Kinetically Controlled, Highly Chemoselective Acylation of Functionalized Grignard Reagents with Amides by N?C Cleavage

Article abstract of DOI:10.1002/chem.201904678

The direct transition-metal-free acylation of amides with functionalized Grignard reagents by highly chemoselective N?C cleavage under kinetic control has been accomplished. The method offers rapid and convergent access to functionalized biaryl ketones through transient tetrahedral intermediates. The direct access to functionalized Grignard reagents by in situ halogen–magnesium exchange promoted by the versatile turbo-Grignard reagent (iPrMgCl?LiCl) permits excellent substrate scope with respect to both the amide and Grignard coupling partners. These reactions enable facile, operationally simple and chemoselective access to tetrahedral intermediates from amides under significantly milder conditions than chelation-controlled intermediates. This novel direct two-component coupling sets the stage for using amides as acylating reagents in an alternative paradigm to the metal-chelated approach, acyl metals and Weinreb amides.

Full text of DOI:10.1002/chem.201904678

A Journal of
Accepted Article
Title: Kinetically-Controlled, Highly Chemoselective Acylation of
Functionalized Grignard Reagents with Amides by N–C Cleavage
Authors: Guangchen Li and Michal Szostak
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Kinetically-Controlled, Highly Chemoselective Acylation of
Functionalized Grignard Reagents with Amides by N–C Cleavage
Guangchen Li and Michal Szostak*
Abstract: The direct transition-metal-free acylation of amides with
functionalized Grignard reagents by highly chemoselective N–C
cleavage under kinetic control has been accomplished. The method
offers rapid and convergent access to functionalized biaryl ketones
via transient tetrahedral intermediates. The direct access to
functionalized Grignard reagents via in situ halogen-magnesium
exchange promoted by the versatile turbo-Grignard reagent (i-
PrMgCl·LiCl) permits for excellent substrate scope with respect to
both the amide and Grignard coupling partners. These reactions
enable facile, operationally-simple and chemoselective access to
tetrahedral intermediates from amides under significantly milder
conditions than chelation-controlled intermediates. This novel direct
two-component coupling sets the stage for using amides as
acylating reagents in an alternative paradigm to the metal-chelated
approach and acyl-metals.
The carbonyl group represents one of the most important
functional groups in organic synthesis.[1] Biaryl ketones are found
in a plethora of bioactive architectures,[2] and importantly serve
as versatile intermediates for the installation of various functional
groups by the direct ipso C=O functionalization.[3] The classic
way of synthesizing ketones involves nucleophilic addition of
organometallic reagents to N-methoxy-N-methylamides[4] that
capitalize on the formation of kinetically-stable, yet unreactive,
metal-chelated intermediates (Figure 1A).[5] In this context, the
Figure 1. Amide bond cleavage in organic synthesis.
discovery that amide functionalization can be accomplished by
the direct insertion of a transition-metal to give the acyl-metal
amide bond (k1) is faster than the rate of the collapse of
tetrahedral intermediate (k2), a highly chemoselective reaction
could ensue. In this scenario, the formation of overaddition
products (k3), a process that plagues direct acyl substitution
reactions,[4,5] could be avoided by tuning the reactivity of the
intermediate from historically unreactive amide bonds (nN→*
C=O
delocalization) was an important achievement that enabled the
construction of important motifs for chemical synthesis (Figure
1B).[6,7] Continuing this theme, herein, we report the third mode
of reactivity of amide bonds, wherein the direct, highly
amide leaving group and organometallic reagent. A central
chemoselective, transition-metal-free acylation of amides with
design in this strategy is the fact that N,N-Boc2-amides unlike N-
functionalized Grignard reagents[8] is accomplished by transient
methoxy-N-methylamides[4] can be readily prepared either from
tetrahedral intermediates under kinetic control (Figure 1C).[9,10]
1° benzamides by double N-selective tert-butoxycarbonylation or
The reaction enables the construction of
a wide variety
from carboxylic acid derivatives,[11] thus providing new avenues
for unconventional C–C bond disconnection. In general, amides
are the least reactive carboxylic acid derivatives due to high
kinetic barrier for nucleophilic addition. In the present case, the
resonance is minimized (ER = 6.3 kcal/mol). Second, the
collapse must be thermodynamically favored. Third, overaddition
must be controlled to prevent the formation of alcohols.[10e,f]
Although our initial studies were conducted using 4-
tolylmagnesium bromide, from the outset we were attracted to
the use of a versatile turbo-Grignard reagent platform (i-PrMgCl·
LiCl) introduced by Knochel and co-workers.[12–15] The facile
halogen magnesium exchange using i-PrMgCl·LiCl permits for a
high yielding preparation of a broad range of functionalized
organomagnesium reagents for the production of high value
motifs in organic synthesis.
functionalized ketones with excellent functional group tolerance,
including ester, cyano, nitro, chloro, bromo, thiomethyl, tosyl,
amino, and trifluoromethyl ether, and sets the stage for using
amides as acylating reagents in an alternative paradigm to the
metal-chelated approach[4,5] and acyl-metals.[6,7]
As shown in Figure 1C, we postulated that the highly
electrophilic nature of N,N-Boc2-amides[11] would permit for the
direct nucleophilic addition of an organometallic reagent to the
N–C(O) bond to generate a transient acyl-metal-intermediate. If
the rate of the nucleophilic addition of organometallic to the
[*]
G. Li, Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (United States)
E-mail: michal.szostak@rutgers.edu
Our investigation started with an examination of the
addition of 4-TolMgBr to N,N-Boc2-benzamide (Table 1). Two
other representative N-Boc-benzamides, namely N-Boc/Ph and
Supporting information for this article is given via a link at the end of
the document.
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The optimization data highlight key differences between
N,N-Boc2-amides and N-methoxy-N-methylamides as acylating
reagents: (a) N,N-Boc2-amides[11] are significantly more reactive
than the present state-of-the-art N-methoxy-N-methylamides[4]
(vide infra); (b) N,N-Boc2-amides[11] react through transient
tetrahedral intermediates vs. metal-chelated intermediates from
N-methoxy-N-methylamides.[4] Furthermore, the optimization
data demonstrate that a selective nucleophilic addition to N-
Ar/Boc and N-alkyl/Boc amides that are readily prepared from
either from 2° benzamides or from carboxylic acid derivatives[10]
is also feasible through the same type of transient tetrahedral
intermediates. Full Table 1, including unselective N–Boc
scission, is presented in the SI.
Table 1. Optimization of the reaction conditions.[a]
With the optimized conditions in hand, the scope of the
direct nucleophilic addition to N,N-Boc2 amides was examined.
To emphasize the utility of i-PrMgCl·LiCl enabling highly
chemoselective preparation of functionalized organomagnesium
reagents,[12–15] all Grignard reagents used in the substrate scope
examination were prepared by in situ halogen-magnesium
exchange promoted by i-PrMgCl·LiCl. As shown in Table 2, the
reaction furnishes the desired ketones with an excellent
efficiency and striking functional group tolerance. Electron-
donating alkyl (3a), alkoxy (3b), thioether (3c) and amine (3d)
functional groups can be readily incorporated. This direct
nucleophilic acylation is compatible with electron-withdrawing
groups, such as chloro (3e), bromo (3f), trifluoromethyl (3g),
cyano (3h), methyl ester (3i), tert-butyl ester (3j) and OTs (3k),
furnishing the desired ketones with excellent levels of selectivity
and providing handles for further functionalization. Ortho-
substitution with a sterically-demanding 2-arylbromide that is
selectively prepared from 1,2-dibromobenzene is compatible
(3l).[12a] Various electronically-differentiated substituents at the
meta-position, such as methoxy (3m), trifluoromethylether (3n),
fluoro (3o), bromo (3p) and cyano (3q) provided the desired
ketone products in good to excellent yields. Furthermore, poly-
chlorinated arenes, including sterically-hindered 2,6-dichloro (3r),
and 3,4-dichloro (3s) formed the products in good yields. Finally,
we were pleased to find that the reaction is compatible with
polyaromatic arenes, such as naphthalene (3t) and heterocycles
such as electron-rich thiophenes (3u-3v) and electron-deficient
pyridines (3w-3x). Overall, the reaction shows superior scope to
all other acyl-substitution reactions of amides by acyl-metal
intermediates[6,7] or using N-methoxy-N-methylamides.[4]
The compatibility with various N,N-Boc2 amides was also
striking (Table 3). These reactions were performed using
representative functionalized organomagnesium reagents[12.13]
containing ester, ether, cyano, heterocycle and bromo functional
groups, resulting in a rapid synthesis of complex ketones. As
shown in Table 3, electron-withdrawing fluoro (3y) and nitro (3z),
electron-rich thiophene (3aa) and cyano (3ab) groups were
compatible on the amide coupling partner. Furthermore, ortho-
sterically hindered (3ac) and polyaromatic (3ad) amides were
well-tolerated. Sensitive functional groups, such as bromo (3ae)
and ester (3af) as well as various electronically-differentiated
substituents (3ag-3ai) provided the desired ketones in high
yields. It is worthwhile to note that 3-pyridyl ketone (3aj) is
derived directly from nicotinamide, thus illustrating the potential
of this method in drug derivatization.[7e] Finally, we were pleased
to find that the method could achieve the synthesis of challenging
[a]Standard conditions: 1 (1.0 equiv), 2 (1.0 equiv), THF (0.25 M), 0 °C, 30 min.
N-Boc/Me benzamides,[16] and the classic N-methoxy-N-methyl-
benzamide[4] were screened at the same time. We anticipated that
the difference in amidic resonance[10] and leaving group aptitude
would influence the reactivity and provide insight into the
reaction pathway. The desired ketone was produced in excellent
90% yield using 4-TolMgBr (fast addition, 1.0 equiv) in THF at
0 °C (entry 1). Under these conditions, the non-selective N-Boc
scission and overaddition to give the ketone were not observed,
consistent with (1) the high electrophilicity of the N–C(O) amide
bond, and (2) a rapid collapse of the tetrahedral intermediate.
Several optimization experiments are worth noting. (1) The
slow dropwise addition of the Grignard reagent resulted in a
non-selective process (entry 2). (2) Likewise, the use of an
excess of the Grignard reagent furnished a clean conversion to
the alcohol product (entry 3). (3) A slight excess of amide (1.1
equiv) was found to be optimal (entry 4). (4) Changes in the
reaction concentration and higher reaction temperature resulted
in lower reaction selectivity (entries 5-6). (5) The reaction was
found to be remarkably fast (i.e. close to full conversion on the
order of the time required for reagent mixing at 0 °C); however,
no reaction was observed at -78 °C (entries 7-9). (6) ArMgCl
was found to be a competent nucleophile, while lower selectivity
was observed in Et2O as a solvent (entries 10-11). (7) As
expected, ArLi led to a non-selective process,[11] resulting in a
full conversion to the tertiary alcohol (entry 12).
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Table 2. Chemoselective acylation of amides with functionalized
Grignard reagents: scope of Grignard reagents.[a]
Table 3. Chemoselective acylation of amides with functionalized
Grignard reagents: scope of amides.[a]
[a]Standard conditions, Br/Mg or I/Mg exchange using i-PrMgCl·LiCl: ArX (1.0
equiv), i-PrMgCl·LiCl (1.05 equiv), THF, -20 °C to RT, 1 (1.0 equiv), -20 °C to
RT. See SI for details.
[a]Standard conditions, Br/Mg or I/Mg exchange using i-PrMgCl·LiCl: ArX (1.0
equiv), i-PrMgCl·LiCl (1.05 equiv), THF, -20 °C to RT, 1 (1.0 equiv), -20 °C to
RT. See SI for details. X = Br unless stated otherwise.
