Tantalum catalyzed hydroaminoalkylation for the synthesis of α- And β-substituted N-heterocycles

Article abstract of DOI:10.1021/ol400729v

Unprotected secondary amines are directly alkylated by C-H functionalization adjacent to nitrogen, thereby opening new routes toward the synthesis of α- and β-alkylated N-heterocycles. α-Alkylated piperidine, piperazine, and azepane products are prepared from heterocycles and alkenes in an atom-economic reaction with excellent regio- and diastereoselectivity. β-Alkylated N-heterocycles are synthesized via a scalable one-pot alkylation/cyclization procedure generating 3-methylated azetidines, pyrrolidines, and piperidines.

Full text of DOI:10.1021/ol400729v

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2182–2185
Tantalum Catalyzed Hydroaminoalkylation
for the Synthesis of r- and β‑Substituted
N‑Heterocycles
Philippa R. Payne, Pierre Garcia, Patrick Eisenberger, Jacky C.-H. Yim, and
Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver,
B.C, Canada, V6T 1Z1
schafer@chem.ubc.ca
Received March 18, 2013
ABSTRACT
Unprotected secondary amines are directly alkylated by CÀH functionalization adjacent to nitrogen, thereby opening new routes toward the
synthesis of R- and β-alkylated N-heterocycles. R-Alkylated piperidine, piperazine, and azepane products are prepared from heterocycles and
alkenes in an atom-economic reaction with excellent regio- and diastereoselectivity. β-Alkylated N-heterocycles are synthesized via a scalable
one-pot alkylation/cyclization procedure generating 3-methylated azetidines, pyrrolidines, and piperidines.
Saturated N-heterocycles are key structural elements found
in a wide variety of natural products,1 pharmaceuticals,2 and
agrochemicals3 (Figure 1).4,5 Consequently, the rapid and
selective alkylation of these compounds from simple,
inexpensive, readily available chemicals is an attractive
route for their preparation. To this end, catalytic CÀH
functionalization has emerged as a selective and powerful
tool for the direct alkylation of sp3 hybridized CÀH bonds
adjacent to the nitrogen of amine substrates.6 The current
state-of-the-art approach for the direct alkylation and
arylation of saturated N-heterocycles has focused on stoi-
chiometric R-lithiation strategies,7 radical-based CÀH
activation,8 photoredox functionalization,9 ruthenium
catalyzed R-alkylation and arylation,10 Cu-catalyzed
cross-dehydrogenative couplings (CDC),11,6b and metal-
catalyzed carbene insertions.12 To date, these strategies all
require stoichiometric reagents, activated substrates, and/or
(7) These include coupled R-lithiation/electrophilic substitution, as
well as R-lithiation/transmetalation/palladium cross coupling: (a) Seel,
S.; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer,
P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774. (b) Beng, T. K.;
Gawley, R. E. Org. Lett. 2011, 13, 394. (c) Barker, G.; McGrath, J. L.;
Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.; O’Brie, P. J. Org.
Chem. 2011, 76, 5936. (d) Coldham, I.; Raimbault, S.; Whittaker,
D. T. E.; Chovatia, P. T.; Leonori, D.; Patel, J. J.; Sheikh, N. S.
Chem.;Eur. J. 2010, 16, 4082. (e) Barker, G.; O’Brien, P.; Campos,
K. R. Org. Lett. 2010, 12, 4176. (f) O’Brien, P.; Bilke, J. L. Angew.
Chem., Int. Ed. 2008, 47, 2734.
(8) For selected examples see: (a) Yoshimitsu, T.; Matsuda, K.;
Nagaoka, H.; Tsukamoto, K.; Tanaka, T. Org. Lett. 2007, 9, 5115. (b)
Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005, 127,
11610. (c) Suga, S.; Suzuki, S.; Yoshida, J.-I. J. Am. Chem. Soc. 2002,
124, 30.
(1) Heterocycles in Natural Product Synthesis; Majumdar, C. K.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2011.
(2) Recent reviews: (a) Dua, R.; Shrivastava, S.; Sonwane, S. K.;
Srivastava, S. K. Adv. Biol. Res. 2011, 5, 120. (b) Baumann, M.; Baxendale,
I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442.
(3) Recent patents featuring saturated N-heterocycles as potential
fungicides: (a) Bayer CropScience AG. WO2012104273 (A1). (b) Bayer
CropScience AG. WO2012052491 (A2).
(4) Miyazawa, M.; Yoshio, K.; Ishikawa, Y.; Kameoka, H. Tetra-
hedron 2004, 60, 7015.
(5) Miyazawa, M.; Yoshio, K.; Ishikawa, Y.; Kameoka, H. J. Agric.
Food. Chem. 1998, 46, 1059.
(6) For recent reviews see: (a) Mitchell, E. A.; Peschiulli, A.; Lefevre,
N.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2012, 18, 10092. (b) Li,
C.-J. Acc. Chem. Res. 2009, 42, 335. (c) Campos, K. R. Chem. Soc. Rev.
2007, 36, 1069. (d) Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351. (e)
Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443.
(9) Zhu, S.; Rueping, M. Chem. Commun. 2012, 48, 11960. For a
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r
10.1021/ol400729v
Published on Web 04/19/2013
2013 American Chemical Society

