Intramolecular carbonylation reactions with recyclable palladium-complexed dendrimers on silica: Synthesis of oxygen, nitrogen, or sulfur-containing medium ring fused heterocycles

Article abstract of DOI:10.1021/ja053650h

Palladium-complexed dendrimers supported on silica were evaluated as catalysts for intramolecular carbonylation reactions. The results showed that dendritic catalysts display high activity, affording oxygen, nitrogen, or sulfur-containing seven- or eight-membered ring fused heterocycles in excellent yields. Moreover, these catalysts have competitive advantages in that they can be easily recovered by simple filtration in air and reused for up to eight cycles with only a slight loss of activity.

Full text of DOI:10.1021/ja053650h

Published on Web 10/01/2005
Intramolecular Carbonylation Reactions with Recyclable
Palladium-Complexed Dendrimers on Silica: Synthesis of
Oxygen, Nitrogen, or Sulfur-Containing Medium Ring Fused
Heterocycles
Shui-Ming Lu and Howard Alper*
Contribution from the Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received June 3, 2005; E-mail: howard.alper@uottawa.ca
Abstract: Palladium-complexed dendrimers supported on silica were evaluated as catalysts for intramo-
lecular carbonylation reactions. The results showed that dendritic catalysts display high activity, affording
oxygen, nitrogen, or sulfur-containing seven- or eight-membered ring fused heterocycles in excellent yields.
Moreover, these catalysts have competitive advantages in that they can be easily recovered by simple
filtration in air and reused for up to eight cycles with only a slight loss of activity.
heterocycles.4 However, the difficulties associated with the
separation of products from the reaction mixture and the
Introduction
Medium-sized heterocycles are receiving a great deal of
attention as their structural units are widely found in numerous
natural products.1 In particular, seven- and eight-membered ring
heterocycles constitute a number of biologically interesting
molecules.2 The abundance of oxygen, nitrogen, or sulfur-
containing medium rings in pharmaceuticals and agrochemicals
continues to ensure that they are important synthetic targets for
organic chemists. For example, dibenzoxazepinone derivatives
represent an exciting field of research in medicinal chemistry
due to their biological activity, including non-nucleoside inhibi-
tors of HIV-1 RT and central nervous system agents.3 Although
these heterocycles can be prepared by conventional methods in
multistep syntheses, the reactions often require severe conditions,
and low yields of products are obtained in some cases.
Therefore, it is important to develop a general and effective
route to medium ring fused heterocycles.
recovery of the expensive, and sometimes toxic, catalysts are
major drawbacks in these transformations. For the above
reasons, many excellent homogeneous catalysts are not used
on an industrial scale despite their benefits. Among the various
approaches to address these problems, immobilization of a metal
complex on a solid support offers the possibility for the recovery
and reuse of catalysts,5 but heterogeneous catalysts obtained in
this way are usually accompanied by a significant decrease in
activity.
Innovative methods for the development of environmentally
friendly and economically viable catalytic systems are becoming
more and more important in view of green chemistry. The
advent of dendrimers provides a unique opportunity to combine
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9
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10.1021/ja053650h CCC: $30.25 © 2005 American Chemical Society

Synthesis of O, N, or S-Containing Ring Fused Heterocycles
A R T I C L E S
the advantages of both homogeneous and heterogeneous cata-
lysts.6,7 In fact, from the beginning, catalysis has been recognized
as one of the most valuable applications of dendrimers. The
key property of dendritic catalysts is their recovery and reuse
by microfiltration8 or precipitation9 under specific conditions.
Soluble dendritic catalysts have been successfully applied to a
variety of organic reactions.8-10 However, relatively few
examples involve insoluble dendritic catalysts.11 For instance,
Dahan and Portnoy11a described the intramolecular Pauson-
Khand reaction catalyzed by heterogeneous metallodendrimers.
Sellner and Seebach11b investigated the use of polymer-
supported chiral dendrimers for the enantioselective addition
of diethylzinc to benzaldehyde. Recently, we reported that
heterogeneous dendrimer-rhodium complexes are highly ef-
ficient catalysts for the hydroformylation of olefins at room
temperature. The systems can be easily recovered by simple
filtration in air and reused without loss of activity and
selectivity.12 These results stimulated us to explore intramo-
lecular carbonylation reactions with recyclable palladium-
complexed dendrimers on silica to form oxygen, nitrogen, or
sulfur-containing medium ring fused heterocycles. We now
demonstrate that heterogeneous dendrimer-palladium com-
plexes are very effective catalysts for the synthesis of seven-
and eight-membered ring fused heterocycles in excellent yields.
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Weinheim, Germany, 1996.
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Yeung, L. K. Acc. Chem. Res. 2001, 34, 181-190.
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van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2001, 123, 8453-8458. (c)
Kleij, A. W.; Gossage, R. A.; Klein Gebbink, R. J. M.; Brinkmann, N.;
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Chem. Soc. 2000, 122, 12112-12124. (d) Eggeling, E. B.; Hovestad, N.
