Lewis-acid catalyzed N-acyliminium ion cyclodimerization: Synthesis of symmetrical 1,4-dioxanes

Article abstract of DOI:10.1016/j.tetlet.2015.01.059

The cyclodimerization reaction of N-substituted-5-hydroxy-pyrrolydinones promoted by BF₃·Et₂O and HCl to obtain symmetrical 1,4-dioxane derivatives was achieved in moderate to good yields, mild conditions, and short reaction times. These transformations render a promising alternative route that provides access to diverse 1,4-dioxane derivatives with a wide structural diversity.

Full text of DOI:10.1016/j.tetlet.2015.01.059

Tetrahedron Letters 56 (2015) 1153–1158
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis-acid catalyzed N-acyliminium ion cyclodimerization: synthesis
of symmetrical 1,4-dioxanes
Bakhat Ali a, Julio Zukerman-Schpector b, Fernando P. Ferreira c, Anwar Shamim d, Daniel C. Pimenta e,
Hélio A. Stefani a,c,d,
⇑
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
b Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil
c Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, SP, Brazil
d Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
e Instituto Butantã, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclodimerization reaction of N-substituted-5-hydroxy-pyrrolydinones promoted by BF3ꢀEt2O and
HCl to obtain symmetrical 1,4-dioxane derivatives was achieved in moderate to good yields, mild
conditions, and short reaction times. These transformations render a promising alternative route that
provides access to diverse 1,4-dioxane derivatives with a wide structural diversity.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 19 December 2014
Revised 6 January 2015
Accepted 7 January 2015
Available online 17 January 2015
Keywords:
Amines
N-Acyliminium
Acid catalysis
Cyclodimerization
1,4-Dioxane
Introduction
(N,O-acetal derivatives) with carbon-based nucleophiles through
activation by a Lewis acid.
The synthesis of heterocycles is a very important area in organic
chemistry because of their strong presence in natural products and
pharmaceutical drugs.1
The reactivity affords exceptionally useful methodologies for
carbon–carbon bond and carbon-heteroatom bond formation, both
in intermolecular and intramolecular processes.3 These species
have been generated from amides or lactams, which bear a good
Heterocyclic compounds, especially containing carbon-nitrogen
and carbon-oxygen bonds, have great importance, and researchers
are constantly searching for new approaches to synthesize these
molecules. Nitrogen-containing heterocyclic compounds, espe-
cially succinimide derivatives, are important intermediates in syn-
thesis and key structures in biologically active products.2,3
Succinimide derivatives are converted to chiral pyrrolidine motifs,
which display activity in many biological systems, by simple
transformations.4
N-Acyliminium ions play an important role in organic synthe-
sis5 since they are reactive intermediates involved in the synthesis
of many compounds with interesting biological properties. Nucle-
ophilic addition to N-acyliminium ions is an important method to
leaving group at the a-position nitrogen atom in acidic media.
The N-acyliminium ion is a key intermediate for the addition of
different nucleophiles including allylsilanes, alkyl-, aryl-, allyl-,
alkynylmetal, isonitriles, enol derivatives, TMSCN, and aromatics.5
1,4-Dioxanes derivatives are important biologically active com-
pounds.7 Due to the importance of 1,4-dioxanes, many approaches
for the synthesis of this six-membered heterocyclic compounds
have been described. Among the methods are: (a) oxyselenylation
of dienes with enantiopure diols;8,9 (b) Mitsunobu cyclization of
diols;10 (c) photoinduction electron transfer cyclization of an
appropriate diene;11 (d) condensation of glyoxalic acid with chiral
hydrobenzoin,12 (e) intramolecular ring opening of oxirane by an
alcohol moiety;13 and (f) cyclodimerization of epoxide,14 phospho-
ric acid-catalyzed desymmetrization of cyclohexadienones.15
Among the many applications14 of 1,4-dioxane derivatives, we
can mention some examples of drugs containing a 1,4-dioxane
ring: doxazosin (Cardura) used to treat the symptoms of an
enlarged prostate (benign prostatic hyperplasia or BPH) to treat
provide
a-functionalized amino compounds such as nitrogen
heterocycles.6 Of particular interest are the intermolecular nucleo-
philic substitution reactions of cyclic N-acyliminium ion precursors
