Pd-NHC catalyzed biaryl coupling by direct C-H activationA novel strategy for the synthesis of dibenzocyclooctane lignans

Article abstract of DOI:10.1080/00397910903531755

Cross-coupling reactions, such as Buchwald-Hartwig arylamination and direct intramolecular biaryl coupling by C-H activation, were carried out using various Palladium-N-heterocyclic carbenes (Pd-NHC) as catalysts. The yields were good to excellent. The la

Full text of DOI:10.1080/00397910903531755

This article was downloaded by: [University of New Hampshire]
On: 04 June 2014, At: 15:43
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Pd–NHC Catalyzed Biaryl Coupling by
Direct C–H Activation—A Novel Strategy
for the Synthesis of Dibenzocyclooctane
Lignans
Ericsson David Coy a , Luis Enrique Cuca a & Michael Sefkow b
a Facultad de Ciencias, Departamento de Química , Universidad
Nacional de Colombia, Laboratorio de Investigación en Productos
Naturales Vegetales , Bogotá, Colombia
b Institut für Chemie, Universität Potsdam , Golm, Germany
Published online: 14 Dec 2010.
To cite this article: Ericsson David Coy , Luis Enrique Cuca & Michael Sefkow (2010) Pd–NHC Catalyzed
Biaryl Coupling by Direct C–H Activation—A Novel Strategy for the Synthesis of Dibenzocyclooctane
Lignans, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 41:1, 41-51, DOI: 10.1080/00397910903531755
To link to this article: http://dx.doi.org/10.1080/00397910903531755
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 41–51, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531755
Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT
C–H ACTIVATION—A NOVEL STRATEGY FOR THE
SYNTHESIS OF DIBENZOCYCLOOCTANE LIGNANS
Ericsson David Coy,1 Luis Enrique Cuca,1 and
Michael Sefkow2
1
´
Facultad de Ciencias, Departamento de Quımica, Universidad Nacional de
Colombia, Laboratorio de Investigacion en Productos Naturales Vegetales,
´
´
Bogota, Colombia
2Institut fu¨r Chemie, Universita¨t Potsdam, Golm, Germany
Cross-coupling reactions, such as Buchwald-Hartwig arylamination and direct intramolecular
biaryl coupling by CꢀH activation, were carried out using various Palladium-N-heterocyclic
carbenes (Pd–NHC) as catalysts. The yields were good to excellent. The latter strategy was
adopted to transform two dibenzylbutane lignans, isolated from the leaves of Ocotea macro-
phylla (Lauraceae), into the corresponding dibenzocyclooctane lignans in good overall yields.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Synthetic Communications1 to view the free supplemental file.
Keywords: Cross-coupling reactions; dibenzylbutane; dibenzocyclooctane; lignans; N-heterocyclic
carbenes (NHC)
INTRODUCTION
Pd-catalyzed cross-coupling reactions have gained significant advances in
the last two decades. They are nowadays extensively used in both laboratory and
industrial scale.[1] Among the cross-coupling reactions the N-arylamination
(Buchwald-Hartwig reaction)[2] has found widespread application.[1,2] Although
Cu- and Ni-catalyzed protocols of this reaction have been developed,[3] Pd remains
the preferred transition metal for this transformation. This is due to the high
efficiency of its complexes for arylamination as well as for several related
Pd-catalyzed cross-coupling reactions.[2] An important application of Pd-catalyzed
cross-coupling reactions is the biaryl coupling. Typically, the reaction requires an
aryl metal (e.g., M ¼ B, Sn, Zn) and an aryl halide as coupling partners. This method
for biaryl formation has emerged as a versatile tool to obtain a large variety of
biaryl compounds. A reliable biaryl coupling method is important since the biaryl
Received September 8, 2009.
