Addition of carbon nucleophiles to cyclic N-acyliminium and oxocarbenium ions under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.09.023

The InCl₃-catalyzed addition of carbon nucleophiles to cyclic N-acyliminium and oxocarbenium ions under solvent-free conditions at room temperature is described. The corresponding α-substituted heterocycles were obtained in moderate to excellen

Full text of DOI:10.1016/j.tetlet.2006.09.023

Tetrahedron Letters 47 (2006) 7853–7856
Addition of carbon nucleophiles to cyclic N-acyliminium and
oxocarbenium ions under solvent-free conditions
Luiz Antonio F. de Godoy, Nilton Soares Camilo and Ronaldo Aloise Pilli*
Institute of Chemistry, State University of Campinas—UNICAMP, 13083-970, Campinas, SP, Brazil
Received 22 July 2006; revised 1 September 2006; accepted 6 September 2006
Abstract—The InCl3-catalyzed addition of carbon nucleophiles to cyclic N-acyliminium and oxocarbenium ions under solvent-free
conditions at room temperature is described. The corresponding a-substituted heterocycles were obtained in moderate to excellent
yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Organic reactions have been traditionally carried out in
organic solvents but the increasing environmental
concern has provided the impetus to investigate the
behavior of organic reactions under less conventional
conditions, water1 and supercritical carbon dioxide2
being two of the most prominent systems under investi-
gation. Many organic solvents currently used are toxic
and their use should be avoided in industrial plants.
The need to reduce the amount of toxic effluents in
industrial processes has stimulated the search for envi-
ronmentally friendly and resource sustainable industrial
processes.
N-acyliminium ions in SDS/water under catalysis by
3 mol % aq HCl or 10 mol % InCl3 revealed that low
to moderate yields of the corresponding 2-substituted
N-Boc pyrrolidines and piperidines were obtained, while
significantly higher yields were observed when 1,3-dicar-
bonyl compounds were employed.3 This limitation on
the nature of the nucleophile was partly rationalized
by the competitive hydrolysis of silyl enol ethers as well
as by the polymerization and hydrolysis of ethyl vinyl
ether.
In order to solve such limitation, we decided to investi-
gate the same reactions in the absence of solvent, and
here we report our results on the addition of silyl enol
ethers to N-Boc-2-methoxypyrrolidine (1) and N-Boc-
2-methoxypiperidine (2) under solvent-free conditions.7
The reactions were carried out with 2 equiv of the nucleo-
phile (1 mmol scale) in the presence of 10 mol % of InCl3
and after stirring at rt, good to excellent yields were ob-
served both for the pyrrolidine and piperidine deriva-
tives, after column chromatography of the crude
reaction mixture (Table 1). For the reaction between 1
and (Z)-1-phenyl-1-trimethylsilyloxypropene (3), the
reaction was faster and provided 7 in a higher yield (Ta-
ble 1, entry 1) when compared to the reaction carried
out in 1 M CH2Cl2 under otherwise the same experimen-
tal conditions (45 min and 84% yield). The reaction con-
dition also proved to be adequate for the addition of
silyl enol ether 3 to the 6-membered N-acyliminium pre-
cursor 2 (Table 1, entry 2). It is a noteworthy feature of
the reaction under solvent-free conditions that the
reaction involving the silylketeneacetal 1-trimethylsilyl-
oxy-1-methoxy-2-methylpropene (4) with both 5- and
We have recently disclosed our efforts in this arena by
reporting the addition of 1,3-dicarbonyl compounds
