Synthesis of Secondary Unsaturated Lactams via an Aza-Heck Reaction

Article abstract of DOI:10.1021/jacs.6b08932

The preparation of unsaturated secondary lactams via the palladium-catalyzed cyclization of O-phenyl hydroxamates onto a pendent alkene is reported. This method provides rapid access to a broad range of lactams that are widely useful building blocks in alkaloid synthesis. Mechanistic studies support an aza-Heck-type pathway.

Full text of DOI:10.1021/jacs.6b08932

Communication
pubs.acs.org/JACS
Synthesis of Secondary Unsaturated Lactams via an Aza-Heck
Reaction
Scott A. Shuler, Guoyin Yin, Sarah B. Krause, Caroline M. Vesper, and Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
In contrast to the use of nucleophilic nitrogen in aza-Wacker
ABSTRACT: The preparation of unsaturated secondary
lactams via the palladium-catalyzed cyclization of O-phenyl
hydroxamates onto a pendent alkene is reported. This
method provides rapid access to a broad range of lactams
that are widely useful building blocks in alkaloid synthesis.
Mechanistic studies support an aza-Heck-type pathway.
reactions, we envisioned that an umpolung strategy involving
electrophilic nitrogen could provide an alternative lactam
synthesis via an aza-Heck cyclization. Reactions involving
nitrogen electrophiles are a burgeoning area of chemical
research;6−12 however, aza-Heck reactions remain nascent.13 In
pioneering studies, Narasaka,14 Bower,15 and others16 have
demonstrated that O-acyl ketooximes can participate in various
types of aza-Heck cyclizations. This work has established this
method as a powerful entry into cyclic ketimines and related
mall nitrogen-containing heterocycles, such as pyrrolidines,
Spyrrolidinones, piperidines, and piperidones, are ubiquitous aromatic aza-heterocycles (Figure 1, middle). Very recently,
in both synthetic and naturally occurring bioactive compounds.1
Secondary, N−H bearing, allylic lactams are highly valued
Bower reported the cyclization of unsaturated N-acyloxysulfona-
mides.17 However, other classes of electrophilic nitrogen centers
have not been reported in aza-Heck reactions.18 In particular, no
synthons for accessing a diverse array of such ring systems
examples of aza-Heck reactions of N−H bearing nitrogen
embedded within complex structures. In addition, allylic lactams
electrophiles have been described.
themselves are prevalent scaffolds within bioactive molecules.2
In the context of our group’s standing interest in heteroatomic-
An attractive approach to these compounds involves
Heck reactions,19 we sought to identify an appropriate nitrogen
cyclization of a primary amide (or equivalent) onto a pendant
electrophile to allow direct lactam synthesis (Figure 1, bottom).
alkene using transition metal catalysis. The aza-Wacker reaction
presents one approach to such a transformation; however, these
reactions are not well developed for amides as they typically
require highlyacidic nitrogennucleophiles, suchassulfonimides.3
Although a few cyclizations of secondary amides (or related
compounds) leading to tertiary amides are known,4 only a single
example of an aza-Wacker cyclization of a primary amide leading
to an unprotected secondary lactam has been reported,5 drawing
into question the generality of this approach (Figure 1, top).
Herein, we disclose an aza-Heck reaction using O-phenyl
hydroxamates that provides access to a variety of unprotected
allylic lactams. Utilizing a commercially available catalyst system,
this reaction allows the direct synthesis of unprotected allylic
lactams with broad substrate scope and exceptional functional
group tolerance.
Inspired by Liebeskind’s copper-catalyzed arylation stud-
ies,6c,20 we first investigated the cyclization of O-benzoyl
hydroxamate ester 1 under conditions reminiscent of our other
heteroatomic-Heck reactions (5 mol % (COD)Pd(CH2SiMe3)2,
7.5 mol % PtBu3, Et3N, DMF, 80 °C). Under these and similar
conditions, none of the desired product was observed (Table 1,
entry 1). Instead, several undesired products (most notably the
symmetric urea 5, attributable to Lossen rearrangement,21 along
with lesser amounts of primary amide 6 were formed. Similar
results were obtained with a more electron-deficient ester (entry
2). Numerous other highly activated hydroxamate ester
derivatives (not shown) proved to be unstable during
preparation.
On the basis of these results, we decided to investigate less
activated hydroxamate derivatives. Following this reasoning, we
were highly encouraged to find trace yield of the desired [6,5]-
fused lactam 4 when the cyclization of O-phenyl hydroxamate
ether3wasinvestigatedundertheseconditions(Table1, entry3).
Also significant, no Lossen byproducts were observed. With a
promisingelectrophileinhand, theroleofligandwasinvestigated.
Received: August 25, 2016
Figure 1. Overview and context of work.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b08932
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Communication
Table 1. Identification of Reaction Conditions
Scheme 1. Substrate Scope
entry
substrate
ligand
PtBu3
solvent
% yield (4/5/6)
1
2
3
4
5
6
1
2
3
3
3
3
3
3
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
0/51/1
0/61/6
1/0/9
PtBu3
PtBu3
PPh3
7/0/18
13/0/16
12/0/2
76/0/8
a
PAr3
P(OEt)3
P(OEt)3
P(OCH2CF3)3
b
7
b
8
99/0/1
a
b
PAr3 = tris(3,5-bis(trifluoromethyl)phenyl)phosphine. 0.05 M
solvent concentration, 5 equiv Bu3N, 10 mol % (COD)Pd-
(CH2TMS)2, 30 mol % ligand.
Using triphenylphosphine (entry 4) both improved the yield of 4
and lowered the relative production of 5. This trend was even
more pronounced with use of tris(3,5-bis(trifluoromethyl)-
phenyl)phosphine, an electron-deficient ligand that has been
successfully used by Bower (entry 5).
a
b
c
d
P(OEt)3 in place of P(OCH2CF3)3. 50 °C. NMR yield. 48 h.
We postulated that the relative success of these aromatic
ligands might lie in part to their π-acidity, which might serve to
stabilize the putative palladium intermediates that bear multiple
π-donor ligands. This line of reasoning led us to investigate other
electron-deficient ligands. Triethylphosphite was notable in this
regard, providing the product in a similar yield (12%) but with
much less primary amide side-product (entry 6). Further
optimization using triethylphosphite revealed that increasing
the ligand-to-metal ratio to 3:1, changing the solvent to
acetonitrile, decreasing the reaction concentration, switching
the base to Bu3N, and slightly increasing the catalyst loading
provided improved yields of 4 (entry 7).22 Although these
improvements provided reasonable production of the desired
product, reduced side product was still observed. Further
investigation revealed that the use of commercially available
tris(2,2,2-trifluoroethyl)phosphite was able to avoid largely the
formation of the reduced side product.23 With this ligand, 4 was
isolated in near quantitative yield (entry 8).
Thescopeofthereactionwasnextexplored(Scheme1). Like4,
[5,5]-fused lactam 7 was prepared in high yield. As expected, both
4 and 7 were formed as a single syn diastereomer. Product 8
demonstrated that acyclic substrates are also viable, and exo-cyclic
alkenes can be prepared with high levels of stereocontrol.
Isoindolinone9wasformedinhighyieldasasinglealkeneisomer.
In this case, we postulate enamide formation is thermodynamic in
nature, and is the result of isomerization of the initially formed
terminal alkene.22 Substitution adjacent to the carbonyl was
tolerated using the fluorinated ligand. For example, 10 was
isolated in 76% yield. Similarly, monomethyl 11, as well as the α-
N-Boc-amine 12, were readily prepared, albeit without significant
diastereoselectivity. In contrast, substitution at the β-position
significantly influences the stereochemical outcome of the
reaction (13).24 Trisubstituted alkenes are competent substrates
for this aza-Heck reaction, and can be used to prepare both
spirocyclic (14) and other lactams (15) bearing fully substituted
carbon centers. Remarkably, even tetrasubstituted alkenes can be
cyclized.Forexample,thehighlysubstitutedisoindolinone16was
isolated in 96% yield. This is the first example of a tetrasubstituted
alkene participating in an aza-Heck reaction.
With only a few exceptions,16d,25 all prior examples of aza-Heck
reactions have been limited to the formation of simple or fused 5-
membered rings. It is thus particularly notable that the bridged
bicycle17canbereadilypreparedusingthischemistry. Thisisone
of the first examples of a transannular cyclization within this class
of reactions.17 In addition, although attempted formation of 18
resultedinonlyreductionofthestartingmaterial, formationofthe
δ-lactam bearing a fused aromatic ring (19) proceeded smoothly.
This latter cyclization provides the prospect that further studies
will expand the scope of these cyclizations to larger ring systems.
This method is broadly tolerant of functional groups, as
revealed by a stoichiometric additive study.22,26 Tolerated
additives include carboxylic acids, nitroalkanes, phenols,
benzaldehydes, styrenes, nitrobenzenes, thiophenes, indoles,
imidazoles, pyrazoles, primary anilines, and benzonitriles. In
addition to these additive studies, several functionalized products
were also prepared. For example, benzodioxazole 20 and the
pyridyl-based 21 were both isolated in high yield (Scheme 1).
Thiophene 22 was not observed; however (on the basis of the
additive screen), we postulate this is a function of ring strain of the
product, and not due to interference of the heterocycle.22
Activation of the hydroxamate occurs in preference to both aryl
chlorides and aryl bromides (23 and 24), providing opportunities
for additional functionalization.
To explore further the utility of this transformation in the
preparation of complex ring systems, we explored the possibility
of a tandem aza-Heck/Heck sequence. Much to our delight,
subjection of diene 25 to the reaction conditions provided a near
quantitative yield of spirocycle 27 (eq 1). This result is consistent
with a tandem cyclization proceeding via the neopentylic
palladium complex 26.27,28
In principle, this reaction could proceed either via an aza-
Wacker or an aza-Heck mechanism. The former would involve
B
DOI: 10.1021/jacs.6b08932
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Journal of the American Chemical Society
Communication
terminal oxidant. Similar studies also show that primary amides
are not substrates for the reaction.22,32
On the basis of the above evidence, we currently favor a Heck-
like pathway involving oxidative addition into the N−O bond,
followed by suprafacial migratory insertion and syn β-hydride
elimination (Figure 2). To date, we have not been able to directly
Pd(II) activation of either the N−H bond or the alkene; the latter
would involve Pd(0) activation of the N−O bond. Circumstantial
evidence suggests that the mechanism does not involve a Wacker
mechanism, as aza-Wacker reactions of aromatic hydroxamate
esters are known (for both O-Me and O-Bn) substrates, and they
lead to cyclic hydroxamates retaining the N−O bond.4b,e
To probe further the mechanism, several studies were
undertaken. First, although other Pd(0) complexes such as
Pd2dba3 provide ineffective catalysis (likely due to competitive
ligation of the dba),22 Pd[P(OEt)3]4 is an extremely competent
catalyst(eq2). With only1mol%ofthis complex, highyieldof 15
is observed.29 This result demonstrates that a Pd(II) precatalyst is
not required.
Figure 2. Proposed aza-Heck mechanism.
observe adducts from metal insertion into the N−O bond;
however, further studies are ongoing to elucidate the details of
that step of the mechanism.33−35
Second, independent cyclization of each isomer of alkene 29
reveals the reaction is stereospecific (Scheme 2). Cyclization of
Insummary, we havedeveloped amild, catalyticmethodforthe
synthesis of unsaturated secondary lactams. This reaction boasts a
broad substrate scope, and tolerates a wide breadth of biologically
relevant functional groups. Mechanistic evidence supports a
Heck-type mechanism, making this the first report of
hydroxamate esters as electrophiles in an aza-Heck reaction and
highly complementary to existing aza-Wacker technology.
Further studies in our laboratory are underway to expand the
scope of the reaction.
Scheme 2. Effect of Alkene Geometry
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.6b08932.
■
S
(Z)-29 leads exclusively to enamide (Z)-30 (E/Z > 1:99),
independent of reaction time. In contrast, subjection of (E)-29
leads predominately to (E)-30 (E/Z = 91:9) after 15 min. After
longer reaction times, however, this ratio erodes to E/Z = 60:40,
indicating that (E)-30 is kinetically formed and slowly converts to
themorestableZ-isomer. Thekineticselectivity isconsistentwith
a pathway defined by suprafacial migratory insertion of a Pd−N
bond, C−C σ-bond rotation, and syn β-hydride elimination. This
outcome rules out a mechanism initiated by Pd(II) activation of
the alkene followed antarafacial attack of nitrogen, but is
consistent with either a Heck-like pathway involving N−O
activation or a Wacker-like pathway involving initial N−H
activation.30,31
Finally, we have examined the viability of N-acyl sulfonamides
as substrates. These highly acidic compounds (pKa ∼ 2) are
known to participate in aza-Wacker reactions via N−H
activation.4d Either alone,22 or in the presence of an O-phenyl
hydroxamate 28 (eq 3), N-acyl sulfonamide 31 does not undergo
cyclization under our conditions. This result argues against a
Wacker-like mechanism involving N−H activation and precludes
the possibility that the hydroxamates are serving simply as a
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*dawatson@udel.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Shi Bai for assistance with NMR spectra. The
University of Delaware (UD) and the NIH (P20 GM104316) are
gratefully acknowledged for support. NMR, MS, and other data
were acquired at UD on instruments obtained with the assistance
of NSF and NIH funding (NSF CHE0421224, CHE1229234,
and CHE0840401; NIH P20GM104316, P30GM110758,
S10RR026962, and S10OD016267).
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