Synthesis of a Spirocyclic Oxetane-Fused Benzimidazole

Article abstract of DOI:10.3390/molecules200813864

A new synthesis of 2-oxa-7-azaspiro[3.5]nonane is described. Spirocyclic oxetanes, including 2-oxa-6-azaspiro[3.3]heptane were converted into o-cycloalkylaminoacetanilides for oxidative cyclizations using Oxone in formic acid. The expanded spirocyclic oxetane successfully gave the [1,2-a] ring-fused benzimidazole. X-ray crystal structure of the resultant new tetracyclic system, 1',2'-dihydro-4'H-spiro[oxetane-3,3'-pyrido[1,2-a]benzimidazole] and the azetidine ring-opened adduct, N-(2-acetamido-4-bromophenyl)-N-{[3-(chloromethyl) oxetan-3-yl]methyl}acetamide are disclosed.

Full text of DOI:10.3390/molecules200813864

Molecules 2015, 20, 13864-13874; doi:10.3390/molecules200813864
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of a Spirocyclic Oxetane-Fused Benzimidazole
Michael Gurry, Patrick McArdle and Fawaz Aldabbagh *
School of Chemistry, National University of Ireland Galway, University Road, Galway SW4 NUI,
Ireland; E-Mails: m.gurry1@nuigalway.ie (M.G.); patrick.mcardle@nuigalway.ie (P.M.)
* Author to whom correspondence should be addressed; E-Mail: Fawaz.Aldabbagh@nuigalway.ie;
Tel.: +353-91-493120; Fax: +353-91-495576.
Academic Editor: Panayiotis A. Koutentis
Received: 24 June 2015 / Accepted: 24 July 2015 / Published: 30 July 2015
Abstract: A new synthesis of 2-oxa-7-azaspiro[3.5]nonane is described. Spirocyclic oxetanes,
including 2-oxa-6-azaspiro[3.3]heptane were converted into o-cycloalkylaminoacetanilides
for oxidative cyclizations using Oxone® in formic acid. The expanded spirocyclic oxetane
successfully gave the [1,2-a] ring-fused benzimidazole. X-ray crystal structure of the resultant
new tetracyclic system, 1ʹ,2ʹ-dihydro-4ʹH-spiro[oxetane-3,3ʹ-pyrido[1,2-a]benzimidazole]
and the azetidine ring-opened adduct, N-(2-acetamido-4-bromophenyl)-N-{[3-(chloromethyl)
oxetan-3-yl]methyl}acetamide are disclosed.
Keywords: annulation; cyclization; diazole; heterocycle; 4-membered rings
1. Introduction
Oxetane is considered as a polar equivalent of the gem-dimethyl group (Figure 1) [1–3]. Spirocyclic
oxetanes such as 2-oxa-6-azaspiro[3.3]heptane (1a) and 2-oxa-7-azaspiro[3.5]nonane (1b) were
proposed as valuable structural alternatives to ubiquitous morpholine in medicinal chemistry [4].
A drug discovery project within our group demanded a substituent that enabled higher binding
affinities to the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site [5]. NQO1 is an enzyme
over-expressed in cancer cell lines. Our attention turned to oxetane due to its heralded metabolic
robustness in comparison to carbonyl alternatives, while offering the hydrogen bonding capacity
necessary for efficient binding to the His194 residue of NQO1 enabling more efficient reduction of
benzimidazolequinone and imidazobenzimidazolequinone substrates. The following article describes

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the first fusion of the spirocyclic oxetane motif onto heterocycles in attempts to prepare [1,2-a] alicyclic
ring-fused benzimidazoles 2a and 2b.
O
O
Br
N
N
n
oxetane
O
n
n
n
N
H
2a
: n = 0
2b
: n = 1
1a
: n = 0
1b
: n = 1
Figure 1. Rationale design of synthetic targets.
