Diverse N-Heterocyclic Ring Systems via Aza-Heck Cyclizations of N-(Pentafluorobenzoyloxy)sulfonamides

Article abstract of DOI:10.1002/anie.201605152

Aza-Heck cyclizations initiated by oxidative addition of Pd⁰-catalysts into the N?O bond of N-(pentafluoro-benzoyloxy)sulfonamides are described. These studies, which encompass only the second class of aza-Heck reaction developed to date, provide direct access to diverse N-heterocyclic ring systems.

Full text of DOI:10.1002/anie.201605152

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605152
German Edition: DOI: 10.1002/ange.201605152
N-Heterocycles
Diverse N-Heterocyclic Ring Systems via Aza-Heck Cyclizations of N-
(Pentafluorobenzoyloxy)sulfonamides
Ian R. Hazelden+, Xiaofeng Ma+, Thomas Langer, and John F. Bower*
Abstract: Aza-Heck cyclizations initiated by oxidative addi-
0
À
tion of Pd -catalysts into the N O bond of N-(pentafluoro-
benzoyloxy)sulfonamides are described. These studies, which
encompass only the second class of aza-Heck reaction
developed to date, provide direct access to diverse N-hetero-
cyclic ring systems.
T
here has been a resurgence of interest in the development
of processes based on the Mizoroki–Heck reaction.[1] Notable
contributions include boryl-Heck alkene functionalizations[2]
[3]
À
and remote redox relay Heck C C bond formations. Our
focus has been on the development of aza-variants of the
Heck reaction, because of the importance of N-containing
ring systems in drug discovery.[4–7] Within this context, the
Narasaka process,[4] which involves the Pd-catalyzed cycliza-
tion of O-pentafluorobenzoyl ketoxime esters with alkenes, is
unique in harnessing key steps that are analogous to the
conventional Heck reaction: 1) an unusual oxidative addition
À
into the N O bond of 1 to afford cationic imino-Pd
intermediate 2;[7,8] 2) C N bond forming alkene migratory
À
insertion;[9] and 3) b-hydride elimination (Scheme 1A).
Imino-PdII intermediates 2 can also be exploited more
widely in redox neutral processes, such as diverse alkene
[7a]
1,2-carboaminations,[8] aryl C H aminations, alkene azir-
À
idinations,[10] alkene 1,2-iodoaminations,[11] aryne aminofunc-
[13]
tionalizations,[12] and C C bond activations.
À
Efforts to expand the range of redox active donors
available for accessing aza-PdII intermediates led us to
consider whether activated hydroxysulfonamide derivatives
might be viable (Scheme 1B).[14] In this approach, N-(penta-
fluorobenzoyloxy)sulfonamides 4a/b, which we have found
easy to prepare on gram scale,[15] act as a formal nitrene
equivalent, but with key distinguishing aspects. First, as with
nitrenes, 4a/b function as both a nucleophile and electrophile,
Scheme 1. Aza-Pd intermediates via redox-active N-donors.
but, importantly, these features are decoupled, such that their
unveiling can be orchestrated in a controlled manner. Second,
nucleophilic modification of 4a/b can be achieved under
stereospecific Mitsunobu conditions and this allows readily
available enantiopure secondary alcohols to be exploited in
synthetic sequences.[16] Third, and most importantly, 5a/b do
not function as an electrophile by direct reaction at nitrogen,
with this reactivity facet instead controlled by the Pd-center
of aza-PdII species 6a/b. Consequently, alkylated derivatives
5a/b can, in principle, be adapted to asymmetric cycliza-
tions[17] and cascade sequences,[18] as well as other processes
typical of Pd-catalysis. Herein, we delineate preliminary
studies towards this broad goal by reporting what is, to the
best of our knowledge, only the second class of aza-Heck
reaction developed to date (Scheme 1B, box).[19] The process
provides high versatility for the synthesis of complex N-
[*] I. R. Hazelden,[+] Dr. X. Ma,[+] Dr. J. F. Bower
School of Chemistry, University of Bristol
Bristol, BS8 1TS (UK)
E-mail: john.bower@bris.ac.uk
Dr. T. Langer
Pharmaceutical Technology & Development, AstraZeneca
Charter Way, Macclesfield, SK10 2NA (UK)
[+] These authors contributed equally.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201605152.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
heterocyclic ring systems[20] and can be integrated into
cascade sequences to provide alkene 1,2-carboamination
products. This validates the broader N-heteroannulation
strategy outlined in Scheme 1B.
