Mimicking the reaction of phenylalanine ammonia lyase by a synthetic model

Article abstract of DOI:10.1002/1522-2675(20000906)83:9<2246::AID-HLCA2246>3.0.CO;2-X

Phenylalanine and histidine ammonia lyases (PAL and HAL) catalyze the reversible conversion of α-amino acids to the corresponding acrylic acids by elimination of ammonia. The prosthetic group 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO) at the active site of both enzymes supposedly undergoes an electrophilic attack at the aromatic nucleus in the first step of the mechanism of action. Since no chemical analogy existed for such an electrophile-assisted elimination, we synthesized model compounds, some portion of which mimicked the essentials of the substrate phenylalanine and another portion the electrophilic Michael acceptor in a sterically appropriate distance. The first model, (±)-rel-(1R,2S,3S)-3-[1-methylidene-2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-phenyl cyclohexanamine (7) did not react under Friedel-Crafts conditions in the expected way (Scheme 2). The second model compound (±)-2-rel-(1R,2S,3S)-3-(dimethylamino)-2-(3-methoxyphenyl)cyclohexyl]prop-2- enal (12) with a more nucleophilic methoxyphenyl and a more electrophilic α,β-unsaturated carbonyl moiety, underwent an intramolecular Friedel-Crafts-type substitution, but no elimination of the dimethylamino group (Scheme 4). The third model compound, (±)-γ-[(dimethylamino)methyl]-3-methoxy-2,4,6-trimethyl-α-methylidenebenze nebutanal (25) eliminated dimethylamine upon treatment with Lewis acids and subsequent hydrolysis of the intermediate (Scheme 6). When the 3-methoxy-2,4,6-trimethylphenyl moiety of 25 was replaced by the 2,4,6-trimethyl-3-nitrophenyl group, no elimination product could be observed (Scheme 7).

Full text of DOI:10.1002/1522-2675(20000906)83:9<2246::AID-HLCA2246>3.0.CO;2-X

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Mimicking the Reaction of Phenylalanine Ammonia Lyase by a
Synthetic Model
by Martin Rettig1), Andreas Sigrist, and JaÂnos ReÂtey*
Institut für Organische Chemie, Lehrstuhl Biochemie der Universität, Richard-Willstätter-Allee,
D-76128 Karlsruhe
Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday
Phenylalanine and histidine ammonia lyases (PAL and HAL) catalyze the reversible conversion of a-
amino acids to the corresponding acrylic acids by elimination of ammonia. The prosthetic group 3,5-dihydro-5-
methylidene-4H-imidazol-4-one (MIO) at the active site of both enzymes supposedly undergoes an electrophilic
attack at the aromatic nucleus in the first step of the mechanism of action. Since no chemical analogy existed for
such an electrophile-assisted elimination, we synthesized model compounds, some portion of which mimicked
the essentials of the substrate phenylalanine and another portion the electrophilic Michael acceptor in a sterically
appropriate distance. The first model, (Æ)-rel-(1R,2S,3S)-3-[1-methylidene-2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-
phenylcyclohexanamine (7) did not react under Friedel-Crafts conditions in the expected way (Scheme 2). The
second model compound (Æ)-2-rel-(1R,2S,3S)-3-(dimethylamino)-2-(3-methoxyphenyl)cyclohexyl]prop-2-enal
(12) with a more nucleophilic methoxyphenyl and a more electrophilic a,b-unsaturated carbonyl moiety,
underwent an intramolecular Friedel-Crafts-type substitution, but no elimination of the dimethylamino group
(Scheme 4). The third model compound, (Æ)-g-[(dimethylamino)methyl]-3-methoxy-2,4,6-trimethyl-a-meth-
ylidenebenzenebutanal (25) eliminated dimethylamine upon treatment with Lewis acids and subsequent
hydrolysis of the intermediate (Scheme 6). When the 3-methoxy-2,4,6-trimethylphenyl moiety of 25 was
replaced by the 2,4,6-trimethyl-3-nitrophenyl group, no elimination product could be observed (Scheme 7).
Introduction. ± The most common degradation pathway of amino acids begins with
transamination to form the corresponding a-keto acids. A notable exception is the non-
oxidative ammonia elimination by two ammonia lyases acting on histidine and
phenylalanine as substrates. The products of these reactions are the corresponding
substituted acrylates trans-urocanate and trans-cinnamate, respectively. Urocanate is
further degraded to glutamate in most organisms, including humans (for a review, see
[2]), while cinnamate is the precursor of important ingredients of plants, like lignin,
flavonoids, and coumarins (for a review, see [3]). Beside their considerable sequence
homology, both ammonia lyases have a common electrophilic prosthetic group that is
necessary for catalysis. Based on biochemical evidence, the prosthetic group was long
believed to be dehydroalanine [4 ± 6]. After some contradictory results [7], it has been
shown that the prosthetic group is formed autocatalytically from a specific serine
residue of the precursor proteins [8][9]. More recently, the X-ray structure of histidine
ammonia lyase was solved at 2.1-Š resolution, revealing the nature of the prosthetic
group [10]. Surprisingly, it is not simply dehydroalanine, but 3,5-dihydro-5-methyl-
idene-4H-imidazol-4-one (MIO), which is formed by cyclization of the internal
tripeptide Ala142-Ser143-Gly144. MIO can be regarded as a modified dehydroalanine the
1
)
Part of the Dissertation.

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electrophilicity of which is enhanced by preventing delocalization of the N-lone pairs
into the a,b-unsaturated system [10]. A precedence for a similar cyclization yielding a
substituted methylideneimidazolone is the transformation of the fluorophore of the
green fluorescent protein [11][12].
Proposals for the role of the catalytic electrophile, now known as MIO, included the
Michael addition of the substrate a-amino group [4][6] and, more recently, a Friedel-
Crafts-like electrophilic attack at the aromatic ring [13][14]. In the intermediate s-
complex, the acidity of the substrate HÀC(b) atoms would be enhanced, facilitating
their abstraction by an enzymic base (see Scheme 1). Ammonia elimination from the
Scheme 1. Proposed Mechanism of Action of Phenylalanine Ammonia Lyase: Involvement of MIO as
Electrophilic Catalyst

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delocalized zwitterion would be driven by restoration of the aromaticity to form the
product and to reform the original electrophile (Scheme 1).
Here we report on the feasibility of the latter mechanism in a synthetic model that
mimicks the essentials of the enzyme-substrate complex.
Results. ± Synthesis of Model 7 (Scheme 2): Model 7 comprised a cyclohexanamine
substituted with a Ph group in position 2 and an a,b-unsaturated amide moiety in
position 3. The starting material for its synthesis was (Æ)-2-phenylcyclohexanone (1)
which was prepared from commercial (Æ)-2-chlorocyclohexanone and phenylmagne-
sium bromide by a modified method of Newman and Farbman [15][16] (Scheme 2).
Bromination of 1 by N-bromosuccinimide (NBS) followed by heating with 2,6-lutidine
(2,6-dimethylpyridine) gave 2-phenylcyclohex-2-en-1-one (2) [17]. Treatment of 2 with
isopropenylmagnesium bromide in the presence of CuCl resulted in the 1,4-addition of
the isopropenyl group [18]. A cis/trans mixture 3/4 was obtained and could be
chromatographically separated and characterized by 1H-NMR spectroscopy. However,
for further work, the crude cis/trans mixture was treated with KtBuO to transform the
cis-isomer 3 into the thermodynamically more stable trans-isomer 4. By simple
1
recrystallization of the equilibrated mixture (cis/trans 1:5, by H-NMR), pure 4 was
Scheme 2. Synthesis of Model Compound 7

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obtained in 74% yield (starting from 2). Oxidation of 4 with SeO2 in dioxane gave,
after chromatography, (Æ)-trans-2-(3-oxo-2-phenylcyclohexyl)prop-2-enal (5) in 49%
yield [19 ± 21]. It is interesting to note that the cis-isomer 3, under identical reaction
conditions, afforded a different product, namely, 3-hydroxy-3-isopropenyl-2-phenyl-
cyclohexanone (for possible reasons of the different regioselectivity, see Discussion).
To make the model as similar as possible to the putative active site, 5 was converted
to the amide 6 in two steps. First the aldehyde function was oxidized to the
corresponding acid by NaClO2 as oxidant [22][23]. An excess of 2-methylbut-2-ene
was added to protect the substrate CˆC bond from oxidation. This acid was then
transformed with pyrrolidine into amide 6 by applying Ph2POCl/Et3N as activating
agent [24][25]. In a final step, the amino group had to be introduced. This was achieved
with ammonium cyanoborohydride by the method of Danheiser et al. [26] which is an
improved variant described in a former work [27]. In this reaction, model compound 7
was generated in 81% yield. The main product was all-trans 7, but 1H-NMR
spectroscopy revealed the presence of ca. 15% of a product in which the NH2 and Ph
groups were cis. This epimer-containing product was used to see whether model
compound 7 could mimic the enzymic ammonia elimination.
In an attempt to initiate the postulated Friedel-Crafts attack, 7 was treated with a
number of Lewis acids under various conditions: AlCl3 in CH2Cl2 at various
temperatures, AlCl3 in MeNO2 under reflux, BF3 ´ Et2O at various temperatures, FeCl3
in CH2Cl2 at various temperatures, (CF3SO2)2O in C2H4Cl2 under reflux, POCl3 at room
temperature, conc. H2SO4, or TiCl4 in CH2Cl2. Under most of these conditions, model
compound 7 was inert. In some cases, partial hydrolysis of the amide group could be
observed, but not the expected Friedel-Crafts-type cyclization or elimination of the
amino group.
Synthesis of Model 12 (Scheme 3). The inert behavior of model 7 suggested that
both the nucleophilicity of the Ph group and the electrophilicity of the a,b-unsaturated
carbonyl system should be enhanced to facilitate a Friedel-Crafts-type attack. These
requirements could be fulfilled by model compound 12.
The synthesis was analogous to that of model 7, except that (3-methoxyphenyl)-
magnesium bromide was used to substitute the Cl-atom in (Æ)-2-chlorocyclohexanone.
The reaction sequence proceeded smoothly in the expected manner up to the inter-
mediate (Æ)-trans-3-isopropenyl-2-(3-methoxyphenyl)cyclohexanone (8) (Scheme 3).
For the introduction of the dimethylamino group, the strategy had to be changed. First
8 was converted to oxime 9 which was then reduced with LiAlH4 to amine 10 [28].
Subsequently, the amino group of 10 was dimethylated by formaldehyde and
NaCNBH3 as reagents [29][30]. The intermediate 11 thus obtained was finally
oxidized with SeO2 as described in the synthesis of model 7. In model 12, now all
prerequisites were met for an intramolecular Friedel-Crafts-type attack of the more
electrophilic a,b-unsaturated aldehyde portion.
Also compound 12 was inert to mild Lewis acids like FeCl3, SnCl4, as well as HCl
and H2SO4, it reacted with BF3 ´ Et2O to afford the tricyclic product 13 in 81% yield
after chromatography (Scheme 4). Compound 13 was fully characterized by its FT-IR,
1H-and 13C-NMR, and mass spectra (see Fig. 1 and Exper. Part). The analogous
reaction of 12 with AlCl3 as Lewis acid gave the tricyclic product in only 46% yield.
Moreover, 1H-NMR spectroscopy showed that ca. 12% of the product was the epimeric

