Stereocontrolled Synthesis of Amino-Substituted Carbocycles by Pd-Catalyzed Alkene Carboamination Reactions

Article abstract of DOI:10.1002/chem.201700466

Amino-substituted alkylidenecyclopentanes were synthesized through a stereoselective intermolecular Pd-catalyzed alkene carboamination reaction between alkenyl triflates bearing a pendant alkene and exogenous amine nucleophiles. The reactions are effective with a range of different substrate combinations, and proceed with generally high diastereoselectivity. Use of (S)-tBuPhox as the ligand in reactions of achiral substrates provides enantioenriched products with up to 98.5:1.5 e.r.

Full text of DOI:10.1002/chem.201700466

A Journal of
Accepted Article
Title: Stereocontrolled Synthesis of Amino-Substituted Carbocycles via
Pd-Catalyzed Alkene Carboamination Reactions
Authors: John P. Wolfe and Derick White
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To be cited as: Chem. Eur. J. 10.1002/chem.201700466
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Supported by

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COMMUNICATION
Stereocontrolled Synthesis of Amino-Substituted Carbocycles via
Pd-Catalyzed Alkene Carboamination Reactions
Derick R. White and John P. Wolfe*
Abstract:
Amino-substituted
alkylidenecyclopentanes
were
The
aminocyclopentanes often requires multi-step sequences, such
as conjugate addition to cyclic α,β-unsaturated ketone
followed by reductive amination and N-functionalization
(alkylation, arylation, etc.); alkylative ring-opening of strained
oxygen heterocycles or hetero-Diels-Alder adducts followed by
subsequent Mitsunobu reaction, deprotection, and N-
functionalization; or substitution reactions between carbocycles
stereocontrolled
assembly
of
substituted
synthesized through a stereoselective intermolecular Pd-catalyzed
alkene carboamination reaction between alkenyl triflates bearing a
pendant alkene and exogenous amine nucleophiles. The reactions
are effective with a range of different substrate combinations, and
proceed with generally high diastereoselectivity. Use of (S)-tBuPhox
as the ligand in reactions of achiral substrates provides
enantioenriched products with up to 98.5:1.5 er.
a
containing
a
2º-leaving
group
and
nitrogen
nucleophiles.[1a,1c,1e,1f,2c,2d, 4 , 5 , 6 ] While these approaches do
provide access to useful products, stereoselectivities are
frequently modest, and separation of stereoisomers can be
challenging.
The stereocontrolled synthesis of functionalized carbocycles
bearing pendant amino groups is an important synthetic
challenge due to the prevalence of these structures in
biologically active compounds and pharmaceuticals.[ 1 ] For
We recently described
a
new asymmetric alkene
example,
amino-substituted
functionalized
carbocycles
peramavir (1)[2] and entecavir (2)[3] both display antiviral activities
carboamination reaction between substituted 2-allylphenyltriflate
derivatives and exogenous amine nucleophiles that affords
aminoindane derivatives (Scheme 1).[7,8] The transformations
proceed via initial oxidative addition of the aryl triflate (e.g., 3) to
Pd(0), followed by complexation/activation of the proximal
alkene to afford a cationic aryl Pd(II)-alkene complex 5. This
complex is captured by the amine nucleophile in an anti-
aminopalladation reaction that affords 6.[ 9 ] The 6-membered
palladacycle 6 then undergoes reductive elimination to provide
enantioenriched 2-aminoindanes (e.g., 4) in excellent yield with
up to >99:1 er.[7]
towards influenza and hepatitis B virus, respectively.
O
N
O
N
N
HN
H
NH
NH2
H
HN
H2N
N
OH
OH
HO
OH
O
1 Peramavir
swine flu anti-viral
2 Entecavir
HBV anti-viral
Previous work: Enantioselective synthesis of 2-aminoindane derivatives
Figure 1. Biologically active amino-substituted cyclopentane derivatives
Pd(OAc)2 (4 mol %)
(S)-tBuPhox (6 mol %)
OTf
N
HN
LiOtBu, toluene
95 oC, 1 h
+
4
98%, >99:1 er
3
OTf
[*]
Prof. Dr. John. P. Wolfe
Department of Chemistry
University of Michigan
Ln
Pd
L
L
Pd
930 N. University Ave.
Ann Arbor, MI, 48109-1055, USA
E-mail: jpwolfe@umich.edu
N
5
6
HN
Derick R. White
Department of Chemistry
University of Michigan
930 N. University Ave.
Ann Arbor, MI, 48109-1055, USA
This work: Stereoselective synthesis of alkylidenecyclopentylamines
Pd(OAc)2 (4 mol %)
Ligand (10 mol %)
R3
R4
R3
OTf
R2
R1
R1
+
HN
N
LiOtBu, toluene
95 oC, 1 h
R4
R2
7
8
Scheme 1. Pd-catalyzed carboamination reactions for the synthesis of amino-
substituted functionalized carbocycles
Supporting information for this article is given via a link at the end of
the document.
We reasoned a related strategy could be utilized for a
concise, stereoselective synthesis of a variety of carbocycles by
employing alkenyl triflate electrophiles.[ 10 - 11 ] As shown in
Scheme 1, substrates such as 7 would be transformed to
monocyclic or bicyclic alkylidenecyclopentanes 8 that contain
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both amine and alkene functional groups that could potentially
be further elaborated. In this Communication we describe our
preliminary studies in this area, which provide access to a broad
array of amino-substituted carbocycles in good yield with
excellent stereocontrol.
and 6:1 dr when conducted without solvent using a catalyst
composed of Pd2(dba)3 (1 mol %) and Phox (4 mol %).[15] The
presence of heteroatoms on the substrate backbone was well
tolerated, which provides access to amino substituted
dihydropyrans 10f-g or dihydropyridines 10h-i in good yields and
with excellent diastereoselectivities. Compounds 10f-g are
structurally related to the iridoid family of natural products, which
are a large class of bicyclic monoterpenes that exhibit interesting
biological activities.[16]
The starting materials for these studies were readily
synthesized from ketones, esters, or β-ketoesters in 2-5 steps
via enolate allylation and subsequent enolate triflation.[12] In our
initial studies we elected to examine the reactivity of
cyclohexenyl triflates containing a pendant alkene (9a-c). Our
previously reported conditions for the coupling of 2-allylphenyl
triflates with amines proved effective for transformations
involving alkenyl triflate substrates.[7] For example, treatment of
2-allylcyclohexen-1-yl triflate 9a with morpholine in the presence
of LiOtBu and a catalyst composed of Pd(OAc)2 and BrettPhos
afforded substituted bicyclo[4.3.0]nonene derivative 10a in 72%
yield with >20:1 dr (Table 1). 13 Similarly high yields and
selectivities were observed with primary amine nucleophiles
To further explore the scope of this method we examined the
reactivity of substrates bearing a substituent on the tether
between the alkenyl triflate and the alkene. A substrate bearing
a methyl group at the homoallylic position (9d) was smoothly
coupled with pyrrolidine to afford 10j in 87% yield and >20:1 dr
[Eq. (1)]. Similarly, bis-triflate substrate 9e bearing a homoallylic
methyl
group
was
converted
to
substituted
bicyclo[4.3.0]nonadiene product 10k, which contains an
unaffected passenger[17] alkenyl triflate that may be used for
further synthetic manipulation, in 67% yield and >20:1 dr [Eq.
(2)]. Aryl triflate substrate 11 bearing an allylic methyl group was
transformed to trans-disubstituted aminoindane product 12 [Eq.
(3)], albeit in slightly lower yield and selectivity (53%, 9:1 dr),
which is likely due to the increased steric bulk near the alkene
group.[18]
such
as
furfurylamine
(10c),
benzylamine
(10d),
cyclohexylamine (10g), and 3,3-diphenylpropylamine (10i).[ 14 ]
The coupling of 9a with morpholine provided comparable yields
on both small (0.1 mmol) and large (1.0 g) scale.
Table 1. Synthesis of amino-substituted bicycle[4.3.0]nonenes[a]
Pd(OAc)2 (4 mol %)
R2
R3
OTf
R2
R3
BrettPhos (6 mol %)
LiOtBu, toluene
Pd(OAc)2 (4 mol %)
BrettPhos (6 mol %)
OTf
HN
+
N
(1)
+
HN
N
Y
Y
95 o
C
LiOtBu, toluene
95 oC, 14 h
10a-i
H
10j
9a: X = CH2; 9b: X = O;
9c: X = NBoc
CH3
CH3
9d
87%, >20:1 dr
O
OTf
Pd(OAc)2 (4 mol %)
RuPhos (6 mol %)
N
O
NEt2
N
+
HN
NH
10c
68%, >20:1 dr[c]
(2)
(3)
LiOtBu (1.1 equiv)
toluene, 95 oC, 1 h
H
H
10a
10b
49%, 2.5:1 dr
CH3
CH3
H
OTf
10k
OTf
72%, >20:1 dr[b, c]
76%, >20:1 dr[b, f]
67%, >20:1 dr
9e
Ph
Ph
NH
OTf
Pd(OAc)2 (4 mol %)
BrettPhos (6 mol %)
N
NH
+
HN
N
O
H
H 10d
H 10e
10f
LiOtBu, toluene
95 oC, 16 h
CH3
73%, 6:1 dr[d]
58%, >20:1 dr
CH3
12
82%, >20:1 dr
11
53%, 9:1 dr
NH
Cy
NH
Cy
10h
66%, >20:1 dr[e]
NH Ph
BocN
BocN
O
The Pd-catalyzed alkene carboamination reactions are also
effective with cyclopentenyl triflate derivatives (13a-d). As shown
in Table 2, the coupling reactions of these substrates with
primary amines or cyclic secondary amines generally proceeded
in good yield, and most products were obtained with high (>20:1)
diastereoselectivity. Substitution at the homoallylic position was
tolerated, as was the presence of an ester functional group (14c-
d) or a second alkene (14e-g). Efforts to employ a substrate
bearing a methyl group at the internal alkene carbon of the
pendant allyl group were unsuccessful; the desired product was
generated in low yield (<10%) along with a complex mixture of
side products. However, use of substrate 13d bearing an E-
alkene afforded 14h in modest 36% yield with 5:1
diastereoselectivity.[19]
Ph
H
H
H
10g
10i
74%,>20:1 dr[e]
68%, >20:1 dr
[a] Conditions: Pd(OAc)2 (4 mol %), BrettPhos (6 mol %), alkenyl triflate (1 equiv),
amine (1.2 equiv), LiOtBu (1.4 equiv), toluene [0.1M], 95 °C, 16 h. [b] The reaction
was conducted at 70 °C. [c]10 mol % BrettPhos was used. [d]The reaction was
conducted using 1 mol % Pd2(dba)3 and 4 mol % Phox as catalyst with no
solvent. Crude dr = 4:1 by 1H NMR analysis. [e]Diastereoselectivity was
determined after cleavage of the Boc group. [f] The reaction was conducted on a 1
gram scale.
The nucleophilicity of the amine has a large impact on
reactivity and stereocontrol, and use of amines that were either
more hindered or less basic resulted in lower yields and
selectivities. For example, the coupling of 9a with diethylamine
afforded 10b in 49% yield and 2.5:1 dr, and attempts to couple
9a with benzenesulfonamide or pyrrolidin-2-one failed to
produce the desired product. Use of aniline as a nucleophile
under standard conditions produced only trace amounts of 10e.
However, after extensive optimization we discovered the
coupling of 9a with aniline to afford 10e proceeds in 73% yield
The high diastereoselectivities observed in reactions of 9, 11,
and 13 are likely due to the highly organized nature of the
transition state for alkene aminopalladation (Scheme 2). In the
case of 9 and 13, these transformations may proceed through
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amines (18c) or acyclic secondary amines (18d) required longer
reaction times (ca. 6 h).
Table 3. Synthesis of 3,3-disubstituted alkylidenecyclopentylamines[a]
chair-like transition state 15 where the alkene is positioned to
avoid a 1,3-diaxial interaction with the homoallylic R-group to
afford 10 or 14, respectively. The trans-disubstituted indane
product 12 formed from 11 appears to be derived from transition
state 16, in which the allylic R-group is positioned anti-periplanar
to the terminal methylene to avoid both allylic strain and
eclipsing interactions with the incoming nucleophile.
Pd(OAc)2 (4 mol %)
BrettPhos (6 mol %)
R3
N
R4
18a-e
OTf
R3
R4
HN
+
R
R
LiOtBu, toluene
95 oC, 1 h
R
R
17a: R = CH3; 17b: R = allyl
Table 2. Synthesis of amino-substituted hexahydropentalenes[a]
Cy
NH
N
N
O
H3C
H3C
H3C
H3C
R2
OTf
Pd(OAc)2 (4 mol %)
BrettPhos (6 mol %)
H3C
R3
R4
H3C
R3
18c, 49%[b]
18a, 79%
18b, 56%
+
R2
HN
N
R4
LiOtBu, toluene
R1
95 o
C
R1
Ph
N
14a-h
13a: R1, R2 = H; 13b: R1 = CO2Et, R2 = H
13c: R1 = allyl, R2 = H; 13d: R1 = H, R2 = Ph
N
H3C
H3C
CH3
18d, 55%[b,c]
18e, 96%[d]
N
NH
Cy
N
O
[a] Conditions: Pd(OAc)2 (4 mol %), BrettPhos (6 mol %), alkenyl triflate (1 equiv),
amine (1.2 equiv), LiOtBu (1.4 equiv), toluene [0.1M], 95 °C, 1 h. [b]The reaction
was conducted for 6 h . [c]The reaction was conducted using P(C6F5)3 as ligand.
[d] RuPhos was used as ligand and this product contained ca 5% of an
inseparable unidentified impurity.
CO2Et
H
H
14c
76%, >20:1 dr
14a
14b
71%, >20:1 dr[b]
71%, >20:1 dr[b]
NH
Cy
14f
>98%, >20:1 dr[b]
N
O
NH
Ph
14d
52%, >20:1 dr
Ph
In order to explore diastereoselectivity in reactions of acyclic
alkenyl triflates, we prepared 3-methyl-1,5-hexadien-2-yl triflate
19a and examined its coupling with pyrrolidine. As shown in
Scheme 3, use of our standard reaction conditions, in which
Brettphos is employed as the ligand, afforded the desired
product 20a with only modest diastereoselectivity (3:1). In hopes
of improving this selectivity we investigated the influence of
ligand structure on stereocontrol, and discovered the nature of
the ligand has a large impact on diastereoselectivity. Use of the
CO2Et
14e
93%, >20:1 dr[b]
Ph
NH
Ph
Ph
N
14g
92%, >20:1 dr
14h
H
36%, 5:1 dr[c]
[a] Conditions: Pd(OAc)2 (4 mol %), BrettPhos (6 mol %), alkenyl triflate (1 equiv),
amine (1.2 equiv), LiOtBu (1.4 equiv), toluene [0.1M], 95 °C, 16 h. [b]10 mol %
Brettphos was used. [c]The reaction was conducted using XPhos as ligand and 2
equiv pyrrolidine at [1M].
t
very bulky Me4 Bu-XPhos ligand resulted in no stereocontrol (1:1
dr). However, tBu-XPhos, which lacks substituents on the
phosphine-bearing aryl ring, led to slightly improved results.
Dicyclohexyl phosphine derivatives gave higher selectivity than
di-tert-butyl phosphine derived ligands, and selectivity was
further improved when ligands bearing more strongly electron
donating groups on the second aromatic ring were employed.
Finally, CPhos was identified as the optimal ligand, furnishing
20a in 87% yield and 12:1 dr.[15]
R2
R2
NH
OTf
( )n
OTf
N
R3
n( )
Y
n( )
Y
R3
H
Pd
Y
R
Ln
R
R
H
R
10: n = 1
15
9: n = 1
13: n = 0
14: n = 0
OTf
Ln
R2
OTf
Pd
N
R3
H
R2
NH
R3
Pd(OAc)2 (4 mol %)
ligand (6 mol %)
OTf
R
R
11
16
12
N
+
HN
LiOtBu, toluene
95 °C, 1 h
H3C
R4
H3C
19a
20a
Scheme 2. Origin of diastereoselectivity in reactions of 9, 11, and 13.
R2
R1
R3
Having
successfully
developed
conditions
for
R2
transformations of cyclic alkenyl triflates, we elected to explore
the reactivity of acyclic substrates. In our initial studies we
prepared gem-disubstituted hexadienyl triflates 17a-b and
examined their coupling with various amines. We were pleased
to discover these reactions afforded the desired monocyclic
alkylidenecyclopentylamine products 18a-e in moderate to
excellent yields (Table 3). However, in some instances
isomerization of the exo-alkene to afford substituted
cyclopentene side products was problematic. After some
experimentation we discovered the isomerization occurred only
during prolonged reaction times, and could be alleviated by
simply monitoring reactions such that heating was stopped and
products were isolated as soon as the alkenyl triflate substrate
had been completely consumed. The necessary reaction times
were considerably shorter (<1.5 h) when stronger nucleophiles
were used (i.e. pyrrolidine and morpholine); whereas, primary
Ligand =
R1
PR2
R3
R1
R2
R3
R4
Ligand Name
R
dr
yield
tBu
Cy
Me
Me
H
iPr
iPr
iPr
iPr
t
Me4 Bu-XPhos
1:1
3:1
80%
49%[a]
OMe
BrettPhos
tBu-XPhos
RuPhos
tBu
Cy
Cy
H
H
H
H
H
H
iPr
iPr
H
4:1
7:1
81%
82%
87%
OiPr
NMe2
12:1
H
CPhos
[a] The reaction was conducted for 14 h.
Scheme 3. Influence of ligand structure on diastereoselectivity
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Having achieved acceptable levels of stereocontrol, we
examined the coupling of 19a and related dienyl triflates with
various amine nucleophiles (Table 4). Although CPhos proved
optimal in our initial experiments with 19a and pyrrolidine,
RuPhos proved superior to CPhos with other amine nucleophiles
that were examined. As observed with cyclic triflates, the
diastereoselectivities in these reactions were dependent on the
nucleophile. For example, although reactions that employed
studies demonstrated that a catalyst composed of Pd(OAc)2 and
(S)-tBuPhox provided high levels of asymmetric induction
(Scheme 1).[7] Gratifyingly, this catalyst also proved to be
effective with alkenyl triflate electrophiles 22a-b. Use of 1º-amine
nucleophiles such as cyclohexylamine and octylamine led to the
generation of products with excellent stereocontrol (98.5:1.5 er),
albeit in low yield (41% and 25% respectively). However, higher
yields were obtained with more nucleophilic amines such as
pyrrolidine or morpholine. In contrast, the bulkier and less
pyrrolidine as
a nucleophile afforded products with high
diastereoselectivity (12:1 to >20:1 dr), use of piperidine (6:1 dr)
or octylamine (4:1 dr) led to lower selectivities. Substrate 19c
bearing two substituents that differ substantially in size (methyl
vs. phenyl) was transformed to product 20e in 78% yield and
>20:1 dr using RuPhos as ligand.
nucleophilic
N-benzylmethylamine
produced
23g
in
comparatively low selectivity (85:15 er) and moderate yield
(50%). Efforts to induce asymmetric induction through coupling
of 22a with enantiomerically pure (99:1 er) (S)-α-
methylbenzylamine were unsuccessful, as product 24 was
generated in only 29% yield with very low (1.2:1)
diastereoselectivity [Eq(4)]. However, both diastereomers were
obtained in 99:1 er, which indicates the amine stereocenter does
not epimerize before or after coupling.
Table
4.
Diastereoselective
synthesis
of
substituted
alkylidenecyclopentylamines
Pd(OAc)2 (4 mol %)
Ligand (6 mol %)
R3
N
OTf
R3
HN
+
R1
R2
R1
R2
LiOtBu, toluene
95 oC, 1.5 h
Table 5. Enantioselective reactions of alkenyl triflates and various amines
R4
R4
20b-e
R2
HN
19a: R1 = CH3, R2 = H; 19b: R1 = Ph, R2 = H;
19c: R1 = Ph, R2 = CH3
R3
R1
R1
Pd(OAc)2 (4 mol %)
C8H17
R2
(S)-tBuPhox (6 mol %)
OTf
N
NH
N
R3
LiOtBu, toluene
H3C
Ph
95 o
C
20b
20c
23a-g
22a: R = H
22b: R = OCH3
70%, 4:1 dr (RuPhos)[b]
91%, 6:1 dr (CPhos)
79% , 4:1 dr (RuPhos)
Cy
N
N
H3C
N
N
O
NH
Ph
Ph
20d
20e
23a
23b
75%, 94:6 er
23c
41%, 98.5:1.5 e.r.
78%, >20:1 dr (RuPhos)
98%, >20:1 dr (RuPhos)
65%, 3:1 dr (BrettPhos)
69%, 98:2 er
H3CO
[a] Conditions: Pd(OAc)2 (4 mol %), Ligand (6 mol %), alkenyl triflate (1 equiv),
amine (1.2 equiv), LiOtBu (1.4 equiv), toluene [0.1M], 95 °C, 1.5 h. [b]The reaction
was conducted for 6h .
C8H17
NH
N
O
The stereoselectivity observed in reactions of acyclic
substrates 19a-c is likely due to similar factors that are in
operation with cyclic alkenyl triflates. As shown in Scheme 4,
these transformations may proceed through chair-like transition
state 21, in which the larger homoallylic substituent (RL) is in a
pseudoequatorial orientation to minimize 1,3-diaxial interactions
with the alkenyl hydrogen atom. The observed product
stereochemistry suggests the allylic strain between RL and the
Pd-bound alkene is less significant than the diaxial interactions,
but may be responsible for the generally lower selectivities
obtained with acyclic alkenyl triflates as compared to cyclic
substrates.
