A new entry to azomethine ylides from allylic amines and glyoxals: Shifting the reliance on amino ester precursors

Article abstract of DOI:10.1021/ol5022614

The first examples of azomethine ylides derived from allylic amine and glyoxal precursors are reported. The condensation of primary allylic and α-aryl amines with glyoxylates or α-aryl glyoxals affords conjugated azomethine ylides that undergo facile [3 +

Full text of DOI:10.1021/ol5022614

Letter
pubs.acs.org/OrgLett
A New Entry to Azomethine Ylides from Allylic Amines and Glyoxals:
Shifting the Reliance on Amino Ester Precursors
Natalie K. Machamer, Xiaoxi Liu, and Stephen P. Waters*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: The first examples of azomethine ylides derived from allylic
amine and glyoxal precursors are reported. The condensation of primary
allylic and α-aryl amines with glyoxylates or α-aryl glyoxals affords conjugated
azomethine ylides that undergo facile [3 + 2] cycloaddition, providing 5-
alkenyl pyrrolidine cycloadducts that cannot be accessed through the classical
use of amino esters as ylide precursors.
he early reports by Grigg1 and Hamelin2 on the
route circumventing these difficulties would therefore be
Tgeneration of ester-stabilized azomethine ylides by desirable.
Our research program is centered on new methodologies for
thermal 1,2-prototropy of α-iminoesters was a notable advance
in heterocyclic chemistry, as access to a variety of pyrrolidines
became available through 1,3-dipolar cycloaddition. Later,
Grigg’s important discovery of metalated azomethine ylides3
derived from aryl aldehydes and α-amino esters enabled
cycloadditions to occur at lower temperatures with enhanced
regio- and stereocontrol.4 Steady progress has been made in the
area since, including catalytic metal/base systems,5 stereo-
induction by chiral auxiliaries,6 and many asymmetric processes
via chiral Lewis acid complexes7 or organocatalysis.8
the formation of structurally advanced azomethine ylide
systems. We previously described a method for the synthesis
of azomethine ylides through the 2-aza-Cope rearrangement of
imines derived from homoallylic amines and glyoxylate esters,
which after [3 + 2] dipolar cycloaddition afforded multi-
substituted 2-allylpyrrolidine products.17 Drawing on this work,
we now report a method for ylide formation that circumvents
the reliance on α-amino esters as ylide precursors, thereby
providing access to new azomethine ylide systems unattainable
by classical methods (Scheme 2). It should be synthetically
feasible to condense an allylic amine (10) onto a α-dicarbonyl
compound such as a glyoxylate ester (11). The enhanced
electrophilicity of the aldehyde function would promote rapid
imine formation (13), thereby satisfying the first criterion for
azomethine ylide formation. Although glyoxylimine 13 is
isolable,18 a deprotonation event must occur at its allylic
carbon to generate the desired, ester-stabilized azomethine
ylide. Unfortunately, the pKa of the allylic protons, though not
unreasonably high, are beyond the reach of most organic bases.
However, if a catalytic, coordinating metal is present to
establish a chelate between the ester and imine moieties, the
acidity of the allylic protons may be reduced to an extent that
would permit deprotonation. A mild amine base would
therefore allow the formation of an azomethine ylide (4)
identical to that seemingly unattainable from acrolein. Dipolar
cycloaddition with a dipolarophile (5) would afford pyrrolidine
scaffolds (6) bearing an alkenyl moiety for further structural
advancement.
Despite these advances, a commonly overlooked drawback is
the almost exclusive reliance on α-amino esters as azomethine
ylide precursors. Instances remain in which the condensation of
a primary amino ester and an aliphatic aldehyde will not
produce the desired azomethine ylide. The condensation of
amino ester 2 (Scheme 1) with an aliphatic, α,β-unsaturated
aldehyde such as acrolein (1) could, in principle, yield a useful,
vinyl azomethine ylide (4) for the preparation of synthetically
versatile 5-alkenyl proline scaffolds (6). Such scaffolds have
been used for the synthesis of Pro-Pro dipeptide mimics,9 novel
pyrrolidine-derived influenza neuraminidase inhibitors,10 ana-
logues of the immunomodulatory macrolide ascomycin,11 and
peptidomimetics for the endocrine hormone thyroliberin.12
However, direct 1,2-addition of the amine onto acrolein is
complicated by competing 1,4-conjugate addition (cf. 7 and 8).
