σ N-C Bond Difunctionalization in Bridged Twisted Amides: Sew-and-Cut Activation Approach to Functionalized Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.7b00913

A rare example of highly selective σ N-C bond difunctionalization in bridged twisted lactams through N-C cleavage has been achieved. In combination with the intramolecular Heck cyclization, this method affords a two-step bond reorganization event (“sew-an

Full text of DOI:10.1021/acs.orglett.7b00913

Letter
pubs.acs.org/OrgLett
σ N−C Bond Difunctionalization in Bridged Twisted Amides: Sew-
and-Cut Activation Approach to Functionalized Isoquinolines
Feng Hu, Pradeep Nareddy, Roger Lalancette, Frank Jordan, and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
*
S Supporting Information
ABSTRACT: A rare example of highly selective σ N−C bond
difunctionalization in bridged twisted lactams through N−C
cleavage has been achieved. In combination with the
intramolecular Heck cyclization, this method affords a two-
step bond reorganization event (“sew-and-cut”) to access
functionalized isoquinoline ring systems directly with high
atom economy. C−H bond functionalizations directed by a
weakly coordinating bridged amide bond increase scaffold diversity. Preliminary mechanistic studies on the effect of amide
distortion and the role of electrophile in this unusual σ N−C amide difunctionalization are described.
he development of new strategies for activation of
bond reorganization event (“sew-and-cut”) to access privileged
isoquinoline ring systems directly with high atom economy
(Figure 1C).
1
2
T
otherwise inert carbon−hydrogen, carbon−carbon, and
3
carbon−nitrogen σ bonds is an important goal in organic
chemistry. Selective σ bond reorganization events in cyclic
scaffolds by unconventional disconnections enable the develop-
ment of atom-economic, chemoselective approaches to com-
Inspired by the recent reports on reactivity of bridged twisted
7
−9
lactams, we envisioned transition-metal catalyzed sewing of a
7b
bridged lactam moiety, followed by selective N−C bond
1
−3
10−12
pounds with broad potential applications.
Recent develop-
cleavage through electrophilic N-activation.
This strategy
ments include a Rh(I)-catalyzed carboacylation of cyclo4-
would result in a geometry-controlled, regioselective amide N−C
13
14
butenones named as the “cut-and-sew” protocol (Figure 1A)
bond difunctionalization with modifiable functional groups,
and would be challenging to achieve by traditional disconnec-
15
tions. The process would provide high selectivity for the
synthesis of heterocyclic 2-isoquinolones and isoquinolines,
which are key structural motifs in numerous pharmaceuticals and
16
biologically important natural products (Figure 2). Methods
Figure 2. Representative pharmaceuticals and natural products
containing isoquinoline scaffold.
Figure 1. Activation of unreactive σ C−C and C−N bonds: (a and b)
previous and (c) this work.
for the synthesis of functionalized isoquinolines are in high
16
demand due to the biological activity of the scaffold. Herein, we
describe the successful realization of this strategy and disclose for
the first time a series of C−H bond functionalizations directed by
5
and Pd(0)-catalyzed olefin addition to β-lactams (Figure 1B).
These approaches rely on insertion of a metal catalyst into
17
6
a weakly coordinating twisted amide bond to access all
positions around the aromatic ring selectively.
particularly strained four-membered rings. Herein, we describe
an alternative strategy that relies on a rare, selective, metal-free
difunctionalization of a σ carbon−nitrogen bond in bridged
twisted lactams through N−C cleavage. In combination with the
intramolecular Heck cyclization, the method affords a two-step
Received: March 28, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00913
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
0,11
The following features of our study are noteworthy: (1) In
contrast to the only example of a σ N−C bond cleavage in
bridged lactams, which focused on bridged lactams featuring a
shown).
Importantly, the scission reaction occurred with
complete regioselectivity, resulting in activation of the σ N−C
18
bond more distorted from the carbonyl plane. Optimization
was performed to gain insight into the role of reaction conditions
with respect to solvent, temperature, and concentration (see
Supporting Information, SI).
10
predominantly twisted amide bond, we demonstrate for the
first time the feasibility of a selective σ N−C bond
difunctionalization in easily accessible (1−2 steps from
commercial materials) bridged lactams showing pyramidaliza-
The scope of this electrophilic bisfunctionalization by σ N−C
bond cleavage is shown in Scheme 2. The reaction tolerates a
wide range of electrophiles bearing various functional groups.
Primary alkyl iodides with increasing steric hindrance such as
MeI (3a−3b), EtI (3c), and n-HexI (3d) are well-tolerated.
Benzyl electrophiles, including bromide (3e) and chloride (3f),
afford the opening products in high yields. Moreover, allylic
electrophiles such as bromide (3g) and chloride (3h) can be used
successfully, introducing either chloride or bromide as the
nucleophile. The use of propargyl bromide (3i) and
bromoacetate (3j) proceeded uneventfully (3i). Notably, the
reaction is compatible with electrophilic functional handles such
as aryl bromide (3k) and styrene (3l) that would be problematic
using metal-catalyzed protocols. The ability to install aliphatic
and aromatic halide functional groups selectively in a single step
provides a synthetic advantage of our protocol. These mild,
metal-free conditions introduce an array of useful electrophilic
7
−9,11
tion as the major geometric distortion feature.
(2) The
present method allows the realization of a rare difunctionaliza-
tion of the amide bond by selective σ N−C bond cleavage,
3
a,b
resulting in an overall amide bond activation by an S 2-type
mechanism.
N
1
0,11
(3) Mechanistic studies on the effect of amide
bond distortion and the role of the electrophile are reported for
the first time. Altogether, this process further advances the amide
3
,7
bond activation concept by N−C bond cleavage.
Initial studies focused on the development of a telescoped
(
one-pot) synthesis of bridged amide 1 from readily available 2-
7b
iodobenzoic acid (Scheme 1). Significantly, this telescoped
a
Scheme 1. One-Pot Large-Scale Synthesis of Twisted Amides
19
handles (I, Br, Cl) for further derivatization.
Although at present unactivated alkyl bromides are not viable
substrates (vide infra), we found that an in situ S 2 displacement
enables the use of these less activated substrates (Scheme 3A).
N
a
See Supporting Information (SI) for details.
a
process represents the easiest scalable route to bridged lactams
bearing significantly distorted amide bonds reported to date.
Scheme 3. In Situ and One-Pot Functionalizations
7
−9
After extensive experimentation, we found that exposure of
twisted amides 1−2 to MeI in CH Cl at 60 °C gave the σ N−C
2
2
bond opening product in quantitative yields (Scheme 2, 3a−3b).
The presence of an internal alkene was not required for the
amide activation (vide infra). Mild olefin reduction in 1 (Pd/C,
EtOAc) can be performed without amide hydrogenolysis (not
Scheme 2. Facile σ N−C Bond Difunctionalization:
a
Electrophile Scope
a
See Supporting Information for details.
The synthetic potential of a halide functional handle has been
demonstrated by one-pot opening/azide installation (Scheme
3
B); we envision that other nucleophiles will be readily available
by this sequence.
To increase scaffold diversity rapidly, we performed a series of
C−H bond functionalizations using twisted amide bonds as
1
7,20,21
weakly coordinating directing groups (Scheme 4).
To our
knowledge, the results provide the first example of selective C−H
functionalizations directed by a twisted amide bond. We
anticipate that twisted amides may serve as suitable substrates
for directed C−H activation processes relying on a decreased
17
basicity of the bridged amide carbonyl group.
As expected, σ N−C difunctionalization of the amide C−H
functionalization products proceeded uneventfully (Scheme 5),
providing a powerful extension of the “sew-and-cut” strategy to
ring functionalized isoquinoline motifs.
The developed chemistry can also be used to install sensitive
functional groups prior to the Heck cyclization owing to the
tolerant Pd-catalyst system employed. For example, a meta-
bromo substituent is well-accommodated in one-pot cyclization/
bond reorganization (Scheme 6), providing yet another
approach to selective σ N−C amide bond cleavage.
a
Conditions: amide (1.0 equiv), R−X (1.2−5.0 equiv), CH Cl or
2
2
CHCl , 60−100 °C. See Supporting Information for details.
3
B
DOI: 10.1021/acs.orglett.7b00913
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Decoration of Twisted Amides by C−H
Scheme 7. Mechanistic Studies: Effect of Electrophiles and
Amide Bond Distortion
a
Functionalizations
a
See Supporting Information for details. [Ru] = [Ru(p-cymene)Cl ] .
2
2
Scheme 5. Facile σ N−C Bond Difunctionalization in C−H
a
Decorated Amides
The present reaction is unusual in that the amide bond
undergoing opening shows predominantly a pyramidalized
7
−9
amide bond (cf. predominantly twisted bond).
We
determined that the ring-expanded, twisted amide analogue 12
(Scheme 7C) is inert to the cleavage conditions. As such, this
study delineates structural parameters required for activation of
a
See Scheme 2.
twisted bridged amides by σ N−C cleavage. Widely available
Scheme 6. Chemoselective Cyclization/N−C
Difunctionalization in the Presence of a Bromo-Substituent
7−9
a
twisted amides
with the sum of amide bond distortion
9c,d
parameters (τ + χ ) of 50−60° undergo efficient N-activation.
N
The finding that pyramidalization serves as the main feature of
the amide bond distortion may lead to new methods for N−C
3
a,b
bond activation of resonance destabilized amides.
In conclusion, we have developed a new approach to the
synthesis of functionalized isoquinolines through a rare, highly
selective σ N−C amide bond difunctionalization by N−C
cleavage. This versatile method tolerates a wide range of
functional groups that would be problematic using metal
catalysis, and proceeds with full cleavage regioselectivity
controlled by the amide bond geometry. This strategy delivers
medicinally relevant isoquinoline products. We have also
described the first C−H functionalizations directed by a bridged
amide bond. More importantly, the study suggests the possibility
of activating C−N bonds in widely accessible distorted amides by
electrophilic N-activation. Further studies to determine the
reactivity of geometrically activated amides are underway.
a
See Scheme 1.
Preliminary studies were conducted to gain insight into the
mechanism of this intriguing N−C bond cleavage. Cleavage
selectivity is independent of the presence of an internal allylic
olefin (Scheme 7A). Moreover, the following order of leaving
group ability is observed: I > Br > Cl (Scheme 7B). A plot of
log(kX/Me) vs Charton ν steric constant using primary alkyl
ASSOCIATED CONTENT
■
2
*
S
Supporting Information
iodides yields a linear correlation (R = 0.88) (not shown). These
effects suggest rate-limiting activation of the amide nitrogen
atom by N-alkylation, followed by nucleophilic cleavage of the σ
N−C bond. These results provide the first examination of steric
and electronic effects in σ N−C bond cleavage of twisted bridged
lactams.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00913.
2
2
Procedures and analytical data (PDF)
X-ray crystallographic data (CIF)
C
DOI: 10.1021/acs.orglett.7b00913
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
9) (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115,
AUTHOR INFORMATION
■
*
6951. (b) Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc.
1996, 118, 8658. (c) Szostak, R.; Aube, J.; Szostak, M. Chem. Commun.
2015, 51, 6395. (d) Szostak, R.; Aube, J.; Szostak, M. J. Org. Chem. 2015,
80, 7905. (e) Wiberg, K. B. Acc. Chem. Res. 1999, 32, 922. (f) Cox, C.;
Corresponding Author
́
́
E-mail: michal.szostak@rutgers.edu.
ORCID
Lectka, T. Acc. Chem. Res. 2000, 33, 849. (g) Kemnitz, C. R.; Loewen, M.
J. J. Am. Chem. Soc. 2007, 129, 2521. (h) Glover, S. A.; Rosser, A. A. J.
Org. Chem. 2012, 77, 5492.
Frank Jordan: 0000-0003-1354-718X
Michal Szostak: 0000-0002-9650-9690
Notes
(
́
10) (a) Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.; Aube, J.
J. Am. Chem. Soc. 2005, 127, 4552. Note that this is the only example of a
metal-free σ N−C cleavage in bridged lactams. This elegant study
focused on a specific class of lactams (typically 10−12 step synthesis),
The authors declare no competing financial interest.
characterized predominantly by an amide bond twist (τ = 51.5°; χ =
N
ACKNOWLEDGMENTS
36.1°). (b) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169.
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Financial support was provided by Rutgers University. The 500
MHz spectrometer was supported by the NSF-MRI grant (CHE-
229030). We thank SEED Grant (Rutgers University) to the
Center for Sustainable Synthesis for partial support of this
project.
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DOI: 10.1021/acs.orglett.7b00913
Org. Lett. XXXX, XXX, XXX−XXX