Exquisite synthesis of a designed PAR-1 antagonist

Article abstract of DOI:10.1002/hlca.201100128

The synthesis of a designed, sterically congested geminal dimethyl-bearing PAR-1 antagonist was achieved by a route of ten steps, with the oxidation of an electron-rich benzaldehyde, the construction of a tertiary alkyl azide, and the selective hydrogenolysis of a 1,5-fused tetrazole to generate the cyclic amidine with Raney-Ni being the key steps. The selective hydrogenolysis of 1,5-fused tetrazole to generate the cyclic amidine with Raney-Ni was discovered and may be generally used for the synthesis of structurally unusual cyclic amidines. Several unsuccessful attempts to construct the desired geminal dimethyl-bearing cyclic amidine were also discussed. Copyright

Full text of DOI:10.1002/hlca.201100128

Helvetica Chimica Acta – Vol. 94 (2011)
1981
Exquisite Synthesis of a Designed PAR-1 Antagonist
by Hua-Ming Miaoa)b), Gui-Long Zhao*b), Lin-Shan Zhangc), Hua Shaob), and Jian-Wu Wang*a)
a) School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China
(phone: þ 86-531-88362708; e-mail: jwwang@sdu.edu.cn)
b) Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical
Research, Tianjin 300193, P. R. China (phone: þ 86-22-23003529; e-mail: zhao_guilong@126.com)
c) College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China
The synthesis of a designed, sterically congested geminal dimethyl-bearing PAR-1 antagonist was
achieved by a route of ten steps, with the oxidation of an electron-rich benzaldehyde, the construction of
a tertiary alkyl azide, and the selective hydrogenolysis of a 1,5-fused tetrazole to generate the cyclic
amidine with Raney-Ni being the key steps. The selective hydrogenolysis of 1,5-fused tetrazole to
generate the cyclic amidine with Raney-Ni was discovered and may be generally used for the synthesis of
structurally unusual cyclic amidines. Several unsuccessful attempts to construct the desired geminal
dimethyl-bearing cyclic amidine were also discussed.
Introduction. – Antiplatelet agents constitute an important class of antithrombotic
compounds and are now widely used in the therapy of arterial thrombotic diseases such
as acute coronary syndrome (ACS). Platelets can be activated by a variety of agonists
such as thrombin, ADP, thromboxane A, collagen, epinephrine, etc., among which
thrombin was the most potent one [1]. Therefore, the thrombin receptor is a promising
target for the discovery of antiplatelet drugs. Since thrombin activates platelets mainly
through protease-activated receptor 1 (PAR-1; also known as thrombin receptor) [2],
PAR-1 antagonists were considered as a class of attractive antiplatelet agents, and
several PAR-1 antagonists such as SCH530348 [3] and E5555 [4] are now in clinical
trials (Fig.).
During the development of our own PAR-1 antagonists, we designed a derivative of
E5555, compound 1, which has a structurally challenging geminal dimethyl group and
was found to be a potent PAR-1 antagonist by in vitro evaluation (Fig.). Although it
appears that only the geminal dimethyl group is additionally present in the molecule of
1 as compared with E5555 (ignoring the F-atom in E5555 in terms of synthetic
methodology), it is the sterically congested geminal dimethyl moiety that leads to a
great challenge in the construction of this molecule.
Results and Discussion. – In Scheme 1, the retrosynthetic analysis of 1 is presented.
First, the molecule 1 can be disconnected to the left fragment, a cyclic amidine A, and
the right fragment, a bromoacetophenone B, based on the SN2 reaction used in the
synthesis of E5555 [4b]. Compound B can be prepared according to a known procedure
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

1982
Helvetica Chimica Acta – Vol. 94 (2011)
Figure. PAR-1 Antagonists
[4b]. Analysis of the cyclic amidine A revealed that such an unusual functionality can
be constructed by intramolecular nucleophilic addition of a tertiary alkyl amine to the
CN group in the ortho-position as shown in C. Subsequently, an a,a-dimethylbenzyl-
amine C was required for this purpose, which bears another structurally challenging
functionality, a tertiary alkyl amine. A literature survey revealed that only a few
methods are available for the creation of this moiety in this case, including Hofmann
degradation of D [5] or similar reactions [6], and reduction of the corresponding
tertiary azido-alkyl derivative E [7]. In view of the difficult access to the starting
material D, used in the Hofmann degradation and similar reactions, the other
procedure involving reduction of E was tentatively selected. The literature search
further revealed that the structurally unusual E can only be prepared by nucleophilic
addition of the Nꢀ3 ion to the corresponding tertiary carbocation [7], which may be
generated from the corresponding hydroxy compound F [7] or olefin G [7a] on
treatment with acid. Both the alcohol F and the olefin G were considered to be
accessible starting from 3,4-dihydroxybenzaldehyde H by conventional multi-step
synthetic routes. As can be seen from the above analysis, there are almost no alternative
synthetic approaches available to build compound 1, since only one or two methods can
be used to create such unusual functionalities as cyclic amidine, tertiary alkyl amine,
and tertiary alkyl azide involved in the key steps.
According to the retrosynthetic analysis described above, the synthesis of 1 was
carried out. After considerable experimentation, an exquisite synthetic route to 1 was
ultimately established (Scheme 2), which turned out to be an optimized version of the
initially proposed one shown in Scheme 1.
As depicted in Scheme 2, the starting material, 3,4-dihydroxybenzaldehyde, was
cleanly diethylated to the known diethoxy derivative 2 [8] with excess EtBr in DMF at
room temperature in the presence of KI as catalyst and K2CO3 as base. Oxidation of the
electron-rich benzaldehyde 2 proceeded smoothly to furnish the desired known benzoic
acid 3 [9] with freshly prepared Ag2O in the presence of NaOH in H2O at room

Helvetica Chimica Acta – Vol. 94 (2011)
1983
Scheme 1. The Retrosynthetic Analysis of Compound 1
temperature, and the isolated benzoic acid 3 was esterified to the corresponding known
ethyl ester 4 [10] with EtOH in the presence of concentrated H2SO4 as a catalyst in
benzene at reflux with azeotropic removal of H2O. The ester 4 was brominated to yield
5 with Br2 in AcOH at 358, and noteworthy is that the polarities of 4 and 5 were too
similar to be discriminated by TLC analysis. Thus, 4 was treated with excess Br2 in
AcOH at 358 for 36 h, and the isolated product was found to be essentially pure 5
almost without contamination by unreacted 4 (1H-NMR), indicating that 4 could be
cleanly brominated to 5 under the reaction condition aforementioned1). Treatment of
5 with excess MeMgCl at ꢀ 58 to 08 furnished the desired tertiary alcohol 6 cleanly,
1
)
The reaction conditions described herein were obtained after optimization. Under some
unfavorable reaction conditions, the isolated ester 5 was found to be contaminated by appreciable
amounts of unreacted starting 4; the isolated crude product was in turn treated with Br2 once again
until all the starting 4 was consumed and not observed in the isolated product according to
1H-NMR. Attempts to monitor the reaction course on-line by 1H-NMR failed in that the spectrum
of the mixture was too complex to draw any meaningful conclusions.