J.; Jastrzebski, J. T. B. H.; Vogt, D.; van Koten, G. J. Org. Chem. 2000,
65, 8857-8865. (e) Hovestad, N.; Eggeling, E. B.; Heidbuchel, H. J.;
Jastrzebski, J. T. B. H.; Kragl, U.; Keim, W.; Vogt, D.; van Koten, G.
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J. Mol. Catal. A: Chem. 1999, 145, 329-333.
Results and Discussion
Synthesis of Dendritic Catalysts and Substrates. Palladium-
complexed dendrimers on silica were synthesized by the
modification of our previously reported method.12c,d Michael-
type addition and amidation reactions were used to construct
dendrimers supported on silica, followed by the phosphonation
of dendrimers with diphenylphosphinomethanol. The resulting
phosphonated dendrimers were then reacted with dichlorobis-
(benzonitrile)palladium(ΙΙ) to give the dendrimer complexes
G0-Pd-G3-Pd (Figure 1), which were characterized by solid-
state 31P NMR (complexed δ ) 11 ppm, uncomplexed δ )
-27 ppm). The ICP results showed the palladium contents of
G0-Pd-G3-Pd are 0.57, 0.80, 0.52, and 0.29 mmol/g,
respectively.
The requisite substrates are readily prepared by coupling and
subsequent reduction reactions. For example, treatment of
substituted 1-fluoro(chloro)-2-nitrobenzene 1 with 2-iodo(bro-
mo)phenol 2 in the presence of potassium carbonate gave the
corresponding nitro haloarenes, which were converted to 2-(2-
halophenoxy)anilines 3 using tin(ΙΙ) chloride dihydrate as the
reducing reagent. The yields were 72-85% for the two steps
(eq 1).13 Other intramolecular carbonylation reaction precursors
were also synthesized in a similar manner (see Supporting
Information).
(10) (a) Zubia, A.; Cossio, F. P.; Morao, I.; Rieumont, M.; Lopez, X. J. Am.
Chem. Soc. 2004, 126, 5243-5252. (b) Esposito, A.; Delort, E.; Lagnoux,
D.; Djojo, F.; Reymond, J.-L. Angew. Chem., Int. Ed. 2003, 42, 1381-
1383. (c) Schlenk, C.; Kleij, A. W.; Frey, H.; van Koten, G. Angew. Chem.,
Int. Ed. 2000, 39, 3445-3447. (d) Chechik, V.; Crooks, R. M. J. Am. Chem.
Soc. 2000, 122, 1243-1244. (e) Zeng, H.; Newkome, G. R.; Hill, C. L.
Angew. Chem., Int. Ed. 2000, 39, 1772-1774. (f) Kleij, A. W.; Gossage,
R. A.; Jastrzebski, J. T. B. H.; Boersma, J.; van Koten, G. Angew. Chem.,
Int. Ed. 2000, 39, 176-178. (g) Maraval, V.; Laurent, R.; Caminade, A.-
M.; Majoral, J.-P. Organometallics 2000, 19, 4025-4029. (h) Reetz, M.
T.; Lohmer, G.; Schwickard, R. Angew. Chem., Int. Ed. Engl. 1997, 36,
1526-1529.
(11) (a) Dahan, A.; Portnoy, M. Chem. Commun. 2002, 2700-2701. (b) Sellner,
H.; Seebach, D. Angew. Chem., Int. Ed. 1999, 38, 1918-1920. (c) Chung,
Y.-M.; Rhee, H.-K. Chem. Commun. 2002, 238-239. (d) Dahan, A.;
Portnoy, M. Org. Lett. 2003, 5, 1197-1200. (e) Sellner, H.; Rheiner, P.
B.; Seebach, D. HelV. Chim. Acta 2002, 85, 352-387. (f) Sellner, H.;
Karjalainen, J. K.; Seebach, D. Chem.sEur. J. 2001, 7, 2873-2887. (g)
Reetz, M. T.; Giebel, D. Angew. Chem., Int. Ed. 2000, 39, 2498-2501.
(h) Arya, P.; Rao, N. V.; Singkhonrat, J.; Alper, H.; Bourque, S. C.; Manzer,
L. E. J. Org. Chem. 2000, 65, 1881-1886. (i) Antebi, S.; Arya, P.; Manzer,
L. E.; Alper, H. J. Org. Chem. 2002, 67, 6623-6631. (j) Reynhardt, J. P.
K.; Alper, H. J. Org. Chem. 2003, 68, 8353-8360. (k) Lu, S.-M.; Alper,
H. J. Org. Chem. 2004, 69, 3558-3561. (l) Reynhardt, J. P. K.; Yang, Y.;
Sayari, A.; Alper, H. Chem. Mater. 2004, 16, 4095-4102.
