Rate-accelerated nonconventional amide synthesis in water: A practical catalytic aldol-surrogate reaction

Article abstract of DOI:10.1002/anie.200604358

(Chemical Equation Presented) An aldol alternative: Cu-catalyzed hydrative amide synthesis is significantly accelerated in aqueous cosolvent systems. Under environmentally friendly conditions and with N₂ released as the single side product, a w

Full text of DOI:10.1002/anie.200604358

Angewandte
Chemie
DOI: 10.1002/anie.200604358
Hydrative Amide Synthesis
Rate-Accelerated Nonconventional Amide Synthesis in Water:
A Practical Catalytic Aldol-Surrogate Reaction**
Seung Hwan Cho and Sukbok Chang*
Dedicated to Professor Hong-Ku Shim on the occasion of his 60th birthday
The aldol reaction is a powerful method for installing b-
hydroxycarbonyl units, which are extremely versatile building
blocks in organic synthesis.[1] Although tremendous progress
has been made during the last few decades in the develop-
ment of highly stereoselective aldol reactions, they usually
rely on a similar basic strategy:the addition of enolizable
carbonyl compounds to an aldehyde or ketone in the presence
of promoters.[2] Accordingly, substrates containing labile
functional groups are not amenable under conditions for
enol formation.[3]
Scheme 1.
Recently, we reported the highly efficient Cu-catalyzed
three-component reactions of terminal alkynes, sulfonyl
azides, and amines or alcohols to afford amidines or
Table 1: Hydrative amide synthesis in various solvent systems.[a]
imidates.[4] It is believed at present that the reaction proceeds
via a common ketenimine intermediate, which is generated
from the copper-mediated intermolecular cycloaddition of
azides and alkynes followed by the release of N2.[5] On the
basis of this postulate, a novel nonconventional amide
synthesis could be realized by allowing the plausible keteni-
mine intermediate to react with water.[6] We subsequently
envisioned that application of this protocol to propargyl
alcohol substrates might lead to b-hydroxy N-sulfonamides
under mild and practical conditions. Since these components
are not easily accessed through traditional aldol processes,[7]
we anticipated that our approach would be an excellent aldol
surrogate for the preparation of these synthetically versatile
compounds. Our results are described herein (Scheme 1).[8]
In initial studies we planned to examine the feasibility of
performing the Cu-catalyzed hydrative amide synthesis in
aqueous solvent systems, as the development of organic
reactions in aqueous solvents is in strong demand these days.
Additionally, reactions are frequently observed to be faster in
aqueous solvent systems than in organic solvents.[9] Various
reaction media were first scrutinized in a test reaction of 4-
tert-butylphenylacetylene with p-toluenesulfonyl azide in the
presence of CuI catalyst and triethylamine (Table 1). We
Entry
Solvent
Conv. [%][b]
Yield [%][b]
1[c]
2
3
4
5
6
7
CHCl3
38
64
54
55
58
35
55
48
47
44
55
87
CHCl3/H2O (2:1)
CH3CN/H2O (2:1)
DMF/H2O (2:1)
tBuOH/H2O (2:1)
tBuOH/H2O (1:5)
H2O
74
>99
[a]Alkyne (0.5 mmol), sulfonyl azide (0.55 mmol), Et 3N (0.55 mmol),
and CuI (2 mol%) were stirred in the indicated solvent (1.0 mL). Ts=4-
MeC6H4SO2, DMF=N,N-dimethylformamide. [b]Conversion and yield
were determined by 1H NMR spectroscopy with 1,1,2,2-tetrachloro-
ethane as an internal standard. [c]2.5 equiv H 2O was added.
found that while the reaction in organic solvents proceeded
with moderate rates in the presence of water as a stoichio-
metric reagent (e.g. entry 1, Table 1), the use of a range of
aqueous cosolvent systems improved the conversion and
product yields to some extent (entries 2–6, Table 1). A more
dramatic rate enhancement was observed when water was
employed as the sole solvent, and the desired N-sulfonyl
amide was obtained in satisfactory yield (entry 7, Table 1).