2. Results and Discussion
2.1. Synthesis of Spirocyclic Oxetanes
The synthesis of the oxalate salt of 2-oxa-6-azaspiro[3.3]heptane 1a starting from the condensation
of 3-bromo-2,2-bis(bromomethyl)propan-1-ol with p-tosylamide has been described [4]. The expanded
analogue 1b is commercially available but expensive, and a new synthetic pathway is now reported
(Scheme 1). N-tosyl-piperidine-4,4-diethyl ester 3 was prepared using the reaction of diethyl malonate
with N-tosylbis(2-bromoethyl)amine, and similar transformations are available in patents [6,7]. Lithium
aluminum hydride reduction provides diol 4, which is subjected to a one-pot mesylation and ring
closure to give the previously unreported oxetane 5. The tosyl group was removed and the oxalate salt of
2-oxa-7-azaspiro[3.5]nonane 1b formed. An alternative synthesis appears in a patent via the ring-closure
of 2,2′-(oxetane-3,3-diyl)bis(ethan-1-ol) to give 1b [8]. The latter multi-step synthesis begins with a
Wittig reaction on 3-oxetanone, and represents a longer more costly preparation of 1b.
Scheme 1. Synthesis of the oxalate salt of 2-oxa-7-azaspiro[3.5]nonane (1b).

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2.2. Synthesis of o-Cycloalkylaminoacetanilides
Nucleophilic aromatic substitution onto 1,4-dibromo-2-nitrobenzene using the oxalate salts of
spirocyclic oxetanes 1a and 1b was possible in yields of >90% when using a large excess of potassium
carbonate in DMF (Schemes 2 and 3). Reduction of the nitro group of 6a and 6b using iron and
aqueous ammonium chloride yielded the corresponding anilines 7a and 7b in 95% yield. The acetylation
was optimized with aniline 7a, where the initial attempt using acetyl chloride gave the desired
acetamide 8a in 64% yield together with adduct 9a of ring-opening of the azetidine in 19% yield
(Scheme 2). By-product 9a was confirmed by X-ray crystallography (Figure 2). As pointed out by
the Reviewer this may have occurred using the chloride ion liberated from the first acetylation.
The ring-opening of azetidines by the nucleophilic attack of halide ions on azetidinium ions has been
previously described [9]. Acetylations using acetic anhydride were in contrast regioselective giving
diacetylated adduct 10a in 90% yield with neat acetic anhydride, while acetylation with acetic
anhydride in methanol gave the desired product 8a in 81% yield. The latter conditions gave the
analogous acetamide of 2-oxa-7-azaspiro[3.5]nonane 8b in 90% yield (Scheme 3).
Scheme 2. Synthesis of N-[5-bromo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]acetamide (8a).

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O
N
Br
NO2
N
O
Br
NO2
K2CO3 (20 equiv), DMF, 80 °C
91%
O
+
O
Br
O
6b
H
H
2
O
oxalate salt of 1b
Br
NH2
N
Br
NHAc
N
Ac2O, MeOH, reflux
Fe, NH4Cl, H2O, EtOH
95%
6b
90%
7b
8b
O
O
Scheme 3. Synthesis of N-[5-bromo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]acetamide (8b).
Figure 2. X-ray crystal structure of N-(2-acetamido-4-bromophenyl)-N-{[3-(chloromethyl)
oxetan-3-yl]methyl}acetamide (9a) [10].
2.3. Fusion of the Spirocyclic Oxetanes
In order to fuse the spirocyclic oxetane of 8a and 8b, the well-established oxidative cyclization
reaction of acetamide onto the neighbouring cyclic amine was used [11–13]. Oxone® in formic acid is
as an expedient means of converting o-cycloalkylaminoacetanilides into [1,2-a] alicyclic ring-fused
benzimidazoles and double annulated imidazobenzimidazoles in high yields [13]. Using the latter
conditions (Scheme 4), acetanilide 8a gave a mixture of products indicating degradation of the spirocyclic
oxetane and an absence of the desired benzimidazole 2a. In contrast the 2-oxa-7-azaspiro[3.5]nonane
fused benzimidazole 2b was isolated in 74% yield at the end of the reaction of 8b without the
requirement for chromatography by simple organic extraction from the basified aqueous mixture. The
structure of the novel tetracyclic system 2b was confirmed by X-ray crystallography (Figure 3).

