Phosphine-catalyzed annulations of azomethine imines: Allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways

Article abstract of DOI:10.1021/ja200231v

In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen

Full text of DOI:10.1021/ja200231v

ARTICLE
pubs.acs.org/JACS
Phosphine-Catalyzed Annulations of Azomethine Imines:
Allene-Dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] Pathways
Risong Na,† Chengfeng Jing,† Qihai Xu,§ Hui Jiang,† Xi Wu,† Jiayan Shi,†
Jiangchun Zhong,† Min Wang,† Diego Benitez,‡ Ekaterina Tkatchouk,‡
William A. Goddard, III,‡ Hongchao Guo,*,† and Ohyun Kwon*,§
†Department of Applied Chemistry, China Agricultural University, Beijing 100193, P.R. China
‡Materials and Process Stimulation Center, California Institute of Technology, Pasadena, California 91125, United States
§Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S Supporting Information
b
ABSTRACT: In this paper we describe the phosphine-cata-
lyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of
azomethine imines and allenoates. These processes mark the
first use of azomethine imines in nucleophilic phosphine
catalysis, producing dinitrogen-fused heterocycles, including
tetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones,
and -diazocinones. Counting the two different reaction modes
in the [3 + 3] cyclizations, there are five distinct reaction
pathways—the choice of which depends on the structure and
chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions,
affording a broad range of 1,2-dinitrogen-containing heterocycles in moderate to excellent yields. A zwitterionic intermediate
formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines,
leading to the [3 + 2 + 3] tetrahydropyrazolo-diazocinone products. The incorporation of two molecules of an allenoate into an
eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis.
The salient features of this protocol—the facile access to a diverse range of nitrogen-containing heterocycles and the simple
preparation of azomethine imine substrates—suggest that it might find extensive applications in heterocycle synthesis.
Scheme 1. Phosphine-Catalyzed [3 + N] Cyclizations of
’ INTRODUCTION
Azomethine Imines with Allenoates
Intermolecular cycloaddition is one of the most powerful tools
for the convergent synthesis of a variety of carbo- and hetero-
cycles from simpler precursors.1 Many metallo- and organocata-
lytic systems have been successfully developed for the cyclo-
additions of a wide range of starting materials. Among the
catalytic systems, nucleophilic phosphine catalysis has been
established as a reliable platform for the efficient assembly of a
wide array of cyclic products from simple building blocks.2 In
particular, activated allenes subjected to nucleophilic phosphine
catalysis conditions exhibit superbly diverse reactivity toward
electrophilic reagents. These allenes can function as one-, two-,
three-, or four-carbon synthons when reacting with a variety of
electrophilic coupling partners (including aldehydes, alkenes,
imines, and aziridines) undergoing [2 + 1],3 [4 + 1],4 [3 + 2],5
[2 + 2 + 2],6 [3 + 3],7 [4 + 2],8 [4 + 3],9 or [8 + 2]10 annulations.11
The particular reactivity of the allene substrate is often induced
by its electrophilic coupling partner. Consequently, the search for
new electrophilic substrates exhibiting suitable reactivity for
effective use in the synthesis of heterocycles with new skeletons
or structural features is a major challenge for the formation of
diverse cycloaddition products from the nucleophilic phosphine
catalysis of allenes. In this context, we conceived the possibility
of introducing a new type of electrophilic coupling reagent,
azomethine imines, that might serve as an NꢀNꢀC trio-of-
atoms synthon in phosphine-catalyzed annulation processes.
Received: January 21, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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Figure 1. Selected examples of biologically active dinitrogen-fused heterocycles.
Herein, we report the phosphine-catalyzed [3 + N] annulations
of allenoates and azomethine imines 1 (Scheme 1).
activated allenoates, the catalysis cycle is typically initiated by the
addition of the Lewis basic phosphine to the electrophilic
β-carbon atom of the R-allenic ester, leading to the formation
of zwitterionic intermediates. We suspected that exposing these
intermediates to azomethine imines might allow new [3 + N]
cycloadditions, with the pathways followed depending on the
number of carbon atoms that the allenoate contributes to the
final cyclic products (Scheme 1). Herein, we report the first
examples of phosphine-catalyzed cycloadditions of various
zwitterionic species to provide functionalized five-, six-, seven-,
and eight-membered dinitrogen-containing heterocycles with
high efficiency.
