Synthesis and reactivity of unsymmetrical azomethine imines formed using alkene aminocarbonylation

Article abstract of DOI:10.1021/ol400542b

Complex cyclic azomethine imines possessing a β-aminocarbonyl motif can be accessed readily from simple alkenes and hydrazones. This alkene aminocarbonylation approach allows formation of ketone-derived azomethine imines of unprecedented complexity. Since unsymmetrical hydrazones are used, two stereoisomers are formed: the reactivity of chiral derivatives is explored in both intra- and intermolecular systems.

Full text of DOI:10.1021/ol400542b

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis and Reactivity of
Unsymmetrical Azomethine
Imines Formed Using Alkene
Aminocarbonylation
Wei Gan, Patrick J. Moon, Christian Clavette, Nicolas Das Neves,
ꢀ
Thomas Markiewicz, Amy B. Toderian, and Andre M. Beauchemin*
Center for Catalysis Research and Innovation, Department of Chemistry,
University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
andre.beauchemin@uottawa.ca
Received February 27, 2013
ABSTRACT
Complex cyclic azomethine imines possessing a β-aminocarbonyl motif can be accessed readily from simple alkenes and hydrazones. This
alkene aminocarbonylation approach allows formation of ketone-derived azomethine imines of unprecedented complexity. Since unsymmetrical
hydrazones are used, two stereoisomers are formed: the reactivity of chiral derivatives is explored in both intra- and intermolecular systems.
Azomethine imines are valuable intermediates in syn-
thetic organic chemistry.1 In addition to being useful 1,3-
dipoles in cycloadditions and rearrangements, azomethine
imines are versatile electrophiles.2 Several stereoselective
reactions have recently emerged, providing access to both
enantioenriched azomethine imines via kinetic resolution
and to useful adducts via asymmetric synthesis.2cꢀi,3 Most
of these recent developments have featured cyclic dipoles
accessed from aldehydes and pyrazolidinones,4 likely
due to their convenient preparation and to the bioactivity
of the products formed.2b However, the condensation
approach used to access such azomethine imines is challeng-
ing with ketones, and consequently the reactivity of these
derivatives has rarely been studied.1 Herein, we report a
simple route to such azomethine imines using an alkene
aminocarbonylation approach and perform stereoselective
reactions using these complex derivatives.
Recently, we reported an alkene aminocarbonylation
reactivity in which symmetrical hydrazones react with
alkenes upon heating to afford azomethine imines posses-
sing a β-aminocarbonyl motif.5 This study focused on the
reactivity of a fluorenone-derived hydrazone, which allows
high reactivity with several alkene classes and subsequent
(1) For reviews, see: (a) Struckwisch, C. G. Synthesis 1973, 469.
(b) Rodina, L. L.; Kolberg, A.; Schulze, B. Heterocycles 1998, 49, 587.
(c) Schantl, J. G. in Science of Synthesis; Padwa, A.; Bellus, D., Eds.;
Thieme Verlag: Stuttgart, 2004; Vol. 27, pp731ꢀ824.
(2) For a review on cycloadditions, see: (a) Oppolzer, W. Angew.
Chem., Int. Ed. Engl. 1977, 16, 10. For recent examples, see: (b) Na, R.;
Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez,
D.; Tkatchouk, E.; Goddard, W. A., III; Guo, H.; Kwon, O. J. Am.
Chem. Soc. 2011, 133, 13337. (c) Hashimoto, T.; Kimura, H.; Kawamata,
Y.; Maruoka, K. Nat. Chem. 2011, 3, 642. (d) Shintani, R.; Fu, G. C.
J. Am. Chem. Soc. 2003, 125, 10778. (e) Shintani, R.; Hayashi, T. J. Am.
Chem. Soc. 2006, 128, 6330. (f) Chan, A.; Scheidt, K. A. J. Am. Chem.
