Carbenylative amination with N-tosylhydrazones

Article abstract of DOI:10.1021/ol301385g

A Pd-catalyzed reaction of vinyl iodides and N-tosylhydrazones that assembles η³-allyl ligands through carbene insertion is demonstrated. Intramolecular trapping with nitrogen nucleophiles generates good yields of cinnamyl and pentadienyl amines like those found in alkaloid natural products. Carbenylative amination was the key reaction to complete the synthesis of the alkaloid caulophyllumine B. Migratory insertion was biased to provide allylamines with optical purity up to 64% ee, but in a lower yield.

Full text of DOI:10.1021/ol301385g

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3233–3235
Carbenylative Amination with
N-Tosylhydrazones
Avinash Khanna, Charles Maung, Kyle R. Johnson, Tom T. Luong, and
David L. Van Vranken*
Department of Chemistry, University of California at Irvine, Irvine,
California 92697-2025, United States
david.vv@uci.edu
Received May 18, 2012
ABSTRACT
A Pd-catalyzed reaction of vinyl iodides and N-tosylhydrazones that assembles η3-allyl ligands through carbene insertion is demonstrated.
Intramolecular trapping with nitrogen nucleophiles generates good yields of cinnamyl and pentadienyl amines like those found in alkaloid natural
products. Carbenylative amination was the key reaction to complete the synthesis of the alkaloid caulophyllumine B. Migratory insertion was
biased to provide allylamines with optical purity up to 64% ee, but in a lower yield.
Palladium-catalyzed carbenylative cross-coupling reac-
tions are gaining increasing attention as analogues of
carbonylative reactions with carbon monoxide. The initial
applications of these reactions involved commercially
available diazo compounds to generate products with
new stereogenic centers;1,2 but aryldiazomethanes are
highly reactive requiring an alternative source of phenyl-
carbene precursors. Metalated N-tosylhydrazones decom-
pose to give aryldiazo compounds in the BamfordÀ
Stevens reaction3 and can be used to generate metal-
carbene intermediates in situ.4 Barluenga and co-workers
have demonstrated their utility in palladium-catalyzed
cross-coupling reactions with aryl halides.5 They can also
be used in a net oxidative sequence with arylboronates.6
Wang and co-workers have shown that they can be used in
three-component cross-coupling reactions to generate a
variety of propargylarenes.7 When vinyl halides are used as
substrates, carbenylative insertions generate η3-allylpalla-
dium intermediates that engage heteroatom nucleophiles.
In this work we show that nitrogen nucleophiles are
compatible with carbenylative insertions involving N-to-
sylhydrazones, providing direct access to alkaloid natural
products.8 Carbenylative insertions are complementary to
the palladium-catalyzed hydroamination of aryl alkynes
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r
10.1021/ol301385g
2012 American Chemical Society
Published on Web 05/30/2012

because they can also be used to generate quaternary
centers.9
phase-transfer catalyst was apparent at 80 °C; a similar
trend was observed at lower temperatures (entries 8À11).
Remarkably, the reactions were completein lessthan1 min
at 80 °C, but as a matter of convenience, reactions were
allowed to proceed for several hours. Lastly, observation
of BuchwaldÀHartwig type products in the aqueous frag-
ments of the workup suggested that the N-tosylhydrazone
was being depleted first and the remainder alkenyl iodide
resulted in a dimer. Inclusion of additional N-tosylhydra-
zone and base afforded high yields (95%) of the desired
(E)-styrenylpyrrolidine (entry 14). Additional N-tosylhy-
drazone and base did not improve the yield at lower
temperature (entries 6 and 15).
Table 1. Optimization of Conditions for Carbenylative
Amination with N-Tosylhydrazone 2a
equiv
equiv of
equiv of temp
yield
entry
of 2
t-BuOLi
BTAC
(°C)
solvent
THF
of 3
1
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
2.0
2.8
2.8
2.2
2.2
2.2
5.2
1.6
2.2
2.2
2.2
2.2
2.2
2.2
2.7
2.6
3.4
3.4
0.1
0.1
1.0
1.6
1.0
1.0
1.0
1.0
0.5
0.1
0
40
40
40
40
40
23
60
80
80
80
80
80
80
80
23
63%
63%
77%
70%
66%
67%
84%
85%
87%
85%
82%
83%
90%
95%
68%
2b
3
THF
THF
Table 2. Scope of Carbenylative Amination with
N-Tosylhydrazonesa
4
THF
5
THF
6
THF
7
THF
8
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
9
10
11
12
13
14
15
1.0
1.0
1.0
1.0
a Conditions: 2.5 mol % Pd2dba3•CHCl3, 15 mol % Ph3P. b 20 equiv
of H2O.
We initiated our investigation using vinyl iodide 1, with
a pendant nitrogen nucleophile, which was mixed with
N-tosylhydrazone 2 and lithium tert-butoxide. To enhance
the solubility of the lithiated sulfonylhydrazone, 0.1 equiv
of benzyl triethylammonium chloride (BTAC) was in-
cluded in the reaction. Then, triethylamine was included
because it had proven beneficial for carbenylative amina-
tions during our previous studies.2a Using these conditions
(Table 1, entry 1) the desired pyrrolidine, (E)-3, was
obtained in 63% yield along with a small amount of the
Z isomer (<10%). Addition of 20 equiv of water (entry 2)
enhanced the solubility of the lithiated hydrazone but did
not change the yield. Notably, a similar yield was obtained
when the Z isomer of vinyl iodide 1 was subjected to the
reaction conditions.2b When the amount of BTAC was
increased from 0.1 to 1.0 equiv the yield improved (entries
1 and 3). Increasing or decreasing the amount of alkoxide
base relative to the hydrazone (entries 4 and 5) led to a
slight reduction in yield. Temperature had a notable effect
on the reaction yield (entries 6À8). As the temperature was
increased, the yield of the desired product went up. Use of
2-methyltetrahydrofuran at 80 °C lead to an improved
yield, but the yield was not improved at 90 °C, with
dioxanes as the solvent. It should be noted that, at higher
temperatures, the Z alkene isomer of the product was
present in less than 1% yield. A beneficial effect of the
a Conditions: 2.5 mol % Pd2dba3•CHCl3, 15 mol % Ph3P, 2.8 equiv
of N-tosylhydrazone, 3.4 equiv of t-BuOLi, 1.0 equiv of BnNEt3Cl, 2.0
equiv of Et3N.
To better appreciate the structural requirements for the
reaction, we applied the optimized reaction conditions to a
series of related vinyl iodides (Table 2, entries 1À5).
Reactions were complete within several minutes. Sterically
(9) (a) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 1622–1623. (b) Kadota, I.; Shibuya, A.; Lutete, L. M.;
Yamamoto, Y. J. Org. Chem. 1999, 64, 4570–4571.
3234
Org. Lett., Vol. 14, No. 12, 2012