Triethylamine was the most efficient additive, whereas the use
of other organic or inorganic bases led to decreased yields
under the otherwise identical conditions.[10]
[*]S. H. Cho, Prof. Dr. S. Chang
Center for Molecular Design and Synthesis (CMDS)
Department of Chemistry and School of Molecular Science (BK21)
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Republic of Korea)
Fax: (+82)42-869-2810
The optimized environmentally friendly protocol for the
hydrative amide synthesis in water proved to be quite general,
and a wide range of alkynes and sulfonyl azides were readily
incorporated leading to the sulfonamide product in high
yields even after simple recrystallization in most cases
E-mail: sbchang@kaist.ac.kr
[**]This research was supported by CMDS and KRF (grant KRF-2005-
015-C00248).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 3: Cu-catalyzed aldol-surrogate reactions.[a]
(Table 2). The reaction was complete usually within 1 h when
2 mol% CuI catalyst was used, and this efficiency was not
significantly affected by electronic and/or steric variation of
the reacting substrates.
Entry
1
R1
R2
H
Product
Yield [%][b]
85
Table 2: Catalytic nonconventional amide synthesis in water.[a]
4-MeC6H4
2
3
H
H
95
88
Entry
R1
R2
Yield [%][b]
1
2
3
C6H5
4-MeC6H4
4-CF3C6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
84
72
87
4
H
90
4
5
4-MeC6H4
4-MeC6H4
91
81
5
(R)-Me
Me
H
90[c]
87
6
7
8
4-MeC6H4
99
6
Me
H
7[d]
C6H5
83
C6H5
C6H5
93[c]
79[c]
[a]Alkyne (0.5 mmol), sulfonyl azide (0.55 mmol), Et 3N (0.55 mmol),
and CuI (2 mol%) were stirred in tBuOH/H2O (2:1, 1.0 mL). R4 =4-
MeC6H4 in all cases. [b]Yield of isolated product. [c]Both the propargyl
alcohol substrate and product were determined to be >96% ee. [d]H 2O
alone was used as solvent; R3 =tert-butyloxycarbonyl (Boc).
[a]Alkyne (0.5 mmol), azide (0.55 mmol), Et 3N (0.55 mmol), and CuI
(2 mol%) were stirred in in H2O (1.0 mL). [b]Yield after recrystallization.
[c]Yield after chromatography.
b-hydroxy amides occur more readily under the reaction
conditions.
An additional notable utility of this methodology was
demonstrated when acetylene gas at atmospheric pressure
was allowed to react with p-toluenesulfonyl azide and water
[Eq. (1)]. The reaction took place more smoothly in an
We applied the optimized conditions to a wide range of
propargyl alcohols bearing aryl, alkyl, and conjugated vinyl
groups with high efficiency (entries 1–4, Table 3). It is
especially noteworthy that the reaction with an enantiomer-
ically enriched propargyl alcohol proceeds without racemi-
zation to afford the product in an optically active form with
high yield (entry 5, Table 3). Additionally, tertiary propargyl
alcohols could be also included as a viable substrate type,
giving tertiary b-hydroxy amides in good yield (entry 6,
Table 3). It was interesting to observe that the same protocol
could be applied successfully to protected propargyl amines in
pure water as solvent to produce b-amino carboxylic acid
derivatives (entry 7, Table 3), which are also versatile syn-
thetic intermediates.[14]
With the developed protocol in our hands, we demon-
strated its utility further with the synthesis of a range of
synthetically valuable building blocks (Scheme 2).[15] When
the optically active propargyl alcohol (R)-1-phenyl-2-propyn-
1-ol (2) was subjected to the synthetic procedure in aqueous
cosolvent system, b-hydroxy amide 3 was isolated in excellent
yield (97%) without racemization even on a gram scale.
