Practical three-component synthesis of crowded arenes with donor-acceptor substitution

Article abstract of DOI:10.1039/c1ob05984j

An operationally simple two-step synthesis of substituted anilides has been developed. The methodology utilizes carboxamides, aldehydes, and olefins (or alkynes) as cheap starting materials and relies upon the sequential combination of condensation, cyclo

Full text of DOI:10.1039/c1ob05984j

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PAPER
Practical three-component synthesis of crowded arenes with donor–acceptor
substitution†
Robert Fichtler, Jo¨rg-M. Neudo¨rfl and Axel Jacobi von Wangelin*
Received 17th June 2011, Accepted 19th July 2011
DOI: 10.1039/c1ob05984j
An operationally simple two-step synthesis of substituted anilides has been developed. The
methodology utilizes carboxamides, aldehydes, and olefins (or alkynes) as cheap starting materials and
relies upon the sequential combination of condensation, cycloaddition, and oxidation reactions. The
intermediate cycloadducts display various functional groups (e.g. Br, OAc, NR2, COR, Cbz) for further
chemical manipulation at the ring periphery or core. Upon oxidation with MnO2, highly crowded
anilides with up to four further substituents (alkyl, aryl, carboxylate, cyano, nitro, bromo) can be
prepared in good overall yields.
dienophiles to give functionalized aminocyclohexenes or aminocy-
Introduction
clohexadienes (Scheme 2).5 The protocol involves initial acid-
Multi-component reactions have attracted considerable interest
catalyzed reaction of the carboxamide with an enolizable aldehyde
owing to their potential to assemble highly diversified and complex
to give an equilibrium of various condensation and aldol products,
molecular architectures from simple starting materials in one
with each of the components being formed in rather low yields
(~25% of aminodiene I).6 The addition of an electron-deficient
synthetic operation. The adoption of such strategies comes along
with the minimization of both waste production and expenditure
of human labour.1 Diels–Alder reactions2 are one of the key
dienophile triggers the selective consumption of I in an irreversible
cycloaddition to selectively drive the equilibria to the aminodiene
methods for the rapid generation of functionalized six-membered
side, thereby providing a high-yield synthesis of the corresponding
cycloadducts II.6 The overall three-component reaction relies on
rings in a cycloaddition process which can also be applied to
the synthesis of functionalized arenes via subsequent skeletal
simple starting materials (amide, aldehyde, dienophile) and results
in the generation of four new bonds in one synthetic operation
rearrangements, eliminations or oxidative transformations.3 The
latter strategy is especially attractive with cheap and readily
with high endo-stereocontrol. The high utility of such carbocyclic
available oxidants. We wish to report on the facile preparation of
building blocks has been demonstrated in the synthesis of fine
chemicals, pharmaceuticals, and materials.7
highly substituted N-acyl aniline derivatives from cheap starting
materials in two synthetic steps involving a multi-component
cycloaddition and an oxidation (Scheme 1). The resultant highly
modular aromatic molecules contain a donor–acceptor substi-
tuted arene core (anthranilic acid derivative) which is central
to various applications as fine chemicals, dyes, pigments, and
materials.4
Scheme 1 Two-step synthesis of anthranilic acid derivatives.
Scheme 2 Domino condensation–cycloaddition mechanism.
We have recently identified conditions for selective three-
component reactions of simple aldehydes, carboxamides, and
Results and discussion
Department of Chemistry, University of Cologne, Greinstr. 4, 50939, Ko¨ln,
Germany. E-mail: axel.jacobi@uni-koeln.de; Fax: +49 221 470 5057;
Tel: +49 221 470 6122
Synthesis of pseudo-four-component aminocyclohexadienes from
aldehydes bearing an a-CH2 group
† Electronic supplementary information (ESI) available: Experimental
procedures, analytical data of all new compounds. CCDC reference
numbers 832706–832713. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob05984j
Table 1 shows a series of pseudo-four-component cycloadducts
from reactions of a carboxamide and dimethyl acetylenedicar-
boxylate (DMAD) with two molecules of aldehyde in refluxing
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Table 1 Pseudo-four-component cyclohexadienes from aldehydesa
Table 2 Three-component cyclohexadienes from unsaturated aldehydesa
R1, R2
Me, H
Aldehyde
Product
Yield [%]
88
R1, R2
Me, H
R3
Product
Yield [%]
69
9
Me
1
Et
2
3
4
5
75
66
88
49
2-BrC6H4, H
Ph, H
BrCH2, H
10
11
12
89
87
66
Bn
i-Pr
Ph
–(CH2)3–
13
89
Ph, H
Bn
6
63
Ph
7
8
52
59
Me, H
14
38
–(CH2)3–
Me
a Carboxamide (1 equiv.), aldehyde (1 equiv.), DMAD (1.5 equiv.) and
p-TSA·H2O (3 mol%) in PhMe were heated for 16 h at 110 ◦C.
a Amide (1 equiv.), aldehyde (2 equiv.), DMAD (1 equiv.), p-TSA·H2O
(3 mol%) and Ac2O (1 equiv.) in PhMe were heated for 16 h at 110 ◦C.
toluene under catalysis of p-toluenesulfonic acid monohydrate
(TSA·H2O)8 The intermediate formation of the aminodiene
species I can also be viewed as a selective telomerization of two
molecules of aldehyde with the carboxamide (with suppression
of further condensations to longer aldol-type products).6,9 The
resultant penta-substituted amidocyclohexadienes 1–8 contain
two equal substituents in a 1,3-relation due to the incorporation of
two aldehyde molecules. The double bonds of the cyclohexadiene
products are subject to thermodynamic equilibration under the
reaction conditions (TSA, 110 ◦C) to give a conjugated diene moi-
ety. Vicinal amino and alkyl moieties adopt a trans configuration
Fig. 1 1H NMR spectrum and 3JH,H coupling constants of 9.
3
as evidenced by the JHH coupling constants (~ 5 Hz, see also
(>130 ◦C) led to low yields of the target compounds (<20%), but
instead facilitated acylamine elimination from the intermediate
cyclohexadienes. Thus, tri-, tetra-, and penta-substituted diethyl
phthalat◦es (15–18) were prepared in good yields after 20 h
at 150 C from a,b-unsaturated aldehydes,12 acetamide, and
diethyl acetylenedicarboxylate (Scheme 3). It is interesting to
note, that one-pot reactions employing crotonaldehyde derivatives
without g-substituents (Scheme 4, R3 = H) afforded phthalates
via sequential aminodiene cycloaddition and formal 1,4-syn-
elimination of acetamide at lower temperatures (110 ◦C). This
explains why the desired amidocyclohexadienes could not be
Fig. 1).
