Synthesis of biaryl ketones by arylation of Weinreb amides with functionalized Grignard reagents under thermodynamic controlvs.kinetic control ofN,N-Boc2-amides

Article abstract of DOI:10.1039/d0ob00813c

A highly efficient method for chemoselective synthesis of biaryl ketones by arylation of Weinreb amides (N-methoxy-N-methylamides) with functionalized Grignard reagents is reported. This protocol offers rapid entry to functionalized biaryl ketones after Mg/halide exchange with i-PrMgCl·LiCl under operationally-simple and practical reaction conditions. The scope of the method is highlighted in >40 examples, including bioactive compounds and pharmaceutical derivatives. Collectively, this transition-metal-free approach offers a major advantage over the recently established cross-coupling of amides by oxidative addition of N-C(O) bonds. Considering the utility of amide acylation reactions in modern synthesis, we expect that this method will be of broad interest.

Full text of DOI:10.1039/d0ob00813c

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DOI: 10.1039/D0OB00813C
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Synthesis of Biaryl Ketones by Arylation of Weinreb Amides with
Functionalized Grignard Reagents under Thermodynamic Control
vs. Kinetic Control of N,N-Boc2-Amides
Received 00th January 20xx,
Accepted 00th January 20xx
Guangchen Lia and Michal Szostaka,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient method for chemoselective synthesis of biaryl In this context, recently our laboratory established arylation of
ketones by arylation of Weinreb amides (N-methoxy-N- N,N-Boc2 amides with functionalized Grignard reagents,12
methylamides) with functionalized Grignard reagents is reported. wherein (1) N,N-Boc2 amides are prepared from 1° amides by
This protocol offers rapid entry to functionalized biaryl ketones selective double N-tert-butoxycarbonylation,8 thus enabling to
after Mg/halide exchange with i-PrMgCl·LiCl under operationally- use common benzamides as arylation precursors; (2) the
simple and practical reaction conditions. The scope of the method reaction proceeds under kinetic control of the tetrahedral
is highlighted in >40 examples, including bioactive compounds and intermediate, whereas the use of excess Grignard reagents
pharmaceutical derivatives. Collectively, this transition-metal-free leads to the overaddition to give alcohol products (Fig. 1). We
approach offers a major advantage over the recently established questioned whether functionalized Grignard reagents
cross-coupling of amides by oxidative addition of N–C(O) bonds. prepared by Mg/halide exchange with i-PrMgCl
·LiCl could be
Considering the utility of amide acylation reactions in modern broadly employed as nucleophiles in the arylation13 of
synthesis, we expect that this method will be of broad interest.
Weinreb amides for the synthesis of biaryl ketones.
As a critical design element, we envisioned the use of
versatile turbo-Grignard (i-PrMgCl·LiCl) elegantly pioneered by
Knochel.14–16 We recognized that the highly chemoselective
Mg/halide exchange with i-PrMgCl·LiCl could enable practical,
operationally-simple and highly functional group tolerant
synthesis of biaryl ketones by exploiting straightforward access
to functionalized organomagnesium reagents under
thermodynamic control of five-membered chelates.
Beyond doubt, Weinreb amides (N-methoxy-N-methylamides)
are among the most successful and important amide
derivatives developed to date in organic synthesis.1–3 The
overwhelming utility of N-methoxy-N-methylamides arises
from the formation of well-defined, five-membered, metal-
chelated intermediates in direct nucleophilic addition of
organolithium and organomagnesium reagents, resulting in
their numerous applications in natural product synthesis, drug
discovery and materials science.4–6
On the other hand, the recent years have witnessed the
emergence of amide bond cross-coupling reactions, wherein
activation of the amide bond is achieved by oxidative addition
of the N–C(O) amid bond to generate an acyl-metal complex.7,8
This mode of amide bond activation has already been
extended to decarbonylative processes to furnish aryl-metal
electrophiles9 and holds promise as a new general cross-
coupling manifold in organic synthesis.10
Simultaneously, remarkable progress has been achieved in
transition-metal-free activation of amides, wherein direct
nucleophilic addition to ground-state-destabilized amides
provides acyl addition products under kinetic control of
tetrahedral intermediates.11 From the practical standpoint,
transition-metal-free methods are vastly preferred because
they obviate the removal of toxic transition-metal impurities.
