Intramolecular additions of various π-nucleophiles to chemoselectively activated amides and application to the synthesis of (±)-tashiromine

Article abstract of DOI:10.1021/jo052141v

Vilsmeier-Haack type cyclizations proved to be particularly efficient for generating parts of the polycyclic cores of many alkaloids, although only monocyclizations have so far been reported. With the goal of rapidly and efficiently constructing polycycli

Full text of DOI:10.1021/jo052141v

Intramolecular Additions of Various π-Nucleophiles to
Chemoselectively Activated Amides and Application to the Synthesis
of (()-Tashiromine
Guillaume Be´langer,* Robin Larouche-Gauthier, Fre´de´ric Me´nard, Miguel Nantel,† and
Francis Barabe´
Laboratoire de synthe`se organique et de de´Veloppement de strate´gies de synthe`se De´partement de Chimie,
UniVersite´ de Sherbrooke 2500 bouleVard UniVersite´, Sherbrooke, Que´bec, J1K 2R1, Canada
guillaume.belanger@usherbrooke.ca
ReceiVed October 13, 2005
Vilsmeier-Haack type cyclizations proved to be particularly efficient for generating parts of the polycyclic
cores of many alkaloids, although only monocyclizations have so far been reported. With the goal of
rapidly and efficiently constructing polycyclic alkaloids, we decided to exploit the Vilsmeier-Haack
reaction by utilizing iminium ions successively generated and trapped with tethered nucleophiles. To
develop such a strategy, we had to set the first cyclization. This constitutes a great challenge in itself
because amide activation conditions are usually not compatible with tethered nucleophiles, except for
indoles and aromatic rings which have already been reported. This paper describes the comprehensive
study of intramolecular addition of silyl enol ethers, allylsilanes, and enamines to chemoselectively activated
formamides, aliphatic amides, and lactams. Good to excellent yields were obtained for the 5-exo, 6-exo,
and 6-endo modes of cyclization. Moreover, we demonstrated that the species in solution after the
cyclization are iminium ions. This is highly encouraging for the development of bis-cyclization strategies.
An expeditious total synthesis of (()-tashiromine is also reported.
Introduction
over the years,2 and these iminium ions are of oxidation state
II (two C-heteroatom bonds) by definition. The use of iminium
ions of a higher oxidation state are known as the Vilsmeier-
Haack reaction. These iminium ions are usually derived from
amides, by various activation means employing oxophilic
reagents.3,4
Alkaloid natural products have very diverse structures, many
of which are polycyclic, and show an extremely wide span of
interesting biological activities. This renders alkaloids very
attractive to synthetic chemists and has been a great source of
motivation for the finding of synthetic strategies and reactions
to construct such complex molecules. In that sense, iminium
ions are certainly among the functional groups most widely used
in total syntheses of alkaloids, especially the intramolecular
Mannich reaction, or Mannich cyclization, which proved to be
extremely efficient at putting together the heterocyclic skeleton
of numerous alkaloids.1 Numerous methods of generating
iminium ions for the Mannich reaction have been developed
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004,
104, 2311.
(3) For various amide activation conditions, see: (a) Nishiyama, H.;
Nagase, H.; Ohno, K. Tetrahedron Lett. 1979, 48, 4671. (b) Keck, G. E.;
McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875. See also
references cited in: (c) Kuhnert, N.; Clemens, I.; Walsh, R. Org. Biomol.
Chem. 2005, 3, 1694. (d) Smith, D. C.; Lee, S. W.; Fuchs, P. L. J. Org.
Chem. 1994, 59, 348.
(4) For addition of heteroatomic nucleophiles to activated amides, see:
(a) Charette, A. B.; Chua, P. Synlett 1998, 163. (b) Charette, A. B.; Chua,
P. Tetrahedron Lett. 1997, 38, 8499. (c) Charette, A. B.; Chua, P. J. Org.
Chem. 1998, 63, 908. (d) Charette, A. B.; Grenon, M. Tetrahedron Lett.
2000, 41, 1677. (e) Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.;
Marchelli, R. Tetrahedron Lett. 1998, 39, 711. (f) Thomas, E. W. Synthesis
1993, 767.
† Current address: MDS Pharma Services, 2350, rue Cohen, St-Laurent
(Montre´al), Que´bec, H4R 2N6, Canada.
(1) (a) Iminium Salts in Organic Chemistry; Bo¨hme, H., Viehe, H. G.,
Eds.; Wiley: New York, 1976, part I; 1979, part 2. (b) Overman, L. E.;
Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Flemming,
I., Heathcock, C. H., Eds; Pergamon: Oxford, UK, 1991; Vol. 2, p 1007.
10.1021/jo052141v CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/08/2005
704
J. Org. Chem. 2006, 71, 704-712

Intramolecular Additions of π-Nucleophiles to Amides
SCHEME 1. Planned Biscyclization Strategy
SCHEME 2. Representative Chemoselective Amide
Activation and Nucleophilic Cyclization
A screening of the literature revealed that iminium ions of
both oxidation states are only used in monocyclizations, which
is a limit inherent in the oxidation state of the iminium ion only
in the Mannich cyclization. However, the higher oxidation state
of the iminium ion in the Vilsmeier-Haack type cyclization
incited us to exploit the idea of performing two sequential
cyclizations in a single operation utilizing iminium ions suc-
cessively generated and trapped with tethered nucleophiles
(Nu¨H, Scheme 1). This strategy offers the possibility of
generating polycyclic alkaloid skeletons in one step from simple
amide substrates. A very limited number of sequential iminium
ion cyclizations have been reported, but these cyclizations were
not performed on the same iminium carbon.5 Our strategy would
thus additionally allow for the creation of a tertiary or a
quaternary center R to nitrogen in the final product from an
initial secondary of tertiary amide, respectively. Because the
cyclization substrates are made from amides or lactams,
connections of diverse branches containing the nucleophiles
should be facile using well-known chemistry. Modulations of
the branches and their position could furthermore lead to a vast
assortment of polycyclic alkaloid skeletons, rendering such a
strategy highly attractive for its straightforwardness and potential
application in total synthesis.