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Br
NHAc
( )
Br
Oxone®, HCO2H, 40 oC
N
N
( )
n
N
O
n
( )
n
( )
O
n
8a-8b
2a
: n = 0 (0%)
2b: n = 1 (74%)
Scheme 4. Oxidative cyclizations to give spirocyclic oxetane fused benzimidazoles.
Figure 3. X-ray crystal structure of 7ʹ-bromo-1ʹ,2ʹ-dihydro-4ʹH-spiro[oxetane-3,3ʹ-pyrido
[1,2-a]benzimidazole] (2b) [10].
3. Experimental Section
3.1. General
All chemicals were obtained from commercial sources and used without further purification. Thin
layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates. Dry vacuum column
chromatography was carried out on silica gel (Apollo Scientific ZEOprep 60/15–35 microns). Melting
points were measured on a Stuart Scientific melting point apparatus SMP1. Infrared spectra were
1
recorded using a Perkin-Elmer Spec 1 with ATR attached. H-NMR spectra were recorded using a
Joel ECX 400 MHz instrument equipped with a DEC AXP 300 computer workstation. The chemical
13
shifts were recorded in ppm relative to tetramethylsilane. C-NMR data were collected at 100 MHz
with complete proton decoupling. High resolution mass spectra (HRMS) were carried out using ESI
time-of-flight mass spectrometer (TOFMS). The precision of all accurate mass measurements were
better than 5 ppm. NMR spectra of all compounds are available in the Supplementary Materials
document accompanying this article.
3.2. Experimental Procedures
3.2.1. Synthesis of Spirocyclic Oxetanes
Bis(2-oxa-6-azaspiro[3.3]heptan-6-ium) ethanedioate (oxalate salt of 1a) was prepared according to
the literature [4].
Diethyl 1-(4-methylbenzene-1-sulfonyl)piperidine-4,4-dicarboxylate (3). Diethyl malonate (0.500 g,
3.1 mmol) and NaH (0.165 g, 6.9 mmol) in DMF (50 mL) were heated at 80 °C for 30 min. N,N-bis(2-
bromoethyl)-4-methyl-1-sulfonamide [14] (1.320 g, 3.4 mmol) was added and heating at 80 °C continued

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for 12 h. The cooled mixture was evaporated, EtOAc (50 mL) added, and washed with aqueous LiCl
(5%) solution (3 × 50 mL). The organic extracts were dried (Na2SO4) and evaporated to dryness, and
the residue purified by column chromatography using gradient elution of petroleum ether/EtOAc to
yield the title compound (0.987 g, 83%) as a white solid; Rf 0.32 (1:4 EtOAc/Pet); mp 90–92 °C; νmax
(neat, cm−1) 2987, 2851, 1742 (C=O), 1598, 1467, 1444, 1367, 1350 (S=O), 1327, 1305, 1261, 1247,
1192, 1162 (S=O), 1092, 1052, 1072, 1015; δH (400 MHz, CDCl3) 1.16 (t, J = 7.3 Hz, 6H, CH3), 2.17
(t, J = 5.5 Hz, 4H), 2.41 (s, 3H), 3.03 (t, J = 5.5 Hz, 4H), 4.13 (q, J = 7.3 Hz, 4H, OCH2), 7.29 (d,
J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H); δC (100 MHz, CDCl3) 14.0, 21.6 (CH3), 30.2, 43.2 (CH2),
52.4 (C), 61.8 (OCH2), 127.7, 129.8 (CH), 133.1, 143.7 (C), 170.4 (C=O); HRMS (ESI) m/z [M + H]+,
C18H26NO6S calcd. 384.1481, observed 384.1483.
