N-Methylamino Pyrimidyl Amides (MAPA): Highly Reactive, Electronically-Activated Amides in Catalytic N-C(O) Cleavage

Article abstract of DOI:10.1021/acs.orglett.7b02288

Despite recent progress in catalytic cross-coupling technologies, the direct activation of N-alkyl-N-aryl amides has been a challenging transformation. Here, we report the first Suzuki cross-coupling of N-methylamino pyrimidyl amides (MAPA) enabled by the controlled n_N → π_Ar conjugation and the resulting remodeling of the partial double bond character of the amide bond. The new mode of amide activation is suitable for generating acyl-metal intermediates from unactivated primary and secondary amides.

Full text of DOI:10.1021/acs.orglett.7b02288

Letter
pubs.acs.org/OrgLett
N‑Methylamino Pyrimidyl Amides (MAPA): Highly Reactive,
Electronically-Activated Amides in Catalytic N−C(O) Cleavage
Guangrong Meng,† Roger Lalancette,† Roman Szostak,‡ and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland
S
* Supporting Information
ABSTRACT: Despite recent progress in catalytic cross-
coupling technologies, the direct activation of N-alkyl-N-aryl
amides has been a challenging transformation. Here, we report
the first Suzuki cross-coupling of N-methylamino pyrimidyl
amides (MAPA) enabled by the controlled nN → πAr
conjugation and the resulting remodeling of the partial double
bond character of the amide bond. The new mode of amide
activation is suitable for generating acyl-metal intermediates
from unactivated primary and secondary amides.
irect activation of N−C amide bonds is receiving
methylamino pyrimidyl amides (MAPA) as highly reactive,
electronically activated amides for catalytic N−C(O) cleavage
(Figure 1). The following features of our findings are
1−5
Dincreasing attention in organic synthesis.
This mode
of reactivity induces traditionally difficult to achieve insertion of
a low-valent metal catalyst into the inert N−C(O) moiety (nN
→ π*CO conjugation, barrier to rotation in planar amides of
15−20 kcal/mol),6 thus enabling amides to participate in acyl-
and decarbonylative cross-coupling reactions of high synthetic
value. In a broader context, the amide bond activation methods
are a subset of a more general strategy to catalytically activate
bench-stable carboxylic acid derivatives under redox neutral
conditions,7 including esters,1a wherein the amide bond offers
the major advantage of selective tuning of the amide bond
geometry by tricoordinate nitrogen that is unavailable in other
acyl-precursors.8 Considering that the amide bond is a
preeminent motif in various bioactive and pharmaceutically
relevant compounds,9 as well as, historically, an irreplaceable
intermediate in organic synthesis,10 new methods for selective
manipulation of amides will beyond doubt find wide application
within the field.
Figure 1. (a) Activation of amides and derivatives. (b) This work:
coupling of MAP amides enabled by selective nN → πAr delocalization.
Recent developments have provided a plethora of examples
for constructing carbon−heteroatom and carbon−carbon
bonds through direct N−C amide bond activation, whereby
the amide bond is engineered by specifically designed N-
substituents that result in the amide bond ground-state steric
destabilization by steric distortion (amide bond twist).1−5,8 In
contrast, methods to activate the amide bond in electronically
biased amides are noticeably lacking. In particular, the direct
activation of N-alkyl-N-aryl amides has been a challenging
transformation because of the high resonance energy of the
amide bond in these precursors (RE, resonance energy, 13.5
kcal/mol).11 Note that these anilides already feature signifi-
cantly decreased amidic resonance (cf. planar amides, 15−20
kcal/mol) as a consequence of electronic activation; however,
these values are still prohibitive for synthetically useful Pd
insertion under mild conditions. Here, we introduce N-
noteworthy: (1) we demonstrate high reactivity of MAP
amides under versatile Pd-catalysis12 using user-friendly,
operationally simple protocols, providing rapid entry to biaryl
ketones; (2) since MAP amides can be readily prepared from
unactivated primary or secondary amides, our method offers a
rapid entry to metal-catalyzed coupling of common amides; (3)
we demonstrate the advantageous effect of Pd-NHC catalysis13
over Pd-phosphines in the amide bond cross-coupling
manifolds. Note that the use of bench-stable, commercially
available, well-defined Pd-NHC precatalysts offers a major
practical advantage;14 (4) mechanistic studies strongly support
Received: July 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
the external N−C(O) amide bond nN → πAr conjugation
pathway. Collectively, our study opens the door for using N-
alkyl-N-aryl amide electrophiles in a wide range of cross-
coupling manifolds via acyl- and decarbonylative pathways in a
rational and predictable manner.
