Stereocontrolled synthesis of angularly substituted 1-azabicyclic rings by cationic 2-aza-cope rearrangements

Article abstract of DOI:10.1021/ol047330z

(Chemical Equation Presented) A new synthesis of 1-azabicyclic molecules having angular substitution is reported. This method can be employed to prepare a range of 1-azabicylic rings, including ones containing vicinal quaternary carbon centers and three c

Full text of DOI:10.1021/ol047330z

ORGANIC
LETTERS
2005
Vol. 7, No. 5
913-916
Stereocontrolled Synthesis of Angularly
Substituted 1-Azabicyclic Rings by
Cationic 2-Aza-Cope Rearrangements
Zachary D. Aron and Larry E. Overman*
Department of Chemistry, UniVersity of California-IrVine, 516 Rowland Hall,
IrVine, California 92697-2025
leoVerma@uci.edu
Received December 27, 2004
ABSTRACT
A new synthesis of 1-azabicyclic molecules having angular substitution is reported. This method can be employed to prepare a range of
1-azabicylic rings, including ones containing vicinal quaternary carbon centers and three contiguous stereocenters.
The cationic 2-aza-Cope rearrangement (2-azonia-[3,3]-
sigmatropic rearrangement), which generally takes place at
(or slightly above) room temperature, is a notably mild
method for forming carbon-carbon bonds (Figure 1).1,2 As
selectively cleaving the iminium ion functional group of one
sigmatropic isomer.6 This paper describes the first directed
cationic 2-aza-Cope rearrangement in which the starting
iminium ion isomer 1 is derived from a ketone (R1 ) R2 )
alkyl), thereby introducing a fully substituted carbon adjacent
to nitrogen in the product 2.
As a prelude to total synthesis endeavors in the alkaloid
area, we became interested in the possibility of constructing
angularly substituted 1-azabicyclic ring systems such as 6
(3) For representative examples where the “product” sigmatropic isomer
predominates by virtue of it being stabilized by delocalization, see: (a)
Knabe, J.; Ruppenthal, V. Arch Pharm. 1966, 299, 159-165. (b) Winter-
feldt, E.; Franzischka, W. Chem. Ber. 1967, 100, 3801-3807. (c) Deloisy,
S.; Kunz, H. Tetrahedron Lett. 1998, 39, 791-794.
Figure 1. Cationic 2-aza-Cope rearrangement.
(4) For representative examples, see: (a) Overman, L. E.; Kakimoto,
M. J. Am. Chem. Soc. 1979, 101, 1310-1312. (b) Agami, C.; Couty, F.;
Lin, J.; Mikaeloff, A.; Poursoulis, M. Tetrahedron 1993, 49, 7239-7250.
For brief reviews, see: (c) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-
359. (d) Overman, L. E. Aldrichem. Acta 1995, 28, 107-120. (e) Royer,
J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311-2352.
(5) For representative examples, see: (a) Rischke, H.; Wilcock, J.;
Winterfeldt, E. Chem. Ber. 1973, 106, 3106-3118. (b) Mooiweer, H. H.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron 1991, 47, 3451-3462. (c)
Gelas-Mailhe, Y.; Gramain, J. C.; Louvet, A.; Remuson, R. Tetrahedron
Lett. 1992, 33, 73-76. (d) ref 4b.
(6) For representative examples, see: (a) Overman, L. E.; Yokomatsu,
T. J. Org. Chem. 1980, 45, 5229-5230. (b) Castelhano, A. L.; Krantz, A.
J. Am. Chem. Soc. 1984, 106, 1877-1879. (c) Hart, D. J.; Yang, T.-K. J.
Org. Chem. 1985, 50, 235-242. (d) Agami, C.; Couty, F.; Poursoulis, M.
Synlett 1992, 847-848. (e) Bennett, D. J.; Hamilton, N. M. Tetrahedron
Lett. 2000, 41, 7961-7964. (f) ref 4b.
the 3-alkenyliminium cations equilibrated in this way are
often of similar energy,3 several methods have been devel-
oped to drive this sigmatropic rearrangement to provide a
single product. These methods range from trapping one
sigmatropic isomer by a Mannich4 or ene5 cyclization to
(1) First described by Geissman; see: Horowitz, R. M.; Geissman, T.
A. J. Am. Chem. Soc. 1950, 72, 1518-1522.
(2) For reviews, see: (a) Heimgartner, H.; Hansen, H. J.; Schmid, H. In
Iminium Salts in Organic Chemistry; Bo¨hme, H., Viehe, H. G., Eds.;
Wiley: New York, 1979; pp 655-732. (b) Przheval’skii, N. M.; Grandberg,
I. I. Russ. Chem. ReV. 1987, 5, 477. (c) Blechert, S. Synthesis 1989, 71-
82.
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Published on Web 02/02/2005