Initial studies focused on aza-Heck cyclization of mono-
substituted alkene 7a, which was prepared in 70% yield by
Mitsunobu alkylation of 4a with pent-4-enol (Scheme 2).[15]
vated variant 7bc offered marginal efficiency gains (entry 3),
whereas an O-Ms activated system 7bb was less effective.
Less dissociating activating groups, such as O-Bz, were
completely ineffective (see below). Fortunately, it was found
that solvent effects were pronounced, with n-BuCN, MeCN,
and THF all promoting cyclization of 7ba to target 8b in
useful yield (entries 4,6,7). The most efficient method used
a mixed-solvent system and sub-stoichiometric quantities of
Et3N (see below; entry 5). The process is highly sensitive to
the nature of the phosphine ligand, and, from an exhaustive
screen of commercial variants, the only other systems found
to provide greater than 20% yield were PPh3, dppp, and
P(4-(CF3)C6H4)3.
The scope of the aza-Heck process is outlined in Table 2,
with fine tuning of reaction solvent required on a case-by-case
basis. Cyclization of 7c, which involves a cyclopentene,
generated bicyclic system 8c in high yield and as a single
diastereomer. Efficient cyclizations were observed for pro-
cesses involving 1,2-disubstituted alkenes. For example, 7d
delivered 8d in 81% yield and with complete selectivity over
the corresponding enamide (cf. 7a to 8a). 1,1-Disubstituted
alkenes are also tolerated, albeit with greater variation in
efficiency. Cyclization of 7 f generated the challenging
tetrasubstituted stereocenter of pyrrolidine 8 f in 80% yield.
More sterically demanding systems 7g and 7h were less
effective, but still delivered targets 8g and 8h in workable
yields. Systems with substitution on the alkene tether can
provide diastereoselective processes. For example, 7k gen-
erated cis-2,5-disubstituted pyrrolidine 8k in 58% yield and
more than 10:1 d.r; for this process, an N-tosyl protecting
group was less effective.[15] Similar efficiencies were observed
for 7j, 7l, and 7m, with the latter affording complex 2,2,5-
trisubstituted pyrrolidine 8m in high diastereoselectivity.
Electron-deficient alkenes also participate: cyclization of
acrylate 7n provided 8n in 78% yield, thereby validating
a novel entry to versatile alkylidene pyrrolidines.
Scheme 2. A feasibility experiment.
Under conditions related to those previously optimized for
aza-Heck cyclizations of oxime esters, where P-
(3,5-(CF3)2C6H3)3 was identified as a privileged ligand,[5]
ketone 8a’ was isolated in 82% yield. H NMR analysis of
crude reaction mixtures indicated that 8a’ forms via hydrol-
ysis of initial aza-Heck product 8a.
1
Cyclization of 7a was considered relatively easy as both
À
the N O bond and alkene are sterically accessible. To
integrate the new process into synthetically attractive settings
we sought substrates where b-hydride elimination to form
hydrolytically sensitive enamides was not possible. Accord-
ingly we focused on cyclic alkene 7ba, which was expected to
deliver bicyclic system 8b, due to the presumed mechanistic
constraints of syn-amino palladation and syn-b-hydride
elimination (Table 1). In the event, this system was challeng-
ing, with initial attempts generating 8b in only 34% yield as
a 3:1 mixture with regioisomer iso-8b (entry 1); this likely
arises via Pd-hydride mediated isomerization of 8b. Ineffi-
ciencies were attributed to competing protodepalladation and
b-hydride elimination at the stage of the aza-PdII intermedi-
ate; this latter pathway led to the isolation of the correspond-
ing aldehyde.[21] Optimization was undertaken focusing on
activating group, solvent, and ligand. O-Trifluoroacetyl acti-
The chemistry can be used to provide challenging bridged
ring systems common to many alkaloid targets (Scheme 3).
For example, cyclization of 7o, which involves a cycloheptene
constructed by RCM,[15] provided
Table 1: Optimization of a demanding cyclization.
tropane 8o in 60% yield; this is the
core structure of multiple natural
products including cocaine.[22]
Alternatively, cyclization of 7p
generated
regioisomeric
6-
azabicyclo[3.2.1]octene scaffold 8p
in 76% yield.[23] The structures of
8o and 8p were confirmed by X-ray
diffraction.[15]
Entry
R
Ligand
Solvent
X
Y
Z
T [8C] Yield [%][a]
1
2
3
4
5
6
7
8
FBz
Ms
P(3,5-(CF3)2C6H3)3 DMF
P(3,5-(CF3)2C6H3)3 DMF
4
4
5
15
15
20
400
400
200
50
80 34 (3:1)
80 4 (n.d.)
80 46 (3:1)
Preliminary studies show that
the chemistry will be of utility in
other contexts. All aza-Heck pro-
cesses described so far involve 5-
exo cyclization; however, even at
the present level of development, 6-
exo cyclization is possible (Sche-
me 4A). Indeed, exposure of styr-
enyl system 7q to optimized con-
ditions provided tetrahydroisoqui-
(CO)CF3 P(3,5-(CF3)2C6H3)3 DMF
FBz
FBz
FBz
FBz
FBz
FBz
FBz
FBz
P(3,5-(CF3)2C6H3)3 n-BuCN
P(3,5-(CF3)2C6H3)3 n-BuCN/DMF (6:1) 2.5 12.5
P(3,5-(CF3)2C6H3)3 MeCN
P(3,5-(CF3)2C6H3)3 THF
P(3,5-(CF3)2C6H3)3 n-BuCN
PPh3
dppp
P(4-(CF3)C6H4)3
2.5 12.5
110 80 (17:1)
110 91 (12:1)
100 76 (3:1)
100 62 (1:0)
110 77 (24:1)
110 51 (13:1)
110 24 (12:1)
110 33 (3:1)
50
5
5
5
5
5
5
20
20
20
20
10
20
100
100
100
100
100
100
9
10
11
n-BuCN
n-BuCN
n-BuCN
[a] In situ yield; 8b:iso-8b ratio is given in parentheses.
2
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Scope of the aza-Heck process.
noline 8q in 42% yield. We have also assessed the possibility
of alkene 1,2-carboamination processes by trapping the alkyl-
PdII intermediate generated after migratory insertion (Sche-
me 4B). Exposure of 7r to aza-Heck conditions afforded
Scheme 4. Examples of further reactivity.
bicycle 8r in 86% yield, via Heck trapping of 7r’. The
development of further alkene aza-functionalizations will be
a focus of future work.
The mechanism of the aza-Heck processes is likely akin to
that of the Narasaka cyclization of O-pentafluorobenzoyl
ketoxime esters (Scheme 5, 7d to 8d).[5,8] Pd0Ln (L = P-
(3,5-(CF3)2C6H3)3) generated in situ effects N-O oxidative
[a] Reaction solvent is specified in parentheses under each starting
material. Full details are given in the Supporting Information.
Scheme 5. Preliminary mechanism based on observations from current
and previous work.
addition of 7d to provide I; despite extensive efforts, we have
so far been unable to isolate aza-PdII intermediates related to
I. Efficient aza-Heck cyclization requires dissociation of
pentafluorobenzoate from I to access cationic intermediate
II.[8] This assertion is based on the observation that less
dissociating leaving groups (for example, O-Bz) are ineffec-
tive, and chloride additives (for example, n-Bu4NCl) com-
Scheme 3. Bridged ring systems by aza-Heck cyclization.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
pletely suppress cyclization; in both cases protodepalladation
to the corresponding sulfonamide predominates. From II, syn-
migratory insertion of the alkene generates alkyl-Pd inter-
mediate III. The intermediacy of III is corroborated by the
cyclization of 7r to 8r, while support for the feasibility of syn-
stereospecific alkene migratory insertion is found in studies
on aza-Wacker cyclizations.[24,25] From III, b-hydride elimi-
nation releases the product (8d) and PdII-hydride IV, which
undergoes base (Et3N) induced reductive elimination to close
the catalytic cycle. The equilibrium between neutral and
cationic complexes I and II is shifted forward by triethylam-
monium mediated protodecarboxylation of the otherwise
inhibitory pentafluorobenzoate leaving group. We have
previously shown that this process is rapid,[8] and 19F NMR
analysis of crude reaction mixtures has confirmed that it is
operative in the current scenario. This also accounts for the
use of sub-stoichiometric (catalytic) quantities of Et3N under
optimized conditions.
also anticipate that the catalysis platform outlined here, which
involves a rare example of oxidative addition of Pd0 into an
N O bond,[7] should find broad applicability in the design of
À
À
redox neutral C N bond forming methods outside the
immediate area of N-heterocyclic chemistry.
Acknowledgements
We acknowledge the European Research Council for support
via the EU’s H2020 Program (grant no. 639594 CatHet),
AstraZeneca and EPSRC (EP/M506473/1) for a studentship
(I.R.H.), and the Royal Society for a University Research
Fellowship (J.F.B.).
Keywords: aza-Heck reaction · cascade reactions ·
N-heterocycles · palladium
It is pertinent to comment on the synthetic scope of the
prototype 5-exo aza-Heck processes outlined here versus
complementary 5-exo aza-Wacker cyclizations of alkenyl NH-
sulfonamides, which require an external oxidant (for example,
air or oxygen).[24] Despite extensive development, this latter
method still has key limitations; for example, cyclization of
systems with large a-substituents (larger than methyl) have
not been achieved (cf. 7j–m), hindered acyclic olefins do not
participate (cf. 7h), and electron-deficient alkenes cannot be
used due to competing conjugate addition (cf. 7n). Addition-
ally, aza-Heck cyclization seems uniquely suited to demand-
ing systems (Scheme 3) and cascade polycyclizations (Sche-
me 4B). Earlier work using oxime esters has also established
N-O oxidative addition as a unified platform for the design of
diverse redox-neutral alkene 1,2-carboamination processes
that cannot be achieved using an aza-Wacker approach.[8]
From a practical viewpoint, a pre-installed internal oxidant
may be preferable for scale-up or redox sensitive substrates.
Importantly, this unit can be brought in directly by Mitsunobu
reaction of 4a/b, enabling a two-step conversion of (enantio-
pure) alcohols to heterocyclic targets. Alkenyl NH-sulfona-
mides required for aza-Wacker cyclization are not usually
prepared directly from the alcohol because the requisite
primary sulfonamides do not engage efficiently in conven-
tional Mitsunobu reactions.[26] Further potential advantages
of the aza-Heck approach are that highly tunable phosphine
ligands can be used (because oxidative conditions are
avoided) and predictable syn-migratory insertion of the
alkene can be expected.[24c]
[1] The Mizoroki-Heck Reaction (Ed.: M. Oestreich), Wiley, Chi-
chester, 2009.
[2] W. B. Reid, J. J. Spillane, S. B. Krause, D. A. Watson, J. Am.
Chem. Soc. 2016, 138, 5539.
[3] H. H. Patel, M. S. Sigman, J. Am. Chem. Soc. 2015, 137, 3462.
[4] a) H. Tsutsui, K. Narasaka, Chem. Lett. 1999, 28, 45. Reviews:
b) M. Kitamura, K. Narasaka, Chem. Rec. 2002, 2, 268.
[5] a) A. Faulkner, J. F. Bower, Angew. Chem. Int. Ed. 2012, 51,
1675; Angew. Chem. 2012, 124, 1707; b) N. J. Race, J. F. Bower,
Org. Lett. 2013, 15, 4616; c) A. Faulkner, J. S. Scott, J. F. Bower,
Chem. Commun. 2013, 49, 1521; d) N. J. Race, A. Faulkner,
M. H. Shaw, J. F. Bower, Chem. Sci. 2016, 7, 1508.
[6] For a Cu-catalyzed variant, see: A. Faulkner, N. J. Race, J. F.
Bower, Chem. Sci. 2014, 5, 2416.
[7] a) Y. Tan, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 3676;
b) W. P. Hong, A. V. Iosub, S. S. Stahl, J. Am. Chem. Soc. 2013,
135, 13664; for a process where N-O oxidative addition of Pd0 is
invoked but not confirmed, see: c) J. He, T. Shigenari, J.-Q. Yu,
Angew. Chem. Int. Ed. 2015, 54, 6545; Angew. Chem. 2015, 127,
6645.
[8] A. Faulkner, J. S. Scott, J. F. Bower, J. Am. Chem. Soc. 2015, 137,
7224.
[9] For migratory insertion of alkenes into N-Pd bonds, see: P. S.
Hanley, J. F. Hartwig, Angew. Chem. Int. Ed. 2013, 52, 8510;
Angew. Chem. 2013, 125, 8668.
[10] K. Okamoto, T. Oda, S. Kohigashi, K. Ohe, Angew. Chem. Int.
Ed. 2011, 50, 11470; Angew. Chem. 2011, 123, 11672.
[11] C. Chen, L. Hou, M. Cheng, J. Su, X. Tong, Angew. Chem. Int.
Ed. 2015, 54, 3092; Angew. Chem. 2015, 127, 3135.
[12] T. Gerfaud, L. Neuville, J. Zhu, Angew. Chem. Int. Ed. 2009, 48,
572; Angew. Chem. 2009, 121, 580.