catalyst development reports have conceded that reactivity
with cyclic dialkylamine substrates is particularly chal-
lenging.14a,b,d,k Furthermore, ongoing catalyst development
efforts in our laboratories have shown that the amidate
supported tantalum complex 1 promotes unique reactivity,
as we have developed new catalysts with improved activity
and alkene substrate scope that cannot be used with piper-
idine.15 Here we explore the broader substrate scope of this
unique reactivity identified for Ta amidate precatalyst 1. The
direct R-alkylation of piperidines is explored and reactions
with azepanes and piperazines are disclosed for the first time.
The improved functional group tolerance observed during
these investigations also promoted the development of a one-
pot synthesis of β-methylated aminoalcohols, azetidines,
pyrrolidines, and piperidines featuring hydroaminoalky-
lation as a key step in their syntheses.
Figure 1. Natural products containing an R- or β-alkylated
N-heterocyclic core.4,5
protecting/directing groups on the nitrogen substituent. A
complementary and atom economic strategy for alkylation at
the R-position of unprotected secondary amines is early
transition-metal catalyzed hydroaminoalkylation (Scheme 1).13
Scheme 1. Intermolecular Hydroaminoalkylation
Figure 2. Tantalum amidate precatalyst 1.
To date, hydroaminoalkylation investigations using group
4 and 5 based catalyst systems have shown that secondary
arylalkyl and dialkyl acyclic amines can be efficiently pre-
pared.14 Indeed, substrate scope investigations of such re-
cently developed systems have repeatedly shown that the only
N-heterocycle that can undergo direct CÀH functionaliza-
tion is 1,2,3,4-tetrahydroquinoline.14e,i,k,m One reported ex-
ample of the hydroaminoalkylation of piperidine (Table 1,
entry 1) was disclosed by our group over 3 years ago using Ta
amidate precatalyst 1 (Figure 2).14i Since that time, several
The exploration of substrate scope builds upon the single
previous report of using piperidine for the hydroaminoalk-
ylation of 1-octene (Table 1, entry 1).14i Typically, pyrroli-
dines are preferred over piperidine substrates for R-lithiation
strategies7e,10c,16 and Ru catalyzed R-alkylation.10a Thus the
direct alkylation of larger N-heterocycles such as piperidines
and azepanes presented here is complementary to other
established approaches. Using 5 mol % of 1, an internal
alkene, norbornene, can undergo hydroaminoalkylation
with piperidine (Table 1, entry 2). Protected alcohols can
be incorporated into the alkene, providing a site for further
functionalization of the amine product (Table 1, entry 3).
Alternatively, a piperidine with a protected carbonyl sub-
stituent is shown to be compatible with this early transition
metal catalyst (Table 1, entry 4).
ꢀ
(10) (a) Bergman, S. D.; Storr, T. E.; Prokopcova, H.; Aelvoet, K.;
Diels, G.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2012, 18, 10393.
For recent reviews, see: (b) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (c)
ꢀ
Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout,
W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J.
2010, 16, 13063 and references therein.
(11) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2011,
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D. W. J. Am. Chem. Soc. 2003, 125, 6462. (b) Doyle, M. P.; Duffy, R.;
Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.
(13) Roesky, P. W. Angew. Chem., Int. Ed. 2009, 48, 4892.
With such functional group tolerance established for 1,
1,2,3,4-tetrahydroquinoline can be used for the hydroamino-
alkylation of olefinic silyl ethers (Table 1, entries 5, 6).
Impressively, larger heterocyclic rings such as azepane can
also be used, however decreased diastereoselectivity is observed
(Table 1, entry 7). The direct alkylation of N-substituted
piperazines was then explored (Table 1, entries 8À12).17
Remarkably, this reaction is tolerant to various substitu-
ents on the distal nitrogen, including p-methoxyphenyl
and benzhydryl which allow for subsequent deprotection.
Good yields are obtained with both alkyl and benzylic
olefins (Table 1, entries 11, 12). Efforts to directly alkylate
€
(14) (a) Dorfler, J.; Doye, S. Angew. Chem., Int. Ed. 2013, 52, 1806.
(b) Reznichenko, A. L.; Hultzsch, K. C. J. Am. Chem. Soc. 2012, 134,
3300. (c) Jaspers, D.; Saak, W.; Doye, S. Synlett 2012, 23, 2098–2102. (d)
€
Reznichenko, A. L.; Emge, T. J.; Audorsch, S.; Klauber, E. G.;
Hultzsch, K. C.; Schmidt, B. Organometallics 2011, 30, 921. (e) Zhang,
F.; Song, H.; Zi, G. Dalton Trans. 2011, 40, 1547. (f) Zi, G.; Zhang, F.;
Song, H. Chem. Commun. 2010, 46, 6296. (g) Kubiak, R.; Prochnow, I.;
Doye, S. Angew. Chem., Int. Ed. 2010, 49, 2626. (h) Bexrud, J. A.;
Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. J. Am. Chem.
Soc. 2009, 131, 2116. (i) Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M. P.;
Schafer, L. L. Angew. Chem., Int. Ed. 2009, 48, 8361. (j) Kubiak, R.;
Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009, 48, 1153. (k)
Prochnow, I.; Kubiak, R.; Frey, O. N.; Beckhaus, R.; Doye, S. Chem.
Catal. Chem. 2009, 1, 162. (l) Herzon, S. B.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 14940. (m) Herzon, S. B.; Hartwig, J. F. J. Am. Chem.
Soc. 2007, 129, 6690. (n) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J.
Organometallics 1983, 2, 161. (o) Preuß, T.; Saak, W.; Doye, S.
Chem.;Eur. J. 2013, 19, 3833.
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Press.
(16) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(17) Attempted hydroaminoalkylation with parent piperazine, mor-
pholine, and thiomorpholine was unsuccessful.
Org. Lett., Vol. 15, No. 9, 2013
2183

