Unusual coupling reactions of aldehydes and alkynes: A novel preparation of substituted phthalic acid derivatives by automated synthesis

Article abstract of DOI:10.1002/chem.200204668

Based upon a highly versatile multicomponent methodology, a new one-pot synthesis of substituted phthalic acid derivatives from α,β-unsaturated aldehydes was developed. The reaction involves the intermediacy of an acetamidodiene species which undergoes Diels-Alder addition to diethyl acetylenedicarboxylate. The resultant acetamidocyclohexadiene is subject to elimination of acetamide under the reaction conditions to give rise to substituted diethyl phthalates in good yields. This domino condensation - cycloadditionelimination sequence has been applied to a variety of α,β-unsaturated aldehydes. Furthermore, we demonstrated the exploitation of parallelized and automated synthesis technology for the rapid screening of reaction conditions and compositions. Detailed studies revealed the catalytic role of the employed acetamide and the occurrence of a stereoselective 1,4-syn elimination pathway under standard conditions.

Full text of DOI:10.1002/chem.200204668

FULL PAPER
Unusual Coupling Reactions of Aldehydes and Alkynes: A Novel Preparation
of Substituted Phthalic Acid Derivatives by Automated Synthesis
Axel Jacobi von Wangelin,[a] Helfried Neumann,[a] Dirk Gˆrdes,[a] Stefan Klaus,[a]
Haijun Jiao,[a] Anke Spannenberg,[a] Thomas Kr¸ger,[b] Christian Wendler,[b]
Kerstin Thurow,[b] Norbert Stoll,[b] and Matthias Beller*[a]
Abstract: Based upon a highly versatile
multicomponent methodology, a new
one-pot synthesis of substituted phthalic
acid derivatives from a,b-unsaturated
aldehydes was developed. The reaction
involves the intermediacy of an acet-
amidodiene species which undergoes
Diels Alder addition to diethyl acety-
lenedicarboxylate. The resultant acet-
amidocyclohexadiene is subject to elimi-
nation of acetamide under the reaction
conditions to give rise to substituted
diethyl phthalates in good yields. This
domino condensation cycloaddition
elimination sequence has been applied
to a variety of a,b-unsaturated alde-
hydes. Furthermore, we demonstrated
the exploitation of parallelized and au-
tomated synthesis technology for the
rapid screening of reaction conditions
and compositions. Detailed studies re-
vealed the catalytic role of the employed
acetamide and the occurrence of a
stereoselective 1,4-syn elimination path-
way under standard conditions.
Keywords: automated synthesis
¥
Diels Alder reaction domino
¥
reaction ¥ multicomponent reaction
¥ organocatalysis
Recently, our group launched a program toward domino
condensation-Diels Alder reaction sequences for the direct
synthesis of amino-functionalized carbo- and heterocyclic
compounds from simple aldehydes and carboxamides. These
multicomponent coupling reactions take advantage of the
intermediacy of 1-(N-acylamino)-1,3-butadiene species (I)[5]
which are subject to in situ trapping with electron-deficient
dienophiles. Upon employment of various amide, aldehyde,
and dienophile combinations, a library of functionalized
aminocyclohexene derivatives was synthesized in good to
excellent yields.[6] The underlying domino condensation-
Diels Alder reaction sequences constitutes the first example
of multicomponent couplings of aldehydes, amides, and
olefins (or alkynes). Up to four stereogenic centers arise
Introduction
In the realm of organic synthesis in which a premium is put on
the rapid construction of highly substituted carbocyclic
compounds, the venerable Diels Alder reaction has emerged
as one of the foremost synthetic tools by virtue of its
versatility and stereocontrol.[1] Well known and extensively
studied for many decades, the Diels Alder reaction has also
gained a strong foothold among time and cost effective
multicomponent and domino reactions.[2] As combinatorial
techniques have burst up on the scene of organic synthesis, the
automated and parallelized screening of multitudes of reac-
tion conditions and compositions has been perceived as a
valuable means for the rapid investigation of chemical
reactions.[3, 4]
À
from the formation of three carbon carbon bonds and one
À
carbon nitrogen bond over the course of the reaction.
Nevertheless, these multicomponent coupling reactions ex-
hibited very high endo selectivity in most cases. It is also
interesting to note that in no case hetero-Diels Alder
adducts have been observed (Scheme 1).
[a] Prof. Dr. M. Beller, Dr. A. Jacobi von Wangelin,
Dr. H. Neumann, Dr. D. Gˆrdes, Dipl.-Chem. S. Klaus,
Dr. H. Jiao, Dr. A. Spannenberg
Leibniz-Institut f¸r Organische Katalyse
The structural diversity of the compound library signifi-
cantly benefited from the employment of a,b-unsaturated
aldehydes which allowed the synthesis of three-component
adducts containing more diverse substitution patterns. As part
of our studies of multicomponent coupling reactions with a,b-
unsaturated aldehydes and amides,[7] we recently investigated
reactions thereof in the presence of electron-deficient
alkynes. Paralleling our experimentations with simple enoliz-
an der Universit‰t Rostock e.V., Buchbinderstrasse 5
18055 Rostock (Germany)
6
Fax : (‡49) 381 466 9324
E-mail: matthias.beller@ifok.uni-rostock.de
[b] Dipl.-Ing. T. Kr¸ger, Dr. C. Wendler,
Prof. Dr.-Ing. K. Thurow, Prof. Dr.-Ing. N. Stoll
Institut f¸r Automatisierungstechnik
Universit‰t Rostock, Richard-Wagner-Strasse 31
18119 Rostock (Germany)
Chem. Eur. J. 2003, 9, 2273 2281
DOI: 10.1002/chem.200204668
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2273

M. Beller et al.
FULL PAPER
Contrary to our expectations, the
targeted diethyl 3-(N-acetylamino)-
4-methyl-trans-3,4-dihydrophtha-
late could not be detected in the
reaction mixture. The unexpected
high Rf values of the crude products
in silica gel TLC were first indica-
tors of a different reactivity pattern.
The surprisingly liquid product
turned out to lack any amide moiety
but constitute an aromatic ring in-
stead. NMR and MS analysis estab-
lished the unexpected formation of
diethyl 4-methylphthalate (1a) as
the only product which was isolated
in 82% yield.
R1
O
R2
NH
R2
O
O
R3
R4
R3
R4
One-pot
2 R2
+
+
> 100
adducts
R1
NH2
H
double
condensation
Diels-Alder
R3
R4
O
H+
R2
N
H
R1
R2
+ isomers
Scheme 1. Multicomponent coupling reaction of amide, aldehyde, and dienophile.
able aldehydes,[6a] we aimed at the one-pot synthesis of
substituted aminodihydrophthalate derivatives. In order to
secure the intermediacy of an 1-(N-acylamino)-1,3-butadiene
species, the a,b-unsaturated aldehydes are required to contain
an aliphatic chain of minimal four carbon atoms and a g-
hydrogen atom.
The net reaction for this one-pot synthesis of phthalic acid
derivative 1a is shown in Scheme 2. The reaction is assumed
to proceed via the known 1-N-acetylamino-1,3-diene and N-
acetylamino-cyclohexadiene intermediates with the latter
undergoing facile elimination of acetamide under the reaction
conditions. There are literature precedents of related synthe-
ses of arenes via domino Diels Alder elimination reactions.[8]
However, these procedures involve several synthetic steps
and largely rely upon rather special, expensive olefinic
starting materials.
A closer look at the underlying reaction mechanism
(Scheme 3) reveals the quasi catalytic role of the employed
acetamide. The sequence commences with the consumption of
acetamide in the synthesis of the aminodiene intermediate.