Fig. 1 Context of this work: synthesis of functionalized ketones via
selective arylation of unreactive amide bonds.
aDepartment of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102,
United States. E-mail: michal.szostak@rutgers.edu.
†Electronic Supplementary Information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the Reaction Conditionsa
Organic & Biomolecular Chemistry
Chemoselective Arylation of N-Methoxy-N-
Scheme
1
View Article Online
a,b
DOI: 10.1039/D0OB00813C
Methylamides: Scope of Functionalized Grignard Reagents
entry
1 (equiv)
1.0
solvent
THF
T (°C)
23
23
23
23
23
23
23
23
0
yield (%)b
66
1
2
1.0
CH2Cl2
CH3CN
Et2O
40
3
1.0
85
4
1.0
62
5
1.0
toluene
toluene
toluene
toluene
toluene
toluene
71
6
1.2
74
7
1.5
74
8
3.0
70
9
1.2
60
10
1.2
60
63
aConditions: X/Mg exchange using i-PrMgCl·LiCl: ArX (1.0 equiv), i-
PrMgCl·LiCl (1.20 equiv), THF, -20 °C to 23 °C, 1 (1.0 equiv), T, solvent. See
ESI for details. bDetermined by 1H NMR and GC/MS.
Several points should be noted. (1) Despite the importance
of Weinreb amides in organic synthesis, few methods for the
synthesis of biaryl ketones using functionalized Grignard
reagents containing sensitive electrophilic groups are
available. Electrophilic functional groups are defined as those
that contain reactive C=O groups and equivalents (e.g., esters,
amides, nitriles) and sensitive halides (e.g. Br) that are not
easily compatible with the traditional generation of Grignard
reagents.17 (2) Furthermore, it should be pointed out that the
synthesis of organomagnesium reagents using the turbo
Grignard approach represents a major synthetic improvement
over established methods,14–16 while no investigation of the
selective nucleophilic addition of ArMgCl·LiCl reagents to yield
important biaryl ketones has been reported.1–16 (3) Biaryl
ketones are among the most prevalent ketones in organic
synthesis, wherein their represent the target building blocks or
versatile C=O electrophiles for functionalization by ipso-
substitution to yield an array of functional groups.18
Herein, we describe the successful development of this
reaction and report
a
highly efficient method for
chemoselective synthesis of biaryl ketones by arylation of
Weinreb amides with functionalized Grignard reagents without
the need for transition-metals. The reaction tolerates excess of
reagents owing to the stability of the five-membered metal
chelate (cf. N,N-Boc2 amides). This method is contrasted with
the arylation of N,N-Boc2 amides by kinetic control.12
Collectively, this approach offers a major advantage over the
recently established cross-coupling of amides by oxidative
addition of N–C(O) electrophiles.7–10,19,20 Considering the utility
of amide acylation reactions in modern organic synthesis, we
expect that this approach will be of broad synthetic interest.
We believe that the organic community will benefit from a
comparative study on acylation reactions using functionalized
organomagnesium reagents and various classes of amides.1,7–13
Our studies started with the addition of 3-
fluorophenylmagnesium chloride, prepared by Mg/halide
aConditions: Br/Mg exchange using i-PrMgCl·LiCl: ArX (1.0 equiv), i-
PrMgCl·LiCl (1.2 equiv), THF, -20 °C to 23 °C,
1
(1.0 equiv), toluene, 23
b
c
d
°C. See SI for details. Isolated yields. I/Mg exchange. N,N-Boc2-3,4,5-
trimethoxybenzamide. Yields obtained using N,N-Boc2 amides are
shown in brackets. See ESI for details.
