Intramolecular [4 + 2] cycloadditions of iminoacetonitriles: A new class of azadienophiles for hetero Diels-Alder reactions

Article abstract of DOI:10.1021/ja034629o

Iminoacetonitriles participate as reactive dienophiles in stereoselective intramolecular hetero Diels-Alder reactions which afford substituted quinolizidines. The cycloadduct with exo-oriented cyano group is obtained as the major or exclusive product of the reaction as a consequence of the α-amino nitrile anomeric effect The α-amino nitrile moieties incorporated in the cycloadducts constitute latent iminium ions, which upon exposure to mild protic or Lewis acids are unmasked, setting the stage for further useful synthetic transformations. For example, reductive decyanation with NaBH₃CN excises the cyano group, while Bruylants reaction with Grignard reagents and acetylides lead to α-substituted amines. The substrates for these [4 + 2] cycloadditions are prepared from readily available alcohols via a Mitsunobu coupling reaction with the previously unknown, easily prepared reagent HN(Tf)CH₂CN followed by cesium carbonate promoted elimination of trifluoromethanesulfinate. Copyright

Full text of DOI:10.1021/ja034629o

Published on Web 04/04/2003
Intramolecular [4 + 2] Cycloadditions of Iminoacetonitriles: A New Class of
Azadienophiles for Hetero Diels-Alder Reactions
David T. Amos, Adam R. Renslo, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 12, 2003; E-mail: danheisr@mit.edu
Scheme 1
Activated imines which can function as reactive 2π components
in cycloadditions are valuable building blocks for the construction
of nitrogen heterocycles.1 In this communication we report on the
preparation and intramolecular Diels-Alder reactions of iminoac-
etonitriles, a class of electron-deficient imines2 whose cycloaddition
chemistry has not previously been examined.3 Our interest in this
class of imines derives from the expectation that they should
function as reactive partners in a variety of cycloaddition and
annulation processes, providing access to cyclic R-amino nitriles
of diverse ring size (Scheme 1). R-Amino nitriles are exceptionally
versatile intermediates for the synthesis of nitrogen heterocycles.4
Metalation provides opportunities for alkylation and other carbon-
carbon bond-forming processes, while exposure to Lewis acids
furnishes iminium ions which can be intercepted with Grignard
reagents (Bruylants reaction) and organosilanes, or engaged in
Mannich reactions and other useful “cation-π”-type cyclization
processes.
Table 1. Synthesis of Iminoacetonitriles
Previously, the synthesis of iminoacetonitriles has been achieved
by the chlorination of R-amino nitriles followed by elimination of
HCl with base.2 In our hands this approach indeed proved work-
able, but for the preparation of our cycloaddition substrates we
have developed a more expeditious route that begins with read-
ily available alcohols5 and employs a Mitsunobu coupling reac-
tion6 with the previously unknown, easily prepared reagent,
HN(Tf)CH2CN.7 Base-promoted elimination of trifluorometh-
anesulfinate8 then furnishes the desired iminoacetonitriles as a
mixture of E and Z isomers, both of which undergo cycloaddition
to afford the same product(s). As summarized in Table 1, this
protocol allows the efficient conversion of a variety of function-
alized alcohols to the desired cycloaddition substrates in excellent
overall yield.
Table 2 delineates the scope of the intramolecular iminoaceto-
nitrile hetero Diels-Alder reaction. Most cycloadditions proceed
smoothly at 85-120 °C in the presence of BHT (as radical
inhibitor), and the E- and Z-imines appear to react at similar rates.9,10
Interestingly, in most cases the cycloadduct with exo-oriented cyano
group is obtained as the major or exclusive product of the reaction.
Our observations suggest that the initially formed epimeric cy-
cloadducts equilibrate to afford the axial cyano isomer which is
favored as a consequence of the “R-amino nitrile anomeric effect.”11
The R-amino nitrile moieties incorporated in these cycloadducts
constitute latent iminium ions, which upon exposure to mild protic
or Lewis acids are unmasked, setting the stage for further useful
synthetic transformations. For example, reductive decyanation with
a 1.05 equiv HN(Tf)CH2CN, 1.2 equiv Ph3P, 1.2 equiv DEAD, 1:1 THF-
toluene, rt, 0.5-4 h (22 h for entry 2). b 3-4 equiv Cs2CO3, THF, 45-55
°C, 2-4 h. c Isolated yield of products purified by column chromatography.
d Enone 9 was converted to the dienol silyl ether (t-BuMe2SiCl, NaI, Et3N,
CH3CN, rt, 16 h, 96-97% yield) prior to elimination with Cs2CO3.
NaBH3CN excises the cyano group and furnishes unadorned
quinolizidines (e.g., 21) in excellent yield. Especially valuable is
the application of the Bruylants reaction for further carbon-carbon
bond construction, as illustrated with the conversion of cycloadduct
20 to the R-alkynylamine 22 (Scheme 2).
Of particular significance are the stereocomplementary trans-
with ethyl iodide followed by reductive decyanation furnishes
formations outlined in Scheme 3. Alkylation of the metalated nitrile
exclusively the endo-ethyl product 23, while Bruylants reaction with
9
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10.1021/ja034629o CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. [4 + 2] Cycloadditions of Iminoacetonitrilesa
The availability of substituted quinolizidines such as 23 and
24 via this strategy is noteworthy, since systems of this type are
not available via cycloadditions of iminium ions according to the
method of Grieco.12 Thus, while the formiminium ion deriva-
tive of amine 25 undergoes smooth cycloaddition in water at
65 °C (eq 1), analogous reaction of 25 with propanal fails to de-
liver any of the corresponding R-substituted product (R1
)
Et).13
Further studies on the application of iminoacetonitriles in organic
synthesis are underway and will be reported in due course.
Acknowledgment. We thank the National Institute of Health
(GM 28273), Pharmacia, and the Merck Research Laboratories for
generous financial support. D.T.A. was supported in part by NIH
Training Grant CA 09112.
Supporting Information Available: Experimental procedures and
characterization for key compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
a Cycloadditions were run in toluene (0.05 M) with 3 equiv of BHT in
a resealable threaded Pyrex tube at 120 °C for 15-36 h (CH3CN, reflux
for entry 2). b Isolated yield of products purified by column chromatography.
c Obtained as a 79:21 mixture of isomers at C-1.
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Scheme 2
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Scheme 3
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EtMgBr leads predominantly to the diastereomeric quinolizidine
24 via exo addition to the less sterically encumbered face of the
intermediate iminium ion.
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