Metallocene catalyzed synthesis of fungistatic vicinal aminoalcohols under solvent free conditions

Article abstract of DOI:10.1016/j.bmcl.2010.08.109

Group 4 and 5 metallocenes, Cp₂TiCl₂, Cp ₂ZrCl₂ and Cp₂VCl₂, have been evaluated as catalyst in the solvent free, room temperature, preparation of vicinal aminoalcohols. The regioselectivity of the reaction and the fungistatic activity of the prepared compounds against Botrytis cinerea and Colletotrichum gloeosporioides are discussed.

Full text of DOI:10.1016/j.bmcl.2010.08.109

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6820–6822
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Metallocene catalyzed synthesis of fungistatic vicinal aminoalcohols
under solvent free conditions
⇑
⇑
Gabriela Mancilla, Rosa M. Durán-Patrón, Antonio J. Macías-Sánchez , Isidro G. Collado
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, s/n, Apdo. 40, 11510 Puerto Real, Cádiz, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2010
Revised 19 August 2010
Accepted 21 August 2010
Available online 21 September 2010
Group 4 and 5 metallocenes, Cp2TiCl2, Cp2ZrCl2 and Cp2VCl2, have been evaluated as catalyst in the sol-
vent free, room temperature, preparation of vicinal aminoalcohols. The regioselectivity of the reaction
and the fungistatic activity of the prepared compounds against Botrytis cinerea and Colletotrichum gloeo-
sporioides are discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Metallocenes
Synthesis aminoalcohol
Fungistatic
Fungi
Botrytis cinerea
Colletotrichum gloeosporioides
Vicinal amino alcohol functionality is a structural component
which can be found in an ample group of naturally occurring and
synthetic molecules. The substitution pattern and stereochemistry
of this moiety play an important role in the biological activity of
molecules containing an 1,2-amino alcohol group in their struc-
ture.1 For instance, sphingosine,2 as well as other related com-
pounds,3 has been described to present antifungal activity.
The classical route for the preparation of these compounds from
epoxides is the direct aminolysis of 1,2-epoxides4 however, this
procedure has limitations such as the requirement of excess of
amines and elevated temperature, often works less well with
poorly nucleophilic and sterically hindered amines and lacks of
appreciable regioselectivity. New methods have been developed
to overcome these handicaps,5 which can broadly be grouped
either in those using metal amides or those using Lewis acids.6
In order to reduce the environmental impact of the use of or-
ganic solvents in the preparation of vicinal aminoalcohols, some
alternative procedures have been described in the literature, such
as the use of supercritical carbon dioxide,7 microwave irradiation,8
or ionic liquids.9 The use of solvent free conditions is an additional
strategy, which can be used on its own,10 combined with micro-
wave irradiation11 or with the use of catalysts,12 some of them
involving transition metals.13
Group 4 and 5 metallocenes, (Ti, Zr, V) have been used as Lewis
acid catalysts in transformations of organic compounds,14 but to
our knowledge, there are not precedents of their application to
the opening of epoxides by amines to yield aminoalcohols. On
the other hand, other complexes of such metals like ZrCl4,15
16
17
Ti(OiPr)4 and VCl3 have been described in the preparation of
aminoalcohols by oxirane ring opening.
OAc
H
H
H
OH
OH
OR
HO
OH
1
R=alkyl
2
1a R=CH2CH2NH2
Our research group is interested in the synthesis of environ-
mentally friendly and selective inhibitors of the fungus Botrytis
cinerea.28 2-Alkoxyclovane-9-ol derivatives 1,29 possess a struc-
tural similarity to the proposed key intermediate 230 in the biosyn-
thesis31 of the phytotoxic32 botryane metabolites produced by the
fungus B. cinerea, and they have been shown to inhibit the growth
of this fungus.33 Some of the more active alkoxyclovanols 1a34
present nitrogen atoms in the side chain at C-2. Further research
requires the exploration of structure–activity relationships, and
we postulated the use of simpler templates, like styrene oxide,
which could yield vicinal aminoalcohols with similar or improved
activities and which could be prepared in better yields.