exchange
with
i-PrMgCl·LiCl,
to
N-methoxy-N-
methylbenzamide (Table 1). It should be noted that typical
acylation using functionalized organomagnesium reagents
requires the use of aroyl chlorides and transmetalation with
CuCN.14a Likewise, our study with N,N-Boc2 amides requires
2 | J. Name., 2012, 00, 1-3
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Scheme
2
Chemoselective Arylation of N-Methoxy-N- Scheme 4 Derivatization of Pharmaceuticals
View Article Online
DOI: 10.1039/D0OB00813C
Methylamides: Scope of Amidesa,b
a–cSee Scheme 1. dN,N-Boc2-4-cyanobenzamide. See ESI for details.
Yields obtained using N,N-Boc2 amides are shown in brackets.
Scheme 3 Gram Scale Arylation
a vast array of sensitive functional groups (Scheme 1). As such,
alkyl, methoxy, thioether, amine, chloro, bromo,
trifluoromethyl, cyano, methyl ester, tert-butyl ester, amide,
and sulfonyl ester were all tolerated, providing the desired
ketones in high to excellent yields (3a-3l). Furthermore, steric
hindrance, meta-substitution, polyaromatic and heterocyclic
substrates, such as indole, thiophene and pyridine rapidly
underwent arylation to give the product ketones in high yields
(3m-3aa). It is worth noting that (1) the yields are generally
slightly higher than with N,N-Boc2 amides, likely due to lower
stability of tetrahedral intermediates derived from N,N-Boc2
amides (see also Fig. 2); (2) the formation of overaddition
products was not observed, resulting in a broadly useful
process that complements the reaction of N,N-Boc2 amides
and expands the cross-coupling approach.
Similarly, we found that the scope of N-methoxy-N-
methylamides is also very broad and accommodates various
functional groups (Scheme 2). As such, sensitive heterocycles,
such as isoxazoles, nitriles, polyaromatic substrates, electron-
rich heterocycles, such as furans, chlorides and iodides were
excellent substrates for the reaction (3ab-3ag). High reaction
efficiency was observed with both electron-rich and electron-
withdrawing substituents on the amide component (3ah-3aj).
Furthermore, functional handles such as ester, bromides,
fluorides and chlorides were well-tolerated and produced the
careful control of the reagent stoichiometry due to rapid
collapse of the tetrahedral intermediate.12 Experiments
indicated that several solvents, such as THF, CH2Cl2, CH3CN,
Et2O, toluene, could be used for the arylation of N-methoxy-N-
methylbenzamide with 3-fluorophenylmagnesium chloride
(Table 1, entries 1-5), with CH3CN and toluene proving to be
the most efficient. Further, the reaction readily tolerates an
excess of Grignard reagent (Table 1, entries 6-8). Importantly,
the reaction was also successful at higher temperature (Table
1, entry 10), thus indicating a high stability of the metal-
chelated intermediate, while arylation of the more reactive
N,N-Boc2 amides leads to the formation of alcohol products
upon heating.12 The optimized conditions involve preparation
of functionalized Grignard by Mg/halide exchange according to
the procedure by Knochel and co-workers,14a followed by the
addition to N-methoxy-N-methylamide.
With optimized conditions in hand, we evaluated the scope
of the reaction (Schemes 1-2). For comparison, the yields
obtained using N,N-Boc2 amides are presented in brackets. We
were delighted to find that the scope of the reaction is very
broad and accommodates a broad range of N-methoxy-N-
methylamides and functionalized Grignard reagents, including
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Organic & Biomolecular Chemistry
2
3
For a recent excellent review of mechanistiVciewstAurtdicileesOnloinne
DOI: 10.1039/D0OB00813C
Hong, Chem. Commun., 2019, 55, 11330.
desired ketones in high yields (3aj-3am). The reactivity of N-
methoxy-N-methylamides in the amide scope compares well
to N,N-Boc2,12 and it should be noted that the methods are
complementary since N,N-Boc2 amides are typically obtained
amide bond activation, see: H. Wang, S. Q. Zhang and X.
For selected monographs, see: (a) B. M. Trost and I. Fleming,
Comprehensive Organic Synthesis, Pergamon Press, 1991; (b)
M. B. Smith and J. March, Advanced Organic Chemistry,
Wiley, 2007; (c) A. Greenberg, C. M. Breneman and J. F.
Liebman, The Amide Linkage: Structural Significance in
Chemistry, Biochemistry and Materials Science, Wiley, 2003.
(a) For a study on isolation of tetrahedral intermediates from
Weinreb amides, see: L. Castoldi, W. Holzer, T. Langer and V.
Pace, Chem. Commun., 2017, 53, 9498; (b) For a review on
tetrahedral intermediates, see: M. Adler, S. Adler and G.
Boche, J. Phys. Org. Chem., 2005, 18, 193.
by N-tert-butoxycarboxylation of 1°
amides8 (cf. N,N-MeO/Me
amides from aroyl chlorides or carboxylic acids).
We were pleased to find that the reaction is scalable to
deliver the product on a gram scale in 78% yield (Scheme 3).
This reaction highlights distinct reactivity of two amide bonds,
wherein the more reactive N-methoxy-N-methylamide reacts
chemoselectivity in the presence of N,N-dialkylbenzamide (see
also Fig 2).8
The synthetic utility of the method is highlighted in the
direct arylation of pharmaceutical derivatives (Scheme 4, 3ao-
3aq). As such, arylation of N-methoxy-N-methylamide derived
from probenecid, an antihyperuricemic drug, delivered the
desired ketone product containing a functional bromide
handle in 65% yield, arylation of N-methoxy-N-methylamide of
ataluren, a drug for muscular dystrophy treatment furnished
the biaryl ketone with cyano functional handle in 70% yield,
while arylation of N-methoxy-N-methylamide of adapalene, a
topical retinoid for the treatment of acne, furnished the
heterocyclic ketone in 82% yield.
4
5
For selected examples of acylation reactions of amides, see:
(a) D. A. Evans, G. Borg and K. A. Scheidt, Angew. Chem. Int.
Ed., 2002, 41, 3188; (b) S. T. Heller, J. N. Newton and R.
Sarpong, Angew. Chem. Int. Ed., 2015, 54, 9839; (c) C. Liu, M.
Achtenhagen and M. Szostak, Org. Lett., 2016, 18, 2375; (d)
J. Nugent and B. D. Schwartz, Org. Lett., 2016, 18, 3834.
For a recent excellent progress in carbenoid addition to
Weinreb amides, see: (a) M. Miele, A. Citarella, N. Micale, W.
Holzer and V. Pace, Org. Lett., 2019, 21, 8261; (b) R.
Senatore, L. Castoldi, L. Ielo, W. Holzer and V. Pace, Org.
Lett., 2018, 20, 2685; (c) R. Senatore, L. Ielo, E. Urban, W.
Holzer and V. Pace, Eur. J. Org. Chem., 2018, 2466; (d) V.
Pace, I. Murgia, S. Westermayer, T. Langer and W. Holzer,
Chem. Commun., 2016, 52, 7584; For a review, see: (e) R.
Senatore, L. Ielo, S. Monticelli, L. Castoldi and V. Pace,
Synthesis, 2019, 51, 2792; See also: (f) V. Pace, L. Castoldi
and W. Holzer, J. Org. Chem., 2013, 78, 7764; (g) S.
Monticelli, W. Holzer, T. Langer, A. Roller, B. Olofsson and V.
Pace, ChemSusChem, 2019, 12, 1147.
For reviews on N–C functionalization, see: (a) S. Shi, S. P.
Nolan and M. Szostak, Acc. Chem. Res., 2018, 51, 2589; (b) C.
Liu and M. Szostak, Chem. Eur. J., 2017, 23, 7157; (c) Y.
