General base-tuned unorthodox synthesis of amides and ketoesters with water

Article abstract of DOI:10.1039/c4cc07961b

We discovered a highly reactive λ³-hypervalent iodane species using an inorganic/organic base for the unorthodox synthesis of amides and ketoesters through grafting terminal alkynes. In contrast to the metal-catalyzed dehydrative approaches the in situ generated nonmetallic reagent efficiently created C-N/C-O and CO bonds with amines/alkynes and water at rt. This journal is

Full text of DOI:10.1039/c4cc07961b

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
General base-tuned unorthodox synthesis of
amides and ketoesters with water†
Cite this: Chem. Commun., 2015,
51, 384
Saikat Khamarui, Rituparna Maiti and Dilip K. Maiti*
Received 8th October 2014,
Accepted 10th November 2014
DOI: 10.1039/c4cc07961b
www.rsc.org/chemcomm
We discovered a highly reactive k3-hypervalent iodane species using
Complete cleavage of the C–C terminal triple bond into func-
an inorganic/organic base for the unorthodox synthesis of amides tional group(s) is challenging and a limited number of approaches
and ketoesters through grafting terminal alkynes. In contrast to the have been described in the literature.5,6 In a continuous effort to
metal-catalyzed dehydrative approaches the in situ generated non- develop new properties of l3-hypervalent iodanes7,8 we wanted to
8,9
Q
metallic reagent efficiently created C–N/C–O and C O bonds with screen inexpensive PhI(OAc)2 for the nonmetallic cleavage of
amines/alkynes and water at rt.
alkynes towards the synthesis of amides and esters through coupling
with amine/alkyne and water. However, only three nonmetallic
Synthesis of amides and esters occurs naturally in plants and approaches have been developed so far for cleavage cum functional-
animals, and these compounds are essential for cellular function, ization of terminal alkynes: Moriarty and colleagues reported
construction of lipids for the cell membrane, many biological fluorine-protected hypervalent iodane C6F5I(OCOCF3)2 in benzene
operations and directing groups in various metal-catalyzed (six examples),6a Ochiai et al. reported the process of heating
reactions.1 These fundamental processes are widely utilized iodomesitylene (10 mol%), m-CPBA, HBF4 (2.2 equiv., 48% aq) in
in academia and industry to access valuable pharmaceuticals, acetonitrile–H2O (9:1) (five examples)6b to obtain the corresponding
agrochemicals, materials, natural products and synthetic com- carboxylic acids (eqn (i) and (ii), Scheme 1); and recently Guo and
pounds.1–4 Development of a general synthetic strategy for co-workers reported an interesting approach (eqn (iii)) to synthesize
R–CO–Nu compounds such as amides and esters remains a esters using fluorine-protected l3-hypervalent iodane and alcohol
long standing challenge in chemical science, particularly if it is under heating conditions.6c
capable of addressing crucial issues such as operational simplicity,
We envisioned the manipulation of the two loosely bound
robustness, speed, high yield, metal-free benign conditions for acetoxy groups of PhI(OAc)2 leading to an enhancement of its
broader substrate scope, diverse syntheses of valuable compounds, reactivity towards organic precursors. This manipulation also
low cost and environmental safety. Conventional synthesis of amides enables organic transformation in water as the environmentally
and esters relies on dehydrative C–N/C–O coupling between activated benign reaction medium as well as the reactant. PhI(OAc)2 was
carboxylic acid analogues and amines or alcohols under anhydrous, used as a Lewis acid-like oxidant for the activation of the
solid phase, metal-catalyzed and/or heating reaction conditions.2a,b terminal alkyne phenyl acetylene (R1 = Ph, eqn (IV), Scheme 1)
In the last two decades, a few pioneering amidation reactions were for the amidation reaction with n-butylamine (R2 = nBu, R3 = H)
Q
developed using new precursors, such as the umpolung approach and water. Gratifyingly, simultaneous coupling of C–N and C
O
of 1,1-bromonitroalkanes,3d [Mn(2,6-Cl2TPP)Cl]-mediated oxidative bonds to construct secondary amide functionality at the non-
addition of amines to the terminal carbon of alkynes,3a the nucleo- terminal carbon of the alkyne was achieved upon addition of a
philic carbene method of 2-haloaldehydes,3b Ru-complex mediated mild base, NaHCO3 (2.1 mol) into the aqueous suspension of
oxidative addition of alcohols and amines,3c decarboxylative phenyl acetylene and PhI(OAc)2 at ambient temperature, and the
amidation3f and the acid-activated silatropic switch strategy.3e
reaction was complete within 4 h (entry 1, Table 1) affording the
n-butyl benzamide (6a, Scheme 2) in 85% yield. For optimization
of the reaction other inorganic bases such as Na2CO3, NaOH,
K2CO3 and KOH were employed (entries 2–5, Table 1), and
comparable yields (80, 83, 82 and 85% respectively) were
obtained. During reaction optimization, we also observed that
the reaction time was reduced to just 1 h if PhI(OAc)2 and alkyne
Department of Chemistry, University of Calcutta, University College of Science, 92,
A. P. C. Road, Kolkata-700009, India. E-mail: dkmchem@caluniv.ac.in;
Fax: +91-33-2351-9755; Tel: +91-33-2350-9937
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, NMR spectra and CIF files. CCDC 973403. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc07961b (1a) were stirred together for a few minutes and treated with
384 | Chem. Commun., 2015, 51, 384--387
This journal is ©The Royal Society of Chemistry 2015

View Article Online
Communication
ChemComm
Scheme 2 Synthesis of amides using NaHCO3-tuned-hypervalent iodane.
