Tandem isomerization-Mannich reactions from allylic alcohols and their use for the preparation of four diastereoisomers of 1-amino-2-methyl-1-phenyloctan- 3-ol

Article abstract of DOI:10.2174/157017809789124858

The tandem isomerization-Mannich reaction of octen-3-ol and benzylidene N-sulfonyl imine affords the corresponding β-aminoketones in good yields. Diastereoselective reduction, followed by the deprotection of the primary amine, gives the expected 1-amino-2

Full text of DOI:10.2174/157017809789124858

Letters in Organic Chemistry, 2009, 6, 507-510
507
Tandem Isomerization-Mannich Reactions from Allylic Alcohols and their
Use for the Preparation of Four Diastereoisomers of 1-Amino-2-Methyl-1-
Phenyloctan-3-ol
Hai T. Caoa, Thierry Roisnelb and René Grée*,a
aUniversité de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue du Général
Leclerc, 35042 Rennes-Cedex France
bSciences Chimiques de Rennes, CNRS UMR 6226, Campus de Beaulieu, 35042 Rennes-Cedex, France
Received January 19, 2009: Revised March 14, 2009: Accepted March 19, 2009
Abstract: The tandem isomerization-Mannich reaction of octen-3-ol and benzylidene N-sulfonyl imine affords the corre-
sponding ꢀ-aminoketones in good yields. Diastereoselective reduction, followed by the deprotection of the primary amine,
gives the expected 1-amino-2-methyl-1-phenyloctan-3-ol derivatives in excellent yields and in diastereomerically pure
forms.
Keywords: Mannich reaction, 1,3 aminoalcohols, allylic alcohols, iron, catalysis.
INTRODUCTION
It is well recognized that the ꢀ-aminoalcohol substructure
is a key factor of many bioactive molecules and drugs. It is
also of much use to design chiral ligands and auxiliaries in
asymmetric synthesis [9]. Therefore it appeared important to
us to check in more detail such a tandem isomerization-
Mannich type reaction by using N-sulfonyl imines as
electrophiles. The purpose of this paper is to describe a short
(3 steps) and efficient sequence starting from octen-3-ol and
The development of new methodologies for the C-C
bond formation is one of the key issues in organic synthesis.
We have introduced recently a new transition metal-
mediated tandem isomerization-aldolisation reaction from
allylic alcohols with carbonyl compounds. It is a full atom
economy process which, furthermore, occurs under mild and
Ph
N
Ph
nC5H11
Ph
nC5H11
2
nC5H11
SO2Ph
+
NH
O
NH
O
OH
Fe(CO)5 10mol%
PhO2S
PhO2S
hꢀ, THF
4
1
3
Scheme 1. Iron carbonyl-mediated tandem isomerization-Mannich reaction from allylic alcohol 1 with imine 2.
benzylidene N-sulfonyl imine affording the four diastereoi-
somers of 1-amino-2-methyl-1-phenyloctan-3-ol.
neutral reaction conditions [1]. It allows the synthesis of
diols and other polyfunctional molecules and corresponding
reactions have been extended to optically active molecules
[2]. This process is catalyzed by various transition metal
derivatives, including Fe [1,2] as well as Rh and Ru
complexes [3,4]. Furthermore, it can be used both in the
inter- and in the intramolecular modes [5]. Detailed mech-
anistic studies have established the key role of the free enol
in this process [6]. On the other hand, very little is known in
the case of the analogous tandem reaction with imines: only
two publications report such a reaction with a few
N-arylimines, catalyzed by ruthenium complexes either in
ionic liquids [7] or in aqueous media [8].
RESULTS AND DISCUSSION
Tandem Isomerization-Mannich Type Reactions
The first step of this study was the development of the
tandem isomerization-Mannich reaction and we used the
octene-3-ol as model for the allylic alcohol component. On
the other hand, the N-phenylsulfonyl imine 2 was selected as
electrophile since it was considered that the SO2Ph group
was not only an appropriate protective group but it should
also activate the imine function during the nucleophilic
addition step. In agreement with our previous results in the
tandem isomerization-aldolisation process, Fe(CO)5 at
10mol%, was found as a suitable catalyst for this reaction. It
affords the desired ꢀ-aminoketones in good yield (71%), as a
55/45 mixture of anti 3/syn 4 diastereoisomers easily
separated by silica gel chromatography.
*Address correspondence to this author at the Université de Rennes 1, Labo-
ratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue
du Général Leclerc, 35042 Rennes-Cedex France; Tel: + 33 (0)2 23 23 57
15; Fax: + 33 (0)2 23 23 69 78; E-mail: rene.gree@univ-rennes1.fr
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

