Zinc triflate as Lewis acid in nucleophilic addition to cyclic N-acyliminium ions

Article abstract of DOI:10.1055/s-2005-872659

Zinc triflate-mediated nucleophilic addition of allytrimethylsilane, silyl enol ethers and terminal acetylenes to cyclic N-acyliminium ions at room temperature in CH₂Cl₂ is described. The corresponding α-substituted heterocycles were

Full text of DOI:10.1055/s-2005-872659

LETTER
2297
Zinc Triflate as Lewis Acid in Nucleophilic Addition to Cyclic
N-Acyliminium Ions
Nucleophilic
A
dd
o
ition to Cyc
n
lic
N
-Acylim
a
iniumIonsldo Aloise Pilli,* Luís Gustavo Robello
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP. 13083-970 Campinas, São Paulo, Brasil
Fax +55(19)37883023; E-mail: pilli@iqm.unicamp.br
Received 9 May 2005
tions.10 Recently, Ishimaru reported the combination of
zinc triflate and water in the stereoselective Mannich-type
reaction of chiral aldimines with 2-silyloxybutadienes.11
Furthermore, the work by Carreira and co-workers has
Abstract: Zinc triflate-mediated nucleophilic addition of allytri-
methylsilane, silyl enol ethers and terminal acetylenes to cyclic N-
acyliminium ions at room temperature in CH2Cl2 is described. The
corresponding a-substituted heterocycles were obtained in moder-
ate to good yields. The versatility of this reagent was demonstrated shown that zinc alkynylides can be generated by the reac-
tion of alkynes with zinc triflate and a tertiary amine.12
in the one-pot generation of the N-acyliminium ion and the zinc
alkynylide species, followed by their coupling reaction to afford
propargylic adducts in moderate yields.
However, to the best of our knowledge there has been no
report describing the ability of zinc triflate to promote the
Key words: zinc triflate, nucleophilic addition, N-acyliminium
formation of N-acyliminium ions and their in situ trapping
by nucleophiles.1 In this work, we report our results on the
ions
zinc triflate-mediated nucleophilic additions of allyltri-
methylsilane, silyl enol ethers and terminal acetylenes to
cyclic N-acyliminium ions.
N-Acyliminium ions are versatile electrophilic species
with many applications in the synthesis of nitrogen-con-
taining compounds, particularly those involving the
addition of carbon nucleophiles to its electrophilic center.1
N-Acyliminium ions are more electrophilic than the cor-
responding iminium species due to the presence of the
electron-withdrawing acyl group at the nitrogen atom and
for most synthetic applications they are generated in situ
from a-haloalkyl, a-hydroxyalkyl, a-alkoxyalkyl, a-acyl-
oxyalkyl, or a-sulfonyl amides, lactams, or carbamates in
view of their limited stabily and high reactivity. Lewis
acids (BF3·OEt2, TiCl4, SnCl4, InCl3, NbCl5) and silylat-
ing agents (TMSOTf) are used to assist the formation of
the electrophilic intermediate, followed by the addition of
carbon nucleophiles to form the C–C bond.1–3 However,
the search for additional protocols to perform Lewis acid
mediated nucleophilic additions to iminium and N-
acyliminium ions aiming high yield and tolerance of
functional groups is actively pursued in organic synthesis,
particularly those which provide concomitant formation
of both the nucleophilic and electrophilic species in the
same pot.
