6-azabicyclo[3.2.1]octanes via copper-catalyzed enantioselective alkene carboamination

Article abstract of DOI:10.1002/adsc.201400317

Bridged bicyclic rings containing nitrogen heterocycles are important motifs in bioactive small organic molecules. An enantioselective copper-catalyzed alkene carboamination reaction that creates bridged heterocycles is reported herein. Two new rings are

Full text of DOI:10.1002/adsc.201400317

UPDATES
DOI: 10.1002/adsc.201400317
6-Azabicyclo
ACHTUNGTRENNUNG
Alkene Carboamination
Barbara J. Casavant,a Azade S. Hosseini,a and Sherry R. Chemlera,*
a
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, USA
Fax : (+1)-716-645-6369; phone: (+1)-715-645-4225; e-mail: schemler@buffalo.edu
Received: March 27, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400317.
Abstract: Bridged bicyclic rings containing nitrogen
heterocycles are important motifs in bioactive small
organic molecules. An enantioselective copper-cata-
lyzed alkene carboamination reaction that creates
bridged heterocycles is reported herein. Two new
rings are formed in this alkene carboamination re-
action where N-sulfonyl-2-aryl-4-pentenamines are
enantioselective alkene carboamination to form the
chiral bicyclic sultam 2 with 94% ee (Scheme 1).[6a]
À
The new N C bond is thought to be set by an
enantioselective aminocupration step. Subsequent
À
C Cu(II) bond homolysis is thought to occur, forming
intermediate A. Carbon-carbon bond formation via
intramolecular addition of the primary carbon radical
of A to the pendant arylsulfonyl group followed by
oxidation/rearomatization provides sultam 2. More re-
cently, we reported that in the presence of 1,1-diphe-
nylethylene, the same carbon radical intermediate can
converted to 6-azabicyclo
ACHTUNGERTN[NUNG 3.2.1]octanes using the
complex [Ph-Box-Cu](OTf)2 or related catalysts in
AHCTUNGTRENNUNG
the presence of manganeses dioxide (MnO2) as stoi-
chiometric oxidant in moderate to good yields and
generally excellent enantioselectivities. Two new
stereocenters are formed in the reaction, and the
À
undergo an intermolecular C C bond formation to
give chiral pyrrolidine 4 with 95% ee.[7] In both exam-
ples, formation of the bridged bicyclic carboamination
product 3a via path b (Scheme 1) is possible but was
not observed.
À
À
C C bond-forming arene addition is a net C H
functionalization.
We hypothesized that in the absence of all other
radical acceptors (tosyl, 1,1-diphenylethylene), 2-aryl-
pentenamines 1 could undergo intramolecular carbo-
Keywords: 6-azabicycloACTHNUTRGNE[UNG 3.2.1]octanes; alkaloids;
carboamination; copper-catalyzed reactions; enan-
tioselectivity
A
ACHTUNGTREN[NGNU 3.2.1]octanes
ACHTUNGTRENNUNG
Bridge-containing organic compounds are attractive more, the reaction could be rendered enantioselec-
molecular scaffolds due to their relative rigidity and tive to give 3b with 67% ee using the commercially
ability to precisely display functional groups in three available (R,R)-Ph-Box ligand complexed with
dimensions.[1] The azabicyclo
ACTHNUGTRENN[UG 3.2.1]octane skeleton is CuACHTUNTGERN(NUGN OTf)2 (Table 1, entry 2). Addition of activated 4ꢀ
at the core of important biologically active natural molecular sieves led to a higher and more reproduci-
products such as cocaine, aphanorphine, and securi- ble level of enantioselectivity (91% ee, Table 1,
nine.[2] In addition, synthetic analogs have demon- entry 3), presumably due to sequestration of adventi-
strated promising therapeutic potential for the treat- tious water, which is deleterious to the reactionꢁs effi-
ment of drug addiction and pain.[3] Although ciency and selectivity. We were able to reduce the cat-
a number of methods for their synthesis have been alyst loading to 15 mol%, the temperature to 1108C,
developed,[4] few form two rings in one step,[5] and of and the reaction time to 12 h without loss of efficien-
these latter examples, none provide azabicyclo- cy or enantioselectivity (Table 1, entry 4).
