Direct, enantioselective iridium-catalyzed allylic amination of racemic allylic alcohols

Article abstract of DOI:10.1002/anie.201108287

The direct route: Iridium-catalyzed direct conversion of branched allylic alcohols into enantioenriched branched primary allylic amines is highly regio- and enantioselective (see scheme; coe=cyclooctene). Copyright

Full text of DOI:10.1002/anie.201108287

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Angewandte
Communications
DOI: 10.1002/anie.201108287
Enantioselective Allylic Amination
Direct, Enantioselective Iridium-Catalyzed Allylic Amination of
Racemic Allylic Alcohols**
Marc Lafrance, Markus Roggen, and Erick M. Carreira*
In memory of Keith Fagnou
Transition-metal-catalyzed asymmetric allylic substitution
reactions constitute one of the most convenient approaches
for the generation of optically active allylic amines.[1] The best
solutions for the enantioselective synthesis of optically active
amines from precursor allylic alcohols to date involve the use
of primary allylic esters,[2a,b] carbonates,[2c–l] and phosphates[2m]
as substrates. Substitution of a racemic mixture of secondary
allylic alcohols to afford optically active amines has not been
achieved to date.[3] This is a shortcoming given that these
starting substrates are conveniently accessed by the addition
of vinylorganometallic reagents to aldehydes. Herein, we
document for the first time the enantioselective displacement
of secondary racemic allylic alcohols with sulfamic acid to
give directly primary amines in a reaction catalyzed by an
optically active Ir-(P,alkene) complex [Eq. (1)].
an iridium-catalyzed stereospecific decarboxylative allylic
amidation of chiral branched benzyl allyl imidodicarboxy-
lates.[9] However, absent from the reported work in this area is
the use of racemic secondary allylic alcohols as the starting
point for the preparation of optically active amines through
an enantioconvergent process.
Recent reports on the use of ammonia as a nucleophile
represent a significant advance, but overalkylation with
accompanying formation of secondary amine products can
be problematic.[10] In order to circumvent this, Kobayashi and
Nagano have prescribed high catalyst loading and high
dilution (0.03–0.04m).[10c] Consequently, much attention has
been devoted to the use of ammonia surrogates in the form of
amides or imides.[1,10a,11]
We have been interested in this problem following our
observation that sulfamic acid can serve as an ammonia
surrogate in the direct displacement of secondary allylic
alcohols to afford optically active primary amines.[12,13] Our
disclosure described the direct displacement of allylic alco-
hols by sulfamic acid to produce racemic amines. We have
documented a single case in which the racemic alcohol could
be converted to the optically active amine in 70% ee using
a catalyst generated from a 1:1 mixture of a P,alkene ligand
and Ir.[12a]
Because the conversion of secondary allylic alcohols to
afford optically active amines in an enantioconvergent
manner is an unsolved problem,[14] we have opted to re-
evaluate the reaction. We have chosen phenyl vinyl carbinol
1a as a substrate in a variety of test reactions in which various
ligands were examined with IrI (Table 1). In order to facilitate
analysis, products were protected in situ as the corresponding
benzamides. Following our previously reported conditions
(2.5 mol% [{Ir(coe)2Cl}2] (coe = cyclooctene, 5 mol% ligand
(S)-L1 (Scheme 1), 1.2 equiv sulfamic acid in dimethylforma-
mide (DMF) at room temperature for 24 h), product 2a was
isolated in 69% yield and 76% ee (Table 1, entry 1), consis-
tent with the modest results previously reported.
The use of allylic alcohols as substrates in allylic
aminations has been limited by the poor aptitude of the
hydroxy group as a leaving group. Several protocols which
rely on high temperatures,[4] Lewis acids, or Brønsted
acids[3a,5] have been developed. For example, Hartwig and
co-workers reported the asymmetric amination of primary
allylic alcohols activated by Lewis acids.[6] In the context of
iridium-catalyzed allylic displacements, the use of branched
secondary allylic alcohols as substrates has been limited,
however, as they afford product amines in low enantioselec-
tivity.[7] This can be circumvented through the implementa-
tion of a sequential Pd-catalyzed isomerization/Ir-catalyzed
allylic substitution process.[8] Han and Singh have developed
Interestingly, however, we observed that increasing ligand
loading was beneficial, leading to dramatic improvement in
the enantioselectivity of the reaction process. Thus, under
otherwise identical conditions, the use of 10 mol% (S)-L1 and
5 mol% IrI (ligand/Ir 2:1) furnished product 2a in 96% ee and
in 52% yield (Table 1, entry 2). In our initial report we had
employed DMF as the reaction solvent, which is a suboptimal
reaction medium in terms of potential preparative-scale
applications. We thus examined the use of DMFas a cosolvent
in combination with common organic solvents. To our delight,
the use of 5 equiv of DMF was sufficient to obtain full
[*] Dr. M. Lafrance, M. Roggen, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Hçnggerberg
8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] M.L. thanks the NSERC for a postdoctoral fellowship. M.R.
acknowledges a fellowship from the Stipendienfonds Schweizeri-
sche Chemische Industrie (SSCI). We are grateful to the Swiss
National Science Foundation for support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108287.