Subsequent protection of the free hydroxy moiety of 3 as a
silyl ether group was followed by N-methylation to provide
the key synthetic precursor 4, from which various valuable b-
hydroxycarbonyl compounds can be derived. For example,
the hydride reduction of 4 afforded aldehyde 5,[16] the AlMe3-
mediated treatment of 4 with a thiol gave thioester 6,[17] and
aqueous cosolvent system in this case, presumably owing to
the poor solubility of acetylene gas in pure water.[11] Although
the reaction with acetylene was slower that with terminal
alkynes, the desired product, N-sulfonyl acetamide, was
obtained in satisfactory yield.
We then turned our attention to utilizing propargyl
alcohol substrates in a practical aldol-surrogate procedure.[12]
We were pleased to observe that the catalytic reaction of
propargyl alcohols with p-toluenesulfonyl azide and water
efficiently produced the corresponding b-hydroxy N-sulfon-
amides in good to excellent yields (Table 3).[13] In this case, the
product yields obtained in tBuOH/H2O (2:1) were higher
than those in pure water.[10] Apparently the reaction is so
exothermic in pure water that side reactions such as
hydrolysis of azides and dehydration of initially generated
1898
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Scheme 2. Reagents and conditions: a) TsN3 (1.1 equiv), Et3N (1.1 equiv), CuI (2 mol%), tBuOH/H2O (2:1), 258C, 2 h; b) TBDMSCl (1.1 equiv),
imidazole (2.0 equiv), CH2Cl2, 258C, 5 h; c) MeI (4.0 equiv), K2CO3 (2.0 equiv), DMF, 258C, 4 h; d) DIBAL (1.1 equiv), CH2Cl2, À788C, 1.5 h;
e) nBuLi (1.5 equiv), BnSH (1.5 equiv), AlMe3 (1.5 equiv), Et2O, 08C, 1 h; f) NaOEt (1.1 equiv), EtOH, 258C, 2 h; g) TMS-acetylene (4.0 equiv),
nBuLi (4.1 equiv), BF3·Et2O (4.0 equiv), THF, À788C, 2 h; h) HF-Pyridine, CH3CN, 258C, 3 h; i) DIBAL (1.1 equiv), THF, À788C, 2 h; j) K2CO3
(2.0 equiv), MeOH, 258C, 2 h; k) CuSO4 (2.0 equiv), PPTS (0.1 equiv), acetone, 258C, 12 h; l) TsN3 (1.1 equiv), Et3N (1.1 equiv), CuI (2 mol%),
H2O, 258C, 1 h; m) 1n HCl/THF (1:1), 258C, 3 h. Bn=benzyl, DIBAL=diisobutylaluminum hydride, PPTS=pyridinium p-toluenesulfonate,
TBDMS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
[3] For instructive aspects of using carboxylic acid derivatives as
aldol donors, see:a) A. Abiko, Acc. Chem. Res. 2004, 37, 387;
b) S. E. Denmark, J. R. Heemstra, G. L. Beutner, Angew. Chem.
2005, 117, 4760; Angew. Chem. Int. Ed. 2005, 44, 4682.
[4] a) I. Bae, H. Han, S. Chang, J. Am. Chem. Soc. 2005, 127, 2038;
b) E. J. Yoo, I. Bae, S. H. Cho, H. Han, S. Chang, Org. Lett. 2006,
8, 1347; c) S. Chang, M. Lee, D. Y. Jung, E. J. Yoo, S. H. Cho,
S. K. Han, J. Am. Chem. Soc. 2006, 128, 12366.
[5] a) M. Whitting, V. V. Fokin, Angew. Chem. 2006, 118, 3229;
Angew. Chem. Int. Ed. 2006, 45, 3157; b) S.-L. Cui, X.-F. Lin, Y.-
G. Wang, Org. Lett. 2006, 8, 4517.
[6] a) S. H. Cho, E. J. Yoo, I. Bae, S. Chang, J. Am. Chem. Soc. 2005,
127, 16046; b) M. P. Cassidy, J. Raushel, V. V. Fokin, Angew.
Chem. 2006, 118, 3226; Angew. Chem. Int. Ed. 2006, 45, 3154.
[7] Recently, an elegant example of catalytic aldol reactions of
amides with aldehydes was reported:S. Saito, S. Kobayashi, J.
Am. Chem. Soc. 2006, 128, 8704.
transesterification under basic conditions resulted in ester 7
with good yields in all cases.[18] The b-O-silyl ester derivative
(7) was readily converted into the propargyl 1,3-diol 8 with
high diastereoselectivity (d.r. 93:7) in 57% yield in four
convenient steps.[19] The relative stereochemistry of the newly
generated hydroxy group in 8 was unambiguously established
by an NOE experiment after conversion to its ketal deriva-
tive.[10]
The second operation of the catalytic hydrative amide
protocol was also successfully carried out with a ketal
derivative of 8 in water, and the subsequent deketalization
afforded the b,d-dihydroxy sulfonamide 9 in 79% yield (three
steps) without racemization. It should be mentioned that this
approach can be potentially utilized as an iterative aldol
surrogate to synthesize polyhydroxy amides (e.g. 10) when the
same procedures are repeated.
[8] Trost and co-workers reported an alkyne hydrosilylation–
In summary, we have shown that Cu-catalyzed hydrative
amide synthesis is significantly accelerated in aqueous solvent
systems. Under environmentally friendly conditions and with
N2 released as the single side product, this reaction can be
applied to a wide range of propargyl alcohols and sulfonyl
azides as highly viable substrates, and b-hydroxy N-sulfona-
mides are obtained in good to excellent yields. It was also
demonstrated that the method can be applied readily in an
iterative manner to produce polyhydroxy amides; in this way
it serves as a new practical aldol-surrogate strategy.
oxidation strategy as
a selective aldol-surrogate reaction:
a) B. M. Trost, Z. T. Ball, T. Jöge, Angew. Chem. 2003, 115,
3537; Angew. Chem. Int. Ed. 2003, 42, 3415; b) B. M. Trost, Z. T.
Ball, K. M. Laemmerhold, J. Am. Chem. Soc. 2005, 127, 10028.
[9] a) C.-J. Li, Chem. Rev. 1993, 93, 2023; b) S. Kobayashi, K.
Manabe, Acc. Chem. Res. 2002, 35, 209; c) S. Narayan, J.
Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless,
Angew. Chem. 2005, 117, 3219; Angew. Chem. Int. Ed. 2005, 44,
3275; d) C.-J. Li, Chem. Rev. 2005, 105, 3095.
[10] For details, see the Supporting Information.
[11] For a recent example of using acetylene gas in organic trans-
formations, see:M. Nakamura, K. Endo, E, Nakamura, Org.
Lett. 2005, 7, 3279.
Received:October 25, 2006
[12] For recent examples of aqueous aldol reactions, see:a) T.
Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro, S.
Kobayashi, J. Am. Chem. Soc. 2003, 125, 2989; b) C. J. Rogers,
T. J. Dickerson, K. D. Janda, Tetrahedron 2006, 62, 352; c) Y.
Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya, M. Shoji,
Angew. Chem. 2006, 118, 5653; Angew. Chem. Int. Ed. 2006, 45,
5527.
[13] In a recent report Fokin et al. included one tertiary propargyl
alcohol as a viable substrate for the formation of amide (68%)
using [Cu(CH3CN)4]PF6 catalyst in the presence of sodium
ascorbate, sodium bicarbonate, and a ligating tristriazolyl amine
Published online:January 19, 2007
Keywords: b-hydroxy amides · alkynes · azides · copper · water
.
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Angew. Chem. Int. Ed. 2007, 46, 1897 –1900
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www.angewandte.org
1899

Communications
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