Functional primary amines and diamines from α-aminoacids. A concise route to substituted 2-aminotetralins

Article abstract of DOI:10.1021/ol901263t

Image Persented S-Phthalimidomethyl xanthates derived from various r-amino acids add efficiently to a range of unactivated alkenes to give a variety of highly functionalized, protected amines. In the case of phenylalanine and tyrosine derived xanthates, the adducts can be further converted into the rare 4-substituted 2-aminotetralines by a radical ring closure onto the aromatic ring.

Full text of DOI:10.1021/ol901263t

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3554-3557
Functional Primary Amines and
Diamines from r-Aminoacids. A Concise
Route to Substituted 2-Aminotetralins
Be´atrice Quiclet-Sire, Guillaume Revol, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, Ecole Polytechnique,
91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received June 5, 2009
ABSTRACT
S-Phthalimidomethyl xanthates derived from various r-amino acids add efficiently to a range of unactivated alkenes to give a variety of highly
functionalized, protected amines. In the case of phenylalanine and tyrosine derived xanthates, the adducts can be further converted into the
rare 4-substituted 2-aminotetralines by a radical ring closure onto the aromatic ring.
We recently described a flexible and quite general radical
aminomethylation of alkenes by addition of S-succimidom-
Scheme 1
ethyl or S-phthalimidomethyl xanthate 1 to various alkenes
to give adducts 2 (Scheme 1, eq 1).1 The analogous
pyrrolidone-derived xanthate 3 leads mostly to oligomer
formation instead of desired adduct 4 (Scheme 1, eq 2).
Success in the former case hinges on the apparent extra
stabilization of the starting radical provided by the imide
group, as indicated by canonical forms 5a-d, which is less
important in the simple lactam. It is essential, in the
degenerative radical xanthate addition-transfer reaction, that
in the absence of special polar effects the initial radical
should be more stable than the adduct radical.2
In view of the fundamental importance of primary amines
in organic chemistry, we considered extending this approach
to more complex amine derivatives. This required a conve-
nient access to the xanthate reagents. While the synthesis of
(1) Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2008, 10, 3279.
the phthalimidomethyl derivative 1 is trivial,3 since the
(2) For reviews of the xanthate transfer chemistry, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., eds; Wiley-VCH: Weinheim,
2001; Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.sEur. J. 2006,
12, 6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
N-chloromethylphthalimide precursor is commercially avail-
able, this is not the case for more elaborate derivatives.
(3) Lo, C.-P. J. Org. Chem. 1961, 26, 3591.
10.1021/ol901263t CCC: $40.75
Published on Web 07/17/2009
 2009 American Chemical Society