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Scheme 2. The Established Synthetic Route to 1
i) KI, K2CO3, EtBr, DMF, room temperature (r.t.). ii) Ag2O, NaOH, H2O, r.t. iii) Conc. H2SO4, EtOH,
benzene, reflux. iv) Br2, AcOH, 358. v) 2 MeMgCl, THF, ꢀ 58 – 08. vi) MeSO3H, CH2Cl2, r.t. vii) CuCN,
i
DMF, N2, reflux. viii) NaN3, CF3COOH (TFA), r.t. ix) Spontaneous cyclization. x) Raney-Ni, PrOH,
N2, reflux. xi) 2-Bromo-1-[3-(tert-butyl)-4-methoxy-5-(morpholin-4-yl)phenyl]ethanone, THF, r.t.
treatment of which with MeSO3H in CH2Cl2 at room temperature led to a rapid
dehydration to afford alkene 7. The alkene functionality is often considered to be labile
to high temperature, in particular, in the presence of acidic heavy metal ions;
fortunately, however, treatment of 7 with CuCN in refluxing DMF under N2
successfully furnished the desired benzonitrile 8. The conversion of 8 to the azido
compound 9 with NaN3 in the presence of CF3CO2H (TFA) in CHCl3 at room
temperature [7] was found to be rather sluggish, with a conversion of only 20% even
after one week. This result may be attributable to the steric hindrance due to the CN
group in the ortho-position. According to the kinetic theory and the reaction
mechanism of this electrophilic addition reaction, the concentrations of both acid
and alkene 8 should be increased in this case. Thus, treatment of 8 with a large excess of
NaN3 in minimal pure CF3CO2H was adopted, and indeed 8 was rapidly and cleanly
consumed. Nonetheless, careful examination of the spectroscopic data, in particular the
IR bands, revealed that the isolated product was tetrazole 10 rather than 9, because an
IR absorption band of neither the C ꢁ N group nor the N3 group was observed,

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indicating that 9 spontaneously underwent an intramolecular [3 þ 2] cycloaddition to
give the isolated tetrazole 102). Although this cycloaddition can be unambiguously
rationalized based on the well-known [3 þ 2] cycloaddition, it was almost unpredictable
why this cycloaddition occurred so readily in this case. This led to another great
challenge: we had to transform tetrazole 10 to the desired cyclic amidine 11, since, if the
synthetic route involving unstable 9 now adopted was bypassed, it seemed difficult, if
even possible, to prepare intermediate C through an alternative pathway, such as that
starting from D. Obviously, it also appeared almost impossible to convert tetrazole 10
to the desired cyclic amidine 11, since it has been shown that the tetrazole ring itself
usually does not react with reductants [12], and it is also hard to predict the products
even though a suitable reductant is found. Fortunately, however, tetrazole 10 was
successfully converted to the desired amidine 11 in high yield after considerable efforts
for the search for reagents and reaction conditions (Table). Thus, treatment of 10 with
freshly prepared Raney-Ni under N2 in refluxing i-PrOH afforded the desired cyclic
amidine 11 in 81% yield. Noteworthy is that, under more vigorous conditions, as
indicated in Entry 10 of the Table, a complex mixture was obtained, which might
contain the over-reduced products. Finally, coupling of 11 with the right fragment
bromoacetophenone B [4b] in THF at room temperature successfully furnished the
desired compound 1 as a hydrobromide salt.
Table. Reagents and Reaction Conditions Screened to Reduce 10 to 11
Entry
Reductant
Condition
Outcome
1
2
3
4
5
6
7
8
9
NaBH4
NaBH4
LiAlH4
LiAlH4
H2, 10% Pd/C
H2, 10% Pd/C
H2, 10% Pd/C
Raney-Ni
Raney-Ni
Raney Ni
r.t., THF
reflux, THF
r.t., THF
reflux, THF
r.t., THF
reflux, THF
reflux, AcOHa), THF
r.t., iPrOH
reflux, iPrOH
H2 (1 mPa), iPrOH, 508
no reaction
no reaction
no reaction
no reaction
no reaction
4%
15%
< 1%
81%
complex mixture
10
a) 1% with respect to THF (v/v).
Several unsuccessful approaches have also been attempted before the establish-
ment of the exquisite synthetic route depicted in Scheme 2, which will be discussed
individually below.
The first unsuccessful attempt is outlined in Scheme 3. Analogously to the
bromination of 4 shown in Scheme 2, 2 was brominated with Br2 in AcOH at 358 to
afford smoothly bromide 12, and noteworthy was that, unlike 4 and 5, although the
2
)
A valuable conclusion can then be drawn that the CN and N3 groups in one molecule can
spontaneously and rapidly undergo [3 þ 2] cycloaddition even at room temperature if they are
sterically favorable; however, under normal circumstances the intermolecular [3 þ 2] cycloadditions
of CN and N3 groups to produce 1,5-tetrazole were rather difficult and often carried out at high
temperatures in a sealed vessel [11].

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polarities of 2 and 12 were similar, they could be readily distinguished by TLC analysis.
The aldehyde moiety of 12 was protected as acetal prior to the cyanation, since direct
cyanation of 12 with CuCN in refluxing DMF under N2 led to complete decomposition
of 12. Thus, treatment of 12 with ethylene glycol in the presence of TsOH as catalyst in
refluxing benzene with azeotropic removal of H2O gave the corresponding acetal 13,
and subsequent cyanation with CuCN in refluxing DMF under N2 smoothly furnished
the benzonitrile 14, which, on treatment with 10% HCl in MeOH at room temperature,
yielded the desired ortho-formylbenzonitrile 15. However, all attempts to oxidize 15
with numerous commonly encountered oxidants (see Scheme 3) to produce the
expected acid 16 failed in that these oxidants were either not sufficiently potent at low
temperatures or too potent at elevated temperatures, leading to unidentified over-
oxidized products by cleavage of the electron-rich diethoxybenzene ring. The subtle
balance, i.e., suitable oxidant under the appropriate reaction condition, has not been
found so far. This unsuccessful attempt was initially considered to be rational, since it
has been expected that the desired compound 16 could be easily converted to
compound 9 by a sequence of conventional functional-group manipulations. Further-
more, all attempts to oxidize the aldehyde 15 to the corresponding acid failed due to the
same reasons.
Scheme 3. The First Unsuccessful Synthetic Route
i) Br2, AcOH, 358. ii) TsOH, (CH2OH)2, benzene, reflux. iii) CuCN, DMF, N2, reflux. iv) 10% HCl,
MeOH, r.t. v) A variety of oxidants, including Ag2O, KMnO4, CrO3, K2Cr2O7, and H2O2.
Based on the attempted oxidations of the three aldehydes 2, 12, and 15 described
above, we learned that the substituents in the ortho-position (Br in 12 and CN in 15)
posed a significant steric hindrance to the aldehyde function during its oxidation,
although neither substituent seems notably bulky, and, therefore, potent oxidants under
vigorous reaction conditions were required to bring about the oxidation. However, they
were not compatible with and decomposed the electron-rich diethoxy-bearing benzene
ring. Fortunately, there is no substituent in ortho-position to the aldehyde functionality
in 2, and a mild oxidant was suitable in this case. This valuable conclusion suggests that,
in an electron-rich benzaldehyde, the aldehyde functionality should be first oxidized to
corresponding acid prior to the introduction of ortho-substituents.
The second unsuccessful attempt is outlined in Scheme 4. The bromide 5 (see
Scheme 2) was treated with CuCN as described above to yield the corresponding
benzonitrile 17, which was treated with excess MeMgCl at ꢀ 58 to 08 with anticipation

