Sulfonyl-1,2,3-triazoles: Convenient synthones for heterocyclic compounds

Article abstract of DOI:10.1002/anie.201206388

As easy as 1,2,3: Readily available and shelf-stable 1-sulfonyl-1,2,3- triazoles react with aldehydes and aldimines in the presence of Rh^II catalysts to produce 4-oxazolines and 1,2,5-trisubstituted imidazoles (see scheme). Copyright

Full text of DOI:10.1002/anie.201206388

Angewandte
Chemie
DOI: 10.1002/anie.201206388
Heterocycles
Sulfonyl-1,2,3-Triazoles: Convenient Synthones for Heterocyclic
Compounds**
Mikhail Zibinsky and Valery V. Fokin*
1-Sulfonyl-1,2,3-triazoles, which are readily available through
copper-catalyzed azide-alkyne cycloaddition,[1] are stable
precursors to RhII–azavinyl carbenes,[2] as well as carbene
complexes of other metals.[3] Among other transformations,
these reactive intermediates can be used for the introduction
of a nitrogen atom into various heterocycles[2b,4] that are
important in both synthetic and medicinal chemistry.
Carbenes generated from diazocarbonyl compounds 1 are
known to react with carbonyl groups to produce ylides 2,
which usually react in subsequent 1,3-dipolar cycloadditions
to access complex structures [Eq. (1)].[5] Herein, we report
that RhII–azavinyl carbenes react with aldehydes to give
adducts that undergo an intramolecular cyclization instead of
a 1,3-dipolar cycloaddition. This transformation results in
homochiral 3-sulfonyl-4-oxazolines 4 [Eq. (2), left], which are
produced in excellent yield and with high enantioselectivity.
These sparsely studied compounds[5] contain an easily instal-
led stereocenter and a synthetically useful electron-rich
double bond.
synthesis of 3-sulfonyl-4-oxazolines are scarce,[11] 3-acyl-4-
oxazolines, their close analogs, have been used in organic
synthesis.[12]
In addition to aldehydes, triazoles 3 react with aldimines
through a cyclization–elimination sequence, leading directly
to 1,2,5-trisubstituted imidazoles 5 [Eq. (2), right].
An initial examination of RhII-catalysts (Table 1) revealed
that [Rh2(piv)4] and [Rh2(oct)4] (piv = pivalate, oct = octa-
noate) catalyzed the formation of oxazolines 4 from triazole 3
and benzaldehyde (3 equiv) at 1008C (Table 1, entries 1 and
2). Attempts to trap the ylide intermediate II with reactive
dipolarophiles were unsuccessful.
Table 1: Optimization of the reaction conditions.[a]
Entry
R
Catalyst
Temp.
Time
Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
[Rh2(oct)4]
[Rh2(piv)4]
[Rh2(piv)4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
1008C[d] 15 min 61
1008C[d] 15 min 83
–
–
–
88
73
45
–
RT
RT
408C
12 h
12 h
9 h
12 h
48 h
12 h
82
75
80
70
[Rh2{(S)-ptad}4] RT
RT
C6H4Me [Rh2{(S)-ptad}4] RT
[e]
C6H4Me [Rh2{(S)-nttl}4]
–
82
55
[a] For the full table, see the Supporting Information. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] Microwave irradiation was used. [e] Less than 50% conversion of 3.
Oxazolines have been exploited in organic synthesis as
protecting groups[6] and chiral auxiliaries,[7] in asymmetric
catalysis as chiral ligands,[8] as well as in medicinal chemistry[9]
and drug delivery applications.[10] Although methods for the
[*] Dr. M. Zibinsky, Prof. V. V. Fokin
Department of Chemistry, The Scripps Research Institute
10550 N. Torrey Pines Rd., La Jolla, 92037 (USA)
E-mail: fokin@scripps.edu
Further investigation of the reaction conditions revealed
that lowering the temperature from 1008C to ambient
resulted in longer reaction times without significantly affect-
ing the yield of oxazolines 4 (Table 1, entry 3). Several chiral
catalysts were also examined at various temperatures
(Table 1, entries 4–8) and in combination with various
Homepage: http://www.scripps.edu/fokin
[**] This work was supported by the National Science Foundation
(CHE-0848982)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206388.