508 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Cao et al.
Fig. (1). X-Ray structure analysis of anti ꢀ-aminoketone 3.
Ph
nC5H11
Ph
nC5H11
Ph
nC5H11
see Table 1
+
NH
OH
NH
O
NH
OH
PhO2S
PhO2S
PhO2S
6
3
5
Ph
nC5H11
Ph
nC5H11
Ph
nC5H11
see Table 1
+
NH
O
NH
OH
NH
OH
PhO2S
PhO2S
PhO2S
4
8
7
Scheme 2. Reduction of the ꢀ-aminoketones 3 and 4.
Table 1. Reduction of the ꢀ-Aminoketones 3 and 4
Reducing Agent
5/6a (yield)b
7/8a (yield)b
NaBH4
NaBH4/CeCl3
Dibal-H
71/29 (99%)
52/48 (99%)
80/20 (85%)
92/8 (73%)
64/36 (99%)
55/45 (99%)
80/20 (85%)
95/5 (77%)
LiAlH4
L-Selectride®
>98/<2 (89%)
>98/<2 (90%)
aRatios established by NMR analysis of the crude reaction mixture. bIsolated yields.
The stereochemistry was established from the NMR data,
by analogy with literature [7,8]. It was confirmed by the
X-Ray analysis of major diastereoisomer 3 (Fig. 1) [10]. It is
worth mentioning that a low syn/anti diastereoselectivity has
been observed during a similar reaction on N-aryl imines
mediated by ruthenium based catalysts [7,8].
amine. Several reducing agents were screened to check the
diastereoselectivity of the reduction and the results are given
in Scheme 2 and Table 1.
Starting from 3, a low selectivity was obtained by using
NaBH4 since a 71/29 mixture of stereoisomers 5 and 6 was
obtained. These derivatives were separated by chromatogra-
phy and the anti/syn structure of 5 was established unambi-
guously by X-Ray analysis (Fig. 2) [11].
Synthesis of the ꢀ-Aminoalcohols 9-12
The use of the Luche reaction conditions affords a lower
selectivity but it could be advantageous if the anti/anti
isomer 6 is the desired molecule. The use of Dibal-H and
The second part of this study was the preparation of the
ꢀ-aminoalcohols. This involves a two steps sequence, the
reduction of the ketone and the deprotection of the primary