Scheme 1. Boronic Acid Scope
In the present study, we were inspired by our recent
development of the reactivity scale of the amide bond, wherein
the amide bond resonance of approximately 10 kcal/mol
represents a guideline for synthetically useful Pd-insertion into
the amide bond.3c In this respect, the use of anilides is
synthetically limited because of the low reactivity of the amide
bond (RE of 13.5 kcal/mol, N-Me-N-Ph-benzamide). The key
electronic interaction15 in our design is the nN → πAr
delocalization into the pyrimidine ring, which, as we
demonstrate, can be readily translated into other heterocycles,
resulting in a gradually varying resonance and thus a generic
activation mode of the amide bond. Note that this new gradual
nN → πAr delocalization mechanism is not readily available by
other destabilization methods of the amide bond, including
steric distortion and Nlp to CO delocalization.8
After extensive optimization, we identified N-methylamino
pyrimidyl amides16 as suitable electrophiles for the process.
Selected optimization results are presented in Table SI-1. We
observed the desired cross-coupling product in our proof-of-
concept reaction using Pd(OAc)2/PCy3 catalyst system and
H3BO3 as the promoter (entry 1). The acid can protonate N-
heterocycle, resulting in a cis−trans isomer switch and selective
metal-insertion along the isomerization pathway.17 From an
early stage we identified the use of acid as essential for the
formation of the desired product using Pd/phosphine catalysis
(entries 1−10). After extensive screening of various conditions,
the yield was increased to 50% (entry 7). At this point, we
examined Pd-NHC-based catalysts systems.3c,d After exper-
imentation, we found that (IPr)Pd(cinnamyl)Cl promoted the
desired reaction with significantly improved efficiency (entry
11). As expected, strong σ-donation of the NHC ligand
facilitates oxidative addition, while flexible steric bulk stabilizes
the active catalyst and promotes reductive elimination.13
Importantly, the reaction temperature could be decreased to
65 °C without a deleterious effect (entry 12). A further
improvement was realized by using water as an additive,
presumably to enhance solubility (entry 14). As expected, the
transformation was found to be strongly dependent on the Pd-
NHC catalyst used, with (IPr)Pd(cinnamyl)Cl providing the
optimal results (entries 14−16). Interestingly, the use of acid
with Pd-NHC catalysis was ineffective (entry 17), indicating
that N-protonation is not required for this catalysis to occur.
The finding that Pd-NHC acts as a superior catalyst to Pd-PR3
systems underscores the potential of well-defined Pd(II)-NHCs
as privileged catalysts for amide N−C cleavage reactivity.
With the optimal conditions in hand, the scope of the
reaction with respect to the boronic acid component was
evaluated (Scheme 1). As shown, the protocol exhibits broad
tolerance, including neutral (3a−c), electron-rich (3d),
electron-deficient (3e), and ortho-substituted (3f−h) sub-
strates. Importantly, electrophilic functional groups, such as
ketones (3i) and esters (3j), are readily accommodated.
Moreover, heterocycles such as 1,3-benzodioxole (3k), furan
(3l), and benzothiophene (3m) are tolerated. Interestingly,
high efficiency is observed for polyaromatic substrates (3n−o),
including sterically demanding arenes (3o). We next focused on
the scope of the amide cross-coupling partner (Scheme 2).
MAP amides afford high efficiency in cross-coupling, regardless
a
Conditions: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (6 mol
b
%), K2CO3 (3.0 equiv), THF (0.25 M), H2O, 65 °C, 15 h. Isolated
yields.
a
Scheme 2. Amide Scope
a
See Scheme 1 footnotes a and b.
of electronic substitution (3b−e), including deactivated amides
such as 3d. Furthermore, polyfluorinated amides (3p) relevant
from the medicinal chemistry point of view are compatible.
