5-mercaptotetrazoles as synthetic equivalents of nitrogen-contaning functional groups. the case of the organocatalytic enantioselective aza-Michael reaction

Article abstract of DOI:10.1021/ol102892f

5-Mercaptotetrazoles have been identified as useful and versatile Michael donors in enantioselective amine-catalyzed aza-Michael reactions with α,β-unsaturated aldehydes, showing excellent behavior as N-nucleophiles instead of their usual trend to react a

Full text of DOI:10.1021/ol102892f

ORGANIC
LETTERS
2011
Vol. 13, No. 2
336-339
5-Mercaptotetrazoles as Synthetic
Equivalents of Nitrogen-Contaning
Functional Groups. The Case of the
Organocatalytic Enantioselective
aza-Michael Reaction
Uxue Uria, Efra´ım Reyes, Jose L. Vicario,* Dolores Bad´ıa, and Luisa Carrillo
Departmento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad
del Pa´ıs Vasco/Euskal Herriko Unibertsitatea, P.O. Box 644, E-48080 Bilbao, Spain
joseluis.Vicario@ehu.es
Received November 30, 2010
ABSTRACT
5-Mercaptotetrazoles have been identified as useful and versatile Michael donors in enantioselective amine-catalyzed aza-Michael reactions
with r,ꢀ-unsaturated aldehydes, showing excellent behavior as N-nucleophiles instead of their usual trend to react as S-nucleophiles. In
addition several unprecedented chemical modifications on the tetrazolothione moiety have been carried out leading to the enantioselective
preparation of different compounds incorporating nitrogen-containing functionalities such as oxazinimines, formamidines, ureas and isoureas.
The aza-Michael reaction is a fundamental transformation
for the stereoselective preparation of nitrogen-containing
chiral compounds, and as a consequence of this, many
different catalytic enantioselective approaches have been
developed,1 most of them involving metal catalysis.1b
Alternatively, a particularly interesting approach is related
to the use of chiral amines as catalysts in Michael-type
reactions because of their ability to activate R,ꢀ-unsaturated
aldehydes or ketones toward conjugate addition by the
reversible formation of an iminium ion.2 However, while a
variety of chiral amine catalysts have been explored for the
conjugate addition of different types of nucleophiles to enals
or enones, the aza-Michael reaction has remained signifi-
cantly less developed.3 The main reason for this is associated
with the additional chemoselectivity issues that have to be
(2) (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107,
5416. (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79.
See also: (c) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065.
(d) Almac¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007,
18, 299. (e) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(1) (a) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.; Etxebarria, J.; Reyes, E.;
Ruiz, N. Org. Prep. Proced. Int. 2005, 37, 513. (b) Xu, L.-W.; Xia, C.-G.
Eur. J. Org. Chem. 2005, 633.
(3) For a recent review on organocatalytic aza-Michael reactions, see:
Enders, D.; Wang, C.; Liebich, J. X. Chem.sEur. J. 2009, 15, 11058.
10.1021/ol102892f  2011 American Chemical Society
Published on Web 12/08/2010

