A new one-pot, four-component synthesis of 1,2-amino alcohols: TiCl 3/t-BuOOH-mediated radical hydroxymethylation of imines

Article abstract of DOI:10.1021/ol802244n

(Chemical Equation Presented) An amine, an aldehyde, and methanol can be readily assembled in one pot under very mild conditions through a free-radical multicomponent reaction by using an aqueous acidic TiCl₃/t-BuOOH system to afford 1,2-amino alcohols in fair to excellent yields.

Full text of DOI:10.1021/ol802244n

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5063-5066
A New One-Pot, Four-Component
Synthesis of 1,2-Amino Alcohols:
TiCl3/t-BuOOH-Mediated Radical
Hydroxymethylation of Imines
Angelo Clerici, Alessandra Ghilardi, Nadia Pastori, Carlo Punta,* and
Ombretta Porta*,†
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico
di Milano - Sezione Chimica, Via Mancinelli 7, 20131 Milano, Italy
carlo.punta@polimi.it
Received September 3, 2008
ABSTRACT
An amine, an aldehyde, and methanol can be readily assembled in one pot under very mild conditions through a free-radical multicomponent
reaction by using an aqueous acidic TiCl3/t-BuOOH system to afford 1,2-amino alcohols in fair to excellent yields.
The ꢀ-amino alcohol motif is a common structure present in a
wide range of bioactive natural products.1 Moreover, 1,2-amino
alcohols are suitable intermediates for the synthesis of unnatural
amino acids, ꢀ-blockers, insecticidal agents, and antibiotics.2
In addition, they are successfully employed in asymmetric
synthesis as chiral auxiliaries or chiral catalysts.3
opening of racemic terminal epoxides,5 the nucleophilic
addition to sulfinyl imines,6 and the use of metallorganic
catalysts.7
Nevertheless, most of these syntheses often require mul-
tistep procedures, expensive reagents, long reaction times,
and highly controlled operating conditions.
For this reason, much effort has been devoted to the
development of new effective methods for the enanctiose-
lective synthesis of these compounds, and a variety of
catalytic procedures has been reported,4 including the ring
Nucleophilic radical addition to imines often represents
an important alternative to classical ionic procedures for the
synthesis of a wide range of derivatives, and in the past
decade, many protocols have been reported based on this
convenient approach.8,9
† Passed away suddenly on May 3, 2008.
(1) Bergemier, S. C. Tetrahedron 2000, 56, 2561–2576.
(2) (a) Yadav, J. S.; Reddy, A. R.; Narsaiah, A. V.; Reddy, B. V. S. J.
Mol. Catal. A 2007, 261, 207–212. (b) Corey, E. J.; Zhang, F. Angew. Chem.,
Int. Ed. 1999, 38, 1931–1934. (c) Bose, D. S.; Narsaiah, A. V. Bioorg.
Med. Chem. 2005, 3, 627–630.
(5) (a) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc.
1996, 118, 7420–7421. (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421–
431. (c) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Org. Lett. 2004, 6, 3973–3975.
(6) (a) Garcia Ruano, J. L.; Aleman, J.; Parra, A. J. Am. Chem. Soc.
2005, 127, 13048–13054. (b) Evans, J. W.; Ellman, J. A. J. Org. Chem.
2003, 68, 9948–9957.
(3) Ager, D. J.; Prakash, I.; Shaad, D. R. Chem. ReV. 1996, 96, 835–
875.
(4) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451–454. (b) Effenberger, T. Angew. Chem., Int. Ed. Engl.
1994, 33, 1555–1564. (c) Onkuma, T.; Ishii, D.; Takeno, H.; Noyori, R.
J. Am. Chem. Soc. 2000, 122, 6510–6511. (d) Adderley, N. J.; Buchanan,
D. J.; Dixon, D. J.; Laine´, D. I. Angew. Chem., Int. Ed. 2003, 42, 4241–
4244.
(7) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F. J. Am.
ˇ
Chem. Soc. 2007, 129, 288–289. (b) Hodgson, D. M.; Stefare, B.; Miles,
T. J.; Witherington, J. Chem. Commun. 2004, 2234–2235. (c) Barrow, J. C.;
Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P. G. Tetrahedron
Lett. 2001, 42, 2051–2054. (d) Jung, D. Y.; Ko, C. H.; Kim, Y. H. Synlett
2004, 7, 1315–1317.
10.1021/ol802244n CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Following the radical route to 1,2-amino alcohols, both
enantiomers (whose configuration may be easily assigned by
NMR)10 would be obtained in their pure forms by employing
one of the several methods reported in the literature.11
Very recently, Tomioka and co-workers reported a new
multistep procedure for the synthesis of 1,2-amino alcohols in
good yields via nucleophilic radical addition to imines by means
of acyloxymethyl radicals, generated from the corresponding
iodomethyl esters by action of dimethylzinc or triethylborane.12
This tin-free methodology operates under very mild conditions
(air at room temperature), but it requires long reaction times,
the aldimine preformation, the employment of halogenated
derivatives, and further hydrolysis of the acyloxy moiety with
potassium hydroxide in aqueous methanol.
multicomponent reaction promoted by the aqueous acidic
TiCl3/t-BuOOH (TiCl3/TBHP) system (Scheme 2).
Scheme 2
.
Synthesis of 1,2-Amino Alcohols Mediated by the
TiCl3/t-BuOOH System
In the past years, we have outlined a new procedure for
the synthesis of polyfunctional derivatives mediated by the
TiCl3/hydroperoxide system. Employing this methodology
a radical version of the Mannich reaction through the
aminoalkylation of ethers (Scheme 1, a)13 and a radical
To the best of our knowledge, this represents the first
example of direct radical hydroxymethylation of imines
generated in situ under aqueous conditions.
Tables 1 and 2 report the results obtained in the presence
of primary and secondary amines, respectively.
Scheme 1
.
Radical Version of the Mannich Reaction (a) and of
the Strecker Synthesis (b)
Table 1. Radical Addition of Methanol to In Situ Generated
Imines from Primary Aminesa
entry
amine
aldehyde
4: yieldb (%)
5: yieldb (%)
5a: 15 (16)
1
2
3
1a
1a
1b
1b
1b
1b
1c
1c
1d
1d
2a
2b
2a
2b
2c
2d
2a
2b
2a
2b
4a: 30 (37)
4b: 66 (75)
4c: 35 (37)
4d: 62 (67)
4e: 46 (50)
4f: 82 (89)d
4g: 35 (37)
4h: 64 (75)
5b: 14 (15)
4
5
6c
7
version of the Strecker synthesis by direct carbamoylation
of imines (Scheme 1, b)14 have been developed.
5c: 20 (21)
5d: 18 (19)
8
9
10
In this paper, we report a new route to obtain 1,2-amino
