Use of (NHC)Pd(η3-allyl)Cl (NHC = N-Heterocyclic Carbene) in a Palladium-mediated Approach to Cryptocarya Alkaloids

Article abstract of DOI:10.1055/s-2003-41468

The palladium-mediated intramolecular aryl amination of 7-benzyloxy-1-(2-bromo-4,5-dimethoxy-benzyl)-1,2,3, 4-tetrahydro-6-methoxy-isoquinoline catalyzed by a recently discovered, air and moisture stable (NHC)Pd(η³-allyl)Cl (NHC = N-heterocycli

Full text of DOI:10.1055/s-2003-41468

LETTER
1871
Use of (NHC)Pd(h3-allyl)Cl (NHC = N-Heterocyclic Carbene) in a Palladium-
mediated Approach to Cryptocarya Alkaloids
P
alladium-me
i
d
A
m
pproach to Crypto
o
a
A
lkalo
n
ids S. Cämmerer, Mihai S. Viciu, Edwin D. Stevens, Steven P. Nolan*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA
E-mail: snolan@uno.edu
Received 23 June 2003
The ammonium salts of these compounds are known to
Abstract: The palladium-mediated intramolecular aryl amination
of 7-benzyloxy-1-(2-bromo-4,5-dimethoxy-benzyl)-1,2,3,4-tet-
enhance therapeutic activity.2,3 Several methods for the
total synthesis of these alkaloids have been developed
since their isolation. The first total synthesis of Kametani1
rahydro-6-methoxy-isoquinoline catalyzed by a recently discov-
ered, air and moisture stable (NHC)Pd(h3-allyl)Cl (NHC = N-
heterocyclic carbene) complex provides 2-benzyloxy-5,6,12,12a- was an excellent general approach but suffered from a low
yield. Application of an enamine photocycization,2 a sili-
tetrahydro-3,9,10-trime-thoxydibenz-[b,g]-indolizine in high
con-mediated approach,3 and a radical cyclization4 are
yield. Effects of the solvent, the catalyst loading and the nature of
the NHC-ancilliary ligand on the efficacy of the reaction were ex-
known. An intramolecular cyclization of a formamidine
amined. Using identical conditions 7-benzyloxy-1-(2-chloro-4,5-
by s-BuLi lead to the first asymmetric route to the diben-
methylendioxybenzyl)-1,2,3,4-tetrahydro-6-methoxyisoquinoline
leads to 2-benzyloxy-5,6-12,12a-tetrahydro-3-methoxy-9,10-meth-
zopyrrocoline alkaloids.5 An intramolecular cyclization
of 1-(2¢-bromobenzyl)-3,4-dihydroisoquinoline in the
presence of K2CO3 in boiling THF was reported recently.6
A transition metal-mediated approach has not been report-
ed to date. In the course of studies dealing with transition
metal N-heterocyclic carbene (NHC) complexes and their
applications to organic synthesis, we have recently syn-
thesized a number of air- and moisture-stable palladium-
NHC catalysts7–9 easily prepared from [(h3-allyl)PdCl]2
and an NHC in Et2O11 most of these (NHC)Pd(h3-allyl)Cl
complexes are obtained in high yield11 and prove to have
high catalytic activity in a number of coupling reactions.
One such successful use of these catalysts is in the aryl
amination10a,b reaction (Buchwald–Hartwig reaction).
ylendioxydibenz-[b,g]-indolizine, also in high yield. Use of the
catalytic intramolecular aryl amination step allows for the straight-
forward synthesis of the alkaloids rac-cryptaustoline and rac-cryp-
towoline.
Keywords: Pd-mediated aryl amination, N-heterocyclic carbene,
dibenzopyrrocoline-alkaloids
The dibenzopyrrocoline-alkaloids cryptaustoline 1 and
cryptowoline 2 (Figure 1) were isolated from the bark of
cryptocarya bowiei.1a The plant, found in northern New
South Wales and southern Queensland, varies in size from
a small shrub to a tree of about 9 m high.1a Whereas the
northern plant contains only cryptaustoline, the southern
species contains cryptowoline as the main alkaloid.1a His-
torically these alkaloids appeared to be the only diben-
zopyrrocoline-alkaloids in existence, until 1988, when
Moskowitz1b isolated two additional alkaloids of this
class. Cryptowolinol 4, was isolated from Cryptocarya
Phyllostemon and Cryptocarya Oubatchensis, two related
plants from New Caledonia and the New Hebrides. Cryp-
towolidine 3 was reported to occur only in Cryptocarya
Phyllostemon. In addition to a curare-like paralytic ac-
tion,1a the alkaloids are reported to have antileukemic and
antitumor properties.2,3
Scheme 1 (NHC)Pd(h3-allyl)Cl complexes
The aryl amination reaction catalyzed by the
(NHC)Pd(h3-allyl)Cl complexes tolerates a wide variety
of functional groups and most aryl halides are usually
converted to the corresponding anilines in high yield.12
(SIPr)Pd(h3-allyl)Cl 6 (Scheme 1) proved to be the best
catalyst for the intermolecular aryl amination12 being ca-
pable of catalyzing some reactions at room temperature
with a reasonable rate. In order to test our catalysts for this
transformation, we chose 8 as a precursor for an alkaloid
from the Cryptocarya Bowiei family.
Figure 1 Cryptacarya alkaloids
Previous results with these Pd-NHC catalysts encouraged
us to test a palladium-mediated intramolecular aryl-ami-
nation of 8 to 9 expecting no interference with functional
SYNLETT 2003, No. 12, pp 1871–1873
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41468; Art ID: S06503ST
© Georg Thieme Verlag Stuttgart · New York

