Rhodium(I)-catalyzed cycloisomerizations of bicyclobutanes

Article abstract of DOI:10.1021/ja802906k

The selection of rhodium precatalyst and phosphine ligand determines the course of the cycloisomerization of N-allylated bicyclo[1.1.0]butylalkylamines. Cyclopropane-fused pyrrolidines and azepines are obtained with high levels of stereo- and regiocontrol. Novel azatricyclo[6.1.0.0^1,5]nonanes are the result of a tandem cycloisomerization-ring closing metathesis sequence. Allylic ethers lead to furans and oxepanes. Copyright

Full text of DOI:10.1021/ja802906k

Published on Web 05/08/2008
Rhodium(I)-Catalyzed Cycloisomerizations of Bicyclobutanes
Maciej A. A. Walczak and Peter Wipf*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue, Pittsburgh, PennsylVania 15260
Received April 19, 2008; E-mail: pwipf@pitt.edu
Table 1. Precatalyst and Ligand Optimizations for the
Cycloisomerization of 1
Among strained ring systems, bicyclo[1.1.0]butanes are of special
significance due to their unique chemical bonding properties.1
Cleavage of the central bond in bicyclo[1.1.0]butane, formally a
3
3
Csp -Csp σ-bond, is facilitated by the release of ∼65 kcal/mol in
strain energy and represents the most common reaction pathway
observed for these molecules. The similarity of the σ-bond to a
2
2
C
sp dCsp π-bond has often been invoked to explain the chemical
behavior of bicyclo[1.1.0]butanes,2 in particular, their participation
in pericyclic, radical, and ionic reactions.1,3 As with other strained
rings,4metal-catalyzedisomerizationreactionsofbicyclo[1.1.0]butanes
have been studied extensively.5 Formation of 1,3-butadiene is a
major reaction pathway, but the selectivity is strongly dependent
on catalysts, reaction conditions, and substituents.5b For example,
reactions catalyzed by Ag(I) are thought to proceed via an initial
cleavage of the lateral C-C bond in bicyclo[1.1.0]butanes followed
by skeletal rearrangement of a carbocation.6 In contrast, group 9
and 10 metals have been shown to operate through a mechanistically
distinct pathway.7–9 Trapping experiments confirmed the formation
of a carbene intermediate,8 but low yields as well as limited scope
in these reactions prevented a further development of general
synthetic methodologies.
We have recently shown that bicyclo[1.1.0]butylalkylamines
undergo highly stereoselective intramolecular cycloadditions with
alkenes and alkynes under mild reaction conditions.3 We further
envisioned that a transient metal carbenoid species resulting from
isomerization of the bicyclo[1.1.0]butane could be trapped intramo-
lecularly by the N-allyl substituent before undergoing isomerization
to a 1,3-butadiene. Mindful of literature precedence5 as well as the
similarity of the carbene-forming step to the metal-catalyzed
decomposition of diazocompounds,10 we selected Rh(I) precatalysts
as potential promoters of the rearrangement reactions. Representa-
tive optimization studies for a rhodium-catalyzed cycloisomerization
of bicyclobutanes are shown in Table 1.11a When 1 was heated
with 5% [Rh(d)2Cl]2 in PhMe at 110 °C in the presence of 10%
n-Bu3P, a 6:1 mixture of 2 and 3 was formed in good overall yield
(entry 1). Addition of Ph3P (10%) improved the yield of pyrrolidine
2 to 87% with 8% of the azepine 3 (entry 2). The reaction was
complete within 10 min and 2 was formed with excellent diaste-
reoselectivity (>95:5).11b When additional Ph3P was added, or the
amount of precatalyst was reduced (entries 3 and 4), the yield of 2
dropped. Phosphines with electron-donating or -deficient aromatic
substituents had a detrimental effect (entries 5 and 6), and bulkier
aliphatic ligands reduced the yield of 2 dramatically (entry 7).
Precatalysts bearing large alkene ligands (entries 9 and 10) also
led to diminished yields and chemoselectivity.
Wilkinson’s catalyst led to a 1:2 ratio of 2 to 3, but a more
striking reversal of selectivity was observed when bidentate
phosphines were used in combination with [Rh(CO)2Cl]2 (entries
11-15). We found that addition of 10% dppe provided the desired
azepine 3 in high yield and excellent diastereoselectivity.11b The
combination of [Rh(d)2Cl]2 and dppe provided the azepine in 77%
yield. Other bidentate phosphines furnished 3 in lower yields and
selectivities, but formation of pyrrolidine 2 was completely sup-
pressed in all cases. In the absence of ligand, both 2 and 3 were
formed in low yield (entry 16). Solvents such as EtOAc, THF,
a Reactions used 5% of precatalyst and 10% of phosphine ligand at
0.05 M concentration of 1 in PhMe at 110 °C. b NMR yields based on
internal standard. c Isolated yield: 77%. d Isolated yield: 77%.
e Concentration: 0.1 M.
Table 2. Rh(I)-Catalyzed Isomerizations of Bicyclo[1.1.0]butanes 4
entry
substrate
method Aa
method Bb
1
2
3
4
5
4a, R ) 3,5-(MeO)2C6H3
4b, R ) 4-ClC6H4
4c, R ) 2-furyl
4d, R ) BnOCH2
4e, R ) cyclohexyl
5a, 67%
5b, 55%
5c, 75%
5d, 63%
5e, 65%
6a, 87%
6b, 80%
6c, 58%
6d, 68%
6e, 75%
a Method A: [Rh(d)2Cl]2 (5 mol %), Ph3P (10 mol %), PhMe (0.05
M), 110 °C. b Method B: [Rh(CO)2Cl]2 (5 mol %), dppe (10 mol %),
PhMe (0.05 M), 110 °C.
CH2ClCH2Cl, and t-BuOMe did not provide improvements. In
addition, we found that the best yields were obtained when the
reactions were carried out at low concentration (0.05 M) (entry
15). Finally, under the optimized conditions for the formation of 2
or 3, isomerization of 1 to the butadiene did not exceed 1%.11a
The systematic variation of precatalysts and ligands for the
cycloisomerization of model system 1 provided selective access to
synthetically useful pyrrolidines and azepines. The scope of this
methodology was further explored using various aromatic, het-
eroaromatic, and functionalized aliphatic substrates (Table 2). In
addition to excellent scaffold chemoselectivity (pyrrolidine 5 vs
azepine 6), all reactions proceeded in high diastereoselectivity. The
9
6924 J. AM. CHEM. SOC. 2008, 130, 6924–6925
10.1021/ja802906k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Furan and Oxepane from Allylic Ether
not accessible for a facile reaction, carbenes 12 and 13 undergo
hydride migration to afford 1,3-butadienes.15
In order to further extend the utility of the Rh-catalyzed
isomerizations of bicyclo[1.1.0]butanes, sulfonamides 16a-c were
subjected to reaction conditions that promoted formation of
pyrrolidines (Scheme 3). Upon completion of the rearrangement,
Ru metathesis catalyst16 was added and the novel tricyclic pyrro-
lidines 17a-c were formed in good yields. In combination with
the ligand-controlled isomerization pathways of bicyclo[1.1.0]butanes
and the facile removal of the nitrogen protecting group, this
synthetic strategy allows for the rapid assembly of a diverse set of
molecular scaffolds17 from a common pool of functionalized
bicyclo[1.1.0]butanes.
Scheme 2. Proposed Mechanism of Cycloisomerization Reactions
In summary, we have developed an efficient rhodium-catalyzed
cycloisomerization of N-allylated bicyclo[1.1.0]butylalkylamines.
Depending on the nature of the Rh(I) phosphine ligands, these
reactions provide pyrrolidines and azepines with high levels of
stereo- and regiocontrol. A related transformation is also feasible
for allylic ethers, providing substituted furans and oxepanes.
Acknowledgment. This work was supported by NIGMS (NIH
P50 GM067082). We thank Dr. Steve Geib for X-ray crystal-
lographic analyses.
Scheme 3. Synthesis of 3-Azatricyclo[6.1.0.01,5]nonanes via
Tandem Isomerization-RCMa
Supporting Information Available: Experimental procedures,
1
copies of H and 13C NMR spectra, and crystal information file. This
material is available free of charge via the Internet at http://pubs.acs.org.
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We also briefly explored the cycloisomerization of allylic ethers
(Scheme 1). With [Rh(d)2Cl]2 precatalyst, an NMR based yield of
66% of a 2.3:1 ratio of furanyl diene 8 and oxepane 9 was obtained.
Other catalysts led to a diminished yield.
Weproposethattheisomerizationreactionsofbicyclo[1.1.0]butanes
proceed via the mechanism depicted in Scheme 2. Oxidative
addition of Rh(I) across the central σ-bond in bicyclo[1.1.0]butane
10 results in the formation of intermediate 11, which subsequently
undergoes rearrangement to carbenes 12 and 13. Formation of the
tricyclic intermediate 11 has been proposed for reactions of electron-
deficient bicyclo[1.1.0]butanes, but it is worth noting that 11 may
also exist in equilibrium with its isomers formed by insertion of
the metal into the lateral bonds of bicyclo[1.1.0]butane 10.12 The
selectivity of the rearrangement of 11 is controlled by the steric
bias exerted by the phosphine ligands. Monodentate phosphines
allow for the formation of internal carbene 12, a process most likely
favored by the proximity of the allyl group.13 Alternatively, in the
presence of bidentate ligands, the saturated complex 11 rearranges
to carbene 13. Although no specific mechanistic data are available,
formation of carbenes 12 and 13 could also be a reversible
process.14 Subsequent cyclopropanation of the allyl group proceeds
via transition states in which the R-substituent adopts a pseudoaxial
orientation leading to 14 and 15. In cases where the allyl group is
JA802906K
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