Efficient silver-catalyzed regio- and stereospecific aziridination of dienes

Article abstract of DOI:10.1002/anie.201003167

Nitrene transfer: Unsymmetric dienes bearing a terminal hydroxy group can be regio- and stereospecifically converted into vinylaziridines upon nitrene transfer from PhINTs using a silver-based catalyst. Stoichiometric mixtures of dienes and PhINTs were employed at low catalyst loadings (0.5□%; see scheme). The method has been applied to the synthesis of (±)-sphingosine and gave good yields in a three-step procedure. Ts=4-toluenesulfonyl.

Full text of DOI:10.1002/anie.201003167

Communications
DOI: 10.1002/anie.201003167
Synthetic Methods
Efficient Silver-Catalyzed Regio- and Stereospecific Aziridination of
Dienes**
Josep Llaveria, ꢀlvaro Beltrꢁn, M. Mar Dꢂaz-Requejo,* M. Isabel Matheu,* Sergio Castillꢃn,*
and Pedro J. Pꢄrez*
The synthesis of aziridine derivatives through metal-mediated
nitrene addition reactions to olefins [Eq. (1)] has been
extensively developed in the last decades; quantitative
Scheme 1. Strategies for the synthesis of vinylaziridines. LG=leaving
conversions as well as complete enantioselection have been
already described.[1,2] However, in spite of the large number
of reports related to the alkene aziridination reaction by this
method and the synthetic interest of vinylaziridines,[3] only
few have dealt with conjugated dienes as the substrate.
Copper-,[4] manganese-, and ruthenium-based[5] catalysts have
provided good yields of vinylaziridines formed by the
group.
imines also provides[7] a facile process as it involves the
regioselective construction of vinylaziridine (path b). These
two methods have usually led to the thermodynamically
stable cis aziridines.[8] trans Aziridines were obtained with
high stereoselectivity by the ylide route driving the reaction
under kinetic control conditions.[9] Vinylaziridines were also
prepared from vinyl epoxides by ring opening with azides
(path e), from 1,2-amino halides (path c),[10] and by conjugate
addition.[11] The aforementioned nitrene addition to dienes
(path d)[4,5] have been described, but they can be yet
considered far from successful in terms of regio- and
stereoselectivity.
On the basis of the above, we planned to develop a
catalytic system capable of inducing the formation of vinyl-
aziridines to achieve the following goals: 1) use of non-
symmetric dienes, 2) tolerance to other functional groups,
3) control of the regioselectivity (given an unsymmetric
diene), and 4) control of the stereoselectivity (to obtain
either cis or trans vinylaziridines). We have previously
reported that complexes of general formula [TpxCu(NCMe)]
(Tpx = homoscorpionate ligand,[12] see Scheme 2 for the
structure) effectively catalyze the aziridination of simple
alkenes through the nitrene-transfer reaction,[13] using
PhINTs as the nitrene source. To drive our work to the
above goals, and because the b-amino alcohol moiety is found
in a wide variety of biologically active compounds,[14] we
chose trans,trans-2,4-hexadien-1-ol (1) as the substrate, which
is a nonsymmetric diene containing a hydroxy group.
The reaction of such diene with PhINTs in the presence of
the appropriate catalyst might afford two different aziridines,
from a regioselective point of view, each of them with a cis or
trans geometry (compounds 2–5, Scheme 2). Aziridines 2 and
3 could be formed by nitrene addition to the double bond
vicinal to the hydroxy end of the substrate, whereas aziridines
4 and 5 would correspond to the addition to the double bond
vicinal to the methyl end.
=
exclusive aziridination of one C C bond of the diene,
although with the following limitations: 1) only symmetric
dienes were employed and 2) selectivity, intended as cis/trans
(or trans/cis) ratio, was low. These two drawbacks strongly
prevent the synthetic application of this method.