Not only does this initial condensation step generate a highly
In order to enhance the efficiency of our screening
experimentations, we considered automation a promising
approach, as analogous reactions have been shown tolerant of
moisture and air. Automated and parallel screenings of
multitudes of reaction parameters have become a valuable
means for the rapid investigation of chemical reactions.
However, applications have largely been limited to pharma-
ceutical problems, and until now, a general usage in standard
organic synthesis has not been demonstrated. In a joint
collaboration between chemists and engineers, we raised the
question whether automated synthesis can be exploited for
the development of organic reactions. Here, we report on a
new and fully automated synthesis of phthalic acid esters from
a,b-unsaturated aldehydes. The potential of commercial
automation technology for the synthesis and screening of
reaction conditions and compositions as well as mechanistic
details are discussed.
O
NHAc
H
Z
O
Z = CO2Et
NH2
Z
Results and Discussion
NHAc
Z
Initially, we performed model studies with the three-compo-
nent system acetamide/tiglic aldehyde (2-methylcrotonalde-
hyde)/diethyl acetylenedicarboxylate. The mixture was con-
fined to a threaded tube in the presence of catalytic amounts
of p-toluenesulfonic acid monohydrate (TSA ¥ H2O) in N-
Z
Z
Z
1a
Scheme 3. Catalytic role of acetamide.
methylpyrrolidinone (NMP) and heated at 1208C for 24 h.
CO2Et
CO2Et
O
O
NH
O
CO2Et
CO2Et
TSA, NMP
∆
CO2Et
CO2Et
+
H
+
NH2
- AcNH2
120°C, 24 h
1a
(82 %)
Scheme 2. One-pot synthesis of diethyl 4-methylphthalate (1a) from 2-methyl-2-butenal.
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2274
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2273 2281

Substituted Phthalic Acid Derivatives
2273 2281
reactive electron-rich diene which facilitates the normal
electron-demand Diels Alder addition to the electron-defi-
cient alkyne, but also cuts off potential side reactions of the
highly reactive free aldehyde. According to previous results,
the cycloaddition step involves the preferential consumption
of the (1E,3E)-1-(N-acetylamino)-2-methyl-1,3-butadiene
isomer and proceeds with extremely high endo selectivity.
The employed acetamide is recovered by the terminating
elimination of acetamide. Altogether, acetamide acts as a
protective group and activator for the aldehyde. Interestingly,
attachment and cleavage occur under the same reaction
conditions with the latter being largely driven by the resultant
aromatization of the six-membered ring. We thus wondered if
it is possible to run the reaction also in the presence of sub-
stoichiometric or catalytic amounts of acetamide. The organo-
catalytic aspect of this one-pot synthesis of phthalic acid
derivatives seemed attractive to us, as organocatalysis,
although known for some time, has emerged as a powerful
catalytic tool. To the best of our knowledge, this principle has
not been applied to the synthetic construction of aromatic
rings.
Consequently, we set out to subject the synthesis of model
compound 1a to a wide screening of reaction conditions and
compositions. The insensitivity towards air and moisture
renders this reaction as ideally suitable for simple, automated
handling and processing. Therefore, a cooperation with the
Institute of Automation at the University Rostock was started
up to ensure high-throughput screening experimentations in a
fully automated, parallelized manner (Figure 1). Sample
preparation (addition of reactant stock solutions), reaction
processing (heating), and work-up (cooling, dilution, analysis)
steps were performed by a Zymate Laboratory Automation
System by Zymark (Hopkinton, MA, USA). It consists of a
Zymate XP Robot mounted on a linear track which uses a
variety of interchangeable hands to move consumables,
liquids, vials, tubes, and containers of various sizes to the
different stations and modules. We used a 60-well Syncore
reactor (B‹CHI Labortechnik AG, Switzerland), different
capping and uncapping stations, and several modules provid-
ing the liquid handling. A GC/MSD system (Agilent
5972MSD with 5890GC) has been integrated for online
analysis. The reactions were run in 4 mL screw cap vials. As
the integrated solid dispenser was not capable of dosing tiny
amounts (< 150 mg), the solid reactants were employed as
stock solutions in the solvent (NMP). The vials were placed
onto a modified Syncore Reactor and were agitated and
heated. Samples of the reaction mixture were taken by
syringe, transferred to a GC vial, diluted with ethyl acetate,
and subjected to auto sampled GC/MSD analysis.
These automated screening experiments significantly en-
hanced the acquisition of reaction data and gave detailed
information on optimal reaction conditions and compositions.
It is important to note that the reactions of automated runs
generally exhibited lower yields (by 15 30%) than analogous
reactions performed in a conventional solitary reaction vessel.
We consider the miniaturization of the reaction stoichiometry,
inaccuracies associated with the automated liquid handling,
and a diminished heat transfer the major reasons for these
discrepancies. However, the general tendencies could be
unambiguously deduced from the vast amount of experiments
that were performed in the aforementioned time effective
parallel manner.
Figure 2 shows a typical series of automated screening
experiments at 1208C. Upon variation of the employed
acetamide and acid amounts and the reaction time, detailed
information on beneficial reaction conditions was obtained in
one set of automated experiments. Generally, the reactions
gave also good yields at sub-stoichiometric amounts of
acetamide. Reactions in the presence of >50 mol% acet-
amide content were completed within 24 h. With regard to
efficient organocatalysis (<50 mol% acetamide), extended
Figure 2. Initial automated screenings of reaction time and composition in
the synthesis of 1a.
Figure 1. Zymate laboratory automation system (left) and 60-well Syncore reactor station (right).
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2273 2281
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2275

M. Beller et al.
FULL PAPER
reaction times significantly increased the product yield. An
analogous behaviour was found for the acid catalysis by p-
toluenesulfonic acid monohydrate: the lower the amount of
employed p-TSA, the longer the required reaction times.
Next, we used the optimized conditions for a detailed
investigation of the organocatalytic aspect of this reaction. A
series of reactions was performed with various understoichio-
metric amounts of acetamide at 120 and 1608C (Figure 3).
Below 50 mol% acetamide content, reactions at 1208C gave
the arene (1a) in yields that exceed the mol% value of the
employed acetamide, thereby unambiguously establishing the
zation with the alkyne gives the phthalic acid ester upon
elimination of water.
As a substitute for acetamide, we also tested the catalytic
activity of other compounds in this reaction. Figure 4 compiles
a series of experimentations in the presence of different
amides and amines. Benzamide and acetamide were shown
equivalent catalysts giving similar yields in phthalate 1a. With
more nucleophilic 1,1-dimethylurea (DMU), aniline (ANI),
and piperidine (PIP), predominantly oligomers and only low
yields (similar to reactions in the absence of any mediator)
were obtained (< 25%).
Figure 4. Yield-temperature plots for synthesis of 1a under standard
conditions (1208C, 24 h) with 25 mol% of different amine sources.
Figure 3. Catalytic performance of acetamide (AcNH2) and acetic anhy-
dride (Ac2O).
catalytic role of acetamide. At 1608C, the catalyst was shown
to be more active giving 5 20% higher yields. Upon further
reduction of the catalyst loading, we still observed good to
moderate conversion. Extended reaction times gave good to
moderate yields in 1a at 1208C even in the presence of
< 10 mol% acetamide catalyst. With 3 mol% acetamide, the
turn over number (TON) of the catalyst amounts to 15.
However, no investigations into the preparative recovery of
the employed acetamide have been performed.
Unlike nucleophilic acetamide, we also employed electro-
philic acetic anhydride as an acylating agent to trap the
intermediate dienol tautomer of the a,b-unsaturated alde-
hyde (Scheme 4). However, acetic anhydride required higher
temperatures for reasonable conversion and proved a less
active mediator in this reaction (Figure 3), presumably due to
the highly acidic conditions associated with the formation of
acetic acid as by-product.
