Sequence of intramolecular carbonylation and asymmetric hydrogenation reactions: Highly regio- and enantioselective synthesis of medium ring tricyclic lactams

Article abstract of DOI:10.1021/ja7111417

The intramolecular cyclocarbonylation reaction with palladium-complexed dendrimers on silica is a very effective method for the regioselective synthesis of methylene 8-, 9-, and 10-membered rings. The heterogeneous dendritic catalysts are easily recovered by simple filtration and reused for up to 10 cycles with only a slight loss of activity. Asymmetric hydrogenation of the resulting unsaturated heterocycles affords optically active tricyclic lactams in excellent yields and in high enantiomeric excess. This process can tolerate a wide array of functional groups, including halide, ether, nitrile, ketone, and ester. Moreover, the variation of heteroatom on the rings does not have any influence on the efficiency and enantioselectivity of the reaction.

Full text of DOI:10.1021/ja7111417

Published on Web 04/30/2008
Sequence of Intramolecular Carbonylation and Asymmetric
Hydrogenation Reactions: Highly Regio- and Enantioselective
Synthesis of Medium Ring Tricyclic Lactams
Shui-Ming Lu and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received December 15, 2007; E-mail: howard.alper@uottawa.ca
Abstract: The intramolecular cyclocarbonylation reaction with palladium-complexed dendrimers on silica
is a very effective method for the regioselective synthesis of methylene 8-, 9-, and 10-membered rings.
The heterogeneous dendritic catalysts are easily recovered by simple filtration and reused for up to 10
cycles with only a slight loss of activity. Asymmetric hydrogenation of the resulting unsaturated heterocycles
affords optically active tricyclic lactams in excellent yields and in high enantiomeric excess. This process
can tolerate a wide array of functional groups, including halide, ether, nitrile, ketone, and ester. Moreover,
the variation of heteroatom on the rings does not have any influence on the efficiency and enantioselectivity
of the reaction.
medicine, nanoscience, and catalysis.5 As an interface between
homogeneous and heterogeneous catalysts,6 the introduction of
Introduction
Heterocyclic compounds are often encountered in many
biologically active natural products as well as drug candidates.1
For example, dibenzoxazocinone derivatives are non-nucleoside
inhibitors of HIV-1 RT, psychotropic, and hypotensive agents.2
Success has been achieved over the past decades in the
construction of cyclic templates by means of transition metal
catalysis.3 Among them, carbonylation reactions represent a
convenient and efficient one-step method to prepare a wide
variety of ring systems.4 On the other hand, dendrimers have
drawn increasing attention due to their valuable applications in
metallodendrimers into the carbonylation reactions is particularly
attractive from a sustainability point of view. Recently, we found
that dendrimer complexes are very effective catalysts for the
cyclocarbonylation reactions to give medium and large ring
fused heterocycles.7
Typically for chiral drugs, only one of the two enantiomers
is responsible for pharmacological activity, while the other is
either inactive or may cause side effects. In this context, an
innovative strategy leading to the enantioselective synthesis of
dibenzoxazocinone derivatives is of considerable merit. Asym-
metric hydrogenation reactions provide a powerful approach to
the preparation of optically active organic molecules.8 Therefore,
it is envisioned that the intramolecular aminocarbonylation of
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Chemistry, 2nd ed.; Pergamon Press: New York, 2000. (b) Joule, J. A.;
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15990–15991. (e) Nlate, S.; Astruc, D.; Neumann, R. AdV. Synth.
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Astruc, D.; Ruiz, J.; Gatard, S.; Neumann, R. Angew. Chem., Int. Ed.
2004, 43, 2924–2928. (g) Lu, S.-M.; Alper, H. J. Org. Chem. 2004,
69, 3558–3561. (h) Arya, P.; Rao, N. V.; Singkhonrat, J.; Alper, H.;
Bourque, S. C.; Manzer, L. E. J. Org. Chem. 2000, 65, 1881–1886.
(6) (a) Andres, R.; De Jesus, E.; Flores, J. C. New J. Chem. 2007, 31,
1161–1191. (b) Mery, D.; Astruc, D. Coord. Chem. ReV. 2006, 250,
1965–1979. (c) Helms, B.; Frechet, J. M. J. AdV. Synth. Catal. 2006,
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2005, 30, 385–402. (e) Astruc, D.; Heuze, K.; Gatard, S.; Mery, D.;
Nlate, S.; Plault, L. AdV. Synth. Catal. 2005, 347, 329–338. (f) Astruc,
D.; Chardac, F. Chem. ReV. 2001, 101, 2991–3023. (g) Lu, S.-M.;
Alper, H. J. Am. Chem. Soc. 2003, 125, 13126–13131. (h) Arya, P.;
Panda, G.; Rao, N. V.; Alper, H.; Bourque, S. C.; Manzer, L. E. J. Am.
Soc. Chem. 2001, 123, 2889–2890.
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(b) Arakawa, S.; Ogawa, S.; Arakawa, E.; Miyazaki, K.; Murofushi,
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 6451–6455 6451

A R T I C L E S
Lu and Alper
alkynes 1 with G1-Pd7,9 as the catalyst, followed by asymmetric
hydrogenation of the resulting prochiral heterocyles 2, could
give enantiomerically pure tricyclic lactams 3 (eq 1). We now
report the interesting results obtained from this investigation.
Table 1. Synthesis of Methylene Eight-Membered Ring Tricyclic
Heterocycles by G1-Pd Catalyzed Intramolecular
Cyclocarbonylation of Substituted 2-(2-Ethynylphenoxy)anilinesa
Results and Discussion
Intramolecular Cyclocarbonylation Reactions: Regioselective Syn-
thesis of Methylene Eight-Membered Ring Tricyclic Heterocycles. The
intramolecular cyclocarbonylation of various aminoalkynes was
used for the synthesis of methylene eight-membered ring
tricyclic heterocycles. Treatment of substituted 2-(2-ethynylphe-
noxy)anilines 19 in anhydrous dichloromethane with 100 psi of
carbon monoxide in the presence of G1-Pd and p-toluene-
sulfonic acid at 80 °C for 22 h afforded the corresponding
dibenzoxazocinones 2 in 89-99% isolated yields, and the results
are presented in Table 1. The heterogeneous dendritic catalyst
facilitated excellent substrate reactivity, irrespective of the
position and the nature of substituents on the aromatic rings.
Furthermore, this process was highly regioselectiVe and gaVe
exclusiVely the exo-methylene products. In all cases, no endo
isomers were detected. For example, aminoalkyne 1a was
converted smoothly to the desired eight-membered ring 2a in
99% yield (Table 1, entry 1). The structure of the product was
unambiguously confirmed by X-ray diffraction (Figure 1). The
cyclocarbonylation of substrates 1b-1e bearing electron-
donating substituents such as methyl and methoxy groups
worked very well, affording the corresponding methylene
tricyclic heterocycles 2b-2e in excellent yields (Table 1, entries
2-5). Electron-withdrawing substituents including chloro, tri-
(8) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis; Ojima, I. , Ed.; Wiley-VCH: New York, 2000. (b) Brown,
J. M. In ComprehensiVe Asymmetric Catalysis; Jacobson, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999. (c) Wu,
J.; Chan, A. S. C. Acc. Chem. Res. 2006, 39, 711–720. (d) Blaser,
H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV.
Synth. Catal. 2003, 345, 103–151. (e) Tang, W.; Zhang, X. Chem.
ReV. 2003, 103, 3029–3069. (f) Knowles, W. S. Angew. Chem., Int.
Ed. 2002, 41, 1998–2007.
a 1 mmol of 1, 15 mg of G1-Pd, 0.03 mmol of p-TsOH, 10 mL of
CH2Cl2, 100 psi of CO, 80 °C and 22 h. b Isolated yield.
fluoromethyl, cyano, acetyl, and methoxycarbonyl groups 1f-1j
were also tolerated in this reaction (Table 1, entries 6-10),
although a slightly lower yield was observed in the case of 1h
(9) See Supporting Information for details.
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Synthesis of Medium Ring Tricyclic Lactams
A R T I C L E S
from oxygen to nitrogen, one can isolate the methylene eight-
membered ring 2l in 99% yield (Table 1, entry 12). It is worth
noting that the dendritic catalyst G1-Pd could be recovered by
simple filtration in air and reused up to the tenth cycle with
only a slight loss of activity.9
Asymmetric Hydrogenation Reactions: Enantioselective
Synthesis of Eight-Membered Ring Tricyclic Lactams. After
accomplishing the synthesis of the exo-methylene eight-
membered rings, we were interested in exploring the asymmetric
hydrogenation of the resulting unsaturated heterocycles 2 to
hopefully attain the corresponding tricyclic lactams 3 in high
enantiomeric excess. Although the enantioselective hydrogena-
tion of acyclic and cyclic enamides has been well documented,8a,e
there are no examples involving the asymmetric hydrogenation
of R,ꢀ-unsaturated lactams of this type. A potential problem is
the nature of the exocyclic double bond; the inability of this
bond to rotate toward the carbonyl oxygen is expected to
diminish the efficiency of chelation of such a substrate to the
metal atom of a catalyst. Substrate chelation has long been
recognized to be an important element in achieving highly
enantioselective hydrogenation.10 Therefore, development of a
superior catalytic system for this transformation is a significant
challenge. Initial studies focused on screening different transition
metals and chiral ligands.9 It is known that ruthenium complexes
(Chart 1) have been applied successfully to the asymmetric
hydrogenation of various olefins.11 Unfortunately, all of them
(three ruthenium complexes in Chart 1) exhibited low enanti-
oselectivity for the hydrogenation of 2a to 3a. The use of an
iridium complex as the catalyst also afforded poor results with
21% yield and 4% ee (Chart 1).
Figure 1. X-ray crystal structure of 7-methylene-5H,7H-12-oxa-5-aza-
dibenzo[a,d]cycloocten-6-one (2a).
Chart 1. Asymmetric Hydrogenation of 2a Catalyzed by Ruthenium
Complexesa or Iridium Complexb
We then turned our attention to rhodium complexes. The
combination of Rh(COD)2BF4 with a wide array of chiral
ligands was examined for the asymmetric hydrogenation of 2a
(Supporting Information Table 8).9 Although BINAP, Mono-
Phos, DIOP, NorPhos, DuPhos, JosiPhos, and other chiral
bidentate and monodentate phosphorus ligands gave unsatisfac-
tory results in terms of the enantiomeric excess of 3a, we were
pleased to observe that (S,S)-BDPP afforded complete conver-
sion of 2a to 3a in 89% ee. Encouraged by these promising
results, (S,S)-BDPP was next used as the ligand for further
optimization of the reaction conditions. As can be seen from
Table 2, the solvent plays a role in this process. Methanol proved
to be the solvent of choice (Table 2, entry 1), but the reaction
of 2a also gave good enantiomeric excesses in ethanol and
tetrahydrofuran (Table 2, entries 2 and 3). The employment of
other solvents such as iso-propanol, dichloromethane, ethyl
acetate, chloroform, and acetone afforded 3a in 79-75% ee
(Table 2 entries 4-8). No hydrogenation occurred in toluene
and benzene (Table 2, entries 9 and 10). The pressure has a
limited impact on this transformation. 89, 90, and 91% ee were
obtained under 600, 300, and 100 psi of hydrogen, respectively
(Table 2, entries 11-13), while decreasing the pressure to 20
psi resulted in 92% ee (Table 2, entry 14). Temperature is
another factor for the successful hydrogenation. When the
reaction was run at 50 °C, 2 h were sufficient to achieve full
conversion of 2a but in low enantiomeric excess (Table 2, entry
a 1 mmol of 2a, 0.01 mmol of ruthenium complex, 5 mL of CH3OH,
1000 psi of H2, 50 °C and 24 h. b 1 mmol of 2a, 0.02 mmol of iridium
complex, 5 mL of CH2Cl2, 1000 psi of H2, rt and 24 h.
Table 2. Asymmetric Hydrogenation of 2a Catalyzed by
Rh(COD)2BF4 and (S,S)-BDPP under Different Reaction
Conditionsa
entry
solvent
pressure (psi)
temp (°C)
time (h)
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
MeOH
EtOH
THF
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
600
22
22
22
22
22
22
22
22
22
22
22
22
22
22
50
0
16
16
16
16
16
16
16
16
16
16
16
16
16
16
2
100
100
100
100
100
100
100
100
0
88
87
85
79
79
79
78
75
0
i-PrOH
CH2Cl2
EtOAc
CHCl3
Acetone
Toluene
Benzene
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
9
10
11
12
13
14
15
16
0
0
100
100
100
100
100
100
89
90
91
92
72
96
300
100
20
20
20
48
a 1 mmol of 2a, 0.01 mmol of Rh(COD)2BF4, 0.01 mmol of (S,S)-
BDPP, 5 mL of solvent. b Determined by GC and/or 1H NMR. c Deter-
mined by chiral HPLC with a Chiralcel OJ-H column.
(10) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106–112. (b) Chan,
A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem. Soc. 1980, 102, 5952–
5954.
(Table 1, entry 8). An aminoalkyne 1k containing a heterocyclic
component was subjected to the standard conditions, and a 97%
yield of the desired product 2k was obtained (Table 1, entry
11). By changing the atom connecting the two aromatic rings
(11) (a) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5356–5362. (b) Noyori, R. Angew. Chem., Int. Ed. 2002,
41, 2008–2022. (c) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23,
345–350.
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A R T I C L E S
Lu and Alper
Table 3. Enantioselective Synthesis of Eight-Membered Ring Tricyclic Lactams by Rhodium Complex Catalyzed Asymmetric Hydrogenation
of 2a
a 1 mmol of 2, 0.01 mmol of Rh(COD)2BF4, 0.01 mmol of (S,S)-BDPP, 5 mL of CH3OH, 20 psi of H2, 0 °C and 48 h.