hydride reduction of this intermediate then delivered cyclo-
hexyl aminoketal 10 in 70% overall yield for the four steps.10
Initial survey experiments showed that 10 was quickly
transformed to the corresponding iminium ion 4 (m ) 2,
n ) 1) when heated in methanol at 60 °C in the presence of
just less than 1 equiv of trifluoroacetic acid (TFA). However,
the transformation of this iminium ion to the desired
angularly substituted bicyclic amine 6 (m ) 2, n ) 1) could
not be realized by selective hydrolysis of formaldiminium
ion 5 (m ) 2, n ) 1). For example, including up to 3 equiv
of water and heating the reaction at temperatures as high as
110 °C left 4 (m ) 2, n ) 1) unchanged. However, the
addition of 2.5 equiv of dimedone11 resulted at 80 °C in slow
but clean formation of octahydroindole 6 (m ) 2, n ) 1).
This reaction takes place at a convenient rate at 120 °C, either
in the absence of solvent or in toluene at high concentration
(Table 1, entry 1).
The scope of this method for preparing 1-azabicyclic
molecules containing angular allyl substituents is outlined
in Table 1. As the transformation is slowed dramatically if
more than 1 equiv of TFA is present, we found it most
convenient to carry out the reaction in the presence of 1 equiv
of this acid and 0.1 equiv of morpholine. To simplify
isolation and purification of the bicyclic amine products, the
crude reaction product was directly converted to the corre-
sponding benzyloxycarbonyl derivative prior to isolation.
Using this two-step procedure, a variety of angularly
functionalized hexahydrocyclopenta[b]pyrrole, octahydro[1]-
pyrindine, octahydroindole, decahydroquinoline, octahydro-
cyclohepta[b]pyrrole, and decahydrocyclohepta[b]pyridine
carbamates were prepared in good yield.
Scheme 1. Preparation of Angularly Substituted 1-Azabicyclic
Ring Systems
by the sequence outlined in Scheme 1. The substantial
challenge would be rendering the sigmatropic reorganization
irreversible, as the fully substituted iminium cation 4 is
considerably more stable than formaldiminium ion sigmat-
ropic isomer 5.7,8 For the sequence posited in Scheme 1 to
succeed, an efficient method for scavenging the methylene
unit of the less stable formaldiminium ion isomer 5 would
be required.
The high-yielding sequence we developed for preparing
the monocyclic aminoketal starting materials is outlined in
Scheme 2. This representative synthesis begins with (2-
Scheme 2. Representative Synthesis of Monocyclic
Aminoketal Starting Materialsa
Several trends are apparent in the data summarized in
Table 1. For example, reaction rate varies substantially with
ring size. For substrates having no additional substituents,
iminium ions generated from five- (entries 2-4) and six-
membered (entries 1 and 8) aminoketals rearrange faster than
those generated from seven-membered precursors (entries 9
and 10).12,13 Incorporation of additional substitution on either
side of the acetal carbon resulted in slower reaction rates;
nonetheless, yields in these cases were high (entries 5 and
7).14 However, aminoketal 18 containing an (E)-3-pentenyl
fragment reacted extremely slowly even at 130 °C to provide
hydroindole 19 in low yield (entry 6). The hexahydrocyclo-
penta[b]pyrrole, octahydro[1]pyrindine, and octahydroindole
products are formed with high cis stereoselectivity; observa-
a Conditions: (a) 1,3-Propanediol, 5 mol % Sc(OTf)3, methyl
orthoformate, MeCN. (b) (i) H2, Pd(OH)2/C; (ii) 3-butenylamine
hydrochloride, EDCI, i-Pr2NEt, CH2Cl2. (c) LiAlH4, Et2O.
oxocyclohexyl)acetic acid benzyl ester (7),9 which is ketal-
ized in the presence of scandium triflate to provide 1,3-
dioxolane 8. Cleavage of the benzyl ester of this product,
followed by coupling of the resulting acid with 3-butenyl-
amine, gave amide 9 in excellent yield. Lithium aluminum
1
tion of a H NOE between the angular hydrogen and the
allylic hydrogens of the angular allyl group confirmed the
(10) Cyclic aminoketals 12, 14, 18, 23, 26, and 29 were generated in a
manner analogous to that of 10, whereas 16 and 20 were accessed by related
routes; details are provided in Supporting Information.
(11) These results contrast with the reaction of related aldehyde-derived
iminium ions described in ref 6a, wherein the hydrolysis-directed reaction
could be realized in the absence of dimedone.
(7) For example, the model rearrangement A to B is calculated to be
endothermic by 14.4 kcal/mol (ab initio calculations using DFT/B3LYP/
6-21G* as implemented in the Spartan 2002 software package).8
(12) This trend parallels the endothermicity of the cationic 2-aza-Cope
rearrangement as analyzed computationally with model compounds analo-
gous to those shown in ref 7.13
(13) Aron, Z. D. Ph.D. Dissertation, University of California-Irvine,
Irvine, CA, 2004; these details will be discussed in a future full account of
this work.
(14) At elevated reaction temperatures, dimedone decomposition was
observed as a competitive process and sequential addition of this reagent
over time was required to achieve useful yields in these cases.
(8) Wavefunction, Inc.: Irvine, CA; 2002.
(9) Usugi, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Bull. Chem.
Soc. Jpn. 2002, 75, 2049-2052.
914
Org. Lett., Vol. 7, No. 5, 2005