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Scheme 3. Synthesis of Model Compound 12
Scheme 4. Intramolecular Friedel-Crafts Substitution in Model Compound 12

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Fig. 1. 1H-NMR Spectrum of phenanthrenecarbaldehyde 13 obtained by Friedel-Crafts substitution of the model
compound 12
compound 14. Neither in the reaction with BF3 ´ Et2O nor in that with AlCl3 could
products arising from the elimination of the dimethylamino group be detected.
Synthesis of Model 25 (Scheme 5). Learning from the behavior of model 12 in the
presence of BF3 ´ Et2O as Lewis acid, we decided to synthesize model 25 in which the
intramolecular Friedel-Crafts-type substitution but not the electrophilic attack at the
aryl moiety would be prevented by appropriately placed Me groups. Retrosynthetic
analysis suggested a strategy different from that applied in the synthesis of models 7
and 12. Thus, 2,4,6-trimethylanisole 15 was obtained by methylation of commercial
2,4,6-trimethylphenol with Me2SO4 [31]. Monobromination of 15 ( ! 16) was followed
by preparation of the corresponding Grignard compound, which readily reacted with
CO2 to afford the carboxylic acid 17 (Scheme 5). The corresponding alcohol 18 was
obtained by reduction with LiAlH4 [32] and then converted via mesylate 19 to nitrile 20
[33]. The a-acidifying effect of the nitrile group was exploited to substitute one of the
methylene protons by the acetal-protected 3-bromopropanal, thus generating inter-
mediate 21 [34]. Reduction by LiAlH4 resulted in amine 22, which was dimethylated by
CH2O/NaCNBH3 [35][36]. Removal of the protecting acetal group in 23 by acid
resulted in aldehyde 24. Finally, introduction of the methylene group to form the a,b-
unsaturated aldehyde 25 was achieved in almost quantitative yield by applying the
‡
Eschenmoser salt (Me2N ˆCH2ClÀ) generated in situ from dimethylamine hydro-
chloride and formaldehyde [37][38]. The 1H-and 13C-NMR, FT-IR, and mass spectra

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Scheme 5. Synthesis of Model Compound 25
were consistent with the structure of the model compound 25 (see also Fig. 2 and Exper.
Part). It is noteworthy that certain NMR signals appeared doubly, representing two
conformers. This phenomenon was also observed in the NMR spectra of compounds
21 ± 24 due to hindered rotation around the bond connecting the aromatic ring to the
stereogenic C-atom.

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Fig. 2. 1H-NMR Spectrum of the model compound 25
Behavior of Model 25 in the Presence of Lewis Acids. In contrast to models 7 and 12,
model 25 gave, upon reaction with the strong Lewis acids BF3 ´ Et2O and AlCl3, a
neutral product 26, i.e., elimination of dimethylamine occurred presumably via 27 and
28 (Scheme 6). The best result with respect to the model reaction was obtained by
treatment of 25 with AlCl3 in CH2Cl2 for 12 h at À788. After aqueous workup and
column chromatography, 5% of a neutral compound 26 could be isolated, besides 50%
of recovered starting material. Increasing the reaction temperature and time did not
raise the yield of the neutral product. Examination of 26 by 1H-and 13C-NMR, UV, FT-
IR, and mass spectrometry corroborated its structure as 4-(3-methoxy-2,4,6-trimethyl-
phenyl)-2-methylpenta-2,4-dienal. Noteworthy is the unusually highfield shift
(1.16 ppm) of the 2-methyl group (see also Fig. 3) suggesting a conformation in which
the aromatic ring is perpendicular to the a,b,g,d-unsaturated system with the 2-methyl
group close to the plane of the aromatic ring. The UV-absorption maximum (lmax
267 nm) is also in agreement with the value (lmax 265 nm) calculated according to the
extended Woodward rules [39].
Synthesis of Less-Active Variants of Model 25. To explore the role of the 3-methoxy-
2,4,6-trimethylphenyl moiety of model 25 in the elimination of dimethylamine, variants
30 and 34 of model 25 were also synthesized (Scheme 7). The starting material was, in
both cases, commercially available 2,4,6-trimethylbenzeneacetonitrile 29. Variant 30
was obtained directly from 29 by the same reaction sequence as described for model 25.
Alternatively, 29 was first converted to 2,4,6-trimethyl-3-nitrobenzeneacetonitrile (31)

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Scheme 6. Reaction of Model Compound 25 with AlCl3; Proposed Mechanism of the Electrophile-Assisted
Elimination of Dimethylamine
[40], which was substituted to give 32. The subsequent reduction of the nitrile group to
the amine function by LiAlH4 had to be modified: BH3 ´ THF specifically reduced the
nitrile group of 32 but not the NO2 group [41]. Thus, 33 was obtained and transformed
to 34 as usual.
Treatment of both variants 30 and 34 of model 25 with AlCl3 or BF3 ´ Et2O gave
product mixtures. All attempts to show elimination of dimethylamine failed.
Discussion. ± The elimination of ammonia from histidine and phenylalanine by the
corresponding lyases is remarkable, and its understanding represents a challenge. In
particular, the abstraction of the non-acidic benzylic proton (pKa ꢀ 43 for toluene [42])
by an enzymic base without touching the more acidic a-ammonium group (pKa ꢀ 9)
poses a chemical problem. To circumvent this obstacle, it was suggested that the
catalytically important electrophilic group of these ammonia lyases attacks the
aromatic ring to form a Friedel-Crafts-type s-complex, in which the benzylic proton is
activated for abstraction. Although this mechanism has been supported by biochemical
results [14][43], there existed no chemical analogy for it. When we decided to mimic
the lyase reaction in a model system, the electrophilic group was believed to be
dehydroalanine [6]. Therefore, our first model had to fulfill the following require-

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Fig. 3. 1H-NMR Spectrum of the dienal 26 obtained from the model compound 25 by elimination of
dimethylamine in the presence of AlCl3
ments: It should incorporate an amide of dehydroalanine placed suitably for a
favorable intramolecular electrophilic attack at a phenyl ring that is also connected to a
cyclohexane moiety carrying an amino group in the correct position (trans to the phenyl
ring; see model 7).
The preparation of 2-phenylcyclohex-2-en-1-one, an early intermediate in our
synthetic route to model 7 (Scheme 2), has been described [17]. We followed this
method, except for the use of commercial (Æ)-2-chlorocyclohexanone instead of (Æ)-2-
bromocyclohexanone, in the preparation of (Æ)-2-phenylcyclohexanone (1). The high
yield (58%) in this step claimed by the original authors [15] could not be confirmed
either by us or by other workers [44] even by exactly following the original procedure
[15]. The stereoselectivity of the 1,4-addition of the isopropenylmagnesium bromide to
form the key intermediate 4 from 2 deserves comment. The kinetically controlled cis-
product 3 was formed first in excess. Equilibration with KtBuO transformed it into the
thermodynamically more stable trans-form 4. The two diastereoisomers exhibited
different regioselectivity in the oxidation by SeO2. While the trans-isomer 4 gave the
desired a,b-unsaturated aldehyde 5, an OH group was introduced at the alternative
allylic position in the same reaction of its cis-counterpart 3. An explanation for the
observed regioselectivity may be that, in the trans-form 4, both the phenyl and the
isopropenyl group may occupy the equatorial position, whereas in the cis-form 3, the
latter is forced into the axial position. In the case of 4, involvement of the axial ring

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Scheme 7. Synthesis of the Variants of Model Compound 25 with a Less-Nucleophilic Aryl Moiety
H-atom in the ene reaction with SeO2 is stereoelectronically disfavored, in the case of
3, it is, however, favored.
The inertness of model 7 in presence of various Lewis acids and under various
conditions prompted the synthesis of model 12 (Scheme 3). Introduction of the MeO
function enhanced the nucleophilicity of the aryl group. On the other hand, the
electrophilicity of the a,b-unsaturated carbonyl moiety could be easily enhanced by
omitting the transformation of the aldehyde to the amide, as it was done in the last two

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steps of the synthesis of model 7. A further modification was made by dimethylation of
the amino group, thus enhancing its basicity.
Model 12 underwent an intramolecular Friedel-Crafts substitution on treatment
with BF3 ´ Et2O at À788 to afford in good yield the tricyclic product 13 (Scheme 4). The
analogous reaction with AlCl3 was less efficient and stereoselective. In no case,
elimination of dimethylamine could be detected. Obviously, in the s-complex
intermediate of the electrophilic substitution, abstraction of the ring proton was
favored leading directly to rearomatization. To give a chance to the formation of an
exocyclic double bond followed by elimination of the amino group, this direct
rearomatization had to be prevented. Therefore, model 25 was synthesized (Scheme 5)
in which the relevant aromatic ring protons were replaced by Me groups. Furthermore,
the cyclohexane ring of models 7 and 12, was replaced by an analogous open-chain
system. The last measure makes the system more flexible and facilitates the abstraction
of the activated benzylic proton by the possible presence of a conformation with
favorable stereoelectronics. It should be noted that model 25 was a racemate, as were
also models 7 and 12.
The generation of 26 on treatment of model 25 with AlCl3 or BF3 ´ Et2O, albeit in a
yield of only 5%, by the elimination mechanism shown in Scheme 6 can be regarded as
a chemical model for the reaction catalyzed by the enzyme PAL (see Scheme 1). We
now know that the catalytic group of PAL is MIO whose electrophilicity equals that of
an a,b-unsaturated aldehyde. The enzyme can also prevent the direct re-aromatization
of the Friedel-Crafts s-complex by excluding a base in the hydrophobic pocket while it
harbors the phenyl group of the phenylalanine substrate. In our model 26, this
protecting function is taken over by the ring Me groups. Survey of the literature
revealed that the postulated final step in the PAL reaction, namely the elimination of
an N-function coupled with the aromatization of a dehydrobenzene moiety carrying an
exocyclic double bond, had already a chemical model [45] (see Scheme 8). Indeed, 35 in
dimethylformamide was transformed under CsF catalysis to the aromatic products 36
(84%) and 37 (16%), while in the presence of stronger bases, like diazabicyclo[5.4.0]un-
dec-7-ene (DBU), only 36 was observed.
Scheme 8. CsF-Catalyzed Aromatization of a Dihydrophenyl Moiety with an Exocyclic Double Bond May
Eliminate a b-Amino Function [45]
Against the reaction sequence postulated for model 25 (see Scheme 6), one can
argue that elimination would occur also without the help of the 3-methoxy-2,4,6-
trimethylphenyl moiety. Although this is unlikely in view of the behavior of models 7
and 12, we synthesized the two variants 30 and 34 of model 25, in which the MeO group
was replaced by an H-atom or a NO2 group, respectively (Scheme 7). The failure of