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1987
Scheme 4. The Second Unsuccessful Synthetic Route
i) CuCN, DMF, N2, reflux. ii) MeMgCl, THF, ꢀ 58 to 08. iii) Spontaneous cyclization. iv) LiAlH4, THF,
08 to r.t. v) NaOH, EtOH, H2O, reflux, and then HCl.
to produce the desired tertiary alcohol 18. However, the isolated product was the cyclic
iminate 19 instead of 18. It has been initially expected that 18 could be readily
converted to 9 by a known method [6b]. Obviously, 18 was indeed formed but
spontaneously underwent intramolecular nucleophilic addition in the alkaline reaction
media to give 19. The isolated 19 was derivatized for further structural elucidation.
Thus, 19 was treated with LiAlH4 and NaOH to furnish 20 and 21, respectively.
The last unsuccessful attempt is depicted in Scheme 5. The bromide 6 (see
Scheme 2) was treated with CuCN as described above also with the expectation to
furnish 18, but only the lactone 21 was isolated. Evidently, the desired 18 was produced
on treatment of 6 with CuCN; however, 18 underwent spontaneous intramolecular
nucleophilic addition to give iminate 19, which was subsequently hydrolyzed by a trace
of H2O in the mixture to furnish the finally isolated lactone 21.
Scheme 5. The Third Unsuccessful Synthetic Route
i) CuCN, DMF, N2, reflux. ii) DMF, reflux. iii) Trace of H2O, DMF, reflux.
As can be seen from the last two attempts (Schemes 4 and 5), the desired key
intermediate 18 was indeed formed in both reactions, but it was stable in neither of the
mixtures and underwent intramolecular cyclization when exposed to strong base
(Scheme 4) or high temperature (Scheme 5), indicating that it seems considerably hard,
if possible, to prepare the key intermediate E via F (Scheme 1). Nevertheless, neither
the strong base nor high temperature could be avoided, since both unfavorable reaction
conditions are necessary for the formation of 18.

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By careful examination of the finally established synthetic route (Scheme 2) and the
unsuccessful ones (Scheme 3 – 5), it can be concluded that two new functionalities, aryl
CN and tertiary N3, are required to be introduced for the construction of the desired
cyclic amidine functionality, and several steps are needed for each introduction.
Therefore, a number of synthetic routes resulting from different combinations of these
steps exist theoretically. Some valuable conclusions about the strategy for the
combination of these steps can be drawn: 1) the aldehyde functionality should be
oxidized prior to the introduction of ortho-Br or ortho-CN; 2) the Br-atom should be
retained during the manipulation of the other substituent, until an alkene functionality
was built; 3) prior to the introduction of N3, the CN should be introduced by
displacement of the Br-atom.
Compound 1 was found to be a potent PAR-1 antagonist by in vitro evaluation
model, and the results will be published separately elsewhere.
Conclusions. – In conclusion, the synthesis of a designed potent PAR-1 antagonist 1
was achieved by a ten-step exquisite approach. The strategy for the introduction of the
two substituents needed for the construction of the geminal dimethyl-bearing cyclic
amidine was intensively explored. Some valuable general conclusions were reached: 1)
as for an electron-rich benzaldehyde, the aldehyde functionality should be first oxidized
to the corresponding acid prior to the introduction of the ortho-substituents; 2) like 18,
the ortho-cyanobenzylic alcohols were labile to bases and high temperatures in that
they often underwent spontaneous intramolecular cycloaddition under the reaction
conditions of their formation; 3) the CN and N3 groups can undergo intramolecular
[3 þ 2] cycloaddition to form a tetrazole moiety spontaneously even at room
temperature, if they are sterically permitted in one molecule; 4) the 1,5-fused tetrazole
can be selectively hydrogenolyzed to the corresponding cyclic amidine by Raney-Ni in
refluxing i-PrOH, which may found wide application in the formation of the
structurally challenging cyclic amidines.
Experimental Part
General. M.p.: XT-4 Microscopic melting-point apparatus; uncorrected. IR: Thermo Nicolet Avtar
FT370 spectrophotometer; KBr discs or thin films. 1H- and 13C-NMR: Bruker AV400 spectrometer;
(D6)DMSO as solvent; TMS as internal standard; coupling constants J in Hz. HR-MS: Agilent Q-TOF
6510 mass spectrometer; electrospray ionization (ESI) technique.
All the commercially available starting materials and reagents were of anal. grade and used as
received unless otherwise noted. Dried THF was distilled from Na/benzophenone ketyl at atmospheric
pressure, and DMF was distilled from CaH2 under reduced pressure.
3,4-Diethoxybenzaldehyde (2). A 250-ml round-bottomed flask was charged with 13.81 g (100 mmol)
of 3,4-dihydroxybenzaldehyde, 1.66 g (10 mmol) of KI, 32.69 g (300 mmol) of EtBr, 27.64 g (200 mmol)
of K2CO3, and 150 ml of dried DMF, and the resulting mixture was stirred at r.t. until all 3,4-
dihydroxybenzaldehyde was consumed (TLC; typically within 12 h). The mixture was diluted with
200 ml of CH2Cl2, stirred for another 5 min and filtered off, and the collected filtrate was washed with
three 300-ml portions of sat. brine, dried (Na2SO4), and evaporated on a rotary evaporator to afford
crude 2 as a deep red oil, which was chromatographed to yield pure 2 as a colorless oil [8]. Yield: 18.06 g
(93%). 1H-NMR: 1.32 – 1.37 (m, 2 Me); 4.08 (q, J ¼ 6.9, CH2O); 4.14 (q, J ¼ 6.9, CH2O); 7.15 (d, J ¼ 8.4, 1
arom. H); 7.37 (d, J ¼ 2.0, 1 arom. H); 7.51 (dd, J ¼ 2.0, 8.4, 1 arom. H); 9.81 (s, CHO).