A
The scope of the enantioselective alkene carboami-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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Barbara J. Casavant
Scheme 1. Possible carboamination pathways.
Table 1. Optimization of reaction conditions.[a]
Entry
Cu
(OTf)2 (amount)
Ligand (amount)
Temperature, time
Yield [%][b]
ee [%][c]
1
2
30 mol%
20 mol%
20 mol%
15 mol%
10 mol%
L1 (40 mol%)
L2 (25 mol%)
L2 (25 mol%)
L2 (19 mol%)
L2 (13 mol%)
1208C, 24 h
1208C, 24 h
1208C, 24 h
1108C, 12 h
1108C, 12 h
84
78
81
76
72
–
67
91
95
66
3[d]
4[d]
5[d,e]
[a]
Conditions: CuACHTUNGTRENNUNG(OTf)2 was combined with L1 or L2 under argon and heated in dry PhCF3 (0.8 mL) for 2 h in a sealed
tube. Substrate 1b (50.0 mg, 0.158 mmol), K2CO3 (0.158 mmol), MnO2 (0.473 mmol) and PhCF3 (0.8 mL) were added and
the mixture was heated and stirred.
[b]
[c]
[d]
[e]
Isolated yield following flash chromatography on silica gel.
Enantiomeric excess determined by chiral HPLC analysis.
Activated flame-dried molecular sieves (20 mgmLÀ1) were used.
Reaction did not go to completion.
90% ee. This sulfonyl group is attractive as it is easily action efficiency and selectivity (Table 2, entries 5–8).
removed with fluoride reagents such as TBAF. The The 2,2-bis(2-methylphenyl)-substituted 4-pentenyl
N-benzylsulfonyl pentenamine 1d gave 83% of 3d sulfonamide 5e underwent the enantioselective car-
with 80% ee. The N-3,5-tert-butyl-4-methoxybenzene- boamination uneventfully, despite the added steric
sulfonyl substrate 1e gave 76% of 3e with 95% ee. hindrance on the aryl acceptor, giving adduct 6e in
This arylsulfonyl groupꢁs ortho positions are hindered 81% yield and 93% ee (Table 2, entry 9). N-Mesyl-4-
by its meta-tert-butyl groups, rendering formation of methyl-4-pentenamine 7, a 1,1-distubstituted alkene,
the fused ring sultam analogous to 2 (Scheme 1) less gave adduct 8 bearing two fully substituted chiral car-
favorable. Electron-rich (OMe, SMe) and more elec- bons in 69% yield with 92% ee (Table 2, entry 10).
tron-deficient (Cl, F) para-substituents on the sub- The internal alkene substrates 9a and 9b, however, re-
strateꢁs backbone aryl rings had little effect on the re- acted poorly, producing intractable mixtures of sub-
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6-AzabicycloACTHNUTRGNEUG[N 3.2.1]octanes via Copper-Catalyzed Enantioselective
Table 2. Scope of the enantioselective carboamination.
Entry
Substrate
Product
Yield [%]
76
ee [%]
1[a]
1b, R=Ms
3b
95
2[b]
3[b]
1c, R=SES
1d, R=SO2Bn
3c
3d
80
83
90
80
4[b]
1e
3e
76
95
5[a]
5a, X=OMe
6a
83
95
6[a]
7[a]
8[a]
5b, X=SMe
5c, X=Cl
5d, X=F
6b
6c
6d
80
80
68
93
90
95
9[b]
5e
6e
81
69
93
92
10[b]
11[b]
7
8
9a, R=Me
9b, R=Ph
–
–
–
–
12[b]
[a]
Conditions from Table 1, entry 4.
