(4+1) vs (4+2): Catalytic Intramolecular Coupling between Cyclobutanones and Trisubstituted Allenes via C-C Activation

Article abstract of DOI:10.1021/jacs.5b09799

Herein we describe a rhodium-catalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a distinct [4.2.1]-bicyclic skeleton containing two quaternary carbon centers. The reaction involves C-C activation of cyclobutanones and employs a

Full text of DOI:10.1021/jacs.5b09799

Article
(4+1) vs (4+2): Catalytic Intramolecular Coupling between
Cyclobutanones and Trisubstituted Allenes via C-C Activation
Xuan Zhou, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09799 • Publication Date (Web): 06 Oct 2015
Downloaded from http://pubs.acs.org on October 6, 2015
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(4+1) vs (4+2): Catalytic Intramolecular Coupling between Cy-
clobutanones and Trisubstituted Allenes via C−C Activation
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Xuan Zhou and Guangbin Dong*
Department of Chemistry, university of Texas at Austin, Austin, Texas 78712, United States
Supporting Information Placeholder
ABSTRACT: Herein we describe a rhodiumꢀcatalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a
distinct [4.2.1]ꢀbicyclic skeleton containing two quaternary carbon centers. The reaction involves C−C activation of cyclobutanones
and employs allenes as a oneꢀcarbon unit. A variety of functional groups can be tolerated, and a diverse range of polycyclic scafꢀ
folds can be accessed. Excellent enantioselectivity can be obtained, which is enabled by a TADDOLꢀderived phosphoramidite ligꢀ
and. The bridged bicyclic products can be further functionalized or derivatized though simple transformations.
1. INTRODUCTION
Scheme 1. Rhodiumꢀcatalyzed (4+1) cycloaddition initiated
by C−C activation
Complementary to cycloaddition reactions, transition metalꢀ
catalyzed C−C σꢀbond cleavage of cyclic compounds followed by
2πꢀinsertion offers a distinct strategy to access complex fused and
bridged systems.1,2 Given the particular challenge for constructing
bridged scaffolds,3 approaches have emerged based on C−C actiꢀ
vation of fourꢀmembered ring ketones. In 1984, Liebeskind2a
reported a Coꢀmediated intramolecular insertion of an alkyne into
a benzocyclobutendione for preparing a bridged benzoquinone,
and demonstrated its usage in the total synthesis of nanaomycin A.
Exemplary work by Murakami and Ito described catalytic carꢀ
boacylations of cyclobutenones with aryl alkenes for building
[3.2.1] and [2.2.2] bicyclic compounds through rhodium (2002)
and nickel catalysis (2006) respectively,2b,4 which can also be
achieved asymmetrically.5 To circumvent the undesired decarꢀ
bonylation pathway, we recently developed an intramolecular
Rh–catalyzed Jun’s cofactorꢀassisted (4+2) coupling between
cyclobutanones and alkenes to access various [3.3.1]ꢀbridged
products.6 In contrast to the rapid developments of alkene inserꢀ
tion into C−C σꢀbonds, the corresponding process with allenes
has not yet been reported. This would be a highly valuable transꢀ
formation because an additional olefin moiety would be installed
in the product serving as a handle for further functionalization. In
this article, we describe an unexpected discovery of an intramoꢀ
lecular coupling between cyclobutanones and trisubstituted alꢀ
lenes leading to an unusual (4+1)7 (instead of (4+2)) transforꢀ
mation. This method provides various [4.2.1] and [3.2.1] bicycles
and, particularly, a rapid entry to azepaneꢀbridged scaffolds that
are difficult to access with conventional approaches.
Allenes are commonly employed as a coupling partner in
catalytic cycloadditions.8 However, they generally serve as a two
or threeꢀcarbon unit,8,9 and are seldom considered as a oneꢀcarbon
component in these transformations.10 Recently, insertion of a
carbenoid carbon into a C−C single bond of benzocyclobutenols
and cyclobutanols were demonstrated by Wang11 and Murakami12
independently. Here we show allenes can formally serve as a
vinyl carbenoid13 equivalent for an intramolecular oneꢀcarbon
ring expansion.
2. RESULTS AND DISCUSSION
Table 1. Control Experimentsa
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a All yields and conversions were determined by crude 1H NMR using 1,1,2,2ꢀtetrachloroethane as the internal standard. b The standard reacꢀ
tions were conducted with 1a (0.03 mmol), [Rh(C2H4)2Cl]2 (0.0015 mmol, 5 mol%), P(3,5ꢀC6H3(CF3)2)3 (0.0072 mmol, 24 mol%), and 1,4ꢀ
dioxane ( 1 mL) at 150 oC. c The reaction was run in 1,4ꢀdioxane (2 mL) for 72 h. d Not determined.
gave more isomerization products (such as 2a’’) (entries 9ꢀ11).