Indeed, the synthesis of aldimines from primary amines and
acrolein are generally not successful,13 primarily attributable to
1,4-additions and oligerimerization upon exposure to protic or
Lewis acids.14 Further, any acrolein present in the reaction
mixture could also compete as a dipolarophile (cf. 9).15 Though
desirable in some cases, it does not permit the general diversity
achievable by varying the dipolarophile. For these reasons,
examples of azomethine ylides derived from amino esters and
aliphatic, α,β-unsaturated aldehydes are not widespread,16
attributable to the difficulty of their preparation. A synthetic
Control experiments attempting to obtain ylide 4 through
classical methods (i.e., Scheme 1) confirmed that the reaction
of glycine methyl ester (2) with acrolein (1), silver acetate,
Received: July 30, 2014
Published: September 23, 2014
© 2014 American Chemical Society
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Letter
Scheme 1. Competing Processes with the Use of α-Amino Esters and α,β-Unsaturated Aldehydes toward Azomethine Ylides
a
Scheme 2. A Conceptually Different Strategy for Azomethine
Table 2. Substrate Survey of the Allylic Amine Component
Ylide Formation
Table 1. Optimization of Reaction Conditions for
a
Cycloadduct Formation
entry amine
base
14/15: 16:17
solvent
product yield (%)
1
2
3
4
5
6
7
8
9
14
15
14
15
15
15
15
14
15
Et3N
Et3N
DBU
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
2:2:1
2:2:1
PhMe
PhMe
PhMe
PhMe
THF
18
19
18
19
19
19
19
18
19
50
60
10
23
36
42
47
84
86
CH2Cl2
MeCN
MeCN
MeCN
a
Conditions for entries 1−7: amine 14 or 15 (1.0 equiv), 16 (1.0
equiv), 17 (1.0 equiv), Et3N or DBU (1.0 equiv), AgOAc (0.1 equiv),
solvent, rt, 24 h. Conditions for entries 8−9: amine 14 or 15 (2.0
equiv), 16 (2.0 equiv), 19 (1.0 equiv), Et3N (2.0 equiv), AgOAc (0.1
equiv), MeCN, rt, 24 h.
a
Reaction conditions: amine 21−25 (2 equiv), 16 (2 equiv), Et3N (2
equiv for 21−24), MeCN, 30 min; then 17 (1 equiv), AgOAc (0.1
equiv), Et3N (2 equiv), rt, 24 h.
Scheme 3. Origins of Stereoselectivity
that clean glyoxylimine formation between 14 and 16 was
achieved within 10 min. Encouragingly, stirring a 1:1:1 mixture
of 14, 16, and 17 in PhCH3 with Et3N (2 equiv) and catalytic
AgOAc (10 mol %) effected azomethine ylide formation and
cycloaddition within 24 h at rt, delivering 5-vinyl pyrrolidine 18
(Table 1, entry 1) in 50% yield as one diastereomer.
Benzylamine (15, Table 1, entry 2) was also investigated on
the basis that the benzylic proton of its glyoxylimine would be
sufficiently acidic through catalysis.19 Prior to our work,
azomethine ylides were generated via the imines of secondary
benzylic amines and glyoxylates under only thermal, proto-
tropic conditions.20
triethylamine, and phenyl maleimide led to no detectable
cycloadduct (6) and only a complex mixture. Therefore, the
feasibility of reaching ylide 4 through the logic outlined in
Scheme 2 was investigated. For our initial optimization studies,
allylamine (14), ethyl glyoxylate (16), and phenyl maleimide
(17) were selected as substrates. Control experiments revealed
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Table 3. Surveying the Dicarbonyl Substrate: Phenyl
Glyoxal
Table 4. Surveying the Dicarbonyl Substrate: Indole
Glyoxal
a
a
a
a
Reaction conditions: amine 14, 15, 21−23, 25 (2 equiv), 37 (2
equiv), Et3N (2 equiv for 21−23), 30 min; 17 (1 equiv), AgOAc (0.1
Reaction conditions: amine 14, 15, 21−23, 25 (2 equiv), 30 (2
equiv), Et3N (2 equiv for 21−23), MeCN, 30 min; 17 (1 equiv),
AgOAc (0.1 equiv), Et3N (2 equiv), rt, 24 h.
b
c
equiv), Et3N (2 equiv), rt, 24 h. In THF. In MeCN.