[1-(4-Methylbenzene-1-sulfonyl)]piperidine-4,4-diyl]dimethanol (4). LiAlH4 (5.2 mL of a 1 M solution
in THF, 5.2 mmol) was added over 5 min to a solution of diethyl ester 3 (1.000 g, 2.6 mmol) in THF
(20 mL), and the solution stirred for 16 h at room temperature. The reaction was quenched with
ethanol (3 mL), a saturated sodium potassium tartrate solution (40 mL), and stirred vigorously for 1 h.
The resulting biphasic mixture was extracted with EtOAc (2 × 50 mL), washed with brine (2 × 30 mL)
and dried (Na2SO4). The solution was evaporated to dryness and the residue purified by column
chromatography using gradient elution of petroleum ether/EtOAc to yield the title compound (0.628 g,
81%) as a white solid; Rf 0.45 (EtOAc); mp 110–114 °C; νmax (neat, cm−1) 3524 (OH), 3257, 2919,
2869, 1725, 1597, 1340, 1320 (S=O), 1248, 1184, 1156 (S=O), 1132, 1090, 1053, 1012; δH (400 MHz,
CDCl3) 1.57 (t, J = 5.7 Hz, 4H), 2.43 (s, 3H), 2.56 (t, J = 4.9 Hz, 2H, OH, disappears with D2O), 2.97
(t, J = 5.7 Hz, 4H), 3.49 (d, J = 4.9 Hz, 4H, CH2OH), 7.31 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.8 Hz,
2H); δC (100 MHz, CDCl3) 21.6 (CH3), 28.4 (CH2), 36.6 (C), 42.1 (CH2), 68.7 (OCH2), 127.8, 129.8
(CH), 132.9, 143.8 (C); HRMS (ESI) m/z [M + H]+, C14H22NO4S calcd. 300.1270, observed 300.1269.
7-(4-Methylbenzene-1-sulfonyl)-2-oxa-7-azaspiro[3.5]nonane (5). Methanesulfonyl chloride (0.4 mL,
5.2 mmol) in THF (5 mL) was added to diol 4 (1.700 g, 5.7 mmol) in THF (50 mL) via syringe pump
at a rate of 1.7 mL/h, while potassium tert-butoxide (0.636 g, 5.7 mmol) was added in portions
(one third per h). The mixture was stirred at room temperature for 1 h with further potassium
tert-butoxide (1.900 g, 17.0 mmol) added, and stirred for 2 h. The mixture was evaporated, EtOAc
(50 mL) added, washed with water (2 × 20 mL), and dried (Na2SO4). The solution was evaporated to
dryness and the residue purified by column chromatography using gradient elution of petroleum
ether/EtOAc to yield the title compound (1.160 g, 73%) as a white solid; Rf 0.44 (1:1 EtOAc/Pet);
mp 168–172 °C; νmax (neat, cm−1) 2928, 2868, 1597, 1597, 1345, 1331 (S=O), 1241, 1163 (S=O),
1140, 1089; δH (400 MHz, CDCl3) 1.93 (bs, 4H), 2.42 (s, 3H), 2.90 (bs, 4H), 4.29 (s, 4H, OCH2), 7.30
(d, J = 7.3 Hz, 2H), 7.60 (d, J = 7.3 Hz, 2H); δC (100 MHz, CDCl3), 21.7 (CH3) 34.1 (CH2), 38.1 (C),
43.3 (CH2), 81.1 (OCH2), 127.7, 129.8 (CH), 133.1, 143.8 (C); HRMS (ESI) m/z [M + H]+, C14H20NO3S
calcd. 282.1164, observed 282.1163.
Bis(2-oxa-7-azaspiro[3.5]nonan-7-ium) ethanedioate (oxalate salt of 1b). 2-Oxa-7azaspiro[3.5]nonane
5 (1.300 g, 4.6 mmol) and Mg turnings (0.780 g, 32.3 mmol) in MeOH (50 mL) were sonicated for 1 h.
