Cu(I)-catalyzed regio- and stereoselective [6 + 3] cycloaddition of azomethine ylides with tropone: An efficient asymmetric access to bridged azabicyclo[4.3.1]decadienes

Article abstract of DOI:10.1021/ja500878c

An unprecedented Cu(I)-catalyzed asymmetric [6 + 3] cycloaddition of tropone with azomethine ylides was reported, which performs well over a broad scope of substrates and offers a unique and facile access to the synthetically useful bridged azabicyclo[4.3.1]decadiene derivatives in good yields with high levels of diastereoselectivities and enantioselectivities under mild conditions.

Full text of DOI:10.1021/ja500878c

Article
pubs.acs.org/JACS
Cu(I)-Catalyzed Regio- and Stereoselective [6 + 3] Cycloaddition of
Azomethine Ylides with Tropone: An Efficient Asymmetric Access to
Bridged Azabicyclo[4.3.1]decadienes
Huai-Long Teng,† Lu Yao,† and Chun-Jiang Wang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China 430072
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, China, 300071
S
* Supporting Information
ABSTRACT: An unprecedented Cu(I)-catalyzed asymmetric [6 + 3]
cycloaddition of tropone with azomethine ylides was reported, which
performs well over a broad scope of substrates and offers a unique and
facile access to the synthetically useful bridged azabicyclo[4.3.1]decadiene
derivatives in good yields with high levels of diastereoselectivities and
enantioselectivities under mild conditions.
Scheme 1. Azomethine Ylides As Hetero Three-Atom
Synthons in [3 + 2] Cycloaddition (Previous Work) and [6 +
3] Cycloaddition (This Work)
INTRODUCTION
■
Transition-metal-catalyzed cycloaddition reactions are one of
the commonly used methods for the construction of bridge-
containing carbocyclic and heterocyclic structures, which exist
in numerous natural products and active pharmaceutical
ingredients.1 Tropone and the related compounds in troponoid
family have been recognized as valuable synthons of natural
products2 and suitable partners in higher order cycloadditions3
since the identification of tropolone moiety as a key unit of
alkaloids.4 Many impressive syntheses of bridge-containing
carbocycles employing tropones as the Cn synthons have been
reported. For example, a phosphoramidite-Pd complex
catalyzed efficient asymmetric [6 + 3] cycloaddition of tropone
with trimethylenemethane has been reported by Trost;5
Yamamoto and co-workers reported an efficient Al-catalyzed
asymmetric inverse-electron-demand [4 + 2] Diels−Alder
reaction of tropones.6 Lu’s seminal studies showed PPh3-
catalyzed [6 + 3] cycloaddition of tropone with allylic
compounds.7,8 One common feature of these tropone-involving
cycloadditions is that the other partner is an all-carbon
(C2∼C4) reactant. Readily available imino esters are
commonly used as heteroatom-containing dipoles in [3 + 2]
cycloadditions with electron-deficient olefins (2-π dipolaro-
phile) for the construction of five-membered heterocyclic
pyrrolidines.9,10 The cycloaddition of imino esters with tropone
could provide an attractive approach toward optically active
molecules possessing an azabicyclic motif (Scheme 1).
decadiene derivatives with high diastereoselectivity and
excellent enantioselectivity.
RESULTS AND DISCUSSION
■
Initial Test to Probe the Possible Reaction Pathway.
Initially, we chose commercially available tropone 1 and N-(4-
chlorobenzylidene)glycine methyl ester 2a as the model
substrates in the presence of 5 mol % of Cu(CH3CN)4BF4/
PPh3 complex as the catalyst and 15 mol % of Et3N as the base
in CH2Cl2 at room temperature. The reaction finished in <5 h
and delivered the azabicyclo[4.3.1]decadiene 3a as a single
isomer via [6 + 3] pathway with excellent regioselectivity and
high diastereoselectivity (>20:1) (Scheme 2). No reaction
occurred in the absence of the Cu(I)/PPh3 complex. Compared
with Ag(I)-complex derived from AgOAc or AgOTf, the Cu(I)-
complex afforded better catalytic activity, leading to a faster
reaction rate and a better yield (see Supporting Information for
In conjunction with our continuing efforts in imino ester
chemistry,11 we envision that in situ-generated azomethine
ylides from imino esters could be employed as the hetero three-
atom synthons in the cycloaddition with tropone (6-π
dipolarophile). Herein we report the asymmetric [6 + 3]
cycloaddition of tropone with azomethine ylides catalyzed by a
Cu(I)/(S,RP)-ferrocenyl-based chiral ligand, providing an
efficient and facile access to optically active azabicyclo[4.3.1]-
Received: January 28, 2014
Published: February 24, 2014
© 2014 American Chemical Society
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disubstituted and monosubstituted ligands L6, L7, and L9
was found to be superior to that of N-unsubstituted chiral
ligand L8 (entries 6, 7, and 10). Catalytic activity decreased
significantly when the phenyl group on the phosphorus atom of
the ligand L7 was replaced by the bulky and electron-donating
xylyl group or electron-withdrawing 3,5-bis(trifluoromethyl)-
phenyl group (entries 11 and 12). The catalyst prepared from
Cu(I):L7 in 1:1 or 1:2 ratio showed the very similar results
(entries 7 and 8). After further optimization of the reaction
temperature and reaction time with L7, cycloadduct 3a was
isolated in 76% yield, > 20:1 dr, and 97% ee after 24 h at −10
°C (entry 14).
