RhI-catalyzed cycloisomerization of vinyl bicyclopropyl compounds to azabicyclo[3.2.2]nona-2, 8-dienes

Article abstract of DOI:10.1002/chem.200902284

(Figure Presented) Important class: Nitrogen-containing heterobicycles are an important structural motif ubiquitous in natural alkaloids. We found that azabicyclo[3.2.2]nona-2, 8-dienes can be synthesized from vinyl bicyclopropropyl derivatives in the pre

Full text of DOI:10.1002/chem.200902284

DOI: 10.1002/chem.200902284
RhI-Catalyzed Cycloisomerization of Vinyl Bicyclopropyl Compounds to
AzabicycloACTHNUGRTENUNG[3.2.2]nona-2,8-dienes
Sun Young Kim,[a] Youn K. Kang,*[b] and Young Keun Chung*[a]
Nitrogen-containing azabicycles are an important class of
structural motif ubiquitous in natural alkaloids. New syn-
thetic methods for these compounds are thus of immense
importance to the pharmaceutical field.[1] During our ongo-
ing endeavor searching for a new transition-metal-catalyzed
reaction pathways, we recently discovered that azabicyclo-
ACHTUNGTRENNUNG
[3.2.2]nona-2,8-diene (1a) could be synthesized via RhI-cata-
lyzed cycloisomerization of vinyl bicyclopropyl (VBC) deriv-
atives.
The azabicycloACHTUNGTRENNUNG[3.2.2]nona-2,8-diene is a higher homo-
logue of tropane alkaloids[2] such as cocaine and atropine.
Moreover, it is also an analogue of morphinomimetic isopa-
vines (Figure 1).[3] These kinds of natural opioid alkaloids
are known to function in the central nervous system (CNS)
by strong binding to G-protein-coupled receptors (GPR).[4]
The detailed mechanism of the interactions between GPR
and binding ligands in the CNS remains elusive, though a
variety of chemical modifications of such opioid alkaloids
are necessary not only for drug addiction treatments but
also for potential remedies for neurological disorders such
as Alzheimerꢀs and Parkinsonꢀs disease, as well as depres-
sion and schizophrenia.[5]
Figure 1. Structures of cocaine, morphine, (+)-isopavine, and 1a.
dienes from the VBCs is the first observation of this kind.
Herein we communicate the synthesis of such compounds
from VBCs in the presence of a RhI catalyst and also pres-
ent the result of DFT calculations about the reaction mecha-
nism.
Recently, we reported a RhI-catalyzed carbonylative [3+
3+1] cycloaddition of the VBC derivatives under atmos-
pheric CO condition (Scheme 1a).[7]
Although there have been a number of synthetic ap-
proaches for the construction of the azabicyclo
2,8-diene skeleton, they are still limited.[2.6] As far as we are
aware, the catalytic formation of azabicyclo[3.2.2]nona-2,8-
ACHTUNGTREN[NUNG 3.2.2]nona-
AHCTUNGTRENNUNG
[a] S. Y. Kim, Prof. Y. K. Chung
Intelligent Textile System Research Center
Department of Chemistry
College of Natural Sciences, Seoul National University
Seoul 151-747 (Korea)
Fax : (+82)2-889-0310
E-mail: ykchung@snu.ac.kr
Scheme 1. RhI-catalyzed cyclization of modified VBC (7-cyclopropyl-3-
azabicycloACTHNUTRGNE[NUG 4.1.0]hept-4-enes, CABH).
[b] Dr. Y. K. Kang
Division of Chemistry and Molecular Engineering
Department of Chemistry
College of Natural Sciences, Seoul National University
Seoul 151-747 (Korea)
E-mail: younkang@snu.ac.kr
When
azabicyclo
a
A
structurally modified VBC (7-cyclopropyl-3-
a
phenyl
group at 6-position (1) was applied to the catalytic reaction
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902284.
in the presence of RhI catalyst without CO pressure, a new
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Chem. Eur. J. 2010, 16, 5310 – 5313