Azomethine imines such as 1 are readily accessible, stable
compounds that have been employed recently as efficient 1,3-
dipoles in various metal-catalyzed and organocatalytic cycloaddi-
tions.12ꢀ14 In 2003, Fu reported an efficient Cu-catalyzed
protocol for enantioselective [3 + 2] cycloaddition of azo-
methine imines with alkynes;14a in 2005, he further extended
this azomethine imine/alkyne cycloaddition strategy to the
kinetic resolution of azomethine imines bearing a stereocenter
at the 5-position of the pyrazolidinone core.14b Sibi demon-
strated another Cu-catalyzed enantioselective [3 + 2] cycloaddi-
tion of azomethine imines with pyrazolidinone acrylates.14i Pale
and Sommer presented a heterogeneous Cu(I)-modified zeolite-
catalyzed [3 + 2] cycloaddition of azomethine imines with
alkynes.14k Hayashi studied Pd-catalyzed [3 + 3] cycloadditions
of azomethine imines with trimethylenemethane to produce
hexahydropyridazine derivatives under mild conditions,14c and
Pd-catalyzed [4 + 3] cycloadditions of azomethine imines with
γ-methylidene-δ-valerolactones.14g Toste reported a Au-catalyzed
[3 + 3] annulation of azomethine imines with propargyl
esters.14j Maruoka developed a Ti-catalyzed enantioselective
[3 + 2] cycloaddition of azomethine imines with R,β-unsatu-
rated aldehydes.14m Suga described a Ni-catalyzed enantioselec-
tive and diastereoselective [3 + 2] cycloaddition of azomethine
imines with 3-acryloyl-2-oxazolidinone.14f Charette also devel-
oped a Ni-catalyzed [3 + 3] cycloaddition of aromatic azo-
methine imines with 1,1-cyclopropane diesters.14l More
recently, Scheidt described an N-heterocyclic carbene-catalyzed
stereoselective formal [3 + 3] cycloaddition of azomethine
imines with enals.14e Chen developed a multifunctional primary
amine (derived from cinchona alkaloids)-catalyzed enantiose-
lective [3 + 2] cycloaddition of azomethine imines and cyclic
enones,14h and a diarylprolinol salt-catalyzed [3 + 2] cycloaddi-
tion of azomethine imines with R,β-unsaturated aldehydes.14d
Despite these extensive efforts at using azomethine imines as
cyclization partners in heterocycle synthesis, the application of
azomethine imines in phosphine-catalyzed cycloaddition has
not been reported previously. This situation prompted us to
design a cycloaddition of azomethine imines and allenoates
using readily available tertiary phosphines as catalysts. It is
widely accepted that, in the phosphine-promoted reactions of
The new annulation reactions provide generally applicable
routes toward dinitrogen-fused heterocycles, including tetrahy-
dropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -
diazocinones, which are key units in or building blocks of many
pharmaceuticals, agrochemicals, biologically active compounds,
and other useful chemicals. Among the dinitrogen-containing
heterocycles, pyrazolone derivatives are often used as dyes in the
food, textile, photography, and cosmetics industries.15 Several
pyrazolones also exhibit bioactivity. For example, phenazone has
been used as a synthetic drug;16 phenylbutazone has anti-
inflammatory activity;16 phenidone and BW755C are inhibitors
of lipoxygenase and cyclooxygenase, respectively;17,18 BW357U
displays anorectic activity (Figure 1).19 Other dinitrogen-fused
heterocycles also exhibit diverse bioactivity and have a variety of
applications. Tetrahydropyrazolo-pyrazolones have been inves-
tigated as antibacterial agents,16 herbicides, pesticides,20 antitu-
mor agents,21 calcitonin agonists,22 and potent drugs to relieve
Alzheimer’s disease.23 Pyrazolopyridazinone derivatives have
been studied extensively as pesticides and, especially, herbicides;
more than 60 patents have been filed according to the CAS
database. Pyrazolodiazepinone and pyrazolodiazocinone deriva-
tives have also been explored as herbicides, insecticides,
acaricides,24 and acetyl-CoA carboxylase inhibitors.25 In addi-
tion, the pyrazolidine derivatives obtained through these annula-
tions are readily transformed into 1,3-diamine derivatives via
NꢀN bond cleavage with SmI2;26 this cleavage strategy has been
demonstrated in several reports.14j,27 Such 1,3-diamine deriva-
tives serve not only as ligands of metal catalysts but also as
biologically important compounds or building blocks for bioac-
tive compounds.28
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’ RESULTS AND DISCUSSION
catalysis reactions. Our initial attempts at phosphine-catalyzed
annulations of azomethine imines commenced with the reactions
of1-(p-nitrobenzylidene)-3-oxopyrazolidin-1-ium-2-ide(1a).Table1
presents the results of screening for appropriate reaction conditions
and catalysts for the model reaction between 1a and allenoate 2a.
Considering the possibility of a background reaction resulting from
direct [3 + 2] cycloaddition of the azomethine imine and the
allenoate,30 we first attempted the reaction between 1a and the
allenoate 2a in the absence of phosphine catalyst in dichloro-
methane (DCM) at room temperature; TLC analysis revealed no
product (Table 1, entry 1). When compound 1a was treated with
ethyl 2-methyl-buta-2,3-dienoate (2a) in DCM31 at room tempera-
ture in the presence of 20 mol % of PPh3, we isolated a new product
in 5% yield (Table 1, entry 2). The efficiency of nucleophilic
phosphine catalysis often depends on the nature of the tertiary
phosphine catalyst; R-alkyl allenoates, such as 2a, oftenrequiremore
nucleophilic phosphines for facile reactions.8a,b Indeed, screening of
a couple of tertiary phosphines for the catalysis revealed that the
reaction efficiency increased as the nucleophilicity of the phosphine
increased, reaching 92% product yield for PMe3 (entries 3ꢀ6).
Using NMR spectroscopy and X-ray crystallography of the homo-
logous tetrahydropyrazolopyrazolone 3ad obtained from the annu-
lation of 1a with the R-isobutyl allenoate 2d, we established the
structure of the new annulation product 3aa to be that from a [3 + 2]
cycloaddition. Not only did the [3 + 2] annulation exhibit great
efficiency, it also provided the tetrasubstituted exocyclic alkylidene
Although the azomethine imines 1 have received much atten-
tion,14 including extensive application in 1,3-diploar cycloadditions
for the preparation of a plethora of pyrazolidinone derivatives,29
they have never previously been used in nucleophilic phosphine
Table 1. Phosphine-Catalyzed [3 + 2] Cycloadditions of the
Azomethine Imine 1a with the Allenoate 2aa
entry
PR3
time (h)
yield (%)b
1 c
2
ꢀ
PPh3
48
24
24
24
14
12
24
0
5
3
MePPh2
Me2PPh
PBu3
24
53
88
92
0
4
5
6
PMe3
7
HMPT
a 1.2 equiv of allenoate was used. b Isolated yield. c Without phosphine
catalyst.
Table 2. Chiral Phosphine-Catalyzed [3 + 2] Cycloadditions of the Azomethine Imine 1b with the Allenoate 2aa
entry
catalyst
time (h)
yield (%)b
ee (%)c
1
2
(R, R)-DiPAMP
(R)-BINAP
120
120
120
120
120
120
120
120
48
<5
<5
<5
19
<5
<5
<5
<5
8
n.d.d
n.d.
n.d.
6
3
(+)-Me-PuPhos
(+)-Et-BPE
4
5
(+)-TangPhos
(R)-Et-BINEPHINE
(R)-t-Bu-BINEPHINE
(S, S)-FerroPHANE
(R)-I
n.d.
n.d.
n.d.
n.d.
93
6
7
8
9
10
(R)-II
48
56e
89
a Reactions were conducted with 0.1 mmol of 1b and 1.5 equiv of allenoate in 1 mL of DCM. The absolute configuration of the major enantiomer has not
been determined. b Isolated yield. c Enantiomeric excess was determined through HPLC analysis on a chiral stationary phase. d Not determined. e The Z
isomer was isolated in 18% yield.
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Table 3. PBu3-Catalyzed [3 + 2] Cycloadditions of
Azomethine Imines 1 with the Allenoate 2aa
Table 4. PMe3-Catalyzed [3 + 2] Annulations of the
Allenoates 2 with the Azomethine Imine 1aa
temp (°C) time (h) product yield (%)b
entry
R
time (h)
product
yield (%)b
entry
R
1
Ph (1b)
24
24
24
30
24
20
20
12
24
24
24
48
48
48
24
20
20
36
72
72
3ba
3ca
3da
3ea
3fa
97
85
89
77
91
93
97
87
98
97
94
70
50
57
96
86
99
55
41
48
1
H (2a)
rt
40
40
40
40
rt
12
20
20
20
24
24
20
20
15
36
36
36
60
3aa
3ab
3ac
3adc
3ae
3af
92
96
92
95
98
87
95
91
99
88
81
45
30
2
4-MeC6H4 (1c)
4-i-PrC6H4 (1d)
4-OMeC6H4 (1e)
4-FC6H4 (1f)
2
Me (2b)
3
3
Et (2c)
4
4
i-Pr (2d)
5
5
t-Bu (2e)
6
4-ClC6H4 (1g)
4-BrC6H4 (1h)
4-CNC6H4 (1i)
4-CF3C6H4 (1j)
3-NO2C6H4 (1k)
2-NO2C6H4 (1l)
2-MeC6H4 (1m)
2-PhC6H4 (1n)
1-naphthyl (1o)
2-naphthyl (1p)
4-pyridyl (1q)
2-furanyl (1r)
cyclohexyl (1s)
n-Bu (1t)
3ga
3ha
3ia
6
Ph (2f)
7
7
2-MeC6H4 (2g)
2-FC6H4(2h)
4-FC6H4 (2i)
4-ClC6H4 (2j)
4-BrC6H4 (2k)
vinyl (2l)
rt
3ag
3ah
3ai
8
8
rt
9
3ja
9
rt
10
11
12c
13c
14c
15
16
17
18
19
20
3ka
3la
10
11
12
13
rt
3aj
rt
3ak
3al
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
rt
styryl (2m)
rt
3am
a 1.2 equiv of allenoate was used. b Isolated yield. c The structure of this
compound was verified through single-crystal X-ray analysis.
electron-withdrawing groups on the benzene ring provided
somewhat higher yields of the cyclization products than did
those bearing electron-donating groups (cf. entries 2ꢀ4 and
5ꢀ11). The reactions employing azomethine imines containing
ortho-substituted benzene rings required elevated temperatures
and longer times and furnished the tetrahydropyrazolopyrazo-
lones in modest yields (entries 12ꢀ14). The azomethine imines
bearing 2-naphthyl, 4-pyridyl, and 2-furyl groups, also underwent
smooth cyclizations with 2a, readily affording the corresponding
pyrazolidinone derivatives in excellent yields (entries 15ꢀ17).
We were delighted to find that even alkylimines could be
employed in [3 + 2] annulations with the allenoate 2a, albeit
in moderate yields (entries 18ꢀ20).
i-Pr (1u)
3ua
a 1.2 equiv of allenoate was used. b Isolated yield. c The reaction was run
at 40 °C.
as a single E isomer. Hexamethylphosphorous triamide (HMPT),
albeit more nucleophilic than PPh3, did not provide any desired
product (entry 7).
A large number of phosphine-catalyzed annulations have been
rendered enantioselective through the use of enantioenriched
chiral phosphines.2k To gauge the feasibility of developing
enantioselective azomethine imine annulation, we tested the
effect of 10 known chiral phosphines (Table 2). DiPAMP,
BINAP, Me-DuPhos, TangPhos, Et-BINEPINE, t-Bu-BINE-
PINE, and FerroPHANE were poor catalysts and provided
negligible amounts of products, even after reaction times
of five days (entries 1ꢀ3 and 5ꢀ8). Et-BPE provided the desired
tetrahydropyrazolopyrazolone 3ba in 19% yield and 6% ee (entry 4).
To our delight, the chiral monophosphines I and II rendered high
enantiomeric excesses with a synthetically useful yield in the case of II
(entries 9 and 10), demonstrating the feasibility of developing an
enantioselective process of synthetic value.
Using 20 mol % of PBu3 as the catalyst, we examined a range of
azomethine imines in the [3 + 2] annulations of ethyl 2-methyl-
buta-2,3-dienoate (2a) under the optimized reaction conditions
(Table 3). Here, we employed PBu3 instead of PMe3 for ease of
operation; the reactions of the azomethine imines 1bꢀ1u with
the allenoate 2a were also highly efficient (up to 99% yield)
when mediated by PBu3. A variety of aryl azomethine imines
underwent the [3 + 2] cycloaddition, providing the antici-
pated tetrahydropyrazolopyrazolones in moderate to excellent
yields (entries 1ꢀ17). In general, azomethine imines bearing
Next, we investigated the reactions of a range of distinctly
substituted allenoates 2 with the azomethine imine 1a in the
presence of 20 mol % of PMe3 (Table 4). For the sterically more
demanding allenoates 2bꢀ2m, we employed the more-reactive
PMe3 as the catalyst. On the basis of the proposed reaction
mechanism (vide infra), we did not anticipate the substituent at
the β0-carbon atom of the allenoate 2 to exert much influence on
the course of the reaction. A variety of β0-alkyl- and β0-aryl-
substituted allenoates underwent the cycloaddition at reasonable
rates, providing the corresponding tetrahydropyrazolopyrazolones
3 in excellent yields (entries 1ꢀ11). In general, alkyl-substituted
allenoates required a slightly elevated temperature (40 °C) for the
reaction to proceed at a reasonable rate (entries 2ꢀ5). Allenoates
featuring phenyl groups with either electron-withdrawing or
-donating substituents worked very well as substrates at room
temperature (entries 6ꢀ11). In contrast, the reactions of β0-vinyl-
and β0-styryl-substituted allenoates were somewhat sluggish, pro-
viding their corresponding products in moderate yields even after
prolonged reaction times (entries 12 and 13).
In contrast to the aforementioned cases wherein excellent
selectivity was observed, the reaction involving diethyl 2-vinyli-
denesuccinate (2n) was more complicated and seemed to follow
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Scheme 2. Phosphine-Catalyzed Annulations of the Azomethine Imine 1a with the Allenoate 2n
several competing pathways. Under conditions otherwise iden-
Scheme 3. Mechanisms for the Azomethine Imineꢀ
Allenoate [3 + 2], [3 + 3], and [4 + 3] Annulations
tical to those described above, 2n underwent the PBu3-mediated
cycloaddition with the azomethine imine 1a in a distinctive
manner: a combination of [3 + 2], [3 + 3], and [3 + 4] reactions,
affording a mixture of the tetrahydropyrazolopyrazolone 3an, the
tetrahydropyrazolopyridazinone 4, and the tetrahydropyrazolo-
diazepinone 5 in 6, 23, and 63% (trans- and cis-5) yields,
respectively (Scheme 2). Intriguingly, the use of PMe3 as the
catalyst afforded strikingly different results. The [3 + 2] product
3an and the [3 + 3] product 4 were obtained in 40 and 42%
yields, respectively, while the [4 + 3] product 5 was isolated in
only 12% yield (trans- and cis-5). We used single-crystal X-ray
analyses to unequivocally verify the structures of the annulation
products 3an, 4, and trans-5. In an effort to force the reaction to
follow one of the cycloaddition modes preferentially, we
screened phosphines with various nucleophilicities under a range
of reaction conditions (solvents, temperatures, other controllable
factors), but we always obtained mixtures of several cycloaddi-
tion products. We also investigated the reactions of other
azomethine imines with the allenoate 2n, but, in general, they
invariably produced more than two products, including those
from [3 + 2], [3 + 3], and [4 + 3] cycloadditions. Although the
[3 + 3] annulation mode had been observed previously for
diethyl 2-vinylidenesuccinate (2n) in its phosphine-mediated
annulation with aziridines,7 the [4 + 3] annulation modality had
not. The distinctive behavior of the diester allenoate 2n relative
to those of the other R-alkylꢀsubstituted allenoates (2aꢀ2m)
was due to the enhanced acidity of its β0-protons, thereby
facilitating the conversion of the phosphonium enoate to the
vinylogous ylide and its subsequent addition at the β0-carbon
atom (see the mechanistic discussion below).
On the basis of the reported mechanistic studies of nucleo-
philic phosphine-catalyzed reactions,2 Scheme 3 presents plau-
sible pathways for the reactions of the azomethine imines 1 and
the allenoates 2. Upon conjugate addition of PBu3 to the
allenoate 2, the zwitterion A is formed. Because of steric
crowding at its R-carbon atom, the β-phosphonium enoate A
undergoes addition at its γ-carbon atom to form the amide B. A
second conjugate addition of the amide to the β-phosphonium
enoate motif of intermediate B accomplishes the [3 + 2]
cyclization. The thus-formed β-phosphonium enoate C under-
goes facile β-elimination to regenerate the catalyst, forming the
final tetrahydropyrazolopyrazolone product 3. On the other
hand, the carboxylic ester substituent at the β0-carbon atom of
the allenoate 2n facilitates the conversion of the phosphonium
enoate A to the vinylogous ylide D,32 which then adds to the
azomethine imine 1 to form the intermediate E. Unlike the 5-exo
cyclization of the intermediate B to form C, the 6-endo cyclization
of the amide E to form F is less efficient when PBu3 is the catalyst
(23% isolated yield of the tetrahydropyrazolopyridazinone 4); in
this case, the intermediate E isomerizes into another amide
species H.33 The ylide I is formed from the 7-endo cyclization
of H; it then expels the catalyst PBu3 through the ylide-to-enoate
conversion to furnish the tetrahydropyrazolodiazepinone 5.
When PMe3 is employed as the catalyst, however, conjugate
addition of the amide to the β-phosphonium enoates in B and E
is the major reaction pathways for the allenoate 2n, due to
decreased steric congestion at the β-carbon atom.
With regard to the high E-selectivity for the exocyclic double
bond of tetrahydropyrazolopyrazolone 3, density functional
calculations at the M06/6-31G** level of theory showed a strong
interaction between the phosphorus atom and the carbonyl of
the β-phosphonium enoate, most likely of electrostatic nature.
This electrostatic interaction is thought to be key for the
strereochemical outcome of the reaction (Scheme 4). Structu-
rally, the phosphonium group points away from the bicycle, as a
consequence of the relatively puckered heterobicycle and the
pyramidalized carbon bearing the phosphonium enoate. This
structural motif causes the phosphonium group to depart away
from the bicyclic structure, thus favoring rotation of the carbonyl
also away from the rest of the molecule. Therefore, it is
anticipated that the magnitude of the electrostatic interaction
should have an impact on the stereochemistry of the reaction.
This lower perceived stereoselectivity (for the E isomer) could be
eroded with increasing phosphine bulkiness. To further analyze
the dominant stereodirecting effects in the elimination reaction,
we performed relaxed coordinate scans for the phosphine-carbon
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Scheme 4. Computational Study of the Stereochemical Preference of PMe3 and (R)-II
Table 5. Phosphine-Catalyzed Annulations of the Azomethine
Imine 1a with Ethyl 2,3-Butadienoate (2o)a
Scheme 5. PBu3-Catalyzed [3 + 3] Annulations of the
Azomethine Imine 1a with γ-Substituted Allenoates
entry
PR3
time (h)
3aob yield (%)c
6b yield (%)c
1 d
2
ꢀ
48
24
24
24
24
24
12
24
0
8
0
19
5
PPh3
3
EtPPh2
MePPh2
Me2PPh
PBu3
27
53
69
45
62
15
3ao and the tetrahydropyrazolopyridazinone 6 in 45 and 36%
yields, respectively, along with an unknown product (Table 5,
entry 6). We used X-ray crystallography to establish the struc-
tures of the [3 + 2] adduct 3ao and the [3 + 3] adduct 6.
Although the reaction provided a mixture of products, each
compound exhibited exquisite stereoselectivity; 3ao was ob-
tained exclusively in the E isomeric form and 6 as a single trans
diastereoisomer. The annulations producing the adducts 3ao and
6 were apparently initiated by the additions at the γ- and R-
carbon atoms, respectively, of the allenoate 2o (see Scheme 3 and
the mechanistic rationale below). In an attempt to improve the
yield and chemoselectivity, we tested the effects of other
phosphines (Table 5). Using PPh3 instead of PBu3 as the catalyst
caused the reaction to proceed much more sluggishly, giving the
cyclized products in poor yields, with the [3 + 3] adduct 6 as the
major product (entry 2). When we used the more-nucleophilic
phosphines EtPPh2, MePPh2, and Me2PPh as catalysts, we
obtained the [3 + 2] cycloaddition product 3ao as the major
product with improved yields (27, 53, and 69%, respectively) and
relatively smaller amounts (5, 2, and 15%, respectively) of the
[3 + 3] product (entries 3ꢀ5). Trimethylphosphine performed
the best in terms of its 3ao/6 selectivity, with a 62% yield of the
tetrahydropyrazolopyrazolone 3ao and a negligible amount (3%)
of 6 (entry 7). Notably, HMPT facilitated the reaction of the
azomethine ylide 1a and the allenoate 2o, albeit in low efficiency
(entry 8). One peculiar observation was that an additional
byproduct, which we isolated in less than 5% yield when using
either PMe3 or PBu3, was isolated in almost 10% yield when
using HMPT as the catalyst (vide infra).
4
2
5
15
36
3
6
7
PMe3
8
HMPT
22
a 1.2 equiv of allenoate was used. b The structure of this compound was
verified through single-crystal X-ray analysis. c Isolated yield. d Without
phosphine catalyst.
elongation with PMe3 and (R)-II. Our calculations show that it is
a combination of factors that lead to the low stereoselectivity
when (R)-II is used. The bulkiness provided by the cyclohexyl
group, the axial chirality, and the high torque of the benzyl groups
in (R)-II, all impose a rigid chiral pocket that changes the
orientation of the departure of the leaving phosphine group. In
addition, we believe that the bulkier (R)-II may not allow for a
PꢀO(dC) interaction as strong as that with less bulky phos-
phines, as a consequence of the slightly longer interatomic
distance and overall structural rigidity. Both, the weaker electro-
static interaction, and the different departing orientation do not
favor the rotation of the enoate in any direction, leading to low
stereoselectivities. This can be observed by the differences in the
dihedral angle of the enoate group at the transition state for
elimination (Scheme 4). The elimination transition state for
PMe3 as phosphine is a much later transition state, where the
dihedral angle is ∼30°, while for (R)-II, it is an early transition
state with an enoate dihedral angle of ∼10°.
