Stereoselective copper-catalyzed intramolecular alkene aminooxygenation: Effects of substrate and ligand structure on selectivity

Article abstract of DOI:10.1002/ejoc.201100444

A new protocol for diastereoselective copper-catalyzed intramolecular alkene aminooxygenation, which provides methyleneoxy-functionalized disubstituted pyrrolidines and five-membered cyclic ureas from the corresponding γ-alkenylsulfonamides and N-allylure

Full text of DOI:10.1002/ejoc.201100444

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100444
Stereoselective Copper-Catalyzed Intramolecular Alkene Aminooxygenation:
Effects of Substrate and Ligand Structure on Selectivity
Monissa C. Paderes[a] and Sherry R. Chemler*[a]
Keywords: Copper / Alkenes / Aminooxygenation / Pyrrolidine / Cyclic urea
A new protocol for diastereoselective copper-catalyzed intra-
molecular alkene aminooxygenation, which provides meth-
yleneoxy-functionalized disubstituted pyrrolidines and five-
membered cyclic ureas from the corresponding γ-alkenyl
sulfonamides and N-allylureas, is reported. In addition, some
success was achieved in enantioselective desymmetrizations
reactions. We discovered that the level of enantioselectivity
and diastereoselectivity could be tuned by choice of cop-
per(II) ligands and substrate N-substituent.
Introduction
Recent advances in metal-catalyzed intramolecular
amino functionalization of unactivated alkenes (carbo-
amination,[1] diamination,[2] aminooxygenation,[3] amino-
halogenation[4]) have rendered these reactions practical syn-
thetic strategies for the efficient, straightforward and stereo-
selective synthesis of nitrogen hetereocycles.[5] Metals that
catalyze these processes include Au, Pd, Os, Ni and Cu,
with Cu being the least expensive and one of the most ver-
satile.[1–5] We recently reported a diastereoselective cop-
per(II)-promoted intramolecular alkene aminooxygenation
protocol that provides 2,5-disubstituted pyrrolidines in high
yields and high levels of diastereoselectivity and 2,3-disub-
stituted pyrrolidines in high yield and moderate selectivity
(Scheme 1).[6] These reactions are thought to involve carbon
radical intermediates and use (2,2,6,6-tetramethylpiperidin-
1-yl)oxyl radical (TEMPO) as the oxygen atom source. The
resulting TEMPO adducts (Scheme 1) can be converted
into the corresponding synthetically useful alcohol or alde-
hyde intermediates.[3a,6] While this copper-promoted proto-
col, which uses commercially available copper(2-ethylhex-
Scheme 1. Copper-promoted and copper-catalyzed intramolecular
alkene aminooxygenation reactions. EH = 2-ethylhexanoate, R =
2,2,6,6-tetramethylpiperidinyl.
During substrate and catalyst screening (vide infra), we
found that we could further optimize the diastereoselectiv-
ity of the reactions with choice of ligand and N-substituent
(e.g., Scheme 1). We have also investigated enantioselective
desymmetrization reactions, and we have expanded the
scope of the alkene aminooxygenation reaction to include
N-allylurea substrates (vide infra).
Results and Discussion
Catalytic reaction conditions were screened with meso-
anoate)2 (1.5 equiv.), is operationally simple and high-yield- sulfonamide 1a (Table 1). When 1a was subjected to cata-
ing, we sought an environmentally more benign method lytic amounts of Cu(OTf)2 (20 mol-%) complexed with 2,2-
that would use copper in catalytic rather than stoichiomet- bis[(4R)-4-phenyl-2-oxazolin-2-yl]propane
[(R)-Ph-box,
ric quantities. Herein is reported the successful development 25 mol-%] in the presence of TEMPO (300 mol-%) and O2
of a high-yielding copper-catalyzed diastereoselective alk- (1 atm, balloon) in PhCF3 at 120 °C for 24 h, 83% of 2,5-
ene aminooxygenation method that uses O2 (1 atm) as the cis-pyrrolidine 2a (dr Ͼ 20:1) was obtained (Entry 1,
stoichiometric oxidant.
