IBX-mediated oxidative Ugi-type multicomponent reactions: Application to the N and C1 functionalization of tetrahydroisoquinoline

Article abstract of DOI:10.1002/anie.200701603

(Chemical Equation Presented) Ugi wonderland: An Ugi-type reaction of tetrahydroisoquinoline with an isocyanide and a carboxylic acid in the presence of iodoxybenzoic acid (IBX) afforded the 1,2-diacylated adduct in good to excellent yields (see scheme).

Full text of DOI:10.1002/anie.200701603

Angewandte
Chemie
DOI: 10.1002/anie.200701603
Multicomponent Reactions
IBX-Mediated Oxidative Ugi-Type Multicomponent Reactions:
Application to the N and C1Functionalization of
Tetrahydroisoquinoline**
Tifelle Ngouansavanh and Jieping Zhu*
Direct functionalization of the a-carbon atom of amines in
general and of tetrahydroisoquinolines in particular has
attracted great attention in recent years,[1] and some of the
this reaction involves nucleophilic addition of the carbon of
an isocyanide to the imine/iminium formed in situ by
condensation of an amine and aldehyde. As a continuation
of our interest in the development of oxidative multicompo-
nent reactions (MCRs),[8] we became interested in the
development of oxidative Ugi-type reactions wherein the
electrophilic iminium species was generated by in situ
oxidation of amines. Here we report the first examples of
oxidative three-component Ugi-type reactions that allow, for
the first time, a dual acylation of the nitrogen and a-carbon
centers of tetrahydroisoquinoline (1) by a carboxylic acid and
an isocyanide under mild conditions (Scheme 2).
À
most important C C bond-forming processes such as Man-
nich,[2] Strecker,[3] aza-Henry,[4] and Friedel–Crafts[5] reactions
can now be performed directly from amines under mild
oxidative conditions. All these protocols involve the forma-
tion of incipient imine/iminium species followed by addition
of suitable nucleophiles. The development of mild oxidation
protocols compatible with the nucleophiles is essential for the
success of the one-pot process.[6] One of the many options that
has been actively pursued recently is the use of a catalytic
amount of transition metal in combination with a stoichio-
metric amount of peroxide as a terminal oxidant. To date, a
number of oxidative protocols that tolerate nucleophiles such
as malonates, nitroalkanes, electron-rich aromatics, and
cyanide have been developed.[2–5] However, multicomponent
reactions involving a key amine oxidation step is, to the best
of our knowledge, unknown.
Ugi four-component reactions (U-4CRs, Scheme 1) which
combine an amine, an aldehyde, an isocyanide, and a
carboxylic acid to give an a-acylamino amide have been
intensively researched over the past few decades and have
found wide applications in the synthesis of medicinally
Scheme 2. Three-component reaction of an amine, a carboxylic acid,
and an isocyanide for the dual functionalization of tetrahydroisoquino-
line (1).
relevant heterocycles.[7] The key C C bond-forming step in
À
To begin our study, tetrahydroisoquinoline (1) was
selected as a substrate because of its importance in medicinal
and natural products chemistry. As 2-iodoxybenzoic acid
(IBX) in dimethyl sulfoxide (DMSO) can oxidize secondary
amines to imines as demonstrated by Nicolaou and co-
workers,[9,10] the three-component condensation of 1, benzoic
acid (2a), and benzyl isocyanide (3a) was first performed in
DMSO in the presence of IBX (Table 1).[11,12] Although it did
provide the desired three-compound adduct 4, the yield of 4
was moderate (22%, entry 1, Table 1).[13] Careful examination
of the reaction mixture at different time intervals indicated
that the oxidation of 1 to 3,4-dihydroisoquioline (5) took
place smoothly. It was the slow reaction of 5 with 2a and 3a in
DMSO that diminished the overall efficiency. On the basis of
this observation, the reaction of 1, 2a, and 3a was carried out
in different organic solvents (Table 1). Performing the
reaction in MeOH, the solvent of choice for the Ugi reaction,
improved the yield of 4 to 50% (entries 2, 3, Table 1). This is
noteworthy as it indicates that oxidation of amine 1 proceeds
much faster than that of methanol in contrast to the dominant
notion.[14] Further increasing the polarity and acidity of the
Scheme 1. Ugi reaction versus an oxidative Ugi-type reaction.
[*] T. Ngouansavanh, Dr. J. Zhu
Institut de Chimie des Substances Naturelles (ICSN), CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
E-mail: zhu@icsn.cnrs-gif.fr
Homepage:
http://www.icsn.cnrs-gif.fr/article.php3?id_article=122
[**] Financial support from the CNRS and the ICSN is gratefully
acknowledged. IBX=2-iodoxybenzoic acid.
Supporting information for this article, including details of
experimental procedures and product characterization for all
compounds 4a–4q, is available on the WWW under http://
www.angewandte.org or from the author.
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Table 1: A survey of reaction conditions for the IBX-promoted oxidative
Ugi-type reaction.[a]
Entry
Solvent
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DMSO
MeOH
MeOH
TFE[d]
Toluene
MeCN
DMF[d]
CH2Cl2
Et2O
25
25
60
25
25
25
25
25
25
25
40
60
60
60
60
72
72
21
72
72
72
72
72
72
72
28
20
20
6
22
50[c]
63[c]
19
29
26
43
36
20[c]
51
THF
THF
83
87
80
51
THF
THF[e]
THF[f]
DMSO/THF (19:1)
20
85
[a] General conditions: 1/2a/3a/IBX=1.5:1.5:1.0:2.0, concentration c=
0.5m. [b] Yields refer to the pure isolated compound after silica gel
chromatography. [c] Contaminated with a small amount of IBA. [d] TFE=
trifluoroethanol; DMF=N,N-dimethylformamide. [e] 4-Š molecular
sieves were added. [f] c=2.0m.
solvent (TFE) provided a mediocre result (entry 4, Table 1).
Only a low to moderate yield of adduct 4 was isolated when
the reaction was performed in toluene,[15] MeCN, DMF,
CH2Cl2, and diethyl ether (entries 5–9, Table 1).[16,17] How-
ever, THF turned out to be an excellent reaction media for
the present domino oxidation/Ugi-type 3CR process
(entry 12, Table 1). A similar result was obtained when a
mixture of DMSO and THF (19:1) was used as solvent
(entry 15, Table 1).[18] Under optimized conditions (THF,
608C, c = 0.5m), compound 4 was isolated in 87% yield
(entry 12, Table 1).[19] Note that IBX is poorly soluble in THF,
and consequently the oxidative U-3CR was realized under
heterogeneous conditions. The excess of IBX as well as its
reduced form IBA were removed by a simple filtration
through a short pad of Celite.
Using IBX as oxidant and THF as solvent, the scope of
this oxidative Ugi reaction was next examined. A variety of
carboxylic acids including benzoic acid, acetic acid, and
functionalized acids such as 2-iodobenzoic acid, cinnamic
acid, (E)-4-ethoxy-4-oxobut-2-enoic acid, phenylpropiolate,
and N-Cbz-glycine can be used as reaction partners to acylate
the secondary amine. Isocyanides with different steric and
electronic properties such as benzyl isocyanide, 2-iodobenzyl
isocyanide, cyclohexyl isocyanide, tert-butyl isocyanide, and
a-benzyl-a-isocyanoacetamide[20] can be used to directly
acylate the a-carbon atom (Figure 1). As expected, no
diastereoselectivity was observed when chiral a-isocyano-a-
benzyl isocyanoacetamide was used as an input. Interestingly,
the Na-unprotected tetrahydro-b-carboline can be similarly
functionalized to afford N and C double-acylated derivative
4o. The indole nucleus is stable although its reaction with
Figure 1. Structures of functionalized tetrahydroisoquinolines.
Bn=benzyl; Cbz=carbobenzyloxy.
(diacetoxyiodo)benzene has been reported.[21] The higher
nucleophilicity of the secondary amine relative to the indolyl
nitrogen might ensure the chemoselective oxidation of the
former without affecting the indole moiety.