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Table 1: Investigation of the enantioselective, Ir-catalyzed direct allylic
amination reaction.
cosolvents, giving the product in 75% yield, 97% ee and 77%
yield, 99% ee, respectively (Table 1, entries 6 and 13). We
opted to employ the environmentally friendly 2-methyltetra-
hydrofuran[15] as our preferred solvent in establishing the
scope of the process.
With the optimized conditions for the conversion of
secondary alcohols to amines in hand, we evaluated a collec-
tion of optically active ligands for IrI, in order to establish
whether (S)-L1 was particularly unique. Consistent with our
previous observations with this class of P,alkene ligands,[16] we
found that the use of ligand (S)-L1 provided the product with
the highest selectivity and yield. When the saturated analogue
(S)-L2 was employed, only trace amounts of the products
were observed (Table 1, entry 14). The results are consistent
with the alkene acting as a donor group; we surmise that it is
labile and following exchange with substrate, alkene ioniza-
tion is initiated to give rise to an allyl iridium intermediate.[12b]
Investigation of a variety of analogous ligands incorporating
a substituted BINOL scaffold resulted only in slower reaction
rates and diminished enantioselectivity. Employing phosphor-
amidites prepared from (R)-SPINOL[17] ((S)-L3) as well as
the more bulky (S)-10,10’-dihydroxy-9,9’-biphenanthryl[18]
((S)-L4), we observed moderate reaction rates and modest
enantioselectivity (Table 1, entries 15–16). The use of Ir
complexes derived from (S)-BINAP ((S)-L5) or (S)-Mono-
phos ((S)-L6) afforded only traces of products (Table 1,
entries 17 and 18). Finally, we note that the reactions may be
conducted with 0.5 mol% catalyst loading ([ {Ir(coe)2Cl}2])
furnishing product in 62% yield and 99% ee (Table 1xtabr1 >
, entry 19). It is worth noting that all reactions proceeded with
complete regioselectivity and with formation of the mono-
allylated amines exclusively. The reaction was performed on
a one-gram scale to give the isolated product in 68% yield and
99% ee (Scheme 2, 2a). The free amine could be protected in
situ as 9-fluorenylmethoxycarbonyl (Fmoc), N-tosyl, and
hydrochloride salt derivatives[12b,19] in 74, 48, and 56% yield,
respectively (2b–d). The scope of the allylic substitution
reaction with respect to aromatic allylic alcohols is summar-
ized in Scheme 2. A wide range of electron-rich and electron-
deficient aromatic allylic alcohols were all found to be
suitable substrates giving rise to the product in moderate to
good yields and good to high enantioselectivity. The enantio-
selectivity of the product formed could be fine-tuned by
employing different cosolvents as demonstrated with 2i and
2i’ (89% ee in 2-MeTHF vs. 93% ee in CHCl3).
Entry
Ligand
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
(S)-L1 (5 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L1 (10 mol%)
(S)-L2 (10 mol%)
(S)-L3 (10 mol%)
(S)-L4 (10 mol%)
(S)-L5 (10 mol%)
(S)-L6 (10 mol%)
(S)-L1 (2 mol%)
DMF
DMF
MeCN
toluene
acetone
iPrOAc
DCE
CH2Cl2
CHCl3
1,4-dioxane
Et2O
THF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
69
52
64
73
53
75
88
58
89
83
59
80
76
96
90
88
98
97
99
97
99
95
82
99
99
–
9
10
11
12
13
14
15
16
17
18
19
77
<5[c]
30[d]
33[d]
<5[c]
12[d]
62[e]
70
67
–
93
99
[a] Yield of isolated product after purification by chromatography after
2 steps; Regioselectivity was>99:1 as shown by the 1H NMR spectrum
of the unpurified reaction mixture. [b] ee was determined by HPLC.
[c] Recovered starting material. [d] Incomplete conversion. [e] Reaction
was performed using 0.5 mol% [Ir(coe)2Cl]2.
Scheme 1. Selected ligands examined for the enantioselective, iridium-
catalyzed direct allylic amination of allylic alcohols with sulfamic acid.