strained metallaziridine intermediate has been consistently
observed for group 5 hydroaminoalkylation.14b,d,f,i,l,m In the
case of hydroaminoalkylation with heterocycles, the alkene
substituent R would be proposed to be on the opposite face
of the 5-membered metallacyclic intermediate A formed
with the heterocyclic ring. This would result in both regio-
selective and diastereoselective hydroaminoalkylation with
N-heterocyclic substrates. Indeed, this selectivity proposal
has been confirmed by X-ray crystallography. Derivitization
of the crude product of Table 1, entry 3 with p-toluenesulfo-
nyl chloride generated a white solid 2 that could be recrys-
tallized for rigorous analysis (Scheme 2). The solid state
molecular structure shows the formation of the anticipated
diastereomer of the branched, monoalkylated product.
Table 1. Hydroaminoalkylation of Saturated N-Heterocycles
Scheme 2. Postulated Mechanism for Tantalum Catalyzed
Hydroaminoalkylation and ORTEP Representation of the
Solid-state Molecular Structure of 2a
a Stereochemistry assigned by analogy to 2. TBS, tert-butyldimethyl-
silyl; Cy, cyclohexyl; Bn, benzyl; PMP, p-methoxyphenyl; Bhyd,
benzhydryl. b Isolated after N-tosylation. c Determined by 1H NMR
spectroscopy of isolated product. d Reaction time was not optimized.
e Reaction at 145 °C and product isolated as the free amine. f 5 mol % 1.
a Ellipsoids plotted at 50% probability, only select hydrogens shown.
Product yields are variable and unreacted heterocyclic
starting materials can be observed upon reaction comple-
tion. Interestingly, no over alkylation is observed under
these rather forcing reaction conditions, even in the pres-
ence of excess alkene. This selective monoalkylation can be
rationalized based upon the sensitivity of this catalyst
system to steric bulk. For example, no reaction is observed
when using 2-methylpiperidine and 1-octene with these
reaction conditions.
Hydroaminoalkylation precatalyst 1 can be used to effi-
ciently prepare a variety of R-alkylated N-heterocycles
(Table 1). Scheme 1 shows that selectively β-methylated
acyclic amines can be prepared using hydroaminoalkylation.
The functional group tolerance of precatalyst 1 suggested
5-membered N-heterocycles such as pyrrolidine and indo-
line were not successful and catalyst decomposition was
observed.18
In all cases the regio- and diastereoselectivity of this
transformation is excellent and typically only one isomer is
detected when monitoring the reaction by NMR spectro-
scopy. Upon the basis of the mechanistic proposal for
hydroaminoalkylation (Scheme 2),14b,i,n excellent selectivity
is anticipated due to the proposed formation of metallacyclic
intermediates. Regioselective alkene insertion into the
(18) Red precipitates observed following addition of indoline and
fully characterized. See Supporting Information.
2184
Org. Lett., Vol. 15, No. 9, 2013