Optimization of Intramolecular Carbonylation Reaction
Conditions. We selected 2-(2-iodophenoxy)aniline (3, R1 ) R2
) H, X ) I) as the model substrate and G1-Pd as the catalyst
for the intramolecular carbonylation reaction in order to
determine the optimized conditions. The influence of reaction
temperature, solvent, and base was investigated, and the results
are summarized in Table 1. The reaction temperature is
(12) (a) Lu, S.-M.; Alper, H. J. Am. Chem. Soc. 2003, 125, 13126-13131. (b)
Arya, P.; Panda, G.; Rao, N. V.; Alper, H.; Bourque, S. C.; Manzer, L. E.
J. Am. Soc. Chem. 2001, 123, 2889-2890. (c) Bourque, S. C.; Alper, H.;
Manzer, L. E.; Arya, P. J. Am. Chem. Soc. 2000, 122, 956-957. (d)
Bourque, S. C.; Maltais, F.; Xiao, W.-J.; Tardif, O.; Alper, H.; Arya, P.;
Manzer, L. E. J. Am. Chem. Soc. 1999, 121, 3035-3038.
(13) See Supporting Information for the preparation details.
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A R T I C L E S
Lu and Alper
Figure 1. Structures of palladium-complexed dendrimers on silica G0-Pd-G3-Pd.
important for this transformation. Attempts to carry out the
reaction of 2-(2-iodophenoxy)aniline in anhydrous toluene under
100 psi of carbon monoxide in the presence of G1-Pd and
diisopropylethylamine at room temperature for 48 h did not
afford the desired product, and the starting material was
recovered unchanged (Table 1, entry 1). Increasing the tem-
perature to 45 °C after 36 h resulted in 36% conversion of the
iodinated arylamine to dibenzoxazepinone (Table 1, entry 2).
When the carbonylation reaction proceeded at 60 and 70 °C
for 22 h, 75 and 90% conversions were obtained, respectively
(Table 1, entries 3 and 4). Complete conversion of the iodinated
arylamine to dibenzoxazepinone was observed by raising the
reaction temperature to 80 °C after 22 h (Table 1, entry 5).
We further explored the effect of solvent and base. Toluene
proved to be the best solvent for this transformation (Table 1,
entry 5). The reaction also worked well in benzene, dimethyl-
formamide, tetrahydrofuran, acetonitrile, and 1,2-dimethoxy-
ethane, affording >92% conversions (Table 1, entries 6-10),
but only 61% conversion of the iodinated arylamine to diben-
zoxazepinone occurred when the carbonylation reaction was run
in dichloromethane (Table 1, entry 11). The use of an organic
base, such as diisopropylethylamine (DIPEA) and 1,8-diaza-
bicyclo[5,4,0]undec-7-ene (DBU), gave the desired product in
full conversions (Table 1, entries 5 and 12), while there was
92% conversion when triethylamine was employed as the base
(Table 1, entry 13). Potassium carbonate was also an effective
base for the carbonylation reaction (Table 1, entry 14), but using
another inorganic base, such as sodium carbonate, for this
transformation resulted in only 73% conversion of the iodinated
arylamine to dibenzoxazepinone (Table 1, entry 15). Intramo-
lecular carbonylation did not take place in the absence of base
(Table 1, entry 16).
Recyclability of Different Dendritic Catalysts. To evaluate
the recyclability of different dendritic catalysts G0-Pd-G3-
Pd, we selected 2-(2-iodophenoxy)aniline (3, R1 ) R2 ) H, X
) I) as the substrate for the intramolecular carbonylation
reaction. In a typical reaction, 1 mmol of 3 in 5 mL of toluene
in the presence of 1.5 mmol of diisopropylethylamine with 15
mg of catalyst was treated with 100 psi of carbon monoxide at
80 °C for 22 h, and the results are listed in Table 2. The catalyst
G0-Pd was found to be highly efficient for the intramolecular
carbonylation reaction. The first two cycles gave quantitative
conversion to the dibenzoxazepinone (Table 2, entries 1 and
2); 98-94% conversions were obtained from the third cycle to
the fifth cycle (Table 2, entries 3-5), but by prolonging the
reaction time to 36 h, the sixth cycle again afforded the desired
product in full conversion (Table 2, entry 6). As seen from Table
2, G1-Pd showed the best recyclability. The dendritic catalyst
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Synthesis of O, N, or S-Containing Ring Fused Heterocycles
A R T I C L E S
Table 1. Intramolecular Carbonylation of 2-(2-Iodophenoxy)aniline
(3, R1 ) R2 ) H, X ) I) with G1-Pd under Different Reaction
Conditionsa
Table 2. Intramolecular Carbonylation of 2-(2-Iodophenoxy)aniline
(3, R1 ) R2 ) H, X ) I) with Different Palladium-Complexed
Dendrimersa
Temp
C)
Time
(h)
Conversionb
(%)
Conversionb
Entry
Solvent
Base
(
°
Entry
Catalyst
Cycle
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
toluene
toluene
toluene
toluene
toluene
benzene
DMF
THF
CH3CN
DME
CH2Cl2
toluene
toluene
toluene
toluene
toluene
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DBU
25
45
60
70
80
80
80
80
80
80
80
80
80
80
80
80
48
36
22
22
22
22
22
22
22
22
22
22
22
22
22
22
NRc
36
75
90
100
98
98
96
95
92
1
2
3
G0-Pd
1
2
3
4
5
6
1
2
3
4
5
6
7
8
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
100
100
98
97
94
100
100
100
98
98
97
96
95
95
100
98
95
93
90
100
83
G0-Pd
G0-Pd
4
G0-Pd
5
G0-Pd
6c
7
G0-Pd
G1-Pd
8
9
G1-Pd
G1-Pd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
G1-Pd
61
100
92
G1-Pd
G1-Pd
Et3N
G1-Pd
K2CO3
Na2CO3
no
100
73
G1-Pd
G2-Pd
NRc
G2-Pd
G2-Pd
a With 1 mmol of 2-(2-iodophenoxy)aniline, 100 psi of CO, 15 mg of
G1-Pd, 1.5 mmol of base and 5 mL of solvent. b Determined by GC. c No
reaction.
