Structure-activity relationships in group 3 metal catalysts for asymmetric intramolecular alkene hydroamination. An investigation of ligands based on the axially chiral 1,1′-binaphthyl-2,2′-diamine motif

Article abstract of DOI:10.1039/c1dt10222b

From a series of N,N′-disubstituted-1,1′-binaphthyl-2,2′- diamines, several group 3 metal complexes were synthesized via an in situ procedure. These chiral complexes were subsequently applied to catalysis of intramolecular alkene hydroamination. Significa

Full text of DOI:10.1039/c1dt10222b

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COMMUNICATION
Structure–activity relationships in group 3 metal catalysts for asymmetric
intramolecular alkene hydroamination. An investigation of ligands based on
the axially chiral 1,1¢-binaphthyl-2,2¢-diamine motif†
Helena M. Lovick, Duk K. An and Thomas S. Livinghouse*
Received 9th February 2011, Accepted 2nd June 2011
DOI: 10.1039/c1dt10222b
From a series of N,N¢-disubstituted-1,1¢-binaphthyl-2,2¢-
diamines, several group 3 metal complexes were synthe-
sized via an in situ procedure. These chiral complexes were
subsequently applied to catalysis of intramolecular alkene
hydroamination. Significant structure–activity relationships
were observed, most notably a reversal of stereoselectivity for
cyclopentyl versus diphenylmethyl substituents.
Scheme 1 Intramolecular hydroamination catalyzed by complexes 4a–g.
The intramolecular hydroamination of alkenes constitutes a
powerful and atom-economical method for the synthesis of
nitrogen-containing heterocycles. Although main-group metal
Synthesis of proligands
complexes have been used as catalysts for alkene hydroamination,1a
the most general cases for the synthesis of amines and their
derivatives involve transition metal catalysis using complexes of
rhodium,1b–d ruthenium,1e–f nickel,1g–i palladium,1j–p and gold1q–s
as well as the group 32a–g and group 42h–o metals. The seminal
group 3 metallocenes developed by Marks and coworkers2 for
hydroamination/cyclization have subsequently been joined by a
variety of nonmetallocene complexes of the group 3 metals as
catalysts for this important reaction.3,4
We have previously disclosed that chelating bis(thiophosphinic
amidate)s and chelating diamido complexes of the group 3 metals
are potent catalysts for intramolecular alkene hydroamination.5a,b
Asymmetric variations of this important reaction have been re-
ported in which the most frequently encountered sources of asym-
metry have derived from the axially chiral 1,1¢-binaphthyl-2,2¢-
diamine3a–f and 6,6¢-dimethyl-1,1¢biphenyl-2.2¢-diamine3g–i plat-
forms. Alternatively, sterically congested 1,1¢-binaphthyl-2,2¢-
diol,3j trans-1,2-cyclohexane- and related diamine derivatives3k
have found utility as chirality sources. In this communication we
present a study of the enantioselectivities and rates associated
with the cyclization of 1-amino-2,2-dimethyl-4-pentene (1) to
the optically enriched pyrrolidine 2 catalyzed by Y, Sm, and
Lu complexes 4, based on the 1,1¢-binaphthyl-2,2¢-diamine motif
(Scheme 1).
Proligands 3a and 3b were synthesized by the sequential dilithi-
ation of (R)-(+)-1,1¢-binaphthyl-2,2¢-diamine or (S)-(-)-1,1¢-
binaphthyl-2,2¢-diamine (n-BuLi) followed by phosphinylation
with chlorodiisopropyl phosphine (2.2 equiv.) and final treatment
with elemental sulfur or selenium respectively.4d Proligands 3c
and 3d were prepared by the exhaustive reductive amination
(NaBH4, H2SO4, MeOH) of (R)-(+)-1,1¢-binaphthyl-2,2¢-diamine
with cyclopentanone3b or 2-indanone respectively. Proligand 3e
was obtained by dialkylation of the aforementioned diamine with
chlorodiphenylmethane. Proligands 3f and 3g were synthesized
by the Pd(0)-catalyzed cross-coupling of this precursor with 2-
bromo-1-isopropylbenzene or 1-bromonaphthalene respectively
(Scheme 2).5
Generation of group 3 precatalysts
We have previously shown that Group 3 precatalysts can be
accessed by the treatment of the appropriate proligand with ho-
moleptic amides of the type M[N(TMS)2]3.4a–f Unfortunately this
process, although successful for some of the proligands reported
◦
here, (e.g., 1 h at 60 C for 3a or 3b) was extremely lethargic for
others (requiring 2 weeks at 120 ◦C for 3c). We therefore applied a
procedure first advanced by Anwander6 for the in situ generation
of the desired complexes. Optimally, reaction of the appropri-
ate MCl3-tetrahydrofuranate [YCl3(THF)3.5, SmCl3(THF)3.5, or
LuCl3(THF)3] suspended in THF with Me3SiCH2Li (3.4 equiv.,
1 M in p-xylene) immediately generated homoleptic group 3 alkyls
of the type 5. Subsequent addition of the proligand of interest
resulted in elimination of Me4Si with concomitant formation
of the precatalysts 4 (Scheme 3). The direct use of preformed
THF solutions of 4 for asymmetric hydroamination/cyclization
Department of Chemistry and Biochemistry, Montana State University,
Bozeman, MT 59717, USA. E-mail: livinghouse@chemistry.montana.edu
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See DOI:
10.1039/c1dt10222b
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The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 7697–7700 | 7697
©

Table 1 NPS and NPSe ligand assays
Entry
Proligand
Metal
ta
eeb (config)c
1
2
3
4
5
6
3a
3a
3a
3b
3b
3b
Y
36 h
36 h
18 h
36 h
48 h
24 h
56% (S)
38% (S)
Sm
Lu
Y
Sm
Lu
64% (S)
-56% (R)
-42% (R)
-58% (R)
a >95% conversion as determined by 1H NMR Spectroscopy.
1
b Enantiomeric excess; based on integration of H NMR spectrum using
(R)-(-)-O-acetylmandelic acid.2j c Assigned based on NMR spectroscopy
of the (S)-(+)-a-trifluoromethylphenylacetyl chloride derivative.3i
samarium complex 4aSm, that possesses a metal center larger
than yttrium, exhibited reduced selectivity, providing 2 with an
ee of 38%. Similarly, 4aLu, with a smaller metal center than
yttrium, proved slightly more selective, furnishing 2 in 64% ee.
The latter results are consistent with the early findings of Marks
and Gagne´, who observed that catalytic turn-over frequencies for
internal hydroamination decrease in direct relation to decreasing
atomic radius of the metal center within group 3 metallocenes.8 A
closely related set of enantioselectivities were obtained for group 3
complexes derived from the NPSe proligand 4b, with the expected
reversal of antipodal selectivity (Table 1).
Scheme 2 Preparation of proligands.
The comparatively simple proligand N,N¢-dicyclopentyl-1,1¢-
binaphthyl-2,2¢-diamine (3c) has been shown to be one of the
most effective proligands leading to chelating diamide complexes
that possess respectable enantioselectivity in internal alkene
hydroamination.3a–d In light of this, we initiated a study to elucidate
factors that might influence structure–activity relationships in
connection with variation of N-alkyl substitution. Subjection of
the known proligand 3c to the standard metallation protocol using
5Y cleanly generated 4cY, that, when used for the enantiocontrolled
Scheme 3 In situ generation of group 3 metal catalysts.
◦
cyclization of 1 (2 d, 23 C) afforded 2 in 72% ee, in agreement
with literature results.3a,c As would be expected, the corresponding
samarium precatalyst 4cSm provided 2 more rapidly (1.5 d, 23 ◦C)
but with slightly suppressed ee (66%). The lutetium analog 4cLu
proved less active, requiring fully 30 d at 23 ◦C (or 1.5 d at 60 ◦C)
providing 2 with 70% (or 66%) ee respectively.
We subsequently explored minor and major perturbations
on the N and N¢- substituents of 1,1¢-binaphthyl-2,2¢-diamine.
Accordingly, the utilization of the N,N¢-2-indanoyl proligand 4d
gave rise to the facile generation of the precatalysts 4dY, 4dSm, and
4dLu. These, in turn, catalyzed the conversion of 1 to scalemic 2 in
70, 48, and 70% ee at 23 ◦C in 4.5, 9, and 24 d respectively. In sharp
contrast to these results, the sterically encumbered precatalysts
4eY and 4eSm that possessed N,N¢-2-(diphenylmethyl) substituents
catalyzedthe conversionof 1 toscalemic 2 in 75 and 72% ee at 23 ◦C
in 7 d and 5 h respectively, but with a surprising and unexpected
inversion of enantioselectivity. The less reactive complex, 4eLu,
required 1.5 d at 60 ◦C for >95% conversion and gave 2 in 33% ee,
also with inverted enantioselectivity (Table 2).
proved undesirable due to extended reaction times and diminished
enantioselectivities. This was conveniently circumvented by simply
evaporating the majority of the THF in vacuo followed by
the addition of C6D6 and subsequent introduction of 1-amino-
2,2-dimethyl-4-pentene (1). It is none the less significant that
precatalysts generated from either the direct “amine elimination”
approach (involving M[N(TMS)2]3) or the preformed homoleptic
alkyls M(CH2TMS)3·(THF)2 (5) proceeded to give pyrrolidine 2
with virtually identical ee’s within experimental error (i.e., for 4aY,
61 and 56% ee respectively).
Results and discussion
The internal hydroamination of 2,2-dimethylpent-4-ene-1-amine
(1) was selected for examination since cyclization of this sub-
strate would be facilitated by the Thorpe–Ingold effect.4e We
have previously demonstrated that chelating bis(thiophosphinic
amidate)s are versatile supporting ligands for the metals of group
3 and 4.4d,e We initiated this investigation by evaluating the
NPS and NPSe proligands 3a and 3b as chirality sources in
asymmetric internal alkene hydroamination. As had been hoped,
precatalyst 4aY, generated from 3a and 5Y readily catalyzed the
conversion of 1 to the corresponding pyrrolidine 2 with good
(56%) enantioselectivity.7 As might be expected, the corresponding
In 2003, Reetz and coworkers reported an efficient method for
the synthesis of sterically hindered N,N¢-diaryl-1,1¢-binaphthyl-
2,2¢-diamines using a modification of the Buchwald N-arylation
procedure.5 Given the opportunity provided by this precedent,
proligands 3f and 3g were assembled and subsequently evaluated
as chirality sources for the enantioselective conversion of 1 to 2.
7698 | Dalton Trans., 2011, 40, 7697–7700
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©

Table 2 Alkyl substituted proligand assays
Unlike its precursor, 4eY, triamide 6eY was stable for several days
in THF. After filtration, the volatiles were removed to provide 6eY.
Within the H NMR spectrum of 6eY (in C6D6) the resonances
Entry
Proligand
Metal
ta
eeb (config)
1
for the N-methylene group of the diethylamido ligand and the
N-methine resonances of the 1,1¢-binaphthyl-2,2¢-diamine were
shifted downfield in comparison to their unligated counterparts.
1
2
3
4
5
6
7
8
9
3c
3c
3c
3c
3d
3d
3d
3e
3e
3e
Y
2 d
72% (S)
66% (S)
70% (S)
66%c(S)
70% (S)
48% (S)
70% (S)
-75% (R)
-72% (R)
-33%c(R)
Sm
Lu
Lu
Y
Sm
Lu
Y
1.5 d
30 d
1.5 dc
4.5 d
9 d
24 d
7 d
1
Furthermore, the H NMR spectrum of 6eY is consistent with
four molecules of THF per 1,1¢-binaphthyl-2,2¢-diamine unit.
Interestingly, there are two distinct O-methylene resonances for
the coordinated THF molecules shifted upfield from free THF.
Additionally, the C2 symmetry of 6eY is evidenced by the sharp
singlet for the methine resonance (5.922 ppm in THF).
Sm
Lu
5 d
10
1.5 dc
a >95% conversion as determined by 1H NMR spectroscopy.
b Enantiomeric excess. c Reaction was performed at 60 ◦C.
Conclusions
In summary, we have optimized an experimentally facile method
for the in situ generation of chiral non-metallocene complexes of
the group 3 metals based on ligand exchange using preformed
homoleptic alkyls M(CH2TMS)3·(THF)2 (5). Little difference was
observed in the catalytic activity/selectivity profiles for the NPS
and NPSe complexes 4aM and 4bM. N-Alkyl substituted complexes
4cM–4eM provided the highest enantioselectivities in this study,
with a remarkable reversal of enantioselection observed for 4eM,
consistent with a significant steric perturbation at the catalytic
site. Although the attempted isolation of 4eY failed due to its
intrinsic instability, the isolation of the corresponding triamide
derivative 6eY was achieved. The synthesis and evaluation of
additional chelating diamine and related proligands as well as
the activity/selectivity signatures of their isolated complexes will
be the topics of a future report from this laboratory.
Table 3 Aryl substituted proligand assays
Entry
Proligand
Metal
ta
eeb (config)
1
2
3
4
5
6
3f
3f
Y
12 h
3 h
16 h
27 h
4 h
28% (S)
38% (S)
32% (S)
12% (S)
16% (S)
12% (S)
Sm
Lu
Y
Sm
Lu
3f
3g
3g
3g
24 h
a Reactions were performed at 60 ◦C; >95% conversion as determined by
1H NMR spectroscopy. b Enantiomeric excess.
The preliminary results obtained with Y, Sm, and Lu precatalysts
derived from 3f and 3g were disappointing as prolonged reaction
times were necessary to achieve >95% conversion and the observed
enantiomeric excesses were uniformly low (Table 3). It should be
emphasized that we have not yet isolated rigorously pure com-
plexes of the type 4fM and 4gM. Should these entities possess low
catalytic activity, as a consequence of an unfavorable steric and/or
electronic environmentatthe metalcenter, the observed decrease in
enantioselectivity would be consistent with a competing reaction
pathway involving a more reactive achiral catalyst derived from
the homoleptic metallating agents 5.
In order to determine the nature of metal species formed via
the in situ methodology, we attempted the isolation of monoalkyl
complex 4eY. Unfortunately, in coordinating (THF) and noncoor-
dinating (C6D6) solvents, the decomposition of complex 4eY occurs
(<2 d at 22 ◦C). This observation is consistent with the reported
instability of other alkyl group 3 metal amide complexes.6 To
circumvent this difficulty, we prepared the more robust triamide
complex 6eY via aminolysis of the yttrium-alkyl bond of 4eY with
diethylamine (Scheme 4).6 Addition of diethylamine to a solution
of 4eY in THF at ambient temperature provided rapid access to
6eY (less than five minutes for complete ligand exchange).
Acknowledgements
Generous financial support for this research was provided by the
National Institute of General Medical Science.
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The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 7697–7700 | 7699
©

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7700 | Dalton Trans., 2011, 40, 7697–7700
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The Royal Society of Chemistry 2011
©