Intramolecular hydroamination of unactived olefins with Ti(NMe 2)4 as a precatalyst

Article abstract of DOI:10.1021/ol0503992

(Chemical Equation Presented) Commercially available Ti(NMe ₂)₄ has been used effectively as a precatalyst in a facile protocol for the intramolecular hydroamination of aminoalkenes to yield pyrrolidine and piperidine heterocyclic pr

Full text of DOI:10.1021/ol0503992

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1959-1962
Intramolecular Hydroamination of
Unactived Olefins with Ti(NMe2)4 as a
Precatalyst
Jason A. Bexrud, J. David Beard, David C. Leitch, and Laurel L. Schafer*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia, Canada V6T 1Z1
schafer@chem.ubc.ca
Received February 23, 2005
ABSTRACT
Commercially available Ti(NMe2)4 has been used effectively as a precatalyst in a facile protocol for the intramolecular hydroamination of
aminoalkenes to yield pyrrolidine and piperidine heterocyclic products with isolated yields up to 92%. Geminally substituted substrates display
the highest reactivity. This precatalyst is also effective for the hydroamination of activated internal alkenes, providing access to more complex
heterocyclic target molecules.
The catalytic addition of N-H across a carbon-carbon
multiple bond (hydroamination) is an intense area of
investigation with many recent results highlighting the
hydroamination of alkynes to yield enamine and imine
products.1 This synthetic transformation is desirable due to
the highly atom-economic synthesis of imines from readily
available starting materials, and the extension of these efforts
toward the hydroamination of alkenes continues to be an
important area of research.2 To this end, Marks and co-
workers have pioneered the area of olefin hydroamination
with a wide range of highly active lanthanide catalysts that
are effective for intramolecular versions of this transforma-
tion3 as well as select intermolecular versions.4 Our research
group and others have furthered these efforts in lanthanide
and group 3 catalyzed olefin hydroaminations to include
noncyclopentadienyl complexes that display desirable reac-
tivity trends.5 Unfortunately, all of the aforementioned group
3 and lanthanide catalysts display limited functional group
tolerance and high moisture sensitivity, making their routine
preparation and application in synthesis problematic.
In an effort to develop catalytic systems that are more
robust, functional group compatible, and easily handled, late
transition metal catalysts are being developed to mediate both
the intermolecular alkene hydroamination reaction2d,6 and,
more recently, the intramolecular hydroamination of ami-
(5) (a) Lauterwasser, F.; Hayes, P. G.; Brase, S.; Piers, W.; Schafer, L.
L. Organometallics 2004, 23, 2234. (b) Hong, S.; Tian, S.; Metz, M. V.;
Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768. (c) O’Shaughnessy, P.
N.; Knight, P. D.; Morton, C.; Gillespie, K. M.; Scott, P. Chem. Commun.
2003, 1770. (d) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. Chem. Eur. J.
2003, 9, 4796. (e) Hultzsch, K. C.; Hampel, F.; Wagner, T. Organometallics
2004, 23, 2601. (f) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron
Lett. 2001, 42, 2933. (g) Kim, Y. K.; Livinghouse, T.; Horino, Y. J. Am.
Chem. Soc. 2003, 125, 9560. (h) Collin, J.; Daran, J.-C.; Schulz, E.;
Trifonov, A. Chem. Commun. 2003, 3048. (i) Zulys, A.; Panda, T. K.;
Gamer, M. T.; Roesky, P. W. Chem. Commun. 2004, 2584.
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123, 4366. (b) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 1166. (c) Fadini, L.; Togni, A. Chem. Commun. 2003, 30. (d) Senn,
H. M.; Blochl, P. E.; Togni, A. J. Am. Chem. Soc. 2000, 122, 4098. (e)
Brunet, J.-J.; Cadena, M.; Chu, N. C.; Diallo, O.; Jacob, K.; Mothes, E.
Organometallics 2004, 23, 1264.
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E.; Yan, Y.-K. Organometallics 2002, 19, 170. (b) Pohlki, F.; Doye, S.
