Stereo- and Regioselective 1,3-Dipolar Cycloaddition of the Stable Ninhydrin-Derived Azomethine Ylide to Cyclopropenes: Trapping of Unstable Cyclopropene Dipolarophiles

Article abstract of DOI:10.1021/acs.joc.9b00753

A stereo- and regioselective 1,3-dipolar cycloaddition of the stable ninhydrin-derived azomethine ylide [2-(3,4-dihydro-2H-pyrrolium-1-yl)-1-oxo-1H-inden-3-olate, DHPO] to differently substituted cyclopropenes has been established. As a result, an efficient synthetic protocol was developed for the preparation of biologically relevant spiro[cyclopropa[a]pyrrolizine-2,2′-indene] derivatives. DHPO has proved to be an effective trap for such highly reactive and unstable substrates as parent cyclopropene, 1-methylcyclopropene, 1-phenylcyclopropene, and 1-halo-2-phenylcyclopropenes. It has also been found that 3-nitro-1,2-diphenylcyclopropene undergoes a nucleophilic substitution reaction in alcohols and thiols to afford 3-alkoxy- and 3-arylthio-substituted 1,2-diphenylcyclopropenes, which can be captured as corresponding 1,3-dipolar cycloadducts in the presence of DHPO. These new approaches provide a straightforward strategy for the synthesis of functionally substituted cyclopropa[a]pyrrolizine derivatives. The factors governing regio- and stereoselectivity have been revealed by means of quantum mechanical calculations (M11 density functional theory), including previously unreported N_ylide-H_cyclopropene second-orbital interactions. The outcome of this work contributes to the study of 1,3-dipolar cycloaddition, as well as enriches chemistry of cyclopropenes and methods for the construction of polycyclic compounds with cyclopropane fragments.

Full text of DOI:10.1021/acs.joc.9b00753

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Article
A stereo- and regioselective 1,3-dipolar cycloaddition of the
stable ninhydrin-derived azomethine ylide to cyclopropenes.
Trapping of unstable cyclopropene dipolarophiles
Alexander S. Filatov, Siqi Wang, Olesya V. Khoroshilova, Stanislav V.
Lozovskiy, Anna G. Larina, Vitali M. Boitsov, and Alexander V. Stepakov
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 May 2019
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A stereo- and regioselective 1,3-dipolar cycloaddition of the
stable ninhydrin-derived azomethine ylide to cyclopropenes.
Trapping of unstable cyclopropene dipolarophiles
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a
a
a
a
Alexander S. Filatov, Siqi Wang, Olesya V. Khoroshilova, Stanislav V. Lozovskiy,
a
b,c
a,d
Anna G. Larina, Vitali M. Boitsov, Alexander V. Stepakov*
a
b
c
d
Saint Petersburg State University, Institute of Chemistry, Universitetskii pr. 26, 198504, St. Petersburg, Russian Federation
Saint Petersburg Academic University, ul. Khlopina 8/3, 194021, St. Petersburg, Russian Federation
Pavlov First Saint Petersburg State Medical University, ul. L'va Tolstogo 6/8, 197022, St. Petersburg, Russian Federation
Saint Petersburg State Institute of Technology, Moskovskii pr. 26, 190013, St. Petersburg, Russian Federation
Graphical abstract
R2
R1
R2
O
O
N
N
H
R1
H
Ph
R1
H, Me, Ph,
TMS, Br, Cl
R1
=
H
O
O
Ph
H
R1
R2
R2
O
N
O
DHPO
R2
NO2
O
O
N
N
R1
Ph
Ph
H
Me
R1 = H, Me
H
RXH as reaction
medium (X = O, S)
R1
O
O
Ph
XR
Me
Ph
R2
ABSTRACT: A stereo- and regioselective 1,3-dipolar cycloaddition of the stable ninhydrin-derived azomethine
ylide [2-(3,4-dihydro-2H-pyrrolium-1-yl)-1-oxo-1H-inden-3-olate, DHPO] to differently substituted
cyclopropenes has been established. As a result, an efficient synthetic protocol was developed for the preparation
of biologically relevant spiro[cyclopropa[a]pyrrolizine-2,2'-indene] derivatives. DHPO has proved to be an
effective trap for such highly reactive and unstable substrates as parent cyclopropene, 1-methylcyclopropene, 1-
phenylcyclopropene and 1-halo-2-phenylcyclopropenes. It has also been found that 3-nitro-1,2-
diphenylcyclopropene undergoes a nucleophilic substitution reaction in alcohols and thiols to afford 3-alkoxy-
and 3-arylthio-substituted 1,2-diphenylcyclopropenes which can be captured as corresponding 1,3-dipolar
cycloadducts in the presence of DHPO. These new approaches provide a straightforward strategy for the
synthesis of functionally substituted cyclopropa[a]pyrrolizine derivatives. The factors governing regio- and
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stereoselectivity have been revealed by means of quantum mechanical calculations (M11 density functional
theory), including previsously unreported Nylide–Hcyclopropene second orbital interactions. The outcome of this work
contributes to the study of 1,3-dipolar cycloaddition, as well as enriches chemistry of cyclopropenes and
methods for the construction of polycyclic compounds with cyclopropane fragments.
Key words: cyclopropenes, ninhydrin, α-amino acids, stable azomethine ylides, 1,3-dipolar
cycloaddition, regioselectivity, cyclopropa[a]pyrrolizines, DFT calculations, reactivity indexes, second
orbital interactions.
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INTRODUCTION
1
,3-Dipolar cycloaddition of azomethine ylides with alkenes is a universal synthetic tool for creating five-
1
membered nitrogen-containing heterocyclic fragments, which are part of many natural alkaloids, as well as
2
pharmacologically and biologically important compounds. The chemistry of azomethine ylides has attracted
considerable attention from synthetic chemists. Remarkable results have been achieved in this area such as the
discovery of metal catalysts that make it possible to use unactivated and electron-rich olefins as dipolarophiles in
3
the [3+2] cycloaddition reactions. Cyclopropenes occupy a special place among alkenes. Their unique reactivity
4
due to high ring strain and low distortion energy makes them valuable synthetic intermediates. Owing to concert
nature of 1,3-dipolar cycloadditions, cyclopropene dipolarophiles are intensively used for the highly
stereoselective synthesis of many significant polycyclic heterocycles containing a cyclopropane fragment. The
first examples of reactions between cyclopropenes (2,3-diphenylcycloprop-2-en-1-one and 1,2,3-
triphenylcycloprop-1-ene) and azomethine ylides generated from aziridines were disclosed by Lown and
Uchida.5 Recently, we have investigated 1,3-dipolar cycloadditions of cyclopropenes with azomethine ylides
6
7
generated in situ by decarboxylative condensation of isatins, 11H-indeno[1,2-b]quinoxaline-11-ones and
8
tryptanthrines with α-amino acids. These cycloadditions were found to be fruitful approaches for the
diastereoselective synthesis of cyclopropa[a]pyrrolizine and 3-azabicyclo[3.1.0]hexane frameworks.
Asymmetric construction of 3-аzabicyclo[3.1.0]hexanes was successfully implemented by copper-catalyzed 1,3-
dipolar cycloaddition of сyclopropenes with azomethine ylides, generated from glycine aldiminoesters.9
However, cyclopropenes as a unique type of unsaturated compounds have rarely been employed as
dipolarophiles in reactions with stable azomethine ylides. A survey of the literature revealed that only two
cyclopropenes
(1,2,3-triphenylcyclopropene
and
methyl
2-(tert-butyldimethylsilyl)oxy-cycloprop-1-
enecarboxylate) were used as dipolarophiles in the reactions with stable pyridazinium, phthalazinium,
pyridinium, isoquinolinium dicyanomethylides and bis(methoxycarbonyl)methylide (Scheme 1).10 In spite of
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these pioneering works, the reactions of cyclopropenes with stable nitrogen ylides are still rather limited and
therefore full of possibilities. In view of the importance of use of cyclopropenes as dipolarophiles and as a
continuation of our efforts in the construction of cyclopropa[a]pyrrolizine scaffolds via azomethine ylide-
involved reactions, we explored the 1,3-dipolar cycloaddition of differently substituted cyclopropenes with the
stable azomethine ylide derived from condensation of ninhydrin and L-proline (Scheme 1).
1
1
1
1
1
1
1
1
1
1
2
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In our recent studies,6-8 we considered reactions involving stabilized azomethine ylides in situ generated
either from 1,2-dicarbonyl compounds (isatins) or from compounds containing the O=C–C=N fragment (11H-
indeno[1,2-b]quinoxalin-11-ones and tryptanthrines). In these cases, the stabilization of azomethine ylides is
achieved by the delocalization of the negative charge with a neighbouring electron-withdrawing group. In this
paper, we set to work questioning whether the addition of a second strong electron-withdrawing group to an
azomethine ylide would affect its reactivity in cycloaddition reactions with cyclopropenes (Scheme 1).
(1) Previous works
toluene, rt
N
CN
CN
(a)
+
CN
Ref. 10a
N
TBSO
CO2Me
H
CN
MeO C
2
OTBS
isoquinolinium
dicyanomethylide
Ph
(b)
N
CO Me
2
DMF, reflux
Ref. 10b
N
CO Me +
2
CO Me
2
Ph
Ph
CO Me
2
Ph
Ph
isoquinolinium
bis-(methoxycarbonyl)methylide
Ph
X
Ph
X
N
CN
CN
(c)
DMF, reflux
Ref. 10c
N
CN +
Ph
Ph
Ph
CN
phthalazinium, pyridazinium
or pyridinium dicyanomethylides
Ph
Ph
(
2) This work
O
O
R3
N
H
MeOH or THF
mild conditions
R1
different cyclopropenes
(including unstable substrates)
N
+
R2
O
R2
R1
O
R3
stable azomethine ylide
from ninhydrin and L-proline
Scheme 1. 1,3-Dipolar cycloaddition of stable azomethine ylides with cyclopropenes
On the other hand, the cyclopropa[a]pyrrolizine skeleton combines structural fragments of pyrrolizine and
3-azabicyclo[3.1.0]hexane. Pyrrolizine derivatives (Figure 1, I and II) demonstrate promising pharmaceutical
activities such as antileukemic,11 anti-inflammatory, antimycobacterial, and as inhibitors for the microsomal
12
13
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1
4
prostaglandin E2 synthase-1 (mPGES-1). 3-Azabicyclo[3.1.0]hexanes (Figure 1, IIIV) are a pharmaceutically
important class of bicyclic compounds with a broad spectrum of biological activities, for example antibacterial,15
antiviral,16 antitumor,17 as well as perspective compounds for treating of neuroinflammations.18 Thus, the
development of cyclopropa[a]pyrrolizines synthesis, particularly with high stereoselectivity, is an important area
of synthetic organic chemistry. Herein, we report 1,3-dipolar cycloadditions of stable ninhydrin-derived
azomethine ylide [2-(3,4-dihydro-2H-pyrrolium-1-yl)-1-oxo-1H-inden-3-olate, DHPO] with various
cyclopropenes, including gaseous and unstable substrates, to obtain biologically relevant
spiro[cyclopropa[a]pyrrolizine-2,2'-indene] framework with complete regio- and diastereoselectivity. The
presumed wealth of DHPO in cycloaddition reactions has not yet been exploited to the full. A number of
symmetrically 1ao, unsymmetrically 2ai substituted cyclopropenes, and also unsubstituted at the double bond
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cyclopropenes 3ac were chosen for this study (Figure 2).
OCONHMe
O
O
F
F
H
H
F
Ph
O
N
N
H
N
N
F
N
OCONHMe
O
CO H
HO
2
O
S
II, anti-inflammatory drug
III, antibacterial activity (ref. 15a)
(
Ketorolac, ref. 12)
I, antileukemic activity (ref. 11b)
Me Me
H
H
O
H
N
O
NH2
H
N
HN
N
N
NHOH
N
H
O
H
O
F
N
t-BuHN
N
O
V, antitumor activity (ref. 17a)
O
t-Bu
IV, antiviral activity (ref. 16b)
Figure 1. Selected bioactive pyrrolizine and 3-azabicyclo[3.1.0]hexane derivatives.
