D
O. Castillo-Aguilera et al.
Letter
Synlett
Acknowledgment
Table 3 Benzimidazol-2-yl Alkylamines Obtained by a Three-Step Syn-
thetic Pathway
We thank the PSM GRITA (Plateau Spectrométrie de Masse, Univ Lille)
for mass spectrometric analyses. The authors declare no conflict of
interest.
R
N
R
n
N
N
O
N
1
n
H
Mitsunobu
reaction
addition–
N
H
NH2
O
elimination
Supporting Information
n = 3, 4, 5
Supporting information for this article is available online at
phthalimido derivative
and/or (for n = 4)
benzimidazol-2-yl alkylamine
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
2a–g
R
N
N
References and Notes
cyclized product
(1) Pullagura, M. K. P.; Avdhut, K. S.; Raja, S. Int. J. Pharm. Pharma-
ceut. Sci. 2016, 8, 22.
3d,f,g
(2) Keri, R. S.; Hiremathad, A.; Budagumpi, S.; Nagaraja, B. M. Chem.
Biol. Drug Design 2015, 86, 19.
(3) Srestha, N.; Banerjee, J.; Srivastava, S. IOSR J. Pharm. 2014, 4, 28.
(4) Elshihawy, H.; Helal, M. A.; Said, M.; Hammad, M. A. Bioorg.
Med. Chem. 2014, 22, 550.
(5) Alaqeel, S. I. J. Saudi Chem. Soc. 2017, 21, 229.
(6) Bastug, G.; Eviolitte, C.; Markó, I. E. Org. Lett. 2012, 14, 3502.
(7) Reppe, W. Justus Liebigs Ann. Chem. 1955, 1208.
Entry
R
n
Cyclized prod-
uct (yield, %)
Product
Three-step
yield (%)b
a
1
2
3
4
5
6
7
t-Bu
t-Bu
t-Bu
H
3
4
5
4
4
4
4
–
2a
2b
2c
2d
2e
2f
20
35
14
0
a
–
a
–
3d (66)c,d
(8) Botta, A. Justus Liebigs Ann. Chem. 1976, 336.
a
OMe
CF3
–
27
3
(9) Olhava, E. J.; Chesworth, R.; Kuntz, K. WO/2012/075492, 2012.
(10) Keurulainen, L.; Vahermo, M.; Puente-Felipe, M.; Sandoval-
Izquierdo, E.; Crespo-Fernández, B.; Guijarro-López, L.;
Huertas-Valentín, L.; de las Heras-Dueña, L.; Leino, T. O.;
Siiskonen, A.; Ballell-Pages, L.; Sanz, L. M.; Castañeda-Casado, P.;
Jiménez-Díaz, M. B.; Martínez-Martínez, M. S.; Viera, S.; Kiuru,
P.; Calderón, F.; Yli-Kauhaluoma, J. J. Med. Chem. 2015, 58, 4573.
(11) Shelton, K. L.; DeBord, M. A.; Wagers, P. O.; Southerland, M. R.;
Williams, T. M.; Robishaw, N. K.; Shriver, L. P.; Tessier, C. A.;
Panzner, M. J.; Youngs, W. J. Bioorg. Med. Chem. 2017, 25, 421.
(12) Indusegaram, S.; Katsifis, A. G.; Ridley, D. D.; Vonwiller, S. C.
Aust. J. Chem. 2003, 56, 819.
(13) Woudenberg, R. C.; Coughlin, E. B. Tetrahedron Lett. 2005, 46,
6311.
(14) Lee, J. E.; Kwon, T. H.; Gu, S. J.; Lee, D.-H.; Kim, B. M.; Lee, J. Y.;
Lee, J. K.; Seo, S. H.; Pae, A. N.; Keum, G.; Cho, Y. S.; Min, S.-J. Org.
Biomol. Chem. 2014, 12, 5669.
3f (42)c
3g (51)b
NO2
2g
0
a Not observed by LC-MS.
b Isolated yield.
c Calculated from the crude material by LC-MS.
d Characterized by NMR.
O
N
O
H
N
R
O
N
N
R
O
N
O
PPh3
3
phthalimidogen
3
N
H
phosphonium intermediate
formed during Mitsunobu reaction
phthalimido derivative
OPPh3
(15) General Conditions A: A mixture of the corresponding ortho-
phenylenediamine (1 equiv) and the corresponding lactone or
lactam (4–6 equiv) in 4N HCl in a sealed tube was heated over-
night (duration is reported in the manuscript). After cooling to
room temperature, the pH was adjusted to pH 11 at 0 °C with
sat. aq. K2CO3. The aqueous layer was extracted three times
with EtOAc, the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
The desired product was obtained by precipitation or by chro-
matography on silica gel [eluting with CH2Cl2–MeOH/ammonia,
9:1 (v/v)]. The final solid or oil obtained was dried over P2O5.
Representative example 1a: Yield: 4.3 mmol (93%); white
powder obtained from diethyl ether; mp 181–183 °C. 1H NMR
(300 MHz, DMSO-d6): = 1.33 (s, 9 H, t-Bu), 1.90 (tt, 3J = 6.0,
7.5 Hz, 2 H, CH2), 2.83 (t, 3J = 7.5 Hz, 2 H, CH2-Ar), 3.49 (t, 3J =
6.0 Hz, 2 H, CH2-OH), 7.17–7.20 (m, 1 H, ArH), 7.35–7.40 (m,
2 H, ArH), 11.86 (br s, 1 H, NH). 13C NMR (75 MHz, DMSO-d6):
= 25.3 (CH2), 30.8 (CH2), 31.7 (t-Bu), 34.3 (Cq), 60.2 (CH2-OH),
R
N
N
cyclized product
Scheme 3 Formation of a cyclized product in the Mitsunobu reaction
Funding Information
This work was supported by the Centre National de la Recherche Sci-
entifique (CNRS) and PlanCancer 2014 (N° EPIG201401) (to P.B.A),
and by a PhD fellowship by the Ecole Doctorale Biologie Santé de Lille
(EDBSL, France) National Council of Science and Technology (Consejo
Nacional de Ciencia y Tecnología; CONACYT, Mexico) (to O.C.A.).
C
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