A new, one-step synthesis of 1-heteroaryl-2-alkylaminoethanols

Article abstract of DOI:10.1016/j.tetlet.2009.12.021

Refluxing a mixture of a heteroarylcarboxaldehyde and an N-alkylamino acid in dry toluene, in the presence of 4 ? molecular sieves, results in the formation of β-hydroxyamines through the 1,3-electrocyclisation of an azomethine ylide and the subsequent ring-opening hydrolysis of an aziridine. The intermediacy of an azomethine ylide in this process is suggested by the isolation of oxazolidines from the cycloaddition of the azomethine ylides to their aldehyde precursors.

Full text of DOI:10.1016/j.tetlet.2009.12.021

Tetrahedron Letters 51 (2010) 843–845
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new, one-step synthesis of 1-heteroaryl-2-alkylaminoethanols
Fuqiang Ning a, Rosaleen J. Anderson a, David E. Hibbs b, Paul W. Groundwater a,
*
a Sunderland Pharmacy School, University of Sunderland, Wharncliffe Street, Sunderland SR1 3SD, UK
b Faculty of Pharmacy, Pharmacy Building A15, University of Sydney, Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Refluxing a mixture of a heteroarylcarboxaldehyde and an N-alkylamino acid in dry toluene, in the pres-
ence of 4 Å molecular sieves, results in the formation of b-hydroxyamines through the 1,3-electrocyclisa-
tion of an azomethine ylide and the subsequent ring-opening hydrolysis of an aziridine. The intermediacy
of an azomethine ylide in this process is suggested by the isolation of oxazolidines from the cycloaddition
of the azomethine ylides to their aldehyde precursors.
Received 30 October 2009
Revised 28 November 2009
Accepted 4 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylides
Decarboxylation
b-Hydroxyamines
Aziridines
Ring-opening
b-Hydroxyamines are an important class of b-blockers, with
medicinal uses as bronchodilators and agents for the treatment of
cardiac arrhythmias,1 and this structural moiety is also a key compo-
nent of many naturally occurring compounds.2 As a consequence of
their importance, many routes have been employed for the prepara-
tion of b-hydroxyamines, usually involving several steps via one of a
range of intermediates, for example, dimethylaminoketones,3 vici-
ation of the iminium salt 4, and subsequent ring-opening
hydrolysis of the aziridine 6, Scheme 1, Table 1. A simple work-
up, consisting of filtration to remove any solid, and column chro-
matography of the residue obtained after evaporation of the
solvent, gave the products in moderate, unoptimised yields.15,16
Such a 1,3-electrocyclisation of azomethine ylides, as depicted in
Scheme 1, step 3 (5?6), is implicit in the cis/trans equilibration of
aziridines17 and has been detected using temperature shock–dilu-
tion conditions.18 Perhaps the most surprising aspect of this one-
step transformation, from the aldehydes 2 to the b-hydroxyamines
7, is the ring-opening hydrolysis of the aziridine 6 to the b-hydroxy-
amines 7, under such mild conditions as, in general, the ring-open-
ing of aziridines which do not have an electron-withdrawing group
on the nitrogen (‘non-activated’) requires either Lewis19 or Brønsted
acid catalysis.20 The relatively mild conditions required for this azi-
ridine ring-opening may be a result of it being facilitated by the elec-
nal haloalcohols,4,5 oxiranes,5 oxazolidines6 and -ketoacetamides.7
a
We describe here a new, one-step synthesis of 1-heteroaryl-2-
alkylaminoethanols involving an azomethine ylide intermediate.
Azomethine ylides 1 can be used in the preparation of a range of
heterocycles through 1,3-dipolar cycloadditions8, 1,5-electrocycli-
sations9 or 1,7-electrocyclisations,10,11 and routes to these versatile
intermediates include the decarboxylation of iminium salts,12 the
ring-opening of aziridines13 and the 1,2-prototropy of
esters.14
a-imino
tron-rich heterocycle, resulting in
a two-step process via a
R2
R2
zwitterionic intermediate 8, Scheme 2.21
CH2
CH2
R1
N
R1
N
Evidence for the possible intermediacy of an azomethine ylide
in this process was obtained by the isolation of a mixture of oxaz-
olidines 11 (as an inseparable mixture of diastereoisomers) and 12
(again as a mixture of diastereoisomers), from the cycloaddition of
the azomethine ylide 10 onto a second molecule of its precursor 9,
when 3,4-dibromothienyl-2-carboxaldehyde 9 was reacted with
sarcosine (3a), Scheme 3. Inseparable mixtures of the diastereoiso-
mers of the hexahydropyrrolo[2,1-b]oxazoles 14a–c were also ob-
tained when the heteroaryl-2-carboxaldehydes 2a,c,d were
Me
Me
1
Refluxing a mixture of a five-membered ring heteroaryl-2-carb-
oxaldehydes 2a–e and N-alkylamino acids 3a,b in dry toluene, in
the presence of 4 Å molecular sieves, resulted in a good yield of
the corresponding b-hydroxyamines 7a–f through the 1,3-electro-
cyclisation of the azomethine ylide 5, formed by the decarboxyl-
* Corresponding author at present address: Faculty of Pharmacy, Pharmacy
Building A15, University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 (0) 2
9114 1232; fax: +61 (0) 2 9351 4391.
reacted with L-proline (3c) to give the azomethine ylides 13, which
subsequently underwent cycloaddition to their aldehyde precur-
sors 2, Scheme 4.
E-mail address: paulg@pharm.usyd.edu.au (P.W. Groundwater).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.021

844
F. Ning et al. / Tetrahedron Letters 51 (2010) 843–845
R2
HN
COOH
R3
3a R2 = Me, R3 = H
3b R2 = Bn, R3 = Bn
Δ
R1
R1
R1
dry toluene
4 Å mol. sieves
R2
N
R2
N
COO
CHR3
CHO
X
X
X
R3
2a X = S, R1 = H
4
5
2b X = S, R1 = Br
1
2c
2d
2e
X = O, R = H
X = NMe, R1 = H
X = NBn, R1 = H
R1
R1
R3
R2
N
H
NHR2
X
X
R3
OH
7a-f
6
Scheme 1.
Table 1
An identical transformation was observed when the heteroaryl-
3-carboxaldehydes 15a–c were employed as the precursors, with
the b-hydroxyamines 18a–c again being obtained in moderate to
good yields via the azomethine ylides 16 and aziridines 17, Scheme
5.
Yields of b-hydroxyamines 7 from the reaction of an N-alkylamino acid 3 and an
aldehyde 2
Product
X
R1
R2
R3
Yield (%)
7a
7b
7c
7d
7e
7f
S
S
S
O
NMe
NBn
H
Br
H
H
H
H
Me
Me
Bn
Me
Me
Me
H
H
Bn
H
H
43
45
44
44
46
64
All the b-hydroxyamines were characterised by IR and 1H, 13C,
HMQC and HMBC spectroscopy, and by high resolution mass
spectrometry, with the 1H NMR spectra for the products 7a,b,d–
f and 18 showing either an A2X or an ABX spin system for the
CH2-CH protons.15 Single crystal X-ray crystallography of the
product of the reaction of thiophene-2-carboxaldehyde 2a with
sarcosine 3a confirmed the structure of the hydroxylamine 7a,
Figure 1.15
H
R1
R1
R2
N
R2
N
H
In conclusion, we have shown that a range of b-hydroxyamines
7 and 18 can be obtained in one-step via the 1,3-electrocyclisation
of azomethine ylides 5 and 16, formed by the reaction of an alde-
hyde 2 or 15 with N-alkylamino acids 3a,b in refluxing toluene
over 4 Å molecular sieves, followed by ring-opening hydrolysis of
the resulting aziridines 6 and 17.
H
7a-f
X
X
R3
R3
H2O
8
6
Scheme 2.
Br
Br
Me
N
Me
HN
S
COOH
O
S
3a
Δ
Br
Br
Br
CHO
Br
Br
dry toluene
4 Å mol. sieves
Br
Me
N
9
11 (56%)
CH2
S
S
9
10
Br
Br
Me
N
S
O
S
Br
Br
12 (25%)
Scheme 3.

F. Ning et al. / Tetrahedron Letters 51 (2010) 843–845
845
HOOC
HN
3c
Δ
N
13
dry toluene
N
X
X
4 Å mol. sieves
O
CHO
X
X
O
X
2a,c,d
H
2
14a X = S (43%)
14b X = O (35%)
14c X = NMe (21%)
Scheme 4.
Me
HN
COOH
3a
Δ
OH
NHMe
CHO
CH2
dry toluene
4 Å mol. sieves
N
N
Me
Me
X
X
X
X
15a X = S
16
17
18a X = S (62%)
18b X = O (43%)
18c X = NBn (46%)
15b X = O
15c X = NBn
Scheme 5.
12. (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069; (b) Grigg, R.; Idle, J.; McMeekin, P.;
Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 49.
13. (a) Heine, H.; Peavy, R. Tetrahedron Lett. 1965, 3123; (b) Huisgen, R.; Scheer,
W.; Mader, H. Angew. Chem., Int Ed. Engl. 1969, 8, 602.
14. (a) Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. J. Chem. Soc., Perkin Trans. 1 1984, 41;
(b) Grigg, R.; Gunaratne, H. Q. N. Tetrahedron Lett. 1983, 24, 4457; (c) Grigg, R.
Chem. Soc. Rev. 1987, 16, 89.
15. Examples of the experimental method and spectroscopic data;
N-Methyl-1-(2-thienyl)-2-aminoethanol 7a;4
A
mixture of thiophene-2-
carboxaldehyde 2a (0.45 g, 4 mmol), N-methylglycine 3a (0.75 g, 8.4 mmol)
and 4 Å molecular sieves (2.0 g), in anhydrous toluene (20 ml), was heated at
reflux, under dry argon, overnight. After cooling to room temperature, the
mixture was filtered to remove any solid. The solvent was evaporated under
reduced pressure and the residue was purified by column chromatography on
silica gel, eluting with EtOAc/MeOH (4:1), to give N-methyl-1-(2-thienyl)-2-
aminoethanol 7a as a yellow resin (0.27 g, 43%) which solidified upon standing,
mp 41–43 °C (from EtOAc); (Found: MH+, 158.0643. Calcd for C7H12NOS: MH+
158.0634); mmax (KBr)/cmꢀ1 3310 (NH), 2889 (broad, OH), 1474 (C@C), 1439
(C@C); dH (300 MHz, CDCl3) 2.35 (3H, s, NMe), 2.77–2.80 (2H, m H-2A,B), 3.10
(2H, br s, OH, NH), 4.95 (1H, dd, J = 6.6, 6.0 Hz, H-1), 6.87–6.90 (2H, m, ArH),
7.15 (1H, m, ArH); dC (75.5 MHz, CDCl3) 35.8 (NMe), 59.0 (CH2, C-2), 67.8 (CH,
C-1), 123.5 (CH), 124.4 (CH), 126.7 (CH), 146.8 (quat., C-20).
Figure 1. ORTEP representation of the single crystal X-ray structure of hydroxyl-
amine 7a.22
References and notes
1. Lednicer, D.; Mitcher, L. A.. In The Organic Chemistry of Drug Synthesis; John
Wiley & Sons: New York, 1980; Vol. 2.
2. Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
3. See for example: (a) Chapman, N. B.; Triggle, D. J. J. Chem. Soc. 1963, 1385; (b)
Raposo, C.; Wilcox, C. S. Tetrahedron Lett. 1999, 40, 1285; (c) Patel, P. J.; Messer,
W. S.; Hudson, R. A. J. Med. Chem. 1993, 36, 1893.
4. Tanis, S. P.; Evans, B. R.; Nieman, J. A.; Parker, T. T.; Taylor, W. D.; Heasley, S. E.;
Herrington, P. M.; Perrault, W. R.; Hohler, R. A.; Dolak, L. A.; Hester, M. R.; Seest,
E. P. Tetrahedron: Asymmetry 2006, 17, 2154.
5. (a) Leonard, N. J.; Klainer, J. A. J. Heterocycl. Chem. 1971, 8, 215; (b) Brown, H. C.;
Pai, G. G. J. Org. Chem. 1983, 48, 1784.
6. Nyerges, M.; Fejes, I.; Virányi, A.; Groundwater, P. W.; Töke, L. Synthesis 2001,
1479.
7. Ishibashi, H.; Miki, Y.; Ikeda, Y.; Kiriyama, A.; Ikeda, M. Chem. Pharm. Bull. 1989,
37, 3396.
N-Methyl-1-(3-furyl)-2-aminoethanol 18b; Furan-3-carboxaldehyde 15b
(0.50 g, 5.2 mmol) was reacted with N-methylglycine (0.70 g, 7.9 mmol) and
4 Å molecular sieves (2.0 g), in anhydrous toluene (20 ml), as described above.
Removal of the solid, by filtration, and the solvent, by evaporation under
reduced pressure, and purification, by column chromatography on silica gel,
eluting with EtOAc/MeOH (10:3), gave N-methyl-1-(3-furyl)-aminoethanol 18b
as a colourless oil (0.30 g, 43%); (Found: MH+, 142.0867. Calcd for C7H12NO2:
MH+ 142.0863); max (liquid film)/cmꢀ1 3317 (NH), 2944 (br, OH), 1501 (C@C),
m
1452 (C@C); dH (300 MHz, CDCl3) 2.44 (3H, s, NMe), 2.77 (2H, d, J = 6.3 Hz, H-2),
2.90 (2H, br s, OH, NH), 4.72 (1H, t, J = 6.3 Hz, H-1), 6.38 (1H, dd, J = 1.8, 0.8 Hz,
H-40), 7.38 (1H, t, J = 1.8 Hz, H-50), 7.40 (1H, dd, J = 1.8, 0.8 Hz, H-20); dC
(75.5 MHz, CDCl3) 35.9 (NMe), 57.9 (CH2, C-2), 64.7 (CH, C-1), 108.5 (CH, C-40),
127.3 (quat., C-30), 139.2 (CH, C-20), 143.2 (CH, C-50).
8. (a) Tsuge, O.; Kanemasa, S.. In Adv. Heterocycl. Chem; Katritzky, A. R., Ed.;
Academic Press, 1989; Vol. 45, pp 232–349; (b) Grigg, R.; Sridharan, V.. In
Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press, 1993; Vol. 3, p 161.
9. (a) Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181; (b) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1980, 19, 947.
10. (a) Arany, A.; Groundwater, P. W.; Nyerges, M. Tetrahedron Lett. 1998, 38, 3267;
(b) Arany, A.; Bendell, D.; Groundwater, P. W.; Garnett, I.; Nyerges, M. J. Chem.
Soc., Perkin Trans. 1 1999, 2605.
16. The relative stereochemistry of the product 7c from the reaction of thiophene-
2-carboxaldehyde 2a and N-benzyl-L-phenylalanine 3b was not determined.
17. Hermann, H.; Huisgen, R.; Mäder, H. J. Am. Chem. Soc. 1971, 83, 1779.
18. Vedejs, E.; Dax, S.; Martinez, G. R.; McClure, C. K. J. Org. Chem. 1987, 52, 3470.
19. Wang, J.-Y.; Wang, D.-X.; Pan, J.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007,
72, 9391.
20. Bisai, A.; Pandey, G.; Pandey, M. K.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5839.
21. We are grateful to a referee for suggesting this mechanism.
22. CCDC 755745 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
11. (a) Marx, K.; Eberbach, W. Tetrahedron 1997, 51, 14687; (b) Groundwater, P.
W.; Nyerges, M.. In Adv. Heterocycl. Chem.; Katritzky, A. R., Ed.; Academic Press,
1999; Vol. 73, pp 97–129.