In fact, vinylaziridines are commonly synthesized by
stoichiometric procedures based on nucleophilic intramolec-
ular substitution. Thus, the Darzens-type reaction (Scheme 1,
path a) is one of the oldest and most flexible methods for
preparation of functional aziridine derivatives including
vinylaziridines.[6] The reaction between an allylic ylide and
[*] ꢀ. Beltrꢁn, Dr. M. M. Dꢂaz-Requejo, Prof. P. J. Pꢃrez
Laboratorio de Catꢁlisis Homogꢃnea, Centro de Investigaciꢄn en
Quꢂmica Sostenible, Departamento de Quꢂmica y Ciencia de los
Materiales, Unidad Asociada al CSIC, Universidad de Huelva
Campus de El Carmen s/n, 21007 Huelva (Spain)
Fax: (+34)95-921-9942
E-mail: perez@dqcm.uhu.es
Homepage: http://www.catalysisatuhu.com
J. Llaveria, Dr. M. I. Matheu, Prof. S. Castillꢄn
Departament de Quꢂmica Analꢂtica i Quꢂmica Orgꢁnica
Facultat de Quꢂmica, Universitat Rovira i Virgili
C/Marcel·lꢂ Domingo s/n, 43007 Tarragona (Spain)
Fax: (+34)977-558446
E-mail: sergio.castillon@urv.cat
maribel.matheu@urv.cat
Homepage: http://www.quimica.urv.es/~w3qo/carbohydrage/
[**] We thank the MICINN (CTQ2008-00042BQU and CTQ2008-
1569BQU) and Consolider Ingenio 2010 (CSD2006-0003) for
funding. J.L. thanks the MICINN and A.B. thanks the Universidad de
Huelva (Plan Propio) for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003167.
7092
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7092 –7095

Angewandte
Chemie
is in agreement with previous proposals in which the
aziridination reaction may occur through stepwise or con-
certed mechanisms.[15] However, it is worth mentioning that in
spite of the low selectivities—the nitrene moiety was exclu-
sively added to the double bonds—the hydroxy group
remained undisturbed throughout the process.
A second group of TpxAg catalysts was then employed
under the same reaction conditions.[16] These catalysts pro-
vided aziridines with excellent regio- and stereoselectivity. In
fact, only trans aziridines were observed with all silver catalyst
(Table 1, entries 5–9). Initial experiments with the complex
bearing the TpBr ligand provided very low yields of aziridines;
3
however, those containing either Tp*,Br or Tp* gave nearly
quantitative conversions (Table 1, entry 10 versus entries 5
and 6) in experiments carried out with a 5% catalyst loading
([cat.]/[PhINTs]/[1] = 1:20:30, with respect to 0.0125 mmol of
catalyst). The excellent performance of the silver catalyst
based on Tp*,Br allowed us to decrease the relative amount of
catalyst to 0.5% without loss of activity (Table 1, entry 7).
Only when a [cat.]/[PhINTs]/[1] ratio of 1:1000:1500 (with
respect to 0.003 mmol of catalyst) was employed, did the
conversion drop to 80% (Table 1, entry 8). All these results
were obtained with initial PhINTs/diene mixtures of 1:1.5.
Remarkably, the use of a 1:200:200 ratio of [cat.]/[PhINTs]/
[diene] (Table 1, entry 9) provided quantitative formation of
aziridines, with an approximate 9:1 mixture of regioisomers
(2/4) and complete retention of configuration. This result is of
importance because usually an excess of the olefin with
respect to the nitrene precursor is employed with this
method—a drawback when the procedure is applied to
more elaborated unsaturated substrates.
Scheme 2. Aziridination of trans,trans-2,4-hexadien-1-ol with TpxM cata-
lysts (M=Cu, Ag) using PhINTs as the nitrene source. Ts=4-toluene-
sulfonyl.