Table 1. Synthesis of Angularly Substituted 1-Azabicyclic Rings by Methylene Transfer-Driven Cationic 2-Aza-Cope
Rearrangementsa
a Typical reaction conditions: TFA (1.0 equiv), morpholine (0.1 equiv), dimedone (2.5 equiv), followed by reaction of the crude product in chloroform
with benzyl chloroformate (2.5 equiv) and Na2CO3. b Product ratios were determined from yields of pure products; these ratios were confirmed by analysis
1
1
of H NMR spectra of the crude reaction product. c As demonstrated by H NMR analysis using an internal standard, a 78% yield was obtained when the
reaction was conducted at 2 M in toluene in a sealed reaction vessel at 120 °C for 2.7 h. d Performed with portionwise addition of 4.0 equiv of dimedone
over 4 h.
cis ring fusion for these products and for the other cis isomers
shown in Table 1. In general, the diastereoselectivities
observed are consistent with the formation of thermodynamic
product mixtures.13
Several additional experiments provide insight into the
mechanism of this synthesis of angularly substituted 1-azabi-
cyclic rings. First, three carbon-bound deuterium atoms are
introduced when the synthesis of hydroindole 36 is carried
out in deuterated methanol (Scheme 3). The location of
deuterium atoms in d3-36 shows that the initially formed
tetrasubstituted iminium ion equilibrates with its two possible
enamonium tautomers faster than it converts to the hydro-
indole product. Such equilibration also rationalizes the result
reported in Table 1, entry 7, in which methyl epimers 21
and 22 of the cis-octahydroindole product were formed from
isomerically pure aminoketal precursor 20.
To examine the reversibility of this synthesis of angularly
substituted 1-azabicyclics, homoallylamine d3-36 was heated
at 60 °C in the presence of 1 equiv of TFA and an excess of
paraformaldehyde in deuterated methanol (eq 1). Within 20
h, complete conversion to iminium ion d3-33 was observed
by 1H NMR. Addition of a large excess of dimedone to this
solution and heating at 120 °C for 20 h returned the starting
azabicyclic amine d3-36, thereby confirming the expected
reversibility of the cationic 2-aza-Cope rearrangement.
Scheme 3. Equilibrium between the Initially Formed Iminium
Ion and Its Enamine Tautomers
The reversibility of the overall synthesis of angularly
substituted 1-azabicyclics was established by the experiment
Org. Lett., Vol. 7, No. 5, 2005
915