a
b
O
O
O
O
O
OH
Br
N
H
N
N
Br
1
2
3a
d
c
O
O
OH
Br
OMe
Br
O
OAc
Br
N
N
N
3a
3b
3c
e
O
SO2Tol
Br
N
3d
In this context, metal triflates are an interesting alternative
because numerous examples in the literature have demon-
strated the ability of metal triflates to promote C–C bond
formation under mild conditions.4 Particularly, zinc trif-
late is an effective catalyst for aldol reactions of silyl enol
ethers with aldehydes,5 ring-opening of chiral aziridines,6
preparation of N(1)- and N(2)-alkylated tetrazoles via
displacement of alcohols,7 regioselective synthesis of 3-
alkylindoles,8 enantioselective reduction of a-alkoxy
ketones9 and enantioselective radical conjugate addi-
Scheme 1 Reagents and conditions: (a) NaH (60% in mineral oil),
DMF, 0 °C, 15 min; then, 2,3-dibromopropene, 0 °C to r.t., 3 h, 65%;
(b) i. Et3BHLi, THF, –78 °C, 2 h, 85%; (c) HCl–MeOH 2 mol L–1, 0
°C to r.t., 18 h, 98%; (d) Ac2O, Et3N, DMAP, 0 °C to r.t., 18 h, 72%;
(e) CHCl3, p-CH3C6H4SO2Na·xH2O, HCO2H (aq), r.t., 48 h, 78%.
The competence of zinc triflate to promote the generation
of cyclic N-acyliminium ions, followed by the addition of
allyltrimethylsilane (4) to provide the corresponding a-
substituted heterocycle was initially evaluated with lac-
tam 3b, prepared from imide 2 as described in Scheme 1.
We initially screened the effect of the solvent and found
out CH2Cl2 to be the best choice. The use of 20 mol%
SYNLETT 2005, No. 15, pp 2297–2300
1
9
.0
9
.2
0
0
5
Advanced online publication: 09.08.2005
DOI: 10.1055/s-2005-872659; Art ID: S04605ST
© Georg Thieme Verlag Stuttgart · New York

2298
R. A. Pilli, L. G. Robello
LETTER
( )
excess of zinc triflate provided the best yield of pyrrol-
idine 5 (78% yield, Table 1, entry 3) with lower yields be-
ing observed when sub-stoichiometric amounts were
employed (Table 1, entries 4 and 5). Surprisingly, the
yields of allyl pyrrolidine 5 prepared from N-acyliminium
ion precursors 3c and 3d (Table 1, entries 7 and 8) which
display better leaving groups at C-a were lower than those
obtained from 3a (Table 1, entry 6) and 3b (Table 1, entry
3).
( )
n
n
OMe
OtBu
OMe
Br
N
OMe
O
O
N
N
OMe
O
9
3b (n = 1)
6 (n = 2)
7 (n = 1)
8 (n = 2)
( )
n
( )
n
N
OMe
O
O
N
N
Table 1 Zn(OTf)2-Mediated Addition of Allyltrimethylsilane (4) to
N-Acyliminium Ions Derived from 3a–d
Br
O
OtBu
Zn(OTf)2
R
13
5 (n = 1)
11 (n = 1)
12 (n = 2)
O
O
10 (n = 2)
N
SiMe3
N
Br
Br
4
Figure 1
(2 equiv)
3a–d
solvent, r.t.
5
Table 2 Zn(OTf)2-Mediated Allylation Reaction of Cyclic
N-Acyliminium Ions Derived from 3b and 6–9
Entry Substrate (R)
Solvent
Zn(OTf)2 Yield of 5
(equiv)
(%)a,17
Entrya
Substrate
Product (%)b
5 (78)
1
2
3
4
5
6
7
8
3b (R = OMe)
3b (R = OMe)
3b (R = OMe)
3b (R = OMe)
3b (R = OMe)
3a (R = OH)
Toluene
MeCN
1.2
52
1
2
3
4
5
3b
6
1.2
60
10 (52)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1.2
78
7
11 (68)
0.5
26
8
12 (52)
0.25
1.2
15
9
13 (72)
65
a Reactions were carried out employing 1.2 equiv of Zn(OTf)2,
2.0 equiv of allyltrimethylsilane (4) in CH2Cl2 at r.t.
b Chemical yields after column chromatography.
