Design, synthesis, and reactivity of 1-hydrazinodienes for use in organic synthesis

Article abstract of DOI:10.1021/ja052383c

A new 1-hydrazinodiene (1) has been developed and utilized in Lewis acid catalyzed, intermolecular Diels-Alder reactions with various electron-deficient alkenes. The hydrazine can then be deprotected, and a molecule of methanesulfinic acid is eliminated t

Full text of DOI:10.1021/ja052383c

Published on Web 05/25/2005
Design, Synthesis, and Reactivity of 1-Hydrazinodienes for Use in Organic
Synthesis
Glenn M. Sammis, Eric M. Flamme, Hao Xie, Douglas M. Ho, and Erik J. Sorensen*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544-1009
Received April 12, 2005; E-mail: ejs@princeton.edu
Since its initial report in 1928,1 the Diels-Alder reaction has
Scheme 2. Synthesis of 1-Hydrazinodiene 7
provided the foundation for some of the most impressive achieve-
ments in the area of natural product synthesis, and much is known
about the factors controlling the regioselectivities and stereochem-
ical outcomes of inter- and intramolecular [4+2] cycloadditions.2
Our laboratory was inspired to contribute a new modification to
this well-studied process when we encountered the general structural
type 5 in the course of a natural product synthesis (Scheme 1). In
would also significantly retard the reactivity of 7 as a diene in
Scheme 1. A New Type of Hydrazine-Substituted Diene for Use
Diels-Alder reactions. The donor capacity of the diene nitrogen
atom is, in fact, significantly tempered by the electron-withdrawing
methanesulfonyl and imide groupings. Under strictly thermal
conditions, compound 7 did not undergo cycloaddition with our
model dienophile methacrolein. However, in the presence of a Lewis
acid, such as scandium(III) triflate or diethylaluminum chloride,
hydrazinodiene 7 reacted cleanly with methacrolein to provide
cycloadduct 8 (Scheme 3).
in Organic Synthesis
Scheme 3. [4+2] Cycloaddition of 1-Hydrazinodiene 7 to
Methacrolein and Subsequent 1,5-Sigmatropic Rearrangement
principle, this compound could originate from the Diels-Alder
reaction of a 1-hydrazinodiene 1 and a suitable dienophile 2 to form
cycloadduct 3. In a subsequent step, liberation of a primary amino
group through cleavage of the two nitrogen-bound protecting groups
might then trigger loss of methanesulfinic acid to provide allylic
diazene 4. Several impressive literature examples demonstrate that
allylic diazenes undergo smooth, suprafacial 1,5-sigmatropic rear-
rangements of hydrogen with loss of dinitrogen in diverse molecular
contexts.3 Allylic diazene 4 is expected to undergo the desired
nitrogen extrusion reaction with alkene transposition. A useful
aspect of this rearrangement step is that a six-membered ring
possessing a 1,2-stereochemical relationship may be stereospecifi-
cally transformed into a six-membered ring having a 1,4-stereore-
lationship.
Nitrogen-substituted 1,3-butadienes are useful, reactive species
that often exhibit excellent behavior in normal electron-demand
Diels-Alder reactions.4 However, 1-hydrazinodienes of the type
1 have not, to the best of our knowledge, been reported in the
literature. Our synthesis of diene 7 commenced with hydrazone 6,
the product of a simple condensation between 3-methyl-2-butenal
and monoallyloxycarbonyl (Alloc) hydrazine5 (Scheme 2). Intro-
duction of the second Alloc group, followed by nitrogen sulfon-
ylation with in situ diene formation, provided exclusively (E)-
hydrazinodiene 7 in excellent yield.6
Having shown that 1-hydrazinodiene 7 is capable of undergoing
Diels-Alder reactions, we turned to the second key transforma-
tion: the suprafacial, allylic diazene rearrangement. Removal of
the Alloc groups from cycloadduct 87 resulted in the formation of
heterocycle 9. This finding necessitated an initial protection of the
aldehyde in the form of a 1,3-dioxolane acetal 10. When the
necessary Alloc cleavage8 was performed in the context of
compound 10, hydrazine 11 could be isolated as a stable white
solid.9 In the presence of tetrabutylammonium acetate at 40 °C,
compound 11 smoothly rearranged to cyclohexene 12 in excellent
yield.
At the outset of this project, we were concerned that the types
of groups that might enable an eventual allylic diazene formation
9
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J. AM. CHEM. SOC. 2005, 127, 8612-8613
10.1021/ja052383c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Synthesis of trans-Fused Decalin 16
Table 1. Dienophile Scope for the Diels-Alder/1,5-Sigmatropic
Rearrangement Process
stereoselectivity. Conversion of aldehyde 15 to a dioxolane,
followed by one-pot deprotection and rearrangement, yields the
desired decalin 16 in excellent yield.
