Ultrasound-assisted addition of alcohols to N-acyliminium ions mediated by In(OTf)3 and synthesis of 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2014.03.104

An easy and mild approach using ultrasound-assisted reaction addition of alcohols to N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the synthesis of ether pyrrolidinones; next, the products were converted to 1,2,3-triazoles using c

Full text of DOI:10.1016/j.tetlet.2014.03.104

Accepted Manuscript
Ultrasound-assisted Addition of Alcohols to N-Acyliminium Ions Mediated by
In(OTf)3 and Synthesis of 1,2,3-Triazoles
Hélio A. Stefani, Bakhat Ali, Fernando P. Ferreira
PII:
S0040-4039(14)00525-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.104
TETL 44426
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
8 March 2014
20 March 2014
21 March 2014
Please cite this article as: Stefani, H.A., Ali, B., Ferreira, F.P., Ultrasound-assisted Addition of Alcohols to N-
Acyliminium Ions Mediated by In(OTf)3 and Synthesis of 1,2,3-Triazoles, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.03.104
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Ultrasound-assisted Addition of Alcohols to
N-Acyliminium Ions Mediated by In(OTf)3 and
Synthesis of 1,2,3-Triazoles
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Hélio A. Stefani,* Bakhat Ali, Fernando P. Ferreira

1
Tetrahedron Letters
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Ultrasound-assisted Addition of Alcohols to N-Acyliminium Ions Mediated by
In(OTf)3 and Synthesis of 1,2,3-Triazoles
*aHélio A. Stefani, aBakhat Ali, bFernando P. Ferreira
aDepartamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP – Brasil. bDepartamento de Biofísica,
Universidade Federal de São Paulo, São Paulo, SP – Brazil
Corresponding author: hstefani@usp.br, Tel 55 11 3091-3654; Fax 55 11 3815-4418
ARTICLE INFO
ABSTRACT
An easy and mild approach using ultrasound-assisted reaction addition of alcohols to N-
acyliminium ion mediated by Lewis acid, In(OTf)3, allowed the synthesis of ether
pyrrolidinones; next, the products were converted to 1,2,3-triazoles using click chemistry
reaction conditions. The products in both reactions were afforded in moderate to good yields.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Acyliminium ion
Addition reaction
Click chemistry
1,2,3-Triazol
Ultrasound
general procedure to access various readily available 5-ether-2-
pyrrolidinones from the corresponding addition reaction of
alcohols to acyliminium ions mediated by In(OTf)3 and further
transformation in 1,2,3-triazolyl 2-pyrrolidinone.
1. Introduction
N-Acyliminium ions are important intermediates in organic
synthesis, mainly in intramolecular reactions;1 therefore, they
have found large use in the synthesis of nitrogen-containing
natural and unnatural products of biological interest.2,3 N-
Acyliminium ions act as electron-deficient carbocations in
reactions with weak nucleophiles.
Results and Discussion
L-Tartaric acid has proven to be a useful precursor for N-
acyliminium ion reactions leading to enantiopure pyrrolidine
derivatives.6 The N-benzyl imide
inexpensive L-tartaric acid 1, according to a procedure from the
2 was prepared from
This reactivity affords exceptionally useful methodologies for
carbon–carbon bond formation, both in intermolecular and
intramolecular processes.3 These species have been generated
from amides or lactams which bear a good leaving group at the
nitrogen atom α-position in acidic media.
literature7 (Scheme 1).
1.CH3COCl, reflux, 24 h
2.Benzyl amine, THF, rt, 4 h
AcO
OAc
O
HO
OH
O
3.CH3COCl, reflux, 5 h
N
HO2C
CO2H
Several classes of carbon nucleophiles can react with N-
acyliminium ions, such as allyl-, alkyl-, aryl-, and alkynylmetals,
cyanotrimethylsilane (TMSCN), isonitriles, enol derivatives, and
aromatics.3
1
2
Ph
AcO
OAc
OH
AcO
OAc
OAc
NaBH4, EtOH
THF, -30 oC, 30 min
Ac2O, Et3N, 4-DMAP
CH2Cl2, rt, 3 h
O
O
N
N
Ph
Ph
The use of ultrasound to promote chemical reactions is called
sonochemistry. The effects of ultrasound observed during organic
reactions are due to cavitation, a physical process that creates,
enlarges, and implodes gaseous and vaporous cavities in an
irradiated liquid. Cavitation induces very high local temperatures
and pressures inside the bubbles (cavities), leading to turbulent
flow of the liquid and enhanced mass transfer.4
(83%)
3
(88%)
4
Scheme 1. Synthesis of N-acyliminium ion precursor
Acid 1 was successively treated with acetyl chloride,
benzylamine and acetyl chloride to afford the respective imide 2.