⇑
Corresponding authors. Tel.: +34 956 016368; fax: +34 956 016193 (A.J.M.-S.);
tel.: +34 956 016368; fax: +34 956 016193 (I.G.C.).
E-mail addresses: antoniojose.macias@uca.es (A.J. Macías-Sánchez), isidro.
gonzalez@uca.es (I.G. Collado).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.109

G. Mancilla et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6820–6822
6821
M = Ti, Zr, V
Cp2MCl2
R2
R1
R1
R2
R2 R1
R
OH
R2 R1
O
N
+
+
+ RNH2
OH
NHR
R2
OH
RHN
HO
Ar, 25ºC.
solvent-free
6
7
R1
5
3
4
1
2
R=p-CH3C6H4, R =Ph, R =H
R=p-CH3C6H4, R1=R2=CH3
6g,7b
R=t-Bu,
5a,6a
5b,6b
5d,6d
6e
R1=CH2
R2=H
1
2
1
2
R=t-Bu, R =Ph, R =H
R=t-Bu, R =R =CH3
5c,6c R=p-NO2C6H4, R1=Ph, R2=H
6f,7a R=p-CH3C6H4, R1=CH2OPh, R2=H
Scheme 1.
In this paper we explore the use of group 4 and 5 metallocenes
(Cp2TiCl2, Cp2ZrCl2 and Cp2VCl2) as catalysts, under solvent free
conditions, in the cleavage of epoxides by amines to give aminoal-
cohols with potential antifungal activity.
Non-symmetrically substituted epoxides styrene oxide (3a),
2-methylpropene oxide (3b) and 2-(phenoxymethyl)oxirane (3c)
(1 mmol) were treated at 25 °C, under absence of further solvents,
with p-methylaniline (4a) and tert-butylamine (4b) (1.1 mmol)
2-(Phenoxymethyl)oxirane (3c) yields a minor regioisomer by
an attack of the amine on two units of epoxide. The amine attaches
at two epoxide units at the substituted (secondary) position of the
oxirane ring, leading to 2,20-(p-tolylazanediyl)bis(3-phenoxypro-
pan-1-ol) (7a) or 2,20-(tert-butylazanediyl)bis(3-phenoxypropan-
1-ol) (7b), depending on the amine.
The preliminary antifungal activity of compounds 5a–d, 6a–f
and 7a–b, against the phytopathogenic fungi Botrytis cinerea and
Colletotriuchum gloeosporioides, was evaluated at a concentration
of 100 mg/L using a reported procedure.33,34 The inhibition rates of
a selection of these compounds are listed in Table 2. Compounds
5a, 5c and 6f are the most active ones for both fungi. Compound 6f
possess an activity against B. cinerea comparable to that of the com-
mercial fungicide dichofluanid (rel. inhib. >95%, 100 mg/L).37 On the
other hand, compounds 6d and 7a are moderately active, but only
against B. cinerea. Compounds not presented in Table 2 were not
active either against B. cinerea or against C. gloeosporioides.
In conclusion, Group 4 and 5 metallocenes, Cp2TiCl2, Cp2ZrCl2
and Cp2VCl2, proved to be efficient catalysts in the opening at
room temperature of epoxides by aromatic amines. Yields are
dependent of the combination of amine and epoxide, and reaction
times were kept between 3 and 1.5 h. Aliphatic amines showed to
be less reactive under evaluated conditions, giving lower yields.
Best and opposite regioselectivities were observed for the
combination of p-methylaniline (4a) and styrene oxide (3a) (most
substituted regioisomer, compound 5a) and of 2-methylpropene
oxide and tert-butyl amine (less substituted regioisomer, com-
pound 6e).
and
a catalytic amount (10 mol%) of metallocene (Cp2TiCl2,
Cp2ZrCl2 and Cp2VCl2) (Scheme 1). Reactions times, yields and
products obtained are detailed in Table 1. All crude reaction mix-
tures were purified by column chromatography on silica gel. The
structures of known compounds were determined by comparison
of spectroscopic and physical data with the literature. A combina-
tion of 1D and 2D NMR techniques, together with IR spectroscopy
and mass spectrometry data allowed the assignation of the struc-
tures for novel compounds.