Address correspondence to Ericsson David Coy, Facultad de Ciencias, Departamento de Qu´ımica,
´
Universidad Nacional de Colombia, AA 14490, Bogota, D.C., Colombia. E-mail: edcoyb@unal.edu.co
and Michael Sefkow, Institut fur Chemie, Universita¨t Potsdam, Am Neuen Palais 10, 14469 Potsdam,
¨
Germany. E-mail: sefkow@uni-potsdam.de
41

42
E. D. COY, L. E. CUCA, AND M. SEFKOW
moiety is found in several natural products[4] as well as in chiral phases, reagents for
chromatography, and liquid crystals.[5]
To avoid any inconvenience associated with an uncertain metal to ligand
ratio from in situ formed catalytic systems, well-defined, air- and moisture-stable
Palladium-N-heterocyclic carbenes (Pd–NHC) complexes with distinct palladium to
ligand ratios have been developed.[1,6–9] The efficiency of NHC ligand-containing com-
plexes, which have been emerged as an important family of complexes employed in tran-
sition metal catalysis is attributed to the strong r-donor properties of their ligands.[6,9]
Lignans, dimers of phenylpropanes evolving from the shikimate biosynthetic
route,[10] play an important role in natural products chemistry.[11] An interesting
class of lignans containing a dibenzocyclooctane moiety exhibits a wide range of
biological activities, such as antihepathotoxic, anti-HIV, antioxidant, cytotoxic,
antitumor and lipidperoxydative activities.[12] For these reasons, several routes to
dibenzocyclooctane lignans have been reported in the literature.[13] However, many
published syntheses suffer from low yield and low atropselectivity.[14]
We have performed a comparative study between the known complexes
[(SIPr)Pd(cinnamyl)Cl][1] 1, ([(IPr)PdCl2]2)[7] 2, [PEPPSI-SIPr][8] 3, and
[(IPr)2PdCl2][9] 4 (Figure 1) with respect to their efficiency in Buchwald-Hartwig
arylamination and in intramolecular biaryl coupling by CꢀH activation. In addition,
starting from dibenzylbutane lignans, isolated from the leaves of Ocotea macrophylla
(Lauraceae), we developed a short and efficient route to the corresponding dibenzo-
cyclooctane lignans using a Pd–NHC-catalyzed direct intramolecular cross-coupling
as the key reaction.
RESULTS AND DISCUSSION
Pd–NHC complexes are very efficient catalysts due to the strong electron donat-
ing ability of the NHC ligands. They act as strong Pd(0) intermediate stabilizers thus
allowing their use without the need of ligand excess. In particular Pd–NHC complexes
Figure 1. Pd–NHC complexes 1–4. Complexes 1–3 were obtained from Umicore AG; complex 4 was
prepared according to Ref.[9]

Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT CꢀH ACTIVATION
43
1 and 2[1] (Figure 1) have previously shown high catalytic activity in Buchwald-
Hartwig arylamination reactions with excellent yields between 80% and 95% even
with poorly active and sterically demanding aryl chlorides.[1] In addition to good
yields, these catalysts offer several advantages, such as short reaction times, low reac-
tion temperature and low catalyst load (1 mol% or less).
In all cross-coupling reactions we examined, complex 1 reacted faster than
complex 2 (minutes vs. hours at the same temperature) and gave slightly better
yields. In addition, complex 2 requires higher reaction temperatures to proceed with
acceptable yields (the conversion of the starting materials in an arylamination was
60% within 20 h at room temperature) (Table 1). However, complex 1 was sensitive
towards air, reducing the yield under aerobic conditions by 50–60%. In contrast,
complex 2 gave similar results under either aerobic or anaerobic conditions. The
tolerance of 2 towards air has been firstly reported by Viciu et al.[15]
According to recently published results by Organ et al.,[8] catalyst 3 became a
good candidate to be employed in cross-coupling reactions. Consequently, a set of
experiments was performed to compare the catalytic ability of complex 3 with com-
plexes 1 and 2 in the Buchwald-Hartwig reaction. The reactions with complex 3 were
performed with 1 mol % catalyst. All experiments were allowed to run until the
catalysts deactivation had occurred. We found that the arylamination could be car-
ried out with very similar yields under either aerobic or anaerobic conditions using
complex 3. Organ et al. previously described an optimized protocol using 3 under
aerobic conditions but with longer reaction times, allowing efficient conversion of
several substrates.[8] In addition, complex 3 converted the starting materials at room
temperature in comparable reaction times than complex 1. The combination of the
Table 1. Buchwald-Hartwig arylaminations using Pd–NHC complexes 1–4
Entry
Ar–Cl
Catalyst
Time
Yield (%)d
Rep.
1
2
20 mina
60 minb
30 mina
24 hc
88 (25)
75 (73)
93e
71e
3
4
80 (79)
12 (8)
–
5e
1
1
2
5 mina
90 (38)
84 (80)
86e
84e
60 minb
2
3
4
20 mina
24 hc
88 (85)
15 (10)
–
10e
aCarried out to room temperature.
bCarried out at 50 ꢁC.
cCarried out at 80 ꢁC.
dYield of isolated product under anaerobic conditions (yield of isolated product under aerobic
conditions).
eReported yield under anaerobic conditions according to Ref.[1]

44
E. D. COY, L. E. CUCA, AND M. SEFKOW
air-stability on the one hand and the high performance at ambient temperature on
the other hand providing complex 3 an excellent alternative to the previously used
complexes 1 and 2. Complex 4 was prepared by a reported procedure.[9] However,
this complex gave poor results in all reactions carried out in the present study. This
result emphasizes the requirement for a 1:1 stoichiometry between the metal and
the ligand rather than a 1:2 ratio.