Scheme 2. Initial Discovery of Cu(I)/PPh3-Catalyzed [6 + 3]
Cycloaddition of Tropone 1 with Azomethine Ylide 2a
the details). Either a [3 + 2] or a [8 + 3] adduct was not
observed.12 The cycloadduct 3a is stable and no further
reaction occurred.
Catalytic Asymmetric [6 + 3] Cycloaddition of
Azomethine Ylides with Tropone. Encouraged by these
results, we then began to develop an asymmetric variant of this
[6 + 3] annulation. A wide variety of chiral ligands was
investigated, and the representative results were summarized in
Table 1. TF-BiphamPhos,11 exhibiting excellent catalytic
Table 1. Optimization for the Catalytic Asymmetric [6 + 3]
a
Cycloaddition of Tropone 1 with Azomethine Ylide 2a
b
c
entry
L
temp (°C)
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L7
L8
L9
L10
L11
L7
L7
rt
rt
24
24
24
24
12
3
60
50
16
45
50
56
72
74
56
32
38
29
65
76
25
30
8
Under the optimized reaction conditions, the substrate scope
of this [6 + 3] cycloaddition was investigated, and the results
are listed in Table 2. To our delight, we found that a wide array
rt
rt
35
10
74
82
82
27
77
87
79
92
97
rt
Table 2. Substrate Scope of the Catalytic Asymmetric [6 + 3]
rt
a
Cycloaddition of Tropone 1 with Aryl Azomethine Ylides 2
rt
3
d
8
rt
3
9
rt
3
10
11
12
13
14
rt
3
rt
24
24
18
24
rt
b
c
0
entry
Ar
prod.
yield (%)
ee (%)
−10
1
p-Cl-C6H4 (2a)
m−Cl-C6H4 (2b)
p-Br-C6H4 (2c)
p-CF3-C6H4 (2d)
p-F-C6H4 (2e)
3a
3b
3c
3d
3e
3f
76
83
80
85
90
82
68
83
75
72
70
62
78
65
72
78
82
71
97
93
97
96
98
91
96
95
96
94
95
95
95
93
95
99
90
90
a
All reactions were carried out with 0.24 mmol of 2a and 0.20 mmol of
1 in 1 mL of CH2Cl2. CuBF4 = Cu(CH3CN)4BF4. Isolated yield. dr
was determined by crude H NMR, and ee was determined by HPLC
analysis. CuBF4 is 5 mol %, and L7 is 11 mol %.
2
b
c
3
1
4
d
5
6
p-NO2−C6H4 (2f)
p-CN-C6H4 (2g)
p-CO2Me-C6H4 (2h)
Ph (2i)
selectivity in the asymmetric reactions of azomethine ylides,
was first tested in this [6 + 3] cycloaddition reaction.