Bourne‐Branchu, C. Gosmini and G. Danoun, Chem. Eur. J.,
2019, 25, 2663; (d) M. B. Chaudhari and B. Gnanaprakasam,
Chem. Asian J., 2019, 14, 76.
For a pertinent study on amide bond destabilization, see: G.
Meng, S. Shi, R. Lalancette, R. Szostak and M. Szostak, J. Am.
Chem. Soc., 2018, 140, 727, and references cited therein.
C. Liu and M. Szostak, Org. Biomol. Chem., 2018, 16, 7998.
6
7
8
9
Fig. 2 Relative reactivity of N,N-Boc2 and N,N-MeO/Me amides.
To gain preliminary insight into the reaction, we conducted
intermolecular competition experiments (see ESI). The
following order of reactivity in acyl addition reactions: N,N-
Boc2 amides > aroyl chlorides > N-methoxy-N-methylamides is
opposite to the capacity of amides to stabilize the tetrahedral
intermediate by chelation (Fig. 2).8
In summary, we have developed a highly efficient method
for chemoselective synthesis of biaryl ketones by arylation of
N-methoxy-N-methylamides with functionalized Grignard
10 For selected examples, see: (a) L. Xiong, R. Deng, T. Liu, Z.
Luo, Z. Wang, X. F. Zhu, H. Wang and Z. Zeng, Adv. Synth.
Catal., 2019, 361, 5383; (b) Z. Luo, L. Xiong, T. Liu, Y. Zhang,
S. Lu, Y. Chen, W. Guo, Y. Zhu and Z. Zeng, J. Org. Chem.,
2019, 84, 10559; (c) Z. Luo, H. Wu, Y. Li, Y. Chen, J. Nie, S. Lu,
Y. Zhu and Z. Zeng, Adv. Synth. Catal., 2019, 361, 4117; (d) H.
Wu, T. Liu, M. Cui, Y. Li, J. Jian, H. Wang and Z. Zeng, Org.
Biomol. Chem., 2017, 15, 536; (e) M. Cui, H. Wu, J. Jian, H.
Wang, C. Liu, D. Stelck and Z. Zeng, Chem. Commun., 2016,
52, 12076, and references cited therein.
reagents prepared by Mg/halide exchange with i-PrMgCl·LiCl.
11 For a review, see: (a) G. Li and M. Szostak, Chem. Rec., 2019,
doi: 10.1002/tcr.201900072. For selected examples, see: (b)
G. Li and M. Szostak, Nat. Commun., 2018, 9, 4165; (c) D. Ye,
Z. Liu, H. Chen, J. L. Sessler and C. Lei, Org. Lett., 2019, 21,
6888; (d) T. Ghosh, S. Jana and J. Dash, Org. Lett., 2019, 21,
6690; (e) H. Wu, W. Guo, D. Stelck, C. Liu and Z. Zeng, Chem.
Eur. J., 2018, 24, 3444; (f) W. Guo, J. Huang, H. Wu, T. Liu, Z.
Luo, J. Jian and Z. Zeng, Org. Chem. Front., 2018, 5, 2950.
12 G. Li and M. Szostak, Chem. Eur. J., 2020, 26, 611.
This method complements and significantly extends the
flourishing amide bond activation manifold by direct metal
insertion into the N–C(O) bond. The utility has been
demonstrated in excellent functional group tolerance,
including in the direct functionalization of pharmaceutical
derivatives. Considering the great utility of amide acylations in
modern organic chemistry, we anticipate that the method will
be of broad synthetic interest. Further studies on amide bond
activation are ongoing and will be reported shortly.
13 For reviews on acylation reactions, see: (a) R. K. Dieter,
Tetrahedron, 1999, 55, 4177; (b) J. Buchspies and M. Szostak,
Catalysts, 2019, 9, 53.
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support.
14 (a) A. Krasovskiy and P. Knochel, Angew. Chem. Int. Ed.,
2004, 43, 3333; (b) A. Krasovskiy, B. F. Straub and P. Knochel,
Angew. Chem. Int. Ed., 2006, 45, 159; (c) H. Ren, A.