Table 1: Reaction of trans,trans-2,4-hexadien-1-ol with TpxM catalysts
(M=Cu, Ag) using PhINTs as the nitrene source.[a]
Entry
Catalyst
Conv. [%][b]
Regio.[b,c]
trans/cis[b,d]
1
2
3
4
5
6
7
8
9
10
[TpPh,4EtCu]
60
80
67
>99
>95
>99
>99
80
83:17
81:19
82:18
86:14
90:10
90:10
89:11
89:11
88:12
–
60:40
51:49
66:34
[TpClPh,Br Cu]
2
[Tp*Cu]
[TpBr Cu]
66:34
3
[Tp*Ag]
>98:<2[e]
>98:<2[e]
>98:<2[e]
>98:<2[e]
>98:<2[e]
–
To test if the high regioselectivity observed in diene 1 can
be attributed to a directing effect of the hydroxy group,[17,18]
we employed O-protected dienes 6a,b bearing acetyl or
benzyl groups [Eq. (2); Bn = benzyl]. Under the same cata-
[Tp*,BrAg]
[Tp*,BrAg][f]
[Tp*,BrAg][g]
[Tp*,BrAg][h]
>99
<5
[TpBr Ag]
3
[a] Reaction conditions: [cat.]/[PhINTs]/[1]=1:20:30, with respect to
0.0125 mmol of catalyst, 5% catalyst loading. Reaction time was 8 hours
in all cases. TsNH2 accounted for 100% of the initial PhINTs that was not
converted into aziridines. [b] Determined by 1H NMR spectroscopy.
[c] As a (2+3)/(4+5) ratio. [d] 2/3 ratio. [e] cis isomer not detected.
[f] [cat.]/[PhINTs]/[1]=1:200:300, with respect to 0.0046 mmol of cata-
lyst, 0.5% catalyst loading. [g] [cat.]/[PhINTs]/[1]=1:1000:1500, with
respect to 0.003 mmol of catalyst, 0.1% catalyst loading. [h] [cat.]/[-
PhINTs]/[1]=1:200:200, with respect to 0.00125 mmol of catalyst, 0.5%
catalyst loading, ratio of diene/PhINTs=1:1. See Scheme 2 for Tp*
structures.
In a first series of experiments, several TpxCu complexes
were employed as the catalyst in the reaction of the diene with
PhINTs. The results are shown in Table 1. Four copper
complexes were tested; variable conversions into aziridines in
the range 60–99% (based in initial PhINTs) were obtained
(no diaziridination products were observed). In all cases,
regioselection toward the aziridine vicinal to the hydroxy end
of the substrate was high (81–90%). Unfortunately, the
copper catalysts did also induce a certain degree of inversion
of the initial trans configuration of the olefin, thus leading to
final trans/cis mixtures in the range of 1:1 to 2:1. This outcome
lytic conditions, the results indicate that these substrates are
converted into aziridines at lower conversions and, more
interestingly, with a substantial decrease in the regioselectiv-
ity (ratio (7 + 8)/(9+10)), which confirms the directing role of
the hydroxy group.[19]
Given this unprecedented outcome for a metal-catalyzed
diene aziridination reaction, we decided to investigate the
scope of this system using the series of six different dienes 11–
16 shown in Table 2. The reactions were carried out in the
presence of silver-based catalysts, with a 5% catalyst loading
and with equimolar mixtures of the dienes and PhINTs. The
Angew. Chem. Int. Ed. 2010, 49, 7092 –7095
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7093

Communications
Table 2: Scope of the diene aziridination reaction with various dienes
using [Tp*,BrAg] as the catalyst.[a]
major isomer corresponding to the aziridine ring vicinal to the
hydroxy group. The final reaction mixture of aziridines was
treated with KOH to induce ring opening and the concom-
itant formation of the N-protected amino alcohol 29. Further
treatment of 29 with Na/naphthalene provided the targeted
(Æ )-sphingosine in 65% yield of isolated product (based on
the starting diene 15).
In conclusion, we have found that several complexes
containing the TpxM fragment (M = Cu, Ag) catalyze the
aziridination of dienes bearing a terminal hydroxy group, thus
affording vinyl aziridines with a low catalyst loading and using
stoichiometric mixtures of diene and PhINTs (the nitrene
source). The [Tp*,BrAg] catalyst was found to be highly
regioselective toward the aziridination of the double bond
vicinal to the hydroxy end of the substrate and highly
stereospecific with an array of dienes, including a precursor
of (Æ )-sphingosine. The results presented here make the
silver-catalyzed aziridination of dienes a promising synthetic
tool in organic synthesis. Work aimed to understand the
mechanism that governs this transformation as well as to
develop the asymmetric version of this catalytic system is
currently underway in our laboratories.
