Primary tert- and sec-allylamines via palladium-catalyzed hydroamination and allylic substitution with hydrazine and hydroxylamine derivatives

Article abstract of DOI:10.1002/anie.200701899

(Chemical Equation Presented) Amines of control: Palladium-catalyzed reactions of hydrazine and hydroxylamine derivatives with dienes and allylic esters form products from C-N bond formation at the more substituted position of the allyl intermediate with

Full text of DOI:10.1002/anie.200701899

Angewandte
Chemie
DOI: 10.1002/anie.200701899
Regioselective Allylation
Primary tert- and sec-Allylamines via Palladium-Catalyzed
Hydroamination and Allylic Substitution with Hydrazine and
Hydroxylamine Derivatives**
Adam M. Johns, Zhijian Liu, and John F. Hartwig*
The challenge of controlling the regiochemistry of palladium-
catalyzed allylic substitution by choice of ancillary ligand has
a long history. Much attention has been focused on controlling
regiochemistry because formation of the more substituted
product could be developed into a mild route to sec- and even
tert-alkylamines (Scheme 1). Škermark and co-workers
substitution and additions to imines, are difficult to conduct at
tertiary electrophiles and at ketimines,[8,9] and fewcatalytic
reactions have been developed that form tert-alkyl-substi-
tuted amines.[10,11]
Herein we report our studies on the reactions of hydrazine
and hydroxylamine derivatives to form allylamine products
from reaction at the more hindered site of aliphatic dienes or
allylic esters. This regioselectivity was observed in the
presence of palladium catalysts bearing a range of bisphos-
phine ligands. Thus, this regioselectivity is controlled by the
reagent and provides a versatile synthesis of sec- and tert-
allylamines by palladium-catalyzed additions or substitutions,
Scheme 1.
À
À
with subsequent N N or N O bond cleavage.
While studying the reactions of hydrazine derivatives with
isoprene as an avenue to expand the scope of the hydro-
amination of dienes,[5–7] we found that these reactions formed
reported that attack can occur at the more substituted
position of a prenyl complex, but that the reversibility of
this attack ultimately leads to formation of the less substituted
amine in many cases.[1] More recently, Hou and co-workers
reported a ligand for palladium that causes benzylamine to
add irreversibly to form secondary and tertiary N-alkyl sec-
butylamines,[2] and Yudin and co-workers have shown that the
attack by aziridine is irreversible and that tert-alkyl-substi-
tuted aziridines can be prepared by allylic substitution.[3,4]
During studies to develop the scope of the hydroamina-
tion of dienes,[5–7] we found that the reactions of hydrazine and
hydroxylamine derivatives occur irreversibly at the more
substituted position of both prenyl and crotyl palladium
intermediates. We explored this transformation further
because, unlike the products from additions of aziridines,[3,4]
the products from addition of hydrazine and hydroxylamine
derivatives could be readily transformed into primary tert-
alkylamines or sec-alkylamines. The synthesis of primary
amines containing tertiary alkyl groups is challenging because
many of the conventional methods, such as nucleophilic
À
the product in which the C N bond is formed between the
hydrazone group and the most substituted carbon atom of the
diene. Table 1 shows these reactions catalyzed by palladium
Table 1: Effect of catalyst components on the hydroamination of
isoprene with benzophenone hydrazone.[a]
Entry
Pd precursor
Ligand
Yield [%][b]
1
2
3
4
5
6
7
1% [{Pd(h3-allyl)Cl}2]
1% [{Pd(h3-allyl)Cl}2]
1% [{Pd(h3-allyl)Cl}2]
1% [{Pd(h3-allyl)Cl}2]
2% Pd(TFA)2
2% xantphos
2% dpephos
2% binap
2% dppf
2% xantphos
2% xantphos
–
95
92
60
77
79
4
1% [Pd2(dba)3]·CHCl3
2% [Pd(PPh3)4]
3
[a] Reaction conditions: 0.5 mmol benzophenone hydrazone, 0.5 mmol
isoprene, 0.5 mL CH2Cl2, 24 h at 238C. [b] GC yields. Ligand abbrevia-
tions:
dpephos=bis(2-diphenylphosphinophenyl)ether, dppf=1,1’-bis(diphe-
nylphosphino)ferrocene, binap=2,2’-bis(diphenylphosphino)-1,1’-
xantphos=9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene,
[*] Dr. Z. Liu, Prof. Dr. J. F. Hartwig
Department of Chemistry
binaphthyl, TFA=trifluoroacetate, dba=trans,trans-dibenzylideneace-
tone.
