A chiral phenoxyamine magnesium catalyst for the enantioselective hydroamination/cyclization of aminoalkenes and intermolecular hydroamination of vinyl arenes

Article abstract of DOI:10.1002/anie.201105079

If Grignard had only known! A chiral magnesium complex catalyzes the intramolecular hydroamination/cyclization of aminoalkenes with high efficiency at temperatures as low as -20 °C and enantioselectivities as high as 93 %ee. The high activity of this system also allows the catalytic intermolecular anti-Markovnikov addition of pyrrolidine and benzylamine to vinyl arenes. Copyright

Full text of DOI:10.1002/anie.201105079

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Angewandte
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DOI: 10.1002/anie.201105079
Asymmetric Hydroamination
A Chiral Phenoxyamine Magnesium Catalyst for the
Enantioselective Hydroamination/Cyclization of
Aminoalkenes and Intermolecular Hydroamination of
Vinyl Arenes**
Xiaoming Zhang, Thomas J. Emge, and Kai C. Hultzsch*
Dedicated to Professor Gerhard Erker on the
occasion of his 65th birthday
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Chemie
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The application of alkaline earth metal complexes as sub-
stitutes for transition-metal catalysts in alkene hydrofunc-
tionalizations has drawn increasing attention in recent years
owing to their abundance, biocompatibility, and chemical
behavior, which resembles that of the rare-earth elements.[1]
A number of magnesium, calcium, and strontium catalysts[2]
have been shown to exhibit activity comparable to catalysts
based on rare-earth metals[3] in the highly desirable hydro-
amination reaction.[4] Unfortunately, alkaline earth metal
complexes are prone to facile Schlenk-type ligand redistrib-
utions[1,5] that can result in catalyst deactivation and hamper
efforts to perform these transformations in a stereoselective[6]
manner. Indeed, previous attempts to elaborate chiral alka-
line earth metal catalysts for asymmetric hydroaminations
have not produced enantioselectivities exceeding 36% ee.[7]
In order to address this issue we have recently developed
achiral phenoxyamine magnesium catalysts that resist ligand-
redistribution reactions under the conditions of hydroamina-
tion catalysis.[8] Herein we disclose our findings on the
development of a chiral magnesium catalyst for the enantio-
selective hydroamination which achieves—unprecedented for
alkaline earth metal catalysts—enantioselectivities of up to
93% ee.[9] The high catalytic activity of this system permits
reactions to be performed at or below room temperature in
several cases, which is unprecedented in the chemistry of
alkaline earth metal complexes as well.[10]
Scheme 1. Synthesis of the chiral phenoxyamine magnesium complex
(R,R)-2.
catalytically active magnesium amide species was found to be
stable under these conditions (vide infra).
The X-ray crystallographic analysis of rac-2 (Figure 1)[16]
revealed the expected tetrahedral geometry around magne-
sium as seen in achiral phenoxyamine magnesium com-
plexes[8,17] and related zinc complexes.[12] The methine proton
on C15 is oriented trans to the N-methyl group at N2 which
results in an R-configured magnesium stereocenter in the
(R,R)-cyclohexyldiamine enantiomer.