COMMUNICATION
Table 1. Optimization of RhI-catalyzed transformation of 1 to 1a and
1b.[a]
type of an azabicycloACTHNUTRGENUG[N 3.2.2]nona-2,8-diene (1a), which struc-
ture was confirmed by an X-ray diffraction study (Figure 2),
was produced along with a concomitant formation of a
triene derivative (1b). Being an interesting molecule 1a as
described earlier, the observation of such a compound with
a subtle modification of the reaction conditions from our
previous work encouraged us to investigate this reaction in
more detail.
Entry
AgX
Solvent
T [8C]
Yield [%]
1
1a
1b
1[b]
2[c]
3
4
5
6
7
8
–
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
toluene
80
80
80
80
110
80
100
100
100
100
87
73
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgBF4
AgOTf
AgSbF6
64
36
72
65
96
82
60
85
15
21
7
41
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
20
9
10[d]
[a] Conditions: 10 mol% [RhCl(CO)
(6 mL), 24 h. [b] Without AgX. [c] Without Rh catalyst. [d] 5 mol%
[RhCl(CO)(PPh3)2], 6 mol% AgSbF6.
ACHTUNGTREN(NNUG PPh3)2], 12 mol% AgX, solvent
AHCTUNGTRENNUNG
Table 2. RhI-catalyzed cycloisomerization to a.[a]
Figure 2. X-ray crystallographic structure of 1a.[12]
Entry
Substrate
Product
Yield [%]
Firstly we attempted to establish the reaction conditions
that would yield 1a rather than 1b. The optimized reaction
conditions were readily achieved after a number of screen-
ing processes (Table 1). The reaction was not catalyzed by
1
2
3
4
5
6
R=H
1
2
3
4
5
6
96 (1a)
68 (2a)
76 (3a)
92 (4a)
95 (5a)
75 (6a)
R=Me
R=OMe
R=Cl
R=Br
R=NO2
the use of [RhCl(CO)ACTHNUTRGNEUNG(PPh3)2] nor AgSbF6, giving rise to the
recovery of the starting material (entries 1 and 2). The de-
sired compound 1a was produced only when the RhI species
was used which was generated in situ by [RhCl(CO)-
ACHTUNGTRENNUNG(PPh3)2]/AgSbF6. An initial attempt with this catalyst system
7
8
9
7
8
9
48 (7a)[b]
43 (8a)
77 (9a)
in 1,2-dichloroethane at 808C gave 64% of 1a with 15% of
1b. When toluene was used, the results were even worse.
Only 36% of 1a with a comparable amount of 1b (21%)
was produced along with the recovery of the reactant (41%,
entry 4). In 1,4-dioxane, the result was similar to that ob-
tained in 1,2-dichloroethane (entry 6).
The yield of 1a was greatly improved when the reaction
temperature was elevated. The best yield (96%) was
ACHTUNGTRENNUNGachievACHTUNGTRENNUNGed in 1,4-dioxane at 1008C (entry 7). In toluene, rais-
ing the reaction temperature to the refluxing point did im-
prove the yield of 1a. Moreover, the formation of 1b still
persisted. Employing AgBF4 or AgOTf instead of AgSbF6
gave rather poor results (entries 8 and 9). Any attempts to
reduce catalyst amount were not successful (entry 10).
Under the optimized reaction conditions, we tested cycloi-
somerization reactions with a series of VBCs (Table 2). The
10
11
12
13
PG=Ms
10
11
12
13
94 (10a)
61 (11a)
44 (12a)
19 (13a)[c]
PG=PhSO2
PG=Cbz
PG=Boc
7-cyclopropylbicycloACHTUNGTRENUG[N 4.1.0]hept-4-ene derivatives used in this
study (1–14) were readily obtained by PtCl2-catalyzed cyclo-
isomerization of the corresponding enynes (Scheme 2).[9]
14
14
55 (14b)[d]
Various 7-cyclopropyl-6-aryl-3-azabicycloACHTNUTRGNEUNG[4.1.0]hept-4-ene
derivatives with a substituent at the para-position of 6-aryl
group could participate in the reaction (entries 2–6). Al-
though varying degrees of electronic effects by these sub-
stituents were seemingly obvious, a clear trend in the prod-
[a] Conditions: 10 mol% [RhCl(CO)ACTHUNTRGNEUNG(PPh3)2], 12 mol% AgSbF6, 1,4-di-
oxane (6 mL), 1008C, 18 h. [b] 20% of the reactant was recovered.
[c] 46% of the reactant was recovered. [d] 2 h.
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www.chemeurj.org
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Y. K. Chung, Y. K. Kang and S. Y. Kim
exclusively leaving another CP ring (C8-C9-C10) peripheral.
ACTHNUTRGNEUNG
The (h1-alkyl)(h3-allyl)RhIII intermediate (PI1) was formed
(Figure 3). This type of the catalytic initiation of VCP by
RhI catalyst has been revealed via DFT study by Houk
et al.[11a] Successive cleavage of the peripheral CP ring gives
Scheme 2. Preparation of modified VBCs (7-cyclopropylbicyclo-
ACHTUNGTRENNUNG[4.1.0]hept-4-enes).
rise to another (h1-alkyl)
(h3-allyl)RhIII intermediate (PI2),
which then evolves to (h2-alkenyl)
AHCTUNGTRENNUNG
b-hydride elimination. The b-hydride elimination step re-
quires 37.4 kcalmolÀ1 of activation free energy, which is the
highest among the six transition states involved in the cata-
lytic cycle, and thus be a rate-determining step. The PI3 has
a trigonal bipyramid geometry with the hydride being posi-
tioned at the axial trans to the carbonyl group. PI4 is the in-
termediate structure where the repositioning of the hydride
atom necessary for the subsequent metal-to-ligand hydride
transfer is conducted. At PI4, the distance between the
metal hydride and terminal C10 atom becomes only 2.44 ꢂ,
short enough for the efficient hydride transfer reaction to
occur. The final step of the cycle can be best described by
migratory reductive elimination with an activation free
