Practical syntheses of enantiomerically pure N-acetylbenzhydrylamines

Article abstract of DOI:10.1002/ejoc.200700193

Two practical routes for the synthesis of benzhydrylamine derivatives in enantiomerically pure form have been developed. N-Acetylbenzhydrylamines can be synthesised in few steps and good yields starting from 1-aryl-1-propargylamines. The key steps are rep

Full text of DOI:10.1002/ejoc.200700193

FULL PAPER
DOI: 10.1002/ejoc.200700193
Practical Syntheses of Enantiomerically Pure N-Acetylbenzhydrylamines
Daniele Castagnolo,[a] Gianluca Giorgi,[b] Raffaella Spinosa,[a] Federico Corelli,[a] and
Maurizio Botta*[a]
Keywords: Alkene–alkyne cross-metathesis / Diels–Alder reaction / Benzhydrylamine
Two practical routes for the synthesis of benzhydrylamine de-
rivatives in enantiomerically pure form have been devel-
oped. N-Acetylbenzhydrylamines can be synthesised in few
steps and good yields starting from 1-aryl-1-propar-
utes and high yields. N-Acetylbenzhydrylamines have been
also converted in both enantiomers of the antifungal agent
bifonazole, emphasizing the importance of these compounds
as scaffolds for the synthesis of biologically active com-
gylamines. The key steps are represented by the alkene- pounds in enatiopure form.
alkyne cross metathesis reaction and alkyne–diene methyl-
ene-free tandem-metathesis reaction; these reactions have
been performed under microwave irradiation in a few min-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
their application.[7] Thus, the development of an efficient
and versatile method for the synthesis of optically active
diarylmethylamines is still highly desiderable.
Introduction
Benzhydrylamine (diarylmethylamine) and its substituted
derivatives are an important class of compounds in organic
synthesis because of their use as protecting groups.[1] More-
over the benzhydryl structural motif is an important substi-
tution pattern in many pharmaceuticals and biologically
active molecules.[2] Specifically, drugs containing the benz-
hydryl motif either in preclinical testing or in clinical appli-
cations include antihypertensives, anti-allergics, hypolipid-
emics, anti-Parkinson agents, opioid agonists, antifungal
agents,[3] aromatase inhibitors and others.[4] A wide array
of syntheses of benzhydrylamines are known, based on
transformations of the corresponding benzhydrols, re-
duction of oxime derivatives, reductive amination of benzo-
phenone precursors, and addition of organometallic rea-
gents to either aldimines, N-boryl imines, quaternary hydra-
zonium salts or nitriles.[5] Otherwise only few methods are
available for the synthesis of diarylmethylamines in op-
tically pure form. Resolution using (+)- or (–)-tartaric acid
salts has previously been used by our group.[3c,6] In recent
years many efforts have been made and great progress has
been achieved in the catalytic enantioselective arylation of
imines. Nevertheless, the use of toxic, moisture-sensitive, or
non-commercially available organometallic reagents and
sometimes the need of sterically tuned substrates or expens-
ive chiral auxiliaries for high enantioselectivity may limit
In the last decade our group has been involved in the
synthesis of enantiomerically pure azole derivatives as anti-
fungal agents and aromatase inhibitors which contain the
benzhydrylamino motif.[3b–3e] In this work we described two
routes for the synthesis of enantiomerically pure N-acetyl-
benzhydrylamines with the general structure A which could
be easily converted into chiral biologically active com-
pounds. The two retrosynthetic approaches are illustrated
in Scheme 1.
N-Protected benzhydrylamines A could be obtained by
aromatization from cyclohexenes B synthesised by Diels–
Alder reaction from dienes C; dienes could be obtained via
alkene–alkyne cross-metathesis from N-acetyl-1-aryl-1-pro-
pargylamines E whose synthesis in enantiomerically pure
form was described previously by our group.[8] Alterna-
tively, N-protected benzhydrylamines A could be prepared
by aromatization from cyclohexadienes D, in turn synthe-
sised via alkyne–diene methylene-free tandem-metathesis
reaction from N-acetyl-1-aryl-1-propargylamines E. In both
cases the starting material is represented by the N-acetyl-1-
aryl-1-propargylamines which can be synthesised in enan-
tiomerically pure form in few steps and high and reproduc-
ible yields via kinetic enzymatic resolution of the corre-
sponding racemic amines.
[a] Dipartimento Farmaco Chimico Tecnologico, Università degli
Studi di Siena,
Via Alcide de Gasperi 2, 53100 Siena, Italy
Fax: +39-0577-234333
E-mail: botta@unisi.it
[b] Dipartimento di Chimica, Università degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Enantiomerically Pure Benzhydrylamines
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Scheme 1.
Furthermore, the reactivity of 1,3-butadienes of type C
with different dienophiles in Diels–Alder cycloaddition re-
actions was also investigated. Finally, N-acetylbenzhy-
drylamines were converted into both enantiomers of anti-
fungal agent bifonazole, which were previously synthesised
by us via resolution of diastereomeric salts of (4-bro-
mophenyl)phenylmethylamine with (+)- and (–)-tartrate,[3c]
thus confirming the initial configuration assignment.
Scheme 2.
Table 1. Yields and ee values for dienes 2a–j.
R
RЈ
ee[a]
Yield (%)[b] Ratio E/
Z[c]
Results and Discussion
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
H
96
97
95
96
95
97
96
0
45
64
70
55
48
88
53
0
4-F
4-Cl
3-F
3-Me
H
H
H
H
H
First Route. Alkyne–Alkene Cross-Metathesis Reaction
H
N-Acetyl-1-aryl-1-propargylamines 1a–e were synthe-
sised in enantiomerically pure form according to our pro-
cedure via enzymatic kinetic resolution of the correspond-
ing racemate using Candida antarctica Lipase B.[8a] In our
previous communication we reported the cross metathesis
reaction of these substrates with ethylene under microwave
irradiation; under these conditions 1,3-dienes 2a–e have
been obtained in good yields and in a few minutes.[8b]
Herein we decided to extend our methodology and to evalu-
ate the efficacy of the microwave-assisted cross-metathesis
reaction; compound (R)-1a was treated with different al-
kenes in the presence of Grubbs’ 2nd generation catalyst (10
mol-%) in toluene at 80 °C and under microwave irradia-
OEt
OAc
TMS
CN
1.0:0.5
1.0:0.5
97
79
58
1.0:0.5
1.0:0.5
2j
3-MeOC6H4 94
[a] Determined by chiral HPLC-MS using an S,S-Whelk-O1 col-
umn. (50% water/methanol, 0.8 mL/min, UV-254). [b] Referred to
isolated and purified materials. [c] Determined by H-NMR inter-
1
gration.
First Route. Diels–Alder Reactions
Product 2f has been chosen to explore the reactivity of
tion, affording dienes 2f–j after only 20 minutes (2 runs of these dienes toward the Diels–Alder cycloaddiction since it
10 min) (Scheme 2). Yields and ee values are reported in is an electron-rich diene due to electron-donating ethoxy
Table 1. Compounds 2f and 2i were obtained in high yields, group. Compound 2f was treated with different dienophiles
while 2g and 2j were isolated in lower yields. Vinyltrimethyl- with the aim to obtain an appropriate cyclohexene synthon
silane did not undergo cross metathesis under these condi- to be further transformed into benzhydrylamines.
tions and compound 2h was not obtained even with higher
At first, compound 2f (E/Z mixture) was reacted under
catalyst loading and longer reaction times. In every in- thermal conditions: methylacrylate and acrylonitrile were
stance, dienes were obtained as a mixture of E/Z isomers selected as dienophiles (Scheme 3). In both cases, after 24
1
(1.0:0.5 E/Z ratio), and the ratios were determined by H- hours, diastereoisomeric mixtures of cyclohexenes 3a–b
NMR spectroscopy.
were detected in 53% and 59% yield respectively, together
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Scheme 3.
Scheme 4.
Scheme 5.
with traces of the “meta” isomers and the unreacted Z iso-
mer of 2f.[9–10]
The reactivity of 2f with chloroacrylonitrile (Corey’s
masked ketene) under thermal condition was also exam-
The resistance of Z isomer to undergo cycloaddition can ined; only a small amount of the desired cycloadduct 3c
be explained on the basis of the favoured s-trans conforma-
tion assumed by Z isomer (Scheme 4). Efforts to convert
the recovered 2f (Z isomer) into the corresponding E isomer
were made according to the literature;[11] 2f (Z isomer) was
heated in toluene at reflux for 24 hours (Scheme 4) but no
traces of E isomer were detected and only a small amount
of 2f (Z isomer) was recovered. Compound 4 was isolated
as major product (70% yield).
