Pd(II)-catalyzed intramolecular 1,2-aminoalkylation of conjugated 1,3-dienes for the synthesis of pyrrolizidines

Article abstract of DOI:10.1021/ol401901h

A palladium(II)-catalyzed tandem cyclization reaction involving an intramolecular 1,2-aminoalkylation of N-4,6-dienyl β-keto amides has been developed. This process provides an efficient method for the rapid assembly of pyrrolizidines starting from linear substrates in moderate to good yields and high to excellent diastereoselectivities.

Full text of DOI:10.1021/ol401901h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd(II)-Catalyzed Intramolecular
1,2-Aminoalkylation of Conjugated
1,3-Dienes for the Synthesis of Pyrrolizidines
Dong Xing†,‡ and Dan Yang*,†
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong,
China, and Shanghai Engineering Research Center of Molecular Therapeutics and New
Drug Development, East China Normal University, No. 3663 North Zhongshan Road,
Shanghai, China
yangdan@hku.hk
Received July 7, 2013
ABSTRACT
A palladium(II)-catalyzed tandem cyclization reaction involving an intramolecular 1,2-aminoalkylation of N-4,6-dienyl β-keto amides has been
developed. This process provides an efficient method for the rapid assembly of pyrrolizidines starting from linear substrates in moderate to good
yields and high to excellent diastereoselectivities.
Pd(II)-catalyzed addition of nitrogen nucleophiles to
alkenes (aminopalladation) is a well-established process
for the construction of CÀN bonds in modern organic
chemistry.1 This process has been involved in different
types of intramolecular difunctionalization of alkenes for
tandem CÀN and CÀX (X = N, O, C, halide, etc.) bond
formations.2À5 Within this context, the intramolecular
aminoalkylation of alkenes (tandem CÀN and CÀC bond
formations) is particularly appealing for their efficiency in
synthesizing different types of nitrogen-containing hetero-
cycles, which are common motifs widely existing in natural
products and pharmaceuticals. Hegedus and Tamaru have
extensively developed the Pd(II)-catalyzed aminocarbony-
lation of alkenes by employing CO as the carbon source.6
† The University of Hong Kong.
‡ East China Normal University.
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r
10.1021/ol401901h
XXXX American Chemical Society

