–149 °C. 1H
NMR (500 MHz, DMSO-d6): δ = 1.13 (t, J = 7.1 Hz, 3 H),
1.90 (s, 6 H), 3.35 (q, J = 7.1 Hz, 2 H), 6.32 (t, J = 5.7 Hz, 1
H), 6.42 (d, J = 2.2 Hz, 1 H), 7.01 (dd, J = 8.4, 2.2 Hz, 1 H),
7.26 (d, J = 8.4 Hz, 1 H), 7.30–7.33 (m, 2 H), 7.40 (dd, J =
6.9, 8.2 Hz, 1 H). 13C NMR (125 MHz, DMSO-d6): δ = 15.0,
17.1, 37.1, 106.6, 116.0, 120.7, 122.7, 128.9, 129.5, 131.3,
135.0, 137.0, 142.2, 154.7. MS (EI): m/z (%) = 301 (35), 300
(23), 299 (100), 284 (19), 271 (20), 257 (18), 256 (17), 255
(49), 228 (23). HRMS (EI): m/z calcd for C17H18N335Cl:
299.1189; found: 299.1194.
Compound 7ab: yellow oil. 1H NMR (500 MHz, DMSO-d6):
δ = 1.15 (t, J = 7.1 Hz, 3 H), 2.42 (s, 3 H), 3.36 (q, J = 7.1
Hz, 2 H), 6.36 (t, J = 5.6 Hz, 1 H), 6.72 (d, J = 2.2 Hz, 1 H),
7.01 (dd, J = 8.4, 2.2 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H),
7.33–7.36 (m, 2 H), 7.42–7.45 (m, 2 H). 13C NMR (125
MHz, DMSO-d6): δ = 14.9, 20.7, 37.3, 107.2, 116.0, 120.8,
122.7, 126.8, 130.7, 131.4, 136.4, 138.2, 141.9, 155.0. MS
(EI): m/z (%) = 287 (37), 286 (24), 285 (100), 271 (20), 259
(22), 258 (27), 257 (68), 256 (53), 241 (27). HRMS (EI): m/z
calcd for C16H16N335Cl: 285.1033; found: 285.1021.
Compound 7eb: grey oil. 1H NMR (500 MHz, DMSO-d6): δ
= 1.15 (t, J = 7.1 Hz, 3 H), 2.42 (s, 3 H), 3.35 (q, J = 7.1 Hz,
2 H), 6.38 (t, J = 5.4 Hz, 1 H), 6.84 (d, J = 2.0 Hz, 1 H), 7.12
(dd, J = 8.3, 2.0 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 7.33–
7.36 (m, 2 H), 7.41–7.45 (m, 2 H). 13C NMR (125 MHz,
DMSO-d6): δ = 15.4, 21.2, 37.8, 110.3, 110.7, 117.1, 124.0,
127.3, 131.2, 131.9, 137.3, 138.7, 142.7, 155.3. MS (EI): m/z
(%) = 332 (19), 331 (98), 330 (27), 329 (100), 303 (52), 302
(48), 301 (45), 287 (21), 285 (24). HRMS (EI): m/z calcd for
C16H16N379Br: 329.0528; found: 329.0530.
Compound 7da: brown oil. 1H NMR (500 MHz, DMSO-d6):
δ = 0.89 (t, J = 7.2, 3 H), 1.28–1.36 (m, 2 H), 1.53–1.59 (m,
2 H), 3.26–3.32 (m, 2 H), 6.34–6.39 (m, 2 H), 6.62–6.65 (m,
1 H), 6.80–6.85 (m, 1 H), 7.23 (dd, J = 8.2 Hz, JHF = 4.7 Hz,
1 H), 7.48–7.53 (m, 2 H), 7.66–7.70 (m, 2 H). 13C NMR (125
MHz, DMSO-d6): δ = 13.7, 19.5, 31.1, 42.2, 95.0 (d, JCF
=
29 Hz), 107.7 (d, JCF = 24 Hz), 115.2 (d, JCF = 9 Hz), 128.9,
130.2, 133.0, 133.2, 135.3 (d, JCF = 13 Hz), 139.3, 154.8,
156.8 (d, JCF = 231 Hz). MS (EI): m/z (%) = 319 (40), 318
(30), 317 (97), 290 (5), 289 (4), 288 (15), 277 (21), 276 (31),
275 (64), 274 (66), 263 (40), 262 (40), 261 (100), 260 (64),
239 (10), 238 (29). HRMS (EI): m/z calcd for
C17H17N335ClF: 317.1095; found: 317.1096.
Compound 7db: colorless crystals; mp 146 °C. 1H NMR
(500 MHz, DMSO-d6): δ = 1.15 (t, J = 7.2 Hz, 3 H), 3.33 (q,
overlapped by H2O peak, 2 H), 6.39 (t, J = 5.7 Hz, 1 H), 6.65
(dd, J = 2.5 Hz, JHF = 9.0 Hz, 1 H), 6.83 (ddd, J = 8.5, 2.5
Hz, JHF = 9.0 Hz, 1 H), 7.23 (dd, J = 8.5 Hz, JHF = 4.8 Hz, 1
H), 7.50–7.53 (m, 2 H), 7.66–7.69 (m, 2 H). 13C NMR (125
MHz, DMSO-d6): δ = 15.3, 37.8, 95.6 (d, JCF = 28 Hz), 108.2
(d, JCF = 24 Hz), 115.8 (d, JCF = 10 Hz), 129.4, 130.7, 133.4,
133.7, 135.7 (d, JCF = 12 Hz), 139.8, 155.1 (d, JCF = 2 Hz),
157.3 (d, JCF = 231 Hz). MS (EI): m/z (%) = 291 (32), 290
(20), 289 (100), 263 (23), 262 (24), 261 (70), 260 (42), 238
(19), 225 (42). HRMS (EI): m/z calcd for C15H13N335ClF:
289.0782; found: 289.0782.