The one-step three-component synthesis of tripeptide 4p
highlighted the potential of the present protocol in the
preparation of tetrahydroisoquinoline-containing peptidomi-
metics (Scheme 3). Interestingly, note that in this reaction a
non-proteinogenic amino acid was synthesized with the
concomitant formation of a peptide bond. The formation of
oxazole resulting from the internal trap of the nitrilium
intermediate by amide oxygen was not observed under these
Scheme 3. Three-component reaction to synthesize a tetrahydroisoqui-
noline-containing tripeptide.
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Angewandte
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reaction conditions.[22] A preliminary experiment indicated
that direct functionalization of an acyclic amine was also
feasible. Thus the reaction of dibenzylamine with benzoic acid
and benzyl isocyanide in DMSO afforded the a-acyloxy
amide 4q in 32% yield (Scheme 4).
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In conclusion, we have documented a highly efficient
IBX-mediated Ugi-type reaction of secondary amines. To the
best of our knowledge, it constitutes the first examples of dual
acylation of the a-carbon and NH group of tetrahydroisoqui-
noline. Mild conditions, simple experiment procedure, and
good to excellent yields characterize the present oxidative
three-component reaction. We believe this transformation is
of significant synthetic value and are working to extend it.[23]
Experimental Section
Typical procedure: The carboxylic acid (1.5 equiv), secondary amine
(1.5 equiv), and isocyanide (1.0 equiv) were added successively to a
suspension of IBX (2.0 equiv) in dry THF (0.5m). The mixture was
then heated at 608C and monitored by TLC (6–72 h). When the
reaction was complete, the mixture was cooled to room temperature,
hydrolyzed with HCl (1n), and stirred for 10 min. The mixture was
then diluted with dichloromethane and filtered through a short pad of
Celite, and the filtrate was evaporated to dryness. The crude product
was dissolved in saturated Na2S2O3 solution, and the aqueous phase
was extracted with dichloromethane. The combined organic layers
were washed with saturated NaHCO3, water, brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel to afford the desired
compound.
[13] For Ugi reactions for the functionalization of azines, see: a) J. L.
Diaz, M. Miguel, R. Lavilla, J. Org. Chem. 2004, 69, 3550 – 3553;
b) G. C. Tron, J. Zhu, Synlett 2005, 532 – 534.
[14] For selective oxidations of amino alcohols to amino ketones in
DMSO, see: M. Frigerio, M. Santagostino, S. Sputore, G.
Palmisano, J. Org. Chem. 1995, 60, 7272 – 7276.
[15] For Ugi reactions in toluene in the presence of weakBrønsted
acids or Lewis acids, see: a) P. Cristau, J. P. Vors, J. Zhu, Org.
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2002, 114, 3785 – 3787; Angew. Chem. Int. Ed. 2002, 41, 3633 –
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Dehkane, J. Zhu, J. Am. Chem. Soc. 2005, 127, 6926 – 6927; see
also: f) V. Z. Parchinsky, O. Shuvalova, O. Ushakova, D. V.
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Hulme, Tetrahedron Lett. 2007, 48, 2213 – 2216.
[16] For the acidity of IBX and IBA, see: M. J. Gallen, R. Goumont,
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2995 – 3000; Angew. Chem. Int. Ed. 2006, 45, 2929 – 2934.
[17] For the oxidation of alcohols in different organic solvents, see:
J. D. More, N. S. Finney, Org. Lett. 2002, 4, 3001 – 3003.
[18] This experiment was suggested by one of the referees.
[19] IBX is able to oxidize THF at elevated temperature (808C and
above); see Ref. [17] and K. C. Nicolaou, P. S. Baran, R.
Kranich, Y. L. Zhong, K. Sugita, N. Zou, Angew. Chem. 2001,
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[20] a) A. Fayol, C. Housseman, X. Sun, P. Janvier, H. BienaymØ, J.
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Received: April 12, 2007
Published online: June 25, 2007
Keywords: acylation · amines · multicomponent reactions ·
.
oxidation · Ugi reaction
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