A Lewis acid catalyzed intramolecular [4+3] cycloaddition route to polycyclic systems that contain a seven-membered ring

Article abstract of DOI:10.1002/anie.200461084

(Chemical equation presented). Two simple steps, including a new intramolecular [4+3] cycloaddition, are required for the preparation of polycycles that contain a seven-membered ring from 2-methyleneaziridines (see scheme). The diene component is introduc

Full text of DOI:10.1002/anie.200461084

Angewandte
Chemie
Cycloadditions
is depicted in Scheme 1. Lithiation and alkylation of 1 with an
appropriately functionalized 1,3-diene is expected to provide
direct entry to cycloaddition precursor 2. Complexation of the
nitrogen atom of 2 to a suitable Lewis acid might then
A Lewis Acid Catalyzed Intramolecular [4+3]
Cycloaddition Route to Polycyclic Systems That
Contain a Seven-Membered Ring**
Gildas PriØ, Natacha PrØvost, Heather Twin,
Stephanie A. Fernandes, Jerome F. Hayes, and
Michael Shipman*
Oxyallyl cations are important intermediates in the synthesis
of seven-membered rings by way of [4+3] cycloadditions with
1,3-dienes.[1] The products commonly serve as useful tem-
plates in organic synthesis.[2] Intramolecular cycloadditions of
oxyallyl cations are especially useful for the construction of
complex polycyclic systems.[1e,f,3] For example, Harmata and
co-workers have used this approach to make aphanamol I,
widdrol, and (+)-dactylol.[1e] Less well-studied are 2-amino-
allyl cations, which also participate in [4+3] cycloadditions.[4]
Interestingly, these N-substituted cations appear to have some
advantages over the more extensively studied oxyallyl cations.
For example, Cha and co-workers have shown that in some
situations cycloadditions that involve 2-aminoallyl cations
proceed in higher yields and/or with enhanced stereocon-
trol.[4g] Furthermore, Kende and Huang have shown that
asymmetric induction (up to 60% ee) is possible in [4+3]
cycloadditions that involve 2-aminoallyl cations by incorpo-
rating a chiral, nonracemic element into the cation.[4h] Despite
these potential benefits, 2-aminoallyl cations are not widely
used because methods for their generation are rather limited.
Typically, they involve the solvolysis of unstable a-chloro-
enamines[4a,d–g] or 2-chloroimines[4c,h] with stoichiometric
amounts of silver(i) salts.
Scheme 1. Proposed Lewis acid catalyzed intramolecular [4+3] cycload-
dition of 2-methyleneaziridines.
generate the highly strained and reactive aziridinium ion 3,[6]
which could be expected to undergo fragmentation to Lewis
acid complexed 2-aminoallyl cation 4. Further intramolecular
reaction with the appended 1,3-diene would lead to cyclo-
heptenone imine 5. Thus, in just two synthetic operations,
polycyclic systems might be produced from the readily
accessible methyleneaziridine 1. Herein we report our initial
studies, which demonstrate the validity of this new approach
to seven-membered rings.
A variety of cycloaddition precursors 6–12 were made to
probe this chemistry in detail with respect to changes in the
1,3-diene and aziridine components as well as in the nature of
the linking tether (Table 1). Lithiation of N-benzyl-2-isopro-
pylidineaziridine (sBuLi, TMEDA, À788C, THF, 5 h) and
further reaction with 2-(3-iodopropyl)furan (13), 2-(4-iodo-
butyl)furan (14), and 7-iodo-hepta-1,3-diene provided 6
(67%), 7 (71%) and 8 (83%), respectively, after column
chromatography. Similarly, reaction of N-benzyl-2-cyclohex-
ylideneaziridine with 13, and separately 14, gave 9 (61%) and
10 (62%), respectively. We used geometrically pure (Z)- and
(E)-N-benzyl-2-ethyleneaziridine,[5d] to produce (Z)-11
(59%) and (E)-11 (71%), respectively, by lithiation and
reaction with 13. Finally, deprotonation and diastereocon-
trolled alkylation of (S)-N-(1-phenylethyl)-2-isopropylidine-
aziridine gave 12 (63%) as a single diastereomer whose
relative configuration was assigned by correlation with
literature data.[5c]
As part of a program aimed at exploring the scope and
