Chemoselective 1,3-dipolar cycloadditions of azomethine ylide with conjugated dienes

Article abstract of DOI:10.1016/j.tetlet.2010.12.042

Methods are described of synthesizing various 3-carboxy-4-vinyl pyrrolidines, versatile building blocks for our drug discovery efforts. The 1,3-dipolar cycloaddition between activated olefins and nonstabilized azomethine ylide is a known method for synthe

Full text of DOI:10.1016/j.tetlet.2010.12.042

Tetrahedron Letters 52 (2011) 872–874
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Tetrahedron Letters
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Chemoselective 1,3-dipolar cycloadditions of azomethine ylide with
conjugated dienes
⇑
Laura C. Blumberg , Brian Costa, Rebecca Goldstein
Pfizer Global Research and Development, Eastern Point Rd. Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2009
Revised 6 December 2010
Accepted 7 December 2010
Available online 21 December 2010
Methods are described of synthesizing various 3-carboxy-4-vinyl pyrrolidines, versatile building blocks
for our drug discovery efforts. The 1,3-dipolar cycloaddition between activated olefins and nonstabilized
azomethine ylide is a known method for synthesizing pyrrolidines in a stereospecific manner. Steric and
electronic effects on the chemoselectivity of the 1,3-dipolar cycloaddition between azomethine ylide and
a,b,c,d-unsaturated carboxylates have been explored.
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrrolidines are common fragments found in various biologi-
cally active small molecules, and as a result new synthetic methods
to prepare highly functionalized pyrrolidines are of great interest
in the field of medicinal chemistry. The 1,3-dipolar cycloaddition
between activated olefins and nonstabilized azomethine ylides is
a known method for synthesizing pyrrolidines in a stereospecific
manner.1 The utility of this cycloaddition has been expanded with
developments of enantioselective dipolar cycloadditions by intro-
ducing chirality to the dipolarophile,2 the azo methine ylide,3 or
chiral catalysts.4
We envisioned the preparation of 3-carboxy-4-vinyl pyrrol-
idines 1 through a chemoselective dipolar cycloaddition of an azo-
methine ylide 2 with simple a,b,d,c–unsaturated esters 3 (Fig. 1). In
addition to the carboxylic acid and deprotected amine as handles
for diversification, the vinyl side chain may be converted to
amines, ethers, esters, and amides through an aldehyde or ketone
intermediate.
Figure 1. Versatility of building block 1.
The dipolar cycloaddition between the azomethine ylide de-
rived from N-benzyl-N-(methoxymethyl)trimethylsilylmethyl-
amine 2 and the terminal olefins of 4-vinyl furanones 4 and 6 is
the only account to date of a chemoselective dipolar cycloaddition
between azomethine ylide and a diene5 (Scheme 1). The author
proposed that despite the stronger electronic effect the ester has
on the a,b-olefin, the terminal olefin is more reactive due to the re-
duced steric hinderance.
We set out to study steric effects on this chemoselectivity with
simplified dienes 3a–e, where R2, R3, R4, and R5 are hydrogen or
methyl groups. As shown in Scheme 2, there are two possible
cycloaddition products, the desired 1 that results from the dipole
addition to the
a,b-positions of the diene, as well as the product
⇑
Corresponding author. Tel.: +1 781 609 6428; fax: +1 781 609 5858.
E-mail address: laura.blumberg@alkermes.com (L.C. Blumberg).
Scheme 1. The chemoselective cycloaddition with 4-vinyl furanones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.042