Regio- and stereoselective reduction of imide
accomplished by the reaction with excess sodium borohydride in
ethanol/THF at -30oC for 30 min to give the 5-hydroxy- 2-
pyrrolidinone derivative 3 as a 95:5 mixture of syn/anti
diastereoisomers.7
2
was
Sonochemistry shares some aims with green chemistry, as it
also uses smaller quantities of hazardous chemicals and solvents,
reduces energy consumption, and increases product selectivity.
In connection with our research interest on the preparation
and reactivity of N-acyliminium ions,5 we wish to report here a
After acylation of the alcohol with acetic anhydride, the
desired N-acyliminium ion precursor 4 was obtained in a good

2
Tetrahedron
54
not
yield. The stereochemistry of the major syn-isomer was
determined on thebasis of the J (H4 and H5) coupling constant of
2.0 Hz.
3
determined
With the starting material in hand, various Lewis acids were
screened for the intermolecular nucleophilic addition to N-
acyliminium ions by using propargyl alcohol as a model reagent
to evaluate the influence of the catalyst in dichloromethane. The
most representative results obtained by using Lewis acids are
presented in entries 1–7 (Table 1).
42
not
4
determined
Table 1. Screening of the ideal conditions for the addition of propagyl
alcohol
5
6
nr
78
syn/anti
10:7
66
syn/anti
10:3
Entry
Catalyst/
mol%
Reaction
Time(h)
Yield
(%)
30
Ratio
syn/anti
50/50
7
8
1
2
3
4
5
6
7
BF3.Et2O/20
BF3.Et2O/ 5 equiv
Sc(OTf)3/10
4
18
18
60
61/39
65
syn/anti
10:4
62
30/70
FeCl3/10
3
3
43
75
58
67
36:64
70:30
16:84
20:80
In(OTf)3/10
Cu(OTf)3/10
Ag(OTf)3/10
18
18
70
syn/anti
10:2
aIsolated product
9
When 4 was reacted with propargyl alcohol in the presence of
BF3.Et2O (20 mol%), under room temperature in
dichloromethane (DCM) for 4 h, the addition product 5 was
isolated in 30% yield (entry 1) with a syn/trans ratio of 50/50.
Increasing the amount of the catalyst BF3.Et2O to 5 equiv.
observed an increased yield to 60% and a ratio of 61/39, but with
a long reaction time (entry 2). In the case of Sc(OTf)3, FeCl3,
Cu(OTf)3, and Ag(OTf)3, the yields achieved ranged from 43% to
67% and the ratio of the enantiomer was anti majority in all
cases. The reaction time was 3 to 18 hours. In(OTf)3 was shown
to be the best catalyst, affording the desired product at a yield of
75% and a ratio of 70:30.
71
syn/anti
10:1
10
11
nr
63
syn/anti
10:2
12
13
Using the conditions from Table 1, entry 5, the scope of the
addition reaction was investigated with a variety of alcohols. As
shown in Table 2, primary, secondary, and aromatic alcohols
were found to react smoothly with N-acyliminium ion to give
products (5a-5r) in yields ranging from 42% to 78%.
67
syn/anti
10:2
58
syn/anti
10:2
Table 2 – Scope of the In(OTf)3-catalyzed addition reaction of alcohols and
N-acyliminium ion
14
15
61
syn/anti
1:10
Entry
Alcohol
Compound
Yield(%)a,b
Ratio
syn/anti
75
75
syn/anti
10:4
16
syn/anti
10:7
1
2
72
syn/anti
10:3
aAll the reactions were carried out with 1 (1.2 mmol), 2 (1 mmol), [In(OTf3
10 %]. bIsolated yield. cReaction time: 3 hours.

3
8
Cu(OTf)3 (0.1)
CuI (0.1)
PMDTA
Na-ascorbate
Na-ascorbate
PMDTA
THF
THF
7
It was found that the reaction carried out with alkyl alcohols
worked well to produce primary and secondary alcohols with
almost the same yields (Table 2, entry 1 and 2). The yield
dropped when diols with carbon chains with four and eight
carbons were reacted, giving yields of 42% and 54% (Table 2,
entries 3 and 4). For all other alcohols, the yields were good.
Alcohols with another functionality and groups such as phenyl,
bromide, allyl, carbocyclic, ester, olefin, and acetylene had yields
ranging from 57% to 78% (Table 2, entries 6, 8, 10, 12, 13 and
15, respectively). The reaction was not effective for amino
alcohol (Table 2, entry 11).