2, regardless of whether the substituents on the aromatic rings
were electron-donating or electron-withdrawing, afforded the
corresponding optically active lactams 3 in 88-99% yields and
90-96% ee. The wide functional group compatibility is a
significant advantage for these transformations, as the asym-
metric hydrogenation reactions can encompass methyl, chloro,
methoxy, trifluoromethyl, cyano, acetyl, and methoxycarbonyl
groups. Furthermore, with 2k as a pyridine-based substrate, the
pyridinyl-fused lactam 3k was obtained in excellent yield and
enantiomeric excess. In the case of 2l, the methylene tricylic
heterocyle was reduced to the nitrogen-containing product 3l
in 99% yield and 94% ee. This reaction indicates that variation
of the atom connecting the two aromatic rings does not have
any influence on the enantioselectivity. The absolute configu-
ration of compound 3f was determined to be R by X-ray
crystallographic analysis, as shown in Figure 2.12
Figure 2. X-ray crystal structure of (R)-9-chloro-7-methyl-5H,7H-12-oxa-
5-azadibenzo[a,d]cycloocten-6-one (3f).
Intramolecular Cyclocarbonylation and Asymmetric Hydro-
genation Reactions: Regio- and Enantioselective Synthesis of
15). Lower temperature had a beneficial effect on the enanti-
Nine- and Ten-Membered Ring Tricyclic Lactams. The se-
oselectivity; performing the hydrogenation of 2a at 0 °C gave
quence of intramolecular cyclocarbonylation and asymmetric
3a in 96% ee (Table 2, entry 16). Therefore, the best reaction
hydrogenation reactions were extended to the regio- and
conditions are 1 mmol of substrate, 0.01 mmol of Rh(COD)2BF4,
enantioselective synthesis of larger ring (9 and 10) tricyclic
and 0.01 mmol of (S,S)-BDPP in 5 mL of methanol under 20
lactams, and the results are illustrated in Table 4. For instance,
psi of hydrogen at 0 °C for 48 h.
aminoalkynes 4a-4c, on reaction with carbon monoxide in the
A variety of methylene tricyclic heterocycles 2a-2l were
reacted under the conditions optimized for 2a to 3a, and the
results are listed in Table 3. The asymmetric hydrogenation of
(12) For the X-ray crystal structure of 3a, see Supporting Information.
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Synthesis of Medium Ring Tricyclic Lactams
A R T I C L E S
Table 4. Regio- and Enantioselective Synthesis of Nine- and Ten-Membered Ring Tricyclic Lactams by Sequence of Intramolecular
Cyclocarbonylationa and Asymmetric Hydrogenationb Reactions
a 1 mmol of 4, 15 mg of G1-Pd, 0.03 mmol of p-TsOH, 10 mL of CH2Cl2, 100 psi of CO, 80 °C and 22 h. b 1 mmol of 5, 0.01 mmol of
Rh(COD)2BF4, 0.01 mmol of (S,S)-BDPP, 5 mL of CH3OH, 20 psi of H2, 0 °C and 48 h.
presence of G1-Pd, regioselectively gave the methylene nine-
membered rings 5a-5c in excellent yields. Asymmetric hydro-
genation of the resulting unsaturated heterocycles afforded the
corresponding products 6a-6c in 88-98% yields and 89-92%
ee. Similarly, the ten-membered ring tricyclic lactam 6d was
obtained in excellent yield and high enantiomeric excess from
4d under the same conditions. These examples further demon-
strate the efficiency and versatility of this approach for the
construction of optically active medium ring fused heterocycles.
asymmetric hydrogenation reactions for the formation of opti-
cally active fused heterocycles.
Acknowledgment. We are grateful to the Natural Sciences and
Engineering Research Council of Canada for financial support of
this research. We also thank Miss Tara J. Burchell for the X-ray
crystal analyses.
Supporting Information Available: Experimental details,
characterization data for all new compounds; Table 5 of
recycling and reuse of the dendritic catalyst G0-Pd–G3-Pd and
G3(C6)-Pd for the intramolecular cyclocarbonylation of 1a;
Tables 6-9 of optimization of asymmetric hydrogenation
Summary
In conclusion, we have developed an effective method for
the highly regio- and enantioselective synthesis of 8-, 9-, and
10-membered ring tricyclic lactams under mild conditions. This
protocol is based on a sequential use of carbonylation and
hydrogenation chemistry: the intramolecular carbonylation reac-
tions with dendrimer palladium complexes as catalysts for
regioselective cyclization, and then the rhodium-catalyzed
1
reaction conditions for 2a to 3a; copies of H NMR and 13C
NMR spectra for products 2, 3, 5, and 6; and X-ray crystal-
lographic analyses for 2a, 3a, and 3f. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA7111417
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