Chem. Soc. ReV. 2003, 104. (c) Muller, T. E.; Beller, M. Chem. ReV. 1998,
98, 675 and references therein.
(2) (a) Brunet, J.-J.; Neibecker, D. In Catalytic Hetero-functionalization;
Togni, A., Grutzmacher, H., Eds.; VCH: Weinheim, 2001; Vol. 98, pp
675-704. (b) Nobis, M.; Driessen-Holscher, B. Angew. Chem., Int. Ed.
2001, 40, 3983. (c) Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed.
2003, 42, 2708. (d) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507 and
references therein.
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12584. (b) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770.
10.1021/ol0503992 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/09/2005

noalkenes.7 However, the intermolecular reactions are largely
limited to activated terminal olefins, such as vinylarenes and
dienes,2d alkenes substituted with electron-withdrawing
groups,6c or highly strained alkenes, such as norbornene.8
While significant progress has been made in this area, the
hydroamination of alkenes remains an important synthetic
challenge with no generally applicable catalysts having been
reported.
utilizes simple syringe techniques to deliVer a modest catalyst
loading of 5 mol % to solutions of aminoalkene substrates.
Initial experiments focused on the intramolecular hy-
droamination of the easily prepared 2,2-diphenyl-4-pente-
nylamine (1) substrate (eq 1).5b The catalytic reaction was
performed in toluene at 110 °C with a 5 mol % precatalyst
Hydroamination catalysis with group 4 transition metals
is an area of intense investigation.9 The hydroamination of
alkynes using these catalyst systems is well established with
several systems having been developed for the regioselective
hydroamination of both internal and terminal alkynes with
a wide range of substrates.9b,e,m,10 Notably, the application
of commercially available Ti(NMe2)4 for both the intra- and
intermolecular hydroamination of alkynes and allenes has
been reported.11 However, the hydroamination of alkenes
using titanium remains a significant challenge with the only
reported examples of early transition metals being used for
this transformation requiring the highly strained norbornene
olefin with select aniline derivatives.12 Alternatively, more
reactive group 4 cationic catalysts, which are isoelectronic
to known group 3 systems, have been shown to carry out
intramolecular alkene hydroamination with secondary amines
exclusively.13 Once again, these cationic complexes are
plagued with extreme moisture sensitivity and furthermore,
they are ineffective for the hydroamination of alkenes with
primary amines. Herein we report the first examples of
titanium-catalyzed hydroamination of unactivated alkenes in
an intramolecular fashion to yield pyrrolidines and pip-
eridines (eq 1) in excellent yields. Most importantly, these
reactions are mediated by the commercially aVailable
titanium precatalyst, Ti(NMe2)4, in a facile protocol that
1
loading for 24 h. By using H NMR spectroscopy, the
characteristic disappearance of two olefin signals centered
at δ 5.44 and 4.95 ppm and the appearance of two new proton
signals at δ 2.38 and 1.80 ppm were used to measure the
progress of the reaction. On an NMR tube scale, it was noted
that the reaction had proceeded to completion within 1 h at
110 °C. We wondered if the highly elevated temperatures
were required, and thus, we also performed this reaction at
reduced temperatures, such as 70 and 45 °C. At these lower
temperatures, within 2.5 h, the desired products were
observed to form in 70% and 38% conversion, respectively,
and no appreciable reaction was seen at room temperature
in this period of time. However, unidentified alkene-
containing side products (as indicated by the appearance of
1
new olefinic peaks in the H NMR spectrum) were also
formed, and prolonged reaction times did not result in the
clean product formation that had been observed in the 110
°C experiment. Consequently, the higher temperature pro-
tocol was employed for all subsequent investigations.