Encouraged by the successful incorporation of the azomethine
ylides 1 as annulation reaction partners in the phosphine catalysis
of R-substituted allenoates, we launched an investigation into the
reaction of ethyl 2,3-butadienoate (2o) with the azomethine
imine 1a. Our anticipation was that the allenoate 2o would serve
as a two- or three-carbon component for [3 + 2] or [3 + 3]
annulation, respectively, with the azomethine ylides 1. In the
event, treatment of the allenoate 2o with the azomethine imine
1a in DCM at room temperature for 24 h under the influence of
20 mol % of PBu3 afforded the tetrahydropyrazolopyrazolone
Evidently, the product 3ao was obtained via addition at the
γ-carbon atom of the allenoate 2o while 6ao was produced via
addition at the R-carbon atom. Consequently, we anticipated
that γ-substituted allenoates would provide compounds 6 ex-
clusively. Screening of the reaction conditions and substrates
revealed that γ-substituted allenoates, namely γ-methyl, ethyl,
isopropyl, tert-butyl, and phenyl allenoates, underwent annula-
tions with the azomethine imine 1a under mild conditions with
tolerable conversions. Nevertheless, these annulations appeared
to proceed through at least two pathways, providing several spots
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Scheme 6. Mechanistic Rationale for the Formation of Compounds 6 and 60
Scheme 7. Phosphine-Catalyzed [3 + 2 + 3] Annulation of
the Azomethine Imine 1 and the Allenoate 2o
two molecules of ethyl 2,3-butadienoate (2o) and a phosphine,
presumably acted as a 1,5-dipole34 synthon to react with the
azomethine imine, providing the [3 + 2 + 3] cycloaddition
products. To the best of our knowledge, this reaction is the
first example of this trimeric 1,5-dipole being captured in a
phosphine-catalyzed intermolecular annulation of allenoates and
electrophiles.5a,35 This intriguing finding prompted us to further
investigate this new reaction modality of the allenoate 2o under
nucleophilic phosphine catalysis conditions. Although the literature
is replete with examples of the incorporation of two molecules of
alkenes, acetylenes, and allenes under transition-metal catalysis
conditions,36 these incidents are relatively rare in the realm of
organocatalysis.37
We varied the reaction conditions in an attempt to improve
the yields of the [3 + 2 + 3] adducts. An initial survey of the
reaction parameters revealed that the highest [3 + 2 + 3] product
yield resulted when we conducted the reaction in DCM/benzene
(4:1) at 0 °C. We employed this mixed solvent because DCM
aided the dissolution of the azomethine imine and benzene
favored the formation of the trimeric zwitterionic intermediate
from a phosphine and two ethyl 2,3-butadienoate (2o) units, as
observed by Lu.5a Varying the solvent or increasing the reaction
temperature was deleterious to the reaction selectivity—specifi-
cally, it increased the amounts of the [3 + 2] and [3 + 3]
cycloaddition products. In the mixed solvent (4:1 DCM/
benzene) at 0 °C, the reaction between the azomethine imine
1a and the allenoate 2o displayed behavior somewhat distinct
from that in DCM at room temperature (cf. Tables 5 and 6). For
instance, the use of PPh3 as the catalyst at 0 °C in 4:1 DCM/
benzene produced the [3 + 2] adduct as the major product
(Table 6, entry 1). The trialkylphosphines PBu3 and PMe3
exhibited similar reaction profiles (entries 2 and 3). Dimethyl-
phenylphosphine consistently provided the highest efficiency for
the formation of the tetrahydropyrazolopyrazolone 3ao (entry 4);
the overall reaction yield increased to 99%, of which 29%
corresponded to the tetrahydropyrazolodiazocinone products
7a/8a. The use of HMPT as catalyst produced even more of the
[3 + 2 + 3] product, but the overall mass recovery was lower
(entry 5). This observation prompted us to test the effects of
tris(sec-alkyl)phosphines (entries 6 and 7). We found that PCy3
was the most effective catalyst, affording the [3 + 2 + 3] adduct
7a/8a as the major product in 65% yield after 120 h (entry 8).
Triisopropylphosphine also produced the tetrahydrodiazocine
7a/8a as the major product, but with lower efficiency. Tris(tert-
butyl)phosphine displayed barely any reactivity at this low
on the TLC plates. With the γ-methyl and γ-phenyl allenoates as
substrates, we could not isolate the pure target products because
the reaction mixtures were too messy. From the γ-ethyl,
γ-isopropyl, and γ-tert-butyl allenoates 2pꢀ2r, we isolated the
[3 + 3] annulation products 60 as major products in moderate
yields (Scheme 5).
Scheme 3 presents a mechanistic rationale for the [3 + 2]
annulation of the azomethine imine 1a and the allenoate 2o to
form 3ao. The [3 + 3] annulation was initiated through the
formation of the β-phosphonium enoate intermediate J
(Scheme 6). Addition of the zwitterion J to the iminium unit
in 1 produced the phosphonium amide K. The 6-endo cyclization
of K furnished the ylide L, which eliminated the phosphine after
conversion to the β-phosphonium ester M to yield the tetra-
hydropyrazolopyridazinone 60. When the allenoate 2o was the
substrate, however, the conjugated enoate 60 was not isolated;
presumably, it isomerized into the enoate 6 because of the more
acidic nature of the γ-proton when R1 was a hydrogen atom. This
reaction marks the first example of a [3 + 3] annulation in which
all three unsaturated carbon atoms of an allene are incorporated
into the six-membered-ring product and suggests the future
development of other [3 + 3] annulations between 1,3-dipoles
and allenoates.
