Rhodium(III)-catalyzed intermolecular direct amidation of aldehyde C-H bonds with N -chloroamines at room temperature

Article abstract of DOI:10.1021/ol400921r

A Rh(III)-catalyzed direct aldehyde C-H amidation from aldehydes and N-chloroamines, prepared in situ from amines, has been developed via C-H bond activation under very mild reaction conditions. A variety of primary and secondary amines were used to afford the corresponding amides in moderate to excellent yields.

Full text of DOI:10.1021/ol400921r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Intermolecular
Direct Amidation of Aldehyde CꢀH Bonds
with N‑Chloroamines at Room
Temperature
Bing Zhou,* Juanjuan Du, Yaxi Yang, and Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
zhoubing2012@hotmail.com; ycli@mail.shcnc.ac.cn
Received April 3, 2013
ABSTRACT
A Rh(III)-catalyzed direct aldehyde CꢀH amidation from aldehydes and N-chloroamines, prepared in situ from amines, has been developed via
CꢀH bond activation under very mild reaction conditions. A variety of primary and secondary amines were used to afford the corresponding
amides in moderate to excellent yields.
The amide bond is the key chemical connection found
in a myriad of natural products, polymers, and pharma-
ceuticals.1 Moreover, more than 25% of known drugs
contain an amide group.2 The most straightforward syn-
thetic route to amides is the condensation of carboxylic
acids with amines.3 However, this strategy has the innate
drawback derived from the poor atom efficiency and
requirement of stoichiometric amounts of activating re-
agents. A milder and atom-economic alternative approach
is the direct amidation of aldehydes which represents an
interesting and recent topic in this area.4 Such approaches
include NHC-catalyzed,5 metal-catalyzed,6 or metal-free7
oxidative amidation ofaldehydeswithamines, the Schmidt
reaction,8 base-mediated amidation of aldehydes with
azide,9 and organocatalytic oxidative amidation of alde-
hydes with activating reagents.10 Despite great advances in
this area, the development of a catalytic process for amide
bond formation under mild reaction conditions remains
highly desirable.
Yet, transition-metal-catalyzed functionalizations of
unactivated CꢀH bonds, which enable the efficient con-
struction of carbonꢀcarbonor carbonꢀheteroatom bonds
(1) (a) Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. Curr.
Opin. Drug Discovery Dev. 2007, 10, 768. (b) Bode, J. W. Curr. Opin.
Drug Discovery Dev. 2006, 9, 765.
(2) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb.
Chem. 1999, 1, 55.
(3) (a) Valeur, E.; Bradely, M. Chem. Soc. Rev. 2009, 38, 606.
(b) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
(4) Ekoue-Kovi, K.; Wolf, C. Chem.;Eur. J. 2008, 14, 6302.
(5) For some selected examples, see: (a) Kuwano, S.; Harada, S.;
Oriez, R.; Yamada, K. Chem. Commun. 2012, 48, 145. (b) Zhang, B.;
Feng, P.; Cui, Y.; Jiao, N. Chem. Commun. 2012, 48, 7280. (c) Sarkar,
S. D.; Studer, A. Org. Lett. 2010, 12, 1992. (d) Maki, B. E.; Chan, A.;
Phillips, E. M.; Scheidt, K. A. Tetrahedron 2009, 65, 3102. (e) Maki,
B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (f) Vora, H. U.; Rovis, T.
J. Am. Chem. Soc. 2007, 129, 13796. (g) Bode, J. W.; Sohn, S. S. J. Am.
Chem. Soc. 2007, 129, 13798.
(6) For some selected examples, see: (a) Ghosh, S. C.; Ngiam, J. S. Y.;
Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth. Catal.
2012, 354, 1407. (b) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem.
Soc. 2007, 129, 14106. (c) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006, 128,
13064. (d) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474.
(7) (a) Liang, J.; Lv, J.; Shang, Z.-C. Tetrahedron 2011, 67, 8532.
(b) Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
(8) (a) Lee, H. L.;Aube, J. Tetrahedron 2007, 63, 9007. (b) Chakraborty,
R.;Franz, V.;Bez, G.;Vasadia, D.;Popuri, C.;Zhao, C. G.Org. Lett. 2005,
7, 4145. (c) Boyer, J. H.; Canter, F. C.; Hamer, J.; Putney, R. K. J. Am.
Chem. Soc. 1956, 78, 325. (d) Boyer, J. H.; Hamer, J. J. Am. Chem. Soc.
1955, 77, 951.
(9) Kulkarni, S. S.; Hu, X.; Manetsch, R. Chem. Commun. 2013, 49,
1193.
(10) Tan, B.; Toda, N.; Barbas, C. F., III. Angew. Chem., Int. Ed.
2012, 51, 12538.
r
10.1021/ol400921r
XXXX American Chemical Society

as a highly atom-economical and direct approach, have
in recent years attracted significant interest.11 Although
great progress has been made in this emerging field, the
selective functionalization of aldehyde CꢀH bonds is
still a great challenge and as of yet limited to coupling with
alkenes and alkynes and yielding ketone derivatives
through oxidative addition of low-valent transition-metal
complexes (especially RhI catalysts) to aldehyde CꢀH
bonds (Scheme 1a).12 To the best of our knowledge,
catalytic direct CꢀN bond formation remains a big chal-
lenge after a chelation-assisted aldehyde CꢀH bond acti-
vation, with no examples reported.
Scheme 1. Coupling Reactions through CꢀH Activation
In this context and inspired by recent reports for the
RhIII-catalyzed direct arene CꢀH amination (Scheme 1b),13
(11) For selected recent reviews on arene C-H bond functionaliza-
tion, see: (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. 2012, 45, 814. (c) Patureau, F. W.; Wencel-Delord, J.; Glorius, F.
Aldrichimica Acta 2012, 45, 31. (d) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (e) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215. (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang,
S. Chem. Soc. Rev. 2011, 40, 5068. (g) Ackermann, L. Chem. Rev. 2011,
111, 1315. (h) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
1780. (i) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (j) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(k) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890. (l) Satoh, T.; Miura, M.
Chem.;Eur. J. 2010, 16, 11212.
(12) Some recent examples of the selective metal-catalyzed function-
alization of aldehyde CꢀH bonds: (a) Chaplin, A. B.; Hooper, J. F.;
Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 4885. (b)
Murphy, S. K.; Petrone, D. A.; Coulter, M. M.; Dong, V. M. Org. Lett.
2011, 13, 6216. (c) Parsons, S. R.; Hooper, J. F.; Willis, M. C. Org. Lett.
2011, 13, 998. (d) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 16354. (e) Tang, B.-X.; Song, R.-J.; Wu, C.-Y.;
Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-H.
J. Am. Chem. Soc. 2010, 132, 8900. (f) Coulter, M. M.; Kou, K. G. M.;
Galligan, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16330. (g)
Crepin, D.; Dawick, J.; Aissa, C. Angew. Chem., Int. Ed. 2010, 49, 620.
(h) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 6932. (i) Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley,
A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232. (j) Suggs, J. W.
J. Am. Chem. Soc. 1979, 101, 489.
herein we report the first example of RhIII-catalyzed CꢀN
bond formation through a chelation-assisted aldehyde
C(sp2)ꢀH bond activation (Scheme 1c).14,15 This catalytic
reaction provides a new approach for the construction
of amide bonds. Most significantly, the present work also
offers novel insights into RhIII-catalyzed CꢀN cross-
coupling reactions after cleavage of an aldehyde CꢀH
bond.
Initially, our study focused on the reaction of 8-quino-
linecarbaldehyde (1a) and N-chloromorpholine (2a) to
optimize the reaction conditions (Table 1). To our delight,
the desired product 3a was observed in a 15% yield with
[Cp*Rh(CH3CN)3](SbF6)2 as the catalyst in toluene at
60 °C despite the low conversion (entry 1). Different
catalysts were tested (entries 1ꢀ5), and (Cp*Rh(OAc)2)2
showed asimilarresult(entry 2). (Cp*RhCl2)2 (5 mol %) in
the presence of AgSbF6 (120 mol %) turned out to be more
reactive, and the yield of 3a was increased to 68% in
toluene at 60 °C (entry 3). Surprisingly, other transition
metal catalysts such as Pd(OAc)2 and ruthenium com-
plexes were completely ineffective in this C(sp2)ꢀH amida-
tion reaction (entries 4ꢀ5). Subsequently, we examined the
role of each reactant through a series of control experi-
ments. Notably, in the absence of AgSbF6 or [Cp*RhCl2]2,
we recovered the starting materials (entries 6 and 7).
Moreover, we also tested morpholine as the substrate,
and it failed to give the product 3a (entry 8). Replacement
of 8-quinolinecarbaldehyde with 1-naphthaldehyde failed
to yield any desired coupling product, suggesting a critical
role for the N-directing group for CꢀH activation (entry 9).
(13) (a) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272. (b)
Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656. For some
reviews for arene CꢀH bond amination reactions, see: (c) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d) Wencel-
€
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
(e) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282.
(14) For selected rhodium(III)-catalyzed direct addition of arene
CꢀH bonds to aldehydes, see: (a) Li, Y.; Zhang, X.-S.; Chen, K.; He,
K.-H.; Pan, F.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2012, 14, 636. (b) Yang, Y.;
Zhou, B.; Li, Y. Adv. Synth. Catal. 2012, 354, 2916. (c) Sharma, S.; Park,
E.; Park, J.; Kim, I. S. Org. Lett. 2012, 14, 906. (d) Zhou, B.; Yang, Y.;
Li, Y. Chem. Commun. 2012, 48, 5163. (e) Lian, Y.; Bergman, R. G.;
Ellman, J. A. Chem. Sci. 2012, 3, 3088. (f) Yang, L.; Correia, C. A.; Li,
C.-J. Adv. Synth. Catal. 2011, 353, 1269. (g) Park, J.; Park, E.; Kim, A.;
Lee, Y.; Chi, K. W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2011,
13, 4390. For selected rhodium(III)-catalyzed direct addition of arene
CꢀH bonds to imines, isocyanates, isocyanide, azides, and diazomalo-
nates, see: (h) Zhou, B.; Yang, Y.; Lin, S.; Li, Y. Adv. Synth. Catal. 2013,
355, 360. (i) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X. Angew. Chem., Int.
Ed. 2013, 52, 2577. (j) Zhou, B.; Hou, W.; Yang, Y.; Li, Y. Chem.;Eur.
J. 2013, 19, 4701. (k) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y.
J. Am. Chem. Soc. 2012, 134, 13565. (l) Kim, J. Y.; Park, S. H.; Ryu, J.;
Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110.
(m) Shi, J.; Zhou, B.; Yang, Y.; Li., Y. Org. Biomol. Chem. 2012, 10,
8953. (n) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew.
Chem., Int. Ed. 2012, 51, 9904. (o) Tsai, A. S.; Tauchert, M. E.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248. (p) Li, Y.; Li,
B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2011, 50, 2115. (q) Hesp, K. D.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 11430. (r) Zhu, C.; Xie, W.;
Falck, J. R. Chem.;Eur. J. 2011, 17, 12591. (s) Tsoi, Y.-T.; Zhou, Z.;
Yu, W.-Y. Org. Lett. 2011, 13, 5370.
(15) Selected rhodium(III)-catalyzed reaction using nonpolar al-
kynes and alkenes as substrates: (a) Guimond, N.; Gorelsky, S. I.;
Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449. (b) Huestis, M. P.;
Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed. 2011, 50,
1338. (c) Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
1977. (d) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (e) Hyster, T. K.; Rovis, T. J. Am. Chem.
Soc. 2010, 132, 10565. (f) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett.
2010, 12, 5688. (g) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem.
Soc. 2010, 132, 9585.
B
Org. Lett., Vol. XX, No. XX, XXXX

A substoichiometric amount (30 mol %) of AgSbF6 led to
a low yield of the product 3a (entry 10).
conditions. First, a number of cyclic and acyclic N,N-
dialkylamines were tested. Analogous to 3a, the Rh-
catalyzed coupling of 4-Boc-piperazine and piperidines
gave products 3bꢀ3c in good yields. Acyclic secondary
amines were also well tolerant providing the desired prod-
ucts 3dꢀ3g in moderate to good yields. Notably, primary
amines were effective coupling partners providing the
corresponding N-monosubstituted amides 3hꢀ3j in mod-
erate yields. The substrate scope was further extended to
a variety of aldehydes. It was found that the electronic
nature of the substituents on the quinoline ring did not
play a key role in this catalytic reaction. Aldehydes with
both electron-donating groups, such as methyl (3kꢀ3m)
and methoxy groups (3n), and electron-withdrawing
groups, such as the chloro group (3o and 3p), were well
tolerated providing the desired amides in moderate to
excellent yields. Notably, the tolerance of the chloro group
offers the opportunity for further functionalization.
To optimize the amidation protocol, the influence of the
solvent on this reaction was studied next (entries 3, 11ꢀ13)
and the most satisfactory yield was obtained in THF
(entry 13). Next, various temperatures were screened
(entries 13ꢀ15), and the best result was obtained by low-
ering the reaction temperature to rt (entry 15). Indeed, the
catalytic reaction can also be carried out with good
efficiency in the presence of 3 mol % of catalyst by simply
lengthening the reaction time to 24 h (entry 16). Notably,
comparedtopreviously reportedprocedures for amidation
of aldehydes with N-chloroamines,16 this catalytic method
proceeds in the absence of external oxidants under very
mild reaction conditions.
Table 1. Reaction Optimizationa
Scheme 2. One-Pot Direct Amidationa
temp
yield
(%)b
entry
catalysts (mol %)
solvents (°C)
1
2
3
4
5
[Cp*Rh(MeCN)3](SbF6)2 (5)
(Cp*Rh(OAc)2)2 (5)
toluene
toluene
60
60
60
60
60
15 (80)
16 (80)
68
(Cp*RhCl2)2 (5)/AgSbF6 (120) toluene
Pd(OAc)2 (5)
toluene
toluene
<5
[Ru(p-cymene)Cl2]2 (5)/
AgSbF6 (120)
<5
6
(Cp*RhCl2)2 (5)
AgSbF6 (120)
toluene
toluene
60
60
60
60
60
60
60
60
40
20
20
0
7
8c
0
(Cp*RhCl2)2 (5)/AgSbF6 (120) toluene
(Cp*RhCl2)2 (5)/AgSbF6 (120) toluene
0
9d
10
11
12
13
14
15
16e
0
(Cp*RhCl2)2 (5)/AgSbF6 (30)
toluene
25
66
60
76
80
90
85
(Cp*RhCl2)2 (5)/AgSbF6 (120) DCM
(Cp*RhCl2)2 (5)/AgSbF6 (120) DCE
(Cp*RhCl2)2 (5)/AgSbF6 (120) THF
(Cp*RhCl2)2 (5)/AgSbF6 (120) THF
(Cp*RhCl2)2 (5)/AgSbF6 (120) THF
(Cp*RhCl2)2 (3)/AgSbF6 (120) THF
a Reaction conditions: 2 mmol of 1a, 2.4 mmol of 2a, 0.1 mmol of
catalyst, and 10 mL of solvent at the indicated temperature for 12 h.
b Yield of isolated product. Yield in parentheses is based on recovered
starting material. c Morpholine was used. d Using 1-naphthaldehyde as
the substrate. e Reaction time is 24 h.
With the success of the Rh-catalyzed amidation reac-
tion, we attempted to develop a one-pot synthesis of amide
from aldehydes and amines (Scheme 2). Toward this end,
treatment of amines 4 with NCS in THF for 20 min gave
the N-chloroamines. Then aldehyde 1, [Cp*RhCl2]2, and
AgSbF6 were added to this THF solution, and the mixture
was stirred at rt for 12 h. To our delight, a broad scope of
amines (3aꢀ3j) can be coupled under standard reaction
a Reaction conditions: 2 mmol of 1, 2.4 mmol of 4, 2.6 mmol of NCS,
0.1 mmol of (Cp*RhCl2)2, 2.4 mmol of AgSbF6, and 10 mL of THF at rt
for 12 h. Yield of isolated product.
(16) (a) Cadoni, R.; Porcheddu, A.; Giacomelli, G.; Luca, L. D. Org.
Lett. 2012, 14, 5014. (b) Porcheddu, A.; Luca, L. D. Adv. Synth. Catal.
2012, 354, 2949.
We then tried to gain some insight into the mecha-
nism by conducting a series of experiments (Scheme 3).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Preliminary Mechanistic Studies
Scheme 4. Proposed Catalytic Cycles
8-Quinolinecarbaldehyde 1a, (RhCp*Cl2)2, and NaOAc
reacted smoothly to give rhodacycle 5, which was further
characterized by X-ray crystallography (Scheme 3a).17
More importantly, complex 5 successfully catalyzed the
coupling of 1a with 2a (Scheme 3b), suggesting the plau-
sible intermediacy of a cyclometalated complex in the
catalytic cycle. Although Rh(III) catalysts have been
widely applied in CꢀH activation, reports on isolated
stable organorhodium(III) intermediates are still limited,18
especially for acyl-rhodium(III) intermediates.19
Based on the above observed data, a plausible catalytic
cycle is presented in Scheme 4. First, treatment of the
[RhCp*Cl2]2 precursor with the AgSbF6 additive provides
a cationic Rh(III) species. A cyclometalation process
through CꢀH bond activation gives five-membered cyclo-
metalated acyl-Rh(III) complexes A with a loss of an
acid.20 Coordination of the N-chloroamine to the acyl-
Rh(III) complex gives the intermediate B. Then the chlo-
ride abstraction with Agþ promotes the migration of the
acyl group to the nitrogen which provides the amides and
regenerates the catalysts.21
In summary, we have developed a Rh(III)-catalyzed
directed amidation of aldehyde CꢀH bonds with N-chloro-
amines, prepared in situ from amines, proceeding in the
absence of external oxidants at rt. A variety of primary and
secondary amines were used to afford the corresponding
amides in moderate to excellent yields. More importantly,
this process may provide a new direction for direct CꢀN
bond formation from aldehyde CꢀH bond activation.
Further studies into the scope, mechanism, and synthetic
application are ongoing in our laboratory.22
(17) CCDC 935272 (5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(18) (a) Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482. (b) Li, Y.; Zhang,
X.-S.; Li, H.;Wang, W.-H.; Chen, K.;Li, B.-J.; Shi, Z.-J. Chem. Sci. 2012,
3, 1634. (c) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li, X. Angew. Chem.,
Int. Ed. 2012, 51, 11819. (d) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am.
Chem. Soc. 2008, 130, 12414.
Supporting Information Available. Experimental proce-
dures, characterization of products, and copies of 1H and
13C NMR spectra are provided. The material is available
free of charge via the Internet at http://pubs.acs.org.
(22) A related work using azides as nitrogen sources to give primary
amides was submitted to Chem.;Eur. J. by our group at this time; see:
(19) (a) Shi, Z.; Scheroder, N.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 8092. (b) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640.
(20) (a) Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics
2009, 28, 3492. (b) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello,
M.; Hilton, S. T.; Russell, D. R. Dalton Trans. 2003, 4132.
(21) Kabalka, G. W.; McCollum, G. W.; Kunda, S. A. J. Org. Chem.
1984, 49, 1656.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX