Synthesis of 2-Substituted 2-Amino Ketones by Rhodium-Catalyzed Reaction of N-Sulfonyl-1,2,3-triazoles with 2-Alkenols

Article abstract of DOI:10.1002/hlca.201600320

A study on a rhodium(II)-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with 2-alkenols is reported. The reaction is initiated by insertion of an α-imino carbene into the O–H linkage of alcohol, forming a 2-alkenoxy enamide intermediate. A thermal [3,3]-sigmatropic rearrangement follows to yield 2-substituted 2-amino ketone in a stereoselective manner. The successful application of this methodology to a formal synthesis of (–)-α-conhydrine is also described.

Full text of DOI:10.1002/hlca.201600320

Received Date: 05-Oct-2016
Revised Date: 01-Dec-2016
Accepted Date: 02-Dec-2016
Article Type: Full Paper
Synthesis of 2-Substituted 2-Amino Ketones by Rhodium-Catalyzed
Reaction of N-Sulfonyl-1,2,3-triazoles with 2-Alkenols
Tomoya Miura*, Takamasa Tanaka, Qiang Zhao, Scott G. Stewart†, and Masahiro
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)
A study on a rhodium(II)-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with 2-alkenols is
reported. The reaction is initiated by insertion of an α-imino carbene into the O–H linkage of
alcohol, forming a 2-alkenoxy enamide intermediate. A thermal [3,3]-sigmatropic
rearrangement follows to yield 2-substituted 2-amino ketone in a stereoselective manner.
The successful application of this methodology to a formal synthesis of (–)-α-conhydrine is
also described.
Keywords: 2-amino ketone • carbenoid • rhodium • sigmatropic rearrangement • triazole
Introduction
2-Amino ketones are a valuable structural motif found in a number of biologically active
compounds, which include commercially available drugs such as amfepramone,[1]
bupropion,[2] and prasugrel.[3] They also act as the key intermediate for the synthesis of chiral
2-amino alcohols[4] and various nitrogen-containing heterocycles.[5] Thus, the development of
an efficient method to synthesize this functionality, starting from readily available compounds
is highly demanded.[6]
S.G.S. is on leave from School of Chemistry and Biochemistry, The University of Western
Australia.
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/hlca.201600320
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We have been studying various rhodium(II)-catalyzed reactions of N-sulfonyl-1,2,3-
triazoles.[7] When reacted with H2O, an intermediary α-imino rhodium(II) carbene complex
undergoes hydration through insertion of the carbenoid carbon into the O–H linkage of H2O
to produce 2-amino ketones.[8] On the other hand, Wood[9] and Davies[10] developed a
reaction of α-diazo carbonyl compounds with 2-alkenols, in which an insertion reaction of the
carbenoid carbon of an intermediary α-oxo rhodium(II) carbene complex into the O–H linkage
was immediately followed by [3,3]- and [2,3]-sigmatropic rearrangement reactions.[11] Their
reports prompted us to examine the use of 2-alkenols in place of H2O, hoping for a
sequential pathway starting from triazoles leading to 2-substituted 2-amino ketones through
sigmatropic rearrangement.[12] Herein, we describe the details of our study on the
rhodium(II)-catalyzed reaction of N-sulfonyl-1,2,3-triazoles with 2-alkenols. The utility of this
method is demonstrated by an application to a formal synthesis of (–)-α-conhydrine. A study
on the use of 2,3-alkadienols is also reported.[13,14]
Results and Discussion
Initially, 4-phenyl-1-tosyl-1,2,3-triazole (1a) was prepared from phenylacetylene and tosyl
azide under Cu(I) catalysis.[15] The triazole 1a (0.20 mmol) was mixed with 2-propen-1-ol (2a,
1.5 equiv), Rh2(OCOtBu)4 (1.0 mol %), molecular sieves 3 Å (MS), and toluene (2 mL). The
mixture was heated at 100 °C for 30 minutes (Scheme 1). Chromatographic purification on
silica gel afforded 2-(2-propenyl) 2-amino ketone 3aa in 91% yield. In this process three
different bonds, i.e. C–O, C–N, and C–C bonds were regioselectively installed across the C–
C triple bond of phenylacetylene.
Scheme 1. Rh(II)-Catalyzed Reaction of Triazole 1a with 2-Propen-1-ol (2a). Ts = 4-toluenesulfonyl.
