A mild and efficient direct α-amination of β-dicarbonyl compounds using iodosobenzene and p-toluenesulfonamide catalyzed by perchlorate zinc hexahydrate

Article abstract of DOI:10.1021/ol203358f

A direct α-amination of β-dicarbonyl compounds has been achieved by using iodosobenzene (PhIO) as an oxidant and p-toluenesulfonamide (TsNH ₂) as an aminating reagent in the presence of a catalytic amount of perchlorate zinc hexahydrate. The present amination reaction proceeds quickly at rt (<30 min needed for most tested substrates) to provide the corresponding α-N-tosylamido β-dicarbonyl compounds in high to excellent yields.

Full text of DOI:10.1021/ol203358f

ORGANIC
LETTERS
2012
Vol. 14, No. 3
832–835
A Mild and Efficient Direct r-Amination of
β-Dicarbonyl Compounds Using
Iodosobenzene and
p-Toluenesulfonamide Catalyzed
by Perchlorate Zinc Hexahydrate
Jun Yu, Shan-Shan Liu, Jian Cui, Xue-Sen Hou, and Chi Zhang*
State Key Laboratory of Elemento-Organic Chemistry, The Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
zhangchi@nankai.edu.cn
Received December 16, 2011
ABSTRACT
A direct R-amination of β-dicarbonyl compounds has been achieved by using iodosobenzene (PhIO) as an oxidant and p-toluenesulfonamide
(TsNH2) as an aminating reagent in the presence of a catalytic amount of perchlorate zinc hexahydrate. The present amination reaction proceeds
quickly at rt (<30 min needed for most tested substrates) to provide the corresponding R-N-tosylamido β-dicarbonyl compounds in high to
excellent yields.
R-Amido β-dicarbonyl compounds are versatile build-
ing blocks in organic synthesis. They not only constitute
versatile intermediates for the synthesis of various hetero-
cyclic compounds,1 peptide mimetics,2 R-amino acids and
their derivatives,3 and β-hydroxyl R-amino esters4 but
also serve as key precursors in the synthesis of a variety of
natural products5 and pharmaceuticals.6 To date, a num-
ber of methods have been developed for the synthesis of
R-amido β- dicarbonyl compounds. Examples include the
strong base-mediated acylation of the ketimine deriva-
tives of R-amino esters2b and NÀC acyl migration of the
N-tert-butoxycarbonyl-N-acylglycine ester;3b,7 the reduc-
tion of R-hydroxyimino8 and phenylazo9 β-dicarbonyl
compounds; the hydrolysis of oxazole-4-carboxylate
(1) (a) Chai, C. L. L.; Elix, J. A.; Huleatt, P. B. Tetrahedron 2005, 61,
8722–8739. (b) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron
2004, 60, 3967–3977. (c) Cohnen, E.; Dewald, R. Synthesis 1987, 566–
568. (d) Maeda, S.; Suzuki, M.; Iwasaki, T.; Matsumoto, K.; Iwasawa,
Y. Chem. Pharm. Bull. 1984, 32, 2536–2543.
(2) (a) Chang, L. L.; Yang, G. X.; McCauley, E.; Mumford, R. A.;
Schmidt, J. A.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 2008, 18,
1688–1691. (b) Singh, J.; Gordon, T. D.; Earley, W. G.; Morgan, B. A.
Tetrahedron Lett. 1993, 34, 211–214.
(3) (a) Nemoto, T.; Harada, T.; Matsumoto, T.; Hamada, Y. Tetra-
hedron Lett. 2007, 48, 6304–6307. (b) Makino, K.; Okamoto, N.; Hara,
O.; Hamada, Y. Tetrahedron: Asymmetry 2001, 12, 1757–1762. (c)
Genet, J. P.; Pinel, C.; Mallart, S.; Juge, S.; Thorimbert, S.; Laffitte,
J. A. Tetrahedron: Asymmetry 1991, 2, 555–567.
(5) (a) Miyake, F.; Hashimoto, M.; Tonsiengsom, S.; Yakushijin, K.;
Horne, D. A. Tetrahedron 2010, 66, 4888–4893. (b) Labeeuw, O.;
Phansavath, P.; Genet, J. P. Tetrahedron: Asymmetry 2004, 15, 1899–
1908.
^
(6) (a) Phansavath, P.; Duprat de Paule, S.; Ratovelomanana-Vidal,
^
V.; Genet, J.-P. Eur. J. Org. Chem. 2000, 3903–3907. (b) Coulon, E.;
~
^
Cristina Cano de Andrade, M.; Ratovelomanana-Vidal, V.; Genet, J.-P.