Synthesis of aminocyclohexadienes and phthalates from
a,b-unsaturated aldehydes
Enhanced product diversity was attained upon employment of
a,b-unsaturated aldehydes. Table 2 shows a selection of six cy-
cloadducts from reactions of primary or secondary carboxamides
with DMAD and a,b-unsaturated aldehydes.10 The presence
of a conjugated diene moiety and a trans substitution in 9–
14 was confirmed by H NMR analysis.11 Higher temperatures
1
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Scheme 3 Synthesis of phthalates under high temperature conditions.10
˚
Fig. 2 Crystal structure of 24. Selected bond lengths [A] and an-
gles [◦]: C1–C2 1.547(5), C2–C11 1.521(2), C3–N2 1.443(5), C4–C5
1.308(4), C4–Br1 1.899(3), C6–C1–C10 113.82(0), C11–C2–C3 112.41(0),
C3–C4–Br1 117.53(0), C11–C2–C3–N2 -53.80(1), N2–C3–C4–Br1
-14.05(1), C13–C6–C1–C10 52.76(1).
endo-geometry with an all-syn substitution pattern about the cen-
tral cyclohexene ring (Table 7). Employment of diethyl fumarate
resulted in the formation of two inseparable diastereomers 33a
and 33b under the standard conditions (Scheme 5).
Scheme
4
Acetamide-mediated synthesis of phthalates via formal
1,4-elimination.10
prepared from crotonaldehydes (R3 = H) under the standard
reaction conditions. Such aromatizations can be used for the facile
synthesis of substituted phthalates, even under acetamide catalysis
(>20 mol%). The operational simplicity of this procedure has
been demonstrated by processing the reaction and the downstream
product analysis in fully automated fashion by a bench top robot
(Scheme 4).10
Synthesis of three-component aminocyclohexenes from
a,b-unsaturated aldehydes
We have then extended the scope of the three-component reaction
to also include olefins as dienophiles (Table 3). Cycloadditions
with symmetrical maleimides proceeded with high stereocontrol
(endo : exo > 95 : 5) for most products. With bulky amides (R1 =
Phenyl, o-Aryl etc.), the exo diastereomer becomes slightly less
disfavoured.13 The choice of aldehyde determines the substitution
pattern of the resultant 1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-
isoindol-4-yl carboxamide structures in positions 4, 5, and 6
(see for example methyl derivatives 19–22). The reaction with
citral (commercial mixture of geranial and neral) afforded two
regioisomers in 39% (23a) and 26% (23b)14 yield. Substituted
1-bromo-1-cyclohexenes (24, 25) were obtained from reactions
with 2-bromocrotonaldehydes.15 Benz-anellated heteroaromatic
substituents were incorporated into the product structures of 26
and 27.
Scheme 5 Synthesis of two diastereomers from diethyl fumarate.
The reactions discussed so far involved symmetrical dienophiles
with two identical electron-withdrawing substituents. A normal
electron-demand Diels–Alder reaction, the second step of the un-
derlying domino sequence, is usually a concerted process obeying
the rules of orbital symmetry. On the other hand, related reactions
with unsymmetrical dienophiles containing only one electron-
withdrawing substituent might favour a stepwise (Michael-type)
pathway via polar intermediates. Reactions with acrylonitrile and
2-benzylidene malononitrile, however, gave cyclohexenes 34 and
35 as endo-adducts in moderate yields (Table 4). Employment
of trans-2-nitrostyrene afforded the cycloadduct 36 in 79% yield
containing the vicinal nitrogen-based substituents (NHAc, NO2)
in a syn relation. The crystal structure of 36 is shown in Fig.
3 (see also Table 7). The observed stereocontrol could be a
consequence of an intramolecular hydrogen bonding interaction
between the acetamido and nitro groups in the transition state.
Related reactions with (more nucleophilic) secondary amines have
been shown to proceed via a stepwise Michael-type mechanism
involving thermodynamic equilibration to give the corresponding
trans-stereoisomer.16
The standard reaction conditions tolerate various carboxam-
ides as reagents. Employment of 2-pyrrolidinone gave three-
component adduct 28 with a tertiary amide moiety. Benzyloxy-
carbonyl (Cbz) protection of the amino function has been realized
for 29–31, while 32 contains an N,N-dimethylurea terminus. The
stereochemical outcome of the reactions has been analyzed for all
1
cycloadducts by H NMR spectroscopy based upon H,H/H,C-
3
COSY and JHH coupling constants. Fig. 2 shows the crystal
The generation of the reactive diene intermediates by reaction
of a (nucleophilic) amide with an unsaturated aldehyde can be
structure of bromocyclohexene 24 which establishes the expected
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Table 3 Synthesis of three-component cyclohexadienes from a,b-unsaturated aldehydes and N-methyl maleimidea
Amide
Aldehyde
Product
Yield [%]
19
76
20
76
21
54
22
76 (80)b
23a
39c (syn : anti = 2 : 1)
24
25
70
71
26
46d
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Table 3 (Contd.)
Amide
Aldehyde
Product
Yield [%]
27e
27
28
77
29
30
98
98
31
32
83
75
a Equimolar carboxamide, aldehyde, and N-methylmaleimide with p-TSA·H2O (3 mol%) in toluene were heated at 110 ◦C for 20–40 h. Oligomeric
aldehyde by-products were detected by GC–MS. b In brackets reaction from propionaldehyde. c 26% regioisomer (23b).14 d 40% aldehyde recovered. e 25%
aldehyde recovered.
modulated to an electrophilic trapping of the aldehyde by acetic
anhydride (Ac2O). The resultant acetoxydienes constitute another
class of activated heteroatom-functionalized dienes for Diels–
Alder reactions with electron-deficient dienophiles.17 Scheme
6 illustrates the reaction of 3,3-dimethylacrolein with trans-b-
nitrostyrene in the presence of Ac2O under otherwise identical
conditions. Cyclohexenyl acetate 37 was isolated in 69% yield as a
mixture of two endo-diastereomers (7 : 1). The major isomer bears
the acetate and nitro groups in a syn relation (pseudo-anomeric,
axial OAc); the minor is the C1 epimer.
Oxidation reactions
Dehydrogenative oxidation of the synthesized aminocyclohexa-
dienes and aminocyclohexenes would render a straightforward
access to polyfunctional anilines which are important substruc-
tures in pharmaceuticals, herbicides, dyes, and materials.18 Several
methods for the aromatization of carbocycles have been reported,
including precious metal catalysts (Pt, Pd, Ni), elemental sulfur or
selenium, quinones (e.g. chloranil, DDQ), oxygen/air, manganese
oxide, selenium oxide, chromic acid, and activated charcoal.19
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Table 4 Synthesis of three-component cyclohexenes from a,b-
unsaturated aldehydes and unsymmetrical dienophilesa
Amide
Aldehyde
Product
Yield [%]
25b
Scheme 6 Synthesis of diastereomeric cyclohexenyl acetates via interme-
diate 3-methylbutadienyl acetate.
34
environmentally friendly and cheap oxidants and were delighted
to find that oxidation of the synthesized amidocyclohexadienes
was best effected with commercial manganese dioxide (MnO2)
in refluxing toluene.20 The methodology shows promise for the
synthesis of crowded arenes with diverse substitution patterns.
A series of 25 polysubstituted anilides have been prepared from
MnO2-mediated oxidative aromatization of three-component
amidocyclohexadienes (Table 5) and amidocyclohexenes (Table
6) in good to excellent yields. A larger excess of MnO2 was
required for the aromatization of aminocyclohexenes (mostly
5 equiv.). No difference in activity was found for commercial,
freshly prepared (from MnSO4, KMnO4 and NaOH),21 or freshly
35
36
46c(syn : anti 3 : 1)
79d
◦
˚
activated MnO2 (oven dried at 130 C with 4 A molecular
sieves). The formation of over-oxidized products (benzoquinones,
azobenzenes, oligoanilines) was not observed. Benzoquinone and
2,3-dichloro-5,6-dicyanoquinone (DDQ) gave far inferior results
(<25% yields for oxidations of model substrates 1 and 19).