Scheme 4. Reversibility of the Rearrangement and Methylene
Scheme 5. Proposed Mechanism
Transfer Steps
summarized in Scheme 4. As the formaldiminium ion derived
from 36 rapidly rearranges to form iminium ion 33, which
is in tautomeric equilibrium with enamonium ions 34 and
35, exposing ammonium ion 36 to the dimedone-formalde-
hyde adduct 37 in deuterated methanol would reveal the
reversibility of both the cationic 2-aza-Cope rearrangement
and the methylene transfer step. Accordingly, the crude
mixture of ammonium ion 36 and dimedone-formaldehyde
adduct 37 formed from aminoketal 10 was heated at 120 °C
in deuterated methanol in a sealed tube for 16 h (Scheme
4). The formation of a 2:1 mixture of ammonium ion 36
and its d3 congener after aqueous workup establishes the
reversibility of the overall reaction.15
The mechanism outlined in Scheme 5 is consistent with
observations made to date. Exposure of an aminoketal such
as 38 to acid at high-temperature results in the formation of
an equilibrium mixture consisting of iminium ion 33, its
enammonium tautomers (not shown), and the rearranged
formaldiminium ion 39. Reaction of the latter with dimedone
gives the 1-azabicyclic product 36 and the formaldehyde-
dimedone adduct 37, likely via the intermediacy of adduct
40 and methylenedione 41. The highly favorable equilibrium
for forming dimedone adduct 37 from the reaction of
dimedone with methylenedione 41 is undoubtedly responsible
for the success of this synthesis.
has been used to prepare a range of 1-azabicylic rings,
including ones containing vicinal quaternary carbon centers
or three contiguous stereocenters. This disclosure constitutes
the first report that the highly endothermic cationic 2-aza-
Cope rearrangement of ketone-derived iminium ions can be
directed by subsequent methylene transfer, thereby forming
amine products containing a fully substituted carbon adjacent
to nitrogen. The development of asymmetric variants of this
synthesis of nitrogen heterocycles and applications of this
chemistry in target directed synthesis are under current
investigation.
Acknowledgment. This research was supported by the
U.S. National Institute of Neurological Disorders and Stroke
(Grant NS-12389) and by a Lilly Graduate Fellowship to
Z.D.A. NMR and mass spectra were determined at UC Irvine
with instruments purchased with the assistance of the NSF
and NIH shared instrumentation programs.
Supporting Information Available: Schemes showing
synthetic routes, reagents, and yields for the synthesis of
compounds 16 and 20; experimental procedures, character-
ization data, and copies of 1H and 13C NMR spectra for key
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, a new synthesis of 1-azabicyclic molecules
containing angular allyl substitution is reported. This reaction
(15) Dimedone decomposes at elevated temperatures in the presence of
ammonium salts, which is likely responsible for the incomplete deuterium
incorporation observed in this experiment.
OL047330Z
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Org. Lett., Vol. 7, No. 5, 2005