Employing DBU as the base (entries 4 and 5) led to a
noticeable decrease in yield through its unfavorable addition
reaction with phenyl maleimide. The use of THF or CH2Cl2 as
solvents led to slightly decreased yields (entries 5 and 6), while
MeCN (entry 7) promoted substrate solubility and a
comparable yield to PhCH3. In each case, the high levels of
stereocontrol were rationalized through two factors: (1) a
conformationally rigid, metal-coordinated W-shaped ylide in
which allylic 1,3-strain is minimized and (2) the endo approach
of the dipolarophile (Scheme 3).
Efforts to account for the mass balance in entries 1−7
revealed that a large portion (up to 43%) of the product was
being consumed in a subsequent process: conjugate addition of
the pyrrolidine nitrogen onto a second equivalent of phenyl
maleimide. To circumvent this problem, it was postulated that
increasing the ratio of glyoxylimine to dipolarophile from 1:1 to
2:1 would facilitate consumption of the dipolarophile through
cycloaddition before subsequent conjugate addition could
occur. Gratifyingly, employing this tactic greatly increased the
yield of the desired cycloadduct for both allyl and benzylamine,
providing 18 and 19 in yields of 84% (entry 8) and 86% (entry
9), respectively.
We next investigated the scope of the amine component. In
principle, amines bearing substituted π functions other than
allyl or benzyl might also serve as azomethine ylide precursors.
With the specific goal of studying the chemical reactivity of
substituted π and aryl functions within this component,
branched allylic systems such as crotyl (21, Table 2), isobutenyl
(22), prenyl (23), and cinnamylamine (24, 25) were subjected
to our optimized conditions with ethyl glyoxylate as the
electrophile. Such π systems were expected to facilitate
azomethine ylide formation upon metal coordination in similar
fashion to 14. For convenience, amines 21−24 were used as
their hydrochloride salts21 and liberated in situ prior to
condensation with 16. Each underwent facile azomethine ylide
formation and cycloaddition to provide cycloadducts 26−29 in
good to excellent yields as one diastereomer (Table 2), whose
configuration was determined by 1D-NOE studies as described
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in our previous work.17a Whether the free base or the HCl-
salted amine was used appeared to have no impact on the
overall yield (compare entries 4 and 5).
(b) Thianpatunagul, S.; Sridharan, V.; Grigg, R. J. Chem. Soc., Perkin
Trans. 1 1986, 1669−1675.
(4) Barr, D. A.; Grigg, R.; Sridharan, V. Tetrahedron Lett. 1989, 30,
4727−4730.
Recognizing the value of accessing pyrrolidines not easily
prepared through classical protocols, we viewed our findings as
an underdeveloped method for ylide formation and set out to
investigate the scope of the electrophile. Based on our success
with ethyl glyoxylate, we hypothesized that additional α-
dicarbonyl systems such as arylglyoxaldehydes and heteroaryl-
glyoxaldehydes, each bearing functional groups available for
both imine condensation and metal coordination, should meet
the criteria for azomethine ylide formation and react
accordingly. Phenyl glyoxal (30, Table 3) was first selected,
and gratifyingly, its ability to furnish azomethine ylides upon
condensation with amines 14, 15, 21−23, and 25 was
successfully demonstrated. Good to excellent yields were
obtained for allylic, substituted allylic, α-aryl, and conjugated
α-aryl systems, each delivering the corresponding cycloadducts
(31−36) as one observable diastereomer.
Indole glyoxal (37, Table 4) was next investigated as our
specific interest in this electrophile centers on its anticipated
utility in alkaloid total synthesis.22 In either MeCN or THF,
good to excellent yields were again achieved for all entries.
In summary, we present the first examples of azomethine
ylides from allylic amine and glyoxylate or glyoxal precursors,
thereby expanding the methods through which these important
ylide intermediates may be prepared. It is also important to
emphasize that because the corresponding cycloadducts are not
readily obtained through the classical method of generating
azomethine ylides from α-amino ester precursors, the scope of
pyrrolidine scaffolds obtainable through dipolar cycloaddition is
also expanded.23 Efforts toward catalytic, asymmetric variants
and applications in alkaloid total synthesis are currently
underway.