Krasovskiy and P. Knochel, Org. Lett., 2004, 6, 4215; (d) H.
Ren, A. Krasovskiy and P. Knochel, Chem. Comm., 2005, 543;
(e) C. Y. Liu and P. Knochel, Org. Lett., 2005, 7, 2543; (f) H.
Ren and P. Knochel, Chem. Comm., 2006, 726; (g) C. Y. Liu, H.
Notes and references
1
For a comprehensive review on organometallic addition to
amides, see: V. Pace, W. Holzer and B. Olofsson, Adv. Synth.
Catal., 2014, 356, 3697.
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Ren and P. Knochel, Org. Lett., 2006, 8, 617; (h) A. H. Stoll. A.
Krasovskiy and P. Knochel, Angew. Chem. Int. Ed., 2006, 45,
606; (i) F. Kopp, S. Wunderlich and P. Knochel, Chem. Comm.,
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Commun., 2009, 3536; (k) C. Despotopoulou, R. C. Bauer, A.
Krasovskiy, P. Mayer, J. M. Stryker and P. Knochel, Chem.
Eur. J., 2008, 14, 2499; (l) F. M. Piller, P. Appukkatan, A.
Gavryushin, M. Helm and P. Knochel, Angew. Chem. Int. Ed.,
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View Article Online
DOI: 10.1039/D0OB00813C
15 For reviews, see: (a) D. S. Ziegler, B. Wei and P. Knochel,
Chem. Eur. J., 2019, 25, 2695; (b) R. L. Y. Bao, R. Zhao and L.
Shi, Chem. Commun., 2015, 51, 6884; (c) N. M. Barl, V.
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2003, 22, 4302.
16 For selected applications, see: (a) S. Yamada, A. Gavryushin
and P. Knochel, Angew. Chem. Int. Ed., 2010, 49, 2215; (b) P.
Anbarasan, H. Neumann and M. Beller, Angew. Chem. Int.
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Beller, Chem. Eur. J., 2010, 16, 4725; (d) P. Anbarasan, H.
Neumann and M. Beller, Chem. Eur. J., 2011, 17, 4217. For
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Knochel, Handbook of Functionalized Organometallics,
Wiley, 2005; (f) Z. Rappoport and I. Marek, The Chemistry of
Organomagnesium Compounds, Wiley, 2008.
17 A comprehensive Scifinder search (April 18, 2020) indicated
very few examples of the addition of functionalized Grignard
reagents to amides to yield biaryl ketones using turbo
Grignard reagent (i-PrMgCl·LiCl). This is consistent with a
higher reactivity of
-alkyl N-methoxy-N-methylamides in
the direct acylation reactions (cf. aryl amides to yield biaryl
ketones). See: (a) 3-MeO-C6H4-MgCl·LiCl: J. Debnath, S.
Siricilla, B. Wan, D. C. Crick, A. J. Lenaerts, S. G. Franzblau and
M. Kurosu, J. Med. Chem., 2012, 55, 3739; (b) 6-Br-C5H3N-
MgCl·LiCl: T. Nakajima, M. Sugawara, S. I. Uchida, T. Ohno, Y.
Nomoto, N. Uesaka and Y. Nakasato. EP1700856, Sep 13,
2006. For a further example of alkyl amides, see: (c) K.
Conrad, Y. Hsiao and R. A. Miller, Tetrahedron Lett., 2005, 46,
8587.
18 For selected references on biaryl ketones, see: (a) I. Jabeen,
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2012, 55, 3261; (b) K. Maeyama, K. Yamashita, H. Saito, S.
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Chem., 2010, 75, 6708; (d) S. K. Vooturi, C. M. Cheung, M. J.
Rybak and S. M. Firestine, J. Med. Chem., 2009, 52, 5020; (e)
M. P. Leze, M. Le Borgne, P. Pinson, A. Palusczak, M. Duflos,
G. Le Baut and R. W. Hartmann, Bioorg. Med. Chem. Lett.,
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