Chemoselective Ketone Synthesis by the Addition of Organometallics to N-Acylazetidines

Article abstract of DOI:10.1021/acs.orglett.6b00842

A general and highly chemoselective method for the synthesis of ketones by the addition of organometallics to N-acylazetidines via stable tetrahedral intermediates is reported for the first time. The transformation is characterized by its wide substrate scope and exquisite selectivity for the ketone products even when a large excess of nucleophilic reagents is used. Even of broader interest is the use of N-acylazetidines as bench-stable, readily available amide acylating reagents, in which the reactivity is controlled by amide pyramidalization and strain of the four-membered ring to afford synthetically valuable building blocks.

Full text of DOI:10.1021/acs.orglett.6b00842

Letter
pubs.acs.org/OrgLett
Chemoselective Ketone Synthesis by the Addition of
Organometallics to N‑Acylazetidines
Chengwei Liu, Marcel Achtenhagen, and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: A general and highly chemoselective method for
the synthesis of ketones by the addition of organometallics to
N-acylazetidines via stable tetrahedral intermediates is reported
for the first time. The transformation is characterized by its
wide substrate scope and exquisite selectivity for the ketone
products even when a large excess of nucleophilic reagents is
used. Even of broader interest is the use of N-acylazetidines as
bench-stable, readily available amide acylating reagents, in which the reactivity is controlled by amide pyramidalization and strain
of the four-membered ring to afford synthetically valuable building blocks.
ucleophilic addition of organometallics to carboxylic acid
derivatives is a fundamental method for the synthesis of
transition-metal-catalyzed transformations to form carbon−
carbon bonds (Suzuki, Heck, directed arylation). Independently,
Garg and Zou reported Suzuki reactions of nonplanar imides.14
A unique feature of these reactions is ground-state amide
distortion, with N-coordination increasing amide electrophilicity
toward N−C cleavage.15 Interestingly, in all examples examined
to date, amide bond twist (cf. pyramidalization) was required for
productive metal insertion.16
N
ketones that is widely used in academic and industrial settings.1
Ketones are valuable compounds that are found in a large
number of biologically active molecules and also serve as
important building blocks in the synthesis of pharmaceuticals,
functional materials, and agrochemicals.2 The major challenge
associated with these protocols is overaddition of the reactive
nucleophilic reagents to ketone products, resulting in the
formation of tertiary alcohols and other side reactions (e.g.,
disproportionation and formation of secondary alcohols).3
In this context, based on the pioneering studies by Weinreb,
N-methoxy-N-methyl amides have been identified as arguably
the most versatile acylating reagents for the synthesis of ketones,
in which the presence of a chelating functional group prevents
collapse of the tetrahedral intermediate (Figure 1).4,5 Significant
progress in the development of new methods to control the
stability of metal-chelated tetrahedral intermediates has been
made.5 In contrast, Evans demonstrated that N-acylpyrroles
form stable tetrahedral intermediates upon addition of organo-
metallics due to pyrrole aromaticity and the lack of nOlp to
σ*C−N overlap.6 The recent report on the pyrrole-bearing
dication linchpin for the synthesis of ketones by the Sarpong
group is noteworthy.7 Other notable advances in the organo-
metallic addition to amides include electrophilic activation of
the amide bond reported by the groups of Charette and Huang8
and cyclopropanation of amides by the Kulinkovich−de Meijere
reaction.9 Despite these advances, however, there is an urgent
need to develop new bench-stable acylating reagents for the
direct synthesis of ketones using cheap and readily available
organometallics with high chemoselectivity.10
Expanding upon this theme, we recently hypothesized that
stable, pyramidalized amides16 (cf. twisted amides) might be
employed as highly chemoselective acylating reagents for
organometallic 1,2-addition by using pyramidalization as the
reactivity-controlling feature. In particular, we considered N-
acylazetidines17 based on the following features: (i) approx-
imately half pyramidalization of the amide bonds (τ = 3.3°; χN =
32.5°;18 4-TolC(O)-azetidine, Winkler−Dunitz parameters)
should allow enhanced N−C(O) reactivity due to diminished
nNlp to π*CO overlap, while preserving high bench stability of
the precursors; (ii) large ring strain in a four-membered ring of
25.4 kcal/mol (cf. aziridines, 27.5 kcal/mol) and high nitrogen
inversion barrier (90° angle) should decrease the aptitude for
collapse of the tetrahedral intermediate;19 (iii) large amide bond
resonance energy in the ground state of 17.7 kcal/mol (cf.
aziridines, 10.5 kcal/mol) should enable high bench stability,
while obviating the need for handling sensitive N-acylating
precursors.20 The unique geometric properties of N-acylazeti-
dines (ca. 30% amide distortion) might provide an opportunity
to interrogate the effect of amide strain on the stability of
tetrahedral intermediates.21,22
Herein, we report the first general and highly chemoselective
method for the addition of organometallics to N-acylazetidines
to give ketones via stable tetrahedral intermediates. The
transformation is characterized by its operational simplicity,
Our group has an ongoing interest in the activation of amide
bonds.11 While the selective nucleophilic addition to amides
(resonance of 15−20 kcal/mol)12 presents a significant
challenge, in 2015, we introduced a new mode of amide N−C
activation by geometric distortion.13 This reactivity platform
allows utilization of amides in a broad range of previously elusive
Received: March 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00842
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Table 1. Optimization of 1,2-Addition of Organometallics to
a
N-Acylazetidines
b
b
entry PhLi (equiv)
temp (°C)
time
conv (%)
yield (%)
1
2
3
4
5
6
7
8
9
1.05
1.05
1.05
2.00
2.00
2.00
2.00
2.00
2.00
3.00
3.00
3.00
−78
−78
−78
−78
−78
−78
0
15 min
1 h
71
62
48
19
37
88
74
78
84
77
66
93
80
81
c
c
c
1 h
69
15 min
1 h
>95
>95
>95
>95
>95
89
1 h
1 h
rt
1 h
rt
1 h
c
10
11
12
−78
−78 to rt
0 to 60
15 min
18 h
1 h
>95
>95
>95
a
Conditions: amide (0.5 mmol), PhLi (1−3 equiv, 1.9 M), THF (0.1
b
c
1
M). Determined by H NMR and/or GC. Reverse addition.
from the nucleophilic addition to N-acylazetidines provides
important practical and mechanistic considerations (vide infra).
Next, the preparative scope of the reaction was explored
(Scheme 1). As shown, the reaction accommodates a broad
range of aryl and alkyl amide and organometallic coupling
partners, providing advantageous selectivity (aryl−aryl, aryl−
Figure 1. (A) General strategies for ketone synthesis from amides. (B)
Activation of N−C amide bonds by ground-state distortion. (C)
Organometallic addition to N-acylazetidines (pyramidalization control).
alkyl, alkyl−alkyl) to the metal-catalyzed protocols.13,14
A
Scheme 1. Addition of Organometallics to N-Acylazetidines:
a
Nucleophile and Amide Scope
wide substrate scope, and exquisite selectivity for the ketone
products. This report introduces N-acylazetidines as bench-
stable, readily available amide acylating reagents, in which the
reactivity is controlled by amide pyramidalization and strain of
the four-membered ring,16 which might be exploited in ways
beyond the organometallic addition described.
We started our investigations by examining 1,2-nucleophilic
addition of phenyllithium to N-acylphenylazetidine under a
variety of conditions (Table 1). N-Acylazetidinyl aryl amide was
selected as a standard electrophile with the aim of providing a
complementary method to the recently reported metal-
catalyzed synthesis of aryl ketones from amides.13,14 After
preliminary experiments, we found that the proposed addition
occurs readily at −78 °C (entry 1). As expected, the reaction
time, temperature, reagent stoichiometry, and addition mode
had a significant influence on the reaction efficiency (entries 1−
10). Importantly, in all cases examined, the overaddition alcohol
and ring-opening products were not detected in crude reaction
mixtures (selectivity >95:5), attesting to the high stability of the
tetrahedral intermediate.6 The best results were obtained in
reactions at −78 °C (entry 10). Experiments designed to probe
the stability of the tetrahedral intermediate (vide infra)
demonstrated that reverse addition of N-acylazetidinyl amide
(entry 10), prolonged reaction time (entry 11), and even high
temperatures (entry 12) did not significantly affect its
propensity to collapse. Similar stability experiments were
conducted with MeLi as the nucleophile (not shown) and
demonstrated that the corresponding tetrahedral intermediate is
stable under the reaction conditions (selectivity >95:5). We
note that the high stability of tetrahedral intermediates resulting
a
b
Amide (0.50 mmol), RLi, THF (0.10 M), −78 or 0 °C. MeMgBr, rt.
c
ArMgBr, 0−60 °C. See Supporting Information for full details.
B
DOI: 10.1021/acs.orglett.6b00842
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Organic Letters
Letter
variety of organometallic reagents, including simple (3a−3b)
and sterically hindered (3c) alkyl, aryl (3d), alkynyl (3e), and
heterocyclic aryl lithium reagents, such as thienyl (3f) and furyl
(3g), are perfectly accommodated. Note that these reagents can
be readily generated by halogen−lithium exchange (3d), direct
deprotonation (3e), or directed metalation (3f−3g).10 Alkyl and
aryl Grignard reagents could be equally accommodated,
highlighting the high electrophilicity of N-acylazetidines
(3a,3h). Furthermore, the procedure could be extended to
simple alkyl (3i−3k) and sterically hindered alkyl N-
acylazetidines as electrophilic coupling partners in high yields
(3l−3n) using both alkyl and aryl nucleophiles. This reactivity is
particularly noteworthy as metal-catalyzed cross-coupling of
alkyl amide electrophiles by N−C insertion cannot be easily
accomplished due to decarbonylation/β-hydride elimination.13a
The scope with respect to functional group tolerance on both
coupling partners was next investigated (Scheme 2). The
Scheme 3. Selectivity Studies with N-Acylazetidines
Scheme 2. Addition of Organometallics to N-Acylazetidines:
Scope of Ketones
a
3A),4 attesting to the high electrophilicity of N-acylazetidines.
Experiments with electronically biased amides revealed that N-
acylazetidines are inherently more reactive substrates (Scheme
3B). Experiments between N-acylazetidines (Scheme 3C) are
consistent with the ease of nucleophilic addition.1,2 The
competition experiments suggest that synthetically useful levels
of selectivity are possible with these substrates.
To probe further the stability of tetrahedral intermediates, the
effect of Lewis acid additives was examined (Scheme 4). It is
Scheme 4. Stability of Tetrahedral Intermediates
well-known that Lewis acids increase the reactivity of N-
containing electrophiles in organometallic addition;24 however,
a profound decrease was found in the present reaction, while
maintaining high selectivity. We hypothesize that switchable N-/
a
Amide (0.50 mmol), RLi, THF (0.10 M), −78 °C.
O-Lewis acid coordination15 in azetidinyl amides (τ + χN
=
35°)16 attenuates the reactivity. In the absence of Lewis acids,
azetidinyl amides react via direct nucleophilic addition, while N-
coordination increases the pathway selectivity.
reaction tolerates a range of electronically varied substituents
under the standard reaction conditions (3d, 3h, 3o, 3p).
Valuable electrophilic functional groups such as para-fluoro
(3q), chloro (3r), and bromo (3s) are readily tolerated,
providing handles for nucleophilic addition/cross-coupling
manipulation. Functionalized (3t) and heterocyclic nucleo-
philes, such as pyridinyl (3u) and indolyl (3v), are compatible.
Finally, we found that alkenyl N-acylazetidinyl amides undergo
selective 1,2-addition to give valuable chalcone products (3w).
The utility of the present reaction is underscored by the
synthesis of ketones with biological activity, such as substituted
benzophenones with fungicidal activity (3t), chloropheniramine
metabolite (3u), and an intermediate in the synthesis of potent
aromatase inhibitors (3v).23
In summary, we have reported the first general addition of
organometallics to N-acylazetidines via stable tetrahedral
intermediates. The reaction adds to the toolbox of traditional
techniques for ketone synthesis from amides, complementing
the recently disclosed methods by N−C amide bond activation.
In a broader context, the present method introduces N-
acylazetidines as bench-stable, readily available amide acylating
reagents, in which the reactivity is controlled by the amide bond
pyramidalization. We anticipate that this mode of amide bond
activation will find widespread use in organic synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
Studies were conducted to gain insight into the reaction
mechanism (Scheme 3). Most importantly, intermolecular
competition studies showed that organometallic addition to
N-acylazetidines is preferred over Weinreb amides (Scheme
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00842.
C
DOI: 10.1021/acs.orglett.6b00842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data
Letter
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anie.201601914. Friedel-Crafts acylation with twisted amides: (g) Liu,
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(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michal.szostak@rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. M.A.
thanks the Chemistry Department (Rutgers University) for a
Summer Undergraduate Research Fellowship. The Bruker 500
MHz spectrometer used in this study was supported by the
NSF-MRI grant (CHE-1229030).
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