Annulation of aromatic imines via directed C-H bond activation

Article abstract of DOI:10.1021/jo050757e

A directed C-H bond activation approach to the synthesis of indans, tetralins, dihydrofurans, dihydroindoles, and other polycyclic aromatic compounds is presented. Cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using (PPh₃)₃RhCl (Wilkinson's catalyst). The cyclization of a range of aromatic ketimines and aldimines provides bi- and tricyclic ring systems with good regioselectivity. Different ring sizes and substitution patterns can be accessed through the coupling of monosubstituted, 1,1- or 1,2-disubstituted, and trisubstituted alkenes bearing both electron-rich and electron-deficient functionality.

Full text of DOI:10.1021/jo050757e

Annulation of Aromatic Imines via Directed C-H Bond Activation
Reema K. Thalji, Kateri A. Ahrendt, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, University of California, and Division of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California 94720
bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
Received April 14, 2005
A directed C-H bond activation approach to the synthesis of indans, tetralins, dihydrofurans,
dihydroindoles, and other polycyclic aromatic compounds is presented. Cyclization of aromatic
ketimines and aldimines containing alkenyl groups tethered at the meta position relative to the
imine directing group has been achieved using (PPh3)3RhCl (Wilkinson’s catalyst). The cyclization
of a range of aromatic ketimines and aldimines provides bi- and tricyclic ring systems with good
regioselectivity. Different ring sizes and substitution patterns can be accessed through the coupling
of monosubstituted, 1,1- or 1,2-disubstituted, and trisubstituted alkenes bearing both electron-
rich and electron-deficient functionality.
Introduction
bonds to simple olefins represents a breakthrough in this
field.3 In this seminal work, chelation-assisted ruthenium-
catalyzed C-H bond activation of aromatic ketones
followed by olefin addition provided exclusively ortho-
alkylated products.4 Since that publication, Brookhart
has developed a rhodium complex [Cp*Rh(C2H3SiMe3)2]
that catalyzes the same reaction,5 and the ruthenium-
catalyzed olefin hydroarylation reaction has been ex-
tended to include various aromatic compounds, such as
thiophene, furan, pyrrole, and electron-deficient aromatic
esters.6 Olefinic C-H bonds at the â-position of R,â-
unsaturated ketones7 and esters8 can also be added to
carbon-carbon double bonds. A range of functional
In contemporary organic synthesis, one of the most
attractive methods for carbon-carbon bond formation is
the transition-metal-catalyzed activation and function-
alization of otherwise unreactive carbon-hydrogen
bonds.1,2 Because C-H bonds are among the most
ubiquitous chemical linkages in nature, the direct con-
version of C-H bonds to C-C bonds represents an
efficient and economical strategy for fine chemical pro-
duction. The greatest challenge in this field of research
is the development of both mild and selective methods
for transforming the relatively inert C-H bonds into
other chemical functionalities. Murai’s 1993 discovery of
a highly efficient and selective catalytic addition of C-H
(3) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
(1) For reviews on stoichiometric C-H activation, see: (a) Labinger,
J. A.; Bercaw, J. E. Nature 2002, 417, 507. (b) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. Rev. 2002, 102, 1731. (c) Shilov, A.; Shul’pin, G. B.
Chem. Rev. 1997, 97, 2879. (d) Arndtsen, B. A.; Bergman, R. G.;
Mobley, T. A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (e)
Ryabov, A. Chem. Rev. 1990, 90, 403.
(2) For reviews on catalytic C-H activation, see: (a) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1699. (b) Guari, Y.; Sabo-Etienne,
S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 7, 1047. (c) Kakiuchi, F.;
Murai, S. In Topics in Organometallic Chemistry; Murai, S., Ed.;
Springer-Verlag: Berlin Heidelberg, 1999; Vol. 3, p 47. (d) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102 (5), 1731. (e) Kakiuchi,
F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (f) Ishiyama, T.;
Miyaura, N. J. Organomet. Chem. 2003, 680, 3. (g) Jia, C. G.;
Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
(4) Bis-alkylation occurs in substrates where both ortho positions
are unsubstituted. The ratio of mono- to bis-alkylation is determined
by the number of olefin equivalents and the reaction time.