9
40
65
67
28
nr
10
11
12
13
Cu(OAc)3
CuI (0.1)
CuI (0.1)
THF
DCM
MeOH
CH3CN
PMDTA
PMDTA
CuI (0.1)
Concerning the amount of copper salt, we carried out the
reaction whilst reducing the amount of CuI to 0.1 equiv; the yield
was almost the same (70%). Other copper sources were tested,
such as CuCl, CuCN, Cu(OAc)2 and CuSO4.5H2O, but lower
results were obtained for all.
In the case of aromatic alcohols, including phenols and
naphthol (Table 2, entries 5, 7, 9, and 14), the yields ranged from
54% to 70%. The presence of electron-withdrawing groups such
as nitro led to no results (Table 2, entry 5) and an acyl group in
the aromatic ring was tolerated in the reaction (Table 2, entry 7).
The stereochemistry of the newly created stereogenic center in
PMDTA was the base only surveyed. The use of sodium
ascorbate as an additive did not improve yields, with just low or
moderate yields being observed (Table 3, entries 9 and 10), even
when 1.1 equivalent was used. The choice of solvent was of
paramount importance for the success of the reaction;
dichloromethane provided the optimal environment, leading to
67% yield and THF gave a similar yield (Table 3, 70%, entries
5). Low or no yields were obtained with the other solvents such
as MeOH and CH3CN (Table 3, entries 12, 13).
1
the products was assigned by H NMR analysis of the crude
reaction mixtures.
The syn relative stereochemistry of the major product was
established by analysis of the multiplicity and vicinal coupling
constants of the hydrogen attached to the carbon that underwent
nucleophilic attack (H-5). In this way, the relative
stereochemistry of compounds was assigned by correlation to the
chemical shifts and coupling constant data of similar compounds
already described in the literature.
The extension of these conditions to a broader range of
organic azides allowed the synthesis of a number of 1,2,3-
triazoles in good yields under mild reaction conditions; the most
representative results are illustrated in Table 4.
Table 4 – Ultrasound-assisted Synthesis of 1,2,3-Triazoles
OAc
3
For analogous the vicinal coupling constant J (H5–H4) for
OAc
O
AcO
AcO
0.1 eq.CuI, PMDTA
THF, N2, ))), 2h
the syn-isomer always has a smaller value than the anti-isomer.
In addition, the H5 of the syn-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 syn.5b
+
R N3
O
O
O
N
N
R
N
N
N
5r
6
Entry
Azide
Product
Yield
(%)
70
As mentioned above, the presence of other functionalities in
the alcohols opened up many opportunities for further
transformations. Using these advantages, we envisioned the
synthesis of 1,2,3-triazole rings through the “click chemistry”
approach.8
N3
syn/anti
1
2
10:7
Initially, we focused our attention on the optimization of the
reaction conditions, investigating parameters including: copper
loading salts, base, additive and solvents. The standard reaction
was carried out with propynyl pyrrolidone (Table 2, entry 16)
(1.0 mmol), propargyl alcohol (1.5 mmol), CuI (0.1 eq.),
PMDETA (1.0 mmol) and dichloromethane (5 mL) as solvent.
Using these conditions, the product 1 (Table 4) was obtained in
70% yield. On the other hand, under the same conditions but in
the absence of a base, the product was isolated in only 21% yield,
thus showing the crucial role of the base in this reaction.
70
syn/anti
10:6
65
3
4
syn/anti
10:6
Table 3 - Screening of the ideal reaction condition for synthesize 1,2,3-
triazoles
63
syn/anti
10:7
Entry
Cu Cat. (equiv)
Base or
additive
(1.1 equiv)
-
Solvent
Yield %
68
5
1
2
3
4
5
6
7
CuI (1.0)
CuI (1.0)
THF
THF
THF
THF
THF
THF
THF
21
68
45
37
70
58
40
syn/anti
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
CuCN (1.0)
CuSO4.5H2O (1.0)
CuI (0.1)
10:8
Cu(OAc)2 (0.1)
CuCl (0.1)

4
Tetrahedron
40
afforded the desired product in low yield (40%; Table 4, entry 6),
but with a very interesting structure.
syn/anti
6
7
10:7
Unfortunately, when coumarin azide (Table 4, entry 7) was
subjected to this reaction, only starting materials were recovered,
even after prolonged reaction times. All of the products9,10 were
characterized by 1H, 13C NMR and high resolution mass
spectrometry.
nr
Conclusion
In conclusion, we have demonstrated an efficient addition
reaction of primary, secondary, aromatic and alkylic alcohols to
N-acyliminum anion catalyzed by In(OTf3), which allows the
assembly of a wide range of ethers and 1,2,3-trizole products in
moderate to good isolated yields. The transformation in 1,2,3-
triazoles by click chemistry is operationally simple, the substrate
scope is wide, and the starting materials are readily available.
This study not only increased our understanding of the character
of the N-acyliminum anion but also shed important light on how
to further expand its scope and utility.
78
8
9
syn/anti
10:7
82
syn/anti
10:7
71
Acknowledgments
10
syn/anti
The authors gratefully acknowledge financial support from
- grant
10:5
the São Paulo Research Foundation (FAPESP
2012/00424-2 and fellowship to BA 2012/17954-4) and The
National Council for Scientific and Technological Development
(CNPq) for a fellowship (308.320/2010–7 to HAS).
90
11
12
syn/anti
10:7
Supplementary data
Supplementary data associated with this article can be found
in the online version.
48
syn/anti
10:6
References and notes
1.Maryanoff, B. E.; Zhang, H-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431-1628.
2.Hubert, J. C.; Wunberg, J. B. P. A.; Speckamp, W. N. Tetrahedron
1975, 31, 1437-1441.
52
13
3.a)N-acyliminium ion chemistry, see: Koning, H.; Speckamp, W. N.
in Houben-Weyl, Stereoselective Synthesis (Eds G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann) 1995, Vol. E21, p. 1953 (Thieme
Verlag: Stuttgart). b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817-3856. c) Pilli, R. A.; Russowsky, D. Trends Org.
Chem. 1997, 6, 101-123. d) Zaugg, H. E. Synthesis 1984, 85-110. e)
Zaugg, H. E. Synthesis 1984, 181-212.
4.Cella, R.; Stefani, H. A. Tetrahedron 2009, 65, 2619-2641.
5.a) Vieira, A. S.; Guadagnin, R. C.; Fiorante, P. F.; Ferreira, F. P.;
Stefani, H. A. Tetrahedron 2008, 64, 3306-3314. b) Vieira, A. S.;
Ferreira, F. P.; Guarezemini, A. S.; Stefani, H. A. Aust. J. Chem. 2009,
62, 909-916. c) Caracelli, I.; Ferreira, F. P.; Vieira, A. S.; Stefani, H.
A.; De Simone, C. A.; Tiekink, E. R. T. Acta Cryst. Section E 2010,
E66, o3044. d) Vieira, A. S.; Fiorante, P. F.; Zukerman-Schpector, J.;
Alves, D. Botteselle, G. V.; Stefani, H. A. Tetrahedron 2008, 64, 7234-
7241.
syn/anti
10:6
When aliphatic azides were employed as the substrates, the
corresponding products were obtained in good yields (Table 4,
entries 1, 6 and 8). The reaction carried out overnight without
ultrasound of benzyl azide (table 4, entry 1) gave a yield of 53%.
Aromatic azides were also used as substrates for Cu(I)-
promoted cycloaddition; when phenylazide was employed, the
corresponding triazolyl pyrrolidone was obtained in a high yield
(90%; Table 4, entry 11). Conversely, substituted aromatic
azides, particularly those with electron-withdrawing groups,
resulted in good yields ranging from 63% to 71% (Table 4,
entries 2-5 and 10). The best result with aromatic azides was
achieved with ortho-methoxyphenyl azide, which gave the
product in an 82% yield (Table 4, entry 9). Substituents in the
ortho, meta and para positions of the aromatic ring seemed to
have no effect on the average yield of aromatic azides (Table 4,
entries 2-5 and 9-10).
6.For reviews of N-acyliminium ion chemistry, see: (a) Yazici, A.;
Pyne, S. S. Synthesis 2009, 3, 339–368. (b) Yazici, A.; Pyne, S. S.
Synthesis 2009, 4, 513–541.x.x.209
7.Louwrier, S.; Ostendorf, M.; Bomm, A.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1996, 52, 2603-2628.
8.Wu, P.; Fokin, V. V. Aldrichim. Acta 2007, 40, 7-17.
9.General procedure for preparation of (2): To a solution of 1 (1
mmol) in dry dichloromethane (5 mL), In(OTf)3 (0.1 mmol) and
propargyl alcohol (1.5 eq) were added at room temperature under N2.
The reaction mixture was stirred at room temperature for 3 h. Then the
reaction was washed with water (10 mL), 2-times. The organic phase
was dried over anhydrous Na2SO4. The solvent was then removed
under reduced pressure. The crude product 2 was purified by column
chromatography on silica gel using ethyl acetate/hexane (1.5:8.5).