In the Scheme 4 the proposed mechanism is reported. We
can assume that above 90 °C the cyclization of 2f (Z isomer)
leading to the stable pyrrole 4 with elimination of ethanol
is faster than the ZǞE isomerization.
Scheme 6.
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Enantiomerically Pure Benzhydrylamines
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Scheme 7.
was recovered in 31% yield as a mixture of diastereoisomers with either ethyl glyoxalate and DEAD to afford respec-
together with pyrrole 4 in 30% yield. (Scheme 5). We hy- tively dihydropyran 3f and dihydropyridazine 3g as mixture
pothesised that during the course of the reaction some HCl of diasteroisomers.[13] Compound 2f was also tried to be
could have been formed and the acidic conditions as well react with different imines under several conditions but in
as the high temperature could have catalyzed and ac- no one case the desired cycloadducts 3h–j were obtained
celerated the formation of the pyrrole. It is known that chlo- (Scheme 7).
roacrylonitrile represents the equivalent of a ketene and
that chloronitrile functionality can be hydrolyzed to a car-
bonyl group. Hence, adduct 3c was treated with DMSO and
KOH following standard procedures[12] in order to obtain
First Route. From N-Acetylbenzhydrylamines to
ketone 5; unfortunately we were unable to isolate from the
reaction mixture the desired compound 5 whereas deriva-
tives 6 and 7 were obtained. The structure of 7 was con-
(S)-Bifonazole
Starting from cycloadduct 3e a synthesis of N-acetyl-
firmed by X-ray analysis. A possible explanation for the benzhydrylamines with general structure A has been devel-
formation of 7 could be that under basic conditions, aroma- oped. The alkoxy group of cyclohexenes could be elimin-
tization of cyclohexane by elimination of hydrochloric acid ated under acidic or basic condition.[10,14] Treatment of 3e
and ethanol may occur with the concomitant formation of with K2CO3 in refluxing methanol afforded the elimination
the amide by hydrolysis of CN group. Under the same con- product cyclohexadiene 8; under these conditions racemiza-
ditions also hydrolisis of acetamide may occurs. The acidic tion was observed and compound 8 showed to have an en-
benzylic proton could be then removed under basic condi- antiomeric excess of 22% as revealed by HPLC-MS analy-
tions leading to an imine, which could be then hydrolysed sis. When 3e was submitted to acidic elimination with
to give the ketone 7 (Scheme 5).
H2SO4 20%, 8 could be obtained in high yield and in enan-
In order to overcome the shortcomings of the thermal tiomerically pure form. Subsequent oxidation of 8 with
cycloaddition, compound 2f was reacted under acid-cata- DDQ[15] led to the benzhydrylamide 9 which was then con-
lyzed conditions using either acrolein or methyl vinyl ketone verted into the acetyl phenol 10 by Baeyer–Villiger oxi-
as dienophiles; in both cases compounds 3d–e were ob- dation. After removal of acetyl ester of 10 under mild basic
tained as a mixture of two major diastereoisomers in high conditions, phenol 11 was obtained and then converted into
yields (89 and 96%, respectively) as “ortho” and endo the corresponding triflate 12. This latter compound is one
adducts[9,10] (Scheme 6). It is well known that most of the of the targets of our synthesis since it represents an impor-
Diels–Alder reactions are accelerated by the presence of a tant enantiomerically pure building block containing a
Lewis acid and that their regio- and stereoselectivities are benzhydrylamino motif and a triflate group which can be
often increased over the uncatalyzed reactions. Both Z and coupled through Suzuki reaction with different boronic ac-
E dienes turned out to be reactive under catalyzed condi- ids. Since compound 12 is unstable, it was immediately con-
tions. In fact, under acidic conditions the Z isomer readily verted into the biary derivative (S)-13, which showed a 95%
isomerizes to the E isomer, which again can readily adapt ee according to HPLC analysis. Compound (S)-13 was then
the s-cis conformation.
transformed in two steps[16] into the enantiopure bifonazole
The reactivity of diene 2f in hetero [4+2] cycloaddiction (S)-15, whose configuration assignment reported in our pre-
was also investigated. Diene 2f underwent cycloaddition vious work was confirmed[3c] (Scheme 8).
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D. Castagnolo, G. Giorgi, R. Spinosa, F. Corelli, M. Botta
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Scheme 8.
Second Route. From N-Acetyl-bromo-benzhydrylamine to
(R)-Bifonazole
octadiene.[17] We reasoned that tandem metathesis could be
a shorter and elegant approach for the synthesis of enantio-
pure benzhydrylamines starting from bromo-propar-
With the aim to develop a shorter and faster synthesis of gylamide (R)-1f which was not reported in our previous
benzhydrylamines with general structure A, another inter- work.[8] The racemic amine 16 was submitted to enzymatic
esting approach has been developed and examined: the kinetic resolution using AcOEt as acylating agent and li-
methylene-free tandem-metathesis reaction. Tandem me- pase B from Candida antarctica, affording enantiopure
tathesis between alkynes and dienes provides an useful and amide (R)-1f and amine (S)-16. Bromo-propargyl amide
efficient way for ring synthesis. Diver and co-workers re- (R)-1f[18] was treated with cyclooctadiene in the presence of
cently reported the synthesis of cyclohexadienes via tandem Grubbs’ 2nd generation catalyst (10 mol-%), following our
metathesis starting from different alkynes and using cyclo- microwave-assisted method.[8b] Under these conditions cy-
Scheme 9.
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Enantiomerically Pure Benzhydrylamines
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the reaction vessel. All the experiments were performed using a
stirring option whereby the contents of the vessel are stirred by
means of rotating magnetic plate located below the floor of the
microwave cavity and a Teflon-coated magnetic stirbar in the vessel.
clohexene 17 was obtained in 60% yield and the unreacted
starting material was recovered. Prolonged reaction times
and higher catalyst loading (15 mol-%) did not afford any
improvement into the yield. Compound 17 was then oxi-
dised with DDQ into 18 which results to be an interesting
synthon containing a benzhydrylamino motif.[19] 18 was
submitted to Suzuki coupling with phenylboronic acid af-
fording (R)-13 which presented an 97% ee according to
HPLC analysis. Transformation of (R)-13 into (R)-bifona-
zole (R)-15 was accomplished in two steps without loss of
enantiomeric purity[16,3c] (Scheme 9).
Synthesis of (R)- [(R)-1f] and (S)-N-Acetyl-1-(4-bromophenyl)prop-
2-ynylamine [(S)-16]: Compounds (R)-1f and (S)-1g such as (R)-
1a–e were synthesised starting from 16 (2 g, 7.93 mmol) as reported
in the literature.[8]
(R)-N-Acetyl-1-(4-bromophenyl)prop-2-ynylamine [(R)-1f]: Time: 25
h. Yield: 900 mg (45%). 1H NMR (CDCl3): δ = 7.46 (d, J = 8.7 Hz,
2 H, Ph), 7.35 (d, J = 8.7 Hz, 2 H, Ph), 5.91 (s, 1 H, CHN), 2.43
(s, 1 H, CCH), 1.95 (s, 3 H, CH3) ppm. 13C NMR (CDCl3): δ =
23.1, 44.0, 73.5, 80.0, 122.3, 128.8, 131.8, 137.4, 168.8 ppm. IR
(KBr): ν = 1669, 1486 cm–1. MS: m/z = 274/276 [M + Na]. [α]20
=
˜
D
Conclusions
+50.1 (c = 0.6, CHCl3). C11H10BrNO (252.11): calcd. C 52.41, H
4.00, N 5.56; found C 52.30, H 4.29, N 5.89.
In conlusion in this work two approaches for the synthe-
sis of N-acetylbenzhydrylamines 12, 13 and 18 in enantio-
merically pure form were developed. Both synthetic pro-
cedures revealed to be very efficient and reproducible for
the synthesis of biarylmethylamines of type A. The alkene-
alkyne metathesis reaction between enantiopure 1-aryl-1-
propargylamides (R)-1a–e and different alkenes under mi-
crowave irradiation as well as the reactivity of resulting
dienes toward Diels–Alder cycloaddition were extensively
investigated. The feasibility of methylene-free tandem me-
tathesis between alkyne (R)-1f and cyclooctadiene was also
been explored. Finally both enantiomers of antifungal
agent bifonazole 15 were synthesised starting from enantio-
merically pure N-acetylbenzhydrylamines 12 and 18.