The aryl–aryl coupling using a CꢀH bond instead of an organometallic inter-
mediate is a straight forward but still non-conventional method for biaryl cou-
plings.[16] Some works using aryl iodides or bromides have been published but aryl
chlorides were excluded with very few exceptions.[7] Again, the use of Pd–NHC
complexes has made aryl chlorides amenable for cross coupling reactions by CꢀH
activation. An alternative route to biaryl systems by activation of CꢀH bonds is
the oxidative coupling using metal salts from either lead or copper[14,17] which often
lacks of reproducibility. Hence, we focused on the Pd-catalyzed reaction and com-
pared the catalytic activity of complexes 1–4 in intramolecular biaryl coupling reac-
tions. This reaction was precedented by Campeau et al.[7] using the catalyst 2 and 4
among others. However, catalysts 1 and 3 have not been previously employed for
this reaction. In our hands, the latter two catalysts were superior to the previously
used catalysts with respect to yield and reaction time (Table 2). Once more, catalysts
1–3 are much more efficient than 4. This fact might be due to the stability of the
intermediates as well as the ease of complex activation prior to the catalytic cycle.[1]
The above mentioned methodology was adopted in a strategy to transform the
naturally occurring dibenzylbutane lignan 5a and 5b into dibenzocyclooctane lignans
7a and 7b, respectively (Scheme 1). The starting material, compounds 5a and 5b,
were isolated from the leaves of Ocotea macrophylla (Lauraceae), a plant native from
the north of South America. The present work is the first report on lignans from this
plant. Although 5a and 5b had not been previously isolated from natural sources,
they are known as synthetic products.[18] The relative configuration of 5a and 5b
was assigned to be erythro and threo, respectively, on the basis of the 13C NMR shifts
of the methyl groups at C(8) and C(80).[19]
For the biaryl coupling compounds 5a and 5b needed to be mono-chlorinated
at C(2). This transformation was effected with NCS in DMF providing chlorides
Table 2. Biaryl coupling by Pd-catalyzed CꢀH activation
Entry
Catalyst
Yield (%)a
Ref.b
1
2
3
4
1
2
3
4
72
55
65
5
–
49
–
2
aYield of isolated product.
bReported yields according to Ref.[7]

Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT CꢀH ACTIVATION
45
Scheme 1. Preparation of dibenzocyclooctane lignans from natural dibenzylbutane lignans by direct
intramolecular biaryl coupling.
6a and 6b in good yields (78–80%).[20] Interestingly, if 3,30,4,40-substitued lignans
were submitted to the same chlorination conditions, the di-chlorinated compounds
(at C(2) and C(2)0) were the major products among several other by-products.[20]
No mono-chlorinated compounds could be detected in these cases. Compounds 6a
and 6b were subsequently employed in the direct intramolecular biaryl coupling using
the air-stable complex 3 as catalyst, which was chosen to this reaction because of its
ease of use under not strictly anaerobic conditions, although 1 would be expected to
give slightly better yields. The coupling reaction afforded the dibenzocyclooctane
lignans 7a and 7b in 65% and 68% yield, respectively. We believe that this reaction
is of great importance, because ring-closing reactions leading to dibenzocyclooctanes
is still a challenging task.[13,14,18] In addition, the formation of biaryls was achieved in
the absence of organometallic intermediates in only two steps and with acceptable
overall yields due to the high catalytic activity of Pd–NHC catalysts, such as
complex 3.
Interestingly, starting from the enantiomerically pure threo-lignan 5b, only one
of the two possible atropisomers was isolated after the biaryl coupling. Assuming
that the two methyl groups in compound 6b are oriented preferentially in a pseudo
equatorial position during the CꢀC bond formation, the atropisomer with R- (P-)
conformation should be preferred. Indeed, the CD spectrum of 7b indicated the
biaryl moiety to be R- (or P-) configurated.[21]

46
E. D. COY, L. E. CUCA, AND M. SEFKOW
The Buchwald-Hartwig arylamination reactions using Pd–NHC complexes 1–3
providing the anilines in good yields. Catalysts with a palladium to ligand ratio of 1:1
were much more efficient than complexes comprising of a 1:2 ratio. The Pd–NHC
complex 3 could be used at room temperature, in either anaerobic or aerobic systems,
and within short reaction times. Thus, catalyst 3 was an excellent compromise
between air-stability of the complex and catalytic activity. The catalysts 1–3 could
be also employed in direct intramolecular biaryl couplings by CꢀH activation. The
products were obtained in acceptable yields. However, according to Campeau
et al.2f the yields might be improved by the addition of NHC salts during the reaction.