In summary, we developed a new type of 1,3-diene that
undergoes efficient Diels-Alder reactions with a range of electron-
deficient alkenes and enables a subsequent reductive transposition
of the initial [4+2] cycloadduct. The suprafacial nature of the latter
transformation enables a 1,3-transfer of stereochemistry to a new
position on the six-membered ring system. We anticipate that this
chemistry could provide an alternative way of perceiving and uti-
lizing the Diels-Alder reaction in the planning and execution of
organic syntheses. Efforts to expand the family of 1-hydrazinodi-
enes, achieve enantioselective cycloadditions, and evaluate the reac-
tivities of these compounds with heterodienophiles are underway.
Acknowledgment. This work was supported by Princeton
University, Bristol-Myers Squibb, Merck, and by postdoctoral
fellowships from the National Institutes of Health to G.M.S. (GM-
072230) and E.M.F. (GM-070268). We would also like to thank
Mr. Jeewoo Lim for the scale-up of the starting materials.
Supporting Information Available: Complete experimental pro-
cedures and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Standard reaction conditions: 1-hydrazinodiene 7 (0.5 mmol), Sc(OTf)3,
3 equiv of dienophile, 150 mg/mmol 4 Å MS, 0.2 M CH2Cl2. b The
References
1
diastereomeric ratio was determined by H NMR. c Isolated yields of the
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(3) For representative examples, see: (a) Hutchins, R. O.; Kacher, M.; Rua,
L. J. Org. Chem. 1975, 40, 923-926. (b) Kabalka, G. W.; Yang, D. T.
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Am. Chem. Soc. 1992, 114, 5898-5900. (e) Myers, A. G.; Zheng, B.
Tetrahedron Lett. 1996, 37, 4841-4844.
(4) (a) Overman, L. E.; Freerks, R. L.; Petty, C. B.; Clizbe, L. A.; Ono, R.
K.; Taylor, G. F.; Jessup, P. J. J. Am. Chem. Soc. 1981, 103, 2816-
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5252-5253.
(5) Mono-Alloc hydrazine was synthesized in two steps from tert-butyl
carbazate. See the Supporting Information for details.
major isomer. d Diethylaluminum chloride catalyzed reaction: 20 mol %
Et2AlCl, 2 equiv of dienophile, 0.2 M toluene. e Isolated yield of both
diastereomers. f Isolated yield after three steps (dioxolane formation, Alloc
deprotection, and Bu4NOAc mediated elimination/diazene rearrangement).
g Isolated yield after two steps (Alloc deprotection and NaOAc mediated
elimination/diazene rearrangement).
The Diels-Alder reaction with 1-hydrazinodiene 7 and the
subsequent rearrangement proved to be successful with a wide range
of substituted aldehydes, including a number of â-substituted
aldehydes (2b-2d) (Table 1). Simple ketones, such as methyl vinyl
ketone (2f), were also excellent substrates for the Diels-Alder
reaction. Reactions with R-substituted dienophiles, such as meth-
acrolein, gave endo cycloadducts,10 while all R-unsubstituted
dienophiles gave exo products.11,12 Although simple R,â-unsaturated
esters employed in this process were not effective dienophiles,
doubly activated dienophiles, such as diethyl maleate (2g) and
diethyl fumarate (2h), were successfully activated with scandium-
(III) triflate. The observation that the products of the reactions of
diene 7 with maleate 2g and fumarate 2h (13a and 13b) are
diastereoisomers suggests that these cycloadditions are concerted,
stereospecific processes. Regardless of the substitution pattern, all
of the Diels-Alder adducts underwent smooth deprotection and
rearrangement to the desired olefins.13
(6) Hydrazinodiene 7 can be stored, in pure form, for extended periods of
time at temperatures <0 °C.
(7) For a review, see: Guibe´, F. Tetrahedron 1998, 54, 2967-3042.
(8) Geneˆt, J. P.; Blart, E.; Savignac, M.; Lemeune, S.; Lemaire-Audoire, S.;
Bernard, J. M. Synlett 1993, 680-682.
(9) Sulfonylhydrazine 11 was stable to elimination, even when subjected to
flash chromatography.
(10) The relative stereochemistry was determined from nOe experiments on
heterocycle 9a. See Supporting Information for experimental details.
(11) The relative stereochemistry was determined via an X-ray crystallographic
analysis of 8d.
The chemistry of 1-hydrazinodienes also provides efficient access
to constitutionally and stereochemically complex decalin architec-
tures, such as 16 (Scheme 4). A diethylaluminum chloride catalyzed
Diels-Alder reaction between 1-hydrazinodiene 14 and methac-
rolein (2a) yields cycloadduct 15 in good yield with excellent
(12) We are currently investigating the nature of the diastereoselectivity for
1-hydrazinodienes in Diels-Alder reactions.
(13) Cycloadducts 8g and 8h did not require protection of the esters prior to
Alloc deprotection.
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