Table 1). Unfortunately, enantioselective desymmetrization
with this meso substrate was not achieved (Ͻ 5% ee). Since
achieving a catalytic diastereoselective process was still a
worthy goal, we simplified the ligand by removing its
phenyl substituents.[1a] Reaction with the resulting complex
of Cu(OTf)2 (20 mol-%) and the unsubstituted bis(oxa-
zoline) ligand 3 (25 mol-%) resulted in good yield (77%,
Entry 2, Table 1) but occurred with a surprising reduction
[a] Department of Chemistry, The State University of New York
at Buffalo,
Buffalo, New York 14260-3000, USA
Fax: +1-716-645-6963
E-mail: schemler@buffalo.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100444.
Eur. J. Org. Chem. 2011, 3679–3684
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M. C. Paderes, S. R. Chemler
SHORT COMMUNICATION
Table 1. Catalytic reaction optimization.[a]
Entry
Ligand or catalyst
Solvent
Temp. [°C]
Yield [%][b]
dr (cis/trans)[c]
1
2
3
4
5
(R)-Ph-box
CF3Ph
CF3Ph
CF3Ph
xylenes
xylenes
xylenes
xylenes
120
120
120
130
120
110
120
83
77
Ͼ20:1[d]
4:1
14:1
3
4
8[e]
4
20[e]
90
14:1
Cu(EH)2
Cu(EH)2
Cu(EH)2
Ͼ20:1
Ͼ20:1
Ͼ20:1
6
65[e]
56[e]
7[f]
[a] All reactions were run under O2 (1 atm) at 0.1 m with respect to 1a. [b] Yield refers to amount of product isolated after purification
by flash chromatography on silica gel. [c] Diastereomeric ratio was determined by analysis of the crude 1H NMR spectrum. [d] 2a,
Ͻ 5% ee. [e] The remainder of the material is the starting olefin 1a. [f] The reaction was run by using 10 mol-% Cu(EH)2; EH =
2-ethylhexanoate, OTf = trifluoromethanesulfonyl.
in diastereoselectivity (dr = 4:1). Reaction with the complex The optimized catalytic conditions (Entry 5, Table 1) pro-
of Cu(OTf)2 and 4,4,4Ј,4Ј-tetramethylbis(oxazoline) 4 re- vide 2a in comparable yield and diastereoselectivity as our
sulted in increased diastereoselectivity (dr = 14:1) but sub- previously reported[6] conditions with the same substrate
stantial reduction in yield (Entry 3, Table 1). Increasing the that use stoichiometric amounts (1.5 equiv.) of Cu(EH)2
temperature provided only a slight increase in yield (En- promoter.
try 4, Table 1). This marginal success with bis(oxazoline) li-
We performed the Cu(EH)2-catalyzed aminooxygenation
gands led us to re-investigate the use of Cu(2-ethylhex- reaction on a variety of α-substituted 4-pentenylsulfon-
anoate)2, but in catalytic quantity (20 mol-%). Gratifyingly, amides (Table 2), and uniformly high yields and diastereo-
under such catalytic conditions (with 1 atm O2) we were selectivities were observed. The 2,5-cis diastereomer is
delighted to obtain both high yield and high diastereoselec- highly favored for substrates where the R1 and R2 substitu-
tivity at 120 °C (90% yield, dr Ͼ 20:1, Entry 5, Table 1). ents are not tethered directly to one another (Entries 1–8,
Further reduction in catalyst loading or reaction tempera- Table 2). In contrast, upon tethering the two substituents in
ture resulted in decreased yield (Entries 6 and 7, Table 1). a ring, the 2,5-trans-pyrrolidine was favored (Entry 9,
Table 2. Scope of the diastereoselective intramolecular aminooxygenation of α-substituted 4-pentenyl sulfonamides;[a] Ns = 4-nitro-
benzenesulfonyl, PMBS = p-methoxybenzenesulfonyl.