N-Chloromethylphthalimide is made by the addition of
phthalimide to formaldehyde followed by treatment of the
resulting N-hydroxymethylphthalimide with thionyl chloride.3
Unfortunately, this approach, with perhaps very rare excep-
tions,4 cannot be generalized to higher aldehydes.
the decomposition of the S-acyl xanthate by way of an ionic
chain reaction resulting in tedious purification and poor
yields.7
With xanthate 9 in hand, its radical addition to a number
of olefins, induced by lauroyl peroxide (DLP), could be
examined. The results are summarized in Scheme 2. Thus,
addition to the dimethylacetal of acrolein afforded adduct
10. To avoid having to characterize mixtures of diastereoi-
somers, the xanthate group was reductively removed using
triethylammonium hypophosphite8 to give compound 11, an
amine with a carboxylate on one end and a masked aldehyde
on the other. Other novel GABA analogues, with an extended
chain and incorporating a number of useful functional groups,
could thus be readily assembled and are displayed in Scheme
2. Several drugs now in clinical use (Baclophen, Pregabalin,
etc.) embody the γ-aminobutyric acid core structure, under-
scoring the enormous importance of GABA analogues to the
medical field.9 It is interesting to note that compound 12a
can be viewed as both a γ-amino carboxylic acid and a
γ-amino phosphonic acid derivative, a kind of double GABA
analogue.
The ready commercial availability of numerous R-amino
acids offered a potentially simple and attractive solution to
this problem. The possibility of replacing the carboxylic acid
function with a xanthate group by way of the radical chain
decarbonylation of the corresponding S-acyl xanthate would
allow access to a variety of functionalized aminoalkyl
precursors.5 This strategy is illustrated by the synthesis and
radical additions of the γ-aminobutyric acid (GABA) synthon
9 from L-glutamic acid as depicted in Scheme 2.
Scheme 2
The use of other amino acid precursors provides
xanthate reagents with different substituents. For instance,
xanthate 18, prepared from protected threonine 1510 via
acid chloride 16 and the corresponding S-acyl xanthate
17 in the same manner, also underwent efficient radical
additions, as indicated by the two examples in Scheme 3.
Scheme 3
Thus, reaction of the acid chloride 7 derived from the
known phthalimido acid 66 with potassium O-ethyl xanthate
furnished S-acyl xanthate 8, which was not purified but
simply irradiated with a tungsten lamp in refluxing ethyl
acetate to give the desired xanthate 9 in good overall yield.
This sequence was easily accomplished on a multigram scale,
and xanthate 9 proved stable to storage, making its handling
very convenient. It is worth underlining that in the synthesis
of S-acyl xanthates in general it is important to resist the
temptation to use the xanthate salt in excess with respect to
the more valuable acid chloride. Any excess xanthate salt
(or any potential nucleophile for that matter) can catalyze
In this case, the products, 19 and 20, are valuable, latent
ꢀ-aminoalcohols containing, respectively, a theobromine-
(7) A mechanism for this ionic chain decomposition is proposed in ref.2a
(8) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1992, 33, 5709. (b) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org.
Lett. 2003, 5, 1645.
(4) For other hydroxyalkyl phthalimides derived from glyoxalic acid,
methylglyoxal, and 2-phenylglyoxal, respectively, see: (a) Serino, A. J. J.
Org. Chem. 1988, 53, 2661. (b) Egyud, L. G. US 4066650, see: Chem.
Abst. 1978, 88, 152432. (c) Cosonni, P.; Favara, D.; Omodei-Sale, A.;
Bartolini, G.; Ricci, A. J. Chem. Soc., Perkin Trans. 2 1983, 967.
(5) For earlier work on S-acyl xanthates, see: (a) Barton, D. H. R.;
George, M. V.; Tomoeda, M. J. Chem. Soc. 1962, 1967. (b) Delduc, P.;
Tailhan, C.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1988, 308. (c)
Heinrich, M.; Zard, S. Z. Org. Lett. 2004, 6, 4969.
(9) For some very recent work on the synthesis of GABA analogues,
see: (a) Kumar, R. J.; Chebib, M.; Hibbs, D. E.; Kim, H.-L.; Johnston,
G. A. R.; Salam, N. K.; Hanrahan, J. R. J. Med. Chem. 2008, 51, 3825. (b)
Alstermark, C.; Amin, K.; Dinn, S. R.; Elebring, T.; Fjellstro¨m, O.;
Fitzpatrick, K.; Geiss, W. B.; Gottfries, J.; Guzzo, P. R.; Harding, J. P.;
Holme´n, A.; Kothare, M.; Lehmann, A.; Mattsson, J. P.; Nilsson, K.;
Sunde´n, G.; Swanson, M.; von Unge, S.; Woo, A. M.; Wyle, M. J.; Zheng,
X. J. Med. Chem. 2008, 51, 4315. (c) Jansen, M.; Rabe, H.; Strehle, A.;
Dieler, S.; Debus, F.; Dannhardt, G.; Akabas, M. H.; Lu¨ddens, H. J. Med.
Chem. 2008, 51, 4430.
(6) Wagner, J.; Kallen, J.; Ehrhardt, C.; Evenou, J. P.; Wagner, D.
J. Med. Chem. 1998, 41, 3664.
Org. Lett., Vol. 11, No. 16, 2009
3555

