Water and organic synthesis: A focus on the in-water and on-water border. Reversal of the in-water breslow hydrophobic enhancement of the normal endo -effect on crossing to on-water conditions for huisgen cycloadditions with increasingly insoluble organic liquid and solid 2π-dipolarophiles

Article abstract of DOI:10.1021/jo400055g

Measurements of the endo/exo product ratios for Huisgen cycloadditions with a series of vinyl ketones, alkyl acrylates, and substituted styrenes as dipolarophiles with phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles in acetonitrile and water show that as the reactions change from in-water (large hydrophobic enhancement of endo-products) to on-water, the hydrophobic enhancement of the endo-products is reduced and partially reversed (relative to acetonitrile). An expected increase of the endo-effect with increasing hydrophobic character of the dipolarophile is overcome by decreasing water solubility causing changeover to on-water conditions. On-water reactions do not show increased cycloaddition endo-effects (relative to organic solvents) as do in-water reactions.

Full text of DOI:10.1021/jo400055g

Article
pubs.acs.org/joc
Water and Organic Synthesis: A Focus on the In-Water and On-Water
Border. Reversal of the In-Water Breslow Hydrophobic Enhancement
of the Normal endo-Effect on Crossing to On-Water Conditions for
Huisgen Cycloadditions with Increasingly Insoluble Organic Liquid
and Solid 2π-Dipolarophiles
Richard N. Butler,*,† Anthony G. Coyne,*,‡ William J. Cunningham,† and Eamon M. Moloney†
†School of Chemistry, National University of Ireland, University Road, Galway, Ireland
‡Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
S
* Supporting Information
ABSTRACT: Measurements of the endo/exo product ratios for Huisgen cycloadditions with a series of vinyl ketones, alkyl
acrylates, and substituted styrenes as dipolarophiles with phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles in
acetonitrile and water show that as the reactions change from in-water (large hydrophobic enhancement of endo-products) to on-
water, the hydrophobic enhancement of the endo-products is reduced and partially reversed (relative to acetonitrile). An expected
increase of the endo-effect with increasing hydrophobic character of the dipolarophile is overcome by decreasing water solubility
causing changeover to on-water conditions. On-water reactions do not show increased cycloaddition endo-effects (relative to
organic solvents) as do in-water reactions.
effects. Some methods are needed to distinguish between these
alternatives and to explore the borderline regions between in-
water and on-water reactions.
INTRODUCTION
■
In recent years there has been an explosion in the use of water
as a medium for organic synthesis.1−11 This remarkable
property of water to facilitate organic synthetic reactions even
for water-insoluble reactants has led to the seminal introduction
of the on-water concept by Sharpless and co-workers.12 When
reactants are soluble in water giving clear solutions, three effects
operate simultaneously, (i) the hydrophobic effect, (ii)
hydrogen bonding effects, and (iii) solvent polarity effects.9
For on-water reactions of highly insoluble reactants the main
effect is a trans-phase H-bonding catalytic effect due to the
penetration by water OHfree groups across the water−organic
phase boundary13,14 (see also ref 3). It has been suggested that
this could extend to penetration of the phase boundary by a
free proton effectively giving acid-catalysis leaving anionic
charge at the boundary.15 For many organic syntheses in the
water medium, the reactant molecules are partially soluble, and
the reaction medium consists of complicated two or three
phase systems.16 Three phase systems can arise with partially
soluble organic liquid and solid reactants, one phase being a
dilute aqueous solution with the remaining phases being the
undissolved organic liquid and the solid still remaining in the
mixture. For such reaction mixtures it is not clear whether the
chemical processes occurring arise from in-water or on-water
Breslow et al. have established that the well-known endo-
effect, which is observed in Diels−Alder cycloadditions, is
significantly enhanced for reactions carried out in water.17,18
This increased endo-enhancement results mainly from the water
hydrophobic effect, which favors more compact transition states
with reduced exposure to water. Smaller contributions may also
come from polarity effects on the endo-favoring secondary
orbital interactions and charge transfer contributions to the
transition state.17,18 It follows that if the reactants are not
within the bulk water medium, i.e., in-water, but rather outside
the water medium, i.e., on-water with trans-phase catalysis, then
hydrophobic enhancement of the endo-effect should not occur.
Herein we look at this endo-enhancement for a series of
increasingly hydrophobic reactants with decreasing water
solubilities as probes of the borderline between in-water and
on-water modes for multiphase reaction mixtures using a
Huisgen cycloaddition that spans the gamut from 4πHOMO to
4πLUMO control with accompanying changes in regioselectivity
Received: January 29, 2013
Published: March 6, 2013
© 2013 American Chemical Society
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Figure 1. Organic reactions using water as a solvent showing different approaches to solubilizing reactants.
and endo−exo-selectivity. Such a reaction is particularly fitting
at the simplest case for achieving a reaction, the reactants A and
B should undergo reaction in water as solvent so as to give the
product in high yield and in high stereo- and regioselectivity. As
mentioned, the main drawback is poor solubility of the
reactants. However if the solubility of the reactants can be
determined, this can give an indication as to whether the
reaction is possible using water as a solvent. Aqueous solubilites
of organic reactants are not routinely measured in organic
chemistry, unlike other areas such as medicinal chemistry where
it is a necessity. A number of factors such as temperature,
pressure, pH, particle size as well as molecular composition can
all affect solubility. In medicinal chemistry, where solubility
measurements are necessary, there are a number of methods
that can be employed. Thermodynamic solubility measure-
ments are carried out using the solid material, which is directly
dissolved in aqueous solutions.28 This method depends upon
the saturation solubility of a compound in equilibrium with an
excess of undissolved compound. This is generally carried out
over 24−48 h time scale in order to confirm that solution
saturation has been achieved. Kinetic solubility measurements
are obtained from a predissolved compound (in a solvent such
as DMSO), and the solution is added to the water until a
precipitation occurs. The kinetic solubility determination is
dependent on the supersaturation that occurs within the
reaction mixture. While the thermodynamic solubility is the
gold standard for solubility measurements, in reality it is very
unlikely that this would be carried out as routine for an organic
reaction. In recent years, a number of research groups have
been looking at determining the solubility of organic
compounds in water using computational methods.29 These
methods of solubility determination are still being refined, but
the computationally derived solubilities now available provide
useful estimates of the solubility of organic compounds in
water. This ability to calculate solubilities computationally has
been built into the chemical search engine SciFinder, where the
solubility of organic compounds for any searchable compound
within the CAS have been calculated using the ACD lab
software. These solubilities give a good assessment of the
solubility of organic compounds in water, and they are the
source of the compound solubilities quoted herein. These
solubility data are readily available.
for this purpose.
RESULTS AND DISCUSSION
■
In organic chemistry the majority of synthetic reactions are
carried out using a solvent, and in general the solvent will
dissolve the reactants. A major criterion for choosing a solvent
is that it must not interfere with the reaction and the product
should be easily isolated. It is partly because of these
requirements that water has not been the solvent of choice
for many organic reactions. With the increasing focus on
greener aspects of organic synthesis, the use of water as a
reaction solvent or medium has greatly expanded in the last two
decades. A wide range of reaction types has been explored using
water as the reaction solvent, including those which were once
considered impossible such as olefin metathesis and cross-
coupling reactions.19,20 While many organic compounds have
poor solubility in water, a variety of strategies have been
employed in order to overcome this problem.
One approach has been to use water in tandem with an
organic solvent, and this has been employed for many different
reaction types especially in the area of organocatalysis
reactions.21−23 Another strategy has been to use solubilizing
groups on either of the reactants or on catalysts to ensure
solubility in water. However a major problem with this is that
these functionalities may have to be removed further down the
synthetic route. A more recent and interesting approach has
been to use molecular encapsulation. This is where self-
assembled “molecular flasks” with a nanometer cavity offer a
different environment in comparison to the bulk water solvent.
These cages have been used to carry out cycloaddition reactions
of unactivated dienes and dienophiles. These reactions can be
carried out using water as a medium, and the cycloadducts are
obtained in excellent yields. A drawback of these reactions is
that the self-assembled cage can be specific for certain reactants,
which leads to separation problems later in the workup (Figure
1).24−27
With all of the above approaches, there has to be a
modification of the reactants or other reagents included in
order for the reaction to proceed in the water medium. Looking
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The solubility of the reactants when using water as the
reaction medium can have a significant effect on the outcome of
the reactions. A number of groups have looked at the effects of
concentration on the endo:exo ratios of Diels−Alder reactions.
Breslow et al. examined the Diels−Alder cycloaddition reaction
of cyclopentadiene and a range of dienophiles using water as
the solvent.17 For the dienophile methyl vinyl ketone, the
reaction was explored using a range of different concentrations
(Scheme 1). In excess cyclopentadiene, the product endo:exo
studies.31,32 This solubility limit is well below that required for
normal in-water synthetic reactions. Nevertheless, high yield
synthetic reactions were readily achieved by vigorous stirring at
ambient temperatures of a wide range of 2π-reactants with
suspensions of 1 in water, Scheme 2.
For the series of alkyl vinyl ketones (Table 1, entries 1−5)
where the alkyl groups contain 1−5 carbon atoms, high yield
reactions in the water medium gave mixtures of endo- and exo-
isomers of compounds 2−6. As the carbon number of the alkyl
group is increased, the vinyl ketones become more hydrophobic
in character, and an increasing hydrophobic enhancement of
the endo/exo ratio would be expected for reactions in the bulk
water medium, i.e., for in-water reactions. This is observed for
alkyl substitutents containing up to two carbon atoms where
the water solubilities of the vinyl ketones are greater than 0.2
mol L−1 (Table 1, entries 1−3). For alkyl substituents
containing 3−5 carbons where the water solubilities of the
vinyl ketones fall below 0.1 mol L−1, there is no enhancement
of the endo-isomer in the water medium, and the endo/exo ratio
is slightly reduced relative to the acetonitrile solvent (Table 1,
entries 4, 5). In Table 1 the percent endo-enhancement is
quoted as the percentage increase in the endo/exo ratio, and
when this ratio decreases the percent enhancement of the
normal endo-effect (compared to MeCN solvent) is then a
negative number. A similar sequence is observed for a series of
alkyl acrylate esters (Table 1, entries 8−13). With methyl
acrylate as dipolarophile (water solubility 0.46 mol L−1),
hydrophobic enhancement of the endo-isomer occurs for an in-
water reaction in which the insoluble 1,3-dipole 1 is passing
through the solution in an equilibrium shifted process (Table 1,
entry 8). As the carbon number of the ester alkyl substituent is
increased to 2, 3, 4 and a phenyl group, with an accompanying
fall in water solubility, there is no increase in the product endo/
exo ratio. As the water solubilities of the acrylates decrease
below 0.1 mol L−1, the reaction changes to the on-water mode
with reductions in the product endo/exo ratios (relative to
MeCN as solvent) (Table 1 entries 10−13). Among the alkyl
vinyl ketone series in Table 1, entries 6 and 7 represent a
special case. p-Chlorobenzylidine acetone gives the product 7
from the cycloaddition reaction with compound 1. We have
discussed this reaction in detail previously.9c The products are
mixtures of the endo- and exo-isomers of compound 7 where
the aryl group is at the 1-position and the acetyl group at the 2-
position of the 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine
products. The reactant p-chlorobenzylidine acetone is a solid
(mp 62 °C) that is highly insoluble in water (10−4 mol L−1),
and when it is vigorously stirred with solid 1,3-dipole 1
(solubility <10−6 mol L−1) in water at ambient temperature,
unsurprisingly no reaction occurs. However when the temper-
ature of the water is raised to 75 °C, above the melting point of
p-chlorobenzylidine acetone, melting occurs providing an oily
liquid phase, and the on-water phenomenon takes over with a
high yield reaction producing a 6.2:1 endo(aryl):exo ratio of
compound 7. In acetonitrile at the same temperature, the
reaction produces the same products in lower yield with a
10.4:1 endo(aryl)/exo ratio (Table 1, entries 6 and 7). This is a
classic on-water reaction, and there is no enhancement of the
favored endo(aryl) isomer, but it is reduced as for the other
cases. We note that McErlean et al. have recently reported a
similar necessary liquefaction of a highly water insoluble solid
allyl aryl ether above its melting point in order to achieve an
on-water Claisen rearrangement for synthetic purposes.33 Our
experience has been that organic solid reactants with water
Scheme 1. Diels−Alder Reaction of Cyclopentadiene and
Methyl Vinyl Ketone Using Water as a Reaction Solvent and
the Role of Concentration17
a
All reactants dissolved in water layer.
ratio was 3.85:1. When the more polar solvent ethanol was
used, the ratio increased to 8.5:1. However when the solvent
was changed to water, a much higher endo:exo ratio of 21.4:1
was observed at a formal concentration of diene and dienophile
of 0.15 M. At this concentration the methyl vinyl ketone is fully
soluble in water, but the cyclopentadiene is not and is seen as a
second phase in the reaction flask. The results are effectively
identical to a true solution reaction (0.007 M) where the
endo:exo ratio observed was 22.5:1. At higher formal
concentrations of up to 0.45 M, the endo:exo ratio decreased
slightly to 17.2:1; however, in comparison to the reaction in
organic solvents, this is a highly enhanced endo-selective
reaction. In each of these cases the reactions are occurring in-
water and exhibiting the enhanced endo-effect arising from the
hydrophobic effect for reactions occurring in the bulk water. At
the higher formal concentrations of reactants, approaching the
solubility limit of methyl vinyl ketone, the results herein suggest
that some of the reaction with the insoluble cyclopentadiene
may have been occurring by the on-water mode, thereby
slightly lowering the in-water endo-enhancement.30 Griesbeck
reported a study on the reaction of the diene dimethylfulvene
and 1,4-benzoquinone using both organic solvents and water.16
A striking rate enhancement was observed using water as the
reaction solvent where the reaction time was cut from 10 days
(EtOH) to 11 h using water. Reactions in the water medium
relative to ethanol showed enhancement of the endo-isomer at
normal concentrations paralleling the enhanced endo-effect
reported by Breslow.