We currently examine whether this modification of our protocol substantially
improve the yields of biaryl products.
The biaryl coupling by C-H activation was used for a new and efficient strategy
to synthesize dibenzocyclooctane lignans from naturally occurring dibenzylbutane
lignans in reasonable yields. The protocol developed was found to be more effective
in comparison with reported protocols for achieving intramolecular biaryl coupling,
possessing advantages such as easy and secure handling and low catalyst load.
EXPERIMENTAL
NMRspectrawere recorded at 300MHz (1H NMR) and at 75 MHz (13C NMR) on
a Bruker Avance 400 spectrometer using TMS as internal standard reference and CDCl3
as solvent. (The spectra of compounds 5, 6, and 7 are provided in the supporting infor-
mation for this article, available online.) Optical rotation values were measured on a Jasco
DIP-1000 digital polarimeter. High resolution mass spectra (HRMS) were recorded on
qTOFmicro Micromass spectrometer, Waters Inc., with an ESI source and in the positive
ion mode. Column chromatography (CC) purifications were carried out using silica gel
(Merck, 40–63 mm, to purify the dibenzylbutane lignans from the natural source and
Acros, particle size 35–70 mm, for purifications of synthetic compounds). The solvents
used in CC were commercial grade and distilled before use. The reactions were monitored
by thin layer chromatography (TLC), which was performed with commercial silica gel on
aluminum sheets (Merck, silica gel 60 F254). If not stated otherwise, the reactions were
performed in dry solvents under nitrogen atmosphere. All reagents were of commercial
quality from freshly opened containers. All substances that are not described in the
following synthetic procedures have been obtained from commercial suppliers (Acros,
Aldrich, Fluka, Merck-Schuchardt or Roth) or the synthesis has been published
elsewhere. Complexes 1–3 were obtained by donation from Umicore AG & Co. KG,
where they are commercially available as NeolystTM CX32 ([(SIPr)Pd(cinnamyl)Cl])
[phenylallylchloro-[1,3-bis(diisopropylphenyl)-2-imidazolidinylidene]palladium(II)] 1,
NeolystTM CX41 ([(IPr)PdCl2]2) (dichloro-[1,3-bis(diisopropylphenyl)imidazole-2-
ylidene]palladium(II)-dimer) 2, and PEPPSI-IPr [(dichloro-[1,3-bis(diisopropylphenyl)
imidazolylidene]-(3-chloropyridyl)palladium(II)] 3, respectively. Complex [(IPr)2PdCl2]
4 was prepared according to the reported procedure.[9]
General Procedure of Buchwald-Hartwig Reaction
Into a vial that was closed with a screw cap fitted with a septum and equipped
with a magnetic stirring bar were added in turn the Pd–NHC complex (1 mol%),

Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT CꢀH ACTIVATION
47
potassium tertbutoxide (1.1 mmol, 124 mg), and anhydrous dimethoxyethane (DME;
1 ml) under N2. Then, morpholine (1 mmol, 87 mg) and an arylhalide (1 mmol) were
in turn injected through the septum. The reaction mixture was stirred at room tem-
perature or at 50 ꢁC. When the reaction was completed, or no further conversion was
observed by TLC, water was added to the reaction mixture. The aqueous layer was
extracted with diethyl ether and the combined organic phases dried over magnesium
sulfate. The solution was filtered and the solvents were evaporated in vacuo. The pro-
duct was purified by flash CC on silica gel (cyclohexane:AcOEt 5:1). The physical
and spectroscopic properties of the products listed in Table 1 are identical with those
reported for the same compounds.[1]
General Procedure for the Direct Intramolecular Biaryl
Coupling Reaction
Crushed K2CO3 (1 mmol), the substrate (0.5 mmol), and a Pd–NHC complex
(0.005 mmol) were placed in a 2 mL screw-cap vial equipped with a magnetic stirring
bar. The vial was purged with nitrogen and 1 mL of N,N-dimethylacetamide (DMA)
was added. The reaction was heated to 130 ꢁC overnight. After the reaction was
completed (as judged by TLC), the reaction mixture was allowed to cool to room
temperature. The crude mixture was directly purified by flash CC (cyclo-
hexane:AcOEt 4:1). The physical and spectroscopic properties of the product listed
in Table 2 are identical with those reported for the same compound.[7]
Plant Material
Plant material corresponding to Ocotea macrophylla (Kunth.) was collected
in June 2006 in Nocaima County (Department of Cundinamarca, Colombia) by
chemist Wilman Delgado. A voucher specimen (number COL517191) was placed
at Herbario Nacional Colombiano, Universidad Nacional de Colombia.