(5) Grigg, R.; Sridharan, V. In Advances in Cycloaddition; Curran, D.
P., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 3, p 161.
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(7) For selected, recent examples, see: (a) Yamashita, Y.; Imaizumi,
T.; Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50, 4893−4896.
(b) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.; Deng, W.-
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(8) Recent reports: (a) Liu, Y.-K.; Liu, H.; Du, W.; Yue, L.; Chen, Y.-
C. Chem.Eur. J. 2008, 14, 9873−9877. (b) Chen, X.-H.; Zhang, W.-
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(9) Zaminer, J.; Brockmann, C.; Huy, P.; Opitz, R.; Reuter, C.;
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Bioorg. Med. Chem. Lett. 2008, 18, 1692−1695.
(11) Bulusu, M.; Waldstatten, P.; Tricotet, T.; Rochais, C.; Steck, A.;
̈
Bacher, M. Tetrahedron Lett. 2004, 45, 5833−5836.
(12) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron 2000,
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(13) Kitayama, T.; Hall, H. K. Macromolecules 1987, 20, 1451−1415.
(14) Hall, H. K. Makromol. Chem.-M. Symp. 1992, 54/55, 73−81.
(15) Gu, Y. G.; Xu, Y.; Krueger, A. C.; Madigan, D.; Sham, H. L.
Tetrahedron Lett. 2002, 43, 955−957.
(16) For a limited example, see: Cheng, M.-N.; Wang, H.; Gong, L.-
Z. Org. Lett. 2011, 13, 2418−2421.
(17) (a) McCormack, M. P.; Shalumova, T.; Tanski, J. M.; Waters, S.
P. Org. Lett. 2010, 12, 3906−3909. (b) McCormack, M. P.; Waters, S.
P. J. Org. Chem. 2013, 78, 1176−1183. (c) Liu, X.; McCormack, M. P.;
Waters, S. P. Org. Lett. 2012, 14, 5574−5577.
(18) (a) De Lamo Marin, S.; Catala, C.; Kumar, S. R.; Valleix, A.;
Wagner, A.; Mioskowski, C. Eur. J. Org. Chem. 2010, 21, 3985−3989.
(b) Barluenga, J.; Mateos, C.; Aznar, F.; Valdez, C. J. Org. Chem. 2004,
69, 7114−7122.
(19) Processes taking advantage of this effect for benzylic amines
have only recently emerged: (a) Tian, L.; Hu, X.-Q.; Li, Y.-H.; Xu, P.-
F. Chem. Commun. 2013, 9, 7213−7215. (b) Guo, C.; Song, J.; Gong,
L.-Z. Org. Lett. 2013, 15, 2676−2679.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(20) (a) Ardill, H.; Fontaine, X. L. R.; Grigg, R.; Henderson, D.;
Montgomery, J. Tetrahedron 1990, 46, 6449−6466. (b) Grigg, R.;
Rankovic, Z.; Thornton-Pett, M.; Somasunderam, A. Tetrahedron
1993, 49, 8679−8690.
*E-mail: Stephen.Waters@uvm.edu.
Notes
(21) Wiecek, M.; Kottke, T.; Ligneau, X.; Schunack, W.; Seifert, R.;
Stark, H.; Handzlik, J.; Kiec-Kononowicz, K. Bioorg. Med. Chem. 2011,
19, 2850−2858.
The authors declare no competing financial interest.
(22) See, for example, the pyrrolidine-containing indole alkaloid
ACKNOWLEDGMENTS
■
borrecapine: Jossang, A.; Pousset, J. L.; Jacquemin, H.; Cave,
́
A.
This work was supported by the Vermont Genetics Network
and Grant Number 8P20GM103449 from the INBRE Program
of the National Institute of General Medical Sciences
(NIGMS), a component of the National Institutes of Health
(NIH). We thank Mr. Bruce O’Rourke and Dr. Ying Wai Lam
at UVM for assistance in obtaining and mass spectral data.
Tetrahedron Lett. 1977, 18, 4317−4318.
(23) To demonstrate the amenability of this process to multigram
synthesis, a scaled-up reaction of 14 (60 mmol), 16 (60 mmol), and
17 (30 mmol) delivered 6.13 g (65% yield) of pyrrolidine 18 after
purification by column chromatography.
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