Stereocontrolled synthesis of bicyclic sulfamides via pd-catalyzed alkene carboamination reactions. Control of 1,3-asymmetric induction by manipulating mechanistic pathways

Article abstract of DOI:10.1021/ol5015976

A new annulation strategy for the synthesis of trans-bicyclic sulfamides is described. The Pd-catalyzed alkene carboamination reactions of 2-allyl and cis-2,5-diallyl pyrrolidinyl sulfamides with aryl and alkenyl triflates afford the fused bicyclic compounds in good yields and with good diastereoselectivity (up to 13:1 dr). Importantly, by employing reaction conditions that favor an anti-aminopalladation mechanism, the relative stereochemistry between the C3 and C4a stereocenters of the products is reversed relative to related Pd-catalyzed carboamination reactions that proceed via syn-aminopalladation.

Full text of DOI:10.1021/ol5015976

Letter
pubs.acs.org/OrgLett
Stereocontrolled Synthesis of Bicyclic Sulfamides via Pd-Catalyzed
Alkene Carboamination Reactions. Control of 1,3-Asymmetric
Induction by Manipulating Mechanistic Pathways
Nicholas R. Babij, Grace M. McKenna, Ryan M. Fornwald, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: A new annulation strategy for the synthesis of
trans-bicyclic sulfamides is described. The Pd-catalyzed alkene
carboamination reactions of 2-allyl and cis-2,5-diallyl pyrrolidinyl
sulfamides with aryl and alkenyl triflates afford the fused bicyclic
compounds in good yields and with good diastereoselectivity
(up to 13:1 dr). Importantly, by employing reaction conditions
that favor an anti-aminopalladation mechanism, the relative stereochemistry between the C3 and C4a stereocenters of the
products is reversed relative to related Pd-catalyzed carboamination reactions that proceed via syn-aminopalladation.
ver the past decade our group has developed a series of
Pd-catalyzed alkene carboamination reactions between
between N-allylsulfamides or N-allylureas and aryl triflates or
bromides.7 During the course of these studies we demonstrated
that either syn- or anti-addition products could be obtained
under appropriate conditions.8 For example, coupling of 4 with
an aryl bromide using a Pd/Dpe-Phos catalyst with NaOtBu as
base and toluene as solvent afforded syn-addition product 5 (eq
1). In contrast, coupling of 4 with an aryl triflate using Pd/
RuPhos and LiOtBu in PhCF3 solvent provided anti-addition
product 6 (eq 2).
O
aryl or alkenyl halides and alkenes bearing pendant nitrogen
nucleophiles.1 These reactions have proven useful for the
stereoselective construction of a broad array of nitrogen
heterocycles2−4 and have been demonstrated to proceed
through a mechanism involving syn-aminopalladation of an
intermediate palladium amido complex that leads to net syn-
addition of the heteroatom and the aryl/alkenyl group to the
double bond (Scheme 1).5 Although these transformations are
Scheme 1. Pd-Catalyzed Alkene Carboamination Reactions
The influence of syn- vs anti-addition pathways on 1,2-
asymmetric induction is quite obvious: 1,2-disubsituted alkenes
such as 4 will be transformed to different stereoisomeric
products depending on reaction mechanism, as the 1,2-addition
to the alkene generates two stereocenters. However, we
reasoned that syn- vs anti-addition pathways may also influence
relative stereochemistry in systems involving monosubstituted
alkene substrates that also contain stereocenters in relatively
close proximity to the alkene. Herein we report the first
examples of reactions in which syn- vs anti-aminopalladation
pathways can be manipulated to control 1,3-asymmetric
synthetically useful, the relative stereochemistry of the
heterocyclic products formed from substrates that contain
stereogenic centers is invariably substrate-controlled. For
example, we have demonstrated that Pd-catalyzed carboamina-
tion reactions between aryl or alkenyl bromides and 2-
allylpyrrolidinyl urea substrates such as 1 provide products 2
that contain a cis-relationship between the C-3 alkyl chain and
the C-4a hydrogen atom when a mixture of Pd2(dba)3 and
PCy3 is employed as the catalyst along with NaOtBu as a base
(Scheme 1).6 This relative stereochemistry arises through syn-
aminopalladation of the alkene via boat-like transition state 3.6
Recently, our group developed a method for the synthesis of
cyclic sulfamides via Pd-catalyzed carboamination reactions
Received: June 3, 2014
Published: June 11, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
induction. These transformations generate synthetically useful
bicyclic sulfamide products that are potentially valuable
intermediates in the synthesis of polycyclic alkaloids.9−11
To probe the influence of aminopalladation mechanism on
1,3-asymmetric induction, we initially elected to examine the
Pd-catalyzed carboamination between 2-allylpyrrolidinyl urea 7
and phenyl triflate (eq 3) using the optimized anti-amino-
making it difficult to obtain consistently high and reproducible
yields. After some experimentation, it was discovered that
