Lewis acid promoted hetero [2 + 2] cycloaddition reactions of aldehydes with 10-propynyl-9(10h)-acridone. A highly stereoselective synthesis of acrylic acid derivatives and 1,3-dienes using an electron deficient variant of ynamine

Article abstract of DOI:10.1021/ol990211c

(matrix presented) Reactivities of 10-propynyl-9(10H)-acridone toward various aldehydes in BF₃·Et₂0-promoted hetero [2 + 2] cycloaddition reactions are described here. This electron deficient variant of ynamine is more stable and eas

Full text of DOI:10.1021/ol990211c

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1237-1240
Lewis Acid Promoted Hetero [2 + 2]
Cycloaddition Reactions of Aldehydes
with 10-Propynyl-9(10H)-acridone. A
Highly Stereoselective Synthesis of
Acrylic Acid Derivatives and 1,3-Dienes
Using an Electron Deficient Variant of
Ynamine
Richard P. Hsung,* Craig A. Zificsak, Lin-Li Wei, Christopher J. Douglas,1
Hui Xiong, and Jason A. Mulder
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received August 4, 1999
ABSTRACT
Reactivities of 10-propynyl-9(10H)-acridone toward various aldehydes in BF3‚Et2O-promoted hetero [2 + 2] cycloaddition reactions are described
here. This electron deficient variant of ynamine is more stable and easier to handle than most ynamines but possesses comparable reactivity.
These reactions lead to a highly stereoselective synthesis of trisubstituted alkenes. A mechanistic model based on the stereochemical assignment
is also described here. 10-Propynyl-9(10H)-acridone is also reactive toward r,â-unsaturated aldehydes and ketones. It provides hetero [2 +
2] products in reactions with r,â-unsaturated aldehydes but gives only the inverse demand [4 + 2] cycloadduct in a reaction with methyl vinyl
ketone.
The synthetic significance of ynamines (A) in organic
chemistry was firmly established by the work of many
organic chemists more than 15 years ago.2 However, since
then there has been significantly less synthetic chemistry
using ynamines, and it has become an area largely ignored
by synthetic chemists.2b,3 This lack of attention could be
attributed to the difficulty in the preparation and handling
of ynamines because of their high reactivity and sensitivity
toward hydrolysis. Although ynol ethers (B, Figure 1) are
relatively more stable, they are less reactive than ynamines,
owing to the greater electronegativity of oxygen. Because
(1) UMN Undergraduate Research Participant: 1998-1999. The recipient
of 1998 Pharmacia-Upjohn and UMN Department of Chemistry Lando/
NSF Program for Summer Research Fellowship.
(2) For reviews on chemistry of ynamines, see: (a) Ficini, J. Tetrahedron
1976, 32, 1448. (b) Himbert, G. Methoden Der Organischen Chemie
(Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg Thieme Verlag:
Stuttgart, 1993; pp 3267-3443.
Figure 1.
10.1021/ol990211c CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/18/1999