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these variants with less-nucleophilic aryl moieties to produce elimination products
supports the involvement of the 3-methoxy-2,4,6-trimethyl group in the elimination
mechanism as outlined in Scheme 6.
Conclusion. ± It is shown that model systems containing a nucleophilic methoxyaryl
moiety and an electrophilic a,b-unsaturated aldehyde function undergo intramolecular
Friedel-Crafts-type reactions upon Lewis acid catalysis. When the direct aromatization
of the intermediate s-complex is prevented by Me substituents at the aryl moiety like in
model 25, then a benzylic proton can be abstracted leading to an exocyclic CˆC bond.
Re-aromatization finally occurs with simultaneous elimination of a b-amino group. The
above reaction sequence represents a model for the recently postulated mechanism of
the enzymic ammonia elimination from phenylalanine.
Experimental Part
1. General. Æ -2-Chlorocyclohexanone, isopropenyl bromide, tBuOH, MnO2 (activated), N,N-dimetylpyr-
idin-4-amine, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), CaOCl, CuCl, BF3 ´ Et2O, m-bromoanisole, 2,4,6-
trimethylphenol, and 2-bromo-1,3-dioxolane were products of Fluka, 2,4,6-trimethylbenzeneacetonitrile
(ˆ mesitylacetonitrile) was from Lancaster, BH3 ´ THF from Acros, and 2-methylbut-2-ene, NaOCl2, 2,6-
dimethylpyridine, Ph2POCl, NaCNBH3, NaOEt, SeO2, mesyl chloride (MeSO2Cl), and KtBuO from Aldrich.
Column chromatography (CC): silica gel 60 from Merck (Darmstadt) and aluminium oxide (Alox type 507c,
neutral) from Fluka. TLC: plates of the types Alugram SIL G/UV254 and Alox N/UV254 from Macherey-Nagel
(Düren). UV Spectra: Perkin-Elmer Lambda-2 spectrophotometer; lmax (e) in nm. IR Spectra: Bruker-IFS-88-
FT-IR spectrometer; KBr pellet or film on KBr; only s and m signals given; nÄ in cmÀ1. 1H-and 13C-NMR Spectra:
CDCl3 or CD3OD solns., Bruker-WH-250, -AM-400, or -DRX-500 spectrometer; conventional Fourier-
transform methods as in our previous studies [46][47]; values in ppm rel. to the CHCl3 signal, coupling constants
J in Hz; Ha and He ˆ axial and equatorial H-atoms, resp.; compounds 21 ± 25, 30, 33, and 34 having two stable
rotamers gave rise to some doubled signals, marked by a*. High resolution MS (HR-MS): Finnigan MAT 90
spectrometer, ionization potential 70 eV; m/z (rel. intensity %).
2. (Æ)-2-Phenylcyclohexanone (1). Phenylmagnesium bromide, prepared from Mg (0.73 g, 30 mmol) and
bromobenzene (4.71 g, 30 mmol) in dry THF (10 ml), was treated at À258 with (Æ)-2-chlorocyclohexanone (4 g,
30 mmol) in benzene (60 ml; thiophene-free): 1 (1.5 g, 29%). M.p. 498, after recrystallization from hexane. Both
yield and m.p. were lower than the literature values [15]. 1H-NMR (250 MHz, CDCl3): 2.02 ± 2.52 (m, CH2(3),
CH2(4), CH2(5)); 3.87 (dd, CH(2)); 7.35 ± 7.45 (m, 2 Ho); 7.47 ± 7.65 (m, 2 Hm, Ho).
3. 2-Phenylcyclohex-2-en-1-one (2). A soln. of 2 (1.746 g, 10 mmol), N-bromosuccinimide (1.783 g,
10 mmol), and 10 mg AIBN (2,2'-azabis[isobutyronitrile]) in CCl4 (40 ml) was heated under reflux for 1 h. After
it was allowed to cool to r.t., the precipitated succinimide was removed by filtration and the solvent by
distillation: crude (Æ)-2-bromo-2-phenylcyclohexanone (1.53 g, 100%). 1H-NMR (250 MHz, CDCl3): 1.72 ± 1.99
(m, CH2(4), CH2(5)); 2.35 ± 2.62 (m, CH2(3)); 2.82 ± 3.03 (m, CH2(6)); 7.17 ± 7.39 (m, Ph).
The crude 2-bromo-2-phenylcyclohexanone was dissolved in 2,6-dimethylpyridine (20 ml) and heated to
reflux for 30 min. After allowing to cool to r.t. the pH of the soln. was brought to 2 by adding dil. HCl soln. The
mixture was extracted with Et2O (2 Â 20 ml), the extract washed with H2O (3Â); dried (MgSO4), and
evaporated, and the crystalline residue recrystallized from hexane/AcOEt 1 :1: 2 (1.204 g, 70%). Colorless
needles. M.p. 788. 1H-NMR (250 MHz, CDCl3): 1.96 ± 2.01 (m, CH2(5)); 2.45 ± 2.58 (m, CH2(4), CH26)); 7.05
(t, CH(3)); 7.21 ± 7.80 (m, Ph).
4. (Æ)-cis-2-Phenyl-3-(prop-2-enyl)cyclohexanone (3). To a stirred suspension of Mg (0.243 g, 10 mmol) in
dry THF (10 ml) under Ar, 2-bromoprop-2-ene (1.21 g, 10 mmol) was added and heated to reflux for 30 min.
After cooling to r.t., CuCl (60 mg, 6 mol-%) was added. Then 2 (0.516 g, 3 mmol) was dropwise introduced at 08.
After stirring at 08 for 15 min, the mixture was heated under reflux for 1.5 h, then cooled, and added to ice-cold
dil. HCl soln. The aq. layer was extracted with Et2O (3 Â 10 ml) and the org. phase washed with H2O (3 Â
10 ml), dried (MgSO4), and evaporated to give a reddish oil (0.49 g, 76%), which was used in the next step. For
characterization, a sample was purified by CC (silica gel, hexane/AcOEt 10 :1): 3. FT-IR (film): 3387m, 3056m,
3037m, 2943s, 1701s, 1643m, 1607m, 503m, 1456m, 1380m, 1337m, 1282m, 1254m, 1232m, 1209m, 1168s, 1108m,