changing the solvent from benzotrifluoride to tert-butanol led
to significantly improved and reproducible yields, and just as
importantly, side products 11−13 were generated in only trace
amounts (entry 6).16,17
With optimized conditions in hand, the scope of the Pd-
catalyzed carboamination methodology was examined by
coupling N-PMP-protected pyrrolidinyl sulfamide substrates
9a and 9b with a variety of different aryl triflates (Table 2). Aryl
palladation conditions described for the synthesis of cyclic ureas
and sulfamides.7 Gratifyingly, the desired product 8 was
generated in excellent yield (92%), and the product stereo-
chemistry was reversed (2:1 dr trans:cis) from that obtained
using syn-aminopalladation conditions (Scheme 1). However,
efforts to improve the selectivity of the transformation through
the use of other protecting groups, ligands, solvents, and
reaction temperatures were largely ineffective.12
a
Table 2. Scope of Pd-Catalyzed Carboamination
Although our preliminary studies with urea substrate 7 did
not provide fully satisfactory results, the observed reversal in
stereoselectivity was encouraging. We felt that selectivities
might be higher in transformations of analogous sulfamide
derivatives due to the differences in atomic geometry
(pyramidal vs trigonal N-atom geometry, tetrahedral sulfur
bearing two O atoms vs trigonal carbon bearing one) and
nitrogen nucleophilicity. To probe this hypothesis, 2-
allylpyrrolidinyl sulfamide substrate 9a was synthesized and
treated with PhOTf using several different catalysts (Table
1).13,14 The coupling of 9a and phenyl triflate under the
b
c
entry
R1
R
product yield (%)
dr (crude)
7:1
1
2
3
4
5
6
7
8
9
H
Ph
10a
10b
10c
10d
10e
10f
89
78
70
61
87
63
45
65
63
H
p-tBu-C6H4
p-MeO-C6H4
p-benzophenone
o-Me-C6H4
1-cyclohexenyl
1-decenyl
6:1
H
7:1
d
H
8:1 (5:1)
5:1
H
d
d
e
H
6:1
10:1 ,
fg
H
10g
10h
10i
allyl
allyl
Ph
20:1 (12:1)
e
a
p-MeO-C6H4
>20:1 (13:1)
Table 1. Ligand and Solvent Optimization
a
Reaction conditions: 1.0 equiv 9a or 9b, 2.0 equiv R-OTf, 2.0 equiv
LiOtBu, 4 mol % Pd(OAc)2, 10 mol % C-Phos, BuOH (0.1 M), 82
t
b
°C, 16 h. Isolated yield (average of two or more runs).
Diastereomeric ratio of the pure isolated material. Diastereomeric
c
ratios of isolated materials were identical to those of the crude
d
products unless otherwise noted. The reaction was conducted with
b
c
e
f
entry
solvent
ligand
NMR yield (isolated yield)
dr
3.0 equiv LiOtBu and 3.0 equiv R-OTf. The reaction time was 2 h. 1-
g
1
2
3
4
5
6
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
tBuOH
RuPhos
DavePhos
BrettPhos
tBuXphos
CPhos
50
30
40
30
80
6:1
6:1
6:1
6:1
6:1
7:1
Decenyl triflate was employed as 5:1 mixture of E:Z isomers. The dr
was determined following hydrogenation of 10g. The crude dr of 10g
could not be determined directly due to the mixture of diastereomers
and E:Z isomer products. However, we estimate the crude dr to be ca.
5−10:1.
d
Cphos
90 (89)
a
triflates bearing either electron-donating or electron-with-
drawing groups afforded bicyclic sulfamide products 10 in
good yields and selectivities (entries 2−4 and 9). Additionally,
the reaction of an ortho-substituted aryl triflate proceeded in
good yield and with similar diastereoselectivity (entry 5).
Alkenyl triflates also proved to be viable substrates, providing
the desired bicyclic products with good selectivity but
decreased yields (entries 6 and 7). Improved selectivities
were observed for the cross-coupling reactions involving meso-
2,5-diallyl-pyrrolidinyl sulfamide substrate 9b (entries 8 and 9),
although shorter reaction times were required to minimize
undesired isomerization of the remaining terminal olefin. In
most cases the Pd-catalyzed carboamination reactions did not
lead to significant amounts of undesired side products;
however, the competing formation of small amounts of 11−
13 was occasionally observed.18
Reaction conditions: 1.0 equiv 9a, 2.0 equiv Ph-OTf, 2.0 equiv
LiOtBu, 4 mol % Pd(OAc)2, 10 mol % ligand, solvent (0.1 M), 100 °C,
16 h. NMR yields were determined using phenanthrene as an internal
standard. Isolated yield (average of two or more runs). The reaction
was conducted at 82 °C.
b
c
d
previously optimized conditions led to an improvement in
selectivity, affording 10a in 6:1 dr favoring the trans-
stereoisomer (entry 1).15 Unfortunately, several of the ligands
screened led to low yields of desired product 9a and generated
significant amounts of side products resulting from Heck
arylation of the alkene (11) and/or β-hydride elimination from
intermediate palladium complexes (12 and 13). CPhos
provided the best results, but side products 11−13 were still
formed in substantial quantities (entry 5). Moreover, the
coupling of 9a with phenyl triflate proved to be highly variable,
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Organic Letters
Letter
To further demonstrate the utility of this methodology, 2-
allylpiperidinyl sulfamide substrate 9c was prepared and
subjected to the optimized reaction conditions (eq 4).