Yields and regioselectivity were variable, but some trends could
be drawn. Best yields and regioselectivity are observed for the
combination of styrene oxide (3a) and p-methylaniline (4a), being
Cp2TiCl2 the catalyst which gives the best results (entry 1). The
preference of attack on the benzylic position of the oxirane has
been described before for the reaction of anilines with styrene
oxide (3a).5,17,35 On the other hand, the opposite regioselectivity
is observed for tertiary epoxide 3b, even when p-methylaniline
(4a) is used. For both epoxides 3b and 3c, the most abundant reg-
ioisomeric aminoalcohol originates by preferential attack on the
least substituted position of the oxirane (compounds 6d–g). Reac-
tion between tert-butyl amine and epoxides 3b and 3c also yield
the least substituted regioisomer.36 This is not the case for styrene
oxide, where little or none regioselection is observed.
Finally, biological activity against B. cinerea seemed to be corre-
lated with the presence of an aromatic moiety in the molecule,
especially if it is bound to the nitrogen atom. On the other hand,
Table 1
Treatment of epoxides (3a–3c), with amines catalyzed by Cp2MCl2 (M = Ti, Zr, V)a
Entry
Epoxide (3)
Amine (4)
Catalyst
Time (h)
Yield (%)b
Product/s (ratio)b
Referencesc
18, 36b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Styrene oxide (3a)
3a
3a
3a
3a
3a
3a
3a
p-Methylaniline (4a)
4a
4a
tert-Butylamine (4b)
4b
4b
p-Nitroaniline (4c)
4c
4c
p-Methylaniline (4a)
4a
4a
tert-Butylamine (4b)
4b
4b
p-Methylaniline (4a)
4a
4a
tert-Butylamine (4b)
4b
4b
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
Cp2TiCl2
Cp2ZrCl2
Cp2VCl2
2
2
2
>99
92
>99
43
89
53
38
68
58
37
49
28
28
30
20
>99
32
98
55
40
88
5a + 6a (99.5:0.5)
5a + 6a (93:7)
5a + 6a (95:5)
5b + 6b (50:50)
5b + 6b (20:80)
5b + 6b (29:71)
5c + 6c (96:4)
5c + 6c (98:2)
5c + 6c (99:1)
5d + 6d (8:92)
5d + 6d (17:83)
5d + 6d (5:95)
6e
70
23
70
48
1.5
48
1.5
1.5
1.5
3.5
3.5
3.5
2
19, 20
35
3a
2-Methylpropene oxide (3b)
3b
3b
3b
3b
3b
21, 22
23
2-(Phenoxymethyl) oxirane (3c)
6f + 7a (70:30)
6f + 7a (75:25)
6f + 7a (70:30)
6g + 7b (70:30)
6g + 7b (67:33)
6g + 7b (75:25)
3c
3c
3c
3c
3c
3
2
18
10
18
24, 25
26, 27
a
b
c
Reaction conditions: epoxide (3): (1 mmol), amine (4): (1.1 mmol), Cp2MCl2: (10 mol%).
Yields and product ratios obtained after chromatographic purification.
References including spectroscopic data.

6822
G. Mancilla et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6820–6822
16. Harden, R. C.; Hakgkinson, T. J.; McKillop, A.; Prowse, W. G.; Urquhart, M. W. J.
Table 2
Tetrahedron 1997, 53, 21.
Antifungal activity (relative inhibition (%), 100 mg/L) of selected aminoalcohols
17. Sabitha, G.; Kiran Kumar Reddy, G. S.; Bhaskar Reddy, K.; Yadav, J. S. Synthesis
2003, 2298.
18. Herweh, J. E.; Foglia, T. A.; Swern, D. J. Org. Chem. 1968, 33, 4029.
19. Ando, A.; Shioiri, T. Tetrahedron 1989, 45, 4969.
20. Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasekhar, M.; Singh, V. K.
Tetrahedron 2002, 58, 4693.