Tetrahedron Lett. 1998, 39, 6467–6470. (c) Schmidt, U.; Leitenberger,
V.; Griesser, H.; Schmidt, J.; Meyer, R. Synthesis 1992, 1248–1254.
(7) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39, 5537–
5540.
(4) (a) Maeda, T.; Makino, K.; Iwasaki, M.; Hamada, Y. Chem.;
Eur. J. 2010, 16, 11954–11962. (b) Seashore-Ludlow, B.; Villo, P.;
€
Hacker, C.; Somfai, P. Org. Lett. 2010, 12, 5274–5277. (c) Makino,
(8) Wiley, R. H.; Borum, O. H. J. Am. Chem. Soc. 1948, 70, 1666.
(9) Bolhofer, W. A. J. Am. Chem. Soc. 1952, 74, 5459–5461.
(10) (a)Suzuki,M.;Iwasaki,T.;Miyoshi,M.;Okumura,K.;Matsumoto,
K. J. Org. Chem. 1973, 38, 3571–3575. (b) Suzuki, M.; Iwasaki, T.;
Matsumoto, K.; Okumura, K. Synth. Commun. 1972, 2, 237–242.
K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784–5785. (d)
€
Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J.-P.
€
Chem. Commun. 2004, 1296–1297. (e) Mordant, C.; Dunkelmann, P.;
Ratovelomanana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem. 2004, 3017–
3026.
r
10.1021/ol203358f
Published on Web 01/19/2012
2012 American Chemical Society

derivatives;10 and NÀH insertion of metal carbene.1b,11
However, these methods suffer from some disadvantages
such as the use of a strong base, inaccessibility of the
substrates, and employment of a multistep synthesis.
Obviously, the direct R-amination of the readily available
β-dicarbonyl compounds is more convenient and efficient
for the synthesis of R-amido β-dicarbonyl compounds.
However, to our knowledge, this strategy has received
little attention and there are only two examples of direct
R-amination of β-dicarbonyl compounds. One is the
insertion reaction of in situ generated (ethoxycar-
bonyl)nitrene at the R-position of β-dicarbonyl com-
pounds, but in this case, the yield of the desired product
is low to moderate.12 Another is the conjugate addi-
tions of β-dicarbonyl compounds to azodicarboxylates.13
Herein, as part of our continuous investigations on oxi-
dation reactions induced by hypervalent iodine re-
agents,14 we report a mild and efficient method for the
direct and fast R-amination of β-dicarbonyl compounds
using PhIO as the oxidant and TsNH2 as the aminating
reagent in the presence of a catalytic amount of perchlo-
rate zinc hexahydrate.
10 min (entry 4). Other Lewis acids including Yb(OTf)3
4H2O, Mg(NO3)2 6H2O, and CuSO4 were also checked,
3
3
but none of them showed superior results compared
with Zn(ClO4)2 6H2O (entries 5À7 vs entry 4). Results
3
of the screening study of the amount of Zn(ClO4)2 6H2O
3
(Table 1, entries 8À12) indicated that 0.1 equiv of
Zn(ClO4)2 6H2O was sufficient for the completion of
3
Table 1. Optimization of the Reaction Conditionsa
catalyst
(equiv)
time
yield
(%)b
entry
solvent
(min)
1
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
2 h
20
10
10
10
7 h
7 h
10
10
10
10
10
10
10
10
10
20
48
56
81
86
69
45c
62d
86
85
87
85
67
78
83
50
50
50
2
BF3 Et2O(1.5)
3
3
LiClO4 (1.5)
4
Zn(ClO4)2 6H2O(1.5)
3
In our initial study, the direct amination of ethyl
benzoylacetate (1a) was examined using 1.5 equiv of PhIO
and 1.5 equiv of TsNH2 in dichloromethane at rt. It was
found that the reaction produced a complex mixture after
2 h and the expected aminated product ethyl 3-oxo-3-
phenyl-2-(tosylamino) propanoate (2a) was obtained
in only 48% yield (Table 1, entry 1). To improve the
efficiency of the reaction, several Lewis acids were tried
which were believed to be capable of activating both the
5
Yb(OTf)3 4H2O (1.5)
3
6
Mg(NO3)2 6H2O(1.5)
3
7
CuSO4(1.5)
8
Zn(ClO4)2 6H2O (0.7)
3
3
3
3
3
3
3
3
9
Zn(ClO4)2 6H2O (0.5)
10
11
12
13
14
15
16
17
Zn(ClO4)2 6H2O (0.25)
Zn(ClO4)2 6H2O(0.1)
Zn(ClO4)2 6H2O (0.05)
Zn(ClO4)2 6H2O(0.1)
Zn(ClO4)2 6H2O(0.1)
CH3CN
CH3CCl3
THF
hypervalent iodine reagent and the substrate. BF3 Et2O,
Zn(ClO4)2 6H2O(0.1)
3
a normally used Lewis acid to activate PhIO, was first
tried, and the reaction afforded 2a in a slightly improved
yield (entry 2). The use of LiClO4 greatly facilitated the
reaction, which gave 2a in 81% yield within a very short
reaction time of 10 min (entry 3). The employment of
Zn(ClO4)2 6H2O(0.1)
3
3
Zn(ClO4)2 6H2O(0.1)
DMF
a The reaction was conducted using 0.5 mmol of 1a. b Isolated yield.
c The conversion of 1a is 67%. d The conversion of 1a is 82%.
Zn(ClO4)2 6H2O led to a more clean reaction, which
produced 2a in the highest yield of 86% also within
3
the reaction. When chloroform and acetonitrile were used
as the solvent, 2a was obtained in a slightly lower yield
compared with that using dichloromethane (entries 13À
14 vs entry 11). Other solvents such as 1,1,1-trichloro-
ethane, THF, and DMF were all less effective (entries
15À17 vs entry 11). Further investigation indicated that
the use of TsNH2 as the aminating reagent was essential
to the reaction. When methanesulfonamide was em-
ployed, the reaction provided the corresponding amina-
tion product in a low yield (38% after 30 min). As for
benzamide and acetamide, no desired amination product
was obtained from the reactions.
With the optimized conditions in hand (Table 1, entry 11),
we then investigated the substrate scope of this method
(Scheme 1). The methyl, benzyl, tert-butyl, and cinna-
myl benzoylacetate were all efficiently transformed to
their corresponding R-N-tosylamido products 2bÀ2e
in high to excellent yields. Substrates bearing either
electron-donating or -withdrawing substituents at the
para or meta positions of the phenyl ring of benzoyl
moiety were also smoothly converted to the expected
(11) (a) Bertelsen, S.; Nielsen, M.; Bachmann, S.; Jørgensen, K. A.
Synthesis 2005, 2234–2238. (b) Honey, M. A.; Blake, A. J.; Campbell,
I. B.; Judkins, B. D.; Moody, C. J. Tetrahedron 2009, 65, 8995–9001.
(12) (a) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Tetrahedron Lett. 2001, 42, 1171–1173. (b) Felice, E.; Fioravanti, S.;
Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1999, 40, 4413–4416.
(13) (a) Yadav, J. S.; Reddy, B. V. S.; Venugopal, C.; Padmavani, B.
~
Tetrahedron Lett. 2004, 45, 7507–7509. (b) Meseguer, M.; Moreno-Manas,
M.; Vallribera, A. Tetrahedron Lett. 2000, 41, 4093–4095. (c) Nelson, J. H.;
Howells, P. N.; Delullo, G. C.; Landen, G. L. J. Org. Chem. 1980, 45, 1246–
1249. (d) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452–
6453. (e) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420–
2421. (f) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 1367–1369. (g) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 8120–8121. (h) Terada, M.; Nakano, M.; Ube, H. J.
Am. Chem. Soc. 2006, 128, 16044–16045. (i) Kang, Y. K.; Kim, D. Y.
Tetrahedron Lett. 2006, 47, 4565–4568.
(14) (a) Zhao, X.-F.; Zhang, C. Synthesis 2007, 551–557. (b) Li,
X.-Q.; Zhao, X.-F.; Zhang, C. Synthesis 2008, 2589–2593. (c) Li, X.-Q.;
Zhang., C. Synthesis 2009, 1163–1169. (d) Yu, J.; Zhang, C. Synthesis
2009, 2324–2328. (e) Li, X.-Q.; Wang, W.-K.; Zhang, C. Adv. Synth.
Catal. 2009, 351, 2342–2350. (f) Li, X.-Q.; Wang, W.-K.; Han, Y.-X.;
Zhang, C. Adv. Synth. Catal. 2010, 352, 2588–2598. (g) Yu, J.; Tian, J.;
Zhang, C. Adv. Synth. Catal. 2010, 352, 531. (h) Cui, L.-Q.; Liu, K.;
Zhang, C. Org. Biomol. Chem. 2011, 9, 2258–2265. (i) Cui, L.-Q.; Dong,
Z.-L.; Liu, K.; Zhang, C. Org. Lett. 2011, 13, 6488–6491.
Org. Lett., Vol. 14, No. 3, 2012
833

pyran-2,4(3H)-dione, the present system produced their
corresponding iodonium ylides in 83% yield for both.16
Further investigation showed that the formation of iodo-
nium ylide product 3u came from the background reac-
tion of 1u with PhIO (Scheme 2, eq 2). And the addition of
Scheme 1. Substrate Scope of R-Amination of β-Dicarbonyl
Compoundsa
a catalytic amount of Zn(ClO4)2 6H2O (10 mol %) could
greatly enhance the reaction rate and therefore shorten
the reaction time to 10 min still with an 80% yield of 3u .
3
Scheme 2. Reactions of Dimedone with PhIO
a The reaction was carried out using 0.5 mmol of β-dicarbonyl
compounds. bThe reaction was carried out at À10 °C using 1.5 equiv
Furthermore, the tosyl group could be readily removed
from 2a upon treatment with MeSO3H in TFA/thioani-
sole at rt to give the detosylation product 4a in an
excellent yield (Scheme 3).15a
of Zn(ClO4)2 6H2O.
3
amination products 2fÀ2j in good to excellent yields
within 30 min. Other aromatic ring systems such as
naphthalene, furan, thiophene, and pyridine were all well
tolerated under the reaction conditions as indicated by
the successful transformation of the substrates to the
products 2kÀ2n. As for aliphatic β-keto esters, their
corresponding R-aminated products 2o and 2p were
obtained in moderate to good yields. Two β-diketones
were also smoothly R-aminated to give 2q and 2r in
87% and 65% yields respectively. A β-ketoamide, N,N-
dimethyl-3-oxobutanamide, was also examined, which
afforded the expected amination product 2s in 80% yield
within 10 min. R-Aminophosphonic acids and their phos-
phonate display a variety of intriguing biological proper-
ties and thus have found broad applications in the field of
modern medicine and agriculture.15 To demonstrate the
further synthetic utility of this amination system, a β-
ketophosphonate was then tested. It was found that the
reaction successfully provided the desired R-N-tosylamido
phosphonate 2t in 87% yield within 5 min.
Scheme 3. Detosylation of 2a
To explore the mechanism, some control experiments
were carried out (Scheme 4). In the amination reaction,
perchloric acid may be generated from Zn(ClO4)2 6H2O.
3
To check whether this Brønsted acid promotes the reac-
tion, 1a was treated with 1.5 equiv of PhIO and TsNH2 in
the presence of 0.2 equiv of HClO4 (utmost amount
generated in situ from 0.1 equiv of Zn(ClO4)2) in CH2Cl2
at rt. The reaction afforded 2a in only 15% yield after 10
min. Hence, HClO4 could not facilitate the amination
reaction. Since cyclic dicarbonyl compounds like 1u were
transformed into their corresponding iodonium ylides,
iodonium ylide was hypothesized as the intermediate in
the present amination reaction. To check this possibility,
iodonium ylide 3a17 was prepared and subjected to
TsNH2 with the catalytic amount of Zn(ClO4)2. It was
found that no desired amination product was observed
while a tricarbonyl compound 5a was provided in 34%
yield. Therefore, the intermediacy of 3a in the amination
reaction was excluded (Scheme 4, eq 3). On the other
hand, when PhIO was treated with TsNH2 in the presence
Notably, as for the cyclic β-diketone dimedone (1u)
and a cyclic β-keto ester 6,6-dimethyldihydro-2H-
(15) (a) Nakamura, S.; Hayashi, M.; Hiramatsu, Y.; Shibata, N.;
Funahashi, Y.; Toru, T. J. Am. Chem. Soc. 2009, 131, 18240–18241. (b)
ꢀ~
Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65,
17–49. (c) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J. Med.
Chem. 2003, 46, 2641–2655. (d) Smith, W. W.; Bartlett, P. A. J. Am.
Chem. Soc. 1998, 120, 4622–4628. (e) Alonso, E.; Alonso, E.; Solıs, A.;
Pozo, C. Synlett 2000, 698–700. (f) Atherton, F. R.; Hassall, C. H.;
Lambert, R. W. J. Med. Chem. 1986, 29, 29–40.
(16) (a) Moriarty, R. M.; Tyagi, S.; Lvanov, D.; Constantinescu, M.
€
J. Am. Chem. Soc. 2008, 130, 7564–7565. (b) Muller, P.; Allenbach,
Y. F.; Ferri, M.; Bernardinelli, G. ARKIVOC 2003, vii, 80–95.
(17) Schank, K.; Lick, C. Synthesis 1983, 392–395.
Org. Lett., Vol. 14, No. 3, 2012
834

Scheme 4. Control Experiments
Scheme 5. Proposed Mechanism
of Zn(ClO4)2 6H2O in CH2Cl2 at rt for 10 min, N-
3
tosyliminoiodane (PhIdNTs) could be obtained in 63%
yield. To verify whether PhIdNTs was the real agent
responsible for the formation of amination product, PhId
NTs was used directly as the oxidant replacing PhIO in the
amination reaction. It was found that the reaction produced
the aminated product 2a in 80% yield within 5 min
(Scheme 4, eq 4). This fact implied that the present amina-
tion reaction might be mediated by the in situ generated
PhIdNTs.18 To check whether a nitrene intermediate was
involved as commonly reported in the reactions using
PhIdNTs,19 styrene was used to react with PhIdNTs in
Scheme 6. Explanation for the Formation of 3u
the presence of Zn(ClO4)2 6H2O. NMR analysis of the
3
reaction mixture revealed that no aziridine product was
formed, which meant that a nitrene intermediate could not
be generated when mixing PhIdNTs and Zn(ClO4)2.
Based ontheaboveresults, aplausiblemechanismforthis
direct and fast R-amination reaction of acyclic β-dicarbonyl
compounds is proposed in Scheme 5. First, PhIO reacted
with TsNH2 to form PhIdNTs. Then, the electrophilic
addition of PhIdNTs to the enol form of linear β-dicarbo-
Moriarty et al.21 Therefore intermediate B was prone to R-H
elimination to produce 3u (Scheme 6).
In summary, we have developed a mild and efficient
method for the direct amination of readily available β-dicar-
bonyl compounds employing commercially available PhIO as
the oxidant and TsNH2 as the aminating reagent catalyzed by
Zn(ClO4)2 6H2O. It is the first time that the activation of
PhIO using Zn(ClO4)2 6H2O with high efficiency is reported,
3
nyl compounds in the presence of Zn(ClO4)2 6H2Ogavethe
key intermediates A, which underwent reductive elimina-
tion20 to provide R-N-tosylamido β-dicarbonyls. The pre-
3
3
which makes the present amination reaction proceed quickly
at rt to provide the aminated products in high to excellent
yields. Also, the reactions are tolerant of a range of functional
groups and thus effective for a broad scope of substrates.
Considering the mildness and efficiency of the present meth-
od, the ready availability of β-dicarbonyl compounds, PhIO,
and TsNH2, this method should be an attractive approach to
synthesize R-amido β-dicarbonyl compounds.
sence of Zn(ClO4)2 6H2O not only activated PhIO but also
promoted the formation of enol of β-dicarbonyl com-
pounds which made the reaction proceed quickly.
3
When cyclic dicarbonyl compound 1u was treated with
PhIdNTs, iodonium ylide 3u was produced in 80% yield, the
same product as that from the standard amination reaction
using PhIOÀTsNH2 (Scheme 2, eq 1). It was believed that a
similar intermediate B to A was formed when 1u reacted
with PhIdNTs. Due to the contribution of the intramo-
lecular secondary bondings between two carbonyls and an
iodine(III) center, the cyclic iodonium ylide 3u was more
stable than the linear one. The same idea was also given by
Acknowledgment. This work was financially supported
by The National Natural Science Foundation of China
(No. 20872064), Program for New Century Excellent
Talents in University (NCET-07-0461), and the Tianjin
Natural Science Foundation (09JCYBJC05900).
Supporting Information Available. The experimental
procedures, the characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢁ
(18) (a) Dauban, P.; Saniere, L.; Rarrade, A.; Dood, R. H. J. Am.
Chem. Soc. 2001, 123, 7707–7708. (b) Duran, F.; Leman, L.; Ghini, A.;
Burton, G.; Dauban, P.; Dodd, R. H. Org. Lett. 2002, 4, 2481–2483.
(19) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem.
SOC. 1994, 116, 2742–2753. (b) Kohmura, Y.; Katsuki, T. Tetrahedron
€
Lett. 2001, 42, 3339–3342. (c) Muller, P.; Fruit, C. Chem. Rev. 2003, 103,
2905–2919.
(21) (a) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903.
(b) Alcock, N. W.; Bozopoulos, A. P.; Hatzigrigoriou, E.; Varvoglis,
A. Acta Crystallogr. 1990, 46, 1300–1303.
(20) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052–9070.
Org. Lett., Vol. 14, No. 3, 2012
835