(S)-1-(4-Bromophenyl)prop-2-ynylamine [(S)-16]: Time: 25 h. Yield:
615 mg (37%). 1H NMR (CDCl3): δ = 7.28 (d, J = 8.4 Hz, 2 H,
Ph), 7.22 (d, J = 8.4 Hz, 2 H, Ph), 4.51 (s, 1 H, CHN), 2.41 (s, 1
H, CCH), 1.75 (br. s, 2 H, NH2) ppm. 13C NMR (CDCl3): δ =
46.0, 72.4, 85.3, 121.0, 128.0, 131.0, 140.1 ppm. IR (KBr): ν =
˜
3295, 1661, 1534 cm–1. MS: m/z = 232/234 [M + Na]. [α]2D0 = +20.0
(c = 2.4, CHCl3). C9H8BrN (210.07): calcd. C 51.46, H 3.84, N
6.67; found C 51.72, H 4.02, N 6.70.
Synthesis of (R)- and (S)-2-[(Acetylamino)arylmethyl]-1,3-butadiene
[(R)-2a–e]. General Procedure: Into an oven-dried pressure vial
equipped with magnetic stirbar and under argon, (R)-1a–e
(0.6 mmol) was dissolved in 4 mL of degassed toluene. Grubbs’ 2nd
generation catalyst (10 mol-%) was then added and the mixture was
submitted to ethylene atmosphere whilst stirring. The vessel was
introduced into the microwave oven and heated at 80 °C twice for
10 minutes under microwave irradiation. Dimethyl sulfoxide
(DMSO) (50 equiv.) was added and the reaction mixture was left
whilst stirring for 12 h; the solvent was then removed in vacuo to
afford a dark brown oil that was purified by flash chromatography
(Et2O/petroleum ether, 2:1) to give (R)-2a–e as a clear oil.
Experimental Section
General: Reagents were obtained from commercial suppliers and
used without further purification. Toluene was dried with Na/
benzophenone prior to use. Anydrous reactions were run under a
positive pressure of dry N2 or Ar. Merck silica gel 60 was used
(R)-2-[(Acetylamino)phenylmethyl]-1,3-butadiene (2a): Yield: 54 mg
1
1
for flash chromatography (23–400 mesh). H NMR and 13C NMR
(45%). Oil. H NMR (CDCl3): δ = 7.47–7.26 (m, 5 H, Ph), 6.39–
6.24 (dd, J = 17.6, J = 11.2 Hz, 1 H, CCHCH2), 5.89 (d, J = 7.9 Hz,
1 H, CHN), 5.81 (br. d, J = 7.9 Hz, 1 H, NH), 5.31 (s, 1 H, CCH2),
5.19 (d, J = 17.7 Hz, 1 H, CCHCH2), 5.09 (s, 1 H, CCH2), 5.05 (d,
J = 12.0 Hz, 1 H, CCHCH2), 2.00 (s, 3 H, CH3) ppm. IR (KBr):
spectra were measured at 200 MHz on a Bruker AC200F spectrom-
eter and at 400 MHz on a Bruker Avance DPX400. Chemical shifts
are reported relative to CDCl3 at δ = 7.24 ppm and tetramethylsil-
ane at δ = 0.00 ppm. Elemental analyses (C,H,N) were performed
in-house.
ν = 1676, 1497 cm–1. MS: m/z = 202 [M + 1], 224 [M + Na]. [α]20
˜
D
= +34.0 (c = 0.8, CHCl3). C13H15NO (201.26): calcd. C 77.58, H
7.51, N 6.96; found C 77.66, H 7.73, N 7.05.
HPLC and MS Analysis: The purity of compounds was assessed
by reverse-phase liquid chromatography and a mass spectrometer
(Agilent series 1100 LC/MSD) with a UV detector at λ = 254 nm
and an electrospray ionization source (ESI). All the solvents were
HPLC grade (Fluka). Mass spectral (MS) data were obtained using
an Agilent 1100 LC/MSD VL system (G1946C) with a 0.4 mL/min
flow rate using a binary solvent system of 95:5 methyl alcohol/
water. UV detection was monitored at 254 nm. Mass spectra were
acquired by using electrospray ionization in positive mode scanning
over the mass range of 50–1500. The following ion source param-
eters were used: drying gas flow: 9 mL/min, nebulize pressure: 40
psi, drying gas temperature: 350 °C.
(R)-2-[(Acetylamino)(4-fluorophenyl)methyl]-1,3-butadiene (2b):
1
Yield: 81.4 mg (62%). Oil. H NMR (CDCl3): δ = 7.27–7.19 (m, 2
H, Ph), 7.09–7.02 (m, 2 H, Ph), 6.36–6.29 (dd, J = 17.8, J =
10.8 Hz, 1 H, CCHCH2), 5.85 (d, J = 7.8 Hz, 1 H, CHN), 5.70 (br.
d, J = 7.9 Hz, 1 H, NH), 5.31 (s, 1 H, CCH2), 5.18 (d, J = 17.8 Hz,
1 H, CCHCH2), 5.08 (d, J = 10.7 Hz, 1 H, CCHCH2), 5.06 (s, 1
H, CCH2), 2.01 (s, 3 H, CH3) ppm. IR (KBr): ν˜ = 1676, 1497 cm–1.
MS: m/z = 220 [M + 1], 242 [M + Na]. [α]2D0 = +36.0 (c = 1.0,
CHCl3). C13H14FNO (219.25): calcd. C 71.21, H 6.44, N 6.39;
found C 71.33, H 6.54, N 6.20.
Microwave Irradiation Experiments: Microwave irradiations were
conducted using a CEM Discover Synthesis Unit (CEM Corp.,
Matthews, NC). The machine consists of a continous focused mi-
crowave source with operator-selectable power output from 0 to
300 W. The temperature of the content of a vessel was monitored
by using a calibrated infrared-based thermometer mounted under
(R)-2-[(Acetylamino)(4-chlorophenyl)methyl]-1,3-butadiene (2c):
Yield: 96.2 mg (68%). Oil. H NMR (CDCl3): δ = 7.30–7.17 (m, 4
H, Ph), 6.38–6.24 (dd, J = 17.7, J = 10.9 Hz, 1 H, CCHCH2), 5.86
(d, J = 7.9 Hz, 1 H, CHN), 5.76 (br. d, J = 7.9 Hz, 1 H, NH), 5.31
(s, 1 H, CCH2), 5.18 (d, J = 17.8 Hz, 1 H, CCHCH2), 5.08 (d, J =
10.9 Hz, 1 H, CCHCH2), 5.05 (s, 1 H, CCH2), 2.02 (s, 3 H, CH3)
1
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ppm. IR (KBr): ν = 1676, 1497 cm–1. MS: m/z (%) = 238 [M + 1],
+ Na]. C15H17NO3 (259.30): calcd. C 69.48, H 6.61, N 5.40; found
C 69.60, H 6.84, N 5.67.
˜
258/260 [M + Na]. [α]2D0 = +69.0 (c = 1.0, CHCl3). C13H14ClNO
(235.71): calcd. C 66.24, H 5.99, N 5.94; found C 66.40, H 6.10, N
6.08.
(R)-N-[(E/Z)-4-Cyano-2-methylene-1-phenylbut-3-enyl]acetamide
1
(2i): Yield: 205.3 mg (79%). H NMR (CDCl3): δ = 7.32–7.00 (m,
(R)-2-[(Acetylamino)(3-fluorophenyl)methyl]-1,3-butadiene (2d): 11 H, Ph, CHCHCN, Z), 6.81 (d, J = 10.2 Hz, 1 H, CHCHCN,
1
Yield: 71.0 mg (54%). Oil. H NMR (CDCl3): δ = 7.38–7.28 (m, 1
E), 6.30 (d, J = 10.2 Hz, 1 H, CHCHCN, E), 6.33 (d, J = 8.0 Hz,
H, Ph), 7.26–6.89 (m, 3 H, Ph), 6.38–6.23 (dd, J = 17.3, J = 1 H, CHN, Z), 6.00 (s, 1 H, C=CHH, E), 5.75 (s, 1 H, C=CHH,
10.8 Hz, 1 H, CCHCH2), 5.88 (d, J = 7.7 Hz, 1 H, CHN), 5.73 (br. Z), 5.73 (d, J = 8.2 Hz, 1 H, CHN, E), 5.53 (s, 1 H, C=CHH, E),
d, J = 7.7 Hz, 1 H, NH), 5.32 (s, 1 H, CCH2), 5.20 (d, J = 17.7 Hz,
5.36 (s, 1 H, C=CHH, Z), 5.22 (m, 1 H, CHCHCN, Z), 2.02 (s, 3
1 H, CCHCH2), 5.10 (d, J = 10.8 Hz, 1 H, CCHCH2), 5.06 (s, 1 H, NCOCH , Z), 2.00 (s, 3 H, NCOCH , E) ppm. IR (KBr): ν =
˜
3
3
H, CCH ), 2.03 (s, 3 H, CH ) ppm. IR (KBr): ν = 1676, 1497 cm–1.