(5) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616.
(6) (a) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62. (b)
Murai, S.; Kakiuchi, F.; Sekine, S.; Yanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Pure Appl. Chem. 1994, 66, 1527. (c) Murai, S.;
Chatani, N.; Kakiuchi, F. Pure Appl. Chem. 1997, 69, 589. (d) Sonoda,
M.; Kakiuchi, F.; Kamatani, A.; Chatani, N.; Murai, S. Chem. Lett.
1996, 109.
(7) Kakiuchi, F.; Tanaka, Y.; Sato, T.; Chatani, N.; Murai, S. Chem.
Lett. 1995, 679.
(8) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995, 117,
5371.
10.1021/jo050757e CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/15/2005
J. Org. Chem. 2005, 70, 6775-6781
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Thalji et al.
groups on the aromatic component are tolerated, includ-
ing ethers, esters, amides, and nitriles.2c,9
less reactive olefins due to the lower entropic barrier of
reaction. Substrates with electron-rich or electron-
deficient olefins, highly substituted olefins, and hetero-
atom-containing olefins would allow access to syntheti-
cally useful compounds that are not otherwise readily
prepared. Furthermore, the construction of aromatic
compounds in which new stereocenters are generated
would allow the development of asymmetric catalytic
C-H bond activation/olefin insertion chemistry.
We have developed an intramolecular variant of the
chelation-assisted C-H bond activation/olefin insertion
reaction that is much more versatile than the intermo-
lecular reaction and have published our preliminary
results in a previous communication.17 Since then, we
have demonstrated its application to the synthesis of a
biologically important molecule18 and have recently com-
municated a highly enantioselective variant of the an-
nulation reaction using chiral phosphoramidite ligands.19
Herein, the details of our studies on the annulation using
achiral catalysts are reported.
The primary factor that hinders the utility of this
chemistry is the limited olefin substrate scope.6a Gener-
ally, vinylsilanes, vinylsiloxanes, and tert-butyl ethylene
couple efficiently, but other olefins such as internal
olefins, dienes, and olefins with electron-withdrawing or
electron-donating groups show a low reactivity toward
ortho-alkylation. In addition, terminal alkenes that can
undergo olefin isomerization do not serve as effective
coupling partners.
More recently, Jun and co-workers reported a more
general reaction involving the ortho-alkylation of aro-
matic ketimines using Wilkinson’s catalyst, (PPh3)3-
RhCl.10,11 Ketimines efficiently coupled with a range of
olefins to afford selectively the linearly-alkylated prod-
ucts. Isomerizable alkenes, 1,1-disubstituted alkenes, 1,2-
disubstituted alkenes, and R,ω-dienes couple with mod-
erate to good efficiency,10 as do R,â-unsaturated carbonyl
systems.11 Interestingly, internal olefins undergo reaction
after isomerization to the terminal olefin. The rhodium-
catalyzed ortho-alkylation of ketimines is believed to
occur by a mechanism analogous to that of the Murai
reaction.12
Despite the advancements achieved through the imine-
directed reaction, there remain several limitations to this
chemistry. First, aldimines are not effective directing
groups for the coupling reaction, a fact that significantly
confines the synthetic versatility of the products.13 Sec-
ond, the formation of only linear alkylated products
precludes the general use of this chemistry in the
synthesis of chiral products.6 Finally, heteroatom-con-
taining olefins, such as vinyl ethers, allylic ethers, and
allylic amines, do not react with the ketimine.6
Prior to our research group’s studies on intramolecular
hydroarylation reactions,14 there were surprisingly few
examples of intramolecular C-H activation/olefin inser-
tion chemistry.15,16 The development of an intramolecular
variant of the Murai reaction (eq 1), in which the alkene
Results and Discussion
The reactions of aromatic ketones with an alkene
tethered at the meta position (eq 2) were initially ex-
amined. Cp*Rh(C2H3SiMe3)2 cleanly converts ketone 1,
containing allylic geminal substitution, into indan
2 in good yield and high regioselectivity (11.5:1 five-
to six-membered ring product ratio by GC).20 How-
ever, the scope of the carbonyl-directed/Cp*Rh(C2H3-
SiMe3)2-catalyzed reaction was not general, as substrates
bearing isomerizable olefins did not undergo annula-
tion.