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1021m, 895s, 841m, 791m, 759s, 651s. 1H-NMR (250 MHz, CDCl3): 1.60 (s, Me); 1.79 (m, HeÀC(4)); 1.96
(m, HevÀC(5)); 2.15 (HaÀC(4), HaÀC(5)); 2.83 (m, HÀC(3)); 2.56 (m, HeÀC(6)); 2.83 (m, HaÀC6)); 4.08
(d, 3Ja,e ˆ 5.7, HÀC(2)); 4.75 (s, 1 H, CH2ˆC); 4.83 (s, 1 H, CH2ˆC); 7.15 ± 7.40 (m, Ph). 13C-NMR (62.5 MHz,
CDCl3): 22.5 (Me); 24.4 (C(4)); 26.0 (C(5)); 39.3 (C(6)); 48.2 (C(3)); 58.8 (C(2)); 112.4 (CH2ˆC); 126.8 (Cp);
‡
128.2 (Co); 129.2 (Cm); 136.6 (Cipso); 144.9 (CH2ˆC); 210.4 (CˆO). HR-MS: 214.3056 (C15H18O ; calc.
214.3063).
5. (Æ)-trans-2-Phenyl-3-(prop-2-enyl)cyclohexanone (4). The crude reddish oil of Exper. 4 was dissolved in
EtOH (20 ml) and cooled to À788. Addition of KtBuO (1.122 g, 10 mmol) and stirring for 1 h at À788 were
followed by hydrolysis with dil. HCl soln. by adjusting the pH to 2. The soln. was then extracted with Et2O (2 Â
20 ml) the org. layer washed with H2O (2 Â 10 ml), dried (MgSO4), and evaporated, and the yellowish solid
recrystallized from hexane/AcOEt 10 :1: to 0.476 g (74% rel. to 2 of 4. Colorless crystals. M.p. 1088. FT- IR
(film): 3391m, 3066m, 3037m, 2944s, 1703s, 1646m, 1605m, 1501m, 1458m, 1382m, 1337m, 1314m, 1282m, 1257m,
1
1223m, 1207m, 1170s, 1105m, 1079m, 1023m, 892s, 845m, 795m, 753s, 659s. H-NMR (250 MHz, CDCl3): 1.59
(s, Me); 1.92 ± 2.02 (m, CH2(4), H2ÀC(5)); 2.20 (m, HaÀC(5)); 2.43 ± 2.61 (m, CH2(6)); 2.83 (m, HaÀC(3));
3.61 (d, 3Jap ˆ 12.2, HaÀC(2)); 4.59 (s, 1 H, CH2ˆC); 4.61 (s, 1 H, CH2ˆC); 7.04 ± 7.49 (m, Ph). 13C-NMR
(62.5 MHz, CDCl3): 18.9 (Me); 26.1 (C(4)); 31.7 (C(5)); 42.0 (C(6)); 53.3 (C(3)); 61.3 (C(2)); 112.8 (CH2ˆC);
‡
126.8 (Cp); 128.0 (Co); 129.3 (Cm); 136.9 (Cipso); 145.6 (CH2ˆC); 209.7 (CˆO). HR-MS: 214.3057 (C15H18O ;
calc. 214.3063.
6. (Æ)-trans-2-(3-Oxo-2-phenylcyclohexyl)prop-2-enal (5). To a soln. of 4 (0.86 g, 4 mmol) in abs. dioxane
(20 ml), SeO2 (0.444 g, 4 mmol) was added and the mixture heated under reflux for 2 h. The product, still warm,
was filtered and the pellet washed with Et2O. The filtrate was evaporated, the residue dissolved in Et2O, the soln.
washed with H2O (2 Â 10 ml), dried (MgSO4), and evaporated, and the residue purified by CC (silica gel,
hexane/AcOEt 10 :1): 5 (0.443 g, 49%). Colorless oil. FT-IR (film): 2967s, 1713s, 1645m, 1556s, 1489m, 1454s,
1367m, 1253s, 1200m, 1156m, 1063s, 896s, 776s, 692s. 1H-NMR (250 MHz, CDCl3): 1.92 ± 2.05 (m, HeÀC(5),
CH2(6)); 2.18 (m, HaÀC(5)); 2.58 (m, CH2(4)); 3.25 (m, HaÀC(1)); 3.97 (d, 3Ja,a ˆ 12.4, HaÀC(2)); 5.86 (s, 1 H,
CH2ˆC); 6.14 (s, 1 H, CH2ˆC); 6.96 ± 7.34 (m, Ph). 13C-NMR (62.5 MHz, CDCl3): 26.1 (C(5)); 3.19 (C(6)); 41.9
(C(4)); 45.0 (C(1)); 60.4 (C(2)); 127.0 (Cp); 128.3 (Co); 129.3 (Cm); 136.3 (CH2ˆC); 136.4 (Cipso); 150.6
‡
(CH2ˆC); 194.0 (CHO); 208.7 (CˆO). HR-MS: 228.2896 (C15H16O2 ; calc. 228.2903).
7. (Æ)-trans-3-[1-Methylidene-2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-phenylcyclohexanone (6). To a soln. of 5
(100 mg, 0.432 mmol) in tBuOH (10 ml), an excess of 2-methylbut-2-ene (2 ml) was added. A soln. of NaClO2
(300 mg, 3.3 mmol) and NaH2PO4 ´ H2O (300 mg, 2.49 mmol) in H2O (10 ml) was then dropwise introduced
during 10 min. The mixture was stirred under Ar for 2 h at r.t. After adjusting the pH to 4 by adding NaH2PO4,
the soln. was stirred for further 12 h. Evaporation and dissolution of the residue in H2O (30 ml) were followed
by further decreasing the pH of 2 by dil. HCl soln. The product was then extracted with Et2O (3 Â 10 ml), the
combined org. layer washed with H2O (10 ml) and dried (MgSO4) and the residue submitted to CC (silica gel,
hexane/AcOEt 1 :1): crystals of (Æ)-trans-2-(3-oxo-2-phenylcyclohexyl)propenoic acid (79 mg, 74%). Colorless
1
crystals. M.p. 1058. FT-IR (drift): 3198s, 2951s, 1712s, 1501m, 1458m, 1100s, 964s, 834m, 702s, 667m. H-NMR
(500 MHz, CDCl3): 1.89 (m, HeÀC(6)); 2.06 ± 2.13 (m, HeÀC(5), HaÀC(6)); 2.18 (HaÀC(5)); 2.53 ± 2.64
(m, CH2(4)); 3.25 (m, HaÀC(1)); 3.99 (d, 3Ja,a ˆ 12.3, HaÀC(2)); 5.57 (s, 1 H, CH2ˆC); 6.21 (s, 1 H, CH2ˆC);
7.03 ± 7.31 (m, Ph); 10.5 (s, OH). 13C-NMR (125 MHz, CDCl3): 25.8 (C(5)); 32.2 (C(6)); 41.8 (C(4)); 47.7 (C(1));
60.9 (C(2)); 127.0 (Cp); 128.3 (Co); 129.0 (CH2ˆC); 129.3 (Cm); 136.4 (Cipso); 140.7 (CH2ˆC); 171.6 (COOH);
‡
209.3 (CˆO). HR-MS: 244.1109 (C15H16O3 ; calc. 244.1099).
A soln. of the above acid (137 mg, 0.473 mmol) in dry AcOEt (5 ml) under Ar was cooled to À108 and
treated first with Et3N (48 mg, 0.473 mmol) and then dropwise with diphenylphosphinic chloride (112 mg,
0.52 mmol). After 1 h, pyrrolidine (34 mg, 0.473 mmol) and additional Et3N (48 mg, 0.473 mmol) were
dropwise introduced. After stirring overnight the mixture was filtered and the clear soln. washed first with 3.5m
HCl (10 ml), then with 10% Na2CO3 soln. (20 ml) and finally with H2O (10 ml). After drying (MgSO4) and
evaporation, the residue was purified by CC (silica gel, hexane/AcOEt 1:1): 111 mg (79%) of 6. M.p. 988. FT- IR
(drift): 2863s, 1715m, 1630m, 1596s, 1445m, 1340m, 1246m, 1168m, 1102m, 1071m, 1036m, 927m, 876m, 838m,
786m, 752m, 709s, 670m. 1H-NMR (500 MHz, CDCl3): 1.40 (m, CH2(b) (pyr)); 1.75 (m, CH2(b') (pyr)); 1.83
(m, HeÀC(6)); 2.06 ± 2.18 (m, HeÀC(5), HaÀC(6)); 2.29 ± 2.43 (m, HaÀC(5), HeÀC(4)); 2.46 ± 2.50
(m, CH2(a) (pyr)); 2.66 (m, HaÀC(4)); 3.05 (m, HaÀC(1)); 3.30 (t, 3J ˆ 7.1, CH2(a') (pyr)); 3.87 (d, 3Ja,a
ˆ
12.5, HaÀC(2)); 5.06 (s, 1 H, CH2ˆC); 5.23 (s, 1 H, CH2ˆC); 7.00 ± 7.26 (m, Ph). 13C-NMR (125 MHz, CDCl3):
24.1 (C(5)); 25.9 (C(b) (pyr)); 26.2 (C(b') (pyr)); 33.9 (C(6)); 41.8 (C(4)); 45.5 (C(a) (pyr)); 48.6 (C(a') (pyr));
50.4 (C(1)); 61.0 (C(2)); 118.1 (CH2ˆC); 127.0 (Cp); 128.1 (Co); 129.6 (Cm); 137.1 (Cipso); 146.3 (CH2ˆC); 168.7
‡
(CON); 209.4 (CˆO). HR-MS: 297.1741 (C19H23NO2 ; calc. 297.1729).