Importantly, electrophilic functional groups such as ketones
(3j) and esters (3j) are well-tolerated. Moreover, conjugated
biaryl amides (3q) that are prone to decarbonylation4d and
heterocyclic amides (3r−s), including those substituted at the
electron-rich 2-position (3s) couple with good levels of
reactivity. Cross-coupling of sterically hindered o-methyl
benzoic acid derived amide proceeds in 84% unoptimized
B
DOI: 10.1021/acs.orglett.7b02288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield (4-MeO-C6H4−B(OH)2) (not shown). At the present
stage, aliphatic amides have not been tested.
Importantly, the coupling could be performed using the
synthetically attractive, well-defined PEPPSI-IPr type of
precatalyst18 without modification of the reaction conditions
(Scheme 3), highlighting the versatility of our protocol.
nN→πAr activation (cf. directed Pd-insertion), which is further
supported by RE values (vide infra).
The X-ray structure of 1b was determined (Figure 2). The
amide shows relatively planar amide bond (τ = 20.9°, χN = 5.2°,
Scheme 3. Cross-Coupling Using PEPPSI-IPr
Primary and secondary amides are some of the most
common intermediates in organic synthesis.9,10 Since MAP
amides can be readily prepared from unactivated primary or
secondary amides (Scheme 4),16 our method offers a rapid entry
to acyl-metal intermediates from generic unactivated amides.
Figure 2. (a) Crystal structure of 1b. (b) Newman projection along
the N−C(O) bond. Bond lengths (Å) and angles (deg): N1−C1,
1.378(2); C1−O1, 1.225(1); C4−C1, 1.497(2); N1−C2, 1.407(1);
N1−C3, 1.469(1); C4−C1−N1−C3, 159.8(1); O1−C1−N1−C2,
158.5(1); O1−C1−N1−C3, −16.3(2); C4−C1−N1−C2, −25.4(2).
Note the short N1−C2 bond.
Scheme 4. Synthesis of MAP Amides from 1° or 2° Amides
χC = 3.9°). The N−C(O), CO, and N−Ar bond lengths are
1.378, 1.225, and 1.407 Å. Compared with the corresponding
N-Me-N-2-pyridyl (τ = 15.0°, χN = 8.4°, χC = 4.0°; N−C(O) =
1.366 Å; CO = 1.226 Å, N−Ar = 1.428 Å)17 and N-Me-N-Ph
benzamide (τ = 9.1°, χN = 6.6°, χC = 2.1°; N−C(O) = 1.355 Å;
CO = 1.232 Å, N−Ar = 1.437 Å),11 these values indicate a
gradual increase in nN→πAr conjugation.
Computations were employed to probe the energetics of the
amide bond undergoing N−C cleavage (see SI). (1) Resonance
energies (RE) determined by the COSNAR method indicate
that the conjugation is in the following order: 1a, 6.7 kcal/mol;
1k, 8.8 kcal/mol; 1l, 10.7 kcal/mol. In agreement with our
design, RE in 1a is much lower than in anilides (RE = 13.5
kcal/mol). (2) Rotational profile in 1a along the O−C−N−
C(Ar) dihedral angle confirms electronic destabilization (vs
twist) (Figure 3). The plot of 1a vs the corresponding anilide
Initial rates revealed the following reactivity: (1a) (νinitial
=
6.9 × 10−2 mM s−1) (see Supporting Information, SI), which
can be compared with the coupling of N,N-Ph,Boc benzamide
under the same reaction conditions (νinitial = 7.5 × 10−2 mM
s−1).3c The high reactivity of N-alkyl MAP amide is
unprecedented and bodes well for applications in amide bond
cross-coupling.
Studies were performed to evaluate the capacity for N-
directed Pd insertion into the N−C(O) bond. Toward this end,
N-Me-N-2-pyridyl (1k) and N-Me-N-4-pyridyl (1l) amides
were prepared and subjected to the reaction (Scheme 5). These
substrates underwent the coupling in 25−26% yield at 110 °C,
while 1l was unreactive at 65 °C, consistent with electronic
Figure 3. Rotational profile (1a, ΔE, kcal/mol, vs O−C−N−C [deg]).
N-Me-N-Ph-benzamide (1m) is shown for comparison.