2238, 1661, 1494 cm–1. MS: m/z = 227 [M + 1], 249 [M + Na].
C14H14N2O (226.27): calcd. C 74.31, H 6.24, N 12.38; found C
74.56, H 6.54, N 12.56.
˜
2
3
MS: m/z (%) = 220 [M + 1], 242 [M + Na]. [α]2D0 = +20.0 (c = 0.6,
CHCl3). C13H14FNO (219.25): calcd. C 71.21, H 6.44, N 6.39;
found C 71.39, H 6.60, N 6.46.
(R)-N-[(E/Z)-4-(3-Methoxyphenyl)-2-methylene-1-phenylbut-3-enyl-
]acetamide (2j): Yield: 204.7 mg (58 %). 1H NMR (CDCl3): δ =
7.42–7.02 (m, 19 H, Ph, CHCHPhOMe, Z), 6.75 (d, J = 11.2 Hz,
1 H, CHCHPhOMe, E), 6.62–6.56 (m, 2 H, CHCHPhOMe, Z/E),
5.99 (s, 1 H, C=CHH, Z), 5.96 (d, J = 8.6 Hz, 1 H, CHN, Z), 5.42
(s, 2 H, C=CHH, Z/E), 5.24 (m, 1 H, CHN, E), 5.14 (s, 1 H,
C=CHH, E), 3.77 (s, 3 H, OCH3, E), 3.73 (s, 3 H, OCH3, Z), 2.02
(R)-2-[(Acetylamino)(3-methylphenyl)methyl]-1,3-butadiene (2e):
1
Yield: 63.2 mg (49%). Oil. H NMR (CDCl3): δ = 7.28–7.04 (m, 4
H, Ph), 6.37–6.23 (dd, J = 17.6, J = 11.0 Hz, 1 H, CCHCH2), 5.94
(br. d, J = 7.7 Hz, 1 H, NH), 5.84 (d, J = 7.9 Hz, 1 H, CHN), 5.30
(s, 1 H, CCH2), 5.19 (d, J = 17.7 Hz, 1 H, CCHCH2), 5.10 (s, 1 H,
CCH2), 5.05 (d, J = 11.1 Hz, 1 H, CCHCH2), 2.31 (s, 3 H, PhCH3),
2.00 (s, 3 H, CH ) ppm. IR (KBr): ν = 1676, 1497 cm–1. MS: m/z
(s, 6 H, NCOCH , Z/E) ppm. IR (KBr): ν = 1664, 1494 cm–1. MS:
m/z = 308 [M + 1], 330 [M + Na]. C20H21NO2 (307.39): calcd. C
˜
˜
3
3
= 216 [M + 1], 238 [M + Na]. [α]2D0 = +35.0 (c = 0.7, CHCl3).
C14H17NO (215.29): calcd. C 78.10, H 7.96, N 6.51; found C 78.23,
H 8.04, N 6.69.
78.15, H 6.89, N 4.56; found C 78.34, H 6.99, N 4.78.
Synthesis of Cyclohexenes 3a–c. General Procedure: Into an oven-
dried baloon equipped with a condenser, 2f (200 mg, 0.8 mmol)
was dissolved in dry toluene (5.6 mL). The appropriate dienophile
(2 equiv/mol) was then added and the mixture stirred at 80–90 °C
for 24 hours. After this time, the solution was cooled, water was
added and the mixture left stirring for 30 min. The mixture was
then extracted with AcOEt two times. The combined organic layers
were washed with brine, dried (Na2SO4), filtered and evaporated
to give the crude 3a–c. The crude products were purified by flash
chromatography on silica gel, using Et2O/petroleum ether (2:1) as
eluant. After purification Z-dienes isomers were recovered. Com-
pounds 3a–c were obtained as a mixture of diastereoismers. Proton
NMR indicate two major diastereoisomers (endo and exo) in 1:2.5
ratio.
Synthesis of (R)-N-[(E/Z)-2-Methylene-1-phenylbut-3-enyl]acet-
amides 2f–j. General Procedure: Into an oven-dried pressure vial
equipped with magnetic stirbar and under argon, (R)-1a
(1.15 mmol) was dissolved in 3 mL of degassed toluene. Grubbs’
2nd generation catalyst (10 mol-%) and the appropriate vinyl com-
pound (9 equiv/mol) were then added. The vessel was introduced
into the microwave oven and heated at 80 °C twice for 10 minutes
under microwave irradiation. After cooling, the solvent was re-
moved in vacuo to afford a dark brown oil that was purified by
flash chromatography (Et2O/petroleum ether, 2:1) to give 2f–j as a
E/Z mixture (proton NMR indicates a 1.0:0.5 E/Z ratio).
(R)-N-[(E/Z)-4-Ethoxy-2-methylene-1-phenylbut-3-enyl]acetamide
1
(2f): Yield: 247.9 mg (88%). H NMR (CDCl3): δ = 7.29–7.18 (m,
10 H, Ph), 6.49 (d, J = 12.9 Hz, 1 H, CHCHOEt, E), 6.44 (d, J =
Methyl 4-[(Acetylamino)(phenyl)methyl]-2-ethoxycyclohex-3-ene-1-
8.0 Hz, 1 H, CNH, Z), 6.14 (d, J = 8.0 Hz, 1 H, CNH, E), 5.85 (d, carboxylate (3a, “ortho”): Yield: 140.3 mg (53 %). 1H NMR
J = 7.0 Hz, 1 H, CHCHOEt, Z), 5.80 (d, J = 8.0 Hz, 1 H, CHN, (CDCl3): δ = 7.27–7.20 (m, 10 H, Ph), 6.15 (d, J = 8.5 Hz, 1 H,
Z), 5.70 (d, J = 8.0 Hz, 1 H, CHN, E), 5.42 (d, J = 12.9 Hz, 1 H,
NH), 6.10 (d, J = 8.6 Hz, 1 H, NH), 5.86 (d, J = 3.7 Hz, 1 H,
CHCHOEt, E), 5.39 (s, 1 H, C=CHH, Z), 5.12 (s, 1 H, C=CHH, C=CH), 5.78 (d, J = 4.3 Hz, 1 H, C=CH), 5.50 (d, J = 8.6 Hz, 1
Z), 5.02 (s, 1 H, C=CHH, E), 4.78 (s, 1 H, C=CHH, E), 4.70 (d, J H, CHN), 5.42 (d, J = 8.5 Hz, 1 H, CHN), 4.12–4.01 (m, 2 H, 2
= 7.0 Hz, 1 H, CHCHOEt, Z), 3.67 (q, J = 7.0 Hz, 4 H, OCH2CH3, CHOEt), 3.65 (s, 6 H, 2 COOCH3), 3.62–3.42 (m, 4 H, 2
E/Z), 1.98 (s, 3 H, CH3, Z), 1.96 (s, 3 H, CH3, E), 1.17 (t, J =
OCH2CH3), 2.55–2.47 (m, 2 H, 2 CHCOOCH3), 2.08–1.81 (m, 8
7.0 Hz, 3 H, OCH2CH3, E), 1.05 (t, J = 7.0 Hz, 3 H, OCH2CH3, H, 2 CCH2CH2CH), 2.02 (s, 3 H, NCOCH3), 2.01 (s, 3 H,
Z) ppm. 13C NMR (CDCl3): δ = 14.7, 15.0, 23.1, 23.4, 55.0, 57.3,
65.4, 68.8, 104.1, 105.8, 111.1, 115.5, 126.9, 127.1, 127.3, 127.9,
128.1, 128.4, 140.3, 140.7, 141.7, 143.4, 145.9, 148.7, 169.1 ppm.