G2-Pd
G2-Pd
G3-Pd
G3-Pd
G3-Pd
72
65
41
100
100
97
97
95
can be recovered and reused up to eight cycles with only a slight
loss of activity (Table 1, entries 7-14). Compared to G0-Pd
and G1-Pd, the catalyst G2-Pd displayed somewhat lower
activity (Table 2, entries 15-19). For example, the use of G2-
Pd as the catalyst resulted in 98-90% conversions from the
second cycle to the fifth cycle, whereas conversions ranged from
100 to 94% with G0-Pd (Table 2, entries 2-5 and 16-19).
The recyclability was considerably less successful when G3-
Pd was used as the catalyst (Table 2, entries 20-24). The low
activity of G3-Pd was attributed to steric crowding at the higher
generation. It was expected that extending the chain length
would relieve steric crowding and allow for increased catalyst
loading. The dendritic catalyst G3(C6)-Pd was prepared by
the use of 1,6-diaminohexane instead of the ethylenediamine
linker, with 0.57 mmol/g palladium loading (see Supporting
Information). Indeed, G3(C6)-Pd exhibited high activity with
good recyclability comparable to the results obtained employing
G0-Pd as the catalyst (Table 2, entries 1-5 and 25-29). Note
that it is very easy to recover and reuse G0-Pd-G3-Pd by
simple filtration in air.
G3-Pd
G3-Pd
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
G3(C6)-Pd
a With 1 mmol of 2-(2-iodophenoxy)aniline, 100 psi of CO, 15 mg of
the dendritic catalyst, 1.5 mmol of DIPEA, 5 mL of toluene, 80 °C and 22
h. b Determined by GC. c Run for 36 h.
methoxycarbonyl groups on the aromatic rings did not have any
impact on the intramolecular carbonylation reaction (Table 3,
entries 6, 9, and 12-14). However, slightly lower yields were
observed when a cyano group was on the aromatic rings (Table
3, entries 5, 8, 11, and 15). Furthermore, with 3p and 3q as
pyridine-based substrates, pyridinyl-fused heterocycles 4p and
4q were obtained in 98 and 96% yields, respectively (Table 3,
entries 16 and 17). It is important to note that the catalyst G1-
Pd can be recovered and reused at least five cycles for all of
these reactions (see Supporting Information).
Scope of the Intramolecular Carbonylation Reaction. (a)
Synthesis of Seven-Membered Ring Fused Heterocycles. The
intramolecular carbonylation of substituted 2-(2-iodophenoxy)-
anilines 3 was effected to form seven-membered ring fused
heterocycles under the optimized conditions, and the results are
presented in Table 3. In all cases, the catalyst G1-Pd displayed
high activity, and the carbonylation reaction proceeded very
well, regardless of the nature of the substituents on the aromatic
rings. Thus, iodinated arylamines 3 bearing either strongly
electron-withdrawing or electron-donating substituents were
efficiently converted to the corresponding dibenzoxazepinones
4 in excellent yields. Importantly, a wide variety of functional
groups can be tolerated in this process, including chloro,
methoxy, trifluoromethyl, cyano, acetyl, and methoxycarbonyl
groups. Somewhat surprisingly, the presence of acetyl and
Encouraged by the excellent results above, we attempted to
utilize the relatively less reactive brominated arylamines as
substrates for the intramolecular carbonylation reaction. When
2-(2-bromophenoxy)aniline14 was subjected to reaction under
the optimized conditions used for iodinated arylamines, 65%
conversion occurred to the desired product. Performing the
carbonylation reaction at 100 °C for 22 h gave 88% conversion.
We were pleased to observe complete conversion of the
brominated arylamine to dibenzoxazepinone 4a by increasing
the reaction temperature to 120 °C after 22 h. In the field of
medicinal chemistry, introduction of a fluorine atom into
molecules is one of the most efficient methods for the modifica-
(14) For the preparation of 2-(2-bromophenoxy)aniline, see: Wilshire, J. F. K.