1872
S. S. Cämmerer et al.
LETTER
groups on 8. The 7-benzyloxy-1-(2-bromo-4,5-dimethoxy-
benzyl)-1,2,3,4-tetrahydro-6-methoxyisoquinoline4 (8) was
prepared according the procedure of Moskowitz.1b We
then applied the (NHC)Pd(h3-allyl)Cl catalysts to the pal-
ladium-mediated intramolecular aryl-amination of 8 to 9.
(Scheme 2).
Scheme 2 Intramolecular aryl-amination leading to 9
Figure 2 ORTEP of 9. Hydrogens have been removed for clarity
We first examined the effects of the catalyst loading and
the nature of the NHC ancillary ligand on the reaction.
Heating a solution of 0.23 mmol of the bromotetrahy-
droisoquinoline 8 in 2 mL of DME with 1.5 equivalents of
t-BuONa and 0.02 equivalent of (IPr)Pd(h3-allyl)Cl 5 to
80 °C for 14 hours produced the indolizine 9 in a yield of
48%. Increasing the catalyst loading under the same reac-
tion conditions to 0.04 equivalent resulted in a yield of
70%. A catalyst loading of 0.06 equivalent resulted in es-
sentially no change. The use of (SIPr)Pd(h3-allyl)Cl 6 as
catalyst gave only 57% at a catalyst loading of 0.02 equiv-
alent and 0.04 equivalent. Using 0.06 equivalent of 6,
64% of the indolizine 9 was obtained. The (IMes)Pd(h3-
allyl)Cl 7 gave the best results of 88% of 9 at a catalyst
loading of 0.06 equivalent. Whereas 6 proved to be the
The chlorotetrahydroisoquinoline 10 was prepared ac-
cording to the procedure of. Moskowitz.1b First, we exam-
ined the effect of the nature of the NHC-ancilliary ligand
on the reaction. (Table 1)
Heating 0.23 mmol of the chlorotetrahydroisoquinoline
10 with 1.5 equivalents of NaOt-Bu and 0.06 equivalent
of 5 in 2 mL DME to 80 °C for 14 hours produced the in-
dolizine 11 in a 60% yield. The use of 0.06 equivalent of
6 resulted in a yield of only 56%. Compound 7 was found
to be the best catalyst, producing 11 in 83%yield. This re-
sult was shown to be consistent with the aryl amination of
8 to 9, 7 seems to be the best catalyst for the intramolecu-
lar aryl-amination resulting in the formation of a sterically
demanding five-membered ring heterocyclic structure.
Using toluene as a solvent increased the yield to 99%. The
solvent effect of this reaction, almost in agreement with
the intramolecular ring-closing aryl-amination of 8 to 9,
best catalyst in the intermolecular aryl-amination,11,12
7
was found to be best catalyst for the intramolecular aryl-
amination of 8 to 9. This can possibly be explained by the
smaller steric hindrance of the aryl substituents of 7 re-
sulting in the smaller repulsive interaction with the bulky
substituents attached to the reaction center compared to a
more sterically encumbered situation in 6.
We then examined the effect of the solvent on the reac-
tion. Heating 0.23 mmol of the bromotetrahydroisoquino-
line 8 with 1.5 equivalents of t-BuONa and 0.06
equivalent of 7 in 2 mL of DME to 80 °C for 14 hours pro-
duced indolizine 9 in a yield of 88%. When the reaction is
performed in toluene under the same conditions, the prod-
uct is obtained in quantitative yield. To confirm the iden-
tity of 9, single crystals were obtained by slow cooling a
hot saturated solution of 9 in degassed EtOH. Results of
the X-ray diffraction study are presented in Figure 2
where the ORTEP confirms the identity and structure of 9.
Scheme 3 Intramolecular aryl amination of 10
Table 1 Effect of the Carbene and the Solvent in the Pd-mediated
Arylamination of 10
Catalyst
Solvent
mMol calatyst
9 mmol
Yield(%)
Having succeeded with the intramolecular aryl-amination
of 7-benzyl-1-(2-bromo-4,5-dimethoxybenzyl)-1,2,3,4-
tetrahydro-6-methoxyisoquinoline (8), we attempted to
perform an intramolecular arylamination of 7-benzyloxy-
1-(2-chloro-4,5-methylen-dioxybenzyl)- 1,2,3,4-tetrahy-
dro-6-methoxyisoquinoline (10) (Scheme 3) in order to
achieve a palladium-mediated approach to cryptowoline
2. (Figure 1)
(mmol)(equiv)
5
6
7
7
DME
0.06
0.06
0.06
0.06
60
56
83
99
DME
DME
Toluene
Synlett 2003, No. 12, 1871–1873 © Thieme Stuttgart · New York

LETTER
Palladium-mediated Approach to Cryptocarya Alkaloids
1873
might lead one to assume that a less polar transition state lyl)Cl system. Toluene was shown to be the best solvent
is involved in the rate-determining step of the catalytic cy- for the reaction resulting in quantitative yields. The sol-
cle. Attempts to lower the catalyst loading, the reaction vent effect suggests a possible involvement of a low po-
temperature or the reaction time did lead to product for- larity transition state in the rate-determining step of the
mation but in lower yields.
catalytic cycle. Transformation of the two indolizine-
structures by straightforward methods leads to the formal
synthesis of two alkaloids from Cryptocarya Bowiei, rac-
cryptaustoline and rac-cryptowoline.
Conversion of the two indolizines 9 and 11 to the corre-
sponding alkaloids according to the procedure of
Kametani4 results in the first formal synthesis of rac-
cryptaustoline4 1 and rac-cryptowoline4 2 involving a
critical palladium-mediated step (Scheme 4).
Acknowledgment
We gratefully acknowledge the National Science Foundation for
financial support of this research.
References
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Scheme 4 Conversion of 9 and 11 to the alkaloids 1 and 2
The application of a (NHC)Pd(h3-allyl)Cl complex to the
palladium-mediated intramolecular ring-closing aryl-
amination of 7-benzyloxy-1-(2-bromo-4,5-dimethoxy-
benzyl)-1,2,3,4-tetrahydro-6-methoxyisoquinoline
(8)
and 7-benzyloxy-1-(2-chloro-4,5-methy-len-dioxyben-
zyl)-1,2,3,4-tetrahydro-6-methoxyisoquinoline (10) re-
sulting in the formation of 2-benzyloxy-5,6,12,12a-
tetrahydro-3,9,10-trimethoxydibenz-[b,g]-indolizine (9)
and 2-benzyloxy-5,6,12,12a-tetrahydro-3-methoxy-9,10-
methylendioxydibenz-[b,g]-indolizine (11), respectively
demonstrates the usefulness of such catalyst in alkaloid
total synthesis. Whereas 6 was proven recently to be the
best catalyst for intermolecular aryl-amination, 7 proved
to be the superior catalyst in the two intramolecular aryl-
amination reactions presented here. One possible explana-
tion for these results can be the lower steric hindrance of
the NHC-ancilliary ligand (IMes vs. IPr and SIPr) of the
catalyst, resulting in the less sterically crowded reactive
center. This hypothesis is presently being tested on even
less sterically demanding NHC in the (NHC)Pd(h3-al-
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2000, 2, 1799.
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4, 4053.
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Synlett 2003, No. 12, 1871–1873 © Thieme Stuttgart · New York