3c (R = OAc)
3d (R = SO2Tol)
1.2
38
1.2
61
a Chemical yields after column chromatography.
amounts (ca. 30% yield) of the corresponding unsaturated
lactam suggesting the lower reactivity of the correspond-
ing six-membered N-acyliminium ion. In the reactions of
prochiral silyl enol ether 15 with a-methoxy carbamates 7
and 8, the preferential formation of erythro-20 and
erythro-21 (Table 3, entries 5 and 6, respectively) was ob-
served with higher diastereoisomeric ratio being achieved
in the reaction of six-membered a-methoxy carbamate 8
(Table 3, entry 6).2b,15 Such behavior has been observed
before in our studies involving the addition of titani-
um(IV) enolates of N-acyl-2-oxazolidinones to exocyclic
five- and six-membered N-acyliminium ions precursors
and might be related to the lower reactivity of six-mem-
bered vs. five-membered exocyclic N-acyliminium ions
toward nucleophiles.
The scope of this transformation was evaluated next em-
ploying a-methoxy pyrrolidines and piperidines 6–9 un-
der the reaction conditions employed in entry 3, Table 1.
The corresponding a-allyl substituted products 10–13
(Figure 1) were isolated in moderate to good yields3 with
better results being observed with five-membered precur-
sors 3b and 7 when compared to the corresponding six-
membered analogues 6 and 8 (Table 2). The resonance
stabilized N-acyliminium ion derived from a-methoxy
tetrahydroisoquinoline 9 also provided the corresponding
allyl derivative in good yield (entry 5, Table 2).
Silyl enol ethers 14 and 15 also proved to be competent
nucleophiles when reacted with N-acyliminium ions pre-
cursors 3b and 6–9 affording 16–22 in moderate to good
yields (Figure 2, Table 3).13
Finally, based on the results recently reported by Carreira
and co-workers on the addition of in situ generated zinc
alkynylide to N-acyliminium prepared from aldimines
and acid halides,16 we explored the ability of zinc triflate
to promote a related sequence of events starting from
substrates 3b and 6–9. In fact, treatment of a mixture of
N-acyliminium ion precursors, acetylene and Zn(OTf)2 in
toluene–CH2Cl2 at room temperature with Et3N and
TMEDA provided the corresponding propargylic adducts
As before, better yields of the corresponding coupling
products were observed when six-membered N-acylimin-
ium ions were involved (Table 3, entries 1, 3 and 5).
These results may be due to a difference in the intrinsic
electrophilic character of the five- and six-membered N-
acyliminium ions14 and/or in their relative rates of forma-
tion. In fact, the reaction of silyl enol ether 14 and a-meth-
oxy lactam 6 (Table 3, entry 2) provided significant
Synlett 2005, No. 15, 2297–2300 © Thieme Stuttgart · New York

LETTER
Nucleophilic Addition to Cyclic N-Acyliminium Ions
2299
Zn(OTf)2
(2 equiv)
R
H
OMe
Br
O
O
N
N
R
Et3N, TMEDA
Br
CH2Cl2, toluene
r.t., 18 h
( )
( )
n
n
NCO2Me
O
N
Ph
N
Ph
Br
O
OtBu
Ph
27
23 (n = 1)
24 (n = 2)
25 (n = 1)
26 (n = 2)
NCO2Me
O
N
SiMe3
N
SiMe3
Br
O
OtBu
SiMe3
30
28
29
Figure 2
Scheme 2
Table 3 Zinc Triflate-Mediated Addition Reaction of Silyl Enol
Ethers 14 and 15 to Cyclic N-Acyliminium Ions Derived from 3b, 6–9
Table 4 Zinc Triflate-Mediated Addition Reaction of Acetylenes to
Cyclic N-Acyliminium Ions Derived from 3b, 6–9
Entrya
Substrate Sylil enol ether Product (%)b
Entrya
Substrate
Acetylene
Product (%)b
23 (58)
24 (42)
25 (59)
26 (40)
27 (69)
28 (58)
29 (48)
30 (60)
1
2
3
4
5
6
7
3b
6
14
14
14
14
15
15
14
16 (69)
1
2
3
4
5
6
7
8
3b
6
H–C≡C–Ph
H–C≡C–Ph
H–C≡C–Ph
H–C≡C–Ph
H–C≡C–Ph
H–C≡C–SiMe3
H–C≡C–SiMe3
H–C≡C–SiMe3
17 (50)
7
18 (71)
7
8
19 (68)
8
7
Erythro-20 (80, dr = 4:1)c
Erythro-21 (63, dr = 10:1)c
22 (80)
9
8
3b
7
9
a Reactions were carried out employing 1.2 equiv of Zn(OTf)2, 1.2
equiv of silyl enol ether in CH2Cl2 at r.t.