Helvetica Chimica Acta – Vol. 94 (2011)
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3,4-Diethoxybenzoic Acid (3). A 1000-ml beaker was charged with 45.86 g (270 mmol) of AgNO3
and 200 ml of doubly distilled H2O, and the mixture was stirred to form a clear soln., to which were added
portionwise 50 ml of an aq. soln. containing 10.80 g (270 mmol) of NaOH. After addition, the resulting
black suspension was stirred, followed by addition of a soln. of 17.48 g (90 mmol) of 2 in 100 ml of MeOH
in a portionwise manner. After addition, the mixture thus obtained was stirred at r.t. until all the starting
aldehyde 2 was consumed (TLC; typically within 1ꢂ2 h). The mixture was filtered off, and the filter cake
was washed with 100 ml of 1% aq. NaOH. The collected filtrate was acidified with conc. HCl to pH 2 and
extracted with three 100-ml portions of CH2Cl2. The combined extracts were washed with sat. brine, dried
(Na2SO4), and evaporated on a rotary evaporator to afford crude 3 as a white solid, which was triturated
with 100 ml of AcOEt/petroleum ether (PE) 1:9 (v/v) to give pure 3 as colorless crystals after suction
1
filtration and drying in vacuo at r.t. Yield: 15.71 g (83%). M.p. 166 – 1678 ([9]: 164 – 1678). H-NMR:
1.31 – 1.36 (m, 2 Me); 4.02 – 4.11 (m, 2 CH2O); 7.02 (d, J ¼ 8.4, 1 arom. H); 7.42 (d, J ¼ 1.2, 1 arom. H); 7.52
(dd, J ¼ 1.6, 8.4, 1 arom. H); 12.59 (br. s, COOH).
Ethyl 3,4-Diethoxybenzoate (4). A 250-ml round-bottomed flask was charged with 15.66 g
(74.49 mmol) of 3, 70 ml of abs. EtOH, and 70 ml of benzene. The mixture was stirred at r.t., followed
by dropwise addition of 5 ml of conc. H2SO4. The flask was fitted with a DeanꢀStark trap and a reflux
condenser, and the mixture was stirred under reflux with azeotropic removal of H2O until all 3 was
consumed (TLC; typically within 12 h). The mixture was poured into 300 ml of ice-water while stirring,
and the resulting mixture thus obtained was extracted with three 100-ml portions of CH2Cl2. The
combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary evaporator
to give crude 4 as a pale brown solid, which was purified by CC (SiO2; AcOEt/PE 1:20) to yield pure 4 as
1
colorless crystals. Yield: 16.86 g (95%). M.p. 53 – 548 ([10]: 52 – 538). H-NMR: 1.27 – 1.35 (m, 3 Me);
4.02 – 4.12 (m, 2 CH2O); 4.26 (q, J ¼ 7.1, COOCH2); 7.04 (d, J ¼ 8.4, 1 arom. H); 7.42 (d, J ¼ 2.0, 1 arom.
H); 7.54 (dd, J ¼ 2.0, 8.4, 1 arom. H).
Ethyl 2-Bromo-4,5-diethoxybenzoate (5). A 250-ml round-bottomed flask was charged with 16.72 g
(70.17 mmol) of 4, 100 ml of glacial AcOH, and 15.98 g (100 mmol) of Br2, and the mixture was stirred at
358 for 36 h. On cooling, the mixture was poured into 500 ml of ice-water, and the mixture was extracted
with three 100-ml portions of CH2Cl2. The combined extracts were washed sequentially with 300 ml of
sat. NaHCO3 and 200 ml of sat. brine, dried (Na2SO4), and evaporated on a rotary evaporator to afford
crude 5 as a pale yellow oil, which was purified by CC (SiO2; AcOEt/PE 1:20) to furnish pure 5 as a white
solid. Yield: 20.25 g (91%). M.p. 48 – 498. IR: 3095w, 1724s (C¼O), 1592s, 1509s, 1470s, 1395s. 1H-NMR:
1.28 – 1.34 (m, 3 Me); 4.03 (q, J ¼ 6.9, CH2O); 4.09 (q, J ¼ 6.9, CH2O); 4.27 (q, J ¼ 7.2, COOCH2); 7.20 (s,
1 arom. H); 7.32 (s, 1 arom. H). 13C-NMR: 13.97 (Me); 14.33 (Me); 14.45 (Me); 60.93 (CH2O); 64.18
(CH2O); 64.35 (CH2O); 112.30 (arom. C); 115.05, 117.64 (2 arom. CH); 123.09, 146.93, 151.27 (3 arom.
C); 164.92 (C¼O). HR-MS (TOF-ESþ): 317.0401 ([M(79Br) þ H]þ, C13H1879BrOþ; calc. 317.0388);
319.0380 ([M(81Br) þ H]þ, C13H1881BrOþ; calc. 319.0368).
2-(2-Bromo-4,5-diethoxyphenyl)propan-2-ol (6). A dried 500-ml round-bottomed flask was charged
with 20.17 g (63.59 mmol) of 5, 200 ml of dried THF, and a magnetic stirring bar, flushed with N2, and
sealed with a rubber septum. The flask was cooled with a cooling bath held at ꢀ 58, and 50 ml (150 mmol)
of 3m MeMgCl in THF were added dropwise through syringe. After addition, the mixture was stirred at
1
08 for another ꢂ2 h. The mixture was poured into 500 ml of ice-water while stirring, and to the mixture
thus obtained were added 200 ml of CH2Cl2, followed by stirring for 10 min. The mixture was filtered
through a pad of Celite, and the org. phase was separated from the filtrate. The aq. phase was back-
extracted with another 100 ml of CH2Cl2. The combined org. phases were washed with sat. brine, dried
(Na2SO4), and evaporated on a rotary evaporator to furnish crude 6 as a colorless oil, which was purified
by CC (SiO2; AcOEt/PE 1:10) to afford pure product 6 as a waxy white solid. Yield: 16.77 g (87%). M.p.
62 – 638. IR: 3518s (OH), 3117w, 3094w, 1598m, 1499s, 1473s, 1391s, 1369s. 1H-NMR: 1.27 – 1.33 (m,
2 Me); 1.57 (s, Me2C); 3.96 – 4.03 (m, 2 CH2O); 5.19 (s, OH); 7.05 (s, 1 arom. H); 7.43 (s, 1 arom. H).
13C-NMR: 14.62 (Me); 14.72 (Me); 29.06 (Me2C); 63.94 (CH2O); 64.19 (CH2O); 71.26 (CꢀOH); 109.06
(arom. C); 113.09, 119.22 (2 arom. CH); 140.41, 146.95, 147.07 (3 arom. C). HR-MS (TOF-ESþ):
285.0488 ([M(79Br) ꢀ H2O þ H]þ, C13H1879BrO2þ ; calc. 285.0490); 287.0466 ([M(81Br) ꢀ H2O þ H]þ,
C13H1881BrOþ2 ; calc. 287.0470).

