C O M M U N I C A T I O N S
Table 2. Intermolecular Alkyne Hydroamination with Precatalyst 3a
efficiently cyclized by 3 (entries 7-10). Impressively, even a sterically
demanding cyclohexyl substituent on nitrogen can be accommodated
(entry 7). A commonly cited limitation for highly Lewis acidic catalysts
is poor functional group tolerance.1b These preliminary results show
that 3 is effective in the presence of an acid-sensitive protected catechol,
a pyrrole, and a tertiary aniline (entries 8, 9, and 10). These represent
the first examples of polar functional group tolerance from a group 4
alkene hydroamination catalyst.
In summary, this work represents a major step forward in the
development of a general group 4 hydroamination catalyst, as complex
3 displays significantly expanded substrate scope for both inter- and
intramolecular hydroamination and meets or exceeds the activity of
other systems.3 This precatalyst is effective with unactivated internal
olefins as well as primary and secondary amines and does not require
gem-disubstituents for cyclization. Importantly, complex 3 is chemo-
selective for hydroamination over hydroaminoalkylation.2b,11 The use
of this complex for the hydroamination of alkynes and alkenes with
secondary amines implies that Zr imido complexes need not be
intermediates for this transformation.2g Detailed kinetic and compu-
tational investigations are underway to gain mechanistic insight.
yield (%)b
entry
amine
alkyne
A
B
1
2
3
R1 ) Me, R2 ) Bn
piperidine
1,2,3,4-THIQ
morpholine
morpholine
morpholine
R3 ) Ph, R4 ) H
R3 ) Ph, R4 ) H
R3 ) Ph, R4 ) H
R3 ) Ph, R4 ) H
R3 ) Ph, R4 ) Me
R3 ) Ph, R4 ) Ph
R3 ) C8H17, R4 ) H
R3 ) C8H17, R4 ) H
93 (78)
80 (68)
92 (70)
97 (82)
57
<2
<2
<2
<2
<2
n/a
44
54e
4
5c
6c
7
44
morpholine
2,6-dimethylaniline
37
8d
29e
a [3] ) 0.075 M, [amine] ) 1.50 M, [alkyne] ) 0.750 M. b Yield
determined by 1H NMR using 1,3,5-trimethoxybenzene as internal
standard. Number in brackets is isolated yield after reduction. c Reaction
at 145 °C. d Reaction at 110 °C. e Yield of imine tautomer.
Table 3. Intramolecular Alkene Hydroamination with Precatalyst 3a
Acknowledgment. This contribution is dedicated to the memory
of Prof. Keith R. Fagnou. The authors gratefully thank Boehringer
Ingelheim (Canada) Ltd. and NSERC for supporting this work.
D.C.L. and P.R.P. thank NSERC for CGSD scholarships. L.L.S. is
an Alfred P. Sloan research fellow.
Supporting Information Available: Experimental details, charac-
terization data, and a CIF. This material is available free of charge via
References
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a Reactions in either d6-benzene or d8-toluene, [3] ) 0.075 M,
[substrate] ) 0.750 M. b Isolated yield. c Yield determined by 1H NMR
using 1,3,5-trimethoxybenzene as internal standard. d Diastereomeric
ratio determined by 1H NMR; major isomer shown. e Isolated yield of
N-tosyl derivative. f [3] ) 0.150 M.
Based on these encouraging results, the substrate scope of 3 for
intramolecular alkene hydroamination was further explored in known
challenging transformations (Table 3).10 First, complex 3 cyclizes
aminoalkenes that do not have gem-disubstituents (entries 1 and 2).
In addition to 5- and 6-membered rings, 3 also forms azepanes in high
yield, an unprecedented result for group 4 hydroamination (entries 3
and 4).11a Unactivated internal olefins are known to be very challenging
substrates for hydroamination;2b,3,4a however, 3 promotes these
reactions well (entries 5 and 6). Complex 3 also exhibits moderate to
excellent diastereoselectivity (entries 2 and 6). In all cases, no evidence
of hydroaminoalkylation side-reactivity is observed; complex 3 is
completely chemoselective for hydroamination, contrary to results with
other Ti and Zr systems.2b,11 Several secondary aminoalkenes are also
(9) See Supporting Information.
(10) Attempts to achieve intermolecular alkene hydroamination have been
unsuccessful thus far.
(11) (a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer,
L. L. J. Am. Chem. Soc. 2009, 131, 2116. (b) Kubiak, R.; Prochnow, I.;
Doye, S. Angew. Chem., Int. Ed. 2009, 48, 1153.
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