9
b Chemical yields after column chromatography.
c The dr was determined by GC analysis.
a Reactions were carried out employing 2.0 equiv of Zn(OTf)2, 1.2
equiv of acetylene, 1.0 equiv of Et3N and 1.0 equiv of TMEDA in
CH2Cl2–toluene at r.t.
b Chemical yields after column chromatography.
23–30 in moderate yields (Scheme 2, Table 4). Studies
are now underway in order to extend the scope of this pro-
tocol to other N-acyliminium ions and acetylenes.
In summary, the use of zinc triflate as a Lewis acid in
nucleophilic additions to a series of cyclic N-acyliminium
ions afforded the corresponding products in moderate to
good yields. The versatility of this reagent was demon-
strated in the in situ generation of the N-acyliminium ion
and zinc alkynylide, followed by their reaction to afford
propargylic adducts in moderate yields.
Acknowledgment
The authors would like to thank FAPESP (Fundação de Amparo a
Pesquisa no Estado de São Paulo) for financial support and fel-
lowship (LGR) and CNPq (Conselho Nacional de Desenvolvimento
Científico e Tecnológico) for research fellowship (RAP).
Synlett 2005, No. 15, 2297–2300 © Thieme Stuttgart · New York

2300
R. A. Pilli, L. G. Robello
LETTER
(13) The allylation reactions and the addition of silyl enol ethers
to N-acyl iminium ion precursors using Zn(OTf)2 gave
comparable yields to those obtained when BF3·OEt2 was
employed.
(14) (a) Pilli, R. A.; Böckelmann, M. A.; Alves, C. F. J. Braz.
Chem. Soc. 2001, 12, 634. (b) D’Oca, M. G. M.; Moraes, L.
A. B.; Pilli, R. A.; Eberlin, M. N. J. Org. Chem. 2001, 66,
3854.
References
(1) For recent reviews on the chemistry of N-acyliminiun ions,
see: (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817; and references cited therein. (b) Pilli, R. A.;
Rosso, G. B. Methods of Molecular Transformations, In
Science of Synthesis (Houben-Weyl), Vol. 27; Padwa, A.,
Ed.; Thieme: Stuttgart, 2004, 375.
(2) (a) Russowsky, D.; Petersen, R. Z.; Godoi, M. N.; Pilli, R. A.
Tetrahedron Lett. 2000, 41, 9939. (b) Camilo, N. S.; Pilli,
R. A. Tetrahedron Lett. 2004, 45, 2821.
(3) Andrade, C. K. Z.; Matos, R. A. F. Synlett 2003, 1189.
(4) Kobayashi, S.; Sugiura, M.; Kitagawa, H. Chem. Rev. 2002,
102, 2227.
(5) Chini, M.; Crotti, P.; Gardelli, C.; Minutolo, F.; Pineschi, M.
Gazz. Chim. Ital. 1993, 123, 673.
(6) Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993,
34, 6513.
(7) Fortin, R.; Brochu, C. Tetrahedron Lett. 1994, 35, 9681.
(8) Zhu, X.; Ganesan, A. J. Org. Chem. 2002, 67, 2705.
(9) Bandini, M.; Cozzi, P. G.; de Angelis, M.; Umani-Ronchi,
A. Tetrahedron Lett. 2000, 41, 1601.
(15) For clarity, only the structures of the major diastereoisomers
erythro-20 and erythro-21 are depicted in Table 3. Data for
erythro-20, see ref. 2b.