⇑
Corresponding author. Tel.: +55 11 30913654; fax: +55 11 3815 4418.
E-mail address: hstefani@usp.br (H.A. Stefani).
http://dx.doi.org/10.1016/j.tetlet.2015.01.059
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1154
B. Ali et al. / Tetrahedron Letters 56 (2015) 1153–1158
H
Table 1
O
N
H
O
O
O
F
H
H
O
H
Synthesis of imides and 5-hydroxy-4-acetoxypyrrolydones
O
O
HO
O
N
OAc
OAc
OH
NH
O
O
N
N
N
H
O
O
OH
1.CH3COCl, reflux, 24 h
NaBH4
EtOH/THF, -30 oC, 30 min
O
O
N
R
O
N
R
3a-n
Fluparoxan
Spectinomycin
N
NH2
2. R NH2, THF, rt, 4 h
3.CH3COCl, reflux, 5 h
Doxazosin
HO2C
CO2H
1
2a-n
Figure 1. Structure of drugs containing 1,4-dioxane ring.
Entry Amine
Product/yield (%) Product/yield (%) Ratio cis/trans
OAc
OAc
NH2
high blood pressure;16 spectinomycin (Trobicin) is a useful antibi-
otic for the treatment of bacterial infection and gonorrhea,17 and
OH
O
O
O
N
N
1
80:20
70:30
fluparoxan (GR-50,360) is a potent and highly selective a2-adren-
I
ergic receptor antagonist which is being investigated as an antide-
pressant18 (Fig. 1).
I
2aI- 70
3a - 65
NH2
OAc
OAc
Results and discussion
O
O
O
OH
N
N
We report here a direct method for the synthesis of heterocyclic
1,4-dioxane derivatives via acid-catalyzed cyclodimerization reac-
tions of cyclic N-acyliminium ions. This opportunity should be
taken to mention that Pyne and co-workers19 published an exam-
ple of this approach in a study on the synthesis of stemocurtisine
employing acyliminium ions, but did not perform a systematic
study.
In continuation of our interest in the chemistry of acyliminium
ions,20–24 we developed the synthesis of 1,4-dioxanes via dimeriza-
tion reactions of N-substituted acyliminium ions.
2
OCH3
OCH3
OCH3
2b - 76
3b - 66
NH2
OAc
OAc
O
O
O
OH
O
O
N
N
3
4
80:20
85:15
2c - 73
3c - 62
OAc
OAc
NH2
We began the synthesis of our starting material using L-malic
acid, which is a precursor of the N-acyliminium ion1,25 reaction
leading to pyrrolidin-2-one derivative 3.
O
OH
N
N
HO
O
O
Acid 1 was successively treated with acetyl chloride, primary
amines, and again with acetyl chloride to afford imide 2. Regio-
and stereoselective reduction of the imide 2 was then achieved
by reaction with an excess of sodium borohydride in ethanol/THF
at ꢁ30 °C for 30 min to afford the 5-hydroxy-2-pyrrolidin-2-one
3 as a mixture of cis/trans diastereoisomers (see Table 1).
Fourteen imides (2) were synthesized containing primary aro-
matic, alkyl-, acetyl-, benzyl-, propargyl-, and triazolyl-amines,
all in moderate to high yields (Table 1, entries 1–14).
The presence of electron-donating or electron-withdrawing
groups at the aromatic rings does not appear to interfere with
the performance of the reaction leading to moderate yields; also,
the occupied position in the ring does not seem to affect yields
in both reactions. Alkynyl groups such as propargyl (Table 1,
entries 12–14) also gave moderate yields. These last compounds
were obtained via click chemistry reaction. The acyl group (Table 1,
entry 8) afforded the product in 56% yield.
AcO
3d - 50
O
AcO
2d - 65
O
NH2
OAc
OAc
O
O
O
O
O
O
O
OH
O
N
N
5
6
90:10
75:25
3e - 56
2e -58
NH2
OAc
OAc
O
OH
N
N
o
O
O
2f - 70
3f - 58
NH2
Br
OAc
OAc
O
The stereochemistry of the newly created chiral center in the
products was assigned by 1H NMR analysis of the crude reaction
mixtures. The cis relative stereochemistry of the major product
was established by an analysis of the multiplicity and vicinal cou-
pling constants of the hydrogen attached to the carbon that under-
went nucleophilic attack (H-5).
O
OH
N
N
7
75:25
Br
Br
3g - 65
2g - 76
O
OAc
OAc
In this way, the relative stereochemistry of compounds was
assigned by correlation to the chemical shifts and coupling con-
stant data of similar compounds already described in the literature.
In addition, the vicinal coupling constant J3 (H5–H4) for the syn-
isomer always has a smaller value than the trans-isomer. In addi-
tion, the H5 of the cis-isomer appears up-field of the anti-isomer.
These chemical correlations are in full agreement with the major
isomer obtained here; thus, the relative stereochemistry of the
major isomer was assigned as cis.26
H2N
O
O
O
O
O
OH
N
N
8
9
80:20
90:10
O
O
3h - 56
2h - 66
OAc
OAc
NH2
O
OH
N
N
Following production of the N-substituted-5-hydroxy-pyrrolid-
inone, we began surveying the best reaction conditions to
obtain the cyclodimer of the acyliminium ion, reacting
2i - 79
3i - 69

B. Ali et al. / Tetrahedron Letters 56 (2015) 1153–1158
1155
Table 2
Table 1 (continued)
Lewis Acid cyclodimerization of N-substituted-5-hydroxy-4-acetoxypyrrolidone
Entry Amine
Product/yield (%) Product/yield (%) Ratio cis/trans
R
N
OAc
OH
O
NH2
OAc
OAc
1. BF3.Et2O, DMSO, rt, 30 min
2. HCl, 0 oC, 0.5-2 h
O
O
O
N
N
R
O
O
O
O
OH
N
N
R
3a-n
4a-n
10
11
60:40
65:35
NO2
Entry
Pyrrolidone
Product
Yield (%)
NO2
NO2
OAc
3j - 66
2j - 75
NH2
OAc
OAc
O
O
N
O
O
OH
N
O
N
O
1
71
O
O
O
OH
N
N
3a
4a
I
OAc
OH
3k - 83
2k - 78
OAc
OAc
NH2
F
F
N
O
O
O
O
OH
O
N
N
O
O
N
12
13
70:30
65:35
O
O
N
N
N
2
60
N
N
N
N
I
3l - 60
OAc
2l - 70
3b
OAc
NH2
I
O
N
N
OH
N
4b
OCH3
OAc
OH
N
N
N
N
N
O
2m - 67
N
3n - 58
O
O
N
NH2
OAc
OAc
O
N
O
3
4
5
62
58
70
O
O
O
OH
N
N
OCH3
14
70:30
3c
N
N ( )11
( )11
N
N
N
H3CO
N
4c
2n - 70
3n - 56
O
O
OAc
HO
N
O
OH
O
N
O
O
5-hydroxy-pyrrolydinone with ethyl triptophane, trying to obtain
the pyrrolidone amino esters. To our surprise, the only product
obtained was the 1,4-dioxane dimer 4g. In view of that interesting
result, various reaction conditions were surveyed using Lewis acids
in different stoichiometries, bases or acids, and solvents to achieve
the cyclodimer.
The Lewis acid that afforded the best yield (88%) of the cyclod-
imer 4g was BF3ꢀEt2O. However, in the presence of a protic solvent
like methanol, no product was detected. The same was observed
when the reaction was carried out in THF and PMDTA
(N,N,N0,N0,N00-pentamethyldiethylenetriamine) as a base. Also, with
POCl3 as a catalyst, the reaction did not afford the dimer. The reac-
tions with bases such Et3N, Py, DMAP, and PMDTA in the presence
of BF3ꢀEt2O produced low to moderate yields ranging from 20% to
52%.
In the absence of a base, the reaction proceeded, leading to
yields from low (20%) to good (80%). Acids such as CF3CO2H and
HCl gave almost the same high yields, 83% to 88%. Reaction in
the presence of tryptophan ester led to good yields of the product
(80%), however its absence led only to traces (in GC–MS) of the
product, in both cases using BF3ꢀEt2O. Using HCl without trypto-
phan ester and BF3ꢀEt2O, the product was achieved in 40%. These
last two reactions were carried out in DMSO as a solvent for
18 h. The use of a glycine ester afforded the same results.
With the optimal reaction conditions determined, we next
explored the substrate scope of 5-hydroxy-4-acetoxypyrrolidone
for dimerization (Table 2).
O
N
AcO
3d
O
OH
4d
Br
OAc
OH
O
N
O
O
N
O
O
N
Br
3e
Br
4e
OAc
OH
O
O
O
N
O
O
N
O
N
O
6
59
O
O
3f
4f
OAc
OH
N
O
O
N
O
O
N
7
88
3g
4g
As shown in Table 2, all starting materials exhibited good reac-
tivity, leading to 1,4-dioxane derivatives in yields ranging from
(continued on next page)