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Cyclopropenes symmetrically substituted at the double bond
Ph
Ph
Et
CO Me
2
Ph
Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph
1a
1b
1c
1d
1e
CO H
CONHiPr
CONMe2
CONH2
CN
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph
1f
1g
1h
1i
1j
CO Me
CO H
NO2
2
2
Ph Me
Ph
Ph Me
Me Me
Me Ph
Ph Ph
Ph
1k
1l
1m
1n
1o
Cyclopropenes unsymmetrically substituted at the double bond
Me
Ph
Ph
Me Ph
TMS
2a
2b
2c
2d
CO H
CO H
2
2
Ph
2
2
X
Me
Ph Me
2h, Ar = 4-Tol
2i, Ar = 4-MeOC H
Ar
e, X = Br
f, X = Cl
2g
6
4
Cyclopropenes unsubstituted at the double bond
Ph Me
Me CO Me
2
3a
3b
3c
Figure 2. Cyclopropenes 1-3 used in the present study.
RESULTS AND DISCUSSION
The condensation reaction of ninhydrin (4) with L-proline (5a) either in lower aliphatic alcohols (MeOH,
EtOH) or in the solid state resulted in formation of DHPO (6) in a high yield (> 90%) (Scheme 2). As a rule,
DHPO (6) is not isolated in its pure form when studying cycloaddition reactions, it is generated in situ in a
solution in the presence of dipolarophiles.19 We considered the cycloaddition of DHPO (6) to 1,2,3-
triphenylcyclopropene (1a) to optimize the reaction conditions. Initially, the one-pot three-component 1,3-
dipolar cycloaddition of ninhydrin (4), L-proline (5a) and cyclopropene (1a) was performed in MeOH (Table 1).
1,2,3-Triphenylcyclopropene (1a) was chosen as a preferred substrate since the one had demonstrated high
reactivity towards various azomethine ylides in previous studies.
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O
O
O
O
1
2
. -H2O
. -CO2
OH
OH
N
CO2H
N
H
MeOH, 25 °C
4
5a
6
, DHPO (96%)
Scheme 2. The synthesis of stable azomethine ylide 6 from ninhydrin (4) and L-proline (5a).
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Table 1. Optimization of the reaction conditionsa,b,c,d
O
Ph
Solvent
A.
N
Ph
Ph
O
N
1a
6
O
H
O
O
Ph
O
Ph
Ph
OH
OH
Solvent
Ph
B.
7a
CO2H
N
Ph
Ph
H
1a
4
5a
Entry
Method
Solvent
MeOH
MeOH
MeOH
T [°C]
Time, h Yield,%d
1
2
3
A
B
A
reflux
reflux
25
4
6
85
72
95
10
4
B
A
B
A
B
A
B
A
B
A
B
MeOH
THF
25
25
25
25
25
25
25
25
25
25
25
10
84
82
69
79
72
63
54
57
19
87
62
5
5
6
THF
8
7
1,4-dioxane
1,4-dioxane
acetonitrile
acetonitrile
5
8
6
9
6
9
10
1
1
CH
2
2
Cl
2
2
8
12
CH
Cl
12
1
3
solvent free
5 min
10 min
1
4
solvent free
a
Reactions of 1a (0.4 mmol) and 6 (0.4 mmol) were carried out in 10 mL of solvent.
Reactions of 1a (0.4 mmol), 4 (0.4 mmol) and 5a (0.6 mmol) were carried out in 10
b
mL of solvent. c The reactants were carefully ground in a porcelain mortar under
solid-state conditions. d Isolated yield.
When the reaction between cyclopropene 1a and DHPO (6) (Method A) was performed using MeOH as
the solvent at reflux for 4 h, cycloadduct 7a was obtained in 85% yield as a single diastereomer (Table 1, entry
1
1). Other possible diastereomers were not detected by H NMR analysis of the crude reaction mixture. The
structure and the relative endo-configuration of 7a were determined by spectroscopic and X-ray analysis (see
Supporting Information, Figure S88). That means that the reaction has been proceeded with complete
diastereoselectivity with the approach of azomethine ylide 6 from less-hindered face of 1,2,3-
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triphenylcyclopropene (1a). The one-pot three-component reaction (Method B) afforded a lower yield in MeOH
at reflux for 6 h (Table 1, entry 2). When the reaction temperature was lowered to 25 °C, the yield was
increased to 95% (Method A) and 84% (Method B) (Table 1, entries 3–4). The reactions could be carried out in
THF at 25 °C within 5-8 h, affording the target product 7a in 82% (Method A) and 69% (Method B) yields
(Table 1, entries 5-6). The reactions which were performed in other media, such as 1,4-dioxane, acetonitrile and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
4
4
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4
4
4
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4
4
4
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5
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5
5
5
5
5
5
5
6
0
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5
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7
8
9
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8
9
0
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5
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7
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9
0
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0
dichloromethane provided the product 7a in moderate to good yields (Table 1, entries 7–11). The use of
dichloromethane as a solvent was found to be ineffective for the three-component reaction (Table 1, entry 12).
The modest yield of DHPO (6) indicates that the reaction rate in a non-polar solvent is a much lower than in
polar ones. Finally, the solid-state reaction between DHPO (6) and 1,2,3-triphenylcyclopropene (1a) was also
investigated. Manual grinding of an equimolar mixture of 1a and DHPO (6) for 5 min in a porcelain mortar gave
the desired product 7a in 87% yield (Table 1, entry 13). Carrying out a one-pot three-component reaction under
similar conditions led to a decrease in a yield to 62% (Table 1, entry 14). Accordingly, the optimal conditions for
further assessment of the reaction scope were set as illustrated in Table 1 (entry 3 and entry 13).
3
2
Next, the effect of C -substituents (R groups) of cyclopropenes on the reaction was studied. Under
optimized reaction conditions, we explored the scope of symmetrically substituted cyclopropenes 1 (Table 2).
Cyclopropenes 1 containing phenyl and methyl substituents at the double bond were used as substrates. As
2
shown in Table 2, the reaction in MeOH tolerates a wide range of cyclopropenes bearing various R groups to
furnish cycloadducts 7 in moderate to high yields with excellent diastereoselectivities. Regardless of electronic
3
nature (electron-donating or electron-withdrawing) of the substituent at the C position of a cyclopropene ring,
the corresponding products 7aj were obtained in good yields (69−95%). As seen from Table 2,
cyclopropenes containing phenyl (1a), ethyl (1b), vinyl (1c), phenylethynyl (1d) substituents, as well as
CO
2
Me (1e), CO
2
H (1f), CONHi-Pr (1g), CONMe
the C position react actively with DHPO (6). In the case of 1,2-diphenyl-3-vinylcyclopropene (1c) and
,2-diphenyl-3-phenylethynylcyclopropene (1d), the cyclopropene double bond was more susceptible to
2 2
(1h), CONH (1i) and CN (1j) functional groups at
3
1
cycloadditions reactions to form cyclopropa[α]pyrrolizines 7c and 7d in 91% and 92% yields,
respectively. When using 1,2-diphenylcyclopropene (1k) as a dipolarophile, the desired endo-cycloadduct 7k
was obtained in 87% yield. However, cyclopropenes 1l,m bearing methyl substituents at the double bond
showed relative sluggish reactivities, resulting in the formation of corresponding products 7l and 7m in modest
yields (42 and 33%, respectively). Based on the relative endo-stereochemistry of 7a, we similarly assigned the
relative configurations of other cycloadducts 7bk as depicted in Table 2. The exo-arrangement of substituents
1
1
attached to a cyclopropane ring of cycloadducts 7l,m was confirmed by analysis of 2D NMR spectrum ( H- H
NOESY) of cycloadduct 7m (Figure S27). Thus, the considered approach is applicable to a large number of
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
5
5
6
2
cyclopropenes with various R groups to provide structurally diverse spiro[cyclopropa[a]pyrrolizine-2,2'-indene]
derivatives 7 in acceptable yields and complete diastereoselectivity. The ability to scale up this method was
demonstrated by the preparation of cycloadduct 7a on a gram scale. The reaction of 1a with DHPO (6)
proceeded readily to furnish the desired product 7a in 92% yield (Scheme 3).
Subsequently, we studied the reactions of 1,2-diphenylcyclopropenes 1ae,h,j,k in solid-state conditions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The solid-state reactions of cyclopropenes 1ad,j,k with DHPO (6) led to the formation of products 7ad,j,k in
7
5-87% yields (preparative yields are given in parentheses in Table 2). However, the solid-state reactions of
3
cyclopropenes 1е,h containing the electron-withdrawing CO
2
Me and CONMe
2
groups at C position are
accompanied by a decrease in the yield of target compounds 7e (31%) and 7h (54%).
Table 2. Reaction of DHPO (6) with symmetrically substituted cyclopropenes 1ama,b,c,d
O
R2
O
N
MeOH
H
N
25 °C
R1
R1
R1
O
R1
6
1a-m
7a-m
O
R2
O
O
O
O
O
N
N
N
N
N
H
H
H
H
H
O
Ph
O
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
CO Me
2
7
a, 95% (87%)
7b, 88% (79%)
7c, 91% (85%)
7d, 92% (80%)
7e, 90% (31%)
Ph
O
N
O
N
O
N
O
N
O
N
H
H
H
H
H
Ph
O
Ph
O
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
Ph
Ph
CO2H
CONHiPr
CONMe2
CONH2
CN
7f, 71%
7g, 78%
7h, 85% (54%)
7i, 69%
7j, 89% (84%)
O
N
O
N
O
N
H
H
H
Me
O
Ph
O
Me
O
Ph
Me
Me
CO2Me
CO2H
7
k, 87% (75%)
7l, 42%
7m, 33%
a
c
b
Reactions of 1 (0.4 mmol), 6 (0.4 mmol) were carried out in 10 mL of MeOH at 25 °C for 10 h. Reaction time for 7l and 7m is 30 h.
Isolated yield. d Preparative yields for the solid-state reactions are given in parentheses.
O
O
Ph
N
MeOH
H
(40 mL)
N
25 °C, 10 h
O
Ph
Ph
Ph
a (0.80 g)
Ph
O
1
6 (0.64 g)
7a (1.38 g)
Ph
Scheme 3. The gram-scale synthesis of 7a.
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In contrast to the cycloaddition reaction with monosubstituted and unsubstituted at the C position
cyclopropenes 1a–m, no cycloadduct was isolated from the reaction of tetrasubstituted cyclopropene 1o and
DHPO (6). This fact could be explained by a diminished reactivity of the double bond of such
cyclopropene towards 1,3-dipolar cycloaddition due to steric hindrance. The reactions involving 3-nitro-1,2-
diphenylcyclopropene (1n) are considered separately since they are accompanied by substitution processes at a
cyclopropene ring (vide infra).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Unfortunately, we failed to obtain stable azomethine ylides from ninhydrin and such secondary α-amino
acids as L-4-thiazolidinecarboxylic acid (5b), pipecolic acid (5c) and azetidine-2-carboxylic acid (5d). However,
the synthesis of cycloadducts 8 and 9 was successfully implemented through three-component reactions (Scheme
4
). The three-component reaction between 1,2,3-triphenylcyclopropene (1a), ninhydrin (4), and L-4-
thiazolidinecarboxylic acid (5b) in EtOH at reflux resulted in the diastereoselective formation of 8 in acceptable
yield (74%). Further, we found that the one-pot 1,3-dipolar cycloaddition reaction of cyclopropene 1a with
the azomethine ylide derived from ninhydrin and pipecolic acid (5c) proceed in ethanol at reflux. Under
these conditions, spiro[cyclopropa[a]indolizine] 9 formed diastereoselectively, albeit in a modest yield
(
36% isolated). The presence of a non-planar dihydropiperidinium fragment in the intermediate
azomethine уlide probably hampers the approach of cyclopropene dipolarophile. The relative endo-
1
1
configurations of resulting cycloadducts 8 and 9 were deduced based on H- H NOESY spectra (see
Supporting Information, Figures S30 and S33, respectively). All attempts to carry out three-component
reactions involving azetidine-2-carboxylic acid have failed.