Data for erythro-21: 1H NMR (CDCl3, 298 K): d = 1.13 (d,
J = 6.95 Hz, 3 H), 1.30–1.70 (s, 6 H); 1.50 (s, 9 H), 2.65–
2.79 (s, 1 H), 4.02–4.23 (m, 2 H), 4.69–4.82 (s, 1 H), 7.50–
7.60 (m, 3 H), 7.99 (d, J = 6.95 Hz, 2 H). 13C NMR (CDCl3,
298 K): d = 15.4, 19.6, 25.4, 27.6, 28.5, 38.8, 39.3, 53.0,
79.8, 128.4, 129.0, 133.5, 137.1, 155.6, 203.5. IR (KBr,
film): 2974, 2933, 1685, 1415, 1365, 1170, 1147, 968 cm–1.
Anal. Calcd for C19H27NO3: C, 71.92; H, 8.51; N, 4.41.
Found: C, 71.59; H, 8.24; N, 4.37.
(16) Carreira, E. M.; Fischer, C. Org. Lett. 2004, 6, 1497.
(17) Representative Procedure.
(10) Murakata, M.; Tsutsui, H.; Hoshino, O. Org. Lett. 2001, 3,
299.
To a suspension of Zn(OTf)2 (0.24 mmol) in dry CH2Cl2 (1
mL) at r.t. was added a substrate 3b (0.20 mmol), diluted in
dry CH2Cl2 (1 mL). After 10 min, allyltrimetylsilane (4, 0.40
mmol) was added. The mixture was stirred 3 h at r.t. and
quenched with sat. NaHCO3 (2 mL), extracted with CH2Cl2
(2 × 5 mL), dried with anhyd Na2SO4. After filtration, the
solvent was evaporated under reduced pressure and the
residue was chromatographed on silica gel (5% MeOH in
CHCl3) to afford 5 in 78% yield.
(11) Ishimaru, K.; Kojima, T. J. Org. Chem. 2003, 68, 4959.
(12) (a) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem.
Soc. 1999, 121, 11245. (b) Frantz, D. E.; Fässler, R.;
Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806.
(c) Boyall, D.; Lopez, F.; Sasaki, H.; Carreira, E. M. Org.
Lett. 2000, 2, 4233. (d) Sasaki, H.; Boyall, D.; Carreira, E.
M. Helv. Chim. Acta 2001, 84, 964. (e) El-Sayed, E.;
Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3, 3017.
(f) Anand, N. K.; Carreira, E. M. J. Am.Chem. Soc. 2001,
123, 9687. (g) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605. (h) Diez, R. S.; Adger, B.; Carreira, E.
M. Tetrahedron 2002, 58, 8341. (i) Fässler, R.; Frantz, D.
E.; Ötiker, J.; Carreira, E. M. Angew. Chem. Int. Ed. 2002,
41, 3054. (j) Reber, S.; Knöpfel, T. F.; Carreira, E. M.
Tetrahedron 2003, 59, 6813.
Data for compound 5: 1H NMR (300 MHz, CDCl3): d = 1.74
(m, 1 H), 2.14 (m, 2 H), 2.34 (m, 3 H), 3.68 (m, 2 H), 4.60
(d, J = 15.8 Hz, 1 H), 5.10 (s, 1 H), 5.12 (d, J = 15.8 Hz, 1
H), 5.58 (s, 1 H), 5.65 (m, 1 H), 5.75 (s, 1 H). 13C NMR (300
MHz, CDCl3): d = 23.4, 29.8, 37.2, 48.2, 56.2, 118.9, 119.1,
128.2, 132.5, 175.2. IR (KBr, film): 3076, 2976, 2920, 1695,
1639, 1426, 1254, 1113, 915 cm–1. HMRS (EI): m/z calcd for
C10H14NOBr: 245.0239; found: 245.0242.
Synlett 2005, No. 15, 2297–2300 © Thieme Stuttgart · New York