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Scheme 1. Asymmetric synthesis of 4-oxazolines 4 from various aldehydes. All yields are of isolated products. Enantiomeric excess was
determined by HPLC analysis on a chiral stationary phase. [a] Enantiomeric composition of the starting aldehyde was retained in the product; the
ee remained at 98%. Ms=methanesulfonyl, TBS=tert-butyldimethylsilyl.
sulfonyl groups at N1 of triazole 3, resulting in the enantio-
selective version of the reaction. Optimal enantioselectivity
was obtained in reactions of 1-mesyl-1,2,3-triazoles per-
formed at ambient temperature with of [Rh2{(S)-nttl}4]
(1 mol%; see Table 1 for structure) catalyst (Table 1,
entry 4). Among the solvents tested, chloroform provided
oxazoline products with consistently high yield and enantio-
selectivity.
Variously substituted aryl and alkyl aldehydes readily
participated in the reaction (Scheme 1). Ketones, esters,
terminal and endocyclic olefins, nitriles, and silyl ethers
were all compatible with the reaction. Prolonged reaction
times significantly lowered the enantiomeric purity of most
products. The reversible ring opening of N,O-aminals (4)
treated with various bases (1,8-diazabicyloundec-7-ene, trie-
thylamine, and potassium carbonate), the enantioselectivity
did not deteriorate. Hemiaminals arising from aliphatic
aldehydes underwent irreversible ring opening at elevated
À
temperature at the C O bond of the aminal, followed by
b-proton elimination (Scheme 2, left side).
Examination of the reaction scope with respect to the C4
substituent of the triazole (Table 2) revealed that aryl-
substituted triazoles provided oxazolines in excellent yield
Table 2: Reaction scope with respect to the substitution at C4 of the
triazole.
À
because of the lability of the C O bond (Scheme 2, right)
could explain this observation. It may also account for the
slightly lower enantioselectivity of this reaction compared to
other transformations of azavinyl carbenes, such as cyclo-
Entry
R1
Yield [%][a]
ee [%][b]
Compound
1
2
3
4
5
6
Ph
85
86
97
93
91
trace
92
92
94
88
80
–
4a
4b
4c
4d
4e
–
[2d–f]
À
propanations and C H insertions.
Acidity of the C2
4-CF3C6H4
4-MeC6H4
4-MeOC6H4
3-thiophenyl
n-C5H11
hydrogen is an unlikely cause of racemization: when 4a was
[a] Yield of isolated product. [b] Determined by HPLC analysis on a chiral
stationary phase.
and enantioselectivity; both were largely unaffected by the
electronic properties of this substituent. Alkyl-substituted
triazoles failed to provide oxazoline products in synthetically
useful yields, likely owing to the facile 1,2-hydride shift of the
carbene intermediate.[2b,c,e]
The key steps of the proposed mechanism of this reaction
are shown in Scheme 3. Triazole 3, upon reaction with
Scheme 2. Isomerization of 4-oxazolines 4.
2
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Scheme 4. Proposed pathway for the formation of imidazoles 5.
Scheme 3. Proposed mechanism for the formation of 4-oxazolines.
1208C in the presence of [Rh2(piv)4] (1 mol%). After the
triazole was consumed, 1,8-diazabicyloundec-7-ene (DBU;
2 equiv) was added and heating continued for one more
minute. The addition of DBU was necessary to achieve full
conversion to 5. The reaction proceeds well with different
4-aryl-substituted triazoles and aldimines prepared from
a variety of aromatic aldehydes and anilines (Scheme 5).