Tandem Isomerization-Mannich Reactions from Allylic Alcohols
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
509
Fig. (2). X-Ray structure analysis of anti-syn ꢀ-aminoalcohol 5.
Ph
nC5H11
Na, NH3
90%
Ph
nC5H11
Na, NH3
90%
7
8
5
6
NH2 OH
NH2 OH
11
9
Ph
nC5H11
10
Ph
nC5H11
Na, NH3
91%
Na, NH3
90%
NH2 OH
NH2 OH
12
Scheme 3. Deprotection of the ꢀ-aminoalcohols 5 to 8.
[2]
(a) Cuperly, D.; Crévisy, C.; Grée R. J. Org. Chem., 2003, 68,
6392; (b) Petrignet, J.; Roisnel, T.; Grée R. Tetrahedron Lett.,
2006, 47, 7745.
Uma, R.; Davies, M.; Crévisy, C.; Grée R. Tetrahedron Lett., 2001,
42, 3069.
A new process employing activation of ruthenium catalysts by
potassium tertiobutylate and involving ruthenium enolates as
intermediates has been proposed recently, see: Bartoszewicz, A.;
Livendahl, M.; Martin-Matute B. Chem. Eur. J., 2008, 14, 10547
and references therein. For early transition metal-mediated
isomerizations of allylic alcoholates see: Gazzard, L. J.;
Motherwell, W. B.; Sandham, D. A. J. Chem. Soc. Perkin Trans 1,
1999, 979 and references therein.
(a) Petrignet, J.; Prathap, I.; Chandrasekhar, S.; Yadav, J. S.; Grée
R. Angew. Chem. Int. Ed. Engl., 2007, 46, 6297; (b) Petrignet, J.;
Roisnel, T.; Grée R. Chem. Eur. J., 2007, 13, 7374.
(a) Branchadell, V.; Crévisy, C.; Grée R. Chem. Eur. J., 2004, 10,
5795; (b) Cuperly, D.; Petrignet, J.; Crévisy, C.; Grée R. Chem.
Eur. J., 2006, 12, 3261.
(a) Yang, X.-F.; Wang, M.; Varma, R. S.; Li, C.-J. Org. Lett., 2003,
5, 657; (b) Yang, X.-F.; Wang, M.; Varma, R. S.; Li, C.-J. J. Mol.
Catal. A: Chem., 2004, 214, 147.
Wang, M.; Yang, X.-F.; Li, C.-J. Eur. J. Org. Chem., 2003, 5, 998.
See for instance: Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem.
Rev., 2007, 107, 767 and references therein.
LiAlH4 improves the syn selectivity at the newly created
stereogenic center and finally a fully stereocontroled reduc-
tion is obtained by using L-Selectride®. Very similar results
are obtained during the reduction of the isomeric
ꢀ-aminoketone 4 (Table 1). Luche's reaction conditions have
to be followed to obtain isomer 8 while L-Selectride® is best
suited for the preparation of 7.
[3]
[4]
The last step is the deprotection of the primary amino
function. After several experiments, it was found that sodium
in liquid ammonia is working best, affording the different
ꢀ-aminoalcohols 9 to 12 in excellent yields (>90%) and in
pure diastereoisomeric forms (Scheme 3) [12,13].
[5]
[6]
[7]
CONCLUSIONS
This tandem isomerization-Mannich reaction strategy
affords in a few steps and good overall yields the desired
diastereoisomeric ꢀ-amino alcohols 9 to 12 ready for further
uses. Extension of this methodology and further applications
in synthesis are under active study in our group.
[8]
[9]
[10]
[11]
[12]
The crystal structure corresponding to ꢀ-aminoketone 3 has been
deposited at the Cambridge Crystallographic Data Centre and
allocated the deposition number CCDC 715430.
The crystal structure corresponding to ꢀ-aminoalcohol 5 has been
deposited at the Cambridge Crystallographic Data Centre and
allocated the deposition number CCDC 715431.
Experimental procedure for the tandem isomerization-Mannich
reaction: to a solution of imine 2 (300mg, 1.2mmol) in anhydrous
THF (3mL) were added, under inert atmosphere, successively
alcohol 1 (57μL, 3.6mmol) and Fe(CO)5 (47μL, 0.36mMol). The
reaction mixture was irradiated with a Philips HPK 125 lamp until
disappearance of the starting imine (2h). The reaction mixture was
filtered on a short silica gel plug which was further rinsed with
ACKNOWLEDGEMENTS
We thank CNRS and MESR for financial support. H. T.
C. thanks the Vietnamese government for a PhD thesis
fellowship.
REFERENCES AND NOTES
[1]
(a) Crevisy, C.; Wietrich, M.; Le Boulaire, V.; Uma, R.; Grée, R.
Tetrahedron Lett., 2001, 42, 395; (b) Uma, R.; Gouault, N.;
Crévisy, C.; Grée R. Tetrahedron Lett., 2003, 44, 6187.