In order to extend the scope of this reaction and sound the
generality of the method, we treated other a,b-unsaturated
aldehydes with diethyl acetylenedicarboxylate at different
reaction temperatures. Surprisingly at a reaction temperature
of 1208C the isolated products were dependent on the
substitution pattern of the aldehyde employed. In the case
of crotonaldehydes bearing solely a- and/or b-substituents,
phthalic acid derivatives were formed. Table 1 compiles a
series of five diethyl phthalates prepared in a one-pot
procedure from the corresponding aldehydes. When employ-
ing crotonaldehydes (1a e), the isolated yields were gener-
ally high (82 91%). On account of the terminating acet-
amide elimination, employment of tiglic aldehyde (2-methyl-
crotonaldehyde) and prenal (3,3-dimethylacrolein) afforded a
congruent product (2) in 82 and 91% yield, respectively.
Generally, substituted crotonaldehydes, which are in short
commercial supply, can be accessed by standard procedures.[9]
2-Phenyl-3-ethylcrotonaldehyde (2-phenyl-3-methyl-2-bute-
nal) was synthesized via Peterson olefination from acetophe-
none and butanal.[10] We assume that any conceivable diethyl
phthalate can be synthesized in this manner, if the a,b-
As can be seen from Figure 3, the reaction also proceeds in
the absence of acetamide, albeit with very low yields. Here,
the a,b-unsaturated aldehyde is believed to tautomerize to
give the corresponding 1,3-dienol. Subsequent cycloaromati-
CO2Et
CO2Et
O
O
O
O
CO2Et
CO2Et
TSA, NMP
- AcOH
∆
CO2Et
CO2Et
+
H
+
O
- AcOH
O
1a
Scheme 4. Acetanhydride-based reaction via cyclohexadienol species.
2276
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2273 2281

Substituted Phthalic Acid Derivatives
2273 2281
Table 1. One-pot reactions with crotonaldehydes containing no g-sub-
stituents.
Interestingly, consumption of linear 2-pentenal in this
reaction led to a cycloadduct with isolated double bonds
(2c). Although double-bond migration to a conjugated
position should be favored by the 6-methyl group (higher
substitution at the double bond), X-ray crystallography
(Figure 5) and NMR spectra clearly establish the presence
of a 1,4-cyclohexadiene system (Scheme 5).
CO2Et
O
R1
R2
CO2Et
CO2Et
O
TSA, NMP
R1
R2
+
H
+
NH2
120 °C, 24 h
CO2Et
H
Entry
1
Aldehyde
Product
Yield [%]
82
CHO
CO2Et
CO2Et
1a
CHO
CHO
2
3
4
91
90
90
CO2Et
CO2Et
CO2Et
CO2Et
1b
1c
CHO
CO2Et
CHO
CHO
5
1d
1e
91
66
CO2Et
CO2Et
6[10]
CO2Et
Figure 5. Crystal structure of diethyl 3-(N-acetylamino)-6-methyl-cis-3,6-
dihydrophthalate (2c): The thermal ellipsoids correspond to 30% proba-
bility.
unsaturated aldehyde is available and stable under the
reaction conditions.
O
CO2Et
O
NH
On the other hand, one-pot reactions employing crotonal-
dehyde derivatives that contain a substituent in g-position
gave different products using similar reaction conditions.
Upon employment of these higher homologues of crotonal-
dehyde with elongated chain lengths, N-acetylamine-bearing
cyclohexadienes were obtained, and elimination of acetamide
was not observed. According to our studies with simple
propanal and butanal, employment of their homo aldol
condensation products 2-methyl-2-pentenal and 2-ethyl-2-
hexenal also gave the dialkyl 3-N-acetylamino-4,6-dimethyl-
trans-3,4-dihydrophthalates in good yields (2a,b, Table 2).
The double bonds are subject to thermodynamic equilibration
to give a conjugated p-bond system. The vicinal amino and
alkyl moieties adopt a trans configuration.
O
TSA, NMP
H
CO2Et
CO2Et
+
+
NH2
120 °C, 24 h
CO2Et
2c (67 %)
Scheme 5. Synthesis of diethyl 3-(N-acetylamino)-6-methyl-cis-3,6-dihy-
drophthalate (2c) from 2-pentenal.
The amino and methyl substituents in 2c adopt a syn
configuration as expected from an endo Diels Alder reaction
of (1E,3E)-1-(N-acetylamino)-1,3-pentadiene and diethyl
acetylenedicarboxylate.[11]
In view of the apparently different products obtained by
employment crotonaldehydes with and without g-substitu-
ents, the mechanism of these domino reactions bears closer
scrutiny. Under the premise of structurally equivalent [4 ‡ 2]
cycloaddition transition states in both cases, the terminating
elimination step should account for the two differing products.
It is interesting to note that substituents in the 4-position
decrease the tendency towards elimination of acetamide. In
principle, one might discuss 1,2- or 1,4-elimination[12] depend-
ing on the nature of the intermediate cyclohexadiene (con-
jugated or isolated diene system).
Table 2. One-pot reactions with crotonaldehydes containing g-substitu-
ents.
O
CO2Et
O
R1
O
R1
NH
R1
TSA, NMP
H
CO2Et
CO2Et
+
+
NH2
120 °C, 24 h
CO2Et
R1
Entry
R1
Product
Yield [%]
Obviously, a 1,2-elimination mechanism (E1 or E2) can be
ruled out as the rather distant 4-substituent cannot explain the
differing reactivities of cyclohexadiene intermediates with or
1
2
Me
Et
2a
2b
70
72
Chem. Eur. J. 2003, 9, 2273 2281
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2277

M. Beller et al.
FULL PAPER
without 4-substitution. The same considerations disfavor 1,4-
elimination in E1 manner which would proceed via a planar
pentadienyl-cation intermediate, though the acidic reaction
conditions might enhance protodeamination.
On the other hand, 4-substitution is likely to affect a
concerted 1,4-pathway. Although intensive studies have been
performed on 1,2-elimination,[13] little is known about 1,4-
conjugate elimination of allylic leaving groups. The stereo-
chemical course of bimolecular eliminations on non-cyclic
polyenes has been discussed on the basis of the Woodward-
Hoffmann rules for sigmatropic reactions.[14] Symmetry argu-
ments show that bimolecular (E2) 1,4-syn eliminations are
favored.[15] The process can be viewed as a thermally allowed
s2s p2s s2s process. If elimination and addition are considered
reverse processes that run through the same transition state,
the symmetry of a thermally allowed process (according to
Woodward Hoffmann) can also be deduced from the
frontier orbital overlap of a 1,4-syn addition involving the
LUMO of the 1,3-diene (Figure 6).
Figure 7. Yield of phthalate 1a vs acid concentration (200 mol% AcNH2,
1208C, 12 h).
Given the high affinity of acetamide-bearing compounds
toward O-protonation, elimination pathways other than a
concerted 1,4-syn elimination, such as E1 (via a planar
pentadienyl cation) and E2 (better leaving group), might also
become competitive at higher temperatures. Indeed, isolated
4-substituted aminocyclohexadienes 2a c that withstood
elimination at standard conditions (1208C, 24 h) were cleanly
converted to the corresponding phthalic acid esters in good
yields after 48 h at 1608C.
Consequently the feasibility of a one-pot procedure was
tested. As expected the desired diethyl phthalates could be
isolated in good to excellent yields (Table 4) from the reaction
of 2-pentenal and other g-substituted a,b-unsaturated alde-
hydes with acetamide and diethyl acetylenedicarboxylate at
1608C.