Entry Diene
Conv. Regio.[b]
[%][b]
trans/cis
[%][b,c]
1
2
3
4
5
6
R1 =R2 =H (11)
>99
>99
>99
>99
17/23, 88:12 >98:<2[d]
18/24, 85:15 >98:<2[d]
19/25, 86:14 >98:<2[d]
20/26, 93:7
21/27, 86:14 >98:<2[d]
22/28, 90:10
<2:>98[e]
R1 =H, R2 =Et (12)
R1 =R2 =Me (13)
R1 =H, R2 =Ph (14)
>98:<2[d]
R1 =H, R2 =C13H27 (15) >99
16
>99
[a] Reaction conditions: [cat.]/[PhINTs]/[diene]=1:20:20, with respect to
0.0125 mmol of catalyst, reaction time was 4 hours. TsNH2 accounted
for 100% of the initial PhINTs that was not converted into aziridines.
[b] Determined by 1H NMR spectroscopy. [c] trans/cis ratio for the major
aziridine. [d] cis isomer not detected. [e] trans isomer not detected.
Experimental Section
General procedure for aziridination of 2,4-dien-1-ol: A 100 mL
Schlenk flask containing a magnetic stirring bar was charged, under
an argon atmosphere, with the catalyst (0.0025 mmol, 1%), the
alcohol (0.25 mmol), and anhydrous dichloromethane (5 mL).
Freshly prepared PhINTs (0.27 mmol) was added in 3–4 portions
over 2 h, and the mixture was stirred for an additional hour after the
last addition. The solvent was removed under vacuum and the
resulting crude residue was characterized without purification
because vinyl aziridines are unstable on silica gel and neutral
alumina. Spectroscopic data were extracted from the spectra of the
isolated crude reaction residues. All procedures for the preparation of
the starting dien-1-ols and for the aziridination of such substrates, as
well as spectroscopic data (including NMR spectra) are given in the
Supporting Information.
results are in agreement with those obtained with 1, and can
be summarized as follows: 1) quantitative conversions into
aziridines were obtained in all cases, even with the sterically
hindered diene 13; 2) the product derived from the aziridi-
nation of the double bond vicinal to the hydroxy group was
preferred in all cases, with regioselectivity being within the
interval of 85:15 to 93:7; 3) complete retention of config-
uration appeared as a constant in all the experiments. It is
worth mentioning that when the cis,trans diene 16 was
employed, aziridination of the internal cis double bond was
preferred (owing to its vicinity to the hydroxy group), and
such geometry was maintained in the resulting aziridine, a fact
that indicates that the reaction is stereospecific.
Driven by our interest in developing new methods for the
synthesis of amino alcohols with biological interest,[20] we
have applied this method to the synthesis of (Æ )-sphingo-
sine.[21,22] As shown in Scheme 3, diene 15 was employed as
the starting material. Aziridination with PhINTs gave a
mixture of aziridines in 86:14 ratio (Table 2, entry 5), the
Received: May 25, 2010
Published online: August 18, 2010
Keywords: aziridination · b-amino alcohols · regioselectivity ·
.
sphingosine · stereospecificity
[1] For reviews in the area of nitrene transfer, see: a) D. N. Zalatan,
J. Du Bois, Top. Curr. Chem. 2010, 292, 347; b) H. Pellissier,
Tetrahedron 2010, 66, 1509; c) F. Collet, R. H. Dodd, P. Dauban,
Chem. Commun. 2009, 5061; d) S. Fantauzzi, A. Caselli, E. Gallo,
Dalton Trans. 2009, 5434; e) H. M. L. Davies, J. R. Manning,
Nature 2008, 451, 417; f) A. R. Dick, M. S. Sanford, Tetrahedron
2006, 62, 2439; g) Modern Rhodium-Catalyzed Organic Reac-
tions (Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005, p. 379;
h) J. A. Halfen, Curr. Org. Chem. 2005, 9, 657; i) T. Katsuki,
Chem. Lett. 2005, 34, 1304; j) P. Mꢀller, C. Fruit, Chem. Rev.