Reactions of 1 and 2 in the presence of catalytic amounts of
Pd/C (10 mol%) and sacrificial cyclohexene (1.5 equiv.) at 100 ◦C
led to major decomposition, with only 15–20% of the desired
anilides being formed. The remarkably good yields for oxidations
to give crowded substrates such as 40–42 and 44–48 document the
efficiency of the MnO2-based methodology. Dibenzyl derivative 3
underwent acetamide elimination under the reaction conditions
to cleanly give dimethyl 3,5-dibenzyl-phthalate in 90% yield. The
crystal structure of penta-substituted benzamidophthalate 46 is
shown in Fig. 4 (see also Table 7). Bromocyclohexene 14 (Table
5) gave clean conversion to the corresponding bromobenzene
49 in 70% yield. Benzothiophene 26 showed no conversion,
while indole derivative 27 gave a complex mixture of products,
presumably initiated by (indole)-N-assisted acetamide elimina-
tion. Cbz-protected aminocyclohexene 29 gave the anilide 60 in
55% yield; the bulkier 4-phenyl analogue 30 showed only low
conversion (<10%) even after 48 h in refluxing toluene. Urea
derivative 32 underwent deacylation to give aniline 62. Oxidation
of amidonitrocyclohexene 35 gave dinitrogen-substituted biaryl
derivative 64 in 75% yield. The related acetate 36 underwent formal
elimination of acetic acid (HOAc) to give o-nitrobiphenyl 65 in
79% yield (Scheme 7).
a Amide (1 equiv.), aldehyde (1 equiv.), p-TSA·H2O (3 mol%) heated
in toluene at 110 ◦C for 24 h. b Acrylonitrile as dienophile (3 equiv.),
polymerization of dienophile observed. c 2-Benzylidene malononitrile as
dienophile (1 equiv.) d trans-2-Nitrostyrene as dienophile (1 equiv.)
˚
Fig. 3 Crystal structure of 36. Selected bond lengths [A] and an-
gles [◦]: C1–C2 1.524(2), C2–C3 1.539(2), C4–C5 1.326(0), C1–C12
1.521(0), C2–N1 1.508(0), C3–N2 1.461(0), C12–C1–C2 114.37(0),
N1–C2–C3 108.74(0), C2–C3–N2 113.21(0), C10–C4–C5 123.39(0),
C6–C1–C12–C13 –115.13(0), C11–C6–C1–C12 71.16(0), C12–C1–C2–N1
-50.35(1), N1–C2–C3–N2 -56.46, N2–C3–C4–C10 74.69(0).
Conclusions
We have applied an operationally simple one-pot protocol to the
synthesis of multi-substituted carbocycles upon three-component
reaction of simple carboxamides, aldehydes, and dienophiles
(olefins or alkynes). The resultant amidocyclohexenes and ami-
docyclohexadienes were mostly obtained as single diastereomers
from a selective endo-cycloaddition in good to excellent yields.
The thermal acid catalyzed reaction tolerates ester, nitrile, ether,
A subsequent aromatization of the three-component amino-
substituted cycloadducts would also afford identical products
from diastereomeric mixtures and thus obviate laborious chro-
matographic separation of the stereoisomers and enhance the
overall yield of the two-step methodology. We focused on rather
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enantiomer is depicted in the schemes. For atom numbering used
in the spectroscopic data assignment, see chemical structures in
Schemes and Tables above. All chemicals were purchased from
commercial suppliers and used without further purification unless
otherwise noted. 1H and 13C NMR spectra were recorded on
a Bruker Avance II 600 (600.20 and 150.94 MHz), a Bruker
DRX 500 (500.13 and 125.77 MHz) and a Bruker Avance 300
(300.13 and 75.48 MHz) at 298 K. Chemical shifts (d in ppm)
are referenced to tetramethylsilane (TMS). Abbreviations for
1H-NMR data: s (singlet), d (doublet), t (triplet), q (quartet),
sept (septet), m (multiplet), q* (apparent quartet), m* (apparent
multiplet). Peaks were assigned based on H,H-COSY, H,C-
HMQC, and H,C-HMBC. IR-ATR spectroscopy was performed
on a Perkin–Elmer 100 Paragon FT-IR. ESI-MS were measured
with a Finnigan MAT 900S and an Agilent LC/MSD VL
G1956A, respectively. EI-MS were measured with a Finnigan
Incos 50 Galaxy and a Finnigan MAT 95, respectively (ionization
70 eV). Exact masses (HR-MS) were determined by peak matching
method. Crystal structure data were collected on a Nonius Kappa
CCD diffractometer using monochromated Mo-Ka radiation,
structures refined by shelxs97 and shelxl97.24
˚
Fig. 4 Crystal structure of 46. Selected bond lengths [A] and angles
[◦]:C1–C2 1.398(2), C3–N1 1.426(0), C4–C14 1.486(0), C6–C16 1.525(0),
C2–C3–N1 120.08(0), C2–C4–C14 123.72(0), C5–C6–C16 120.76(0),
C1–C2–C3–N1 -177.28(0), C2–C3–C4–C14 -178.21(0), C3–C4–C14–C15
-56.38(0), C5–C6–C16–C17 -89.65(0).
General procedure for the synthesis of cycloadducts from aldehydes
bearing an a-CH2 group
A 50 mL test tube was charged with carboxamide (6 mmol),
aldehyde (12 mmol), the dienophile (6 mmol), p-toluenesulfonic
acid monohydrate (3 mol%), acetic anhydride (6 mmol), and
toluene (8 mL). The tube was sealed with a septum and the reaction
stirred at 110 ◦C oil bath temperature. After 24 h, the solvent and
other volatile compounds were removed by oil pump vacuum. The
crude product was purified by SiO2 flash column chromatography
(ethyl acetate (ea) : cyclohexane (ch)) or crystallized from solution
(for details see below).
Dimethyl 6-acetylamino-3,5-diisopropylcyclohexa-1,3-dien-1,2-
dicarboxylate (4). Work-up: SiO2, ea : ch 2 : 1, Rf 0.35, colorless
oil; yield: 88%. IR (ATR): 1/l [cm-1] 3385 (w), 2948 (w), 2354 (w),
1721 (s), 1680 (s), 1490 (m), 1432 (m), 1367 (w), 1259 (s), 1065 (w),
1031 (w); LR-MS (pos. ESI, MeOH, CH2Cl2): m/z 360 [M+Na]+,
259; HR-MS (ESI, [u]): found: 360.179 [M+Na]+, calcd: 360.1787;
1H-NMR (300 MHz, CDCl3): d 5.59 (d, 1H, 4.1 Hz, H-5), 5.47
(dd, 1H, 9.9/4.5 Hz, H-3), 5.05 (d, 1H, 9.9 Hz, H-7), 3.78 and 3.73
(2 s, 6H, H-12, H-13), 3.17 (q*, 1H, 4.1 Hz, H-4), 2.33 (sept, 1H,
7.0 Hz, H-16), 2.06 (m, 1H, H-14), 1.96 (s, 3H, H-9), 1.06 (m, 9H)
and 0.73 (d, 3H, 6.7 Hz) (H-15, H-15¢, H-17, H-17¢); 13C-NMR
(150 MHz, APT, CDCl3): d 169.4 (C-8), 168.4 and 166.8 (C-10,
C-11), 143.9 (C-6), 141.5 (C-1), 132.3 (C-2), 118.5 (C-5), 52.5 and
52.4 (C-12, C-13), 45.1 (C-3), 44.0 (C-4), 30.2 and 29.6 (C-14,
C-16), 23.5, 22.7, 21.5, 21.1 (C-15, C15¢, C17, C-17¢), 17.3 (C-9).