Table 2. One-pot Synthesis of β-Methyl N-Heterocycles
Scheme 3. Synthesis of β-Methylated γ-Aminoalcohols by
Hydroaminoalkylation
that hydroaminoalkylation could also be used for the cata-
lytic synthesis of β-methylated aminoalcohols (Scheme 3)
and β-methylated N-hetereocycles (Table 2).
As shown in Scheme 3, various β-methylated aminoal-
cohols can be prepared by the hydroaminoalkylation of
alkenes with t-butyldimethyl silyl protected alcohol sub-
stituents and subsequent deprotection. Notably, here we
report the first example of hydroaminoalkylation of an
allylalcohol derivative with N-methyl-p-methoxyaniline.
After deprotection, the β-methylated γ-aminoalcohol 3 is
isolated in 91% yield.
a Isolated yields. b Performed on gram scale.
medicinal chemistry perspective.20 These preliminary re-
sults show that hydroaminoalkylation affords an alternative
disconnection for the general and straightforward access to
β-methylated azetidines, pyrrolidines, and piperidines.
In summary, we have shown that hydroaminoalkylation
can be used as a key synthetic step in substituted hetero-
cycle synthesis. Two complementary methods to access
R- and β-substituted N-heterocycles, as well as β-methy-
lated aminoalcohols from simple amine and alkene start-
ing materials have been explored. The R-CÀH activation/
alkylation of unprotected piperidine, piperazine, and aze-
pane substrates with precatalyst 1 proceeds with excellent
selectivity generating one diastereomer of the branched
product. The formation of β-methylated azetidine, pyrro-
lidine, and piperidine compounds in an alkylation/cycliza-
tion, one-pot procedure highlights an alternative approach
for the synthesis of these medicinally relevant compounds.
On-going work focuses on catalyst development to reduce
reaction times and temperatures, improve substrate
scope, and functional group tolerance. Most impor-
tantly, broadly useful enantioselective catalysts for this
emerging catalytic route for amine and N-heterocycle
synthesis are targeted.
Alternatively, rather than a simple deprotection, the
conversion of the silyl protected alcohol into a suitable
leaving group for nucleophilic substitution was envisioned,
using the recently developed method of Gembus.19 Thus,
β-methylated N-heterocycles can be prepared using a one-
pot method with commercially available p-toluenesulfonyl
fluoride to install a leaving group in situ (Table 2). We
examined first the R-alkylation and cyclization using
N-methylaniline and t-butyldimethyl(pent-4-enyloxy)silane
(Table 2, entry 1). After full conversion of the starting
amine, using 5 mol % of 1, to the alkylated intermediate,
as monitored by 1H NMR spectroscopy, TsF and DBU can
be added directly to the reaction mixture and then warmed
to 130 °C for cyclization. This transformation is also
applicable to anilines bearing electron donating and with-
drawing substituents (Table 2, entries 2, 3). Most impor-
tantly, this synthetic approach has been shown to be
ammenable to gram scale reactions (Table 2, entries 2, 3).
The possibility of incorporating aryl halogen containing
substrates is attractive due to the high utility of such
functionalities in late transition metal catalyzed synthetic
transformations (Table 2, entry 3). Entries 4 and 5 show that
pyrrolidines can also be accessed. Notably, this procedure is
even applicable to the construction of small, strained rings
such as methylated azetidines (Table 2, entry 6).
Acknowledgment. We gratefully thank Boehringer In-
gelheim (Canada) Ltd. and NSERC for supporting this
work. P.R.P and J.C.-H.Y. thank NSERC for doctoral
scholarships. P.E. thanks the Swiss National Science
Foundation for a PDF.
Such β-substituted N-heterocycles are of particular in-
terest as they are present in the cores of natural products,
and their efficient, modular syntheses are desirable from a
(19) Gembus, V.; Marsais, F.; Levacher, V. Synlett 2008, 1463.
(20) (a) Han, Y.; Han, M.; Shin, D.; Song, C.; Hahn, H.-G. J. Med.
Chem. 2012, 55, 8188. (b) Trump, R. P.; Blanc, J.-B. E.; Stewart, E. L.;
Brown, P. J.; Caivano, M.; Gray, D. W.; Hoekstra, W. J.; Willson,
T. M.; Han, B.; Turnbull, P. J. Comb. Chem. 2007, 9, 107. (c) Provins, L.;
Supporting Information Available. Experimental details,
characterization data, and CIF files. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
ꢀ ꢀ
Christophe, B.; Danhaive, P.; Dulieu, J.; Gillard, M.; Quere, L.;
Stebbins, K. Bioorg. Med. Chem. Lett. 2007, 17, 3077.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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