1156
B. Ali et al. / Tetrahedron Letters 56 (2015) 1153–1158
Table 2 (continued)
Table 2 (continued)
Entry
Pyrrolidone
Product
Yield (%)
Entry
Pyrrolidone
Product
Yield (%)
OAc
OAc
N
11( )
N
N
O
O
O
OH
O
OH
O
N
N
N
O
N
O
O
N
O
N
O
8
66
O
O
14
60
O
N
N
( )11
N
3h
N ( )11
3n
N
N
4h
4n
O
OAc
OH
Reaction conditions: 3g (0.249 g, 1.0 mmol, 1.0 equiv) in DMSO (5 mL) at 25 °C
under N2 atmosphere was added BF3ꢀEt2O (4.0 equiv) dropwise. The reaction mix-
ture was stirred at room temperature for 30 min. Then HCl (1.5 equiv) was added
drop by drop for 5 min and left for 1 h.
O
N
O
O
N
O
N
O
9
70
O
55% to 88% (Table 2, entries 1–14). N-Aryl substituted pyrrolidones
with electron-withdrawing groups in the benzene ring (such as 4-I,
4-Br, and 4-NO2) provided products in moderate yields (see Table 2,
entries 4b, 4e, 4k, 60%, 70%, and 55%, respectively). Electron-donat-
ing groups such as MeO-, regardless of the position (o, m or p) on
the ring, showed no significant electronic effects and afforded the
desired 1,4-dioxane derivatives products 4c in 62%, 4h in 66%
and 4i in 70% in very similar yields (Table 2). On the other hand
the benzene ring gave a high yield, 80% (Table 2, entry 4j).
Groups such as alkyl and acetyl provided the corresponding
products in moderate yields: 4d and 4f in almost the same yields
of 58% and 59%, respectively (Table 2). However, when the reaction
was carried out with the N-benzyl group, the 1,4-dioxane deriva-
tive was achieved in 88% yield (Table 2, entry 4g).
The N-propargyl pyrrolidone (2l) was converted into a 1,4-diox-
ane derivative in 71%. The presence of the terminal alkyne at the N-
propargyl pyrrolidone allowed the preparation via click chemistry
of 1,2,3-triazole-1,4-disubstituted and the further conversion of
three triazoles into the 1,4-dioxane derivatives in almost the same
yields (Table 2, entries 4l, 4m, and 4n), 56%, 55%, and 60%, respec-
tively, with interesting structural architecture. This reaction sys-
tem tolerated electron-poor and electron-rich substituents at the
N-atom in the pyrrolidone ring, leading to 1,4-dioxane derivatives.
A plausible reaction mechanism for the formation of 1,4-diox-
ane derivative is proposed. The starting material (a) is treated with
BF3.etherate, which generates N-acyliminium ion (b, calcd
232.0968, found 232.0722). The reduction of b took place in the
presence of catalytic HCl to give intermediate c (calcd 189.0863,
found, 189.0799 (MꢁH)). Then intermediate c reacts with the
intermediate b to give intermediate d (calcd 420.1758, found,
420.1700 (MꢁH)), which after reduction cyclizes to form dioxane
product (Fig. 3). This information was obtained through HRMS in
a negative mode.
3i
O
4i
OAc
OH
O
O
O
N
N
O
N
O
10
80
3j
4j
NO2
N
OAc
OH
O
N
O
O
O
N
O
11
55
NO2
3k
NO2
4k
F
OAc
OH
O
N
N
N
N
N
N
N
O
O
N
F
O
O
N
12
56
3l
N
N
N
F
Similar reactions with the diacetate N-benzyl-3,4-diacetoxy-
pyrrolidone 6a–b afforded the 1,4-dioxane dimer in good yields
in both cases, using 7a with the free hydroxyl group (70%) or in
the acetyl form 7b (80%) (Scheme 1).
Confirmation of the NMR results was accomplished with the
X-ray crystal structure of the 1,5-dibenzyloctahydro-[1,4]
dioxino[2,3-b:5,6-b0]dipyrrole-2,6-dione 4g (Fig. 2). Slow recrystal-
lization from ethyl acetate provided suitable crystals for determi-
nation of the crystal structure.
Studies aimed at examining the mechanism for the cyclodimer-
ization reactions and the possible biological activities of these novel
1,4-dioxane derivatives are currently being evaluated; further
applications of this method to other targets are now underway.
4l
OAc
N
N
N
O
OH
N
N
O
O
N
O
N
O
N
N
13
55
3m
N
N
N
4m

B. Ali et al. / Tetrahedron Letters 56 (2015) 1153–1158
1157
acidic conditions employing Lewis acid/HCl in moderate to good
yields. These transformations render a promising alternative route
that provides access to symmetrical 1,4-dioxane derivatives with a
wide structural diversity.
AcO
O
OAc
OR
AcO
O
O
N
BF3.Et2O, DMSO, rt, 30 min
HCl, rt, 30 min
N
O
O
N
OAc
Acknowledgments
6a-b
R = H (70%); R= Ac (80%)
7a,b
The authors are grateful for the financial support provided by
FAPESP—São Paulo Research Foundation (Grant 2012/00424-2
and 2011/11499-0 for fellowship to B.A.—2012/17954-4), CNPq—
National Council for Scientific and Technological Development
(308.320/2010-7 to H.A.S. and 305626/2013-2 to J.Z.-S.) and FINEP
(grant 01.09.0278.04, D.C.P.).
Scheme 1. Cyclodimerization of 3,4-diacetoxypyrrolydone.
Supplementary data
Experimental details and analytical data for all new compounds,
including 1H and 13C NMR spectra. CCDC-1031271 (for compound
4g Table 2) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2015.01.059.
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d
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