Scheme 7 Oxidations of nitrocyclohexenes 36 and 37.
chloro, bromo, thioether, amine, urea, and carbamate substituents.
Upon wide variations of the starting materials, the synthesis
allows access to diverse cycloadducts in a combinatorial fashion.
The three-component carbocycles can be subjected to oxidative
aromatizations in the presence of MnO2 to give crowded anilides22
in good to excellent yields. The tri-, tetra-, and penta-substituted
arenes constitute building blocks with interesting stereoelectronic
and synthetic properties: high steric encumbrance at the arene
core, donor–acceptor substitution, strong fluorescence of the
aminophthalimide derivatives,23 a synthetically useful inherent
anthranilic acid motif, access to substituted b-amino acids7a The
overall two-step synthesis is highly modular and operates under
practical reaction conditions with cheap starting materials and
reagents (1st step: catalytic TSA, toluene as solvent; 2nd step:
MnO2 as oxidant, toluene as solvent).
Dimethyl 6-benzoylamino-3,5-diphenylcyclohexa-1,3-dien-1,2-
dicarboxylate (7). Work-up: SiO2, ea : ch 1 : 1; Rf 0.30; white
solid; yield: 52%. Mp 76 ◦C; IR (ATR): 1/l [cm-1] 3340 (w), 3033
(w), 2940 (w), 2366 (w), 2240 (w), 1717 (s), 1652 (s), 1513 (s), 1481
(s), 1430 (m), 1264 (s), 1156 (m), 1070 (m), 906 (m),883 (m), 696
(s); LR-MS (pos. ESI, MeOH, CH2Cl2): m/z 490 [M+Na]+, 347,
315, 303, 244, 105; HR-MS (ESI, [u]): found: 490.163 [M+Na]+,
Experimental section
General
1
Unless otherwise noted, all synthesized cycloadducts are racemic
mixtures of one diastereomer. For reasons of clarity, only one
calcd: 490.1631; H-NMR (300 MHz, CDCl3): d 7.57 (m, 2H,
Ph), 7.47–7.23 (m, 13H, Ph), 6.40 (dd, 1H, 9.5./5.7 Hz, H-3),
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Table 5 MnO2-mediated aromatization of aminocyclohexadienesa
Table 5 (Contd.)
Cycloadduct
Arene
Yield [%]
96b,e
Cycloadduct
Arene
Yield [%]
86b,e
1
38
39
10
45
46
47
2
4
5
84b,e
79d,g
84b,f
11
94b,e
40
41
12
44c,h
13
14
48
49
63b,e
7
42
65b,g
70b,e
8
9
43
44
65b,f
a Cycloadduct (1 equiv.) and MnO2 (85%, 3–10 equiv.) were heated in
toluene (2.0–20 mL mmol-1 cyclohexene) at 110 ◦C for 5–48 h. With bulky
aminocyclohexadienes, conversions were not quantitative. In some cases,
elimination of the amide was observed (~10%). b 3 equiv. MnO2. c 6 equiv.
MnO2. d 10 equiv. MnO2. e 5 h. f 15 h. g 24 h. h 48 h.
88b,e
6.34 (d, 1H, 4.5 Hz, H-5), 5.95 (d, 1H, 9.5 Hz, H-7), 4.67
(m, 1H, H-4), 3.80 and 3.61 (2 s, 6H, H-12, H-13); 13C-NMR
(75 MHz, APT, CDCl3): d 167.4 (C-8), 140.1 (C-9), 137.1, 137.0,
134.5, 133.7, 133.2 (C-1, C-2, C-6, C-14, C-15), 131.7, 129.3,
128.8, 128.7, 128.5, 128.3, 128.1, 127.6, 127.2, 127.0, 126.1 (CHarom
and C-5), 52.9 and 52.4 (C12, C-13), 45.6 (C-3), 44.1 (C-4); C-10,
C-11 and 4 CHarom obscured.
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Table 6 MnO2-mediated aromatization of aminocyclohexenesa
Table 6 (Contd.)
Cycloadduct
Arene
Yield [%]
65c,g
Cycloadduct
Arene
Yield [%]
19
50
51
52
53
54
27
58
59
60
decomp.c,f
20
58c,f
74b,f
66c,f
71c,e
28
29
30
72b,e
55b,f
21
22
61
<10% conv.c,g
32
34
62
63
78c,f
23a
75c,g
24
25
26
55
56
57
68c,g
a Cycloadduct (1 equiv.) and MnO2 (85%, 5–10 equiv.) were heated in
toluene (2.0–20 mL mmol-1 cyclohexene) at 110 ◦C for 12–48 h. With
bulky aminocyclohexenes, conversions were not quantitative. In some
cases, elimination of the amide was observed (~10%). b 5 equiv. MnO2.
c 10 equiv. MnO2. d 12 h. e 19 h. f 24 h. g 48 h. h Mostly decomposition.
<5c,d,h
General procedure for the synthesis of cycloadducts from
a,b-unsaturated aldehydes
A 50 mL test tube was charged with carboxamide (4 mmol),
aldehyde (4 mmol), the dienophile (4 mmol), p-toluenesulfonic
acid monohydrate (3 mol%), and toluene (6 mL). The tube
was sealed with a septum and the reaction stirred at 110 ◦C
oil bath temperature. After 24 h, the solvent and other volatile
compounds were removed by oil pump vacuum. The crude product
was purified by SiO2 flash column chromatography (ethyl acetate
(ea) : cyclohexane (ch)) or crystallized from solution (for details
see below).
no conv.c,g
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Dimethyl 6-(2-bromobenzoyl)amino-3-isopropyl-5-phenylcyclo-
hexa-1,3-dien-1,2-dicarboxylate (10). Work-up: SiO2, ea : ch 1 : 2,
Rf 0.22; yellow solid; yield: 89%. Mp 65 ◦C; IR (ATR): 1/l [cm-1]
3423 (w), 3340 (w), 2946 (w), 1721 (s), 1666 (s), 1503 (s), 1433 (m),
1263 (s), 1163 (m), 1066 (m), 900 (w), 729 (m); LR-MS (pos. ESI,
MeOH/CH2Cl2): m/z 534 [M+Na]+, 520, 456; HR-MS (ESI, [u]):
found: 534.089, calcd: 534.0892; 1H-NMR (300 MHz, CDCl3): d
7.55 (m, 2H, Ar), 7.46 (m, 1H, Ar), 7.37–7.24 (m, 4H, Ar), 7.23–
7.16 (m, 2H, Ar), 6.38 (dd, 1H, 9.9/4.7 Hz, H-3), 6.29 (d, 1H,
4.6 Hz, H-5), 5.80 (d, 1H, 9.9 Hz, H-7), 3.84 and 3.82 (2 s, 6H,
H-12, H-13), 3.45 (q*, 1H, 4.6 Hz, H-4), 2.21 (m, 1H, H-15), 1.20
and 0.85 (2d, 6H, 6.8 Hz, H-16, H-16¢); 13C-NMR (75 MHz, APT,
CDCl3): d 167.6 and 167.0 (C-10 and C-11), 166.4 (C-8), 139.8,
137.8, 137.4, 136.9 (all Cquart), 133.5 (CHarom), 133.1 (Cquart), 131.4,
129.7, 128.7, 128.3, 127.6, 126.6, 125.0 (all CHarom and C-5), 119.1
(Cquart), 52.8 and 52.6 (C-12, C-13), 45.4 (C-3), 44.3 (C-4), 30.3
(C-15), 21.2 and 17.7 (C-16, C-16¢).
