TaMe3Cl2-catalyzed intermolecular hydroaminoalkylation: A simple complex for enhanced reactivity and expanded substrate scope

Article abstract of DOI:10.1002/chem.201300992

Tantalizingly simple: The common organometallic starting material TaMe ₃Cl₂ can be used for the catalytic C-H functionalization reaction, hydroaminoalkylation. The substrate scope for this readily accessed compound includes unactivat

Full text of DOI:10.1002/chem.201300992

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DOI: 10.1002/chem.201300992
TaMe3Cl2-Catalyzed Intermolecular Hydroaminoalkylation: A Simple
Complex for Enhanced Reactivity and Expanded Substrate Scope
Zhengxing Zhang, Jean-Denys Hamel, and Laurel L. Schafer*[a]
Amines are common naturally occurring compounds that
attract the interest of organic chemists and medical scientists
due to their prevalence in biologically active molecules.
Atom-economic synthetic routes for the efficient prepara-
tion of amines rely on the development of catalytic reac-
tions, such as hydroamination[1] and more recently hydro-
Doye and co-workers showed that the replacement of the
amido ligands of Ti(NMe2)4 with the benzyl ligands of Ti-
(CH2Ph)4 both enhanced hydroaminoalkylation reactivity
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
and eliminated the formation of amine by-products derived
from the ligand itself.[4c,7]
Furthermore, Doye and co-workers have shown that by
introducing an auxiliary ligand, catalysts with enhanced sub-
strate scope and alternative regioselectivities can be acces-
sed.[4d,g] Inspired by their achievements by using Ti alkyls
and Herzon and Hartwigꢀs demonstration that chloride com-
ACHTUNGTRENNUNG
aminoalkylation.[2]
Hydroaminoalkylation, or the a-alkylation of amines, is
À
an emerging catalytic C H functionalization technology for
3
À
the addition of an sp -hybridized C H bond a to nitrogen
across the C=C double bond of an alkene. Late transition
plexes of Ta (e.g., [Cl3TaACTHUNGTER(UNNG NMePh)2]2) realize reactivity with
metals, such as Ir and Ru, can be used in combination with
temperatures as low as 908C with selected substrates
pyridyl-substituted amines to realize chelation-assisted sp3
(Table 1, entry 5),[5b] we undertook the investigation of the
[3]
À
C H bond functionalization with alkenes. However, early-
transition-metal-catalyzed hydroaminoalkylation is particu-
larly attractive because unprotected amines can be used as
substrates.
Table 1. Reactivity comparison of Group 4 and Group 4 hydroamino-
AHCTUNGERTGaNNUN lkylation precatalysts.
Recent achievements in hydroaminoalkylation catalyst de-
velopment include the use of Group 4[4] and Group 5[5]
metal complexes, in which Group 5 complexes have shown
particular promise for the intermolecular variant of this re-
action with excellent regioselectivity for the branched prod-
uct and even high enantioselectivity with selected substra-
tes.[5f,g] With these promising reactivity trends identified, cur-
rent efforts are focused on improving the performance of
these catalysts to address limitations of high reaction tem-
peratures (often over 1308C), long reaction times (up to
60 h), and significant substrate-scope limitations. Herein, we
Entry
Catalyst
Ti(NMe2)4
TiBn4
Ind2TiMe2
Conditions
Conv. [%]
1
2
3
4
5
G
10 mol%, 1608C, 96h
10 mol%, 1608C, 96 h
2 mol%, 1058C, 24 h
5 mol%, 1108C
32[a,4c]
77[a,4c]
90[a,4d]
n.r.
Ta
ACHTUNGTRENNUNG
A
U
2 mol%, 908C, 24 h
72[a,5b]
6
5 mol%, 1108C, 63 h
96[a,5c]
91
7
TaMe3Cl2
10 mol%, 1108C, 30 h
[6]
show that the simple TaMe3Cl2 organometallic complex, a
[a] Reported yields; n.r.=no reaction.
common Ta starting material, can be used to realize such
transformations at 1108C. Most importantly, a broad range
of terminal and even internal alkenes can undergo hydro-
common TaMe3Cl2 complex as a catalyst for hydroamino-
alkylation. By using this precatalyst, methane gas is elimi-
aminoalkylation with both alkylaryl- and dialkylamines to
ACHTUNGTRENNUNG
give b-substituted secondary amine products in high yields.