Compound 7fb: grey oil. 1H NMR (500 MHz, DMSO-d6): δ
= 1.13 (t, J = 7.2 Hz, 3 H), 1.96 (s, 3 H), 3.34 (q, J = 7.2 Hz,
2 H), 6.31 (t, J = 5.5 Hz, 1 H), 6.48 (d, J = 2.0 Hz, 1 H), 7.00
(dd, J = 8.3, 2.0 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.32–
7.35 (m, 1 H), 7.42–7.46 (m, 2 H), 7.50–7.52 (m, 1 H). 13
NMR (125 MHz, DMSO-d6): δ = 15.0, 17.0, 37.2, 106.9,
115.9, 120.7, 122.6, 127.7, 128.9, 129.7, 131.7, 132.5,
C
Compound 7dc: orange oil. 1H NMR (500 MHz, DMSO-d6):
δ = 1.41 (s, 9 H), 5.57 (s, 1 H), 6.66 (dd, J = 2.5 Hz, JHF = 9.1
Hz, 1 H), 6.84 (ddd, J = 8.6, 2.5 Hz, JHF = 10.1 Hz, 1 H), 7.28
(dd, J = 8.6 Hz, JHF = 4.7 Hz, 1 H), 7.49–7.53 (m, 2 H), 7.65–
7.68 (m, 2 H). 13C NMR (125 MHz, DMSO-d6): δ = 28.6,
51.5, 95.1 (d, JCF = 28 Hz), 107.8 (d, JCF = 24 Hz), 115.7 (d,
JCF = 9 Hz), 128.8, 130.2, 132.7, 133.6, 134.5 (d, JCF = 13
Hz), 139.2, 152.9 (d, JCF = 2 Hz), 157.0 (d, JCF = 232 Hz).
MS (EI): m/z (%) = 319 (17), 318 (12), 317 (39), 263 (46),
262 (40), 261 (100), 260 (45), 226 (16), 225 (32). HRMS
(EI): m/z calcd for C17H17N335ClF: 317.1095; found:
317.1087.
136.2, 136.5, 142.0, 155.1. MS (EI): m/z (%) = 287 (34), 286
(21), 285 (100), 270 (17), 259 (18), 258 (22), 257 (55), 256
(42), 241 (28). HRMS (EI): m/z calcd for C16H16N335Cl:
285.1033; found: 285.1032.
(17) For recent development, see: (a) Correa, R. G.; Khan, P. M.;
Askari, N.; Zai, D.; Gerlic, M.; Brown, B.; Magnuson, G.;
Spreafico, R.; Albani, S.; Sergienko, E.; Diaz, P. W.; Roth,
G. P.; Reed, J. P. Chem. Biol. (Oxford, UK) 2011, 18, 825.
(b) Cook, B. N.; Bentzien, J.; White, A.; Nemoto, P. A.;
Wanga, J.; Mana, C. C.; Soleymanzadeh, F.; Khine, H. H.;
Kashem, M. A.; Kugler, S. Z. Jr.; Wolak, J. P.; Roth, G. P.;
Lombaert, S.; Pullen, S. S.; Takahashi, H. Bioorg. Med.
Chem. Lett. 2009, 19, 773. (c) Das, P.; Kumar, C. K.;
Kumar, K. N.; Innus, M.; Iqbal, J.; Srinivas, N. Tetrahedron
Lett. 2008, 49, 992. (d) Zhu, J.; Wu, C. F.; Li, X.; Wu, G. S.;
Xie, S.; Hua, Q.-N.; Deng, Z.; Zhu, M. X.; Luo, H.-R.; Hong,
X. Bioorg. Med. Chem. 2013, 21, 4218. (e) Hranjec, M.;
Sovcić, I.; Ratkaj, I.; Pavlović, G.; Ilić, N.; Valjalo, L.;
Pavelić, K.; Pavelić, S. K.; Karminski-Zamola, G. Eur. J.
Med. Chem. 2013, 111.
Compound 7dd: white solid; mp 164–166 °C. 1H NMR (500
MHz, DMSO-d6): δ = 6.76 (dd, J = 2.4 Hz, JHF = 8.9 Hz, 1
H), 6.93–6.99 (m, 2 H), 7.27–7.31 (m, 2 H), 7.44 (dd, J = 8.6
Hz, JHF = 4.9 Hz, 1 H), 7.59–7.63 (m, 2 H), 7.69–7.73 (m, 2
H), 7.76–7.79 (m, 2 H), 8.71 (s, 1 H). 13C NMR (125 MHz,
DMSO-d6): δ = 95.7 (d, JCF = 29 Hz), 108.7 (d, JCF = 24 Hz),
116.9 (d, JCF = 10 Hz), 118.3, 121.3, 128.4, 129.4, 130.3,
133.1, 133.4, 134.6 (d, JCF = 13 Hz), 138.3, 140.5, 150.4,
Synlett 2014, 25, 217–220
© Georg Thieme Verlag Stuttgart · New York