[13] T. Nishimura, S. Uemura, J. Am. Chem. Soc. 2000, 122, 12049.
[14] For Cu-catalyzed radical cyclizations of activated hydroxysulfo-
namides with alkenes, see: W.-M. Liu, Z.-H. Liu, W.-W. Cheong,
L.-Y. T. Priscilla, Y. Li, K. Narasaka, Bull. Korean Chem. Soc.
2010, 31, 563.
In summary, we report aza-Heck cyclizations initiated by
0
À
oxidative addition of Pd -catalysts into the N O bond of N-
(pentafluorobenzoyloxy)sulfonamides. These studies provide
direct access to N-heterocyclic ring systems that are not
accessible using the Narasaka aza-Heck procedure.[20] The
approach exploits stepwise unveiling of the nitrenoid charac-
ter embedded within N-(pentafluorobenzoyloxy)sulfonamide
[15] Details are given in the Supporting Information.
CCDC 1482096 (7ba), 1482097 (8o), and 1482098 (8p) contain
the supplementary crystallographic data for this paper. These
data are provided free of charge by The Cambridge
Crystallographic Data Centre.
À
reagents. Sequential nucleophilic-electrophilic C N bond
forming strategies of this type, which involve the intermediacy
of a tunable aza-PdII intermediate, should enable a wide array
of N-heteroannulation processes. By analogy to the utility of
oxime ester derived imino-Pd intermediates (2),[4,5,8–13] we
[16] A study on the stereospecificity of this process is given in the
Supporting Information.
4
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
[17] We have demonstrated the feasibility of asymmetric Narasaka–
[23] M. Betou, L. Male, J. W. Steed, R. S. Grainger, Chem. Eur. J.
Heck cyclizations (see Ref. [5c]). An optimized system will be
reported in due course.
[18] Redox active nitrogen donors provide high flexibility for cascade
design (see Ref. [8]).
[19] We use the term “aza-Heck” to describe a Pd-catalyzed process
that encompasses steps analogous to the conventional Heck
2014, 20, 6505.
[24] For selected methods, see: a) M. Rçnn, J.-E. Backvꢁll, P. G.
Andersson, Tetrahedron Lett. 1995, 36, 7749; b) R. I. McDonald,
P. B. White, A. B. Weinstein, C. P. Tam, S. S. Stahl, Org. Lett.
2011, 13, 2830; c) Aza-Wacker cyclizations proceed via con-
dition-dependent syn- or anti-amino-palladation pathways; see:
G. Liu, S. S. Stahl, J. Am. Chem. Soc. 2007, 129, 6328; d) Review:
R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981.
[25] Addition of TEMPO to cyclizations of 7c and 7d did not result
in any TEMPO trapping products, with 8c and 8d formed in
yields similar to those reported in Table 2 (see Ref. [5d]).
[26] J. R. Henry, L. R. Marcin, M. C. McIntosh, P. M. Scola, G. D.
Harris, Jr., S. M. Weinreb, Tetrahedron Lett. 1989, 30, 5709.
À
reaction: a) oxidative initiation at nitrogen, b) C N forming
alkene migratory insertion, and c) b-hydride elimination. “Aza-
Heck” cyclizations of N-chloroamines have been reported but
do not generate alkene products; see: a) J. Helaja, R. Gçttlich,
Chem. Commun. 2002, 720; b) G. Heuger, S. Kalsow, R.
Gçttlich, Eur. J. Org. Chem. 2002, 1848.
[20] The Narasaka–Heck reaction is limited to cyclizations that
generate initially ketimines.
[21] The aldehyde likely forms via hydrolysis of an intermediate N-
tosyl aldimine.
Received: May 26, 2016
[22] A. J. Humphrey, D. OꢀHagan, Nat. Prod. Rep. 2001, 18, 494.
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
N-Heterocycles
I. R. Hazelden, X. Ma, T. Langer,
J. F. Bower*
&&&& — &&&&
Diverse N-Heterocyclic Ring Systems via
Aza-Heck Cyclizations of N-
(Pentafluorobenzoyloxy)sulfonamides
Aza-Heck cyclizations initiated by oxida-
aza-Heck reaction developed to date,
provide direct access to diverse N-heter-
ocyclic ring systems (18 examples, 42–
91% yield).
0
À
tive addition of Pd catalysts into the N
O bond of N-(pentafluorobenzoyloxy)-
sulfonamides are described. These stud-
ies, which are only the second class of
6
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!