NCOCH ), 1.24–1.02 (m, 6 H, 2 OCH CH ) ppm. IR (KBr): ν =
˜
3 2 3
1725, 1671, 1496 cm–1. MS: m/z = 332 [M + 1], 354 [M + Na].
C19H25NO4 (331.41): calcd. C 68.86, H 7.60, N 4.23; found C
68.59, H 7.69, N 4.36.
IR (KBr): ν = 1667, 1496 cm–1. MS: m/z = 246 [M + 1], 268 [M +
˜
Na]. C15H19NO2 (245.32): calcd. C 73.44, H 7.81, N 5.71; found C
73.55, H 7.93, N 5.88.
N-[(4-Cyano-3-ethoxycyclohex-1-enyl)(phenyl)methyl]acetamide
(3b): Yield: 140.6 mg (59%). H NMR (CDCl3): δ = 7.32–7.12 (m,
1
(R)-N-[(E/Z)-4-Acetoxy-2-methylene-1-phenylbut-3-enyl]acetamide 10 H, Ph), 5.87 (d, J = 7.6 Hz, 1 H, NH), 5.83 (d, J = 7.5 Hz, 1
1
(2g): Yield: 157.8 mg (53%). H NMR (CDCl3): δ = 7.29–7.23 (m,
H, NH), 5.72 (d, J = 1.8 Hz, 1 H, C=CH), 5.68 (m, 1 H, C=CH),
11 H, Ph, CHCHOAc, E), 6.97 (d, J = 7.4 Hz, 1 H, CHCHOAc, 5.48 (d, J = 7.6 Hz, 1 H, CHN), 5.45 (d, J = 7.5 Hz, 1 H, CHN),
Z), 6.93 (br. s, 1 H, CNH, E), 6.21 (br. s, 1 H, CNH, Z), 5.94 (d,
J = 12.3 Hz, 1 H, CHCHOAc, E), 5.90 (d, J = 8.2 Hz, 1 H, CHN,
Z), 5.72 (d, J = 8.0 Hz, 1 H, CHN, E), 5.54 (s, 2 H, C=CHH,
4.06 (m, 2 H, 2 CHOEt), 3.72–3.43 (dq, J = 7.3 Hz, 4 H, 2
OCH2CH3), 2.83–2.69 (m, 2 H, 2 CHCN), 2.05–1.76 (m, 8 H, 2
CCH2CH2CH), 1.98 (s, 6 H, 2 NCOCH3), 1.25–1.16 (dt, J =
Z/E), 5.26 (s, 1 H, C=CHH, Z), 5.08 (s, 1 H, C=CHH, E), 4.19 (d, 7.3 Hz, 6 H, 2 OCH CH ) ppm. IR (KBr): ν = 2239, 1667,
˜
2
3
J = 7.4 Hz, 1 H, CHCHOAc, Z), 2.04 (s, 3 H, OCOCH3, E), 2.01
(s, 3 H, OCOCH3, Z), 2.00 (s, 6 H, NCOCH3, Z/E) ppm. IR (KBr):
˜
1496 cm–1. MS: m/z = 299 [M + 1], 321 [M + Na]. C18H22N2O2
(298.38): calcd. C 72.46, H 7.43, N 9.39; found C 72.59, H 7.65, N
9.57.
ν = 3442, 1759, 1673, 1496 cm–1. MS: m/z = 260 [M + 1], 282 [M
3682
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3676–3686

Enantiomerically Pure Benzhydrylamines
FULL PAPER
N-[(4-Chloro-4-cyano-3-ethoxycyclohex-1-enyl)(phenyl)methyl]acet-
amide (3c): Yield: 82.3 mg (31%). 1H NMR (CDCl3): δ = 7.35–7.19
loon (R)-2f (0.12 mmol) was dissolved in dry toluene (2 mL).
DEAD (1.2 equiv/mol) was then added and the mixture stirred at
(m, 10 H, Ph), 5.94 (d, J = 8.5 Hz, 1 H, NH), 5.89 (d, J = 7.9 Hz, room temperature for 1 hour. The solvent was then removed under
1 H, NH), 5.67 (m, 1 H, C=CH), 5.61 (d, J = 3.1 Hz, 1 H, C=CH), reduced pressure to give the crude 3f which was purified by flash
5.53 (d, J = 8.6 Hz, 1 H, CHN), 5.43 (d, J = 7.9 Hz, 1 H, CHN), chromatography on silica gel, using AcOEt/petroleum ether (1:1)
4.14–4.02 (m, 2 H, 2 CHOEt), 3.88–3.70 (m, 4 H, 2 OCH2CH3), as eluant. Compound 3f was obtained as a mixture of two dia-
2.49–2. 33 (m, 2 H, 2 CHClCN), 2. 28 –1 . 7 8 ( m, 8 H , 2 stereoisomers in 1:0.6 ratio. Yield: 37.71 mg (75 %). 1H NMR
CCH CH CH), 1.99 (s, 6 H, 2 NCOCH ) ppm. IR (KBr): ν = (CDCl3): δ = 7.27–7.15 (m, 10 H, Ph), 6.13 (d, J = 7.9 Hz, 1 H,
˜
2
2
3
2240, 1667, 1496 cm–1. MS: m/z = 333/335 [M + 1], 355/357 [M +
Na]. C18H21ClN2O2 (332.82): calcd. C 64.96, H 6.36, N 8.42; found
C 64.78, H 6.53, N 8.74.
CHOEt), 6.03 (d, J = 7.3 Hz, 1 H, CHOEt), 5.77 (m, 1 H, CHN),
5.59–5.55 (m, 2 H, CHN and C=CH), 5.50 (d, J = 8.0 Hz, 1 H,
C=CH), 4.47–4.07 (m, 8 H, 2 COOCH2CH3), 3.80–3.49 (m, 4 H,
2 OCH2CH3), 1.95 (s, 3 H, NCOCH3), 1.94 (s, 3 H, NCOCH3),
1.25–1.14 (m, 18 H, 2 COOCH2CH3 and 2 OCH2CH3) ppm. IR
Synthesis of Cyclohexenes 3d–e. General Procedure: A solution of
BF3·Et2O (1.1 mmol) and dienophile (1.1 mmol) in CH2Cl2 (3 mL)
was stirred at –30 °C under argon for 20 min. To the mixture cooled
to –78 °C was added a solution of the diene (1 mmol) in CH2Cl2
(3 mL) and stirring was continued for an additional 60 min. The
mixture was quenched with NaHCO3 (10 mL) and extracted with
AcOEt. The combined organic layers were washed with brine, dried
(Na2SO4), filtered and evaporated to give the crude 3d–e. The crude
products were purified by flash chromatography on silica gel, using
Et2O/petroleum ether (2:1) as eluant. Compounds 3d–e were ob-
tained as a mixture of diastereoisomers. Proton NMR indicate two
major diastereoisomers in 1:0.5 ratio.
(KBr): ν = 1740, 1660 cm–1. MS: m/z = 420 [M + 1], 442 [M +
˜
Na]. C21H29N3O6 (419.47): calcd. C 60.13, H 6.97, N 10.02; found
C 60.35, H 7.09, N 10.27.
Synthesis of Ethyl 5-[(Acetylamino)(phenyl)methyl]-6-ethoxy-3,6-di-
hydro-2H-pyran-2-carboxylate (3g): Into an oven-dried balloon (R)-
2f (0.24 mmol) was dissolved in dry CH2Cl2 (2 mL) and the mixture
was cooled to –30 °C. Ethyl glyoxalate (2 equiv./mol) was then
added and the mixture stirred at room temperature for 24 hours.