Scheme 1 Cleavage of terminal alkynes with l3-hypervalent iodane.
Table 1 Development and optimization of the amidation reaction
n-butyl amine (2a), the amidation reaction proceeded quickly as
we observed transformation of the gel-like material to an oily
product that was deposited in the reaction container. The catalytic
amount of NaHCO3 was instrumental for this nonmetallic benign
process. Two equivalents of NaHCO3 were spared to neutralize
the in situ-generated acetic acid from PhI(OAc)2. To overcome
the problem of using excess amounts of NaHCO3, another
l3-hypervalent iodane PhIO13 was employed (entry 6, Table 1);
however, the yield was drastically reduced (25%). Herein, the
base played the pivotal role because the reaction was completely
blocked in the absence of NaHCO3 (entries 7 and 8). As expected,
the reaction was unsuccessful upon replacing the water medium
with commonly-used volatile toxic organic solvents such as
CH2Cl2, MeCN, THF, toluene and MeOH (entries 9–13).
The tolerance of various functionalities was successfully
examined for this new methodology (eqn (1), Scheme 2) through
synthesis of a wide range of compounds bearing both unsub-
stituted (6a,b) and substituted (6c,d) aromatic rings, heterocycles
(6e,l), secondary (6a–f), activated secondary (6g) and tertiary
amides (6h). This benign strategy was successfully used to
transform cyclic amine (6f), substituted aromatic rings (6c,d),
Hypervalent
iodanea
Time
(h)
6a, yieldd
(%)
Entry
Solventb
Basec
1
2
3
4
5
6
7
8
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
PhI(OAc)2
PhIO
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
MeCN
THF
PhCH3
MeOH
NaHCO3
Na2CO3
NaOH
K2CO3
KOH
NaHCO3
—
4
12
4
12
4
24
48
48
48
48
48
48
48
85
80
83
82
85
25
nde
nd
nd
nd
nd
nd
nd
—
9
NaHCO3
Na2CO3
NaHCO3
Na2CO3
Na2CO3
10
11
12
13
a
b
c
d
2 mmol. 5 mL. 2.1 mmol. Yield of the isolated product after
e
column chromatography. Not detected.
aqueous NaHCO3 before the addition of n-butyl amine (2a) instead heterocycles (6e,l), secondary (6a–f), activated secondary (6g) and
of adding all reactants simultaneously. The physical appearance, tertiary amides (6h). It was also successfully used to transform
texture and colour of the reaction mixture changed over time. It chiral monoamine (2g) and diamine (2h) into the corresponding
transformed into a fluorescent gel-like material, which was ready optically pure amides (6i,j) without formation of racemization
for coupling with amine (2) in 1 h. Upon addition of precursor products, which was confirmed by the chiral HPLC technique (ESI†).
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 384--387 | 385

View Article Online
ChemComm
Communication
The unorthodox benign amidation strategy for functionalized
amides (6a–l) was rapid (2.0–5.0 h) and high yielding (60–85%).
However moderate yields (60–65%) were obtained for the
amides 6g, 6m and 6n upon use of activated aliphatic amine,
aromatic amine and aliphatic alkyne respectively.