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Helvetica Chimica Acta – Vol. 94 (2011)
1-Bromo-4,5-diethoxy-2-(1-methylethenyl)benzene (7). A 250-ml round-bottomed flask was charged
with 16.59 g (54.72 mmol) of 6 and 100 ml of CH2Cl2, and the soln. was stirred at r.t., followed by
addition of 0.96 g (10 mmol) of MeSO3H. The mixture thus obtained was stirred at r.t., until all the
starting 6 was consumed (TLC; typically within 1 h). The mixture was poured into 200 ml of sat. brine
while stirring, and the org. phase was separated. The aq. phase was back-extracted with another 100 ml of
CH2Cl2. The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to afford crude 7 as a pale yellow oil, which was purified by CC (SiO2; AcOEt/PE 1:15) to
furnish pure 7 as a colorless oil. Yield: 14.36 g (92%). IR: 3082w, 1641w (C¼C), 1596w, 1500s, 1390s.
1H-NMR: 1.28 – 1.32 (m, 2 Me); 2.01 (s, ¼CMe); 3.98 – 4.04 (m, 2 CH2O); 4.87 (s, ¼CH); 5.19 – 5.20 (m,
¼CH); 6.79 (s, 1 arom. H); 7.09 (s, 1 arom. H). 13C-NMR: 14.54 (Me); 14.57 (Me); 23.45 (Me); 64.02
(CH2O); 64.21 (CH2O); 110.48 (¼C); 114.25 (¼CH2); 116.06, 117.06 (2 arom. CH); 136.01, 144.77, 147.47,
147.87 (4 arom. C). HR-MS (TOF-ESþ): 285.0494 ([M(79Br) þ H]þ, C13H1879BrOþ2 ; calc. 285.0490);
287.0473 ([M(81Br) þ H]þ, C13H1881BrOþ2 ; calc. 287.0470).
4,5-Diethoxy-2-(1-methylethenyl)benzonitrile (8). A dried 250-ml round-bottomed flask was charged
with 14.23 g (49.90 mmol) of 7, 5.37 g (60 mmol) of CuCN, and 70 ml of dried DMF, and the mixture was
stirred at reflux under N2, until starting 7 was consumed (TLC; typically within 5 h). On cooling, the
mixture was poured into 300 ml of sat. brine, and the mixture was extracted with three 100-ml portions of
CH2Cl2. The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to afford the crude product as a deep brown oil, which was purified by CC (SiO2; AcOEt/PE
1:7) to yield pure 8 as a white solid. Yield: 10.39 g (90%). M.p. 83 – 858. IR: 3088w, 2212s (C ꢁ N), 1598s,
1560m, 1516s, 1475m, 1457m, 1388s, 1356s. 1H-NMR: 1.30 – 1.35 (m, 2 Me); 2.11 (s, ¼CMe); 4.06 (q, J ¼
7.1, CH2O); 4.12 (q, J ¼ 7.1, CH2O); 5.16 (s, ¼CH); 5.31 – 5.32 (m, ¼CH); 6.97 (s, 1 arom. H); 7.29 (s, 1
arom. H). 13C-NMR: 14.33 (Me); 14.40 (Me); 22.90 (Me); 64.07 (CH2O); 64.21 (CH2O); 100.10 (¼C);
111.89 (¼CH2); 116.30, 117.04 (2 arom. CH); 118.81 (CN); 140.64, 141.72, 147.11, 151.63 (4 arom. C). HR-
MS (TOF-ESþ): 232.1345 ([M þ H]þ, C14H18NO2þ ; calc. 232.1338); 249.1607 ([M þ NH4]þ, C14H21N2Oþ2 ;
calc. 249.1603).
2-(1-Azido-1-methylethyl)-4,5-diethoxybenzonitrile (9) and 7,8-diethoxy-5,5-dimethyl-5H-tetrazo-
lo[5,1-a]isoindole (10). A 250-ml round-bottomed flask was charged with 13.00 g (200 mmol) of NaN3
and 130 ml of CF3COOH (TFA), and the slurry thus obtained was stirred at r.t., followed by addition of
10.18 g (44.01 mmol) of 8. The stirring was continued at r.t. until all 8 was consumed (TLC; typically
within 12 h). The mixture was poured into 500 ml of ice-water, and the resulting mixture was extracted
with three 100-ml portions of CH2Cl2. The combined extracts were washed with sat. brine, dried
(Na2SO4), and evaporated on a rotary evaporator to afford crude 10 as a brown solid, which was purified
by CC (SiO2; AcOEt/PE 1:10) to yield pure 10 as a white solid. Yield: 10.50 g (87%). M.p. 125 – 1268. IR:
3055w, 1624m, 1587w, 1550w, 1495s, 1472s, 1448s, 1393m. 1H-NMR: 1.34 – 1.39 (m, 2 Me); 1.76 (s, Me2C);
4.12 – 4.19 (m, 2 CH2O); 7.50 (s, 1 arom. H); 7.52 (s, 1 arom. H). 13C-NMR: 14.45 (Me); 14.50 (Me); 25.75
(Me2C); 64.29 (CH2O); 64.32 (CH2O); 65.51 (CꢀN); 106.36, 107.79 (2 arom. CH); 112.35, 147.40, 148.87,
151.11 (4 arom. C); 158.31 (C¼N). HR-MS (TOF-ESþ): 275.1529 ([M þ H]þ, C14H19N4O2þ ; calc.
275.1508); 549.2943 ([2M þ H]þ, C28H37N8Oþ4 ; calc. 549.2938).
5,6-Diethoxy-2,3-dihydro-3,3-dimethyl-1H-isoindol-1-imine (11). A 1000-ml beaker was charged
with 50 g of NiꢀAl alloy (containing 0.927 mol of Al) and 200 ml of H2O, and the mixture was stirred,
followed by portionwise addition of 150 ml (1.125 mol) of 30% aq. NaOH at such a rate that the
evolution of gas (H2) was in control. Cooling of the beaker with an ice-water bath may be necessary
during the addition. Then, the beaker was heated in a H2O bath held at 708 for another 1ꢂ2 h. The stirring
was ceased, and the mixture was left to stand at r.t. The supernatant was decanted carefully, and H2O was
added. The mixture was stirred and left to stand, and the supernatant was decanted once again. This
procedure was repeated until the pH value of the supernatant was in the range of 7 – 9. The Raney-Ni
thus obtained was stored at r.t. in H2O and used within one week. A 250-ml round-bottomed flask was
charged with 10.37 g (37.80 mmol) of 10, 150 ml of i-PrOH, and the Raney-Ni prepared above (ca. 20 g),
and the mixture was stirred at reflux under N2 until all 10 was consumed (TLC; typically within 12 h). On
cooling, the mixture was filtered with suction in such a manner that the Raney-Ni was always covered
with liquid. The collected filtrate was evaporated on a rotary evaporator to afford crude 11 as a pale
yellow oil, which was purified by CC (SiO2; MeOH) to yield pure 11 as a white solid. Yield: 7.60 g (81%).