Aust. J. Chem. 1988, 41, 995-1001.
9
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A R T I C L E S
Lu and Alper
Table 3. Synthesis of Seven-Membered Ring Fused Heterocycles by G1-Pd-Catalyzed Intramolecular Carbonylation of Substituted
2-(2-Iodophenoxy)anilinesa
a With 1 mmol of 3, 100 psi of CO, 15 mg of G1-Pd, 1.5 mmol of DIPEA, 5 mL of toluene, 80 °C and 22 h. b Isolated yield.
tion of the lead compounds in view of biological activity.15 For
example, fluorinated aryl rings are often used as drug candidates
in which a fluorine is substituted for a hydrogen to help block
oxidation of the aromatic ring, alter metabolism pathways, and
increase lipophilicity, which affects drug distribution.16 In this
context, seven fluorine-containing substrates 3r-3x were
prepared for G1-Pd catalyzed the intramolecular carbonylation
reaction, and the results are illustrated in Table 4. As expected,
all of these transformations took place smoothly and gave the
desired products 4r-4x in >90% isolated yields.
(b) Synthesis of Eight-Membered Ring Fused Hetero-
cycles. The intramolecular carbonylation reaction was extended
to the synthesis of eight-membered ring fused heterocycles. As
can be seen from Table 5, the dendritic catalyst G1-Pd was
found to be very efficient for carbonylation in all cases. Under
the optimized conditions, the reactions of iodinated arylamines
513 with either electron-withdrawing or electron-donating groups
on the aromatic rings afforded the corresponding dibenzoxazo-
cinones 6 in excellent yields. The wide functional group
compatibility is a significant advantage for these transformations,
as the intramolecular carbonylation reaction can encompass
fluoro, chloro, methoxy, acetyl, and methoxycarbonyl groups.
One can apply the reaction to a sterically hindered ortho-
substituted arylamine 5c, giving the desired product 6c in slightly
reduced yield (Table 5, entry 3). Heterocycles having piperidinyl
or morpholinyl groups are the basic structures of many
pharmacologically important compounds. Iodinated arylamines
(15) (a) O’Hagen, D.; Rzepa, H. S. Chem. Commun. 1997, 645-652. (b) Filler,
R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical Aspects of Fluorine
Chemistry; Elsevier: Amsterdam, 1993. (c) Mann, J. Chem. Soc. ReV. 1987,
16, 381-436. (d) Welch, J. T. Tetrahedron 1987, 43, 3123-3197.
(16) (a) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R., Jr.; Yumibe,
N.; Clader, J. W.; Burnett, D. A. J. Med. Chem. 1998, 41, 973-980. (b)
Park, B. K.; Kitteringham, N. R. Drug Metab. ReV. 1994, 26, 605-643.
(c) Abel, S. M.; Back, D. J.; Maggs, J. L.; Park, B. K. J. Steroid Biochem.
Mol. Biol. 1993, 46, 833-839.
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Synthesis of O, N, or S-Containing Ring Fused Heterocycles
A R T I C L E S
Table 4. Synthesis of Seven-Membered Ring Fused Heterocycles
by G1-Pd-Catalyzed Intramolecular Carbonylation of Substituted
2-(2-Bromophenoxy)anilinesa
5k and 5l were subjected to the intramolecular carbonylation
reaction, and the corresponding dibenzoxazocinones 6k and 6l
were obtained in 94 and 96% yields, respectively (Table 5,
entries 11 and 12). The use of 5p as the substrate afforded the
naphthyl tetracyclic heterocycle 6p (Table 5, entry 16). In the
case of 5q, the intramolecular carbonylation reaction furnished
the desired product 6q in 99% isolated yield, in which oxygen
is on the other side of eight-membered ring (Table 5, entry 17).
The dendritic catalyst G1-Pd can be recovered and reused at
least five times for all of these transformations (see Supporting
Information).
The brominated arylamines 5r-5x also proved to be viable
substrates for the intramolecular carbonylation reaction. Treat-
ment of substituted 2-(2-bromobenzyloxy)anilines 5r-5x in
anhydrous toluene with 100 psi of carbon monoxide in the
presence of G1-Pd and diisopropylethylamine at 120 °C for
22 h afforded the corresponding eight-membered ring fused
heterocycles 6r-6x in high yields. The results are presented in
Table 6.
(c) Synthesis of Nitrogen or Sulfur-Containing Medium
Ring Fused Heterocycles. By changing the atom connecting
the two aromatic rings from oxygen to nitrogen, one can isolate
dibenzodiazepinones 8 in excellent yields. Specifically, substi-
tuted N-methyl-N-(2-iodophenyl)-1,2-benzenediamines 713 (R
) H, CF3) were used as the substrates for the intramolecular
carbonylation reaction in the presence of G1-Pd, affording 98
and 96% yields of the desired products 8a and 8b, respectively
(eq 2).
a With 1 mmol of 3, 100 psi of CO, 15 mg of G1-Pd, 1.5 mmol of
DIPEA, 5 mL of toluene, 120 °C and 22 h. b Isolated yield.
