Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of N-Mesylamides by N-C Cleavage: Electronic Effect of the Mesyl Group

Article abstract of DOI:10.1021/acs.orglett.7b00373

A general Pd-catalyzed Suzuki-Miyaura cross-coupling of N-mesylamides with arylboronic acids by selective N-C cleavage has been developed. The presented results represent the first example of a transition-metal-catalyzed cross-coupling of amides activated by an atom-economic, cheap, and benign mesyl group. The reaction delivers arylated products featuring a range of useful functional groups by chemoselective cleavage of the amide N-C bond with high efficiency. Both the scope and the origin of high selectivity are discussed. A beneficial effect of the N-mesyl substituent on the bond activation in acyclic amides is presented.

Full text of DOI:10.1021/acs.orglett.7b00373

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling of
N‑Mesylamides by N−C Cleavage: Electronic Effect of the Mesyl
Group
Chengwei Liu,† Yongmei Liu,†,‡ Ruzhang Liu,‡ Roger Lalancette,† Roman Szostak,§
and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡College of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Road, Yangzhou 225002, China
§Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
S
* Supporting Information
ABSTRACT: A general Pd-catalyzed Suzuki−Miyaura cross-cou-
pling of N-mesylamides with arylboronic acids by selective N−C
cleavage has been developed. The presented results represent the first
example of a transition-metal-catalyzed cross-coupling of amides
activated by an atom-economic, cheap, and benign mesyl group. The
reaction delivers arylated products featuring a range of useful
functional groups by chemoselective cleavage of the amide N−C
bond with high efficiency. Both the scope and the origin of high selectivity are discussed. A beneficial effect of the N-mesyl
substituent on the bond activation in acyclic amides is presented.
tunities in chemoselective synthesis while utilizing bench-stable
amide precursors of potential biomedical relevance.4 Nitrogen
substitution enables controlled access to generic acylmetal
intermediates5 to accomplish rational variation of sterics and
amidic resonance.6 The highly attractive tricoordinate nitrogen
geometry is unavailable in acyl halides,7 esters,8 and thioesters,9
furtheraddingtotheadvantagesofusingamidesascross-coupling
partners. Moreover, significant progress has been achieved using
low cost, nucleophilic Ni catalysis.1c Despite the significant
progress,10 however, only three classes of amides have been
identifiedthatenableselectivecarbon−carbonbondformationby
metal insertion into the N−C amide bond,11 and no general
activating group featuring high atom economy in acyclic amides is
currently available.
midebond N−C cross-coupling reactions have emergedas a
Apowerful tool for the construction of carbon−carbon and
carbon−heteroatom bonds (Figure 1A).1−3 Among many
advantages of using amides as electrophilic cross-coupling
partners is the availability of various activation methods of the
amide bond.1 In particular, a combination of steric and electronic
destabilization in common amides has provided new oppor-
Recently, significant progress has been reported in the use of
aryl mesylates as cross-coupling partners (Figure 1B).12,13 Their
key advantages include higher atom economy, lower cost, and
higher stability as compared to the related aryl tosylates or
unstable triflates.12 Moreover, the methanesulfonic acid by-
product undergoes natural biodegradation,14 adding to the
environmentally friendly profile of these precursors. However,
the major challenge in cross-coupling of mesylates stems from the
poor leaving group ability of the mesylate.13a
Based on our experience in amide bond cross-coupling and
inspired by the highly desirable features of the mesyl substituent,
we questioned whether the mesyl group might be strategically
employed to trigger amide bond activation in common acyclic
amides. Similartothepropertiesofmesylates, metalinsertioninto
Figure 1. (a) Metal-catalyzed activation of amides and derivatives. (b)
Cross-coupling of aryl mesylates. (c) Cross-coupling of N-mesylamides.
Received: February 5, 2017
© XXXX American Chemical Society
A
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Letter
the N−C(O) amide bond N-activated by mesyl is more
challenging than into the related N-tosyl.15 The nitrogen leaving
groupability parallels the effectsobserved inthemesylate series.16
Herein, wereportthefirstgeneralpalladium-catalyzedSuzuki−
Miyaura cross-coupling17 of N-mesylamides with arylboronic
acids (Figure 1C). Of broad interest, the reported studies open
the door to the use of N-mesylamides as precursors for the
controlled generation of acylmetal intermediates under catalytic
conditions.5 The reaction delivers functionalized arylated
products featuring a range of useful functional groups, including
aldehyde, ketone, ester, nitro, andcyano, withhighefficiency. The
first examples of Suzuki-Miyaura cross-coupling in simple acyclic
amides tolerating an aryl chloride18 and a sterically hindered di-
ortho-substituted nucleophile19 are presented.
