One-pot procedure for the introduction of three different bonds onto terminal alkynes through N-sulfonyl-1,2,3-triazole intermediates

Article abstract of DOI:10.1002/anie.201209603

Triple strike: Copper(I) and rhodium(II) complexes can cooperate to facilely convert terminal alkynes into α-allyl-α-amino ketones through triazole intermediates. This synthetic process achieves the regioselective multifunctionalization of terminal alkyne

Full text of DOI:10.1002/anie.201209603

Angewandte
Chemie
DOI: 10.1002/anie.201209603
Multifunctional Reactions
One-Pot Procedure for the Introduction of Three Different Bonds onto
Terminal Alkynes through N-Sulfonyl-1,2,3-Triazole Intermediates**
Tomoya Miura,* Takamasa Tanaka, Tsuneaki Biyajima, Akira Yada, and Masahiro Murakami*
Alkynes constitute a fundamental class of organic compounds
À
and a variety of alkynes can be readily synthesized by C C
bond-forming reactions of nucleophilic ethynyl species with
electrophiles. The resulting alkynes provide versatile plat-
forms for synthetic transformations.[1] In particular, a [3+2]
dipolar cycloaddition reaction with azides to give triazoles has
attracted much attention in the last decade.[2] Recent studies
by the groups of Fokin and Gevorgyan, as well as our own,
have disclosed that the resulting triazoles could act as
precursors for reactive a-imino metal carbenoid species,
which can subsequently couple with nitriles,[3] alkynes,[4]
alkenes,[5] and alkanes.[6] A semi-pinacol rearrangement
reaction is induced by the electrophilic nature of the
a-imino carbenoid species.[7] Nucleophiles such as water[8]
and arylboronic acids[9] also add to the electrophilic a-imino
carbenoid species. The reaction with water regioselectively
introduces amino and hydroxy groups in juxtaposition onto
terminal alkynes. On the other hand, it has been reported by
the groups of Wood[10] and Davies[11] that [3,3]- and [2,3]-
sigmatropic rearrangements become feasible when a-diazo
carbonyl compounds are reacted with allylic alcohols in the
presence of rhodium(II) catalysts. Their studies prompted us
to use allylic alcohols instead of water in the reaction of
mixture was further stirred at 1008C for 30 min, and then
cooled. Isolation by preparative thin-layer chromatography
furnished 2-allyl-2-tosylamino-1-phenylethanone (3aa) in
74% yield based on 1a. Thus, terminal alkynes were
regioselectively multifunctionalized with the formation of
À
À
À
C O, C N, and C C bonds in one pot. The outcome of this
process stands in contrast to that of the reaction reported by
Chang et al., which used the same substrates, but a different
catalyst system (Scheme 1).[14,15]
À
triazoles in pursuit of further functionalization with C C
bond formation through sigmatropic rearrangement. Herein,
we report an extremely facile one-pot process to convert
terminal alkynes into a-allyl-a-amino ketones through tria-
zoles and allyl vinyl ether intermediates. During the one-pot
process, three different bonds are regioselectively introduced
[12]
ꢀ
onto the C C bond.
Phenylethyne (1a), tosyl azide (TsN3; 1.0 equiv), allyl
alcohol (2a; 1.5 equiv), CuTC (10 mol%; TC = thiophene-2-
carboxylate), Rh2(tBuCO2)4 (1.0 mol%), 3ꢀ molecular sieves
(MS 3ꢀ),[13] and toluene (2 mL) were put in a reaction vessel
[Eq. (1)]. The reaction mixture was simply stirred at room
temperature for 6 h, whereupon NMR analysis showed that
both 1a and tosyl azide were consumed. Next, the reaction
Scheme 1. Two pathways of the reaction of phenylethyne (1a) with
tosyl azide and allyl alcohol (2a).
Scheme 2 shows the proposed mechanism of the one-pot
process, which consists of three steps. The first step is a [3+2]
cycloaddition reaction of 1a with tosyl azide, which has been
reported by the groups of Fokin, Sharpless, and Chang to
[*] Dr. T. Miura, T. Tanaka, T. Biyajima, Dr. A. Yada,
Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
E-mail: tmiura@sbchem.kyoto-u.ac.jp
murakami@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
[**] This work was supported in part by MEXT (Grant-in-Aid for
Scientific Research on Innovative Area Nos. 22105005 and
22106520, Young Scientists (A) No. 23685019), Takeda Science
Foundation, and Asahi Glass Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209603.
Scheme 2. Proposed mechanism for the rhodium(II)-catalyzed synthe-
sis of 3aa from 1a, tosyl azide, and 2a.
Angew. Chem. Int. Ed. 2013, 52, 3883 –3886
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3883

.
Angewandte
Communications
occur at room temperature with copper(I) catalysis.[16] The
resulting N-sulfonyl-1,2,3-triazole 4a engages in the second
step when heated to 1008C. The second step, which forms C
from 4a, consists of a ring–chain tautomerization[17] and
a subsequent rhodium(II)-catalyzed reaction with allyl alco-
hol 2a.[18] The a-diazo imine 4a’, which is formed from 4a by
the ring–chain tautomerization, reacts with the rhodium(II)
dimer to afford a-imino rhodium(II) carbenoid A, along with
the release of molecular nitrogen. Compound 2a then adds to
the electrophilic carbene center of A to furnish zwitterionic
intermediate B. The anionic rhodium releases an electron
pair, which eventually results in the imine moiety abstracting
a proton from the oxygen. Thus, (Z)-allyl vinyl ether C is
stereoselectively formed. The third and final step is a Claisen-
type [3,3]-sigmatropic rearrangement, which proceeds via six-
membered chairlike transition state D, to give product 3aa.
Although the copper(I) and rhodium(II) catalysts coexist in
the reaction media, they scarcely interfered with each other in
playing their catalytic roles in the cycloaddition and carbene
reactions.
tosylamino-1-phenylethanone [3ac; Eq. (3)]. These results
À
confirmed that the C C bond was formed regioselectively at
the g position of allylic alcohols, which supports the involve-
ment of a [3,3]-sigmatropic rearrangement in the mechanism.
The g-selectivity even led to the production of a-allenyl-
substituted compound 3ad from propargyl alcohol (2d)
[Eq. (4)].
Various other terminal alkynes 1 were subjected to
reaction with 2a to demonstrate the generality of the one-
pot process (Table 1). The corresponding products, which
include alkyl-substituted ketones, were obtained in yields
ranging from 53% to 80%.
Table 1: Synthesis of a-allyl-a-amino ketones 3 from terminal alkynes 1,
tosyl azide, and allyl alcohol (2a) in one pot.[a]
The stereochemical aspects were also investigated. The
configuration of the double bond of product 3ae, which was
produced from a-substituted allylic alcohol 2e, was obtained
with an exclusively E orientation [Eq. (5)]. This outcome is
well accounted for by assuming six-membered chairlike
transition state D’ with an a-substituent at the pseudo-
equatorial position.
Entry
1
R1
3
Yield [%][b]
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1 f
1g
1h
1i
4-Me-C6H4
4-MeO-C6H4
4-CF3-C6H4
4-EtO2C-C6H4
3-thienyl
n-hexyl
iso-butyl
(CH2)4OBz
(CH2)4N(Phth)
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
80
73
69
58[c]
72
53[d]
64[d]
66[d]
72[d]
1j
3ja
[a] Conditions: 1 (0.2 mmol), TsN3 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol,
1.5 equiv), CuTC (20 mmol), Rh2(tBuCO2)4 (2 mmol), and MS 3ꢀ (40 mg)
in toluene (2 mL) were stirred at RT for 6 h, then at 1008C for 30 min
unless otherwise noted. [b] Yield of isolated product (average of 2 runs).
[c] The reaction was stirred at RT for 12 h. [d] Using Rh2(tBuCO2)4
(5 mmol) in CHCl3 (0.5 mL), then at 1008C for 1 h under microwave
(MW) irradiation. Bz=benzoyl, Phth=phthaloyl.
The use of an E/Z crotyl alcohol resulted in moderate
stereospecificity [Eqs. (6) and (7)]. These results implied that
the initially formed Z isomer, which corresponds to C in
The second and third steps were examined in more detail
using isolated triazole 4a. Thus, a mixture of 4a and
a-disubstituted allylic alcohol 2b (1.5 equiv) in toluene was
heated at 1008C for 30 min in the presence of Rh2(tBuCO2)4
(1.0 mol%) and MS 3ꢀ. Chromatographic purification
afforded
2-(3,3-dimethylallyl)-2-tosylamino-1-phenyletha-
none [3ab; Eq. (2)]. On the other hand, the reaction of
g-disubstituted allylic alcohol 2c gave 2-(1,1-dimethylallyl)-2-
3884
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3883 –3886

Angewandte
Chemie
8). Thus, the reaction was highly general with respect to the R1
and R2 groups.
Whereas the reaction of unsubstituted triazole 4l was
sluggish (Table 2, entry 4), 4,5-disubstituted triazole 4m was
reactive enough to furnish the product 3ma, which possesses
a quaternary a-carbon in 79% yield [Eq. (9)].[19]
Scheme 2, partially isomerized to the E isomer before the
[3,3]-sigmatropic rearrangement.
When (S)-1-methyl-2-propen-1-ol (2g) was used, a good
level of chirality transfer was observed [Eq. (8)].
The synthetic utility of a-allyl-a-amino ketones was
exemplified by further transformation [Eq. (10)]. Allylation
of 3aa with allyl bromide and subsequent ring-closing meta-
thesis using the 2nd generation Grubbs catalyst afforded 3,4-
dehydropiperidine 6.
The substrate scope of triazoles 4 was also examined in the
reaction with the allyl alcohol (2a; Table 2). Triazoles 4a and
4g, which are substituted with 4-phenyl- and 4-(n-hexyl)
groups, respectively, reacted to afford the corresponding
Table 2: RhII-catalyzed denitrogenative reaction of 4-substituted 1-(N-
sulfonyl)-1,2,3-triazoles 4 with 2a.[a]
In conclusion, we have developed an extremely facile
method for the synthesis of a-substituted a-amino ketones,
which are often key substructures of bioactive compounds,[20]
as well as synthetic intermediates for a-amino alcohols,[21]
both in general and in various natural products.[22] Terminal
alkynes are functionalized with three different bonds using
sulfonyl azides and allylic alcohols, which would otherwise
require multiple synthetic steps. High generality with respect
to the terminal alkyne substituents, as well as a good level of
chirality transfer from chiral allylic alcohols, are observed.
The three starting materials are readily accessible, even from
commercial sources. This one-pot synthetic method is envi-
ronmentally benign, as the only waste generated throughout
the entire process is molecular nitrogen.
Entry
4
R1
R2
3
Yield [%][b]
1
2
3
4
5
6
7
8
4a
4g
4k
4l
4n
4o
4p
4q
Ph
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
Me
3aa
3ga
3ka
3la
3na
3oa
3pa
3qa
91
n-hexyl
OEt
H
Ph
Ph
77[c]
75[d]
13[e]
91
93
94
94
Ph
Ph
(CH2)2SiMe3
[a] Conditions: 4 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv), Rh2(tBuCO2)4
(2 mmol), and MS 3ꢀ (40 mg) in toluene (2 mL) were heated at 1008C for
30 min, unless otherwise noted. [b] Yield of isolated product (average of
2 runs). [c] Using Rh2(tBuCO2)4 (5 mmol) and MS 3ꢀ (10 mg) in CHCl3
(0.5 mL) for 1 h under MW irradiation. [d] Using Rh2(tBuCO2)4 (1 mmol)
Experimental Section
1
and 2a (1.0 mmol, 5.0 equiv). [e] Yield determined by H NMR spec-
Typical procedure for the one-pot reaction of terminal alkynes with
allylic alcohols [Eq. (1)]: 1a (20.4 mg, 0.2 mmol), TsN3 (39.4 mg,
0.2 mmol; Ts = p-toluenesulfonyl), 2a (17.4 mg, 0.3 mmol), CuTC
(3.8 mg, 20 mmol), Rh2(tBuCO2)4 (1.2 mg, 2 mmol), MS 3ꢀ (40 mg),
and toluene (2 mL) were added to an oven-dried 4 mL-vial equipped
with a stir bar. The vial was capped with Teflon film. The reaction
mixture was stirred at room temperature for 6 h, and then, heated at
1008C for 30 min. Afterwards, the reaction mixture was cooled and
passed through a cotton stopper with CH2Cl2, the filtrate was
concentrated under reduced pressure. The residue was purified by
preparative thin-layer chromatography (CHCl3/ethyl acetate 25:1) to
give product 3aa as a white solid (48.8 mg, 0.15 mmol, 74%).
troscopy.
products 3aa and 3ga in 91% and 77% yields, respectively
(entries 1 and 2). The yield of 3ga was slightly lower because
b-hydride migration occurred with the rhodium carbenoid
intermediate, which corresponds to A in Scheme 2, to give
a,b-unsaturated N-tosyl imine as a by-product,[7] as was the
case with the one-pot reaction (Table 1, entry 6). 4-Ethoxy-
substituted triazole 4k, which was prepared from ethoxye-
thyne, afforded a-amino acid derivative 3ka (Table 2,
entry 3). As for the sulfonyl groups, not only arylsulfonyl
groups, but also alkylsulfonyl groups were suitable (entries 5–
Received: November 30, 2012
Published online: February 25, 2013
Angew. Chem. Int. Ed. 2013, 52, 3883 –3886
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3885

.
Angewandte
Communications
[13] In the absence of 3ꢀ molecular sieves, a small amount of 2-
tosylamino-1-phenylethanone (> 5%) was formed as a by-
product by hydration.
[14] E. J. Yoo, I. Bae, S. H. Cho, H. Han, S. Chang, Org. Lett. 2006, 8,
1347.
Keywords: allylation · copper · rhodium · terminal alkynes ·
triazoles
.
[1] R. C. Larock, Comprehensive Organic Transformations:
A
[15] For selected reviews on multicatalyst cooperative systems, see:
a) J. M. Lee, Y. Na, H. Han, S. Chang, Chem. Soc. Rev. 2004, 33,
302; b) J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001; c) L. M. Ambrosini, T. H. Lambert,
ChemCatChem 2010, 2, 1373; for recent examples, see: d) M.
Asikainen, N. Krause, Adv. Synth. Catal. 2009, 351, 2305; e) G.
Dong, P. Teo, Z. K. Wickens, R. H. Grubbs, Science 2011, 333,
1609; f) B. M. Trost, X. Luan, J. Am. Chem. Soc. 2011, 133, 1706;
g) J. Panteleev, L. Zhang, M. Lautens, Angew. Chem. 2011, 123,
9255; Angew. Chem. Int. Ed. 2011, 50, 9089; h) N. D. Litvinas,
P. S. Fier, J. F. Hartwig, Angew. Chem. 2012, 124, 551; Angew.
Chem. Int. Ed. 2012, 51, 536; i) D. Fuchs, G. Rousseau, L. Diab,
U. Gellrich, B. Breit, Angew. Chem. 2012, 124, 2220; Angew.
Chem. Int. Ed. 2012, 51, 2178.
[16] a) E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin, K. B.
Sharpless, S. Chang, Angew. Chem. 2007, 119, 1760; Angew.
Chem. Int. Ed. 2007, 46, 1730; b) J. Raushel, V. V. Fokin, Org.
Lett. 2010, 12, 4952; c) Y. Liu, X. Wang, J. Xu, Q. Zhang, Y.
Zhao, Y. Hu, Tetrahedron 2011, 67, 6294.
[17] a) P. Grꢁnanger, P. V. Finzi, Tetrahedron Lett. 1963, 4, 1839;
b) R. E. Harmon, F. Stanley, Jr., S. K. Gupta, J. Johnson, J. Org.
Chem. 1970, 35, 3444; c) G. Himbert, D. Frank, M. Regitz, Chem.
Ber. 1976, 109, 370.
[18] For the addition of alcohols to rhodium carbenoids, see: a) R.
Paulissen, H. Reimlinger, E. Hayez, A. J. Hubert, P. Teyssiꢂ,
Tetrahedron Lett. 1973, 14, 2233; b) P. Bulugahapitiya, Y.
Landais, L. Parra-Rapado, D. Planchenault, V. Weber, J. Org.
Chem. 1997, 62, 1630; c) Z. Li, V. Boyarskikh, J. H. Hansen, J.
Autschbach, D. G. Musaev, H. M. L. Davies, J. Am. Chem. Soc.
2012, 134, 15497, and references therein.
[19] For the synthesis of 4,5-disubstituted 1-(N-sulfonyl)-1,2,3-tria-
zoles, see: M. E. Meza-AviÇa, M. K. Patel, C. B. Lee, T. J. Dietz,
M. P. Croatt, Org. Lett. 2011, 13, 2984.
Guide to Functional Group Preparations, Wiley-VCH, New
York, 1999, pp. 563 – 606.
[2] For recent reviews, see: a) J. E. Hein, V. V. Fokin, Chem. Soc.
Rev. 2010, 39, 1302; b) A. Qin, J. W. Y. Lam, B. Z. Tang,
Macromolecules 2010, 43, 8693; c) D. Astruc, L. Liang, A.
Rapakousiou, J. Ruiz, Acc. Chem. Res. 2012, 45, 630.
[3] a) T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan, V. V.
Fokin, J. Am. Chem. Soc. 2008, 130, 14972. For a review on
transannulation reactions of triazoles, see: b) B. Chattopadhyay,
V. Gevorgyan, Angew. Chem. 2012, 124, 886; Angew. Chem. Int.
Ed. 2012, 51, 862.
[4] a) T. Miura, M. Yamauchi, M. Murakami, Chem. Commun. 2009,
1470; b) B. Chattopadhyay, V. Gevorgyan, Org. Lett. 2011, 13,
3746.
[5] a) S. Chuprakov, S. W. Kwok, L. Zhang, L. Lercher, V. V. Fokin,
J. Am. Chem. Soc. 2009, 131, 18034; b) N. Grimster, L. Zhang,
V. V. Fokin, J. Am. Chem. Soc. 2010, 132, 2510; for a related
report, see: c) E. Lourdusamy, L. Yao, C.-M. Park, Angew.
Chem. 2010, 122, 8135; Angew. Chem. Int. Ed. 2010, 49, 7963.
[6] a) S. Chuprakov, J. A. Malik, M. Zibinsky, V. V. Fokin, J. Am.
Chem. Soc. 2011, 133, 10352. For a related report, see: b) N.
Selander, V. V. Fokin, J. Am. Chem. Soc. 2012, 134, 2477.
[7] a) T. Miura, Y. Funakoshi, M. Morimoto, T. Biyajima, M.
Murakami, J. Am. Chem. Soc. 2012, 134, 17440; b) N. Selander,
B. T. Worrell, V. V. Fokin, Angew. Chem. 2012, 124, 13231;
Angew. Chem. Int. Ed. 2012, 51, 13054; for a related report, see:
c) R. Liu, M. Zhang, G. Winston-McPherson, W. Tang, Chem.
Commun. 2013, DOI: 10.1039/c2cc34609e.
[8] T. Miura, T. Biyajima, T. Fujii, M. Murakami, J. Am. Chem. Soc.
2012, 134, 194.
[9] N. Selander, B. T. Worrell, S. Chuprakov, S. Velaparthi, V. V.
Fokin, J. Am. Chem. Soc. 2012, 134, 14670.
[10] a) J. L. Wood, B. M. Stoltz, H.-J. Dietrich, D. A. Pflum, D. T.
Petsch, J. Am. Chem. Soc. 1997, 119, 9641; b) J. L. Wood, G. A.
Moniz, Org. Lett. 1999, 1, 371; c) J. L. Wood, G. A. Moniz, D. A.
Pflum, B. M. Stoltz, A. A. Holubec, H.-J. Dietrich, J. Am. Chem.
Soc. 1999, 121, 1748.
[11] a) Z. Li, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 396;
b) B. T. Parr, Z. Li, H. M. L. Davies, Chem. Sci. 2011, 2, 2378;
c) Z. Li, B. T. Parr, H. M. L. Davies, J. Am. Chem. Soc. 2012, 134,
10942.
[20] a) D. M. Perrine, J. T. Ross, S. J. Nervi, R. H. Zimmerman, J.
Chem. Educ. 2000, 77, 1479; b) K. F. Foley, N. V. Cozzi, Drug
Dev. Res. 2003, 60, 252.
[21] a) R. D. Pace, G. W. Kabalka, J. Org. Chem. 1995, 60, 4838; b) S.
Sengupta, D. Das, S. Mondal, Synlett 2001, 1464; c) R. V.
Hoffman, N. Maslouh, F. Cervantes-Lee, J. Org. Chem. 2002,
67, 1045; d) N. Arai, H. Ooka, K. Azuma, T. Yabuuchi, N.
Kurono, T. Inoue, T. Ohkuma, Org. Lett. 2007, 9, 939.
[22] a) M. Anada, M. Tanaka, T. Washio, M. Yamawaki, T. Abe, S.
Hashimoto, Org. Lett. 2007, 9, 4559; b) M. Tanaka, S. Nakamura,
M. Anada, S. Hashimoto, Heterocycles 2008, 76, 1633.
[12] For intramolecular 1-allyl-1,2-aminohydroxylation of 2-alkynyl
arylazides with allyl alcohol catalyzed by gold(I), see: A. Wetzel,
F. Gagosz, Angew. Chem. 2011, 123, 7492; Angew. Chem. Int. Ed.
2011, 50, 7354.
3886
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3883 –3886