Rhodium-catalyzed asymmetric intramolecular hydroamination of unactivated alkenes

Article abstract of DOI:10.1002/anie.200905402

(Figure Presented) One for the Rh(oad): The first rhodiumcatalyzed asymmetric intramolecular hydroamination of unactivated olefins was developed by using dialkylbiaryl phosphine ligands (see scheme; cod = 1,5-cyclooctadiene, Cy = cyclohexyl). A variety of 2-methylpyrrolidines have been synthesized with high enantioselectivities.

Full text of DOI:10.1002/anie.200905402

Communications
DOI: 10.1002/anie.200905402
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination of
Unactivated Alkenes**
Xiaoqiang Shen and Stephen L. Buchwald*
Metal-catalyzed enantioselective intramolecular hydroami-
nation of olefins[1] is one of the most conceptually simple and
atom-economical approaches to the construction of enan-
tioenriched nitrogen heterocycles,[2] which are valuable syn-
thons in the preparation of natural products and biologically
active molecules.[3] Despite significant advances,[4–6] no gen-
eral solution for this challenging transformation has yet been
realized. Some of the most reactive catalysts are based on
lanthanides[5] and Group 4 transition metals,[6] but only a
small number of highly enantioselective (> 90% ee) reactions
have been described.[5a,6b,c] Noteworthy is the elegant report
by Schafer and co-workers[6c] on chiral zirconium amidate
complexes which provide good enantioselectivity for a range
of terminal alkenes, but require a geminal dialkyl group[7] to
bias the substrates toward cyclization. Furthermore, the
sensitivity of rare-earth and Group 4 metal catalysts toward
air and moisture, and their low functional group tolerance,
have limited their synthetic utility and motivated efforts to
develop alternative systems. Some late-transition-metal com-
plexes have been investigated for enantioselective hydro-
amination, with good results for alkynes,[8] allenes,[9] dienes,[10]
and vinylarenes.[11] Very recently one example of an inter-
molecular hydroamination of unactivated 1-alkenes with an
ee value up to 78% was reported.[12,13] To the best of our
knowledge, however, there are no examples of late transition
metal catalyzed enantioselective intramolecular hydroamina-
tion of unactivated olefins. Herein we disclose the first
example of a rhodium-catalyzed[14] asymmetric intramolecu-
lar addition of amines to olefins for the synthesis of a variety
of enantioenriched 2-methylpyrrolidines with good enantio-
selectivity (up to 91% ee).
nyl)[15c] in rhodium-, platinum-, and gold-catalyzed intra-
molecular hydroamination by Liu and Hartwig[14a] and
Widenhoefer and co-workers,[16,17] respectively, stimulated
us to develop a late transition metal catalyzed enantioselec-
tive version of this process using chiral ligands of the type
developed in our laboratory.[15] We began by examining the
cyclization of N-benzyl-2,2-diphenyl-4-pentenamine (1a) into
1-benzyl-2-methyl-4,4-diphenylpyrrolidine (1b) as
a test
reaction (Table 1). Following the seminal work of Liu and
Hartwig,[14a] we exposed 1a to 5 mol% [Rh(cod)2]BF4 and
6 mol% KenPhos (L1),[18] which provided pyrrolidine 1b in
95% yield (GC) and 38% ee (Table 1, entry 1). Varying the
size of the substituent on either the nitrogen or phosphorus
atoms provided ligands[19,20] that gave the product in good
Table 1: Effect of the ligand on the enantioselectivity of the intra-
molecular hydroamination.[a]
Recent reports of the successful application of the
dialkylbiaryl
phosphines
DavePhos
(2-dicyclohexyl-
phosphine-2’-(N,N-dimethylamino)biphenyl),[15a] tBuDave-
Phos,[15b] and JohnPhos (2-(di-tert-butylphosphino)biphe-
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
95
83
8
95
94
96
98
95
94
9
38 (S)
20 (S)
n.d.
39 (S)
42 (S)
53 (S)
70 (S)
75 (S)
80 (S)
n.d.
[*] Dr. X. Shen, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490, Massachusetts Institute of
Technology
Cambridge MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] Generous financial support from the National Institutes of Health
(GM46059) is gratefully acknowledged. We thank Merck and
Boehringer-Ingelheim for additional funds. The Varian 300 MHz
used in this work was purchased with funding from the National
Institutes of Health (GM 1S10RR13886-01). We are grateful to Dr.
David S. Surry (MIT) for initial studies on asymmetric hydro-
amination process and help in the preparation of the manuscript.
10
[a] Reaction conditions: aminoolefin (0.15 mmol), Rh (5 mol%) and
ligand (6 mol%) in 0.15 mL of dioxane at 708C for 7–15 h. [b] Yields as
determined by GC methods. [c] The ee values were determined by chiral
HPLC analysis on a Chiralcel OJ column. The absolute configuration was
determined by converting 1b into the known (S)-MTPA amide. See the
Supporting Information for details. Bn=benzyl, cod=1,5-cycloocta-
diene, n.d.=not determined.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905402.
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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.
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565

Communications
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Functional groups including esters and aryl chlorides were
tolerated under the reaction conditions, rendering the prod-
ucts amenable to additional synthetic manipulation (Table 2,
entry 11 and 13). The absolute configuration of the products
was determined to be S by conversion of 1b into the known
(S)-MPTA-derived amide (MPTA = a-methoxy-a-(trifluoro-
methyl)phenylacetic acid),[6c] 6b–10b into the known N-
naphthyl amides,[5e] and 11b into the previously reported N-
acetyl-2-methylindoline.[24]
The N-protecting groups in the products in Table 2 were
easily removed to reveal the free amines by catalytic transfer
hydrogenation[25] with ammonium formate as the hydrogen
source. For example, treatment of the cyclized product 2b
(Table 2, entry 5) with palladium on activated carbon and
ammonium formate at 688C in methanol afforded the 2-
methylpyrrolidine 2c in 92% yield [Eq. (1)].
In summary, we have developed the first enantioselective
rhodium-catalyzed intramolecular hydroamination of unac-
tivated terminal alkenes. A variety of enantioenriched
pyrrolidines have been synthesized in up to 91% ee using a
binaphthyl-based electron-rich phosphine ligand. Additional
investigations to increase the generality of the process and to
expand the scope to include intermolecular reactions are
currently underway in our laboratories.
Experimental Section
Typical procedure: The aminoalkene (0.50 mmol) was added to a dry,
screw-capped test tube at room temperature and the tube was then
transferred into
a
glovebox. At this point, [Rh(cod)2]BF4
(0.025 mmol, 10.2 mg), phosphine ligand (0.030 mmol) and 0.5 mL
of dioxane were added. The vial was sealed with a PTFE cap and
removed from the glovebox. The reaction mixture was stirred at the
temperature and for the time shown in Table 2. The reaction mixture
was cooled to ambient temperature and then brine (20 mL) was
added and the resulting mixture was extracted with CH2Cl2 (2 ꢀ
20 mL). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product mixture was purified by
flash chromatography on silica gel (n-hexane/EtOAc).
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Received: September 25, 2009
Revised: November 17, 2009
Published online: December 14, 2009
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Keywords: asymmetric catalysis · heterocycles ·
hydroamination · P ligands · rhodium
.
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