energy of only 9.1 kcalmolÀ1. Demetalation of the catalyst
wraps up the catalytic cycle.
uct yield was not observed for this series. The yield of the
reaction seemed to be affected by the steric effect rather
than by the electronic effect of the 6-aryl group. When the
aryl group was o-tolyl, the yield was only 48% with a 20%
recovery of the reactant (entry 7). In case of 1-naphthyl
group, the desired product was obtained in 43% (entry 8).
Another important factor that affects the reaction yield was
the nature of the protecting group on the nitrogen tether
(see entries 1, 10–13). When sulfonyl groups were used as
protecting groups, the yield was moderate (entry 11, 61%)
to high (entry 1, 96% and entry 10, 94%). However, sub-
strates with carbamate protecting groups gave rise to low
yields (entry 12, 44% and entry 13, 19%). In contrast to the
N-tethered substrates, a triene 14b was isolated in 55%
yield for an oxygen-tethered substrate 14 (entry 14).
In summary, we have demonstrated that VBC can be effi-
To elucidate the reaction mechanism, we performed DFT
ciently transformed to azabicycloACTHUNGETRNNU[G 3.2.2]nona-2,8-dienes in
calculations.[10] Initially, a cationic [Rh(CO)
(PPh3)2] might
the presence of a RhI catalyst. The overall reaction pathway
obtained by the DFT calculations shows the catalytic cycle
can be described as 1) complexation between RhI catalyst
and CABH, 2) oxidative addition by the CP ring cleavage,
3) migratory insertion of the second CP ring, 4) b-hydride
elimination, 5) rearrangement of the hydride, 6) metal-to-
ligand hydride transfer, 7) migratory reductive elimination,
and 8) demetalation. Further efforts on the synthetic utility
of the reactions as well as more detailed mechanistic investi-
gations that include the conformation dependent mechanis-
tic variation are in progress.
coordinate to the CABH. This complex can enter the cata-
lytic cycle by losing one phosphine ligand since a 14-electron
Rh species is commonly accepted as an active catalyst in the
RhI-catalyzed cycloaddition of vinyl cyclopropanes
(VCPs).[11] Thus we started the calculation from the struc-
ture formed by the complexation between CABH and
[Rh(CO)ACHTUNGTRENNUNG(PPh3)]. Among many possible conformations of
the reactant state, PR was chosen based on the previously
reported structural information of the CABH with an R
configuration at the C7 atom.[8c] This conformation leads to
oxidative addition of the C1-C6-C7 cyclopropyl (CP) ring
Figure 3. Free energy reaction profile of RhI-catalyzed transformation of CABH to azabicyclo
ACTHNUTRGNEUNG[3.2.2]nona-2,8-dienes. Geometries of all stationary points
are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ level. Zero-point energy (ZPE) corrected free energies calculated in gas phase
are given in kcalmolÀ1
.
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RhI-Catalyzed Cycloisomerization
COMMUNICATION
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Experimental Section
General procedure: [RhCl(CO)ACHTUNGTRENUNG(PPh3)2] (0.03 mmol), AgSF6 (0.04 mmol)
and 1,4-dioxane (2 mL) were added to a tube-type Schenk flask equipped
with a stirring bar and capped with a rubber septum. The reaction mix-
ture was stirred at room temperature for 5 min. Then
a substrate
(0.3 mmol) and 1,4-dioxane (4 mL) were added to the flask. The resulting
mixture was stirred until the substrate was completely disappeared (as
checked by TLC) at 1008C. The reaction products were purified by flash
chromatography on a silica gel column eluting with n-hexane/ethyl ace-
tate (v/v, 6:1).
Acknowledgements
This work was supported by the Korea Government (MOEHRD) (KRF-
2008-341-C00022), Korea Research Foundation (KRF 2009-0076513) and
the Korea Science and Engineering Foundation (KOSEF) grant funded
by the Korea Government (MEST) (R11-2005-065). We thank S. Y. Choi
for the X-ray crystallographic analysis. S.Y.K. thanks the Brain Korea 21
fellowships and the Seoul Science Fellowships.
[9] The synthetic procedures and spectroscopic data of new compounds
are summarized in the Supporting Information.
[10] In the computational model, the PPh3 ligand was represented by
PH3. Tosyl group at the nitrogen atom was replaced with H. For
more details about the calculations, see the Supporting Information.
[11] a) Z. X. Yu, P. A. Wender, K. N. Houk, J. Am. Chem. Soc. 2004, 126,
9154–9155; b) P. A Wender, G. G. Gamber, T. J. Williams in Modern
Rhodium-Catalyzed Organic Reactions (Ed.: P. A. Evans), Wiley-
VCH, Weinheim, 2005, pp. 263–299.
Keywords: alkaloids
·
bicyclic
compounds
·
[12] CCDC-716233 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
cycloisomerization · rhodium
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Rev. 2008, 108, 264–287; c) G. P. Pollini, S. Benetti, C. De Risi, V.
Zanirato, Chem. Rev. 2006, 106, 2434–2454; d) S. M. Weinreb,
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Received: August 18, 2009
Revised: February 1, 2010
Published online: March 29, 2010
Chem. Eur. J. 2010, 16, 5310 – 5313
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www.chemeurj.org
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