L. C. Blumberg et al. / Tetrahedron Letters 52 (2011) 872–874
873
Scheme 2. 1,3 Dipolar cycloaddition between 1 and 3 provides three possible products.
which are reflected in the even distribution of LUMO orbital size
across both double bonds; therefore, both products 1g and 13g
are expected. Since the LUMO energies are relatively low for all
of the products, 1f–g and 13f–g, the bis adducts 14f–g are also ex-
pected. (2E,4E)-Methyl 5-nitropenta-2,4-dienoate 3f was synthe-
sized according to Cote’s two step method for the condensation
of ethyl-trans-4-oxo-2-butenoate and nitromethane.11 The cyano
containing (2Z,4E)-methyl 5-cyanopenta-2,4-dienoate 3g was pre-
pared by modifying Vogel’s published synthesis.12 (Caution: this
procedure will release hydrogen cyanide.) In order to avoid release
of cyanide gas, we treated the cyanide containing mixture directly
with excess potassium carbonate and methyl iodide, and isolated
the methyl ester with a basic aqueous work up (Scheme 4).
We coupled these dienes 3a–g with N-benzyl-N-(methoxy-
methyl)trimethylsilylmethylamine 2 in the presence of TFA. The
general procedure for these 1,3-dipolar cycloadditions is as fol-
lows: Trifluoroacetic acid (1 M in THF, 0.1 equivalent) is slowly
added to a 0 °C solution of diene (1 equivalent) and dipole
(1 equivalent) in toluene. The reaction is slowly warmed to 25 °C
over 18 h, and then quenched with saturated aqueous sodium
bicarbonate. The distribution of products was established through
integration of the crude 1H NMR spectra. The observed product dis-
tributions in these reactions are all consistent with the predictions
made with the analysis of frontier molecular orbital energies and
coefficients.6 In our simplest case, (E)-methyl penta-2,4-dienoate
3a, the major product 1a is formed by the dipole coupling to the
Scheme 3. The synthesis of dienes 3c–e.
13 formed when the methine ylide dipole adds to the c,d-positions
of the diene. According to the calculated LUMO energies and orbital
coefficients for the dienes 3a–e and products 1a–e and 13a–e,6 we
expected preferential dipole cycloaddition to the a,b olefin to form
product 1, which is predicted to be unreactive in the reaction con-
ditions, since its LUMO energy is quite high. On the other hand
based on its calculated low energy LUMO we expected the unde-
sired product 13 to react further to form the bis adduct 14. Dienes
3a and 3b are commercially available; dienes 3c, 3d, and 3e were
synthesized as shown in Scheme 3.7–9
We designed dienes 3f and 3g to explore the electronic effects
on the chemoselectivity of this reaction.10 The calculated LUMO,
a,b-olefin. However, the crude material contains <10% of what is
the orbital coefficients for 3f are largest at the c,d positions; there-
fore, 13f is expected to be the major product. In the case of 3g, the
cyano and ester groups have similar electron withdrawing effects,
proposed to be 13a. Evidence for this side product as well as bis ad-
duct 14a, is also found in the GCMS and 1H NMR of the crude reac-
tion mixture.13 In the cases of dienes 3b, 3c, and 3d the additional
steric hinderance around the
c,d-olefin coupled with the stronger
electronic effects on the ,b-olefin results in selective formation
a
of products 1b–d. However, this selectivity is reversed in the case
of 3e, where the methyl substituent at the alpha position sterically
blocks the dipole addition to the a,b-olefin. This ratio of products is
degraded with longer reaction times, when 13e further reacts to
form the bisadduct 14e. In fact, the bis-adduct 14e is the major
product when this reaction is allowed to run overnight. In the case
of nitro containing 3f, we only observe product 13f, and bis adduct
14f. We were unable to prevent this second addition from taking
place even in conditions of lower temperature and shorter reaction
times. Since the calculated LUMO energy for product 1f is still quite
Scheme 4. The synthesis of dienes 3f and 3g.
Table 1
1,3 Dipolar cycloaddition run under general conditions.
Diene ID
R1
R2
R3
R4
R5
Reaction time/temperature
Crude yield (%)
Ratio of products 1:13:14a
Isolated yield
3a
3b
3c
3d
3e
3e
3f
CH3
CH3
CH3
CH3
CH2 CH3
CH2 CH3
CH2 CH3
CH2 CH3
CH3
H
H
H
H
CH3
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
1 h/0 °C then 15 h/rt
1 h/0 °C then 15 h/rt
1 h/0 °C then 15 h/rt
1 h/0 °C then 15 h/rt
1 h/0 °C then 15 h/rt
1 h/0 °C then 5 h/rt
1 h/0 °C then 1.5 h/rt
4 h/0 °C
148
167
97
100
152
72
69
50
184
5/1/4b
1/0/0
1/0/0
37% 1a
38% 1b
60% 1c
64% 1d
31% 13e 6% 1e
—
CH3
CH3
H
H
H
NO2
NO2
CN
1/0/0
1/4/12
1/5.8/2
0/1/4.4
0/1/2.7
1/1/1
c
—
—
c
3f
3g
1 h/0 °C then 15 h/rt
22% 13g 22% 1g
a
b
c
The ratio of products 1/13/14 was determined by integration of the crude 1H NMR spectrum.
This product distribution has been determined by GC-MS.
The product 13f of this reaction was isolated and characterized from a reaction run under different stoichiometry.