Scheme 5. Effect of Directing Group: Amides Employed in
Computational Studies
a
(1m) clearly indicates that N-substitution results in a
significantly lowered barrier to rotation. (3) Resonance energy
in N-ring protonated 1a, 1k, and 1l are as follows: 1a, 3.0 kcal/
mol; 1k, 5.0 kcal/mol; and 1l, 2.4 kcal/mol, clearly
demonstrating that N-coordination significantly weakens
amidic resonance. (4) The difference between N-/O-proto-
nation affinities (ΔPA) indicates that 1a, 1k, and 1l strongly
favor coordination at the amide oxygen (vs amide nitrogen,
ΔPA = 9.0, 7.8, and 11.5 kcal/mol). However, protonation of
a
Note a gradual increase of RE by changing a single N-substituent on
the aromatic ring. RE of Ph-C(O)NMePh = 13.5 kcal/mol.11 Note
that RE of Ph-C(O)NMeAr (Ar = 4-CF3−C6H4) = 11.8 kcal/mol.11
C
DOI: 10.1021/acs.orglett.7b02288
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1960. (d) Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2017, 19, 2158.
(e) Amani, J.; Alam, R.; Badir, S.; Molander, G. A. Org. Lett. 2017, 19,
2426. (f) Ni, S.; Zhang, W.; Mei, H.; Han, J.; Pan, Y. Org. Lett. 2017,
19, 2536. (g) Lei, P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.;
Szostak, M. Chem. Sci. 2017, DOI: 10.1039/C7SC02692G, and
references cited therein. For primary references on ester and amide
Suzuki couplings, see: (h) Tatamidani, H.; Kakiuchi, F.; Chatani, N.
Org. Lett. 2004, 6, 3597. (i) Li, X.; Zou, G. Chem. Commun. 2015, 51,
5089. (j) Meng, G.; Szostak, M. Org. Biomol. Chem. 2016, 14, 5690 and
references cited therein.
(4) For representative decarbonylative coupling, see: (a) Meng, G.;
Szostak, M. Angew. Chem., Int. Ed. 2015, 54, 14518. (b) Shi, S.; Meng,
G.; Szostak, M. Angew. Chem., Int. Ed. 2016, 55, 6959. (c) Meng, G.;
Szostak, M. Org. Lett. 2016, 18, 796. (d) Dey, A.; Sasmal, S.; Seth, K.;
Lahiri, G. K.; Maiti, D. ACS Catal. 2017, 7, 433. (e) Yue, H.; Guo, L.;
Liao, H. H.; Cai, Y.; Zhu, C.; Rueping, M. Angew. Chem., Int. Ed. 2017,
56, 4282. (f) Yue, H.; Guo, L.; Lee, S. C.; Liu, X.; Rueping, M. Angew.
Chem., Int. Ed. 2017, 56, 3972. (g) Shi, S.; Szostak, M. Org. Lett. 2017,
19, 3095 and references cited therein.
(5) For representative tandem coupling, see: Walker, J. A.;
Vickerman, K. L.; Humke, J. N.; Stanley, L. M. J. Am. Chem. Soc.
2017, 139, 10228 and references cited therein.
(6) Review on electrophilic activation of amides: (a) Kaiser, D.;
Maulide, N. J. Org. Chem. 2016, 81, 4421. For an overview of amide
cross-coupling, see: (b) Ruider, S. A.; Maulide, N. Angew. Chem., Int.
Ed. 2015, 54, 13856. For a report on using amides as latent substrates,
see: (c) Valerio, V.; Petkova, D.; Madelaine, C.; Maulide, N. Chem. -
Eur. J. 2013, 19, 2606.
the ring nitrogen is favored in 1a, 1k, and 1l (ΔPA = 2.6, 4.0,
16.1 kcal/mol).
Collectively, the structural and energetic parameters of the
amide bond in MAP amides indicate that nN→πAr delocaliza-
tion is the major factor enabling selective N−C activation. The
capacity to switch RE in a rational manner could open up new
avenues for activating amides in N−C coupling reactions.