1284 (m), 1130 (w), 1015 (w); LR-MS (EI, ethyl acetate): m/z 316
[M]+, 273 [M-CH3CO]+, 235 [M-Br]+, 186, 161, 124, 107; HR-
1
MS (ESI, [u]): found: 337.016 [M]+, calcd: 337.0164; H-NMR
(300 MHz, CD2Cl2): d 7.26 (d, 1H, 8.4 Hz, H-7), 4.82 (m, 1H,
H-3), 3.29 (dd, 1H, 8.9/5.6 Hz, H-2), 3.15 (dt, 1H, 7.2/1.6 Hz,
H-1), 2.91 (s, 3H, H-12), 2.72 (dd, 1H, 15.3/1.6 Hz, H-6), 2.43
(dd, 1H, 15.3/7.1 Hz, H-6¢), 2.09 (s, 3H, H-9), 1.85 (m, 3H, H-13);
13C-NMR (75 MHz, APT, CD2Cl2): d 178.5 and 178.2 (C-10, C-
11), 170.1 (C-8), 134.8 (C-5), 118.5 (C-4), 48.4 (C-3), 43.5 (C-2),
39.0 (C-1), 31.8 (C-6), 25.3 (C-12), 23.9 (C-13), 23.5 (C-9).
4-N-(Benzyloxycarbonylamino)-2-methyl-5-phenyl-7-iso-propyl-
1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole (31). Work-up:
precipitated from ea : ch 1 :◦1, washed with cold Et2O; colorless
solid; yield: 83%. Mp 171 C; IR (ATR): 1/l [cm-1] 3404 (w),
3029 (w), 2957 (w), 2868 (w), 1716 (s), 1687 (s), 1507 (s), 1435
(m), 1338 (m), 1330 (m), 1286 (m), 1230 (m), 1171 (w), 1117 (w),
1078 (m), 1057 (m), 1027 (m), 982 (w), 910 (m), 763 (s), 729 (s);
LR-MS (pos. ESI, MeOH, CH2Cl2): m/z 455 [M+Na]+, 389,
372, 282, 91; HR-MS (ESI, [u]): found: 455.195 [M+Na]+, calcd:
455.1947; 1H-NMR (300 MHz, CDCl3): d 7.35–7.24 (m, 8H, Ph),
6.99 (m, 2H, Ph), 6.35 (d, 1H, 9.9 Hz, H-7), 5.79 (m, 1H, H-5),
5.15 and 5.01 (2d, 2H, 12.2 Hz, H-9), 4.57 (m, 1H, H-3), 3.44 (dd,
1H, 8.5/6.0 Hz, H-2), 3.35 (dd, 1H, 8.5/5.7 Hz, H-1), 2.96 (s, 3H,
H-13), 2.24 (m, 1H, H-15), 2.04 (m, 1H, H-6), 1.24 and 1.06 (2d,
6H, 6.3 Hz, H-16, H-16¢); 13C-NMR (75 MHz, APT, CDCl3): d
178.8 and 177.0 (C-10, C-11), 156.1 (C-8), 143.0 (C-10), 137.6
(Cquart), 136.6 (C-4), 129.7–127.6 (10 CHarom, C-5), 66.9 (C-9), 50.1
(C-3), 45.0 (C-2), 44.8 (C-6), 41.4 (C-1), 28.4 (C-14), 24.9 (C-12),
22.3 and 21.3 (C-15, C-15¢).
Dimethyl 6-acetylamino-5-bromo-3-ethylcyclohexa-1,3-dien-1,2-
dicarboxylate (14). Work-up: SiO2, ea : ch 1 : 1; Rf 0.15; yellow
oil; yield: 38%. IR (ATR): 1/l [cm-1] 3272 (br, s), 2952 (w), 1721 (s),
1666 (s), 1518 (m), 1433 (m), 1370 (m), 1250 (s), 1062 (m), 948 (w),
920 (w), 730 (w); LR-MS (pos. ESI, MeOH): m/z 383 [M+Na]+,
381, 378, 333; HR-MS (ESI, [u]): found: 382.026 [M+Na]+, calcd:
1
382.0266; H-NMR (300 MHz, CDCl3): d 6.21 (d, 1H, 4.4 Hz,
H-5), 5.65 (dd, 1H, 9.7/5.1 Hz, H-3), 5.30 (d, 1H, 9.7 Hz, H-7),
3.79 and 3.75 (2 s, 6H, H-12, H-13), 3.31 (m, 1H, H-4), 2.03 (s, 3H,
H-9), 1.76 (m, 1H, H-14), 1.61 (m*, 1H, 7.0 Hz, H-14¢), 0.91 (t,
3H, 7.4 Hz, H-15); 13C-NMR (75 MHz, APT, CDCl3): d 169.3 (C-
8), 167.2 and 165.8 (C-10, C-11), 139.0 (C-1), 132.5 (C-5), 132.4
(C-2), 120.1 (C-6), 53.0 and 52.9 (C-12, C-13), 49.5 (C-3), 41.5
(C-4), 25.6 (C-14), 23.3 (C-9), 10.3 (C-15).
N -(2,4-Dimethyl-6-nitro-5-phenylcyclohex-2-enyl)-acetamide
(36). Work-up: suspended in diethyl ether, filtration; white solid;
Rf 0.21 (ea : ch 1 : 1); yield: 79%. Mp 203 ◦C; IR (ATR): 1/l
[cm-1] 3271 (w), 2970 (w), 1733 (m), 1653 (s), 1550 (s), 1454 (m),
1371 (s), 1241 (s), 1042 (m), 913 (w), 725 (m); LR-MS (pos. ESI,
MeOH/CH2Cl2): m/z 289 [M+H]+, 242 [M-NO2]+, 200, 183, 157;
HR-MS (ESI, [u]): found: 289.154 [M+H]+, calcd: 289.1552; 1H-
NMR (300 MHz, CDCl3): d 7.26-7.19 (m, 5H, Ph), 5.64 (d, 1H,
9.6 Hz, H-7), 5.52 (s, 1H, H-5), 5.26 (m, 1H, H-3), 5.22 (dd, 1H,
12.3/4.9 Hz, H-2), 2.81 (dd, 1H, 12.3/10.3 Hz, H-1), 2.36 (m, 1H,
H-6), 2.02 (s, 3H, H-9), 1.80 (s, 3H, H-10), 0.91 (d, 3H, 6.9 Hz,
H-11); 13C-NMR (75 MHz, APT, CDCl3): d 170.3 (C-8), 138.9
(C-12), 131.5 (C-5), 130.3 (C-4), 128.9, 128.0, 127.7 (5C, Ph), 89.0
(C-2), 49.3 (C-3), 46.7 (C-1), 38.1 (C-6), 23.2 (C-9), 20.6 (C-10),
19.5 (C-11).