Helvetica Chimica Acta – Vol. 94 (2011)
1991
M.p. 85 – 878. IR: 3440s (NH), 3336m (NH), 3099m, 1668s, 1601s, 1569s, 1498s, 1448s, 1389s. 1H-NMR:
1.33 – 1.37 (m, 2 Me); 1.39 (s, Me2C); 4.04 (q, J ¼ 6.9, CH2O); 4.11 (q, J ¼ 6.9, CH2O); 7.22 (s, 1 arom. H);
7.60 (s, 1 arom. H); 8.79 (br. s, 2 NH). 13C-NMR: 14.69 (Me); 14.77 (Me); 27.55 (Me2); 63.94 (CH2O);
64.08 (CH2O); 68.49 (CꢀN); 105.62, 105.76 (2 arom. CH); 125.44, 147.32, 149.27, 151.59 (4 arom. C);
160.26 (C¼NH). HR-MS (TOF-ESþ): 249.1631 ([M þ H]þ, C14H21N2Oþ2 ; calc. 249.1603).
1-[3-(tert-Butyl)-4-methoxy-5-(morpholin-4-yl)phenyl]-2-(5,6-diethoxy-1,3-dihydro-3-imino-1,1-di-
methyl-2H-isoindol-2-yl)ethanone Hydrobromide (1). A dried 100-ml round-bottomed flask was charged
with 7.41 g (29.84 mmol) of 11, 11.05 g (29.84 mmol) of 2-bromo-1-[3-(tert-butyl)-4-methoxy-5-
(morpholin-4-yl)phenyl]ethanone [4b] and 100 ml of dried THF, and the mixture was stirred at r.t.
until all the starting materials were consumed (TLC; typically within 12 h), when a pale yellow slurry was
obtained. The mixture was filtered with suction, and the collected crystals were washed with 20 ml of
dried THFand dried in vacuo at r.t. to furnish pure 1 in the form of hydrobromide as a white solid. Yield:
17.17 g (93%). M.p. 154 – 1568. IR: 3435(w), 3357w (NH), 3220w (NH), 3038s, 1693s (C¼O), 1671s
1
(C¼N), 1603m, 1494s, 1471m. H-NMR: 1.36 – 1.41 (m, Me3C, 2 Me); 1.48 (s, Me2C); 3.04 (s, 2 CH2O);
3.83 (s, 2 CH2N); 3.97 (s, MeO); 4.11 (q, J ¼ 7.1, CH2O); 4.20 (q, J ¼ 6.9, CH2O); 5.40 (s, CH2N); 7.44 (s, 1
arom. H); 7.60 (s, 1 arom. H); 7.68 (s, 1 arom. H); 7.84 (s, 1 arom. H); 9.15 (br. s, 1 arom. H); 9.47 (br. s,
NH). 13C-NMR: 14.37 (Me); 14.45 (Me); 23.69; 30.18; 34.85; 48.01; 50.22; 58.51; 64.25 (CH2O); 64.51
(CH2O); 66.38; 70.18; 105.57; 106.36; 116.55; 117.59; 121.18; 129.01; 143.13; 145.01; 146.58; 148.65;
153.72; 156.86; 160.77 (C¼NH); 190.35 (C¼O). HR-MS (TOF-ESþ): 538.3285 ([M þ H]þ, C31H44N3O5þ ;
calc. 538.3281).
2-Bromo-4,5-diethoxybenzaldehyde (12). A 250-ml round-bottomed flask was charged with 14.62 g
(75.27 mmol) of 2 and 100 ml of glacial AcOH, and the mixture was stirred at r.t., followed by addition of
15.98 g (100 mmol) of Br2. The resulting mixture was stirred at 358, until all 2 was consumed (TLC;
typically within 24 h). On cooling, the mixture was poured into 500 ml of ice-water, and the resulting
mixture was extracted with three 100-ml portions of CH2Cl2. The combined extracts were washed
sequentially with 200 ml of sat. NaHCO3 and 200 ml of sat. brine, dried (Na2SO4), and evaporated on a
rotary evaporator to afford crude 12 as a red oil, which was triturated with 100 ml of AcOEt/PE 1:9 (v/v)
to furnish pure 12 as colorless crystals after suction filtration and drying in vacuo at r.t. Yield: 18.09 g
(88%). M.p. 68 – 698. IR: 3080w, 1675s (C¼O), 1589s, 1507s, 1472s, 1396s. 1H-NMR: 1.31 – 1.36 (m, 2 Me);
4.07 (q, J ¼ 7.1, CH2O); 4.17 (q, J ¼ 6.9, CH2O); 7.28 (s, 1 arom. H); 7.30 (s, 1 arom. H); 10.04 (s, CHO).
13C-NMR: 14.28 (Me); 14.37 (Me); 63.99 (CH2O); 64.71 (CH2O); 111.55, 116.54 (2 arom. CH); 119.10,
125.51, 147.74, 153.90 (4 arom. C); 190.02 (CHO). HR-MS (TOF-ESþ): 273.0124 ([M(79Br) þ H]þ,
C11H1479BrO3þ ; calc. 273.0126); 275.0104 ([M(81Br) þ H]þ, C11H1481BrOþ3 ; calc. 275.0106).
2-(2-Bromo-4,5-diethoxyphenyl)-1,3-dioxolane (13). A 250-ml round-bottomed flask was charged
with 18.02 g (65.98 mmol) of 12, 13.40 g (200 mmol) of ethylene glycol, 1.90 g (10 mmol) of TsOH · H2O,
and 150 ml of benzene, and fitted with a DeanꢀStark trap and a reflux condenser. The mixture was stirred
at reflux with azeotropic removal of H2O, until all the aldehyde 12 was consumed (TLC; typically within
12 h). On cooling, the mixture was poured into 500 ml of ice-water containing 3.02 g (20 mmol) of
Na2CO3 while stirring, and the resulting mixture was extracted with three 100-ml portions of CH2Cl2. The
combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary evaporator
to give crude 13 as a pale brown oil, which was purified by CC (neutral Al2O3; AcOEt/PE 1:15) to yield
pure 13 as a colorless oil. Yield: 17.16 g (82%). IR: 3080w, 1600s, 1510s, 1477s, 1395s. 1H-NMR: 1.29 – 1.32
(m, 2 Me); 3.92 – 4.09 (m, 4 CH2O); 5.82 (s, HꢀCꢀNO); 7.03 (s, 1 arom. H); 7.11 (s, 1 arom. H).
13C-NMR: 14.45 (Me); 14.54 (Me); 64.07 (CH2O); 64.19 (CH2O); 64.81 (OCH2CH2O); 101.79 (OCHO);
112.26 (arom. CH); 112.48 (arom. C); 116.61 (arom. CH); 128.08, 147.48, 149.56 (3 arom. C). HR-MS
(TOF-ESþ): 317.0398 ([M(79Br) þ H]þ, C13H1879BrOþ4 ; calc. 317.0388); 319.0379 ([M(81Br) þ H]þ,
C13H1881BrOþ4 ; calc. 319.0368).
2-(1,3-Dioxolan-2-yl)-4,5-diethoxybenzonitrile (14). A 250-ml round-bottomed flask was charged
with 17.02 g (53.66 mmol) of 13, 6.27 g (70 mmol) of CuCN, and 100 ml of dried DMF, and mixture was
refluxed under N2, until all 13 was consumed (TLC analysis; typically within 5 h). On cooling, the
mixture was poured into 300 ml of sat. brine, and the mixture was extracted with three 100-ml portions of
CH2Cl2. The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to afford crude 14 as a black oil, which was purified by CC (neutral Al2O3; AcOEt/PE 1:7) to

