Remarkable effect of CF3CH2OH for the halogen induced oxidative rearrangement reaction of aminals leading to 3,4-dihydroquinazolines

Article abstract of DOI:10.1039/c3ob40132d

CF₃CH₂OH was found to be a useful solvent for the oxidative rearrangement reactions of aminals promoted by N-chlorosuccinimide, which proceed via the intermediacy of in situ formed chloro-aminals and that produce 3,4-dihydroquinazolines.

Full text of DOI:10.1039/c3ob40132d

Organic &
Biomolecular Chemistry
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Remarkable effect of CF3CH2OH for the halogen
induced oxidative rearrangement reaction of aminals
Cite this: Org. Biomol. Chem., 2013, 11,
2648
leading to 3,4-dihydroquinazolines†
Kenichi Murai, Masato Shimura, Ryu Nagao, Daisuke Endo and Hiromichi Fujioka*
Received 22nd January 2013,
Accepted 8th February 2013
CF3CH2OH was found to be a useful solvent for the oxidative rearrangement reactions of aminals pro-
moted by N-chlorosuccinimide, which proceed via the intermediacy of in situ formed chloro-aminals and
that produce 3,4-dihydroquinazolines.
DOI: 10.1039/c3ob40132d
www.rsc.org/obc
The fluorine containing alcohols, 2,2,2-trifluoroethanol
(CF3CH2OH) and 1,1,1,3,3,3-hexafluoroisopropanol
((CF3)2CHOH), have attracted much attention in modern
organic synthesis. These alcohols have unique properties that
include high polarity, low nucleophilicity, high hydrogen
bonding donor strength, low hydrogen bonding acceptor
strength, and high ionizing power. Owing to these properties,
fluorous alcohols remarkably enhance reactivity and, as a
result, they have been used as solvents for a variety of
reactions.1–3
We recently described a novel rearrangement reaction of
spirocyclic cyclobutane aminals that are derived from o-amino-
benzyl amine and cyclobutanones (Scheme 1).4 In this process,
3,4-dihydroquinazoline derivatives are produced via a pathway
that involves in situ formation of the corresponding chloro-
amines (e.g., i), generated by treatment of the substrates with
N-chlorosuccinimide (NCS). In contrast to the related
rearrangement reaction of simple chloro-amines, which
require activation by silver salts,5 transformations of o-amino-
benzyl amine and cyclobutanone derived chloro-aminals
proceed via spontaneous ring expansion reactions via a C-to-N
migration mechanism. The electron donating ability of the
neighboring non-chlorinated nitrogen in the aminal moiety
significantly assists the ring expansion process. Although this
reaction serves as a new method for 3,4-dihydroquinazoline
synthesis, it is limited to starting aminals that contain cyclo-
butane structures where the release of ring strain is an
important driving force.6
Scheme 1 Previously described ring strain induced rearrangement reactions of
cyclobutanone derived aminals.
rearrangement reactions of chloro-aminals. Importantly, the
use of CF3CH2OH as the solvent for these processes removes
the previously described substrate limitation and, con-
sequently, the reaction now represents a general methodology
for the preparation of
derivatives.7
a variety 3,4-dihydroquinazoline
Our initial investigation of the effect of solvents on the
rearrangement reactions of N-chloro-aminals focused on
aminal 1a, prepared from o-aminobenzylamine and cyclo-
pentanone. In contrast to observations made in our earlier
studies with cyclobutanone aminals, we observed that treat-
ment of 1a with NCS in CH2Cl2 does not promote formation of
the desired rearrangement product 2a (Table 1, entry 1). Similar
observations were made when 1a was treated with NCS in
other solvents, such as toluene, THF, and CH3CN. Even when
EtOH was used as the solvent, the reaction produced only a
trace amount of the desired product that is detected by using
TLC (entries 2–5). In contrast, we found that 1a reacts with
NCS in CF3CH2OH to generate the desired rearrangement
product 2a in 45% yield (entry 6). Interestingly, use of the
more polar fluorinated alcohol, (CF3)2CHOH, results in a
process that generates only a low yield of the desired product
along with a complex mixture of other substances (entry 7).
The drastic effect of CF3CH2OH in promoting the rearrange-
ment of the reaction of the N-chloro-derivative of 1a is interest-
ing. Although, to the best of our knowledge, there is no report
on the reaction of halo-amines and N-chloro-aminals in
CF3CH2OH, we postulate that the observed efficiency
In the investigation described below, we uncovered a
remarkable accelerating effect of a fluorous alcohol on the
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan. E-mail: fujioka@phs.osaka-u.ac.jp;
Fax: +81 6 6879 8229; Tel: +81 6 6879 8226
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40132d
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Table 1 Optimizationa
Table 2 Reactions using AgBF4
Entry
Solvent
Time
Yield (%) (2a : 2b)b,c
Entry
Solvent
AgBF4
Yielda (2a + 2b)
2a : 2bb
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
THF
CH3CN
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
N.D.d
N.D.d
1
2
3
4
Toluene (0.1 M)
CH2Cl2 (0.1 M)
CH2Cl2 (0.1 M)
1.1 eq.
1.1 eq.
3.0 eq.
1.1 eq.
N.D.
22%
29%
68%
—
—
c
N.D.d
N.D.d
3 : 1
2 : 1
CF3CH2OH (0.02 M)
EtOH
Trace
CF3CH2OH
(CF3)2CHOH
CF3CH2OH (0.02 M)
54 (5 : 1)
35 (1 : 1)
82 (7 : 1)
a Combined yield. b Ratios were determined by using 1H NMR analysis
of crude reaction mixtures. c Only 2a was obtained.
a Unless otherwise noted, reactions were carried out on a 0.1 M
solution of 1a with 1.1 eq. of NCS. b Combined yields. c Ratios were
determined by using 1H NMR analysis of crude reaction mixtures.
d N.D. = not detected.
enhances the N–Cl bond cleavage reaction and that this
enhancement is responsible for both the intramolecular
rearrangement and intermolecular aromatic ring chlorination
reactions. This reasoning suggests that the efficiencies of the
undesired intermolecular chlorination reactions would
decrease when the process is conducted using dilute solutions.
Indeed, we observed that the yield of 2a increases to 82%
when a dilute solution of 1a (0.02 M) is subjected to the NCS
promoted reaction in CF3CH2OH (Table 1, entry 8).
Owing to their reported use for activation of chloro-
amines,5 the effects of silver salts, such as AgBF4, on the yield
of the rearrangement reaction of 1a were investigated
(Table 2). Although AgBF4 did not promote the reaction when
toluene was employed as the solvent (entry 1), it was found
that the reaction of 1a with NCS in CH2Cl2 followed by the
addition of either 1.1 or 3.0 equivalents of AgBF4 to the result-
ing solution results in production of the rearrangement
product 2a but in low yield (entries 2 and 3). In addition, the
use of a combination of CF3CH2OH as the solvent and AgBF4
as the activator does not improve the efficiency or the selecti-
vity (2a : 2b = 2 : 1) of the process (entry 4) over that observed
when AgBF4 is not utilized (Table 1, entry 8).
The substrate scope of the rearrangement reaction, carried
out using NCS in CF3CH2OH, was explored (Table 3).10,11 The
results show that reactions of cyclopentanone derived aminals
1b–d, derived from cyclopentanone and aromatic ring substi-
tuted (e.g., Cl, Br, and Me) o-aminobenzyl amine, proceed in
good yields (entries 2–4). Moreover, aminals prepared from
cyclohexanone and cycloheptanone as well as the acyclic
ketone, 3-pentanone, undergo the rearrangement reaction
(entries 5–7). Furthermore, the presence of various functional
groups, such as TBS ethers, esters, olefins, and p-methoxy-
benzyl ether does not significantly alter the efficiency of the reac-
enhancement is a consequence of the highly polar and low
nucleophilic properties of this fluorinated alcohol, which
could aid in facilitating the N–Cl bond cleavage reaction that
promotes rearrangement.
Further studies were carried out to optimize the yields of
the aminal ring expansion reaction.8 To determine if the only
moderate yield of 2a of the reaction of 1a with NCS is a con-
sequence of competitive chlorination of the aromatic rings in
the starting aminal and/or 3,4-dihydroquinazoline product,
control experiments were performed (Scheme 2). The results of
the first experiment show that the reaction of 2a with NCS in
CF3CH2OH (eqn (1)) does not give chlorinated product 2b. Sec-
ondly, we observed that the reaction of 1a with NCS in CH2Cl2
produces the chloro-aminal intermediate and no aromatic ring
chlorinated product ( judged by TLC). Addition of CF3CH2OH
(in the same volume as CH2Cl2 (total 0.1 M)) to the above reac-
tion mixture leads to formation of the rearrangement product
2a along with its chlorinated analog 2b, and chlorinated
aminals 1b and 1b′ (eqn (2)).9 These observations suggest that
the initial chloro-aminal formed in CH2Cl2 likely acts as the
reagent for aromatic ring chlorination taking place in
CF3CH2OH. Thus, it is plausible to consider that CF3CH2OH
tion (entries 8–11). However, aminal 1l containing
a
tetrahydropyran ring reacts to generate the rearrangement
product in a low yield (entry 12), probably because of the elec-
tron withdrawing nature of the ether oxygen and its effect on
the migration ability of carbon.12
In conclusion, the studies described above have led to the
development of a general method for promoting oxidative
Scheme 2 The results of control experiments.