510 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Cao et al.
13C NMR (75 MHz, CDCl3) ꢀ (ppm): 14.2, 15.1, 22.8, 24.5, 32.2,
35.4, 43.3, 63.4, 77.5, 126.3; 127.2; 128.9; 146.4.
HRMS: Calcd for C10H14NO [M-.C5H11]+ 164.10754; Found
[M-.C5H11]+ 164.1066 (5 ppm).
ether. The solvents were removed under vacuum and the ꢀ-
aminoketones 3 and 4 were separated by chromatography on silica
gel. CAUTION: all reactions involving Fe(CO)5 have to be carried
out under a well ventilated hood. These iron carbonyl-mediated
reactions have been performed in usual pyrex glassware equipment.
At the end of the reaction the residue of Fe(CO)5 can be destroyed
by addition of strong oxidizing agents such as Ce(NH4)2(NO3)6 or
FeCl3.
1
- diastereoisomer 11: H NMR (300 MHz, CDCl3) ꢀ (ppm): 7.40-
7.30 (m, 5H (HAr)); 4.39 (d, J= 3.2 Hz, 1H (CHC6H5)); 3.58-3.20
(m; 3H (CHOH, NH2)); 1.97-1.78 (m, 1H (CHCH3)); 1.22-1.60 (m,
8H ((CH2)4CH3)); 0.98-0.88 (t, J= 6.9 Hz, 3H (CH2CH3)); 0.83 (d,
J= 7.1 Hz, 3H (CHCH3).
[13]
All new compounds have been fully characterized by spectral and
analytical data. Main spectroscopical and MS data for the final ꢀ-
aminoalcohols:
13C NMR (75 MHz, CDCl3) ꢀ(ppm): 12.6, 14.1, 22.7, 25.3, 32.1,
36.0, 42.7, 58.5, 74.6, 126.9; 127.1; 128.2; 142.7.
HRMS: Calcd for C10H14NO [M-.C5H11]+ 164.10754; Found
[M-.C5H11]+ 164.1066 (5 ppm).
- diastereoisomer 9: 1H NMR (300 MHz, CDCl3) ꢀ (ppm): 7.40-
7.25 (m, 5H (HAr)); 4.11 (d, J=6.1 Hz, 1H (CHC6H5)); 3.71-3.66
(m; 1H (CHOH), 2.80 (broad s, 3H (OH, NH2)); 1.87-1.78 (m, 1H
(CHCH3)); 1.55-1.15 (m, 8H ((CH2)4CH3)); 0.94 (d, J=7.1 Hz, 3H
(CHCH3)); 0.87 (d, J=7.0 Hz, 3H (CH2CH3)).
- diastereoisomer 12: 1H NMR (300 MHz, CDCl3) ꢀ (ppm): 7.40-
7.25 (m, 5H (HAr)); 4.21 (d, J= 2.9 Hz, 1H (CHC6H5)); 4.04-4.00
(m; 1H (CHOH)); 3.06 (bs, 3H (OH, NH2)); 1.85-1.76 (m, 1H
(CHCH3)); 1.62-1.32 (m, 8H ((CH2)4CH3)); 0.91 (t, J= 6.7 Hz, 3H
(CH2CH3)); 0.77 (d, J= 7.1 Hz, 3H (CHCH3)).
13C NMR (75 MHz, CDCl3) ꢀ (ppm): 12.5, 14.1, 22.7, 26.0, 32.0,
33.9, 42.8, 60.3, 72.2, 126.3; 127.1; 128.6; 144.7.
13C NMR (75 MHz, CDCl3) ꢀ (ppm): 3.83, 14.1, 22.7, 25.9, 32.0,
35.1, 42.6, 60.8, 76.6, 125.7; 126.8; 126.9; 128.2; 128.4; 145.2.
HRMS: Calcd for C7H8N [M-C8H17O]+ 106.06567; Found
[M-C8H17O]+ 106.0662 (5 ppm).
HRMS: Calcd for C15H25NO [M]+ 235.19361; Found [M]+
235.1936 (0 ppm).
1
- diastereoisomer 10: H NMR (300 MHz, CDCl3) ꢀ (ppm): 7.38-
7.19 (m, 5H (HAr)); 3.70-3.62 (m, 4H (CHC6H5; CHOH, NH2));
1.80-1.27 (m, 9H (CHCH3, (CH2)4CH3)); 0.90 (t, J= 6.8 Hz, 3H
(CH2CH3)); 0.53 (d, J= 6.8 Hz, 3H (CHCH3)).