and enol ethers to cyclic N-acyliminium ions in sodium
dodecyl sulfate(SDS)/water and in organoindate ionic
liquid.3,4 These electrophilic intermediates have found
widespread application in the total synthesis of nitro-
gen-containing natural products, particularly alkaloids,
and pharmaceuticals.5 Despite our earlier successful
efforts, the development of chemical transformations
under solvent-free conditions remains the most attrac-
tive alternative from the perspective of environment,
cost, and ease of handling and, in fact, many reactions
proceed effectively, and in some cases even better, in
the absence of solvent.6
Our investigation on the addition of trimethylsilyl enol
ethers and ethyl vinyl ether to 5- and 6-membered
*
Corresponding author. Fax: +55 19 37883023;
pilli@iqm.unicamp.br
e-mail:
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.023

7854
L. A. F. de Godoy et al. / Tetrahedron Letters 47 (2006) 7853–7856
Table 1. InCl3-catalyzed addition of activated olefins (3–6) to N-
acyliminium ions derived from 1 and 2 under solvent-free conditions
Table 2. InCl3-catalyzed addition of 1,3-dicarbonyl compounds (15–
17) to N-acyliminium ions derived from 1 and 2 under solvent-free
conditions
n
n
OSiMe3
R1
O
H
R2
InCl3 (10 mol%)
r.t 20-40 min
( )n
( )n
O
O
O
+
InCl3 (10 mol%)
rt, 3-10 h
OMe
N
R1
R1
N
+
OMe
N
Boc
N
Boc
O
R1
R2
R3
R3
R2
Boc
Boc
R2
7 n=1, R1=Ph, R2=Me, R3=H
8 n=2, R1=Ph, R2=Me, R3=H
9 n=1, R1=OMe, R2= R3=Me
10 n=2, R1=OMe, R2= R3=Me
11 n=1, R1=R3=-(CH2)4 , R2=H
12 n=2, R1=R3=-(CH2)4 , R2=H
13 n=1, R1=Ph, R2=R3=H
3 R1=Ph, R2=Me, R3=H
4 R1=OMe, R2=R3=Me
5 R1=R3=-(CH2)4 , R2=H
6 , R1=Ph, R2=H, R3=H
18 n=1, R1= CH3; R2 = OEt
19 n=1, R1=R2= CH3
1 n=1
2 n=2
15 R1= CH3; R2 = OEt
16 R1-R2= CH3
17 R1-R2= OEt
1 n=1
2 n=2
20 n=1, R1= R2 = OEt
21 n=2, R1= CH3; R2 = OEt
22 n=2, R1=R2= CH3
23 n=2, R1= R2 = OEt
14 n=2, R1=Ph, R2=R3=H
Entry
n
Nucleophile
Time (h)
Product
Yield (%)
Entry
n
Nucleophile Time (min) Product Yield (%)
1
2
3
4
5
6
1
2
1
2
1
2
15
15
16
16
17
17
5
7
3
7
7
18
19
20
21
22
23
92
53
94
38
83
53
1
2
3
4
5
6
7
8
1
2
1
2
1
2
1
2
3
3
4
4
5
5
6
6
20
30
30
30
30
40
20
30
7
8
97
92
100
87
93
84
9
10
11
12
13
14
10
92
79
stereoselective preparation of trans-2,5-disubstituted tet-
rahydrofurans from N-propionyl and N-20-bromoacetyl
oxazolidin-2-ones.11
6-membered N-acyliminium ions provided the corre-
sponding substituted products 9 and 10 in excellent
yields, while these reactions failed when carried out in
SDS/H2O (Table 1, entries 3 and 4). Additionally, high-
er yields were always observed for a-substituted pyrrol-
idines, a pattern that results from the competitive
elimination of methanol from 2 leading to the corre-
sponding enecarbamate.
Inspired by the good results observed in the reaction of
N-acyliminium ion precursors with silyl enol ethers and
1,3-dicarbonyl compounds, we decided to investigate the
addition of these nucleophiles to 5- and 6-membered
oxocarbenium ion precursors 24 and 25 under InCl3
catalysis and solvent-free conditions. We have initially
carried out the reaction between 2-methoxytetrahydro-
pyran (25) and acetylacetone (16) (pKa 13.3) under the
experimental conditions described in Tables 1 and 2
(10 mol % of InCl3). The reaction proved to be
significantly slower than the corresponding reaction
with N-Boc-2-methoxypiperidine (2) as a 40% yield of
tetrahydropyran 33 was isolated after a long reaction
time (160 h). Under these conditions, a 50% conversion
of 2-methoxytetrahydropyran (25) was observed and an
additional reaction time did not provide better yields.
We then decided to use 20 mol % of InCl3 in order to
achieve better yields and a shorter reaction time and,
in fact, this modification provided 33 in 90% yield after
stirring for 60 h at rt (Table 3).
The use of 1,3-dicarbonyl compounds as nucleophiles
also provided the corresponding products in a good to
excellent yield of the corresponding pyrrolidine deriva-
tives when ethyl acetylacetonate (15), acetylacetone
(16), and ethyl malonate (17) were employed (Table 2,
entries 1, 3, 5). However, low to moderate yields (Table
2, entries 2, 4, 6) of the corresponding piperidines 19, 21,
and 23 were obtained when the reaction was carried out
with N-Boc-2-ethoxypiperidine (2).
Tetrahydrofurans and tetrahydropyrans with substitu-
ents adjacent to the ring oxygen atom are found in sev-
eral biologically active natural products and several
methodologies are now available to introduce substitu-
ents at the anomeric position.8 In this respect, lactols
and their derivatives display a central role since they
are readily available and react under smooth conditions
with a plethora of nucleophiles and the corresponding
oxocarbenium ions are considered to be involved under
acid conditions. Our interest in the addition of nucleo-
philes to chiral 5-substituted tetrahydrofuran-derived
lactols led us to explore the addition of allylsilanes pro-
moted by Lewis acid, which stereoselectively afforded
trans-2,5-disubstituted tetrahydrofurans in a good yield
and diastereoselectivity with bulky allylsilanes.9 In order
to circumvent the intrinsic low diastereofacial preference
of chiral 5-substituted 5-membered lactols,10 we
explored the use of titanium(IV) enolates derived from
chiral oxazolidon-2-ones, which has allowed the
The use of ethyl acetoacetate (15) (pKa 14.2) as the
nucleophile required longer reaction times to provide
the corresponding tetrahydrofuran 30 and tetrahydro-
pyran 31 in 77% and 64% yield, after 85 and 172 h,
respectively. Sonication of the reaction mixture pro-
vided a significant increase in the yield of tetrahydro-
pyran 31 (93%) and a shorter reaction time (35 h). A
further decrease in the acidity of the nucleophile led to
an excessively long reaction time and a low yield as ob-
served when diethyl malonate (17) (pKa 16.4) was em-
ployed: low yields (43% and 25%, respectively) were
observed in the reaction of 2-hydroxytetrahydrofuran
(24) and an 2-methoxytetrahydropyran (25) even after
excessively long reaction time (110 and 280 h). As ob-
served above, sonication provided a significant increase

L. A. F. de Godoy et al. / Tetrahedron Letters 47 (2006) 7853–7856
7855
Table 3. InCl3-catalyzed addition of nucleophiles to oxocarbenium
ions derived from 24 and 25 under solvent-free conditions
Acknowledgements
The authors would like to thank FAPESP (Fundac¸ao de
˜
( )
n
O
( )
InCl3 (20 mol%)
r.t.
n
`
Amparo a Pesquisa no Estado de Sao Paulo) for the
˜
3, 6 or 15-17
OR
R2
O
O
financial support and fellowship and CNPq (Conselho
R1
´
´
Nacional de Desenvolvimento Cientıfico e Tecnologico)
1
2
26 n=1, R =Me, R =Ph
24 n=1, R=H
25 n=2, R=Me
for the research fellowship.
1
2
27 n=2, R =Me, R =Ph
1
2
28 n=1, R =H, R =Ph
1
2
29 n=2, R = H, R =Ph
1
2
References and notes
30 n=1, R =COCH , R =OEt
3
1
2
31 n=2, R =COCH , R =OEt
3
1
2
1. Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: Chichester, 1997.
2. Chemical Synthesis Using Supercritical Fluids; Jessop,
P. G., Leitner, W., Eds.; Wiley-VCH: Weinheim, 1999.
3. Camilo, N. S.; Pilli, R. A. Tetrahedron Lett. 2004, 45,
2821.
32 n=1, R =COCH , R =CH
3
3
3
1
2
33 n=2, R =COCH , R =CH
3
1
2
34 n=1, R =CO Et, R =OEt
2
1
2
35 n=2, R =CO Et, R =OEt
2
Entry
n
Nucleophile
Time (h)
Product
Yield (%)
4. Pilli, R. A.; Robello, L. G.; Camilo, N. S.; Dupont, J.;
Lapis, A. A. M.; Silveira Neto, B. A. Tetrahedron Lett.
2006, 47, 1669.
5. For recent reviews on the chemistry of N-acyliminium
ions, see: (a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817; (b) Pilli, R. A.; Rosso, G. B.
In Science of Synthesis. Houben-Weyl Methods of Mole-
cular Transformations; Padwa, A., Ed.; Thieme: Stuttgart,
2004; Vol. 27, p 375.
6. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
7. (a) Matsumura, Y.; Ikeda, T.; Onomura, O. Heterocycles
2006, 67, 113; (b) Tranchant, M-J.; Moine, C.; Othman,
R. B.; Bousquet, T.; Othman, M.; Dalla, V. Tetrahedron
Lett. 2006, 47, 4477.
1
2
3
4
5
6
7
8
9
1
2
1
2
1
2
2
1
2
1
2
2
3
3
0.5
0.5
0.5
0.5
85
172
35
40
26
27
28
29
30
31
31
32
33
34
35
35
98
97
94
95
77
64
93a
93
90
43
25
63a
6
6
15
15
15
16
16
17
17
17
60
10
11
12
110
280
57
a Reaction carried out under sonication.
8. (a) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V.
Tetrahedron 1989, 45, 4293; (b) Bihovsky, R.; Kumar, M.
U.; Ding, S.; Goyal, A. J. Org. Chem. 1989, 54, 4291; (c)
Brown, D. S.; Ley, S. V.; Bruno, M. Heterocycles 1989, 28,
773.
in the yield of tetrahydropyran 35 (63% yield) and a
shorter reaction time (57 h).
9. Pilli, R. A.; Riatto, V. B. Tetrahedron: Asymmetry 2000,
11, 3675.
The reactions of trimethylsilyl enol ethers 3 and 6 pro-
ceeded in excellent yields and a shorter reaction time
both for 24 (98% and 94% yield for 26 and 28, respec-
tively) and 25 (97% and 95% yield for 27 and 29, respec-
tively) while 2-substituted tetrahydropyran 27 was
isolated in a 77% yield when the reaction was carried
in 1 M CH2Cl2 after 3 h (20 mol % of InCl3 employed).
10. For the diastereoselective addition of nucleophiles to
substituted oxocarbenium ions, see: (a) Shaw, J. T.;
Woerpel, K. A. Tetrahedron 1999, 55, 8747; (b) Larsen,
C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208; (c) Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000,
122, 168; (d) Chamberland, S.; Ziller, J. W.; Woerpel, K.
A. J. Am. Chem. Soc. 2005, 127, 5322; (e) Ayala, L.;
Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521; (f) Shenoy, S.
R.; Woerpel, K. A. Org. Lett. 2005, 7, 1157; (g) Smith, D.
M.; Woepel, K. A. Org. Lett. 2004, 6, 2063; (h) Schmitt,
A.; Reissig, H.-U. Eur. J. Org. Chem. 2001, 1169; (i)
Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893;
(j) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40.
11. Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2,
53.
The longer reaction times observed in the reactions
involving oxocarbenium intermediates (derived from
24 and 25) when compared to the corresponding
N-acyliminium ions may result from the faster forma-
tion of the latter species: when a competition experiment
was carried out with equimolar amounts of N-Boc-2-
methoxy piperidine (2), 2-methoxy tetrahydropyran
(25) and 1-phenyl-1-trimethylsilyloxy ethene (6) under
catalysis by InCl3 (20 mol %), an exclusive consumption
of 2 and formation of the corresponding 2-substituted
N-Boc piperidine 14 in a 80% yield was observed after
stirring for 20 min at rt.