of our interest in heteroatom-substituted allenes4 and alkynes,
and in developing methodologies for synthesis of hetero-
cycles,5 we have been exploring the synthesis and reactivity
of a class of ynamines that may combine the stability of ynol
ethers with the reactivity of ynamines.
Table 1
Specifically, this class includes electron deficient ynamines
or ynamides (C) in which the nitrogen atom is substituted
with an electron-withdrawing group. Reactivities of ynamides
are almost unknown,3a,c although preparations and thermal
stabilities of ynamides have been documented.6,7 We report
here the first reactivity study of an electron deficient ynamine
toward aldehydes in hetero [2 + 2] cycloaddition reactions.
As shown in Scheme 1, hetero [2 + 2] cycloaddition
reactions of the ynamide 1 with aldehydes could lead to an
Scheme 1
stereoselective manner. We elected to examine this reaction
using the known electron deficient ynamine 4 which is a
vinylogous ynamide.9 Given the synthetic availability of 4
and its ease of handling [a stable crystalline solid],10 it serves
as an excellent model system for exploring reactivities of
electron deficient ynamines.
As shown in Table 1, the ynamide 4 was very reactive
toward an array of aldehydes under Lewis acidic conditions
to provide trisubstituted alkenes 5-1212- in high yields as
well as high E selectivities. These reactions were carried out
in the presence of either 0.1 or 0.25 equiv of BF3‚Et2O and
proceeded with equal efficiency as well as stereoselectivity
at -78 °C or room temperature. Dichloromethane was the
better solvent from a solubility perspective, but toluene was
a good solvent despite the reaction mixture being heteroge-
neous.
oxetene intermediate (2) that would undergo an electrocyclic
ring opening to give alkene 3.2,8 In addition, if such a reaction
can be rendered feasible with R,â-unsaturated aldehydes, then
dienes (also shown as 3) may also be prepared in a
(3) For recent examples, see: (a) Imbriglio, J.; Rainier, J. Abstracts of
Papers, 217th National Meeting of the American Chemical Society,
Anaheim, CA, Spring 1999; American Chemical Society: Washington, DC,
1999; ORGN-502. (b) Bernstein, R.; Foote, C. S. Tetrahedron Lett. 1998,
7051. (c) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. Engl. 1998, 37,
489. (d) Bloxham, J.; Dell, C. P. J. Chem. Soc., Perkin Trans. 1 1993,
3055. (e) Padwa, A.; Gareau, Y.; Harrison, B.; Rodriguez, A. J. Org. Chem.
1992, 57, 3540.
(4) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 6903.
(5) (a) Hsung, R. P. J. Org. Chem. 1997, 62, 7904. (b) Hsung, R. P.
Heterocycles 1998, 48, 421. (c) Granum, K. G.; Merkel, G.; Mulder, J. A.;
Debbins, S. A.; Hsung, R. P. Tetrahedron Lett. 1998, 9597. (d) Hsung, R.
P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J.
Org. Chem. 1999, 64, 690. (e) Degen, S. J.; Mueller, K. L.; Shen, H. C.;
Mulder, J. A.; Golding, G. M.; Wei, L.-L.; Zificsak, C. A.; Hsung, R. P.
Bioorg. Med. Chem. Lett. 1999, 973. (f) Hsung, R. P.; Wei, L.-L.; Sklenicka,
H. M.; Douglas, C. J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org.
Lett. 1999, 1, 509. (g) Douglas, C. J.; Sklenicka, H. M.; Shen, H. C.;
Golding, G. M.; Mathias, D. S.; Degen, S. J.; Morgan, C. D.; Shih, R. A.;
Mueller, K. L.; Seurer, L. M.; Johnson, E. W.; Hsung, R. P. Tetrahedron
1999, 55, in press.
(6) (a) Novikov, M. S.; Khlebnikov, A. F.; Kostikov, R. R. J. Org. Chem.
USSR 1991, 27, 1576. (b) Tikhomirov, D. A.; Eremeev, A. V. Chem.
Heterocycl. Compd. 1987, 23, 1141. (c) Balsamo, A.; Macchia, B.; Macchia,
F.; Rossello, A. Tetrahedron Lett. 1985, 4141. (d) Janousek, Z.; Collard,
J.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1972, 11, 917.
(7) Joshi, R V.; Xu, Z.-Q.; Ksebati, M. B.; Kessel, D.; Corbett, T. H.;
Drach, J. C.; Zemlicka, J. J. Chem. Soc., Perkin Trans. 1 1994, 1089.
(8) For a related account using ynamines, see: Fuks, R.; Viehe, H. G.
Chem. Ber. 1970, 103, 564.
The configuration of the double bond was assigned by
carrying out NOE experiments on alkene 5 and by obtaining
an X-ray crystal structure of compound 7. Assignments for
1
other compounds in Table 1 were determined by H NMR
(9) (a) Katritzky, A. R.; Ramer, W. H. J. Org. Chem. 1985, 50, 852. (b)
Ra´dl, S.; Kova´rova´, L. Collect. Czech. Chem. Commun. 1991, 56, 2413.
(c) Reisch, J.; Salehi-Artimani, R. A. J. Heterocycl. Chem. 1989, 26, 1803.
(d) Mahamoud, A.; Galy, J. P.; Vincent, E. J. Synthesis 1981, 917.
(10) We prepared compound 4 from acridone in two high-yielding steps
(89% overall). Deprotonated acridone was propargylated with propargyl
bromide in THF, and a subsequent isomerization of the terminal alkyne to
the ynamide 4 was carried out by using KOH in DMSO at room temperature.
Also see ref 9a.
(11) Marshall, J. A.; Shearer, B. G.; Crooks, S. L. J. Org. Chem. 1987,
52, 1236.
1
(12) All new compounds are identified and characterized by H NMR,
13C NMR, FTIR, and LRMS (see Supporting Information).
1238
Org. Lett., Vol. 1, No. 8, 1999