Solvent effect was also surveyed: THF afforded the desired prodꢀ
uct albeit with a lower conversion (entry 12); in contrast, toluene
gave complete decomposition of the starting material (entry 13).
Decreasing the temperature to 130 oC or 110 oC resulted in lower
conversion (entries 14 and 15). Interestingly, when the reaction
was run at 110 oC, a higher selectivity for the (4+1) pathway was
2.1 Rhodiumꢀcatalyzed intramolecular (4+1) cyclization beꢀ
tween cyclobutanones and allenes.
Allene 1a was employed as the initial substrate. Surprisingly,
under the conditions previously optimized for the (4+2) addition
with olefins (5 mol% [Rh(C2H4)2Cl]2, 24 mol% P(3,5ꢀ
C6H3(CF3)2)3, and 100 mol% 3ꢀmethylꢀ2ꢀaminopyridine), the
expected 6ꢀ6 bridged bicycle ((±)ꢀ2a’) was only obtained in 8%
yield; instead, an unusual 7ꢀ5 bridged molecule ((±)ꢀ2a) was isoꢀ
lated in 40% yield as the major product (Table 1, entry 2). This
compound exhibits a number of interesting features: first, it has a
[4.2.1] scaffold which should come from a (4+1) cyclization
through cleavage of the cyclobutanone α C−C bond followed by
insertion of the allene central carbon; second, it contains two
quaternary carbon centers; third, it is rich in functional motifs
including a ketone and an olefin that can offer further derivatizaꢀ
tion (vide infra, Scheme 3); lastly, the azepane moiety holds poꢀ
tential for pharmaceutical applications.14 Further optimization
revealed that, in the absence of 3ꢀmethylꢀ2ꢀaminopyridine but
with 5 mol% of [Rh(C2H4)2Cl]2 and 24 mol% of P(3,5ꢀ
C6H3(CF3)2)3, in 1,4ꢀdioxane, compound (±)ꢀ2a can be formed in
69% yield (entry 1). The (4+2) addition ((±)ꢀ2a’, 10% yield) and
allene isomerization (1,3ꢀdiene 2a’’, 12% yield) were observed as
the minor reaction pathways.
o
observed. Attempt to improve the conversion at 110 C by inꢀ
creasing the reaction concentration was unsuccessful. It is likely
that, according to a recent report by Wender and Houk,16 the reacꢀ
tivity of the Rh catalyst can be inhibited at high allene concentraꢀ
tion, due to a competitive cyclometalation of the Rh with two
allenes. Nevertheless, using a higher loading of the catalyst at a
o
lower temperature (110 C), 77% yield of the desired product
((±)ꢀ2a) was obtained with minimal olefin isomerization (entry
17).
Control experiments were subsequently conducted to underꢀ
stand the role of each component (Table 1). In the absence of the
Rh catalyst, no conversion was observed (entry 3). Without P(3,5ꢀ
C6H3(CF3)2)3 the reaction gave full conversion, but led to a comꢀ
plex mixture of unidentifiable products (entry 4). Decreasing or
increasing the ligand loading led to more decomposition or lower
conversion (entries 5 and 6). P(3,5ꢀC6H3(CF3)2)3 plays a key role
in this reaction,15 and use of other ligands proved to be much less
efficient. For example, bidentate ligands such as dppp, or a more
electronꢀdeficient monodentate phosphine, such as P(C6F5)3, only
resulted in a complex mixture of unidentifiable products (entries
Figure 1. Crystal structure of compound (±)ꢀ2a at 50% probꢀ
ability level. Hydrogen atoms are omitted for clarity.
With the optimized conditions in hand, we next investigated
the substrate scope. First, various substitutes at the C3 of cyclobuꢀ
tanones were found suitable for this reaction (Table 2). The subꢀ
strate (1b) with a hydrogen substitution at the C3 position can
potentially undergo βꢀhydrogen elimination after C−C cleavage
7
and 8). Other Rh(I) catalysts, such as [Rh(cod)Cl]2,
[Rh(CO)2Cl]2, and [Rh(1,5ꢀhexadiene)Cl]2 were less efficient and
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R
of the cyclobutanone; however, it still afforded the desired prodꢀ
R
R
R1
R2
O
1
2
3
4
5
6
7
8
uct ((±)ꢀ2b). Besides methyl group ((±)ꢀ2a), other alkyls and aryl
groups, such as ethyl ((±)ꢀ2c), benzyl ((±)ꢀ2d) and phenyl ((±)ꢀ2e)
groups, were found compatible for this transformation. A high
chemoselectivity was also observed: benzyl ethers ((±)ꢀ2f), esters
((±)ꢀ2g) and even unprotected primary alcohols ((±)ꢀ2h) can be
tolerated.