Combined with L1 and L2, CuBF4 showed high catalytic
activity and provided the desired adduct exclusively in good
yields with excellent diastereoselectivity albeit with low
enantioselectivity. Then, other commercially available chiral
ligands were tested: bisphosphine ligand (S)-BINAP(L3)13
showed pretty low catalytic activity and enantioselectivity, while
35% ee and 10% ee were achieved when (S)-Monophos(L4)14
and bidentate (S,S)-Bn-Box(L5)15 were used as the chiral
ligand, respectively (Table 1, entries 3−5). Considering the
significant role of ferrocenyl-phosphine ligands playing in the [3
+ 2] cycloaddition of azomethine ylides,16 we further screened
chiral ferrocenyl-based P,N-ligands.17 Ligand L7 exhibited the
best performances affording the desired cycloadduct 3a in good
yield with excellent stereoselectivity (>20:1 dr, 82% ee) (entry
7). It is noteworthy that asymmetric induction of N-
7
3g
3h
3i
8
9
10
11
p-OMe-C6H4 (2j)
m-OMe-C6H4 (2k)
o-OMe-C6H4 (2l)
p-Me-C6H4 (2m)
m-Me-C6H4 (2n)
o-Me-C6H4 (2o)
p-tBu-C6H4 (2p)
2-naphthyl (2q)
2-Thienyl (2r)
3j
3k
3l
d
12
13
14
3m
3n
3o
3p
3q
3r
d
15
16
e
17
e
18
a
All reactions were carried out with 0.24 mmol of 2 and 0.20 mmol of
b
c
1 in 1 mL of CH2Cl2. Isolated yield. dr was determined by the crude
d
1H NMR, and ee was determined by HPLC analysis. Carried out at
e
−10 °C for 30 h. Carried out at −20 °C for 48 h.
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of azomethine ylide precursors 2a−2p derived from aryl
aldehydes bearing electron-deficient (Table 2, entries 1−8),
electron-neutral (entry 9), and electron-rich substituents
(entries 10−16) on the aryl rings were readily applicable in
this reaction, providing the corresponding cycloadducts in good
yields (62−90%), exclusive regioselectivity, excellent diaster-
eoselectivities (>20:1 dr), and high enantioselectivities (91−
99% ee). The catalyst system also tolerated changes in the
substitution pattern of the aromatic ring. It is noteworthy that
high diastereoselectivity and excellent enantioselectivity could
be achieved with sterically hindered ortho-methoxyl 2l and
ortho-methyl substituted imino esters 2o, although longer
reaction time was required (entries 12 and 15). Additionally,
heteroaromatic 2-thienylaldehyde derived imino ester 2r was
also viable azomethine ylide precursor as 2-naphthylaldehyde
derived imino ester 2q, delivering the corresponding cyclo-
adduct 3r in 71% yield with >20:1 dr and 90% ee (entry 18).
Encouraged by the excellent results with imino esters derived
from aryl aldehydes, we then investigated the [6 + 3]
cycloaddition with the aliphatic aldehyde-derived imino esters.
Due to the lower reactivity of the aliphatic imino esters,9 strong
inorganic base Cs2CO3 was used instead of Et3N. As shown in
Table 3, the length of the linear alkyl group in the imino moiety
had little effect on the stereoselectivity of this tropone-involved
annulation, and substrates with primary n-alkyl substituent such
as n-propyl, n-butyl, and n-octyl groups all have afforded high
diastereoselectivity and excellent enantioselectivity (Table 3,
entries 1−4). Both benzyl and homobenzyl groups were well
tolerated, giving rise to the cycloadducts in good yield with
excellent enantioselectivity (entries 8 and 9). To further probe
the impact of varying the alky substituent on this reaction,
several substrates with branched and sterically bulky alkyl
substituents such as iso-butyl, iso-propyl, and cyclohexyl were
employed, and the cycloaddition proceeded smoothly to form
the desired adducts with similarly high levels of regio- and
diastereo-/enantioselectivity (entries 5−7). Imino esters
derived from aliphatic aldehyde bearing CC bond, ether,
and ester moiety were also viable substrates providing the
desired cycloadducts in good yield with high stereoselectivity
(entries 10−12). In most cases, nearly one isomer was observed
with the exception of benzyl substituted cycloadduct 3z (entry
8). The limitation is that ester-substituted tropones were not
tolerated in this system delivering unidentified mixtures
probably due to the lability of those compounds under basic
reaction conditions.18 The relative and absolute configuration
of the cycloadduct 3a was determined to be (1S,6R,7R,9S) by
X-ray analysis19 (Figure 1).
Table 3. Substrate Scope of the Catalytic Asymmetric [6 + 3]
Cycloaddition of Tropone 1 with Alkyl Azomethine Ylides
2
a
a
All reactions were carried out with 0.24 mmol of 2 and 0.20 mmol of
b
1 in 1 mL CH2Cl2. Isolated yield, and around 15% tropone was
recovered. dr was determined by the crude H NMR, and ee was
c
1
determined by HPLC analysis.
Linear Effect and Proposed Reaction Mechanism. In
order to obtain some mechanistic information on the
coordination environment around the metal center and the
possible active species, we investigated the relationship between
the ee values of the chiral ligand and the corresponding ee
values of the cycloadduct in this transformation (Figure 2).