The key reaction is presented in Scheme 2 with a representa-
tive amide substrate 1 tethered to a π-nucleophile. When the
nucleophile is an aldehydic silyl enol ether (1, R ) OTBDMS,
R′ ) H) or a ketonic silyl enol ether (1, R ) OTBDMS, R′ )
alkyl), a cyclic enaminal or enaminone9 6 is formed, respec-
tively. Enamines (1, R ) NMePh) lead to vinylogous amidinium
ions 4, that could for instance be hydrolyzed to the correspond-
ing enaminals 6, whereas allylsilanes (1, R ) CH2TMS) lead
to amines 7 R to a tertiary (NaBH(OAc)3 quench, R′′′ ) H) or
potentially quaternary center (C-nucleophile addition, R′′′ )
alkyl), which could both be derived to the corresponding chiral
â-amino acids 8.
A major challenge to the development of our strategy is,
however, to find chemoselective amide activation conditions
compatible with the required tethered nucleophiles. The amide
activation conditions generally use, or generate during the
reaction, Lewis or Bronsted acids3 that would easily destroy or
deactivate nucleophiles such as vinylsilanes, allylsilanes, enol
ethers, enamines, amines, thiols, alcohols, etc. This is probably
why only indoles6 or activated benzene rings7 have been so far
reported to intramolecularly trap activated amides, whereas all
other reported nucleophiles are externally added once the amide
activation is completed.4,3d
We recently published our preliminary successful results for
amide activation and cyclization with tethered carbon nucleo-
philes other than indoles or benzene rings.8 We now wish to
report the full account of this work emphasizing general trends
that emerged from detailed comparisons between the different
nucleophiles we used, the nature of the amide substrates, and
ring sizes generated.
Results and Discussion
The following sections will first describe the syntheses of
all of the cyclization substrates, followed by the optimization
of the amide activation-cyclization conditions on a particular
substrate and the application of these conditions to the intramo-
lecular 5-exo, 6-exo, 5-endo, and 6-endo additions of tethered
silyl enol ethers, allylsilanes, and enamines to chemoselectively
activated amides and lactams. An application of our new strategy
to the synthesis of tashiromine will finally be presented.
Synthesis of Indole Substrate 11. To compare the various
nucleophiles we elected to study with the indole ring used in
the typical Bischler-Napieralski cyclization, we synthesized the
5-exo cyclization substrate 11 (Scheme 3). Starting from Boc-
protected indole, an ortho lithiation and quench with methyl
chloroformate gave the indole ester, which was then reduced
to the alcohol 9 in 59% overall yield. Bromination and
displacement with the copper enolate of N,N-diethylacetamide
furnished the amide 10.10 We then pyrolyzed the Boc and
methylated the nitrogen to furnish the desired product 11 in
83% yield.11 Although 11 was successfully activated and
cyclized (vide infra), an attempted amide activation of 10 and
(5) For selected examples, see: (a) Jackson, A. H.; Shannon, P. V. R.;
Wilkins, D. J. Tetrahedron Lett. 1987, 28, 4901. (b) He, F.; Bo, Y.; Altom,
D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771.
(6) Typically the Bischler-Napieralski cyclization: Bischler, A.;
Napieralski, B. Chem. Ber. 1893, 26, 903.
(7) (a) Marson, C. M. Tetrahedron 1992, 48, 3659. (b) Martinez, A. G.;
Alvarez, R. M.; Barcina, J. O.; Cerero, S. M.; Vilar, E. T.; Fraile, A. G.;
Hanack, M.; Subramanian, L. R. J. Chem. Soc., Chem. Commun. 1990,
1571.
(8) Be´langer, G.; Larouche-Gauthier, R.; Me´nard, F.; Nantel, M.; Barabe´,
F. Org. Lett. 2005, 7, 4431.
(9) Enaminones are particularly interesting and versatile intermediates
used for natural product synthesis. See: Michael, J. P.; de Koning, C. B.;
Gravestock, D.; Hosken, G. D.; Howard, A. S.; Jungmann, C. M.; Krause,
R. W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure Appl. Chem.
1999, 71, 979.
J. Org. Chem, Vol. 71, No. 2, 2006 705

Be´langer et al.
SCHEME 4. 5- and 6-exo Cyclization Amide Substrates
SCHEME 3. Synthesis of the Indole Substrate
indole trapping of the resulting iminium ion was not productive,
presumably because of the poor nucleophilicity of the Boc-
protected indole.
Synthesis of 5- and 6-exo Cyclization Substrates.12 The
chosen 5- and 6-exo cyclization substrates contain either an
amide or a lactam as the iminium ion precursor, giving rise to
either monocyclic or bicyclic adducts. The synthesis of the
secondary amide compound 13 started with the formation of
the silyl enol ether 12 from the known ethyl 6-oxohexanoate,13
using TBDMSOTf (Scheme 4). A DIBALH-benzylamine
complex14 was then used to convert the ester 12 to the required
secondary amide 13. A series of tertiary amides was also
prepared. The enamine 1615 was formed by the condensation
of N-methylaniline with the known aldehyde 14,16 whereas the
silyl enol ether 18 was derived from the aldehyde 17 generated
by a Wittig olefination of 158 and hydrolysis of the resulting
methyl enol ether in 93% yield for these two steps.
SCHEME 5. 5- and 6-exo Cyclization Lactam Substrates
A series of lactams was also prepared, starting with the
oxidation of the C-branched N-methylpyrrolidinone 19 (Scheme
5). The resulting aldehyde 20 was then subjected to TBDMSOTf
to give the corresponding silyl enol ether 21, or olefinated17 to
the allylsilane 22 in good yields.
Synthesis of 5- and 6-endo Cyclization Substrates.12 The
preparation of the 5- and 6-endo cyclization substrates containing
an amide started with a condensation-reduction sequence
performed on the aldehyde 2318 to generate the secondary amine
26 (Scheme 6). The four carbon analogue 25 was obtained by
the N-alkylation of benzylamine with the iodide 24.19
A
sequence of N-acetylation, acidic methanolysis of the silyl ethers
27 and 28, and Swern oxidation furnished the desired aldehydes
29 and 30 respectively in high yields. They were both
transformed to the corresponding silyl enol ethers 31 and 32
by using either TBDMSOTf with a weak base (Et3N) or
TBDMSCl with a stronger base (KHMDS). Each of these
silylation conditions were empirically determined to be the most
suitable for these aldehydes.
(10) The lithium enolate, from LDA deprotonation of N,N-diethylaceta-
mide, gave less than 20% yield of alkylated product 10. Addition of lithium
chlorocuprate was essential for the success of this reaction. For use of Li2-
CuCl4 as catalyst for enolate alkylations, see: Gelin, J.; Mortier, J.; Moyroud,
J.; Chene, A. J. Org. Chem. 1993, 58, 3473.
(11) We also tried the same sequence of reactions but starting with
N-methylindole instead of N-Boc-indole. It turns out that the bromo
derivative was too unstable and could not be purified before the nucleophilic
displacement with the acetamide copper enolate.
Finally, we prepared lactams branched on nitrogen with an
allylsilane or an enamine as the tethered nucleophiles. The
known aldehyde 348 was condensed with N-methylaniline to
give the desired enamine 35, whereas the aldehyde 338 was
subjected to the Seyferth-Wittig olefination to furnish the
allylsilane 36 as a 3:1 ratio of geometric isomers (Scheme 7).
(12) The use of exo and endo in this paper refers to the amide portion of
the substratres. For a more appropriate description of cationic cyclizations
involving π-nucleophiles, see: (a) Ben-Ishai, D. J. Chem. Soc., Chem.
Commun. 1980, 687. (b) Lochead, A. W.; Proctor, G. R.; Caton, M. P. J.
Chem. Soc., Perkin Trans. 1 1984, 2477.
(13) Taber, D. F.; Teng, D. J. Org. Chem. 2002, 67, 1607.
(14) Huang, P.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron Lett. 2001, 42,
9039.
(15) This enamine was unstable, as aldehydic enamines usually are, and
had to be used without further purification in the cyclization step. Only the
trans enamine was formed.
(16) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 2066.
(17) Fleming, I.; Paterson, I. Synthesis 1979, 446.
(18) Marshall, J. A.; Shearer, B. G.; Crooks, S. L. J. Org. Chem. 1987,
52, 1236.
(19) Fall, Y.; Vidal, B.; Alonso, D.; Go´mez, G. Tetrahedron Lett. 2003,
44, 4467.
706 J. Org. Chem., Vol. 71, No. 2, 2006

Intramolecular Additions of π-Nucleophiles to Amides
TABLE 1. Optimization of the Chemoselective Amide Activation and 5-exo Cyclization with Substrate 37
activating agent
(1.1 equiv)
base
(1.1 equiv)
solvent
(0.1 M)
entry
quench
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
yield of 39
1
2
3
4
POCl3
iPr2NEt
CH2Cl2
0% (15 was the only identifiable product)
0% (decomposition)
0% (15 was the only identifiable product)
0% (55% of 38)
(CF3CO)2O
(CCl3O)2CO
TMSOTf
BrCOCOBr
Tf2O
DTBMPa
iPr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
iPr2NEt
5
DTBMPa
DTBMPa
0% (3% of 15 + 7% of 38)
6b
89%
7
8
9
10
11
Tf2Oc
Tf2O
Tf2O
Tf2O
Tf2O
pyridined
pyridine
DMAPe
iPr2NEt
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NaOH
NaOH
NaOH
NaOH
NaOH
0% (no reaction)
46%
16% (+32% of 38)
85%
31% (+28% of 38)
12
13
Tf2O
Tf2O
DTBMPa
DTBMPa
toluene
1,4-dioxane
NaOH
NaOH
63% (+11% of 38)
28% (+26% of 38)
14
15
16
17
Tf2O
Tf2O
Tf2O
Tf2O
DTBMPa
DTBMPa
iPr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Pyr‚HF
MeONa
nBu4N+F-
Al2O3
85%
65%
57%
55%
iPr2NEt
a DTBMP: 2,6-di-tert-butyl-4-methylpyridine. b Taken from ref 8. c 1.3 equiv, -50 to 0 °C. d 1.3 equiv. e DMAP: 4-(N,N-dimethylamino)pyridine.
SCHEME 6. 5- and 6-endo Cyclization Amide Substrates
FIGURE 1. Aldol product 38 from activation of substrate 37.
1). A study of all of these variables was conducted on the
previously reported 5-exo cyclization substrate 378 and the
results are presented in Table 1.
Many activating agents are known to generate iminium ions
from amides.3 However, most of them proved to be incompatible
with the acid sensitive silyl enol ether present on compound
37. For example, POCl3 (entry 1), TFAA (entry 2), and
triphosgene (entry 3) all destroyed the silyl enol ether prior to
amide activation, leading to the corresponding aldehyde 15 or
to decomposition. With TMSOTf (entry 4), the silyl enol ether
moiety was partially cleaved during the reaction and the aldol
product 38 was obtained in 55% yield and was fully character-
ized (Figure 1). The same byproducts (aldehyde 15 and aldol
product 38) were obtained in the case of activation with oxalyl
bromide, albeit in much lower yields (3% and 7%, respectively,
entry 5). The best activating agent proved to be Tf2O (entry 6).
The intermediate iminium ion 3 (cf. scheme in Table 1) was
characterized by 1H NMR spectroscopy and gave, after a sodium
SCHEME 7. 6-endo Cyclization Lactam Substrates
hydroxide hydrolysis, the desired enaminal 39 in 89% yield
(entry 6).
The effect of the base was also surveyed. Excess of pyridine
(3 equiv) at low temperature (-50 to 0 °C, Table 2, entry 7)4c
gave no reaction at all. The same base (1.1 equiv) used at 0 °C
furnished a 46% yield of the desired adduct (entry 8). This
modest yield could arise from a partial reaction of pyridine with
Optimization of the Chemoselective Amide Activation and
Tf2O at that temperature, resulting in the formation of N-
Cyclization. Four different parameters were studied to set up
triflylpyridinium triflate, which is a weaker activating agent than
the most convenient and reproducible reaction conditions for
amide activation without altering the tethered nucleophile: (1)
(20) For this screening, the base used was either 2,6-di-tert-butyl-4-
methylpyridine or diisopropylethylamine. This is not critical, since entries
6 and 10 of Table 1 gave essentially the same cyclization yield for both of
these bases.
the nature of the activating agent,20 (2) the need for and the
nature of the base, (3) the solvent, and (4) the neutralization
(quench)20 of the resulting iminium ions (cf. 3, scheme in Table
J. Org. Chem, Vol. 71, No. 2, 2006 707

Be´langer et al.
TABLE 2. Cyclization of Indole and Silyl Enol Ethers on Activated Amides and Lactams
a Reagents and conditions: (A) Tf2O, DMAP, CH2Cl2, reflux; (B) POCl3, ClCH2CH2Cl, reflux; (C) Tf2O, Pyr, CH2Cl2, -50 to 0°C, 3 h; (D) Tf2O,
2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 0°C, 15 min; (E) TMSOTf, iPr2NEt; Tf2O. b 1 N NaOH, THF, 25°C, 15 h. c Pyr‚HF, 0 °C, 1 h. d Taken from ref
8. e Basic Al2O3, rt, 1 h.
Tf2O toward amides.4c The same reaction of Tf2O with the base
was observed when 4-(N,N-dimethylamino)pyridine was used
and the even less reactive N-triflyl-4-(N,N-dimethylamino)pyr-
idinium triflate could account for the poor 16% yield of entry
9.21 That side reaction was, however, not encountered when
Hu¨nig’s base (entry 10) or 2,6-di-tert-butyl-4-methylpyridine
(entry 6) were used. The latter gave the cleanest conversion
and only 1.1 equiv of base was necessary. The reaction was
also run in the absence of base (entry 11) and still gave the
desired cyclized product 39 without extensive cleavage of the
nucleophilic moiety by the triflic acid produced,22 but the yield
was lower (31%) and the conversion was less clean.
rise to 89% of the desired enaminal 39 without any formation
of the aldol byproduct 38 (entry 6). Interestingly, the nonpolar
solvent toluene still gave a good yield (63%) of cyclized product
39, accompanied by 11% of aldol product 38 (entry 12). The
proportion of the aldol product was even higher when 1,4-
dioxane was used, giving an almost 1:1 ratio of enaminal 39
and aldol product 38 (54% combined yield, entry 13).
Finally, to our surprise, the most crucial parameter to control
to get high yields of the desired cyclized product 39 turned out
to be the cleavage of the silyl group on the iminium ion
intermediate 3 in the quench procedure (cf. scheme in Table
1).20 Pyr‚HF and NaOH gave very similar results for this
substrate (Table 1, 85% and 89%, entries 14 and 6, respectively),
although this was not found to be true for all the cyclized
products as will be shown (Tables 2 and 3). With sodium
methoxide, a moderate 65% yield was observed (Table 1, entry
15). An additional drop in the yield occurred when tetrabutyl-
The solvent also has a significant effect on the yield of the
reaction. Dichloromethane was by far the best solvent, giving
(21) A white precipitate is formed in the reaction vessel as soon as Tf2O
is added to the solution of 37 and 4-(N,N-dimethylamino)pyridine.
1
(22) As observed on H NMR spectra of aliquots of the reaction.
708 J. Org. Chem., Vol. 71, No. 2, 2006

Intramolecular Additions of π-Nucleophiles to Amides
TABLE 3. Cyclization of Enamines and Allylsilanes on Activated Amides and Lactams
a Reagents and conditions: (A) Tf2O, CH2Cl2, 0°C, 20 min; (B) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 0°C, 15 min. b Taken from ref 8.
c Concentrated then purified directly. d NaBH3CN, -78 to 0 °C, 15 h. e 15 h. f ClCH2CH2Cl, reflux, 15 h.
ammonium fluoride (57% yield, entry 16) or basic alumina (55%
yield, entry 17) was used. We do not fully understand the large
influence of the quench reagents on the reaction yield, but a
possible explanation could be the ease with which highly water
soluble hydrates form in certain quench conditions, as will be
discussed below.
FIGURE 2. Proposed water soluble carbonyl hydrate of 50.
5-exo, 6-exo, 5-endo, and 6-endo Cyclizations of Various
Tethered Nucleophiles on Amides and Lactams. The opti-
procedure (cf. 3, scheme in Table 1) show significant variations.
The most remarkable example is with the 6-exo cyclization
substrate 41 (entry 10, Table 2). Although the cyclization was
always complete and very clean, as indicated by the analysis
of 1H NMR spectra of reaction aliquots, the hydrolysis step was
particularly problematic. In fact, the bicyclic enaminal 50 was
obtained in a much lower yield with a NaOH quench (32%)
than with a Pyr‚HF quench (81%). Intrigued by that result, we
stirred pure 6-exo cyclization product 50 in a 1:1 mixture of
THF and water for 15 h and observed a complete loss of the
product (the yield dropped to 0%). Evaporation of the aqueous
phase led to various unidentifiable products. We suggest that a
polar, water soluble carbonyl hydrate with strong hydrogen
bonding might be responsible for the loss of material (Figure
2). The formation of a stable hydrate may also account for the
difference in yields of the 6-exo cyclization of silyl enol ether
substrate 18. Again, the Pyr‚HF quench was superior to the
NaOH quench (51% and 35% yield, respectively, entry 6, Table
2), although a basic alumina quench was even better (55% yield,
entry 7). Such hydrogen bond stabilized hydrates are impossible
for the endo cyclization products with allylsilanes or enamines
(cf. Table 3, entries 6 and 3, respectively).
mized cyclization conditions were applied to the cyclization of
other 5-exo cyclization substrates, as well as to 6-exo, 5-endo,
and 6-endo cyclization substrates (Tables 2 and 3). In the case
of substrates containing a silyl enol ether branch (Table 2), Pyr‚
HF and NaOH were systematically used to cleave the silyl group
on the iminium ion intermediate in the quench procedure (cf.
3, scheme in Table 1), whereas other quench procedures
specifically noted were used in the cases of substrates tethered
to an enamine or an allylsilane (Table 3).
Comparison of the Cyclization Types (5- or 6-, exo or
endo). A comparison could be made over four cyclization types
only with silyl enol ether nucleophiles, tethered to aliphatic
amides or to lactams (Table 2). For comparison purposes, we
looked at the yields obtained with the Pyr‚HF quench. Only in
the case of the activation of aliphatic amides and cyclization
did the yields indicate that the 5-exo mode is by far the best
(85%, entry 4), followed by the 6-endo (71%, entry 12), the
6-exo (51%, entry 6), and the 5-endo (39%, entry 11) modes.
This order was somewhat different with lactams: the 6-exo
mode is the best (81%, entry 10), followed by the 6-endo (73%,
entry 15), the 5-exo (57%, entry 9), and the 5-endo (29%, entry
14) modes.
However, the yields obtained with the NaOH cleavage of the
silyl group on the iminium ion intermediate in the quench
Although this explains well the difference in yields of the
two quench procedures applied to the same products for the
J. Org. Chem, Vol. 71, No. 2, 2006 709

Be´langer et al.
SCHEME 8. Proposed Mechanism for the Rearrangement
of 51 to 52 in 1 N NaOH
93%, entry 5, Table 3) and 41 (silyl enol ether, 81%, entry 10,
Table 2). Intriguingly, this order does not reflect the π-nucleo-
philicity tabulated by Mayr,24 which places enamines on top of
the list, followed by silyl enol ethers then allylsilanes. Because
we could not report yields for the cyclization step only,25 we
cannot make a precise correlation between the π-nucleophilicity
of the tethered nucleophiles used and the yields of cyclized
products.
cleavage of the silyl group on the iminium ion intermediate, it
does not explain all of the differences observed. For example,
while enaminal 51 was the only product formed when the Pyr‚
HF quench was used, a rearranged product 52 appeared with
the NaOH quench (entry 11, Table 2). In theory, the enaminal
51 should be the only product of a direct cyclization of the silyl
enol ether moiety onto the activated amide of 31. We suggest
that compound 51 arises from the 1,4-addition of hydroxide
anion to the enal of 52, followed by the ring opening to the
amino â-keto aldehyde 57, and condensation of the amine with
the aldehyde (Scheme 8). This hypothesis was confirmed:
mixtures of compounds 51 and 52 were observed when both
51 and 52 were treated independently with 1 N NaOH.
The hydrolysis problems were not encountered in the case
of the enamines and the allylsilanes we cyclized (Table 3) and
should allow for a more accurate comparison between the
cyclization modes. However, the yields given for the enamines
include their in situ preparation from the corresponding alde-
hydes, which are not uniform over the different substrates. Thus,
we could not draw any precise conclusion about the ease of
cyclization of enamines for the different modes of cyclization.
In the case of the activation and cyclization of lactams tethered
to allylsilanes, the 6-exo mode (93% yield, entry 5) proved to
be more efficient than the 6-endo mode (70% yield, entry 6),
following the trend observed with the silyl enol ethers (entries
10 and 15, Table 2, with the Pyr‚HF quench). Although the
cyclizations of silyl enol ether onto aliphatic amides or lactams
were all completed within 15 min, cyclizations of allylsilanes
onto activated lactams were much slower (15 h) than on the
activated amide (15 min). This is probably due to a higher steric
congestion of lactams (additional substitution R to lactam
carbonyl) compared to the aliphatic amide and a lower reactivity
of the allylsilane compared to the TBDMS enol ether, resulting
in a higher sensitivity of the allylsilane to steric hindrance
(earlier transition state with TBDMS enol ether than with
allylsilane).
Comparison of the Nucleophiles. A series of tethered
nucleophiles were screened with use of substrates that cyclized
by the same mode (5/6-endo/exo) and having the same amide
or lactam. All enolizable carbonyl groups (ketones and â-keto-
esters, not tabulated) we tested proved to be incompatible with
the amide activation conditions: either the enol tautomer was
more reactive than the amide toward the activating agent, or
the activated amide could not be trapped with the enolized
carbonyl.23 We obtained the best results with silyl enol ethers,
enamines, and allylsilanes, as shown in Tables 2 and 3. For the
5-exo cyclizations, the silyl enol ether 37 gave the highest yield
(89%, entry 4, Table 2), followed by the allylsilane 59 (81%,
entry 4, Table 3) and the enamine 58 (74%, entry 1, Table 3).
This order was somewhat different with 6-endo cyclizations of
lactams 44 (silyl enol ether, 93%, entry 15, Table 2), 35
(enamine, 78%, entry 3, Table 3), and 36 (allylsilane, 70%, entry
6, Table 3) or with 6-exo cyclizations of lactams 22 (allylsilane,
As enamines were prepared from the corresponding aldehydes
and cyclized one-pot, we wanted to see if the same could be
done with silyl enol ethers. In entry 8 of Table 2, the aldehyde
15 was silylated with TMSOTf in the presence of a base, then
Tf2O was added to the reaction mixture without isolation of
the silyl enol ether intermediate. After hydrolysis, the enaminal
39 was isolated in 24% yield (NaOH quench), compared to a
53% overall yield for the stepwise silylation (60% yield, ref 8)
and cyclization (89% yield, entry 4, Table 2). There is thus an
obvious advantage of preparing the silyl enol ether in a separate
operation, before the cyclization. Looking at the result obtained
from the one-pot preparation and cyclization of enamine 58
(entry 1, Table 3), it seems that the enamine formation is much
more compatible with the following one-pot activation-
cyclization step than is the silyl enol ether formation.
After a Pyr‚HF quench, the ketonic silyl enol ether 40 cyclized
in about half the yield of that obtained with the corresponding
aldehydic silyl enol ether 37 (Table 2, entries 5 and 4, 43%
and 85% yield, respectively), although this difference was less
important when a NaOH quench was used (80% and 89% yield,
respectively). These results indicate a small influence of the
substitution of the silyl enol ether on the cyclization, but a
greater influence on the procedure used to cleave the TBDMS
group on the iminium ion intermediate (such as 3, Scheme 2).
The indole 11 (entry 1, Table 2) and the nonaromatic enamine
16 (entry 2, Table 3) cyclized in 89% and 78% yield,
respectively. The amide activation and cyclization requires
heating at 40 °C during several hours for the indole 11,
compared to enamine 16, which cyclized within 15 min at 0
°C. Because the only difference between these substrates is the
nature of the tethered nucleophile, the difference in the reaction
temperatures and time is indicative of the greater reactivity of
aliphatic enamine relative the indole ring toward activated
amide. It should be noted that activation of the indole tethered
amide 11 with POCl3 (entry 2, Table 2) was less efficient than
the activation with Tf2O (entry 1), as was observed for
compound 37 (Table 1, entries 1 and 6).26
Comparison between Amides and Lactams. We compared
the cyclization of identical nucleophilic moieties tethered to
either aliphatic amides or butyrolactams. For the 5-exo cycliza-
tion of silyl enol ethers (entries 4 and 9, Table 2), the yield is
much higher with the aliphatic amide (85-89%) than with the
lactam (29-57%), whereas this order is reversed for the 6-exo
(24) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(25) (a) For allylsilanes, the yields are reported for their cyclization and
reduction. Attempts to hydrolyze the â,γ-unsaturated iminium ion (such as
5, Scheme 1) after cyclization gave inseparable mixtures of R,â- and â,γ-
enones. The reduction of the same iminium was also a lot cleaner than the
hydrolysis. (b) For silyl enol ethers, the yields are reported for their
cyclization and hydrolysis. (c) For aldehydic enamines, which are unstable
and could not be isolated, the yields are reported for their formation and
cyclization. Hydrolysis of the resulting vinylogous amidinium ions (such
as 4, Scheme 2) was not necessary because they were easily isolated and
characterized.
(26) The intermediate vinylogous amidinium ion was characterized by
(23) Nantel, M. M.Sc. Thesis, Universite´ de Sherbrooke, 2004, 183 pages.
1H NMR spectroscopy prior to hydrolysis (see the Supporting Information).
710 J. Org. Chem., Vol. 71, No. 2, 2006

Intramolecular Additions of π-Nucleophiles to Amides
SCHEME 9. Synthesis of (()-Tashiromine
(entries 6 and 10, respectively) and the 6-endo cyclizations
(entries 12 and 15) . For both amides and lactams, as expected,
5-endo cyclizations are difficult but possible (39% and 29%
yield, entries 11 and 14, respectively), showing the high
reactivity of activated amides toward the π-nucleophiles we
used.
We also demonstrated that a tertiary amide (entry 4, Table
2) gives a much higher yield of enaminal than does a secondary
amide (entry 3). The latter was not as easy to activate cleanly,
and the nucleophilic addition of silyl enol ether was not as
efficient. The activated secondary amide being a neutral imidate,
it was anticipated that this imidate would be less reactive that
the parent iminium ion from activation of tertiary amide.27 When
we compared the formamide 42 (entry 13, Table 2) to the
corresponding acetamide 32 (entry 12) and lactam 44 (entry
15), the resulting enaminals 54, 53, and 56 respectively were
obtained in similar yields (63%, 71%, and 73%, respectively)
with the Pyr‚HF quench. This suggests a low influence of the
iminium congestion in the cyclization step. However, when
looking at the same entries but with the NaOH quench, there
are large variations in the isolated yields (78% of 54, 34% of
53, and 93% of 56). The ease of hydrolysis may explain the
better yield for the formation of adduct 54 (78%, entry 13) over
53 (34%, entry 12), but we do not have a clear explanation for
the high yield of 56 (93%). Finally, when we compare N,N-
dibenzylamide 58 (74% yield, entry 1, Table 3) with N,N-
diethylamide 16 (78% yield, entry 2), the nature of the alkyls
on the amide nitrogen does not seem to have a large influence
on the cyclization yield.
Application to the Synthesis of (()-Tashiromine. Tashi-
romine (66) is an indolizidine alkaloid isolated in 1990 from
the stems of a leguminous plant Maackia tashiroi, a deciduous
shrub of subtropical Asia.28 Six syntheses have been reported
to date.29 In our synthesis, we make use of the 6-endo cyclization
of a TBDMS enol ether onto the activated butyrolactam 448 to
generate the bicyclic core of (()-tashiromine in 93% yield. Upon
treatment of the enaminal 56 with H2 and Pd on carbon in the
presence of Na2CO3,30 a 20:1 mixture of (()-tashiromine (66)
and (()-epitashiromine was obtained in 73% yield (or 79%
yield, based on recovered starting material, Scheme 9). Because
the syn-addition of hydrogen to the enaminal 56 alkene should
lead to (()-epitashiromine, we think that once the alkene in 56
is hydrogenated, a Na2CO3 catalyzed epimerization R to the
remaining aldehyde is faster than the hydrogenation of that
aldehyde. The epimerization prior to the aldehyde reduction
places the formyl group in the thermodynamic equatorial
orientation. The synthesis of (()-tashiromine was thus ac-
complished in 6 steps with an overall yield of 26%, which
compares favorably to previously reported syntheses.29 This
expeditious synthesis is a prelude to the potential of amide
activation and nucleophilic cyclization for the total synthesis
of alkaloids.
Conclusions
We demonstrated for the first time that activated amides could
be trapped with tethered nonaromatic carbon nucleophiles in
good to excellent yields. We showed that silyl enol ethers,
enamines, and allylsilanes are compatible with amide activation
and are the most efficient and well-suited nucleophiles for
adding to the resulting iminium ion. Tashiromine is an example
of the alkaloids that are accessible by the new monocyclizations
we developed. We also confirmed that the species in solution
after cyclization are iminium ions, whatever nucleophile is used
for the cyclization. This is highly encouraging for the pursuit
of our work toward our planned bis-cyclization strategy. The
latter will furthermore open applications to the synthesis of
polycyclic alkaloids. The results will be reported in due course.
Experimental Section
4-Methyl-3,4-dihydro-2H-cyclopenta[b]indol-1-one (45). Ac-
tivation with POCl3: To a solution of the amide 11 (100 mg, 0.390
mmol) in toluene (3.9 mL) at room temperature was added POCl3
(43 µL, 0.46 mmol). The mixture was then heated to reflux and
kept at that temperature overnight. The dark mixture was cooled
to room temperature and the solvent was evaporated under reduced
pressure to yield the iminium chloride salt intermediate as a solid:
1H NMR (300 MHz, CDCl3) δ 7.63 (d, J ) 7.5 Hz, 1H), 7.28 (d,
J ) 7.5 Hz, 1H), 7.16 (t, J ) 7.5 Hz, 1H), 7.07 (t, J ) 7.5 Hz,
1H), 4.14 (q, J ) 7.5 Hz, 2H), 3.89-3.82 (m, 5H), 3.73-3.72 (m,
2H), 3.43-3.40 (m, 2H), 1.58 (t, J ) 7.5 Hz, 3H), 1.49 (t, J ) 7.5
Hz, 3H); MS (m/z) 240 (M+). The crude iminium salt was dissolved
in a 1:1 solution of THF (2 mL) and 3 N NaOH (2 mL) and allowed
to stir at room temperature overnight. After hydrolysis, most of
the THF was removed by evaporation under reduced pressure. The
resulting aqueous phase was extracted three times with CH2Cl2.
The combined organic phases were dried with anhydrous sodium
sulfate, filtered, and evaporated under reduced pressure. The crude
product was purified by flash chromatography (silica gel, 2:98
MeOH-EtOAc) to give 60 mg (78%) of pure 45 as a solid.
Activation with Tf2O: To a solution of the amide 11 (100 mg,
0.390 mmol) in dichloromethane (3.9 mL) at room temperature was
added 4-(N,N-dimethylamino)pyridine (47 mg, 0.39 mmol), fol-
lowed by Tf2O (130 µL, 770 µmol). The solution was stirred at
room temperature for 2 h, then was heated to reflux overnight. The
reaction was worked up and purified as described in the POCl3
activation method (vide supra) to give 64 mg (89%) of pure 45 as
a solid.31
(27) Charette, A. B.; Chua, C. Tetrahedron Lett. 1998, 39, 245.
(28) Ohmiya, S.; Kubo, H.; Otomasu, H.; Saito, K.; Murakoshi, I.
Heterocycles 1990, 30, 537.
(29) (a) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E.
J. Org. Chem. 1990, 55, 1148. (b) Paulvannan, K.; Stille, J. R. J. Org.
Chem. 1994, 59, 1613. (c) Gage, J. L.; Branchaud, B. P. Tetrahedron Lett.
1997, 38, 7007. (d) David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued,
M.-C.; Haviari, G.; Ce´le´rier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette,
D. J. Org. Chem. 1999, 64, 3122. (e) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha,
J. K. J. Org. Chem. 1999, 64, 6771. (f) Banwell, M. G.; Beck, D. A. S.;
Smith, J. A. Org. Biomol. Chem. 2004, 2, 157.
(30) Paulvannan, K.; Schwarz, J. B.; Stille, J. R. Tetrahedron Lett. 1993,
34, 215.
J. Org. Chem, Vol. 71, No. 2, 2006 711

Be´langer et al.
1,2,3,5,6,7-Hexahydroindolizine-8-carbaldehyde (56). Tf2O (33
µL, 0.19 mmol) was added dropwise to a solution of 448 (50 mg,
0.18 mmol) and 2,6-di-tert-butyl-4-methylpyridine (40 mg, 0.19
mmol) in CH2Cl2 (2 mL) at 0 °C, then the reaction mixture was
stirred at 0 °C during 20 min. Pyr‚HF quench: a prepared solution
of Pyr‚HF/pyridine/THF (4:5:20, 0.11 mL) was added dropwise at
0 °C, and the reaction mixture was stirred at 0 °C for 20 min. NaOH
(1 N) was added, layers were separated, and the aq phase was
extracted with CH2Cl2. Organic phases were combined, dried over
anhyd Na2SO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash chromatography (basic
alumina, 100:2 EtOAc-MeOH) to give pure 56 as a yellowish oil.
NaOH quench: the reaction mixture was concentrated by using a
nitrogen flow, then THF (2 mL) and 1 N NaOH (2 mL) were added
and the mixture was vigorously stirred overnight at room temper-
ature. THF was evaporated under reduced pressure and the aq phase
was extracted with CH2Cl2. The combined organic phases were
dried over anhyd Na2SO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromatography
(basic alumina, 100:2 EtOAc-MeOH) to give 25 mg (93%) of pure
56 as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H),
3.45 (t, J ) 7.0 Hz, 2H), 3.26 (t, J ) 5.5 Hz, 2H), 2.99 (t, J ) 7.0
Hz, 2H), 2.33 (t, J ) 5.5 Hz, 2H), 2.05 (qi, J ) 7.0 Hz, 2H), 1.83
(qi, J ) 5.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 183.0, 164.4,
103.6, 53.4, 45.2, 28.5, 20.8, 20.6, 17.7; IR (film) ν 2939, 1577,
1438, 1108 cm-1; HRMS (EI) calcd for C9H13NO (M+) 151.0997,
found 151.0994.
MHz, DMSO-d6) δ 186.3, 158.6, 148.8, 140.0, 135.2, 133.9, 133.2,
132.4, 132.0, 128.7, 110.3, 65.3, 55.4, 41.2, 36.6, 26.3; IR (film)
ν 3032, 2950, 2867, 1608, 1541, 1495, 1262, 1149, 1031 cm-1
;
HRMS (EI) calcd for C27H28N2+ (M+) 380.2252, found 380.2246.