Scheme 1. Boronic Acid Scope in the Palladium-Catalyzed
Cross-Coupling of N-Mesylamides
a,b
Foroptimization, N-Ms-amide1and4-tolylboronicacid2were
selected (see Table SI-1). As expected, our optimized conditions
for the cross-coupling of highly reactive N-glutarimide amides10h
provided the coupling product in negligible quantities (<10%).
After extensive screening of various parameters (temperature,
solvent, Pd source), the yield could be improved to 53% (see the
SI for details). The key finding involved identifying Na2CO3 as a
competent base in the absence of added H3BO3. Boric acid was
routinely used in previous studies to prevent protodeboronation
and induce switchable N-/O-activation of the amide bond. In the
cross-coupling of N-Ms-amides, the addition of boric acid shuts
down the reaction in agreement with the relative reactivity of the
amide bond (vide infra). Other bases, such as NaHCO3 and
KHCO3, also gave the desired product, albeit in lower yields.
Exploration of different Pd sources, ligands, and Pd/ligand
stoichiometry resulted in identifying the optimum conditions for
the coupling [>98% yield: Pd2(dba)3 (3 mol %), PCy3HBF4 (12
mol %), Na2CO3, dioxane, 120 °C]. Importantly, the coupling
could ensue at temperatures as low as 80 °C (37% yield),
providing an entry point for future studies. Similarly, even when
the amount of boronic acid was decreased to 1.2−1.5 equiv, the
desired product was obtained in good yields (72−84%),
consistent with efficient insertion/transmetalation in the catalytic
cycle. A turnover number (TON) of 168 was measured under the
optimized conditions.
Using the standard conditions, the scope of the reaction was
next explored with respect to the boronic acid component
(Scheme 1). As shown, the reaction tolerates a range of
electronically varied boronic acids (3a−e). Sensitive functions,
including nitro (3e), ester (3i), ketone (3j), and aldehyde groups
(3k,l), are well-accommodated. It is worth noting that these
groups are not tolerated in the classic Weinreb amide synthesis,20
providing an important advantage. Moreover, ortho-steric
hindrance (3f), polyarenes (3g,h), electronically diverse
substitution at the meta position (3m,n), and highly electron-
rich (3o) and electron-withdrawing (3p) functional groups are
compatible with the reaction conditions. At present, alkyl boronic
acids are incompatible with the reaction conditions.
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (2.0 equiv), Pd2(dba)3
(3 mol %), PCy3HBF4 (12 mol %), Na2CO3 (2.5 equiv), dioxane (0.25
b
c
M), 120 °C, 15 h. Isolated yields. Pd(OAc)2 instead of Pd2(dba)3.
d
140 °C.
obtain best results. The challenging N-Ms/alkylamides are also
viable coupling partners (1o,p).
To gain insight into the mechanism, preliminary experiments
were conducted (Figure 2). (1) Electron-deficient amides are
inherently more reactive (4-CF3/4-MeO = 4.3:1). (2) Electron-
deficient nucleophiles react preferentially (4-CF3/4-MeO =
2.8:1). (3) The reactivity order with respect to the amide
activating group has been determined and is as follows: N-
glutarimide ≫ N-R/Ts ≈ N-R/Ms ≫ N-Ar/R (anilide). High
cross-coupling selectivity between these amides demonstrates the
advantageoftheamideN-activationplatform.10 (4)Thereactivity
order of N-Ms/R substituents has been determined R = Ph > R =
alkyl (R = Bn, 1.4:1.0) and is consistent with the nitrogen leaving
group ability.
The X-ray structure of 1a was determined (Figure 3). The
amide shows a pyramidalized amide bond (τ = 6.8°, χN = 17.2°, χC
= 1.5°). The N−C(O) and CO bond lengths are 1.398 and
1.217 Å. Compared with the corresponding N-Ts-amide (τ =
18.8°, χN = 19.9°, χC = 1.0°; N−C(O) = 1.410 Å; CO = 1.215
Å), these values indicate a smaller amide bond destabilization in
1a, as expected. The acyl CO bond in 1a is antiperiplanar to the
N−Ar bond and bisects the Me−S−O angle.