utility of 2-methyleneaziridines 1 in organic synthesis,[5] we
realised that these heterocycles might serve as alternative
precursors to 2-aminoallyl cations. As methyleneaziridines
can be functionalised readily at C3,[5c] we felt that this
methodology might be especially useful for the development
of intramolecular [4+3] cycloadditions. The general strategy
[*] G. PriØ,S. A. Fernandes,M. Shipman
Department of Chemistry
University of Warwick
Coventry,CV4 7AL (UK)
Fax: (+44)24-7652-4429
E-mail: m.shipman@warwick.ac.uk
N. PrØvost,H. Twin
Department of Chemistry
University of Exeter
Initial cycloaddition studies were conducted on furan-
tethered aziridine 6, which bears a three-carbon linking chain
between the reaction partners. After some experimentation, it
was determined that treatment of 6 with excess BF3·OEt2
(150 mol%) in dichloromethane at room temperature for
16 h yielded tricyclic imine 15 in 67% yield as a single
stereoisomer after silica-gel chromatography (Table 1,
entry 1). The structure and stereochemistry of 15 were
unambiguously confirmed by X-ray crystallography after
reduction of the imine from the Si face with sodium
cyanoborohydride and conversion of the resulting amine
Stocker Road,Exeter,EX4 4QD (UK)
J. F. Hayes
GlaxoSmithKline
Old Powder Mills
Tonbridge,Kent,TN11 9AN (UK)
[**] This work was supported by the Engineering and Physical Sciences
Research Council (Grant no. GR/R82586/02) and GlaxoSmithKline.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461084
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Table 1: Lewis acid catalyzed intramolecular [4+3] cycloaddition of 2-methyleneaziridines 6–12.
diastereomer, after workup with aqueous
H2SO4 in methanol (Table 1, entries 3 and
4). The reaction is not limited to electron-
rich dienes such as furan. For example,
aziridine 8, which incorporates a simple
monosubstituted 1,3-diene, reacts to give 17
as a mixture of diastereomers. In this case,
better yields were obtained by heating 8 and
BF3·Et2O in 1,2-dichloroethane at reflux for
48 h prior to acidic hydrolysis (Table 1,
entry 5). The reaction also accommodates
changes in the nature of the structure of the
methyleneaziridine component (Table 1,
entries 6–10). However, we have been
unable to determine if intramolecular cyclo-
additions proceed with methyleneaziridines
that do not bear carbon substituents on the
alkene terminus.[8] Interestingly some ster-
eochemical “memory” is apparent in the
cycloaddition of (Z)- and (E)-11. Both
produce 20 and 21, but the relative amounts
of these two diastereomers is dependent on
the alkene geometry in the starting material
(Table 1, entries 8 and 9). The assignment of
the relative stereochemistry within 20 and
21 was made on the basis of the vicinal
coupling constant between 7-H and 8-H (20:
Entry Aziridine
Lewis acid
(method)[a]
Cycloadducts
Yield Ratio
[%][b]
1
2
BF3·OEt2 (A)
Sc(OTf)3 (B)
67[d]
57
–
–
3
4
BF3·OEt2 (C)
Sc(OTf)3 (D)
70[e]
60
–
–
5
6
7
BF3·OEt2 (E)
BF3·OEt2 (A)
BF3·OEt2 (C)
53
56:44
67[f]
–
–
65[e]
J
7,8 = 5.3 Hz; 21: J7,8 = 0.0 Hz).[9] The con-
version of diastereomerically pure 12 into
near equal quantities of tricycles 22 and 23 is
mechanistically significant as it reveals that
the stereochemical homogeneity at C3 of 12
is almost completely lost during the cyclo-
addition (Table 1, entry 10).
20/21
80:20
8
9
BF3·OEt2 (C)[c]
BF3·OEt2 (C)[c]
56[f]
45[f]
20/21
32:68
We propose that the cycloadditions of 6,
8, 9, 11, and 12 proceed via a compact
transition state, with the tethering arm
orientating itself anti to the bulky Lewis
acid complexed amino substituent. This is
illustrated for the conversion of (Z)- and
(E)-11 into the major products 20 and 21 via
24 and 25, respectively (Scheme 2). In
support of this hypothesis, it is known that
cyclic 2-aminoallyl cations favor compact
transition states.[4a] Furthermore, the loss of
stereochemical integrity in the conversion
of 12 into 22 and 23 is consistent with the
formation of a planar 2-aminoallyl cation.
