Angewandte
Chemie
Table 2: Rhodium-catalyzed enantioselective intramolecular hydroami-
yield but with poor ee values (Table 1, entries 2 and 4).
Control experiments in which the metal was omitted or
replaced by a protic acid resulted in no product formation. No
improvement in yield or enantioselectivity was seen if
alternative Rh sources were employed (see the Supporting
Information).
nation of aminoalkenes.[a]
Entry Alkenyl amine
Product
T
t
Yield
ee
[8C] [h] [%][b]
[%][c]
We next turned our attention to Mop [(R)-2-(diarylphos-
phino)-2’-methoxy-1,1’-binaphthalene][21] derivatives; the use
of Cy-Mop (L6),[22] afforded 1b in 96% yield with 53% ee
(Table 1, entry 6). Given this promising result, several Cy-
Mop-type ligands were prepared using a slight modification of
the literature procedure.[22] The selectivity of the hydro-
amination reaction improved with increasing size of the
oxygen substituent (Table 1, entries 6–8). We found that the
dialkylphosphino group was essential for high activity;
attempts to employ the diphenylphosphine L10 furnished
less than 10% yield of product (Table 1, entry 10). Among the
ligands evaluated, L9, having a (diphenyl)methyl-substituted
alkoxy group, provided the best combination of reactivity and
enantioselectivity, affording 1b in 95% yield and 80% ee
(Table 1, entry 9).
The scope of the reaction is summarized in Table 2.
Cyclization of substrates with geminal substitution in the
homoallylic position proved to be the most facile; these
reactions proceeded in the highest yields and with good
enantioselectivities. Typically these reactions could be carried
out at 708C with 5 mol% rhodium. However, for the easiest
substrates the reaction still proceeded at an acceptable rate at
508C, affording a slight increase in enantioselectivity (Table 2,
entries 2 and 5). In the case of substrates lacking substitution
that facilitate cyclization, the use of the less sterically
demanding ligand L8 was more efficient. By using a catalyst
system based on L8, these substrates could be cyclized with
comparable enantioselectivity, although in somewhat lower
yield (Table 2, entries 10–13). These results are some of the
best reported for the enantioselective cyclization of unbiased
substrates using a transition metal based catalyst.[5a,d] In the
case of racemic N-2-methylbenzyl-2-phenyl-4-pentenamine
(5a) no kinetic resolution was observed, and the diastereo-
meric products were obtained in a 1.1:1 ratio with high
enantiomeric excess (87% and 91% ee respectively; Table 2,
entry 8).
1
2
1a
1a
1b
1b
70 15 91
50 24 90
80 (S)
83 (S)
3
2a Ar=2-
CH3C6H4
2a
2b
70 15 92
84 (S)
4[d]
5
2b
2b
70 20 88
50 24 91
84 (S)
88 (S)
2a
6
7
3a Ar=2-
CH3C6H4
3b
4b
70 20 75
62 (S)
63 (S)
4a Ar=2-
CH3C6H4
70 20 80
87
(2S,4S)
5a Ar=2-
CH3C6H4
80
8
5b
70 20
(1.1:1)[e] 91
(2S,4R)
9[f]
6a Ar=C6H5
6b
7b
70 20 48
70 20 50
90 (S)
86 (S)
10[g] 7a Ar=2-
CH3C6H4
11[g] 8a Ar=4-ClC6H4 8b
70 20 63
70 30 35
85 (S)
85 (S)
12[g] 9a Ar=4-
MeOC6H4
9b
13[g] 10a Ar=4-
CO2MeC6H4
10b
70 20 61
83 (S)
The nature of the protecting group on the nitrogen atom
had a pronounced influence on the outcome of the reaction.
We found that N-(2-methyl)benzyl aminoolefins gave higher
enantioselectivity than N-benzyl aminoolefins in some cases,
without adversely effecting the yield (Table 2, entries 3–8).
Presumably the substituent at the 2-position results in a more
ordered transition state. Increasing the size of this substituent
or using a 2,6-dimethylbenzyl protecting group, however,
elicited a profound decrease in reactivity, perhaps as a result
of inhibition of metal binding. Varying the para substituent on
the aryl ring of the nitrogen atom protecting group had little
effect on the enantioselectivity, but electron-donating sub-
stituents retarded the reaction and resulted in a lower yield.[23]
Typically, unprotected aminoolefins exhibited poor reactivity,
however, 2-allylaniline did undergo hydroamination to yield
2-methylindoline with moderate enantioselectivity (Table 2,
entry 14).
14[h] 11a
11b
100 10 85
64 (S)
[a] Reaction conditions: alkenyl amine (0.5 mmol), [Rh(cod)2]BF4
(5 mol%), ligand L9 (6 mol%), dioxane (0.5 mL). [b] Yields of isolated
products (average of two runs). [c] The ee values were determined by
chiral HPLC, GC, or 1H NMR analysis of its derivatives. The absolute
configuration of 1b was determined by converting it into the known (S)-
MTPA amide. The configuration of 6b, 7b, 8b, 9b, and 10b were
determined by converting them into the known N-a-naphthyl amide. The
configuration of 11b was determined by converting it into the known N-
acetyl-2-methylindoline. See the Supporting Information for details. The
configurations of other amines were assigned by analogy. [d] 2.5 mol%
Rh and 3 mol% ligand L9. [e] Diastereomeric ratio given in parentheses.
[f] 10 mol% Rh and 12 mol% ligand L9. [g] 5 mol% Rh and 6 mol%
ligand L8. [h] Yield of isolated product following derivatization with
acetic anhydride.
Angew. Chem. Int. Ed. 2010, 49, 564 –567
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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