To explore the scope of this operationally simple strategy, we
attempted the direct synthesis of tripodal ligands which were
recently found to have tremendous application as chemosensors for
the detection and estimation of unsafe metallic and nonmetallic
ions.10 Interesting results were obtained using the tripodal ligand
tris(aminoethyl)amine (2i, eqn (2), Scheme 2), in which all three
amine groups were simultaneously converted into their respective
benzamide and thiophene amide analogues (6k,l) within 5 h. Herein
we have introduced creative hypervalent iodane involving an
unorthodox synthetic approach using water as a source of carbonyl
oxygen, an amine for C–N bond formation and a carboxylate moiety
for direct O–C couplings with the precursor alkyne in nontoxic
(‘green’)11 aqueous media at ambient temperature as the C–C triple
bond can now be selectively grafted to various molecules. Terminal
alkynes are inexpensive precursors that can be synthesized using
calcium carbide and alkyl halide (R–X) or aldehyde using a simple
green approach.12 Investigation of the mechanism of the amidation
process involving the active l3-hypervalent iodane reagent PhI(OH)2
Scheme 3 Amidation through C–N and C–H cleavage.
is under progress using innovative DFT and Mid-IR techniques, 4-methylbenzylamine and deactivated 2-nitrobenzylamine, all
which will be reported in due course. four possible amides [8g (42%), 8b (20%), 8h (2%) and 8e (1%)]
The activation of C–H and C–C triple bonds and their were isolated after purification by column chromatography.
transformation into carbon–heteroatom bonds was a revolutionary The result revealed that a benzylamine derivative bearing an
achievement in modern chemical science.13,14 In comparison to the activated aromatic ring is more favourable for benzylic sp3C–H
great success achieved using metal-activated transformations,13 activation and that an amine bearing an electron-deficient
only a few nonmetallic bond-activated functionalization processes group is preferred for C–N coupling.
have been reported.14 Activation of sp3C–H and sp3C–N bonds of a
a-Oxycarbonyl-b-ketone is an important class of compounds
primary amine and its selective transformation have tremendous that recently exhibited excellent bioactivity against prostate
potential in organic synthesis. However, the high reactivity of cancer.4a Surprisingly only two approaches were found in the
primary amine functionality towards most reagents is the main literature for the synthesis of complex a-oxycarbonyl-b-ketones
obstacle in executing the reaction.13e To explore the reactivity of the which were based on lactonization of keto acids2d and gold-
NaHCO3-activated-l3-hypervalent iodane species toward both the catalyzed coupling of carboxylic acid.4b However, transfer of the
benzylic sp3C–H and amine sp3C–N bonds of a primary amine, a acetate group from PhI(OAc)2 was investigated to afford simple
mixture of phenylacetylene (1a) and benzyl amine (4a) was treated a-ketoacetates.15 The limited number of reported methodology
with PhI(OAc)2 in aqueous sodium bicarbonate solution at ambient for complex a-oxycarbonyl-b-ketones led us to develop a new
temperature to obtain 8a (eqn (3), Scheme 3). The benzylic sp3C–H efficient approach for their synthesis utilizing the in situ-
and sp3C–N bonds were activated, and amidation took place by generated transient l3-hypervalent iodane. To our delight, it was
coupling between two molecules of 4a. It is expected that the in situ- found to be a powerful reagent under the alkaline conditions
generated l3-hypervalent iodane reagent selectively activates both undergoing the cleavage of the terminal CRC bond. Upon treat-
the benzylic sp3C–H bonds and the sp3C–N bond of amines (4) and ment with alkynes (1) with the in situ-generated l3-hypervalent
simultaneously allowed the creation of C–N and CQO bonds by iodane reagent in aqueous NaHCO3, a-oxycarbonyl-b-ketones (9a–e,
reacting with amine and water, respectively, leading to the eqn (5), Scheme 4) were obtained in 10–11 h with good yield
construction of amides (8).
(62–70%). The reaction is expected to pass through a concerted
Direct involvement of the terminal triple bond was verified pathway because in the presence of potassium cinnamate (excess) in
by performing a reaction without phenylacetylene, in which D2O the corresponding cross over ester (D2–10a, eqn (6)) was not
case the amide formation reaction became slow (24 h) and low found. The deuterium incorporated D2–9a was furnished as the sole
yielding (30%). Herein, the exact role of phenylacetylene (1a) is product. Structure of 9a was confirmed through XRD analysis.16
unknown to us, which eventually transformed to a-acetoxy-
To investigate the reaction course using organic base, we
acetophenone (7a). The reaction is rapid enough (1.0–1.5 h) added excess (4 mmol) potassium trans-cinnamate (5a), optically
for methyl-, nitro-, fluoro-substituted benzylamines to afford pure lactate (5b) and decanoate (5c) in the reaction mixture
the secondary amide 8a–f with good yield (60–80%). During containing phenylacetylene (1a) and benzylamine (4a, eqn (7)).
the cross over experiment (eqn (4), Scheme 3) with activated Surprisingly the organic base played an important role, allowing
386 | Chem. Commun., 2015, 51, 384--387
This journal is ©The Royal Society of Chemistry 2015

View Article Online
Communication
ChemComm
(c) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471;
(d) M. Uyanik, D. Suzuki, T. Yasui and K. Ishihara, Angew. Chem.,
Int. Ed., 2011, 50, 5331; (e) W. S. Bechara, G. Pelletier and A. B.