Figure 6. Symmetry of frontier orbitals in a concerted 1,4-addition of HX
to a butadiene.
The inertness of cyclohexadienes 2a c toward elimination
at 1208C also supports the general preference for a stereo-
specific 1,4-syn elimination.[16] Although an identical stereo-
chemical result would be the consequence of an initial
suprafacial 3,3-sigmatropic rearrangement of the allylic ester
followed by 1,2-syn elimination, the relatively low reaction
temperature (1208C) make the sigmatropic process unlikely.
The Woodward Hoffmann selection rules deduced here
apply only in those cases where orbital symmetry is the
decisive criterion for the stereochemical course of the
reaction. Moreover, alternative mechanisms of elimination
might become competitive at higher temper-
Summary
The reaction of an a,b-unsaturated aldehyde and diethyl
acetylenedicarboxylate in the presence of acetamide was
shown to provide a new straightforward access to substituted
phthalates. The substitution pattern of the intermediate three-
component adduct is decisive to the outcome of the reaction
under standard conditions, as rationalized from orbital
symmetry analysis of the underlying 1,4-syn elimination
atures. The acidic reaction conditions
Table 3. High-temperature elimination of acetamide from aminocyclohexadienes 2a c.
Entry Reaction
R1 Product Yield [%]
(1.5 mol% p-TSA) are likely to effect pro-
tonation of the acylamine substituent and
thus facilitate elimination, though both 1,2-
and 1,4-pathway are not dependent on pro-
tonation. Based upon the model reaction of
2-methyl-2-butenal with acetamide and di-
ethyl acetylenedicarboxylate to give 1a, we
performed reactions with varied amounts of
acid. As can be seen from Figure 7, the
reaction is also amenable for acid-free con-
ditions (67% yield). However, best results
(> 87%) were obtained in the presence of
O
R1
NH
R1
CO2Et
CO2Et
R1
CO2Et
CO2Et
1
2
Me 3a
Et 3b
91
89
TSA, NMP
160°C, 24 h
R2
O
NH
CO2Et
CO2Et
CO2Et
CO2Et
TSA, NMP
3
Me 3c
83
160 °C, 24 h
2
3 mol% p-toluenesulfonic acid monohy-
R1
R1
drate.
2278
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2273 2281

Substituted Phthalic Acid Derivatives
2273 2281
Table 4. High-temperature one-pot synthesis of substituted diethyl phtha-
lates.
(853 mg, 5 mmol), and p-toluenesulfonic acid monohydrate (22 mg,
1.5 mol%) were combined in a threaded tube, and NMP (3 mL) was
added. The reaction was stirred at elevated temperature (120 1608C).
After 24 h, the solvent and other volatile compounds were removed by oil
pump vacuum. Silica gel chromatography (heptane/ethyl acetate 2:1; Rf
values in TLC indicated below) afforded the analytically pure products.
CO2Et
O
R1
R2
CO2Et
CO2Et
O
TSA, NMP
24 h
R1
R2
+
H
+
NH2
CO2Et
R3
R3
Diethyl 4-methyl phthalate (1a): 1208C, 24 h; Rf ˆ 0.50; Yield: 82%/91%
from 2-methyl-2-butenal (210 mg, 2.5 mmol)/3,3-dimethylacrolein (210 mg,
2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ 2983s, 2939m, 2906w, 1724vs,
1610m, 1575m, 1465m, 1447m, 1367s, 1287vs, 1202s, 1130s, 1071s, 1023s,
Entry Aldehyde
T [8C] Product
Yield [%]
CHO
CO2Et
CO2Et
‡
‡
839m, 781m, 703m; MS-EI: m/z (%): 236 (21) [M] , 191 (73) [M À OEt] ,
1
160
3a
86
89
69
50
‡
‡
163 (100) [M À CO2Et] , 119 (19) [M À CO2Et À OEt] , 105 (14), 91 (15),
77 (24); HRMS: m/z: calcd for C13H16O4: 236.10486; found: 236.10402;
1H NMR (CDCl3): d ˆ 7.47 (d, J ˆ 7.8 Hz, 1H, Ph), 7.27 (s, 1H, Ph), 7.11 (d,
J ˆ 7.8 Hz, 1H, Ph), 4.19 4.12 (2q, J ˆ 7.2/7.2 Hz, 4H, 2CH2), 2.21 (s, 3H,
Me), 1.18 1.14 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me); 13C{1H}: d ˆ 168.1/167.2
(2CO), 141.7/132.9 (2C), 131.1/129.1/129.0 (3CH), 128.6 (C), 61.4/61.3
(2CH2), 21.2 (Me), 14.1/14.0 (2Me).
CHO
CO2Et
CO2Et
2
160
3b
3c
3d
CHO
CO2Et
CO2Et
Diethyl phthalate (1b): 1208C, 24 h; Rf ˆ 0.45; Yield: 90% from crotonal-
dehyde (175 mg, 2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ 3069w, 2983s,
2939w, 2906w, 1724vs, 1681s, 1601m, 1580m, 1520s, 1490s, 1448m, 1368s,
1286vs, 1125s, 1074s, 1041s, 1019s, 862m, 745s, 703s; MS-EI: m/z (%): 222
3
160
140
‡
‡
‡
(8) [M] , 177 (47) [M À OEt] , 149 (100) [M À CO2Et] , 121 (17), 105 (34),
93 (18); HRMS: m/z: calcd for C12H14O4: 222.08921; found: 222.09146;
1H NMR (CDCl3): d ˆ 7.53 7.50 (dd, J ˆ 5.7/3.2 Hz, 2H, Ph), 7.34 7.31
(dd, J ˆ 5.7/3.2 Hz, 2H, Ph), 4.19 4.14 (q, J ˆ 7.0 Hz, 4H, 2CH2), 1.19 1.15
(t, J ˆ 7.0 Hz, 6H, 2Me); 13C{1H}: d ˆ 167.5 (CO), 132.2 (C), 130.9/128.8
(CH), 61.5 (CH2), 14.0 (Me).
CHO
CO2Et
CO2Et
4[10]
CHO
CO2Et
CO2Et
Diethyl 4-ethylphthalate (1c): 1208C, 24 h; Rf ˆ 0.60; Yield: 90% from
2-ethyl-2-butenal (245 mg, 2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ 2980s,
2938m, 2905w, 2876w, 1724vs, 1608m, 1464m, 1367s, 1286vs, 1197s, 1130s,
5[10]
140
140
3e
3 f
88
52
‡
1072s, 1023s, 848m, 791m, 707m; MS-EI: m/z (%): 250 (9) [M] , 205 (28)
CHO
CO2Et
CO2Et
‡
‡
‡
[M À OEt] , 177 (100) [M À CO2Et] , 149 (11) [M À CO2Et À OEt] , 133
(10), 125 (12), 115 (10), 77 (12), 53 (21); HRMS: m/z: calcd for C14H18O4:
250.12051; found: 250.11942; 1H NMR ([D6]DMSO): d ˆ 7.66 (d, J ˆ 7.9 Hz,
1H, Ph), 7.50 (d, J ˆ 1.6 Hz, 1H, Ph), 7.47 (dd, J ˆ 7.9/1.6 Hz, 1H, Ph), 4.28
4.22 (2q, J ˆ 7.0/7.0 Hz, 4H, 2CH2), 2.68 (q, J ˆ 7.5 Hz, 2H, CH2), 1.28 1.24
(2t, J ˆ 7.0/7.0 Hz, 6H, 2Me), 1.17 (t, J ˆ 7.5 Hz, 3H, Me); 13C{1H}: d ˆ 167.3/
166.6 (2CO), 148.0/132.6 (2C), 130.4/129.0 (2CH), 128.5 (C), 127.7 (CH),
61.2/61.1 (2CH2), 27.8 (CH2), 15.1 (Me), 13.9/13.8 (2Me).
6[10]
pathway. Higher temperatures obviate these stereochemical
restrictions and elimination occurs via other, unselective
pathways. Mechanistic investigations revealed the catalytic
role of the employed amide. We also demonstrated the
applicability of parallelization and automation techniques to
enhance the screening throughput, thereby speeding up the
acquisition of synthetic and mechanistic information. We
believe that a more general use of this type of equipment will
be not only beneficial for the time effective optimization of
reactions but also for the development of new reactions.
Diethyl 4-phenylphthalate (1d): 1208C, 24 h; Rf ˆ 0.50; Yield: 91% from
2-phenyl-2-butenal (370 mg, 2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ
3033w, 2983s, 2938m, 2904w, 1724vs, 1607m, 1450m, 1367s, 1291vs,
1132s, 1074s, 1016m, 906w, 849w, 759s, 699s; MS-EI: m/z (%): 298 (38)
‡
‡
‡
‡
[M] , 253 (22) [M À OEt] , 225 (100) [M À CO2Et] , 152 (16) [PhC6H3] ,
‡
105 (28), 91 (14), 77 (15) [Ph] ; HRMS: m/z: calcd for C18H18O4: 298.12051;
found: 298.12077; 1H NMR ([D6]DMSO): d ˆ 7.94 (s, 1H, Ph), 7.93 (dd, J ˆ
7.8/1.8 Hz, 1H, Ph), 7.83 (d, J ˆ 7.8 Hz, 1H, Ph), 7.73 (d, J ˆ 7.1 Hz, 2H, Ph),
7.50 (dd, J ˆ 7.4/7.1 Hz, 2H, Ph), 7.43 (t, J ˆ 7.4 Hz, 1H, Ph), 4.33 4.26 (2q,
J ˆ 7.1/7.1 Hz, 4H, 2CH2), 1.31 1.27 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me); 13C{1H}:
d ˆ 167.0/166.4 (2CO), 143.2, 137.9, 133.1, 129.8 (4C), 129.6, 129.2, 129.1,
128.6, 127.0, 126.5 (6CH), 61.4/61.3 (2CH2), 13.9/13.8 (2Me).
Diethyl 4-ethyl-5-phenylphthalate (1e): 1208C, 24 h; Rf ˆ 0.50; Yield: 66%
from 2-ethyl-3-phenyl-2-butenal (437 mg, 2.5 mmol), colorless liquid. IR
(cap.): nÄ ˆ 3057w, 3027w, 2979s, 2936m, 2904m, 2875m, 2255w, 1724vs,
1609m, 1556m, 1464s, 1447s, 1367s, 1306vs, 1247vs, 1175s, 1136s, 1071s,
Experimental Section
General: Starting materials and solvent were used as received from
commercial suppliers. Threaded ACE pressure tubes were used for
preparative reactions. For automated runs, all reagents (amide, aldehyde,
diethyl acetylenedicarboxylate, and p-TSA) were employed as freshly
prepared 0.5m stock solutions in NMP. Automated reactions were run on a
Zymate Laboratory Automation System by Zymark Corp. (Hopkinton,
MA, USA) at the Institute of Automation at the University of Rostock
(http://www.iat.uni-rostock.de).
‡
1030s, 914s, 855m, 769m, 733s, 704s; MS-EI: m/z (%): 326 (96) [M] , 281
‡
(63) [M À OEt] , 253 (100), 225 (21), 209 (12), 181 (13), 165 (29); no other
peaks of > 10%. HRMS: m/z: calcd for C20H22O4: 326.15179; found:
326.15610; 1H NMR (CDCl3): d ˆ 7.54/7.50 (2s, 2H, Ph), 7.34 7.27 (m, 3H,
Ph), 7.18 (dm, J ˆ 6.5 Hz, 2H, Ph), 4.30/4.24 (2q, J ˆ 7.1/7.1 Hz, 4H, 2CH2),
2.54 (q, J ˆ 7.5 Hz, 2H, CH2), 1.31 1.23 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me), 1.01
(t, J ˆ 7.5 Hz, 3H, Me); 13C{1H}: d ˆ 167.9/167.3 (2CO), 145.2, 144.1, 139.9,
131.4 (4CH), 130.5 (CH), 129.1 (C), 129.0 (CH), 128.8, 128.2, 127.5 (3CH),
61.5/61.4 (2CH2), 26.0 (CH2), 15.1 (Me), 14.0/13.9 (2Me).
NMR spectra were recorded on a Bruker ARX400 and are reported in
ppm. EI mass spectra were recorded on an AMD402 spectrometer (70 eV).
IR spectra were obtained from KBr pellets on a Nicolet Magna550.
Melting points are uncorrected.
Diethyl 3-(N-acetylamino)-4,6-dimethyl-trans-3,4-dihydrophthalate (2a):
1208C, 24 h; Rf ˆ 0.10; Yield: 69% from 2-methyl-2-pentenal (245 mg,
2.5 mmol), white solid. M.p. 79 838C; IR (cap.): nÄ ˆ 3260s, 2985s, 1734vs,
1713vs, 1640vs, 1540vs, 1449s, 1378s, 1307s, 1264vs, 1161s, 1115s, 1075s,
General procedure for preparative one-pot syntheses starting from a,b-
unsaturated aldehydes: Acetamide (287 mg, 5 mmol), a,b-unsaturated
aldehyde (cis and/or trans, 2.5 mmol), diethyl acetylenedicarboxylate
‡
‡
1047s; MS-EI: m/z (%): 309 (1) [M] , 263 (14) [M À OEt] , 248 (72) [M À
Chem. Eur. J. 2003, 9, 2273 2281
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2279

M. Beller et al.
FULL PAPER
236.10107; found: 236.10129; 1H NMR (CDCl3): d ˆ7.82 (dm, J ˆ 7.5 Hz,
1H, Ph), 7.39 (dm, J ˆ 7.2 Hz, 1H, Ph), 7.34 (t*, J ˆ 7.5 Hz, 1H, Ph), 4.42/
4.34 (2q, J ˆ 7.1/7.1 Hz, 4H, 2CH2), 2.36 (s, 3H, Me), 1.38/1.36 (2t, J ˆ 7.1/
7.1 Hz, 6H, 2Me); 13C{1H}: d ˆ 169.2/165.8 (2CO), 135.3 (C), 134.2/128.8
(2CH), 128.1 (C), 127.4 (C, CH), 61.3 (2CH2), 19.0 (Me), 14.1/14.0 (2Me).
‡
‡
AcNH] , 204 (17) [M À OEt À AcNH] , 190 (24) [M À OEt À Me À
‡
‡
AcNH] , 178 (100) [M À CO2Et À AcNH] , 148 (30) [M À (CO2Et)2 À
‡
‡
‡
Me] , 43 (43) [Ac] , 29 (30) [Et] ; no other peaks of > 15%; elemental
analysis calcd (%) for C16H23NO5: C 62.12, H 7.49, N 4.53; found: C 62.40, H
7.29, N 4.53; 1H NMR ([D6]DMSO): d ˆ 7.92 (d, J ˆ 9.1 Hz, 1H, NH), 5.53
(d, J ˆ 3.4 Hz, 1H, CH), 5.10 (dd, J ˆ 4.8/9.1 Hz, 1H, CH), 4.13/4.05 (2q,
J ˆ 7.1/7.1 Hz, 4H, 2CH2), 3.01 (m, 1H, CH), 1.81 (s, 3H, Me), 1.60 (s, 3H,
Me), 1.20 (d, J ˆ 6.9 Hz, 3H, Me), 1.19/1.15 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me);
13C{1H}: d ˆ 168.9 (CON); 166.7/166.4 (2CO), 138.8, 132.8, 130.0 (3C), 127.1
(CH), 60.8/60.6 (2CH2), 46.2 (CHN), 32.4 (CH), 22.3 (Me), 20.3 (Me), 19.4
(Me), 13.8 (2Me).
Diethyl 3,5-dimethyl-4-phenylphthalate (3d): 1408C, 24 h; Rf ˆ 0.65; Yield:
50% from 2-methyl-3-ethylcinnamic aldehyde (436 mg, 2.5 mmol), color-
‡
‡
less oil. MS-EI: m/z (%): 326 (15) [M] , 280 (100) [M À OEt] , 251 (87),
207 (22), 179 (17), 165 (31); no other peaks of > 10%; HRMS: m/z: calcd
for C20H22O4: 326.15179: found: 326.15150; 1H NMR(CDCl3): d ˆ 7.69 (s,
1H), 7.36 (t*, J ˆ 7.5 Hz, 2H, Ph), 7.28 (t, J ˆ 7.5 Hz, 1H, Ph), 7.00 (dd, J ˆ
1.5/7.5 Hz, 2H, Ph), 4.34/4.28 (2q, J ˆ 7.1/7.1 Hz, 4H, 2CH2), 1.97/1.92 (2s,
6H, 2Me), 1.30 (2t, J ˆ 7.2/7.2 Hz, 6H, 2Me); 13C{1H}: d ˆ 169.8, 165.8, 146.7,
139.6, 137.4, 133.5, 133.4 (7C), 128.7, 128.6, 128.3, 127.2 (4CH), 126.5 (C),
61.3/61.2 (2CH2), 20.9/17.5 (2Me), 14.2/14.0 (2Me).
Diethyl 3-(N-acetylamino)-4,6-diethyl-trans-3,4-dihydrophthalate (2b):
1208C, 24 h; Rf ˆ 0.10; Yield: 84% from 2-ethyl-2-hexenal (315 mg,
2.5 mmol), white solid. M.p. 70 728C; IR (KBr): nÄ ˆ 3324s, 2974s,
‡
1728vs, 1709vs, 1647vs, 1524s, 1271vs; MS-EI: m/z (%): 337 (1) [M] ,
Diethyl 4-methyl-5,6,7,8-tetrahydronaphthene-1,2-dicarboxylate (3e):
1408C, 24 h; Rf ˆ 0.55; Yield: 88% from 2-cyclohexylidenepropanal
(347 mg, 2.5 mmol), colorless, pasty solid. M.p. 528C; IR (KBr): nÄ ˆ
3438brm, 2981m, 2953m, 2937s, 2868m, 1734vs, 1714vs, 1595m, 1571m,
1451m, 1389m, 1364m, 1311vs, 1274vs, 1237vs, 1186vs, 1156vs, 1113m,
‡
‡
‡
292 (3) [M À OEt] , 262 (83) [M À CO2Et] , 232 (12) [M À CO2Et À Et] ,
‡
‡
218 (17) [M À CO2Et À OEt] , 205 (15) [M À CO2Et À AcNH] , 192 (100)
‡
‡
‡
[M À (CO2Et)2] , 176 (100) [M À CO2Et À Ac À OEt] , 43 (40) [Ac] ; no
other peaks of > 10%; elemental analysis calcd (%) for C18H27NO5: C
64.07, H 8.07, N 4.15; found: C 64.07, H 7.99, N 4.18; 1H NMR ([D6]DMSO):
d ˆ 7.74 (d, J ˆ 9.3 Hz, 1H, NH), 5.60 (d, J ˆ 4.2 Hz, 1H, CH), 5.22 (dd, J ˆ
5.1/9.3 Hz, CHN), 4.12/4.05 (2q, v7.1/7.1 Hz, 4H, 2CH2), 2.96 (m, 1H, CH),
1.88 2.05 (brm, 2H, CH2), 1.82 (s, 3H, Me), 1.71 (m, 1H of CH2), 1.46 (m,
1H of CH2), 1.18/1.14 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me), 0.96 (t, J ˆ 7.3 Hz, 3H,
Me), 0.88 (t, J ˆ 7.3 Hz, 3H, Me); 13C{1H}: d ˆ 168.9, 166.7, 166.3 (3CO),
138.1, 136.8, 133.4 (3C), 123.0 (CH), 60.8/60.5 (2CH2), 44.7 (CHN), 38.1
(CH), 26.9 (CH2), 25.4 (CH2), 22.3, 13.7, 12.1, 10.9 (5Me).
‡
1051s, 1029s, 804m, 785s, 691m; MS-EI: m/z (%): 290 (1) [M] , 244 (100)
‡
[M À OEt] , 216 (81), 188 (21), 172 (13), 143 (17), 129 (22), 115 (11); no
other peaks of > 10%; HRMS: m/z: calcd for C17H22O4: 290.15179; found:
290.15310; 1H NMR (CDCl3): d ˆ 7.63 (s, 1H, Ph), 4.40, 4.33 (2q, J ˆ 7.1/
7.1 Hz, 4H, 2CH2), 2.75, 2.60 (2t, J ˆ 6.0/6.0 Hz, 4H, 2CH2), 2.25 (s, 3H,
Me), 1.85 1.75 (m, 4H, 2CH2), 1.40 1.34 (2t, J ˆ 7.1 Hz, 6H, 2Me);
13C{1H}: d ˆ 169.8/166.0 (2CO), 141.3, 137.6, 134.0, 133.5 (4C), 128.2 (CH),
124.4 (C), 61.2/61.0 (2CH2), 27.4/26.7 (2CH2), 22.4/22.2 (2CH2), 19.6 (Me),
14.2/14.1 (2Me).
Diethyl 3-(N-acetylamino)-6-methyl-cis-3,6-dihydrophthalate (2c): 1208C,
24 h; Rf ˆ 0.15; Yield: 67% from 2-pentenal (211 mg, 2.5 mmol), white
solid. M.p. 778C; IR (KBr): nÄ ˆ 3248s, 3050m, 2976m, 2938m, 2906w,
1721vs, 1642vs, 1546s, 1369m, 1279m, 1252vs, 1182s, 1097m, 1059s,
Diethyl
4-methyl-9,10-dihydrophenanthrene-1,2-dicarboxylate
(3 f):
1408C, 24 h; Rf ˆ 0.60; Yield: 52% from 2-(3,4-dihydro-2H-naphthalen-1-
ylidene)propanal (467 mg, 2.5 mmol), white solid. M.p. 1038C; IR (cap.):
nÄ ˆ 3427brw, 2979w, 2948w, 2901w, 2838w, 1722vs, 1707vs, 1446m, 1365m,
1302s, 1226s, 1200m, 1174m, 1148m, 1065s, 1028m, 776m, 750m, 654w;
‡
1030m, 868w, 779w, 759m, 644w, 604w; MS-EI: m/z (%): 295 (2) [M] , 249
‡
(19) [M À OEt] , 234 (84), 191 (19), 178 (23), 164 (100), 134 (31), 106 (10),
‡
43 (36) [Ac] ; no other peaks of > 10%; HRMS: m/z: calcd for C15H21NO5:
‡
‡
MS-EI: m/z (%): 338 (29) [M] , 292 (75) [M À OEt] , 263 (100) [M À
295.14197; found: 295.14200; 1H NMR ([D6]DMSO): d ˆ 8.08 (d, J ˆ
8.7 Hz, 1H, NH), 5.82 (dd, J ˆ 3.9/9.8 Hz, 1H, CH), 5.55 (dd, J ˆ 3.9/
9.9 Hz, 1H, CH), 5.18 (m, 1H, Me), 4.15, 4.07 (2q, J ˆ 7.1/7.1 Hz, 4H,
2CH2), 3.08 3.00 (m, 1H, CH), 1.78 (s, 3H, Me), 1.21 (d, J ˆ 7.1 Hz, 3H,
Me), 1.20/1.15 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me); 13C{1H}: d ˆ 168.4, 166.6, 166.2
(3CO), 139.2/132.2 (2C), 131.2/123.2 (2CH), 60.8/60.6 (2CH2), 42.8 (CHN),
31.7 (CH), 22.3, 20.1, 13.8, 13.7 (4Me).
‡
CO2Et] , 236 (14), 219 (16), 191 (33), 178 (25), 165 (18); no other peaks of
> 10%; HRMS: m/z: calcd for C21H22O4: 338.15179; found: 338.15280;
1H NMR (CDCl3): d ˆ 7.84 (s, 1H, Ph), 7.62 (dt, J ˆ 6.5/1.6 Hz, 1H, Ph),
7.31 7.24 (m, 3H, Ph), 4.42, 4.36 (2q, J ˆ 7.1/7.1 Hz, 4H, 2CH2), 2.73 (brs,
4H, 2CH2), 2.64 (s, 3H, Me), 1.40 1.35 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me);
13C{1H}: d ˆ 169.5/165.7 (2CO), 139.9, 139.0, 137.0, 135.3, 133.2, 131.9 (6C),
131.7, 128.4, 128.0, 127.4, 125.9 (5CH), 125.5 (C), 61.4/61.2 (2CH2), 29.0/26.9
(2CH2), 22.9 (Me), 14.2/14.0 (2Me).
Diethyl 3,5-dimethylphthalate (3a): 1608C, 24 h; Rf ˆ 0.55; Yield: 86%
from 2-methyl-2-pentenal (245 mg, 2.5 mmol), colorless liquid. IR (cap.):
nÄ ˆ 2982s, 2935m, 1724vs, 1611m, 1446m, 1367m, 1309s, 1269s, 1208s,
1155s, 1084s, 1034s, 870m, 791m, 765m, 619w; MS-EI: m/z (%): 250 (5)
General procedure for high-temperature elimination of acetamide from
2a c: Aminocyclohexene 2a c (2.5 mmol) and p-toluenesulfonic acid
monohydrate (22 mg, 1.5 mol%) were combined in a threaded tube, and
NMP (3 mL) was added. The reaction was stirred at elevated 1608C. After
24 h, the solvent and other volatile compounds were removed by oil pump
vacuum. Silica gel chromatography (heptane/ethyl acetate 2:1) afforded
the analytically pure products 3a c.
‡
‡
‡
[M] , 204 (94) [M À OEt] , 177 (100), 148 (43) [M À CO2Et À OEt] , 132
‡
(37), 103 (15) [C6H2(Me)2] , 91 (19), 77 (30); HRMS: m/z: calcd for
C14H18O4: 250.12051; found: 250.12422; 1H NMR (CDCl3): d ˆ 7.56 (s, 1H,
Ph), 7.12 (s, 1H, Ph), 4.36 4.24 (2q, J ˆ 7.1/7.1 Hz, 4H, 2CH2), 2.28, 2.26 (2s,
6H, 2Me), 1.30 (2t, J ˆ 7.1/7.1 Hz, 6H, 2Me); 13C{1H}: d ˆ 169.1/165.8
(2CO), 138.7/135.1 (2C), 134.6 (CH), 132.3/128.1 (2C), 127.6 (CH), 61.0/60.9
(2CH2), 20.7/20.6 (2Me), 13.9/13.8 (2Me).
Diethyl 3,5-dimethylphthalate (3a): 1608C, 24 h; Rf ˆ 0.55; Yield: 91%
from 2a (245 mg, 2.5 mmol), colorless liquid. See section above for
spectroscopic data.
Diethyl 3,5-diethylphthalate (3b): 1608C, 24 h; Rf ˆ 0.55; Yield: 89% from
2-ethyl-2-hexenal (315 mg, 2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ
3434w, 2971vs, 2937s, 2904w, 2876m, 1732vs, 1608s, 1464s, 1367s,
1291brvs, 1251s, 1203vs, 1154vs, 1088vs, 1027s, 891s, 865m, 795m; MS-
EI: m/z (%): 278 (1) [M] , 232 (100) [M À OEt] , 205 (34), 176 (71), 160
(21), 133 (29), 117 (10); no other peaks of > 10%; HRMS: m/z: calcd for
C16H22O4: 278.15179; found: 278.15360; 1H NMR ([D6]DMSO): d ˆ 7.56 (d,
J ˆ 1.0 Hz, 1H, Ph), 7.40 (d, 1.0 Hz, 1H, Ph), 4.26/4.24 (2q, J ˆ 7.1/7.1 Hz,
4H, 2CH2), 2.65/2.57 (2q, J ˆ 7.5/7.5 Hz, 4H, 2CH2), 1.26 1.25 (2t,
J ˆ 7.1/7.1 Hz, 6H, 2Me), 1.17/1.13 (2t, J ˆ 7.5/7.5 Hz, 6H, 2Me); 13C{1H}:
d ˆ 168.1/165.7 (2CO), 145.5/141.5 (2C), 132.6 (CH), 131.5/128.4 (2C), 126.3
(CH), 61.1/60.8 (2CH2), 27.7/25.7 (2CH2), 15.7/15.2 (2Me), 13.9/13.8 (2Me).
Diethyl 3,5-diethylphthalate (3b): 1608C, 24 h; Rf ˆ 0.55; Yield: 89% from
2b (315 mg, 2.5 mmol), colorless liquid. See section above for spectroscopic
data.
‡
‡
Diethyl 3-methylphthalate (3c): 1608C, 24 h; Rf ˆ 0.65; Yield: 83% from
2c (211 mg, 2.5 mmol), colorless liquid. See section above for spectroscopic
data.
Acknowledgement
Diethyl 3-methylphthalate (3c): 1608C, 24 h; Rf ˆ 0.65; Yield: 79% from
2-pentenal (211 mg, 2.5 mmol), colorless liquid. IR (cap.): nÄ ˆ 3435brw,
2983vs, 2938w, 2906w, 1724vs, 1595m, 1463s, 1446s, 1390m, 1367s,
1281brvs, 1184vs, 1152vs, 1113vs, 1073vs, 1030s, 864m, 753s, 697m; MS-
EI: m/z (%): 236 (2) [M] , 190 (73) [M À OEt] , 163 (100), 134 (36), 89
(11), 77 (14); no other peaks of > 10%; HRMS: m/z: calcd for C13H16O4:
The authors thank Prof. Thorsten Bach (TU Munich) for valuable
discussions. Excellent analytical service by Dr. W. Baumann (NMR), H.
Baudisch (MS, GC/MS), and S. Buchholz (GC) is gratefully acknowledged.
Generous financial support was provided by the state of Mecklenburg-
Western Pomerania (Landesschwerpunkt), the Fonds der Chemischen
Industrie, and the Bundesministerium f¸r Bildung und Forschung (BMBF).
‡
‡
2280
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2273 2281

Substituted Phthalic Acid Derivatives
2273 2281
[1] a) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogiannakis,
Angew. Chem. 2002, 114, 1742 1773; Angew. Chem. Int. Ed. 2002, 41,
1668 1698; b) W. R. Roush in Comprehensive Organic Synthesis, Vol.
5 (Ed.: B. M. Trost), Pergamon Press, New York, 1991, p. 513; c) W.
Carruthers, Cycloaddition Reactions in Organic Synthesis, Pergamon
Press, New York, 1990 (Tetrahedron Organic Chemistry Series Vol. 8).