N-[2,6-Dimethyl-7-(3-methylbut-2-enyl)-1,3-dioxo-2,3,3a,4,7,
7a-hexahydro-1H-isoindol-4-yl]-acetamide
(23a). Work-up:
SiO2, ea : ch 1 : 2; Rf 0.15; white solid; yield: 39% of two
inseparable diastereomers (syn : anti (2 : 1) at C-6). Mp ~ 137 ◦C;
IR (ATR): 1/l [cm-1] 3379 (br, w), 3286 (br, w), 2912 (w), 1767
(w), 1691 (s), 1517 (br, m), 1433 (m), 1379 (m), 1336 (w), 1285
(m), 1111 (m), 1030 (w), 992 (w); LR-MS: (EI, ethyl acetate):
m/z 304 [M]+, 260, 193, 177, 150, 107, 91, 69; HR-MS (EI,
1
[u]): found: 304.178 [M]+, calcd: 304.1787; H-NMR (300 MHz,
CDCl3): major (syn) diastereomer, d 7.18 (d, 1H, 8.2 Hz, H-7¢),
5.37 (m, 1H, H-4), 5.19 (m, 1H, H-15), 4.57 (m, 1H, H-3), 3.15
(m, 2H, H-1, H-2), 2.90 (s, 3H, H-12), 2.75 and 2.51 (2 m, 2H,
H-14), 2.35 (m, 1H, H-6), 2.07 (s, 3H, H-9), 1.73 and 1.71 (2 s,
6H, H-17, H-18), 1.58 (s, 3H, H-13); 13C-NMR (75 MHz, APT,
CDCl3): syn : anti mixture: d 179.2 and 177.4 (C-10, C-11), 170.1,
170.0 (C-8, C-8¢), 140.5, 140.4 (C-16, C-16¢), 134.4 (C-5), 133.2
(C-5¢), 125.4 (C-4), 124.5 (C-4¢), 122.4 (C-15), 121.3 (C-15¢), 46.1,
44.2, 43.3, 42.5, 42.2, 42.1, 41.7, 40.0 (C-1, C-1¢, C-2, C-2¢, C-3,
C-3¢, C-6, C-6¢), 30.3 (C-14¢), 26.3 (C-14), 26.0 (C-13, C-13¢),
25.2 (C-12¢), 24.8 (C-12), 23.6 (C-9), 23.1 (C-9¢), 19.2, 18.1 (C-17,
C-17¢, C-18, C-18¢).
General procedure for the aromatization of aminocyclohexadienes
and aminocyclohexenes
The cycloadduct (1 equiv.), MnO2 (85%, 3–10 equiv.) and toluene
(~5–10 mL mmol-1) were combined in a reaction tube. The tube
was sealed with a septum and the reaction stirred at 110 ◦C
in an oil bath. After 5–48 h, the solvent and other volatile
compounds were removed by oil pump vacuum. Silica gel flash
chromatography (ethyl acetate : cyclohexane) gave the aromatic
product in analytically pure form.
N-[5-Bromo-2,6-dimethyl-1,3-dioxo-2,3,3a,4,7,7a-hexa-hydro-
1H-isoindol-4-yl]-acetamide (25). Work-up: crude residue sus-
pended in diethyl ether, then filtered, white solid; Rf (ea : ch 2 : 1)
0.15; yield: 71%. Mp 142 ◦C; IR (ATR): 1/l [cm-1] 3392 (w), 2944
(w), 1772 (w), 1691 (s), 1512 (m), 1434 (m), 1382 (m), 1321 (m),
Dimethyl 3-benzylamino-4,6-diphenylphthalate (42). Work-up:
SiO2, ea : ch 1 : 1; Rf 0.55; yellow solid; yield: 65%. Mp 203 ◦C; IR
(ATR): 1/l [cm-1] 3302 (w), 3025 (w), 2947 (w), 2245 (w), 1726
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(s), 1652 (m), 1508 (m), 1480 (s), 1432 (m), 1343 (m), 1287 (s),
1232 (s), 1132 (w), 1068 (m), 905 (m), 728 (s); LR-MS (pos. ESI,
MeOH/CH2Cl2) m/z 488 [M+Na]+, 434, 402, 367; HR-MS (ESI,
N-[2,6-Dimethyl-7-(3-methylbut-2-enyl)-1,3-dioxo-2,3-dihydro-
1H-isoindol-4-yl]-acetamide (54). Work-up: SiO2, ea : ch 1 : 1; Rf
◦
0.58; white solid; yield: 71%. Mp 143 C; IR (ATR): 1/l [cm-1]
1
[u]): found: 488.147 [M+Na]+, calcd: 488.1474; H-NMR (300
3326 (w), 2920 (w), 1692 (s), 1610 (m), 1513 (m), 1436 (m), 1376
(m), 1236 (m), 1046 (w), 993 (w); LR-MS (EI, ethyl acetate): m/z
300 [M]+, 285 [M-CH3]+, 245, 228, 203, 186, 172, 258, 143, 128;
HR-MS (EI, [u]): found: 300.147 [M]+, calcd: 300.1474; 1H-NMR
(300 MHz, CDCl3): d 9.50 (s, 1H, H-7), 8.53 (s, 1H, H-4), 4.97 (t,
1H, 6.8 Hz, H-15), 3.78 (d, 2H, 6.8 Hz, H-14), 3.12 (s, 3H, H-12),
2.39 (s, 3H, H-13), 2.24 (s, 3H, H-9), 1.80 (s, 3H, H-17), 1.68 (s,
3H, H-18); 13C-NMR (75 MHz, APT, CDCl3): d 169.5 and 169.4
(C-10, C-11), 169.1 (C-8), 147.4 (C-6), 135.4 (C-5), 133.3 (C-16),
126.0 (C-4), 120.9 (C-15), 114.1 (C-3), 26.7 (C-14), 25.9 (C-18),
25.1 (C-9), 23.7 (C-12), 20.3 (C-13), 18.2 (C-17), C-1 and C-2
obscured.
MHz, CDCl3): d 8.51 (s, 1H, H-7), 7.67 (m, 2H, Ph), 7.50–7.28
(m, 14H, Ph), 3.83 and 3.61 (2 s, 6H, H-12, H-13); 13C-NMR (75
MHz, APT, CDCl3): d 168.7 and 167.1 (C-10, C-11), 140.8, 140.7,
139.8, 139.4, 138.9, 138.5, 134.1, 132.5 (8 Cquart), 129.0–127.2 (16
CHarom), 53.2 and 52.5 (C-12, C-13), C-8 obscured.
Dimethyl 3-(2-bromobenzamido)-4-phenyl-6-isopropyl-phthalate
(45). Work-up: SiO2, ea : ch 2 : 1, Rf 0.43; yellow solid; yield: 86%.