Gratifyingly, the coupling of 9c and phenyl triflate afforded
the desired 6,6-fused bicyclic ring system in good chemical yield
(80%) and with good stereocontrol (5:1 dr).
is that the stereochemical outcome is thermodynamically
controlled and arises due to differences in the stability of
chair-like intermediates 19 and 20, and/or 21 and 22 (Scheme
3).22,23 It appears that there are unfavorable 1,3-diaxial
Scheme 3. Stereochemical Model
In order to illustrate the potential of these compounds as
possible intermediates in the total synthesis of polycyclic
alkaloid natural products, we sought to effect cleavage of the
sulfamide bridge and removal of the N-PMP group. After some
experimentation we found that treatment of 10a with HBr to
effect desulfonylation19 followed by addition of CAN to
oxidatively cleave the N-aryl group led to the formation of 15
in 75% yield (eq 5).
interactions in intermediates 20 and 22, where the olefin or
alkylpalladium moiety occupies a pseudoaxial position. These
steric interactions drive the equilibria toward 19 and 21. This
model is consistent with the observed stereochemical outcome
as aminopalladation from 19 and reductive elimination from 21
both lead to the major stereoisomer, whereas reductive
elimination from 22 generates the minor diastereomer. The
aminopalladation step is likely reversible in this system given
the electron-deficient nature of the cyclizing nitrogen atom.5e,24
Since there are not obvious reasons why the relative rates of
reductive elimination from 21 vs 22 should be significantly
different, we favor a model where selectivity is thermodynami-
cally controlled rather than dictated by kinetic factors.
The mechanism of the Pd-catalyzed reactions for the
formation of bicyclic sulfamides likely proceeds as depicted in
Scheme 2.7 The catalytic cycle is initiated by oxidative addition
Scheme 2. Catalytic Cycle
In conclusion, we have developed a new method for the
synthesis of bicyclic sulfamides via the Pd-catalyzed alkene
carboamination of 2-allylpyrrolidinyl sulfamides. The reactions
proceed in good yields and with good control of stereo-
selectivity (up to 13:1 dr). Importantly, this work illustrates that
control of 1,3-asymmetric induction in Pd-catalyzed carboami-
nation reactions of closely related substrates can be achieved by
varying catalyst structure, reaction conditions, and substrate
structure (e.g., sulfamides vs ureas). These transformations
provide access to synthetically useful bicyclic sulfamides and
substituted pyrrolidin-2-yl-ethylamine derivatives. Studies on
applications of this chemistry toward the total synthesis of
polycyclic alkaloid natural products are currently underway.
of the aryl triflate to palladium(0) to generate cationic
palladium complex 16.20 Activation of the olefin through
coordination of the Pd-complex produces 17 and leads to
outer-sphere nucleophilic attack of the sulfamide group onto
the alkene (anti-aminopalladation). Reductive elimination from
Pd-alkyl intermediate 18 affords the desired sulfamide product
(10) and regenerates the palladium catalyst.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, descriptions of
1
stereochemical assignments, and copies of H and 13C NMR
The stereochemical outcome of the Pd-catalyzed reactions
for the synthesis of trans-bicyclic sulfamides is particularly
interesting given the stereoselectivity of related carboamination
reactions and the low selectivity generally observed for
transformations involving anti-aminopalladation.21 Despite
seemingly minor changes to the substrate, catalyst, and reaction
conditions, the stereoselectivity of the carboamination reactions
are dramatically altered, reversing a preference for the cis-
stereoisomer (up to 20:1 dr) to form the trans-bicycle as the
major product with good levels of stereocontrol (up to 13:1
crude dr). One possible explanation for the observed selectivity
spectra for all new compounds reported in the text. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jpwolfe@umich.edu.
Notes
The authors declare no competing financial interest.
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Organic Letters
Letter
Chem. Commun. 1995, 1369. (h) Babij, N. R.; Wolfe, J. P. Angew.
Chem., Int. Ed. 2013, 52, 9247.
(12) Employing the ligand Trixiephos did lead to some improvement
in diastereoselectivity (2.6:1 dr) without compromising the chemical
yield of the reaction (91% NMR yield).
ACKNOWLEDGMENTS
■
The authors acknowledge the NIH-NIGMS (GM-071650) for
financial support of this work.
(13) The sulfamide substrates 9a, 9b, and 9c were prepared in 3 or 4
steps from commercially available materials.
(14) Structures of the ligands named in Table 1 are provided in the
Supporting Information.
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