S
CO2H
5b
S
O
O
N
O
H
N
S
1a
H
N
EtOH
reflux
O
Ph
Ph
Ph
8
, 74%
O
O
O
N
CO2H
5c
O
H
N
OH
OH
1a
H
N
EtOH
reflux
O
Ph
O
Ph
4
Ph
9
, 36%
O
CO2H
N
+
1a
H
N
H
5
d
O
Ph
Ph
EtOH
reflux
Ph
1
0, no product
Scheme 4. The one-pot three-component 1,3-dipolar cycloaddition reactions of ninhydrin (4),
α-amino acids 5b d and cyclopropene 1a.
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2
2
2
2
2
2
2
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3
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4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
In order to evaluate the regioselectivity of 1,3-dipolar cycloaddition reaction involving cyclopropenes and
DHPO, we further extended the scope of this reaction with unsymmetrically substituted at the double bond
cyclopropenes 2a–i. Initially, we considered the reactions of 1-methylcyclopropene (2a) and 1-
phenylcyclopropene (2b) with DHPO (6). To the best of our knowledge, the 1,3-dipolar cycloadditions of
monosubstituted cyclopropenes 2a and 2b have never been investigated. Cyclopropene 2a was generated from 1-
lithio-2-methylcyclopropene by slow addition of MeOH to its ether solution20 and introduced with a stream of
argon to a suspension of DHPO (6) in THF over 5 min at -30 °C. Complete dissolution of ylide 6 was
reached by gradually increasing the temperature of the reaction mixture to 0 °C (Scheme 5). Evaporation
of the solvent followed by purification using preparative thin layer chromatography (PTLC), gave pure product
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1a with total regio- and diastereoselectivity in 92% yield. The 2D NMR spectroscopy (NOESY) and X-ray
analysis of cycloadduct 11a have disclosed that the compound 11a has a relative endo-configuration, and the
methyl group of the cyclopropane ring is adjacent to the spiro-atom (the 1,5-orientation) (see Supporting
Information, Figures S36 and S89).
After that, we carried out our investigation with 1-phenylcyclopropene (2b). As previously reported by
Lee, 1-phenylcyclopropene is a highly unstable compound that undergoes ene dimerization and trimerization, as
well as [2+2]-dimerization. At the same time, cyclopropene 2b can be trapped in solution as a Diels-Alder
2
1
adduct with cyclopentadiene. In this study, we have made an effort to use the 1,3-dipole 6 as a trap for unstable
cyclopropene 2b (Scheme 5). 1-Lithio-2-phenylcyclopropene was served as a precursor for the generation of 1-
phenylcyclopropene. This salt was readily prepared by treatment of 1,1,2-tribromo-2-phenylcyclopropane with
2
.5 equiv of methyllithium. Subsequently, the ether solution of 1-lithio-2-phenylcyclopropene was carefully
added to the mixture of DHPO (6) and acetic acid in THF. 1-Phenylcyclopropene (2b) that formed during the
protonation of 1-lithio-2-phenylcyclopropene with acetic acid reacted smoothly with DHPO (6) to give the
corresponding endo-cycloadduct 11b (88% isolated) in a totally 1,5-regio- and diastereoselective fashion.
O
N
DHPO (6)
MeOH
H
Et2O, 0 °C
-30 °C to 0 °C
argon stream
Me
Ph
2
a
O
H
Me
1
1a, 92%
R
Li
R = Me, Ph
O
N
DHPO (6)
AcOH
H
THF, RT
25 °C
2b
O
H
Ph
1b, 88%
1
Scheme 5. Trapping of monosubstituted cyclopropenes 2a,b with DHPO (6).
Then we examined the reactions of cyclopropenes 2ci with different substituents at the double
bond with DHPO (6) under the optimal conditions (THF or methanol at 25 °C). The results are
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summarized in Table 3. As it turned out, 1-methyl-2-phenylcyclopropene (2с) proved to be a suitable
reactant which successfully participated in 1,3-dipolar cycloaddition with DHPO (6), affording the endo-
adduct 11c in 96% yield with full 1,5-regioselectivity. Furthermore, when cyclopropenes with a
heteroatom substituent at the double bond 2df were tested, it was found that the cycloaddition process
proceeded easily for 5 min by employing THF as a solvent. The desired adducts 11d
f
were obtained in high
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yields with excellent regio- and diastereoselectivities. 2-Aryl-3-methylcycloprop-2-enecarboxylic acids 2gi also
reacted in a highly regio- and stereoselective manner. However, it needed more time (48 h) to achieve complete
conversion of reactants into products. The structures and relative configurations of spirocyclic compounds
1
1bf,h were ambiguously corroborated by 2D NMR spectra of 11bf and X-ray analysis of 11h (see
Supporting Information, Figures S39, S42, S45, S48, S51 and S90).
Table 3. Reaction of DHPO (6) with unsymmetrically substituted cyclopropenes 2cia,b,c
O
R3
O
N
solvent
H
N
25 °C
R1
R2
R2
O
2c-i
R1
O
6
11
R3
O
O
O
N
N
N
H
H
H
Me
O
TMS
O
Br
O
Ph
Ph
Ph
11c, 96%
11d, 87%
11e, 82%
O
O
O
N
N
N
H
H
H
Me
O
Me
O
O
Cl
R1
Ph
Ph
CO H
CO2H
2
11h, R1 = 4-Tol, 72%
1
1f, 75%
11g, 63%
11i, R1 = 4-MeOC H , 51%
6
4
a
Reactions of cyclopropenes 2cf (1.5 mmol) with 6 (1.0 mmol) were carried out in 5 mL of
THF at 25 °C for 5 min. b Reactions of cyclopropenes 2gi (0.4 mmol), 6 (0.4 mmol) were
c
performed in 5 mL of MeOH at 25 °C for 48 h. Isolated yield.
Parent cyclopropene (3a) is a very active dienophile in the Diels-Alder reaction.22 Nevertheless, less
attention has been paid to its activity as a dipolarophile in 1,3-dipolar cycloaddition reactions. This highly
reactive cycloalkene has been explored only with 1,3-dipoles of the propargyl/allenyl anion type - nitrile oxides
and nitrilimines.23 We have suggested that azomethine ylide 6 may act as an effective trap for cyclopropene 3a
(Scheme 6). To validate this hypothesis, we obtained parent cyclopropene (3a) from allyl chloride and NaHMDS
in anhydrous toluene and introduced with a slow stream of dry argon into a suspension of DHPO (6) in THF at -
7
8 °C for 10 min. A gradual increase in the temperature of the reaction mixture to 0 °C led to the complete
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
dissolution of the ylide 6. Subsequent purifιcation by PTLC afforded exclusively endo-cycloadduct 12a in 89%
yield. The relative configuration of cycloadduct 12a was established by considering of its 2D NMR spectrum
(see Supporting Information, Figure S61). The 1,3-dipolar cycloaddition reaction of parent cyclopropene (3a)
with DHPO (6) provides a good opportunity for the synthesis of parent spiro[cyclopropa[a]pyrrolizine]
derivative.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
DHPO (6)
N
NaHMDS
Cl
H
toluene
reflux
THF
o
3a -78 to 0 C
H
O
argon stream
H
12a, 89%
Scheme 6. The generation of parent cyclopropene (3a) and its reaction with DHPO (6).
Contrary to parent cyclopropene (3a), 3,3-disubstituted cyclopropenes 3b,c reacted with poor
diastereoselectivity to furnish cycloadducts 12b,c as inseperable mixtures of two diastereomers approximately in
1
ratio 1.9:1 and 1.6:1, [the original diastereomeric ratio was examined by analysis of H NMR spectra of
crude mixtures], respectively (Scheme 7). After work-up procedure, the mixtures were obtained in 61% and
4
7% isolated yields, respectively, and characterized by increase in diastereomeric ratio, 3:1 for 12b and 2:1 for
2c (See Supporting Information, Figures S62 and S65).
1
O
O
R1 R2
N
H
MeOH
5-60 °C
N
+
2
H
O
3b,c
H
R2
O
6
R1
1
2
1
2b, R = Me, R = Ph, 3:1 dr, 61%
1
2
1
2c, R = Me, R = CO Me, 2:1 dr, 47%
2
Scheme 7. Reactions of DHPO (6) with 3,3-disubstituted cyclopropenes 3b,c.
The next phase of the study focused on the reaction involving DHPO (6) and 3-nitro-1,2-
diphenylcyclopropene (1n). As it turned out, this reaction did not proceed in aprotic polar solvents (such as THF
or 1,4-dioxane), whereas the reaction in MeOH at 25 °C gave a methoxy derivative 13a in 57% yield (Table 4).
The compound 13a was isolated in a low yield (15%) by carrying out the reaction in MeOH-THF mixture. Next,
we considered the possibility of using other primary and secondary alcohols under similar conditions [6 (0.4
mmol), 1n (0.4 mmol), 10 mL ROH at 25 °C] as shown in Table 4. For example, the reaction in ethanol
proceeded smoothly to give ethoxy substituted spiro[cyclopropa[a]pyrrolizine] 13b in a fully diastereoselective
fashion. The relative configuration of cycloadduct 13b was unequivocally ascertained by single-crystal X-ray
diffraction (see Supporting Information, Figure S91). When we performed reactions in other primary alcohols
such as 1-propanol and 2-methoxyethanol, the resulting cycloadducts 13c and 13d were obtained in moderate
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yields (55% and 41%, respectively). The reaction in isopropanol furnished the adduct 13e in 49% yield.
Treatment of a mixture of 3-nitro-1,2-diphenylcyclopropene (1n) and DHPO (6) by t-BuOH at 40 °C for 24 h
resulted in the diastereoselective formation of spirocyclic product 13f containing a tert-butoxy group.
Some thiols were also utilized as nucleophilic medium to expand the synthetic usability of this
methodology. Thiophenol, p-thiocresol and 1-hexanethiol were chosen for these reactions (Table 4). The first
experiments revealed that the reaction involving DHPO (6), cyclopropene 1n and thiophenol did not take place
in THF. Nevertheless, the reaction proceeded slowly in the thiophenol medium at 25 °C. To reach the full
conversion within a short period of time, the mixture of 1n, 6 and thiophenol under an argon atmosphere was
heated to 140 °C and kept at this temperature for 5 min. After purification of the crude mixture by PLTC, the
phenylthio substituted product 13g was obtained in a moderate yield (65%). The transformation also worked
efficiently under similar conditions by employing 4-methylbenzenethiol as a reactant. The corresponding
cycloadduct 13h was obtained in 67% yield with high diastereoselectivity. As illustrated in Table 4, 1-
hexanethiol proved to be an ineffective reactant, which reacted with cyclopropene 1n followed by cycloaddition
with DHPO (6) to give the product 13i in a modest yield (27%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. The three-component reactions of cyclopropene 1n, DHPO (6), and RXH (X = O, S)a,b,c,d
non-
nucleophilic
solvent
O
O
NO2
O
N
RXH
H
no reaction
N
Ph
Ph
O
Ph
Ph
6
1n
13
XR
O
O
O
N
N
N
H
H
H
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
1
3a (57%) OMe
OEt
OPr
13b (43%)
13c
(55%)
O
N
O
O
N
N
H
H
H
O
Ph
O
Ph
O
Ph
Ph
Ph
Ph
O(CH ) OMe
13e (49%)
OiPr
13f (37%) OtBu
13d (41%)
2 2
O
N
O
N
O
N
H
H
H
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
S(n-Hexyl)
SPh
13h (67%)
S(4-Tol)
13i (27%)
13g (65%)
a
All reactions in alcohol medium were carried out with 1n (0.4 mmol), 6 (0.4 mmol) and ROH
(10 mL) at 25 °C for 24 h. b The reaction in t-BuOH was conducted at 40 °C for 24 h. c All
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reactions in a thiol medium were carried out with 1n (0.4 mmol), 6 (0.4 mmol) and RXH (10
mL) at 140 °C for 5 min. d Isolated yield.
We assume that these reactions proceed through the formation of the 2,3-diphenylcycloprop-2-en-1-ylium
cation (14) due to the heterolytic C-N bond cleavage of the starting 3-nitro-1,2-diphenylcyclopropene (1n)
(Scheme 8). The aromatic cation 14 reacts with a nucleophile RXH to give the cyclopropene 15. The latter
cycloadds to azomethine ylide 6 to form products 13. To confirm this mechanism, we kept 3-nitro-1,2-
diphenylcyclopropene (1n) in absolute methanol at 25 °C for 24 h (TLC control). After evaporation of the
solvent, 3-methoxy-1,2-diphenylcyclopropene (15a, XR = OMe) was obtained as a yellow oil (see Supporting
Information, Figures S86 and S87).24 The reaction of cyclopropene 15a with 6 in MeOH (or THF) resulted in
the formation of cycloadduct 13a (44% yield, two steps). It is noteworthy that (E)-2,3-diphenylacrylaldehyde
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
16) was detected as a by-product (a yield up to 10%) in these reactions. The aldehyde presumably formed as a
result of oxidation of the intermediate 2,3-diphenylcycloprop-2-en-1-ylium cation (14) under the reaction
conditions.6
NO2
XR
RXH
DHPO (6)
13
Ph
Ph
Ph
Ph
1n
15
S 1
N
RXH
H
O
[O]
NO2
Ph
Ph
Ph
Ph
14
1
6 (by-product)
Scheme 8. The proposed mechanism for the three-component reaction of 3-nitro-1,2-diphenylcyclopropene (1n), DHPO (6)
and RXH.
A comprehensive DFT computational study was perfomed to reveal factors controlling regio- and
stereoselectivity in the observed reactions (Scheme 9). At the first stage of the study, global electrophilicity
indexes (ω) were obtained for DHPO (6) and starting cyclopropenes 1–3 using the equations recommended
by Parr25 and Domingo.26 These global descriptors were applied to further use within the framework of
FMO theory (Table 5). The index (ω) increases with the number of substituents attached to a cyclopropene ring,
starting from 0.27 eV for parent cyclopropene (3a) (Table 5, entry 2) and ending with diphenylcyclopropenes 1
bearing an electron-withdrawing group such as 2,3-diphenylcyclopropene-1-carboxylate (1e, 0.54 eV), 2,3-
diphenylcyclopropene-1-carbonitrile (1j, 0.59 eV) and 3-nitro-1,2-diphenylcyclopropene (1n, 0.62 eV) (Table 5,
entries 16, 17, 19). Thus, the main observed trend is an energetically more favorable interaction between the
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LUMO of DHPO (6) (ω = 0.50 eV, Table 5, entry 1) and the HOMO of cyclopropenes 1–3. The 1,3-dipolar
cycloadditions should strictly occur under inverse electron demand (IED). That being said, 3-nitro-1,2-
diphenylcyclopropene (1n) cannot interact with the DHPO (6) along the IED channel due to a sufficiently large
value of its ω in comparison to the index of DHPO (Δω = 0.12 eV). The presence of the strong electron-
withdrawing nitro group considerably suppresses nucleophilic power of 1n and dramatically affects the reactivity
of 3-nitro-1,2-diphenylcyclopropene towards DHPO under aprotic conditions (Table 4). However, 3-nitro-1,2-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
diphenylcyclopropene can undergo a nucleophilic substitution reaction in alcohols and thiols via S 1 mechanism
to give less electrophilic XR-substituted cyclopropenes 15 (Scheme 8). The latter readily cycloadd to DHPO (6)
under IED (Scheme 8 and Table 5, entry 19).
NED vs IED
global electrophilicity index 
1
,4-isomers (head-to-tail) vs 1,5-isomers (head-to-head)
charge control 
orbital control 
Fukui functions 
Exo vs Endo
kinetic control due to
NDHPO-Hcyclopropene
second orbital interactions 
Scheme 9. General route of DFT study on regio- and stereoselectivity in the observed reactions
NED - normal electron demand, IED – inverse electron demand).
(
Table 5. FMO energies (a.u.), electronic chemical potential (μ, eV), chemical hardness (η, eV) and global electrophilicity
index (ω, eV) for DHPO (6) and starting cyclopropenes 13.a,b
Entry
Reactant
6
HOMO
-0.28783
-0.35735
-0.31788
-0.38046
-0.34216
-0.3075
-0.29723
-0.30187
-0.30823
-0.3107
-0.31353
-0.28655
-0.28024
-0.28063
-0.29102
-0.29346
-0.29962
-0.28152
-0.30857
LUMO
0.06166
0.15559
0.12124
0.135
0.15959
0.08764
0.09444
0.08237
0.08115
0.08197
0.087
μ
η
9.51
ω
NED
-
IED
-
Channel
-
IED
IED
IED
IED
IED
IED
IED
1
2
3
4
5
6
7
8
9
-3.08
-2.74
-2.67
-3.34
-2.48
-2.99
-2.76
-2.99
-3.09
-3.11
-3.08
-3.06
-2.93
-3.06
-3.16
-3.20
-3.36
-2.96
-3.49
0.50
0.27
0.30
0.40
0.23
0.42
0.36
0.43
0.45
0.45
0.44
0.50
0.46
0.49
0.52
0.54
0.59
0.47
0.62
3a
3b
3c
2a
2b
2c
2d
2e
2f
2g
1a
1b
1c
1d
1e
1j
1k
1n
13.96
11.95
14.03
13.65
10.75
10.66
10.45
10.59
10.68
10.90
9.47
9.39
9.45
9.53
9.56
9.58
9.39
9.81
12.07
11.13
11.51
12.17
10.22
10.40
10.07
10.04
10.06
10.20
9.50
9.60
9.49
9.43
9.41
9.26
9.56
9.24
11.40
10.33
12.03
10.99
10.04
9.77
9.89
10.06
10.13
10.21
9.47
9.30
9.46
9.60
9.66
9.83
9.34
10.07
IED
IED
IED
1
1
0
1
12
13
0.06138
0.065
IED/NED
IED
1
1
1
1
1
1
4
5
6
7
8
9
0.06115
0.05907
0.05805
0.05263
0.06369
0.05185
IED/NED
IED/NED
IED/NED
IED/NED
IED
NED
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2
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2
2
2
2
2
2
3
3
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3
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5
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6
2
0
15a
-0.29283
0.06342
-3.12
9.69
0.50
9.56
9.65
IED/NED
a
b
FMO energy (eV) were computed by using HF/6-311g single point calculation on the M11/cc-pVDZ optimized geometries.
Energy gaps for both possible HOMO–LUMO interactions between DHPO (6) and cyclopropenes 1–3 are given in eV.
The complete regioselectivity (exclusive formation of 1,5-regioisomers) in the cyclopropene
cycloadditions to DHPO (6) was accounted for by considering the theoretically calculated NBO charges, FMO
coefficients and Fukui functions for cyclopropenes 2a–g and DHPO (6) (Table 6). The LUMO coefficients
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
corresponding to C
carbon atoms of cyclopropenes 2a–g are listed in Table 6. The carbon atom of DHPO (6) referred as C3
dominates over C in terms of energy contributions for the LUMO (Table 6, entry 1, columns 5–7). In turn,
the C carbon atom provides major contribution to the HOMO of cyclopropenes 2 (Table 6, entries 2–8,
columns 5–7). According to FMO theory, the preferred orientation is the result of the interaction of the
atoms with the largest coefficients. Thus, the more favorable interaction between C and C atoms
1 3 4 5
and C carbon atoms of DHPO (6) and HOMO coefficients corresponding to C and C
1
4
3
4
providing major contributions to FMO of the DHPO (6) and cyclopropenes 2, respectively, should result in
formation of 1,5-regioisomers 11, that is in full agreement with the experimental data. As further
-
+
confirmation of the above, the condensed Fukui functions for the electrophilic (f ) and the nucleophilic (f )
3
attacks for cyclopropenes 2a–g and DHPO (6), respectively, were considered closely. The C carbon atom of
+
DHPO (6) presents a large f value than the C
1
site, 0.042 and 0.015, respectively (Table 6, entry 1, columns 10
and 11). Consequently, the C
3
position of DHPO (6) should be a preferred position for a nucleophilic attack by
-
cyclopropenes 2. Simultaneously, values of condensed Fukui functions for electrophilic attack (f ) of
cyclopropenes 2 demonstrate that the strongest nucleophilic reaction center is always the C
4
carbon atom (Table
6
, entries 2–8, columns 8 and 9). For instance, the C
4
carbon atom of 1-phenylcyclopropene (2b) has a larger f –
value than the C
dipolar cycloadditions should proceed via the C
atom of cyclopropenes 2 to the more electrophilic C
NBO atomic charges are also consistent with regioselectivity of cycloaddition for most of reactant pairs (Table 6,
entries 1, 2 3, 5–7, columns 3 and 4)
5
one, 0.181 and 0.097, respectively (Table 6, entry 3, columns 8 and 9). In this context, the 1,3-
-C bond-formation by the nucleophilic attack of the C carbon
site of DHPO (6). Moreover, it is worth mentioning that
3
4
4
3
–
.
Table 6. NBO charges, orbital coefficients of the LUMO of DHPO (6) and the HOMO of cyclopropenes 2a–g and
-
+
a,b
condensed Fukui functions for the electrophilic (f ) and the nucleophilic (f ) attacks (M11/cc-pVDZ).
O
R3
N
1
2
R1
cyclopropenes
4
5
R2
3
O
2a, R = R = H, R2 = Me
1
3
DHPO
(
6)
2
2
2
b-f, R1 = H, Me, TMS, Br, Cl, R = Ph, R3 = H
g, R1 = Me, R2 = Ph, R = CO H
3
2
Entry
Ylide
q (C
1
)
q (C
3
)
FMO
C
1
C
3
f - (C
1
)
f - (C
3
)
f + (C
1
)
f + (C
)
3
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6
-0.157
q (C
-0.218
-0.176
0.048
-0.455
-0.129
-0.050
0.082
0.170
q (C
0.012
-0.019
-0.027
0.002
0.002
-0.005
LUMO
0.0146
0.6423
-
-
0.015
0.042
-
Cyclopropenes
4
)
5
)
FMO
C
4
C
5
f - (C
4
)
f - (C
5
)
f + (C
4
)
f + (C
)
5
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
HOMO
HOMO
HOMO
HOMO
HOMO
HOMO
HOMO
0.6247
0.5354
0.5054
0.5345
0.4499
0.4627
0.4848
0.5560
0.3764
0.4213
0.3885
0.3895
0.3922
0.3772
0.244
0.181
0.143
0.148
0.113
0.123
0.126
0.188
0.097
0.109
0.097
0.088
0.092
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2g
0.015
b
0.079
aThere are values of the p
-
+
z
coefficients. Condensed Fukui functions for the electrophilic (f ) and the nucleophilic (f )
attacks were calculated for cyclopropenes 2a–g and DHPO (6), respectively, using Hirshfeld's population scheme.
At the next stage of our theoretical study, we estimated Gibbs energies of activation corresponding to the
two alternative regiopathways (1,4-endo and 1,5-endo) and the optimal geometries of TSs for the reactions of
cyclopropenes 2b–e with DHPO (6). An analysis of the potential energy surface indicates that the studied
1
,3-dipolar cycloadditions proceed by a one-step mechanism. Eight TSs TS-(11b–e)-1,4-endo and TS-
11b–e)-1,5-endo associated with the two regioisomeric channels were successfully found and
characterized. As depicted in Scheme 10, free energies of activation (ΔG ) clearly identify that the 1,5-
(
#
regiopathway is kinetically favored for all investigated reactions, i.e. the 1,5-regioisomers are preferred
products of these reactions.
O
N
O
O
N
Ph
R
#
O
TSs-1,4-endo
R
Ph
#
TSs-1,5-endo
3
N 2
1
7.3 kcal/mol, R = H
1
12.4 kcal/mol, R = H
16.2 kcal/mol, R = Me
13.5 kcal/mol, R = TMS
12.8 kcal/mol, R = Br
17.6 kcal/mol, R = Me
17.5 kcal/mol, R = TMS
16.6 kcal/mol, R = Br
O
O
R
=
G#(1,4)
G (1,5) =
#
4
5
Ph
2b-e
6
Scheme 10. Schematic representation of potential energy surfaces (PES) corresponding to the studied 1,3-dipolar
cycloaddtions of DHPO (6) wih cyclopropenes 2be in two pathways (1,5-endo and 1,4-endo).
When considering geometries of TSs, we have observed that these regioselective cycloadditions are
of course asynchronous processes taking place through a dipolaroid-like transition state. For instance, the
geometry of the TS-11b-1,5-endo (leading to the experimentally observed regioisomer 11b) displays that
the σ bond between C
4
carbon atom of 1-phenylcyclopropene (2b) and C
3
carbon atom of DHPO (6) is
more advanced [2.15 Å] than that between C
5
carbon atom of 2b and C of ylide 6 [2.73 Å], as suggested
1
by the atom distances measured between these reaction centers (Table 7, entry 1). Similar high
asynchronicities were identified for other TSs-1,5-endo corresponding to reactions of 2c–e with DHPO (6)
(
Table 7, entries 2–4). It is essential to note that asynchronicities shown at all the 1,5-TSs are in full
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
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3
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4
4
4
4
4
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5
5
5
5
5
5
5
6
agreement with the results based on DFT reactivity indexes. Actually, the σ bonds formed at 1,5-ΤSs
between the most electrophilic center of DHPO (6) – C carbon atom and the most nucleophilic site of
cyclopropenes 2 – C carbon atom are shorter and more advanced than C –C ones. In contrast to the head-
to-head orientations, 1,4-regiopathways are characterized by less asynchronicity, though σ bonds between
carbon atoms of cyclopropenes 11c–e and C carbon atom of DHPO (6) are a little more developed
Table 7, entries 5–8). This indicates that the azomethine ylide DHPO (6) controls the asynchronicity of
3
4
1
5
C
5
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
the cycloaddition by a larger bond-formation process at the most electrophilic center of the ylide 6. In other
words, DHPO (6) partially acts as an iminium cation in the 1,3-dipolar cycloaddtions with cyclopropenes.
It can be сoncluded that regioselectivity of cyclopropene cycloadditions to DHPO (6) is governed by
electronic effects of the substituents at the cyclopropene double bond. In case of cyclopropenes 2b–e, the
1 5
presence of the electron-donating phenyl group at C position (referred as C one in this discussion)
polarizes the HOMOcyclopropene through the C
4
carbon atom. As a consequence, the β-carbon atom C is the
4
3
strongest nucleophilic center which is subsequently subjected to electrophilic attack of the C site of DHPO
(6), resulting in formation of cycloadducts with full 1,5-regioselectivity.
Table 7. Values of the asynchronicity in TS-1,5-endo and TS-1,4-endo for the reactions of DHPO (6) with cyclopropenes
be.
2
Entry
TS
d (C C ), Å
d (C C ), Å
Δd = d
1
– d
2
(Å)
1
1
5
2
3
4
1
2
3
4
-
TS-11b-1,5-endo
TS-11c-1,5-endo
TS-11d-1,5-endo
TS-11e-1,5-endo
TS
2.73
2.67
2.69
2.66
2.15
2.18
2.19
2.23
0.58
0.49
0.50
0.43
d (C C ), Å
1
1
4
d (C C ), Å
2
3
5
Δd = d
1
– d
2
(Å)
5
6
7
8
TS-11b-1,4-endo
TS-11c-1,4-endo
TS-11d-1,4-endo
TS-11e-1,4-endo
2.40
2.25
0.15
0.37
0.37
0.26
2.55
2.57
2.52
2.18
2.20
2.26
To rationalize the origins of the endo and exo stereoselectivity in reactions of cyclopropenes 1–3 with
DHPO (6), full geometry optimization of the four possible transition states TS-11a-1,5-endo, TS-11a-1,5-exo,
TS-11a-1,4-endo, TS-11a-1,4-exo for the reaction between 1-methylcyclopropene (2a) and DHPO (6) was
performed using M11/cc-pVDZ (Figure 3). The Gibbs energies of activation corresponding to the two endo and
two exo approaches were also evaluated at 298.15 K and 1.0 atm (Figure 4). According to Figure 4, the 1,5-
endo-regioisomer 11a is ca. 2.5 kcal/mol more kinetically favorable than its opposite endo-regioisomer due to
4
nucleophilic activation of unsubstituted carbon atom (C ) of MCP (2a) induced by the neighboring electron-
releasing methyl group. Together with this, TS-11a-1,5-endo and TS-11a-1,4-endo are the energetically more
stable than their corresponding TS-11a-1,5-exo and TS-11a-1,4-exo (ca. 1.8 kcal/mol and 3.0 kcal/mol,
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respectively), that in combination with a preference for the 1,5-regiopath is in good accordance with
experimental results. Moreover, with parent cyclopropene (3a) the endo cycloaddition is favored by 1.8 kcal/mol
(see Supporting Information, Figure S92, Table S6).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Transition states of the four possible approaches for the cycloaddition between 1-methylcyclopropene (2a) and
DHPO (6). The bond lengths for primary interactions (PI) and second orbital interactions (SOI) are given in angstroms.
Figure 4. Free energy profile for the 1,3-dipolar cycloaddition reaction of 1-methylcyclopropene (2a) to DHPO (6).
A closer look at the geometries of the endo TSs reveals that there is a crucial interaction between nitrogen
atom of ylide 6 (NDHPO) and syn hydrogen (Hcyclopropene) attached to the saturated carbon atom of cyclopropene
ring of 2a, contributing to stabilization of the endo transition state. The s-orbital coefficients of endo hydrogen
z
corresponding to cyclopropenes 2ae, 3a, LUMO p coefficient of ΝDHPO, NBO charges for the hydrogen of
cyclopropenes 2ae, 3a and for ΝDHPO of DHPO (6) and the distances between these atoms in endo-1,5-TSs were
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considered to validate the proposed idea (Table 8). Firstly, such interactions may occur because hydrogen atom
provides considerable contribution to HOMO of cyclopropenes 2ae, 3a as nitrogen atom to LUMO of DHPO
(6) (Table 8, entries 16, columns 3 and 4). Electrostatic interactions between these atoms in the endo transition
states are also supported by examining NBO charges (Table 8, entries 16, columns 5 and 6). In addition to this,
all endo-1,5-TS were found to have distances (ranging from 2.38 to 2.44 Å) between NDHPO (6) and endo
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0
hydrogen of cyclopropenes 2ae, 3a noticeably shorter than N-H vdw radius (r = 2.65 Å) (Table 8, entries 16,
w
column 7). All this suggests that the observed endo stereoselectivity in the 1,3-dipolar cycloadditions of
cyclopropenes with DHPO results from favorable secondary orbital overlap of the endo hydrogen s-orbital in the
HOMO of cyclopropene with the nitrogen π-orbital of the ylide LUMO (see Figure 3). Previously, second orbital
interactions (SOI) providing stabilization of endo transition states in the Diels-Alder reaction of butadiene with
2
7
28
29
cyclopropenes were comprehensively explored in works of Apeloig , Jursic and Houk.
Table 8. S-orbital coefficients in the HOMO of cyclopropenes 2ae, 3a for the syn hydrogen and the p
the LUMO of DHPO (6) for the nitrogen atom in the ground state, natural charges at the syn hydrogen of cyclopropenes
ae, 3a, the charge at nitrogen of DHPO (6) and N-H distance in the endo transition states.
z
-orbital coefficient in
2
Entry
TS
H s-orbital
N p
z
-orbital
q (syn H),
q (N), DHPO
N-H distance
coefficient
coefficient
cyclopropene
(Å)
(
HOMO)
-0.3038
-0.2906
-0.2121
-0.2165
-0.2101
-0.1961
(LUMO)
-0.4223
1
2
3
4
5
6
TS-12a-1,5-endo
TS-11a-1,5-endo
TS-11b-1,5-endo
TS-11c-1,5-endo
TS-11d-1,5-endo
TS-11e-1,5-endo
0.199
0.206
0.208
0.210
0.214
0.216
-0.368
-0.375
-0.365
-0.367
-0.369
-0.360
2.43
2.39
2.38
2.38
2.38
2.44
-
-
-
-
-
CONCLUSIONS
In summary, the construction of the biologically interesting spiro[cyclopropa[a]pyrrolizine-2,2'-indene] scaffold
with quaternary stereogenic centers with complete regio- and diastereoselectivities has been established by using
the 1,3-dipolar cycloaddition of the stable ninhydrin-derived azomethine ylide (DHPO) to various
cyclopropenes. Importantly, the [3+2]-cycloaddition reactions proceed smoothly under mild conditions and
allow highly reactive and unstable cyclopropene substrates to be introduced into the reaction process. Moreover,
unusual cascade substitution-cycloaddition reaction for 3-nitro-1,2-diphenylcyclopropene has been described for
the first time. The 1,5-regio- and endo-stereoselective product formation in the observed reactions arises from
charge and orbital control along with second orbital interactions as it has been shown by DFT calculations. We
also expect that this work will inspire the search for new 1,3-dipoles  effective traps for cyclopropenes.
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EXPERIMENTAL SECTION
1
General Information: Melting points were measured on a melting point apparatus and are uncorrected. H (400
MHz) and 13C (100 MHz) spectra were recorded on an NMR spectrometer in CDCl
3
6
or DMSO-d at ambient
temperature. 13C NMR spectra were registered with broad-band proton decoupling. Chemical shifts () in ppm
are reported relative to residual undeuterated solvent in CDCl
3
(7.26 ppm for H and 77.2 ppm for 13C) and
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
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4
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5
6
0
1
2
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9
0
1
2
3
4
5
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7
8
9
0
1
2
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
DMSO-d
6
(2.50 ppm for H and 39.5 ppm for 13C). The signal patterns are indicated as follows: s = singlet, d =
doublet, dd = doublet of doublets, t = triplet, m = multiplet, br = broad. Integrals are given in accordance with
assignments, coupling constants are reported in Hz. IR spectra were recorded in KBr pellets and reported in
-1
wave number (cm ). Electrospray ionization (ESI) mass spectra were recorded on a mass spectrometer, HRMS-
ESI-QTOF, electrospray ionization, positive mode. Single-crystal X-ray diffraction experiments were conducted
on a diffractometer at 100 K using monochromated Mo Kα and Cu Kα radiation. The progress of reactions was
monitored by thin-layer chromatography (TLC) on aluminum sheets with 0.2 mm silica gel with fluorescent
indicator using UV-light and iodine for visualization. Preparative thin-layer chromatography (PTLC) was
performed on silica gel (5-40 mesh). All air- or moisture-sensitive reactions were carried out under an argon
atmosphere in oven-dried glassware. Unless otherwise stated, all reagents were purchased from commercial
suppliers and used as received. Solvents were dried by standard procedures and freshly distilled prior to use:
tetrahydrofuran, diethyl ether and benzene were distilled from sodium and benzophenone ketyl, dichloromethane
and dimethyl sulfoxide from calcium hydride, acetonitrile and acetone from phosphorus pentoxide. Technical
grade hexane and ethyl acetate used for PTLC were distilled prior to use. Commercial methanol of HPLC-grade
was used without purification.
Preparation of Reactants. Cyclopropenes 1a,30 1b,c,o,31 1d,32 1e,f,l,m,33 1gj,34 1k,35 1n,36 2a,20 2b,21 2c,37
2d,38 2e,39 2f,40 2gi,41 3b,42 3c43 were prepared according to literature data. Parent cyclopropene (3a) was
4
4
obtained according to a literature procedure with slight modifications. 2-(3,4-Dihydro-2H-pyrrol-1-ium-1-yl)-1-
oxo-1H-inden-3-olate (DHPO, 6) was synthesized by the method of Grassmann and Arnim.45
General procedure A for the 1,3-dipolar cycloaddition reaction of cyclopropenes to DHPO. Α 50-mL
round-bottom flask was charged with cyclopropene 13 (0.4 mmol), DHPO (6, 85 mg, 0.4 mmol) and MeOH (5
mL). The reaction mixture was stirred at 25 °C for 10 h. Full consumption of reagents was monitored by TLC.
All volatiles were evaporated under reduced pressure. The residue was purified by PTLC on silica gel using an
2
appropriate eluent followed by crystallization from a mixture of MeOH-H O (2:1) to furnish the target 1,3-
dipolar cycloadduct 7, 11, 12.
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6
General procedure B for the one-pot three-component reaction of 1,2,3-triphenylcyclopropene, ninhydrin,
and cyclic α-amino-acids. A mixture of 1,2,3-triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71
mg, 0.4 mmol) and α-amino-acid 5b,c (0.6 mmol) was refluxed in EtOH (5 mL) for 6 h. After completion of the
reaction as monitored by TLC, the solvent was evaporated in vacuo. The residue was chromatographed on silica
gel using a mixture of hexaneEtOAc (3:1) followed by crystallization from a mixture of MeOHH
2
O (2:1) to
0
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8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
give the title 1,3-dipolar cycloadduct 8, 9.
General procedure
C
for the solid-state 1,3-dipolar cycloaddition reaction of 3-R-1,2-
diphenylcyclopropenes to DHPO. DHPO (6, 85 mg, 0.4 mmol) and cyclopropene 1ae,h,j,k (0.4 mmol) were
placed in a porcelain mortar and manually ground with a pestle for 5 min at ambient temperature. The resulting
crude product was chromatographed on silica gel using a mixture of hexaneEtOAc (3:1 or 2:1) followed by
2
crystallization from a mixture of MeOHH O to afford the pure 1,3-dipolar cycloadduct 7.
(±)-(1R,1aR,6aR,6bS)-1,1a,6b-Triphenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2'-
indene]-1',3'-dione (7a). The reaction was performed according to General procedure A employing
cyclopropene 1a (107 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel
2
(hexaneEtOAc, 3:1) followed by crystallization from a mixture of MeOHH O (2:1) afforded 7a (183 mg,
9
5%) as a single diastereomer. Following to General procedure C, the solid-state reaction of cyclopropene 1a
with DHPO (6) also led to the desired cycloadduct 7a (168 mg, 87%). Yellow solid; mp 254255 °C
1
(MeOHH
2
O, 2:1); R
f
0.49 (SiO
2
, hexaneEtOAc, 3:1). H NMR (400 MHz, CDCl
3
):  = 7.857.79 (m, 1H),
7
.717.59 (m, 3H), 7.467.39 (m, 2H), 7.307.16 (m, 3H), 7.026.84 (m, 5H), 6.826.71 (m, 3H), 6.476.37
(m, 2H), 4.70 (t, J = 6.8 Hz, 1H), 3.853.75 (m, 1H), 3.30 (s, 1H), 2.852.74 (m, 1H), 2.222.10 (m, 1H),
1
2
1
1
1
.021.87 (m, 3H). 13C{ H} NMR (101 MHz, CDCl
3
):  = 202.3, 198.8, 142.5, 141.7, 136.7, 135.9, 135.4,
34.7, 133.0 (2C), 132.5 (2C), 131.9, 131.2 (2C), 128.0 (2C), 127.6 (2C), 127.0, 126.9, 126.6 (2C), 125.4, 123.3,
22.9, 78.9, 77.1, 56.6, 50.4, 49.4, 31.7, 27.6, 27.5. IR (KBr): 3058, 3031, 2940, 2889, 2857 1737, 1703, 1598,
-1
+
497, 1447, 1344, 1322, 1263, 1208, 1152, 1038, 764, 706 cm . HRMS (ESI): m/z [M + H] calcd for
+: 482.2115; found: 482.2124.
34 2
C H28NO
(±)-(1R,1aR,6aR,6bS)-1-Ethyl-1a,6b-diphenyl-1a,4,5,6,6a,6b-hexahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1',3'-dione (7b). The reaction was performed according to
General procedure A employing cyclopropene 1b (88 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 3:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7b (153 mg, 88%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1b with DHPO (6) also led to the desired cycloadduct 7b (137 mg, 79%).
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1
Yellow solid; mp 147148 °C (MeOHH
CDCl ):  = 7.92 (d, J = 7.3 Hz, 1H), 7.737.62 (m, 3H), 7.507.44 (m, 2H), 7.337.25 (m, 2H), 7.247.19 (m,
1H), 7.006.94 (m, 2H), 6.926.85 (m, 3H), 4.70 (t, J = 7.1 Hz, 1H), 3.613.47 (m, 1H), 2.802.62 (m, 1H),
2 f 2
O, 2:1); R 0.46 (SiO , hexaneEtOAc, 3:1). H NMR (400 MHz,
3
2
.182.05 (m, 2H), 2.031.91 (m, 2H), 1.901.79 (m, 1H), 1.551.42 (m, 1H), 1.381.25 (m, 1H), 0.99 (t, J =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
7
.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ):  = 201.5, 199.3, 142.4, 141.8, 137.4, 136.0, 135.4, 133.4, 131.7
3
(
2C), 130.4 (2C), 128.1 (2C), 127.7 (2C), 126.9, 126.4, 123.5, 123.0, 75.9, 75.5, 52.5, 49.4, 46.5, 29.8, 28.8,
27.7, 19.7, 14.2. IR (KBr): 3057, 3025, 2968, 2933, 2894, 2873, 1737, 1702, 1596, 1498, 1445, 1268, 1198,
1156, 1079, 769, 706 cm . HRMS (ESI): m/z [M + H] calcd for C30H28NO
2
+: 434.2115; found: 434.2129.
-1
+
(±)-(1R,1aR,6aR,6bS)-1a,6b-Diphenyl-1-vinyl-1a,4,5,6,6a,6b-hexahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1',3'-dione (7с). The reaction was performed according to
General procedure A employing cyclopropene 1с (87 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 3:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7с (157 mg, 91%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1с with DHPO (6) also led to the desired cycloadduct 7с (147 mg, 85%).
1
Yellow solid; mp 232233 °C (MeOHH
CDCl
2
O, 2:1); R
f
0.48 (SiO
2
, hexaneEtOAc, 3:1). H NMR (400 MHz,
3
):  = 7.86 (d, J = 6.6 Hz, 1H), 7.707.60 (m, 5H), 7.357.29 (m, 2H), 7.237.18 (m, 1H), 6.996.91 (m,
2
2
H), 6.906.81 (m, 3H), 5.505.40 (m, 1H), 5.044.93 (m, 2H), 4.64 (t, J = 7.1 Hz, 1H), 3.683.58 (m, 1H),
.87 (d, J = 9.7 Hz, 1H), 2.752.67 (m, 1H), 2.162.03 (m, 1H), 1.981.80 (m, 3H). 13C{ H} NMR (101 MHz,
1
CDCl
3
):  = 202.5, 198.8, 142.4, 141.7, 137.3, 136.5, 135.9, 135.5, 133.0, 132.6 (2C), 131.7 (2C), 128.3 (2C),
1
2
27.7 (2C), 127.0, 126.9, 123.3, 123.0, 114.5, 77.5 (overlapping with CDCl ), 76.5, 54.3, 49.2, 49.0, 30.9, 27.6,
3
7.5. IR (KBr): 3059, 3023, 2954, 2876, 1738, 1706, 1592, 1497, 1272, 1176, 1158, 980, 904, 741, 725, 703 cm-
1.
HRMS (ESI): m/z [M + H] calcd for C30
+
H
26NO
+: 432.1958; found: 432.1973.
2
(
±)-(1R,1aR,6aR,6bS)-1a,6b-Diphenyl-1-(phenylethynyl)-1a,4,5,6,6a,6b-hexahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1',3'-dione (7d). The reaction was performed according to
General procedure A employing cyclopropene 1d (117 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 2:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7d (186 mg, 92%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1d with DHPO (6) also led to the desired cycloadduct 7d (162 mg, 80%).
1
Yellow solid; mp 210211 °C (MeOHH
CDCl
2
O, 2:1); R
f
0.52 (SiO
2
, hexaneEtOAc, 2:1). H NMR (400 MHz,
3
):  = 7.90 (d, J = 7.4 Hz, 1H), 7.767.60 (m, 5H), 7.347.27 (m, 2H), 7.257.11 (m, 6H), 7.097.03 (m,
2
H), 6.966.87 (m, 3H), 4.86 (t, J = 7.4 Hz, 1H), 3.653.54 (m, 1H), 3.10 (s, 1H), 2.822.70 (m, 1H), 2.202.07
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
(m, 2H), 2.061.87 (m, 2H). 13C{ H} NMR (101 MHz, CDCl
):  = 201.5, 198.0, 142.1, 141.5, 136.1, 135.6,
1
3
135.3, 132.6 (2C), 131.5, 131.3 (2C), 130.7 (2C), 128.1 (2C), 127.9 (2C), 127.7, 127.5 (2C), 127.4, 126.9, 123.9,
123.4, 123.1, 87.3, 87.1, 75.8, 75.1, 55.6, 49.0, 48.6, 27.9, 27.6, 18.9. IR (KBr): 3051, 2973, 2940, 2870, 2228,
-1
+
1
743, 1708, 1596, 1491, 1443, 1209, 1152, 751, 701, 692 cm . HRMS (ESI): m/z [M + H] calcd for
+: 506.2115; found: 506.2134.
36 2
C H28NO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl
(±)-(1R,1aR,6aR,6bS)-1',3'-dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carboxylate (7e). The reaction was performed according to
General procedure A employing cyclopropene 1e (100 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 2:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7e (167 mg, 90%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1e with DHPO (6) also led to the desired cycloadduct 7e (57 mg, 31%).
1
Yellow solid; mp 186187 °C (MeOHH
CDCl
2
O, 2:1); R
f
0.40 (SiO
2
, hexaneEtOAc, 2:1). H NMR (400 MHz,
3
):  = 7.89 (d, J = 7.0 Hz, 1H), 7.727.63 (m, 3H), 7.557.48 (m, 2H), 7.377.29 (m, 2H), 7.277.20 (m,
1
1
1
H), 7.157.05 (m, 2H), 6.936.81 (m, 3H), 4.66 (t, J = 6.6 Hz, 1H), 3.613.51 (m, 1H), 3.45 (s, 3H), 3.02 (s,
H), 2.732.63 (m, 1H), 2.142.01 (m, 1H), 1.991.78 (m, 3H). 13C{ H} NMR (101 MHz, CDCl
1
):  = 201.2,
3
98.0, 169.4, 142.4, 141.7, 136.2, 135.6, 134.4, 132.3, 131.2 (2C), 130.8 (2C), 128.2 (2C), 127.7 (2C), 127.3
(
2C), 123.5, 123.1, 77.8, 76.2, 56.3, 52.0, 51.5, 49.1, 28.6, 27.5, 27.4. IR (KBr): 3067, 3031, 2998, 2975, 2948,
-1
+
2
906, 1742, 1704, 1590, 1498, 1441, 1363, 1270, 1207, 1168, 771, 703 cm . HRMS (ESI): m/z [M + H] calcd
for C30H26NO
4
+: 464.1856; found: 464.1865.
(
±)-(1R,1aR,6aR,6bS)-1',3'-Dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrro-lizine-2,2'-indene]-1-carboxylic acid (7f). The reaction was performed according to
General procedure A employing cyclopropene 1f (95 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
2 2
Purification by PTLC on silica gel (CH Cl MeOH, 40:1) followed by crystallization from a mixture of
MeOHH
2
O (2:1) afforded 7f (128 mg, 71%) as a single diastereomer. Light yellow solid; mp > 260 °C
1
(MeOHH
2
O, 2:1); R
f
0.42 (SiO
2
, hexaneEtOAc, 1:1). H NMR (400 MHz, DMSO-d
6
):  = 12.20 (s, 1H),
7
.967.91 (m, 1H), 7.907.81 (m, 2H), 7.777.70 (m, 1H), 7.537.45 (m, 2H), 7.407.32 (m, 2H), 7.287.21
(
m, 1H), 7.066.98 (m, 2H), 6.956.95 (m, 3H), 4.39 (t, J = 6.6 Hz, 1H), 3.463.36 (m, 1H), 2.81 (s, 1H),
2
1
.632.53 (m, 1H), 2.101.96 (m, 1H), 1.891.66 (m, 3H). 13C{ H} NMR (101 MHz, DMSO-d
1
6
):  = 199.8,
97.3, 169.5, 141.4, 140.7, 137.0, 136.5, 134.4, 132.2, 130.8 (2C), 130.4 (2C), 127.9 (2C), 127.2 (2C), 126.8
(
2C), 123.1, 123.0, 77.2, 75.4, 55.3, 51.1, 48.5, 27.6, 26.8, 26.6. IR (KBr): 3429, 3064, 3029, 2983, 2967, 2951,
-1
+
2
881, 1740, 1710, 1674, 1591, 1501, 1425, 1275, 1211, 1184, 976, 746, 703 cm . HRMS (ESI): m/z [M + Na]
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2
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7
8
9
calcd for C29
H23NNaO
4
+: 472.1519; found: 472.1544.
(±)-(1R,1aR,6aR,6bS)-N-Isopropyl-1',3'-dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carboxamide (7g). The reaction was performed according to
General procedure A employing cyclopropene 1g (111 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 1:1) followed by crystallization from a mixture of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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7
8
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0
1
2
3
4
5
6
7
8
9
0
MeOHH
2
O (2:1) afforded 7g (153 mg, 78%) as a single diastereomer. Yellow solid; mp 206207 °C
1
(MeOHH
2
O, 2:1); R
f
0.44 (SiO
2
, hexaneEtOAc, 1:1). H NMR (400 MHz, CDCl
3
):  = 7.91 (d, J = 7.3 Hz,
1
4
H), 7.787.63 (m, 5H), 7.407.31 (m, 2H), 7.307.23 (m, 1H), 7.227.15 (m, 2H), 7.006.84 (m, 3H),
.674.51 (m, 1H), 4.03 (d, J = 7.7 Hz, 1H), 3.803.67 (m, 1H), 3.653.51 (m, 1H), 2.86 (s, 1H), 2.792.62 (m,
1H), 2.142.02 (m, 1H), 2.001.79 (m, 3H), 0.60 (d, J = 6.5 Hz, 3H), 0.52 (d, J = 6.5 Hz, 3H). 13C{ H} NMR
1
(101 MHz, CDCl
3
):  = 200.5, 197.7, 167.1, 142.4, 141.7, 136.2, 135.7, 134.0, 131.9, 131.7 (4C), 128.3 (2C),
128.2 (2C), 127.8, 127.6, 123.6, 123.3, 78.0, 76.0, 53.5, 50.1, 49.5, 41.1, 31.3, 27.5, 27.3, 22.0 (2C). IR (KBr):
-1
3
421, 3053, 3023, 2966, 2930, 2905, 2862, 1737, 1705, 1645, 1527, 1445, 1265, 1155, 774, 709 cm . HRMS
+
+: 491.2329; found: 491.2323.
(ESI): m/z [M + H] calcd for C32
H
31
N
2
O
3
(±)-(1R,1aR,6aR,6bS)-N,N-Dimethyl-1',3'-dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carboxamide (7h). The reaction was performed according to
General procedure A employing cyclopropene 1h (105 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 1:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7h (162 mg, 85%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1h with DHPO (6) also led to the desired cycloadduct 7h (103 mg, 54%).
1
Yellow solid; mp 199200 °C (MeOHH
CDCl
2
O, 2:1); R
f
0.27 (SiO
2
, hexaneEtOAc, 1:1). H NMR (400 MHz,
3
):  = 7.89 (d, J = 7.4 Hz, 1H), 7.747.67 (m, 1H), 7.677.63 (m, 2H), 7.497.43 (m, 2H), 7.317.24 (m,
2
3
H), 7.237.16 (m, 1H), 7.026.95 (m, 2H), 6.876.79 (m, 3H), 4.68 (t, J = 7.0 Hz, 1H), 3.553.45 (m, 1H),
.36 (s, 3H), 3.19 (s, 1H), 2.802.71 (m, 1H), 2.80 (s, 3H), 2.182.07 (m, 1H), 2.071.91 (m, 2H), 1.901.78
m, 1H). 13C{ H} NMR (101 MHz, CDCl
1
):  = 201.1, 198.7, 167.4, 142.1, 141.7, 136.3, 135.6, 135.0, 132.1,
(
3
1
3
1
31.5 (2C), 130.8 (2C), 127.8 (2C), 127.3 (2C), 127.0, 126.8, 123.4, 123.0, 76.6, 76.0, 56.1, 49.4, 48.4, 37.9,
6.0, 27.6, 27.4, 27.2. IR (KBr): 3077, 3060, 3027, 2977, 2944, 2902, 2847, 1739, 1707, 1649, 1497, 1271,
-1
+
29 2 3
149, 703 cm . HRMS (ESI): m/z [M + H] calcd for C31H N O
+: 477.2173; found: 477.2188.
(±)-(1R,1aR,6aR,6bS)-1',3'-Dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carboxamide (7i). The reaction was performed according to
General procedure A employing cyclopropene 1i (94 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
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2 2
Purification by PTLC on silica gel (CH Cl MeOH, 20:1) followed by crystallization from a mixture of
MeOHH
2
O (2:1) afforded 7i (124 mg, 69%) as a single diastereomer. Light yellow solid; mp > 260 °C
1
(MeOHH
2
O, 2:1); R
f
0.30 (SiO
2
, CH
2
Cl
2
MeOH, 20:1). H NMR (400 MHz, DMSO-d
6
):  = 8.00 (br s, 1H),
7
.947.88 (m, 1H), 7.877.78 (m, 2H), 7.747.68 (m, 1H), 7.527.43 (m, 2H), 7.367.28 (m, 2H), 7.247.16
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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7
8
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(m, 1H), 7.056.92 (m, 2H), 6.906.72 (m, 4H), 4.35 (t, J = 6.8 Hz, 1H), 3.613.48 (m, 1H), 2.85 (s, 1H),
1
2
.592.50 (m, 1H, overlapping with DMSO), 2.071.94 (m, 1H), 1.911.64 (m, 3H). 13C{ H} NMR (101 MHz,
):  = 200.2, 197.6, 168.9, 141.5, 140.7, 136.8, 136.3, 135.5, 133.1, 130.9 (2C), 130.5 (2C), 127.6
2C), 126.8 (2C), 126.4, 126.2, 123.0, 122.9, 77.3, 75.6, 54.3, 49.9, 48.3, 27.9, 26.8, 26.7. IR (KBr): 3439, 3310,
DMSO-d
6
(
-1
+
3
196, 3062, 3029, 2978, 2952, 2873, 1734, 1696, 1501, 1448, 1273, 971, 703 cm . HRMS (ESI): m/z [M + H]
+: 449.1860; found: 449.1880.
24 2 3
calcd for C29H N O
(±)-(1R,1aR,6aR,6bS)-1',3'-Dioxo-1a,6b-diphenyl-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carbonitrile (7j). The reaction was performed according to
General procedure A employing cyclopropene 1j (87 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 2:1) followed by crystallization from a mixture of
2
MeOHH O (2:1) afforded 7j (153 mg, 89%) as a single diastereomer. Following to General procedure C, the
solid-state reaction of cyclopropene 1j with DHPO (6) also led to the desired cycloadduct 7j (145 mg, 84%).
1
Yellow solid; mp 251252 °C (MeOHH
CDCl
2
O, 2:1); R
f
0.67 (SiO
2
, hexaneEtOAc, 1:1). H NMR (400 MHz,
3
):  = 7.91 (d, J = 7.6 Hz, 1H), 7.777.62 (m, 5H), 7.427.33 (m, 2H), 7.327.24 (m, 1H), 7.227.12 (m,
2H), 7.056.90 (m, 3H), 4.75 (t, J = 7.1 Hz, 1H), 3.503.35 (m, 1H), 2.94 (s, 1H), 2.772.64 (m, 1H), 2.172.01
(m, 2H), 2.001.88 (m, 1H), 1.841.71 (m, 1H). 13C{ H} NMR (101 MHz, CDCl
1
):  = 200.4, 197.1, 141.9,
3
141.5, 136.6, 136.0, 132.9, 131.8 (2C), 130.1 (2C), 129.8, 128.7 (2C), 128.5, 128.4 (2C), 128.0, 123.6, 123.4,
1
1
4
17.9, 75.1, 74.9, 54.7, 49.1, 48.1, 27.5, 27.4, 14.7. IR (KBr): 3052, 3032, 2975, 2947, 2889, 2234, 1740, 1706,
-
1
+
23 2 2
593, 1500, 1446, 1352, 1271, 1202, 1156, 772, 704 cm . HRMS (ESI): m/z [M + H] calcd for C29H N O
+:
31.1754; found: 431.1760.
(±)-(1aR,6aR,6bS)-1a,6b-Diphenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2'-
indene]-1',3'-dione (7k). The reaction was performed according to General procedure A employing
cyclopropene 1k (77 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel
(hexaneEtOAc, 3:1) afforded 7k (141 mg, 87%) as a single diastereomer. Following to General procedure C,
the solid-state reaction of cyclopropene 1k with DHPO (6) also led to the desired cycloadduct 7k (122 mg,
1
7
7
5%). Yellow-orange amorphous powder; R
f
0.41 (SiO
2
, hexaneEtOAc, 3:1). H NMR (400 MHz, CDCl
3
):  =
.897.82 (m, 1H), 7.747.60 (m, 3H), 7.437.36 (m, 2H), 7.297.20 (m, 2H), 7.187.11 (m, 1H), 7.026.95
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(m, 2H), 6.876.81 (m, 3H), 4.94 (t, J = 6.7 Hz, 1H), 3.603.50 (m, 1H), 2.802.67 (m, 1H), 2.131.90 (m, 4H),
1.831.69 (m, 1H), 1.51 (d, J = 5.3 Hz, 1H). 13C{ H} NMR (101 MHz, CDCl
1
):  = 202.2, 198.4, 142.1, 141.6,
3
137.8, 136.1, 135.5, 135.2, 131.9 (2C), 129.3 (2C), 128.3 (2C), 127.7 (2C), 127.2, 126.8, 123.4, 123.0, 75.9,
73.4, 51.8, 48.9, 44.3, 27.8, 27.7, 17.6. IR (KBr): 3056, 3025, 2963, 2904, 2866, 1741, 1705, 1596, 1498, 1447,
-1
+
H24NO
2
+: 406.1802; found: 406.1800.
1
271, 1211, 1153, 768, 701 cm . HRMS (ESI): m/z [M + H] calcd for C28
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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5
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0
1
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6
7
8
9
0
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9
0
1
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6
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Methyl (±)-(1R,1aS,6aR,6bR)-1a,6b-dimethyl-1',3'-dioxo-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa-[a]pyrrolizine-2,2'-indene]-1-carboxylate (7l). The reaction was performed according to
General procedure A employing cyclopropene 1l (50 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
Purification by PTLC on silica gel (hexaneEtOAc, 2:1) followed by crystallization from a mixture of
MeOHH
2
O (2:1) afforded 7l (57 mg, 42%) as a single diastereomer. Yellow-brown solid; mp 145146 °C
1
(MeOHH
2
O, 2:1); R
f
0.41 (SiO
2
, hexaneEtOAc, 2:1). H NMR (400 MHz, CDCl
3
):  = 8.027.95 (m, 2H),
7
1
.907.81 (m, 2H), 4.09 (t, J = 7.3 Hz, 1H), 3.65 (s, 3H), 3.273.18 (m, 1H), 2.52 (t, J = 7.6 Hz, 1H), 2.25 (s,
H), 2.061.96 (m, 2H), 1.931.80 (m, 1H), 1.651.54 (m, 1H), 1.35 (s, 3H), 1.04 (s, 3H). 13C{ H} NMR (101
1
MHz, CDCl ):  = 202.1, 198.5, 171.1, 142.4, 141.6, 136.5, 136.0, 123.7, 123.5, 74.5, 74.3, 51.6, 48.1, 46.8,
3
4
1
1.3, 28.0, 27.6, 26.1, 9.9, 8.1. IR (KBr): 2977, 2948, 2925, 2862, 1730, 1709, 1592, 1436, 1367, 1275, 1206,
+: 340.1543; found: 340.1549.
-1
+
158, 1127, 1077, 773 cm . HRMS (ESI): m/z [M + H] calcd for C20H22NO
4
(±)-(1R,1aS,6aR,6bR)-1a,6b-Dimethyl-1',3'-dioxo-1a,1',3',4,5,6,6a,6b-octahydro-1H-
spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-1-carboxylic acid (7m). The reaction was performed according to
General procedure A employing cyclopropene 1m (45 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol).
2 2
Purification by PTLC on silica gel (CH Cl MeOH, 40:1) followed by crystallization from a mixture of
MeOHH
2
O (2:1) afforded 7m (43 mg, 33%) as a single diastereomer. Light yellow solid; mp 218219 °C
1
(MeOHH
2
O, 2:1); R
f
0.38 (SiO
2
, hexaneEtOAc, 1:1). H NMR (400 MHz, DMSO-d
6
):  = 12.09 (br s, 1H,
6
a
4
CO H), 8.097.98 (m, 4H, Harom.), 3.91 (t, J = 7.2 Hz, 1H, C H), 3.123.03 (m, 1H, C H), 2.40 (t, J = 7.5 Hz,
2
4
1
6
5
6
1
H, C H''), 2.04 (s, 1H, C H), 2.021.91 (m, 2H, C H + C H), 1.791.64 (m, 1H, C H''), 1.551.43 (m, 1H,
5
6b
1a 13
1
C H''), 1.25 (s, 3H, CH
3
C ), 0.94 (s, 3H, CH
3
C ). C{ H} NMR (101 MHz, DMSO-d
6
):  = 200.6, 197.7,
1
3
71.2, 141.5, 140.7, 137.2, 136.7, 123.3 (2C), 73.7, 73.5, 47.4, 45.0, 39.9, 27.3, 26.9, 25.5, 9.6, 7.6. IR (KBr):
-1
+
437, 2963, 2930, 2907, 1746, 1712, 1594, 1366, 1273, 1222, 1165, 620 cm . HRMS (ESI): m/z [M + H] calcd
for C19H20NO
4
+: 326.1387; found: 326.1371.
(±)-(5aR,6R,6aS,6bS)-5a,6,6a-Triphenyl-1,3,5a,6,6a,6b-hexahydrospiro[cyclopropa[3,4]pyrrolo[1,2-
c]thiazole-5,2'-indene]-1',3'-dione (8). The reaction was performed according to General procedure B
employing 1,2,3-triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71 mg, 0.4 mmol) and L-4-
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5
5
6
thiazolidinecarboxylic acid (5b, 80 mg, 0.6 mmol). Purification by PTLC on silica gel (hexaneEtOAc, 2:1)
followed by crystallization from a mixture of MeOHH
diastereomer. Yellow solid; mp 220221 °C (MeOHH
400 MHz, CDCl
.317.18 (m, 3H, Harom.), 7.016.95 (m, 1H, Harom.), 6.936.83 (m, 4H, Harom.), 6.826.71 (m, 3H, Harom.), 6.43
2
O (2:1) afforded 8 (148 mg, 74%) as a single
1
2
O, 2:1); R
f
0.34 (SiO
2
, hexaneEtOAc, 3:1). H NMR
(
3
):  = 7.78 (d, J = 7.3 Hz, 1H, Harom.), 7.707.57 (m, 3H, Harom.), 7.437.36 (m, 2H, Harom.),
0
1
2
3
4
5
6
7
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4
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6
7
8
9
0
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2
3
4
5
6
7
8
9
0
7
6b
6
3
(
d, J = 7.6 Hz, 2H, Harom.), 4.79 (dd, J = 8.4, 5.4 Hz, 1H, C H), 4.05 (s, 1H, C H), 4.03 (d, J = 5.3 Hz, 1H, C H),
3
1
1
13
1
3.81 (d, J = 5.3 Hz, 1H, C H''), 2.93 (t, J = 8.9 Hz, 1H, C H), 2.67 (dd, J = 9.5, 5.4 Hz, 1H, C H''). C{ H}
NMR (101 MHz, CDCl ):  = 203.4, 198.3, 142.0, 141.0, 136.1, 136.1, 135.9, 133.8, 132.8 (2C), 132.5 (2C),
131.5 (2C), 131.1, 128.3 (2C), 127.8 (2C), 127.5, 127.4, 126.7 (2C), 125.7, 122.9, 122.7, 78.2, 75.5, 56.4, 46.0,
3
-1
45.1, 30.1, 30.0. IR (KBr): 3058, 3034, 2949, 2849, 1741, 1706, 1601, 1497, 1445, 1258, 1227, 769, 707 cm .
+
S+: 522.1498; found: 522.1497.
HRMS (ESI): m/z [M + Na] calcd for C33
H
25NNaO
2
(±)-(1R,1aR,7aR,7bS)-1,1a,7b-Triphenyl-1,1a,4,5,6,7,7a,7b-octahydrospiro[cyclopropa[a]indolizine-2,2'-
indene]-1',3'-dione (9). The reaction was performed according to General procedure B employing 1,2,3-
triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71 mg, 0.4 mmol) and DL-pipecolic acid (5c, 77
mg, 0.6 mmol). Purification by PTLC on silica gel (hexaneEtOAc, 3:1) followed by crystallization from a
mixture of MeOHH
2
O (2:1) afforded 9 (71 mg, 36%) as a single diastereomer. Yellow solid; mp 212213 °C
1
(MeOHH
2
O, 2:1); R
f
0.49 (SiO
2
, hexaneEtOAc, 3:1). H NMR (400 MHz, CDCl
3
):  = 7.75 (d, J = 6.6 Hz,
1
H, Harom.), 7.657.55 (m, 3H, Harom.), 7.427.34 (m, 2H, Harom.), 7.297.17 (m, 3H, Harom.), 6.996.91 (m, 2H,
1
H
arom.), 6.906.82 (m, 3H, Harom.), 6.796.69 (m, 3H, Harom.), 6.476.40 (m, 2H, Harom.), 4.00 (s, 1H, C H), 3.87
7
a
4
4
6
(
dd, J = 9.9, 3.3 Hz, 1H, C H), 2.652.50 (m, 2H, C H + C H''), 1.841.74 (m, 1H, С H), 1.721.61 (m, 1H,
5
5
7
7
6
13
1
C H), 1.591.50 (m, 1H, C H''), 1.491.37 (m, 2H, C H + C H''), 1.291.14 (m, 1H, C H''). C{ H} NMR (101
MHz, CDCl ):  = 205.5, 201.6, 142.6, 141.2, 137.3, 135.8, 135.6, 134.3, 133.1 (3C), 133.0, 131.9, 131.5 (2C),
27.8 (2C), 127.7 (2C), 127.0, 126.9, 126.5 (2C), 125.2, 122.5, 122.1, 79.7, 71.7, 50.7, 47.5, 46.7, 30.1, 26.7,
3
1
2
-1
5.9, 24.1. IR (KBr): 3058, 3029, 2939, 2859, 1737, 1703, 1599, 1498, 1447, 1344, 1325, 1264, 764, 706 cm .
+
+: 496.2271; found: 496.2279.
HRMS (ESI): m/z [M + H] calcd for C35
H
30NO
2
Trapping of 1-methylcyclopropene with DHPO. An ether solution of 1-lithio-2-methylcyclopropene which
2
0
had been synthesized according to Magid’s method using 3-chloro-2-methyl-1-propene (980 μL, 10 mmol) and
freshly prepared phenyllithium (1.0 M in ether, 30 mL, 30 mmol) was placed in a 100-mL three-necked round-
bottom flask. The latter was provided with a condenser, a 10-mL dropping funnel, a magnetic stir bar and an
inlet tube connected to a 10-mL screw-cap tube containing DHPO (6, 213 mg, 1 mmol), absolute THF (5 mL)
and a small magnetic stirrer. Argon flow was introduced from the top of the condenser. To a thoroughly stirred
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
solution of 1-lithio-2-methylcyclopropene at 0 °C was carefully added MeOH (10 mL) over 15 min while a slow
stream of argon was swept through the flask and into the tube at -30 °C. Having finished neutralization, the cap
was tightly screwed, and the tube was allowed to warm to 0 °C with stirring until complete dissolution of DHPO
(6). After 5 min, full conversion of starting azomethine ylide 6 into 1,3-dipolar cycloadduct 11a was identified
by TLC-control. All volatiles were evaporated in vacuo, and the residue was purified by PTLC on silica gel
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
using a hexaneEtOAc mixture (2:1) as the eluent followed by crystallization from a MeOHH
2
O mixture (2:1)
to give the title cycloadduct 11a as a single diastereomer.
(±)-(1aS,6aR,6bR)-1a-Methyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-
1
2 f 2
',3'-dione (11a). Yellow-orange solid; yield: 246 mg (92%); mp 9899 °C (MeOHH O, 2:1); R 0.42 (SiO ,
1
hexaneEtOAc, 2:1). H NMR (400 MHz, CDCl
3
):  = 8.048.00 (m, 1H, Harom.), 7.997.94 (m, 1H, Harom.),
6
a
4
4
7
.907.81 (m, 2H, Harom.), 4.454.36 (m, 1H, C H), 3.243.14 (m, 1H, C H), 2.622.53 (m, 1H, C H''),
5
5
6
6
6b
1
2
.021.81 (m, 3H, C H + C H'' + C H), 1.661.52 (m, 2H, C H'' + C H), 1.271.22 (m, 1H, C H), 0.98 (s, 3H,
1
a
1
13
1
CH
3
C ), 0.500.44 (m, 1H, C H''). C{ H} NMR (101 MHz, CDCl ):  = 201.9, 198.9, 142.3, 141.4, 136.4,
3
1
1
35.9, 123.7, 123.3, 73.3, 67.6, 48.7, 36.6, 29.9, 28.6, 28.3, 17.4, 13.2. IR (KBr): 2966, 2946, 2897, 2860, 2844,
+: 268.1332;
-1
+
736, 1708, 1591, 1445, 1214, 1152, 759 cm . HRMS (ESI): m/z [M + H] calcd for C17H18NO
2
found: 268.1341.
Trapping of 1-phenylcyclopropene with DHPO. A 100-mL two-necked flask was equipped with a 25-mL
dropping funnel, a calcium chloride tube, and magnetic stirring bar. The flask was charged with DHPO (6, 213
mg, 1 mmol), THF (10 mL), and AcOH (570 μL, 10 mmol). A solution of 1-lithio-2-phenylcyclopropene in
2
1
ether that had been prepared by the literature procedure using 1,1,2-tribromo-2-phenylcyclopropane (710 mg, 2
mmol) and methyllithium (1.6 M in ether, 3.1 mL, 5 mmol) was slowly added to the vigorously stirred
suspension of the ylide 6 at 25 °C over a period of 5-10 min. Upon completion of addition, the DHPO (6)
completely dissolved, whereas a white precipitate of AcOLi was formed. Full consumption of starting material 6
was ascertained by TLC. All volatiles were evaporated in vacuo. To the crude mixture was added 10 mL of
Et
funnel. The organic phase was washed twice with saturated NaHCO
dried over anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was purified by
PTLC on silica gel using a mixture of hexaneEtOAc (3:1) as the eluent followed by crystallization from a
MeOHH O mixture (2:1) to afford the title cycloadduct 11b as a sole diastereomer.
±)-(1aS,6aR,6bR)-1a-Phenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2'-indene]-
2
O, aqueous saturated sodium bicarbonate (10 mL), and the resulting mixture was transferred into a separatory
3
and brine. The washed organic phase was
2
4
2
(
1
2 f 2
',3'-dione (11b). Yellow-orange solid; yield: 290 mg (88%); mp 9495 °C (MeOHH O, 2:1); R 0.49 (SiO ,
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