8-Ethylidene-2,3,5,6,7,8-hexahydro-1H-indolizinylium Triflu-
oromethanesulfonate (65). Tf2O (77 µL, 0.46 mmol) was added
dropwise to a solution of 36 (100 mg, 0.42 mmol) and 2,6-di-tert-
butyl-4-methylpyridine (95 mg, 0.46 mmol) in CH2Cl2 (4 mL) at 0
°C. After 20 min at 0 °C, the resulting mixture was allowed to
warm to room temperature over 2 h, stirred overnight, then
concentrated. 1,2-Dichloroethane (4 mL) was added and the solution
was heated to reflux for 15 h, then was allowed to cool to room
temperature and concentrated. The crude material was purified by
flash chromatography (silica gel, 2:5:100 AcOH-MeOH-CH2Cl2)
to afford 88 mg (70%) of pure 65 as a yellowish semisolid: 1H
NMR (300 MHz, CDCl3) δ 6.93 (q, J ) 7.0 Hz, 1H), 4.28 (t, J )
7.5 Hz, 2H), 3.81 (br t, J ) 6.0 Hz, 2H), 3.37 (t, J ) 7.5 Hz, 2H),
2.57 (t, J ) 6.0 Hz, 2H), 2.33 (qi, J ) 7.5 Hz, 2H), 2.10 (qi, J )
6.0 Hz, 2H), 2.03 (d, J ) 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 178.8, 149.9, 128.0, 60.6, 48.0, 33.7, 20.4, 20.0, 18.2, 15.7; IR
(film) ν 2966, 1641, 1260, 1156, 1029 cm-1; MS (EI) m/z (rel %)
149 (70) [M+], 148 (100) [M+ - H], 122 (25); HRMS (EI) calcd
for C10H15N (M+) 149.1204, found 149.1194.
(()-Tashiromine (66). Pd/C (10%, 37 mg, 0.034 mmol) was
added to a solution of 56 (48 mg, 0.32 mmol) and Na2CO3 (36
mg, 0.34 mmol) in EtOH (99%, 4 mL) in a hydrogenation bomb.
The bomb was purged with H2 (3×) then filled with H2 (1000 psi)
and the solution was stirred for 24 h ar room temperature, followed
by filtration on Celite (EtOAc washings). The filtrate was concen-
trated, then resubmitted to the same hydrogenation conditions (37
mg of 10% Pd/C, 36 mg of Na2CO3, 4 mL of EtOH, 1000 psi of
H2) at room temperature for 72 h. The reaction mixture was filtered
on Celite (EtOAc washings) and the filtrate was concentrated. The
crude material was purified by flash chromatography (basic alumina,
50:1 CH2Cl2-MeOH) to give 42 mg of a 20:1:2 inseparable mixture
of (()-tashiromine (66) (73%, 79% corrected), recovered starting
material 56, and (()-epitashiromine (4%), respectively, as a
yellowish oil. The characterization of a small amount of separated
pure (()-tashiromine corresponds to the one previously reported.29e
(E)-N,N-Dibenzyl-N-[2-(N′-methyl-N′-phenylaminomethylene)-
cyclopentylidene]ammonium Trifluoromethanesulfonate (60).
Molecular sieves ( 4 Å, 600 mg) were added to a solution of 158
(200 mg, 0.647 mmol) in CHCl3 (5.0 mL) at 20 °C. N-Methylaniline
(0.17 mL, 1.6 mmol) was added and the reaction mixture was stirred
for 24 h at room temperature. Conversion of 15 to the enamine 58
1
was followed by H NMR of 0.1 mL aliquots sampled from the
heterogeneous reaction mixture and diluted with CDCl3 in an NMR
tube.32 The reaction mixture was cooled to 0 °C, then iPr2NEt was
added (0.32 mL, 1.86 mmol), followed by a dropwise addition of
Tf2O (0.29 mL, 1.86 mmol) over 15-20 min. The reaction mixture
was stirred for 15 min at 0 °C, then allowed to warm to room
temperature and filtered on Celite (CH2Cl2 washing). The clear
orange filtrate was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica gel, 2:5:100
AcOH-MeOH-CH2Cl2) affording 254 mg (74%) of pure 60 as
an amorphous semisolid: 1H NMR (300 MHz, DMSO-d6) δ 7.79
(s, 1H), 7.48-6.97 (m, 15H), 5.10 (br s, 4H), 4.48 (br s, 3H), 3.45
(s, 2H), 2.99 (t, J ) 7.5 Hz, 2H), 1.70 (br s, 2H); 13C NMR (75
Acknowledgment. We thank Ghislain Boucher for his early
work on this project. This research was supported by the Natural
Science and Engineering Research Council (NSERC) of Canada,
FQRNT (Que´bec), the Canadian Fund for Innovation (CFI), and
the Universite´ de Sherbrooke. An NSERC doctoral fellowship
to R.L.-G. and an NSERC predoctoral fellowship to F.B. are
also gratefully acknowledged.
(31) The characterization is identical with the one reported for the same
compound, but prepared through another route. See: (a) Bergman, J.;
Baeckvall, J. E. Tetrahedron 1975, 31, 2063. (b) Gardette, D.; Gramain, J.
C.; Lepage, M. E.; Troin, Y. Can. J. Chem. 1989, 67, 213.
(32) Ratios were determined from the characteristic signal for the protons
R to the amide carbonyl of 14 and 58 appearing at 2.18 ppm (4H) versus
the overlapping multiplets at 1.7-1.6 ppm accounting for a total of 6H
(4H, â and γ to the amide carbonyl, in 15, and 2H â to the amide carbonyl
in 58).
Supporting Information Available: Experimental procedures
for compounds 9-13, 17, 18, 20-22, 25-32, 36, 38, 46, 48, 49,
1
51-53, 61, 62, and 64, as well as H and 13C NMR spectra for
compounds 10-13, 17-22, 25-32, 36, 38, 46, 48, 49, 51-53,
61, 62, 64, and 65. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052141V
712 J. Org. Chem., Vol. 71, No. 2, 2006