Wolfe and co-workers reported the Pd(0)-catalyzed ami-
noarylation of amino-tethered alkenes with aryl bromides.7
Michael and co-workers reported a novel example in which
a Pd(II)-catalyzed aminoarylation of alkenes was utilized
via CÀH activation of arenes.8 In recent years, our research
group has developed a series of Pd(II)-catalyzed intramole-
cular aminoalkylation of alkenes by applying a Heck-type
termination of the aminopalladation process with an in-
tramolecularly tethered alkene moiety.9 As part of our
continuous interest in developing new tandem cyclization
reactions under Pd(II)-catalyzed oxidative conditions, here-
in we report a highly efficient Pd(II)-catalyzed intramole-
cular 1,2-aminoalkylation of N-4,6-dienyl β-keto amides for
the synthesis of pyrrolizidines.
CÀC bond formations) have not been explored. Based on
this 1,3-diene-involving catalytic mode, we hypothesized
that, under Pd(II) catalytic conditions, in the presence of a
tethered diene, a β-keto amide would act as a 2-fold
nucleophile responsible for both CÀN and CÀC bond
formation to undergo an overall intramolecular 1,2-ami-
noalkylation via a sequence of aminopalladation/Pd(II)
π-allyl species formation/2nd nucleophilic addition (Figure 1).
Table 1. Optimization of Reaction Conditionsa
yieldb
entry
cat.
additive
solvent
(%)
1
2
3
4
5c
6
7
8
9
Pd(OAc)2
À
DMSO
DMSO
24
Pd(OAc)2 Cu(OTf)2
Pd(OAc)2 Cu(OTf)2
Pd(OAc)2 Cu(OTf)2
Pd(OAc)2 Cu(OTf)2
Pd(TFA)2 Cu(OTf)2
35
47
DMSO/PhMe (1/4)
Figure 1. Proposed intramolecular 1,2-aminoalkylation.
DMSO/PhMe (5% v/v) 56
PhMe <5
DMSO/PhMe (5% v/v) 78(76)d
It has been reported that, under Pd(II) catalytic condi-
tions, 1,3-dienes could undergo different types of oxidative
nucleophilic difunctionalization.10 In the presence of the
adjacent alkene moiety, the Pd(II)-alkyl intermediate gen-
erated by the initial nucleopalladation could be rapidly
converted into a more electrophilic π-allyl species, there-
fore allowing a second nucleophilic attack to establish an
Pd(TFA)2 Cu(OAc)2 DMSO/PhMe (5% v/v) <5
Pd(TFA)2
À
DMSO/PhMe (5% v/v) 34
DMSO/PhMe (5% v/v) <5
À
Cu(OTf)2
a All reactions were carried out on a 0.3 mmol scale. b Yield deter-
mined by 1H NMR using nitrobenzene as internal standard. c With
20 mol % (0.06 mmol) DMSO. d Isolated yield shown in the parentheses.
overall tandem sequence.2f,10 Following Backvall’s pioneer-
€
The Pd(II) catalyst in DMSO has been proven as an
efficient catalyst system for both oxidative amination
reactions12 and the alkylation of Pd(II) π-allyl species;13
therefore it would be a good catalytic system for the initial
investigation of our hypothesized intramolecular 1,2-ami-
noalkylation. As the starting point, (E)-N-(2,2-diphenyl-
hepta-4,6-dienyl)-3-oxobutanamide 1a was synthesized
and subjected to 10 mol % of Pd(OAc)2 in DMSO under
1 atm of O2. To our delight, the desired product 2a was
obtained as a single diastereomer in 24% yield (Table 1,
entry 1). Inspired by this result, further optimizations were
conducted toimprovethe efficiencyof this transformation.
To enhance the nucleophilic ability of the acidic methylene
moiety, different Lewis acids were tested,14 however, only
Cu(OTf)2 could slightly enhance the product yield
(Table 1, entry 2). Changing the solvent from DMSO to
a 1:4 mixture of DMSO in toluene enhanced the yield to
47% (Table 1, entry 3); an even higher yield was achieved
when5% v/v DMSOin toluene wasused (Table1, entry 4).
ing work on a series of Pd(II)-catalyzed 1,4-difunctionaliza-
tion of 1,3-dienes,11 intramolecular 1,4-diamination,10a 1,2-
diamination,10b and 1,2-dialkylation of 1,3-dienes10c,d have
been recently developed. However, intramolecular transfor-
mations involving different bond formations (i.e., CÀN and
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J. P. Synthesis-Stuttgart 2012, 44, 351. (b) Ney, J. E.; Wolfe, J. P. Angew.
Chem., Int. Ed. 2004, 43, 3605. (c) Ney, J. E.; Wolfe, J. P. J. Am. Chem.
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J. Am. Chem. Soc. 2009, 131, 9488.
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J. Am. Chem. Soc. 2006, 128, 3130. (b) He, W.; Yip, K.-T.; Zhu, N.-Y.;
Yang, D. Org. Lett. 2009, 11, 5626. (c) Yip, K. T.; Zhu, N. Y.; Yang, D.
Org. Lett. 2009, 11, 1911. (d) Yip, K.-T.; Yang, D. Org. Lett. 2011, 13,
2134. (e) Yip, K.-T.; Yang, D. Chem.ÀAsian. J. 2011, 6, 2166.
€
(10) (a) Andersson, P. G.; Backvall, J. E. J. Am. Chem. Soc. 1992,
114, 8696. (b) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
J. Am. Chem. Soc. 2005, 127, 7308. (c) Houlden, C. E.; Bailey, C. D.;
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Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
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M. S.; Liao, L.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 4167.
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€
Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9281. (b) Ronn, M.;
€
Backvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749. (c)
€
(11) For selected examples, see: (a) Backvall, J. E.; Bystroem, S. E.;
€
Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org.
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(14) For details, see Supporting Information.
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€
Backvall, J. E.; Andersson, P. G. J. Am. Chem. Soc. 1990, 112, 3683. (d)
€
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B
Org. Lett., Vol. XX, No. XX, XXXX