23d
23e
60%, 93:7 er
25%, 98.5:1.5 er
H3CO
H3CO
CH3
N
Bn
N
23f
60%, 98:2 er
23g
50%, 85:15 er
[a] Conditions: Pd(OAc)2 (4 mol %), (S)-tBu-Phox (6 mol %), alkenyl triflate (1 equiv),
amine (1.2 equiv), LiOtBu (1.4 equiv), toluene [0.1M], 95 °C, 16 h.
H3C
NH
Pd(OAc)2 (4 mol %)
BrettPhos (6 mol %)
H
OTf
+
R3
NH
R4
NH2
Ph
OTf
(4)
R3
OTf
LiOtBu, toluene
95 °C, 16.5 h
RL
Pd
24
Ph
CH3
N
R4
RS
RL
RS
RL
99:1 er
22a
29% yield, 1.2:1 dr
both diastereomers ca. 99:1 er
H
Ln
RS
19
20
21
In conclusion, the Pd-catalyzed coupling of alkenyl triflates
bearing pendant alkenes with amine nucleophiles provides a
straightforward and stereoselective means of generating amino
substituted alkylidenecyclopentane or cyclopentene derivatives.
The transformations proceed via a key anti-aminopalladation
reaction of a Pd(II)-alkene complex, which occurs through a
Scheme 4. Origin of diastereoselectivity in reactions of 19
Finally, given our prior success in developing
enantioselective reactions between substituted 2-allylphenyl
triflate derivatives and amines, we briefly surveyed analogous
asymmetric reactions of alkenyl triflates (Table 5). Our prior
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10.1002/chem.201700466
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highly organized chair-like transition state. Use of the chiral (S)-
tBuPhox ligand in reactions of achiral substrates 22a-b provides
products with up to 98.5:1.5 er. Future studies will be directed
towards further expanding the scope of these reactions to a
broader array of nucleophiles, and to afford a variety of different
carbocyclic systems.
derivatives and exogenous alkenes, see: c) T. Piou, T. Rovis, Nature, 2015,
527, 86.
[9] For reviews on stereochemical pathways of Pd-catalyzed nucleopalladation,
see: a) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem. 2008, 6, 4083; b) R. I.
McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981; c) P. Kočovský,
J.-E. Bäckvall, Chem. Eur. J. 2015, 21, 36.
[ 10 ]
A
previous enantioselective synthesis of indanes via C(sp2)-H
functionalization was reported which utilized alkenyl triflates and a Pd-catalyst:
M. R. Albicker, N. Cramer, Angew. Chem. Int. Ed. 2009, 48, 9139; Angew.
Chem. 2009, 121, 9303.
[11] For a review on the synthesis of indane systems, see: B.-C. Hong, S.
Sarshar, Org. Prep. Proc. Int. 1999, 31, 1.
Acknowledgements
[12] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299.
[13] Attempts to decrease reaction temperature or catalyst loading (to 0.5
mol % Pd) through use of the Buchwald Brettphos precatalyst have thus far
been unsuccessful.
The authors thank the University of Michigan for financial
support of this work. DRW’s studies were also supported in part
by a Bristol Myers Squibb Graduate Research Fellowship, for
which he is grateful.
[14] Products resulting from a reaction between the secondary amine product
and
a second equivalent of alkenyl triflate were not observed in
transformations of primary amine nucleophiles.
[15] See the Supporting Information for details of optimization studies.
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[18] Products resulting from competing N-arylation of the substrate were not
observed.
Keywords: stereoselective synthesis • asymmetric catalysis •
enantioselective synthesis • carbocycle • palladium
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Rh-catalyzed carboamination reactions between N-enoxyphthalimide
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10.1002/chem.201700466
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COMMUNICATION
Derick R. White and John P. Wolfe*
R4
Page No. – Page No.
OTf
R2
R3
R2
R3
Pd-catalyst
n
n
R2
R3
+
N
HN
OR
LiOtBu, toluene
95 °C
Stereocontrolled Synthesis of Amino-
Substituted Carbocycles via Pd-
Catalyzed Alkene Carboamination
Reactions
N
R1
30 examples
up to >20:1 d.r.
R1
7 examples
up to 98.5:1.5 e.r.
The Palladium-catalyzed coupling of amines with enol triflates derived from 2-
allylcycloalkanones provides substituted alkylidenecyclopentylamine derivatives in
good yield with high levels of stereoselectivity. Achiral substrates are transformed
with up to 98.5:1.5 er.
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