Enantioselective synthesis of 3-Azabicyclo[4.1.0]heptenes and 3-Azabicyclo[3.2.0]heptenes by Ir-catalyzed asymmetric allylic amination of N-iosyl propynylamine and Pt-catalyzed cycloisomerization

Article abstract of DOI:10.1002/chem.201000467

[Chemical equation presented] Irresistible! Highly regio- and enantioselective Ir-catalyzed allylic amination reactions of N-tosyl propynylamines have been realized. The resulting Ntosyl allylpropynylamines were transformed into highly enantioenriched 3-a

Full text of DOI:10.1002/chem.201000467

DOI: 10.1002/chem.201000467
Enantioselective Synthesis of 3-AzabicycloACTHNUTRGNE[NUG 4.1.0]heptenes and
3-AzabicycloACTHNUTRGENUGN[3.2.0]heptenes by Ir-Catalyzed Asymmetric Allylic Amination
of N-Tosyl Propynylamine and Pt-Catalyzed Cycloisomerization
Ji-Bao Xia, Wen-Bo Liu, Tian-Min Wang, and Shu-Li You*[a]
3-Azabicyclo
G
G
catalyst to afford bicycloACTHGNUTERNNUG
[3.2.0]hept-6-enes.[6] To the best of
frameworks exist as two important skeletons for many bio-
our knowledge, their asymmetric version is still unknown.
Ir-catalyzed asymmetric allylic amination reactions have
been studied extensively in the past decade.[7,8] Recently,
studies by Hartwig et al. and Helmchen et al. demonstrated
the cyclometallated iridium as the active catalytic species.[9]
With this catalytic system, we envisaged that the use of
propargyl amines would afford the enantioenriched substi-
tuted N-allylpropynylamines (Scheme 1). Although this
seems a straightforward synthesis, there is no direct utiliza-
tion of propargyl nucleophiles in Ir-catalyzed allylic substitu-
tion reactions.[10] Notably, Ueno and Hartwig found that ad-
dition of alkyne was crucial for allylic substitution of alkyl
alkoxide, probably due to the coordination of the triple
bond with the iridium catalyst, which eliminated the isomer-
ization of ether product.[11] Interestingly, Helmchen and co-
workers realized an elegant synthesis of enantioenriched
carbon-tethered 1,6-enyne by allylic alkylation of dimethyl
malonate and then alkylation of the product thereof with
propargyl bromide.[12]
logically interesting compounds (Scheme 1).[1] Development
Scheme 1. Synthesis of 3-azabicycloACHTUGNTREN[NUGN 4.1.0]heptene and 3-azabicyclo-
ACHTUNGTRENNUNG[3.2.0]heptene derivatives. TMS=trimethylsilyl, Ts=tosyl.
of efficient syntheses, particularly enantioselective syntheses,
towards these two scaffolds has been an intense subject in
organic synthesis.[2] Over the past several decades, 1,6-
enynes were recognized as the key intermediates for struc-
turally diverse polycyclic compounds through transition-
metal-catalyzed cycloisomerization reactions.[3] Construction
Intrigued by the enantioselective synthesis of 3-
of the 3-azabicyclo
G
azabicycloACTHNGUTREN[UNG 4.1.0]heptenes and 3-azabicycloACHTUNGTNER[NUNG 3.2.0]heptenes,
metal catalyzed cycloisomerization of substituted N-allylpro-
pynylamines has been documented in the literature,[4]
whereas their catalytic asymmetric studies are less explored,
with only handful examples to date.[5] In addition, the effi-
we recently found that N-tosyl propynylamine could be used
directly in Ir-catalyzed allylic amination reaction. The enan-
tioenriched N-tosyl allylpropynylamines were converted
smoothly into 3-azabicycloACHTNUTRGNE[NUG 4.1.0]hept-4-enes by catalytic
cient synthesis of 3-azabicyclo
[3.2.0]heptanes by cycloisome-
amount of PtCl2. Moreover, starting from products derived
rization is limited with only one recent report in which
from N-tosyl 3-trimethylsilylpropynylamine (R2 =TMS,
amide-tethered 1,6-enynes were used with the aid of an AuI
Scheme 1),
highly
enantioenriched
3-azabicyclo-
AHCTUNGTREG[NNNU 3.2.0]heptenes were obtained under the same reaction con-
ditions. Herein, we report our studies on this subject.
We began our studies to test the suitability of propynyl-
amine as a nucleophile in Ir-catalyzed allylic amination reac-
[a] J.-B. Xia, W.-B. Liu, T.-M. Wang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Lingling Lu
Shanghai 200032 (China)
ꢀ
tion. Methyl cinnamyl carbonate (1a) and CH3C
CCH2NHTs (2a) were chosen as the model substrates. With
[{IrACTHUNTRGENNG(U cod)Cl}2] (cod=1,5-cyclooctadiene) and phosphorami-
Fax : (+86)21-5492-5087
dite L1 in THF at 508C, no reaction occurred without base
(Table 1, entry 1). Fortunately, the reaction proceeded in the
presence of base (K2CO3, Cs2CO3, K3PO4, KOAc, LiHMDS,
E-mail: slyou@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000467.
6442
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Chem. Eur. J. 2010, 16, 6442 – 6446

COMMUNICATION
Table 1. Optimizing reaction conditions.[a]
The catalyst derived from L4, the diastereoisomer of L1,
could catalyze the reaction, but in a lower yield with de-
creased selectivities (Table 1, entry 15). To our delight, when
the reaction was performed at room temperature with
ligand L2, significant improvement of yield and selectivities
was resulted (Table 1, entry 16, 3aa/4aa: 95:5, 3aa:
99% ee).
Under the above optimized reaction conditions, various
allyl carbonates 1 and propargyl amines 2 were investigated.
The data are summarized in Table 2. Several propargyl
Entry Ligand Base
t [h] Conv. [%][b] 3aa/4aa[c] ee [%][d]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L2
–
15
28
3
3
28
<5
93 (53)
>99 (77)
>99 (94)
95 (89)
52 (52)
37 (33)
52 (45)
>99 (72)
>99 (97)
>99 (92)
73 (65)
>99 (90)
78 (75)
–
–
K2CO3
Cs2CO3
K3PO4
KOAc
LiHMDS 24
BSA
90:10
87:13
88:12
88:12
89:11
86:14
88:12
90:10
89:11
89:11
84:16
90:10
89:11
69:31
95:5
93
94
95
95
93
95
95
92
95
95
92
97
94
74
99
48
24
3
3
3
80
3
24
24
12
Table 2. The substrate scope of allylic amination.
TBD
DBU
9
10
11[e]
12[f]
13[e]
14[e]
15[e]
16[e,g]
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
Entry 1, R1
2
t [h] 3, Yield [%][a] 3/4[b]
ee [%][c]
63 (61)
>99 (97)
1
2
3
4
5
6
7
8
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1a, C6H5
1b, 4-Me-C6H4
1c, 4-MeO-C6H4 2a 12
1d, 4-Br-C6H4
1e, 4-CF3-C6H4
2a 12
2b
2c 12
2d
2e 24
2a
3aa, 93
3ab, 83
3ac, 84
3ad, 89
NR[d]
95:5
90:10
94:6
95:5
–
99
99
97
99
–
99
99
>99
>99
99
99
>99
92
99
99
98
98
98
99
3
[a] [{IrACHTUNGTRENNUNG(cod)Cl}2] (2 mol%), L (4 mol%), 1a, 2a (1.1 equiv), and base
(1.0 equiv) in THF at 508C. LiHMDS=lithium hexamethyldisilazide,
BSA=N,O-bis(trimethylsilyl)acetamide, TBD=1,5,7-triazabicyclo-
[4.4.0]dec-1-ene, DBU=1,5-diazabicyclo[5.4.0]undec-5-ene, DABCO=
1,4-diazabicyclo
[2.2.2]octane. [b] Determined by 1H NMR spectroscopy
4
A
ACHTUNGTRENNUNG
4
3ba, 76
3ca, 93
3da, 95
3ea, 82
3 fa, 85
3ga, 86
3ha, 83
3ia, 70
3bb, 76
3cb, 92
3db, 84
3 fb, 77
3gb, 81
3hb, 81
3ib, 82
1
96:4
98:2
97:3
96:4
97:3
96:4
95:5
90:10
91:9
99:1
90:10
91:9
88:12
94:6
90:10
ACHTUNGTRENNUNG
and isolated yields of 3aa and 4aa in the parenthesis. [c] Determined by
1H NMR spectroscopy. [d] Determined by chiral HPLC analysis.
[e] 0.5 equiv of DABCO was used. [f] 0.1 equiv of DABCO was used.
[g] At RT.
2a 12
9
2a
4
3
10
11
12
13
14
15
16
17
18
19
20
1 f, 3-MeO-C6H4 2a
1g, 3-Cl-C6H4
1h, 2-thienyl
1i, Me
2a 10
2a 10
2a
3
BSA, TBD, DBU, DABCO), affording amination product
with excellent regio- and enantioselectivity (Table 1, en-
tries 2–10). DABCO was found to be the optimal base,
yielding quantitative amination product with 89:11 regiose-
lectivity in favor of branch product 3aa (95% ee). The reac-
tion was found to be compatible with various solvents, such
as toluene, dioxane, DMF, CH3CN, Et2O, CH2Cl2, DME,
and EtOH (see the Supporting Information); THF was
found to be the best solvent. Excellent yield and selectivities
were maintained with DABCO (0.5 equiv) in THF, but fur-
ther lowering the loading resulted in a sluggish reaction with
reduced yield (Table 1, entries 11 and 12).
1b, 4-Me-C6H4
2b 12
1c, 4-MeO-C6H4 2b 10
1d, 4-Br-C6H4 2b 12
1 f, 3-MeO-C6H4 2b 12
1g, 3-Cl-C6H4
1h, 2-thienyl
1i, Me
2b 12
2b 12
2b 10
92
[a] Isolated yields of 3. [b] Determined by H NMR spectroscopy. [c] De-
termined by chiral HPLC analysis. [d] No reaction.
amines 2a–d bearing methyl, TMS, phenyl, and n-butyl
group were tolerated. In all cases, branch products 3 were
isolated in 83–93% yields with 97–99% ee (Table 2, en-
tries 1–4). No reaction occurred with unsubstituted proparg-
yl amine 2e, probably due to interference between the
acidic terminal alkyne proton and the Ir-catalyst (Table 2,
entry 5). With propargyl amines 2a and 2b, a wide range of
allyl carbonates 1 with different substituents, including elec-
tron-donating or -withdrawing groups containing aryl, hetero-
aryl, and aliphatic groups, has been tested (Table 3, en-
tries 6–20). Delightfully, good to excellent yields and
branch-to-linear selectivities were generally obtained. In
most cases, branch allylic amination products
3 were
Different, readily available chiral phosphoramidite ligands
were tested. The catalysts derived from ligands L2 and L3
afforded the amination product with excellent regioselectivi-
ties in favor of branch product 3a with 97 and 94% enantio-
meric excess (ee), respectively (Table 1, entries 13 and 14).
obtained with excellent level of enantioselectivities
(>98% ee).
With highly enantioenriched N-tosyl allylpropynylamines
in hand, their cycloisomerization reactions were examined.
With PtCl2 as the catalyst, 3-azabicyclo
ACHTUNGTRENNUNG
Chem. Eur. J. 2010, 16, 6442 – 6446
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S.-L. You et al.
Table 3. The scope of platinum-catalyzed cycloisomerization reaction.
Entry
R1
R2
3
t
5 or 6, Yield [%]
ACHTUNGTRENNUNG
(ee [%])[a]
(ee [%])
[h]
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
3aa (99)
3ba (99)
3ca (99)
3da (99)
3ea (99)
3 fa (99)
3ga (99)
3ha (99)
3ia (92)
3ab (99)
3bb (99)
3cb (99)
3db (98)
3 fb (99)
3gb (98)
3hb (97)
3ib (92)
3ad (97)
24
27
28
28
27
27
34
34
23
48
46
48
48
45
47
58
54
24
5aa, 52 (99)
5ba, 61 (98)
5ca, 51 (99)
5da, 71 (99)
5ea, 60 (99)
5 fa, 58 (99)
5ga, 61 (99)
5ha, 24 (99)
5ia, 68 (93)
6ab, 53 (99)
6bb, 60 (99)
6cb, 31 (99)
6 db, 57 (98)
6 fb, 54 (98)
6gb, 55 (98)
6hb, 21 (97)
6ib, 51 (90)
5ad, 70 (97)
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
4-CF3-C6H4
3-MeO-C6H4
3-Cl-C6H4
2-thienyl
Me
9
Me
10
11
12
13
14
15
16
17
18
C6H5
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
C6H5
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
3-MeO-C6H4
3-Cl-C6H4
2-thienyl
Me
C6H5
[a] Isolated yields, and ee values were determined by chiral HPLC analy-
sis.
rivatives 5 were obtained when N-tosyl allyl but-2-ynyl
amines 3 (R2 =Me) and N-tosyl allyl phenylprop-2-ynyl
amine 3ad (R2 =Ph) were used. As summarized in Table 3,
with 10 mol% PtCl2 in THF at reflux, 3-azabicyclo-
ACHTUNGTRENNUNG[4.1.0]hept-4-ene derivatives 5 were obtained in moderate
yields with ee values greater than 98% in most cases
(Table 3, entries 1–9, 18). The reactions proceeded to give
the cycloisomerization product as a single diastereomer and
there was no notable loss of the optical purity relative to the
starting materials. To determine the absolute configuration
of the product, X-ray crystallographic analysis of enantio-
pure bromine-containing compound 5da disclosed the con-
figuration as (1S,2S,6S) (Figure 1).[13] To our surprise, when
3ab, containing a TMS group on the alkyne moiety, was sub-
jected to the same reaction conditions, 3-azabicyclo-
Figure 1. ORTEP representation of 5da (top) and 6ab (bottom).
A
ucts 8 (normally less than 10%) were not isolated during
the examination of the substrate scope. To understand the
unusual chemoselectivities controlled by different substitu-
ents, enantioenriched N-tosyl allylpropynylamine 9 was syn-
product (Scheme 2a). The relative stereochemistry of 6ab
was further confirmed by X-ray analysis (Figure 1).[14] After
tuning the reaction conditions, heating a solution of the
crude products in tetrabutylam-
monium fluoride (TBAF)/THF
at reflux led to the conversion
of
azabicyclo
rivatives 6. In general, 3-
azabicyclo[3.2.0]hept-6-ene de-
3
(R2 =TMS) into 3-
ACHTUNGTRENNUNG[3.2.0]hept-6-ene de-
ACHTUNGTRENNUNG
rivatives 6 were obtained in
moderate yields without loss of
the optical purity (Table 3, en-
tries 10–17). Notably, the corre-
sponding saturated side prod- Scheme 2. Role of the TMS group.
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Enantioselective Synthesis of 3-AzabicycloACHTUNTRGENNUG[4.1.0]heptenes and 3-AzabicycloHCATUNGTREN[NUNG 3.2.0]heptenes
COMMUNICATION
thesized by treating 3ab with K2CO3 in methanol (Sche-
me 2b). When 9 was subjected to the standard cycloisomeri-
cellent yields with excellent regio- and enantioselectivities.
PtCl2-catalyzed cycloisomerization reactions of N-tosyl allyl-
propynylamines led to enantioenriched 3-azabicyclo-
ACHUTNGRENU[NG 4.1.0]heptenes and 3-azabicycloCAHTUNGTRENN[UGN 3.2.0]heptenes, respectively,
simply by tuning substituents on the alkyne. The current re-
actions provide an efficient way to prepare 3-azabicyclo-
zation conditions, 3-azabicyclo
was obtained in 41% yield without observation of the corre-
sponding 3-azabicyclo[3.2.0]hept-6-ene product. These re-
sults indicate that the TMS group plays a key role for the
formation of 3-azabicyclo[3.2.0]hept-6-ene skeleton.
ACHTUNGTRNE[NUNG 4.1.0]hept-4-ene derivative 10
T
A
ACHUTGTNREN[NUG 4.1.0]heptenes and 3-azabicycloACHTUNTGREN[NUGN 3.2.0]heptenes with multi-
A plausible mechanism for the Pt-catalyzed cycloisomeri-
zation was proposed, as depicted in Scheme 3.[15] When R2 is
a methyl or phenyl group (Scheme 3a), the reaction of 3 in
ple chiral centers with an excellent level of optical purity.
Experimental Section
Full experimental details and characterization data are given in the Sup-
porting Information.
General procedure A for the Ir-catalyzed allylic amination: Propylamine
(0.3 mL) was added to
a dry schlenk tube containing [{IrACHTUNGTRENNUNG(cod)Cl}2]
(2.7 mg, 0.004 mmol) and phosphoramidite ligand L2 (4.8 mg,
0.008 mmol) in THF (0.5 mL). The reaction mixture was heated at 508C
for 30 min and then the volatile solvents were removed under vacuum to
give a yellow solid. After that, allylic carbonate 1 (0.20 mmol), propargyl
amine 2 (0.22 mmol), DABCO (0.10 mmol), and THF (2.0 mL) were
added. The reaction was stirred at room temperature until the carbonate
1
was fully consumed (monitored by TLC or H NMR spectroscopy). Then
the crude reaction mixture was filtered through a pad of Celite and
washed with CH2Cl2. The solvents were removed under reduced pressure.
The ratio of regioisomers was determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. The crude residue was purified by
flash column chromatography (petroleum ether/ethyl acetate) to give the
desired products 3.
Scheme 3. Plausible mechanism of Pt-catalyzed cycloisomerization reac-
tion.
General procedure B: Synthesis of 5aa by Pt-catalyzed cycloisomeriza-
tion: Compound 3aa (65.0 mg, 0.191 mmol) and PtCl2 (5.1 mg,
0.019 mmol) were dissolved in THF (1.9 mL). The reaction mixture was
heated at reflux until 3aa was fully consumed (monitored by TLC). The
reaction mixture was cooled to room temperature, filtered through a pad
of Celite, and the Celite was washed with CH2Cl2. The filtrate was con-
centrated under reduced pressure, and the residue was subjected to flash
column chromatography with ethyl acetate/petroleum ether (1:45) as
eluent to afford the desired product 5aa as a white solid (34.0 mg, 52%).
the presence of PtCl2 would undergo 6-endo cyclization, fol-
lowed by elimination of the platinum catalyst in intermedi-
ate I to afford cyclized product 5. When R2 is a TMS group
(Scheme 3b), 5-exo cyclization might occur first to afford
carbenoid intermediate II. Then a 1,2-shift of the TMS
group results in a ring expansion, leading to intermediate
III. Loss of the TMS group in III leads to the formation of
carbenoid IV, which eliminates the platinum catalyst to
afford cyclized product 6. The formation of 7 is likely to be
due to the fact that the elimination of platinum occurs prior
to the loss of the TMS group. As evidence for the loss of
TMS group followed by protonation with trace amount of
water in the reaction mixture, when 3ab and catalytic PtCl2
were heated at reflux in THF in the presence of D2O
(3 equiv), product 6ab was obtained with Ha being deuterat-
ed at 70% (Scheme 4).
General procedure C: Synthesis of 6ab by Pt-catalyzed cycloisomeriza-
tion: Compound 3ab (59.6 mg, 0.15 mmol) and PtCl2 (4.0 mg,
0.015 mmol) were dissolved in THF (1.5 mL). The reaction mixture was
heated at reflux until 3ab was fully consumed (monitored by TLC). Then
Bu4NF (0.3 mL, 0.1m in THF) was added. The reaction mixture was
heated at reflux for another 24 h. The reaction mixture was cooled to
room temperature, filtered through a pad of Celite, and the Celite was
washed with CH2Cl2. The filtrate was concentrated under reduced pres-
sure, and the residue was subjected to flash column chromatography with
ethyl acetate/petroleum ether (1:25) as eluent to afford the desired prod-
uct 6ab as a white solid (25.8 mg, 53%).
Acknowledgements
We thank the NSFC (20872159, 20821002, 20923005) and National Basic
Research Program of China (973 Program 2010CB833302) for generous
financial support. We also thank Professor Gꢁnter Helmchen, Organisch-
Chemisches-Institut der Ruprecht-Karls-Universitꢂt Heidelberg, for
sending us a manuscript describing his work on Ir-catalyzed allylic amina-
tion with but-2-ynylamine.
Scheme 4. Results of deuteration experiments.
In conclusion, the Ir-catalyzed allylic amination reaction
Keywords: amination
·
asymmetric
catalysis
·
of N-tosyl propynylamines has been realized in good to ex-
cycloisomerization · enantioselectivity · iridium
Chem. Eur. J. 2010, 16, 6442 – 6446
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6445

S.-L. You et al.
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[10] Highly selective Ir-catalyzed allylic amination with but-2-ynylamine
and enantioselective total synthesis of (À)-a-kainic acid have been
carried out by G. Helmchen and co-workers at Organisch-Chemisch-
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[13] CCDC-759758 contains the supplementary crystallographic data for
(1S,2S,6S)-5da. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[14] CCDC-759757 contains the supplementary crystallographic data for
6ab. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[15] E. Soriano, J. Marco-Contelles, Acc. Chem. Res. 2009, 42, 1026–
1036.
Received: February 22, 2010
Published online: May 6, 2010
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