1992
Helvetica Chimica Acta – Vol. 94 (2011)
yield pure 14 as a colorless oil. Yield: 12.29 g (87%). IR: 3096w, 3069w, 2222 (CꢁN, s), 1600s, 1517s,
1
1475s, 1393s. H-NMR: 1.30 – 1.37 (m, 2 Me); 3.96 – 4.02 (m, CH2O); 4.06 – 4.14 (m, 3 CH2O); 5.81 (s,
HꢀCꢀNO); 7.16 (s, 1 arom. H); 7.38 (s, 1 arom. H). 13C NMR: 14.30 (Me); 14.33 (Me); 64.18 (CH2O);
64.33 (CH2O); 65.31 (OCH2CH2O); 101.19 (OCHO); 101.42 (CN); 111.75, 116.69 (2 arom. CH); 117.31,
134.84, 148.46, 151.53 (4 arom. C). HR-MS (TOF-ESþ): 264.1233 ([M þ H]þ, C14H18NO4þ ; calc.
264.1236).
4,5-Diethoxy-2-formylbenzonitrile (15). A 250-ml round-bottomed flask was charged with 12.16 g
(46.18 mmol) of 14 and 100 ml of MeOH, and the mixture was stirred at r.t., followed by addition of 1 ml
of 10% HCl. The stirring was continued, until all 14 was consumed (TLC; typically within 5 h). The
mixture was poured into 300 ml of sat. brine, and the mixture was extracted with three 100-ml portions of
CH2Cl2. The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to afford crude 15 as a colorless oil, which was purified by CC (SiO2; AcOEt/PE 1:12) to
yield pure 15 as a white solid. Yield: 9.42 g (93%). M.p. 116 – 1178. IR: 2225m (CꢁN), 1697s (C¼O),
1585s, 1516m, 1359m. 1H-NMR: 1.30 – 1.38 (m, 2 Me); 4.16 – 4.22 (m, 2 CH2O); 7.55 (s, 1 arom. H); 7.57 (s,
1 arom. H); 10.00 (s, CHO). 13C-NMR: 14.34 (2 Me); 64.49 (CH2O); 64.93 (CH2O); 104.51 (CN); 113.23,
116.76 (2 arom. CH); 116.93, 130.88, 151.50, 152.33 (4 arom. C); 188.53 (CHO). HR-MS (TOF-ESþ):
220.0968 ([M þ H]þ, C12H14NOþ3 ; calc. 220.0974).
Ethyl 2-Cyano-4,5-diethoxybenzoate (17). A dried 250-ml round-bottomed flask was charged with
19.96 g (62.93 mmol) of 5, 7.16 g (80 mmol) of CuCN, and 150 ml of dried DMF, and the mixture was
stirred at reflux under N2, until all 5 was consumed (TLC; typically within 5 h). On cooling, the mixture
was poured into 500 ml of sat. brine, and the mixture was extracted with three 100-ml portions of CH2Cl2.
The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to afford crude 17 as a deep brown oil, which was purified by CC (SiO2; AcOEt/PE 1:7) to
furnish pure 17 as a white solid. Yield: 14.75 g (89%). M.p. 138 – 1408. IR: 2227m (CꢁN), 1707s (C¼O),
1591s, 1528s, 1473w, 1393m, 1367s. 1H-NMR: 1.31 – 1.37 (m, 3 Me); 4.13 – 4.20 (m, 2 CH2O); 4.34 (q, J ¼
7.2, COOCH2); 7.48 (s, 1 arom. H); 7.50 (s, 1 arom. H). 13C-NMR: 14.08 (Me); 14.43 (Me); 62.01
(CH2O); 64.91 (CH2O); 65.07 (CH2O); 105.15 (CN); 114.28, 117.11 (2 arom. CH); 118.08, 126.05, 151.41,
151.52 (4 arom. C); 164.03 (C¼O). HR-MS (TOF-ESþ): 264.1232 ([M þ H]þ, C14H18NO4þ ; calc.
264.1236); 281.1501 ([M þ NH4]þ, C14H21N2O4þ ; calc. 281.1501); 286.1055 ([M þ Na]þ, C14H17NNaOþ4 ;
calc. 286.1047).
5,6-Diethoxy-3,3-dimethyl-2-benzofuran-1(3H)-imine (19). A dried 250-ml round-bottomed flask
was charged with 14.51 g (55.11 mmol) of 17, a magnetic stirring bar, and 150 ml of dried THF, sealed
with a rubber septum, and cooled with a bath held at ꢀ 58. The mixture was stirred, followed by dropwise
addition of 40 ml (120 mmol) of 3m MeMgCl in THF through syringe. After addition, the mixture was
stirred at 08 for another 1/2 h. The mixture was poured into 500 ml of ice-water, and to the mixture were
added 200 ml of CH2Cl2, followed by stirring for 10 min. The mixture thus obtained was filtered through a
pad of Celite, and the filtrate was collected, from which the org. phase was separated. The aq. phase was
back-extracted with another 100 ml of CH2Cl2. The combined extracts were washed with sat. brine, dried
(Na2SO4) and evaporated on a rotary evaporator to furnish crude 19 as a pale yellow oil, which was
purified by CC (SiO2; AcOEt) to afford pure 19 as a waxy white solid. Yield: 11.54 g (84%). M.p. 88 –
908. IR: 3280s (NH), 1676s (C¼N), 1605m, 1505s, 1478s, 1445s. 1H-NMR: 1.32 – 1.36 (m, 2 Me); 1.50 (s,
Me2C); 4.02 – 4.13 (m, 2 CH2O); 7.12 (s, 1 arom. H); 7.28 (s, 1 arom. H); 7.74 (br. s, NH). 13C-NMR: 14.47
(Me); 14.54 (Me); 27.61 (Me2C); 54.82 (CꢀO); 64.00 (CH2O); 64.10 (CH2O); 85.11, 104.60, 106.36,
119.33, 145.26, 148.74 (6 arom. C); 152.07 (C¼N). HR-MS (TOF-ESþ): 250.1451 ([M þ H]þ, C14H20NO3þ ;
calc. 250.1443).
2-[2-(Aminomethyl)-4,5-diethoxyphenyl]propan-2-ol (20). A dried 100-ml round-bottomed flask
was charged with 5.12 g (20.54 mmol) of 19 and 50 ml of dried THF, and the mixture was stirred on an
ice-water bath, followed by portionwise addition of 0.76 g (20 mmol) of LiAlH4. The resulting mixture
was stirred at r.t., until all 19 was consumed (TLC; typically within 3 h). The mixture were carefully
poured into 300 ml of ice-water while stirring, and to the resulting mixture were added 200 ml of CH2Cl2.
The mixture thus obtained was stirred for 5 min and filtered through a pad of Celite with suction. The org.
phase was separated from the filtrate, and the aq. phase was back-extracted with another 100 ml of
CH2Cl2. The combined org. phases were washed with sat. brine, dried (Na2SO4), and evaporated on a

Helvetica Chimica Acta – Vol. 94 (2011)
1993
rotary evaporator to afford crude 20 as a colorless oil, which was purified by CC (SiO2; MeOH) to give
pure 20 as a waxy white solid. Yield: 4.37 g (84%). M.p. 288. IR: 3440 (OH, w), 3182s (NH), 3136s (NH),
3026s, 1581s, 1517s, 1466s, 1393s. 1H-NMR: 1.26 – 1.31 (m, 2 Me); 1.47 (s, Me2C); 3.65 (s, CH2N); 3.96 –
4.00 (m, 2 CH2O); 6.85 (s, 1 arom. H); 6.89 (s, 1 arom. H). 13C-NMR: 14.74 (Me); 14.80 (Me); 32.12
(Me2); 41.40 (CꢀN); 63.91 (CH2O); 64.02 (CH2O); 72.54 (CꢀOH); 112.02, 118.06 (2 arom. CH); 123.87,
140.65, 146.35, 147.36 (4 arom. C). HR-MS (TOF-ESþ): 236.1646 ([M ꢀ H2O þ H]þ, C14H22NO2þ ; calc.
236.1651).
5,6-Diethoxy-3,3-dimethyl-2-benzofuran-1(3H)-one (21). A 100-ml round-bottomed flask was
charged with 4.76 g (19.09 mmol) of 19 and 20 ml of EtOH, and the mixture was stirred at r.t., followed
by addition of 20 ml of 20% aq. NaOH. The stirring was continued at reflux, until all 19 was consumed
(TLC). On cooling, the mixture was poured into 200 ml of H2O, and the mixture was acidified by conc.
HCl to pH 2, stirred for another 10 min, and extracted with three 50-ml portions of CH2Cl2. The
combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary evaporator
to furnish crude 21 as a pale yellow solid, which was purified by CC (SiO2; AcOEt/PE 1:30) to afford
pure 21 as a white solid. Yield: 3.82 g (80%). M.p. 98 – 998. 1H-NMR: 1.33 (t, J ¼ 7.0, Me); 1.37 (t, J ¼ 7.0,
Me); 1.56 (s, Me2C); 4.08 (q, J¼ 6.9, CH2O); 4.16 (q, J¼ 6.9, CH2O); 7.16 (s, 1 arom. H); 7.29 (s, 1 arom. H).
5,6-Diethoxy-3,3-dimethyl-2-benzofuran-1(3H)-one (21). A dried 50-ml round-bottomed flask was
charged with 1.77 g (5.84 mmol) of 6, 0.52 g (7 mmol) of CuCN, and 15 ml of dried DMF, and the mixture
was stirred at reflux under N2, until all 6 was consumed (TLC; typically within 5 h). On cooling, the
mixture was poured into 200 ml of H2O, and the mixture was extracted with three 50-ml portions of
CH2Cl2. The combined extracts were washed with sat. brine, dried (Na2SO4), and evaporated on a rotary
evaporator to give crude 21 as a deep brown oil, which was purified by CC (SiO2; AcOEt/PE 1:30) to
yield pure 21 as a waxy white solid. Yield: 1.18 g (81%). M.p. 98 – 998. IR: 3077w, 1731s (C¼O), 1598m,
1503m, 1477m, 1364m. 1H-NMR: 1.31 – 1.38 (m, 2 Me); 1.56 (s, Me2C); 4.08 (q, J ¼ 6.9, CH2O); 4.16 (q,
J ¼ 6.9, CH2O); 7.16 (s, 1 arom. H); 7.29 (s, 1 arom. H). 13C-NMR: 14.33 (Me); 14.42 (Me); 26.94 (2 Me);
64.09 (CH2O); 64.35 (CH2O); 84.28 (CꢀO); 104.50, 106.77 (2 arom. CH); 115.65, 149.08, 149.47, 154.03 (4
arom. C); 168.93 (C¼O). HR-MS (TOF-ESþ): 251.1302 ([M þ H]þ, C14H19Oþ4 ; calc. 251.1283); 273.1105
([M þ Na]þ, C14H18NaOþ4 ; calc. 273.1103).
The authors are very grateful for the financial support of the division program of the National
Platform of Key Innovative Drug of PRC (2009ZX09301-008-P-05).
RERERENCES
[1] S. Chackalamannil, J. Med. Chem. 2006, 49, 5389.
[2] H. C. Zhang, D. F. McComsey, K. B. White, M. F. Addo, P. Andrade-Gordon, C. K. Derian, D.
Oksenberg, B. E. Maryanoff, Bioorg. Med. Lett. 2001, 11, 2105.
[3] S. Chackalamannil, Y. G. Wang, W. G. Greenlee, Z. Y. Hu, Y. Xia, H. S. Ahn, G. Boykow, Y. Hsieh, J.
Palamanda, J. Agans-Fantuzzi, S. Kurowski, M. Graziano, M. Chintala, J. Med. Chem. 2008, 51, 3061;
Y. Xia, S. Chackalamannil, WO Pat. 2009124103, 2009, p. 54; Chem. Abstr. 2009, 151, 136.
[4] a) S. Suzuki, M. Kotake, M. Miyamoto, T. Kawahara, A. Kajiwara, I. Hishinuma, K. Okano, S.
Miyazawa, WO Pat. 02085855, 2002, p. 142; Chem. Abstr. 2002, 137, 632; b) K. Yoshizawa, T.
Nakamura, S. Negi, WO Pat. 2006018955, 2006, pp. 11 – 20; Chem. Abstr. 2006, 144, 1011.
[5] A. Kalir, Z. Pelah, Isr. J. Chem. 1967, 5, 223.
[6] a) V. H. Maddox, E. F. Godefroi, R. F. Parcell, J. Med. Chem. 1965, 8, 230; b) C. Kaiser, J.
Weinstock, Org. Synth. 1971, 51, 48.
[7] a) D. Balderman, A. Kalir, Synthesis 1978, 24; b) A. Kalir, D. Balderman, Org. Synth. 1981, 60, 104.
[8] W. H. Gray, G. A. H. Buttle, D. Stephenson, Biochem. J. 1937, 31, 724.
[9] T. K. Kirk, E. Alder, Acta. Chem. Scand. 1970, 24, 3379.
[10] I. A. Pearl, D. L. Beyer, J. Am. Chem. Soc. 1952, 74, 3188.
[11] D. H. Klaubert, J. H. Sellstedt, C. J. Guinosso, S. C. Bell, R. J. Capetola J. Med. Chem. 1981, 24, 748;
D. H. Klaubert, S. C. Bell, T. W. Pattison, J. Heterocycl. Chem. 1985, 22, 333.
[12] G. I. Koldobskii and V. A. Ostrovskii, Russ. Chem. Rev. 1994, 63, 797.
Received March 25, 2011