O
R
R1
standard conditions
R3
Ts
R2
R3
N
N
Ts
Entry
1
Substrate
Product/Isolated Yield
O
Me
O
O
Me
Me
Me
Table 2. Substrate Scope Ia
Me
Me
Me
Me
Me
Me
+
Me
O
N
N
Me
N
Me
Ts
O
(±)-2i' 17%
(±)-2i 35%
(x-ray obtained)
9
Ts
R
Ts
(±)-1i
Me
standard conditions
10
11
12
13
14
15
16
17
18
19
20
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Me
O
Me
Me
H
O
3
H
N
Me
O
R
N
Ts
2
Me
Ts
1a-h
(±)-2a-h
+
N
N
N
(±)-2j'
(±)-2j
(x-ray obtained)
19%
31%
Ts
O
O
Ts
Ts
Me
Me
(±)-1j
Me
H
O
Me
Me
O
Me
O
Me
N
Me
N
3
Ts
Ts
+
N
51%b
N
N
(±)-2a
67%
(±)-2b
H
Ts
H
(±)-2k'
32%
Ts
(±)-1k
(±)-2k
30%
(dr: 7:1)
Ts
(±)-2b
x-ray of
O
O
O
O
Me
O
Et
Me
Me
Ph
Me
Me
Me
4
5
N
N
H
Ts
N
N
N
(±)-2l
81%
(±)-1l
Ts
Ts
Ts
Ts
(±)-2c
x-ray
71%
(±)-2d 63%
(±)-2e
65%
O
O
O
O
O
Me
Me
AcO
HO
BnO
Me
Me
Me
N
N
N
(±)-2m
Ts
1m
45%
Ts
Ts
N
Ts (±)-2h
N
N
O
O
Ts
65%
Ts
(±)-2f
(±)-2g
58%
63%
Me
6
Me
a Each reaction was run on a 0.1 mmol scale using 5 mol% [Rh(C2H4)2Cl]2,
N
o
(±)-2n 31% (61%)b,c
Ts
1n
24 mol% P(3,5ꢀC6H3(CF3)2)3, in 1,4ꢀdioxane (3 mL) at 150 C for 36 h. The
1
(4+2) products were observed in 3ꢀ10% yield judged by crude H NMR. All
Me
N
O
yields are isolated yield. b The reaction was run with 10 mol% [Rh(C2H4)2Cl]2,
48 mol% P(3,5ꢀC6H3(CF3)2)3, in 1,4ꢀdioxane (8 mL) at 110 oC for 72 h.
Me
O
Me
Me
7
N
Me
Ns
In general, αꢀsubstituted cyclobutanones are challenging subꢀ
strates for C−C activation due to the steric hindrance around the
carbonyl group. To our delight, using allene as the coupling partꢀ
ner, αꢀmethyl substituted cyclobutanone (1i) still provided the
desired 7ꢀ5 bridged bicycle in 35% isolated yield as a single diaꢀ
stereomer, along with 17% of the (4+2) product. The xꢀray strucꢀ
ture of product (±)ꢀ2i clearly indicated that the less hindered C−C
bond was selectively activated. In addition, the substrate with a
fused cyclohexane ring (1j) exhibited similar reactivity and selecꢀ
tivity as 1i, leading to a complex tricycle system. Substrates 1k
and 1l, containing a spirocyclic center, were also viable for this
transformation. Interestingly, they showed vast different selectiviꢀ
ty for the (4+1) versus (4+2) cyclization. While the cyclopentaneꢀ
spiro substrate did not differentiate these two pathways, the cyꢀ
clohexane one gave almost complete selectivity for the (4+1)
product; the 6ꢀ7ꢀ5 fused/bridged scaffold ((±)ꢀ2l) was isolated in
81% yield. It is likely that the substrate conformation plays an
important role in the (4+1) vs (4+2) selectivity. Not surprisingly,
the (4+1) cyclization became more sluggish when increasing the
steric bulk on the allene substituents. For example, cyclopentyl or
cyclohexylꢀfused allenes showed lower reactivity but still providꢀ
ed the desired products ((±)ꢀ2m and (±)ꢀ2n). Changing the proꢀ
tecting group on the nitrogen from Ts to 2ꢀnitrobenzenesulfonyl
(Ns) did not affect the reactivity ((±)ꢀ2o).17 Furthermore, subꢀ
strates with an arene (allꢀcarbon) linkage (1p and 1q) were found
1od
(±)-2o
70%
Ns
O
O
O
Me
Me
Me
Me
8
Me
(±)-2p 96%
1p
Ph
O
Me
Me
Ph
9
Me
(±)-2q 95%
1q
82%e
O
O
Me
Me
O
O
Me
10
Me
+
N
N
Me
Me
N
1r
Ts
(±)-2r
(±)-2r'
Ts
Ts
32%
35%
H
H
11
0%
N
1s
Ts
a
Each reaction was run on a 0.1 mmol scale using 5 mol%
[Rh(C2H4)2Cl]2, 24 mol% P(3,5ꢀC6H3(CF3)2)3, in 1,4ꢀdioxane (3
mL) at 150 C for 36 h. Unless otherwise mentioned, single diaꢀ
o
stereomers were isolated and the (4+2) products were observed in
3ꢀ10% yield judged by crude 1H NMR.
With 10 mol%
b
Table 3. Substrate Scope IIa
[Rh(C2H4)2Cl]2, 48 mol% P(3,5ꢀC6H3(CF3)2)3, in 1,4ꢀdioxane (8
mL) at 110 oC for 72 h. c Number in parentheses is the yield based
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d
e
on recovered starting material. Ns: 2ꢀnitrobenzenesulfonyl. 2.5
mol% [Rh(C2H4)2Cl]2, 12 mol% P(3,5ꢀC6H3(CF3)2)3 was used.
Table 5. Substrate Scope of the Enantioselective (4+1) Cy
clization for Preparing Chiral Azepane Scaffoldsa,b
1
2
3
4
5
6
7
8
9
to be remarkable, providing the desired 6ꢀ5 bridged bicycle
((±)ꢀ2p and (±)ꢀ2q) in 96% and 95% yields respectively. In parꢀ
ticular, substrate 1q with a phenyl/methylꢀsubstituted allene (unꢀ
symmetrical allenes) can be efficiently transformed to the desired
[3.2.1] bridged product. 1,3ꢀDiꢀsubstituted allene, such as subꢀ
strate 1r, can also react under the standard conditions to afford
the desired 7ꢀ5 bridged bicycle, albeit with a poor (4+1) vs (4+2)
selectivity. The exact reason for such a selectivity remains to be
defined. In contrast, use of monoꢀsubstituted allene substrates, e.g.
1s, mainly resulted in a complex of dimeric products, which is
consistent with the previous observation by Wender and Houk.16
R
R
R
Ph
O
P
R1
R2
O
Ph
O
5 mol% [Rh(C2H4)2Cl]2
24 mol% L4
Me
O
O
R
N
R1
Me
1,4-dioxane, 130oC
20 h
O
R3
R2
R3
N
Ph Ph
N
Ts
L4
Ts
2
1
eec
Substrate
O
Product
Yield
Entry
1
O
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
64%
Me
99%
N
N
2.2 Rhodiumꢀcatalyzed enantioselective intraꢀ
molecular (4+1) cyclization between cyclobutaꢀ
nones and allenes for constructing chiral azepaneꢀ
based scaffolds
Ts
1a
1b
Ts
2a
O
O
O
Me
Me
O
2
3
4
H
50%d
H
Me
99%
N
N
Ts
(x-ray obtained)
Ts
2b
Table 4. Selected Optimization for the Enantioselective
Reactiona
Me
Me
O
Et
Et
Me
Me
66%
72%
99%
99%
N
N
Ts
1c
2c
Ts
O
Me
Me
Ph
Ph
N
N
Ts
1d
Ts
2d
O
O
Me
Me
O
68%
99%
5
6
Me
Me
N
N
Ts
1e
1f
2e
Ts
O
Me
Me
BnO
BnO
52%
54%
99%
96%
N
N
Ts
2f
Ts
O
O
O
Me
Me
7
8
Me
N
N
2m
Ts
1m
Ts
Ts
O
43%d
Me
90%
N
N
N
Ts
1n
2n
O
Me
N
Me
O
Me
Me
9
70%
99%
Me
Ns
1o
2o
Ns
a Each reaction was run on a 0.1 mmol scale using 5 mol% [Rh(C2H4)2Cl]2,
24 mol% ligand L4, in 1,4ꢀdioxane (3 mL) at 130 oC for 20 h. Unless otherwise
mentioned, single diastereomers were isolated and the (4+2) products were
observed in 3ꢀ10% yield judged by crude H NMR. The absolute configuraꢀ
tions of the (4+1) products were assigned based on the analogy to the one of
a
The reactions were conducted with 1a (0.03 mmol), [Rh(C2H4)2Cl]2
(0.0015 mmol, 5 mol%), ligands (0.0072 mmol, 24 mol%), and solvent ( 1
mL) for 20 h. b All yields and conversions were determined by crude 1H NMR
using 1,1,2,2ꢀtetrachloroethane as the internal standard. c Determined by HPLC
analysis using a chiral stationary phase. d The reactions were conducted with 1a
(0.03 mmol), [Rh(C2H4)2Cl]2 (0.003 mmol, 10 mol%), ligands (0.0144 mmol,
48 mol%), and solvent ( 2 mL) at 110oC for 36 h. e Not determined. (R)ꢀSITCP
1
b
c
compound 2b, which was determined by heavyꢀatom Xꢀray crystallography.