The solubility of the high melting point (252−254 °C)
yellow azinium dicyanomethanide 1,3-dipole 1 in water is ≤5 ×
10−6 mol L−1 at 37 °C. This limit was measured from the UV
spectra of saturated neat water solutions using the λmax of 413
nm and the extinction coefficient of solutions of 1 in H2O−
MeCN (9:1 v/v), which were used previously for kinetic
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Scheme 2. Huisgen Cycloaddition Reaction of Phthalazinium-2-dicyanomethanide 1,3-Dipole with a Range of Electron-Rich
and Electron-Poor Dipolarophiles
solubilities of 10−4 mol L−1 do not display on-water reactions
without liquefaction of one of them.,9a
All of the substrates in Table 1 (entries 1−17) contain a C
O group bonded to the 2π-reaction site. Could hydrogen
bonding be playing a significant role in these results? The
generally accepted explanation for the on-water phenomenon is
a catalytic trans-phase H-bonding effect due to the presence of
OHfree groups at the oil−water interface. In previous kinetic and
theoretical studies, we have shown that strong water H-bonding
occurs at the CO of the vinyl ketones in the cycloaddition
endo-transition state and that structured water clusters grow
around this from the initially H-bonded water molecules.31
Similar strong H-bonding does not arise with the cyclo-
additions of acrylate esters. The water rate enhancement for
vinyl ketones in these reactions is 10 times greater than for
acrylates because of this H-bonding.31,32 The H-bonding
The series of N-substituted maleimides in Table 1 (entries
14−17) represents cases where the endo-transition states are
fully dominant and only endo-products are formed for both on-
water and in-water conditions. The designation of the reactions
as in-water and on-water (Table 1) is based on the solubilities,
by comparison with the other cases. There are no steric
constraints in the endo-transition states of these cycloadditions.
We have observed exclusive endo-reactions in acetonitrile for a
series of maleimides with N-substituents ranging from Me, aryl,
tBu and adamantyl.34b Four cases with appropriate water
solubility were chosen for comparison in the water medium
(Table 1, entries 14−17).
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Table 1. Huisgen Cycloaddition Reaction of Phthalazinium-2-dicyanomethanide 1 with a Range of Electron-Poor and Electron-
Rich Dipolarophiles
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Table 1. continued
a
b
c
d
Physical state of dipolarophile at ambient temperature. Ambient temperature is 20 °C. Liquid at 75 °C. In the case of entries 8−12, a small
e
amount (<2%) of the reverse isomer was detected by NMR. In the case of entry 13, none of this minor isomer was detected by NMR. With entry
23, the reaction in MeCN occurred in 16 h. In the case of the reaction using water, no reaction was observed after 48 h; this was then heated to 82
°C, where it was stirred for a further 48 h, and the reaction was deemed complete.
catalytic effect for on-water processes is much stronger than for
in-water reactions,14 but the H-bond acceptor sites are the same
in both cases. Hence, if the H-bonding were influencing the
endo/exo ratios, the endo-isomers should be more favored for
on-water reactions, the reverse of the experimental results.
Furthermore, similar results are obtained with substituted
styrenes and norbornene (Table 1, part B), where there are no
H-bond acceptor sites on the dipolarophiles.
water. Only with styrene, where the reaction is necessarily on-
water, is there again a decrease in the endo/exo ratio. The
contrasting behavior of acrylonitrile and styrene (entries 3 and
5) is of added interest. It is likely hydrogen bonding would have
little effect in either case, and it could not account for the fall in
the endo-effect for the on-water reaction with styrene.
Some reactions with alkyne dipolarophiles in acetonitrile and
water are compared in Scheme 4. There is no steric component
here, and the designation of the reactions as in-water and on-
water are based on solubilities and the above examples. The
reactions with solid diphenylacetylene (mp 61 °C) are again of
special interest (entries 3, 4). At ambient temperatures, since
both solid reactants diphenylacetylene and compound 1 have
very low water solubilities (<10−5 mol L−1), not surprisingly no
reaction occurs for vigorous stirring over 24 h. However on
raising the temperature above the melting point of
diphenylacetylene, an oily phase is produced in the mixture,
and this again allows the on-water process to occur giving a
good yield of product 31 (71%) for 24 h of stirring and better
than in acetonitrile (60%).
Compound 1 is an example of a Sustmann Type II 1,3-
dipole, which can react also with electron rich dipolarophiles
through inverse electron demand LUMODipole interactions in
the transition state.31,32,34 Examples of such reactions are
shown in Table 1 part B. For these cases the regioselectivity is
reversed, and the products 18−22 are 2-substituted pyrrolo-
[2,1-a]phthalazines. When endo/exo-isomer pairs are formed,
the exo-isomers are the major products because for the inverse
demand transition state this is the favored orientation.34 With
n-butyl vinyl ether as the dipolarophile, the exo-isomer is
exclusively formed in acetonitrile and water (Table 1, entry 18).
Solubilities suggest that this reaction is on the borderline of
both in-water and on-water processes. For the series of
hydrophobic styrenes and norbornene (Table 1, entries 19−
23), both isomers were formed with measurable endo/exo
ratios. These liquid reactants (which do not have a H-bond
acceptor sites) are all highly insoluble in water (ca. 10−3 mol
L−1), and the reactions with insoluble compound 1 are on-
water processes where catalytic trans-phase H-bonding can only
occur at compound 1. In each case there is again no increase in
the endo/exo ratio when going from acetonitrile to water but
rather a decrease, which is recorded as a minus endo-
enhancement in Table 1.
CONCLUSION
■
For organic synthesis in the water medium, hydrophobic
enhancement of the preferred endo isomer from cycloadditions
arises for reactions in the bulk water solution (relative to
organic solvents), but it does not occur with water insoluble
reactants when on-water processes prevail. This allows the
endo/exo product ratios to be used to distinguish between in-
water and on-water conditions. Successful synthetic reactions
between two insoluble organic solids can be achieved by the
on-water process if one is liquefied to provide an oily layer in
the water mixture.
Some comparable reactions of the 1,3-dipole 1A pyridazi-
nium dicyanomethanide are shown in Scheme 3. Compound
1A is soluble in water at small scale synthetic levels. In Scheme
3, for entries 1−4 there is the expected hydrophobic-based large
increase in the endo/exo product ratio on moving from
acetonitrile to water, where the reactions are occurring in-
EXPERIMENTAL SECTION
■
Melting points were measured on an electrothermal apparatus. IR
spectra were measured using an FT-IR instrument. All the NMR
spectra were measured on either a 400 or 500 MHz instrument for 1H
NMR and 100 or 125 MHz for 13C NMR. The NMR spectra were
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Scheme 3. Huisgen Cycloaddition Reaction of Pyridazinium Dicyanomethanide 1a with a Range of Dipolarophiles (s =
Dipolarophile Solubility in Water)
a
b
c
Stirring at ambient temperature (96 h). Stirring for 7 days (168 h). Stirring for 96 h.
measured with tetramethylsilane as an internal reference and either
CDCl3 or DMSO-d6 as a solvent. The structures were also examined
using COSY, NOEDS and DEPT. J values are given in Hertz (Hz).
The dipole 1 was prepared as previously described.35 The
pyridazinium dicyanomethanide dipole 1A was prepared by the
same procedure. The phenyl-substituted maleimides were prepared
according to the literature procedure.36 Water used for synthesis was
ultrapure grade. The stereochemistries of the endo-products and their
exo-isomers were established from NOE difference spectra (NOEDS),
which showed strong (7−10%) enhancements from H-10b to the cis-
H-1 in the endo-compounds and the absence of a through-space
enhancement for the exo-products. Isomer ratios (endo−exo) for
product solutions in acetonitrile solvent were determined by NMR
analysis. For reactions in the water medium, the water insoluble
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Scheme 4. Huisgen Cycloaddition Reaction of Phthalazinium-2-dicyanomethanide 1 and Pyridizanium Dicyanomethanide 1A
with a Range of Electron Rich and Electron Poor Dipolarophiles (s = Dipolarophile Solubility in Water)
product mixtures were separated and each product isolated as
described after prior NMR estimation of the isomer ratio. All of the
reactions described herein in the water medium were carried out in the
formal concentration ranges 0.077−1.38 mol L−1. Because of the low
water solubilities of the reactants, the reaction milieu appeared as
insoluble multiphase mixtures in water. X-ray crystal structures of
products from earlier work in MeCN solvent are also available in refs
31, 32, and 34.
Synthesis of Tetracyanoethylene Oxide.35 A solution of
tetracyanoethylene (3.0 g, 34 mmol) in acetonitrile (22 mL) was
cooled to −5 °C in an acetone−ice bath. Hydrogen peroxide (30%)
(2.66 mL, 34 mmol) was added dropwise at such a rate that the
temperature of the reaction remained between 10 and 12 °C. When
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the addition was complete, the reaction mixture was stirred for a
further 5 min and then diluted with ice cold water (150 mL). The
precipitated solid was collected by filtration and washed with water.
The solid was left to dry on a suction pump for 1 h and then used
immediately. The product was obtained as a white solid (3.62 g, 74%),
mp 177−179 °C (sealed tube) (lit mp 177−178 °C);35 (Found C,
50.0; N, 38.7, C6N4O requires C, 50.0; N, 38.9%). Caution! Both
TCNE and TCNEO evolve hydrogen cyanide when exposed to water. All
operations must be carried out in a fumehood.
temperature for 4 h. After which time the solvent was removed under
reduced pressure, and the residue was dissolved in dichloromethane (3
mL). The residue was placed onto a flash column of silica gel (230−
400 mesh ASTM) and eluted with a mixture of dichloromethane:pe-
troleum spirit (bp 40−60 °C) in the gradient 1:1 to 1:0. Overall yield:
94% (endo:exo 3.0:1) 1-endo-isomer: (71% 0.31 g) mp 123−125 °C
(ethanol); (Found C, 68.6; H, 5.1; N, 19.9, C16H14N4O requires C,
69.0; H, 5.0; N, 20.1%); νmax cm−1 (Nujol mull) 1712 (CO); δH
(400 MHz, CDCl3) 0.79 (t, 3H, J = 7.3, CH3), 2.34 (q, 2H, J = 7.3,
CH2), 2.92 (dd, 1H, J = 3.9, 14.2, H-2), 3.05 (dd, 1H, J = 9.2, 14.2, H-
2), 3.65−3.69 (m, 1H, H-1exo), 2.82 (d, 1H, J = 7.3, H-10b), 7.08 (d,
1H, J = 6.8, H-10), 7.26−7.45 (m, 3H, H-7 to H-9), 7.62 (s, 1H, H-6);
δC (100 MHz, CDCl3) 7.3 (CH3), 35.6 (CH2), 38.8 (C-2), 49.8 (C-1),
58.7 (C-10b), 113.2, 113.3 (CN), 124.9 (C-10a), 125.0 (C-10),
127.0 (C-9), 129.3 (C-8), 130.9 (C-6a), 131.9 (C-7), 144.8 (C-6),
208.3 (CO). 1-exo isomer: (23% 0.098 g gum); νmax cm−1 (CCl4
liquid cell) 1725 (CO); δH (400 MHz, CDCl3) 1.16 (t, 3H, J = 6.8,
CH3), 2.65 (q, 2H, J = 6.8, CH2), 2.92 (dd, 1H, J = 6.3, 13.9, H-2endo),
3.06 (dd, 1H, J = 10.9, 13.9, H-2exo), 3.55−3.62 (m, 1H, H-1endo), 4.60
(d, 1H, J = 9.3, H-10b), 6.99 (d, 1H, J = 7.3, H-10), 7.26−7.49 (m, 3H,
H-7 to H-9), 7.76 (s, 1H, H-6); δC (100 MHz, CDCl3) 7.5 (CH3),
35.7 (CH2), 38.3 (C-2), 49.1 (C-1), 58.1 (C-10b), 112.5, 113.1 (C
N), 123.2 (C-10a), 125.6 (C-10), 126.3 (C-9), 128.7 (C-6a), 132.0
(C-7), 146.2 (C-6), 206.7 (CO).
Phthalazinium-2-dicyanomethanide 1,3-dipole (1).35 A sol-
ution of phthalazine (0.91 g, 7.0 mmol) in ethyl acetate (40 mL) was
cooled to below 0 °C in an ice-bath. This was treated dropwise with a
cooled ethyl acetate solution (5 mL) of TCNEO (1.0 g, 7.0 mmol).
The yellow product precipitated immediately and was collected by
filtration (1.25 g, 92%): mp 263−265 °C (acetonitrile); (Found C,
67.9, H, 3.1; N, 28.7, C11H6N4 requires C, 68.0, H, 3.1, N, 28.9%); νmax
(mull)/cm−1 2191, 2159 (CN); δH (400 MHz, DMSO-d6, 80 °C)
7.92−7.96 (m, 1H, H-5), 8.02−8.06 (m, 1H, H-8), 8.18−8.24 (m, 2H,
H-6 and H-7), 9.40 (s, 1H, H-4), 9.60 (s, 1H, H-1); δC (100 MHz,
DMSO-d6, 80 °C) 63.5 (methanide C), 117.2 (CN), 122.8 (C-8a),
126.4, 128.0 (C-6 and C-7), 129.8 (C-4a), 132.8 (C-8), 135.5 (C-5),
150.9 (C-1), 153.9 (C-4).
Pyridazinium dicyanomethanide 1,3-dipole (1A).35 A solution
of pyridazine (0.98 mL, 7.0 mmol) in ethyl acetate (20 mL) was
cooled to below 0 °C in an ice-bath. This was treated dropwise with a
cooled ethyl acetate solution (5 mL) of TCNEO (1.0 g, 7.0 mmol).