Next, we studied in further detail the unidentified byproduct
generated from the above-mentioned reaction of ethyl 2,3-
butadienoate (2o) and the azomethine imine 1a. To our delight,
using a combination of NMR spectroscopy and X-ray crystal-
lography, we determined the structures of these unknown
products to be an equilibrating mixture of unexpected [3 + 2 + 3]
products: the 1-oxo-2,3,5,6-tetrahydro-1H-pyrazolo[1,2-a][1,2]-
diazocine derivative 7 and the 1-oxo-2,3,5,10-tetrahydro-1H-pyr-
azolo[1,2-a][1,2]diazocine derivative 8 (Scheme 7). In this parti-
cular reaction, a trimeric zwitterionic intermediate, formed from
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Table 6. Phosphine-Catalyzed [3 + 2 + 3] Annulations of the Azomethine Imine 1a and the Allenoate 2oa
entry
PR3
PPh3
3ao yield (%)b
6 yield (%)b
7a/8ac,d yield (%)b
1
2
3
4
5
6
7
8e
29
26
51
65
50
24
5
19
12
3
<2
4
PBu3
PMe3
6
PMe2Ph
HMPT
P(i-Pr)3
PCy3
5
29
32
26
61
65f
4
10
2
PCy3
7
2
a 2.4 equiv of allenoate was used. b Isolated yield. c The structure of this compound was verified through single-crystal X-ray analysis. d The 7a:8a ratios
were not determined, except the case in entry 8. e The reaction was run for 120 h. f The 7a:8a ratio was 19:81, based on integration of signals in the 1H
NMR spectrum recorded in CDCl3.
Table 7. Phosphine-Catalyzed [3 + 2 + 3] Cycloadditions of the Azomethine Imines 1 with the Allenoate 2oa
entry
R
product
yield (%)b
ratio of 7:8c
1
Ph (1b)
7b + 8b
7c + 8c
7d + 8d
7e + 8e
7f + 8f
81
64
67
76
68
63
77
51
77
79
82
75
92
90
88
73
76
34:66
39:61
42:58
44:56
27:73
37:63
29:71
21:79
17:83
25:75
24:76
22:78
28:72
24:76
25:75
9:91
2
4-MeC6H4 (1c)
4-i-PrC6H4 (1d)
4-OMeC6H4 (1e)
4-FC6H4 (1f)
3
4
5
6
4-ClC6H4 (1g)
4-BrC6H4 (1h)
4-CNC6H4 (1i)
3-NO2C6H4 (1k)
3-FC6H4 (1v)
7g + 8g
7hd + 8h
7id + 8i
7k + 8k
7v + 8v
7w + 8w
7x + 8x
7y + 8y
7z + 8z
7zz + 8zz
7l + 8l
7
8
9
10
11
12
13
14
15
16
17
3-ClC6H4 (1w)
3-BrC6H4 (1x)
2-BrC6H4 (1y)
2-ClC6H4 (1z)
2-FC6H4 (1zz)
2-NO2C6H4 (1l)
2-naphthyl (1p)
7p + 8p
32:68
a 2.4 equiv of allenoate was used. b Isolated yield. c Based on integration of signals in the 1H NMR spectrum recorded in CDCl3; the solvent had a very
strong effect on the ratio. d The structure of this compound was verified through single-crystal X-ray analysis.
temperature, presumably because of steric hindrance; TLC
revealed almost no cycloaddition products.
Under these optimized reaction conditions (in 4:1 DCM/
benzene at 0 °C with 20 mol % of PCy3), we investigated the
reactions of a variety of azomethine imines 1 with the allenoate
2o (Table 7). When the azomethine imines 1 were derived from
benzaldehydes featuring electron-donating or -withdrawing sub-
stituents at the para position, the reactions proceeded smoothly
to afford the tetrahydropyrazolodiazocinones 7/8 in moderate to
good yields (Table 7, entries 1ꢀ8); thus, electron-withdrawing
and -donating groups at the para position provided similar
reaction efficiencies. In contrast, meta and ortho substitution
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Scheme 8. Mechanism for the [3 + 2 + 3] Cycloadditions of the Azomethine Imines 1 and the Allenoate 2o
Scheme 9. Reactions of the Tetrahydropyrazolopyrazolone 3ba and the Tetrahydropyrazolodiazocinone 7b
favored electron-withdrawing substituents (entries 9ꢀ16). In
particular, ortho-halogen-substituted aryl groups produced the
bicyclic products 7/8 in excellent yields (88ꢀ92%; entries
13ꢀ15). The 2-naphthaldehyde-derived azomethine imine 1m
was also a viable substrate (entry 17).
tetrahydropyrazolodiazocinone 8. In turn, we isolated com-
pound 8 as an equilibrating mixture with its tautomer 7.
To compare the relative ground state energies of the tetra-
hydropyrazolodiazocinones S (R = phenyl), 7b, and 8b, we
studied these three molecules computationally using density
functional theory (DFT) with the M06 functional, a hybrid
meta-GGA functional that can be a good choice for main-group
thermochemistry.39 Given the conformer-rich landscape of the
tetrahydropyrazolodiazocinones, we used the M06/6-31G**
level of theory to perform a conformational study, focusing
on the positioning of the ring substituents and inversion of
the sp3-hybridized nitrogen atom. We further minimized at
least two of the lowest-energy conformers for each isomer
(S, 7b, 8b) using finer grids and calculated the analytic Hessian
for each minimum. Electronic energies were calculated using the
M06 functional and the correlation-consistent polarized triple-ζ
basis set cc-pVTZ++40 as implemented in Jaguar 7.6.110.41 For
S, 7b, and 8b, the computed relative ground state free energies
(ΔG; including zero-point, solvation for DCM, and thermo-
dynamic corrections to the free energy at 298 K) at the M06/
cc-pVTZ++ level were 4.1, 0.8, and 0.0 kcal/mol, respectively;
thus, isomerization of the intermediate S to the product 8b is
thermodynamically favored, and compounds 8b and 7b would
Scheme 8 provides a mechanistic proposal for this unprece-
dented cyclization reaction. The key event is the formation of the
trimeric zwitterionic intermediate N, which is then captured
in situ by the azomethine imine 1. The trimeric zwitterionic
intermediate N is generated via the conjugate addition of the
β-phosphonium dienloate J to another molecule of the allenoate
2o. The self-cycloaddition of the allenoate 2o to form P under
phosphine catalysis has been reported previously, by Lu in
1995.5a Here, for the first time, we have realized the intermole-
cular cycloaddition of the trimeric intermediate N with the
azomethine imine. In a scenario where the fewest zwitterionic
intermediates are involved,38 the intermediate N adds to the
azomethine imine 1 to form the intermediate Q. The 8-endo
cyclization of Q produces the ylide R. Well-established proton
transfers and subsequent β-elimination of the phosphine leads to
formation of the tetrahydropyrazolodiazocinone product S. It
appears that the cross-conjugated exomethylene group in com-
pound S isomerizes into the endocyclic double bond to give the
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be in equilibrium at ambient temperature, as observed experi-
mentally (Table 7, entry 1).
catalysis conditions. In addition, we investigated spectroscopi-
cally and computationally the unique tautomerization behavior
of the tetrahydropyrazolodiazocinone products. Studies to ad-
dress the further applications of azomethine imines in nucleo-
philic phosphine catalysis and the development of asymmetric
variants of these annulations, as well as their use in the synthesis of
biologically relevant molecules, are ongoing in our laboratories.
In determining the structures of the [3 + 2 + 3] annulation
products, all of our 1H and 13C NMR spectra, recorded in CDCl3
at room temperature, indicated that the products existed as
mixtures of the tautomers 7 and 8 in solution, with 8 as the
major isomer. To further study the interconversion of compound
7 and its tautomer 8 in solution, we recorded 1H NMR spectra of
the 7a/8a and 7h/8h pairs in various deuterated solvents and at
various temperatures—making some interesting observations.
For the 7a/8a pair, 8a was the major isomer in either CDCl3 or
CD2Cl2 at room temperature; the ratio of 7a to 8a was
approximately 1:4. Even in CD2Cl2 at ꢀ80 °C, the ratio of 7a
to 8a remained unchanged, although the two signals of the
aromatic protons broadened as the temperature increased.42
Relative to the behavior of the 7a/8a pair, the 7h/8h equilibrium
was very sensitive to the solvent and temperature. In CDCl3 at
room temperature, 8h was the major isomer, and the ratio of 8h
to 7h was 71:29. In contrast, in CD2Cl2 at room temperature, 7h
existed as the sole isomer. When we decreased the temperature
from room temperature to ꢀ20 °C, the two signals of the
aromatic protons each resolved from one broad peak to two
distinct sharp peaks. More interestingly, in CDCl3 at 0 or
ꢀ20 °C, the mixture of the two tautomers 7h and 8h completely
converged into 7h.42 These observations are consistent with the
crystal growth behavior. When we left the 7h/8h compound pair
in DCM/MeOH, we isolated single crystals of 7h exclusively.
From the mixture of compounds 7a and 8a, we grew single
crystals of the single tautomer 8a from DCM/hexane or DCM/
MeOH.
The fused pyrazolidinone heterocycles, arising from the
phosphine-catalyzed annulations of azomethine imines with
allenoates, can be transformed into other useful compounds.
For example, SmI2 selectively reduced the exocyclic double bond
to provide pyrazolopyrazolone 9 as a single diastereoisomer43,44
while treatment with NaBH4 in EtOH furnished the ring-opened
product 10 as a mixture of diastereoisomers (Scheme 9). The
dihydropyrazolopyrazolone 11, obtained through the CuBr/
TBHP oxidation,45 should be a useful precursor for further
functionalization through cross-coupling reactions. Treatment
of the tetrahydrodiazocine 7b/8b with SmI2 reduced the enam-
ine double bond selectively to provide the dihydrodiazocine 12 in
73% isolated yield.43,44
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and characterization data for all new compounds. Crystal-
lographic data of compounds 3ad, 3an, 3ao, 4, trans-5, 6, 7h, 7i,
and 8a. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
hchguo@gmail.com; ohyun@chem.ucla.edu
’ ACKNOWLEDGMENT
This study was supported by the National Natural Science
Foundation of China (H.G.), the startup research funding from
China Agricultural University (H.G.), Chinese Universities
Scientific Fund (Project Nos. 2011JS029 and 2011JS031) (H.G.),
the National Scientific and Technology Supporting Program of
China (2011BAE06B05-5) (H.G.), Nutriechem Company (H.G.),
and the U.S. National Institutes of Health (NIH; O.K.: R01GM-
071779 and P41GM081282). Computational facilities were funded
by grants from ARO-DURIP and ONR-DURIP.
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