Furthermore, we show that this catalyst system can be incor-
porated into one-pot synthetic transformations, as illustrated
in the efficient catalytic preparation of 3-methyl-N-phenylin-
doline.
nated to generate the requisite tantalaziridine reactive inter-
mediate (Figure 1).[8] Thus, the use of readily prepared
TaMe3Cl2 for hydroaminoalkylation provides access to reac-
tions with high yield at reduced reaction temperatures, rea-
sonable reaction times, and with a significantly expanded
substrate scope, while avoiding amine by-product formation.
For a common screening reaction of N-methylaniline with
1-octene, it is shown in Table 1 that by changing from amido
ligands on the Ti precatalyst to benzyl ligands, improved
conversions were achieved, although reaction temperatures
of 1608C were required (Table 1, entries 1 and 2).[4b,c] Fur-
ther tuning of the reactivity of the metal center using an
auxiliary ligand, for example using Ind2TiMe2, results in en-
[a] Dr. Z. Zhang, J.-D. Hamel, Prof. Dr. L. L. Schafer
Department of Chemistry
University of British Columbia
2036 Main Mall, Institution
Vancouver, BC, V6T 1Z1 (Canada)
E-mail: schafer@chem.ubc.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300992.
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Table 2. Alkene substrate scope by using TaMe3Cl2 as a precatalyst.
Entry
1
Alkene
Product
t [h]
Yield [%][a]
88
15
2
3
30
31
81
93
4
5
35
20
84
81
Figure 1. Simplified proposed catalytic cycle showing methane elimina-
tion.
6
7
102
30
73
83
hanced conversions and short reaction times (Table 1,
entry 3).[4d] Notably, Ind2TiMe2 performed well on this par-
ticular substrate combination, but did suffer from a limited
substrate scope. For example, the reaction of p-methoxy-N-
methylaniline and styrene gave less than 5% yield.[4d] In a
shift to Group 5 catalysts for this transformation, the com-
8[b]
88
144
65
47
61
36
mercially available TaACHTNUGTRNEUG(N NMe2)5 gave no product at modest
reaction temperatures of 1108C (Table 1, entry 4). The
effect of the aforementioned electron-withdrawing chloride
substituent is shown in entry 5, in which good reactivity was
observed at only 908C.[5b] Our previously reported Ta ami-
9[c]
10[b]
date precatalyst [(2,6-iPr2C6H3NCACHTNUGTRENNUG(tBu)O)TaAHCTUNGTREN(NUGN NMe2)4] can
realize this transformation with extended reaction times at
1108C (Table 1, entry 6).[5c] The reactivity of TaMe3Cl2 is
comparable to the aforementioned Ta amidate complex
(Table 1, entry 7) and a catalyst loading of 10 mol% resulted
in near complete conversion in 30 h. Most importantly, fur-
ther investigation revealed a dramatically improved sub-
strate scope for the synthesis of a-alkylated unprotected sec-
ondary alkylaryl- and dialkylamines with this precatalyst.
By using simple TaMe3Cl2, we investigated the substrate
scope of this system with N-methylaniline as the limiting re-
agent and two equivalents of various alkenes. To our delight,
the reaction of N-methylaniline and methylenecyclohexane
was completed in only 15 h at 1108C (Table 2, entry 1). This
reaction generates a quaternary center b to N in one simple
catalytic transformation. In comparison, previous reports for
this substrate combination required reaction temperatures
of 1408C for 48 h to give the desired product in 72%
yield.[5g] As shown for entry 2 (Table 2), the more sterically
demanding terminal alkene, vinylcyclohexane, underwent
hydroaminoalkylation smoothly to give the corresponding
branched product in good yield. Notably, the results present-
ed herein are consistent with previous reports for Group 5
catalyzed hydroaminoalkylation catalysis, in which regiose-
lective alkene insertion results in the formation of the
branched product (Figure 1).[5] Styrene substrates also
worked very well in spite of its propensity for polymeriza-
11[b]
72
16
[a] Isolated yields. [b] T=1458C. [c] T=1308C.
tion in the presence of such Lewis acidic catalysts (Table 2,
entry 3). Implication of p-chlorostyrene gave products in
good yield with slightly longer reaction times (Table 2,
entry 4). Allylsilane is an effective reaction partner, and this
substituent pattern could allow further functional-group ma-
nipulation (Table 2, entry 5). Although extended times are
required, the reaction at the internal double bond of cyclo-
octene occurred at 1108C in 73% yield (Table 2, entry 6).
The ring strain of the cycloalkene starting material dramati-
cally affected hydroaminoalkylation reactivity, as shown in
entries 7 and 8 (Table 2), in which cycloheptene is much
more reactive than cyclohexene. Elevated reaction tempera-
tures were required for cyclohexene to give a product in
moderate yield. To the best of our knowledge, this is the
first report of cyclohexene as a possible substrate for hydro-
aminoalkylation. a-Methylstyrene has been previously re-
ported to be unreactive with Group 5 metal–binaphtholate
complexes.[5g] Using TaMe3Cl2, a-methylstyrene reacted with
N-methylaniline to give the corresponding hydroaminoalky-
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TaMe3Cl2-Catalyzed Intermolecular Hydroaminoalkylation
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lation product in moderate yield at 1308C with extended re-
action times (Table 2, entry 9). Impressively, the linear un-
strained internal alkene cis-3-hexene could also be used
with our catalyst, although a higher temperature and longer
reaction time were required. This is the first time that such
linear internal alkenes have been reported to be viable sub-
strates for hydroaminoalkylation reactivity (Table 2,
entry 10). To our delight, even the sterically demanding in-
ternal alkene 2-methyl-2-butene was observed to undergo
regioselective hydroaminoalkylation with N-methylaniline
to give the desired product, albeit in low isolated yield
(Table 2, entry 11).
conditions. However, as shown in entry 6, the heterocyclic
secondary amine tetrahydroquinoline shows good reactivity
at 1108C, although piperidines have not been successful sub-
strates, even when high reaction temperatures and long re-
actions times are used. Previously, dialkylamines have been
reported to be more challenging substrates than arylalkyl-
AHCTUNGTRENNUNG
amines for hydroaminoalkylation.[5b] However, TaMe3Cl2
can be used with cyclohexylmethylamine at only 1108C to
give both alkyl- or aryl-substituted products in good yields
(Entries 7 and 8).
For Group 5 precatalysts reported to date, only modest
functional-group incorporation at the olefin has been ex-
plored.[5] Halogen-substituted styrene derivatives are partic-
ularly attractive reaction partners, because they allow subse-
quent transformations through palladium-catalyzed coupling
protocols. Accordingly, we envisaged a facile, tandem reac-
tion to efficiently prepare indoline derivatives based on se-
quential Ta-catalyzed hydroaminoalkylation and Pd-cata-
lyzed Buchwald–Hartwig coupling in one pot. Biorelevant
targets, such as indolines,[9] are important heterocycles in the
pharmaceutical and agrochemical industries, and efficient
approaches for their syntheses are highly desirable. Herein,
we showed that by using the atom-economic TaMe3Cl2 pre-
catalyst, which eliminates amine by-product formation, the
clean formation of the hydroaminoalkylation product of N-
methylaniline and o-bromostyrene was achieved. This inter-
mediate can then undergo palladium-catalyzed intramolecu-
lar amination to give 3-methyl-N-phenylindoline in one pot
in 66% overall yield from commercially available precursors
(Scheme 1). This compares favorably with the reported syn-
thesis of 20 by reduction of an indoline-2-thione intermedi-
The observed broad alkene substrate scope encouraged us
to further evaluate viable amine substrates that can be used
with this catalyst system (Table 3). The reaction of p-me-
thoxy-N-methylaniline with 1-octene shows similar reactivity
Table 3. Amine substrate scope by using TaMe3Cl2 as a precatalyst.
Entry Amine
Alkene Product
t
Yield
[h] [%][a]
1
30
86
46
74
69
89
2
3[b]
4
5
39
76
6
86
71
6
7
8
46
Scheme 1. One-pot synthesis of 3-methyl-N-phenylindoline: one-pot
TaMe3Cl2-catalyzed hydroaminoalkylation of a-bromostyrene and palla-
dium-catalyzed cyclization.
37 84[c]
65 85[c]
ate in 37% yield.[10] This synthetic approach demonstrates
the compatibility of d0 Ta catalysts with late-transition-metal
redox-active catalysts for the development of one-pot se-
quential syntheses that take advantage of the atom-econom-
ic hydroaminoalkylation reaction.
[a] Isolated yields. [b] T=1008C. [c] Isolated as the tosyl-protected
amine.
to that of N-methylaniline, while the reaction with styrene
as a reaction partner is much slower (Entries 1 and 2). How-
ever, p-chloro-N-methylaniline showed improved reactivity
to that of N-methylaniline when reacted with styrene or cy-
cloheptene (Entries 3 and 4). The reaction of p-chloro-N-
methylaniline with methylenecyclohexane finished in only
6 h at 1108C (Entry 5). Ethyl- rather than methyl-substitut-
ed aniline derivatives were unreactive under these reaction
In conclusion, we have shown that TaMe3Cl2 is a readily
accessible and highly efficient hydroaminoalkylation catalyst
that can be used with a broad range of amine and alkene
substrates, including some known challenging starting mate-
rials, such as styrene, disubstituted terminal alkenes, internal
unstrained alkenes, and dialkylamines. To further distinguish
this catalyst system from previously reported tantalum–
amido complexes, TaMe3Cl2 did not generate any amine by-
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L. L. Schafer et al.
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products during the reaction due to the release of CH4 upon
precatalyst activation. This catalyst system can be used to ef-
ficiently install quaternary-carbon centers b to N and is
amenable to the development of one-pot reaction protocols,
as was illustrated in the efficient preparation of 3-methyl-N-
phenylindoline. Future work focuses on mechanistic investi-
gations to guide the development of auxiliary ligands to re-
alize asymmetric catalysis with Group 5 alkyl precatalysts.
Experimental Section
General procedure for TaMe3Cl2-catalyzed hydroaminoalkylation of al-
kenes: In
a nitrogen-filled glove box, TaMe3Cl2 (10 mol%), amine
(1 equiv), and olefin (1 equiv) were put into three small vials. TaMe3Cl2
was dissolved in C6D6 (0.50 mL). The amine and olefin were mixed and
added to the TaMe3Cl2 solution. The solution was transferred to an NMR
tube equipped with a Teflon cap, and the vials were rinsed with C6D6
(total volume 0.50 mL), in three rinses. The NMR tube was closed,
shaken, and the 1H NMR spectrum was recorded. The NMR tube was
placed in a preheated oil bath at the indicated temperature for the given
time. After confirmation of conversion by 1H NMR spectroscopy, the
crude reaction mixture was directly loaded onto a silica-gel column and
eluted by using a mixture of hexanes/EtOAc or hexanes/CH2Cl2.
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[7] Hydroaminoalkylation reactions by using Group 4 and Group 5
metal–amido precatalysts can require laborious product purification
protocols because of the contaminating dialkylamine by-products re-
sulting from hydroaminoalkylation of the dimethyl amine generated
upon precatalyst activation; see Ref. [3e–g, 4c].
Acknowledgements
J.-D.H. thanks NSERC for a USRA. L.L.S. thanks Dr. Pierre Garcia for
helpful discussion. The authors thank GreenCentre Canada for financial
support of this work. This research was undertaken, in part, thanks to the
Canada Research Chairs program.
À
C H
Keywords: alkylation
functionalization · hydroaminoalkylation · tantalum
·
atom-economic catalysis
·
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Received: March 15, 2013
Published online: && &&, 0000
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TaMe3Cl2-Catalyzed Intermolecular Hydroaminoalkylation
COMMUNICATION
Alkylation
Z. Zhang, J.-D. Hamel,
L. L. Schafer* ................. &&&& — &&&&
TaMe3Cl2-Catalyzed Intermolecular
Hydroaminoalkylation: A Simple
Complex for Enhanced Reactivity and
Expanded Substrate Scope
Tantalizingly simple: The common
organometallic starting material
TaMe3Cl2 can be used for the catalytic
for this readily accessed compound
includes unactivated terminal and
internal alkenes, styrene derivatives,
À
C H functionalization reaction, hydro-
aminoalkylation. The substrate scope
and both alkylaryl- and dialkyl sec
ACHTUNGERTNaNUNG ry amines (see scheme).
ACHTUNGTNERoNUNG nd-
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