Scheme 1. Gram-scale acylation.
nucleophilic and electrophilic handle[17] leads to highly selective
acylation (3an, Scheme 2A). Perhaps more importantly, the
synthesis of a potent anticancer 5-indol-yl-functionalized biaryl
ketone 3ao (Scheme 2B)[18] demonstrates the potential of this N–
C acylation in the synthesis of medicinally-relevant compounds.
We also conducted intermolecular competition studies to
gain preliminary insight into the reaction mechanism (Scheme 3).
The studies highlight that the observed reactivity is consistent
with the nucleophilicity of the organomagnesium reagent
(Scheme 3A) and electrophilic properties of the amide bond
(Scheme 3B).[9a] Remarkably, the competition experiments
unsymmetrical bromo-substituted (3ak), polyfluorinated ketones
(3al) and Boc protected phenols (3am).
To illustrate the scalability of the method, the reaction was
performed on a gram scale using an ester-containing Grignard
reagent, furnishing the desired ketone in 82% yield (Scheme 1),
clearly demonstrating the potential of this method in acylation
reactions of amides by N–C cleavage.
Finally, we also sought to evaluate this acylation method in
using more complex Grignard reagents. We were pleased to find
that the bis-functional aryl-Grignard reagent containing both the
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established a higher order of reactivity of N,N-Boc2 amides than
aroyl chlorides. This unexpected finding suggests a significant
potential of N,N-Boc2 amides as highly reactive acylating
reagents in organic synthesis in a non-conventional C–C bond
disconnection by N–C cleavage. It is interesting to note that the
chelation with N-Boc is less effective in this case (six-membered
chelate) than with the classic Weinreb amides (five-membered
chelates). The collapse is thermodynamically favored due to
expulsion of the non-nucleophilic NBoc2 moiety. As expected,
the ketone products react under the reaction conditions at much
higher rate than the amide starting materials. At the present
stage of reaction development, alkyl Grignard reagents are not
tolerated. Future studies will focus on expanding the substrate
scope to alkyl Grignard reagents.
cleavage and operates under kinetic control via transient
tetrahedral intermediates. The reaction conditions are
exceedingly mild, operationally-simple and tolerate a wide range
of functional groups. The reaction capitalizes on the use of i-
PrMgCl·LiCl to enable highly effective halogen-metal exchange,
providing rapid access to functionalized ketones by an
unconventional amide bond acylation. Taken together, our
findings represent an important advance that demonstrates
amides as highly reactive acylating reagents in an alternative
paradigm to metal-chelation and acyl-metals. Studies directed at
better understanding of the mechanism by computation methods
as well elucidation of the nature of the Grignard reagent are
currently underway. We expect that the scope of this protocol
will be expanded to other broadly useful methods by N–C
functionalization.
Acknowledgements
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The 500 MHz spectrometer
was supported by the NSF-MRI grant (CHE-1229030). We thank
Mr. Qi Wang and Prof. Hao Chen (NJIT) for assistance with
HRMS measurements.
Keywords: functionalized Grignard reagents
transition-metal-free • N–C activation • amides
• acylation •
Scheme 2. Bis-functional Grignard reagents and application in
medicinal chemistry.
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direct acylation of amides with functionalized Grignard reagents.
The reaction proceeds by
a highly chemoselective N–C
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Guangchen Li and Michal Szostak*
Page No. – Page No.
Kinetically-Controlled, Highly
Chemoselective Acylation of
Functionalized Grignard Reagents
with Amides by N–C Cleavage
We report a direct transition-metal-free acylation of amides with functionalized
Grignard reagents by highly chemoselective N–C cleavage under kinetic control.
The method operates under exceedingly mild conditions. This novel direct two-
component coupling sets the stage for using amides as acylating reagents in an
alternative paradigm to the metal-chelated approach and acyl-metals.
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