Computations were employed to confirm the effect of N-Ms
substituent on the amide destabilization (see the SI). (1)
Resonance energy (RE) in 1a determined by the COSNAR
method6c indicates that the conjugation in 1a (RE = 10.3 kcal/
mol) is much lower than in planar amides.6 (2) The rotational
profile of 1a determined by systematic rotation along the O−C−
N−C(Ar) dihedral angle identifies the energy minimum at ca. 40°
O−C−N−C angle (τ = 31.19°; χN = 19.32°) in a syn O−C−N−S
Next, the substrate scope with respect to the amide coupling
partner was explored (Scheme 2). As shown, a variety of
functional groups are well-tolerated, including electron-donating
(3b′,c′) and electron-poor (3d′) substituents at the conjugating
para-position. Sensitive functional groups, such as nitrile (3r),
ester(3i′), andketone(3j′), arewell-tolerated. Ortho-substituted
(3s−f′) and heterocyclic amides (3t) are competent coupling
partners. Finally, primary (3u) and secondary aliphatic amides
(3v) could be coupled, albeit in modest yields. The reactions of
these amides were conducted at slightly higher temperature to
B
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Scheme 2. Amide Scope in the Palladium-Catalyzed Cross-
a,b
Coupling of N-Mesyl Amides
Figure 2. Competition experiments.
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (2.0 equiv), Pd2(dba)3
(3 mol %), PCy3HBF4 (12 mol %), Na2CO3 (2.5 equiv), dioxane (0.25
M), 120 °C, 15 h. Isolated yields. 140 °C.
b
c
conformation (ca. 20.7° O−C−N−S dihedral angle). The energy
maximum is located at ca.180° O−C−N−C dihedral angle (τ =
13.79°; χN = 19.47°) in an antiperiplanar O−C−N−S
destabilizing conformation. The less stable conformation at 0°
O−C−N−C dihedral angle corresponds to a τ = 6.43°; χN =
13.05° geometry (13.1° O−C−N−S dihedral angle). (3) The
difference between N-/O-protonation affinities (ΔPA) indicates
that 1a strongly favors protonation at the amide oxygen (ΔPA =
10.3 kcal/mol). Protonation of the N-acyl group is favored over
sulfonamide oxygens (ΔPA = 10.0, 13.5 kcal/mol).
Figure 3. (a) Crystal structure of 1a. (b) Newman projection along the
N−C(O) bond. Bond lengths (Å) and angles (deg): N1−C1, 1.398(2);
C1−O1, 1.217(2); C8−C1, 1.495(2); N1−S1, 1.700(1); C1−C2,
1.452(2); C8−C1−N1−S1, 178.9(1); O1−C1−N1−C2, − 165.4(1);
O1−C1−N1−S1, − 2.6(2); C8−C1−N1−C2, 16.1(2). Note that the
N−S bond is much weaker than the N−C(O) bond.
Scheme 3. Cross-Coupling in the Presence of Aryl Chloride
Altogether, the structural and energetic parameters of the
amide bond in N-Ms-amides point at (1) nitrogen pyramidaliza-
tion and (2) electronic destabilization as the factors enabling
selective N−C activation.
Studies to determine the order of amide vs halide selectivity
were conducted (Scheme 3). Interestingly, the cross-coupling of
amide 1a in the presence of a chloro substituent is possible. While
the yield is moderate, prior to this study the cross-coupling of
simple acyclic amides in the presence of halides, including N-Ts-
amides, was not feasible.10 The cross-coupling of 1a with a di-
ortho-substituted boronic acid is also feasible (Scheme 4).
Notably, this is the first example of the amide N−C bond cross-
coupling using a di-ortho-substituted nucleophile, providing an
entry point for further studies.
Scheme 4. Use of Di-Ortho-Substituted Nucleophile
hindrance of the N-Ms group favors amide rotation. In several
examples, the N-Ms group allows new amide bond reactivity,
likely due to more facile insertion and/or transmetalation.
The structural and mechanistic studies show that N-Ms-amides
are less destabilized than N-Ts-amides. The lower steric
C
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(c) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951.
