Asymmetric hydroamination catalyzed by a new chiral zirconium system: Reaction scope and mechanism

Article abstract of DOI:10.1039/c4cc10032h

A new class of chiral zirconium complexes supported by chiral tridentate [O^-NO^-]-type of ligands derived from amino acids were synthesized and structurally characterized. They catalyzed asymmetric hydroamination/cyclization of primar

Full text of DOI:10.1039/c4cc10032h

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Asymmetric hydroamination catalyzed by a new
chiral zirconium system: reaction scope and
mechanism†
Cite this:DOI: 10.1039/c4cc10032h
Received 16th December 2014,
Accepted 19th February 2015
Xiaoguang Zhou,ab Bing Wei,ab Xiu-Li Sun,a Yong Tang*a and Zuowei Xie*bc
DOI: 10.1039/c4cc10032h
www.rsc.org/chemcomm
A new class of chiral zirconium complexes supported by chiral We wondered if chiral ligands derived from such a tridentate
tridentate [OÀNOÀ]-type of ligands derived from amino acids were backbone system would offer both high catalytic activity and
synthesized and structurally characterized. They catalyzed asym- enantioselectivity in asymmetric hydroamination. Here we report
metric hydroamination/cyclization of primary aminoalkenes to give the new chiral catalyst systems for asymmetric hydroamination of
five- and six-membered N-heterocyclic amines with up to 94% ee. aminoalkenes with up to 94% ee and Z95% conversion. The
reaction mechanism is also discussed.
Hydroamination as a highly atom-economic reaction for efficient
Initially, a series of new chiral auxiliary [OÀNÀO] ligands were
synthesis of nitrogen containing compounds has received great synthesized via the condensation of salicylaldehyde with O-alkylated
attention. In particular, chiral intramolecular hydroamination pro- chiral aminoalcohol, followed by reduction with LiAlH4 (see ESI†).
vides a convenient way to obtain chiral N-heterocycles, which plays an They were treated with 1 equiv. of tetrabenzyl-zirconium in toluene
important role in pharmaceuticals.1 Since the first report on asym- to give new chiral dibenzyl zirconium complexes 1–4 (Chart 1).
metric hydroamination in 1992 based on chiral ansa-lanthanocenes,2 Screening results on catalytic hydroamination of 2,2-diphenyl-4-
several chiral catalyst systems have been developed, including group pentenamine (6A) indicated that 4b offered the best ee value
4 metals,3 alkaline earth metals,4 alkali metals,5 late transition and the lability of the OR2 group disfavored the chiral induction
metals,6 rare earth metals2,7–12 and chiral Brønsted acids.13 Though (Table S3 in ESI†). To fix this problem, a covalent bond between the
significant progress has been made in the past decade in this field, Zr atom and O(2) was desirable, which led to the design of a new
the reported enantioselective systems remain very limited. In view of ligand backbone. Subsequently, a series of new ligands with a
the recent progress in asymmetric catalysis,14 it is envisioned that [OÀNOÀ] backbone were prepared. Their Zr complexes 5a–f were
new ligand design, new catalyst synthesis, and mechanism tests may also synthesized and characterized by various spectroscopic data and
offer strategies for addressing challenging issues in asymmetric single-crystal X-ray analyses (Fig. S8–S11 in ESI†). Scheme 1 shows
olefin hydroamination, thus further advancing this field.
the screening results of 5a–f. The enantioselectivity of the reaction
Very recently, we reported a highly active cationic zirconium was greatly improved, 74% ee for 5a, 89% ee for 5b and 68% ee for
system based on a tridentate [OÀNÀS] ligand for catalytic hydro- 5c. It was clear that gem-disubstituents had a large impact on ee
amination with a broad substrate scope from primary amines values with gem-dimethyl being the best choice. Replacement of a
to secondary amines, and from terminal alkenes to much less five-membered N-heterocycle by a six-membered one (5e) or a
reactive internal alkenes.15 This system also catalyzed tandem fused five-membered ring (5f) offered similar enantioselectivity.
intramolecular hydroamination of primary aminoalkenes to give After identifying 5b as the best catalyst for hydroamination of 6A,
bicyclic amines, and was tolerant of many functional groups. the effect of reaction temperature on enantioselectivity was exam-
ined and the results are listed in Table S4 (ESI†).
Under the optimal reaction conditions, several substrates were
examined, and the results are summarized in Table 1. Both five- and
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry (SIOC), Chinese Academy of Sciences, 345 Lingling Lu,
six-membered N-heterocyclic ring products were generated with up
Shanghai 200032, P. R. China. E-mail: tangy@sioc.ac.cn
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, SIOC, P. R. China
c Department of Chemistry, The Chinese University of Hong Kong, Shatin,
New Territories, Hong Kong, P. R. China. E-mail: zxie@cuhk.edu.hk
† Electronic supplementary information (ESI) available: Complete experimental
details, characterization data, kinetic plots, and crystallographic data. CCDC
1016330–1016342 for 1–3, 4a,b,c,d, 5a,b,c,d, 8, and 9. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc10032h
Chart 1 Chiral Zr complexes 1–4.
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Scheme 2 Reaction of 8 with t-BuNH2.
reaction intermediate from the stoichiometric reaction of 5b with 6A
were unsuccessful. We then prepared an achiral Zr complex 8 with
the same [OÀNOÀ] backbone. It could catalyze the hydroamination
of 6A to a racemic mixture of 7A with a comparable activity to 5b.
Reaction of 8 with an excess amount of t-BuNH2 in toluene at
room temperature gave an imido-bridged zirconium amide complex
9 in 44% yield. Complex 9 also catalyzed the hydroamination of 6A
to offer (Æ)7A in a similar activity to that of 8. Single-crystal X-ray
Scheme 1 Screening results of asymmetric hydroamination catalyzed by 5a–f.
t
analyses reveal that 9 is a dimer with bridging imido BuN and
to 94% ee. The substrate 6B gave spiro[4,5] product 7B in 93% ee
(entry 2), and the substrate 6C offered spiro[4,4] product 7C in 87% ee
(entry 3). Desymmetrization with the two allyl groups in aminodiene
6F produced both diastereomers with 88% ee and 92% ee, respec-
tively, whereas the diastereoselectivity was low (1 : 1.7) (entry 6). Upon
replacing phenyl in 6F with methyl, even higher ee values of 90% and
93% were achieved (entry 5). The gem-dialkyl effect was also observed.
As anticipated, replacement of gem-diphenyl substitutes in 6A by gem-
dimethyl-ones resulted in a much lower activity (entry 4). Complex 5e
was found to give 7G in 66% ee, which represents the best enantio-
selectivity so far observed for the hydroamination of 6G (entry 7).
Since 5b did not show catalytic activity toward secondary amino-
alkenes, it seemed that the above [ONO]Zr(CH2Ph)2 system might
proceed via a Zr-imido intermediate. Many attempts to isolate the
alkoxy units, respectively (Scheme 2). One of the Zr atoms is five
coordinated, and the other is six coordinated. In addition, each Zr
atom is s-bonded to one amido unit BuNH, and the two BuNH
moieties are oriented in trans positions (Fig. S13 in ESI†).
t
t
To gain further insight into the reaction mechanism, a kinetic
analysis of hydroamination/cyclization of aminoalkene 6A catalyzed by
5b was performed for the determination of an empirical rate law using
in situ 1H NMR monitoring. Ferrocene was employed as an internal
1H NMR integration standard, as it was readily differentiated from the
substrate, product, and catalyst resonances in deuterated toluene. The
appearance of the product 7A CH2CH signal was monitored as a
function of time and normalized versus the internal standard.16
The results show that there is a first-order dependence on
both catalyst and substrate concentration, giving the empirical
rate law in the following equation on the basis of initial rate
measurements: rate = kobs[catalyst][substrate].
Table 1 Substrate scope of hydroamination catalyzed by 5b
To gauge the effect of N-deuteration on the reaction cata-
lyzed by 5b, the conversion of d2-6A was studied (Scheme 3). It
was found that the cyclization of N-deuterated d2-6A was much
slower than for the proteo counterpart 6A, giving kH/kD = 5.2 at
60 1C (see Fig. S19 in ESI†).
Entry
1c
Substrate
Product
Time (h)
19
Yield f/eed (%)
84/94
To further probe the nature of the turnover-limiting step, the
temperature dependence of the cyclization rate of 6A was investi-
gated by determining the kobs values at 50 1C, 60 1C, 70 1C and 80 1C
(see Fig. S20 in ESI†). The Eyring plot generated from these data
is shown in Fig. S21 in ESI.† The calculated thermodynamic
parameters are DHa = 9.9 Æ 0.3 kcal molÀ1 and DSa = À53.4 Æ
0.9 cal KÀ1 molÀ1, which are very comparable to DHa = 6.7 Æ
0.2 kcal molÀ1 and DSa = À43 Æ 7 cal KÀ1 molÀ1 observed for
the [PhB(C6H4)(OX)]Zr(NMe2)2 system.3f These values may also be
compared to DHa = 17 to 21 kcal molÀ1 and DSa = À13 to
À23 cal KÀ1 molÀ1 in the salicyloxazoline zirconium system17 and
DHa = 20.1 Æ 0.5 kcal molÀ1 and DSa = À21 Æ 1 cal KÀ1 molÀ1 in
2a,e
3a,e
4a,e
5a,e
6a,e
21
72
97/93
91/87
96/89
120
89
89/90, 93
dr = 1 : 1.2
91/88, 92
dr = 1 : 1.7
24
7b
2
91/66
a
b
c
d
Temp. = 85 1C. Using 10 mol% 5e at 130 1C. Temp. = 70 1C. The
e
ee value measured by chiral HPLC. Products were converted to N-Ts
compounds and the ee value was measured by chiral HPLC, the dr value
was determined by the analyses of the 1H NMR spectrum of the crude
Scheme 3 Primary kinetic isotopic effect observed in the cyclization of
6A (E = H/D).
f
product. Isolated yield.
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We are grateful for the financial support from the National
Natural Science Foundation of China (21121062 to YT) and the
CAS-Croucher Funding Scheme.
Notes and references
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dependence on precatalyst concentration was observed. Accordingly,
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was observed (see Fig. S22 in the ESI†), as would be expected for the
exclusively monomeric mechanism. In addition, the 1H NMR spec-
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[ONO]Zr(NHBut)2 in the presence of excess t-BuNH2 (see Schemes
S1 and S2 in ESI†). These results suggest that the reaction may
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reaction’s enantioselectivity, where the % ee’s for deutero-
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the values for the corresponding proteo-pyrrolidines (see Table S7
in ESI†). Such effects show that an N–H (or N–D) bond is involved
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On the basis of aforementioned experimental data, a plausible
catalytic mechanism is proposed in Scheme 4. Initial aminolysis of the
precatalyst 5b by excess substrates liberates toluene to give a mono-
meric species I. The third substrate binds reversibly to the Zr atom to
give the species II. Intramolecular hydroamination takes place via
irreversible C–H and C–N bond formation through a highly ordered
transition state. This is supported by a very large and negative value of
DSa (À53.4(9) cal KÀ1 molÀ1) as well as a large KIE value of 5.2. The
dissociation of neutral pyrrolidine regenerates the active catalyst 1 to
complete the catalytic cycle. Such a mechanism is similar to those
reported in the literature.3d,18
In summary, this work describes our journey of exploring new
chiral zirconium catalysts for asymmetric hydroamination/cyclization.
Through systematic studies, we have developed a class of new pincer-
like [OÀNOÀ]Zr systems that can efficiently catalyze the hydroamination
of primary aminoalkenes with up to 94% ee and Z95% conversion.
The catalyst structure–enantioselectivity relationships have also been
addressed, which may shed some light on the ligand design of new
catalyst systems. A mechanism has also been proposed to account for
all of the experimental observations, which involves a highly ordered
transition state and a concerted bond formation pathway.
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