874
L. C. Blumberg et al. / Tetrahedron Letters 52 (2011) 872–874
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bisadduct 14f. Therefore, we cannot eliminate the possibility that
the methine ylide also reacts with the
a,b-olefin of the starting
diene 3f. In the case of the cyano substituted diene 3g, a 1:1 ratio
of mono addition products 1g and 13g is produced. In addition,
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in the crude 1H NMR.
Our results are consistent with those reported by Gerlach et al.
As observed in our reaction with 3e, the steric effects can out-
weigh the electronic effects, resulting in preferred cycloaddition
on the less hindered terminal olefin. However, based on our expe-
rience it is somewhat surprising that Gerlach did not report any bis
adduct formation as a result of the dipole reacting with the still
activated olefin in the products 5 and 7. While it may be possible
that further reaction with product 7 is prevented by the steric bulk
of the chiral center on the furanone, we would expect that cycload-
dition to 5 would be possible under our reaction conditions. It is
important to note that the activation of the dipole with LiF, basic
conditions, could also result in a difference in the reactivity.
Our study demonstrates that the 1,3-dipolar cycloaddition of
unactivated azomethine ylide to activated 1,4-dienes is a powerful
method to synthesize highly versatile building blocks. With the
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6. Calculations of the HOMO LUMO energies and orbital coefficients have been
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publication.
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introduction of a simple methyl substitution on either the
positions of these dienes the chemoselectivity can be ensured, to
provide a single product in synthetically useful yields (Table 1).
c or d
Acknowledgments
Funding was provided by the Pfizer Groton Discovery Chemistry
Summer Internship Program. Diane Rescek provided 2D NMR sup-
port for the structure elucidation of several products, and George
Perkins provided the High Resolution Mass Spectrometry data.
Supplementary data
Supplementary data (the 1H NMR and GS-MS spectra of the
crude reaction mixtures produced from all of the dipolar cycload-
ditions, the experimental and characterization data for all isolated
products, and calculated HOMO and LUMO energies and coeffi-
cients, have been included in the supplementary data) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.12.042.
References and notes
1. For reviews on 1,3 dipolar cycloadditions of nonstabilized azomethine ylides:
(a) Harwood, L. M.; Vickers, R. J. The Chemistry of Heterocyclic Compounds In
Padwa, A., Pearson, W. H., Eds.; Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley:
New York, NY, 2002; Vol. 59, pp 169–252; (b) Vedejs, E. In Advances in
Cycloaddition; Curran, D. P., Ed.; Jai Press: Greenwich, CT, 1988; pp 33–51; (c)
Eberbach, W. Sci. Synth. 2004, 27, 441–498; (d) Najera, C.; Sansano, J. M. Curr.
Org. Chem. 2003, 7, 1105–1150; (e) Terao, Y.; Aono, M.; Achiwa, K. Heterocycles
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Commun. 2002, 32, 935–939; (j) Pearson, W. H.; Stoy, P. Synlett 2003, 7, 903–
10. (a) 1,3-Cycloadditions to nitro olefins and cyan olefins are known.; (b) Xie, J.;
Yoshida, K.; Takasu, K.; Takemoto, Y. Tetrahedron Lett. 2008, 49, 6910–6913; (c)
Boruah, M.; Konwar, D.; Sharma, S. D. Tetrahedron Lett. 2007, 48, 4535–4537;
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13. The peaks for all three products are evident in the 1H NMR of the crude mix,
(1a/13a 6.7:1) we were unable to definitively determine the relative amount of
bis adduct 14a.