The yellow product precipitated from the solution and was collected in
three crops as the 1,3-dipole gradually separated from the solution
(0.69 g, 70%): mp 208−210 °C (methanol); νmax (nujol mull)/cm−1
2194, 2166 cm−1 (CN); (Found C, 58.0; H, 2.5; N, 39.1, C7H4N4
requires C, 58.3; H, 2.8; N, 38.8%); δH (400 MHz, DMSO-d6) 7.46−
7.49 (m, 1H, H-4), 8.00−8.04 (m, 1H, H-5), 8.77 (d, 1H, J = 5.9, H-
3), 8.95 (d, 1H, J = 5.2, H-6); δC (100 MHz, DMSO-d6) 65.5
(methanide C), 116.1 (CN), 122.3 (C-4), 130.7 (C-5), 134.4 (C-6),
152.0 (C-3).
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 96%
(endo:exo ratio 11:1).
endo-3,3-Dicyano-1,2-cyclopentano-5-one-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine and exo-3,3-Dicyano-1,2-
cyclopentano-5-one-1,2,3,10b-tetrahydropyrrolo[2,1-a]-
phthalazine (4).32 A suspension of compound 1 (0.30 g, 1.54 mmol)
in acetonitrile (20 mL) was treated with an excess of 2-cyclopenten-1-
one (0.64 mL, 7.7 mmol) and was stirred under reflux for 24 h. The
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (3 mL). This was placed on a flash
column of silica gel (230−400 mesh ASTM) and eluted with a
petroleum spirit (bp 40−60 °C)/dichloromethane mixture in the
gradient 1:1 to 0:1. The products were eluted from the column as
follows. Overall yield: 80% (endo:exo 3:1). endo-isomer: (60%, 0.27 g)
mp 228−229 °C (ethanol); (Found C, 69.8; H, 4.1; N, 19.8,
C16H12N4O requires C, 69.5; H, 4.4; N, 20.2%); νmax cm−1 (Nujol
mull) 1748 (CO); δH (400 MHz, DMSO-d6) 2.08−2.58 (m, 4H, H-
3′ and H-4′), 3.55 (dd, 1H, H-1), 3.80−3.82 (m, 1H, H-2), 4.72 (d,
1H, J = 6.3, H-10b), 7.37−7.55 (m, 3H, H-7 to H-9), 7.56 (d, 1H, J =
7.3, H-10), 7.82 (s, 1H, H-6); δC (100 MHz, DMSO-d6) 24.5 (C-3′),
38.2 (C-2), 38.5 (C-4′), 47.6 (C-1), 60.5 (C-10b), 112.8, 113.5 (C
N), 124.4 (C-10a), 126.6 (C-10), 127.1 (C-9), 130.7 (C-8), 131.3 (C-
7), 131.2 (C-6a), 146.6 (C-6), 213.6 (CO). exo-isomer: 20%, 0.09
g, Gum (recolumed crude sample); νmax /cm−1 (CCl4 Liquid cell)
1734 (CO); δH (400 MHz, DMSO-d6) 2.20−2.52 (m, 4H, H-3′ and
H-4′), 3.49 (dd, 1H, H-1), 3.83−3.85 (m, 1H, H-2), 4.19 (d, 1H, J =
9.2, H-10b), 7.34−7.78 (m, 4H, H-7 to H-10), 7.89 (s, 1H, H-6); δC
(100 MHz, DMSO-d6) 22.9 (C-3′), 37.8 (C-4′), 51.1 (C-1), 57.0 (C-
10b), 60.4 (C-3), 112.2, 114.3 (CN), 124.5 (C-10), 126.3 (C-9),
128.9 (C-8), 132.5(C-7), 133.2 (C-6a), 146.7 (C-6), 211.2 (CO).
Synthesis in Water. The reaction was carried out using water as the
reaction medium by heating at 82 °C, and products were isolated as
described. Overall yield: 95% (endo:exo ratio 16:1).
1-endo-Acetyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-
a]phthalazine and 1-exo-Acetyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (2).32 A suspension of
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
with an excess of methyl vinyl ketone (0.64 mL, 7.7 mmol) and stirred
at ambient temperature for 4 h to give a pale yellow solution. The
solvent was removed under reduced pressure, and the residue was
placed on a flash column of silica gel (230−400 mesh ASTM) and
eluted with dichloromethane to give both the endo- and exo-isomers.
Overall yield: 96% (1-endo:1-exo 3.2:1). 1-endo-isomer: (73%, 0.31 g)
mp 152−154 °C (ethanol); (Found C, 68.0;, H, 4.3; N 21.2;
C15H12N4O requires C, 68.2; H, 4.5; N, 21.2%); νmax cm−1 (nujol
mull) 1715 (CO); δH (400 MHz, CDCl3) 2.05 (s, 3H, CH3), 3.63−
3.67 (m, 1H, H-1exo), 2.93 (dd, 1H, J = 3.4, 14.6, H-2endo), 3.09 (dd,
1H, J = 8.7, 14.6, H-2exo), 4.80 (d, 1H, J = 6.8, H-10b), 7.27−7.46 (m,
3H, H-7 to H-9), 7.65 (s, 1H, H-6); δC (100 MHz, CDCl3) 29.4
(CH3), 38.5 (C-2), 50.5 (C-1), 55.2 (C-3), 58.5 (C-10b), 113.1, 113.3
(CN), 124.6 (C-10a), 127.1, 129.3, 124.8 (C-8 to C-10), 130.7 (C-
6a), 132.0 (C-7), 145.3 (C-6) 205.5 (CO). 1-exo-isomer: 23%,
0.098 g gum; νmax cm−1 (CCl4 liquid cell) 1716 (CO); δH (400
MHz, CDCl3) 2.93 (s, 3H, CH3), 2.95 (dd, 1H, J = 5.8, 13.9, H-2endo),
3.10 (dd, 1H, J 11.7, 13.9, H-2exo), 4.53 (d, 1H, J = 9.2, H-10b), 7.03
(d, 1H, J = 6.8, H-10), 7.28- 7.48 (m, 3H, H-7 to H-9), 7.76 (s, 1H, H-
6); δC (100 MHz, CDCl3) 29.2 (CH3), 37.8 (C-2), 49.8 (C-1), 57.6
(C-10b), 112.8, 113.1 (CN) 123.5 (C-10), 124.8 (C-10a), 126.2
(C-9), 128.9 (C-8), 129.3 (C-6a), 131.2 (C-7), 146.4 (C-6), 203.9
(CO).
1-endo-Butyryl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo-
[2,1-a]phthalazine and 1-exo-Butyryl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (5). A suspension of com-
pound 1 (0.10 g, 0.51 mmol) in acetonitrile (7 mL) was treated with
an excess of 1-hexen-3-one (0.288 mL, 2.56 mmol) and stirred at
ambient temperature for 4 h to give a pale yellow solution. The solvent
was removed under reduced pressure, and the residue was placed on a
flash column of silica gel (230−400 mesh ASTM). The endo/exo-
isomers proved difficult to isolate separately. The characterization
given is for the mixture of the endo- and exo-isomers, and the ratio of
endo/exo-isomers was determined through integration of the H-10b
signals. 1-endo- and 1-exo-isomers: (0.128 g, 86%, endo:exo 7.6:1),
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield: 95%
(endo:exo ratio 7:1).
1-endo-Propionyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo-
[2,1-a]phthalazine and 1-exo-Propionyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine. (3).32 A suspension of
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
with ethyl vinyl ketone (0.76 mL, 7.7 mmol) and stirred at room
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Gum; HRMS (ESI) calcd for C17H16N4O (M + H)+ 293.1403, found
293.1417; δH (500 MHz, CDCl3) 0.65 (t, 3H, J = 7.4, CH3 endo),
0.96−1.00 (m, 3H, CH3 exo), 1.30−1.38 (m, 2H, CH3 endo), 1.68−
1.77 (m, 2H, CH2 endo) 2.23−2.37 (m, 2H, CH2 exo), 2.59−2.63 (m,
2H, CH2 exo), 2.89−2.93 (m, 1H endo, 1H exo, H-2), 3.01−3.11 (m,
1H endo, 1H exo, H-2), 3.55−3.59 (m, 1H, H-1 exo), 3.62−3.66 (m,
1H, H-1 endo), 4.60 (d, 1H, J = 9.2, H-10b exo), 4.82 (d, 1H, J = 7.4,
H-10b endo), 6.98 (d, 1H, J = 7.6, H-10 exo), 7.09 (d, 1H, J = 7.1, H-
10 endo), 7.30−7.53 (m, H-7 to H-9 endo and H-7 to H-9 exo), 7.62
(s, 1H, H-6 endo), 7.76 (s, 1H, H-6 exo); δC (125 MHz, CDCl3) 13.4
(CH3 endo), 13.6 (CH3 exo), 16.5 (CH2 endo), 16.8 (CH2 exo), 38.3
(C-2 exo), 38.9 (C-2 endo), 44.2 (CH2 endo and exo), 49.9 (C-1 exo),
50.0 (C-1 endo), 54.7 (C-3 exo), 55.8 (C-3 endo), 58.0 (C-10b exo),
58.5 (C-10b endo), 112.9, 113.2 (CN exo), 113.0, 113.5 (CN
endo), 123.6 (C-10a exo), 124.7 (C-10a endo), 125.0 (C-10 exo),
125.2 (C-10 endo), 126.3 (C-9 exo), 127.1 (C-9 endo), 128.9 (C-8
exo), 129.4 (C-8 endo), 130.5 (C-6a endo and exo) 131.9 (C-7 endo),
132.1 (C-7 exo), 144.8 (C-6 endo), 145.9 (C-6 exo), 206.2 (CO
exo), 207.6 (CO endo). The terms endo and exo refer to the isomers
to which the signal belongs. Some of the exo-isomer peaks are missing
in the 13C NMR due to overlap with the major endo-isomer
caused the major product to separate as a yellow solid. The ethereal
filtrate contained the minor isomer as well as traced on the major
1
isomer and some intractable gum. H NMR analysis of this mixture,
combined with separation by flash chromatography on silica gel using
petroleum ether (bp 40−60 °C)/dichloromethane in the gradient 1:1
to 1:0 afforded the separated regioisomers. Overall yield: 57% (endo-
aryl:exo-aryl 10.4:1). major isomer (endo p-ClC6H4): Yield 52%,
colorless solid, 162−163 °C (ethanol); νmax/cm−1 761 (C−Cl) 1725
(CO); HRMS (ESI) calcd for C21H15N4OCl (M + H)+ 375.1013,
found 375.1048; δH (400 MHz, CDCl3) 1.87 (s, Me); 3.86 (dd, J =
7.8, 7.3, H-1), 4.26 (d, J = 7.8, H-2), 5.25 (d, J = 7.3, H-10b), 7.21 (d, J
= 7.3, H-10), 7.34 (d, J = 7.3, H-7), 7.41−7.47 (m, H-8 and H-9, H-2′
and H-3′), 7.63 (s, H-6); δC (100 MHz, CDCl3) 31.6 (Me), 57.2 (C-
10b), 58.9, 59.4 (C-1, C-2), 65.9 (C-3), 111.2, 111.9 (CN), 124.3
(C-10a), 126.2 (C-10), 127.5 (C-9), 129.3 (C-1′), 129.8 (C-2′), 129.9
(C-8), 130.1 (C-3′), 130.4 (C-6a), 132.1 (C-7), 136.1 (C-4′), 144.6
(C-6), 204.5 (CO). minor isomer (exo p-ClC6H4): Yield 5%; δH
(400 MHz, CDCl3) mixture with the major isomer; key signals 3.67
(dd, 8.7, 8.3, H-1), 4.19 (d, J = 7.3, H-2), 4.66 (d, J = 8.7, H-10b).
Synthesis in Water. A suspension of compound 1 (0.20 g, 1.03
mmol) and 4-(4-chlorophenyl)-3-buten-2-one (0.19 g, 1.05 mmol) in
water (10 mL) was stirred vigorously at 75 °C for 24 h. During this
time the suspended solids compacted into a sticky mass surrounding
the stir bar and were converted to the products, which were collected
by filtration and scraping from the stir bar to give a mixture of
compounds. Overall yield 86%, endo-aryl:exo-aryl isomer ratio 6.2:1.
endo-1-Methoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-Methoxycar-
bonyl isomer and endo-2-Methoxycarbonyl-3,3-dicyano-
1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine (8).34b A suspen-
sion of the compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL)
was treated with methyl acrylate (0.69 mL, 7.7 mmol) stirred at
ambient temperature for 12 h, giving a pale yellow solution. The
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (4 mL). This was placed on a flash
column of silica gel (230−400 mesh ASTM) and eluted with a
gradient mixture of dichloromethane and petroleum spirit (bp 40−60
°C) in the range 1:1 to 1:0. The products from the column were
isolated in the following order. Overall yield 65% (1-isomer) (1-
endo:1-exo 8.3:1). 2-endo-isomer: (0.008 g, 2%); gum (recolumned
crude sample); νmax(CCl4 liquid cell)/cm−1, 1742 (CO); δH (400
MHz, CDCl3) 2.53−2.98 (m, 2H, H-1), 3.96 (s, 1H, OMe), 3.90−3.96
(m, 1H, H-2exo), 4.34 (dd, 1H, J = 8.6, 8.5, H-10b), 7.13−7.53 (m, 4H,
H-7 to H-10), 7.81 (s, 1H, H-6). 1-exo-isomer: (0.03 g, 7%), gum
(recolumned crude sample); νmax(CCl4 liquid cell)/cm−1, 1751 (C
O); δH (400 MHz, CDCl3) 3.00−3.22 (m, 2H, H-2), 3.86 (s, 3H,
OMeendo), 3.54−3.59 (m, 1H, H-1exo), 4.46 (d, 1H, J = 8.8, H-10b),
7.40−7.61 (m, 4H, H-7 to H-10), 7.89 (s, 1H, H-6); δC (100 MHz,
CDCl3) 42.3 (OMe), 58.7 (C-10b), 113.2, 113.5 (CN), 123.4,
124.9, 126.0, 128.8 (C-7 to C-10), 131.5 (C-6a), 145.8. 1-endo
isomer: (0.25 g, 58%); white crystalline solid, mp 132−133 °C
(ethanol); (Found C, 63.9; H, 4.3; N, 19.9. C15H12N4O2 requires C,
64.3; H, 4.3; N, 19.9%) νmax(mull)/cm−1 1742 (CO); δH (400
MHz, CDCl3) 2.99−3.05 (m, 1H, H-2exo), 3.12−3.16 (m, 1H, H-
2endo), 3.55 (s, 3H, OMeendo), 3.63−3.68 (m, 1H, H-1exo), 4.82 (d, 1H,
J = 6.6, H-10b), 7.26−7.45 (m, 4H, H-7 to H-10), 7.66 (s, 1H, H-6);
δC (400 MHz, CDCl3) 39.2 (C-2), 42.9 (OMe), 52.4 (C-1), 55.8 (C-
3), 59.2 (C-10b), 113.3, 113.9 (CN), 124.7 (C-10a), 125.1,126.1,
127.1(C-8 to C-10), 129.7 (C-7), 130.2 (C-6a), 144.4 (C-6), 170.6
(CO).