Extraction and Isolation of Erythro- and Threo-
3,4,5,3’,4’,5’-hexamethoxy-8,8’-lignan 5a and 5b
Air-dried leaves of Ocotea macrophylla (Lauraceae) were extracted with 96%
ethanol. The solvent was removed by evaporation in vacuo. The dry extract (30 g)
was fractionated by size exclusion CC on sephadex LH-20 (cyclohexane:CHCl3:
MeOH 3:1:1 to 1:1:10) affording 9 fractions. Fraction 8 (2.85 g) was subjected
to flash CC on silica gel (cyclohexane:AcOEt 10:1 to 10:5) to afford additional 7
fractions. Fraction 8.4 (116 mg) was found to be a crystalline mixture of the two dia-
stereomers 5a and 5b which were separated by flash CC on silica gel (cyclohexane:
Et2O:MeCN 14:5:1) affording in order of elution 5a (45 mg) as colorless crystals,
1
mp 115–117 ꢁC (from MeOH); H NMR: d 0.88 (d, J ¼ 6.7 Hz, 6H, H3-9,90),
1.61–1.74 (m, 2H, H-8,80), 2.32 (dd, J ¼ 13.2, 8.5 Hz, 2H, H-7a,7a0), 2.68 (dd,
J ¼ 13.2, 4.8 Hz, 2H, H-7b,70b), 3.83 (s, 18H, 3,30,4,40,5,50-OCH3), 6.36 (s, 4H,
13
H-2,20,6,60); C NMR: d 16.2 (C-9,90), 39.5 (C-8,80), 38.7 (C-7,70), 55.5 (3,5,30,50
-OCH3), 60.3 (4,40-OCH3), 104.9 (C-2,20,6,60), 134.8 (C-1,10), 138.7 (C-4,40), 152.0
(C-3,30,5,50); HRMS-ESI m=z 419.2423 [MþH]þ (calcd. for C24H35O6, 419.2434);

48
E. D. COY, L. E. CUCA, AND M. SEFKOW
25
and 5b (52 mg) as colorless crystals, mp 125–127 ꢁC (from MeOH); ½aꢂD ¼ꢀ25:8
1
(CHCl3; c 0.6); H NMR: d 0.85 (d, J¼ 6.0 Hz, 6H, H-9,90), 1.62–1.76 (m, 2H,
H-8,80), 2.36 (dd, J¼ 13.2, 7.3 Hz, 2H, H-7a, 7a0) 2.53 (dd, J¼ 13.2, 7.0 Hz, 2H,
13
H-7b,70b), 3.78 (s, 6H, 4,40-OCH3), 3.84 (s, 12H, 3,5,30,50-OCH3), 6.30 (s, 4H, H-2,
6,20,60); C NMR: d 13.8 (C-9,90), 37.2 (C-8,80), 41.3 (C-7,70), 55.4 (3,5,30,50-OCH3),
60.1 (4,40-OCH3), 104.8 (C-2,20,6,60), 134.7 (C-1,10), 138.6 (C-4,40), 151.8 (C-3,30,5,50);
HRMS-ESI m=z 419.2427 [MþH]þ (Anal. calcd. for C24H35O6, 419.2434).
Preparation of Erythro- and Threo-
2-chloro-3,4,5,3’,4’,5’-hexamethoxy-8,8’-neolignan 6a and 6b
A solution of N-chlorosuccinimide (NCS) (7.2 mg, 0.05 mmol) in 1 ml of DMF
was added dropwise to a solution of the lignan (5a or 5b) (22 mg, 0.05 mmol) in 1 ml
of DMF. The resulting mixture was stirred at room temperature for 5 h. The reaction
mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous
magnesium sulfate. Filtration, removal of the solvents and purification by flash CC
(hexane-AcOEt 5:1) afforded 18 mg (80% yield) of 6a and 17 mg (78% yield) of 6b,
respectively.