[2] a) L. F. Tietze, Chem. Rev. 1996, 96, 115 136; b) J. D. Winkler, Chem.
Rev. 1996, 96, 167 176; c) P. J. Parsons, C. S. Penkett, A. J. Shell,
Chem. Rev. 1996, 96, 195 206; d) G. H. Posner, Chem. Rev. 1986, 86,
831 844.
[3] For recent reviews on automated synthesis technologies in organic
chemistry, see: a) J. Yoshida, S. Suga, K. Itami, Kagaku Kogyo 2002,
53, 6 12; b) S. V. Ley, I. R. Baxendale, Nat. Rev. Drug Discov. 2002, 1,
573 586; c) T. Sugawara, J. Syn. Org. Chem. Jpn. 2002, 60, 465 475;
d) A. Hagemeyer, B. Jandeleit, Y. Liu, D. M. Poojary, H. W. Turner,
A. F. Volpe, W. Henry Weinberg, Appl. Catal. A 2001, 221(1 2), 23
43.
[4] Recent applications of automated synthesis to non-DNA chemistry:
a) R. G. Gentles, D. Wodka, D. C. Park, A. Vasudevan, J. Comb.
Chem. 2002, 4, 442 456; b) b) F. Sch¸th, O. Busch, C. Hoffmann, T.
Johann, C. Kiener, D. Demuth, J. Klein, S. Schunk, W. Strehlau, T.
Zech, Top. Catal. 2002, 21, 55 66; c) M. S. Schiedel, C. A. Briehn, P.
B‰uerle, J. Organomet. Chem. 2002, 653, 200 208.
[5] For syntheses and applications of other types of Oppolzer Overman
dienes, see: a) J. M. Janey, T. Iwama, S. A. Kozmin, V. H. Rawal, J.
Org. Chem. 2000, 65, 9059 9068; b) M. B. Smith, Org. Prep. Proceed.
Int. 1990, 22, 315 397; c) L. E. Overman, R. L. Freerks, C. B. Petty,
L. A. Clizbe, R. K. Ono, G. F. Taylor, P. J. Jessup, J. Am. Chem. Soc.
1981, 103, 2816 2822; d) W. Oppolzer, L. Bieber, E. Francotte,
Tetrahedron Lett. 1979, 16, 4537 4540.
[6] a) H. Neumann, A. Jacobi von Wangelin, D. Gˆrdes, M. Beller J. Am.
Chem. Soc. 2001, 123, 8398 8399; b) H. Neumann, A. Jacobi von -
Wangelin, D. Gˆrdes, A. Spannenberg, W. Baumann, M. Beller,
Tetrahedron 2002, 58, 2381 2387.
[7] A. Jacobi von Wangelin, H. Neumann, D. Gˆrdes, A. Spannenberg,
M. Beller, Org. Lett. 2001, 3, 2895 2898.
[8] a) C. F. Huebner, E. Donoghue, J. Org. Chem. 1963, 28, 1732; b) Y.
Arai, T. Kamikawa, T. Kubota, Tetrahedron Lett. 1972, 10, 1615;
c) J. A. Profitt, T. Jones, D. S. Watt, Synth. Commun. 1975, 5, 457 460;
d) S. Danishefsky, R. K. Singh, R. K. Gammill, J. Org. Chem. 1978, 43,
379 380; e) S. Danishefsky, T. Kitahara, C. F. Yan, J. Morris, J. Am.
Chem. Soc. 1979, 101, 6996 7000; f) G. Shi, S. Cottens, S. A. Shiba, M.
Schlosser, Tetrahedron 1992, 48, 10569 10574; g) A. Roy, K. R.
Reddy, H. Ila, H. Junjappa, J. Chem. Soc. Perkin Trans. 1 1999, 3001
3004; h) M. M. Abdel-Khalik, M. H. Elnagdi, Synth. Commun. 2002,
32, 159 164.
Tetrahedron Lett. 1981, 29, 3779 3780; c) Meyer-Schuster rearrange-
ment: J. March, Advanced Organic Chemistry, 4th ed., Wiley, New
York, 1992, p. 330.
[10] The aldehyde was prepared according to: E. J. Corey, D. Enders, M. G.
Bock, Tetrahedron Lett. 1976, 14, 7 10.
[11] Crystal structure analysis of 2c: X-ray data of 2c were collected on a
STOE-IPDS diffractometer using graphite monochromated MoKa
radiation, l ˆ 0.71069 ä. The structure was solved by direct methods
(SHELXS-86: G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467)
and refined by full-matrix least-squares techniques against F2 (G. M.
Sheldrick, SHELXL-93, University of Gˆttingen (Germany), 1993).
XP (Bruker AXS) was used for structure representation. All non-
hydrogen atoms were refined anisotropically. The hydrogen atoms
(except the hydrogen attached to nitrogen) were included at
calculated positions and refined by using the riding model. Crystal
data: 0.4 Â 0.3 Â 0.2 mm3, colorless prism, space group P21/c, mono-
clinic, a ˆ 8.901(2), b ˆ 19.429(4), c ˆ 9.530(2) ä, b ˆ 107.79(3)8, Vˆ
1569.3(6) ä3, Z ˆ 4, 1calcd ˆ 1.250 gcmÀ3, 4663 reflections measured,
2489 were independent of symmetry, of which 1653 were observed
(I > 2s(I)), R1 ˆ 0.041, wR2 (all data) ˆ 0.102, 194 parameters, resid-
ual electron density (max.): 0.246 eäÀ3
.
[] CCDC-195184 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (‡44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).
[12] Numbering (1,2 vs. 1,4) does not follow the IUPAC nomenclature of
the compounds (3-amino...) but refers to the mechanism pursued
(amine-substituent: 1-position).
[13] a) D. V. Banthorpe, Elimination Reactions, Elsevier, New York, 1963;
b) W. H. Saunders, Jr., A. F. Cockerill, Mechanisms of Elimination
Reactions, Wiley, New York, 1973; c) R. A. Bartsch, J. Zavada, Chem.
Rev. 1980, 80, 453 494.
[14] I. Fleming, Frontier Orbitals and Organic Reactions, Wiley, London,
1976.
[15] a) K. Fukui, Tetrahedron Lett. 1965, 3, 2427; b) K. Fukui, H. Fujimoto,
Bull. Chem. Soc. Jpn. 1966, 39, 2116 2126; c) N. T. Anh, J. Chem. Soc.
Chem. Commun. 1968, 1089; d) O. S. Tee, J. A. Altmann, K. Yates, J.
Am. Chem. Soc. 1974, 96, 3141 3146.
[16] Similar reactions that involve dominating 1,4-syn eliminations have
been reported: a) S. J. Cristol, Acc. Chem. Res. 1971, 4, 393 400;
b) R. K. Hill, M. G. Bock, J. Am. Chem. Soc. 1978, 100, 637 639;
c) R. J. Moss, R. O. White, B. Rickborn, J. Org. Chem. 1985, 50, 5132
5139; d) R. J. Moss, B. Rickborn, J. Org. Chem. 1986, 51, 1992 1996;
e) J. J. Rabasco, S. R. Kass, J. Org. Chem. 1993, 58, 2633 2636; f) S.
Gronert, S. R. Kass, J. Org. Chem. 1997, 62, 7991 8000.
[9] a) Sequential Wittig Horner olefination, reduction, Swern oxidation:
H. J. Bestmann, K. Roth, M. Ettlinger, Chem. Ber. 1982, 115, 161 171;
b) Weinreb route: J.-M. Nuzillard, A. Boumendjel, G. Massiot,
Received: December 16, 2002 [F4668]
Chem. Eur. J. 2003, 9, 2273 2281
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2281