In summary, the reactions of azavinyl carbenes with
aldehydes and aldimines described herein exhibit excellent
functional group tolerance and proceed under simple exper-
imental conditions, thus underscoring the unique reactivity of
azavinyl carbenes and expanding the repertoire of the useful
transformations of these reactive intermediates.
a catalyst, extrudes dinitrogen and forms RhII–azavinyl
carbene species I. Interaction of the carbonyl group with
the carbene center leads to the formation of ylide II, which
undergoes cyclization, leading to the formation of oxazoline
4. An alternative pathway, through the formation of epoxide
III, cannot be ruled out at this time, however, we have no
evidence supporting the intermediacy of these species.
Similar to aldehydes, aldimines react with rhodium(II)
azavinyl carbenes to produce imidazoles. Thus, triazole 3
reacted with benzylidene-4-bromo-benzenamine within
30 min at 1008C in the presence of [Rh2(piv)4] to produce
imidazole 5. Lowering the temperature to 408C allowed the
isolation of intermediate imidazoline 7, which was thermally
unstable and underwent elimination of sulfinic acid
(Scheme 4). The bulky substitutents at the 1-, 2-, 3-, and
5-positions of imidazoline 7 impose considerable steric
demands on this intermediate, which explains the facility of
aromatization.
Experimental Section
Typical procedure for the [Rh2{(S)-nttl}4]-catalyzed reaction of
1-sulfonyl-1,2,3-triazoles with aldehydes: 1-methanesulfonyl-4-aryl-
1,2,3-triazole (3; 0.36 mmol) and [Rh2{(S)-nttl}4] (5.2 mg, 1 mol%,
0.0036 mmol) were added under inert atmosphere to an oven-dried
5 mL vial equipped with a stir bar. The vial was sealed and a mixture
of aldehyde (1.08 mmol, 3.0 equiv) in dry chloroform (1.5 mL) was
added via syringe. The reaction was stirred at room temperature for
3–12 h until complete conversion was observed. The content was then
The optimized conditions for the preparation of imida-
zoles 5 required the heating of a chloroform solution of
triazole 3 (0.2m) and an aldimine (1.5 equiv) for 5–10 min at
Scheme 5. Preparation of 1,2,5-trisubstituted imidazoles 5 from aldimines. All yields are of isolated products.
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transferred directly onto silica and purified by eluting with hexanes/
ethyl acetate (8:2). Removal of the solvent followed by drying under
vacuum afforded 4-oxazoline 4 in high purity.
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Typical procedure for the [Rh2(piv)4]-catalyzed reaction of
1-sulfonyl-1,2,3-triazoles with aldimines: 1-methanesulfonyl-4-aryl-
1,2,3-triazole (3; 0.3 mmol), [Rh2(piv)4] (1.8 mg, 1 mol%,
0.003 mmol), and an aldimine (1.5 equiv, 0.45 mmol) were added
under inert atmosphere to an oven-dried 5 mL vial equipped with
a stir bar. The vial was sealed and dry chloroform (1.5 mL) was added
via syringe. The vial was placed in an oil bath, which was heated to
1208C. After 5–10 min, DBU (2.0 equiv, 0.6 mmol) was added via
syringe and the reaction mixture was heated for an additional minute.
Then, the vial was cooled down to room temperature and its content
was transferred directly onto silica and purified by eluting with
hexanes/ethyl acetate (7:3). Removal of the solvent followed by
drying under vacuum afforded imidazole 5 in high purity.
Received: August 8, 2012
Published online: && &&, &&&&
Keywords: carbenes · imidazoles · oxazolines · rhodium ·
.
triazoles
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Heterocycles
M. Zibinsky, V. V. Fokin*
&&&& — &&&&
Sulfonyl-1,2,3-Triazoles: Convenient
Synthones for Heterocyclic Compounds
As easy as 1,2,3: Readily available and
shelf-stable 1-sulfonyl-1,2,3-triazoles
react with aldehydes and aldimines in the
presence of RhII catalysts to produce 4-
oxazolines and 1,2,5-trisubstituted imi-
dazoles.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!