Erythro-2-chloro-3,4,5,3’,4’,5’-hexamethoxy-8,8’-neolignan 6a
Colorless crystals; mp 138–140 ꢁC (from MeOH); 1H NMR: d 0.84 (d,
J ¼ 6.0 Hz, 6H, H-9,90), 1.64–1.78 (m, 2H, H-8,80), 2.30–2.62 (m, 2H, H-7a,70a),
2.80–2.95 (m, 2H, H-7b,70b), 3.82 (s, 3H, 40-OCH3), 3.84 (s, 9H, 3,4,5-OCH3),
3.87 (s, 3H, 50-OCH3), 3.90 (s, 3H, 30-OCH3), 6.20 (s, 1H, H-60), 6.35 (s, 2H,
H-2,6); HRMS-ESI m=z 453.2037 [MþH]þ (Anal. calcd. for C24H34ClO6, 453.2044).
Threo-2-chloro-3,4,5,3’,4’,5’-hexamethoxy-8,8’-neolignan 6b
25
Colorless crystals; mp 155–158 ꢁC (from MeOH); ½aꢂD ¼ þ8:3 (CHCl3; c 0.5);
1H NMR: d 0.85 (d, J ¼ 6.0 Hz, 6H, H-9,90), 1.65–1.77 (m, 2H, H-8,80), 2.16–2.32
(m, 2H, H-7a,70a), 2.48–2.60 (m, 2H, H-7b,70b), 3.78 (s, 3H, 4-OCH3), 3.82 (s, 3H,
40-OCH3), 3.84 (s, 6H, 3,5-OCH3), 3.87 (s, 3H, 50-OCH3), 3.89 (s, 3H, H-30
-OCH3), 6.18 (s, 1H, H-60), 6.29 (s, 2H, H-2,6); HRMS-ESI m=z 453.2033 [MþH]þ
(Anal. calcd. for C24H34ClO6, 453.2044).
Preparation of cis- and trans-Deoxyschizandrin 7a and 7b
Compounds 7a and 7b were prepared by means of the general procedure pre-
viously described for the Pd-catalyzed direct intramolecular biaryl coupling starting
from compounds 6a (0.036 mmol) and 6b (0.036 mmol), respectively, under aerobic
conditions. After work-up, the crude mixture was then directly purified by flash
CC (cyclohexane:AcOEt 3:1) affording 9.7 mg of 7a (65% yield) and 10.3 mg of 7b
(68% yield) from the corresponding starting material.

Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT CꢀH ACTIVATION
49
Cis-5,6,7,8-tetrahydro-1,2,3,10,11,12-hexamethoxy-6,7-
dimethyldibenzo[a,c] cyclooctene; cis-Deoxyschizandrin 7a
Colorless crystals, mp 112–113 ꢁC (from Me2CO); 1H NMR: d 0.73 (d,
J ¼ 6.8 Hz, 3H, H-90), 1.00 (d, J ¼ 7.0 Hz, 3H, H-9), 1.85–1.98 (m, 2H, H-8,80),
2.04 (dd, J ¼ 13.1, 1.3 Hz, 1H, H-70b), 2.27 (dd, J ¼ 13.1, 9.3 Hz, 1H, H-7a),
2.45–2.58 (m, 2H, 7’a,b), 3.84 (s, 6H, H-4,40-OMe), 3.90 (s, 12H, H-3,5,30,50-OMe),
13
6.55 (s, 2H, H-6,60); C NMR: d 151.4 (C-30), 150.1 (C-3), 146.1 (C-5, 50), 139.7
(C-4,40), 134.5 (C-10), 133.3 (C-1), 115.3 (C-60), 114.4 (C-6), 107.8 (C-20), 104.3 (C-2),
61.6 (40-OCH3), 61.0 (4-OCH3), 60.6 (5-OCH3), 60.1 (30-OCH3), 56.3 (3-OCH3), 55.9
(50-OCH3), 40.9 (C-70), 39.3 (C-7), 35.7 (C-80), 33.8 (C-8), 21.5 (C-9), 13.2 (C-90);
HRMS-ESI m=z 417.2261 [MþH]þ (Anal. calcd. for C24H33O6, 417.2277).