However, the use of 10 mol % of Pd(OAc)2 and 20 mol %
of DMSO in toluene resulted in a poor yield (Table 1,
entry 5), indicating that the role of DMSO is not merely a
ligand. The best result was achieved when Pd(TFA)2 was
used as a palladium source, yielding the desired product
in 76% isolated yield as a single diastereomer (Table 1,
entry 6). Replacing Cu(OTf)2 with Cu(OAc)2 gave no
desired product (Table 1, entry 7), indicating that Cu(OTf)2
acts as a Lewis acid rather than a co-oxidant. However,
at this stage we could not preclude the possibility that
Cu(OTf)2 played both roles. Control experiments revealed
that both the Pd(II) salt and Cu(OTf)2 are indispensable
for this transformation (Table 1, entries 8 and 9).
assigned in analogy with 2c as determined by single-crystal
X-ray diffraction (Figure 2).16
Table 2. Substrate Scope of Pd(II)-Catalyzed Intramolecular
1,2-Aminoalkylation of N-4,6-Dienyl β-Keto Amidesa
With the optimized reaction conditions in hand, the
substrate scope of this Pd(II)-catalyzed tandem cyclization
reaction was investigated. Different substituents on the
amide unit were first tested. With a 3-oxopropanoate sub-
stituent (1b), no desired product was observed (Table 2,
entry 2). However, in the presence of a 3-oxo-3-phenyl-
propanamide unit (1c), the corresponding product 2c was
obtained in 86% yield with high diastereoselectivity
(>20:1) (Table 2, entry 3). Since 1b did not give an efficient
ketoÀenol tautomerization compared with 1a and 1c,
these experimental outcomes indicated that the efficiency
of the second nucleophilic addition from the acidic methy-
lene unit to the Pd(II) π-allyl species is highly responsible
for the overall transformation. Different (E)-dienyl units
were further investigated. Substrates with methyl substi-
tuents at the C6 (1d) or C4 position (1e) could be readily
converted to the corresponding products in good yields
with excellent diastereoselectivities (>20:1) (Table 2, en-
tries 4 and 5). Other substrates bearing different gem-
disubstituents at the C2 position were also tested. With
cyclohexyl (1f) or dimethyl substituents (1h) at the C2
position, the transformation was less efficient, yielding the
desired product 2f and 2h in 59% and 54% yield, respec-
tively (Table 2, entries 6 and 8). When there was no
additional substituent on the alkyl chain (1j), an even
poorer reactivity was observed, and the desired product
2j could only be formed in 32% yield (Table 2, entry 10).
These results indicate that the C2-diphenyl substituent is
crucial for this tandem process to proceed in good yield,
probablybecauseitpromotesthe ringclosurebyrestricting
the substrate to a more rigid structure and therefore short-
ening the distance between the β-keto amide and the diene
unit (ThorpeÀIngold effect).15 Aniline-derived substrate
1g also underwent the desired cyclization to afford tricyclic
compound 2g in 51% yield (Table 2, entry 7). For those
substrates bearing less hindered substituents on the alkyl
chain, replacing the methyl group on the β-keto amide unit
with a phenyl group improved the product yields from
54% to 74% and 32% to 43%, respectively, albeit with
slightly decreased diastereoselectivities (Table 2, entries 9
and 11). The relative stereochemistry of products was
a All reactions were carried out on a 0.3 mmol scale with 10 mol %
Pd(TFA)2 and 1 equiv of Cu(OTf)2 in 5% v/v of DMSO/toluene (6 mL).
b Isolated yield. c Diastereomeric ratio determined by 1H NMR, unless
otherwise stated; the diastereoselectivities were larger than 20:1.
Figure 2. X-ray crystal structure of 2c.
Shown in Scheme 1 is a proposed mechanism for this
Pd(II)-catalyzed intramolecular 1,2-aminoalkylation.
Substrate 1a first coordinates with both the Pd(II) catalyst
and Cu(OTf)2 to generate complex 3. Intramolecular
nucleophilic attack from the amide nitrogen toward the
Pd(II)-coordinated diene (aminopalladation) would form
(15) (a) Beesley, R. M.;Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080. (b) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
(16) A stereoselective intramolecular diamination of urea-tethered
1,3-dienes in which the two hydrogen atoms of the former internal
double bond also displayed anti positioning was reported; see ref 3e.
Org. Lett., Vol. XX, No. XX, XXXX
C

would be oxidized into Pd(II), completing the catalytic
cycle.1f,2f,18
Scheme 1. Proposed Mechanism for the Pd(II)-Catalyzed
Intramolecular 1,2-Aminoalkylation of N-4,6-Dienyl β-Keto
Amides
In summary, we have developed an efficient Pd(II)-
catalyzed intramolecular 1,2-aminoalkylation of β-keto
amide-tethered 1,3-dienes. This tandem cyclization reaction
allows the rapid synthesis of a series of pyrrolizidines in
moderate to good yields with high to excellent diastereoselec-
tivities. The expansion of this method toward the synthesis of
other types of nitrogen-bridged bicyclic compounds and
exploration toward the asymmetric control of this transfor-
mation are currently underway in our laboratory.
Acknowledgment. We thank the University of Hong
Kong and Hong Kong Research Grants Council (HKU
706109P and HKU 706112P) for financial support. We
thank Dr. N.-Y. Zhu from the Department of Chemistry,
the University of Hong Kong for performing the X-ray
crystallographic analysis. We thank Dr. J. F. Zhao from
the Department of Chemistry, the University of Hong Kong
for proofreading this manuscript.
a Pd(II)-alkyl intermediate with the five-membered ring
formation. ThisPd(II)-alkylintermediatewouldberapidly
converted into a more electrophilic π-allyl intermediate
4.3e,10,17 A second nucleophilic attack from the enol to the
π-allyl moiety would produce the desired product 2 and
generate a Pd(0) species which, in the presence of O2,
Supporting Information Available. Experimental pro-
cedures, spectral data for 1 and 2, and X-ray crystal data
of compound 2c. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) A similar mechanism involving the aminopalladation/π-allyl
intermediate formation/second nucleophilic addition sequence was
proposed and studied for an intramolecular diamination of urea-teth-
ered 1,3-dienes; see ref 3e.
(17) For the involvement of π-allyl intermediates in a series of
Pd(0)-catalyzed diamination of butadienes, see: (a) Du, H.; Zhao, B.;
Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Xu, L.; Du, H.; Shi, Y.
J. Org. Chem. 2007, 72, 7038. (c) Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am.
Chem. Soc. 2010, 132, 3523.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX