Asymmetric synthesis of 5-(1-hydroxyalkyl)tetrazoles by catalytic enantioselective passerini-type reactions

Article abstract of DOI:10.1002/anie.200804213

(Chemical Equation Presented) Three-part harmony: Three-component Passerini reactions (P-3CR, see Scheme) of a wide range of aldehydes 2 and isocyanides 3, with hydrazoic acid 4 in toluene, in the presence of a [(salen)AlMe]-complex catalyst afford 5-(1-hydroxyalkyl)tetrazoles 1 in good-to-excellent yields and enantiomeric excess. A tandem Michael addition/enantioselective P-3CR, using an acrolein substrate, affords highly functionalized tetrazoles.

Full text of DOI:10.1002/anie.200804213

Communications
DOI: 10.1002/anie.200804213
Asymmetric Synthesis
Asymmetric Synthesis of 5-(1-Hydroxyalkyl)tetrazoles by Catalytic
Enantioselective Passerini-Type Reactions**
Tao Yue, Mei-Xiang Wang,* De-Xian Wang, and Jieping Zhu*
Tetrazoles have long been recognized as carboxylic acid
isosteres[1] and are important heterocycles in medicinal
chemistry, owing to their increased stability towards meta-
bolic degradation pathways.[2] The acidity of the tetrazole NH
group corresponds roughly to that of the carboxylic acid.[3]
Consequently, chiral 5-substituted tetrazoles have been
investigated as efficient organocatalysts.[4] In addition, the
1,5-disubstituted tetrazole ring has been considered as a
surrogate for the cis-amide bond, making it a valuable tool in
the design of conformationally constrained peptidomimet-
ics.[5] Several methods have been developed for the synthesis
of 1,5-disubstituted tetrazoles, including the 5-(1-hydroxyal-
kyl)tetrazoles (1).[6,7] However, to our knowledge, no enan-
tioselective synthesis of 1 has yet been reported. We report
herein a [(salen)AlIIIMe]-catalyzed (salen = N,N’-bis(salicyl-
idene)ethylenediamine dianion) enantioselective Passerini-
type reaction of aldehydes 2, isocyanides 3 and hydrazoic acid
have subsequently developed a TMSN3-modified (TMS =
trimethylsilyl) P-3CR for the synthesis of cis-constrained
norstatine-mimetic libraries.[14,15] Recently, we reported that
[(salen)AlIIICl][11b–c,16] is an effective catalyst for the enantio-
selective addition of isocyanides to aldehydes and predicted
that using a chiral Lewis acid with a single coordination site
was important for the development of enantioselective P-
3CR. We subsequently set out to investigate the enantiose-
lective synthesis of 1-(4-methoxyphenyl)-5-(1-hydroxyisobu-
tyl)tetrazole 1a (Scheme 1) using isobutyraldehyde (2a), 4-
methoxyphenylisocyanide (3a) and TMSN3, as a test reaction.
Carrying out the reaction at 08C in the presence of catalyst 5a
(Figure 1), 1a was formed with 52% ee (Table 1, entry 1).
4, affording
1 with good-to-excellent enantioselectivity
(Scheme 1).[8–11]
Scheme 1. Catalytic enantioselective synthesis of 5-(1-hydroxyalkyl)te-
trazole 1 by three-component Passerini reaction (P-3CR).
The three-component Passerini reaction (P-3CR)[12] has
seldom been used for the preparation of tetrazoles. Ugi and
Meyr reported in 1961 that hydrazoic acid can be used in the
Passerini reaction instead of carboxylic acids, for the produc-
tion of 1 in moderate-to-good yields.[13] Nixey and Hulme
Figure 1. Catalysts screened for enantioselective synthesis of 1-(4-
methoxyphenyl)-5-(1-hydroxyisobutyl)tetrazole 1a by P-3CR.
[*] T. Yue, Dr. M.-X. Wang, Dr. D.-X. Wang
National Laboratory for Molecular Sciences, Laboratory of Chemical
Biology, Institute of Chemistry, Chinese Academy of Sciences
Beijing 10080 (P.R. China)
E-mail: mxwang@iccas.ac.cn
Homepage: http://mxwang.iccas.ac.cn
However, a significant amount of 2-hydroxy-N-(4-methoxy-
phenyl)-3-methylbutanamide 6 was also produced under
these conditions. Decreasing the reaction temperature
(Table 1, entry 2), adding additives (Na2SO4, 4 ꢀ molecular
sieves) or using HN3 did not avoid the formation of 6.[17]
Control experiments indicated that, in the absence of Al
catalyst under otherwise identical conditions, formation of 6
did not occur and the yield of 1a was significantly reduced.
These results indicated that the formation of both 1a and 6
was catalyzed by [(salen)AlIIICl] complex 5a. Indeed, asym-
metric induction also occurred in the formation of compound
6 (55% ee). Reasoning that reaction of TMSN3 or HN3 with
Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
E-mail: zhu@icsn.cnrs-gif.fr
Homepage:
http://www.icsn.cnrs-gif.fr/article.php3?id_article=122
[**] We gratefully acknowledge the National Science Foundation of
China (NSFC), the Chinese Academy of Science, and CNRS for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804213.
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entry 6). With [(salen)AlIIIMe] (5d), 1a was isolated in 53%
Table 1: Reaction of isobutyraldehyde (2a), 4-methoxyphenylisocyanide
(3a) and TMSN3/HN3: Screening of reaction conditions.
yield a much-improved ee value of 83%. By increasing the
amount of HN3 to 2.5 equivalents, 1a was produced in almost
quantitative yield and 83% ee (Table 1, entry 8) under other-
wise identical conditions. Further decreasing the reaction
temperature reduced the yield of 1a without gain of
enantiomeric excess of the product (Table 1, entry 10). More-
over, increasing the loading of catalyst 5d to 0.2 equivalents
did not have significant positive impact on the yield and the ee
value of the product (Table 1, entry 11). Interestingly, carry-
ing out the reaction with only 0.05 equivalents of catalyst 5d
resulted in similar enantioselectivity, albeit with a reduced
yield of 1a (Table 1, entry 12). Replacing HN3 with TMSN3
under otherwise identical conditions led to the reduced yield
of tetrazole 1a.
Entry[a]
Cat* (mol%)
RN3
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
5a (10)
5a (10)
5a (10)
5b (10)
5b (10)
5c (10)
5d (10)
5d (10)
5d (10)
5d (10)
5d (20)
5d (5)
TMSN3
TMSN3
HN3
HN3
HN3
0
À20
À20
À20
À40
À20
À20
À20
À40
À60
À40
À40
65[d]
80[d]
80[d]
58
50
48
53
97
99
55
52
57
57
66
80
60
83
83
85
80
85
86
HN3
HN3
HN3
HN3
HN3
HN3
HN3
[e]
[e]
[e]
10
11
12
[e]
95
69
[e]
[a] General conditions: molar ratio 2a/3a/HN3 =1.2/1/1, toluene, final
concentration 0.2m. [b] Yields refer to chromatographically pure prod-
uct. [c] Determined by chiral column (AD stationary phase, eluent: 9:1
hexane/iPrOH). [d] Total combined yield of 1a and 6; the ratio of 1a/6 is
approximately 3:1 (determined by NMR spectroscopy). [e] Using
2.5 equivalents HN3.
The absolute configuration of 1a was determined accord-
ing to Trostꢁs empirical model.[19] Esterification of 1a with (S)-
and (R)-O-methylmandelic acid afforded esters 7 and 8,
respectively, in excellent yields (Figure 2). The calculated
chemical shift difference for the proton Ha (see Figure 2,
DdH (7À8) = 0.18) allowed us to tentatively attribute the (S)
a
configuration to tetrazole 1a.
5a might produce TMSCl (or HCl), with concurrent gener-
ation of an Al–azide complex, a potential mechanism for the
formation of 1a and 6 was proposed (Scheme 2). Herein,
nucleophilic addition of isocyanide 3 to the aldehyde–Al
complex (A) affords the nitrilium ion (B), which is trapped by
Figure 2. (S)- and (R)-O-methylmandelic acid-derived esters, used for
determination of absolute configuration of 1a. PMP=p-methoxy-
phenyl.
Having optimized conditions and stoichiometries for the
reaction (2a/3a/HN3/5d = 1.2:1:2.5:0.1), we next examined
the generality of this catalytic enantioselective process by
varying the structure of the aldehyde 2 and isocyanide 3. A
range of linear and a-branched aliphatic aldehydes were
effective substrates for this reaction. The presence of a
potentially coordinating pyridine ring was also tolerated
although the reaction yield was significantly reduced (Table 2,
entry 21). Aromatic isocyanides with electron-donating
(OMe, Me, NMe2) or electronic-withdrawing groups (Br)
were both effective reaction partners. However, the sterically
encumbered 2,6-dimethylphenylisocyanide 3j afforded the
corresponding adduct 1r with diminished yield and enantio-
selectivity (Table 2, entry 18). Aliphatic isocyanides (3b, 3c,
3l) were equally acceptable substrates (Table 2, entries 2, 5,
10, 11, and 20). The use of a-isocyanoacetate is of particular
interest since it afforded directly the dipeptide mimic 1t
(Table 2, entry 20). In addition, the adduct 1t can easily be
converted, in 82% yield, into bicyclic compound 9, following
a standard hydrolysis/lactonization sequence (Scheme 3).
When 5-isocyanobenzo[d][1,3]dioxole 3i was used, the cor-
responding adduct 1q was isolated in 88% yield with 97% ee
(Table 2, entry 17).
Scheme 2. Proposed mechanism for the formation of tetrazole 1 and
amide byproduct 6.
hydrazoic acid to provide tetrazole 1. Concurrently, reaction
of B with TMSCl or HCl affords the chloroimidate C, which,
in the presence of adventitious water, is converted into the a-
hydroxyamide 6.
Although the enantioselective preparation of 6 is of
interest,[8] our present study focused on the asymmetric
synthesis of tetrazole 1. Since, according to our mechanistic
hypothesis, the presence of chloride seemed to be responsible
for the formation of 6, the discrete m-oxo dimer 5b was
synthesized (Figure 1).[18] Using this catalyst in conjunction
with HN3, formation of 6 was suppressed and compound 1a
was isolated in 58% yield and 66% ee (Table 1, entry 4).
When the reaction was carried out at À408C, the ee value of
1a increased to 80% (Table 1, entry 5). The similar bimetallic
catalyst (5c), prepared from (1R,2R)-1,2-diphenyl-1,2-dieth-
anediamine, afforded 1a with reduced yield and ee (Table 1,
Salen–Al complexes are known to catalyze the nucleo-
philic addition of azide to a,b-unsaturated imides and to a,b-
unsaturated ketones. We investigated the possibility of
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Table 2: Catalytic enantioselective three-component synthesis of a range of chiral 5-(1-hydroxyalkyl)te-
trazoles (1).
hydrazoic acid rather than from the
Al-bound azide. Furthermore, pre-
mixing
[(salen)AlIIIMe],
with
Entry[a]
R1[b]
Aldehyde
R2
Isocyanide
Yield [%][c]
ee [%][d]
0.1 equivalents of enantioenriched
tetrazole 1a and subsequent addi-
tion of aldehyde 2a, isocyanide 3a,
and HN3 under otherwise standard
conditions afforded the adduct 1a
with a similar ee value, indicating
that the tetrazole itself does not
significantly modify the catalytic
properties of the aluminum com-
plex.[21]
In summary, we have developed
the first catalytic enantioselective
synthesis of 5-(1-hydroxyalkyl)te-
trazoles by a [(salen)AlIIIMe]-cata-
lyzed three-component Passerini
reaction (P-3CR) of aldehydes, iso-
cyanides, and hydrazoic acid. The
reaction is applicable to a wide
range of aliphatic aldehydes and to
both aromatic and aliphatic isocya-
nides, affording the corresponding
tetrazoles in good-to-excellent
yields and enantiomeric excesses.
By using acrolein as a substrate, a
tandem Michael addition/enantio-
1
2
3
4
5
6
7
8
iPr
iPr
Et
Cy
iPr
Bn
PhCH2CH2
n-hexyl
iBu
Cy
Cy
Cy
Cy
Cy
Cy
Cy
2a
2a
2b
2c
2a
2d
2e
2 f
2g
2c
2c
2c
2c
2c
2c
2c
4-MeOC6H4
Cy
4-MeOC6H4
4-MeOC6H4
Bn
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Bn
3a
3b
3a
3a
3c
3a
3a
3a
3a
3c
3b
3d
3e
3 f
99 (1a)
90 (1b)
88 (1c)
90 (1d)
76 (1e)
97 (1 f)
92 (1g)
88 (1h)
96 (1i)
91 (1j)
93 (1k)
68 (1l)
80 (1m)
70 (1n)
60 (1o)
95 (1p)
85
95
87
91
92
64
87
85
84
83
84
92
95
85
87
94
9
10
11
12
13
14
15
16
Cy
Ph
4-MeC6H4
3-MeC6H4
4-BrC6H4
4-NMe2C6H4
3g
3h
17
Cy
2c
3i
88 (1q)
97
18
19
20
Cy
Cy
Cy
2c
2c
2c
2,6-(Me)2C6H3
4-MeO-2-NO2C6H3
MeOOCCH2
3j
3k
3l
53 (1r)
48 (1 s)
93 (1t)
51
62
75
21
2h
4-MeOC6H4
3a
45 (1u)
80
[a] General conditions: molar ratio 2a/3a/HN3/5d=1.2/1/2.5/0.1, toluene, final concentration 0.2m,
À408C. [b] Cy=cyclohexyl. [c] Yields refer to chromatographically pure product. [d] Determined by chiral
column (AD stationary phase, eluent: hexane/iPrOH=9:1).
Scheme 3. Lactonization of dipeptide mimic 1t: a) potassium hydrox-
ide, methanol, room temperature, 6 h; b) dicyclohexylcarbodiimide/4-
dimethylaminopyridine, N,N-dimethylformamide/dichloromethane,
room temperature, 24 h, 82%.
Scheme 4. Tandem Michael addition/enantioselective P-3CR to func-
tionalized tetrazoles: a) 5d (0.1 equiv), toluene, À408C.
performing a tandem Michael addition/enantioselective P-
3CR using an a,b-unsaturated aldehyde as the carbonyl
substrate, if the Michael addition took place faster than the P-
3CR. Indeed, reaction of acrolein with hydrazoic acid and 4-
methoxyphenylisocyanide occurred in an ordered manner, to
afford the 1-(4’-methoxyphenyl)-5-(1’-hydroxy-3-azidopro-
pyl)tetrazole (1v) in 80% yield with 80% ee. Compounds
1w and 1x were similarly prepared using 5-isocyanobenzo[d]-
[1,3]dioxole (3i) and isocyanoacetate (3l) as isocyanide inputs
(Scheme 4).
selective P-3CR provided the highly functionalized tetrazoles
1v–1x. In light of the wide-ranging applicability of isocya-
nide-based multicomponent reactions,[22] the possibility to
develop chiral enantioselective versions tremendously broad-
ens their synthetic utility.[23]
The complex 5d most probably acts as a precatalyst in this
transformation, as it is known that 5d reacts rapidly with
hydrazoic acid to afford the corresponding azide complex.[20]
Two additional control experiments were performed in order
to gain some mechanistic insights. Reaction of a stoichiomet-
ric amount of [(salen)AlIIIN3] complex with aldehyde 2a in
the absence of HN3 afforded only a trace amount of adduct
1a, indicating that the azide group is directly transferred from
Experimental Section
1a: In a flame-dried round-bottom flask equipped with a stirrer bar, a
mixture of [(salen)AlIIIMe] (0.025 mmol, 15.0 mg) and dry toluene
(0.3 mL) was stirred at room temperature until the catalyst had
completely dissolved. Isobutyraldehyde (0.3 mmol, 27.7 mL) was then
introduced and the resulting mixture was stirred at room temperature
for a further 30 min. The mixture was cooled to À408C, and a solution
of 1-isocyano-4-methoxybenzene (0.25 mmol, 33.0 mg) in toluene
(0.4 mL) was added, followed by hydrazoic acid[17] (0.5 mL, 1.3m in
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toluene). After being stirred at À408C for 48 h, the reaction mixture
was purified by flash chromatography on silica gel (eluent: 2:1
petroleum ether/ethyl acetate) to afford the tetrazole 1a (61.4 mg,
0.248 mmol, 99%, 85% ee).
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Received: August 26, 2008
Published online: October 29, 2008
Keywords: asymmetric synthesis · homogeneous catalysis ·
.
isocyanides · multicomponent reactions · nitrogen heterocycles
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