12. A representative procedure for the reactions of carbamates
1 and 2 follows: A mixture of N-Boc-2-methoxypiperidine
1
(0.25 mmol) and 1-methoxy-1-trimethylsilyloxy-2-
methyl prope-1-ene (4, 0.50 mmol) was stirred at room
temperature for 30 min. The crude mixture was chro-
matographed on silica gel (20% ethyl acetate/hexanes) to
afford 9 in a quantitative yield. IR (neat): 2933, 2862,
In summary, the use of catalytic amounts of InCl3 in the
nucleophilic addition of enol ethers and 1,3-dicarbonyl
compounds to cyclic N-acyliminium and oxocarbenium
ion precursors under solvent-free conditions at room
temperature was successfully demonstrated.12,13 The
corresponding a-substituted heterocycles were obtained
in moderate to excellent yields.
.
1699, 1415, 1365, 1169 and 769 cmꢀ1 1H NMR
(300 MHz, CDCl3): d 4.24 (m, 1H), 3.66 (s, 3H), 3.18
(m, 1H), 1.95 (m, 1H), 1.75 (m, 4H), 1.46 (s, 9H), 1.18 (s,
3H), 1.13 (s, 3H). 13C NMR (75 MHz, CDCl3): d 177.0,
155.5, 79.3 (br), 62.8, 51.8, 47.8 (br), 29.7, 28.4, 27.4 (br),
24.2 (br), 21.7 (br), 20.8 (br). HRMS: calcd for

7856
L. A. F. de Godoy et al. / Tetrahedron Letters 47 (2006) 7853–7856
C14H25NO4 (M+Å) ꢀ271.1784. Found: 271.1763. Analyt-
.
1691, 1375, 1149 and 769 cmꢀ1 1H NMR (300 MHz,
CDCl3): d 4.28 (s, br, 1H), 4.07 and 3.91 (2 · s, br, 1H),
3.67 (s, 3H), 2.85 (s, br, 1H), 1.72–1.41 (m, 6H), 1.46 (s,
9H), 1.23 (s, 3H), 1.21 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 177.3, 156.1, 79.3 (br), 57.3 (br), 51.9, 47.3 (br),
39.8 and 40.2 (rotamers), 28.7 and 28.5 (rotamers), 25.5
(br), 24.2 (br), 23.5, 22.2, 19.4. HRMS: calcd for
C15H27NO4 (M+Å)—285.1940. Found: 285.1948.
(3, 1.00 mmol) was stirred at room temperature for
30 min. The crude mixture was chromatographed on silica
gel (20% ethyl acetate/hexanes) to afford 26 as a colorless
oil in a 98% yield (2.9:1 ratio of diastereoisomers). IR
(neat): 2970, 2933, 2873, 1678, 1448, 1217, 1068, 976 and
ical data for compound 10—IR (neat): 2974, 2947, 1730,
1
708 cmꢀ1. H NMR (300 MHz, CDCl3): d 7.98 (m, 2H),
7.51 (m, 3H), 4.13 (m, 1H), 3.78 (m, 2H), 3.60 (m, 1H),
3
2.04 (m, 1H), 1.86 (m, 2H), 1.53 (dq, J 12.1 and 8.1 Hz,
1H), [1.33 (d, 3J 7.0 Hz) and 1.17 (d, 3J 7.0 Hz), 3H,
diastereoisomers]. 13C NMR (75 MHz, CDCl3): d 202.9,
136.8, 132.9, 132.8, 128.5, 128.4, 81.1, 80.9, 68.1, 67.9,
46.0, 45.9, 29.8, 29.2, 25.8, 25.7, 15.6, 13.9. HRMS: calcd
for C13H17O2 (M+H+)—205.1229. Found: 205.1265.
13. A representative procedure for the reactions of 24 and 25
follows: A mixture of 2-hydroxytetrahydrofuran (24,
0.50 mmol) and (Z)-1-phenyl-1-trimethylsilyloxypropene