Conditions from Table 1, entry 3.
[b]
strate and unidentified products under the reaction
conditions (Table 2, entries 11 and 12).
An N-mesyl-2,2-diaryl-4-pentenamine bearing meta
substitution on its aryl rings produced a 2.5:1 ratio of
regioisomers favoring the more hindered ortho isomer
6f [Eq. (1)]. The level and direction of regioselectivity
is consistent with addition of a carbon radical to the
arene (e.g., path b, Scheme 1)[6b,c,8] as electrophilic ar-
omatic substitution would be expected to favor the
less hindered para product 6g.[9]
The absolute configuration of 3b was confirmed by
its X-ray structure (Figure 1) and all other enantioen-
riched products were assigned by analogy to 3b.
We next examined the desymmeterization reactions the (R,R)-Ph-Box ligand gave 11a in 30% yield with
of bis(2-allyl) substrates 10a and 10b (Scheme 2). The a disappointing 35% ee (not shown), thus we turned
use of our standard conditions (Table 1, entry 3) with to the (4R,5S)-cis-diphenylbis(oxazoline) ligand,
ACHTUNGTRENNUNG
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The proposed catalytic cycle is given in Scheme 3.
The stereoselectivity of the reaction is achieved in the
cis-aminocupration step, where the the phenyl rings
on the chiral ligand are “trans” to the substrateꢁs
mesyl and alkene groups to avoid steric interaction.[11]
The resulting organocopper(II) intermediate under-
goes homolysis to form a primary carbon radical
which adds across the pyrrolidine ring to the aryl
group it is cis to. Oxidation of the resulting aryl radi-
cal under the reaction conditions provides the azabi-
cyclic product 3. It should be noted that analogous
transannular additions of carbon radicals to alkenes
have been reported,[12] but transannular radical addi-
tions to arenes are more rare.[8b,13]
In conclusion, the copper(II)-catalyzed enantiose-
lective alkene carboamination reaction is an efficient
method to prepare a variety of chiral 6-azabicyclo-
AHCTUNGTREG[NNNU 3.2.1]octanes. Further investigations into the scope
and utility of this method for its application in organic
synthesis will be reported in due course.
Experimental Section
For experimental details and spectral data for all new com-
pounds, see the Supporting Information.
Figure 1. X-ray crystal structure of 3b (CCDC 991873 con-
tains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via Representative Procedure for the Enantioselective
www.ccdc.cam.ac.uk/data_request/cif).
Carboamination: (1S,4R)-3-(Methylsulfonyl)-1-
phenyl-2,3,4,5-tetrahydro-1H-1,4-methanobenzo[d]-
azepine (3b)
CuACTHUNTRGENNG(U OTf)2 (8.5 mg, 0.024 mmol, 15 mol%), (R,R)-Ph-Box
(10.0 mg, 0.030 mmol, 19 mol%) and dry PhCF3 (0.8 mL)
were placed in a flame-dried glass reaction tube under
argon. The tube was capped and the reaction heated at
608C for 2 h. After cooling, sulfonamide 1b (50.0 mg,
0.158 mmol), K2CO3 (21.8 mg, 0.158 mmol, 1 equiv.), MnO2
(41.1 mg, 0.473 mmol, 3 equiv.) and PhCF3 (0.8 mL) were
added. Flame-dried molecular sieves (4ꢀ, 35 mg) were
added to the reaction mixture, the tube was flushed with
argon, capped and the mixture was heated at 1108C for
12 h. Upon cooling, the mixture was diluted with EtOAc
and filtered through a pad of silica gel. The filtrate was con-
centrated under vacuum and the crude residue was purified
by flash chromatography on silica gel, providing 6-
Scheme 2. Desymmetrization reactions.
azabicycloACHTGNUTREN[NUNG 3.2.1]octane 3b as a white solid; yield: 38 mg
(76%).
