Synthesis of optically active 6-substituted 2-(aminomethyl)chromans

Article abstract of DOI:10.1016/j.tetlet.2004.05.037

Three novel, optically active, 6-substituted 2-(aminomethyl)chromans were synthesized from readily available chroman 2-carboxylic acid precursors. These chroman-containing primary amines are useful building blocks for the synthesis of chroman-derived phar

Full text of DOI:10.1016/j.tetlet.2004.05.037

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5229–5231
Synthesis of optically active 6-substituted
2-(aminomethyl)chromans
Mingbao Zhang,* Raymond Reeves, Cheng Bi, Robert Dally, Gaetan Ladouceur,
William Bullock and Jefferson Chin
Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA
Received 26 March 2004; revised 29 April 2004; accepted 10 May 2004
Abstract—Three novel, optically active, 6-substituted 2-(aminomethyl)chromans were synthesized from readily available chroman 2-
carboxylic acid precursors. These chroman-containing primary amines are useful building blocks for the synthesis of chroman-
derived pharmaceutical agents.
Ó 2004 Elsevier Ltd. All rights reserved.
Chroman-derived compounds continue to attract a
great deal of attention in the pharmaceutical industry
due to their potential wide-ranging pharmacological
properties.1 2-(Aminomethyl)chroman analogues, in
particular, have shown inhibition of iron-dependent
Retrosynthetic analysis of the targets (R)-7 and (R)-13
led to the identification of (R)-chroman-2-carboxylic
acid 1a as the key common starting material (Scheme 1).
The target (S)-13, by analogy, could then be derived
from (S)-chroman-2-carboxylic acid 1b. The two
enantiomers of 1 can be readily obtained via chemical4
as well as enzymatic5 resolution of the racemate for
which facile syntheses have been reported.6 For the
acetic acid derivative 7, the key step is the Friedel–Crafts
alkylation of the trifluoroacetamide protected form of
the chroman amine 3. The propionic t-butyl ester
derivative 13 involves the Heck reaction of the Cbz-
protected form of chroman amine intermediate 10 as its
key step.
lipid peroxidation,
a
pathophysiological process
involved in many disease states.2 Some newer genera-
tions of dopaminergic agents also contain 2-(amino-
methyl) chromans.3 In connection with a drug discovery
project, we required multigram quantities of several
novel optically active 2-(aminomethyl)chroman inter-
mediates substituted at the C-6 position as building
blocks for rapidly synthesizing chroman-derived ana-
logues. In this paper, we wish to describe practical
syntheses of three such novel chroman intermediates as
their hydrochloride salts (Fig. 1).
The synthesis of (R)-7 is outlined in Scheme 2. The (R)-
chroman-2-carboxylic acid 1a was first converted to the
corresponding acid chloride using oxalyl chloride fol-
lowed by treatment with concentrated ammonium
hydroxide in ethyl acetate to afford the chroman car-
boxamide intermediate 2 in near quantitative yield. A
simple borane reduction,7 after a HCl workup, con-
verted 2 to the corresponding amine 3 as its HCl salt in
87% yield. The primary amine group was then protected
as trifluoroacetamide 4 in 92% yield. Friedel–Crafts
alkylation of 4 with a-chloro-2-(methylthio) acetate
catalyzed by tin(IV) chloride afforded the crude inter-
mediate 5 as a mixture of diastereomers. Removal of the
thiomethyl group, upon a Raney nickel treatment, led to
the penultimate precursor 6. Heating crude 6 in 6 N HCl
at reflux for 2 h removed the trifluoroacetyl group and
simultaneously hydrolyzed the ethyl ester group to
R
R
H2N
HCl
H2N
HCl
O
O
(S) -13: R = CH2CH2CO2-t-Bu
(R) - 7: R = CH2CO2H
(R) -13: R = CH2CH2CO2-t-Bu
Figure 1. (R)- and (S)-2-(aminomethyl) chroman building blocks.
Keywords: Chromans; Friedel–Crafts alkylation; Heck reaction;
Building blocks.
* Corresponding author. Tel.: +1-203-812-5906; fax: +1-203-812-2452;
e-mail: mingbao.zhang.b@bayer.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.037