Sugar azides gave only moderate yields of the 1,2,3-triazolyl
pyrrolidinone (Table 4, entries 12 and 13). The alkyl diazides

5
(3R,4R)-1-benzyl-2-oxo-5-(prop-2-yn-1-yloxy)pyrrolidine-3,4-diyl
diacetate - Syn: 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3 H), 2.10
(s, 3 H), 2.35 (t, J = 2.35 Hz, 1 H), 4.01 - 4.09 (m, 4 H), 4.93 (t, J =
3.20 Hz, 1 H), 5.07 (dd, J = 3.49, 1.79 Hz, 1 H), 5.27 (d, J = 3.6 Hz, 1
H), 7.25 - 7.29 (m, 5 H). 13C NMR (75 MHz, CDCl3) δ ppm 20.5, 20.6,
44.7, 57.6, 71.6, 73.3, 75.7, 78.6, 89.0, 128.0, 128.3 (2C), 128.9 (2C),
135.2, 167.3, 169.8, 170.4.
Anti: 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (s, 3 H), 2.11 (s, 3 H),
2.38 (t, J = 2.35 Hz, 1 H), 4.01 - 4.09 (m, 4 H), 4.93 (t, J = 3.20 Hz, 5
H), 5.00 - 5.05 (m, 1 H), 5.32 (dd, J = 7.72, 0.75 Hz, 1 H), 7.25 - 7.29
(m, 5 H). 13C NMR (75 MHz, CDCl3) δ ppm 20.5, 20.6, 43.8, 55.8,
72.4, 73.3, 75.7, 78.6, 83.9, 127.9, 128.3 (2C), 128.9 (2C), 135.2,
167.3, 169.6, 169.8. HRMS calcd for C18H19NO6 (M + Na): 368.1116;
found: 368.1116. Light yellow oil, yield 75% (260 mg).
solution, brine, dried over anhydrous Na2SO4. The solvent was then
removed under reduced pressure. The crude product was purified by
column chromatography on silica gel using ethyl acetate/hexane (4:6).
(3R,4R)-1-benzyl-2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-
oxopyrrolidine-3,4-diyl diacetate (Table 4, entry 1): Syn 1H NMR
(300 MHz, CDCl3) δ ppm 2.04 (s, 3H), 2.15 (s, 3 H), 4.11 - 4.17 (m, 2
H), 4.68 (s, 2 H), 4.88 (m, 1 H), 5.15 - 5.19 (m, 1H), 5.35 (d, J = 3.96
Hz, 1 H), 5.50 (s, 2 H), 7.19 - 7.41 (m, 11 H). 13C NMR (75 MHz,
CDCl3) δ ppm 20.5, 20.9, 43.8, 54.2, 61.7, 71.6, 73.5, 84.6, 122.8,
127.9 (2C), 128.1 (4C), 129.2 (4C), 129.2(2C), 135.1, 167.1, 169.8,
171.0.
Anti: 1H NMR (300 MHz, CDCl3) δ ppm 2.04 (s, 3 H), 2.18(s, 3H),
4.11 - 4.17 (m, 1H), 4.56 (m, 2H), 4.68 (s, 1H), 4.73-4.74 (m, 1 H),
5.17 - 5.18 (m, 1 H), 5.50 (s, 2 H), 5.71 (d, J = 8.90 Hz, 1 H), 7.19 -
7.41 (m, 11 H). 13C NMR (75 MHz, CDCl3) δ ppm 20.5, 20.6, 45.0,
54.2, 63.5, 72.6, 75.9, 89.4, 122.5, 127.9 (2C), 128.2 (4C), 129.1 (4C),
134.3(2C), 135.1, 167.2, 169.6, 170.5. HRMS calcd for C25H26N4O6
(M+Na): 501.1750; found: 501.1759. Light yellow oil, yield 70% (336
mg).
10.General procedure for preparation of 1,2,3-triazoles: To
a
solution of (3R,4R)-1-benzyl-2-oxo-5-(prop-2-ynyloxy)pyrrolidine-
3,4-diyl diacetate (1 mmol) in dry THF (5 mL), CuI (0.1 mmol),
PMDTA (1.1 mmol) and azide (1.3 mmol) were added at room
temperature under N2. The reaction mixture was sonicated at room
temperature for 2 h. The reaction mixture was filtered through Celite®,
filtrate was concentrated under reduced vacuum. The concentrate was
dissolved in ethyl acetate, extracted with 1 M hydrochloric acid (10
mL x 2). Then organic phase was washed with aqueous NaHCO3 10 %