The carbonylation of sulfur-containing compounds is a
challenge in palladium-based methods because of the strong
affinity of sulfur for palladium, often resulting in low, if any,
catalytic activity. We were gratified to observe that G1-Pd
efficiently catalyzed the intramolecular carbonylation of sub-
stituted 2-(2-iodobenzylthio)anilines 913 (R ) H, Cl, CF3) and
gave rise to the corresponding dibenzothiazocinones 10 in 92-
97% yields. Therefore, the sulfur atom did not have any
influence on these transformations (eq 3).
subjected to 100 psi of carbon monoxide at 80 °C for 22 h,
affording the desired products 12 in 90-93% yields (eq 4).
Similarly, the iodinated arylamine 1313 was smoothly con-
verted to the corresponding pentacyclic heterocycle 14 in 88%
yield under the same conditions (eq 5). These examples further
demonstrate the efficiency of the intramolecular carbonylation
reaction for the construction of fused heterocycles in the
presence of dendritic catalysts.
(d) Intramolecular Double Insertion of Carbon Monoxide.
The intramolecular double insertion of carbon monoxide was
next carried out with G1-Pd as the catalyst. Typically, 0.5
mmol of substituted 3-amino-4-(2-iodophenoxy)phenyl sulfones
1113 (R ) H, CH3, Cl) and 1.5 mmol of diisopropylethylamine
in 5 mL of anhydrous toluene with 15 mg of G1-Pd were
(e) Synthesis of a Six-Membered Ring Fused Heterocycle.
After the synthesis of seven- and eight-membered ring fused
9
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A R T I C L E S
Lu and Alper
Table 5. Synthesis of Eight-Membered Ring Fused Heterocycles by G1-Pd-Catalyzed Intramolecular Carbonylation of Substituted
2-(2-Iodobenzyloxy)anilinesa
a With 1 mmol of 5, 100 psi of CO, 15 mg of G1-Pd, 1.5 mmol of DIPEA, 5 mL of toluene, 80 °C and 22 h. b Isolated yield.
heterocycles, we were interested in exploring whether the
intramolecular carbonylation reaction could be applied to the
preparation of a six-membered ring. 2-(2-Iodophenyl)aniline
(15),17 on reaction with carbon monoxide in the presence of
G1-Pd, gave 6(5H)-phenanthridinone (16) in 97% yield (eq
6).
Summary
In conclusion, we have developed a general and highly
efficient method for the synthesis of oxygen, nitrogen, or sulfur-
containing medium ring fused heterocycles by intramolecular
(17) For the preparation of 2-(2-iodophenyl)aniline (15), see: Cade, J. A.;
Pilbeam, A. J. Chem. Soc. 1964, 114-121.
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14782 J. AM. CHEM. SOC. VOL. 127, NO. 42, 2005

Synthesis of O, N, or S-Containing Ring Fused Heterocycles
A R T I C L E S
Table 6. Synthesis of Eight-Membered Ring Fused Heterocycles
by G1-Pd-Catalyzed Intramolecular Carbonylation of Substituted
2-(2-Bromobenzyloxy)anilinesa
and washed with dichloromethane. The combined solvent was evapo-
rated in vacuo, and the residue was purified by silica gel chromatog-
raphy with a mixture of hexane and ethyl acetate as the eluant to afford
the product. The recovered catalyst was reused for subsequent cycles.
2-Methyl-8-acetyldibenz[b,f][1,4]oxazepin-11(10H)-one (4i): mp
1
269-270 °C; IR (neat) 1685, 1660 cm-1; H NMR (500 MHz, CD3-
SOCD3) δ 10.60 (s, 1H), 7.74-7.71 (m, 2H), 7.56 (d, J ) 2.0 Hz,
1H), 7.43-7.40 (m, 2H), 7.24 (d, J ) 8.5 Hz, 1H), 2.52 (s, 3H), 2.29
(s, 3H); 13C NMR (500 MHz, CD3SOCD3) δ 197.29, 166.43, 156.92,
154.68, 135.97, 135.94, 135.36, 132.35, 132.23, 126.69, 125.73, 122.46,
122.13, 121.34, 27.54, 20.92; MS (EI) m/z 267 [M+]; HRMS calcd for
C16H13NO3 267.0895, found 267.0875.
8-Fluoropyrido[2,3-b][1,4]benzoxazepin-6(5H)-one (4w): mp 296-
297 °C; IR (neat) 1658 cm-1; 1H NMR (500 MHz, CD3SOCD3) δ 10.78
(s, 1H), 8.04 (dd, J ) 1.8, 5.0 Hz, 1H), 7.61 (dd, J ) 1.5, 8.0 Hz, 1H),
7.53-7.47 (m, 2H), 7.41 (dd, J ) 5.0, 8.5 Hz, 1H), 7.32 (dd, J ) 4.7,
7.8 Hz, 1H); 13C NMR (500 MHz, CD3SOCD3) δ 164.83, 159.65 (d,
J ) 241.2 Hz), 155.86, 153.74, 143.93, 131.81, 127.43 (d, J ) 7.8
Hz), 126.68, 124.06 (d, J ) 8.5 Hz), 123.65, 122.23 (d, J ) 23.5 Hz),
117.80 (d, J ) 25.3 Hz); MS (EI) m/z 230 [M+]; HRMS calcd for
C12H7FN2O2 230.0492, found 230.0471.
3-(4-Morpholinyl)-6H-dibenz[b,f][1,4]oxazocin-11(12H)-one (6l):
;
mp 242-243 °C; IR (neat) 1660 cm-1 1H NMR (500 MHz, CD3-
SOCD3) δ 9.41 (s, 1H), 7.40-7.28 (m, 4H), 6.80 (d, J ) 8.5 Hz, 1H),
6.49-6.44 (m, 2H), 5.33 (s, 2H), 3.64 (t, J ) 4.6 Hz, 4H), 2.97 (t, J
) 4.6 Hz, 4H); 13C NMR (500 MHz, CD3SOCD3) δ 173.22, 152.78,
151.68, 137.86, 132.47, 130.92, 129.77, 129.66, 128.84, 128.26, 121.65,
110.36, 107.71, 73.13, 66.78, 48.69; MS (EI) m/z 310 [M+]; HRMS
calcd for C18H18N2O3 310.1317, found 310.1301.
8-Fluoro-3-methyl-6H-dibenz[b,f][1,4]oxazocin-11(12H)-one (6x):
;
mp 220-221 °C; IR (neat) 1660 cm-1 1H NMR (500 MHz, CD3-
SOCD3) δ 9.61 (s, 1H), 7.38 (dd, J ) 5.5, 8.0 Hz, 1H), 7.17-7.14 (m,
2H), 6.84 (d, J ) 8.0 Hz, 2H), 6.73 (dd, J ) 1.5, 8.0 Hz, 1H), 5.33 (s,
2H), 2.15 (s, 3H); 13C NMR (500 MHz, CD3SOCD3) δ 172.14, 163.02
(d, J ) 245.6 Hz), 151.68, 138.44, 135.59 (d, J ) 7.6 Hz), 133.62,
131.13 (d, J ) 8.6 Hz), 128.25, 127.50, 124.90, 122.49, 116.48 (d, J
) 21.2 Hz), 115.45 (d, J ) 21.9 Hz), 73.07, 21.10; MS (EI) m/z 257
[M+]; HRMS calcd for C15H12FNO2 257.0852, found 257.0828.
5,10-Dihydro-5-methyl-8-trifluoromethyl-11H-dibenzo[b,e][1,4]-
diazepin-11-one (8b): mp 240-241 °C; IR (neat) 1662 cm-1; 1H NMR
(500 MHz, CD3SOCD3) δ 10.40 (s, 1H), 7.64 (dd, J ) 1.8, 7.8 Hz,
1H), 7.50 (dt, J ) 1.5, 7.5 Hz, 1H), 7.43 (dd, J ) 2.5, 8.5 Hz, 1H),
7.35-7.33 (m, 2H), 7.21 (d, J ) 8.5 Hz, 1H), 7.10 (dt, J ) 1.0, 8.0
Hz, 1H), 3.29 (s, 3H); 13C NMR (500 MHz, CD3SOCD3) δ 168.87,
152.68, 148.42, 148.40, 134.02, 133.77, 127.30, 125.02 (q, J ) 32.1
Hz), 124.84 (q, J ) 269.9 Hz), 124.05, 122.30 (q, J ) 3.7 Hz), 120.92,
118.95, 118.63 (q, J ) 3.6 Hz), 38.51; MS (EI) m/z 292 [M+]; HRMS
calcd for C15H11F3N2O 292.0823, found 292.0801.
2-Chloro-6H-dibenzo[b,f][1,4]thiazocin-11(12H)-one (10b): mp
294-295 °C; IR (neat) 1665 cm-1; 1H NMR (500 MHz, CD3SOCD3)
δ 9.93 (s, 1H), 7.31-7.27 (m, 2H), 7.20-7.16 (m, 4H), 7.10 (dd, J )
2.5, 8.5 Hz, 1H), 4.39 (s, 1H), 4.10 (s, 1H); 13C NMR (500 MHz, CD3-
SOCD3) δ 173.15, 140.81, 138.38, 134.36, 132.33, 132.11, 131.92,
130.94, 129.70, 129.30, 128.53, 128.26, 126.03, 35.53; MS (EI) m/z
275 [M+]; HRMS calcd for C14H10ClNOS 275.0172, found 275.0151.
10,11-Dihydro-2-methyl-11-oxodibenz[b,f][1,4]oxazepine-8-sul-
fone (12b): mp 192-194 °C; IR (neat) 1660 cm-1; 1H NMR (500 MHz,
CD3SOCD3) δ 10.63 (s, 2H), 7.69 (d, J ) 2.0 Hz, 2H), 7.64 (dd, J )
2.0, 8.5 Hz, 2H), 7.49 (d, J ) 5.8 Hz, 4H), 7.35-7.33 (m, 2H), 7.18-
7.16 (m, 2H), 2.24 (s, 6H); 13C NMR (500 MHz, CD3SOCD3) δ 166.15,
156.53, 154.63, 138.79, 136.16, 136.04, 133.37, 132.22, 125.44, 125.27,
123.84, 121.48, 121.28, 20.91; MS (EI) m/z 512 [M+]; HRMS calcd
for C28H20N2O6S 512.1042, found 512.1019.
a With 1 mmol of 5, 100 psi of CO, 15 mg of G1-Pd, 1.5 mmol of
DIPEA, 5 mL of toluene, 120 °C and 22 h. b Isolated yield.
carbonylation reactions with recyclable palladium-complexed
dendrimers on silica as catalysts. This process can tolerate a
wide array of functional groups, including halide, ether, nitrile,
ketone, and ester. The dendritic catalysts show high activity
for these transformations, affording the desired heterocycles in
excellent yields. Importantly, these catalysts are easily recovered
by simple filtration in air and can be reused up to the eight
cycles with only a slight loss of activity. This research should
have broad applications in organic synthesis.
Experimental Section
Carbon monoxide, a powerful asphyxiant, should be used with care.
To use and work with carbon monoxide safely, reactions must be carried
out in a properly working fumehood with carbon monoxide detectors
installed nearby.
General Procedure for the Intramolecular Carbonylation Reac-
tion. A glass liner containing the substrate (1 mmol), dendritic catalyst
(15 mg), diisopropylethylamine (1.5 mmol), and toluene (5 mL) was
placed in a 45 mL autoclave equipped with a magnetic stirring bar.
The autoclave was flushed three times with carbon monoxide and
pressurized to 100 psi. The autoclave was then placed in an oil bath
preset to the desired temperature on a stirring hot plate (80 °C for
iodides and 120 °C for bromides). After 22 h, the autoclave was
removed from the oil bath and cooled to room temperature prior to the
release of excess carbon monoxide. The reaction mixture was filtered
8H,16H-5,13-Dioxa-8,16-diazadibenzo[d,d′]benzo[1,2-a;4,5-a′]di-
cycloheptene-7,15-dione (14): mp >300 °C; IR (neat) 1662 cm-1; 1H
NMR (500 MHz, CD3SOCD3) δ 10.76 (s, 2H), 7.67 (s, 2H), 3.38 (dd,
9
J. AM. CHEM. SOC. VOL. 127, NO. 42, 2005 14783

A R T I C L E S
Lu and Alper
J ) 1.3, 7.8 Hz, 2H), 7.19-7.11 (m, 6H); 13C NMR (500 MHz, CD3-
SOCD3) δ 164.56, 155.74, 150.55, 130.99, 130.01, 126.60, 125.94,
123.64, 122.18, 121.80; MS (EI) m/z 344 [M+]; HRMS calcd for
C20H12N2O4 344.0797, found 344.0771.
118.22, 116.78; MS (EI) m/z 195 [M+]; HRMS calcd for C13H9NO
195.0684, found 195.0662.
Acknowledgment. We are grateful to Sasol Technology, and
to the Natural Sciences and Engineering Research Council of
Canada for support of this research.
6(5H)-Phenanthridinone (16):18 mp 292-293 °C; IR (neat) 1660
cm-1; 1H NMR (500 MHz, CD3SOCD3) δ 11.68 (s, 1H), 8.49 (d, J )
8.5 Hz, 1H), 8.37 (d, J ) 7.5 Hz, 1H), 8.31 (dd, J ) 1.5, 8.0 Hz, 1H),
7.84 (dt, J ) 1.7, 7.5 Hz, 1H), 7.64 (dt, J ) 1.0, 7.5 Hz, 1H), 7.47 (dt,
J ) 1.5, 7.5 Hz, 1H), 7.35 (dd, J ) 1.3, 8.2 Hz, 1H), 7.25 (dt, J ) 1.5,
7.7 Hz, 1H); 13C NMR (300 MHz, CD3SOCD3) δ 161.48, 137.22,
134.92, 133.48, 130.24, 128.60, 128.14, 126.34, 123.93, 123.29, 122.94,
Supporting Information Available: Experimental details,
characterization data, Tables 7-14 of recycling and reuse of
the dendritic catalyst G1-Pd for intramolecular carbonylation
reactions, and copies of 1H NMR and 13C NMR spectra for the
final products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Lamba, J. J. S.; Tour, J. M. J. Am. Chem. Soc. 1994, 116, 11723-11736.
JA053650H
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14784 J. AM. CHEM. SOC. VOL. 127, NO. 42, 2005