◦
Mp 160 C; IR (ATR): 1/l [cm-1] 3300 (br, w), 2953 (w), 1730
(s), 1670 (m), 1593 (w), 1493 (m), 1430 (m), 1320 (m), 1266 (m),
1206 (s), 1103 (m), 1020 (w), 903 (w), 726 (m); LR-MS (pos. ESI,
MeOH): m/z 532 [M+Na]+, 478, 430, 249, 234; HR-MS (ESI, [u]):
1
found: 532.073 [M+Na]+, calcd: 532.0736; H-NMR (300 MHz,
N-(5-Bromo-2,7-dimethyl-1,3-dioxo-2,3-dihydro-1H-isoindol-4-
yl)-acetamide (55). Work-up: SiO2, ea : ch 2 : 1, Rf 0.35; white
CDCl3): d 7.95 (s, 1H, H-7), 7.52–7.25 (m, 10H, Ph), 3.91 and 3.86
(2 s, 6H, H-12, H-13), 3.17 (sept, 1H, 6.8 Hz, H-15), 1.20 (d, 6H, 6.8
Hz, H-16, H-16¢); 13C-NMR (75 MHz, APT, CDCl3): d 168.5 and
167.2 (C-10, C-11), 165.8 (C-8), 145.6, 141.6, 140.0, 138.8, 137.4
(Cquart), 133.6 (CHarom), 132.2 (Cquart), 131.6, 130.9 (CHarom), 130.0
(Cquart), 129.2, 129.1, 128.8, 128.5, 128.4, 128.2 (all CHarom), 128.1
(Cquart), 127.0 (CHarom), 53.1 and 52.6 (C-12, C-13), 30.7 (C-15),
24.0 (C-16, C-16¢).
◦
solid; yield: 68%. Mp 234 C; IR (ATR): 1/l [cm-1] 3226 (w),
3181 (w), 2923 (w), 1766 (m), 1703 (s), 1677 (s), 1518 (m), 1433
(m), 1378 (m), 1259 (m), 1099 (w), 1014 (m), 903 (w); LR-MS
(EI, ethyl acetate): m/z 311 [M]+, 295 [M-CH3]+, 269 [M-Ac]+,
253 [M-AcNH]+, 231 [M-Br]+, 211, 189, 145; HR-MS (ESI, [u]):
1
found: 332.984 [M+Na]+, calcd: 332.9845; H-NMR (300 MHz,
CDCl3): d 7.72 (s, 1H, H-5), 7.56 (s, 1H, H-7), 3.12 (s, 3H, H-12),
2.64 (s, 3H, H-13), 2.28 (s, 3H, H-9); 13C-NMR (125 MHz, APT,
CDCl3): d 168.8 (C-8), 167.9 and 166.8 (C-10, C-11), 140.8 (C-5),
137.0 (C-1), 131.1 (C-2), 128.6 (C-6), 127.0 (C-4), 126.6 (C-3),
24.0 (C-12), 23.7 (C-9), 17.2 (C-13).
Dimethyl 3-acetylamino-4-bromo-6-ethylphthalate (49). Work-
up: SiO2, ea : ch 2 : 1; Rf 0.32; yellow oil; yield: 70%. IR (ATR):
1/l [cm-1] 3260 (w), 2953 (w), 1731 (s), 1680 (m), 1570 (w), 1434
(m), 1278 (m), 1203 (m), 1123 (m), 1030 (w), 960 (w), 923 (w),
880 (w); LR-MS (EI, ethyl acetate): m/z 358 [M]+, 342 [M-CH3]+,
326 [M-CH3CH2]+, 278, 246, 199, 159; HR-MS (ESI, [u]): found:
380.010 [M+Na]+, calcd: 380.0110; 1H-NMR (300 MHz, CDCl3):
d 7.62 (s, 1H, H-5), 7.52 (s, 1H, H-7), 3.87 and 3.83 (2 s, 6H, H-12,
H-13), 2.65 (q, 2H, 7.5 Hz, H-14), 2.18 (s, 3H, H-9), 1.23 (t, 3H,
7.5 Hz, H-15); 13C-NMR (75 MHz, APT, CDCl3): d 168.6 (C-8),
167.8 and 166.3 (C-10, C-11), 141.9 (C-6), 135.7 (C-5), 132.4 (C-1),
131.8 (C-3), 129.4 (C-2), 123.3 (C-4), 53.0 and 52.7 (C-12, C-13),
26.5 (C-14), 23.7 (C-9), 15.4 (C-15).
N-(3-Cyano-5-isopropylbiphenyl-2-yl)acetamide (63). Work-
up: SiO2, ea : ch 1 : 1; Rf 0.41; yellow oil; yield: 75%. IR (ATR): 1/l
[cm-1] 3235 (w), 2960 (w), 1664 (s), 1593 (w), 1499 (m), 1367 (w),
1286 (w), 1007 (w); LR-MS (EI, ethyl acetate): m/z 278 [M]+, 236
[M-Ac]+, 221 [M-AcNH]+, 206, 192, 165; HR-MS (EI, [u]): found:
1
278.142 [M]+, calcd: 278.1419; H-NMR (300 MHz, CDCl3): d
7.54–7.30 (m, 7H, Ph), 6.98 (s, 1H, H-7), 2.97 (sept, 1H, 6.9 Hz,
H-10), 2.06 (s, 3H, H-9), 1.28 (d, 6H, 6.9 Hz, H-11, H-11¢); 13C-
NMR (75 MHz, APT, CDCl3): d 169.2 (C-8), 148.7 (C-6), 140.1,
Table 7 Crystal structure data for compounds 24, 36 and 46
Compound reference
24
36
46
Chemical formula
Formula Mass
Crystal system
C12H15BrN2O3
315.17
Monoclinic
10.8021(12)
10.5357(7)
13.5435(12)
90.00
124.200(6)
90.00
1274.8(2)
100(2)
C16H20N2O3
288.34
Monoclinic
11.9261(5)
17.9405(14)
15.2365(11)
90.00
96.061(4)
90.00
3241.8(4)
100(2)
C26H25NO5
431.47
Monoclinic
14.6003(6)
17.4066(8)
9.8449(3)
90.00
115.519(2)
90.00
2257.91(16)
100(2)
˚
a/A
˚
b/A
˚
c/A
a (◦)
b (◦)
g (◦)
3
˚
Unit cell volume/A
T/K
Space group
P21/c
P21/n
Cc
No. of formula units per unit cell, Z
No. of reflections measured
No. of independent reflections
Rint
Final R1 values (I > 2s(I))
Final wR(F2) values (I > 2s(I))
Final R1 values (all data)
Final wR(F2) values (all data)
4
8
4
6562
2769
0.0445
0.0372
0.0777
0.0608
0.0840
15 743
7009
0.0484
0.0504
0.0984
0.1160
0.1154
4577
2478
0.0237
0.0334
0.0713
0.0450
0.0749
7234 | Org. Biomol. Chem., 2011, 9, 7224–7236
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137.7, 134.2 (3 Cquart), 133.4–128.4 (7 CHarom), 117.2 (C-12), 113.0
(C-1), 33.7 (C-10), 23.8 (C-11, C-11¢), 23.3 (C-9).
Chem., 2004, 2, 845–851; (b) A retro-Diels–Alder reaction of the
cycloadduct could not be accomplished. The aminodiene intermediate,
however, undergoes partial retro-condensation when water is present.
