Addition of tethered nonaromatic carbon nucleophiles to chemoselectively activated amides

Article abstract of DOI:10.1021/ol0516519

(Chemical Equation Presented) In an effort to develop new ways of synthesizing polycyclic alkaloids, we successfully added silyl enol ethers, allylsilanes, and enamines to iminium ions generated from amides. Because of their higher oxidation state, such i

Full text of DOI:10.1021/ol0516519

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4431-4434
Addition of Tethered Nonaromatic
Carbon Nucleophiles to
Chemoselectively Activated Amides
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 July 13, 2005
ABSTRACT
In an effort to develop new ways of synthesizing polycyclic alkaloids, we successfully added silyl enol ethers, allylsilanes, and enamines to
iminium ions generated from amides. Because of their higher oxidation state, such iminiums show a yet unexploited advantage of potential
double cyclizations over standard Mannich monocyclizations. We report herein the first example of tethered nonaromatic carbon nucleophiles
adding to activated amides for the generation of enaminals of various ring sizes, with endo- or exo-cyclic nitrogen.
Numerous efficient approaches to construct biologically
active polycyclic alkaloids use intramolecular Mannich
addition to an iminium ion.1 These iminium ions usually bear
Scheme 1. Representative Example of the Projected
Biscyclization on Chemoselectively Activated Amides
a carbon of oxidation state II (two C-heteroatom bonds), due
to the ways they are usually generated,1b,2 inherently limiting
the approach to a monocyclization. Our goal is to exploit a
higher level of oxidation state by generating iminium ions
from amides.3 With nucleophiles tethered to the amide (e.g.,
1, Scheme 1), we would have an access to polycyclic alkaloid
skeletons in one synthetic step from linear precursors through
† Current address: MDS Pharma Services, 2350 rue Cohen, St-Laurent
novel sequential nucleophilic cyclizations on the same amide
(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, 1991; Vol. 2, p 1007.
carbon,4 thus creating a tertiary (3, R ) H) or a quaternary
(3, R ) alkyl) center R to nitrogen, as found in the skeleton
of a myriad of alkaloids. Since the ways to attach the
(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,
various complex alkaloid skeletons could be prepared, thus
104, 2311.
nucleophiles to the amide are diverse (C- and/or N-bound),
(3) The next level of oxidation state would be carbamates or ureas. For
a precise example using carbamates, see: Magnus, P.; Gazzard, L.; Hobson,
L.; Payne, A. H.; Rainey, T. J.; Westlund, N.; Lynch, V. Tetrahedron 2002,
58, 3423. This work was published while we were already engaged in our
studies with amides.
(4) For selected examples of sequential iminium cyclizations, although
not performed on the same carbon, 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.
10.1021/ol0516519 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/31/2005

presenting a great versatility through rapid increase of
complexity from easily assembled substrates.
Silyl enol ethers from ketones were also investigated. We
prepared the phenyl ketone silyl enol ether 813 by adding
phenylmagnesium bromide to the aldehyde 5, followed by
a Swern oxidation and silylation. We also extended our study
to other types of nucleophiles. The allylsilane 11 was thus
synthesized in three steps from commercially available
carboxylic acid 9, which was coupled with dibenzylamine,
ozonized and olefinated.14 Finally, a 6-exo cyclization model
substrate (14) was built by addition of the iodosilyl ether
branch 1215 to N-methylpyrrolidinone enolate, followed by
methanolysis of the silyl ether, oxidation and silylation.
Endo types of cyclizations were also investigated. N-
Alkylation of pyrrolidinone with iodides 1516 or 12 followed
by the usual sequence furnished the 5-endo and 6-endo
cyclization precursors 18 and 19 (Scheme 3). A formamide
substrate 22 was also prepared using the usual route.
The only reported examples of tethered carbon nucleo-
philes adding to iminium ions generated from amides5 are
either indoles6 or activated benzene rings.7 We wanted to
find out if tethered nonaromatic carbon nucleophiles would
participate in the cyclization. This however presents a serious
difficulty: the usual amide activation conditions involve
Lewis or Brønsted acids that react with most nucleophiles.8
This paper summarizes the successful additions of different
tethered nonaromatic carbon nucleophiles to activated amides
(1 f 2). Additionally, this approach is very interesting
because it offers an efficient way to generate various
enaminals and enaminones known to be especially useful
and versatile intermediates for natural product synthesis.9
Before attempting the entire bicyclization (1 f 3), we
opted to set the monocyclization first. To this end, five- and
six-membered rings were studied, as they are the most
common in the vast majority of alkaloid skeletons. We
elaborated a series of model substrates to tackle three
different aspects of nucleophilic cyclizations on activated
amides: (1) determining the nature of the nucleophiles that
could trap the activated amides, (2) comparing five- and six-
membered ring closures, and (3) investigating endo and exo
types of cyclization. Both amides and lactams have been
looked at, since they generate mono- or bicyclic adducts.
The syntheses of 5- and 6-exo cyclization10 substrates
started with the ring opening of ꢀ-caprolactone (4) with a
DIBALH-dibenzylamine complex,11 followed by a Swern
oxidation to furnish the aldehyde 5 (Scheme 2). The latter
was treated either with TBDMSOTf to give the correspond-
ing silyl enol ether 6 or with methyl aniline to lead to
enamine 7.12
Scheme 3. Syntheses of 5- and 6-endo Cyclization Substrates
Table 1 shows the variety of nucleophiles that all gave
5-exo cyclizations upon amide activation. Among the as-
Scheme 2. Syntheses of 5- and 6-exo Cyclization Substrates
(5) 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. (g) Smith, D. C.; Lee, S. W.; Fuchs, P. L. J. Org. Chem. 1994,
59, 348.
(6) Typically the Bischler-Napieralski cyclization: Bischler, A.; Napi-
eralski, 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) For various amide activation conditions, see references cited in ref
5g and in: Kuhnert, N.; Clemens, I.; Walsh, R. Org. Biomol. Chem. 2005,
3, 1694, See also: Nishiyama, H.; Nagase, H.; Ohno, K. Tetrahedron Lett.
1979, 48, 4671. Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron
2000, 56, 9875.
(9) For the use of enaminones in 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.
(10) The use of exo and endo in this manuscript refers to the amide
portion of the substratres. For a more appropriate description of cationic
cyclizations involving π-nucleophiles, see: (a) Ben-Ushai, 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.
(11) Huang, P.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron Lett. 2001, 42,
9039.
(12) Enamine 7 was unstable and had to be used without further
purification in the cyclization step.
4432
Org. Lett., Vol. 7, No. 20, 2005

the cyclization yield from 7 to 26 is evaluated at around 85%.
This means that silyl enol ethers, allylsilanes, and enamines
add to activated amides with comparable ease and yields
under mild conditions.
The Pyr‚HF (or NaOH as found in Table 2)19 quench is
essential to cleave the TBDMS group still attached to the
Table 1. 5-exo Cyclizations of Various Tethered Nucleophiles
on Activated N,N-Dibenzylamides
Table 2. 5-exo, 6-exo, 5-endo, and 6-endo Cyclizations of
Tethered TBDMS Enol Ethers on Activated Amides and
Lactamsa
a Activation conditions: (A) Tf2O (1.1 equiv), 2,6-di-tert-butyl-4-
methylpyridine (1.1 equiv), CH2Cl2, 0 °C, 20 min; (B) Tf2O (2.5 equiv),
iPr2NEt (3.0 equiv), CHCl3, 0 °C, 20 min. b Yields of isolated product.
c Pyr‚HF, 0 °C, 20 min. d Concentrated and then diluted in 1 N NaOH,
THF, 25 °C, overnight. e NaBH(OAc)3, -78 °C to rt, overnight. An
inseparable 94:6 mixture of Z/E-25, respectively, as established by nOe.
f Concentrated and then purified directly.
sortment of amide activating agents we surveyed, triflic
anhydride (Tf2O) is the reagent of choice and gave reproduc-
ible results with all of the substrates tested. POCl3 and
triphosgene led to the cleavage of the silyl enol ethers (the
corresponding aldehydes were recovered), whereas TMSOTf
and TFAA gave undesired side products.
a Activation conditions: Tf2O (1.1 equiv), 2,6-di-tert-butyl-4-methylpy-
ridine (1.1 equiv), CH2Cl2, 0 °C, 20 min. b Yields of isolated product.
d
c Concentrated and then diluted in 1 N NaOH, THF, 25 °C, overnight.
Pyr‚HF, 0 °C, 20 min.
The amide activation with Tf2O was always completed
within 20 min at 0 °C17 in the presence of 2,6-di-tert-butyl-
4-methylpyridine or di-isopropylethylamine to prevent the
generation of triflic acid. These rather mild conditions were
tolerated by TBDMS enol ethers from aldehydes or from
ketones (Table 1, entries 1 and 2 respectively), as well as
by allylic trimethylsilane (entry 3) and N-methyl-N-phenyle-
namine (entry 4). The aldehyde TBDMS enol ether 6 gave
the highest yield, cyclizing in 85% yield (entry 1). The
phenyl ketone analogue 8 was also successfully cyclized even
though the yields were slightly lower (entry 2 versus 1),
presumably because of a higher steric congestion developed
during cyclization. When the allylsilane 11 was cyclized
(entry 3), a reductive quench (NaBH(OAc)3) was necessary,
since the iminium ion resulting from the cyclization was not
stable.18 An overall yield of 81% was obtained for the
cyclization-reduction sequence.
carbonyl when enol ethers were cyclized.17 Such a detail is
highly important: regardless of the tethered nucleophile used,
there is always an activated species in solution before
quenching the reaction.
A study comparing ring sizes as well as endo and exo
cyclizations was also performed with aldehyde silyl enol
ethers. The 5-exo and the 6-endo cyclizations of alkylamides
6 and 19 gave the highest yields (Table 2, entries 1 and 4
respectively), followed by the 6-exo cyclization of 14 (entry
2). As expected, the 5-endo cyclization of substrate 18 was
quite difficult, which is in accordance with the Baldwin
rules,10,20 but nonetheless successful (35% yield, entry 3).
Surprisingly, the 6-endo cyclization of the less congested
iminium ion upon formamide 22 activation gave lower
conversion than the cyclization of pyrrolidinone 19. This
could be due to a lower stability of the iminium ion derived
from 22.
Finally, upon activation of amide 7, we were able to isolate
and characterize the vinylogous amidinium ion 26. As the
conversion of aldehyde 5 to enamine 7 was estimated at 80-
85%17 and the overall yield of 26 from aldehyde 5 is 74%,
In summary, we demonstrated for the first time that
activated amides could be trapped with various tethered
nonaromatic carbon nucleophiles very efficiently. The result-
ing enaminals cover a wide range of skeletons of various
(13) The phenyl was essential since we had to control on which side the
ketone would enolize during the final silyl enol ether preparation.
(14) Fleming, I.; Paterson, I. Synthesis 1979, 446.
(15) Deng, Y.; Salomon, R. C. J. Org. Chem. 1998, 63, 3504.
(16) Ott, M. M.; Little, R. D. J. Org. Chem. 1997, 62, 1610.
(17) As observed by H NMR.
(19) The quench procedure has a crucial influence on the cyclization
yield that we do not yet fully understand. Investigation in that direction is
underway and will be published in due course.
1
(18) The resulting iminium ion after the cyclization was not conjugated
with the remaining alkene according to 1H NMR spectroscopy, presumably
because of high allylic strain resulting from conjugation.
(20) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736.
Org. Lett., Vol. 7, No. 20, 2005
4433

ring sizes containing either an endo- or exo-cyclic nitrogen.
The alkenes of the enaminals are either tetra- or trisubstituted
depending on whether the initial amide carbonyl was
alkylated or not. Ultimately, upon double nucleophilic
additions, related systems (such as 1, Scheme 1) could lead
to quaternary or tertiary centers R to nitrogen (such as 3).
Moreover, we also demonstrated that the intermediates
obtained before quenching of the cyclization reaction were
still iminium ions, thus conferring optimistic perspective to
our planned biscyclization with two nucleophilic moieties
tethered to the amide. Work in that direction is currently in
progress.
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.
NSERC doctoral fellowship to R.L.-G. and NSERC predoc-
toral fellowship to F.B. are also gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra for compounds 5-8,
10, 11, 13, 14, 16-19, and 21-30. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0516519
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Org. Lett., Vol. 7, No. 20, 2005