After this time, the solution was cooled, NaHCO3 was added and
the mixture left stirring for 30 min. The mixture was then extracted
with AcOEt two times. The combined organic layers were washed
with brine, dried (Na2SO4), filtered and evaporated to give the
crude 3g. The crude product was purified by flash chromatography
on silica gel, using AcOEt/petroleum ether (1:1) as eluant. Com-
pound 3g was obtained as a mixture of diastereoisomers. Proton
NMR indicate two major diastereoisomers (endo and exo) in 1:0.5
N-[(3-Ethoxy-4-formylcyclohex-1-enyl)(phenyl)methyl]acetamide
1
(3d): Yield: 267.9 mg (89%). H NMR (CDCl3): δ = 9.73 (s, 1 H,
CHO), 9.42 (s, 1 H, CHO), 7.31–7.15 (m, 10 H, Ph), 6.33 (d, J =
7.6 Hz, 1 H, NH), 6.05 (d, J = 8.0 Hz, 1 H, NH), 5.91 (d, J =
2.1 Hz, 1 H, C=CH), 5.75 (d, J = 4.3 Hz, 1 H, C=CH), 5.58 (d, J
= 8.0 Hz, 1 H, CHN), 5.48 (d, J = 7.6 Hz, 1 H, CHN), 4.26–4.19
(m, 2 H, 2 CHOEt), 3.67–3.40 (m, 4 H, 2 OCH2CH3), 2.55–2.45
(m, 2 H, 2 CHCOH), 2.40–1.75 (m, 8 H, 2 CCH2CH2CH), 1.97 (s,
3 H, NCOCH3), 1.96 (s, 3 H, NCOCH3), 1.24–1.06 (m, 6 H, 2
1
ratio. Yield: 52.3 mg (70%). H NMR (CDCl3): δ = 7.27–7.20 (m,
10 H, Ph), 6.00–5.96 (m, 2 H, 2 C=CH), 5.63–5.55 (m, 2 H, 2
CHN), 5.15 (m, 2 H, 2 CHOEt), 4.50–4.26 (m, 2 H, 2 CHCOOEt),
4.16 (dq, J = 7.1 Hz, 4 H, 2 COOCH2CH3), 3.86–3.51 (m, 4 H, 2
OCH2CH3), 2.25–1.87 (m, 4 H, 2 CCH2CH), 1.99 (s, 3 H,
NCOCH3), 1.95 (s, 3 H, NCOCH3), 1.29–1.13 (m, 12 H, 2 CO-
OCH CH ) ppm. IR (KBr): ν = 1729, 1665, 1496 cm–1. MS: m/z =
˜
2
3
302 [M + 1], 324 [M + Na]. C18H23NO3 (301.38): calcd. C 71.73,
H 7.69, N 4.65; found C 71.91, H 7.84, N 4.79.
OCH CH and 2 OCH CH ) ppm. IR (KBr): ν = 1743, 1653 cm–1.
˜
2
3
2
3
N-[(4-Acetyl-3-ethoxycyclohex-1-enyl)(phenyl)methyl]acetamide
MS: m/z = 348 [M + 1], 370 [M + Na]. C19H25NO5 (347.41): calcd.
C 65.69, H 7.25, N 4.03; found C 65.89, H 7.43, N 4.32.
1
(3e): Yield: 302.4 mg (96%). H NMR (CDCl3): δ = 7.24–7.08 (m,
10 H, Ph), 6.84 (d, J = 8.3 Hz, 1 H, NH), 5.85 (d, J = 4.5 Hz, 1
H, C=CH), 5.79 (d, J = 4.5 Hz, 1 H, C=CH), 5.41 (d, J = 8.3 Hz,
1 H, CHN), 5.35 (d, J = 8.2 Hz, 1 H, CHN), 4.10–4.03 (m, 2 H, 2
CHOEt), 3.47 (q, J = 7.0 Hz, 2 H, OCH2CH3), 3.27 (q, J = 7.0 Hz,
2 H, OCH2CH3), 2.58–2.28 (m, 2 H, 2 CHCOCH3), 2.18–1.43 (m,
8 H, 2 CCH2CH2CH), 2.05 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3),
1.86 (s, 3 H, NCOCH3), 1.82 (s, 3 H, NCOCH3), 1.02–0.93 (dt, J
Synthesis of Ketones 6 and 7: KOH (47 mg, 0.84 mmol) was dis-
solved in DMSO (4 mL) and H2O (1.5 mL) and heated at 50 °C
for 10 min. After cooling to room temperature, a solution of 3c
(140 mg, 0.42 mmol) in DMSO (1 mL) was added dropwise and
the mixture was stirred at 70 °C for 24 hours. The solution was
cooled and water was added. The mixture was stirred for an ad-
ditional 10 min. and then extracted with AcOEt. The combined
organic layers were washed with brine once more, dried (Na2SO4),
filtered and evaporated to give the crude mixture of 6 and 7. The
crude products were purified by flash chromatography on silica gel,
using AcOEt/petroleum ether (1:1) as eluant. Ketone 7: Yield:
41.6 mg (44%). 1H NMR (CDCl3): δ = 7.88–7.72 (m, 6 H, Ph),
7.59–7.41 (m, 3 H, Ph), 6.26 (br. s, 2 H, NH2) ppm. 13C NMR
(CDCl3): δ = 127.5, 128.7, 130.3, 130.4, 133.2, 136.7, 137.2, 140.8,
= 7.1 Hz, 6 H, 2 OCH CH ) ppm. IR (KBr): ν = 1740, 1661,
˜
2
3
1494 cm–1. MS: m/z = 316 [M + 1], 338 [M + Na]. C19H25NO3
(315.41): calcd. C 72.35, H 7.99, N 4.44; found C 72.54, H 8.09, N
4.73.
Synthesis of N-Acetyl-3-methyl-2-phenyl-1H-pyrrole (4): Diene 2f
(Z isomer, 2 mmol) was dissolved in dry toluene (14 mL) and the
mixture was refluxed for 24 hours. After cooling, the solvent was
removed in vacuo to afford a dark brown oil that was purified by
flash chromatography (Et2O/petroleum ether, 2:1) to give 4 as a
168.6, 195.8 ppm. IR (KBr): ν = 1731, 1661, 1598 cm–1. MS: m/z
˜
1
= 226 [M + 1], 248 [M + Na]. C14H11NO2 (225.24): calcd. C 74.65,
H 4.92, N 6.22; found C 74.76, H 5.10, N 6.35.
dark red oil. Yield: 278.6 mg (70%). H NMR (CDCl3): δ = 7.22–
7.08 (m, 6 H, Ph and CHN), 6.01 (d, J = 3.4 Hz, 1 H, CHCHC),
1.99 (s, 3 H, NCOCH3), 1.77 (s, 3 H, CCH3) ppm. 13C NMR
(CDCl3): δ = 11.8, 25.0, 114.2, 120.7, 123.6, 127.8, 128.4, 130.5,
Synthesis of Acetamide (S)-8: To a stirred solution of 3e (3.8 mmol)
in THF (50 mL) at 0 °C, H2SO4 20% (38 mL) was added and the
resulting solution was stirred at room temperature for 24 hours.
The reaction mixture was poured into AcOEt/brine and extracted
with AcOEt. The combined organic layers were washed with brine,
130.7, 134.0, 168.9 ppm. IR (KBr): ν = 1661, 1494 cm–1. MS: m/z
˜
= 200 [M + 1], 222 [M + Na]. C13H13NO (199.25): calcd. C 78.36,
H 6.58, N 7.03; found C 78.56, H 6.76, N 6.89.
Synthesis of Diethyl 5-[(Acetylamino)(phenyl)methyl]-3-ethoxy-3,6- dried (Na2SO4), filtered and evaporated to give the crude 8. The
dihydropyridazine-1,2-dicarboxylate (3f): Into an oven-dried bal- crude product was purified by flash chromatography on silica gel,
Eur. J. Org. Chem. 2007, 3676–3686
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3683

D. Castagnolo, G. Giorgi, R. Spinosa, F. Corelli, M. Botta
FULL PAPER
using AcOEt/petroleum ether (4:1) as eluant. Yield: 817.7 mg CH2Cl2 (5 mL) and cooled to –20 °C. Pyridine (1.0 mmol) was
1
(80%). H NMR (CDCl3): δ = 7.33–7.24 (m, 5 H, Ph), 6.92 (d, J added dropwise and the mixture stirred at this temperature for
= 5.0 Hz, 1 H, CHCH), 6.06 (d, J = 5.0 Hz, 1 H, CHCH), 5.86 (d, 10 min. Then (TfO)2O (0.26 mmol) was added and the resulting
J = 7.3 Hz, 1 H, NH), 5.59 (d, J = 7.7 Hz, 1 H, CHN), 2.45–1.94 solution was stirred at room temperature for 2 hours. The reaction
(m, 4 H, CH2CH2), 2.28 (s, 3 H, COCH3), 1.98 (s, 3 H, NCOCH3) was quenched with HCl 2  and extracted with CH2Cl2. The com-
ppm. 13C NMR (CDCl3): δ = 20.3, 23.3, 25.1, 25.3, 58.0, 119.2,
bined organic layers were washed with brine, dried (Na2SO4), fil-
127.6, 128.2, 129.0, 141.7, 141.9, 146.3, 133.9, 171.9, 198.4 ppm.
tered and evaporated to give the crude 12 which was used in the
next step without any further purification. H NMR (CDCl3): δ =
7.91 (m, 2 H, Ph), 7.53–7.21 (m, 7 H, Ph), 6.24 (d, J = 7.7 Hz, 1
H, CHN), 2.09 (s, 3 H, NCOCH3) ppm. MS: m/z = 394/396 [M +
Na].
1
IR (KBr): ν = 1740, 1661, 1494 cm–1. MS: m/z = 270 [M + 1], 292
˜
[M + Na]. [α]2D0 = –12.0 (c = 1.0, CHCl3). C17H19NO2 (269.34):
calcd. C 75.81, H 7.11, N 5.20; found C 75.99, H 7.32, N 5.44.
Synthesis of N-[(S)-(4-Acetylphenyl)(phenyl)methyl]acetamide (9):
Compound 8 (2.97 mmol) was dissolved in toluene (100 mL). DDQ
(5.94 mmol) was added and the reaction was refluxed and stirred
for 3 hours. The reaction mixture was quenched with water (50 mL)
and extracted with Et2O. The combined organic layers were washed
with brine, dried (Na2SO4), filtered and evaporated to give the
crude 9. The crude product was purified by flash chromatography
on silica gel, using AcOEt/petroleum ether (4:1) as eluant. Yield:
380 mg (48%). 1H NMR (CDCl3): δ = 7.84 (d, J = 8.4 Hz, 2 H,
Ph), 7.30–7.04 (m, 7 H, Ph), 6.66 (d, J = 7.7 Hz, 1 H, NH), 6.19
(d, J = 7.7 Hz, 1 H, CHN), 2.51 (s, 3 H, COCH3), 2.01 (s, 3 H,
NCOCH3) ppm. 13C NMR (CDCl3): δ = 23.1, 26.6, 56.9, 121.7,
127.6, 127.4, 128.6, 128.8, 136.1, 140.7, 146.8, 169.5, 197.7 ppm.
Synthesis of (S)-N-[(Biphenyl-4-yl)(phenyl)methyl]acetamide [(S)-
13]: Triflate 12 was dissolved in toluene (4 mL) and K2CO3
(0.24 mmol) and phenylboronic acid (0.32 mmol) were added. The
mixture was stirred at room temperature for 15 min. Then a cata-
lytic amount of Pd(PPh3)4 was added and the resulting solution
was stirred at 90 °C for 12 hours. The reaction was quenched with
NaHCO3 and extracted with AcOEt. The combined organic layers
were washed with brine, dried (Na2SO4), filtered and evaporated
to give the crude (S)-13. The crude product was purified by flash
chromatography on silica gel, using AcOEt/petroleum ether (1:1)
1
as eluant. Yield: 42.1 mg (70%, for two steps). H NMR (CDCl3):
δ = 7.56–7.18 (m, 14 H, Ph), 6.28 (d, J = 7.8 Hz, 1 H, CHN), 6.07
(d, J = 7.8 Hz, 1 H, NH), 1.99 (s, 3 H, NCOCH3) ppm. 13C NMR
(CDCl3): δ = 23.2, 56.4, 121.4, 127.4, 127.7, 127.9, 128.0, 128.5,
IR (KBr): ν = 1701, 1664, 1494 cm–1. MS: m/z = 268 [M + 1], 290
˜
[M + Na]. [α]2D0 = +16.4 (c = 1.5, CHCl3). C17H17NO2 (267.32):
128.7, 129.1, 134.1, 140.5, 142.0, 148.6, 169.2 ppm. IR (KBr): ν =
˜
calcd. C 76.38, H 6.41, N 5.24; found C 76.45, H 6.67, N 5.39.
1665, 1450 cm–1. MS: m/z = 302 [M + 1], 324 [M + Na]. [α]2D0
=
Synthesis of (S)-N-[(4-Acetoxyphenyl)(phenyl)methyl]acetamide
(10): Compound 9 (1 mmol) was dissolved in CH2Cl2 (10 mL). m-
Choroperbenzoic acid (m-CPBA) (3 mmol) was added in portions
and the reaction was refluxed and stirred for 8 hours. The reaction
was quenched with NaHCO3 and extracted with AcOEt. The com-
bined organic layers were washed with Na2SO3, brine and finally
dried (Na2SO4), filtered and evaporated to give the crude 10. The
crude product was purified by flash chromatography on silica gel,
using AcOEt/petroleum ether (4:1) as eluant. Yield: 212.2 mg
(75%). 1H NMR (CDCl3): δ = 7.85 (d, J = 7.9 Hz, 2 H, Ph), 7.31–
7.01 (m, 7 H, Ph), 6.73 (d, J = 7.8 Hz, 1 H, NH), 6.17 (d, J =
7.8 Hz, 1 H, CHN), 2.25 (s, 3 H, OCOCH3), 2.01 (s, 3 H,
NCOCH3) ppm. 13C NMR (CDCl3): δ = 19.4, 21.1, 56.4, 121.7,
127.6, 127.9, 128.0, 128.7, 133.1, 139.1, 146.7, 169.2, 169.4 ppm.
–30.2 (c = 0.8, CHCl3). C21H19NO (301.38): calcd. C 83.69, H 6.35,
N 4.65; found C 83.92, H 6.54, N 4.81.
Synthesis of (S)-[(Biphenyl-4-yl)(phenyl)methyl]amine [(S)-14]: Acet-
amide (S)-13 (0.1 mmol) was dissolved in HCl conc. (5 mL) and
the mixture was stirred at 80 °C for 12 hours. The mixture contain-
ing (S)-14 hydrochloride was cooled and alkalinized with solid
NaHCO3 to pH7–8 and extracted three times with AcOEt. The
combined organic layers were washed with brine, dried (Na2SO4),
filtered and evaporated to give the crude (S)-14. The crude product
was purified by flash chromatography on silica gel, using AcOEt/
petroleum ether (1:1) as eluant. Spectroscopic data are identical to
those reported in the literature. Yield: 22.0 mg (85%). 1H NMR
(CDCl3): δ = 7.65–7.54 (m, 4 H, Ph), 7.42–7.26 (m, 10 H, Ph), 5.63
(s, 1 H, CHN) ppm. IR (KBr): ν = 3320, 1640 cm–1. MS: m/z =
˜
IR (KBr): ν = 1661, 1454 cm–1. MS: m/z = 284 [M + 1], 306 [M +
˜
260 [M + 1], 282 [M + Na], 243 [M – 16]. [α]2D0 = –11.2 (c = 1.2,
CHCl3). C19H17N (259.35): calcd. C 87.99, H 6.61, N 5.40; found
C 88.12, H 6.92, N 5.65.
Na]. [α]2D0 = ․. (c  ., CH2Cl2). C17H17NO3 (283.32): calcd.
C 72.07, H 6.05, N 4.94; found C 72.34, H 6.29, N 5.09.
Synthesis of (S)-N-[(4-Hydroxyphenyl)(phenyl)methyl]acetamide
(11): Compound 10 (1 mmol) was dissolved in a mixture of H2O/
MeOH (15:30 mL) and then a saturated solution of NaHCO3
(20 mL) was added dropwise. The reaction was stirred at room tem-
perature for 1.5 hours. The reaction was quenched with HCl 2 
and extracted with AcOEt. The combined organic layers were
washed with brine, dried (Na2SO4), filtered and evaporated to give
the crude 11. The crude product was purified by flash chromatog-
raphy on silica gel, using AcOEt/petroleum ether (4:1) as eluant.
Synthesis of (S)-Bifonazole [(S)-15]: Amine (S)-14 (0.38 mmol) was
dissolved into a solution of H2O/dioxane (3:1 mL) and H3PO4 was
added until pH2. Then solid paraformaldehyde (15 mg) and gly-
oxal sol. 40% in water (0.1 mL) were added and the mixture stirred
at 80 °C for 10 min. NH4Cl saturated solution (0.5 mL) was added
at this temperature and the resulting solution was refluxed for 12
hours. The mixture was then cooled to 0 °C and NaOH was added
until pH12. The alkaline solution was extracted with AcOEt two
times. The combined organic layers were washed with brine, dried
(Na2SO4), filtered and evaporated to give the crude (S)-15. The
crude product was purified by flash chromatography on silica gel,
using AcOEt/petroleum ether (1:1) as eluant. Spectroscopic data
are identical to those reported in the literature. Yield: 37.6 mg
1
Yield: 228.9 mg (95%). H NMR (CDCl3): δ = 7.59–7.21 (m, 7 H,
Ph), 7.03 (m, 2 H, Ph), 6.15 (d, J = 7.9 Hz, 1 H, NH), 6.10 (br. s,
1 H, OH), 5.28 (s, 1 H, CHN), 2.10 (s, 3 H, NCOCH3) ppm. 13C
NMR (CDCl3): δ = 23.4, 56.5, 115.5, 127.2, 127.4, 128.6, 128.7,
1
133.4, 141.7, 155.4, 169.4 ppm. IR (KBr): ν = 3598, 1673,
˜
(32%). H NMR (CDCl3): δ = 7.65–7.54 (m, 4 H, Ph), 7.42–7.26
1496 cm–1. MS: m/z = 242 [M + 1], 264 [M + Na]. [α]2D0 = –38.0 (c
= 0.5, MeOH). C15H15NO2 (241.29): calcd. C 74.67, H 6.27, N
5.81; found C 74.86, H 6.45, N 5.98.
(m, 10 H, Ph), 5.63 (s, 1 H, CHN) ppm. MS: m/z = 311 [M + 1],
333 [M + Na]. [α]2D0 = +3.2 (c = 0.9, CHCl3). C22H18N2 (310.39):
calcd. C 85.13, H 5.85, N 9.03; found C 85.42, H 5.98, N 9.32.
Synthesis of 4-[(Acetylamino)(phenyl)methyl]phenyl (S)-Trifluoro-
methanesulfonate (12): Phenol 11 (0.2 mmol) was dissolved in
Synthesis of (R)-N-[(4-Bromophenyl)(cyclohexa-1,5-dienyl)methyl]-
acetamide (17): Into an oven-dried pressure vial equipped with
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Eur. J. Org. Chem. 2007, 3676–3686

Enantiomerically Pure Benzhydrylamines
FULL PAPER
magnetic stirbar and under argon, (R)-1f (3.4 mmol) was dissolved
in 40 mL of degassed toluene. Grubbs’ 2nd generation catalyst
(10 mol-%) and cyclooctadiene (9 equiv./mol) were then added. The
vessel was introduced into the microwave oven and heated at 80 °C
twice for 10 minutes under microwave irradiation. After cooling,
structure was solved by the direct methods, while structure refine-
ment was carried out by full-matrix anisotropic least-squares on F2
for all reflections for all non-H atoms. The hydrogen atoms were
located on Fourier difference maps and were included in the struc-
ture-factor calculations without any constraint for both the struc-
the solvent was removed in vacuo to afford a dark brown oil that tures. Structure solution and refinement were carried out by using
was purified by flash chromatography (Et2O/petroleum ether, 1:1)
the SHELX-97 package.[20] Molcular graphics was performed by
1
to give 17. Yield: 624 mg (60%). H NMR (CDCl3): δ = 7.31 (d, J using WinGX package.[21]
= 8.4 Hz, 2 H, Ph), 7.03 (d, J = 8.4 Hz, 2 H, Ph), 6.53 (d, J =
CCDC-638969 (for 7) contains the complete set of crystallographic
7.0 Hz, 1 H, CNH), 5.65 (m, 1 H, CCHCH2), 5.55 (m, 1 H,
CHCHCH2), 5.40 (m, 1 H, CHCHCH2), 5.36 (d, J = 7.0 Hz, 1 H,
CHN), 2.13–1.97 (m, 4 H, CH2CH2), 1.99 (s, 3 H, CH3) ppm. 13C
NMR (CDCl3): δ = 22.1, 22.2, 23.1, 55.9, 121.2, 122.9, 124.4, 128.2,
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Supporting Information (see also the footnote on the first page of
this article): Copies of HPLC chromatograms for (R,S)-13, (R)-13
and (S)-13. Selected crystal data and Ortep view of 7.
129.1, 131.9, 134.9, 139.4, 169.5 ppm. IR (KBr): ν = 1661,
˜
1445 cm–1. MS: m/z = 306/308 [M + 1], 328/330 [M + Na]. [α]2D0
=
+57.8, (c 1.7 MeOH). C15H16BrNO (306.20): calcd. C 58.84, H
5.27, N 4.57; found C 58.97, H 5.46, N 4.76.
Acknowledgments
Synthesis of (R)-N-[(4-Bromophenyl)(phenyl)methyl]acetamide (18):
Compound 17 (1.0 mmol) was dissolved in toluene (30 mL). DDQ
(2.0 mmol) was added and the reaction was refluxed and stirred for
3 hours. The reaction was quenched with water (20 mL) and ex-
tracted with Et2O. The combined organic layers were washed with
brine, dried (Na2SO4), filtered and evaporated to give the crude 18.
The crude product was purified by flash chromatography on silica
gel, using AcOEt/petroleum ether (4:1) as eluant. Yield: 145.9 mg
Fondo per gli Investimenti della Ricerca di Base (FIRB)
(RBAU01LR5P) “Developement of a Common Pharmacophore
Model for Microtubule-stabilising Anticancer Agents to be used to
Design and Sinthesise Novel Paclitaxel Mimics” is gratefully ac-
knowledged. Elena Galletti is gratefully acknowledged for helpfull
discussions (University of Siena). M. B. thanks the Merck Research
Laboratories for the 2004 Academic Development Program (ADP)
Chemistry Award.
1
(48%). H NMR (CDCl3): δ = 7.40–7.08 (m, 9 H, Ph), 6.60 (d, J
= 7.8 Hz, 1 H, NH), 6.03 (d, J = 7.8 Hz, 1 H, CHN), 1.90 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3): δ = 23.0, 56.6, 121.3, 127.7, 128.8,
129.7, 131.7, 132.5, 140.5, 140.8, 169.7 ppm. IR (KBr): ν = 1661,
˜
[1] a) Y. Ito, Y. Kobayashi, T. Kawabaka, M. Takase, S. Terash-
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=
+22.0 (c = 1.4, MeOH). C15H14BrNO (304.18): calcd. C 59.23, H
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4.64, N 4.60; found C 59.53, H 4.87, N 4.81.
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13]: Compound 18 (0.33 mmol) was dissolved in toluene (10 mL)
and K2CO3 (0.49 mmol) and phenylboronic acid (0.66 mmol) were
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Then a catalytic amount of Pd(PPh3)4 was added and the resulting
solution was stirred at 90 °C for 12 hours. The reaction was
quenched with NaHCO3 and extracted with AcOEt. The combined
organic layers were washed with brine, dried (Na2SO4), filtered and
evaporated to give the crude (R)-13. The crude product was puri-
fied by flash chromatography on silica gel, using AcOEt/petroleum
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1
ether (1:1) as eluant. Yield: 82.4 mg (83%). H NMR (CDCl3): δ
= 7.56–7.18 (m, 14 H, Ph), 6.28 (d, J = 7.8 Hz, 1 H, CHN), 6.07
(d, J = 7.8 Hz, 1 H, NH), 1.99 (s, 3 H, NCOCH3) ppm. 13C NMR
(CDCl3): δ = 23.2, 56.4, 121.4, 127.4, 127.7, 127.9, 128.0, 128.5,
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128.7, 129.1, 134.1, 140.5, 142.0, 148.6, 169.2 ppm. IR (KBr): ν =
˜
1665, 1450 cm–1. MS: m/z = 302 [M + 1], 324 [M + Na]. [α]2D0
=
+32.2 (c = 1.0, CHCl3). C21H19NO (301.38): calcd. C 83.69, H 6.35,
N 4.65; found C 83.92, H 6.54, N 4.81.
Synthesis of (R)-[(Biphenyl-4-yl)(phenyl)methyl]amine [(R)-14]: The
same procedure used for (S)-14 was followed. All the spectroscopic
data are identical to those of (S)-14. [α]2D0 = +7.4, (c = 0.5 CHCl3).
Synthesis of (R)-Bifonazole [(R)-15]: The same procedure used for
(S)-15 was followed. All the spectroscopic data are identical to
those of (S)-15. [α]2D0 = –2.9 (c = 1.5, CHCl3).
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graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The
Eur. J. Org. Chem. 2007, 3676–3686
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3685

D. Castagnolo, G. Giorgi, R. Spinosa, F. Corelli, M. Botta
FULL PAPER
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[20] G. M. Sheldrick, SHELX-97, rel. 97-2, University of
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Published Online: June 18, 2007
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Eur. J. Org. Chem. 2007, 3676–3686