2003, 103, 2905.
[2] For some key contributions in the area of nitrene transfer, see:
a) C. Liang, F. Collet, F. Robert-Peillard, P. Mꢀller, R. H. Dodd,
P. Dauban, J. Am. Chem. Soc. 2008, 130, 343; b) K. Williams, J.
Du Bois, J. Am. Chem. Soc. 2007, 129, 562; c) H. Lebel, K.
Huard, S. Lectard, J. Am. Chem. Soc. 2005, 127, 14198; d) C. G.
Scheme 3. Application of the diene aziridination method to the syn-
thesis of (Æ)-sphingosine. DME=1,2-dimethoxyethane, DMSO=di-
methyl sulfoxide.
7094 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7092 –7095

Angewandte
Chemie
Espino, J. Du Bois, Angew. Chem. 2001, 113, 618; Angew. Chem.
Int. Ed. 2001, 40, 598; e) X.-Q. Yu, J.-S. Huang, X.-G. Zhou, C.-
M. Che, Org. Lett. 2000, 2, 2233; f) K. Guthikonda, J. Du Bois, J.
Am. Chem. Soc. 2002, 124, 13672; g) P. Dauban, L. Saniꢁre, A.
Tarrade, R. H. Dodd, J. Am. Chem. Soc. 2001, 123, 7707; h) P.
Mꢀller, C. Baud, Y. Jacquier, Tetrahedron 1996, 52, 1543; i) D. A.
Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116,
2742.
Akaji, H. Ohno, Y. Miwa, T. Taga, K. Nakai, H. Tamamura, N.
Fujii, J. Org. Chem. 1997, 62, 999.
[9] X.-F. Yang, M.-J. Zhang, X.-L. Hou, L.-X. Dai, J. Org. Chem.
2002, 67, 8097.
[10] I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39,
194.
[11] A. Armstrong, R. D. C. Pullin, C. R. Jenner, J. N. Scutt, J. Org.
Chem. 2010, 75, 3499.
[3] a) H. Ohno in Aziridines and Epoxides in Organic Synthesis
(Ed.: A. K. Yudin), Wiley-VCH, Weinheim, 2006, p. 37; b) F.
Fontana, G. C. Tron, N. Barbero, S. Ferrini, S. P. Thomas, V. K.
Aggarwal, Chem. Commun. 2010, 46, 267; c) S. Fantauzzi, E.
Gallo, A. Caselli, C. Piangiolino, F. Ragaini, N. Re, S. Cenini,
Chem. Eur. J. 2009, 15, 1241; d) M. Brichacek, D. Lee, J. T.
Njardarson, Org. Lett. 2008, 10, 5023; e) B. M. Trost, D. R.
Fandrick, J. Am. Chem. Soc. 2003, 125, 11836; f) S. V. Ley, B.
Middleton, Chem. Commun. 1998, 1995; g) J. ꢂhman, P. Somfai,
Tetrahedron Lett. 1995, 36, 303; h) I. Coldham, A. J. Collis, R. J.
Mould, R. E. Rathmell, Tetrahedron Lett. 1995, 36, 3557; i) G. W.
Spears, K. Nakanishi, Y. Ohfune, Synlett 1991, 91.
[4] a) L. Ma, D.-M. Du, J. Xu, Chirality 2006, 18, 575; b) D.
Sureshkumar, S. Maity, S. Chandrasekaran, J. Org. Chem. 2006,
71, 1653; c) J. G. Knight, M. P. Muldowney, Synlett 1995, 949.
[5] a) C. Piangiolino, E. Gallo, A. Caselli, S. Fantauzzi, F. Ragaini, S.
Cenini, Eur. J. Org. Chem. 2007, 743; b) M. Nishimura, S.
Minakata, S. Thongchant, I. Ryu, M. Komatsu, Tetrahedron Lett.
2000, 41, 7089.