which has demonstrated superior enantioselectivity in
challenging cases in copper catalysis.[10] Encouraging-
ly, 11a was formed in 39% yield and 80% ee using
this ligand. We were also able to achieve enantiose-
lective desymmeterization using the bis(2-methylallyl)
substrate 10b, which gave 11b in 40% yield, with 92%
ee. The reduced yield in these reactions is likely due
to the additional demand for diastereoselectivity in
Compound 3b was further purified via HPLC and found
to be in 95% enantiomeric excess as determined by analysis
on chiral HPLC [Chiralpak AD-RH, 50% CH3CN/H2O,
0.5 mLminÀ1]:
tACTHNGUTREN(UNG minor)=15.93 min, tACHTUNGTREN(NUNG major)=18.63 min],
[a]23: À88.38 (c 0.6, CHCl3); mp 209–2118C; 1H NMR
(30D0 MHz, CDCl3): d=7.45–7.28 (m, 5H), 7.16–7.13 (m,
2H), 7.01–6.95 (m, 1H), 6.53 (d, J=8.4 Hz, 1H), 4.58–4.54
(m, 1H), 3.88 (ABq, JAB =9.0 Hz, dn=17.0 Hz, 2H), 3.30 (d,
J=17.1 Hz, 1H), 3.18 (dd, J=17.1, 2.4 Hz, 1H), 2.80 (s,
3H), 2.61 (d, J=11.1 Hz, 1H), 2.30 (ddd, J=12.0, 5.8,
1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=143.8, 142.2,
132.7, 129.5, 127.6, 127.3, 126.8, 126.2, 61.0, 57.0, 51.3, 40.6,
À
the N C bond forming step, although we were unable
to isolate and identify minor products from these re-
actions.
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6-AzabicycloACTHNUTRGNEUG[N 3.2.1]octanes via Copper-Catalyzed Enantioselective
Scheme 3. Proposed catalytic cycle.
38.5, 36.5; IR (neat, thin film): n=3061, 3031, 2955, 2868,
1485, 1450, 1331, 1157, 1061 cmÀ1; HR-MS (ESI): m/z=
314.1219, calcd. for C18H19NO2S [M+H]+: 314.1209.
[4] a) J. H. Rigby, F. C. Pigge, Synlett 1996, 631; b) J. H.
Rigby, F. C. Pigge, Tetrahedron Lett. 1996, 37, 2201;
c) G. Han, M. G. LaPorte, J. J. Folmer, K. M. Werner,
S. M. Weinreb, J. Org. Chem. 2000, 65, 6293; d) O.
Tamaru, T. Yanagiamachi, T. Kobayashi, H. Ishibashi,
Org. Lett. 2001, 3, 2427; e) H. Zhai, S. Lou, C. Ye, Y.
Ma, J. Org. Chem. 2003, 68, 8268; f) X. Yang, H. Zhai,
Z. Li, Org. Lett. 2008, 10, 2457; g) J. R. Fuchs, R. L.
Funk, Org. Lett. 2001, 3, 3923; h) D. N. Mai, B. R.
Rosen, J. P. Wolfe, Org. Lett. 2011, 13, 2932; i) M. Med-
jahdi, J. C. Gonzalez-Gomez, F. Foubelo, M. Yus, Eur.
J. Org. Chem. 2011, 12, 2230.
[5] a) T. de Haro, C. Nevado, Angew. Chem. 2011, 123,
936; Angew. Chem. Int. Ed. 2011, 50, 906; b) D. M.
Schultz, J. P. Wolfe, Org. Lett. 2011, 13, 2962; c) A.
Kong, S. B. Blakey, Synthesis 2012, 44, 1190; d) Q. Li,
X. Jiang, C. Fu, S. Ma, Org. Lett. 2011, 13, 466. For re-
lated synthesis of [3.3.1]azabicycles using asymmetric
catalysis, see: e) B. Bradshaw, C. Parra, J. Bonjoch,
Org. Lett. 2013, 15, 2458; f) F. Diaba, J. Bonjoch, Org.
Biomol. Chem. 2009, 7, 2517.
Acknowledgements
The National Institute of General Medical Science
(GM078383) is gratefully acknowledged for support of this
research. We thank Dr. William W. Brennessel and the X-ray
Crystallographic Facility at the University of Rochester for
the X-ray structure of 3b. We thank Timothy W. Liwosz and
Michael T. Bovino for the synthesis of bis(oxazoline) ligands
as well as Nicole E. Kendal for the preparation of some race-
mic products.
References
[6] a) W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007,
129, 12948; b) L. Miao, I. Haque, M. R. Manzoni, W. S.
Tham, S. R. Chemler, Org. Lett. 2010, 12, 4739; c) E. S.
Sherman, P. H. Fuller, D. Kasi, S. R. Chemler, J. Org.
Chem. 2007, 72, 3896.
[7] T. W. Liwosz, S. R. Chemler, J. Am. Chem. Soc. 2012,
134, 2020.
[8] a) S. R. Conrad, J. Kong, B. N. Laforteza, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2009, 131, 11640; b) Y.
Miller, L. Miao, A. S. Hosseini, S. R. Chemler, J. Am.
Chem. Soc. 2012, 134, 12149.
[1] Synthetic methods for bridged-ring compounds: a) W.
Zhao, Chem. Rev. 2010, 110, 1706; b) J. Bonjoch, F.
Diaba, B. Bradshaw, Synthesis 2011, 993.
[2] a) S. Singh, Chem. Rev. 2000, 100, 925; b) N. Gulavita,
A. Hori, Y. Shimizu, P. Laszlo, J. Clardy, Tetrahedron
Lett. 1988, 29, 4381; c) J. A. Beutler, E. W. Karbon,
A. N. Malik, D. R. Curtis, J. J. Enna, Brain Res. 1985,
330, 135.
[3] a) P. Abraham, J. B. Pinter, A. H. Lewin, J. W. Boja,
M. J. Kuhar, F. I. Carroll, J. Med. Chem. 1992, 35, 141;
b) M. Takeda, H. Inoue, K. Noguchi, Y. Honma, M.
Kawamori, G. Tsukamoto, Y. Yamawaki, S. Saito, K.
Aoe, T. Date, S. Nurimoto, G. Hayashi, J. Med. Chem.
1977, 20, 221.
[9] K.-T. Yip, D. Yang, Org. Lett. 2011, 13, 2134.
[10] a) F. C. Sequeira, M. T. Bovino, A. J. Chipre, S. R.
Chemler, Synthesis 2012, 44, 1481; b) M. T. Bovino,
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ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. R. Chemler, Angew. Chem. 2012, 124, 3989; Angew.
Chem. Int. Ed. 2012, 51, 3923.
[11] The pro-S and pro-R transition states for similar reac-
tions have been modeled with density functional theory
calculations: L. Belding, S. R. Chemler, T. Dudding, J.
Org. Chem. 2013, 78, 10288.
[12] These methods also form azabicyclic products: a) M.-L.
Bennasar, T. Roca, D. Garcia-Diaz, J. Org. Chem. 2008,
73, 9033; b) J. Quirante, X. Vila, C. Escolano, J. Bon-
joch, J. Org. Chem. 2002, 67, 2323.
[13] Transannular addition to arene: S. L. Kostiuk, T. Wood-
cock, L. F. Dudin, P. D. Howes, D. C. Harrowven,
Chem. Eur. J. 2011, 17, 10906.
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6-Azabicyclo
G
7
Enantioselective Alkene Carboamination
Adv. Synth. Catal. 2014, 356, 1 – 7
Barbara J. Casavant, Azade S. Hosseini, Sherry R. Chemler*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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