The mixture was evaporated to give a viscous grey residue to which Et2O (50 mL) and Na2SO4⋅10H2O

Molecules 2015, 20
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(2.000 g) were added. After 30 min of stirring, the mixture was filtered, and anhydrous oxalic acid
(0.210 g, 2.3 mmol) added to the filtrate to form a precipitate. The precipitate was collected and dried
under vacuum to yield the title compound (0.580 g, 73%) as a white solid; mp 148–152 °C; νmax
(neat, cm−1) 3389 (NH), 3124, 2931, 2866, 1713, 1610 (C=O), 1475, 1444, 1397, 1171; δH (400 MHz,
D2O) 1.94 (t, J = 5.7 Hz, 4H), 2.98 (t, J = 5.7 Hz, 4H), 4.38 (s, 4H, OCH2); δC (100 MHz, D2O) 30.2
(CH2), 36.6 (C), 41.1 (CH2), 81.1 (OCH2), 165.7 (C=O).
3.2.2. Synthesis of Acetanilide Cyclization Precursors
General Procedure for the Synthesis of Nitrobenzenes 6a and 6b
1,4-Dibromo-2-nitrobenzene (1.000 g, 3.6 mmol), K2CO3 (9.820 g, 71.2 mmol) and spirocyclic
oxetane 1a–1b oxalate salts (3.6 mmol) were heated in DMF (50 mL) at 80 °C for 4 h. The cooled
mixture was evaporated, EtOAc (50 mL) added, and washed with aqueous LiCl (5%) solution
(3 × 20 mL). The organic extracts were dried (Na2SO4), evaporated to dryness, and purified by column
chromatography using gradient elution of petroleum ether/EtOAc to yield:
6-(4-Bromo-2-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (6a). (0.987 g, 93%) as an orange solid; Rf
0.49 (1:1 EtOAc/Pet); mp 148–150 °C; νmax (neat, cm−1) 2955, 2861, 1672, 1602, 1558 (NO2), 1502,
1484, 1458, 1373, 1362, 1348 (NO2), 1276, 1246, 1203, 1123, 1070; δH (400 MHz, CDCl3) 4.11 (s,
4H, NCH2), 4.81 (s, 4H, OCH2), 6.47 (d, J = 9.2 Hz, 1H, 6-H), 7.45 (dd, J = 9.2, 2.3 Hz, 1H, 5-H),
7.93 (d, J = 2.3 Hz, 1H, 3-H); δC (100 MHz, CDCl3) 38.3 (C), 62.8 (NCH2), 80.9 (OCH2), 108.3 (C),
117.4 (6-CH), 128.8 (3-CH), 136.2 (C), 136.5 (5-CH), 143.8 (C); HRMS (ESI) m/z [M + H]+,
79
C11H12N2O3 Br calcd. 299.0031, observed 299.0038.
7-(4-Bromo-2-nitrophenyl)-2-oxa-7-azaspiro[3.5]nonane (6b). (1.061 g, 91%) as an orange oil; Rf
0.58 (1:4 EtOAc/Pet); νmax (neat, cm−1) 2931, 2861, 1599, 1519 (NO2), 1485, 1462, 1384, 1331 (NO2),
1271, 1231, 1168, 1131, 1091; δH (400 MHz, CDCl3) 1.99–2.02 (m, 4H), 2.90–2.93 (m, 4H, NCH2), 4.46
(s, 4H, OCH2), 6.97 (d, J = 8.7 Hz, 1H, 6-H), 7.53 (dd, J = 8.7, 2.3 Hz, 1H, 5-H), 7.89 (d, J = 2.3 Hz, 1H,
3-H); δC (100 MHz, CDCl3) 34.9 (CH2) 38.3 (C), 49.2 (NCH2), 81.6 (OCH2), 113.3 (C), 122.8 (6-CH),
79
128.7 (3-CH), 136.4 (5-CH), 143.3, 145.5 (C); HRMS (ESI) m/z [M + H]+, C13H16N2O3 Br calcd.
327.0344, observed 327.0355.
General Procedure for the Synthesis of Anilines 7a and 7b
Nitrobenzene 6a or 6b (2.00 mmol), Fe powder (0.370 g, 6.6 mmol), NH4Cl (59 mg, 1.0 mmol) and
water (1.5 mL) in EtOH (5 mL) were heated at 80 °C for 5 h. EtOAc (50 mL) was added to the cooled
mixture, which was filtered, washed with water (50 mL), and dried to yield:
5-Bromo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)aniline (7a). (0.508 g, 95%) as a brown oil; νmax (neat,
cm−1) 3414, 3334, 2940, 2870, 1614, 1575, 1497, 1292, 1255, 1134, 1046; δH (400 MHz, CDCl3)
3.50 (bs, 2H, NH2), 3.91 (s, 4H, NCH2), 4.82 (s, 4H, OCH2), 6.41 (d, J = 8.4 Hz, 1H, 3-H), 6.75 (d,
J = 2.0 Hz, 1H, 6-H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H, 4-H); δC (100 MHz, CDCl3) 39.1 (C), 62.1

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(NCH2), 81.2 (OCH2), 114.1 (C), 115.8 (3-CH), 118.4 (6-CH), 121.7 (4-CH), 137.8 (C), 139.1 (C);
HRMS (ESI) m/z [M + H]+, C11H14N2O79Br calcd. 269.0289, observed 269.0290.
5-Bromo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)aniline (7b). (0.564 g, 95%) as a brown solid;
mp 160–162 °C; νmax (neat, cm−1) 3400, 3317, 2931, 2865, 2811, 1618, 1577, 1493, 1459, 1231, 1210,
1133, 1122; δH (400 MHz, CDCl3) 1.98 (bs, 4H), 2.72 (bs, 4H, NCH2), 3.99 (bs, 2H, NH2), 4.47 (s, 4H,
OCH2), 6.76–6.84 (m, 3H); δC (100 MHz, CDCl3) 35.8 (CH2), 38.5 (C), 48.7 (NCH2), 81.9 (OCH2),
117.6 (C & CH), 121.2, 121.4 (CH), 138.7, 143.1 (C); HRMS (ESI) m/z [M − H]−, C13H16N2O79Br
calcd. 295.0446, observed 295.0448.
Procedures for the Synthesis of N-[5-Bromo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]acetamide (8a)
AcCl (0.2 mL, 2.5 mmol) was added over 5 min to aniline 7a (0.420 g, 1.6 mmol) and Et3N (0.4 mL,
2.7 mmol) in CH2Cl2 (10 mL) at 0 °C, and stirred for 3 h at room temperature. The solution was
evaporated, EtOAc (50 mL) added, and washed with water (50 mL). The organic extracts were dried
(Na2SO4), evaporated, and purified by column chromatography using gradient elution of petroleum
ether/EtOAc to yield:
N-(2-acetylamido-4-bromophenyl)-N-{[3-(chloromethyl)oxetan-3-yl]methyl}acetamide (9a). 0.114 g,
19%; brown solid; mp 160–164 °C; Rf 0.25 (EtOAc); νmax (neat, cm−1) 3296, 3262, 2953, 2876, 1691
(C=O), 1657 (C=O), 1578, 1518, 1403, 1364, 1313, 1259, 1193, 1089; δH (400 MHz, CDCl3) 1.85 (s,
3H), 2.12 (s, 3H), 3.57 (d, J = 14.2 Hz, 1H), 3.67 (d, J = 11.2 Hz, 1H), 3.79 (d, J = 11.2 Hz, 1H), 4.12
(d, J = 7.1 Hz, 1H, CHHO), 4.42 (d, J = 14.2 Hz, 1H), 4.59–4.63 (m, 2H, OCH2), 4.68 (d, J = 7.1 Hz,
1H, CHHO), 7.09 (d, J = 8.5 Hz, 1H, 6-H), 7.32 (dd, J = 8.5, 2.1 Hz, 1H, 5-H), 8.43 (d, J = 2.1 Hz, 1H,
3-H), 9.18 (bs, 1H, NH); δC 22.3, 24.2 (CH3), 45.9 (C), 48.3, 53.2 (CH2), 76.8, 77.2 (OCH2), 122.8 (C),
127.0 (3-CH), 128.8 (2 × CH), 133.9, 137.2 (C), 169.3, 173.7 (C=O); HRMS (ESI) m/z [M + H]+,
