[3 + 2]-Cycloadditions of Azomethine Imines and Ynolates

Article abstract of DOI:10.1021/acs.orglett.6b01104

A novel [3 + 2]-cycloaddition between azomethine imines and lithium ynolates is described to synthesize bicyclic pyrazolidinones. These bicyclic pyrazolidinones are versatile intermediates to form β-amino acids and monocyclic pyrazolidinones. High diaster

Full text of DOI:10.1021/acs.orglett.6b01104

Letter
pubs.acs.org/OrgLett
[3 + 2]-Cycloadditions of Azomethine Imines and Ynolates
Sarah E. Winterton and Joseph M. Ready*
Department of Biochemistry, Division of Chemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas
75390-9038, United States
S
* Supporting Information
ABSTRACT: A novel [3 + 2]-cycloaddition between azomethine
imines and lithium ynolates is described to synthesize bicyclic
pyrazolidinones. These bicyclic pyrazolidinones are versatile
intermediates to form β-amino acids and monocyclic pyrazolidi-
nones. High diastereoselectivity and stereospecificity allow access to
optically active products.
1,3-Dipolar cycloadditions are useful reactions to synthesize
five-membered heterocycles with high stereo- and regioselec-
tivity in a single step.1 A useful dipole for dipolar cycloadditions
is the azomethine imine 1 due to its facile synthesis and
benchtop stability.2 Azomethine imines react with various
dipolarophiles including olefins, alkynes, enones, isocyanides,
and allenes to provide dinitrogen heterocycles.3,4 Recently, Cu-
catalyzed cycloadditions of alkynes with azomethine imines
have been described. They involved either copper acetylides5 or
Lewis acid activation of alkynyl ketones6 to form 3-pyrazolines
2 (Scheme 1, eq 1). These cycloadditions generate a new
heterocyclic ring and one new stereocenter on the pyrazolines.
Additionally, Studer and co-workers showed that the N-
iminoisoquinolinium ylide 3 could participate in a [3 + 2]-
cycloaddition with ketenes generated in situ (Scheme 1, eq
2).7,8 These reactions involved N-heterocyclic carbene catalysts
and formed pyrazolidinones 4 in high ee. However, the reaction
is limited to forming isoquinoline-derived adducts.8,9
Here, we report a general synthesis of pyrazolidinones
involving a [3 + 2]-cycloaddition of azomethine imines with
lithium ynolates10,11 (Scheme 1, eq 3). Compared to previous
cycloadditions between alkynes and azomethine imines, this
transformation provides bicyclic pyrazolidinones 5, which are at
a higher oxidation state than the pyrazolines 2. Moreover, the
cycloaddition sets two contiguous stereocenters with high
stereoselectivity. Additionally, our reaction design envisioned
removing the three-carbon chain from the initial azomethine
imine to form disubstituted pyrazolidinone products 6. We
reasoned that this strategy might enable a general enantiose-
lective synthesis of pyrazolidinones 6 by starting with optically
active azomethine imines (Scheme 1, eq 3, R3 ≠ H). In turn, we
anticipated that the heterocyclic products could be useful in
drug discovery given the high percentage of pharmaceutical
agents that contain nitrogen heterocycles.12 Indeed, pyrazoli-
dinones are substructures within compounds displaying diverse
biological properties.13 Finally, optically active pyrazolidinones
have found use as organocatalysts in Diels−Alder reactions14
and in kinetic resolutions,15 rendering methods for their
synthesis valuable.
Scheme 1. Representative [3 + 2]-Cycloadditions of
Azomethine Imines or N-Iminoisoquinolinium Ylides To
Synthesize 3-Pyrazolines and Pyrazolidinones
For our initial experiments, azomethine imine 1a was
exposed to a lithium ynolate that was synthesized from
phenylacetylene in a three-step, two-pot procedure16 (Table
1). Specifically, lithium phenylacetylene was prepared and
added to premade lithium tert-butyl peroxide (t-BuOOLi) to
generate the ynolate. By quenching the cycloaddition with
NaHCO3, the desired bicyclic pyrazolidinone 8 was isolated,
albeit in 30−40% yields (data not shown). However, despite
the low yields, the reaction afforded bicycle 8 with 90:10
Received: April 15, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01104
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Letter
a
a
Table 1. Optimization of the [3 + 2]-Cycloaddition of 1a
Scheme 2. Substrate Scope of [3 + 2]-Cycloaddition
yield of 8
b
entry
1
variation from the “standard” conditions
(%)
two pot: lithium phenylacetylide + t-BuOOLi instead of
in situ formation
77
2
none
84
68
66
58
81
54
58
1
3
n-BuLi instead of LiHMDS
LDA instead of LiHMDS
4
5
1.2 equiv of t-BuOOH
6
1.2 equiv of azomethine imine
quench with NaHCO3 instead of AcOH
quench with 1 M HCl instead of AcOH
quench with H2O instead of AcOH
7
8
9
10
quench with MeOH instead of AcOH
3
a
b
The reaction was conducted at 0.3 mmol. Isolated yield.
diastereoselectivity favoring the trans configuration. The initial
product was likely enolate 7, which could have formed from
either a stepwise or concerted process.17 Protonation of the
enolate upon workup afforded imide 8 and set the relative
stereochemistry. To improve the yield, we optimized the
quenching protocol to use acetic acid, and we modified the
stoichiometry of phenylacetylene, t-BuOOH,18 and LiHMDS to
obtain pyrazolidinone 8 in 77% yield (Table 1, entry 1). While
the three-step, two-pot ynolate procedure worked well, we
developed a more convenient one-pot protocol with an
improved yield (84%) (Table 1, entry 2). Thus, under
optimized conditions, phenylacetylene and t-BuOOH were
combined and treated with LiHMDS to form the ynolate in
situ. Subsequent addition to azomethine imine 1a yielded the
cycloadduct 8 after quenching under mildly acidic conditions.
When n-BuLi or LDA was used as the base instead of LiHMDS,
the yield decreased due to incomplete conversion (Table 1,
entries 3 and 4). Excess t-BuOOH decreased the yield
substantially (Table 1, entry 5), while excess azomethine
imine had no effect (Table 1, entry 6). We hypothesized that
excess t-BuOOH provided a surplus of t-BuOOLi, which
decreased the yield by reacting with enolate 7 and product 8.
Therefore, the precise stoichiometry of t-BuOOH was
imperative for high yields.18 Quenching with basic, acidic, or
neutral aqueous solutions hydrolyzed the imide bond to form
byproduct 9 (Table 1, entries 7−9). When methanol was used,
methyl ester 10 was formed. Therefore, it was essential to use
an acidic, nonaqueous reagent such as acetic acid to quench
both the enolate and the lithium tert-butoxide.
a
0.5 mmol scale reaction. Experimental details in Supporting
Information. Yield of isolated product and the average of two
b
1
experiments unless otherwise noted. Dr determined by H NMR.
mmol scale. From ethynyltrimethylsilane. 2 h for cycloaddition.
5
c
d
(8, 11−13, 75−84%). The ynolate derived from 3-ethynylpyr-
idine generated cycloadduct 14 in good yield and dr >99:1.
Ethynyltrimethylsilane afforded the monosubstituted bicyclic
pyrazolidinone 15 in 88% yield. In addition, the reaction
proceeded smoothly with aliphatic alkynes, including those
containing protected alcohols (16−19). After determining that
aliphatic, aromatic, and pyridyl alkynes worked well in the [3 +
2]-cycloaddition, we next turned to varying the azomethine
imine. The transformation tolerates a wide range of electronics
for aromatic substituents on the azomethine imine, from
With an optimized procedure for the [3 + 2]-cycloaddition,
we next evaluated the scope of the method by examining
various alkynes and aomethine imines (Scheme 2). Electron-
donating, -withdrawing, and -neutral aromatic alkynes provided
bicyclic pyrazolidinones in high yields and diastereoselectivities
B
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strongly electron-donating (20, 4-NMe2, 72%) to strongly
electron-withdrawing (24, 4-NO2, 77%) (20−24). Ortho-,
meta-, and para-chloro substitution was tolerated (25−27,
75−80%), with the diastereoselectivity decreasing for the dipole
derived from o-chlorobenzaldehyde due to sterics. Bicyclic
pyrazolidinones with 2-pyridyl 28, cyclohexene 29, and
thiophene 30 were isolated in good yields, while hetero-
aromatics (thiazole 31, indole 32) were isolated along with
their respective tert-butyl esters. Aliphatic azomethine imines
are not suitable reaction partners currently. The cycloaddition
is scalable, with identical yields obtained on both 0.5 and 5
mmol scales (see pyrazolidinone 8).
be removable to convert the bicyclic pyrazolidinones to their
monocyclic derivatives. To that end, we next turned to
removing the three-carbon bridge from the original dipole
(Table 2).
We envisioned that the imide bond would readily hydrolyze
and the C(R3)−N bond could cleave upon protonation of the
nitrogen, followed by elimination. In this regard, we discovered
that heating bicyclic pyrazolidinones to 100 °C in 37% HCl/
H2O or a 1:1 mixture of 37% HCl/H2O/AcOH provided their
respective monocyclic pyrazolidinones in excellent yields (81−
99%) (Table 2). The C−N bond cleavage proved general and
has been applied to bicyclic pyrazolidinones containing either
aliphatic or aromatic moieties at R2. The diphenyl pyrazolidi-
none 38 was synthesized from both the unsubstituted (Table 2,
entry 1) and substituted dipoles (Table 2, entry 2). Fortunately,
several bicyclic pyrazolidinones with low diastereoselectivities
epimerized during the hydrolysis to give monocyclic products
with higher diastereomer ratios. Most notably, a 3:2 mixture of
the triphenyl-substituted bicycle 34 provided the product 38
with dr >99:1 (Table 2, entry 2). To our knowledge, this is the
first example in which the three bridging carbons of the
azomethine imine are completely removed following cyclo-
addition.19
Next, we examined 5-substituted azomethine imines (R3 =
phenyl or methyl) in the cycloaddition. These dipoles provided
bicyclic pyrazolidinones 33−37 in excellent yields and high
diastereoselectivities. The major diastereomers were the trans
and cis isomers involving R1 and R2; we only observed products
with a cis relationship between R1 and R3. The [3 + 2]-
cycloaddition yielded bicyclic pyrazolidinones with an average
diastereoselectivity of 90:10 (trans:cis). Higher diastereoselec-
tivity was achieved through epimerization with DBU. For
example, the diastereoselectivity of bicyclic pyrazolidinone 34
increased from dr 81:19:−:− to a higher 95:5:−:− in the
presence of DBU. The cis stereochemical relationship between
R1 and R3 was determined by X-ray crystallography (Figure 1a).
During hydrolysis of the bicyclic pyrazolidinones, we
observed some oxidation to the corresponding pyrazolones
(see Table 2, product 41). Taking advantage of this reactivity,
we identified optimal conditions for aerobic oxidation.
Specifically, stirring the monocyclic pyrazolidinones with
Et3N under air provided pyrazolones in good yield (Scheme
3, eq 4).
Scheme 3. Pyrazolone Formation
Figure 1. (a) Crystal structure of 36. (b) Stereochemical model of [3
+ 2] cycloaddition.
To obtain this stereochemistry, the ynolate must approach from
the less hindered face of the azomethine imine ring (Figure 1b).