With complex (R,R)-2 in hand we were eager to evaluate
its catalytic performance in intramolecular hydroaminations
(Table 1). We were pleased to find that (R,R)-2 displayed high
catalytic activity as well as outstanding enantioselectivities in
the cyclizations of aminopentenes 3a–d. Reactions with 2–
5 mol% catalyst were complete within 1.5–10 h at 228C. More
intriguingly and unprecedented for alkaline earth metal
catalysts, the cyclization of the more activated substrates
3a–c proceeded also readily at À208C (Table 1, entries 2, 5,
and 9) with the highest enantioselectivity of 90% ee observed
Chiral phenoxyamine ligands incorporating a chelating
cyclohexyldiamine arm have been applied in indium-[11] and
zinc-catalyzed[12] lactide polymerizations. We decided to
utilize the related phenoxyamine ligand (R,R)-1 in which
the increased steric demand of the triphenylsilyl substituent
should eliminate undesired ligand-exchange processes and
improve stereoselectivity. Reaction of (R,R)-1 with [Mg-
(CH2Ph)2(thf)2] produced the phenoxyamine magnesium
complex (R,R)-2 as a 9:1 mixture of diastereomers (based
on 1H NMR spectroscopy) in 63% yield of crystallized
product (Scheme 1).[13] The two diastereomers differ in the
chirality at magnesium and the central N-methyl amine
group.[12] A second recrystallization furnished pure (R,R)-2-
MgR (Figure S1a in the Supporting Information).[14]
A
solution of pure (R,R)-2-MgR in [D6]benzene slowly returned
to the 9:1 equilibrium mixture of diastereomers within 5 h at
258C (Figure S1b).[14] The complex was stable at 808C for
12 h, and a mixture of both diastereomers was obtained in a
5:1 ratio (Figure S1c);[14] this composition was retained for
24 h when the mixture was allowed to cool to room temper-
ature.[15] Higher temperatures (1208C) resulted in decompo-
sition of the precatalyst 2, but a model complex for the
[*] Dr. X. Zhang, Dr. T. J. Emge, Prof. Dr. K. C. Hultzsch
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
610 Taylor Road, Piscataway, NJ 08854-8087 (USA)
E-mail: hultzsch@rci.rutgers.edu
Homepage: http://chem.rutgers.edu/~hultzsch/
[**] Financial support by the ACS Petroleum Research Fund (PRF
no.49109-ND1) is gratefully acknowledged.
Figure 1. ORTEP diagram of the molecular structure of rac-2. Thermal
ellipsoids are shown at the 50% probability level, and hydrogen
atoms, except for those attached to C10 and C15, are omitted for
clarity. Selected bond lengths [ꢀ] and angles [8]: Mg1–O1 1.896(4),
Mg1–N1 2.157(5), Mg1–N2 2.149(5), Mg1–C1 2.152(6); O1-Mg1-N1
111.22(18), O1-Mg1-N2 95.17(17), O1-Mg1-C1 121.9(2), N1-Mg1-C1
113.9(3), N2-Mg1-C1 124.2(2), N1-Mg1-N2 83.25(18), Mg1-O1-C19
129.1(3), Mg1-C1-C2 114.8(5).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105079.
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Table 1: Asymmetric intramolecular hydroamination/cyclization of ami-
noalkenes catalyzed by (R,R)-2.[a]
Overall, (R,R)-2 exhibits at room temperature catalytic
activity comparable to that of Hillꢀs b-diketiminate magne-
sium complex,[2e,k] but it is more active than our achiral
phenoxyamine complexes[8] and Sadowꢀs tris(oxazolinyl)phe-
nylborato magnesium complexes.[2l,7c]
Entry
Substrate
Product
T [8C]; t [h][b]
ee
[%][c]
1
2
22; 1.5[d]
74
80
À20; 12[d,e]
The presence of a mixture of diastereomers could pose a
problem in obtaining reproducible selectivities with different
batches of precatalyst. However, we were unable to find a
significant difference in the selectivity when either diastereo-
merically pure (R,R)-2-MgR or a 5:1 diastereomeric mixture
of the precatalysts were applied in the cyclization of 3b and
3g (Table 1, entries 6, 7, and 17). The stoichiometric reaction
of (R,R)-2 with 1–3 equiv of pyrrolidine in [D6]benzene at
various temperatures uniformly showed a 9:1 diastereomeric
ratio and no decomposition became apparent after 3 h at
1208C (Figures S2 and S3 in the Supporting Information).[14]