(relative inhibition at 100 mg/L P30%)
Compound
Botrytis cinerea
Colletotrichum gloeosporioides
5a
5c
6d
6f
7a
7b
63
69
62
87
53
43
40
55
a
21. Compound 5d. Yellow oil. IR (KBr) mmax (cmꢀ1): 3390, 2972, 2866, 1620, 1380,
1365, 1318, 1250, 1126, 808; 1H NMR (400 MHz, CDCl3): d (ppm) 1.20 (s, 6H,
H-3, H-4), 2,08 (br s, 2H, OH, NH), 2.25 (s, 3H, H–ArCH3), 3.49 (s, 2H, H-1), 6.73
(d, J = 8.3 Hz, 2H, H-20, H-60), 7.00 (d, J = 8.0 Hz, 2H, H-30, H-50); 13C NMR
(100 MHz, CDCl3): d (ppm) 22.5 (c, C-ArCH3), 27.1 (c, 2C, C-3, C-4), 57.7 (s, C-2),
71.1 (t, C-1), 122.4 (d, 2C, C-20, C-60), 131.5 (d, 2C, C-30, C-50), 132.2 (s, C-40),
144.8 (s, C-10); EIMS m/z (rel. int.): 179 [M]+ (35); 106 (100); 91(29); 77 (9);
HREIMS: for C11H17NO calcd 179.1310, found 179.1314.
—
72
a
—
—
a
a
Relative inhibition at 100 mg/L <30%.
22. Nishiyama, T.; Kishi, H.; Kitano, K.; Yamada, F. Bull. Chem. Soc. Jpn. 1994, 67,
1765.
the presence of an aniline fragment seems to be necessary for
activity against C. gloeosporioides.
23. Coates, R. M.; Cummins, C. H. J. Org. Chem. 1986, 51, 1383.
24. Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2007, 17, 2683.
25. Compound 7a. White solid: mp: 58–61 °C; IR (KBr) mmax (cmꢀ1): 3345, 3063,
2922, 1599, 1245, 1043, 753, 691. 1H NMR (400 MHz, (CD3)2CO): d (ppm) 2.15
(s, 3H, H–CH3), 3.72 (dd, J = 11.2, 5.6 Hz, 2H, H-1a (bis)), 3.81 (dd, J = 11.2,
4.8 Hz, 2H, H-1b (bis)), 4.07 (d, J = 5.6 Hz, 4H, H-3 (bis)), 4.19 (q, J = 4.6 Hz, 2H,
H-2 (bis)), 4.32 (br s, 2H, OH), 6.56 (dt, J = 6.4, 2.0 Hz, 2H, H-300, H-500), 6.86 (dd,
J = 8.0, 0.8 Hz, 2H, H-200, H-600), 6.95 (dd, J = 8.0, 0.8 Hz, 6H, H-30 (bis), H-40 (bis),
H-50 (bis)), 7.28 (dd, J = 8.8, 7.2 Hz, 4H, H-20 (bis), H-40 (bis)); 13C NMR
(100 MHz, (CD3)2CO): d (ppm) 20.4 (c, C–CH3), 47.1 (t, 2C, C-1 (bis)), 69.8 (t, 2C,
C-3 (bis)), 70.4 (d, 2C, C-2 (bis)), 115.3 (d, 6C, C-30 (bis), C-50 (bis), C-300, C-500),
121.6 (d, 2C, C-40 (bis)), 126.1 (s, C-400), 130.1 (d, 2C, C-200, C-600), 130.2 (d, 4C, C-
20 (bis), C-60 (bis)), 146.6 (s, C-100), 159.6 (s, 2C, C-10 (bis)); EIMS m/z (rel. int.):
407 [M]+ (11); 270 (100); 134 (70); 120 (20); 77 (10); 91 (8); HREIMS: for
Acknowledgments
This research was supported by grants from MICIN, AGL2009-
13359-C02-01, and the Junta de Andalucía, P07-FQM-02689
(Spain). G.M. thanks CONACYT (Mexico) and the Fundación Caro-
lina (Spain) for a studentship.
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(s, 9H, H–C(CH3)3), 2.60 (dd, J = 14.4, 8.5 Hz, 2H, H-1a (bis)), 3.07 (dd, J = 14.4,
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(bis)), 160.0 (d, 4C, C-30 (bis), C-50 (bis)); EIMS m/z (rel. int.): 373 [M]+ (1); 358
[MꢀCH3]+ (4); 236 (100); 180 (54); HREIMS: for C22H31NO4 calcd 373.2253,
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