controlled in this case because both the catalyst and the
Michael donor are primary or secondary amine species.
Moreover, the reversibility of the reaction is an additional
problem which often leads to the low configurational stability
of the final aza-Michael adducts.
tions with R,ꢀ-unsaturated aldehydes using a chiral secondary
amine as a catalyst (Figure 1). On one hand, it was envisaged
In this context, after the first pioneering report by
MacMillan involving the use of N-silyloxycarbamates as
nucleophiles,4 only a few number of other amine-catalyzed
enantioselective aza-Michael reactions have been reported,
most of them integrated into cascade processes, in which
a subsequent intramolecular reaction occurs avoiding the
retro-addition.5 In fact, only a few examples can be found
in which a pure intermolecular aza-Michael reaction has
been carried out,6 which include the one initially devel-
oped by MacMillan4 and other later examples by Jør-
gensen,7 our group,8 and two others9 using nitrogen
heterocycles as N-nucleophiles. However, an important
drawback of all the later methodologies is the lack of
reactivity of the nitrogen heterocycle incorporated as the
nucleophile, which makes the obtained adducts not suitable
for their transformation into other chiral building blocks,
consequently limiting the applicability of these method-
ologies in organic synthesis. On the other hand, while
N-silyloxycarbamates have shown to perform well in this
kind of chemistry, these are not commercially available
and have to be prepared from the corresponding N-
protected hydroxylamines.
Figure 1. 5-Mercaptotetrazoles as Michael donors in organocatalytic
conjugate additions under iminium activation.
that the tetrazolothione moiety incorporated at the final aza-
Michael products could show an interesting reactivity profile
which would allow its conversion into compounds with
different nitrogen-based functionalities by means of an
unprecedented process involving reductive N-N bond cleav-
age, developed in our laboratories and presented herein. In
addition, many members of this family of compounds are
cheap and commercially available reagents and are also
highly acidic compounds which guarantee the formation of
a reactive anionic species in the reaction medium under the
neutral or slightly basic reaction conditions associated with
iminium catalysis.
With all these precedents in mind, we turned our attention
to the possibility of employing 5-mercaptotetrazoles as
suitable N-nucleophiles in enantioselective aza-Michael reac-
It should also be noted that the ambident nucleophilic
nature of these 5-mercaptotetrazoles might also lead to the
formation of two products arising from the N- and the
S-addition pathways and therefore the chemoselectivity of
the reaction constitutes a relevant issue to be considered,
which implies that conditions had to be found that allowed
controlling the selectivity of the addition toward the forma-
tion of the desired N-addition product vs the undesired
S-addition pathway, which is on the other hand the usual
behavior of 5-mercaptotetrazoles when employed as nucleo-
philes.
(4) (a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 9328. For other related examples involving the same type
of N-nucleophiles, see: (b) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.-L.;
Xu, Y.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 2193. (c) Lu, X.; Deng,
L. Angew. Chem., Int. Ed. 2008, 47, 7710. (d) Chen, L.-Y.; He, H.; Pei,
B.-J.; Chan, W.-H.; Lee, A. W. M. Synthesis 2009, 1573.
(5) (a) Gerasyuto, A. I.; Hsung, R. P.; Syrodenko, N.; Slafer, B. J. Org.
Chem. 2005, 70, 4248. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.;
Co´rdova, A. Chem. Commun. 2007, 849. (c) Li, H.; Wang, J.; Xie, H.; Zu,
L.; Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett. 2007, 9, 965. (d) Vesely,
J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Co´rdova, A. Angew. Chem., Int. Ed.
2007, 46, 778. (e) Sunde´n, H.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson,
L.; Co´rdova, A. AdV. Synth. Catal. 2007, 349, 827. (f) De Pesciaioli, F.;
Vicentis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.;
Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703. (g) Zhao, G.-L.;
Rios, R.; Vesely, J.; Eriksson, L.; Co´rdova, A. Angew. Chem., Int. Ed. 2008,
47, 8468. (h) Li, H.; Zu, L.; Xie, H.; Wang, J.; Wang, W. Chem. Commun.
2008, 5636. (i) Enders, D.; Wang, C. Synthesis 2009, 4119. (j) Simmons,
B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48,
4349. (k) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem.sEur. J.
2010, 16, 746. (l) Bae, J.-Y.; Lee, H.-J.; Youn, S.-H.; Kwon, S.-H.; Cho,
C.-W. Org. Lett. 2010, 12, 4352.
Our studies began with the identification of the best
catalyst and reaction conditions for this transformation (Table
1). We also decided to carry out the in situ reduction of the
aza-Michael adduct in order to prevent racemization during
the purification.10 We started using MacMillan catalyst 3a
under the conditions previously employed by us before,8 but
no aza-Michael reaction product was observed (entry 1), even
though we isolated small amounts of S-adduct 5a (31%
yield).11 Running the reaction at -30 °C resulted in an
unselective process with the preferential formation of 5a and
obtaining the minor N-adduct 4a with very low enantiose-
lectivity (entry 2). Alternatively, we evaluated the use of
diarylprolinol derivatives 3b-d as catalysts which, in
general, resulted in a highly chemoselective reaction favoring
(6) A few intramolecular examples of amine-catalyzed aza-Michael
reactions have also appeared: (a) Fustero, S.; Moscardo´, J.; Jime´nez, D.;
Pe´rez-Carrio´n, M. D.; Sa´nchez-Rosello´, M.; del Pozo, C. Chem.sEur. J.
2008, 14, 9868. (b) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett,
N. D.; Carter, R. G. J. Org. Chem. 2008, 73, 5155. (c) Fustero, S.; Jime´nez,
D.; Moscardo´, J.; Catala´n, S.; del Pozo, C. Org. Lett. 2007, 9, 5283. (d)
Takasu, K.; Maiti, S.; Ihara, M. Heterocycles 2003, 59, 51.
(7) (a) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2007, 46, 1983. (b) Jiang, H.; Nielsen, J. B.; Nielsen, M.;
Jørgensen, K. A. Chem.sEur. J. 2007, 13, 9068. (d) For the addition to
enones, see: Luo, G.; Zhang, S.; Duan, W.; Wang, W. Synthesis 2009, 1564.
(8) Uria, U.; Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Chem. Commun. 2007,
2509.
(9) (a) Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.;
Li, M.; Galya, L.; Metcalf, B.; Yue, T.-Y.; Liu, P.; Zhou, J. Org. Lett.
2009, 11, 1999. (b) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett. 2009, 11,
2249.
(10) All aza-Michael products were found to be configurationally
unstable, undergoing fast racemization upon standing at rt.
(11) In all cases in which the S-adduct 5a was isolated, it was obtained
as a racemic mixture.
Org. Lett., Vol. 13, No. 2, 2011
337

Table 1. Screening for the Best Reaction Conditions
Table 2. Scope of the Reactiona
entry compd
R1
R2
Ph
yield(%)b ee(%)c
1d
2
3
4
5
4a
4b
4c
4d
4e
4f
Me
Et
n-Pr
i-Pr
n-Bu
n-C5H11
n-C6H13
n-C8H17
78
79
76
74
77
78
77
67
50
67
74
74
73
77
81
71
87
51
51
39
53
91
90
94
94
90
90
89
90
92
89
92
95
94
94
94
97
98
92
94
99
96
Ph
Ph
Ph
Ph
Ph
Ph
Ph
temp
yield 4a ee 4a
(%)
6
entry catalyst additive solvent (°C) 4a/5ac
(%)d
7
8
9
4g
4h
4i
1
2
3
4
5
6
3a
3a
3b
3c
3d
3d
TFAa
EtCN
EtCN
-78 n.d.e
-30 1:1.5
<5
35
45
57
76
78
n.d.e
26
TFAa
Z-EtCHdCHCH2CH2 Ph
PhCO2Hb Toluene -30 >10:1
PhCO2Hb Toluene -30 >10:1
PhCO2Hb Toluene -30 >10:1
PhCO2Hb Toluene -40 >10:1
12
10
11
12
13
14
15
16
17
18
19e
20e
21e
4j
4k
4l
CO2Et
Me
Et
Ph
26
86
PMP
PMP
PMP
PMP
PMP
Me
Me
Me
PMP
PMP
PMP
91
a 10 mol % of TFA was used. b 20 mol % of PhCO2H was used.
4m
4n
4o
4p
4q
4r
4s
4t
n-Bu
c Determined by NMR analysis of crude reaction mixture. d Calculated by
chiral HPLC analysis (see Supporting Information). e n.d.: not determined.
n-C6H13
CO2Et
Et
n-Bu
CO2Et
Ph
the N-addition pathway (entries 3-6). For this kind of
catalysts, PhCO2H was used as a Brønsted acid cocatalyst
to assist the formation of the intermediate iminium ion. The
use of OH-containing catalyst 3b led to 4a in moderate yield
and low ee (entry 3), while the reaction using the O-TMS
derivative 3c provided the addition product in better yield
and with improved enantioselectivity (entry 4). Importantly,
a more enantioselective reaction was observed using catalyst
3d which incorporates bulkier aryl substituents (entry 5).
Finally, the enantioselectivity of the process could be further
improved up to 91% by carrying out the reaction at a slightly
lower temperature (entry 6).
p-NO2C6H4
p-FC6H4
4u
a Reactions were carried out in a 0.5 mmol scale of 1 using 10 mol %
of catalyst 3d and 20 mol % of PhCOOH in 2.0 mL of toluene. b Isolated
yield; only formation of the N-addition product was observed in all cases.
c Determined by chiral HPLC (see Supporting Information for details).
d Reaction was carried out at -40 °C. e Reaction was carried out at -60
°C and LiBH4 was used as reducing agent.
noted that ꢀ-aryl substituted enals have been found to be
elusive substrates in other reported amine-catalyzed enan-
tioselective aza-Michael reactions.4,7-9
Having established the best protocol for the reaction, we
extended this methodology to a series of R,ꢀ-unsaturated
aldehydes and 5-mercaptotetrazoles with different substitu-
ents (Table 2). As Table 2 indicates, the reaction showed to
have a broad substrate scope regarding the substituent both
at the R,ꢀ-unsaturated aldehyde and at the mercaptotetrazole
reagent, obtaining a wide variety of reduced aza-Michael
compounds 4a-u with excellent yields and, remarkably, as
single regioisomers in all the cases. In addition, the reaction
proceeded with excellent enantioselectivity for all substrates
tested, furnishing the final compounds 4a-u as highly
enantioenriched compounds.
For compound 4a, which had been obtained in 91% ee,
we were also able to grow crystals suitable for single-crystal
X-ray analysis (Figure 2).12 This allowed us to establish the
It is to be noted that ꢀ-aryl substituted enals could also
be used as substrates furnishing excellent levels of enantio-
control, although in these cases yields were highly dependent
on the electronic nature of this ꢀ-aryl substituent (entries
19-21). The use of these particular R,ꢀ-unsaturated alde-
hydes required a lower temperature (-60 °C) in order to
achieve high enantiocontrol and also the use of the more
reactive LiBH4 for the subsequent reduction step. It is to be
Figure 2. X-ray structure of compound 4a.
absolute configuration for the stereocenter that had been
generated in the conjugate addition reaction as 3R in 4a.
According to the stereostructure obtained for this compound,
the configuration of all other adducts 4b-u was established
by analogy. This absolute configuration is in good agreement
338
Org. Lett., Vol. 13, No. 2, 2011

with the sense of enantioinduction exerted by catalyst 3d
and related ones in other conjugate addition reactions to R,ꢀ-
unsaturated aldehydes.13
The ability of the tetrazolothione substructure to undergo
chemical modification was next surveyed (Scheme 1). In this
explored other possible transformations to be carried out on
these adducts 4 in order to illustrate their potential applica-
tions as chiral building blocks in organic synthesis. For
example, using adduct 4l as a model substrate, we found
that isourea 9l was obtained when the hydrogenolytic
cleavage was carried out under the same reaction conditions
but after protection of the primary alcohol moiety, as a result
of the intermolecular reaction of the intermediate generated
during the reductive cleavage with the solvent. Moreover,
and in a noteworthy transformation, when O-protected
derivative 8l was treated with H2 in the presence of Raney-
Ni but using THF as solvent, the clean formation of chiral
formamidine 10l was observed, which was explained in terms
of the initial formation of the already mentioned intermediate
thiourea after the reductive cleavage of the heterocycle, which
in this case was unable to undergo the intra- or intermolecular
reaction that led to the formation of cyclic oxazinimines 6
or acyclic isourea 9l and therefore could remain in solution
for a sufficient time to participate in a reductive desulfuration
process exerted by Raney-Ni.
Scheme 1. Survey of Transformations Carried out on Adducts 4
In summary, we have developed a new procedure for
carrying out enantioselective aza-Michael reactions to a wide
range of R,ꢀ-unsaturated aldehydes using a chiral secondary
amine catalyst and 5-mercaptotetrazoles as N-nucleophiles.
Interesting features of the methodology are (1) the high yields
and enantioselectivities obtained, (2) the fact that all reagents
employed are commercially available, (3) the exceptional
selectivity shown by the mercaptotetrazol reagents to undergo
N-addition rather than their usual behavior as S-nucleophiles,
and (4) the ability of the tetrazolothione moiety incorporated
at the aza-Michael adducts to undergo an unprecedented
reductive ring cleavage which, under different conditions has
led to the enantioselective preparation of important reagents
in organic and medicinal chemistry such as oxazinimines,
formamidines, ureas and isoureas.
context, we initially found that treating a representative
family of adducts 4 with H2 in the presence of Raney-Nickel
and HCl led to the formation of 1,3-oxazin-2-imines 6 in
good yields (see Scheme 1 and Supporting Information). This
unprecedented reaction consisted of the hydrogenolytic
cleavage of the tetrazole moiety leading most likely to the
formation of a thiourea intermediate, which subsequently
would be ready to undergo intramolecular reaction with the
free OH group. This transformation exhibited a remarkable
substrate scope, proceeding smoothly with a variety of
differently substituted representative substrates. We could
also access ureas 7a (R1 ) Me, R2 ) Ph) and 7l (R1 ) Et,
R2 ) PMP) from 1,3-oxazinimines 6a and 6l respectively
by simple base-promoted hydrolysis. In addition, we also
Acknowledgment. The authors thank the UPV/EHU
(fellowship to E.R.), MICINN (CTQ2008-00136/BQU),
DFB/BFA (DIPE08/03), and EJ/GV (Grupos IT328-10 and
fellowship to U.U.) for financial support.
(12) CCDC 782265 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(13) For reviews on the use of diarylprolinol derivatives as catalysts,
see: (a) Mielgo, A.; Palomo, C. Chem.sAsian J. 2008, 3, 922. (b) Palomo,
C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876. See also: (c) Grosˇelj,
U.; Seebach, D.; Badine, M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.;
Klose, P.; Hayashi, Y.; Uchimaru, T. HelV. Chim. Acta 2009, 92, 1225.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102892F
Org. Lett., Vol. 13, No. 2, 2011
339