Trans-5,6,7,8-tetrahydro-1,2,3,10,11,12-hexamethoxy-6,7-
dimethyldibenzo[a,c] cyclooctene; trans-Deoxyschizandrin 7b
25
Colorless crystals, mp 129–131 ꢁC (from Me2CO:MeOH 1:1); ½aꢂD ¼ 97
1
(c ¼ 0.51, CHCl3). CD (c ¼ 0.12, MeOH) [h] 297 (þ6.7), 253 (þ33,4); H NMR: d
1.05 (d, J ¼ 6.4 Hz, 6H, H-9,90), 1.20–1.42 (m, 2H, H-8,80), 2.15 (dd, J ¼ 13.3,
8.5 Hz, 2H, H-7b,70b), 2.38 (dd, J ¼ 13.3, 1.2 Hz, 2H, H-7a,70a), 3.64 (s, 6H, H-
4,40-OMe), 3.90 (s, 12H, H-3,5,30,50-OMe), 6.57 (s, 2H, H-6,60); 13C NMR: d 150.5
(C-3,30), 147.2 (C-5,50), 136.7 (C-4,40), 134.2 (C-1,10), 118.5 (C-6,60), 105.3 (C-2,20),
61.5 (4,40-OCH3), 60.5 (5,50-OCH3), 56.0 (3,30-OCH3), 41.3 (C-7,70), 36.4 (C-8,80),
21.5 (C-9,90); HRMS-ESI m=z 417.2268 [MþH]þ (Anal. calcd. for C24H33O6,
417.2277).
ACKNOWLEDGMENTS
The authors thank Umicore AG & Co. KG. for the donation of catalysts 1–3
and the Institut fur Chemie, Universita¨t Potsdam for analytical support. E. D. Coy
¨
acknowledges the DAAD (Deutscher Akademischer Austausch Dienst) for a
scholarship at the Universita¨t Potsdam.
REFERENCES
1. Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. Modified
(NHC)Pd(allyl)Cl (NHC ¼ N-Heterocyclic Carbene) complexes for room-temperature
Suzuki–Miyaura and Buchwald–Hartwig reactions. J. Am. Chem. Soc. 2006, 128, 4101–
4111.
2. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A simple catalytic method for the con-
version of aryl bromides to arylamines. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348–1350;
(b) Louie, J.; Hartwig, J. F. Palladium-catalyzed synthesis of arylamines from aryl halides.
Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett. 1995,
36, 3609–3612; (c) Muci, A. R.; Buchwald, S. L. Practical palladium catalysts for C–N and
C–O bond formation. Top. Curr. Chem. 2002, 219, 131–209.
3. (a) Antilla, J. C.; Buchwald, S. L. Copper-catalyzed coupling of arylboronic acids and
amines. Org. Lett. 2001, 3, 2077–2079; (b) Kwong, F. Y.; Buchwald, S. L. Mild and
efficient copper-catalyzed amination of aryl bromides with primary alkylamines. Org.

50
E. D. COY, L. E. CUCA, AND M. SEFKOW
Lett. 2003, 5, 793–796; (c) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.;
Fort, Y. Efficient nickel-mediated intramolecular amination of aryl chlorides. Org. Lett.
2003, 5, 2311–2313; (d) Desmarets, C.; Schneider, R.; Fort, Y. Nickel(0)=
dihydroimidazol-2-ylidene complex catalyzed coupling of aryl chlorides and amines.
J. Org. Chem. 2002, 67, 3029–3036.
4. Lloyd-Williams, P.; Giralt, E. Atropisomerism, biphenyls and the Suzuki coupling:
Peptide antibiotics. Chem. Soc. Rev. 2001, 30, 145–157.
5. Pu, L. 1,10-binaphthyl dimers, oligomers, and polymers: Molecular recognition, asymmet-
ric catalysis, and new materials. Chem. Rev. 1998, 98, 2405–2494.
6. Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Stable carbenes. Chem. Rev. 2000,
100, 39–92.
7. Campeau, L. C.; Thansandote, P.; Fagnou, K. High-yielding intramolecular direct
arylation reactions with aryl chlorides. Org. Lett. 2007, 7, 1857–1860.
8. Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.;
O’Brien, C. J.; Sayah, M.; Valente, C. Pd-catalyzed aryl amination mediated by well
defined, N-heterocyclic carbene (NHC)–Pd precatalysts, PEPPSI. Chem. Eur. J. 2008,
14, 2443–2452.
9. Magill, A. M.; McGuinness, D. S.; Cavell, K. J.; Britovsek, G. J. P.; Gibson, V. C.; White,
A. J. P.; Williams, D. J.; White, A. H.; Skelton, B. W. Palladium(II) complexes containing
mono-, bi- and tridentate carbene ligands. Synthesis, characterisation and application
as catalysts in C—C coupling reactions. J. Organomet. Chem. 2001, 617–618, 546–560.