7 Somatostatin analogues: (a) M. Sukopp, R. Schwab, L. Marinelli, E.
Biron, M. Heller, E. Varkondi, A. Pap, E. Novellino, G. Keri and H.
Kessler, J. Med. Chem., 2005, 48, 2916–2926; Bicyclo[2.2.2]-octenes:
(b) D. Stru¨bing, A. Jacobi von Wangelin, H. Neumann, D. Go¨rdes, S.
Hu¨bner, S. Klaus, A. Spannenberg and M. Beller, Eur. J. Org. Chem.,
2005, 107–113; Luminols: (c) H. Neumann, S. Klaus, M. Klawonn,
D. Stru¨bing, S. Hu¨bner, D. Go¨rdes, A. Jacobi von Wangelin, M. Lalk
and M. Beller, Z. Naturforsch., 2004, 59b, 431–438; Aza-Corollosporin
analogues: (d) H. Neumann, D. Stru¨bing, M. Lalk, S. Klaus, S. Hu¨bner,
A. Spannenberg, U. Lindequist and M. Beller, Org. Biomol. Chem.,
2006, 4, 1365–1375; Phenanthridones: (e) A. Jacobi von Wangelin, H.
Neumann, D. Go¨rdes, S. Hu¨bner, C. Wendler, S. Klaus, D. Stru¨bing,
A. Spannenberg, H. Jiao, L. El Firdoussi, K. Thurow, N. Stoll and M.
Beller, Synthesis, 2005, 2029–2038.
N-(4,6-Dimethyl-2-nitrobiphenyl-3-yl)acetamide (64). Work-
up: SiO2, ea : ch 1 : 1; Rf 0.56; yellow oil; yield: 75%. IR (ATR):
1/l [cm-1] 2920 (m), 2860 (w), 1720 (w), 1607 (m), 1486 (m), 1441
(m), 1383 (m), 1250 (m), 1223 (s), 1061 (s), 926 (m), 759 (s), 700 (s);
LR-MS (ESI, MeOH): m/z 238 [M-NO2]+, 223 [M-NO2-CH3]+,
213, 186, 137, 129, 105; 1H-NMR (500 MHz, MeOD-d4): d 7.46–
7.35 (m, 5H, Ph), 7.08 (s, 1H, H-5), 2.54 (s, 3H, H-9), 2.52 and 2.27
(2 s, 6H, H-10, H-11), H-7 obscured; 13C-NMR (125 MHz, APT,
MeOD-d4): d 165.1 (C-8), 150.5 (C-2), 138.9, 136.4 and 133.5 (3
Cquart), 131.0 and 129.4 (CHarom), 128.7 (Cquart), 128.6 and 128.5
(CHarom), 123.7 (Cquart), 19.8 (C-9), 16.3 and 14.1 (C-10, C-11).
8 The yield of the cycloadducts showed a strong dependence on the pKa
of the employed acid catalyst: p-TSA·H2O (pKa -2.8) had equal activity
as water-free TSA; camphorsulfonic acid (pKa 1.2), ortho-phosphoric
acid (2.1), and other Lewis acids gave much lower conversion under
otherwise identical conditions. For more details, see also: R. Fichtler,
Dissertation, University of Cologne, 2011.
9 Examples of amide–aldehyde condensations and subsequent reactions
of N-acylimines and N-acyliminium ions: (a) W. A. Noyes and D. B.
Forman, J. Am. Chem. Soc., 1933, 55, 3493–3494; (b) A. M. Kraft
and R. M. Herbst, J. Org. Chem., 1945, 10, 483–497; (c) A. Couture,
R. Dubiez and A. Lablache-Combier, J. Org. Chem., 1984, 49, 714–
717; (d) H. E. Zaugg, Synthesis, 1984, 181–212; (e) A. R. Katritzky,
A. V. Ignatchenko and H. Lang, Synth. Commun., 1995, 25, 1197–
1204; (f) C. M. Marson and A. Fallah, Chem. Commun., 1998, 83–84;
(g) A. Guirado, R. Andreu, A. Cerezo and J. Ga´lvez, Tetrahedron,
2001, 57, 4925–4931; (h) C. M. Marson, Arkivoc, 2001, (i), 1–16; (i) J.
Elaridi, A. Thaqi, A. Prosser, W. R. Jackson and A. J. Robinson,
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L. Hu, Tetrahedron Lett., 2010, 51, 4746–4749.
10 A. Jacobi von Wangelin, H. Neumann, D. Go¨rdes, S. Klaus, H. Jiao,
A. Spannenberg, T. Kru¨ger, C. Wendler, K. Thurow, N. Stoll and M.
Beller, Chem.–Eur. J., 2003, 9, 2273–2281.
11 1,4-Cyclohexadiene isomers have been isolated from similar reactions
with 2-pentenal and 2-hexenal: D. Stru¨bing, H. Neumann, A. Jacobi
von Wangelin, S. Klaus, S. Hu¨bner and M. Beller, Tetrahedron, 2006,
62, 10962–10967.
12 Aldehydes for the synthesis of 17 and 18 were prepared via a Peterson
olefination according to: E. J. Corey, D. Enders and M. G. Bock,
Tetrahedron Lett., 1976, 17, 7–10.
13 (a) For computational studies on the reaction mechanism, see the
Supporting Information of ref. 5a; Diastereoselective reactions with
(S)-methyl pyroglutamate: (b) S. Hu¨bner, D. Michalik, H. Jiao, H.
Neumann, S. Klaus, D. Stru¨bing, A. Spannenberg and M. Beller,
Chem.–Asian J., 2007, 2, 734–746.
14 For identity and analytical data of regioisomer 23b containing a
methylpentenyl side chain in 5-position, see ESI†.
15 2-Bromocrotonaldehydes were prepared from the aldehyde and aque-
ous bromine in the presence of triethylamine: (a) C. J. Kowalski, A.
E. Weber and K. W. Fields, J. Org. Chem., 1982, 47, 5088–5093;
(b) H. Lu¨tjens and P. Knochel, Tetrahedron: Asymmetry, 1994, 5, 1161–
1162.
16 (a) B. Potthoff and E. Breitmeier, Chem. Ber., 1987, 120, 255–257; (b) G.
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1995, 36, 6551–6554; (d) K. Bogdanowicz-Szwed and A. Budzowski,
Monatsh. Chem., 2001, 132, 947–957; (e) A. K. Weber and A. Jacobi
von Wangelin, manuscript in preparation.
17 Acetoxydienes in related reactions: (a) D. Stru¨bing, A. Kirschner, H.
Neumann, S. Hu¨bner, S. Klaus, U. T. Bornscheuer and M. Beller,
Chem.–Eur. J., 2005, 11, 4210–4218; Other oxadienes in Diels–Alder
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18 (a) Z. Rappoport, (Ed.), The Chemistry of Anilines, Part 1, Wiley, 2007;
Selected examples of aniline syntheses: (b) A. Padwa, M. Dimitroff,
A. G. Waterson and T. Wu, J. Org. Chem., 1997, 62, 4088–4096; N.
Acknowledgements
This work was financed by the 7th European framework program
(Cataflu. Or). We thank Prof. H.-G. Schmalz for excellent technical
support.
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