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Table 3 Generalitya
Experimental section
General procedure for preparation of aminal
Entry
Aminal
Product
Yieldb
3′,4′-Dihydro-1′H-spiro[cyclopentane-1,2′-quinazoline]
(1a).
o-Aminobenzylamine (3a) (273.0 mg, 2.23 mmol) and
ketone 2 (1.0 or 1.2 eq.) was dissolved in CHCl3 (0.2 M) and
the reaction mixture was stirred for 1 day at 60 °C. The result-
ing solution was cooled to rt and evaporated in vacuo to give
aminal 1a as a yellow solid. Mp: 48 °C; 1H NMR (300 MHz,
CDCl3): δ = 7.00 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H), 6.92 (dd, J = 7.5,
1.5 Hz, 1H), 6.66 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.48 (dd, J =
7.5, 1.2 Hz, 1H), 4.01 (s, 2H), 1.87–1.66 ppm (m, 8H); 13C NMR
(126 MHz, CDCl3) δ = 143.0, 127.1, 126.0, 120.5, 117.3, 114.9,
76.0, 43.3, 39.7(2C), 23.7(2C) ppm; IR (KBr): 3296, 2955, 1607,
1416, 1193 cm−1; HRMS (EI): calcd for C12H16N2 [M]: 188.1313,
found 188.1325.
1
2
3
4
5
1a (X = H)
1b (X = Cl)
1c (X = Br)
1d (X = Me)
2a (X = H)
2b (X = Cl)
2c (X = Br)
2d (X = Me)
71%
76%
79%
86%
73%
6
72%
69%
65%
61%
66%
7
General procedure for oxidative rearrangement of aminal
7,8,9,11-Tetrahydro-6H-pyrido[2,1-b]quinazoline (2a).14 To
the solution of aminal 1a (41.9 mg, 0.223 mmol) in
CF3CH2OH (11.0 mL) was added NCS (32.8 mg, 0.246 mmol)
at 0 °C and the mixture was stirred for 30 min. The resulting
solution was allowed to warm to rt and stirred for 1 day. The
reaction was quenched with sat. Na2S2O3 aq. and CF3CH2OH
was evaporated in vacuo. To the residue was added 0.5 N NaOH
aq. followed by extraction with CH2Cl2. The organic layer was
dried over Na2SO4 and evaporated in vacuo. The residue was
purified by column chromatography (AcOEt–MeOH–triethyl-
amine = 20/2/1) to give amidine 2a as a red oil. 1H NMR
(300 MHz, CDCl3): δ = 7.13 (ddd, J = 8.4, 8.4, 2.4 Hz, 1H),
7.05–6.98 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.53 (s, 2H), 3.54 (t,
J = 6.0 Hz, 2H), 2.59 (t, J = 6.8 Hz 2H), 2.02–1.94 (m, 2H),
1.83–1.74 ppm (m, 2H).
8
9
10
11
12
62%
25%
Acknowledgements
This work was financially supported by a Grant-in-Aid for
Scientific Research (B) and for Young Scientists (B) from JSPS.
a Conditions: 1 (1 eq.), NCS (1.1 eq.), CF3CH2OH (0.02 M), 0 °C–rt.
b Isolated yield.
Notes and references
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rearrangement reactions of aminals that generate 3,4-dihydro-
quinazolines. Observations made in this effort show that
CF3CH2OH is an ideal solvent for this process owing to its
enhancement effect on rearrangement reactions of chloro-
aminal intermediates formed by the reaction with NCS. To the
best of our knowledge, reactions of halo-amines as well as
chloro-aminals in CF3CH2OH have not been described pre-
viously. Thus, it is possible that the effects of CF3CH2OH
observed in this investigation are applicable to other trans-
formations of halo-amines,13 a question that is being pursued
in further studies in our laboratory.
2650 | Org. Biomol. Chem., 2013, 11, 2648–2651
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