derived purine motif and a Boc-protected hydrazine.11 While
the chiral center bearing the methyl group initially present
in threonine remains intact, its presence does not unfortu-
nately allow any significant asymmetric induction at the
adjacent center carrying the phthalimido group.
Scheme 5
By starting with the known acid chlorides 22 and 35
derived, respectively, from ornithine and lysine,12 a flexible
and general route to 1,4- and 1,5-diamines can be imple-
mented. The results, displayed in Schemes 4 and 5, dem-
Scheme 4
32 followed by elimination of a methylsulfonyl radical
furnished 33 in useful yield.15 The obtention of fluorous
diamine 38 and ꢀ-lactam 44 is also worthy of note. In adduct
40, the xanthate was not reductively removed but used
instead to accomplish a ring closure onto the aromatic ring
to give indoline 41 in high yield.16 Oxidation of the latter
with activated manganese dioxide provided 3-substituted
indole 42 quantitatively.
Diamines are highly valuable substances from a medicinal
chemistry perspective. Du Bois and co-workers have recently
described a route to 1,2- and 1,3-diamines involving an
elegant rhodium-catalyzed intramolecular amination of C-H
bonds starting with monoamine derivatives.17 This strategy
cannot, however, be easily extended to the preparation of
1,4- and 1,5-diamines. The xanthate transfer technology
therefore nicely complements transition-metal-catalyzed in-
sertion reactions.
onstrate once again the power and flexibility of this approach
in terms of functional group compatibility. The addition of
xanthate 24 to Boc-protected R-phenyl-allylamine and xan-
thate 37 to Boc-protected allylamine leads, after dexanthy-
lation, to triamines 27 and 45, where one of the amine groups
is protected differently from the other two. The synthesis of
unsymmetrical polyamines by traditional routes is very
tedious indeed,13 contrasting starkly with the straightforward-
ness of the present approach.
The intermolecular addition of xanthate 24 to 3-cyanoin-
dole, mediated by stoichiometric amounts of lauroyl perox-
ide, occurred at the 2-position affording indole derivative
30 in 77% yield. The addition of xanthates to heteroaromatics
is not general but can lead to interesting and otherwise
inaccessible substances.14 In the case of olefin 31, a 1,2-
shift of the aromatic ring via spirocyclohexadienyl radical
(13) For a review on the synthesis of monoprotected diamines, see: (a)
Bender, J.; Meanwell, N. A.; Wang, T. Tetrahedron 2002, 58, 3111. See
also: (b) Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T.
Org. Lett. 2003, 5, 3399.
(14) Reyes-Gutie´rrez, P. E.; Torres-Ochoa, R. O.; Martnez, R.; Miranda,
L. D. Org. Biomol. Chem. 2009, 7, 1388. (b) Guerrero, M. A.; Miranda,
L. D. Tetrahedron Lett. 2006, 47, 2517. (c) Osornio, Y. M.; Cruz-Almanza,
R.; Jimenez-Montano, V.; Miranda, L. D. Chem. Commun. 2003, 2316.
(15) (a) Ouvry, G.; Zard, S. Z. Synett 2003, 1627. (b) Georghe, A.;
Quiclet-Sire, B.; Vila, X.; Zard, S. Z. Tetrahedron 2007, 63, 7187. For a
review of radical aryl migrations, see: (c) Studer, A.; Bossart, T. Tetrahedron
2001, 57, 9649.
(10) Soldevilla, A.; Griesbeck, A. G. J. Am. Chem. Soc. 2006, 128,
16472.
(16) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37,
5877.
(11) Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Synlett 2002, 903.
(12) Medjahed, W.; Zatla, A. T.; Mulengi, J. K.; Ahmed, F. Z. B.;
Merzouk, H. Tetrahedron Lett. 2004, 45, 1211.
(17) (a) Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248.
(b) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48,
2777.
3556
Org. Lett., Vol. 11, No. 16, 2009

Another interesting feature of this chemistry was revealed
in the study of xanthates 52 and 53, derived, respectively,
from acid chlorides 47 and 49 of protected phenylalanine
and tyrosine (Scheme 6).18 While the addition of xanthate
2-Aminotetralins represent a family of compounds that is
of high medicinal importance. For example, [(S)-(-)-5-OH-
DPAT] 63 and [(R)-(+)-7-OH-DPAT] 64 are much studied
dopamine agonists.19 Yet, even though hundreds of analogues
have been prepared, access to these structures remains
surprisingly limited, hinging essentially on the reductive
amination of 2-tetralones. The latter are generally prepared
from 2-methoxynaphthalenes through a Birch reduction or,
more seldom, using an intramolecular Friedel-Crafts reac-
tion. The present radical based route is not only convergent
and flexible but also provides ready access to derivatives
substituted in the 4-position, which are difficult to obtain by
existing routes and are consequently very rare.
Scheme 6
The preliminary results described herein give only a
glimpse of the synthetic potential attached to the use of
R-amino acids as precursors of the corresponding xanthates.
Not all the possibilities have been explored, and the approach
is obviously not limited to naturally occurring R-amino acids.
Amines associated with a very broad combination of
functional groups can now be easily assembled, simply by
modifying the reacting partners.
Acknowledgment. We respectfully dedicate this paper to
Professor Larry E. Overman (University of California-Irvine).
G. R. thanks Ecole Polytechnique for a studentship.
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901263T
(19) For the original work on isomeric OH-DPAT, see: (a) Wikstrom,
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52 to t-butyl 3-indolecarboxylate 54 to give indole 55 proved
particularly effective, we found it possible to convert the
usual olefin adducts into 2-aminotetralines by treatment with
further amounts of lauroyl peroxide, as shown by the
formation of compounds 57 and 58 and 61 and 62. Such
ring closures on an aromatic nucleus, leading to six-
membered rings, are generally difficult if not impossible to
perform with most radical processes and can be quite
capricious even with the xanthate-based process.2 In the
present case, a small amount of dexanthylated material and
compounds apparently derived from an ipso- ring closure
mode were observed as side products, which sometimes
complicated purification.
(18) Effenberger, F.; Steegmueller, D.; Null, V.; Ziegler, T. Chem. Ber.
1988, 121, 125.
Org. Lett., Vol. 11, No. 16, 2009
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