To verify that this precatalyst is amenable to the milligram-
scale preparation of this class of desirable heterocyclic
products, the reaction shown in eq 1 was performed using
131 mg (0.55 mmol) of the starting material. The requisite
aminoalkene 1 was purified by distillation from CaH2. In
the other cases reported here, amines were purified by
distillation and dried over 4 Å molecular sieves for ap-
proximately 24 h before use. Under inert atmosphere, a
solution of 1 was prepared in approximately 2 mL of toluene
before loading 9.0 µL of commercially available Ti(NEt2)4
precatalyst by microsyringe. (It should be noted that Ti-
(NMe2)4 and Ti(NEt2)4 can be used interchangeably for these
reactions.) The reaction mixture was heated to 110 °C for
24 h and quenched with CH2Cl2, and then all volatiles were
removed in vacuo to give a brown oily solid that could be
purified by column chromatography and isolated in 92%
yield (Table 1, entry 1). With both catalytic activity and ease
of synthetic protocol established for Ti(NR2)4 as a precatalyst,
preliminary investigations of the scope of the reaction were
undertaken.
(7) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
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tallics 2001, 20, 5011. (c) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem.,
Int. Ed. 1999, 38, 3389. (d) Johnson, J. S.; Bergman, R. G. J. Am. Chem.
Soc. 2001, 123, 2923. (e) Khedkar, V.; Tillack, A.; Beller, M. Org. Lett.
2003, 5, 4767. (f) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer,
L. L. Chem. Commun. 2003, 2462. (g) Walsh, P. J.; Baranger, A. M.;
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Organometallics 2002, 21, 2839. (k) Pohlki, F.; Doye, S. Angew. Chem.,
Int. Ed. 2001, 40, 2305. (l) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.;
Odom, A. L. Chem. Commun. 2003, 586. (m) Tillack, A.; Castro, I. G.;
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A.; Pohlki, F.; Doye, S. Chem. Eur. J. 2004, 10, 3059. (c) Tillack, A.;
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20, 3967. (b) Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475.
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2519.
In Table 1, the dramatic Thorpe-Ingold effect on the
intramolecular hydroamination, as mediated by this catalyst,
is apparent. Only the geminally substituted substrates undergo
intramolecular hydroamination within 24 h (entries 1-3),
and as the steric bulk of the substituent is reduced, the
efficiency of this reaction is also reduced (entry 1 compared
with entry 3). In the case of the 2,2-dimethyl-4-penteny-
lamine substrate (entry 3) it should be noted that the volatility
(13) (a) Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004,
43, 5542. (b) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P.
Chem. Commun. 2004, 894.
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Org. Lett., Vol. 7, No. 10, 2005

Table 1. Scope of Reactivity with Ti(NMe2)4 as a Precatalyst
Figure 1. Proposed mechanism for titanium catalysis of olefin
hydroamination.
possibility of olefin insertion into a Ti-N σ-bond, as has
been established in the case of group 3, lanthanide, and
cationic group 4 mediated intramolecular olefin hydroami-
nation, could not be ruled out with the aforementioned
experiments.4b,5a,13 Consequently, the related substrate con-
taining a secondary amine was prepared (2) and was tested
for olefin hydroamination activity with Ti(NMe2)4 precatalyst
(eq 2). Elevated reaction temperatures and prolonged reaction
times did not result in the formation of the desired N-
substituted pyrrolidine product. Our observations support the
proposal that catalysis is proceeding via the in situ prepara-
tion of a titanium imido species, consistent with the better-
understood alkyne hydroamination examples reported in the
literature. However, rigorous isolation, characterization, and
comparative reactivity studies of related titanium imido
complexes is an area of current research focus.
a Isolated yield. b Yield determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. c Isolated yield following
derivatization using benzoyl chloride. d Ratio determined by GCMS.
of the resultant product required its derivatization with
benzoyl chloride to obtain an isolated yield. Both five-
membered (entry 1) and six-membered (entry 2) heterocyclic
products can be prepared using this precatalyst in very good
isolated yields. It should be noted that by 1H NMR
spectroscopy these reactions were observed to proceed to
>98% conversion. However, the comparable seven-mem-
bered ring could not be prepared, even when the appropriate
geminally substituted substrate and extended reaction times
(up to 240 h) were used. With only a single substituent on
the ring, the reaction times need to be extended up to 170 h
to obtain even modest yields. However, in the absence of
substituents on the substrate, no intramolecular hydroami-
nation activity is observed, regardless of reaction times and
reaction temperatures up to 140 °C in xylenes-d10 (entry 7).
The dramatic effect of geminally substituted substrates is
consistent with a chairlike transition state (B, Figure 1) that
has been proposed as the transition state for intramolecular
hydroamination reactions.3b,5a However, what was not clear
from these experiments was the nature of the reactive Ti-N
bond in the catalytically reactive species (A, Figure 1).
Bergman, Doye, Odom, Mountford, and work in our
laboratories have shown that for the catalytic hydroamination
of alkynes A is a titanium imido species.9d,k,14 However, the
The proposed chairlike transition state and dramatic impact
of steric effects upon the observed rates of reaction suggest
that diastereoselectivity could be achieved in the cases of
entries 4-6. Indeed, modest diastereoselectivities were
observed in the case of monosubstituted substrates (entries
4 and 5). Interestingly, when two different substituents of
more similar steric demands (Ph and Me) were incorporated
into the geminally substituted substrate (entry 6), comparable
(14) (a) Li, Y.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2004, 126, 1794.
(b) Ward, B. D.; Maisse-Francois, A.; Mountford, P.; Gade, L. H. Chem.
Commun. 2004, 704. (c) Li, C. M.Sc. Thesis, University of British Columbia,
Vancouver, BC, 2003.
Org. Lett., Vol. 7, No. 10, 2005
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diastereoselectivity to the Ph, H substituted example (entry
4) was observed. For entries 4 and 6, the major diastereomer
was isolated by column chromatography, and selective NOE
NMR spectroscopic experiments confirmed that the syn
products were preferred over the anti products. The observed
diastereoselectivity is consistent with the chairlike transition
state and the equatorial location of the larger of the two
substituents.15 Due to the elevated temperatures required to
promote the desired reactivity and the distal location of the
stereo-differentiating substituents, the poor diastereoselec-
tivity observed in this reaction is not surprising and is
consistent with previous reports of diastereoselectivity for
the intramolecular hydroamination of substrates with sub-
stituents in the 2 position.16
revealed that an activated olefin, such as the styrene
derivative shown in 3, is required and bis-alkyl substituted
olefins remained inert to the catalytic conditions described
above.
In summary, we have established that commercially
available Ti(NMe2)4 may be used in a facile protocol for
the catalytic preparation of pyrrolidine and piperidine
heterocyclic products from aminoalkene substrates in good
yields. This reaction is particularly efficient for geminally
substituted substrates and proceeds with predictable, although
modest, diastereoselectivity due to the chairlike transition
state of the intramolecular hydroamination reaction. Substrate
screening provided qualitative results consistent with a
catalytic mechanism invoking the in situ preparation of a
catalytically active titanium imido species, and more detailed
mechanistic investigations are underway. Most importantly,
this simple precatalyst is effective for the intramolecular
hydroamination of not only terminal alkenes, but also
activated internal alkenes. These preliminary results encour-
age the development of new, neutral, titanium catalysts for
the hydroamination of alkenes and current efforts focus on
the development of chiral titanium catalysts for the enanti-
oselective synthesis of N-containing heterocycles.
To further probe the substrate tolerance of the Ti(NMe2)4
precatalyst, we investigated its use for the hydroamina-
tion of internal alkenes. In particular, substrate 3 was pre-
pared and tested for intramolecular hydroamination (eq 3).
Acknowledgment. We thank the Natural Science and
Engineering Research Council of Canada (NSERC), Boe-
hringer Ingelheim Canada Ltd., and the University of British
Columbia for financial support of this work.
A prolonged reaction time of 4 days (96 h) was required to
obtain the desired product with an isolated yield of 67% (77%
conversion as observed by 1H NMR spectroscopy). However,
further investigations into the application of internal alkenes
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Based on the relative A values for Ph and Me substituents; see:
Allinger, N. L.; Freiberg, L. A. J. Org. Chem. 1966, 31, 804. Eliel, E. L.;
Manoharan, M. J. Org. Chem. 1981, 46, 1959.
(16) Kim, Y. K.; Livinghouse, T. Angew. Chem., Int. Ed. 2002, 41, 3645.
OL0503992
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