10. Knaggs, A. R. The biosynthesis of shikimate metabolites. Nat. Prod. Rep. 2003, 20,
119–136.
11. Whiting, D. A. Natural phenolic compounds 1900–2000: a bird’s eye view of a century’s
chemistry. Nat. Prod. Rep. 2001, 18, 583–606.
12. (a) Maeda, S.; Sudo, K.; Miyamoto, Y.; Takeda, S.; Shinbo, M.; Aburada, M.; Ikeya, Y.;
Taguchi, H.; Harada, M. Pharmacological studies on Schizandra fruits. II. Effects of con-
stituents of Schizandra fruits on drug induced hepatic damage in rats. Yakugaku Zasshi
1982, 102, 579–588; (b) Kuo, Y. H.; Huang, H. C.; Yang Kuo, L. M.; Chen, C. F. Novel
C19 homolignans, taiwanschirin A, B, and cytotoxic taiwanschirin C, and a new C18
lignan, schizanrin A, from Schizandra arisanensis. J. Org. Chem. 1999, 64, 7023–7027;
(c) Chen, D. F.; Zhang, S. X.; Kozuka, M.; Sun, Q. Z.; Feng, J.; Wang, Q.; Mukainaka,
T.; Nobukuni, Y.; Tokuda, H.; Nishino, H.; Wang, H. K.; Morris-Natschke, S. L.; Lee,
K. H. Interiotherins C and D, two new lignans from Kadsura interior and antitumor-
promoting effects of related neolignans on Epstein–Barr virus activation. J. Nat. Prod.
2002, 65, 1242–1245.
13. Chang, J.; Reiner, J.; Xie, J. Progress on the chemistry of dibenzocyclooctadiene lignans.
Chem. Rev. 2005, 105, 4581–4609.
14. Coleman, R. S.; Gurrala, S. R. Asymmetric synthesis of the dibenzocyclooctadiene lignans
Interiotherin A and Gomisin R. Org. Lett. 2005, 7, 1849–1852.
15. Viciu, M. S.; Kelly III, R. A.; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P. Synthesis,
characterization, and catalytic activity of N-heterocyclic carbene (NHC) palladacycle
complexes. Org. Lett. 2003, 5, 1479–1482.
16. (a) Kakiuchi, F.; Murai, S. Catalytic CꢀH=olefin coupling. Acc. Chem. Res. 2002, 35,
826–834; (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Ru-, Rh-, and Pd-catalyzed CꢀC bond
formation involving CꢀH activation and addition on unsaturated substrates: Reactions
and mechanistic aspects. Chem. Rev. 2002, 102, 1731–1770.
17. Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. Asymmetric carbon–carbon coupling of
phenols or anilines with aryllead triacetates. J. Am. Chem. Soc. 2002, 124, 5365–5373.
18. Biftu, T.; Hazra, B. G.; Stevenson, R. Synthesis of (ꢃ)-deoxyschizandrin. J. Chem. Soc.
Perkin Trans. I 1979, 2276–2281.

Pd–NHC CATALYZED BIARYL COUPLING BY DIRECT CꢀH ACTIVATION
51
19. Herath, H. M. T. B.; Priyadarshini, A. M. A. Lignans from Myristica dactyloides.
Phytochemistry 1997, 44, 699–703.
20. (a) Hu, H.; Wang, Z. Q.; Liu, S. Y.; Cheng, Y.-C.; Lee, K.-H. Antitumor agents. 123.
Synthesis and human DNA topoisomerase II inhibitory activity of 20-chloro derivatives
of etoposide and 4.beta.-(arylamino)-40-O-demethylpodophyllotoxins. J. Med. Chem.
1992, 35, 866–871; (b) Whitman, S.; Gezginci, M.; Timmermann, B. N.; Holman, T. R.
Structure–activity relationship studies of nordihydroguaiaretic acid inhibitors toward
soybean, 12-human, and 15-human lipoxygenase. J. Med. Chem. 2002, 45, 2659–2661.
21. (a) Lian-Niang, L.; Hung, X.; Rui, T. Dibenzocyclooctadiene lignans from roots and
stems of Kadsura coccinea. Planta Medica 1985, 51, 297–300; (b) Chattopadhyay, S. K.;
Rao, K. V. Chemistry of Saururus cernus IV: cyclooctadiene systems derived from
austrobailignan-5. Tetrahedron 1987, 43, 669–678.