hindered amines, such as the benzhydryl derivative in 3b,
are tolerated on the nitrogen. Moreover, the reaction also
tolerates a methyl group at the site of alkylation, generat-
ing a quaternary center in 3c. Such products cannot be
accessed through the intramolecular hydroamination of
alkynes.9 Six-membered rings (piperidines) such as 3d are
also formed in good yield. Lastly, 1e, which contains an
oxidatively labile amino protecting group, is also tolerated
under the reaction conditions.
lower with (S)-BINAP (19% yield and 17% ee). When
chiral ligands were applied to the reaction of the (Z)-vinyl
iodide 6, the yields of allylic amine 7 were dramatically
reduced: 54% with (R,R)-DIOP and 6% with (S)-BINAP.
More importantly, with (S)-BINAP, the product was
obtained in 64% ee, suggesting that the carbene insertion
step, which sets the absolute stereochemistry (Scheme 3),
has significant potential for ligand control, particularly
when the vinyl iodide has a cis-substituent.
We next set out to test the scope of the reaction with
respect to N-tosylhydrazone (Table 2, entries 6À10) using
the same conditions employed in Table 2. Vinyl iodides 1a,
1d, 1e, and 1f were reacted with various N-tosylhydrazones
to produce products in 50À96% yield. The ortho bromine
substituent of hydrazone 2baffords productinhigh yield in
a 5:1 ratio of E and Z isomers. The bromine in3f provides a
functional handle for lithiation or further palladium-
catalyzed transformations. Both electron-rich methoxy sub-
stituents and electron-deficient nitro groups (entries 7À11)
are tolerated. The low yield in the case of aryl carbonate 3k is
probably due in part to its nucleophilic sensitivity.10 The
reaction also works well with vinyl hydrazones such as 2f,
which was derived from cinnamaldehyde.
Given the functional group tolerance and broad sub-
strate scope, the carbenylative amination is well suited for
the synthesis of alkaloid natural products. Vinyl iodide 1f,
with an N-methyl group, and N-tosylhydrazone 2e were
successfully coupled via a carbenylative amination to
provide methoxystyrene 4 in a 70% yield (Scheme 1).
The methyl group was removed under nucleophilic condi-
tions in 68% yield to provide the natural product caulo-
phyllumine B.
Scheme 2. Intermolecular Carbenylative Amination and
Asymmetric Induction
It was noted that rapid reactions and high yields corre-
lated inversely with enantiomeric excess. Reactions with
BINAP were particularly slow, taking several hours. We
believe that two types of catalytic species are competing in
our asymmetric reactions: an agile achiral palladium species
and a sluggish chiral palladiumÀphosphine complex. The
achiral catalyst is clearly dominant over the chiral palladiumÀ
phosphine complex under the conditions that were optimized
for triphenylphosphine. We expect those fortunes to be
reversed with the right choice of ligand and conditions.
Scheme 3. Enantioselection Model: Carbene Insertion
Scheme 1. Synthesis of (()-Caulophyllumine B
In conclusion we have demonstrated that N-tosylhydra-
zones containing both aryl and vinyl substitutents can
participate in a powerful palladium-catalyzed carbenyla-
tive amination reaction to generate pyrrolidine and piper-
idine ring systems that are common to alkaloid natural
products. The reaction is tolerant of a wide range of
functional groups on the amine nucleophile and the hy-
drazone substituent. The ligand (S)-BINAP provided
promising levels of asymmetric induction but in low yield.
Under our optimized conditions, the carbenylative ami-
nation reaction is less efficient when the amine is not
tethered to the vinyl iodide (Scheme 2), mainly due to the
fact that the N-tosylhydrazone generates a diazo compound
too quickly for the catalytic cycle. When the reaction was
performed at lower temperature (Table 1, entry 2 conditions,
without Et3N) the yield was slightly improved to 38%.
Mixed results were achieved when we tried to control
asymmetry in the carbenylative amination using chiral
phosphine ligands. When triphenylphosphine (Table 2,
entry 1) was replaced with (R,R)-DIOP in the reaction of
(E)-vinyl iodide 1a, pyrrolidine 3a was obtained in 86%
yield but only 12% ee; the yield of 3a was significantly
Acknowledgment. A.K. is supported by a graduate
fellowship from the National Science Foundation.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Nakamura, K.; Nakajima, T.; Kayahara, H.; Nomura, E.;
Taniguchi, H. Tetrahedron Lett. 2004, 45, 495–499.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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