Charette, Nat. Chem., 2012, 4, 228.
3 (a) W.-K. Chan, C.-M. Ho, M.-K. Wong and C.-M. Che, J. Am. Chem.
Soc., 2006, 128, 14796; (b) H. U. Vora and T. Rovis, J. Am. Chem. Soc.,
2007, 129, 13796; (c) C. Gunanathan, Y. Ben-David and D. Milstein,
Science, 2007, 317, 790; (d) B. Shen, D. M. Makley and J. N. Johnston,
Nature, 2010, 465, 1027; (e) W. Wu, Z. Zhang and L. S. Liebeskind,
J. Am. Chem. Soc., 2011, 133, 14256; ( f ) J. Liu, Q. Liu, H. Yi, C. Qin,
R. Bai, X. Qi, Y. Lan and A. Lei, Angew. Chem., Int. Ed., 2014, 53, 502.
4 (a) Y. Chen, D. Wen, Z. Huang, M. Huang, Y. Luo, B. Liu, H. Lu,
Y. Wu, Y. Peng and J. Zhang, Bioorg. Med. Chem. Lett., 2012, 22, 6867;
(b) K. Ji, Y. Zhao and L. Zhang, Angew. Chem., Int. Ed., 2013, 52, 6508.
5 (a) K. Lee, Y.-H. Kim, S. B. Han, H. Kang, S. Park, W. S. Seo,
J. T. Park, B. Kim and S. Chang, J. Am. Chem. Soc., 2003,
125, 6844; (b) M. C. Willis, Chem. Rev., 2010, 110, 725; (c) T. Shen,
T. Wang, C. Qin and N. Jiao, Angew. Chem., Int. Ed., 2013, 52, 6677.
6 (a) R. M. Moriarty, R. Penmasta, A. K. Awasthi and I. Prakash, J. Org.
Chem., 1988, 53, 6124; (b) K. Miyamoto, Y. Sei, K. Yamaguchi and
M. Ochiai, J. Am. Chem. Soc., 2009, 131, 1382; (c) Q. Jiang, A. Zhao,
B. Xu, J. Jia, X. Liu and C. Guo, J. Org. Chem., 2014, 79, 2709.
7 (a) N. Chatterjee, P. Pandit, S. Halder, A. Patra and D. K. Maiti, J. Org.
Chem., 2008, 73, 7775; (b) P. Pandit, N. Chatterjee, S. Halder, S. K. Hota,
A. Patra and D. K. Maiti, J. Org. Chem., 2009, 74, 2581; (c) D. K. Maiti,
N. Chatterjee, P. Pandit and S. K. Hota, Chem. Commun., 2010, 46, 2022;
(d) P. Pandit, N. Chatterjee and D. K. Maiti, Chem. Commun., 2011,
47, 1285.
Scheme 4 Inorganic and organic base-tuned synthesis of ketoesters.
8 (a) P. Pandit, K. S. Gayen, S. Khamarui, N. Chatterjee and D. K. Maiti,
Chem. Commun., 2011, 47, 6933; (b) S. Khamarui, D. Sarkar, P. Pandit
and D. K. Maiti, Chem. Commun., 2011, 47, 12667.
the formation of the corresponding a-oxycarbonyl-b-ketones
(11a–c). Significantly, a non-concerted reaction path with an
excellent reaction rate (10–15 min) was observed by exchanging
the inorganic base with an organic base (eqn (7)).
In conclusion, we have demonstrated base-tuned prepara-
tion of a new l3-hypervalent iodane species from inexpensive
PhI(OAc)2 and used it for the selective cleavage of spC–H, sp2C–
H, sp3C–H, sp3C–N and triple bonds under metal-free benign
reaction conditions. The valuable amides and ketoesters were
directly synthesized in the unprecedented general unorthodox
approach through construction of CQO and C–N/C–O bonds
with amines/alkynes and water.
9 (a) T. Wirth, M. Ochiai, A. Varvoglis, V. V. Zhdankin, G. F. Koser,
H. Tohma and Y. Kita, Hypervalent iodine: modern developments in organic
synthesis, Springer-Verlag, Berlin Heidelberg, 2003; (b) V. V. Zhdankin and
P. J. Stang, Chem. Rev., 2008, 108, 5299; (c) R. Moriarty and M. S. Tyagi,
Org. Lett., 2010, 12, 364; (d) A. Parra and S. Reboredo, Chem. – Eur. J., 2013,
19, 17244; (e) L. Xuming, Y. Liu, Z. Xiang, Z.-N. Daisy, D. Yunfei and
Z. Kang, J. Org. Chem., 2014, 79, 955; ( f ) L. Jinglei, Z.-N. Daisy, D. Jun,
D. Yunfei and Z. Kang, J. Org. Chem., 2014, 79, 1111.
10 (a) N. Singh and D. O. Jang, Org. Lett., 2007, 9, 1991; (b) M. H. Lee,
J.-S. Wu, J. W. Lee, J. H. Jung and J. S. Kim, Org. Lett., 2007, 9, 2501;
´
(c) E. Carbonell, E. Delgado-Pinar, J. Pitarch-Jarque, J. Alarcon and
´
˜
E. Garcıa-Espana, J. Phys. Chem. C, 2013, 117, 14325.
11 (a) E. Kang, Tetrahedron, 2010, 66, 1029; (b) R. N. Butler and A. G. Coyne,
Chem. Rev., 2010, 110, 6302; (c) K. Sanderson, Nature, 2011, 469, 18;
(d) K. S. Gayen, T. Sengupta, Y. Saima, A. Das, D. K. Maiti and A. Mitra,
Green Chem., 2012, 14, 1589; (e) T. Chatterjee, S. Bhadra and B. C. Ranu,
Green Chem., 2011, 13, 1837.
12 Y. N. Sum, D. Yu and Y. Zhang, Green Chem., 2013, 15, 2718.
13 (a) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417;
(b) J. F. Hartwig, Nature, 2008, 455, 314; (c) P. B. Arockiam, C. Bruneau
and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (d) S. Ghosh, S. Khamarui,
S. Gayen and D. K. Maiti, Sci. Rep., 2013, 3, 2987; (e) S. Samanta, D. Roy,
S. Khamarui and D. K. Maiti, Chem. Commun., 2014, 50, 2477.
The authors gratefully acknowledge the financial support of
DST (no. SR/S4/GC-05/2012 and SR/S1/OC-05/2012), India, and
research fellowship (SRF to SK) from CSIR, India.
Notes and references
´
1 (a) A. C. Alecio, V. d. S. Bolzani, M. C. M. Young, M. J. Kato and 14 (a) A. T. Biju, N. E. Wurz and F. Glorius, J. Am. Chem. Soc., 2010,
M. Furlan, J. Nat. Prod., 1998, 61, 637; (b) Z. Q. Yuan, D. Blomberg,
I. Sethson, K. Brickmann, K. Ekholm, B. Johansson, A. Nilsson and
J. Kihlberg, J. Med. Chem., 2002, 45, 2512; (c) Y.-M. Zhang and
C. O. Rock, J. Lipid Res., 2008, 49, 1867; (d) M. Figueroa, H. Raja,
132, 5970; (b) S. C. Pan, Beilstein J. Org. Chem., 2012, 8, 1374; (c) R. Niu,
J. Xiao, T. Liang and X. Li, Org. Lett., 2012, 14, 676; (d) T. Sengupta,
S. Khamarui, S. Samanta and D. K. Maiti, Chem. Commun., 2013,
49, 9962; (e) D. Das and D. Seidel, Org. Lett., 2013, 15, 4358.
J. O. Falkinham III, A. F. Adcock, D. J. Kroll, M. C. Wani, C. J. Pearce 15 (a) M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda and K. J. Miyamoto,
and N. H. Oberlies, J. Nat. Prod., 2013, 76, 1007.
2 (a) A. L. J. Beckwith, Synthesis of amides, in Amides, ed. J. Zabicky, John
Wiley & Sons, Ltd, 2010; (b) J. Otera and J. Nishikido, Esterification: Methods,
J. Am. Chem. Soc., 2005, 127, 12244; (b) D.-L. Mo, L.-X. Dai and X.-L.
Hou, Tetrahedron Lett., 2010, 50, 5578; (c) G. Deng and J. Luo,
Tetrahedron, 2013, 69, 5937.
Reactions, and Applications, Wiley-VCH Verlag GmbH & Co. KGaA, 2010; 16 CCDC No. of 9a: 973403.
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 384--387 | 387