alcohols in one pot in good yields and high selectivity by
readily combining three commercial products (an amine 1,
an aldehyde 2, and methanol) through a radical domino
4i: 60 (65)
a Unless otherwise stated, the molar ratio of 1/2/TBHP/TiCl3 was
1:3.75:2.5:4. b Yields of isolated products are based on the starting amine;
yields based on converted amines were always g90%; yields in parentheses
1
were determined by H NMR with an appropriate internal standard added
(8) For reviews in the field, see: (a) Friestad, G. K. Tetrahedron 2001,
57, 5461–5496. (b) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 7, 1140–
1157. (c) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157–3172.
(9) For some leading references, see: (a) Friestad, G. K.; Ji, A. Org.
Lett. 2008, 10, 2311–2313. (b) Ueda, M.; Miyabe, H.; Sugino, H.; Naito,
T. Org. Biol. Chem 2005, 3, 1124–1128. (c) Yamada, K.; Yamamoto, Y.;
Maekawa, M.; Akindele, T.; Umeki, H.; Tomioka, K. Org. Lett. 2006, 8,
87–89. (d) Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada,
K.; Tomioka, K. Org. Lett. 2006, 8, 5729–5732.
to the crude reaction mixture. c The molar ratio of 1/2 was 1:0.625. d Yield
is based on the starting aldehyde.
Both aliphatic and aromatic amines (Figure 1) and alde-
hydes (Figure 2) were suitable for this protocol, thus
confirming the general applicability of the present procedure.
The reactions with primary amines were carried out by
adding dropwise TiCl3 (ca. 8 mmol of a 15% aqueous acidic
solution) over 30 min at room temperature to a solution
containing 1a-d (2 mmol), 2 (7.5 mmol), and TBHP (5
mmol) in 10 mL of methanol under N2 atmosphere until a
pale blue color was barely maintained to ensure the complete
decomposition of the peroxide. Thus, the procedure looks
(10) (a) Leiro, V.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Org. Lett. 2008,
10, 2729–2732. (ba) Leiro, V.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Org.
Lett. 2008, 10, 2733–2736.
(11) Nandhakumar, R.; Guo, Y.-E.; Tang, L.; Nam, W.; Kim, K. M.
Tetrahederon Lett. 2007, 48, 6582–6585, and references therein.
(12) Yamada, K.; Nakano, M.; Maekawa, Akindele, T.; Tomioka, K.
Org. Lett. 2008, 10, 3805–3808.
(13) Clerici, A.; Cannella, R.; Pastori, N.; Panzeri, W.; Porta, O.
Tetrahedron 2006, 62, 5986–5994.
(14) Cannella, R.; Clerici, A.; Panzeri, W.; Punta, C.; Porta, O. J. Am.
Chem. Soc. 2006, 128, 5358–5359.
5064
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Radical Addition of Methanol to In Situ Generated
Scheme 3. Reaction Mechanism
Imines from Secondary Aminesa
entry
amine
aldehyde
6: yieldb (%)
1
2
3
4c
5
6
7
8
9
1e
1e
1e
1e
1f
2a
2b
2c
2d
2a
2b
2a
2b
2a
6a: 83 (87)
6b: 65 (73)
6c: 50 (55)
6d: 30 (33)d
6e: 95 (95)
6f: 17 (22)
6g: 80 (82)
6h: 23 (22)
6i: 30 (36)
1f
1g
1g
1h
a Unless otherwise stated, the molar ratio of 1/2/TBHP/TiCl3 was
1:3.75:1.25:2. b See footnotes b-d of Table 1. c See footnotes b-d of Table
1. d See footnotes b-d of Table 1.
In the higher (IV) oxidation state, titanium behaves as a
strong Lewis acid promoting the formation of the imine in
aqueous medium (path iii) and its activation toward the
hydroxymethyl radical addition by increasing the electro-
philicity of the carbon atom of the CdN bond (path iV).
Steric effects seem to have a crucial role in the process,
affecting both the yields and the selectivity in the desired
products.
When primary amines (Table 1) were employed in the
presence of formaldehyde, a mixture of mono- (4) and
disubstituted (5) ꢀ-amino alcohols was obtained (entries 1,
3, 7, and 9) due to the competition between the starting amine
1a-d and the corresponding product 4 in the imine forma-
tion. However, the use of an aldehyde bearing an alkyl or
an aryl substituent allowed us obtain monosubstituted
products in good yields and with complete selectivity because
the enhanced steric hindrance around the CdN bond inhibits
the further reaction of 4 to afford 5. As a representative
primary amine we tested p-methoxyaniline (PMP-NH2) 1b
with a wider range of aldehydes, since the protective PMP
group can be further removed according to different meth-
odologies.15
For the same steric reasons, secondary amines, which
cannot undergo disubstitution, showed opposite reactivity
affording the highest yields in the presence of formaldehyde
(Table 2, entries 1, 5, and 7). When crowded aldehydes were
employed in place of 2a, yields decreased because of the
concomitant presence of two additional substituents on the
CdN bond.
Figure 1. Representaive amines 1a-h.
Figure 2. Representative aldehydes 2a-d.
like a simple titration and occurs under very mild conditions.
A similar procedure was followed in the presence of
secondary amines 1e-h, but in this case no benefit was
observed by operating with an excess of the TiCl3/TBHP
system. Thus, a lower amount of TiCl3 (ca. 4 mmol) and of
TBHP (2.5 mmol) was sufficient in order to obtain the
desired products.
This simple one-pot selective hydroxymethylation would
proceed by the sequence (i-V) reported in Scheme 3, where
titanium species play a multiple key role.
In the lower (III) oxidation state, titanium acts as a radical
initiator inducing the decomposition of TBHP to the corre-
sponding alkoxyl radical (path i), which is responsible for
the formation of the hydroxymethyl radical by hydrogen
abstraction from methanol (path ii); Ti(III) also acts as a
radical terminator in the reduction of the final aminium
radical intermediate (path V).
The relatively low yields observed in the presence of 1h
and 2a (entry 9) may also be ascribed to an enhanced steric
(15) (a) Hasegawa, M.; Tanijama, D.; Tomioka, K. Tetrahedron 2000,
56, 10153–10158. (b) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg,
P. J. L. M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron
Lett. 2006, 47, 8109–8113. (c) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Schoemaker, H. E.; Schu¨rmann, M.; van Delft,
F. L.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2007, 349, 1332–1336.
Org. Lett., Vol. 10, No. 21, 2008
5065

hindrance due to the long aliphatic chains directly bonded
to the nitrogen atom. In fact, no side products were detected,
and the starting reagents were quantitatively recovered.
Future efforts will focus on the extension of the methodol-
ogy on a wider range of alcohols, whose behavior, from
preliminary results, seems to be quite different from metha-
nol.
When the reactions were conducted in the presence of 2d,
the side acyl radical addition occurred because hydrogen
abstraction from the aldehyde competed with the hydroxym-
ethyl radical formation. However, when an excess of amine
was used, it significantly increased the selectivity and avoided
side product formation (entry 6 of Table 1 and entry 4 of
Table 2).
Acknowledgment. Financial support from MURST (PRIN
2006) is gratefully acknowledged. We thank Professor
Francesco Minisci (Politecnico di Milano) for chemical
discussions. We are grateful to Professor Ombretta Porta,
coauthor of this manuscript, who passed away suddenly on
May 3, 2008, for having shared with us her passion for
chemistry and life.
In conclusion, we have developed a new general and
convenient one-pot multicomponent reaction for the synthesis
of aliphatic and aromatic 1,2-amino alcohols, utilizing cheap
and commercially available starting materials. The reaction
does not require either the preformation of the imine or the
protection of the amino group and may be easily conducted
under aqueous conditions.
Supporting Information Available: General experimental
procedures, chracterization data, and spectral data for
products 4a-i, 5a-d, and 6a-i. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802244N
5066
Org. Lett., Vol. 10, No. 21, 2008