35
C15H19N2O3 Cl79Br calcd. 389.0268, observed 389.0271 and N-[5-bromo-2-(2-oxa-6-azaspiro[3.3]
heptan-6-yl)phenyl]acetamide (8a). (0.312 g, 64%) as a white solid; Rf 0.18 (EtOAc); mp 185–189 °C;
νmax (neat, cm−1) 3218, 2929, 2864 1652 (C=O), 1591, 1569, 1520, 1485, 1408, 1368, 1317, 1279,
1254, 1132, 1060, 1011; δH (400 MHz, (CD3)2SO) 1.99 (s, 3H, CH3), 3.94 (s, 4H, NCH2), 4.65 (s, 4H,
OCH2), 6.43 (d, J = 8.7 Hz, 1H, 3-H), 7.15 (dd, J = 8.7, 2.3 Hz, 1H, 4-H), 7.25 (d, J = 2.3 Hz, 1H,
6-H), 9.23 (s, 1H, NH); δC (100 MHz, (CD3)2SO) 23.7 (CH3), 39.0 (C), 62.4 (NCH2), 80.3 (OCH2),
109.3 (C), 115.9 (3-CH), 126.5 (C), 129.0 (4-CH), 130.4 (6-CH), 145.7 (C), 169.2 (C=O); HRMS
79
(ESI) m/z [M − H]−, C13H14N2O2 Br calcd. 309.0239, observed 309.0249.
N-Acetyl-N-[5-bromo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]acetamide (10a). Aniline 7a (0.850 g,
3.2 mmol) in Ac2O (30 mL) was heated at 100 °C for 2 h. The cooled solution was evaporated,
ice-water (50 mL) added, and stirred for 3 h. The resultant precipitate was purified by column
chromatography using gradient elution of petroleum ether/EtOAc to yield the title compound (1.020 g,
90%) as a white solid; Rf 0.34 (1:1 EtOAc/Pet); mp 152–156 °C; νmax (neat, cm−1) 2932, 2861, 1707
(C=O), 1702 (C=O), 1591, 1493, 1479, 1458, 1408, 1366, 1334, 1300, 1284, 1225, 1156, 1126, 1073,
1022; δH (400 MHz, CDCl3) 2.29 (s, 6H, CH3), 3.96 (s, 4H, NCH2), 4.76 (s, 4H, OCH2), 6.41 (d,
J = 8.7 Hz, 1H, 3-H), 7.05 (d, J = 2.3 Hz, 1H, 6-H), 7.34 (dd, J = 8.7, 2.3 Hz, 1H, 4-H); δC 26.5 (CH3),

Molecules 2015, 20
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39.0 (C), 62.2 (NCH2), 80.9 (OCH2), 111.1 (C), 115.9 (3-CH), 126.7 (C) , 132.7, 133.0 (CH), 146.4
79
(C), 174.0 (C=O); HRMS (ESI) m/z [M + H]+, C15H18N2O3 Br calcd. 353.0501, observed 353.0501.
N-[5-Bromo-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]acetamide (8b). Ac2O (0.9 mL, 10.0 mmol)
and aniline 7b (0.594 g, 2.0 mmol) in methanol (20 mL) were heated at reflux for 1 h. The cooled
mixture was evaporated, ice-water added (40 mL), and stirred for 3 h. The resultant precipitate was
washed with water, and dried under vacuum to yield the title compound (0.611 g, 90%) as a white
solid; mp 164–166 °C; νmax (neat, cm−1) 3353, 2934, 2860, 2811, 1687 (C=O) 1578, 1507, 1445, 1410,
1372, 1224, 1132, 1109; δH (400 MHz, CDCl3) 2.02 (bs, 4H), 2.18 (s, 3H), 2.69 (bs, 4H, NCH2), 4.48
(s, 4H, OCH2), 6.92 (d, J = 8.2 Hz, 1H, 3-H), 7.12 (dd, J = 8.2, 1.8 Hz, 1H, 4-H), 8.36 (bs, 1H, NH),
8.53 (d, J = 1.8 Hz, 1H, 6-H); δC (100 MHz, CDCl3) 25.0 (CH3), 35.8 (CH2), 38.3 (C), 49.9 (NCH2),
81.6 (OCH2), 118.8 (C), 121.8 (3-CH), 122.3 (6-CH), 126.6 (4-CH), 134.6, 140.2 (C), 168.1 (C=O);
79
HRMS (ESI) m/z [M + H]+, C15H20N2O2 Br calcd. 339.0708, observed 339.0707.
3.2.3. Oxidative Cyclization to Give the Spirocyclic Oxetane Fused Benzimidazole
7ʹ-Bromo-1ʹ,2ʹ-dihydro-4ʹH-spiro[oxetane-3,3ʹ-pyrido[1,2-a]benzimidazole] (2b). Acetanilide 8b
(0.150 g, 0.44 mmol) and Oxone® (0.820 g, 1.32 mmol) were stirred in formic acid (20 mL) at 40 °C
for 6 h. The mixture was evaporated, water added (30 mL), neutralized with solid Na2CO3, and
extracted with CH2Cl2 (3 × 10 mL). The organic extracts were dried (Na2SO4), and evaporated dryness
to yield the title compound (96 mg, 74%) as a white solid; mp 178–181 °C; νmax (neat, cm−1) 2926,
2856, 1721, 1511, 1481, 1450, 1406, 1307, 1269, 1163, 1047; δH (400 MHz, CDCl3) 2.44 (t, J = 6.4 Hz,
2H, 2ʹ-CH2), 3.36 (s, 2H, 4ʹ-CH2), 4.09 (t, J = 6.4 Hz, 2H, 1ʹ-CH2), 4.54–4.59 (m, 4H, 2,4-CH2), 7.14
(d, J = 8.7 Hz, 1H, 9ʹ-H), 7.32 (dd, J = 8.7, 1.8 Hz, 1H, 8ʹ-H), 7.79 (d, J = 1.8 Hz, 1H, 6ʹ-H); δC
(100 MHz, CDCl3) 30.6 (2ʹ-CH2), 34.9 (4ʹ-CH2), 37.9 (C), 39.0 (1'-CH2), 80.6 (2,4-CH2), 110.2 (9ʹ-CH),
115.6 (C), 122.1 (6ʹ-CH), 125.2 (8ʹ-CH), 133.3, 144.5, 150.8 (C); HRMS (ESI) m/z [M + H]+,
C13H14N2O79Br calcd. 293.0289, observed 293.0287.
4. Conclusions
The new spirocyclic oxetane fused system, 1ʹ,2ʹ-dihydro-4ʹH-spiro[oxetane-3,3ʹ-pyrido[1,2-a]
benzimidazole] has been prepared through oxidative cyclization of the o-cycloalkylaminoacetanilide,
where 2-oxa-7-azaspiro[3.5]nonane is the cycloamino substituent. Future work will focus on preparing
quinone analogues for anti-cancer studies, as well as investigating conditions for the synthesis of the
more strained tetracycle 2a. The acetanilide containing 2-oxa-6-azaspiro[3.3]heptane system proved
to be unstable under the presented oxidative cyclization conditions giving an intractable mixture.
Research is on-going in the group to establish milder conditions for oxidative cyclizations of o-cyclic
amine substituted anilines [15] and acetamides to give ring-fused benzimidazoles.
Supplementary Materials
Supplementary materials can be accessed at: http:www.mdpi.com/1420-3049/20/08/13864/s1.

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Acknowledgments
Michael Gurry is funded by the College of Science, National University of Ireland Galway.
Author Contributions
Michael Gurry and Patrick McArdle performed experimental and X-ray crystallography work
respectively. Fawaz Aldabbagh conceived the project and directed the research. All authors read and
approved the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of all compounds are available from the authors upon request.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).