To account for the switch in stereochemical
outcome in the preparation of 16 (and 19),
an extended transition state may prevail
10
BF3·OEt2 (A)
72
45:55
[a] Method A: BF3·OEt2 (150 mol%),CH 2Cl2, À308C,1 h; then room temperature,16 h; method B:
Sc(OTf)3 (10 mol%),CH 2Cl2, À308C,1 h; then room temperature,16 h; method C: same as method A;
then aqueous H2SO4 (10%),MeOH,16 h,room temperature; method D: same as method B; then
aqueous H2SO4 (10%),MeOH,16 h,room temperature; method E: BF 3·OEt2 (150 mol%),ClCH 2CH2Cl,
À608C to reflux,48 h; then aqueous H 2SO4 (10%),MeOH,16 h. [b] Yield of isolated product.
[c] Cycloaddition and hydrolysis conducted at 508C. [d] Structure determined by X-ray crystallography
after reduction of the imine and formation of the HCl salt (see text). [e] Structure determined by X-ray
crystallography. [f] Ring junction stereochemistry confirmed by NOE difference experiments.
into its crystalline hydrochloride salt (data not shown).
Significantly, 6 could also be converted into 15 by using just
with a longer linking tether.[10] However, in considering the
analysis of these reactions, it is important to bear in mind that
other mechanistic alternatives cannot be ruled out. For
example, the formation of 15–23 might proceed in a stepwise
manner by direct nucleophilic attack of the 1,3-diene unit
onto the aziridinium cation 3, followed by subsequent ring
closure of the resulting enamine onto the allylic cation
derived from the diene.[11] Efforts to obtain direct evidence
a
catalytic amount (10 mol%) of scandium(iii) triflate
(Table 1, entry 2).[7] Representative procedures are provided
in the Supporting Information. Ketone products can be
isolated from these reactions by inclusion of an acidic workup
step. For example, reaction of aziridine 7 with either BF3·OEt2
or Sc(OTf)3 provided tricyclic ketone 16, again as a single
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[7] Examples of catalytic [4+3] cycloadditions of allyl cations are
uncommon; for a recent example with scandium(iii) triflate, see:
M. Harmata, U. Sharma, Org. Lett. 2000, 2, 2703.
[8] Attempts to make substrates that bear two hydrogen atoms on
the exocyclic double bond of the methyleneaziridine have been
hampered by their lack of stability during silica-gel chromatog-
raphy. However, preliminary experiments establish that 2-
methyleneaziridines do participate in intermolecular [4+3]
cycloadditions. For example, the reaction of 1-(1-phenylethyl)-
2-methyleneaziridine with excess furan (BF3·Et2O (1.5 equiv),
CH2Cl2, room temperature, 16 h; then aqueous AcOH (1m), 2 h)
yields 8-oxabicyclo[3.2.1]octan-3-one in 24% yield (unopti-
mized).
Scheme 2. Postulated transition states for the formation of 20 and 21.
[9] A. M. Montaꢀa, S. Ribes, P. M. Grima, F. Garcia, Magn. Reson.
Chem. 1998, 36, 174.
[10] In the case of 16 (and 19), it is conceivable that the switch in the
preferred diastereomer is not due to a change in the cyclo-
addition transition state but results from thermodynamic
equilibration of the a stereocenter of the ketone during hydrol-
ysis. From labeling experiments, we know that hydrolysis
(D2SO4/D2O in CD3OD) leads to some deuterium incorporation
(ꢀ 36% D) into 16 at the center a to the ketone.
for the involvement of allylic cation 4 have thus far proved
unsuccessful.[12]
To conclude, a very concise new entry into a range of
polycyclic systems that contain seven membered rings has
been devised based on an intramolecular Lewis acid catalyzed
[4+3] cycloaddition of methyleneaziridines. Efforts to
develop asymmetric variants of this chemistry by using
chiral Lewis acid catalysts or chiral, nonracemic methylene-
aziridines are currently ongoing in our laboratory.
[11] For recent theoretical studies on [4+3] cycloadditions that
support stepwise mechanisms, see: M. Harmata, P. R. Schreiner,
Org. Lett. 2001, 3, 3663; J. A. Sꢁez, M. Arnꢂ, L. R. Domingo,
Org. Lett. 2003, 5, 4117.
[12] A large downfield shift of the signal for the aziridine methylene
group is observed in the 1H NMR spectrum (400 MHz, CD2Cl2)
of N-benzyl-2-isopropylideneaziridine upon addition of
BF3·Et2O (150 mol%) which suggests coordination of the nitro-
gen atom of the aziridine to the Lewis acid. Selected data:
uncomplexed: d = 2.37 ppm (2H, s); complexed: d = 3.09 (1H,
s), 2.52 ppm (1H, s). However, signals for the allylic cation were
not observed.
Received: June 25, 2004
Keywords: aziridines · cycloaddition · Lewis acids ·
.
nitrogen heterocycles · strained molecules
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