Kinetic studies show that the cyclization of 3b is first-
order in catalyst and substrate (Figures S8 and S9).[14] This
contrasts our finding for related achiral triphenylsilyl-sub-
stituted phenoxyamine complexes that exhibited zero-order
kinetics in substrate.[8] Certainly, the cyclohexyl ring side
chain in (R,R)-2 is significantly more rigid than the propyl-
idene side chain in the achiral phenoxyamine complexes. The
slow rate of diastereomer interconversion observed for (R,R)-
2-MgR in [D6]benzene indicates that dissociation of the side
arm in (R,R)-2 is hampered. The catalytic reaction proceeded
also with a considerable primary kinetic isotope effect (kH/
kD = 3.6, Figure S10),[14] but no significant change in enantio-
selectivity was observed (84% ee for 4b vs. 82% ee for
[D2]4b). These findings suggest that the cyclization of amino-
alkenes by (R,R)-2 proceeds by means of a concerted alkene-
insertion/protonolysis mechanism[21,22] analogous to that
recently proposed by Hill et al.[2k] and Sadow et al.[2l]
In order to further exploit the catalytic activity of the
magnesium catalyst 2 we decided to investigate the signifi-
cantly more challenging intermolecular hydroamination of
alkenes.[2f,3a,23] Hill and co-workers recently reported that
homoleptic calcium and strontium amides catalyze the anti-
Markovnikov addition of amines to vinyl arenes, but the
corresponding magnesium amide was much inferior.[2f,24]
Gratifyingly, complex 2 is also capable of catalyzing these
transformations efficiently. The addition of pyrrolidine to
styrene proceeded to 87% conversion with exclusive anti-
Markovnikov regioselectivity within 16 h at 608C in neat
solution using 5 mol% of (R,R)-2 (Table 2, entry 1). The
addition of pyrrolidine to the more-electron-deficient p-
chlorostyrene required only 4 h at 608C to reach 89%
conversion, and even at room temperature the reaction
proceeded to 69% conversion in 48 h. The reaction of
benzylamine required a higher reaction temperature of
808C to give 76% conversion in 8 h. Overall, the activity of
the magnesium complex (R,R)-2 seems to be of comparable
magnitude to the calcium and strontium amides investigated
by Hill et al.[2f]
3
4
5
6
7
22; 2
22; 4.5[f]
À20; 48[e]
22; 2
84
85
90
84[g]
83[h]
22; 2
8
9
22; 3
76/76[i]
82/82[i]
À20; 72[e]
10
11
22; 10
79
51
80; 72[j,k]
12
13
14
22; 0.1
22; 0.2[f]
88
90
À20; 12[e,f]
93[l]
15
16
17
22; 2[m]
À20; 36[e]
22; 3
88
92[l]
86[h]
[a] Reaction conditions: 0.1 mmol substrate, 5 mol% (R,R)-2 (d.r. =9:1),
0.6 mL [D6]benzene, Ar atmosphere. [b] Time required to achieve ꢀ95%
yield (NMR analysis; ferrocene as internal standard). [c] Determined by
19F NMR analysis of Mosher amides. [d] 3 mol% (R,R)-2. [e] Reaction in
[D8]toluene. [f] 2 mol% (R,R)-2. [g] Pure (R,R)-2-MgR. [h] (R,R)-2
(d.r.=5:1). [i] d.r. =1.2:1. [j] 10 mol% (R,R)-2. [k] 81% yield (NMR
analysis). [l] Enantiomeric excess was also confirmed by HPLC with a
chiral stationary phase. [m] Preparative-scale reaction: 86% yield of
isolated product.
in the cyclization of 3b. The reaction of the unsubstituted
aminopentene 3e required heating to 808C and proceeded
with a reduced selectivity of 51% ee.[18]
Substrates 3 f and 3g containing an 1,2-disubstituted
double bond were cyclized rapidly at 228C as a result of the
activating effect of the electron-withdrawing phenyl substitu-
ent. Both substrates could also be cyclized at À208C to furnish
the pyrrolidines 4 f and 4g in 93 and 92% ee (Table 1,
entries 14 and 16), respectively. The enantioselectivities
obtained for 4b, 4 f, and 4g are among the highest published
results so far.[19,20]
The potential of our magnesium catalyst was also
demonstrated in a intramolecular/intermolecular tandem
reaction (Scheme 2). Cyclization of 3b (neat) with (R,R)-2
at room temperature produced 4b quantitatively in slightly
lower selectivity than under more dilute conditions (cf.
396
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(0.2 mmol). The vial was then placed in a preheated metal block
Table 2: Catalytic intermolecular hydroamination of vinyl arenes with
amines.[a]
(25–808C), and conversion was monitored by 1H and 13C NMR
spectroscopy from samples taken from the reaction mixture. Final
conversions were determined from the disappearance of character-
istic olefinic signals. For
Supporting Information.
a preparative-scale reaction see the
Entry
R
Amine
T [8C]
t [h]
Conv. [%][b]
1
2
3
4
H
Cl
Cl
Cl
(CH2)4NH[c]
(CH2)4NH
(CH2)4NH
PhCH2NH2
60
60
22
80
16
4
48
8
87
89 (62)
69
Received: July 20, 2011
Published online: October 5, 2011
76
Keywords: alkenes · amines · enantioselectivity ·
.
hydroamination · magnesium
[a] Reaction conditions: 0.24 mmol vinyl arene, 0.2 mmol amine,
5 mol% (R,R)-2, Ar atmosphere. [b] Determined by 1H NMR spectros-
copy. The value given in parenthesis is the yield of isolated product from
a preparative-scale reaction. [c] Vinyl arene/amine=3:2.
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Scheme 2. Magnesium-catalyzed tandem intramolecular/intermolecu-
lar hydroamination.
Table 1, entry 3). Subsequently, the addition of 4b to p-
chlorostyrene proceeded at 808C in 20 h to 75% conversion
to give the tertiary pyrrolidine 5 (56% yield of isolated
product) in 68% ee.[25]
The results presented herein highlight the great potential
of alkaline earth metal catalysts in the very challenging areas
of asymmetric and intermolecular hydroamination. The
suppression of Schlenk-type ligand-redistribution processes
is an important prerequisite to achieve high enantioselectiv-
ities. With the catalyst system (R,R)-2 presented herein we
have successfully demonstrated that this goal is attainable
utilizing a sterically demanding phenoxyamine ligand set. The
enantioselectivities achieved with catalyst (R,R)-2 in the
cyclization of aminoalkenes significantly surpass all previous
attempts reported for alkaline earth metal based catalysts. At
the same time, complex (R,R)-2 displays high catalytic activity
and reactions have been carried out below room temperature
for the first time using alkaline earth metal catalysts. Finally,
we have shown that magnesium-based complexes can be
viable catalysts for intermolecular hydroamination reactions
(including tandem intramolecular/intermolecular processes)
with activities comparable in magnitude to the usually much
more reactive calcium- and strontium-based catalysts. There-
fore, it can be anticipated that the corresponding phenoxy-
amine complexes of the heavier alkaline-earth metals will
exhibit even greater catalytic performance.
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[5] D. Seyferth, Organometallics 2009, 28, 1598 – 1605.
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K. C. Hultzsch in Chiral Amine Synthesis: Methods, Develop-
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2710.
Experimental Section
Typical catalytic intermolecular hydroamination reaction: A screw-
cap vial was charged with the catalyst precursor (R,R)-2 (6.9 mg,
0.01 mmol, 5 mol%), the olefin (0.24 mmol), and the amine
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These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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[17] A. R. F. Cox, V. C. Gibson, E. L. Marshall, A. J. P. White, D.
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[9] There are only a limited number of transition-metal and alkali-
metal catalysts that achieve enantioselectivities exceeding
90% ee in the hydroamination/cyclization of aminoalkenes,
see: a) Sc, Lu; up to 95% ee: D. V. Gribkov, K. C. Hultzsch, F.
Hampel, J. Am. Chem. Soc. 2006, 128, 3748 – 3759; b) Zr; up to
93% ee: M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak,
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[10] Generally, only few catalyst systems have been reported to
cyclize aminoalkenes at or below À208C, see: M. A. Giardello,
V. P. Conticello, L. Brard, M. R. Gagnꢃ, T. J. Marks, J. Am.
Chem. Soc. 1994, 116, 10241 – 10254. See also Refs. [9a,d,f].
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2010, 49, 5444 – 5452.
[18] Enantioenriched 2-methylpiperidines can be prepared with
slightly reduced rates and moderate enantioselectivities. For
example, cyclization of 2,2-diphenylhex-5-en-1-amine is carried
out with 5 mol% (R,R)-2 at 228C within 6 h in 98% yield (NMR
analysis) and 25% ee. Similarly, the cyclization of aminopen-
tenes containing a secondary amino group requires elevated
temperatures and provides moderate enantioselectivities. Thus,
cyclization of N-benzyl-2,2-diphenylpent-4-en-1-amine proceeds
at 708C using 10 mol% (R,R)-2 within 15 h in 98% yield (NMR
analysis) and 20% ee.
[19] Reported ee values in the literature: a) Ref. [9a]: 4b 85%; 4g
72%; b) Ref. [9b]: 4b 82%; c) Ref. [9f]: 4b 94%; d) Ref. [20a]:
4g 82%; e) Ref. [20b]: 4b 87%; f) Ref. [20c]: 4 f 55%.
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[21] a) This mechanism was first proposed by Marks for lanthanide-
catalyzed hydroamination reactions as a rationale for the
significant primary kinetic isotope effect observed in these
transformations, see: M. R. Gagnꢃ, C. L. Stern, T. J. Marks, J.
Am. Chem. Soc. 1992, 114, 275 – 294; b) For a computational
study of this mechanism for lanthanide-catalyzed aminodiene
cyclizations see: S. Tobisch, Chem. Eur. J. 2010, 16, 13814 –
13824; c) A noninsertive mechanism was also proposed for
group-4-metal-catalyzed hydroaminations of alkenes, see
Ref. [9f] and L. E. N. Allan, G. J. Clarkson, D. J. Fox, A. L.
Gott, P. Scott, J. Am. Chem. Soc. 2010, 132, 15308 – 15320.
[22] Owing to the catalytically active Mg – amide species, this
mechanism differs from purely Lewis acid catalyzed hydro-
aminations, e.g. with Zn(OTf)2, see: V. Neff, T. E. Mꢁller, J. A.
Lercher, Chem. Commun. 2002, 906 – 907.
[12] G. Labourdette, D. J. Lee, B. O. Patrick, M. B. Ezhova, P.
Mehrkhodavandi, Organometallics 2009, 28, 1309 – 1311.
[13] The racemic complex rac-2 was prepared in a similar manner and
exhibits identical spectroscopic properties. See the Supporting
Information.
[14] See the Supporting Information.
[15] This is in agreement with observations made for related
phenoxyamine zinc complexes, see Ref. [12]. However, addition
of 3 equiv of pyrrolidine to a 5:1 mixture of (R,R)-2-MgR and
(R,R)-2-MgS produced a pyrrolidinide complex that equilibrated
to a 10:1 mixture of diastereomers within 30 min.
[23] A. L. Reznichenko, H. N. Nguyen, K. C. Hultzsch, Angew.
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8984 – 8987.
ꢀ
[16] Crystal size 0.30 ꢄ 0.03 ꢄ 0.02 mm, trigonal, space group P3, Z =
[24] For alkali-metal-catalyzed hydroaminations of vinyl arenes, see:
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[25] The slight erosion of enantiomeric excess of the tandem
hydroamination product 5 in comparison to intermediate 4b
presumably results from a weak kinetic discrimination of the two
enantiomers of 4b by the chiral catalyst (R,R)-2 in the
intermolecular hydroamination. Unreacted pyrrolidine 4b was
found to have a slightly increased enantiomeric excess of
75% ee.
6; a = 25.467(3), b = 25.467(3), c = 11.2793(15) ꢅ, V=
6335.5(14) ꢅ3,
d
calcd = 1.124 gcmÀ3
,
T= 100(2) K, 1.88 < q <
20.88, (MoKa 0.71073 ꢅ, m = 0.106 mmÀ1), 34459 reflections
measured, 4422 independent [Rint = 0.2191]. Cell parameters
were obtained from 4693, reflections within the range 2.4 < q <
23.38. Lorentz, polarization, and empirical absorption correc-
tions were applied. The space group was determined from
systematic absences (XPREP program). The structure was
solved by direct methods (SHELXS-97). All positional and
atomic displacement parameters (ADP) were refined with all
reflections data by full-matrix least squares on F2 using
SHELXL-97. Non-hydrogen atoms were refined anisotropically,
506 parameters, R = 0.0723, wR2 = 0.1990, min./max. residual
electron density 0.497/À0.366 eAÀ3. CCDC 835382 (rac-2) con-
tains the supplementary crystallographic data for this paper.
398
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Angew. Chem. Int. Ed. 2012, 51, 394 –398