As seen from Figure 2, a clear linear effect was observed in
the asymmetric [6 + 3] cycloaddition of imino ester 2a with
tropone 1 catalyzed by various Cu(I) complex coordinated by
ferrocene-based L7 with varying ee values. Such linear
correlation of ee values cycloadduct with that of chiral ligand
indicates that the possible active species in the current efficient
catalytic system is a monomeric metal complex, which was
formed by 1:1 ratio of Cu(I) and the bidentate chiral ligand
(S,RP)-L7.20
Figure 1. ORTEP representation of (1S,6R,7R,9S)-3a at 30%
probability for the drawing of thermal ellipsoids (hydrogen atoms
are omitted for clarity).
A plausible mechanism for this cycloaddition was shown in
Scheme 3. The in situ-formed azomethine ylide is coordinated
to the active Cu complex (A) leading to the tetracordinated
species (B) based on the linear correlation results. The
formation of cycloadduct 3 may be rationalized via a stepwise
mechanism: highly steric congestion imposed by the phenyl
ring on the phosphorus atom in the chiral ligand effectively
blocks tropone (1) approach from the upside of the
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Scheme 4. Synthetic Applications of the Bridged-
a
Cycloadduct 3a
Figure 2. Result of linear effect for the Cu(I)/L7-catalyzed [6 + 3]
cycloaddition reaction of tropone 1 with 2a.
Scheme 3. Plausible Reaction Mechanism
a
i
Reaction conditions: (a) Pd/C, H2, PrOH; (b) NaBH4, MeOH; (c)
NH2OH·HCl, NaHCO3, MeOH; (d) TsCl/DMAP, Et3N, CH2Cl2;
(e) MeCN, 65 °C.
lactam 7 in good yield without loss of diastereo-/enantiomeric
excess.
In order to further evaluate the synthetic utility of this
annulation process, the [6 + 3] cycloaddition reaction was
enlarged to a gram scale. Under the optimized reaction
conditions, the reaction completed in <24 h, and satisfied
results of 80% yield and 97% ee were obtained (Scheme 5).
Scheme 5. Scale-up Reaction
coordinated azomethine ylide, and the initial nucleophilic
addition of the metallo-azomethine ylide (B) to the α-position
of tropone generates the zwitterionic intermediate (C). This is
followed by intramolecular Mannich addition to yield the
species (D) containing the bridged azabicyclo[4.3.1]decadiene
moiety. Finally, protonation regenerates the catalytically active
species A. In the six-membered chair-like transition state, the
two substituents on the metallo-azomethine ylide are placed at
the equatorial positions throughout the intramolecular
cyclization step, delivering the cycloadduct 3 with excellent
stereoselective control.
Synthetic Transformations and Scale-up Reaction.
The optically active bridged-cycloadduct 3a can serve as
synthetically useful precursors for other stereochemically rich
structures (Scheme 4). Direct hydrogenation of 3a in the
present of Pd/C afforded 4 in 90% yield. The carbonyl group in
3a was reduced by NaBH4 in a highly diastereoselective fashion
to afford compound 5 containing five consecutive tertiary
stereogenic centers in high yield. Additionally, 3a was
successfully converted into oxime 6 in 2:1 ratio, and the
relative configuration of the major isomer of oxime 6 was
determined by X-ray analysis (see X-ray structure in Scheme 4,
hydrogen atoms are omitted for clarity).19 Subjection of the
major isomer of 621 to Beckmann rearrangement provided the
CONCLUSIONS
■
In summary, we have developed a direct and facile synthesis of
bridged azabicyclo[4.3.1]decadiene derivatives, a potentially
valuable structural motif for medicinal chemistry. This approach
resulted from the development of an unprecedented Cu(I)-
catalyzed [6 + 3] cycloaddition reaction of tropone with
azomethine ylides. This new asymmetric cycloaddition afforded
high yield, complete regioselectivity, and excellent diastereo-
and enantioselectivity for imino esters from aryl as well as
aliphatic aldehydes. Mechanistic and synthetic studies aiming to
understand the origin of catalytic selectivity and to expand the
synthetic utility of this asymmetric [6 + 3] cycloaddition are
ongoing in this lab. This research work was originally submitted
as JACS Communication on July 24th, 2012. When we revised
this manuscript as a JACS article, a just accepted manuscript
reported the same cycloaddition reaction.22
EXPERIMENTAL SECTION
■
General Information. 1H NMR spectra were recorded on a
VARIAN Mercury 300 or 400 MHz spectrometer in CDCl3. Chemical
shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a
standard. The data are reported as (s = single, d = double, t = triple, q
= quarte, m = multiple or unresolved, brs = broad single, coupling
constant(s) in Hz, integration). 13C NMR spectra were recorded on a
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VARIAN Mercury 75 or 100 MHz spectrometer in CDCl3. Chemical
shifts are reported in ppm with the internal chloroform signal at 77.0
ppm as a standard. Commercially obtained reagents were used without
further purification. All reactions were monitored by TLC with silica
gel-coated plates. Enantiomeric ratios were determined by HPLC,
using chiralpak AS-H and AD-H columns and chiralcel OD-H column
with hexane and i-PrOH as solvents. Tropone23 was prepared
according to the literature procedure.
General Procedure for Cu(I)-Catalyzed Asymmetric [6 + 3]
Cycloaddition of Azomethine Ylides with Tropone. Under argon
atmosphere, Cu(CH3CN)4BF4 (3.1 mg, 0.010 mmol) and (S,RP)-L7
(4.7 mg, 0.011 mmol) were dissolved in 1 mL CH2Cl2 and stirred at
room temperature for 1 h. Then, aldimino ester 2 (0.24 mmol) and
tropone 1 (21 mg, 0.20 mmol) were added sequentially, and the
mixture was dropped to −10 °C, and then Et3N (0.03 mmol, for aryl
imino esters) or Cs2CO3 (0.4 mmol, for alkyl imino esters) was added.
The reaction mixture was stirred at this temperature until the
consumption of 1 (monitored by TLC analysis). The residue was
purified by flash chromatography on silica gel and gave the
corresponding product 3, which was then directly analyzed by
HPLC to determine the enantiomeric excess.
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cyclo[4.3.1]deca-2,4-diene-7-carboxylate (3a, Table 2, entry
1). Yield (76%); White solid, mp: 146 °C; [α]25 = −84.3 (c 0.62,
D
1
CHCl3); H NMR (CDCl3, TMS, 400 MHz) δ 7.34 (d, J = 8.4 Hz,
2H), 7.23 (d, J = 8.4 Hz, 2H), 6.12 (dd, J1 = 7.6 Hz and J2 = 11.2 Hz,
1H), 6.00 (dd, J1 = 7.6 Hz and J2 = 11.6 Hz, 1H), 5.41 (dd, J1 = 8.0 Hz
and J2 = 11.6 Hz, 1H), 5.01 (dd, J1 = 7.6 Hz and J2 = 11.6 Hz, 1H),
4.37 (m, 1H), 4.15 (dd, J1 = 4.0 Hz and J2 = 9.6 Hz 1H), 3.81 (s, 3H),
3.74 (m, 1H), 3.63 (m, 1H), 2.29 (t, J1 = 10.4 Hz, 1H); 13C NMR
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127.1, 127.6, 128.3, 128.7, 133.4, 136.7, 169.8, 203.8; IR (KBr) ν 3020,
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deca-2,4-diene-7-carboxylate (3s, Table 3, entry 1). Yield
(70%); Colorless oil; [α]25 = +19.3 (c 0.48, CHCl3); 1H NMR
D
(CDCl3, TMS, 400 MHz) δ 6.11−6.06 (m, 2H), 5.52 (m, 1H), 5.29
(m, 1H), 4.02 (d, J = 4.4 Hz, 1H), 3.77 (s, 3H), 3.66 (m, 1H), 3.31
(m, 1H), 3.13 (m, 1H), 1.53−1.40 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, TMS, 100 MHz) d 13.9, 19.4, 35.1, 52.2, 55.8, 57.7,
63.5, 65.7, 120.3, 122.3, 126.7, 127.9, 170.2, 204.3; IR (KBr) ν 3019,
2068, 1635, 1524, 1476, 1424, 1215, 908, 771, 669 cm−1. HRMS calcd.
For C14H19NO3 + H+: 250.1438, found: 250.1441. The product was
analyzed by HPLC to determine the enantiomeric excess: 93% ee
(Chiralpak AS-H, i-propanol/hexane =20/80, flow rate 1.0 mL/min, λ
= 220 nm); tr = 17.95 and 23.45 min.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
cjwang@whu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by 973 Program (2011CB808600),
NSFC (21172176, 21372180), NCET-10-0649,
2011YQ12003504, and Hubei Province NSF (ZRZ0273).
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