[a] Refer to Table 1, Entry 5 for reaction conditions. [b] Yield refers to amount of product isolated after purification by column chromatog-
raphy on SiO2. Diastereomeric ratio was determined by analysis of the crude 1H NMR spectrum. [c] Reaction was run at 130 °C. [d]
1.5 equiv. of TEMPO was used.
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Stereoselective Aminooxygenation
Table 2). The relative placement of these two groups in the
aminocupration cyclization transition state is proposed to
account for the difference in diastereoselectivity of the two
substrate types.[6]
The meso substrate 1i functionalized with the bulky 3,5-
di-tert-butylphenylsulfonyl group also gave 2i in Ͻ 5% ee
in an attempted enantioselective desymmetrization reaction
with the Cu(OTf)2·(R)-Ph-box catalyst (reaction not
shown).
The proposed catalytic cycle is illustrated in Scheme 2.
Upon copper(II) complexation, the resulting N–Cu inter-
mediate undergoes syn aminocupration through transition
state A or B to generate the 2,5-cis-pyrrolidine. In these
transition states, interaction between the adjacent SO2Ar
and R groups are minimized. The resulting organocop-
per(II) species readily undergoes C–Cu homolysis to form
the primary radical, which is rapidly trapped with TEMPO.
The CuI complex is re-oxidized by TEMPO in the presence
of O2, thereby regenerating the CuII catalyst.
Scheme 2. Proposed alkene aminooxygenation catalytic cycle.
We next investigated the catalytic diastereoselective reac- diastereoselectivities. We also observed an increase in dia-
tions of β- and γ-monosubstituted 4-pentenylsulfonamides stereoselectivity in changing the N-substituent from tosyl to
(Table 3). Under conditions A, Cu(EH)2 (20 mol-%), was 3,5-di-tert-butylphenylsulfonyl (compare Entry 6 to 10 and
used as the catalyst. Under conditions B, Cu(OTf)2 (20 mol- Entry 16 to 18, Table 3).
%) complexed to bis(oxazoline) 3 (25 mol-%) was used as
We reinvestigated the possibility of a catalytic enantiose-
the catalyst. The trans diastereomers of the 2,3-disubsti- lective desymmetrization reaction with the meso-β-allyl-4-
tuted pyrrolidines 6 were formed as the major products pentenylsulfonamides 7b and 7c (Scheme 3). In this case,
from γ-substituted 4-pentenylsulfonamides 5, and the cis although the diastereoselectivity was modest (2–2.5:1),
diastereomers of the 2,4-disubstituted pyrrolidines 8 were enantioselective desymmetrization was achieved. Notably,
formed as the major products from β-substituted 4-penten- the N-(3,5-di-tert-butylphenylsulfonyl)-2,4-cis-pyrrolidine
ylsulfonamides 7. In all cases, conditions B gave superior 8c was produced in 98% ee. When compared to the 75% ee
Table 3. Diastereoselective aminooxygenation of β- and γ-substituted 4-pentenylsulfonamides; R3 = 2,2,6,6-tetramethylpiperidine.
[a] Reaction conditions: A: Cu(EH)2 (20 mol-%), O2 (1 atm, balloon), K2CO3 (1 equiv.), TEMPO (3 equiv.), xylenes, 120 °C, 24 h. B:
Cu(OTf)2 (20 mol-%), bis(oxazoline) 3 (25 mol-%), K2CO3 (1 equiv.), TEMPO (300 mol-%), CF3Ph, O2 (1 atm, balloon), 120 °C (oil-bath
temp.), 24 h. [b] Yield refers to the sum of the products isolated by chromatography on SiO2. [c] Diastereomeric ratio was determined by
1
analysis of the crude H NMR spectrum.
Eur. J. Org. Chem. 2011, 3679–3684
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M. C. Paderes, S. R. Chemler
SHORT COMMUNICATION
Scheme 3. Catalytic enantioselective desymmetrization.
Table 4. Diastereoselectivity in the formation of 4,5-disubstituted cyclic ureas.
[a] Reaction conditions: A: Cu(EH)2 (20 mol-%), K2CO3, TEMPO (3 equiv.), xylenes, O2 (1 atm, balloon), 120 °C, 24 h. B: Cu(OTf)2
(20 mol-%), bis(oxazoline) 3 (25 mol-%), K2CO3, TEMPO (300 mol-%), CF3Ph, O2 (1 atm), 120 °C (oil-bath temp.), 24 h. [b] Yield refers
to the sum of the products isolated by chromatography on SiO2. [c] Diastereomeric ratio was determined by analysis of the crude 1H
NMR spectrum.
obtained for N-tosylpyrrolidine 8b (Scheme 3), it is clear
that the N-sulfonyl group strongly influences the level of
Conclusions
enantioselectivity in this reaction. The 3,5-di-tert-butyl-
We have developed an intramolecular catalytic diastereo-
phenylsulfonyl group is not commonly used, but in this re- selective aminooxygenation protocol for unactivated alk-
action (Scheme 3) it provides the right degree of steric hin- enes. The reaction of α-substituted 4-pentenylsulfonamides
drance to increase reaction selectivity without interfering 1 with catalytic Cu(EH)2 under O2 affords 2,5-cis- and 2,5-
with substrate reactivity. In contrast, we have observed that trans-pyrrolidines 2 in good to excellent yields and Ͼ 20:1
the more commonly used sterically demanding 2,4,6-tri- selectivity. In contrast, β- and γ-substituted 4-pentenyl-
methylphenylsulfonyl (mesityl) moiety shuts down reactiv- sulfonamides 5 and 7 gave higher diastereoselectivities with
ity completely in our copper-catalyzed reactions (not the use of a Cu(OTf)2·bis(oxazoline) catalyst. The reaction
shown). The stereoselective formation of 8c is rationalized of substituted N-allylureas 9 uniformly provided high 4,5-
by the chair-like transition state C, which places the allyl trans selectivity irrespective of the ligands on the copper
substituent in a pseudo-equatorial position where the N- atom. The size of the N-substituent also influenced the level
substituent adopts a position anti to the closest bis(ox- of diastereoselectivity with some substrates. Catalytic enan-
azoline) substituent. The minor 3,4-trans diastereomer is tioselective desymmetrization was investigated with meso-
formed with lower enantioselectivity. It is possible that a α- and -β-substituted 4-pentenylsulfonamides. While the α-
less selective boat-like transition state accounts for the substituted sulfonamides 1a and 1i gave no enantio-
lower enantioselectivity in this case.
selectivity, enantioselective desymmetrization was achieved
Lastly, the catalytic, diastereoselective aminooxygena- (up to 98% ee) with β-allyl-4-pentenylsulfonamide 7c. The
tions of N-allylureas 9 were investigated. These substrates origin of enantioselectivity is best rationalized by invoking
provided the corresponding 4,5-trans-disubstituted cyclic chair-like transition states such as C (Scheme 3). It is pos-
ureas 10 in uniformly high diastereoselectivities with both sible that the participation of a boat-like transition state
Cu(EH)2 and Cu(OTf)2·bis(oxazoline) catalysts (Table 4).
(e.g. B) is responsible for the poor enantioselectivity ob-
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Stereoselective Aminooxygenation
(s, 3 H), 1.08 (s, 3 H), 1.00 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.1, 139.6, 136.7, 128.5, 128.3, 126.6, 126.1, 121.7,
78.8, 63.4, 59.8, 47.8, 43.4, 39.5, 39.1, 35.1, 33.1, 33.0, 31.3, 29.1,
served in reactions with the meso substrate 1a (e.g. Table 1,
Entry 1). Transition state C (substrate 7c) may be more
favorable than transition state A (substrate 1a) since the α-
substituent in TS A is in an axial position. We are currently
investigating this further with molecular modeling calcula-
tions.
20.3, 20.1, 17.0 ppm. IR (neat, thin film): ν = 2965, 2870, 1599,
˜
1475, 1348, 1160, 1137, 1116, 1049, 757, 701 cm–1. HRMS (ESI)
calcd. for C35H55O3N2S [M + H]+ 583.3928; found 583.3941.
Minor Pyrrolidine (؎)-cis-6e was obtained as a clear, colorless oil:
1H NMR (500 MHz): δ = 1.95 (m, 1 H), 1.82 (m, 1 H), 1.64 (m, 1
H), 1.46–1.49 (m, 6 H), 1.35 (s, 18 H), 1.33 (s, 3 H), 1.26 (s, 3 H),
1.16 (s, 3 H), 1.11 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
151.9, 140.5, 137.0, 128.4, 128.3, 126.5, 126.0, 121.4, 77.8, 62.0,
60.1, 59.6, 47.5, 43.7, 39.8, 35.5, 35.0, 33.4, 32.8, 31.2, 30.3, 20.4,
Experimental Section
Representative Procedures for Catalytic Diastereoselective Amino-
oxygenation of Alkenes
17.0 ppm. IR (neat, thin film): ν = 2964, 2366, 1599, 1454, 1348,
˜
1-{[(2S,5S)-5-Methyl-1-tosylpyrrolidin-2-yl]methoxy}-2,2,6,6-tetra-
methylpiperidine (2c): Table 2, Entry 2. Sulfonamide 1c (40 mg,
0.158 mmol, 1 equiv.), Cu(EH)2 (11 mg, 0.032 mmol, 0.2 equiv.),
TEMPO (74 mg, 0.474 mmol, 3 equiv.), K2 CO3 (22 mg,
0.158 mmol, 1 equiv.) and xylenes (1.6 mL) were combined in a
100 mL round-bottom flask equipped with a magnetic stir bar. The
flask was fitted with a glass side-arm adapter tapered to connect
to a short rubber vacuum hose, through which O2 (balloon) was
introduced. The reaction mixture was heated to 120 °C and stirred
for 24 h. The cooled solution was filtered through an SiO2 plug,
with Et2O washing. Concentration in vacuo and flash chromatog-
raphy on SiO2 (5% EtOAc in hexanes) afforded disubstituted pyr-
rolidine 2c (61 mg, 94%) as a white solid. The diastereoselectivity
1246, 1166, 1030, 751, 701 cm–1. HRMS (ESI) calcd. for [M +
H]+ C35H55O3N2S: 583.3928; found 583.3938.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details and spectroscopic data for all
new compounds.
Acknowledgments
We gratefully acknowledge the National Institutes of Health,
NIGMS (GM078383) for financial support of this project.
1
[1] Representative recent metal-catalyzed intramolecular carbo-
aminations: Cu-catalyzed: a) L. Miao, I. Haque, M. R. Man-
zoni, W. S. Tham, S. R. Chemler, Org. Lett. 2010, 12, 4739–
4741; b) W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007, 129,
12948–12949; Pd-catalyzed: c) D. N. Mai, J. P. Wolfe, J. Am.
Chem. Soc. 2010, 132, 12157–12159; d) W. He, K. T. Yip, N. Y.
Zhu, D. Yang, Org. Lett. 2009, 11, 5626–5628; Au-catalyzed:
e) G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc.
2010, 132, 1474–1475; f) W. E. Brenzovich Jr., D. Benitez, A. D.
Lackner, H. P. Shunatona, E. Tkatchouk, W. A. Goddard III,
F. D. Toste, Angew. Chem. Int. Ed. 2010, 49, 5519–5522; g) T.
de Haro, C. Nevado, Angew. Chem. Int. Ed. 2011, 50, 906–910.