Soc. 2007, 129, 5334. (g) Shintani, R.; Murakami, M.; Hayashi, T. J. Am.
Chem. Soc. 2007, 129, 12356. (h) Perreault, C.; Goudreau, S. R.; Zimmer,
L. E.; Charette, A. B. Org. Lett. 2008, 10, 689. (i) Shapiro, N. D.; Shi, Y.;
Toste, F. D. J. Am. Chem. Soc. 2009, 131, 11654.
ꢀ
(3) For recent examples, see: (a) Suarez, A.; Downey, C. W.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 11244. (b) Chen, W.; Yuan, X.-H.; Li,
R.; Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal. 2006,
348, 1818. (c) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97.
(d) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2007, 46, 7667. (e) Sibi, M. P.; Rane, D.; Stanley,
L. M.; Soeta, T. Org. Lett. 2008, 10, 2971. (f) Hashimoto, T.; Maeda, Y.;
Omote, M.; Nakatsu, H.; Maruoka, K. J. Am. Chem. Soc. 2010, 132,
4076.
(4) Godteredsen, W. O.; Vangedal, S. Acta Chem. Scand. 1955, 9,
1498Usually an aldehyde (or a derivative): see reviews in ref 1.
(5) (a) Clavette, C.; Gan, W.; Bongers, A.; Markiewicz, T.; Toderian,
A.; Gorelsky, S. I.; Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134,
16111. See also: (b) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Whipp,
C. J.; Gorelsky, S. I.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131,
8740. (c) Jones, D. W. J. Chem. Soc., Chem. Commun. 1982, 766.
r
10.1021/ol400542b
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derivatization of the crystalline azomethine imines adducts
into β-amino amides, esters, and acids. Since only one
unsymmetrical hydrazone was used, the applicability of
this approach to access complex azomethine imines
via unsymmetrical imino isocyanates was not established.
We thus performed a systematic study of the alkene
aminocarbonylation reactivity with both aldehydes and
unsymmetrical ketones.
hydrazone 3a is present mostly as the E stereoisomer
(E:Z ratio = 3.6:1).
Table 1. Scope of Alkene Aminocarbonylation Using Aldehyde-
Derived Hydrazonesa
The alkene aminocarbonylation reaction of aldehyde-
derived hydrazones is particularly challenging, as the
azomethine imine adducts can further react in a [3 þ 2]
cycloaddition with the alkene present.6 For example, the
use of more forcing conditions or more stable hydrazones
(e.g., O-t-Bu rather than OPh) initially led to such double
addition products. Fortunately, the use of more reactive
hydrazones (e.g., OPh as leaving group) improved the
aminocarbonylation reactivity and under optimized con-
ditions aldehyde-derived hydrazones provide the desired
azomethine imines in modest to good yields (Table 1). This
reactivity is applicable to form various aromatic (entries
3ꢀ8, 12ꢀ15) and heteroaromatic dipoles (entries 1ꢀ2,
9ꢀ11). In all cases, only one stereoisomer was observed.
This reactivity proved superior with reactive alkenes such
as norbornene (entries 1ꢀ8) and dihydrofuran (entries
8ꢀ15). Exploratory trials with aliphatic aldehydes and
less reactive alkenes also allowed dipole formation, but
typically in lower yields.
Nevertheless, hydrazones derived from aliphatic alde-
hydes can be effective when the azomethine imine can
perform a subsequent [3 þ 2] cycloaddition (eq 1). The
preference for an intermolecular over an intramolecular
aminocarbonylation event in eq 1 is noteworthy. In con-
trast to 3a,7 methylketone 3b performed an intramolecular
aminocarbonylation in the absence of norbornene
(eq 2). The stereochemical outcome of eq 1 also suggests
that isomerization occurred under the reaction con-
ditions, since product 4a can only be formed from the
Z isomer of the azomethine imine. Thus, isomeriza-
tion must occur under the reaction conditions since
a Conditions: hydrazone (1 equiv), alkene (1.2ꢀ10 equiv, see above)
in PhCF3 (0.05 M) heated in a sealed vial (microwave reactor, 130 °C,
1ꢀ3 h). Typical scale: 0.2 mmol of 1aꢀn. b The identity of the major
stereoisomer was secured by NOE experiments on 2a. Stereochemistry
of other dipoles was assigned by analogy. c 120 °C. d NMR yield. e 150 °C.
f 140 °C.
(6) Such “criss-cross” reactivity has been observed with azines. For
examples, see: (a) Burger, K.; Thenn, W.; Gieren, A. Angew. Chem., Int.
Ed. 1974, 13, 474. (b) Burger, K.; Thenn, W.; Rauh, R.; Schickaneder,
H.; Gieren, A. Chem. Ber 1975, 108, 1460.
(7) Heating in the absence of C7H10 did not afford the desired dipole,
but a 35% unoptimized yield of a dimer in which the dipole reacted in a
[3 þ 2] with an equivalent of the imino isocyanate.
We then surveyed the use of hydrazones derived from
unsymmetrical ketones to form complex azomethine
imines (Table 2). To allow comparison, the reactivity was
surveyed using norbornene as the substrate and using
hydrazones prone to formation of the imino isocyanate
B
Org. Lett., Vol. XX, No. XX, XXXX

(OPh as leaving group). We observed two differences using
these reagents: (1) stereoisomeric mixtures were typically
obtained; (2) higher yields were isolated suggesting that the
[3 þ 2] cycloaddition side reaction is more difficult with
these more hindered dipoles.5a
As shown in Table 2 the aminocarbonylation reactivity
occurs with a variety of unsymmetrical ketones. Both acyclic
(entries 1ꢀ9) and cyclic hydrazones (entries 10ꢀ13) react
efficiently, and alkyl (entries 7ꢀ8), aryl (entries 1ꢀ2),
heteroaryl (entries 3ꢀ5, 9), and alkenyl (entries 6 and 12)
substituents are tolerated. This reactivity is not limited to
norbornene: encouraging reactivity using other alkene
classes also provided the desired azomethine imines under
similar conditions (entries 11, 14ꢀ16). Several dipoles
shown in this table were targeted to show the complemen-
tary of this reactivity with the condensation of ketones
and pyrazolidinones,4 which would be challenging on
hindered ketones (entries 7 and 13) or could result in
1,4-addition with enones (entries 6 and 12). To demon-
strate the robustness of this methodology, entry 3 was also
performed on a 5-g scale: a 94% yield was obtained and
the two stereoisomeric dipoles were separated using silica
gel chromatography. The ability to separate these stereo-
isomers allowed us to study their interconversion and
reactivity.
Table 2. Scope of Alkene Aminocarbonylation Using Ketone-
Derived Hydrazonesa
As indicated above, there are very few examples of un-
symmetrical azomethine imines in the literature.8 Seeking
to determine if the isomeric mixtures obtained in Table 2
were the result of thermodynamic equilibration or were
dependent on the stereoisomeric ratio of the imino iso-
cyanate, we subjected each stereoisomer to the reaction
conditions (heating in the presence of the leaving group
released under the reaction conditions, Scheme 1).
Scheme 1. Equilibration Studies on Z and E Azomethine Imines
The results in Scheme 1 show the importance of the
leaving group (released during iminoisocyanate formation)
on the stereochemical outcome of the reactions. Encoura-
gingly, the use of thiophenol as an additive favored the Z
stereoisomer. In contrast, the absence of an additive or the
presence of phenol appeared to induce an equilibrium
toward a ca. 3:1 stereoisomeric mixture (likely due to the
increased ability of E-6c to engage in hydrogen bonding
due to the anti orientation of the electron-rich furan ring
system relative to the Lewis basic part of the dipole9).
a Conditions: hydrazone (1 equiv), alkene (10 equiv) in PhCF3
(0.05 M) heated in a sealed vial (microwave reactor, 130 °C, 1ꢀ3 h).
Typical scale: 0.2 mmol of 5aꢀm. b The identity of the major stereo-
isomer was secured by NOE experiments on 6c, 6f, 6l, and 6k and by
X-ray crystallographic analysis of 6c. Stereochemistry of other dipoles
was assigned by analogy. c 5 equiv of norbornene was used. d O-t-Bu
substituted hydrazone was used at 150 °C.
(8) (a) Taylor, E. C.; Haley, N. F.; Clemens, R. J. Am. Chem. Soc.
1981, 103, 7743. (b) Taylor, E. C.; Clemens, R. J.; Davies, H. M. L.
J. Org. Chem. 1983, 48, 4567. (c) Tomaschewski, G.; Geissler, G.;
ꢀ
Schauer, G. J. Prakt. Chem. 1980, 322, 623. (d) Panfil, I.; Urbanczyk-
ꢀ
Lipkowska, Z.; Suwinska, K.; Solecka, J.; Chmielewski, M. Tetrahedron
2002, 58, 1199. See reference 8c.
Org. Lett., Vol. XX, No. XX, XXXX
C

Importantly, these results clearly highlight the importance
of additives under the reaction conditions and provide the
opportunity to access unsymmetrical azomethine imines
with high stereocontrol, as illustrated by the use of a
modified aminocarbonylation reagent (eq 3).
In summary, we have shown that a variety of unsymme-
trical hydrazones react with alkenes to form complex
azomethine imines. Intra- and intermolecular variants of
this reactivity were reported. This alkene aminocarbonyla-
tion reactivity provides a versatile approach to complex
dipoles, and conditions allowing for equilibration and
high stereocontrol in the synthesis of unsymmetrical
azomethine imines were identified. Further development
and applications of this reactivity in target oriented synth-
esis will be reported in due course.
Acknowledgment. We thank the University of Ottawa,
NSERC (Discovery Grant, Discovery Accelerator Supple-
ment, CRD and CREATE grants to A.M.B.; USRA to
P.J.M.), the Canadian Foundation for Innovation, and
the Ontario Ministry of Research and Innovation for
generous financial support. Support of this work by
AstraZeneca Canada, GreenCentre Canada, and Omega-
Chem is also gratefully acknowledged. C.C. is thankful
to NSERC (CREATE on medicinal chemistry and bio-
pharmaceutical development) and OGS for scholar-
ships. W.G. thanks the University of Ottawa (Vision
2020 Postdoctoral fellowship). We also thank Dr. Ilia
Korobkov (University of Ottawa) for X-ray crystallo-
graphic analyses.
Conditions allowing for high stereocontrol during the
formation of unsymmetrical azomethine imines allow the
use of these complex dipoles in stereoselective synthesis.
We thus explored nucleophilic additions to aldehyde and
ketone-derived azomethine imines (2c and 6c respectively,
eq4) and werepleasedtoobserve high diastereoselectivities
for the formation of adducts 7a and 7b.10
Supporting Information Available. Complete experi-
mental procedures, characterization data, X-ray crystal
structures (4a, 6c), and NMR spectra. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(9) In the crystal structure of Z-6c the furyl ring system is conjugated
with the azomethine imine. Similarly, in E-6c the furyl ring system could be
conjugated to increase the electron density of the amide portion of the
dipole, thus increasing its ability to act as H-bond acceptor relative to Z-6c.
Arguably, such H-bonding would result in increased stabilization of a
dipole that should otherwise be quite disfavored sterically. Additional
experiments to probe the generality of this observation and to provide
additional insight on the effect of additives will be reported in due course.
(10) For precedence on a diastereoselective addition to an aldehyde-
derived azomethine imine see ref 3a.
The authors declare no competing financial interest.
D
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