correlations. The ∆δ values for olefinic protons of the E and
Z isomers are within the range of 0.2-0.4 ppm, although in
several cases (entries 1, 4, 6, and 10) the Z isomer was not
observed.
The stereoselectivity observed here is likely a kinetic
selectivity based on our preliminary experiments as well as
related precedents.8 When ynamide 4 was reacted with
cyclohexylcarboxaldehyde at -80 °C for 3 h, the only
observed isomer was E-12, and no Z isomer was seen after
35% conversion.
rotating methyl group. This model suggests the significance
of the acridone moiety of ynamide 4 as well as the adjacent
methyl group.
We also examined reactions of 4 with R,â-unsaturated
aldehydes and ketones. Under the same reaction conditions,
ynamide 4 reacted with R,â-unsaturated aldehydes to give
dienes 14 and 1512 in excellent yields as well as stereose-
lectivities via the hetero [2 + 2] pathway (Scheme 2). In
A working model (Spartan Program AM1) was proposed
on the basis of the stereochemical assignment (Figure 2).
Scheme 2
contrast, hetero [4 + 2] cycloadduct 16 was obtained in 64%
yield as the only product when MVK was used. It was also
observed that the reaction with MVK was much slower and
1.0 equiv of BF3‚Et2O was necessary to drive the reaction
to completion. Compounds 14-16 represent unique synthetic
building blocks for further transformation. We are currently
exploring the mechanistic details behind these two diverse
reaction pathways.
The acridone moiety of alkenes 5-12 could be removed
and recovered efficiently under mild basic conditions. For
example, treatment of the alkene 7 with LiOH at room
temperature afforded hydrolysis product 17 in 90% yield with
no observable isomerization, and acridone was recovered in
g90% after simple acid-base workup (Scheme 3). Hence,
Figure 2. A working model for the observed stereoselectivity.
Two rotations for the ring opening are possible for the
oxetene intermediate 13 (rotation a and rotation b). The most
stable conformation of 13 indicates that the acridone moiety
is nearly orthogonal to the plane of the oxetene ring (Views
1 and 2), providing the least steric interaction with the
adjacent Me group (circled, the original propargyl methyl
of 4).
Scheme 3
In addition, the model shows that the acridone moiety is
not completely eclipsed with the H and CH3 groups (View
1). This is mechanistically intriguing because without this
slight bias, there would be no bias in the rotation during the
electrocyclic ring opening. As a result, rotation a should be
more favored, thereby leading to the major E isomer. On
the other hand, rotation b is less favored because of the steric
hindrance between the proton at C-8 of acridone and the
the acridone moiety of ynamide 4 essentially serves as an
auxiliary in this stereoselective olefination reaction.
We have described here the first studies of reactivities of
an electron deficient variant of ynamine in hetero [2 + 2]
Org. Lett., Vol. 1, No. 8, 1999
1239

and [4 + 2] cycloaddition reactions. An in-depth mechanistic
model for the [2 + 2] reaction has been proposed. This study
demonstrates a significant principle that with improved
stability over ynamines, ynamides should maintain compa-
rable reactivities, leading to stereoselective and synthetically
useful preparations of trisubstituted alkenes and dienes under
Lewis acidic conditions. We are currently exploring other
synthetic applications involving various ynamides.
58-001-40-IRG-26). R.P.H. especially thanks R. W. Johnson
Pharmaceutical Research Institute for a generous grant from
the Focused Giving Program. C.A.Z. thanks University of
Minnesota for a Departmental Fellowship. C.J.D. thanks
Pharmacia-Upjohn, Pfizer, and UMN for Summer Research
Fellowships. The authors also thank Drs. Victor Young and
Maren Pink for solving the X-ray structure.
Supporting Information Available: Experimental pro-
cedures and H NMR spectral and characterization data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. The authors would like to thank
University of Minnesota for financial support in the forms
of a Start-up Fund and a Grant-in-Aid of Research, Artistry
and Scholarship (CUFS 1003-519-5984). R.P.H. thanks the
American Cancer Society for an institutional grant (IRG-
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