[6] a) J. Sweeney, Eur. J. Org. Chem. 2009, 4911; b) A. L. Williams,
J. N. Johnston, J. Am. Chem. Soc. 2004, 126, 1612; c) T. Akiyama,
T. Suzuki, K. Mori, Org. Lett. 2009, 11, 2445; d) J. M. Concellꢃn,
H. Rodriguez-Solla, C. Simal, Org. Lett. 2008, 10, 4457; e) J. M.
Concellꢃn, H. Rodrꢄguez-Solla, P. L. Bernad, C. Simal, J. Org.
Chem. 2009, 74, 2452.
[7] See for example: a) B.-H. Zhu, J.-C. Zheng, C.-B. Yu, X.-L. Sun,
Y.-G. Zhou, Q. Shen, Y. Tang, Org. Lett. 2010, 12, 504; b) J.-C.
Zheng, W.-W. Liao, X.-X. Sun, X.-L. Sun, Y. Tang, L-X. Dai, J.-
G. Deng, Org. Lett. 2005, 7, 5789; c) V. K. Aggarwal, E. Alonso,
G. Fang, M. Ferrara, G. Hynd, M. Porcelloni, Angew. Chem.
2001, 113, 1482; Angew. Chem. Int. Ed. 2001, 40, 1433.
[8] a) T. Ibuka, N. Mimura, H. Ohno, K. Nakai, M. Akaji, H.
Habashita, H. Tamamura, Y. Miwa, T. Taga, N. Fujii, J. Org.
Chem. 1997, 62, 2982; b) T. Ibuka, N. Mimura, H. Aoyama, M.
[12] a) S. Trofimenko, Scorpionates, The Coordination Chemistry of
Polypyrazolylborate Ligands, Imperial College Press, London,
1999; b) C. Pettinari, Scorpionates II: Chelating Borate Ligands,
Imperial College Press, London, 2008.
[13] M. A. Mairena, M. M. Dꢄaz-Requejo, T. R. Belderrain, M. C.
Nicasio, S. Trofimenko, P. J. Pꢅrez, Organometallics 2004, 23,
253.
[14] S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998, 120,
431, and references therein.
[15] a) A. N. Vedernikov, K. G. Caulton, Org. Lett. 2003, 5, 2591; b) P.
Brandt, M. J. Sꢆdergren, P. G. Andersoon, P.-O. Norrby, J. Am.
Chem. Soc. 2000, 122, 8013; c) Z. Li, R. W. Quan, E. N. Jacobsen,
J. Am. Chem. Soc. 1995, 117, 5889.
[16] A dinuclear silver complex as catalyst for alkene aziridination
has been described: Y. Cui, C. He, J. Am. Chem. Soc. 2003, 125,
16202.
[17] A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93,
1307.
[18] D. Caine, P. OꢇBrien, C. M. Rosser, Org. Lett. 2002, 4, 1923.
[19] a) M. Cakici, S. Karabuga, H. Kilic, S. Ulukanli, E. Sahin, F.
Sevin, J. Org. Chem. 2009, 74, 9452; b) R. S. Atkinson, B. J. Kelly,
J. Chem. Soc. Chem. Commun. 1988, 624.
[20] a) J. Llaveria, Y. Dꢄaz, M. I. Matheu, S. Castillꢃn, Org. Lett. 2009,
11, 205; b) J. A. Morales-Serna, J. Llaveria, Y. Dꢄaz, M. I.
Matheu, S. Castillꢃn, Org. Biomol. Chem. 2008, 6, 4502.
[21] For a review on the synthesis of sphingosines, see: J. A. Morales-
Serna, J. Llaveria, Y. Dꢄaz, M. I. Matheu, S. Castillꢃn, Curr. Org.
Chem., in press.
[22] For nitrene transfer reactions employed in synthetic routes, see:
a) P. M. Wehn, J. Du Bois, Angew. Chem. 2009, 121, 3860;
Angew. Chem. Int. Ed. 2009, 48, 3802; b) B. M. Trost, T. Zhang,
Angew. Chem. 2008, 120, 3819; Angew. Chem. Int. Ed. 2008, 47,
3759; c) B. M. Trost, G. Dong, Chem. Eur. J. 2009, 15, 6910.
Angew. Chem. Int. Ed. 2010, 49, 7092 –7095
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7095