In summary, we have described the first general palladium-
catalyzed Suzuki−Miyaura cross-coupling of N-mesyl-activated
amides with arylboronic acids. Using a Pd/PCy3 catalyst system
andNa2CO3 asabase, highyieldsfortheselectiveN−C(O) metal
insertion/cross-coupling in the presence of various sensitive
functional groups have been achieved. The mesyl group features
highly desirable properties, including high atom economy, low
cost, high stability, and low toxicity. The present method
demonstrates the beneficial effect of the N-Ms substituent on
the chemoselectivity of amide cross-coupling. The origin of high
selectivity has been demonstrated through structural and
mechanistic studies. More importantly, we anticipate that using
N-mesylamides will enable other reactions by selective N−C
activation, in particular when high atom economy or low steric
hindrance is required.
(d)Tani, K.;Stoltz, B. M. Nature 2006, 441, 731. (e)Szostak, R.;Aube,
́
J.;
Szostak, M. Chem. Commun. 2015, 51, 6395.
(7) Blangetti, M.; Rosso, H.; Prandi, C.; Deagostino, A.; Venturello, P.
Molecules 2013, 18, 1188.
(8) (a) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun.
2015,6,7508. (b)BenHalima, T.;Zhang, W.;Yalaoui, I.;Hong, X.;Yang,
Y. F.; Houk, K. N.; Newman, S. G. J. Am. Chem. Soc. 2017, 139, 1311.
(9) Prokopcova, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276.
(10) (a) Hie, L.; Nathel, N. F. F.; Shah, T. K.; Baker, E. L.; Hong, X.;
Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79.
(b) Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75.
(c) Simmons, B. J.; Weires, N. A.; Dander, J. E.; Garg, N. K. ACS Catal.
2016, 6, 3176. (d)Baker, E. L.;Yamano, M. M.;Zhou, Y.;Anthony, S. M.;
Garg, N. K. Nat. Commun. 2016, 7, 11554. (e) Dander, J. E.; Weires, N.
A.;Garg,N. K.Org.Lett. 2016,18,3934. (f)Hie, L.;Baker, E.L.;Anthony,
S. M.;Desrosiers, J. N.;Senanayake, C.;Garg, N. K. Angew. Chem., Int. Ed.
2016, 55, 15129. (g) Li, X.; Zou, G. Chem. Commun. 2015, 51, 5089.
(h) Meng, G.; Szostak, M. Org. Lett. 2015, 17, 4364. (i) Meng, G.;
Szostak, M. Org. Biomol. Chem. 2016, 14, 5690. (j) Shi, S.; Szostak, M.
Chem. - Eur. J. 2016, 22, 10420. (k) Meng, G.; Szostak, M. Angew. Chem.,
Int. Ed. 2015, 54, 14518. (l) Shi, S.; Meng, G.; Szostak, M. Angew. Chem.,
Int. Ed. 2016, 55, 6959. (m) Meng, G.; Szostak, M. Org. Lett. 2016, 18,
796. (n) Meng, G.; Shi, S.; Szostak, M. ACS Catal. 2016, 6, 7335. (o) Shi,
S.; Szostak, M. Org. Lett. 2016, 18, 5872. (p) Liu, C.; Meng, G.; Liu, Y.;
Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M. Org. Lett. 2016, 18, 4194.
(q) Liu, C.; Meng, G.; Szostak, M. J. Org. Chem. 2016, 81, 12023. (r) Lei,
P.; Meng, G.; Szostak, M. ACS Catal. 2017, 7, 1960. (s) Hu, J.; Zhao, Y.;
Liu, J.; Zhang, Y.; Shi, Z. Angew. Chem., Int. Ed. 2016, 55, 8718. (t) Cui,
M.; Wu, H.; Jian, J.; Wang, H.; Liu, C.; Daniel, S.; Zeng, Z. Chem.
Commun. 2016, 52, 12076. (u) Wu, H.; Cui, M.; Jian, J.; Zeng, Z. Adv.
Synth. Catal. 2016, 358, 3876. (v) Wu, H.; Liu, T.; Cui, M.; Li, Y.; Jian, J.;
Wang, H.; Zeng, Z. Org. Biomol. Chem. 2017, 15, 536. (w) Dey, A.;
Sasmal, S.; Seth, K.; Lahiri, G. K.; Maiti, D. ACS Catal. 2017, 7, 433.
(x) Liu, L.; Chen, P.; Sun, Y.; Wu, Y.; Chen, S.; Zhu, J.; Zhao, Y. J. Org.