University of Illinois Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: jhartwig@uiuc.edu
Dr. A. M. Johns, Prof. Dr. J. F. Hartwig
Department of Chemistry
Yale University
complexes containing a series of bidentate phosphine ligands.
Analysis of the crude reaction mixtures by H NMR spec-
1
troscopy revealed that the less substituted N-prenyl regioiso-
mer was typically formed in less than 3% yield, regardless of
the identity of the ligand in the catalyst. This regioselectivity
contrasts that obtained from reactions of arylamines, even
with the same catalyst.[5]
New Haven, CT 06520-8107 (USA)
[**] We are grateful to the NIH (NIGMS GM-55382) for support of this
work and Johnson-Matthey for palladium.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Consistent with the high activity of palladium–xantphos
monoallylation product. Because the catalyst generated from
xantphos was poorly soluble in tetrahydrofuran, these reac-
tions were conducted with the catalyst generated from 2,7-di-
tert-butyl-9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
(dtBu-xantphos).
Because catalytic amination of allylic esters is likely to
occur through the same h3-allylpalladium complexes as the
hydroamination of dienes, we examined the addition of
benzophenone hydrazone to ethyl 3-methylbut-2-enyl car-
bonate (Table 3). This substitution reaction formed only the
branched regioisomer after 12 h at room temperature in the
presence of the catalyst generated from xantphos and [{Pd-
complexes as catalyst for the hydroamination of 1,3-dienes
with arylamines,[5] the reaction of benzophenone hydrazone
with isoprene occurred in the highest yields when catalyzed by
the combination of [{Pd(allyl)Cl}2] and xantphos. Neverthe-
less, this reaction catalyzed by palladium complexes of several
other bisphosphines or generated from alternative precursors
formed the hydroamination product in substantial yields. The
addition of HCl as an acid cocatalyst had no significant impact
on the activity or regioselectivity of the reaction.[12]
Studies on the scope of the hydroamination of dienes with
benzophenone hydrazone and related nitrogen nucleophiles
are summarized in Table 2. A variety of nucleophiles con-
Table 3: Palladium-catalyzed addition of H2NX nucleophiles to allylic
esters.[a]
Table 2: Palladium-catalyzed hydroamination of acyclic and cyclic 1,3-
dienes with H2NX (X=N, O) nucleophiles.[a]
Entry Nucleophile
1,3-Diene Product
Yield [%][b]
95
Conv.
[%][b]
Yield
[%][d]
Entry XNH2
b/l/d[c]
1
2
3
4
Ph2CNNH2
1
2
3
Ph2CNNH2
100
100
100
98:2:0 98
83:17:0 77[e]
95:5:0 90
90
89
98
BnONH2
4
5
Ph3CONH2
100
100
90:10:0 75
85:15:0 82
6
100
85:15:0 76
5
96
[a] Reaction conditions: 1.0 mmol benzophenone hydrazone or O-
tritylhydroxylamine or 1.3 mmol O-benzylhydroxylamine, 1.0 mmol allylic
carbonate, 1.0 mL CH2Cl2, 12 h at 238C. [b] Determined by GC.
[c] Branched/linear/diallylation. [d] Yield of the isolated branched regio-
isomer (average of two runs). [e] Full conversion was observed after 2 h;
the b/l ratio decreased with extended reaction times.
6
7
97
88
(allyl)Cl}2]. Like the hydroamination of isoprene, this allylic
substitution favored the branched isomer with catalysts
generated from all ligands tested (dpephos, binap, dppf,
dpppent, and xantphos; see the Supporting Information). The
identity of the leaving group of the allylic ester did affect the
regioselectivity. A comparison of the reactions of the two
regioisomers of prenyl ethyl carbonate revealed some
memory effect,[13,14] and significant amounts of linear product
were observed from reactions of prenyl acetates and phos-
phates. Nevertheless, reactions of allylic carbonates formed
the branched products selectively.
Table 3 shows the reactions of benzophenone hydrazone,
O-benzylhydroxylamine, and O-tritylhydroxylamine with a
selection of alkyl-substituted allylic carbonates to form the
branched substitution products. Additions of all three nucle-
ophiles to prenyl ethyl carbonate yielded the branched
regioisomer in good to excellent yield of isolated product
(Table 3, entries 1,3,4). Reactions of O-tritylhydroxylamine
with phenyl ethyl carbonate, but-2-enyl ethyl carbonate, and
geraniol ethyl carbonate also yielded the branched regioiso-
8
78
76
9[c]
BnONH2
[a] Reaction conditions: 1.0 mmol H2NX nucleophile, 1.0 mmol diene,
1.0 mL CH2Cl2. [b] Yield of isolated product (average of two runs).