Under the conditions described above with generation of
the catalyst in situ and a ligand/Ir ratio of 2:1, aliphatic allylic
alcohols reacted sluggishly giving the products in good
enantioselectivity, albeit in low yield.[20] However, the use of
a protocol prescribing a ligand/Ir ratio of 1:1 provides
products in good to high selectivity and synthetically useful
yields, as shown in Scheme 3.
In summary, we report the direct enantioselective iridium-
catalyzed substitution of racemic secondary allylic alcohols
using sulfamic acid to give optically active primary amines.
The salient features of the method include the preparation of
amine products through the displacement of the alcohols
without the need for prior activation and without resorting to
high dilution or use of a protected amine. Additionally, the
conversion to the allylic amine with a wide range of
cosolvents. As can be seen in Table 1, with the exception of
diethyl ether and toluene, the reaction enantioselectivity is
relatively insensitive to the nature of the media employed
(entries 3–13). When the substitution reactions were con-
ducted in acetonitrile or acetone, the product was obtained
with high enantioselectivity, albeit in moderate yields
(Table 1, entries 3 and 5). Better results were obtained with
chlorinated solvents (1,2-dichloroethylene (DCE), CH2Cl2,
CHCl3), 1,4-dioxane, and THF (Table 1, entries 7–10 and 12).
Industry-preferred solvents such as isopropyl ethyl acetate
and 2-methyltetrahydrofuran (2-MeTHF) were also suitable
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Scheme 3. Scope of enantioselective, direct, allylic amination of ali-
phatic allylic alcohols. Yield of the isolated product after purification by
chromatography after 2 steps; regioselectivity was >99:1 as shown by
the 1H NMR spectrum of the unpurified reaction mixture; ee was
determined by HPLC. [a] Absolute configuration was assigned by
comparison with reported compounds.
ture was stirred vigorously for 10 min during which time the solution
turned dark red. Allylic alcohol 1 (0.500 mmol, 1.00 equiv) was added
as a solution in 2-methyltetrahydrofuran (0.500 mL) to the reaction
mixture which resulted in a yellow solution. The reaction mixture was
stirred at room temperature for 24 h. Triethylamine (0.300 mL,
2.00 mmol) was then added followed by benzoyl chloride
(0.110 mL, 1.00 mmol), and the resulting mixture was stirred at
room temperature for 4 h. The product was obtained by flash
chromatography of the reaction mixture diethyl ether/hexane.
Scheme 2. Scope of the direct, enantioselective, allylic amination of
aromatic racemic allylic alcohols. Yield of the isolated product after
purification by chromatography after 2 steps; regioselectivity was
Received: November 24, 2011
Published online: February 17, 2012
1
>99:1 as shown by the H NMR spectrum of the unpurified reaction
mixture after full consumption of starting material 1; the ee value was
determined by HPLC. [a] Reaction performed on 1 g scale. [b] Protec-
tion was performed with 4 equiv NEt3 and 2 equiv of TsCl. [c] Protec-
tion was performed with 4 equiv NEt3 and 2 equiv of FmocCl.
[d] Generated upon treatment of amine with 2m HCl in Et2O.
[e] Generated upon treatment of amine with 1.2 equiv of NaH and
1.2 equiv of BzCl. [f] Reaction performed in CHCl3 as cosolvent.
[g] Absolute configuration assigned by comparison with known com-
pounds.
Keywords: amination · direct substitution · enantioselectivity ·
iridium · sulfamic acid
.
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Experimental Section
General procedure: [{Ir(coe)2Cl}2] (11.2 mg, 13.0 mmol), ligand (S)-L1
(26.0 mg, 50.0 mmol), and sulfamic acid (60.0 mg, 0.610 mmol,
1.20 equiv) were placed in a screw-capped vial (2.00 mL) or round-
bottom flask with a magnetic stir bar. The reaction vessel was purged
with argon. Dimethylformamide (5.00 equiv, 0.200 mL) was added
followed by 2-methyltetrahydrofuran (1.00 mL). The reaction mix-
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Thus, upon removal of reaction solvent in vacuo, the residue was
partitioned between 1m HCl and dichloromethane. The organic
layer was removed and the aqueous layer was washed twice with
dichloromethane. The aqueous layer was cooled in an ice bath
and made alkaline by addition of solid NaOH pellets. The amine
was then extracted by washing the alkaline aqueous layer with
dichloromethane five times. After the organic layer had been
dried over Na2SO4 and the volume had been decreased to
approximately 80% under reduced pressure, the remaining
solution was treated with HCl (2m solution in Et2O). Evapo-
ration of the volatile materials left the allylic amine hydrochlo-
ride as an off-white powder.
[20] Incomplete conversion with concomitant formation of elimina-
tion reaction to form the diene as a by-product was observed.
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