We refocused our efforts to the annulation of aromatic
imines shortly after the report by Jun appeared in the
literature describing a broader reaction scope with
respect to the olefin coupling partner. The cyclization
of an acetophenone imine with a tethered isomeriz-
able olefin was initially examined. Treatment of imine 3
(14) For intramolecular heterocyclic C-H activation/olefin inser-
tions, see: (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 2685. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2002, 124, 3202. (c) Tan, K. L.; Vasudevan, A.;
Bergman, R. G.; Ellman, J. A.; Souers, A. J. Org. Lett. 2003, 5, 2131.
(f) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 13964. (g) Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 1685. (h) Lewis, J. C.; Wiedemann, S. H.; Bergman, R.
G.; Ellman, J. A. Org. Lett. 2004, 6, 35.
is tethered meta to the carbonyl or imine directing group,
was expected to broaden the substrate scope to include
(9) (a) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. J. Orga-
nomet. Chem. 1995, 504, 151. (b) Sonoda, M.; Kakiuchi, F.; Chatani,
N.; Murai, S. Bull. Chem. Soc. Jpn. 1997, 70, 3117.
(10) Jun, C. H.; Hong, J.-B.; Kim, Y.-H.; Chung, K. Y. Angew. Chem.,
Int. Ed. 2000, 39, 3440.
(11) Lim, S.-G.; Ahn, J.-A.; Jun, C.-H. Org. Lett. 2004, 6, 4687-
4690.
(12) Jun, C. H.; Moon, C. W.; Hong, J.-B.; Lim, S.-G.; Chung, K. Y.;
Kim, Y.-H. Chem. Eur. J. 2002, 8, 485.
(13) (a) Lim has shown that aldimines can be coupled to isomeriz-
able alkenes using [RhCl(coe)2]2/Cy3P as the catalyst; however, bis-
ortho-alkylated products predominate over the desired monoalkylated
products: Lim, Y. G.; Han, J. S.; Yang, S. S.; Chun, J. H. Tetrahedron
Lett. 2001, 42, 4853. (b) Murai used Ru3(CO)12 to couple ald-
imines intermolecularly to terminal alkenes with no allylic hydro-
gens: Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett.
1996, 111.
(15) Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani, N.; Murai, S. Bull.
Chem. Soc. Jpn. 1998, 285, 5.
(16) For reports on related, nondirected intramolecular C-H activa-
tion/alkene insertion reactions, see: (a) Pastine, S. J.; Youn, S. W.;
Sames, D. Org. Lett. 2003, 5, 1055. (b) Pastine, S. J.; Youn, S. W.;
Sames, D. Tetrahedron 2003, 59, 8859. (c) Youn, S. W.; Pastine, S. J.;
Sames, D. Org. Lett. 2004, 6, 581-584.
(17) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 9692.
(18) Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2003,
5, 1301.
(19) Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2004, 126, 7192.
(20) Murai’s most successful catalyst for the analogous intermo-
lecular reaction, RuH2(CO)(PPh3)3, gave a poor yield (∼20% NMR yield)
of the five-membered ring product, and Ru3(CO)12 was ineffective.