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Helvetica Chimica Acta ± Vol. 83 (2000)
8. (Æ)-rel-(1R,2S,3S)-3-[1-Methylidene-2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-phenylcyclohexanamine (7). A
soln. of 6 (271 mg, 0.913 mmol) in abs. MeOH (5 ml) under Ar was cooled to À788 and the following was
added: NH4Ac (835 mg, 10.84 mmol), (NH4)CNBH3 (57 mg, 0.913 mmol), and 3-Š molecular sieves (1 g). After
2 h at À788, the cooling bath was removed and the mixture kept at r.t. for 10 h. After filtration and removal of
the solvent under reduced pressure, the residue was dissolved in Et2O (20 ml) and extracted with 5% HCl soln.
(3 Â 10 ml). The combined aq. layer was brought to pH 12 by addition of 2n NaOH and extracted with Et2O
(3 Â 10 ml). After drying (MgSO4), the solvent was evaporated and the yellowish oil chromatographed (Alox,
CH2Cl2/MeOH 10 :1): 7 (221 mg, 81%). Colorless oil. FT-IR (drift): 3332m, 2928s, 1599s, 1445s, 1355m, 1164m,
940m, 791m, 759s, 703s, 639m. 1H-NMR 250 MHz, CDCl3): 1.18 ± 1.82 (m, CH2(b), CH2(b') (pyr), HÀC(4),
HÀC(5), HÀC(6)); 1.89 ± 1.93 (s, NH2); 2.31 (m, 3Ja,a ˆ 10.3, HaÀC(3)); 2.43 ± 2.56 (m, CH2(a) (pyr)); 2.68 ±
2.80 (m, HaÀC(1), HaÀC(2)); 3.14 ± 3.26 (m, CH2(a') (pyr)); 4.97 (s, 1 H, CH2ˆC); 5.16 (s, 1 H, CH2ˆC);
7.06 ± 7.26 (m, Ph). 13C-NMR (62.5 MHz, CDCl3): 24.1 (C(5)); 25.1 (C(b) (pyr)); 26.0 (C(b) (pyr)); 34.5 (C(6));
35.2 (C(4)); 45.4 (C(a) (pyr)); 46.1 (C(3)); 48.5 (C(a') (pyr)); 50.4 (C(1)); 56.2 (C(2)); 116.5 (CHÀC); 126.2
‡
(Cp); 128.2 (Co); 128.8 (Cm); 142.3 (Cipso); 148.4 (CH2ˆC); 170.0 (CONH2). HR-MS: 298.2032 (C19H26N2O ;
calc. 298.2045).
9. (Æ)-trans-2-(3-Methoxyphenyl)-3-(prop-2-enyl)cyclohexanone (8). The synthesis of 8 was carried out as
described for 4, except that 1-bromo-3-methoxybenzene was used as starting material in the first step (Grignard
reaction). The 3-methoxy derivative of 1 (Æ)-2-(3-methoxyphenyl)cyclohexanone, was obtained in 31% yield.
1H-NMR (250 MHz, CDCl3): 2.04 ± 2.54 (m, CH2(3), CH2(4), CH2(5)); 2.63 ± 2.87 (m, CH2(6)); 3.74 (s, MeO);
3.97 (dd, HÀC(2)); 6.43 ± 6.53 (m, 2Ho); 6.55 (m, Hp); 7.09 (m, Hm).
Bromination according to Exper. 3 gave (Æ)-2-bromo-2-(3-methoxyphenyl)cyclohexanone in 98% yield.
1H-NMR (250 MHz, CDCl3): 1.70 ± 1.86 (m, CH2(4), CH2(5)); 2.30 ± 2.68 (m, CH2(3)); 2.87 ± 3.09 (m, CH2(6));
3.72 (s, MeO); 6.48 (m, Ho, Ho'); 6.59 (m, Hp); 7.15 (m, Hm').
Elimination according to Exper. 2 furnished 2-(3-methoxyphenyl)cyclohex-2-en-1-one in 79% yield.
1H-NMR (250 MHz, CDCl3): 1.97 ± 2.09 (m, CH2(5)); 2.42 ± 2.57 (m, CH2(4), CH2(6)); 3.73 (s, MeO); 6.78
(m, 2 Ho, HÀC(3)); 6.94 (m, Hp); 7.15 (m, Hm).
The methoxy derivative of 3 (Æ)-cis-3-(prop-2-enyl)-2-(3-methoxyphenyl)cyclohexanone was synthesized
according to Exper. 4. The crude product (cis/trans 4 :1 by 1H-NMR) was obtained in 80% yield. 1H-NMR
(250 MHz, CDCl3; cis-isomer): 1.59 (s, Me; 1.77 (m, HeÀC(4)); 1.99 (m, HeÀC(5)); 2.14 (m, HaÀC(4),
HaÀC(5)); 2.35 (m, HeÀC(3)); 2.56 (m, HeÀC(6)); 2.83 (m, HaÀC(6)); 3.76 (s, MeO); 3.95 (d, 3Ja,e ˆ 5.6
HaÀC(2)); 4.68 (s, 1 H, CH2ˆC); 4.78 (s, 1 H, CH2ˆC); 6.80 (m, Ho, Ho'); 6.93 (m, Ho); 7.14 (m, Hm').
Equilibration of the crude cis/trans mixture according to Exper. 5 and CC (silica gel, hexane/AcOEt 10 :1)
gave pure 8 (60% yield, including the last two steps). Colorless oil. FT-IR (film): 2938s, 1714s, 1646m, 1586s,
1492m, 1455s, 1376m, 1257s, 1168s, 1104m, 1049s, 892s, 778s, 697s. 1H-NMR (250 MHz, CDCl3): 1.61 (s, Me);
1.80 ± 2.01 (m, CH2(4), HeÀC(5)); 2.17 (m, HaÀC(5)); 2.44 ± 2.57 (m, CH2(6)); 2.82 (m, HaÀC(3)); 3.64
(d, 3Ja,a ˆ 10.3, HaÀC(2)); 3.76 (s, MeO); 4.61 (s, 1 H, CH2ˆC); 4.64 (s, 1 H, CH2ˆC); 6.63 (m, Ho, Ho'); 6.79
(m, Hp); 7.22 (m, Hm'). 13C-NMR (62.5 MHz, CDCl3): 19.0 (Me); 26.0 (C(4)); 31.7 (C(5)); 42.0 (C(6)); 53.1
(C(3)); 55.0 (MeO); 61.2 (C(2)); 111.9 (Cp); 112.7 (Ch2ˆC); 115.5 (Co); 121.8 (Co'); 128.9 (Cm'); 138.6 (Cipso);
‡
145.6 (CH2ˆC); 159.3 (MeOÀCm); 209.5 (CˆO). HR-MS: 244.1448 (C16H20O2 ; calc. 244.1463).
10. (Æ)-trans-2-(3-Methoxyphenyl)-3-(prop-2-enyl)cyclohexanone Oxime (9). To a soln. of 8 (161 mg,
0.66 mmol) in abs. MeOH (10 ml), NH2OH ´ HCl (2.9 g, 3 mmol) was added under stirring, and subsequently
the pH was adjusted to 5 by addition of N,N-dimethylpyridin-4-amine (DMAP). Heating to reflux for 2 h
followed, while keeping the pH at 5 by further addition of DMAP. After solvent removal under reduced
pressure, Et2O (20 ml) and H2O (10 ml) were added, the aq. layer was further extracted with Et2O (2 Â 10 ml),
the combined org. layer washed with sat. NaHCO3 soln. (10 ml) and brine (10 ml) dried (MgSO4), and
evaporated, and the residue chromatographed (silica gel, hexane/AcOEt 5 :1): 123 mg (72%) of 9 ((E/Z)
mixture). Colorless oil. 1H-NMR (250 MHz, CDCl3): 1.61 (s, Me); 1.75 ± 2.04 (m, CH2(4), HeÀC(5)); 2.12
(m, HaÀC(5)); 2.23 ± 2.56 (m, CH2(6)); 2.80 (m, HaÀC(3)); 3.19 (m, HaÀC(2)); 3.76 (s, MeO); 4.60 (s, 1 H,
CH2ˆC); 4.67 (s, 1 H, CH2ˆC); 6.64 (m, 2 Ho); 6.72 (m, Hp); 7.15 (m, Hm).
11. (Æ)-rel-(1R,2S,3S)-2-(3-Methoxyphenyl)-3-(prop-2-enyl)cyclohexanamine (10). To a vigorously stirred
suspension of LiAlH4 (38 mg, 1 mmol) in abs. THF (10 ml), a soln. of 9 (107 mg, 0.413 mmol) in abs. THF
(5 ml) was dropwise added under Ar at r.t. Reflux (2 h) and cooling were followed by careful addition of AcOEt
(30 ml) and then of 2n NaOH (5 ml). The org. layer was washed with H2O (10 ml), dried (MgSO4), and
evaporated and the remaining colorless oil purified by CC (silica gel, hexane/AcOEt 1:1): 77 mg (76%) of 10.
FT-IR (film): 2924s, 1601s, 1486m, 1375m, 1262m, 1156m, 1048m, 886m, 781m, 734m, 701m. 1H-NMR
(500 MHz, CDCl3): 1.49 (s, Me); 1.50 (m, HeÀC(4), CH2(5)); 1.73 (m, HaÀ(4)); 1.86 (m, HeÀ(6)); 2.07

Helvetica Chimica Acta ± Vol. 83 (2000)
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3
(m, HaÀC(6)); 2.31 (m, 3Ja,a ˆ 11.3, 11.1, Ja,e ˆ 3.2, HaÀC(3)); 2.38 (dd, 3Ja,a ˆ 11.3, 10.0, HaÀC(2)); 2.88
(m, 3Ja,a ˆ 10.0, 3J ˆ 10.2, 3Ja,e ˆ 3.2, HaÀC(1)); 3.35 (s, NH2); 3.77 (s, MeO); 4.47 (d, 2J ˆ 1.4, 1 H, CH2ˆC); 4.49
(s, 1 H, CH2ˆC), 6.73 (m, Ho, Ho', Hp); 7.17 (dd, 3J ˆ 8.5, 7.6, Hm'). 13C-NMR (125 MHz, CDCl3): 19.5 (Me);
24.6 (C(5)); 32.1 (C(4)); 33.9 (C(6)); 50.8 (C(3)); 55.1 (MeO); 55.2 (C(1)); 55.8 (C(2)); 111.8 (C(4)); 111.8
(CH2ˆC); 111.9 (Co); 129.4 (Cm'); 129.4 (Co'); 143.0 (Cipso); 147.0 (CH2ˆC); 159.6 (MeOÀCm). HR-MS:
‡
245.1841 (C16H23NO ; calc. 245.1835).
12. (Æ)-rel-(1R,2S,3S)-2-(3-Methoxyphenyl)-N,N-dimethyl-3-(prop-2-enyl)cyclohexanamine (11). To
a
soln. of 10 (392 mg, 1.6 mmol) in abs. MeOH (10 ml) under Ar, first a 37% aq. formaldehyde soln. (0.4 ml,
5 mmol) was added. Then, at r.t. and under vigorous stirring, a soln. of NaCNBH3 (101 mg, 1.6 mmol) and ZnCl2
(109 mg, 0.8 mmol) in abs. MeOH (5 ml) was dropwise and slowly introduced. After 10 h, the mixture was
treated with 0.5m aq. NaOH (10 ml), and most of the MeOH was distilled off in vacuo. After extraction with
Et2O (3 Â 20 ml), washing with H2O, and drying (MgSO4), the product was purified by CC (silica gel, hexane/
AcOEt 1:1): 376 mg (86%) of 11. Colorless oil. FT-IR (film): 2928s, 2777m, 1645m, 1608s, 1585m, 1487s, 1453s,
1373m, 1262s, 1154s, 1084s, 886s, 804s, 772s, 698s. 1H-NMR (500 MHz, CDCl3): 1.47 (s, Me); 1.34 ± 1.48
(m, HeÀC(4), CH2(5)); 1.68 (m, HaÀC(4)); 1.94 (m, CH2(6)); 2.14 (s, Me2N); 2.25 (m, HaÀC(3)); 2.56
(m, HaÀC(1)); 2.75 (m, HaÀC(2)); 3.76 (MeO); 4.43 (s, 1 H, CH2ˆC); 4.44 (s, 1 H, CH2ˆC); 6.71 (m, Ho, Ho',
Hp); 7.16 (m, Hm'). 13C-NMR (125 MHz, CDCl3): 19.6 (Me); 23.9 (C(5)); 25.0 (C(4)); 32.4 (C(6)); 40.2 (Me2N);
51.2 (C(3)); 53.0 (C(2)); 54.9 (MeO); 67.2 (C(1)); 110.3 (C(4)); 111.2 (CH2ˆC); 114.3 (Co); 120.5 (Co'); 128.5
‡
(Cm'); 145.2 (Cipso); 147.5 (CH2ˆC); 159.0 (MeOÀCm). HR-MS 273.2083 C18H27NO ; calc. 273.2093).
13. (Æ)-2-[rel-(1R,2S,3S)-3-(Dimethylamino)-2-(3-methoxyphenyl)cyclohexyl]prop-2-enal (12). Oxidation
of 11 with SeO2 according to Exper. 6 and CC (silica gel, hexane/AcOEt 1:1) gave 12 in 54% yield. Colorless oil.
FT-IR (film): 2931s, 1689s, 1601m, 1453m, 1262s, 1155m, 1046s, 953m, 781m, 700m. 1H-NMR (500 MHz, CDCl3):
1.41 ± 1.58 (m, HeÀC(4), CH2(5)); 1.67 (m, HaÀC(4)); 1.93 (m, HeÀC(6)); 2.00 (m, HaÀC(6)); 2.14 (s, Me2N);
3
2.88 (m, 3Ja ˆ 10.2, Ja,e ˆ 9.3, HaÀC(3)); 2.97 (m, HaÀC(1), HaÀC(2)); 3.73 (s, MeO); 5.87 (s, 1 H, CH2ˆC);
6.27 (s, 1 H, CH2ˆC); 6.69 (m, 2 Ho, Hp); 7.10 (dd, 3J ˆ 8.4, 3J ˆ 7.5, Hm). 13C-NMR (125 MHz, CDCl3): 24.4
(C(5)); 25.1 (C(4)); 32.7 (C(6)); 40.4 (Me2N); 44.4 (C(1)); 50.8 (C(2)); 55.1 (MeO); 67.5 (C(3)); 111.1 (C(4));
114.3 (C(2)); 120.6 (C(6)); 129.0 (Cm'); 135.6 (CH2ˆC); 144.1 (Cipso); 152.1 (CH2ˆC); 159.4 (MeOÀCm); 194.1
(CHO). EI-MS (70 eV, 258): 47.0(8), 49.0(6), 58.1(5), 71.1(22), 83.9(84), 85.1(3), 85.9(31), 121.1(3), 138.1(7),
‡
166.1(100), 167.1(9), 287.2(12), 288.2(2). HR-MS: 287.1904 (C18H25NO2 ; calc. 287.1885).
14. (Æ)-rel-(4bS,5R,8aS,9S)-5-(Dimethylamino)-4b,5,6,7,8,9,10-octahydro-3-methoxyphenanthrene-9-carb-
aldehyde (13). A soln. of 12 (100 mg, 0.35 mmol) in CH2Cl2 (5 ml) was cooled to À788 under Ar. BF3 ´ Et2O
(248 mg, 1.75 mmol) was then added and stirred for 12 h at À788. After removing the cooling bath and reaching
r.t., 0.5n aq. NaOH (10 ml) was added. The aq. layer was extracted with CH2Cl2 (3 Â 10 ml), the combined org.
layer washed with H2O (5 ml), dried (MgSO4), and evaporated, and the residue submitted to CC (silica gel,
hexane/AcOEt 1:1): 81 mg (81%) of 13. Colorless oil. 1H-NMR (400 MHz, CDCl3): 1.21 ± 1.53 (m, CH2(7),
CH2(8)); 1.90 (m, CH2(6)); 2.05 (m, HÀC(8a)); 2.40 (s, NMe2); 2.48 (m, HÀC(9), 1 HÀC(10)); 2.87
(m, HÀC(5)); 2.98 (m, HÀC(4b), 1 HÀC(10)); 3.79 (s, MeO); 6.68 (m, HÀC(2)); 7.01 (d, 3J ˆ 8.2, HÀC(1));
7.43 (s, HÀC(4)); 9.44 (d, 3J ˆ 2.2, CHO). 13C-NMR (100.6 MHz, CDCl3): 21.6 (C(7)); 24.3 (C(8)); 26.9 (C(6));
33.7 (C(10)); 39.6 (C(8a)); 40.0 (Me2N); 42.0 (C(9)); 53.8 (C(4b)); 55.1 (MeO); 63.6 (C(5)); 110.5 (C(2)); 112.7
(C(4)); 127.7 (C(1)); 128.3 (C(10a)); 144.1 (C(4a)); 158.2 (C(3)); 203.2 (CHO). FT-IR (film): 2927s, 1722s,
1580m, 1491s, 1264m, 1155m, 857m, 732s. EI-MS (70 eV, 258): 47.0 (12), 49.0 (9), 56.0 (4), 58.1 (25), 71.1 (38),
83.9 (100), 85.1 (4), 85.9 (38), 87.9 (5), 99.0 (9), 115.1 (4), 128.1 (4), 129.1 (3), 144.1 (3), 159.1 (6), 171.1 (10),
174.1 (4), 213.1 (11), 214.3 (14), 216.2 (4), 258.2 (50), 259.2 (27), 260.2 (4), 286.2 (7), 287.2 (31), 288.2 (5). HR-
‡
MS: 287.1905 (C18H25NO2 ; calc. 287.1885).
15. 1-Methoxy-2,4,6-trimethylbenzene (15). A suspension of 2,4,6-trimethylphenol (10 g,73.42 mmol) in
H2O (20 ml) placed in an ice bath was vigorously stirred and rapidly treated with KOH (5.14 g, 91.18 mmol) in
H2O (50 ml). Under continuous cooling, Me2SO4 (9.26 g, 73.42 mmol) was added. Then the ice bath was
replaced by an oil bath and the mixture heated to 608 for 2 h. After cooling to r.t., the mixture was diluted with
Et2O (50 ml) and the org. layer washed with 20% aq. KOH (4 Â 20 ml) and H2O (2 Â 20 ml), dried (MgSO4),
1
and evaporated: 9.815 g (89%) of 15. Colorless liquid. H-NMR (250 MHz, CDCl3): 2.12 (s, MeÀC(4)); 2.13
(s, MeÀC(2), MeÀC(6)); 3.60 (s, MeO); 6.72 (s, 2 arom. H).
16. 2-Bromo-4-methoxy-1,3,5-trimethylbenzene (16). To a soln. of 15 (10 g, 66.6 mmol) in CCl4 (100 ml),
cooled to 08 and vigorously stirred, a soln. of Br2 (10.65 g, 66.6 mmol) in CCl4 (20 ml) was slowly added. After
the addition, the mixture was heated to 608 for 2 h until no vapor of Br2 was observed. Usual workup and
distillation in vacuo afforded 8.694 g (57%) of 16. Colorless liquid. B.p. 798/1 mbar. 1H-NMR (250 MHz,
CDCl3): 2.12 (s, MeÀC(5)); 2.25 (s, MeÀC(3)); 2.27 (s, MeÀC(1)); 3.60 (s, MeO); 6.85 (s, arom. H).