[c] THF and dtBu-xantphos were used in the place of CH2Cl2 and
xantphos.
À
À
taining an N N or N O bond underwent addition to 1,3-
dienes to produce the branched addition product in excellent
yields. Benzophenone hydrazone, fluorenone hydrazone, 1-
aminobenzotriazole, and phenylhydrazine all reacted with
acyclic 1,3-dienes to yield the corresponding branched
monoallylation products in excellent yields. O-benzylhydrox-
ylamine also reacted with isoprene to yield the branched
monoallylation product. Reactions of this hydroxylamine
conducted in dichloromethane or toluene yielded predom-
inantly the diallylation product, but reactions in tetrahydro-
furan occurred with excellent selectivity for the branched,
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was stirred at 238C for 24 h, and yields were determined by gas
chromatography.
mer in good yield (Table 3, entries 4–6). Like the published
reactions of aziridines, the regioselectivities of the reactions in
Table 3 were independent of the reaction time.[4] By compar-
ison, these reactions with morpholine formed the opposite
regioisomeric products that result from substitution at the less
hindered position of the allyl intermediate, just as reported
with related bisphosphine ligands.[4] Reactions with cinnamyl
carbonate catalyzed by [{Pd(h3-allyl)Cl}2] and xantphos in
dichloromethane also formed the linear product.
Although hydroxylamine and hydrazine derivatives can
be valuable for certain applications, we sought to exploit the
regioselectivity from these N-allylations of hydrazine and
hydroxylamine derivatives to generate the more common
amine functionality. The reactions in Equation (1) showthat
General procedure for the hydroamination of 1,3-dienes with
H2NX nucleophiles (Table 2): In a drybox, [{Pd(allyl)Cl}2] (3.7 mg,
0.010 mmol), xantphos (11.6 mg, 0.020 mmol), 1,3-diene (1.0 mmol),
the H2NX nucleophile (1.00 mmol), and dodecane (10 mL,
0.044 mmol) as an internal standard were placed into a small vial,
dissolved in dichloromethane (1.00 mL), and sealed with a cap
containing a PTFE septum. The reaction mixture was stirred at 238C
for 24 h. Upon completion, as determined by gas chromatography, the
reaction mixture was purified by flash chromatography using a
solvent gradient ranging from 3:97 v/v ethylacetate/hexanes to
20:80 v/v ethylacetate/hexanes.
Received: April 30, 2007
Published online: June 26, 2007
Keywords: allylic substitution · homogeneous catalysis ·
.
hydroamination · palladium
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N-prenyl-O-benzylhydroxylamine,
N-3-crotyl-O-tritylhy-
droxylamine, and N-prenyl benzophenone hydrazone all
undergo cleavage to the primary amine with powdered Zn
in acetic acid. The volatile amine products were isolated as
the HCl salts.[15] Although cleavage of hydroxylamines and
hydrazides by zinc is well-known,[16,17] cleavage of hydrazones
under these conditions is less established.
In summary, we have demonstrated that the regioselec-
tivity for the hydroamination of dienes and the amination of
allylic esters with hydrazine and hydroxylamine derivatives
favors formation of the branched N-allyl products. This
process gains particular synthetic value because the benzo-
phenone hydrazone and hydroxylamine products form sec-
À
ondary and tertiary carbinamines after N X bond cleavage
with zinc. Because the regioselectivity occurs for a wide
variety of bisphosphines, this sequence provides opportunities
to develop newclasses of enantioselective amination, and
studies on this process are ongoing.
[14] G. Poli, C. Scolastico, Chemtracts 1999, 12, 837.
[15] Because of the volatility of the prenylamine and similar
solubility of the two amine hydrochloride salts, the prenylamine
was not separated from the diphenylmethylamine. To isolate this
amine, the use of a hydroxylamine derivative is recommended.
[16] M. Atobe, N. Yamazaki, C. Kibayashi, J. Org. Chem. 2004, 69,
5595.
Experimental Section
General procedure for the hydroamination of isoprene with benzo-
phenone hydrazone (Table 1): In a drybox, [{Pd(allyl)Cl}2] (1.9 mg,
0.0052 mmol), bisphosphine (0.010 mmol), isoprene (50 mL,
0.50 mmol), and benzophenone hydrazone (98 mg, 0.50 mmol) were
placed into a small vial, dissolved in dichloromethane (0.50 mL), and
sealed with a cap containing a PTFE septum. The reaction mixture
[17] H. Miyabe, A. Matsumura, K. Moriyama, Y. Takemoto, Org.
Lett. 2004, 6, 4631.
Angew. Chem. Int. Ed. 2007, 46, 7259 –7261
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7261