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 90%
(endo:exo ratio 7.4:1).
1-endo-Hexanoyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo-
[2,1-a]phthalazine and 1-exo-Hexanoyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (6). A suspension of com-
pound 1 (0.100 g, 0.51 mmol) in acetonitrile (6.4 mL) was treated
with an excess of 1-octen-3-one (0.38 mL, 0.255 mmol) and stirred at
ambient temperature for 4 h to give a pale yellow solution. The solvent
was removed under reduced pressure, and the residue was placed on a
flash column of silica gel (230−400 mesh ASTM The endo/exo-
isomers proved difficult to isolate separately. The characterization
given is for the mixture of the endo- and exo-isomers, and the ratio of
endo/exo-isomers was determined through integration of the H-10b
signals. 1-endo- and 1-exo-isomers: (0.161 g, 99%, endo:exo 8.7:1),
Gum; HRMS (ESI) calcd for C19H20N4O (M + H)+ 321.1716, found
321.1725; δH (500 MHz, CDCl3) 0.75 (t, 3H, CH3 endo), 0.87−0.98
(m, 2H CH2 endo, 3H CH3 exo), 1.06−1.14 (m, 2H, CH2 endo),
1.22−1.36 (m, 2H, CH2 endo, 2H, CH2 exo), 1.64−1.73 (m, 2H, CH2
exo), 2.25−2.30 (m, 2H, CH2 exo), 2.29−2.32 (m, 2H, CH2 endo, 2H
CH2 exo), 2.88−2.92 (m, 1H endo, 1H exo, H-2), 3.03 (dd, 1H, J =
13.8, 9.1, H-2 endo), 3.10 (dd, 1H, J = 13.8, 11.2, H-2 exo), 3.55−3.60
(m, 1H, H-1 endo), 3.64−3.68 (m, 1H, H-1 exo), 4.50 (d, 1H, J = 9.4,
H-10b exo), 4.81 (d, 1H, J = 7.5, H-10b endo), 6.97 (d, 1H, J = 7.8, H-
10 exo), 7.09 (d, 1H, J = 7.4, H-10 endo), 7.26−7.53 (m, 3H, H-7 to
H-9 endo, 3H, H-7 to H-9 exo), 7.57 (s, 1H, H-6 endo), 7.73 (s, 1H,
H-6 exo); δC (125 MHz, CDCl3) 13.8 (CH3 endo), 13.9 (CH3 exo),
22.1 (CH2 endo), 22.7 (CH2 exo), 23.1 (CH2 exo), 22.3 (CH2 endo),
30.8 (CH2 exo), 30.9 (CH2 endo), 38.2 (C-2 exo), 38.8 (C-2 endo),
42.5 (CH2 endo), 42.3 (CH2 exo), 49.2 (C-1 exo), 50.0 (C-1 endo),
55.9 (C-3 endo), 58.0 (C-10b exo), 58.9 (C-10b exo), 112.9, 113.3
(CN exo), 113.1, 113.6 (CN endo), 123.6 (C-10a exo), 124.6
(C-10a endo), 125.3 (C-10 endo), 126.2 (C-9 exo), 127.0 (C-9 endo),
128.9 (C-8 exo), 129.3 (C-8 endo), 130.5 (C-6a), 131.8 (C-7 endo),
132.0 (C-7 exo), 144.5 (C-6 endo), 146.3 (C-6 exo), 207.1 (CO
exo), 208.0 (CO endo). The terms endo and exo refer to the isomers
to which the signal belongs. Some of the exo-isomer peaks are missing
in the 13C NMR due to overlap with the major endo-isomer.
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 92%
(endo:exo ratio 8.2:1).
Synthesis in Water. The product and was stirred at ambient
temperature and isolated as described. Overall yield 91% (1-endo:exo
ratio 9.8:1). A small amount (<2%) of the 2-endo-isomer was observed
1-endo-2-exo-2-Acetyl-1-(4-chlorophenyl)-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine-3,3-dicarbonitrile and 1-
exo-2-endo-2-Acetyl-1-(4-chlorophenyl)-1,2,3,10b-
1
by H NMR.
endo-1-Ethoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-Ethoxycarbon-
yl isomer and endo-2-Ethoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (9).34b A suspension of the
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
with ethyl acrylate (0.83 mL, 7.7 mmol) stirred at ambient
tetrahydropyrrolo[2,1-a]phthalazine-3,3-dicarbonitrile (7).9c
A
suspension of compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20
mL) was treated with 4-(4-chlorophenyl)-3-buten-2-one (0.834 g, 4.62
mmol) and stirred under reflux for 4h. The solvent was removed under
reduced pressure, and the residue was taken up in ice-cold Et2O, which
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temperature for 24 h, giving a pale yellow solution. The solvent was
removed under reduced pressure, and the residue was dissolved in
dichloromethane (4 mL). This was placed on a flash column of silica
gel (230−400 mesh ASTM) and eluted with a gradient mixture of
dichloromethane and petroleum spirit (bp 40−60 °C) in the range 1:1
to 1:0. The products from the column were isolated in the following
order. Overall yield 69% (1-isomer) (1-endo:1-exo 6.6:1) 2-endo-
isomer: (0.018 g, 4%), gum (recolumned crude sample); νmax(CCl4
Liquid cell)/cm−1 1743 (CO); δH (400 MHz, CDCl3) 1.34 (t, 3H,
CH3), 2.96−3.05 (m, 1H, H-2), 3.18−3.23 (m, 1H, H-2), 3.51−3.56
(m, 1H, H-1), 4.31 (q, 2H, CH2), 4.45 (dd, 1H, J = 10.8, 6.9, H-10b),
7.40−7.60 (m, 4H, H-7 to H-10), 7.78 (s, 1H, H-6); δC (100 MHz,
CDCl3) 14.0 (CH3), 38.2 (CH2), 58.8 (C-10b), 62.5 (C-2) 112.6,
113.2 (CN), 128.7, 128.9, 133.1 (C-7 to C-10), 148.8 (C-6), 170.4
(CO). 1-exo-isomer: (0.04 g, 9%), gum (recolumned crude
sample); νmax(CCl4 Liquid cell)/cm−1 1752 (CO); δH (400 MHz,
CDCl3) 1.42 (t, 3H, CH3), 2.51−2.57 (m, 1H, H-1), 2.92−2.99 (m,
1H, H-1), 3.83−3.89 (m, 1H, H-2), 4.36 (q, 2H, CH2), 4.46 (d, 1H, J
= 9.2, H-10b), 7.13−7.15 (d, 1H, H-10), 7.26−7.53 (m, 3H, H-7 to H-
9), 7.80 (s, 1H, H-6). 1-endo-isomer: (0.27 g, 60%), 130−131 °C
(ethanol); Found C, 65.7; H, 4.4; N, 19.2. C16H14N4O2 requires C,
65.3; H, 4.7; N, 19.1; νmax(mull)/cm−1 1753 (CO); δH (400 MHz,
CDCl3) 1.07 (t, 3H, CH3), 2.90−3.03 (m, 1H, H-2), 3.13−3.17 (m,
1H, H-2), 3.60−3.64 (m, 1H, H-1), 4.00 (q, 2H, CH2), 4.85 (d, 2H, J
= 6.2, H-10b), 7.20−7.43 (m, 4H, H-7 to H-10), 7.60 (s, 1H, H-6); δC
(100 MHz, CDCl3) 13.8 (CH3), 39.2 (CH2), 39.5 (C-2), 55.0 (C-3),
59.2 (C-10b), 61.8 (C-1), 113.9 (CN), 124.7 (C-7), 125.5 (C-6a),
126.6 (C-9), 129.4 (C-7), 131.4 (C-10), 144.1 (C-6), 170.1 (CO).
Synthesis in Water. The product and was stirred at ambient
temperature and isolated as described. Overall yield 82% (1-isomer)
(1-endo:1-exo ratio 6.4:1). A small amount <2% of the 2-endo-isomer
endo-1-tert-Butoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-tert-Butoxycar-
bonyl isomer and endo-2-tert-Butoxycarbonyl-3,3-dicyano-
1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine (11). A suspen-
sion of the compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL)
was treated with t-butyl acrylate (1.12 mL, 7.7 mmol) stirred at
ambient temperature for 24 h, giving a pale yellow solution. The
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (4 mL). This was placed on a flash
column of silica gel (230−400 mesh ASTM) and eluted with a
gradient mixture of dichloromethane and petroleum spirit (bp 40−60
°C) in the range 30:70 to 100:0. The products from the column were
isolated in the following order. Overall yield 76% (1-isomer) (1-
endo:1-exo 2.8:1). 2-endo-isomer: (0.05 g, 10%), gum (recolumned
crude sample); νmax(CCl4 Liquid cell)/cm−1 1725 (CO); δH (400
MHz, CDCl3) 1.48 (s, 9H, t-Bu), 2.40 (dd, 1H, J = 12.9, 22.9, H-1exo),
2.82 (dd, 1H, J = 12.9, 5.8, H-1endo), 3.68 (dd, 1H, J = 5.8, 5.9, H-2exo),
4.23 (dd, 1H, J = 8.7, 8.5 H-10b), 7.06 (d, 1H, J = 7.3, H-10), 7.25−
7.46 (m, 3H, H-7 to H-9), 7.43 (s, 1H, H-6); δC (100 MHz, CDCl3)
27.9 (t-Bu), 51.2 (C-10b), 55.6 (C-2), 85.0 (C(CH3)3), 112.0, 113.1
(CN), 123.3 (C-10a), 134.6 (C-6a), 132.1(C-7), 128.1, 126.1, 129.0
(C-8 to C-10), 147.0 (C-6), 165.9 (CO). 1-exo-isomer: (0.10 g,
20%), gum (recolumned crude sample); νmax(CCl4 Liquid cell)/cm−1
1732 (CO); δH (400 MHz, CDCl3) 2.50 (s, 9H, t-Bu), 2.93 (dd,
1H, J = 13.6, 11.2, H-2exo), 3.15 (dd, 1H, J = 13.6, 5.3, H-2endo), 3.43
(m, 1H, H-1), 4.36 (d, 1H, J = 8.8, H-10b), 7.31 (d, 1H, J = 6.8, H-
10), 7.39−7.67 (m, 3H, H-7 to H-9), 7.75 (s,1H, H-6); δC (100 MHz,
CDCl3) 27.8 (t-Bu), 38.1 (C-2), 43.5 (C-1), 53.1 (C-3), 59.0 (C-10b),
84.3 (C(CH3)3), 112.5, 113.2 (CN), 123.4 (C-10a), 125.0, 126.0,
128.8 (C-7 to C-9), 132.1 (C-10a), 133.7 (C-6a), 146.7 (C-6), 169.4
(CO). 1-endo-isomer: (0.28 g, 56%) white crystalline solid; mp
142−143 °C (ethanol); (Found C, 67.1; H, 5.8; N,17.2. C18H18N4O2
requires C, 67.0; H, 5.6, N, 17.3%); νmax(mull)/cm−1 1721 (CO);
δH (400 MHz, CDCl3) 2.10 (s, 9H, t-Bu), 2.96 (dd, 1H, J = 14.1, 8.3,
H-2endo), 3.10 (dd, 1H, J = 14.1, 2.9, H-2exo), 3.48−3.53 (m, 1H, H-
1exo), 4.83 (d, 1H, J = 6.3, H-10b), 7.28 (d, 1H, J = 8.3, H-10), 7.31−
7.45 (m, 3H, H-7 to H-9), 7.56 (s, 1H, H-6); δC (100 MHz, CDCl3)
27.7 (t-Bu), 39.7 (C-2), 44.6 (C-1), 55.1 (C-3), 59.3 (C-10b), 83.0
(C(CH3)3), 113.5, 114.2 (CN), 124.3 (C-10a), 130.3 (C-6a), 131.4
(C-7), 126.1, 126.7, 129.1 (C-8 to C-10), 143.8 (C-6), 166.0 (CO).
Synthesis in Water. The product and was stirred at ambient
temperature and isolated as described. Overall yield 95% (1-isomer)
(1-endo:1-exo ratio 2.1:1).
endo-1-Butoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-Butoxycarbon-
yl-3,3-dicyano-1,2,3,10b-tetrahydropyrollo[2,1-a]phthalazine
(12). A suspension of compound 1 (0.10 g, 0.512 mmol) in
acetonitrile (6.4 mL) was treated with an excess of n-butylacrylate
(0.364 mL, 2.56 mmol) and stirred at ambient temperature for 5 h to
give a pale yellow solution. The solvent was removed under reduced
pressure, and the residue was dissolved in dichloromethane (4 mL).
This was placed on a flash column of silica gel (230−400 mesh
ASTM) and eluted with a gradient mixture of dichloromethane and
petroleum spirit (bp 40−60 °C) in the range 30:70 to 100:0. The
products from the column were isolated in the following order. Overall
yield 95% (1-isomer) (1-endo:1-exo 5.3:1). 1-exo-isomer: gum (0.025
g, 15%); νmax(neat)/cm−1 1721(CO); δH (500 MHz, CDCl3) 0.86
(t, 3H, J = 7.1, CH3), 1.30−1.41 (m, 2H, CH2), 1.55−1.68 (m, 2H,
CH2), 3.03−3.13 (m, 2H, H-2), 4.10−4.29 (m, 3H, CH2 and H-1),
4.38 (d, 1H, J = 9.3, H-10b), 7.27−7.44 (m, 4H, H-7 to H10), 7.72 (s,
1H). The 1-exo and 2-endo products were isolated as a mixture and
could not be separated using column chromatography. The 2-endo-
isomer was present at 4% as observed by 1H NMR; however, because
of overlap, it was not possible to fully assign the 2-endo-isomer. 1-endo-
isomer: off-white solid (0.128 g, 80%) mp 79−81 °C (ethanol);
(Found C, 67.2; H, 5.4; N, 17.5. C18H16N4O2 requires C, 67.1; H, 5.6;
N, 17.4%); νmax(neat)/cm−1 1720 (CO); δH (500 MHz, CDCl3)
0.77 (t, 3H, J = 7.1, CH3), 1.10−1.23 (m, 2H, CH2), 1.32−1.46 (m
2H, CH2), 3.00 (dd, 1H, J = 13.5, 8.4, H-1endo), 3.13 (dd, 1H, J = 14.1,
2.7, H-2exo), 3.60−3.64 (m, 1H, H-1exo), 3.86 (m, 1H, CH2), 3.96−
1
was observed by H NMR.
endo-1-Propoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-Propoxycar-
bonyl isomer and endo-2-Propoxycarbonyl-3,3-dicyano-
1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine (10). A suspen-
sion of compound 1 (0.10 g, 0.51 mmol) in acetonitrile (6.4 mL) was
treated with an excess of n-propylacrylate (0.316 mL, 2.56 mmol)
(Caution! n-propylacrylate is a severe lachrymator and should be handled
in a fumehood) and stirred at ambient temperature for 4 h to give a
pale yellow solution. The solvent was removed under reduced
pressure, and the residue was dissolved in dichloromethane (4 mL).
This was placed on a flash column of silica gel (230−400 mesh
ASTM) and eluted with a gradient mixture of dichloromethane and
petroleum spirit (bp 40−60 °C) in the range 30:70 to 100:0. The
products from the column were isolated in the following order. Overall
yield 79% (1-isomer) (1-endo:1-exo 5.6:1). 1-exo-isomer: gum (0.018
g, 12%) νmax(neat)/cm−1 1731(CO); δH (500 MHz, CDCl3) 0.87−
0.98 (m, 3H, CH3), 1.31−1.47 (m, 2H, CH2), 2.91−2.98 (m, 1H, H-
1), 3.83−3.89 (m, 2H, H-2), 4.21−4.36 (m, 2H, CH2), 4.39 (d, 1H, J
= 9.1, H-10b), 7.25−7.53 (m, 4H, H-7 to H-10), 7.80 (s, 1H, H-6).
The 1-exo- and 2-endo-products were isolated as a mixture and could
not be separated using column chromatography. The 2-endo-isomer
1
was present at 5% as observed by H NMR; however, because of
overlap, it was not possible to fully assign the endo-2-isomer. 1-endo-
isomer: off-white solid (0.105 g, 67%) mp 122−124 °C (ethanol);
(Found C, 66.4; H, 5.2; N,18.0, C17H16N4O2 requires C, 66.2; H, 5.2;
N, 18.2%); νmax (neat)/cm−1 1721 (CO); δH (500 MHz, CDCl3)
0.75 (t, 3H, J = 7.5, CH3), 1.39−1.49 (m, 2H, CH2), 3.01 (dd, 1H, J =
14.2, 8.4, H-2endo), 3.15 (dd, 1H, J = 14.2, 2.9, H-2exo), 3.61−3.64 (m,
1H, H-1), 3.83−3.88 (m, 1H, CH2), 3.91−3.96 (m, 1H CH2), 4.83 (d,
1H, J = 6.7, H-10b), 7.25−7.43 (m, 4H, H-7 to H-10), 7.58 (s, 1H, H-
6); δC (125 MHz, CDCl3) 10.1 (CH3), 21.6 (CH2), 39.5 (C-2), 43.3
(CH2), 54.9 (C-3), 59.2 (C-10b), 67.4 (C-1), 113.3, 113.9 (CN),
124.8 (C-8), 125.3 (C-6a), 126.6 (C-9), 129.1 (C-7), 130.4 (C-10a),
131.5 (C-10), 144.2 (C-6), 170.2 (CO).
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 81% (1-
isomer) (1-endo:1-exo ratio 4.1:1).
3286
dx.doi.org/10.1021/jo400055g | J. Org. Chem. 2013, 78, 3276−3291

The Journal of Organic Chemistry
Article
4.01 (m, 1H, CH2), 4.81 (d, 1H, J = 6.4, H-10b), 7.25−7.42 (m, 4H,
H-7 to H-10), 7.58 (s, 1H, H-6); δc (500 MHz, CDCl3) 13.5 (CH2),
30.0 (CH2), 39.2 (C-2), 43.2 (CH2), 54.8 (C-3), 59.2 (C-10b), 65.6
(C-1), 113.4, 114.0 (CN), 124.8 (C-8), 125.3 (C-6a), 126.1 (C-9),
129.0 (C-7), 129.2 (C10a), 130.4 (C-10), 144.1 (C-6), 170.2 (CO).
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 88% (1-
isomer) (1-endo:1-exo ratio 3.6:1).
58.2 (C(CH3)3), 59.2 (C-1), 59.5 (C-3), 110.8, 112.4 (CN), 123.6
(C-10a), 126.9, 127.6, 129.1 (C-8 to C-10), 129.8 (C-6a), 131.7 (C-7),
146.5 (C-6), 171.6 and 173.8 (CO).
Synthesis in Water. The product was prepared and isolated as
described. Overall yield: 90% (endo:exo ratio 1:0). This structure of
this compound was confirmed previously by an X-ray crystal structure.
endo-1,2-(Dicarboxy-N-phenylimido)-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine. (16). A suspension of
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
with N-phenylmaleimide (0.26 g, 1.54 mmol) and stirred at ambient
temperature for 24 h. During this time the product precipitated from
solution and was collected by filtration to give the title compound
(0.51 g, 88%): mp 252−253 °C (ethanol); HRMS (ESI) calcd for
C21H13N5O2 (M + H)+ 368.1148, found 368.1175; νmax cm−1 (nujol
mull) 1715, 1795 (CO); δH (400 MHz, DMSO-d6) 4.41 (dd, 1H, J
= 7.8, 7.6, H-1), 4.77 (d, 1H, J = 7.8, H-2), 5.19 (d, 1H, J = 7.6, H-
10b), 7.19 (d, 2H, J = 7.1, H-2′ of N-Ph), 7.51−7.66 (m, 6H, H-3′ and
H-4′ of N-Ph and H-7 to H-9), 7.82 (d, 1H, J = 7.8, H-10), 8.07 (s,
1H, H-6); δC (100 MHz, DMSO-d6) 45.3 (C-2), 51.3 (C-1), 59.2 (C-
3), 59.7 (C-10b), 110.8, 112.4 (CN) 123.9 (C-10a), 128.9 (C-1′ of
N-Ph), 129.6 (C-6a), 131.9 (C-7), 126.5, 127.1, 127.8, 129.2, 131.5
(C-8 to C-10 and C-2′ and C-3′ of N-Ph respectively), 146.8 (C-6),
170.4, 172.4 (CO).
endo-1-Phenoxycarbonyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrollo[2,1-a]phthalazine and exo-1-Phenoxycar-
bonyl-3,3-dicyano-1,2,3,10b-tetrahydropyrollo[2,1-a]-
phthalazine (13). A suspension of compound 1 (0.10 g, 0.51 mmol)
in acetonitrile (6.4 mL) was treated with an excess of phenyl acrylate
(0.352 mL, 2.56 mmol) and stirred at ambient temperature for 12 h to
give a pale yellow solution. The solvent was removed under reduced
pressure, and the residue was dissolved in dichloromethane (4 mL).
This was placed on a flash column of silica gel (230−400 mesh
ASTM) and eluted with a gradient mixture of dichloromethane and
petroleum spirit (bp 40−60 °C) in the range 30:70 to 100:0. The
products from the column were isolated in the following order. Overall
yield 88% (1-isomer) (1-endo:1-exo 7.8:1). 1-exo-isomer: Gum (0.017
g, 10%) νmax(neat)/cm−1 1750 (CO); δH (500 MHz, CDCl3) 3.14
(m, 1H, H-2endo), 3.27 (dd, 1H, J = 14.2, 5.3, H-2exo), 3.68−3.74 (m,
1H, H-2endo), 4.55 (d, 1H, J = 9.2, H-10b), 6.74 (d, 1H, J = 8.6, 1H,
Ph), 7.09−7.48 (m, 6H, H-7 to H-9, Ph), 7.74 (s, 1H, H-6). 1-endo-
isomer: off-white solid (0.156 g, 78%) mp 126−128 °C (ethanol);
(Found C, 70.2; H, 4.2; N,16.5. C20H14N4O2 requires C, 70.1; H, 4.1;
N, 16.4%); νmax(neat)/cm−1 1748 (CO); δH (500 MHz, CDCl3)
3.11 (dd, 1H, J = 13.7, 8.1, H-2endo), 3.24 (dd, 1H, J = 13.7, 3.1, H-
2exo), 3.82−3.86 (m, 1H, H-1exo), 4.97 (d, 1H, J = 6.7, H-10b), 6.60 (d,
2H, J = 7.8, Ph), 7.16 (d, 1H, J = 7.3, H-10), 7.23−7.26 (m, 2H, Ph),
7.31−7.33 (m, 1H, Ph), 7.40−7.48 (m, 3H, H-7 to H-9), 7.60 (s, 1H,
H-6); δC (125 MHz, CDCl3) 39.6 (C-2), 43.7 (C-3), 55.3 (C-10b),
59.5 (C-1), 113.1, 113.9 (CN), 120.9 (Ph), 124.8 (C-8), 125.8 (C-
6a), 126.4 (C-9), 126.9 (Ph), 129.4 (C-7), 129.9 (C-10a), 131.7 (Ph),
144.1 (C-6), 149.9 (Ph), 169.0 (CO).
Synthesis in Water. Product was prepared in water as described and
isolated by direct filtration. Yield 96% (endo:exo ratio 1:0).
endo-1,2-(Dicarboxy-N-p-chlorophenylimido)-3,3-dicyano-
1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine (17).34c A sus-
pension of compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL)
was treated with N-(p-chlorophenyl)maleimide (0.32 g, 1.54 mmol)
and stirred at ambient temperature for 24 h. During this time the
product precipitated from solution and was collected by filtration to
give the title compound (0.53 g, 92%): mp 237−238 °C (ethanol);
(Found C, 62.9; H, 3.1; N, 17.4, C21H12N5O2Cl requires C, 62.7; H,
3.0; N, 17.4%); νmax cm−1 (nujol mull) 1781, 1716 (CO); δH (400
MHz, DMSO-d6) 4.31 (dd, 1H, J = 7.8, 8.1, H-1), 4.68 (d, 1H, J = 7.8,
́
H-2), 5.07 (d, 1H, J = 7.8, H-10b), 7.13 (d, 2H, J = 8.8, H-2 of N−
Synthesis in Water. The reaction was carried out under identical
conditions using water as the reaction medium. Overall yield 90%(1-
isomer) (1-endo:1-exo ratio 6.8:1).
C6H4Cl), 7.41−7.57 (m, 5H, H-3′ of C6H4Cl and H-7 to H-9), 7.71
(d, 1H, J = 7.3, H-10), 7.95 (s, 1H, H-6); δC (100 MHz, DMSO-d6)
45.2 (C-2), 51.2 (C-1), 59.1 (C-3), 59.8 (C-10b), 110.6, 112.2 (C
N), 123.5 (C-10a), 127.0, 127.7, 129.2 (C-8 to C-10), 129.3, 128.8,
133.3 (C-1′, C-2′, C-4′ of C6H4Cl respectively), 130.2 (C-6a), 131.8
(C-7), 146.7 (C-6), 170.2, 172.4 (CO).
endo-1,2(Dicarboxy-N-methylimido)-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (14).34b A suspension of
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
with N-methylmaleimide (0.17 g, 1.54 mmol) and stirred at ambient
temperature for 24 h. The solvent was removed under reduced
pressure to give the title compound (0.41 g, 87%): 233−235 °C
(ethanol); (Found C, 62.9; H, 3.7; N, 23.2, C16H11N5O2 requires C,
62.9; H, 3.6; N, 22.9); νmax /cm−1 2300 (CN), 1785, 1716 (CO);
δH (400 MHz, DMSO-d6) 2.78 (s, 3H, CH3), 4.18 (dd, 1H, J = 7.9,
7.7, H-1), 4.45 (d, 1H, J = 7.7, H-2), 4.85 (d, 1H, J = 7.9, H-10b),
7.45−7.55 (m, 3H, H-7 to H-9), 7.77 (d, 1H, J = 7.7, H-10), 7.91 (s,
1H, H-6); δC (100 MHz, DMSO-d6) 25.4 (CH3), 43.4 (C-2), 50.0 (C-
1), 57.4 (C-3), 58.7 (C-10b), 110.9, 112.1 (CN), 124.0 (C-10a),
127.0, 127.7, 129.0 (C-8 to C-10), 130.2 (C-6a), 131.7 (C-7), 147.6
(C-6), 171.2, 173.2 (CO).
Synthesis in Water. the product was prepared in water as described
and isolated by direct filtration, Yield 94% (endo:exo ratio 1:0).
exo-2-Butoxy-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-
a]phthalazine (18).34b A suspension of compound 1 (0.30 g, 1.54
mmol) in acetonitrile (20 mL) was treated with n-butyl vinyl ether
(1.47 mL, 15.4 mmol) and stirred under reflux for 12 h. The solvent
was removed under reduced pressure to give the title compound.
Yield: 86%, white crystalline solid, mp 140−141 °C (ethanol); (Found
C, 69.3; H, 6.2; N, 19.0. C17H18N4O requires C, 69.1; H, 6.1; N,
18.9%); δH (400 MHz CDCl3) 0.96 (t, 3H, CH3); 1.42−1.49 (m, 2H,
CH2), 1.65−1.70 (m, 2H, CH2), 2.39−2.45 (m, 1H, H-1exo), 2.64−
2.72 (m, 1H, H-1endo), 3.65−3.71 (m, 1H, H-1 n-Bu), 3.83−3.89 (m,
1H, H-1 n-Bu), 4.44 (dd, 1H, J = 8.3, 8.1, H-10b), 4.58−4.61 (m, 1H,
H-2), 7.07 (d, 1H, J = 7.3, H-10), 7.28−7.50 (m, 3H, H-7 to H-9),
7.72 (s, 1H, H-6); δC (100 MHz, CDCl3) 13.6 (CH3), 18.8 (CH2),
31.7 (CH2), 32.9 (C-1), 55.2 (C-10b), 61.6 (C-3), 72.2 (CH2), 83.8
(C-2), 110.2, 113.9 (CN), 123.4 (C-10), 124.7 (C-10a), 126.1,
128.5,125.9 (C-8 to C-10) 132.1(C-7), 134.2(C-6a), 146.3 (C-6).
Synthesis in Water. The reaction was carried out under identical
conditions as to that in acetonitrile. The reaction was carried out by
heating at 82 °C. The product was isolated by direct filtration, Yield
87% (2-endo:2-exo 0:1).
Synthesis in Water. The product and was stirred at ambient
temperature and isolated as described. Overall yield 89% (endo:exo
ratio 1:0).
Synthesis of endo-1,2-(Dicarboxy-N-tert-butylimido)-3,3-di-
cyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine (15).34b
A suspension of compound 1 (0.30 g, 1.54 mmol) in acetonitrile
(20 mL) was treated with N-tert-butylmaleimide (0.24 mL, 1.54
mmol) and stirred at ambient temperature for 24 h. The solvent was
removed under reduced pressure to give the title compound (80%):
white crystalline solid; mp 212−214 °C (ethanol); (Found C, 65.5; H,
5.0; N, 19.8. C19H17N5O2 requires C, 65.7; H, 4.9; N, 20.2%); νmax
(mull)/cm−1 2263 (CN) 1702, 1774 (CO); δH (400 MHz,
DMSO-d6), 1.35 (9H, s, tBu protons), 3.92−3.95 (1H, dd, J = 7.7, 7.8,
H-1), 4.29 (1H, d, J = 7.8, H-2), 4.93 (1H, d, J = 7.7, H-10b), 7.44−
7.57 (3H, m, H-7 to H-9), 7.67 (1H, d, J = 7.3, H-10), 7.87 (1H, s, H-
6); δC (100 MHz, DMSO-d6) 27.3 (C(CH3)), 44.4 (C-2), 50.8 (C-1),
This structure of compound 18 was confirmed by an X-ray crystal
structure.
exo-2-Phenyl-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-
a]phthalazine and endo-2-Phenyl-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine (19).9c A suspension of
compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was treated
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with styrene (0.352 mL, 3.08 mmol) and stirred under reflux for 24 h.
After this time the solvent was removed under reduced pressure, and
the residue was dissolved in dichloromethane (4 mL). This was placed
onto a flash column of silica gel (ASTM 230−400 mesh) packed with
petroleum spirit (bp 40−60 °C)/dichloromethane in the ratio 1:1.
The products were eluted with a mixture of petroleum spirit (bp 40−
60 °C)/dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v)
changing gradient. The products came off the column as follows. 2-
exo-isomer: (0.34 g, 74%), mp 158−160 °C (ethanol); (Found C,
76.2; H, 4.4; N, 18.5; C19H14N4 requires C, 76.5; H, 4.7; N, 18.7%);
νmax (mull)/cm−1 666, 759 (-Ph); δH (400 MHz, CDCl3) 2.74−2.85
(m, 2H, H-1), 4.15 (dd, 1H, J = 10.7, 7.3, H-2), 4.52 (dd, 1H, J = 8.8,
8.5, H-10b), 7.18 (d, 1H, J = 7.3, H-10), 7.25−7.54 (m, 8H, H-7, H-8,
H-9 and Ph), 7.80 (s, 1H, H-6); δC (100 MHz, CDCl3) 29.7 (C-1),
52.2 (C-2), 56.3 (C-10b), 63.7 (C-3), 110.8, 113.3 (CN), 123.1 (C-
10), 125.1 (C-10a), 126.0 (C-9), 128.7, 129.2, 134.7 (Ph, C-1′ to C-
4′), 129.4 (C-8), 132.0 (C-7), 133.7 (C-6a), 146.5 (C-6), C-4′ signal
masked by C-3′. 2-endo-isomer: (0.06 g, 13%) isolated as a gum; δH
(400 MHz, CDCl3) 2.56−2.64 (m, 1H, H-1endo), 2.99−3.03 (m, 1H,
H-1exo), 4.18 (dd, 1H, J = 8.8, 8.3, H-2), 4.54 (dd, 1H, J = 10.2, 5.8, H-
10b), 7.13−7.57 (m, 9H, H-7 to H-10 and Ph), 7.78 (s, 1H, H-6); δC
(100 MHz, CDCl3) 33.5 (C-1), 53.2 (C-2), 56.3 (C-10b), 111.7, 113.2
(CN), 122.9 (C-10), 128.7, 129.2, 136.7 (Ph, C-1′, C-2′, C-3′),
124.2, 129, 132.2 (C-7 to C-10), 145.9 (C-6), C-3 signal was too weak
to be seen with the small quantity available.
column of silica gel (ASTM 230−400 mesh) packed with petroleum
spirit (bp 40−60 °C)/dichloromethane in the ratio 1:1. The products
were eluted with a mixture of petroleum spirit (bp 40−60 °C)/
dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v) changing
gradient. The products could not be separated by this chromato-
graphic procedure, and the ratio of products, 5.1:1, was found by
proton NMR. The main product, the exo-isomer (0.31 g, 56%), was
purified by recrystalisation from ethanol, and the remaining mixture
was composed of 1:1 of the 2-exo and 2-endo-isomers. 2-exo-isomer:
(0.38 g, 76%), mp 152−154 °C (ethanol); (Found C, 71.8; H, 4.1; N,
18.0; C19H13N4F requires C, 72.1; H, 4.1; N, 17.7%); νmax (mull)/
cm−1 774 (o-disustituted benzene), 2146 (CN); δH (400 MHz,
CDCl3) 2.71−2.79 (m, 1H, H-1exo), 2.82−2.90 (m, 1H, H-1endo) 4.17
(dd, 1H, J = 11.2, 6.8, H-2), 4.54 (dd appearing as t, 1H, J = 8.8, 8.8,
H-10b), 7.13−7.55 (m, 8H, H7 to H-10 and H-2′ and H-4′ to H-6′),
7.81 (s, 1H, H-6); δC (100 MHz, CDCl3) 29.6 (C-1), 51.7 (C-2), 56.1
(C-10b), 63.0 (C-3), 110.6, 113.1 (CN), 115.7 (d, JF−C= 22.5, C-2′
or C-4′), 116.5 (d, JF−C= 18.2, C-2′ or C-4′), 123.1 (C-10a), 124.5 (C-
10), 126.1 (C-6′), 128.7 (C-9 and C-5′), 130.9 (C-8), 132.0 (C-7),
136.0 (C-1′), 136.1 (C-6a), 146.6 (C-6), 163.0(d, JF−C, 143.1, C-3′).
2-endo-isomer: (0.07 g, 15%) gum; δH (400 MHz, CDCl3) 2.49−2.53
(m, 1H, H-1endo), 2.99−3.02 (m, 1H, H-1exo), 7.03−7.67 (m, 8H, H7
to H-10 and H-2′ and H-4′, H-5′, H-6′), 7.71 (s, 1H, H-6). H-8a was
masked by the H-8a of the main isomer. H-2 was masked by the H-2
of the main isomer in the mixture. This fraction was an inseperable 1:1
mixture of endo:exo-isomers
Synthesis in Water. The reaction was carried out by stirring at 82
°C. For the work up the reaction was allowed to cool, and the
products were extracted into dichloromethane (2 × 10 mL) and dried
over MgSO4. The purification step was identical to the reaction carried
out in acetonitrile. Overall yield 78% (2-endo:2-exo 1:6.1).
Synthesis in Water. The reaction was carried out by stirring at 82
°C. For the work up the reaction was allowed to cool, and the
products were extracted into dichloromethane (2 × 10 mL) and dried
over MgSO4. The purification step was identical to the reaction carried
out in acetonitrile. Overall yield: 82% (2-endo:2-exo 1:6.4)
exo-2-(4-Methoxyphenyl)-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine and endo-2-(4-Methoxy-
phenyl)-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]-
phthalazine (20).9c A suspension of compound 1 (0.30 g, 1.54
mmol) in acetonitrile (20 mL) was treated with 4-methoxystyrene
(0.410 mL, 3.08 mmol) and stirred under reflux for 24 h. After this
time the solvent was removed under reduced pressure, and the residue
was dissolved in dichloromethane (4 mL). This was placed onto a flash
column of silica gel (ASTM 230−400 mesh) packed with petroleum
spirit (bp 40−60 °C)/dichloromethane in the ratio 1:1. The products
were eluted with a mixture of petroleum spirit (bp 40−60 °C)/
dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v) changing
gradient. The products came off the column as follows. 2-exo-isomer:
(0.32 g, 63%), mp 159−162 °C (ethanol); (Found C, 72.8; H, 4.5; N,
17.2; C20H16N4O requires C, 73.15; H, 4.9; N, 17.1%); νmax (mull)/
cm−1 831 (−C6H4), 1036, 1260 (C−O−C), 2213 (CN); δH (400
MHz, CDCl3) 2.69−2.87 (m, 2H, H-1), 3.85 (s, 3H, CH3) 4.13(dd,
1H, J = 11.3, 6.8, H-2), 4.52 (dd, 1H, J = 8.7, 8.3, H-10b), 6.98−7.77
(m, 8H, H7 to H-10 and H-2′, H-3′), 7.80 (s, 1H, H-6); δC (100 MHz,
CDCl3) 29.8 (C-1), 51.7 (C-2), 55.3 (OCH3), 56.3 (C-10b), 63.5 (C-
3), 111.0, 113.5 (CN), 114.6 (C-3′), 123.4 (C-10), 125.0 (C-10a),
125.5 (C-1′), 126.0 (C-9), 128.5 (C-8), 129.9 (C-2′), 132.0 (C-7),
134.7 (C-6a), 146.4 (C-6), 160.3 (C-4′). 2-endo-isomer: (0.04 g, 8%)
isolated as a gum; δH (400 MHz, CDCl3) 2.54−2.59 (m, 1H, H-1endo),
2.97−2.99 (m, 1H, H-1exo), 3.79 (s, 3H, OCH3), 4.15 (dd, 1H, J = 8.8,
8.3, H-2), 4.54 (dd, 1H, H-10b), 6.90 (d, 1H, J = 8.8, H-10) 7.12−7.50
(m, 7H, H7 to H-9 and H-2′, H-3′), 7.75 (s, 1H, H-6).
Synthesis in Water. The reaction was carried out by stirring at 82
°C. For the work up the reaction was allowed to cool, and the
products were extracted into dichloromethane (2 × 10 mL) and dried
over MgSO4. The purification step was identical to the reaction carried
out in acetonitrile. Overall yield: 87% (2-endo:2-exo 1:8.6).
exo-2-(3-Fluorophenyl)-3,3-dicyano-1,2,3,10b-
tetrahydropyrrolo[2,1-a]phthalazine and endo-2-(3-Fluoro-
phenyl)-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]-
phthalazine (21).9c A suspension of compound 1 (0.30 g, 1.54
mmol) in acetonitrile (20 mL) was treated with 3-fluorostyrene (0.367
mL, 3.08 mmol) and stirred under reflux for 24 h. After this time the
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (4 mL). This was placed onto a flash
e x o - 2 -( 3 - N i t r o p h e n yl ) - 3 , 3 - d i c ya n o- 1 , 2, 3 , 10 b -
tetrahydropyrrolo[2,1-a]phthalazine and endo-2-(3-Nitroro-
phenyl)-3,3-dicyano-1,2,3,10b-tetrahydropyrrolo[2,1-a]-
phthalazine (22).9c A suspension of compound 1 (0.30 g, 1.54
mmol) in acetonitrile (20 mL) was treated with 3-nitrostyrene (0.429
mL, 3.08 mmol) and stirred under reflux for 24 h. After this time the
reaction was allowed cool, and the exo-2 isomer precipitated from
solution and was collected by filtration (0.36 g, 68%). The solvent was
removed from the filtrate under reduced pressure, and the residue was
dissolved in dichloromethane (4 mL). This was placed onto a flash
column of silica gel (ASTM 230−400 mesh) packed with petroleum
spirit (bp 40−60 °C)/dichloromethane in the ratio 1:1. The products
were eluted with a mixture of petroleum spirit (bp 40−60 °C)/
dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v) changing
gradient to afford a inseperable mixture of the 2-endo- and 1-endo-
isomers. Overall yield 79% (2-isomer) (2-endo:2-exo 1:6.2). 2-exo-
isomer: (0.36 g, 68%), mp 235−238 °C (ethanol); (Found C, 66.6; H,
3.9; N, 20.6; C19H13N5O2 requires C, 66.5; H, 3.8; N, 20.4%); νmax
(mull)/cm−1 763 (o-disustituted benzene); δH (400 MHz, DMSO-d6)
2.79−2.88 (m, 1H, H-1endo), 2.96−3.03 (m, 1H, H-1exo), 4.58(dd, 1H,
J = 8.8, 8.3, H-10b), 4.86 (dd, 1H, J = 11.2, 5.8, H-2), 7.36 (d, 1H, J =
7.3, H-10), 7.49−7.64 (m, 3H, H7 to H-9), 7.86 (dd, 1H, J = 8.3, 7.8,
H-5′), 8.07 (s, 1H, H-6), 8.14 (d, 1H, J = 7.8, H-6′), 8.35 (d, 1H, J =
8.3, H-4′), 8.50 (s, 1H, H-2′); δC (100 MHz, DMSO-d6) 29.1 (C-1),
49.9 (C-2), 56.5 (C-10b), 63.0 (C-3), 111.4, 113.5 (CN), 123.8 (C-
10), 124.2 (C-10a), 126.3 (C-9), 128.6 (C-8), 130.8 (C-7), 132.4 (C-
6a), 124.6, 135.8, 137.2 (C-1′ to C-2′ and C-3′ to C-6′), 147.3 (C-6),
148.0 (C-3′). 2-endo-isomer: (0.06 g, 11%); δH (400 MHz, CDCl3)
2.54−2.61 (m, 1H, H-1endo), 3.11−3.18 (m, 1H, H-1exo), 4.32 (dd, 1H,
J = 8.3, 8.3, H-2), 4.58 (dd, 1H, J = 9.3, 3.3, H-10b), 7.13−8.08 (m,
8H, H-7 to H-10 and H-2′ and H-4′, H-5′, H-6′), 8.23 (s, 1H, H-6). 1-
endo-isomer: (0.03 g, 6%); δH (400 MHz, CDCl3) 2.82 (dd, 1H, J =
14.6, 2.9, H-2endo), 3.51 (dd, 1H, J = 14.6, 9.3, H-2exo), 4.12 (m, 1H, H-
1), 4.90 (d, J = 6.3, H-10b), 6.48 (d, 1H, J = 7.8, H-10), 7.13−8.08 (m,
7H, H7 to H-9 and H-2′ and H-4′, H-5′, H-6′), 8.27 (s, 1H, H-6).
Synthesis in Water. The reaction was carried out by stirring at 82
°C. For the work up the reaction was allowed to cool, and the
products were extracted into dichloromethane (2 × 10 mL) and dried
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over MgSO4. The purification step was identical to the reaction carried
out in acetonitrile. Overall yield: 82% (2-isomer) (2-endo:2-exo 1:7).
exo-8a,9,10,11,12,12a-Hexahydro-9,12-methanoisoindolo-
[1,2-a]phthalazine-8,8(12bH)-dicarbonitrile and endo-
8a,9,10,11,12,12a-Hexahydro-9,12-methanoisoindolo[1,2-a]-
phthalazine-8,8(12bH)-dicarbonitrile (23). A suspension of
compound 1 (0.100 g, 0.512 mmol) in acetonitrile (6.4 mL) was
treated with an excess of norbornene (0.48 g, 5.12 mmol) and stirred
at ambient temperature for 16 h to give a pale yellow solution. The
solvent was removed under reduced pressure, and the residue was
dissolved in dichloromethane (4 mL). This was placed on a flash
column of silica gel (230−400 mesh ASTM) and eluted with a
gradient mixture of dichloromethane and petroleum spirit (bp 40−60
°C) in the range 30:70 to 100:0. The endo/exo-isomers proved difficult
to isolate separately. The characterization given is for the mixture of
the endo- and exo-isomers, and the ratio of endo/exo-isomers was
determined through integration of the H-10b signals. endo- and exo-
isomers: (0.135 g, 92%, endo:exo 1:1.8), off-white solid; HRMS (ESI)
calcd for C18H17N4 (M + H)+ 289.1454, found 289.1465; δH (500
MHz, CDCl3) 1.13 (d, 2H endo, J = 10.6), 1.28−1.48 (m, 5H exo, 4H
endo), 1.75−1.77 (m, 2H exo), 1.91−1.94 (m, 1H exo, 1H endo), 2.41
(s, 1H endo), 2.63−2.66 (app t, 1H exo, 1H endo), 2.69 (s, 1H exo),
2.85 (app t, 1H exo, 1H endo), 3.86 (d, 1H, J = 8.6, H-10b exo), 4.51
(d, 1H, J = 6.7, H-10b endo), 7.19 (d, 1H, J = 7.5, H-10 endo), 7.24
(d, 1H, J = 7.8, H-10 exo), 7.27−7.30 (m, 1H exo, 1H endo), 7.35−
7.42 (m, 1H exo, 1H endo), 7.45−7.58 (m, 1H exo, 1H endo), 7.61 (s,
1H, H-6 endo), 7.71 (s, 1H, H-6 exo); δC (125 MHz, CDCl3) 27.5
(endo), 27.8 (exo), 28.6 (exo), 29.3 (endo), 34.5 (exo), 34.5 (endo),
36.2 (endo), 37.6 (exo), 38.6 (exo), 40.2 (endo), 45.0 (endo), 50.2
(exo), 54.5 (endo), 55.2 (exo), 59.1 (exo), 59.2 (endo), 59.6 (exo),
60.2 (endo), 112.2, 114.8 (CN exo) 112.4, 113.3 (CN endo),
123.0 (exo), 125.0 (exo), 125.2 (endo), 125.9 (exo), 126.6 (exo),
128.5 (exo), 131.4 (endo), 131.9 (exo), 133.1 (endo), 134.5 (exo),
145.6 (C-6 endo), 146.2 (C-6 exo).
purification step was identical to the reaction carried out in
acetonitrile. Overall yield: 92% (1-endo:1-exo 22:1).
endo-1-Methoxycarbonyl-3,3-dicyano-1,2,3,8a-
tetrahydropyrrolo[1,2-b]pyridazine and exo-1-Methoxycar-
bonyl-3,3-dicyano-1,2,3,8a-tetrahydropyrrolo[1,2-b]-
pyridazine (25).31 A solution of compound 1A (0.30 g, 2.08 mmol)
in acetonitrile (15 mL) was treated with methyl acrylate (0.94 mL,
10.4 mmol) and stirred at 60 °C for 24 h. After this time the solvent
was removed under reduced pressure, and the residue was dissolved in
dichloromethane (4 mL). This was placed onto a flash column of silica
gel (ASTM 230−400 mesh) packed with petroleum spirit (bp 40−60
°C)/dichloromethane in the ratio 1:1. The products were eluted with
a mixture of petroleum spirit (bp 40−60 °C)/dichloromethane in the
range 1:1 to 0:1 with a 2.5% (v/v) changing gradient. 1-endo-isomer:
(0.38 g, 86%), red gum; HRMS (ESI) calcd for C11H10N4O2 (M + H)+
231.0883, found 231.0888; νmax (mull)/cm−1 1738 (CO); δH (400
MHz, CDCl3) 2.85 (dd, 1H, J = 14.4, 8.3, H-2endo), 3.24 (dd, 1H, J =
14.4, 2.9, H-2exo), 3.29−3.36 (m, 1H, H-1), 3.69 (s, 3H, CH3), 4.24 (d,
1H, J = 6.8, H-8a), 5.96 (d, 1H, J = 9.7, H-7), 6.28 (d, 1H, J = 9.7, H-
8), 7.16 (s, 1H, H-6); δC (100 MHz, CDCl3) 37.5 (C-2), 42.0 (C-1),
52.7 (CH3) 53.4 (C-3), 56.1 (C-8a), 113.5 and 113.6 (CN), 119.8
(C-7), 128.6 (C-8), 142.8 (C-6), 170.4 (CO). 1-exo-isomer: (0.03
g, 6%) gum; δH (400 MHz, CDCl3) 2.95 (dd, 1H, J = 14.1, 10.2, H-
2exo), 3.07 (dd, 1H, J = 14.1, 7.8, H-2endo), 3.24−3.28 (m, 1H, H-1),
3.80 (CH3), 4.02 (d, 1H, J = 9.7, H-8a), 5.98 (d, 1H, J = 9.7, H-7),
6.25 (d, 1H, J = 9.7, H-8), 7.22 (s, 1H, H-6).
Synthesis in Water. The reaction was carried out under identical
conditions to the reaction in acetonitrile. For the work up, the reaction
was allowed to cool, and the products were extracted into
dichloromethane (2 × 10 mL) and dried over MgSO4. The
purification step was identical to the reaction carried out in
acetonitrile. Overall yield: 94% (1-endo:1-exo 1:0). None of the exo-
isomer was observed.
S y n t h e s i s o f e n d o - 1 , 3 , 3 - T r i c y a n o - 1 , 2 , 3 , 8 a -
tetrahydropyrrolo[1,2-b]pyridazine and exo-1,3,3-Tricyano-
1,2,3,8a-tetrahydropyrrolo[1,2-b]pyridazine (26). A solution of
compound 1A (0.30 g, 2.08 mmol) in acetonitrile (15 mL) was treated
with acrylonitrile (0.685 mL, 10.4 mmol) and stirred at 60 °C for 48 h.
After this time the solvent was removed under reduced pressure, and
the residue was dissolved in dichloromethane (4 mL). This was placed
onto a flash column of silica gel (ASTM 230−400 mesh) packed with
petroleum spirit (bp 40−60 °C)/dichloromethane in the ratio 1:1.
The products were eluted with a mixture of petroleum spirit (bp 40−
60 °C)/dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v)
changing gradient. The column was flushed with methanol, and only
intractable resins were present. 1-endo-isomer: (0.22 g, 54%), white
solid. mp 152−153 °C (ethanol); (Found C, 60.9; H, 3.45; N, 35.6;
C10H7N5 requires C, 60.9; H, 3.6; N, 35.5%); νmax (mull)/cm−1 2240,
2341, 2360 (CN); δH (500 MHz, CDCl3) 3.03 (dd, 1H, J = 14.1,
3.9, H-2exo), 3.12 (dd, 1H, J = 14.1, 8.8, H-2endo), 3.47−3.52 (m, 1H,
H-1), 4.20 (d, 1H, J = 6.3, H-8a), 6.16 (d, 1H, J = 9.7, H-7), 6.31 (d,
1H, J = 9.7, H-8), 7.26 (s, 1H, H-6); δC (125 MHz, CDCl3) 31.5 (C-
2), 40.5 (C-1), 54.8 (C-3), 57.6 (C-8a), 115.9 (CN), 120.2 (C
N), 122.6 (C-7), 130.4 (C-8), 145.8 (C-6). 1-exo-isomer: (0.04 g,
10%) gum; δH (400 MHz, CDCl3) 2.95 (dd, 1H, J = 14.0, 8.3, H-
2endo), 3.15 (dd, 1H, J = 14.0, 9.9, H-2exo), 3.27−3.34 (m, 1H, H-1),
4.27 (d, 1H, J = 9.7, H-8a), 6.09 (d, 1H, J = 9.7, H-7), 6.26 (d, 1H, J,
9.7, H-8), 7.24 (s, 1H, H-6); δC (100 MHz, CDCl3) 28.8 (C-2), 38.4
(C-1), 50.0 (C-3), 56.9 (C-8a), 115.9 (CN), 120.7 (C-7), 126.9 (C-
8), 143.0 (C-6).
The terms endo and exo refer to the isomers to which the signal
belongs. Some of the exo-isomer peaks are missing in the 13C NMR
due to overlap with the major endo-isomer.
Synthesis in Water. The reaction stirred at room temperature for
48 h; however, no product was observed by TLC. The reaction was
heated to 82 °C for 24 h where the reaction went to completion. Yield
91% (endo:exo 1:2.3).
endo-1-Propanoyl-3,3-dicyano-1,2,3,8a-tetrahydropyrrolo-
[1,2-b]pyridazine and exo-1-Propanoyl-3,3-dicyano-1,2,3,8a-
tetrahydropyrrolo[1,2-b]pyridazine (24).31 A solution of com-
pound 1A (0.30 g, 2.08 mmol) in acetonitrile (15 mL) was treated
with ethyl vinyl ketone (1.03 mL, 10.4 mmol) and stirred at 60 °C for
24 h. After this time the solvent was removed under reduced pressure,
and the residue was dissolved in dichloromethane (4 mL). This was
placed onto a flash column of silica gel (ASTM 230−400 mesh)
packed with petroleum spirit (bp 40−60 °C)/dichloromethane in the
ratio 1:1. The products were eluted with a mixture of petroleum spirit
(bp 40−60 °C)/dichloromethane in the range 1:1 to 0:1 with a 2.5%
(v/v) changing gradient. 1-endo-isomer: (0.38 g, 80%) mp 110−112
°C (ethanol); (Found C, 63.4; H, 4.9; N, 25.0; C12H12N4O requires C,
63.2; H, 5.3; N, 24.6%); νmax (mull)/cm−1 1712 (CO); δH (400
MHz, CDCl3) 1.07 (t, 3H, J = 7.3, CH3), 2.51−2.67 (m, 2H, CH2),
2.78 (dd, 1H, J = 13.9, 8.8, H-2endo), 3.03 (dd, 1H, J = 13.9, 4.4, H-
2exo), 3.43−3.48 (m, 1H, H-1), 4.26 (d, 1H, J = 7.3, H-8a), 5.97 (d,
1H, J = 9.7, H-7), 6.12 (d, 1H, J = 9.7, H-8), 7.15 (s, 1H, H-6); δC
(100 MHz, CDCl3) 7.07 (CH3), 36.7 (CH2), 37.0 (C-2), 47.2 (C-1),
53.6 (C-3), 55.7 (C-8a), 113.2 and 113.3 (CN), 119.9 (C-7), 127.9
(C-8), 142.2 (C-6), 207.7 (CO). 1-exo-isomer: (0.03 g, 6%) gum;
δH (400 MHz, CDCl3) 1.12 (t, 3H, J = 7.3), 2.43−2.74 (m, 2H, CH2),
2.87 (dd, 1H, J = 13.9, 9.9, H-2exo), 2.99 (dd, 1H, J, 13.9, 7.8, H-2endo),
3.31−3.38 (m, 1H, H-1), 4.03 (d, 1H, J = 9.7, H-8a), 5.99 (d, 1H, J =
9.5, H-7), 6.18 (d, 1H, J = 9.5, H-8), 7.21 (s, 1H, H-6).
Synthesis in Water. The reaction was carried out under identical
conditions to the reaction in acetonitrile. For the work up, the reaction
was allowed to cool, and the product was precipitated from solution
and isolated by filtration. Overall yield: 71% (1-endo:1-exo 1:0). None
of the exo-isomer was observed.
endo-1,2-(Dicarboxy-N-methylimido)-3,3-dicyano-1,2,3,8a-
tetrahydropyrrolo[1,2-b]pyridazine and exo-1,2-(Dicarboxy-N-
methylimido)-3,3-dicyano-17,2,3,8a-tetrahydropyrrolo[1,2-b]-
pyridazine (27). A solution of compound 1A (0.30 g, 2.08 mmol) in
acetonitrile (15 mL) was treated with N-methylmaleimide (0.254 g,
2.31 mmol) and stirred under reflux for 24 h. After this time the
Synthesis in Water. The reaction was carried out under identical
conditions to the reaction in acetonitrile. For the work up the reaction
was allowed to cool, and the products were extracted into
dichloromethane (2 × 10 mL) and dried over MgSO4. The
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Article
solvent was removed under reduced pressure to yield an oily residue,
which quickly crystallized. The crude solid was recrystalised from
ethanol to yield the title compound. endo-isomer: (0.41 g, 75%), mp
190−191 °C (ethanol); (Found C, 56.45; H, 3.4; N, 27.3; C12H9N5O2
requires C, 56.5; H, 3.55; N, 27.4%); νmax (mull)/cm−1 1693 (CO),
2195 (CN); δH (500 MHz, CDCl3) 3.06 (s, 3H, CH3), 3.49 (dd,
1H, J = 7.8, 7.8, H-1), 3.80 (d, 1H, J = 7.8, H-2), 4.16 (d, 1H, J = 7.8,
H-8a), 6.01 (d, 1H, J = 9.7, H-7), 6.69 (d, 1H, J = 9.7, H-8), 7.30 (s,
1H, H-6); δC (125 MHz, DMSO-d6) 25.3 (CH3), 41.8 (C-1), 49.0 (C-
2), 54.2 (C-8a), 57.1 (C-3), 110.7 and 111.5 (CN), 119.4 (C-7),
130.6 (C-8), 146.4 (C-6), 171.3 and 174.0 (CO). exo-isomer: (0.04
g, 10%) obtained as a gum by removal of the ethanol under reduced
pressure from the filtrate; δH (400 MHz, CDCl3) 3.08 (s, 3H, CH3),
3.58 (dd, 1H, J = 9.7, 8.3, H-1), 3.97 (d, 1H, J = 8.3, H-2), 4.06 (d, 1H,
J = 9.7, H-8a), 6.06 (d, 1H, J = 9.7, H-7), 6.43 (d, 1H, J = 9.7, H-8),
7.27 (s, 1H, H-6).
Synthesis in Water. The reaction was carried out by stirring the
reaction at 20 °C for 96 h. Once the reaction was finished, the reaction
precipitated from solution and was collected by filtration. Overall
yield: 85% (endo:exo 1:0). None of the exo-isomer was observed.
exo-2-Phenyl-3,3-dicyano-1,2,3,8a-tetrahydropyrrolo[1,2-b]-
pyridazine and endo-1-Phenyl-3,3-dicyano-1,2,3,8a-
tetrahydropyrrolo[1,2-b]pyridazine (28). A solution of compound
1A (0.30 g, 2.08 mmol) in acetonitrile (15 mL) was treated with
styrene (2.38 mL, 20.8 mmol) and stirred at 60 °C for 7 days. After
which time the solvent was removed under reduced pressure, and the
residue was placed onto a flash column of silica gel. The products were
eluted with a mixture of petroleum spirit (bp 40−60 °C)/
dichloromethane in the range 1:1 to 0:1 with a 2.5% (v/v) changing
gradient. The products coeluted from the column together. 2-exo-
isomer: (0.38 g, 73%) precipitated out of solution, mp 160−161 °C
(ethanol); (Found C, 72.7; H, 4.5; N, 23.1; C15H12N4 requires C, 72.6;
H, 4.8; N, 22.7%); νmax (mull)/cm−1 706 (-Ph), 2199 (CN); δH
(500 MHz, CDCl3) 2.46−2.58 (m, 2H, H-1), 4.07 (dd, 1H, J = 10.2,
7.3, H-2endo), 4.14 (dd, 1H, J = 8.7, 8.7, H-8a), 5.98 (d, 1H, J = 9.7, H-
7), 6.22 (d, 1H, J = 9.7, H-8), 7.26 (s, 1H, H-6), 7.45 (s, 5H, C6H5);
δC (125 MHz, CDCl3) 31.2 (C-1), 51.9 (C-2), 52.9 (C-8a), 62.9 (C-
3), 110.6 and 113.0 (CN), 119.2 (C-7), 128.5 (C-2′), 129.0 (C-3′),
129.2 (C-4′), 131.6 (C-8), 133.5 (C-1′) 143.5 (C-6). The solvent of
the filtrate was removed under reduced pressure to yield the 2-endo-
isomer: (0.11 g, 21%) which was isolated as a gum; δH (400 MHz,
CDCl3) 2.36−2.44 (m, 1H, H-1endo), 2.61−2.68 (m, 1H, H-1exo), 3.97
(dd, 1H, J = 9.7, 7.3, H-2exo), 4.25 (m, 1H, H-8a), 5.92 (d, 1H, J = 9.7,
H-7), 6.04 (d, 1H, J = 9.7, H-8), 7.17 (s, 1H, H-6), 7.41 (s, 5H, Ph).
Synthesis in Water. A suspension of compound 1A (0.30 g, 2.08
mmol) in water (15 mL) was treated with styrene (2.38 mL, 20.8
mmol) and stirred at 60 °C for 4 days. The reaction was allowed to
cool, and the products were extracted into dichloromethane (2 × 10
mL) and dried over MgSO4. The solvent was removed under reduced
pressure, and the reaction was worked up as with the reaction in
acetonitrile. Overall yield 95% (2-endo:2-exo 1:12)
acetonitrile (20 mL) was treated with an excess of phenylacetylene-d1
(1.69 mL, 15.4 mmol), stirred under reflux in an anhydrous
atmosphere for 24 h, cooled to ambient temperature, and filtered to
give the title compound (0.36 g, 86%): white needles, mp 213−214 °C
(acetonitrile); HRMS (ESI) calcd for C18H10DN3 (M + H)+ 271.1095,
found 271.1113; νmax (mull)/cm−1 2215 (CN); δH (400 MHz,
DMSO-d6 60 °C) 7.43 (t, 1H, J = 6.3, Ph H-4′), 7.51−7.57 (m, 2H, Ph
H-3′), 7.71−7.75 (m, 1H, H-9), 7.85−7.87 (m, 2H, Ph H-2′), 7.90−
7.92 (m, 1H, H-8), 8.06 (d, 1H, J = 7.7, H-10), 8.31 (d, 1H, J = 8.1, H-
7), 8.90 (s, 1H, H-6), the H-1 signal at 7.57 was absent; δC (100 MHz,
DMSO-d6 60 °C) 113.5 (CN), 120.6 (C-2), 122.5 (C-4′), 125.9
(C-3), 127.7 (C-10b),128.4, 128.6, 128.9, 129.0 (C-8 to C-10 and C-2′
and C-3′), 131.8 (C-1′) 133.5 (C-7),133.9 (C-6a) 146.2(C-6), the C-1
signal at 99.2 ppm was reduced almost to zero.
Synthesis in Water. The product was prepared by heating in water
at 82 °C as described and isolated by direct filtration. Yield 87%.
1,2-Diphenyl-3-cyanopyrrolo[2,1-a]phthalazine (31).32 A sus-
pension of compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL)
was treated with diphenylacetylene (2.74 g, 15.4 mmol) and stirred
under reflux for 24 h, after which time the product precipitated from
solution and was filtered to give the title compound (0.32 g, 60%): mp
213−214 °C (acetonitrile); HRMS (ESI) calcd for C24H15N3 (M +
H)+ 346.1345, found 346.1349; νmax cm−1 (nujol mull) 2216 (CN);
δH (400 MHz, DMSO-d6 60 °C) 7.31−7.64 (m, 13H, H-7 to H-9, H-
2′ to H-4′ and H-2″ to H-4″), 8.06 (d, 1H, J = 7.3, H-10), 8.95 (s, 1H,
H-6); δC (100 MHz, DMSO-d6, 60 °C) 112.5 (CN), 116.3 (C-3),
120.9 (C-2), 121.2 (C-10), 123.1 (C-1), 126.0 (C-10b), 127.6, 127.9,
128.6, 128.7, 129.0, 130.6, 130.8, 132.1 (C-7 to C-9, C-1′ to C-4′ and
C-1″ to C-4″ some overlap of signals), 146.1 (C-6).
Synthesis in Water. The product was prepared at 82 °C in water as
described for acetonitrile and isolated by direct filtration. Yield 71%.
1,2-Dimethoxycarbonyl-3-cyano-pyrrolo[1,2-b]pyridazine
(32).37 A solution of compound 1A (0.30 g, 2.08 mmol) in acetonitrile
(15 mL) was treated with DMAD (1.23 mL, 10.4 mmol) and stirred
under reflux for 5 h. After this time the solvent was removed under
reduced pressure, and the residue was dissolved in dichloromethane (4
mL). This was placed onto a flash column of silica gel (ASTM 230−
400 mesh) packed with petroleum spirit (bp 40−60 °C)/dichloro-
methane in the ratio 1:4. The products were eluted with a mixture of
petroleum spirit (bp 40−60 °C)/dichloromethane in the ratio of 1:4
up to 19:1 dichloromethane/diethylether with a 2.5% (v/v) changing
gradient (0.51 g, 95%): mp 134−136 °C (ethanol); (Found C, 55.4;
H, 3.2; N, 15.9; C12H9N3O4 requires C, 55.6; H, 3.5; N, 16.2%); νmax
(mull)/cm−1 1734, 1693 (CO), 2232 (CN); δH (400 MHz,
CDCl3) 3.94 (s, 3H, CH3), 4.03 (s, 3H, CH3), 7.21 (dd, 1H, J = 9.3,
4.4, H-7), 8.53 (dd, 1H, J = 4.4, 1.9, H-6), 8.57 (dd, 1H, J = 9.3, 1.9,
H-8); δC (100 MHz, CDCl3) 52.0, 53.0 (CH3), 102.6 (C-3), 104.7 (C-
1), 109.8 (CN), 118.5 (C-7), 128.9 (C-8), 145.8 (C-6), 161.8, 162.0
(CO).
Synthesis in Water. The reaction using water as the reaction
medium was stirred at 82 °C for 5 h. The reaction was cooled, and the
compound precipitated from solution and was collected by suction
filtration. Yield: 89%.
2-Phenyl-3-cyanopyrollo[2,1-a]phthalazine (29).34b A suspen-
sion of compound 1 (0.30 g, 1.54 mmol) in acetonitrile (20 mL) was
treated with an excess of phenylacetylene (1.69 mL, 15.4 mmol),
stirred under reflux in an anhydrous atmosphere for 24 h, cooled to
ambient temperature, and filtered to give the title compound (0.34 g,
82%): white needles, mp 210−212 °C (acetonitrile); (Found C, 80.0;
H, 4.0; N, 15.4. C18H11N3 requires C, 80.2; H, 4.1; N, 15.6%); νmax
(mull)/cm−1 2214 (CN); δH (400 MHz, DMSO-d6, 60 °C) 7.41−
7.45 (m, 1H, H-4′), 7.51−7.57 (m, 2H, H-3′), 7.57 (s, 1H, H-1),
7.71−7.75 (m, 1H, H-9), 7.85−7.87 (m, 2H, H-2′), 7.90−7.92 (m,
1H, H-8), 8.06 (d, 1H, J = 7.7, H-10), 8.31 (d, 1H, J = 8.1, H-7), 8.90
(s, 1H, H-6); δC (100 MHz, DMSO-d6, 60 °C) 99.2 (C-1), 113.5
(CN), 120.6 (C-2), 122.5 (Ph C-4′), 125.9 (C-3), 127.7 (C-
10b),128.4, 128.6, 128.9, 129.0 (C-8 to C-10 and C-2′ and C-3′),
131.8 (C-1′) 133.5 (C-7),133.9 (C-6a) 146.2(C-6).
ASSOCIATED CONTENT
■
S
* Supporting Information
Examples of the typical NOEDS enhancements observed for
1
both endo- and exo-isomers. H and 13C NMR spectra of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
Synthesis in Water. The product was prepared by heating in water
at 82 °C as described and isolated by direct filtration. Yield 78%.
1-Deuterio-2-phenyl-3-cyano-pyrrolo[2,1-a]phthalazine
(30).34b A suspension of compound 1 (0.30 g, 1.54 mmol) in
*E-mail: r.debuitleir@nuigalway.ie; agc40@cam.ac.uk.
Notes
The authors declare no competing financial interest.
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P.; Cunningham, D.; Burke, L. A. J. Chem. Soc., Perkin Trans 1 2001,
1391−1397. (c) Butler, R. N.; Coyne, A. G.; Moloney, E. M.
Tetrahedron Lett. 2007, 48, 3501−3503.
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(30) (a) A referee has suggested that this comment is unwarranted
because when there is an excess of insoluble methyl vinyl ketone it will
dissolve in the cyclopentadiene layer and give a neat reaction for which
no catalysis is required. The reaction would be highly exothermic, and
indeed the temperature of this neat reaction mixture has been
measured approaching 90 °C, and higher temperatures tend to favour
the thermodynamic exo-isomer.30b We are happy to state the referees
point of view. Our view is that once the excess of water insoluble
methyl vinyl ketone dissolves in the cyclopentadiene, which is in
contact with a water layer, the conditions for an on-water reaction are
present, and on-water catalysis will occur irrespective of whether it is
necessary or not, and all the more because methyl vinyl ketone is a
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3291
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