Base-Induced Cyclisation of ortho -Substituted 2-Phenyloxazolines to Give 3-Aminobenzofurans and Related Heterocycles

Article abstract of DOI:10.1055/s-0036-1588503

Treatment of ortho -benzyloxyphenyloxazolines with butyllithium and potassium tert -butoxide results in cyclisation with ring opening of the oxazoline to give 2-aryl-3-aminobenzofurans. The reaction also occurs with the corresponding benzylthio and benzylamino compounds to give benzothiophenes and indoles, respectively. Use of an ortho -allyloxyphenyloxazoline gives the corresponding 2-vinylbenzofuran, while both α-methylbenzyloxy and benzylsulfonyl compounds form stable spirooxazolidine products. The X-ray structure of an aminobenzothiophene product has been determined.

Full text of DOI:10.1055/s-0036-1588503

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
R. A. Aitken et al.
Letter
Synlett
Base-Induced Cyclisation of ortho-Substituted 2-Phenyloxazolines
to Give 3-Aminobenzofurans and Related Heterocycles
R. Alan Aitken*
0
0
0
0
0-
0
0
1
6-
9
5
9
5-
3
1
1
Me
Me
HN
Me
Me
OH
BuLi
t-BuOK
THF
Andrew D Harper
N
X
Alexandra M. Z. Slawin
O
Ar
X
EaStCHEM School of Chemistry, University of St Andrews,
North Haugh, St Andrews, Fife, KY16 9ST, UK
raa@st-and.ac.uk
Ar
X = O, S, NMe
8 examples
11–80% yield
Received: 30.04.2017
Accepted after revision: 12.06.2017
Published online: 18.07.2017
excellent selectivity for 3 was achieved (Scheme 1). We in-
terpret this in terms of the mechanism shown in Scheme 2
where initial ortho metallation is followed by deprotona-
tion of the benzyl group allowing equilibration with cy-
clised forms, but it is only the third deprotonation leading
to formation of the aromatic furan ring that decisively leads
to product 3.
DOI: 10.1055/s-0036-1588503; Art ID: st-2017-b0311-l
Abstract Treatment of ortho-benzyloxyphenyloxazolines with butyl-
lithium and potassium tert-butoxide results in cyclisation with ring
opening of the oxazoline to give 2-aryl-3-aminobenzofurans. The reac-
tion also occurs with the corresponding benzylthio and benzylamino
compounds to give benzothiophenes and indoles, respectively. Use of
an ortho-allyloxyphenyloxazoline gives the corresponding 2-vinylbenzo-
furan, while both α-methylbenzyloxy and benzylsulfonyl compounds
form stable spirooxazolidine products. The X-ray structure of an amino-
benzothiophene product has been determined.
Table 1 Optimisation of the Reaction for Formation of 3
Me
Me
Me
HN
Me
+
Me
Me
N
N
OH
Key words cyclisation, oxazoline, benzofuran, benzothiophene, in-
dole, Schlosser’s base, spiro heterocycle
base
O
O
Ph
Ph
O
O
Ph
OH
3
Me
1
2
Me
N
Although the chemistry of 4,5-dihydrooxazoles (2-oxaz-
olines) has been extensively developed over the last 40
years,1–3 new useful reactions facilitated by this auxiliary
group continue to be discovered. We have recently exam-
ined the ability of this group to facilitate the [1,2]-Wittig re-
arrangement of an adjacent benzyl ether in compounds
such as 1 and the success of this strategy will be reported
elsewhere. However, in the course of this work, it was dis-
covered that treatment of 1 with both n-butyllithium (BuLi)
and potassium tert-butoxide (t-BuOK) (‘Schlosser’s base’)
resulted in unexpected cyclisation with ring opening of the
oxazoline to give the 3-aminobenzofuran 3 in high yield.4
Optimisation of the process is shown in Table 1. While the
Wittig rearrangement product 2 was formed using BuLi in
THF, 2.2 equivalents were required to obtain a good yield
and this gave 3 as a major byproduct. Most other solvents
gave mixtures with lower selectivity for 2 vs. 3 and the only
two that gave complete reaction, MTBE and toluene, actual-
ly favoured the debenzylation product 4. Better selectivity
for 3 was obtained using the BuLi/t-BuOK mixture but 1.1
equivalents gave mostly starting material and it was only
with just over three equivalents that high conversion with
O
+
OH
4
Conditions
Ratio of products (%)
1
2
3
4
1.1 equiv BuLi, THF
1.1 equiv NaH, THF
2.2 equiv BuLi, THF
2.2 equiv BuLi, Et2O
57
100
0
29
0
8
0
6
0
6
75
38
24
47
64
17
13
4
19
39
27
6
13
0
10
49
8
2.2 equiv BuLi, t-BuOMe
2.2 equiv BuLi, 2-MeTHF
2.2 equiv BuLi, dioxane
2.2.equiv BuLi, DME
39
4
19
30
29
33
79
95
13
11
58
6
42
0
2.2 equiv BuLi, PhMe
1.1.equiv BuLi, t-BuOK, THF
2.2 equiv BuLi, t-BuOK, THF
3.3 equiv BuLi, t-BuOK, THF
57
17
3
0
4
0
2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
R. A. Aitken et al.
Letter
Synlett
Me
Me
Me
Me
Me
HN
Me
Me
Me
3.3 equiv BuLi
3.3 equiv t-BuOK
Me
OH
Me
OH
3.3 equiv BuLi
3.3 equiv t-BuOK
THF, r.t., 2 h
N
N
O
N
O
HN
1) NaH, DMF
2) ArCH2Br
O
O
O
THF, r.t., 2 h
Ar
Ph
80%
O
O
OH
Ph
Ar
6
3
4
1
5
Me
HN
Me
HN
Scheme 1 Optimised conditions for cyclisation of 1 to give 3
Me
Me
OH
OH
Me
Me
Me
F
OMe
Me
O
Me
Me
Me
O
O
M
N
O
M
M
N
MN
OM
6a 12%
6b 66%
O
M
Ph
Ph
Me
HN
Me
HO
Me
NH
Me
Me
O
Ph
O
OH
OH
HN
1 equiv
base
2 equiv
base
1 equiv
base
O
O
O
OMe
MeO
MeO
6e 47%
1
Me
Me
O
Me
Me
6c 13%
6d 11%
M
M
MN
MN
OM
Me
NH
Me
Ph
Ph
HO
M
O
O
O
O
aq NH4Cl
O
3
7a 4-Me
7b 2-Me
Me
Scheme 2 Proposed mechanism for conversion of 1 into 3
Scheme 3 Preparation of compounds 5a–j and their reaction to give
6a–e and 7a,b
As far as we are aware, the only previous examples of
intramolecular base-induced cyclisation of a carbanion
onto an oxazoline resulting in ring opening of the latter are
a single example of naphtho[2,3-b]thiophene formation
upon treatment of a 1-bromo-2-naphthyloxazoline with
the sodium salt of 4-chlorobenzylmercaptan,5 and two re-
ports in which fluorenone products are formed as byprod-
ucts in treatment of an ortho-lithiated phenyloxazoline
with an aryne.6,7 The current process does bear a close re-
semblance to the Gewald reaction,8 in which an ortho-
alkoxybenzonitrile is treated with base leading to a 3-ami-
nobenzofuran. Although this process originally required a
strongly electron-withdrawing substituent on the alkoxy
group, more recent examples show that it also works with
less stabilised anions,9–11 including the cyclisation of 2-ben-
zyloxy-3-cyanopyridine.12
It might also be mentioned that heterocycle formation
by intramolecular cyclisation of both alkoxide13 and imide14
anions onto 2-oxazolines are well known, giving phthalides
and isoquinolines, respectively, after hydrolysis. There are
relatively few direct cyclisation routes to 3-aminobenzofu-
rans but one notable recent method involves treatment of
2-alkynylphenols with O-benzoylhydroxylamines and a
copper catalyst under basic conditions, although this was
only used to obtain 3-dialkylamino products.15,16
with substituted benzyl groups were more conveniently
synthesised from the phenol 4, itself derived from dealkyla-
tion of the allyl compound 12 (vide infra). In this way com-
pounds 5a–j were prepared and characterised (Scheme 3).
When these were subjected to the conditions of Scheme
1, a varied pattern of reactivity was observed. Compounds
5a–e all gave the expected benzofurans 6a–e in moderate
to low yield with the latter being caused by extensive de-
composition during chromatographic purification. In the
case of 5f and 5g, the products isolated were those of oxida-
tive cleavage of the benzofuran ring, 7a and 7b, and it is
likely that similar 2-benzoyloxybenzamides were also
formed in many of the other cases. The ready oxidative C2–
C3 bond cleavage of a 3-hydroxybenzofuran was noted as
early as 1916,17 and the same process has been reported
more recently for 2,3-diaminobenzofurans.18 For the three
isomeric nitrobenzyl compounds 5h–j, base treatment re-
sulted in extensive decomposition and no useful products
were obtained.
The oxazolines 8 and 10 with secondary alkoxy groups
were readily prepared by alkylation of 4 and also under-
went cyclisation. The products were, respectively, the spiro
oxazolidine 9 obtained as a 5:3 mixture of diastereomers
and the dihydrobenzofuran-3-imine 11 (Scheme 4). The
potential of chiral oxazoline analogues of 8 for the synthesis
Although the starting oxazoline 1 was readily prepared
by conventional stepwise construction of the oxazoline ring
with the benzyl group already in place, a range of examples
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
R. A. Aitken et al.
Letter
Synlett
product 16 was confirmed by X-ray diffraction, which also
showed an interesting pattern of hydrogen bonding involv-
ing the amino alcohol function.20 The sulfide 15 was oxi-
dised to both the sulfoxide 17 and the sulfone 18 using
standard methods and, in the latter case, there was partial
breakdown of the oxazoline to give the nitro ester 19 as a
byproduct. This is a known reaction of oxazolines with
mCPBA.21 Base treatment of the sulfoxide 17 led to exten-
sive decomposition and gave no useful products while the
sulfone 18 reacted cleanly to give the spiro compound 20 as
a 3:2 mixture of diastereomers.
Me
Me
Me
O
Me
3.3 equiv BuLi
3.3 equiv t-BuOK
THF, r.t., 2 h
N
HN
O
Me
Me
Ph
26%
Ph
O
O
9
8
Me
Me
Me
Me
3.3 equiv BuLi
3.3 equiv t-BuOK
THF, r.t., 2 h
N
N
OH
O
Ph
Ph
Ph
Ph
72%
O
O
11
10
Me
Me
Me
Me
OH
2.5 equiv BuLi
2.5 equiv t-BuOK
THF, r.t., 2 h
Scheme 4 Reactions observed with secondary alkoxy groups
N
HN
O
Ph
78%
S
S
Ph
of 2-chiral benzofuran-3-ones is currently being investigat-
ed.
16
15
NaIO4
MeOH (17)
or
MCPBA
CH2Cl2 (18)
NO2
Me
O
The 2-allyloxyphenyloxazoline 12 was also found to un-
dergo the same process giving the 2-vinylbenzofuran 13
(Scheme 5). While we were unable to get this to react as a
diene with a wide range of dienophiles, it did undergo a
Diels–Alder reaction as the dienophile with tetrachloro-
thiophene dioxide19 with extrusion of SO2 to give adduct
14.
Me
O
S
Ph
O2
Me
Me
19 29%
Me
Me
N
2.5 equiv BuLi
HN
O
O
2.5 equiv t-BuOK
THF, r.t., 2 h
Ph
S
Ph
S
66%
On
O2
Me
Me
Me
17 n = 1, 32%
18 n = 2, 56%
Me
OH
20
3.3 equiv BuLi
3.3 equiv t-BuOK
THF, r.t., 2 h
N
HN
O
Scheme 6 Cyclisation of sulfur-containing oxazolines
63%
O
O
13
12
The formation of 3-aminobenzothiophenes by the base-
induced cyclisation of 2-(benzylthio)benzonitrile as well as
the corresponding sulfoxide and sulfone has been report-
ed,22 and there are numerous other reports of Gewald-type
benzothiophene formation11,23–27 but, apart from the exam-
ple already mentioned,5 none involving cyclisation onto an
oxazoline.
Finally the method was extended to indole formation.
The oxazoline 21 was prepared by nucleophilic substitution
of the 2-methoxyphenyloxazoline28 with N-methylbenzyl-
amine and, upon treatment with 2.5 equivalents of BuLi/t-
BuOK, gave the aminoindole 22 (Scheme 7). There have
been several reports of aminoindole formation by Gewald
cyclisation of ortho-aminobenzonitriles,10,11,29 and in the
last case, involving cyclisation of an N-benzyl group, it was
noted that the 3-amino-2-phenylindoles could not be iso-
lated as such due to instability and they were instead di-
rectly acylated before isolation. This perhaps goes some
way to explain the low yield obtained for 22. The copper-
catalyzed cyclisation of 2-alkynylanilines with O-benzoyl-
hydroxylamines also gives 3-aminoindoles but is restricted
to 3-dialkylamino products.16
Cl
Cl
Cl
, PhMe
2.2 equiv BuLi
2.2 equiv t-BuOK
PhMe, r.t., 2 h
18%
89%
Me
Cl
S
O2
Me
Me
Me
N
HN
OH
Cl
O
Cl
O
OH
Cl
14
4
Cl
Scheme 5 Reactions of the 2-allyloxyphenyloxazoline
A most useful observation was that by changing the re-
action solvent to toluene, treatment of 12 with just over
two equivalents of BuLi/t-BuOK gave the phenol 4 in high
yield, presumably with elimination of hept-1-ene and this
was the method used to obtain 4 for synthesis of 5a–j, 8,
and 10, effectively using O-allyl as a protecting group
through the oxazoline formation.
The method is also applicable to formation of 3-amino-
benzothiophenes from 2-(benzylthio)phenyloxazolines and
conversion of 15 into 16 proceeded in good yield with 2.5
equivalents of BuLi/t-BuOK (Scheme 6). The structure of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
R. A. Aitken et al.
Letter
Synlett
IR: 1718, 1645, 1038, 967, 871, 848, 751, 733, 695 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.72 (dd, J = 7.5, 2.0 Hz, 1 H), 7.52 (d, J =
7.5 Hz, 2 H), 7.38–7.35 (m, 3 H), 7.29 (t, J = 7.3 Hz, 1 H), 7.01–
6.97 (m, 2 H), 5.18 (s, 2 H, OCH2Ar), 4.11 (s, 2 H, oxazoline CH2),
1.41 (s, 6 H, CH3). 13C NMR (125 MHz, CDCl3): δ = 161.2 (C=N),
157.3 (C–O), 137.0 (C), 131.9 (CH), 131.1 (CH), 128.2 (2 CH),
127.5 (CH), 126.7 (2 CH), 120.6 (CH), 118.6 (C), 113.5 (CH), 78.8
(oxazoline CH2), 70.5 (OCH2Ar), 67.5 (C), 28.4 (CH3). HRMS
(ESI+): m/z calcd for C18H20NO2 [M + H]+: 282.1489; found:
282.1478.
Me
Me
HN
Me
Me
OH
2.5 equiv BuLi
2.5 equiv t-BuOK
THF, r.t., 2 h
N
O
Ph
36%
N
N
Ph
Me
Me
22
21
Scheme 7 Cyclisation of a benzylaminophenyloxazoline to an indole
Under a nitrogen atmosphere, n-BuLi (2.5 M in hexane, 6.6 mL,
16.5 mmol) was added to a stirred mixture of 2-[2-(benzyl-
oxy)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1, 1.41 g, 5.01
mmol) and t-BuOK (1.88 g, 16.8 mmol) in dry THF (50 mL). The
reaction mixture was stirred at r.t. for 2 h before being
quenched by addition of sat. aq NH4Cl and extracted with Et2O
(3×). The combined organic layers were dried and evaporated to
give, after purification by column chromatography (Al2O3, gradi-
ent elution, Et2O/hexane 3:2 to EtOAc), 3 (1.13 g, 80%) as orange
crystals, mp 59–63 °C. IR: 3325, 2974, 2933, 1605, 1452, 1362,
1256, 1043, 1026, 739, 694 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.08–8.05 (m, 2 H), 7.64–7.62 (m, 1 H), 7.46–7.41 (m, 3 H),
7.34–7.30 (m, 1 H), 7.29–7.25 (m, 1 H), 7.24–7.20 (m, 1 H), 3.42
In summary, we have developed a convenient new route
to form 2-aryl-3-aminobenzofurans, also applicable to the
corresponding benzothiophenes and indoles. Extension of
the method to other fused ring heterocycles, such as vari-
ous isomeric thienofurans, is currently being investigated
and will be reported shortly.
Funding Information
We thank EPSRC (UK) for
a DTA studentship (Grant No.
EP/L505079/1) and the EPSRC UK National Mass Spectrometry Facili-
(s, 2 H, CH2), 2.65 (br s, 2 H, NH and OH), 1.07 (s, 6 H, CH3). 13
C
ty at Swansea University
E
n
gn
i
e
enri
g
a
n
d
P
h
ycsai
l
S
ecin
c
es
Reseacrh
C
o
u
n
lc
i
E(PL/5
0
5
0
7
9
1/
)
NMR (125 MHz, CDCl3): δ = 153.0 (C), 148.5 (C), 131.1 (C), 129.5
(C), 128.5 (2 CH), 128.0 (CH), 126.5 (2 CH), 124.4 (CH), 122.5
(CH), 122.2 (C), 119.6 (CH), 111.2 (CH), 70.3 (CH2), 58.1 (C), 24.7
(CH3). HRMS (ESI+): m/z calcd for C18H20NO2 [M + H]+: 282.1489;
found: 282.1482.
Supporting Information
Supporting information for this article (Full experimental procedures
and spectroscopic data for all compounds, copies of H and 13C NMR
1
(5) Baker, R. W.; Hockless, D. C. R.; Pocock, G. R.; Sargent, M. V.;
Skelton, B. W.; Sobolev, A. N.; Twiss (née Stanojevic), E.; White,
A. H. J. Chem. Soc., Perkin Trans. 1 1995, 2615.
(6) Yalcouye, B.; Berthelot-Bréhier, A.; Augros, D.; Panossian, A.;
Choppin, S.; Chessé, M.; Colobert, F.; Leroux, F. R. Eur. J. Org.
Chem. 2016, 725.
spectra and details of X-ray structure for 16) is available online at
https://doi.org/10.1055/s-0036-1588503.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(7) Augros, D.; Yalcouye, B.; Berthelot-Bréhier, A.; Chessé, M.;
Choppin, S.; Panossian, A.; Leroux, F. R. Tetrahedron 2016, 72,
5208.
(8) Gewald, K.; Jänsch, H.-J. J. Prakt. Chem. 1973, 315, 779.
(9) Sarodnick, G.; Kempter, G. E. DD 292001, 1991; Chem. Abstr.;
1991, 115: 232294
(1) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(2) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(3) Meyers, A. I. J. Org. Chem. 2005, 70, 6137.
(4) Typical Experimental Procedures
A solution of 2-(benzyloxy)benzoic acid (10.00 g, 43.8 mmol)
and thionyl chloride (6.4 mL, 10.44 g, 87.7 mmol) in toluene (90
mL) was heated under reflux for 3 h and then cooled and evapo-
(10) Radl, S.; Hezky, P.; Urbánková, J.; Váchal, P.; Krejcí, I. Collect.
Czech. Chem. Commun. 2000, 65, 280.
rated to give 2-(benzyloxy)benzoyl chloride (10.80 g, 100%) as a
pale yellow oil which was used without further purification.
This was dissolved in CH2Cl2 (40 mL) and added dropwise to a
solution of 2-amino-2-methylpropan-1-ol (7.81 g, 87.6 mmol)
in CH2Cl2 (50 mL) stirred at 0 °C. Once the addition was com-
plete, the reaction mixture was allowed to warm to r.t. for 18 h
before being poured into water. The two layers were separated
and the aqueous layer was re-extracted with CH2Cl2 (2×). The
combined organic layers were washed successively with 2 M
HCl, 2 M NaOH, and water before being dried and evaporated to
give the amide (12.68 g, 97%) as a colourless solid, mp 115–
117 °C, which was used without further purification.
SOCl2 (3.7 mL, 6.03 g, 50.7 mmol) was added to a solution of 2-
(benzyloxy)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide
(12.68 g, 42.4 mmol) in CH2Cl2 (210 mL), and the reaction
mixture was stirred at r.t. for 18 h. The mixture was washed
with 2 M NaOH and water before being dried and evaporated to
give, after purification by Kugelrohr distillation (185 °C/9.2
Torr), 1 (10.14 g, 85%) as a colourless oil which formed a low-
melting solid on standing.
(11) Radl, S.; Obadalova, I. ARKIVOC 2005, (xv), 4.
(12) Yang, J.; Wangweerawong, A.; Dudley, G. B. Heterocycles 2012,
85, 1603.
(13) Meyers, A. I.; Hanagan, M. A.; Trefonas, L. M.; Baker, R. J. Tetrahe-
dron 1983, 39, 1991.
(14) Poindexter, G. S. J. Org. Chem. 1982, 47, 3787.
(15) Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2395.
(16) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2012,
77, 617.
(17) von Auwers, K. Ber. Dtsch. Chem. Ges. 1916, 49, 820.
(18) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron Lett. 2007, 48, 401.
(19) Raasch, M. S. J. Org. Chem. 1980, 45, 856.
(20) Crystal Data for 16
C
18H19NOS, M = 297.41, colourless prism, crystal dimensions
0.20 0.20 0.20 mm, monoclinic, space group P21/c,
×
×
a = 11.976(2), b = 12.4118(15), c = 20.997(3) Å, β = 95.825(6)°,
V = 3105.0(8) Å3, Z = 8, Dc = 1.272 Mg m–3, T = 173 K, R1 =
0.0345, Rw2 = 0.0801 for 4529 reflections with I > 2σ(I) and 395
variables. Data were collected using graphite monochromated
Mo Kα radiation, λ = 0.71075 Å and have been deposited at the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
R. A. Aitken et al.
Letter
Synlett
Cambridge Crystallographic Data Centre as CCDC 1540330. The
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/getstruc-
tures.
(24) Beck, J. R. J. Org. Chem. 1972, 37, 3224.
(25) Beck, J. R.; Yahner, J. A. J. Org. Chem. 1974, 39, 3440.
(26) Markert, J.; Hagen, H. Liebigs Ann. Chem. 1980, 768.
(27) Kobayashi, K.; Yamashita, K. Heterocycles 2017, 94, 772.
(28) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978, 43,
1372.
(29) Seong, C. M.; Park, C. M.; Choi, J.; Park, N. S. Tetrahedron Lett.
2009, 50, 1029.
(21) Lee, T. D.; Keana, J. F. W. J. Org. Chem. 1976, 41, 3237.
(22) Beck, J. R. J. Heterocycl. Chem. 1978, 15, 513.
(23) Carrington, D. E. L.; Clarke, K.; Scrowston, R. M. J. Chem. Soc. C
1971, 3903.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E