6776 J. Org. Chem., Vol. 70, No. 17, 2005

Annulation of Aromatic Imines
TABLE 1. Synthesis of Indan Derivativesa
TABLE 2. Synthesis of Tetralin Derivativesa
a Conditions: 5 mol % (PPh3)3RhCl, toluene, heat; then 1 N HCl.
b Isolated yields of purified products after silica gel chromatogra-
phy. c trans-Isomer determined to be the major product by NOESY
experiment and X-ray crystallography.
a Conditions: 5 mol % (PPh3)3RhCl, toluene, heat; then 1 N HCl.
b Isolated yields of purified products after silica gel chromatogra-
phy.
with Wilkinson’s catalyst at elevated temperature, fol-
lowed by aqueous acid workup, provided the indan
product 4 in high yield (eq 3). No double-bond isomer was
The annulation of vinylsilane substrate 8 (entry 3)
illustrates a method of introducing a hydroxyl functional-
ity in the product, as the phenyldimethylsilyl group can
be converted to an alcohol using oxidation conditions
developed by Fleming23 and Tamao.24 The cyclization of
cinnamyl-tethered substrate 10 demonstrates, for the
first time, the direct coupling of an acyclic 1,2-disubsti-
tuted alkene to an aromatic ring.25 Even the sterically
hindered alkene 12 could be cyclized with good yield and
high diastereoselectivity. In this case, the observed
preference for trans substitution is presumably a result
of a syn addition of the Rh-H bond to the olefin. The
minor cis indan product observed is most likely due to
in situ double bond isomerization of 12 to its cis-double
bond isomer followed by cyclization.
In contrast to the intermolecular variant using Wilkin-
son’s catalyst,10 aldimines direct the C-H activation/
olefin insertion reaction (Tables 1-6). Importantly, this
increases the synthetic utility of our annulation strategy
due to the facility with which carboxaldehydes can be
converted into other functionalities.
detected.21 Encouraged by this initial result, the sub-
strate generality of the annulation reaction was ex-
plored.
Synthesis of Indan Derivatives. A variety of other
indans are readily accessed with this methodology, as
outlined in Table 1. Cyclization of the allyl-substituted
ketimine 5 occurs, providing a 52% yield of 6 (entry 2).
Competing olefin isomerization takes place in this case,
forming the styrenyl isomer 7 in addition to the desired
product (6:7 ) 3:1). As might be expected from the
estimated exothermicity of the reaction (∼18 kcal/mol22),
the imine corresponding to product 6 does not react with
Wilkinson’s catalyst, establishing that isomer 7 and the
indan product are not in equilibrium. This result suggests
that the ratio of products formed by the reaction of
ketimine 5 is kinetically determined.
Synthesis of Tetralin Derivatives. Various tetralins
can also be prepared via rhodium(I)-catalyzed C-H
activation/olefin insertion, as shown in Table 2. The
presence of allylic R,R-branching (entry 1) and internal
geminal alkene substitution (entry 2) directs the reac-
tions to yield exclusively the six-membered ring products.
Interestingly, the regioselectivity in the cyclization of
imine 14 is opposite to that of ketone 1 (eq 2), which bears
(21) The remainder of the mass balance for the reaction of this
substrate and others is presumably lost to oligomerization and/or
polymerization of starting material. An evaluation of the reaction
concentration revealed that performing the reaction at a substrate
concentration of 0.1 M afforded higher yields than performing the same
reaction at either higher or lower concentrations.
(22) This value was calculated using the heats of formation of
compounds 5 and 6 estimated by the Benson group equivalent method
(Benson, S. W. Thermochemical Kinetics, 2nd ed., Wiley: New York,
1976; <http://webbook.nist.gov/chemistry/grp-add/ga-app.shtml>). The
entropy change counteracts this exothermicity to a significant extent
at 125 °C, but the free energy change is still predicted to be negative
at this temperature.
(23) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.;
Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 4, 317. (b)
Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1.
(24) Tamao, K. Adv. Silicon Chem. 1996, 3, 1.
(25) Murai used RuH2(CO)(PPh3)3 to couple aromatic ketones to
norbornene and cyclopentene. See ref 6a.
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Thalji et al.
TABLE 4. Synthesis of Dihydroindole Derivativesa
TABLE 3. Synthesis of Dihydrobenzofuran Productsa
a Conditions: 5 mol % (PPh3)3RhCl, toluene, heat; then 1 N HCl.
b Isolated yields of purified products after silica gel chromatogra-
phy.
The cyclohexenyl aryl ether 35 (entry 6) generates the
hexahydrodibenzofuran product 36 in modest yield, in
addition to a minor amount of tetrahydrodibenzofuran
product 37, presumably due to hydrogen transfer be-
tween starting olefin and cyclized product. As observed
for the allylic ethers in Table 3, transient olefin isomer-
ization of 35 occurs. In this case, cyclization is believed
to occur directly from the allylic double bond because
independently synthesized vinyl ether isomer 38 does not
undergo reaction in the presence of Wilkinson’s catalyst
(eq 4). Consistent with a syn Rh-H addition to the allylic
a Conditions: 5 mol % (PPh3)3RhCl, toluene, heat; then 1 N HCl.
b Isolated yields of purified products after silica gel chromatogra-
phy.
the same olefin tether. In the one observed case of a
nonregioselective cyclization to a mixture of tetralin and
indan products, the ketimine lacks substitution in the
alkyl tether (entry 3). Isomerization to the internal olefin
double bond, the cis-fused product 36 is obtained exclu-
sively. Direct cyclization of vinyl ether 38 would yield
the undetected trans-fused product.
1
occurs in this case, as determined by H NMR studies.
In addition to bicyclic ring systems, tricyclic products can
be prepared with this methodology. Thus, the biaryl
aldimine 21 (entry 4) readily yields dihydrophenanthrene
22 under the reaction conditions.
Synthesis of Dihydroindole Derivatives. Dihy-
droindoles are synthesized by subjection of aryl ally-
lamine derivatives to the cyclization conditions (Table 4).
N-Alkyl, N-acyl, and N-sulfonyl functionalities are toler-
ated. In all cases, the five-membered ring products are
formed in >95:5 selectivity over the six-membered ring
products. Although the yields are moderate (50-53%
yield), these cyclizations are significant because they
represent the first examples of directed C-H activation/
olefin insertion using allylamine derivatives as coupling
partners.
Synthesis of Functionalized Heterocycles. Func-
tionalization of heterocycles with our annulation strategy
is demonstrated in Table 5. The C-3 substituted benzyl
imine directs C-H activation at the C-2 position of
N-methallyl indoles (entry 1) and an N-methallyl pyrrole
(entry 2) to provide the alkylated heterocyclic systems
in good to high yield.
Synthesis of Dihydrobenzofuran Products. Allyl
ethers couple efficiently, selectively providing dihydroben-
zofuran products (Table 3). The formation of a five-
membered ring system from the crotyl ether 27 (entry
2) demonstrates direct coupling of an acyclic 1,2-disub-
stituted alkene to an aromatic ring. Additionally, the R,â-
unsaturated ester 29 (entry 3) undergoes this transfor-
mation. The successful coupling of allylic ethers is
significant because in the intermolecular reactions of
aromatic ketones and ketimines these are ineffective
substrates. Olefin isomerization occurs in the reactions
of substrates 23 and 24 (entry 1), 27 (entry 2), and 29
1
(entry 3) as observed by H NMR, though it is unclear
whether cyclization proceeds from the allylic or the
vinylic ether. The aryl vinyl ethers 31 and 33 (entries 4
and 5) undergo efficient transformation to the dihy-
drobenzofuran, suggesting the allylic ethers can cyclize
from their internal olefin isomers.
Limitations. The intramolecular C-H bond activa-
tion/olefin addition strategy provides access to a number
of useful polycyclic compounds. We did, however, identify
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Annulation of Aromatic Imines
TABLE 5. Functionalization of Heterocyclesa
TABLE 6. Effect of para-Substitution of Benzyl Imines
on Isolated Yield of 25
a Isolated yield after 1 N HCl hydrolysis.
a Conditions: 5 mol % (PPh3)3RhCl, toluene, heat; then SiO2.
b Isolated yields of purified products.
8). Consistent with the above hypothesis, no reaction
occurred.
limitations to this methodology during the course of our
studies. For instance, a chroman product was expected
from subjection of the gem-dialkyl-substituted allylic
ether 51 to the cyclization conditions (eq 5), because the
Optimization Efforts. Other imine directing
groups were examined. Imines were prepared from a
variety of amines and subjected to the cyclization condi-
tions with Wilkinson’s catalyst (eq 9). Most of the imines
analogous carbon-tethered olefin cyclized to the six-
membered ring system in high yield (Table 2, entry 1).
However, in the case of the allylic ether, the product yield
was low, and efforts to improve the cyclization with
increased catalyst loading or decreased temperature were
unsuccessful.
Control experiments demonstrated substrate 51 un-
dergoes a facile Claisen rearrangement in the absence
of catalyst at elevated temperature (eq 6). Interest-
cyclized less efficiently than the benzyl imine, although
an interesting trend was observed with para-substituted
benzyl imines. The electron-donating p-methoxy group
decreased product yield and the electron-withdrawing
p-trifluoromethyl group provided a higher yield of cy-
clized product (Table 6).26
In addition to Wilkinson’s catalyst, a number of other
transition metal complexes were surveyed in the model
cyclization reaction of allyl ether 23, including (PPh3)2-
Ru(Cp)Cl, Ru3(CO)12, RuH2(CO)(PPh3)3, (PPh3)3RuCl2,
(PPh3)3CoCl, (PPh3)2Co(Cp), (PPh3)3CoCl2, and [IrCl-
(coe)2]2/PPh3. No cyclized product was observed with the
cobalt or iridium complexes, and only trace product was
detected with the use of (PPh3)2Ru(Cp)Cl.
ingly, the unsubstituted allylic ether 23 (Table 3)
does not undergo Claisen rearrangement after extended
heating at 150 °C, indicating that rearrangement of
51 is promoted by a Thorpe-Ingold (gem-dimethyl)
effect.
The aryl allyl thioether 52 did not undergo reac-
tion when subjected to Wilkinson’s catalyst at el-
evated temperature (eq 7). We presumed the thio-
In an effort to improve the efficiency of the annulation
reaction, a diverse set of phosphines was screened in the
presence of [RhCl(coe)2]2 (Chart 1). Bidentate phosphines
were unsuccessful for the reaction of allyl ether 23 (Table
ether coordinated too strongly to the rhodium center,
poisoning the catalyst. To ascertain if this was the case,
a substrate that is known to undergo annulation (aldi-
mine 8, Table 1) was subjected to the reaction conditions
with an equivalent amount of the thioether present (eq
(26) The reason for this trend is unclear; the substituent presumably
plays a role in the reaction by altering the basicity of the imine nitrogen
or by changing the electrophilicity of the aromatic ring involved in the
C-H activation.
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Thalji et al.
TABLE 7. Optimization of the Tandem C-H Activation/
CHART 1. Phosphines Surveyed in the
Cyclization of 23
Olefin Insertion Reaction
entry
Rh catalysta
(PPh3)3RhClc
t (h)
% yieldb
1
2
3
4
5
6
7
20
3
10
0
18
48
34
75
52
SCHEME 1. Postulated Mechanism for the
Annulation Reaction
P(t-Bu)3, [RhCl(coe)2]2
P(n-Bu)3, [RhCl(coe)2]2
PCy3, [RhCl(coe)2]2
17
8
FcPPh2, [RhCl(coe)2]2
FcPCy2, [RhCl(coe)2]2d
FcPCy2, [RhCl(coe)2]2
4
2
5
a Reactions were performed using 20 mol % Rh(I) and 20 mol
% phosphine. b Yields were determined by 1H NMR relative to an
internal standard. c 20 mol % Wilkinson’s catalyst was used.
d Reaction was performed using 20 mol % Rh(I) and 40 mol %
phosphine. Abbreviations: coe ) cyclooctene; Fc ) ferrocenyl.
Application to the Synthesis of a Mescaline Ana-
logue. To date, only a few examples of C-H activation
in the synthesis of natural products or biologically active
molecules have been reported.29,30 Our interest in mes-
caline analogue 5831 (Scheme 2) was generated by the
ability to rapidly assemble the tetrahydrobis(benzofuran)
functionality utilizing the catalytic C-H activation/olefin
insertion reaction. As outlined in Scheme 2, precursor
56 was prepared from (4′-O-methyl)methyl gallate 5332
by transformation of the bis-phenol to the bis-vinyl ether
5433 followed by ester reduction34 and conversion of alde-
hyde 55 to the benzyl imine. Evaluation of a range of
catalyst systems (Table 7) led to the identification of con-
ditions (10% [RhCl(coe)2]2, 20% FcPCy2, 150 °C) that pro-
vided the tetrahydrobis(benzofuran) 57 in 65% yield after
imine hydrolysis. Compound 57 was subsequently con-
verted to the target mescaline analogue via a Henry reac-
tion followed by reduction of the intermediate nitroalk-
ene. The tetrahydrobis(benzofuran) mescaline analogue
58 was prepared in six steps and 38% overall yield from
(4′-O-methyl)methyl gallate. This annulation sequence
can potentially be applied to the synthesis of other
biologically relevant dihydrobenzofurans.
3). This is consistent with the observation that excess
phosphine hinders the cyclization reaction. The mono-
dentate phosphines surveyed gave catalysts of compa-
rable or lower efficiency than PPh3 for this model system.
However, with certain substrates, the rhodium catalyst
generated from PCy3 was found to provide more efficient
cyclization than that based on PPh3. For example, the
cyclization of 3 using 2.5 mol % [RhCl(coe)2]2 and 7.5 mol
% PCy3 proceeds to completion within 8 h at 80 °C. With
more challenging substrates such as 23, the catalyst
decomposes before the reaction is complete.
Mechanism. The mechanism of the annulation reac-
tion most likely involves a catalytic cycle analogous to
that proposed by Jun et al.12 for his intermolecular C-H
activation/alkene insertion reaction (Scheme 1). Imine
precoordination, followed by C-H oxidative addition to
the Rh center, would generate a Rh-H complex, as
shown in Scheme 1.27 This step may be followed by
coordination of the olefin to the metal. Migratory inser-
tion into the Rh-H bond would provide a metalacycle
that can undergo reductive elimination to afford the
product. Deuterium labeling studies performed by Jun
et al. on the analogous intermolecular reaction indicate
that the reductive elimination step is rate-determining.12
An alternative mechanism for the C-H activation step
(not shown) may involve precoordination of both the
imine and the olefin, which would form a pincer-type
complex that would be well-suited for C-H activation of
the hindered ortho C-H bond.28
(28) Similar pincer-type cyclometalations have been described by
other researchers: (a) Rietveld, M. H. P.; Grove, D. M.; van Koten, G.
New J. Chem. 1997, 21, 751-771. (b) Nemeh, S.; Jensen, C.; Binamira-
Soriaga, E.; Kaska, W. C. Organometallics 1983, 2, 1442-1447.
(29) For examples of the application of C-H bond activation in
target-oriented synthesis, see: (a) Harris, P. W. R.; Woodgate, P. D.
J. Organomet. Chem. 1997, 530, 211. (b) Johnson, J. A.; Sames, D. J.
Am. Chem. Soc. 2000, 122, 6321. (c) Dangel, B. D.; Godula, K.; Youn,
S. W.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2002, 124, 11856. (d)
Wehn, P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 12950. (e)
Pastine, S. J.; Sames, D. Org. Lett. 2003, 5, 4053.
(30) For examples of the application of rhodium-carbenoid insertions
into C-H bonds in target-oriented synthesis, see: (a) Taber, D.; Song,
Y. J. Org. Chem. 1997, 62, 6603. (b) Davies, H. M. L.; Stafford, D. G.;
Hansen, T. Org. Lett. 1999, 1, 233. (c) Davies, H. M. L.; Gregg, T. M.
Tetrahedron Lett. 2002, 43, 4951 and references therein.
(31) Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott,
D. B.; Nelson, D. L.; Sanders-Bush, E.; Nichols. E. J. Med. Chem. 1997,
40, 2997.
(32) 4′-(O-Methyl)methyl gallate is prepared by alkylation of com-
mercially available methyl benzoate. Cardona, M. L.; Fernandez, M.
I.; Garcia, M. B.; Pedro, J. R. Tetrahedron 1986, 42, 2725.
(33) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043.
(34) Abe, T.; Haga, T.; Negi, S.; Morita, Y.; Takayanagi, K.; Hama-
mura, K. Tetrahedron 2001, 57, 2701.
(27) Alternatively, reversible ortho, meta, and para C-H activation
may precede functional group coordination, which would then serve
to trap the ortho C-H addition product: Zhang, X.; Kanzelberger, M.;
Emge, T. J.; Goldman, A. S. J. Am. Chem. Soc. 2004, 126, 13192.
6780 J. Org. Chem., Vol. 70, No. 17, 2005

Annulation of Aromatic Imines
SCHEME 2. Synthesis of Mescaline Analog 58 Using C-H Activation Methodology
was concentrated, 1 N HCl was then added, and the resulting
Conclusion
mixture was stirred vigorously for 3 h. The mixture was then
diluted with EtOAc, the organic layer was separated, and the
aqueous phase was re-extracted. The combined organic ex-
tracts were washed with brine, dried, filtered, and concen-
trated in vacuo. The crude product was purified by silica gel
chromatography.
A novel method has been developed for the synthesis
of functionalized indans, tetralins, dihydrobenzofurans,
dihydroindoles, and other polycyclic compounds from
simple starting materials using directed C-H bond acti-
vation. The cyclizations generally proceed with high se-
lectivity, and the reactions are tolerant of various func-
tional groups, different tether lengths, a number of al-
kene substitution patterns, and the incorporation of het-
eroatoms in the tether. Furthermore, the annulation of
aldimine substrates provides additional synthetic oppor-
tunities due to the facility with which the product car-
boxaldehydes can be converted into other functionalities.
Acknowledgment. This work was supported by
NIH grant GM069559 (to J.A.E.), and by the Director,
Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U. S. Department
of Energy, under Contract DE-AC03-76SF00098 (to
R.G.B.). We thank Dr. Fred Hollander and Dr. Allen
Oliver of the UC Berkeley CHEXRAY facility for car-
rying out the X-ray diffraction study.
Experimental Section
General Procedure for Cyclization of Benzyl Imino
Substrates. In an inert atmosphere drybox, to a medium-
walled glass reaction vessel was added a solution of (PPh3)3-
RhCl (5 mol %) and the benzyl imine in toluene (0.1 M). The
vessel was sealed with a Kontes stopcock and placed in an oil
bath at 125 or 150 °C. After the noted reaction time, the vessel
was removed and cooled to room temperature. The solution
Supporting Information Available: Full experimental
details, including analytical data for all compounds described
in the article and X-ray diffraction data for 13 in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050757E
J. Org. Chem, Vol. 70, No. 17, 2005 6781