Chem. 2016, 81, 11686.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00373.
Experimental procedures and characterization data (PDF)
X-ray crystallographic data for 1a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Chengwei Liu: 0000-0003-1297-7188
Michal Szostak: 0000-0002-9650-9690
Notes
The authors declare no competing financial interest.
(11) (a) N-Glutarimide amides introduced by our laboratory.10h (b)N-
Acyl-tert-butylcarbamates (Boc) and (c) N-Acyltosylamides (Ts)
introduced by Garg10a and Zou.10g Cross-coupling of N-saccharides
has been reported.10p N-Saccharides are cyclic imide alternatives to N-
glutarimides with a flat rotational profile around the N−C(O) bond.
(12) (a) So, S. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963.
(b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita,
A. M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(13) Select examples: (a) So, C. M.; Zhou, Z.; Lau, C. P.; Kwong, F. Y.
Angew. Chem., Int. Ed. 2008, 47, 6402. (b)So, C. M.;Lau, C. P.;Kwong, F.
Y. Angew. Chem., Int. Ed. 2008, 47, 8059. (c) Fors, B. P.; Watson, D. A.;
Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552.
(d) Zhang, L.; Qing, J.; Yang, P.; Wu, J. Org. Lett. 2008, 10, 4971. (e) So,
C. M.; Lee, H. W.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2009, 11, 317.
(f) Dooleweerdt, K.;Fors, B. P.;Buchwald, S. L. Org. Lett. 2010, 12, 2350.
(g) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed.
2010, 49, 8918. (h) Molander, G. A.; Shin, I. Org. Lett. 2012, 14, 3138.
(i) Song, B.; Knauber, T.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52,
2954. (j) Alsabeh, P. G.; Stradiotto, M. Angew. Chem., Int. Ed. 2013, 52,
7242. (k) Ferguson, D. M.; Rudolph, S. R.; Kalyani, D. ACS Catal. 2014,
4, 2395.
(14) Baker, S. C.; Kelly, D. P.; Murrell, J. C. Nature 1991, 350, 627.
(15) (a) Crabtree, R. H. The Organometallic Chemistry of the Transition
Metals; Wiley: New York, 2005. (b) Barrios-Landeros, F.; Carrow, B. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8141.
(16) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268.
(17) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(18) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(19) Partyka, D. V. Chem. Rev. 2011, 111, 1529.
(20) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The
Bruker 500 MHz spectrometer used in this study was supported
by an NSF-MRI grant (CHE-1229030). We thank the Wrocław
Center for Networking and Supercomputing (grant number
WCSS159). Y.L. is thankful for a scholarship from the National
Natural Science Foundation of China (No. 21472616) and the
Priority Academic Program Development of Jiangsu Higher
Education−Yangzhou University
REFERENCES
■
(1) Reviews on N−C amide cross-coupling: (a) Meng, G.; Shi, S.;
Szostak, M. Synlett 2016, 27, 2530. (b) Liu, C.; Szostak, M. Chem. - Eur. J.
2017, DOI: 10.1002/chem.201605012. (c) Dander, J. E.; Garg, N. K.
ACS Catal. 2017, 7, 1413.
(2) (a) Metal-Catalyzed Cross-Coupling Reactions and More; de Meijere,
A., Brase, S., Oestreich, M., Eds.; Wiley: New York, 2014. (b) Science of
̈
Synthesis: Cross-Coupling and Heck-Type Reactions; Molander, G. A.,
Wolfe, J. P., Larhed, M., Eds.; Thieme: Stuttgart, 2013.
(3) Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062.
(4) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The Amide
Linkage: Structural Significance in Chemistry, Biochemistry, and Materials
Science; Wiley: New York, 2000.
(5) (a) Gooßen, L. J.; Rodriguez, N.; Gooßen, K. Angew. Chem., Int. Ed.
2008, 47, 3100. (b) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew.
̈
Chem., Int. Ed. 2009, 48, 4114.
(6) (a) Szostak, R.; Shi, S.; Meng, G.; Lalancette, R.; Szostak, M. J. Org.
Chem. 2016, 81, 8091. (b) Pace, V.; Holzer, W.; Meng, G.; Shi, S.;
Lalancette, R.; Szostak, R.; Szostak, M. Chem. - Eur. J. 2016, 22, 14494.
D
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