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Helvetica Chimica Acta ± Vol. 83 (2000)
17. 3-Methoxy-2,4,6-trimethylbenzoic Acid (17). To a suspension of Mg (0.53 g, 21.8 mmol) in abs. THF
(20 ml), a soln. of 16 (5 g, 21.8 mmol) in abs. THF (20 ml) was added in portions at r.t. To complete the reaction,
the mixture was gently boiled for further 30 min. The Grignard reagent thus prepared was poured on dry ice
(100 g). After the excess CO2 had sublimed, H2O (10 ml) was added, the THF evaporated, Et2O (30 ml) added,
and the org. phase extracted with 2n NaOH (5 ml) and 1n NaOH (20 ml). The pH of the combined aq. layer was
brought to 2 by addition of dil. HCl soln., the acid soln. extracted with Et2O (2 Â 20 ml), and the combined org.
1
layer dried (MgSO4) and evaporated: 3.175 g (75%) of 17. Colorless solid. H-NMR (250 MHz, CDCl3): 2.20
(s, MeÀC(4)); 2.30 (s, MeÀC(2), MeÀC(6)); 3.62 (s, MeO); 6.83 (s, 1 arom. H); 10.6 (s, COOH).
18. 3-Methoxy-2,4,6-trimethylbenzenemethanol (18). To a suspension of LiAlH4 (1.17 g, 30.9 mmol) in abs.
THF (20 ml) a soln. of 17 (6 g, 30.9 mmol) in abs. THF (20 ml) was dropwise added at a rate that kept the
mixture gently boiling. Subsequent heating to reflux for 4 h was followed by careful addition of H2O (10 ml) and
then of 1n HCl (5 ml). Most of the THF was removed by distillation in vacuo and the residue diluted wtih Et2O
(50 ml). Adjustment of the pH to 10 by 0.5n NaOH, extraction with Et2O (2 Â 20 ml), washing of the combined
org. layers with brine, followed by the usual workup and distillation afforded 4.73 g (85%) of 18. Colorless
1
liquid. FT-IR (drift). 3308s, 2916m, 1479s, 1307m, 1230s, 1099s, 1008s, 984m, 865s, 736m. H-NMR (250 MHz,
CDCl3): 1.89 (s, OH); 2.26 (s, MeÀC(4)); 2.35 (s, MeÀC(2), MeÀC(6)); 3.68 (s, MeO); 4.65 (s, CH2OH); 6.87
(s, arom. H). 13C-NMR (100.6 MHz, CDCl3): 11.8 (MeÀC(4)); 16.0, 19.0 (MeÀC(2), MeÀC(6)); 59.9 (MeO);
130.4 (arom. C); 130.4 (arom. C); 130.5 (C(5)); 132.6 (C(4)); 135.6 (C(1)); 155.1 (C(3)). HR-MS: 180.1144
‡
(C11H16O2 ; calc. 180.1150).
19. 3-Methoxy-2,4,6-trimethylbenzyl Methanesulfonate (19). To a soln. of 18 (2 g, 7.14 mmol) and Et3N
(1.98 ml, 14.28 mmol) in abs. CH2Cl2 (10 ml), a soln. of MeSO2Cl (0.84 ml, 10.71 mmol) in abs. CH2Cl2 (5 ml)
was added dropwise at À258, and within 10 min, the mixture was allowed to warm to 108 and then stirred at 108
for 2 h. The reaction was terminated by addition of H2O (5 ml), the aq. layer separated and extracted with
CH2Cl2 (2 Â 10 ml), and the combined org. layer washed with ice-cold H2O (2 Â 10 ml), dried (MgSO4), and
evaporated at 08: 2.48 g (97%) of 19. Colorless oil. 1H-NMR (250 MHz, CDCl3): 2.28 (s, MeÀC(4)); 2.38
(s, MeÀC(2), MeÀC(6)); 3.43 (s, MeSO3; 3.67 (s, MeO); 4.87 (s, CH2); 6.88 (s, arom. H).
20. 3-Methoxy-2,4,6-trimethylacetonitrile (20). To a soln. of 19 (2.48 g, 6.93 mmol) in abs. DMF at 08, KCN
(451 mg, 6.93 mmol) was added in portions. After stirring for 24 h, Et2O (100 ml) and 1n NaOH (20 ml) were
added. The org. layer was washed with 0.1n NaOH (4 Â 10 ml) and H2O (2 Â 10 ml); dried (MgSO4), and
evaporated, and the product purified by CC (silica gel, hexane/AcOEt 10 :1): 0.917 g (70%) of 20. Colorless
1
solid. FT-IR (drift): 2952s, 2246m, 1480s, 1309m, 1236s, 1219m, 1088s, 1000s, 869s, 734m. H-NMR (250 MHz,
CDCl3): 2.27 (s, MeÀC(4)); 2.32, (2s, MeÀC(2), MeÀC(6)); 3.61 (s, CH2CN); 3.69 (s, MeO); 6.92 (s, arom. H).
13C-NMR (100.6 MHz, CDCl3): 12.4 (MeÀC(4)); 16.0, 18.0 (MeÀC(2), MeÀC(6)); 19.62 (CH2); 60.1 (MeO);
117.5 (CN); 126.3 (arom. C); 129.8 (arom. C); 130.8 (C(5)); 131.8 (C(1)); 155.5 (C(3)). HR-MS: 189.1141
‡
(C12H15NO ; calc. 189.1153).
21. (Æ)-a-(3-Methoxy-2,4,6-trimethylphenyl)-1,3-dioxolane-2-butanenitrile (21). To a stirred soln. of 20
(1.89 g, 10 mmol) and 2-(2-bromethyl)-1,3-dioxolane (1.99 g, 11 mmol) in benzene (10 ml), NaNH2 (0.43 g,
11 mmol) was added at r.t. After the addition, the mixture was heated to reflux, the cooled soln. diluted with
Et2O (30 ml), and the excess NaNH2 hydrolyzed by careful addition of H2O (10 ml). The aq. phase was
extracted with Et2O (2 Â 10 ml), the combined org. phase dried (MgSO4) and evaporated, and the residue
chromatographed (silica gel, hexane/AcOEt 10 :1): 2.46 g (85%) of 21. Colorless oil. FT-IR (film): 2950s,
2236m, 1481s, 1305m, 1238m, 1142s, 1002m, 945m, 735m. 1H-NMR (250 MHz, CDCl3): 1.76 ± 2.22 (m, (CH2)2);
2.22 (s, MeÀC(4')); 2.35, 2.36 (2s, MeÀC(2'), MeÀC(6')); 3.69 (s, MeO); 3.80 ± 3.97 (m, O(CH2)2O); 4.25
(dd, 3J ˆ 9.9, 6.0, HÀC(a)); 4.90 (m, HÀC(2)); 6.86 (s, arom. H). 13C-NMR (100.6 MHz, CDCl3): 12.8
(MeÀC(4')); 15.9, 20.1 (MeÀC(2'), MeÀC(6')); 26.1 (CH2); 31.1 (CH2); 31.6 (C(a)); 59.8 (MeO); 64.9
(O(CH2)2O); 103.4 (C(2)); 120.5 (CN); 129.4 (arom. C); 130.4 (arom. C); 130.9 (arom. C); 131.3 (C(5')); 131.6
‡
(C(1')); 155.7 (C(3')). HR-MS: 289.1689 (C17H23NO3 ; calc. 289.1677).
22. (Æ)-b-(3-Methoxy-2,4,6-trimethylphenyl)-1,3-dioxolane-2-butanamine (22). To a stirred suspension of
LiAlH4 (132 mg, 3.5 mmol) in abs. THF (5 ml), a soln. of 21 (1 g, 3.5 mmol) in abs. THF (10 ml) was dropwise
and slowly added at r.t. After heating to reflux for 5 h, the excess LiAlH4 was destroyed by addition of H2O
(5 ml) under cooling in an ice bath. Most of the solvent was removed by distillation, and then Et2O (20 ml) and
0.5n NaOH (5 ml) were added to the residue. The aq. phase was extracted with Et2O (2 Â 20 ml), the combined
org. layer dried (MgSO4) and evaporated, and the residue chromatographed (silica gel, hexane/AcOEt 1 :1):
739 mg (72%) of 22. Colorless oil. FT-IR (film): 2950s, 1572m, 1478m, 1402s, 1301m, 1236m, 1142s, 1032m,
943m, 755m. 1H-NMR (250 MHz, CDCl3): 1.55 (m, CH2); 1.84 (m, CH2); 2.17 (s, MeÀC(4')); 2.25, 2.27 (2s,
MeÀC(2'), MeÀC(6')); 3.02 (m, CH2NH2); 3.26 (m, HÀC(b)); 3.42 (s, NH2); 3.62 (3.60)* (s, MeO); 3.85 ± 3.95

Helvetica Chimica Acta ± Vol. 83 (2000)
2263
(O(CH2)2O); 4.74 (t, 3J ˆ 4.6, HÀC(2)); 6.79 (6.73)* (s, arom. H). 13C-NMR (100.6 MHz, CDCl3): 13.3 (13.4)*
(MeÀC(6')); 15.8 (MeÀC(4')); 20.9 (21.8)* (MeÀC(2')); 25.6 (25.9)* (CH2); 32.2 (32.4)* (CH2); 44.7 (44.9)*
(CH2NH2); 49.9 (C(b)); 59.6 (59.9)* (MeO); 64.8 (O(CH2)2O); 104.3 (C(2)); 128.4 (129.4)* (arom. C); 131
(C(4')); 131.4 (133.3)* (C(5')); 132.5 (C(1')); 136.7 (136.8)* (arom. C); 155.0 (156.2)* (C(3')). HR-MS: 293.1976
‡
(C17H27NO3 ; calc. 293.1991).
23. (Æ)-b-(3-Methoxy-2,4,6-trimethylphenyl)-N,N-dimethyl-1,3-dioxolane-2-butanamine (23). To a soln. of
22 (469 mg, 1.6 mmol) in abs. MeOH (10 ml), 37% aq. CH2O soln. 0.4 ml, 5 mmol) was added, and then, under
vigorous stirring and at r.t., a soln. of NaCNBH3 (101 mg, 1.6 mmol) and ZnCl2 (109 mg, 0.8 mmol) in abs.
MeOH (5 ml) was slowly introduced. After 10 h, 0.5n aq. NaOH (10 ml) was added, and most of the MeOH was
distilled off in vacuo. The aq. layer was extracted with Et2O (3 Â 20 ml), the combined org. layer washed with
H2O (2 Â 10 ml), dried (MgSO4), and evaporated, and the concentrated crude product purified by CC (silica
gel, hexane/AcOEt 1 :1): 416 mg (81%) of 23. Colorless oil. FT-IR (film): 2944s, 2764m, 1459s, 1220m, 1141s,
1034m. 1H-NMR (250 MHz, CDCl3): 1.55 (m, CH2); 1.92 (m, CH2); 2.19 (s, MeÀC(4')); 2.22, 2.23 (2s, Me2N);
2.27, 2.29 (2s, MeÀC(2'), MeÀC(6')); 2.45 (m, 1 H, CH2N); 2.73 (m, 1 H, CH2N); 3.26 (m, HÀC(b)); 3.64
(3.62)* (s, MeO); 3.85 ± 3.95 (m, OCH2CH2O); 4.76 (m, HÀC(2)); 6.80 (6.75)* (s, arom. H). 13C-NMR
100.6 MHz, CDCl3): 13.1 (13.6)* (MeÀC(6')); 15.8 (MeÀC(4')); 21.3 (21.5)* (MeÀC(2')); 26.7 (27.0)* (CH2);
32.4 (32.6)* (CH2); 39.4 (39.8)* (Me2N); 46.0 (C(b)); 59.6 (59.9)* (MeO); 64.4 (64.7)* (CH2N); 64.8
(O(CH2)2O); 104.5 (C(2)); 127.9 (C(4')); 129.5 (129.8)* (arom. C); 130.8 (C(5')); 131.6 (132.3)* (arom. C);
‡
139.0 (C(1')); 154.9 (C(3')). HR-MS: 321.2315 (C19H31NO3 ; calc. 321.2304).
24. (Æ)-g-[(Dimethylamino)methyl]-3-methoxy-2,4,6-trimethylbenzenebutanal (24). To
a soln. of 23
(418 mg, 1.3 mmol) in THF (5 ml), 3n HCl (2 ml) was added under vigorous stirring, and the mixture was
allowed to stand for 24 h at r.t. After addition of Et2O (30 ml) and 0.5n NaOH (10 ml), the aq. layer was
extracted with Et2O (2 Â 10 ml) and the combined org. layer dried (MgSO4) and evaporated: 360 mg (100%) of
24. Colorless oil. FT-IR (film): 2943s, 1723m, 1460s, 1300m, 1236m, 1009m, 866m. 1H-NMR (500 MHz, CDCl3):
2.04 (m, CH2); 2.19 (s, MeÀC(4)); 2.24 (s, Me2N); 2.26, 2.29 (2s, MeÀC(2), MeÀC(6)); 2.15 ± 2.45 (m, 1 H of
CH2N, CH2CHO, CH2); 2.80 (m, 1 H of CH2N); 3.25 (m, HÀC(g)); 3.63 (3.64)* (s, MeO); 6.76 (6.81)*
(s, arom. H); 9.48 (9.50)* (s, CHO). 13C-NMR (125 MHz, CDCl3): 12.9 (13.7)* (MeÀC(6')); 15.8 (MeÀC(4'));
21.3 (MeÀC(2')); 24.7 (25.0)* (CH2); 38.7 (39.0)* (Me2N); 42.0 (42.6)* (CH2); 45.9 (C(g)); 59.5 (59.8)*
(MeO); 64.1 (64.4)* (CH2N); 128.4 (C(4)); 129.6 (129.8)* (arom. C); 130.9 (132.4)* (C(5)); 131.6 (132.4)*
(arom. C); 138.1 (C(1)); 155.0 (156.2)* (C(3)); 199.2 (CHO). EI-MS (70 eV, 408): 42.0 (1), 43.0 (3), 57.1 (1),
‡
58.1 (100), 59.1 (4), 84.0 (2), 91.1 (1), 161.1 (1), 176.1 (1), 277.2 (3), 278.2 (1). HR-MS: 277.2054 (C17H27NO2
calc. 277.2042).
;
25. (Æ)-g-[(Dimethylamino)methyl]-3-methoxy-2,4,6-trimethyl-a-methylidenebenzenebutanal (25). A soln.
of 24 (277 mg, 1 mmol), Et2N ´ HCl (98 mg, 1.2 mmol), and 37% aq. CH2O (97 mg, 1.2 mmol) in THF (10 ml)
was heated under reflux for 3 h. After cooling to r.t., Et2O (30 ml) and 0.5n NaOH (10 ml) were added. The aq.
layer was extracted with Et2O (2 Â 20 ml), the combined org. phase dried (MgSO4), and evaporated, and the
crude product chromatographed (silica gel, hexane/AcOEt 1 :1): 283 mg (98%) of pure 25. FT-IR (drift): 2941s,
1685m, 1458s, 1235m, 1012m, 866m. 1H-NMR (500 MHz, CDCl3): 2.19 (m, MeÀC(2), MeÀC(4), MeÀC(6),
1 MeN); 2.33 (2.34)* (s, 1 MeN); 2.10 ± 2.85 (m, CH2N, CH2); 3.50 (m, HÀC(g)); 3.61 (3.65)* (s, MeO); 5.80
(s, 1 H, CH2ˆC); 5.96 (d, 3J ˆ 9.5, 1 H, CH2ˆC); 6.76 (6.78)* (s, arom. H); 9.40 (9.42)* (s, CHO). 13C-NMR
(125 MHz, CDCl3): 12.8 (13.9)* (MeÀC(6')); 15.8 (MeÀC(4)); 21.1 (21.3)* (MeÀC(2')); 30.7 (30.9)* (CH2);
38.1 (38.4)* (Me2N); 45.6 (C(g)); 59.5 (59.8)* (MeO); 63.3 (63.6)* (CH2N); 128.1 (C(4)); 129.5 (129.9)*
(arom. C); 130.8 (132.2)* (C(5)); 131.6 (132.4)* (arom. C); 133.8 (CH2ˆC); 138.4 (C(1)); 148.8 (148.9)*
(CH2ˆC); 154.9 (156.1)*(G(s3)); 194.1 (CHO). EI-MS (70 eV, 908): 42.0 (1), 44.0 (1), 45.0 (1), 47.0 (2), 57.1 (1),
58.1 (100), 59.1 (3), 82.9 (4), 83.9 (3), 84.9 (2), 85.9 (3), 91.1 (1), 105.1 (1), 163.1 (1), 289.2 (10), 290.2 (3). HR-
‡
MS: 289.2058 (C18H27NO2 ; calc. 289.2042).
26. (Æ)-4-(3-Methoxy-2,4,6-trimethylphenyl)-2-methylpenta-2,4-dienal (26). To a soln. of 25 (100 mg,
0.36 mmol) in CHCl3 (5 ml), AlCl3 (233 mg, 1.75 mmol) was added under Ar at À788. After 12 h, the cooling
bath was removed and the mixture brought to r.t. and poured onto an ice-cold 1m AcONa soln. (100 ml). After
stirring (1 h), Et2O (50 ml) was added and the aq. layer further extracted with Et2O. To the combined org.
extract, 0.1n NaOH (50 ml) was added, the org. layer further extracted with 0.1n NaOH (2 Â 20 ml), then
washed with H2O (2 Â 20 ml), dried (MgSO4), and evaporated, and the residue chromatographed (silica gel,
hexane/AcOEt 10 :1): 4.2 mg (ca. 5%) of 26. UV (6.2 ´ 10À5m MeOH): 267 (31800). FT-IR (drift): 2926s, 1687s,
1454m, 1234s, 1087m, 1057m. Colorless oil. 1H-NMR (500 MHz, CD3OD): 1.16 (s, Me); 2.08 (s, MeÀC(2'));
MeÀC(6')); 2.26 (s, MeÀC(4')); 3.67 (s, MeO); 5.39 (s, 1 H, CH2ˆC); 6.02 (s, 1 H, CH2ˆC); 6.92 (s, arom. H);
7.16 (s, CH ˆ ); 9.44 (s, CHO). 13C-NMR (125 MHz, CD3OD): 11.2 (Me) 13.5 (MeÀC(6')); 16.1 (MeÀC(4'));

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Helvetica Chimica Acta ± Vol. 83 (2000)
20.0 (MeÀC(2')); 60.2 (MeO); 121.3 (CH2ˆC); 128.9 (arom. C); 130.1 (arom. C); 130.8 (C(5')); 131.0
(arom. C); 135.0 (ˆCCHO); 141.9 (C(1')); 146.7 (CH2ˆC); 151.5 (CH ˆ ); 156.2 (C(3')); 197.8 (CHO). EI-MS
(70 eV, 458): 75.0 (16), 78.1 (28), 81.1 (29), 115.1 (7), 118.1 (9), 128.1 (7), 129.6 (8), 131.1 (8), 150.1 (13), 171.1
(7), 173.1 (8), 185.1 (11), 186.1 (16), 187.2 (12), 188.2 (9), 200.2 (15), 201.2 (28), 213.2 (12), 215.2 (28), 227.2
‡
(7), 229.1 (17), 230.2 (4), 243.2 (8), 244.2 (100, M ), 245.2 (14), 246.2 (5).
27. (Æ)-g-[(Dimethylamino)methyl]-2,4,6-trimethyl-a-methylidenebenzenebutanal (30). According to Ex-
per. 21 ± 25 (preparation of 25), with 2,4,6-trimethylbenzeneacetonitrile (29; 5.17 g, 32.5 mmol): 1 g (10% over
5 steps) of 30. Yellow oil. FT-IR (film): 2966s, 2931s, 2856s, 2817s, 2765s, 1688s, 1612m, 1458s, 1374m, 1262m,
1097m, 1033s, 943m, 852s, 804m, 757m, 734m. 1H-NMR (500 MHz, CDCl3): 2.20 (s, MeÀC(2)); 2.21
(s, MeÀC(4)); 2.24 (s, MeÀC(6)); 2.38 (s, Me2N); 2.14 ± 2.86 (m, CH2, CH2N); 3.50 (m, HÀC(g)); 5.81
(s, 1 H, CH2ˆC); 5.97 (s, 1 H, CH2ˆC); 6.77 (s, arom. H); 9.43 (s, CHO). 13C-NMR (125 MHz, CDCl3): 20.6
(MeÀC(6')); 21.5 (MeÀC(4)); 21.7 (MeÀC(2')); 30.8 (CH2); 37.6 (C(g)); 45.6 (Me2N); 63.5 (CH2N); 129.3
(C(3)); 131.2 (C(5)); 133.8 (CH2ˆC); 135.4 (arom. C); 136.2 (arom. C); 136.3 (arom. C); 136.9 (C(1)); 149.0
(CH2ˆC); 194.2 (CHO). EI-MS (70 eV, 308): 42.1 (2), 43.1 (2), 44.1 (1), 57.1 (1), 58.1 (100), 59.1 (2), 84.1 (1),
86.1 (16), 91.1 (1), 129.1 (1), 131.1 (1), 133.1 (1), 205.2 (4), 217.2 (5), 220.2 (1), 259.3 (3). HR-MS: 259.1931
‡
(C17H25NO ; calc. 259.1936).
28. 2,4,6-Trimethyl-3-nitrobenzeneacetonitrile (31). To 29 (5 g, 31.4 mmol), fuming nitric acid (5 ml) was
added dropwise under stirring. After the soln. had turned orange, it was heated to 408 for 5 min. Then H2O
(10 ml) was added slowly, the mixture extracted with Et2O (3 Â 5 ml), and the combined org. layer washed with
sat. NaHCO3 soln. (20 ml), dried (MgSO4), and evaporated: 633 g (99%) of 31. Yellow solid. M.p. 858 ([40]:
908). FT-IR (drift): 3181m, 2981s, 2942s, 2882s, 2740m, 2254s, 1525s, 1369s, 1033s, 882s, 843s, 803s. 1H-NMR
(500 MHz, CDCl3): 2.26 (s, MeÀC(2)); 2.30 (s, MeÀC(4)); 2.41 (s, MeÀC(6)); 3.66 (s, CH2); 7.04 (s, HÀC(5)).
13C-NMR (125 MHz, CDCl3): 14.7 (MeÀC(4)); 17.1 (MeÀC(6')); 17.9 (CH2); 20.2 (MeÀC(2')); 116.2
(arom. C); 126.8 (arom. C); 128.1 (arom. C); 129.3 (arom. C); 131.1 (G(5)); 138.9 (CꢁN); 151.3 (C(3)). EI-MS
(70 eV, 908): 39.0 (4), 77.1 (9), 91.1 (19), 105.1 (7), 115.1 (22), 116.1 (16), 119.1 (11), 131.1 (21), 132.1 (23), 147.1
‡
(8), 160.1 (100), 161.1 (10), 187.1 (49), 204.1 (59), 205.1 (9). HR-MS: 204.0901 (C11H12N2O2 ; calc. 204.0899).
29. (Æ)-b-(2,4,6-Trimethyl-3-nitrophenyl)-1,3-dioxolane-2-butanamine (33). (Æ)-a-(2,4,6-Trimethyl-3-nitro-
phenyl)-1,3-dioxolane-2-butanenitrile (32; prepared from 31 as described for 21 in Exper. 21; 2.597 g, 8.53 mmol)
was dissolved in 1m BH3 ´ THF (12.8 ml, 12.8 mmol) under Ar at r.t. The stirred soln. was refluxed (1 h) and,
after cooling, H2O (10 ml) was added carefully. The soln. was extracted with Et2O (3 Â 10 ml) and the combined
org. phase dried (MgSO4) and evaporated: 1 g (38%) of 33. FT-IR (film): 3371m, 2957s, 2883s, 1527s, 1370s,
1142s, 1036s, 913s, 843s, 734s. 1H-NMR (500 MHz, CDCl3): 1.46 ± 1.64 (m, CH2); 1.84 ± 1.94 (m, CH2); 2.19
(s, MeÀC(4')); 2.26 (2.24)* (s, MeÀC(2')); 2.37 (2.39)* (s, MeÀC(6')); 3.04 ± 3.12 (m, CH2NH2); 3.30 ± 3.34
(m, HÀC(b)); 3.80 ± 3.93 (m, O(CH2)2O); 4.78 ± 4.80 (m, HÀC(2)); 6.94 (6.89)* (s, HÀC(5')). 13C-NMR
(125 MHz, CDCl3): 15.0 (16.9)* (MeÀC(6')); 16.8 (MeÀC(4')); 22.4 (21.5)* (MeÀC(2')); 25.9 (25.4)* (CH2);
32.5 (32.2)* (CH2); 44.4 (C(b)); 64.9 (O(CH2)2O); 104.1 (C(2)); 127.1 (126.6)* (arom. C); 128.6 (C(4')); 131.0
(132.6)* (C(5')); 138.0 (C(1')); 140.2 (138.4)* (arom. C); 152.8 (151.7)* (C(3')). EI-MS (70 eV, 758): 43.0 (19),
45.0 (11), 47.0 (15), 49.0 (12), 73.1 (17), 84.0 (100), 86.0 (63), 88.0 (10), 119.0 (3), 174.1 (3), 191.1 (4), 262.2
‡
(14), 308.2 (2). HR-MS: 308.1740 (C16H24N2O4 ; calc. 308.1736).
30. (Æ)-g-[(Dimethylamino)methyl]-2,4,6-trimethyl-a-methylidene-3-nitrobenzenebutanal (34). According
to Exper. 25, with 33 (989 mg, 3.21 mmol): 343 mg (35% over 3 steps of 34. Yellow oil. 1H-NMR (500 MHz,
CDCl3): 2.09 ± 2.79 (m, Me, CH2, CH2N); 3.47 (m, HÀC(g)); 5.86 (s, 1 H, CH2ˆC); 6.04 (s, 1 H, CH2ˆC); 6.82
(s, HÀC(5)); 9.42 (s, CHO). 13C-NMR (125 MHz, CDCl3): 15.3 (MeÀC(6')); 16.7 (MeÀC(4)); 21.6
(MeÀC(2')); 30.9 (CH2); 37.9 (C(g)); 45.7 (Me2N); 63.4 (CH2N); 126.6 (126.2)* (arom. C); 127.1 (C(4));
127.6 (127.4)* (C(5)); 130.8 (132.4)* (arom. C); 134.5 (CH2ˆC); 139.4 (arom. C); 148.3 (CH2ˆC); 151.5 (151.7)
(C(3)); 194.1 (CHO). EI-MS (70 eV, 1508): 43.0 (3), 58.1 (100), 71.1 (2), 86.1 (2), 105.1 (1), 115.1 (2), 128.1 (2),
‡
129.1 (2), 141.1 (1), 174.1 (1), 247.2 (1), 262.2 (5), 304.2 (1). HR-MS: 304.1791 (C17H24N2O3 ; calc. 304.1787).
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Received May 19, 2000