Mechanistically, the reaction consists of two distinct steps with 2-propenoxy enamide C
intervening as the intermediate (the bottom row of Scheme 1). The reaction is initiated by a
ring/chain tautomerization of 1a to generate the α-diazo imine 1a’, which reacts with a
rhodium(II) catalyst. The resulting α-imino rhodium(II) carbene complex A possesses an
electrophilic carbenoid carbon, to which 2a adds at its oxygen atom to give zwitterionic
intermediate B. A proton shift from the oxygen to the imino nitrogen follows to release
rhodium(II) and the 2-propenoxy enamide C equipped with (Z) stereochemistry. A Claisen
[3,3]-sigmatropic rearrangement ensues to afford the product 3aa.
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A variety of N-sulfonyl-1,2,3-triazoles 1, having a substituent at the C4-position, were
subjected to the reaction with 2-propen-1-ol (2a) (Table 1). Aryl and heteroaryl-substituted
triazoles 1b–g reacted efficiently to afford the corresponding products 3ba–ga in yields
ranging from 86% to 96% (entries 1–6). Even alkyl-substituted triazoles 1h–k gave the
products 3ha–ka in good yields, despite a potential of a 1,2-hydride shift reaction pathway
from the intermediary rhodium(II) carbene complex (entries 7–10).[16] Ethoxy-substituted
triazole 1l also successfully participated in the reaction (entry 11).[17] As for the substituent of
the sulfonyl group, not only aryl but also alkyl groups were suitable (entries 12–18).
Table 1. Rh(II)-Catalyzed Reaction of Various Triazole 1b-s with 2-Propen-1-ol (2a)a
aConditions: 1 (0.20 mmol), 2a (0.30 mmol), Rh2(OCOtBu)4 (2.0 μmol), and MS (40 mg) in toluene (2 mL) were heated at 100 °C for 30 min, unless
otherwise noted. bIsolated yield (average of 2 runs). cHeated in CHCl3 (0.5 mL) at 100 °C in a sealed tube for 1 h under microwave irradiation
using Rh2(OCOtBu)4 (5.0 μmol) and MS (40 mg). dUsing Rh2(OCOtBu)4 (1.0 μmol) and 2a (5.0 equiv).
4,5-Disubstituted triazoles 1t-x were also subjected to the reaction with 2-propen-1-ol (2a).
The reaction of 1t afforded the corresponding product 3ta possessing a quaternary carbon
center in 79% yield (eq 1). In contrast, other 4,5-disubstituted triazoles 1u–x were all
unreactive and failed to give any of the desired products.
Next, the scope of 2-alkenols 2 was investigated (Table 2). The reaction of 2-methyl-2-
propen-1-ol (2b) with the triazole 1a afforded 2-(2-methyl-2-propenyl) 2-amino ketone 3ab in
85% yield (entry 1). Whereas 3-methyl-2-buten-1-ol (2c) produced 2-(2-methyl-3-buten-2-yl)
2-amino ketone 3ac (entry 2), 2-methyl-3-buten-2-ol (2d) gave 2-(3-methyl-2-butenyl) 2-
amino ketone 3ad (entry 3). These regiochemical outcomes are consistent with the
occurrence of a Claisen [3,3]-sigmatropic rearrangement. When the E- and Z-isomers of 2-
buten-1-ol (2e and 2f, respectively) were employed, moderate diastereoselectivities were
observed (entries 4 and 5).
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Table 2. Rh(II)-Catalyzed Reaction of Triazole 1a with 2-Alkenols 2b–fa
aConditions: 1a (0.20 mmol), 2 (0.30 mmol), Rh2(OCOtBu)4 (2.0 μmol), and MS (40 mg) in toluene (2 mL) were heated at 100 °C for 30 min.
bIsolated yield (average of 2 runs).
An analogous cascade reaction was examined using 2,3-alkadienols 4a–f (Table 3). Thus, a
chloroform solution of the triazole 1a and 2,3-butadien-1-ol (4a) was heated at 100 °C for 30
minutes under microwave irradiation, and the reaction mixture was concentrated under
reduced pressure. 1H NMR analysis of the residue showed that 2-(2-buta-1,3-dien-2-yl) 2-
amino ketone 5aa was formed in ca. 90% yield confirming an analogous sequential pathway,
although 5aa was too unstable to be isolated by chromatography (entry 1). On the other
hand, the products 5ab–af derived from substituted 2,3-alkadienols 4b–f were stable enough
to be isolated by standard chromatography (entries 2–6). As is the case with 2-alkenols, the
regiochemical outcomes are in consistent with involvement of a [3,3]-sigmatropic
rearrangement.[18]
Table 3. Rh(II)-Catalyzed Reaction of Triazole 1a with 2,3-Alkadienols 4a–fa
aConditions: 1a (0.20 mmol), 4 (0.30 mmol), Rh2(OCOtBu)4 (2.0 μmol), and MS (40 mg) in CHCl3 (2 mL) were heated at 100 °C for 30 min under
microwave irradiation (MW). bIsolated yield (average of 2 runs). c1H NMR yield.
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When enantiomerically enriched (S)-but-3-en-2-ol (97% ee) was reacted with 1a, the double
bond geometry of the product 3ag was exclusively (E), and a good level of chirality transfer
(94% es)[19] was observed (Scheme 2). These stereochemical outcomes can be accounted
for by assuming a six-membered chair-like transition state with the α-substituent taking the
pseudo-equatorial position.[20] The reaction of 2g with 1l resulted in a decrease in the level of
chirality transfer, although the double bond geometry was exclusively (E). The absolute
configuration of 3lg was determined as (R) by derivatization to the amino acid ester known in
literature,[21] and those of the others 3ag and 5ag were assigned by analogy.
Scheme 2. The Reaction with Chiral Secondary Alcohols.
Finally, the reaction was applied to a formal synthesis of (1S,2R)-2-(1-
hydroxypropyl)piperidine [(–)- α-conhydrine] (Scheme 3). Conhydrine is a piperidine alkaloid
isolated from the seeds and leaves of the poisonous plant Conium maculatum L, and its
structure was elucidated in 1933.[22] Their potent biological activities have induced a number
of investigations into their synthesis.[23] In our approach, the required triazole 8 was initially
prepared from 1-propyne (7) and tosyl azide using copper(I) thiophene-2-carboxylate (CuTC)
as the catalyst.[15] The rhodium(II)-catalyzed reaction of 8 with (S)-but-3-en-2-ol (2g, 97% ee)
afforded (R,E)-2-(2-butenyl) 2-amino ketone 9 in 67% yield. A good level of chirality transfer
(85% es) was also observed. Chelation-controlled reduction of the kenotic carbonyl group
with Zn(BH4)2 led to the formation of the desired anti-amino alcohol 10 in 81% yield with
89:11 dr.[24] Acetylation of 10 furnished amino acetate 11 in 91% yield as a white solid.
Enantiomerically pure crystals were obtained when recrystallization from ethyl
acetate/hexane was carried out twice. N-allylation with allyl bromide afforded N,N-
disubstituted amine derivative 12. A ring-closing metathesis using the Grubbs’ second
generation catalyst gave 3,4-dehydropiperidine 13 in 98% yield. Hydrogenation of 13 on
Pd/C afforded piperidine 14. Removal of the acetyl group with K2CO3 in methanol gave the
desired amino alcohol 15. The spectral data of this compound was identical with those
reported in literature.[25] The enantiomeric purity was determined to be 99% by HPLC
analysis. The absolute configuration of 15 was determined as (1S,2R) based on the direction
28
of its optical rotation ([α]D24 +60.1 (c 1.10, CHCl3), the literature value for (1R,2S)-15 [α]D
–
33.2 (c 0.026, CHCl3). Since a procedure for deprotection of the tosyl group of 15 has been
reported,[25] (–)- α-conhydrine was formally synthesized in nine steps starting from 1-propyne
(7).
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Scheme 3. Synthesis of (–)-α-Conhydrine.
Conclusions
We have developed a rhodium(II)-catalyzed reaction of triazoles with 2-alkenols which is an
efficient method for the stereoselective synthesis of 2-substituted 2-amino ketones.
α
Experimental Section
General
All reactions were carried out under an argon atmosphere unless otherwise noted. The
reaction was performed in Biotage® Initiator Robot Eight & Robot Sixty Microwave Machine.
IR measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted with a
Pike Technologies MIRacle Single Reflection ATR adapter. 1H and 13C NMR spectra were
recorded on a Varian Mercury-vx400 (1H at 400.44 MHz and 13C at 100.69 MHz)
spectrometer and Varian 400-MR (1H at 399.88 MHz) spectrometer, and JEOL JNM-ECA600
(1H at 600 MHz, 13C at 150 MHz) spectrometer. NMR data were obtained in CDCl3 and C6D6.
Proton chemical shifts were referenced to the residual proton signal of the solvent at 7.26
ppm (CDCl3) and 7.16 ppm (C6D6). Carbon chemical shifts were referenced to the carbon
signal of the solvent at 77.0 ppm (CDCl3) and 128.06 ppm (C6D6). High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer. Flash column
chromatography was performed with silica gel 60N (Kanto). Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator (Merck). Gel
permeation chromatography (GPC) was carried out with a Japan Analytical Industry LC-9210
NEXT [JAIGEL-1H (20 x 600 mm)]. Chiral HPLC analysis was carried out with Waters
Alliance 2695 [Daicel CHIRALPAK IC (4.6 x 250 mm)]. Optical rotation was measured on a
JASCO P-1020 polarimeter.
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CAUTION
Sulfonyl azides are potentially explosive materials and must be handled with caution,
although we have never encountered any difficulty in handling them!
Typical Procedure for the Reaction of N-Sulfonyl-1,2,3-triazoles with 2-Alkenols
μ
The vial was capped with a Teflon film. The
reaction mixture was heated at 100 °C for 30 minutes. After the reaction mixture was cooled
and passed through cotton wool eluting with dichloromethane, the filtrate was concentrated
under reduced pressure. The residue was purified by preparative thin-layer chromatography
(chloroform/ethyl acetate = 25:1) to give the product 3aa as a white solid (60.0 mg, 0.18
mmol, 91%). 3aa: M.p. 122 – 125 °C. IR (ATR): 3273, 2928, 1678, 1472, 1252 cm-1. 1H
NMR: δ = 2.30 (s, 3H), 2.32–2.41 (m, 1H), 2.53–2.62 (m, 1H), 4.94–5.00 (m, 1H), 4.95 (dd, J
= 15.2, 1.6 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 5.63 (ddt, J = 16.8, 10.0, 7.2 Hz, 1H), 5.67 (d,
J = 9.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H),
7.67 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H). 13C NMR: δ = 21.3, 38.2, 57.0, 119.4,
127.0, 128.3, 128.8, 129.5, 131.2, 133.8, 134.0, 136.9, 143.4, 197.1. HRMS (ESI+): Calcd for
C18H20NO3S, M+H+ 330.1158. Found m/z 330.1142.
Typical Procedure for the Reaction of N-Sulfonyl-1,2,3-triazoles with 2,3-Alkadienols
Freshly prepared 1a (59.9 mg, 0.2 mmol), Rh2(OCOtBu)4 (1.2 mg, 2 μmol), MS 3 Å (42 mg),
chloroform (2 mL) and 4a (21.0 mg, 0.3 mmol) were
0.5–2 mL Biotage® microwave vial equipped with a stirrer bar. The vial was capped with a
Teflon film. The reaction mixture was heated at 100 °C for 30 minutes under microwave
irradiation. After the reaction mixture was cooled and passed through cotton wool eluting
ethyl acetate, the filtrate was concentrated under reduced pressure. In the case of 5aa, the
yield was estimated by 1H NMR analysis of the residue using mesitylene as an internal
standard, being ca. 90%. Others were purified by preparative thin-layer chromatography.
5aa: IR (ATR): 3288, 3057, 1678, 1595, 1331, 1290, 1157 cm-1. 1H NMR: δ = 2.34 (s, 3H),
4.98 (s, 1H), 5.19 (s, 1H), 5.23 (d, J = 11.2 Hz, 1H), 5.65 (d, J = 8.8 Hz, 1H), 5.66 (d, J = 17.6
Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 6.26 (dd, J = 17.6, 11.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H),
7.35–7.42 (m, 2H), 7.52–7.57 (m, 1H), 7.64–7.73 (m, 4H). 13C NMR: δ = 21.4, 58.3, 116.6,
120.7, 127.3, 128.3, 128.6, 129.4, 133.91, 133.94, 134.9, 136.9, 141.6, 143.5, 195.0. HRMS
(ESI+): Calcd for C19H20NO3S, M+H+ 342.1158. Found m/z = 342.1153.
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This work was supported in part by Grants-in-Aid for Scientific Research (S) (15H05756) and
(C) (16K05694) from MEXT. Q.Z. acknowledged JSPS fellowship for young scientists. S.G.S.
is grateful for the JSPS invitation fellowship for research in Japan.
Q.Z., and S.G.S. performed the experiments.
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