5230
M. Zhang et al. / Tetrahedron Letters 45 (2004) 5229–5231
R
H2N
HCl
H2N
O
O
Friedel-Crafts
3
(R)-7
R = CH2CO2H
HO
O
O
1a (R)
1b (S)
I
R
H2N
H2N
HCl
Heck
O
O
10
(R)-13 R = CH2CH2CO2-t-Bu
Scheme 1.
e
c, d
a, b
H2N
HCl
H2N
O
3
HO
O
O
O
1a
2
O
SCH3
O
g
f
H
N
H
F3C
O
F3C
N
O
O
O
O
5
4
OH
O
h
H
H2N
HCl
O
F3C
N
O
O
O
O
6
(R)-7
Scheme 2. Reagents and conditions: (a) (COCl)2, CH2Cl2, DMF (cat.), room temperature; (b) NH4OH (concd), EtOAc; (c) BH3/DMS, THF, reflux;
(d) MeOH, HCl/ether; (e) (CF3CO)2O/pyridine, CH2Cl2; (f) a-chloro-2-(methylthio)acetate, tin(IV) chloride, CH2Cl2; (g) Raney nickel, ethanol;
(h) 6 N HCl, reflux.
afford target compound (R)-7, which precipitated out of
the reaction cleanly as an HCl salt (46% yield from 4).
85% yield, was reduced to the corresponding amine
intermediate (R)-10 using a borane/DMS complex in
44% yield. (R)-10 was then protected as the benzyl car-
bamate 11, which underwent the Heck reaction
smoothly to afford the vinyl intermediate 12 in near
quantitative yield. Though the unprotected amine
underwent Heck reaction, it gave lower yields and an
impure product. Transfer hydrogenation (ammonium
formate, Pearlman’s catalyst, ethanol) of intermediate
12 afforded the free base amine in 88% yield, which was
The synthesis of the tert-butyl propionate analogue (R)-
13 is shown in Scheme 3. The (R)-chroman carboxylic
acid 1a was converted to the corresponding iodo chro-
man carboxylic acid 8 in 84% yield upon stirring with
benzyltrimethylammonium dichloroiodate and zinc
chloride in glacial acetic acid at room temperature. The
amide 9, formed via the carbonyldiimidazole route in
I
I
b
a
H2N
O
HO
HO
O
O
O
O
O
9
8
1a
I
I
c
d
CbzHN
H2N
HCl
O
O
11
10
CO2t-Bu
CO2t-Bu
f, g
e
H2N
HCl
CbzHN
O
O
(R)-13
12
Scheme 3. Reagents and conditions: (a) C6H5CH2N(CH3)3ICl2, ZnCl2, HOAc; (b) CDI, DMF, NH4OAc; (c) BH3/DMS, THF, reflux; MeOH,
HCl/ether; (d) Cbz-Cl, NaOH; (e) tert-butyl acrylate, Pd(OAc)2 (cat.), CH3CN; (f) NH4CO2H, Pd(OH)2/C, ethanol; (g) 1 M HCl/diethyl ether.

M. Zhang et al. / Tetrahedron Letters 45 (2004) 5229–5231
5231
Mazandarani, H.; Cockett, M. I.; Ochalski, R.; Coupet, J.;
Andree, T. H. J. Med. Chem. 1997, 40, 4235; (b) Gross, J.
L. Tetrahedron Lett. 2003, 44, 8563.
readily converted to the hydrochloride salt (R)-13 using
1 M HCl/diethyl ether.
4. Schaaf, T. K.; Johnson, M. R.; Constantine, J. W.; Bindra,
J. S.; Hess, H.-J.; Elger, W. J. Med. Chem. 1983, 26, 328.
5. Urban, F. J.; Moore, B. S. J. Heterocycl. Chem. 1992, 29,
431.
6. (a) Augstein, J.; Monro, A. M.; Potter, G. W. H.;
Scholfield, P. J. Med. Chem. 1968, 11, 844; (b) Witiak, D.
T.; Stratford, E. S.; Nazareth, R.; Wagner, G.; Feller,
D. R. J. Med. Chem. 1971, 14, 758; (c) For this work, we
obtained both the (R)-chroman-2-carboxylic acid and (S)-
isobutyl-chroman-2-carboxylate from the Bayer Chemical
Development group in Wuppertal, Germany, both in >98%
ee.
The synthesis of (S)-13 was achieved in similar fashion
from the (S)-chroman carboxylic acid 1b.
In summary, three novel 2, 6-disubstituted chiral chro-
man derivatives containing an amino methyl functional
group at the C-2 position were synthesized from the
corresponding chiral chroman-2-carboxylic acids.8
These intermediates are useful building blocks for rap-
idly synthesizing novel chroman-containing compounds
possessing interesting pharmacological properties.
7. Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981,
441.
8. (a) Compound characterization data: (R)-7: white solid; IR
1
Acknowledgements
(KBr) 3001, 2910, 1703, 1502, 1257, 1220 cmꢀ1; H NMR
(DMSO-d6) d 8.46 (s, broad, 3H), 6.94 (m, 2H), 6.71 (d,
J ¼ 8:1, 1H), 4.25 (m, 1H), 3.43 (s, 2H), 3.13 (dd, J ¼ 13:1,
J ¼ 3:3, 1H), 2.99 (dd, J ¼ 13:2, J ¼ 8:4, 1H), 2.72 (m, 2H),
2.04 (m, 1H), 1.67 (m, 1H); 13C NMR (DMSO-d6) d 172.03,
151.44, 129.78, 127.58, 126.37, 120.92, 115.71, 71.87, 42.43,
39.98, 24.35, 23.61; LCMS (+esi) m=z 222 (M+Hþ); Anal.
The authors thank Donald Wolanin, Qingjie Liu and
Mareli Rodriguez for helpful discussions. We are
indebted to the Bayer Chemical Development group for
providing the chiral chroman starting materials.
Calcd for C12H15NO3ÁHCl: C, 55.93; H, 6.26; N, 5.43.
25
Found: C, 56.20; H, 6.12; N, 5.17; ½aŠ )90.0 (c 1.02,
D
DMSO). (R)-13: white solid; IR (KBr): 2983, 2904, 1730,
1502, 1250, 1147 cmꢀ1 1H NMR (DMSO-d6) d 8.46 (s,
;
References and notes
broad, 3H), 6.89 (m, 2H), 6.67 (d, J ¼ 8:3, 1H), 4.23 (m,
1H), 3.10 (m, 1H), 2.99 (m, 1H), 2.61–2.82 (m, 4H), 2.42 (t,
J ¼ 7:4, 2H), 2.04 (m, 1H), 1.66 (m, 1H), 1.35 (s, 9H); 13C
NMR (DMSO-d6) d 170.61, 150.95, 131.78, 128.63, 126.39,
120.79, 115.65, 79.32, 71.75, 42.37, 36.69, 29.81, 27.85,
24.35, 23.64; LCMS (+esi) m=z 292 (M+H); Anal. Calcd for
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L.; Shi, X.; Kagan, M. Z.; Webb, M. B.; Katz, A. H.; Park,
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C17H25NO3ÁHCl: C, 62.28; H, 7.99; N, 4.27. Found: C,
25
61.97; H, 8.26; N, 4.28; ½aŠ )71.3 (c 1.02, DMSO). (S)-13:
D
white solid, its spectroscopic characteristics are identical to
those of (R)-13. Anal. Calcd for C17H25NO3ÁHCl: C, 62.28;
25
D
H, 7.99; N, 4.27. Found: C, 62.16; H, 8.27; N, 4.25; ½aŠ
+73.4 (c 1.03, DMSO). (b) The optical purities of (R)- and
(S)-13 were determined to be 98% and 97% ee, respectively,
using 1H NMR in CDCl3 with (R)-())-1,10-binaphthyl-2,20-
diyl hydrogenphosphate as the chiral resolving agent (in the
presence of excess pyridine). The optical purity of (R)-7 was
similarly determined to be >96% ee using the same chiral
resolving agent in CD3OD.