[2] Representative metal-catalyzed intramolecular alkene diamin-
ations: Cu-catalyzed: a) F. C. Sequeira, B. W. Turnpenny, S. R.
Chemler, Angew. Chem. Int. Ed. 2010, 49, 6365–6368; Pd-cata-
lyzed: b) J. Streuff, C. H. Hovelmann, M. Nieger, K. Muniz, J.
Am. Chem. Soc. 2005, 127, 14586–14587; c) P. A. Sibbald, F. E.
Michael, Org. Lett. 2009, 11, 1147–1149; Ni-catalyzed d) K.
Muniz, J. Streuff, C. H. Hoevelmann, A. Nunez, Angew. Chem.
2007, 119, 7255; Angew. Chem. Int. Ed. 2007, 46, 7125–7127;
Au-catalyzed: e) A. Iglesias, K. Muniz, Chem. Eur. J. 2009, 15,
10563–10569.
[3] Representative metal-catalyzed intramolecular aminooxygen-
ations: Cu-catalyzed: a) P. H. Fuller, J. W. Kim, S. R. Chemler,
J. Am. Chem. Soc. 2008, 130, 17638–17639; b) E. S. Sherman,
S. R. Chemler, Adv. Synth. Catal. 2009, 351, 467–471; c) D. E.
Mancheno, A. R. Thornton, A. H. Stoll, A. D. Kong, S. B.
Blakey, Org. Lett. 2010, 12, 4110–4113; Pd-catalyzed: d) E. J.
Alexanian, C. Lee, E. J. Sorensen, J. Am. Chem. Soc. 2005, 127,
7690–7691; e) L. V. Desai, M. S. Sanford, Angew. Chem. 2007,
119, 5839; Angew. Chem. Int. Ed. 2007, 46, 5737–5740; f) P.
Szolcsanyi, T. Gracza, Chem. Commun. 2005, 3948–3950; g)
D. V. Liskin, P. A. Sibbald, C. F. Rosewall, F. E. Michael, J.
Org. Chem. 2010, 75, 6294–6296; Os-catalyzed: h) T. J. Don-
ahoe, G. H. Churchill, K. M. P. Wheelhouse, P. A. Glossop,
Angew. Chem. 2006, 118, 8193; Angew. Chem. Int. Ed. 2006,
45, 8025–8028.
(Ͼ 20:1) was determined from the crude H NMR spectrum. The
cis stereochemistry of 2c was assigned by NOE experiments. Data
for cis-2c: M.p. 121–125 °C. [α]2D0 = –63.9° (c = 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.29 (d,
J = 8.0 Hz, 2 H), 3.90 (dd, J = 9.0, 3.5 Hz, 1 H), 3.84 (t, J = 8.0 Hz,
1 H), 3.72 (m, 1 H), 3.62 (m, 1 H), 2.41 (s, 3 H), 1.91 (m, 1 H),
1.67–1.55 (m, 3 H), 1.50–1.43 (m, 6 H), 1.36 (d, J = 6.0 Hz, 3 H),
1.18 (s, 3 H), 1.16 (s, 3 H), 1.09 (s, 3 H), 1.08 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 143.1, 135.0, 129.5, 127.6, 78.6, 60.0,
57.4, 39.6, 32.9, 32.5, 27.3, 22.8, 21.4, 20.2, 17.0 ppm. IR (neat,
thin film): ν = 2976, 2931, 2877, 1591, 1460, 1351, 1261, 1211,
˜
1161, 1098, 1052, 957, 812, 663 cm–1. HRMS (ESI): calcd. for
C22H37N2O3S [M + H]+ 409.2519; found 409.2522.
(؎)-cis- and (؎)-trans-{3-Benzyl-1-[(3,5-di-tert-butylphenylsulfonyl)-
pyrrolidin-2-yl]methoxy}-2,2,6,6-tetramethylpiperidine (cis-6e and
trans-6e): Table 3, Entry 10. Cu(OTf)2 (7.0 mg, 0.019 mmol,
0.2 equiv.) and bis(oxazoline) 3 (4.3 mg, 0.024 mmol, 0.25 equiv.)
were allowed to complex in CF3Ph (0.7 mL) in a 100 mL round-
bottomed flask at 60 °C for 2 h. The heat was removed, and the
resulting room-temperature solution was treated with TEMPO
(44 mg, 0.282 mmol, 3 equiv.), K2CO3 (13 mg, 0.094 mmol,
1 equiv.) and a solution of sulfonamide 5e (40 mg, 0.094 mmol,
1 equiv.) in CF3Ph (0.3 mL). The reaction mixture was heated to
120 °C (oil-bath temp.) under O2 (1 atm, balloon, see above) for
24 h. Filtration of the cooled solution through an SiO2 plug
(washed with Et2O) and removal of the solvent in vacuo afforded
the crude product. Purification by flash chromatography on SiO2
(5% EtOAc in hexanes) gave a 14:1 trans/cis mixture of pyrrolidines
6e (46 mg, 83% yield). The diastereomers were further separated
by HPLC (5% EtOAc in hexanes); (Ϯ)-cis-6e eluted first.
Major Pyrrolidine (؎)-trans-6e was obtained as a clear, colorless
1
oil. H NMR (500 MHz, CDCl3): δ = 7.72 (s, 2 H), 7.67 (s, 1 H),
7.19 (t, J = 7.0 Hz, 2 H), 7.13 (t, J = 7.5 Hz, 1 H), 6.83 (d, J =
7.5 Hz), 3.96 (dd, J = 9.0, 3.5 Hz, 1 H), 3.84 (dd, J = 9.5, 8.0 Hz,
1 H), 3.46 (m, 1 H), 3.36 (m, 2 H) 2.49 (m, 1 H), 2.29 (dd, J =
14.0, 7.0 Hz, 1 H), 1.89 (m, 1 H), 1.76 (dd, J = 13.5, 8.5 Hz, 1 H),
1.40–1.49 (m, 6 H), 1.36 (s, 18 H), 1.27 (m, 1 H), 1.18 (s, 3 H), 1.15
[4] Recent metal-catalyzed intramolecular aminohalogenations:
Pd-catalyzed: a) M. R. Manzoni, T. P. Zabawa, D. Kasi, S. R.
Chemler, Organometallics 2004, 23, 5618–5621; b) A. W. Lei,
X. Y. Lu, G. S. Liu, Tetrahedron Lett. 2004, 45, 1785–1788; c)
F. E. Michael, P. A. Sibbald, B. M. Cochran, Org. Lett. 2008,
Eur. J. Org. Chem. 2011, 3679–3684
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10, 793–796; T. Wu, G. Yin, G. Liu, J. Am. Chem. Soc. 2009,
131, 16354–16355.
[5] Reviews: a) S. R. Chemler, J. Organomet. Chem. 2011, 696,
150–158; b) S. R. Chemler, Org. Biomol. Chem. 2009, 7, 3009–
3019; c) J. P. Wolfe, Synlett 2008, 2913–2937; d) A. Minatti, K.
Muniz, Chem. Soc. Rev. 2007, 36, 1142–1152; e) V. Kotov, C. C.
Scarborough, S. S. Stahl, Inorg. Chem. 2007, 46, 1910–1923; f)
T. J. Donohoe, C. K. A. Callens, A. Flores, A. R. Lacy, A. H.
Rathi, Chem. Eur. J. 2011, 17, 58–76; g) G. G. Li, S. R. S. S.
Kotti, C. Timmons, Eur. J. Org. Chem. 2007, 2745–2758.
M. C. Paderes, S. R. Chemler, Org. Lett. 2009, 11, 1915–1918.
Received: March 30, 2011
[6]
Published Online: May 10, 2011
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Eur. J. Org. Chem. 2011, 3679–3684