Determined by HPLC analysis using a chiral stationary phase. d With 10 mol%
[Rh(C2H4)2Cl]2, 48 mol% ligand L4, in 1,4ꢀdioxane (6 mL) at 110 oC for 36 h.
=
(11aR)ꢀ(+)ꢀ5,6,10,11,12,13ꢀHexahydroꢀ5ꢀphenylꢀ4Hꢀdiindeno[7,1ꢀcd:1,7ꢀ
ef]phosphocin, (R)ꢀMOP = (R)ꢀ(+)ꢀ2ꢀ(Diphenylphosphino)ꢀ2′ꢀmethoxyꢀ1,1′ꢀ
binaphthyl.
cyclobutanones and allenes. Cyclobutanone 1a was again emꢀ
ployed as the model substrate (Table 4). Given the inefficienꢀ
cy of bidentate ligands in this transformation (vide supra, Taꢀ
ble 1), a range of chiral monodentate phosphine ligands were
examined first. While (R)ꢀSITCP showed a promising level of
Optically pure azepaneꢀbased scaffolds are expected to be atꢀ
tractive for pharmaceutical applications.14 Next we continued to
explore the enantioselective intramolecular coupling between
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different pathways. If direct reductive elimination occurs with
enantioselectivity, only 21% yield was observed (entry 1). On
1
2
3
4
5
6
7
8
intermediate b, the (4+2) product, [3.3.1]ꢀbicycle 2a’ꢀd6, would
be generated. On the other hand, intermediate b can undergo βꢀ
hydrogen elimination to give enone species c. It is worthy to menꢀ
tion that similar sequences involving 2πꢀinsertion followed by βꢀ
hydrogen elimination were proposed in Murakami19b and Bowꢀ
er’s20 studies. From intermediate c, either Rh−H (d) or Rh−C
migratory insertion (e) followed by reductive elimination should
result in the (4+1) product and regenerate the RhI catalyst. The
observed stereochemistry of the transferred deuterium (2aꢀd6) is
consistent with this proposed pathway.
the other hand, the (R)ꢀMOP and ligand L3 proved to be not efꢀ
fective (entries 2 and 3). Fruitful results were obtained when
TADDOLꢀderived phosphoramidites18 were surveyed; in particuꢀ
lar, excellent enantioselectivity was obtained with L4 ligand (enꢀ
try 4). Surprisingly, the reaction is highly sensitive to the nitrogen
substitution on the phosphine; replacing of the dimethylamino
group with a 4ꢀmorpholinyl group (L6) led to no desired product
(entry 6). After further examination of the solvent and temperaꢀ
ture effects, we found 68% yield with 99% ee can be afforded
with 5 mol% [Rh(C2H4)Cl]2 and 24 mol% of L4 in 1,4ꢀdioxane at
9
o
130 C (entry 11), which was used as the standard conditions for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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Scheme 2. Proposed Catalytic Cycle
investigating the substrate scope. It is worthy to note that the
o
enantioselective reaction can also be run at 110 C with reasonaꢀ
bly good yields (entries 10 and 12).
With the optimized conditions in hand, the generality of this
enantioselective (4+1) cyclization was next studied for constructꢀ
ing chiral [4.2.1] scaffolds (Table 5). To our delight, a range of
substrates with different substitutes at the C3 position of cyclobuꢀ
tanones gave almost perfect enantioselectivity (Table 5). In parꢀ
ticular, the substrate (1b) with a hydrogen substitution at the C3
position still provided the desired product (2b) with 99% ee. Inꢀ
creasing the steric bulkiness on the allene substituents diminished
the yields, which is consistent with the observation in the racemic
studies (vide supra, Table 3); nevertheless, excellent enantioselecꢀ
tivity can still be obtained. For example, cyclopentyl and cycloꢀ
hexylꢀfused allenes gave 96% ee and 90% ee separately (entries 7
and 8). In addition, use of 2ꢀnitrobenzenesulfonyl (Ns) as the
nitrogen protecting group did not affect the reactivity or the enanꢀ
tioselectivity (entry 9).
2.3 Mechanistic studies of (4+1) cyclization between cycloꢀ
butanones and allenes.
To gain mechanistic information about this (4+1) cyclization,
the following two experiments were conducted. First, since 1,3ꢀ
diene 2a’’ was found as the major byꢀproduct in this cyclization,
one natural question is whether (±)ꢀ2a came from allene 1a or the
isomerized diene (2a’’). When 2a’’ was treated under the standꢀ
ard coupling conditions, no (4+1) product was observed (Eq. 1).
This result suggests that the (4+1) product directly comes from
the allene precursor. Second, a deuteriumꢀlabeled substrate (1aꢀd6)
was synthesized, in which two deuteratedꢀmethyl groups were
installed on the allene. Treatment of allene 1aꢀd6 under the standꢀ
ard reaction conditions led to the desired product in 66% isolated
yield with greater than 95% deuteration at the C3 position. Acꢀ
cording to the 2D NMR and NOESY experiments, the C3 deuterꢀ
ium is cis to the alkenyl side chain.
2.4 Derivatization of the (4+1) products
Scheme 3. Synthetic Applications
Based on the above experiments and previous studies on
As expected, the 7ꢀ5 bridged bicyclic products can undergo a
number of facile transformations to access other structures or
functional groups (Scheme 3). First, while removal of sulfonyl
protecting groups from nitrogen is often nontrivial, for this
bridged system the Ts or Ns group can be smoothly removed. The
olefin moiety can be efficiently reduced to the corresponding
alkyl group (5) or oxidized to a ketone motif (6). The ketone
group can be rapidly converted to the corresponding exoꢀcyclic
transition
metalꢀcatalyzed
alleneꢀmediated
cycloaddiꢀ
tions,8a,9a,d,f,i,10a the following plausible catalytic cycle was proꢀ
posed (Scheme 2). The reaction is expected to start with insertion
of the RhI into the cyclobutanone α C−C bond2b,19 to give a fiveꢀ
membered rhodacycle (a) likely with the allene group coordinated
to the rhodium. This is followed by migratory insertion to afford a
πꢀallyl intermediate (b),8a,9d,10a which can undergo at least two
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olefin (7) via Wittig reaction or an oxime (8) through condensaꢀ
We thank CPRIT, NIGMS (R01GM109054ꢀ01) and the Welch
1
2
3
4
5
6
7
8
tion. A subsequent Beckmann rearrangement with oxime 8 can be
adopted to give ringꢀexpanded bridged lactams (9).
Foundation (F 1781) for research grants. G.D. is a Searle Scholar
and Sloan fellow. We thank Dr. M. C. Young for proofreading the
manuscript. We also thank Dr. V. Lynch and Dr. M. C. Young for
Xꢀray structures. Johnson Matthey is acknowledged for a generꢀ
ous donation of Rh salts. Chiral Technologies is thanked for their
generous donation of chiral HPLC columns.
3. CONLUSIONS
In summary, a rhodiumꢀcatalyzed (4+1) cyclization between
cyclobutanones and allenes was developed, leading to a distinct
[4.2.1]ꢀbicyclic skeleton, containing two quaternary carbon cenꢀ
ters. The reaction involves C−C activation of cyclobutanones and
employs allenes as a oneꢀcarbon unit. A variety of functional
groups can be tolerated, and a diverse range of bridged/fused
scaffolds can be accessed. In addition, a highly enantioselective
version of this transformation can also be achieved. This new
method is expected to offer a new rapid entry to nitrogenꢀ
containing polycyclic systems, and is potentially useful for
streamlining the synthesis of complex bioactive compounds. Deꢀ
tailed mechanistic study (e.g. why the (4+1) is favored) is ongoꢀ
ing.
REFERENCES
(1) For selected reviews on C−C activation, see: (a) Jones, W. D. Nature
1993, 364, 676. (b) Murakami, M.; Ito, Y. Top. Organomet. Chem. 1999,
3, 97. (c) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38,
870. (d) Jun, C.ꢀH. Chem. Soc. Rev. 2004, 33, 610. (e) Satoh, T.; Miura,
M. Top. Organomet. Chem. 2005, 14, 1. (f) Necas, D.; Kotora, M. Curr.
Org. Chem. 2007, 11, 1566. (g) Crabtree, R. H. Chem. Rev. 1985, 85, 245.
(h) Ruhland, K. Eur. J. Org. Chem. 2012, 2683. (i) Korotvicka, A.; Necas,
D.; Kotora, M. Curr. Org. Chem. 2012, 16, 1170. (j) Seiser, T.; Saget, T.;
Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (k) Muꢀ
rakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (l) Dermenci,
A.; Coe, P. W.; Dong, G. Org. Chem. Front. 2014, 1, 567. (m) C−C bond
activation. In Topics in Current Chemistry; Dong, G., Ed.; Springerꢀ
Verlag: Berlin, 2014, Vol. 346. (n) Chen, F.; Wang, T.; Jiao, N. Chem.
Rev. 2014, 114, 8613. (o) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115,
9410.
(2)For two seminal studies, see: (a) South, M. S.; Liebeskind, L. S. J. Am.
Chem. Soc. 1984, 106, 4181. (b) Murakami, M.; Itahashi, T.; Ito, Y. J.
Am. Chem. Soc. 2002, 124, 13976.
(3) (a) Mei, G.; Liu, X.; Qiao, C.; Chen, W.; Li, C.ꢀC. Angew. Chem., Int.
Ed. 2015, 54, 1754. For related reviews, see: (b) Kuwajiama, I.; Tanino, K.
Chem. Rev. 2005, 105, 4661. (c) Kim, S.; Winkler, J. Chem. Soc. Rev.
1997, 26, 387. (d) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113,
2244.
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4. EXPERIMENTAL SECTION
General conditions for the Rhꢀcatalyzed (4+1) cyclization
between cyclobutanones and allenes:
In a nitrogen filled glove box, a 8 mL vial was charged with
[Rh(C2H4)2Cl]2 (1.95 mg, 0.005 mmol, 5 % mmol) and tris[3,5ꢀ
bis(trifluoromethyl)phenyl]phosphine (16.0 mg, 0.024 mmol,
24% mmol). A solution of the cyclobutanone substrate (0.1 mmol)
in 1,4ꢀdioxane (3 mL) was added, and then the vial was capped.
After stirring at room temperature for 5 minutes, the solution was
maintained at 150 °C for 36 h. The reaction was removed from
the glove box and concentrated under reduced pressure. The resiꢀ
due was purified by silica gel chromatography (iodine chamber
was used to visualize the location of the sample on the TLC plate).
(4) Murakami, M.; Ashida, S. Chem. Commun. 2006, 643.
(5) (a) Souillart, L.; Parker, E.; Cramer, N. Angew. Chem., Int. Ed. 2014,
53, 9640. (b) Souillart, L.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53,
3001. (c) Parker, E.; Cramer, N. Organometallics 2014, 33, 780. (d) Liu,
L.; Ishida, N.; Murakami, M. Angew. Chem., Int. Ed. 2012, 51, 2485.
(6) Ko, H. M.; Dong, G. Nat. Chem. 2014, 6, 739.
(7) For a recent review of (4+1) transformation, see: Chen, J.ꢀR.; Hu, X.ꢀ
Q.; Lu, L.ꢀQ.; Xiao, W.ꢀJ. Chem. Rev. 2015, 115, 5301.
General Conditions for the Rhꢀcatalyzed enantioselective
C−C activation:
(8) For recent reviews, see: (a) López, F.; Mascareñas, J. L. Chem. Soc.
Rev., 2014, 43, 2904. (b) Yu. S.; Ma. S. Angew. Chem., Int. Ed., 2012, 51,
3074. (c) Croatt, M. P.; Wender, P. A. Eur. J. Org. Chem. 2010, 19. (d)
Kitagaki, S.; Inagaki, F.; Mukai, C. J. Synth. Org. Chem., Jpn. 2009, 67,
618. (e) Ma, S. Aldrichimica Acta 2007, 40, 91. (f) Ma, S. Chem. Rev.,
2005, 105, 2829. (g) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev., 2002,
31, 12.
(9) For selected examples of allenes as a two or threeꢀcarbon unit in cataꢀ
lytic cycloadditions, see: (a) Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He,
Q.; Gu, Z.; Jiang, X.; Jin, X. Angew. Chem., Int. Ed. 2005, 44, 5275. (b)
Wender, P. A. Deschamps, N. M.; Sun, R. Angew. Chem., Int. Ed. 2006,
45, 3957. (c) Wender, P. A.; Croatt, M. P.; Deschamps, N. M. Angew.
Chem., Int. Ed. 2006, 45, 2459. (d) Trillo, B.; López, F.; Gulίas, M.;
Castedo, L.; Mascareñas, J. L. Angew. Chem., Int. Ed. 2008, 47, 951. (e)
Fujiwara, Y.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 12293. (f) Oonishi,
Y.; Hosotani, A.; Sato, Y. J. Am. Chem. Soc. 2011, 133, 10386. (g) Shu,
D.; Li, X.; Zhang, M, Robichaux, P. J.; Tang, W. Angew. Chem., Int. Ed.
2011, 50, 1346. (h) Evans, P. A.; Negru, D. E.; Shang, D. Angew. Chem.,
Int. Ed. 2015, 54, 4768. (i) Mei, L. Y.; Wei, Y.; Tang, X. Y.; Shi, M. J.
Am. Chem. Soc. 2015, 137, 8131.
(10) For examples of allenes serving as a oneꢀcarbon component in cataꢀ
lytic cycloadditions, see: (a) Casanova, N.; Seoane, A.; Mascareñas, J. L.;
Gulίas, M. Angew. Chem., Int. Ed. 2015, 54, 2374. (b) Szeto, J.;
Sriramurthy, V.; Kwon, O. Org. Lett. 2011, 13, 5420. (c) Kuppusamy, R.;
Gandeepan, P.; Cheng, C.ꢀH. Org. Lett. 2015, 17, 3846.
(11) Xia, Y.; Liu, Z.; Liu, Z.; Ge, R.; Ye, F.; Hossain, M.; Zhang, Y.;
Wang, J. J. Am. Chem. Soc. 2014, 136, 3013.
(12) Yada, A.; Fujita, S.; Murakami, M. J. Am. Chem. Soc. 2014, 136,
7217.
In a nitrogen filled glove box, a 8 mL vial was charged with
[Rh(C2H4)2Cl]2 (1.95 mg, 0.005 mmol, 5 % mmol) and L4 (12.9
mg, 0.024 mmol, 24% mmol). A solution of the cyclobutanone
substrate (0.1 mmol) in 1,4ꢀdioxane (3 mL) was added, and then
the vial was capped. After stirring at room temperature for 5
minutes, the solution was maintained at 130 °C for 20 h. The
reaction was removed from the glove box and concentrated under
reduced pressure. The residue was purified by silica gel chromaꢀ
tography (iodine chamber was used to visualize the location of
the sample on the TLC plate).
ASSOCIATED CONTENT
Supporting Information Experimental procedures; specꢀ
tral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gbdong@cm.utexas.edu
Notes
The authors declare no competing financial interests.
(13) For selected reviews on vinyl carbenoids, see: (a) Davies, H. M. L.
Aldrichimica Acta 1997, 30, 107. (b) Davies, H. M. L. Curr. Org. Chem.
1998, 2, 463. For selected examples on vinyl carbenoidꢀinsertion into
C−H bonds, see: (c) Wang, X.; Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am.
ACKNOWLEDGMENT
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Chem. Soc. 2011, 133, 16402. (d) Lian, Y.; Davies, H. M. L. J. Am.
Chem. Soc. 2011, 133, 11940.
1
(14) For selected drugs containing azepane structures, see: Mianserin,
Imipramine hrdrochloride, Tolazamide, (ꢀ)ꢀGalanthamine hydrobromide,
Clomipramine hydrochloride, Azelastine hydrochloride, Amdinocillin,
Meptazinol.
2
3
4
(15) For selected recent examples of P(3,5ꢀC6H3(CF3)2)3 serving as a key
ligand for πꢀinsertion into rhodacyclopentanones, see (a) Shaw, M. H.;
Melikhova, E. Y.; Kloer, D. P.; Whittingham, W. G.; Bower, J. F. J. Am.
Chem. Soc. 2013, 135, 4992. (b) Shaw, M. H.; McCreanor, N. G.; Whitꢀ
tingham, W. G.; Bower. J. F. J. Am. Chem. Soc. 2015, 137, 463, and ref 6.
(16) Hong, X.; Stevens, M. C.; Liu, P.; Wender, P. A.; Houk, K. N. J. Am.
Chem. Soc. 2014, 136, 17273.
(17) Other nitrogen protecting groups, such as PMB, TFA, and Bz, did
not afford the desired product.
(18) For selected reviews on TADDOLꢀderived phosphoramidites ligands,
see: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Teichert. J. F.;
Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(19) (a) Matsuda, T.; Shigeno, M.; Murakami, M. Chem. Lett. 2006, 35,
288. (b) Matsuda, T.; Fujimoto, A.; Ishibashi, M.; Murakami, M. Chem.
Lett. 2004, 33, 876.
(20) Shaw, M. H.; Croft, R. A.; Whittingham, W. G.; Bower, J. F. J. Am.
Chem. Soc. 2015, 137, 8054.
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