Therefore, the substituent on the 5-position of the azomethine
imine controls the stereochemical outcome of the cyclo-
addition. This observation suggested that optically active
dipoles would give rise to nonracemic pyrazolidinones. For
maximum synthetic utility, however, the chiral controller should
With a protocol to hydrolyze the bicyclic cycloadducts, the
azomethine imine can act as a chiral auxiliary to access optically
active cycloadducts. Thus, a diastereoselective [3 + 2]-
cycloaddition with optically active azomethine imines was
followed by removal of the azomethine imine skeleton. Several
chiral nonracemic 5-phenyl azomethine imines14 were used in
a
Table 2. C−N Bond Cleavage of Bicyclic Pyrazolidinones
b
c
c
entry
product
R1
R2
Ph
R3
yield (%)
dr
S.M. dr
1
2
3
4
5
38
38
39
40
41
Ph
Ph
Ph
H
81
85
87
99
90:10
>99:1
91:9
90:10:−:−
61:39:−:−
86:14:−:−
87:13:−:−
90:10:−:−
Ph
Ph
Ph
Ph
Ph
n-C4H9
Ph
4-BrC6H4
4-BrC6H4
92:8
d
n-C4H9
84
91:9
a
b
c
1
0.2 mmol scale reaction in a sealed vial at 100 °C. Expemental details in Supporting Information. Isolated yield. Dr determined by H NMR.
95% yield of a 7.6:1 mixture with the corresponding pyrazolone. S.M. = starting material.
d
C
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Organic Letters
Letter
the [3 + 2]-cycloaddition to obtain bicyclic pyrazolidinones
34−37 with high enantiomeric excesses (Table 3). The
azomethine imine auxiliary was sequentially removed to yield
monocyclic pyrazolidinones without loss of optical activity
(38−41).
REFERENCES
■
(1) For selected reviews, see: (a) Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: Hoboken, NJ, 2002.
(b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
(2) Dorn, H.; Otto, A. Angew. Chem., Int. Ed. Engl. 1968, 7, 214.
(3) For a review on 1,3-dipolar cycloadditions of azomethine imines,
see: Najera, C.; Sansano, J. M.; Yus, M. Org. Biomol. Chem. 2015, 13,
8596.
Table 3. [3 + 2]-Cycloaddition with Optically Active
Azomethine Imines and C−N Cleavage to Remove
a
Auxiliary
(4) See Supporting Information for recent examples of azomethine
imine cycloadditions.
(5) Recent [3 + 2] cycloadditions with azomethine imine and copper
acetylides: (a) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778. (b) Imaizumi, T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2012, 134, 20049. (c) Hashimoto, T.; Takiguchi, Y.; Maruoka, K.
J. Am. Chem. Soc. 2013, 135, 11473. (d) Keller, M.; Sido, A. S. S.; Pale,
P.; Sommer, J. Chem. - Eur. J. 2009, 15, 2810.
(6) Recent [3 + 2] cycloadditions with azomethine imines and
alkynyl ketones: (a) Hori, M.; Sakakura, A.; Ishihara, K. J. Am. Chem.
Soc. 2014, 136, 13198. (b) Arai, T.; Ogino, Y.; Sato, T. Chem.
Commun. 2013, 49, 7776.
(7) Hashimoto, T.; Maeda, Y.; Omote, M.; Nakatsu, H.; Maruoka, K.
J. Am. Chem. Soc. 2010, 132, 4076.
b
c
d
compd
R1
R2
Ph
yield (%)
dr
ee (%)
(−)-34
(−)-35
(+)-36
(+)-37
(−)-38
(−)-39
(+)-40
(+)-41
Ph
Ph
84
92
86
83
95
86
85
79:21:−:−
83:17:−:−
76:24:−:−
85:15:−:−
91:9
nd
nd
nd
nd
n-C4H9
Ph
4-BrC6H4
4-BrC6H4
Ph
n-C4H9
Ph
(8) Hesping, L.; Biswas, A.; Daniliuc, C. G.; Muck-Lichtenfeld, C.;
Studer, A. Chem. Sci. 2015, 6, 1252.
f
>99
f
Ph
n-C4H9
Ph
87:13
99
(9) Other tetrahydroisoquinoline−pyrazolidinone products from N-
iminoisoquinoline ylide cycloadditions: (a) Li, B.-S.; Wang, Y.; Jin, Z.;
Chi, Y. R. Chem. Sci. 2015, 6, 6008. (b) Gao, Z.-H.; Chen, X.-Y.;
Cheng, J.-T.; Liao, W.-L.; Ye, S. Chem. Commun. 2015, 51, 9328.
(10) Reviews on ynolates: (a) Shindo, M. Chem. Soc. Rev. 1998, 27,
367. (b) Shindo, M. Synthesis 2003, 15, 2275. (c) Shindo, M.
Tetrahedron 2007, 63, 10.
g
4-BrC6H4
4-BrC6H4
90:10
94
e
g
n-C4H9
78
88:12
95
a
b
c
Expemental detail in Supporting Information. Isolated yield. Dr
d
determined by 1H NMR. ee determined by HPLC. nd = not
e
determined. 88% yield of a 8.8:1 mixture with the corresponding
pyrazolone. Azomethine imine ee >99%. Azomethine imine ee 92%.
f
g
(11) Cycloadditions of ynolates: (a) Schollkopf, U.; Hoppe, I. Angew.
̈
Chem., Int. Ed. Engl. 1975, 14, 765. (b) Kai, H.; Iwamoto, K.; Chatani,
N.; Murai, S. J. Am. Chem. Soc. 1996, 118, 7634. (c) Iwamoto, K.;
Kojima, M.; Chatani, N.; Murai, S. J. Org. Chem. 2001, 66, 169.
(d) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett. 2002, 4,
3119. (e) Shindo, M.; Yoshimura, Y.; Hayashi, M.; Soejima, H.;
Yoshikawa, T.; Matsumoto, K.; Shishido, K. Org. Lett. 2007, 9, 1963.
(f) Austin, W. F.; Zhang, Y.; Danheiser, R. L. Org. Lett. 2005, 7, 3905.
(12) For analysis of nitrogen heterocycles in U.S. FDA approved
pharmaceuticals, see: Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med.
Chem. 2014, 57, 10257.
In summary, we developed a novel [3 + 2]-cycloaddition of
ynolates and azomethine imines to synthesize bicyclic
pyrazolidinones in high yields and diastereoselectivities. At
this time, it is not clear if the reaction is stepwise or
concerted.17 Nonetheless, this is the first example in which
the azomethine imine acts as a chiral auxiliary to control the
cycloaddition. We have defined conditions for its removal to
yield optically active monocyclic pyrazolidinones.
(13) For examples of biologically active dinitrogen pyrazolidinones,
see Supporting Information.
(14) Gould, E.; Lebl, T.; Slawin, A. M. Z.; Reid, M.; Smith, A. D.
Tetrahedron 2010, 66, 8992.
(15) Ma, G.; Deng, J.; Sibi, M. P. Angew. Chem., Int. Ed. 2014, 53,
11818.
(16) (a) Julia, M.; Saint-Jalmes, V. P.; Verpeaux, J.-N. Synlett 1993,
1993, 233. (b) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 7442.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01104.
■
S
X-ray crystal data for (−)-36 (CIF)
Experimental methods, characterization data, and NMR
spectra (PDF)
(17) Roca-Lop
2015, 80, 4076.
́
ez, D.; Polo, V.; Tejero, T.; Merino, P. J. Org. Chem.
t
(18) Commercially available BuOOH (∼5.5 M solution in decane)
t
AUTHOR INFORMATION
Corresponding Author
was used. For a detailed discussion of BuOOH and for the effects of
■
tBuOOH, see Supporting Information and Figure S1.
(19) Examples where part of the azomethine imine is removed: (a)
Reference 6a. (b) Jungheim, L. N.; Sigmund, S. K. J. Org. Chem. 1987,
52, 4007.
*E-mail: joseph.ready@utsouthwestern.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Dr. M. Kevin Brown (Indiana
University) for the suggestion of utilizing ethynyltrimethyl-
silane. Financial support provided by the NIH (GM102403)
and the Welch Foundation (I-1612). X-ray crystallography
performed by Dr. V. Lynch (UT Austin).
D
DOI: 10.1021/acs.orglett.6b01104
Org. Lett. XXXX, XXX, XXX−XXX