In summary, we have developed the first method for the
direct activation of N-methylamino pyrimidyl amides (MAPA)
by selective N−C amide bond cleavage. The reported reaction
uses commercially available and bench-stable Pd-NHC
precatalysts, occurs with high N−C activation chemoselectivity,
and is operationally simple. Most importantly, this report
introduces MAP amides as resonance-controlled, practical
alternatives to anilides for a range of catalytic coupling
reactions via acyl- and decarbonylative pathways. In these
amides, the N−X cleavage reaction, the most common side
process in the amide bond activation, is not observed. MAP
amides provide rapid entry to acyl metal intermediates from
unactivated primary and secondary amides. Mechanistic studies
strongly support nN→πAr delocalization. Studies on expanding
the scope of the amide bond cross-coupling are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) Review on acyl-metal intermediates: (a) Dzik, W. I.; Lange, P. P.;
Gooßen, L. J. Chem. Sci. 2012, 3, 2671. For the seminal study on
cross-coupling of unactivated aryl esters, see: (b) Amaike, K.; Muto,
K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573.
(8) (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.
(c) See ref 1c.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02288.
Experimental procedures and characterization data
(PDF)
X-ray crystallographic data for 1b (CIF)
(9) (a) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The
Amide Linkage: Structural Significance in Chemistry, Biochemistry, and
Materials Science; Wiley: New York, 2000. Pharmaceuticals:
(b) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
Polymers: (c) Marchildon, K. Macromol. React. Eng. 2011, 5, 22.
Peptides: (d) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(10) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis;
Pergamon Press: Oxford, 1991.
(11) Szostak, R.; Meng, G.; Szostak, M. J. Org. Chem. 2017, 82, 6373.
(12) Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062.
(13) (a) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40, 5151.
(b) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(14) (a) Nolan, S. P., Cazin, C. S. J., Eds. Science of Synthesis: N-
Heterocyclic Carbenes in Catalytic Organic Synthesis; Thieme: Stuttgart,
2017. (b) Hazari, N.; Melvin, P. R.; Beromi, M. M. Nat. Rev. Chem.
2017, 1, 25.
(15) For a review on stereoelectronic effects, see: Vatsadze, S. Z.;
Loginova, Y. D.; dos Passos Gomes, G.; Alabugin, I. V. Chem. - Eur. J.
2017, 23, 1521.
(16) For the seminal report on MAP amides, see: (a) Meyers, A. I.;
Comins, D. L. Tetrahedron Lett. 1978, 19, 5179. Note that these
amides could also be referred to as N-methyl-N-pyrimidyl amides.
(b) Bennet, A. J.; Somayaji, V.; Brown, R. S.; Santarsiero, B. D. J. Am.
Chem. Soc. 1991, 113, 7563. (c) See SI for additional details.
(17) Okamoto, I.; Nabeta, M.; Yamamoto, M.; Mikami, M.; Takeya,
T.; Tamura, O. Tetrahedron Lett. 2006, 47, 7143.
(18) (a) Lei, P.; Meng, G.; Ling, Y.; An, J.; Szostak, M. J. Org. Chem.
2017, 82, 6638. For a review, see: (b) Valente, C.; Calimsiz, S.; Hoi,
K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed. 2012,
51, 3314.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Guangrong Meng: 0000-0002-3023-0654
Michal Szostak: 0000-0002-9650-9690
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz
spectrometer was supported by the NSF-MRI grant (CHE-
1229030). We thank the Wrocław Center for Networking and
Supercomputing (grant number WCSS159).
REFERENCES
■
(1) (a) Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev. 2017,
DOI: 10.1039/C7CS00182G. (b) Meng, G.; Shi, S.; Szostak, M.
Synlett 2016, 27, 2530. (c) Liu, C.; Szostak, M. Chem. - Eur. J. 2017,
23, 7157. (d) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413.
(2) (a) de Meijere, A., Brase, S., Oestreich, M., Eds. Metal-Catalyzed
̈
Cross-Coupling Reactions and More; Wiley: New York, 2014. (b) Mo-
lander, G. A., Wolfe, J. P., Larhed, M., Eds. Science of Synthesis: Cross-
Coupling and Heck-Type Reactions; Thieme: Stuttgart, 2013.
(3) For representative acyl coupling, see: (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) Meng, G.; Szostak, M. Org. Lett.
2015, 17, 4364. (c) Lei, P.; Meng, G.; Szostak, M. ACS Catal. 2017, 7,
D
DOI: 10.1021/acs.orglett.7b02288
Org. Lett. XXXX, XXX, XXX−XXX