Amine-catalyzed addition of azide ion to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ol9909076

(matrix presented) A new protocol for the β-azidation of α,β-unsaturated carbonyl compounds is described. The method employs tertiary amines as catalysts for azide addition. The azide source is a 1:1 mixture of TMSN₃ and AcOH. Tertiary amines, either in solution or bound to a solid support, are efficient catalysts for the reaction.

Full text of DOI:10.1021/ol9909076

ORGANIC
LETTERS
1
999
Vol. 1, No. 7
107-1109
Amine-Catalyzed Addition of Azide Ion
to r,â-Unsaturated Carbonyl
Compounds
1
David J. Guerin, Thomas E. Horstmann, and Scott J. Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467-3860
scott.miller.1@bc.edu
Received August 3, 1999
ABSTRACT
A new protocol for the â-azidation of r,â-unsaturated carbonyl compounds is described. The method employs tertiary amines as catalysts for
azide addition. The azide source is a 1:1 mixture of TMSN and AcOH. Tertiary amines, either in solution or bound to a solid support, are
efficient catalysts for the reaction.
3
â-Amino acids represent important substructures in a variety
of natural products. In addition, their importance in natural
present Letter, we report an exceedingly mild preparation
of â-azido carbonyl compounds. Advantages of the protocol
include high-yielding reactions that can be conducted at
ambient temperature, the application of readily available
amines as catalysts, and the use of readily available and stable
1
and unnatural polymers represents an exciting new frontier
in the realm of artificial protein structures that hold promise
2
as biostable analogues of peptidomimetic pharmaceuticals.
As such, mild and efficient methods for their synthesis are
of increasing importance.3,4 While several impressive ad-
vances have been made in this area, there is a need for the
development of flexible strategies that will accommodate a
range of structural types. In addition, synthetic methods that
are readily amenable to combinatorial catalyst and substrate
screening may prove to be particularly valuable. In the
3
trimethylsilyl azide (TMSN ) as the azide source.
Our interest in studying this reaction was stimulated by
the 1997 study of Lakshmipathi and Rama Rao who reported
that triethylamine catalyzed the addition of hydrazoic acid
(HN
3
) to crotonate esters at elevated temperature (80 °C).5
-7
One drawback of the procedure includes the need to generate
the highly toxic and explosive HN
speculated that premixing of TMSN
3
as a stock solution. We
and acetic acid (AcOH)
3
(
1) For a review with an excellent bibliography, see: Cole, D. C.
Tetrahedron 1994, 50, 9517-9582 (refs 1-19).
2) For representative studies in the field, see: (a) Appella, D. H.; Barchi,
J. J.; Durrell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-
310. (b) Gademan, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew. Chem.
would initiate a disproportionation reaction leading to
controlled stoichiometries of HN with the production of
(
3
8
trimethylsilyl acetate (TMSOAc) as a byproduct. Introduc-
tion of the R,â-unsaturated ketone in the presence of an
amine catalyst could then lead to conjugate addition. Indeed,
2
Int. Ed. . 1999, 38, 1223-1226. (c) Smith, A. B.; Guzman, M. C.;
Sprengeler, P. A.; Keenan, T. P.; Halcomb, R. C.; Wood, J. L.; Carroll, P.
J.; Hirschmann, R. J. Am. Chem. Soc. 1994, 116, 9947-9962. (d) Hagihara,
M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1992, 114, 6568-6570.
(5) Lakshmipathi, P.; Rama Rao, A. V. Tetrahedron Lett. 1997, 38,
2551-2552.
(6) For a related azide conjugate addition employing Et2AlN3, see:
Chung, B. Y.; Park, Y. S.; Cho, I. S.; Hyun, B. C. Bull. Korean Chem.
Soc. 1988, 9, 269-270.
(7) For an alternative â-azidonation reaction involving conversion of a
ketone to the corresponding silylenol ether, followed by treatment with PhId
O and TMSN3, see: Magnus, P.; Lacour, J. Evans, P. A.; Roe, M. B.;
Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406-3418.
(
3) For recent reviews, see: (a) EnantioselectiVe Synthesis of â-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (b) See also: ref 1.
4) For excellent recent advances, see: (a) Kobayashi, S.; Nagayama,
(
S. J. Am. Chem. Soc. 1997, 119, 10049-10053. (b) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-4549. (c)
Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998,
1
20, 6615-6616. (d) Kim, B. J.; Park, Y. S.; Beak, P. J. Org. Chem. 1999,
6
4, 1705-1708.
1
0.1021/ol9909076 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

treatment of cyclohexenone (1) with 5 equiv of TMSN
AcOH in the presence of catalytic quantities (0.2 equiv) of
Et N (CH Cl , 25 °C) for 20 h resulted in clean conversion
to azidoketone 2 in 90% isolated yield (eq 1).
3
and
most active of the catalysts we have screened, resulting in
rapid, quantitative conversion to product (90% isolated yield),
within the same 5 h period (entry 3). In contrast, pyridine
and the non-amine base hexamethylphosphoramide (HMPA)
were less efficient catalysts, allowing only 26% and 11%
isolated yields, respectively, within the same period (entries
3
2
2
9-11
4
and 5). In a control experiment where the Lewis base was
omitted completely, no product was formed (entry 6).
Likewise, if the AcOH is omitted, no reaction occurs. Finally,
in an experiment intended to prospect the feasibility of
screening large numbers of catalysts for this reaction, a solid-
support bound alkylimidazole was found to possess excellent
1
2
activity, producing a 90% isolated yield of the product after
an 18 h period (entry 7).
A survey of Lewis bases revealed that there is reasonable
generality with respect to the Lewis base that is employed
We then turned our attention to examining the substrate
scope of these reaction conditions (Table 2). A number of
(Table 1). Triethylamine and the aromatic heterocycle
Table 1. Evaluation of Lewis Bases as Catalystsa
Table 2. Substrate Scope for Catalytic â-Azidationa
N-methylimidazole proved comparably competent as cata-
lysts, resulting in 77% and 82% isolated yields, respectively,
when the reactions were terminated after 5 h (entries 1 and
2). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) proved the
1
(
8) Examination of this equilibrium by both H NMR and IR spectroscopy
reveals that the disproportionation reaction is extremely sluggish in the
absence of an amine base. Introduction of Et3N, however, results in the
production of TMSOAc in an amount approximately equal to the amount
of amine catalyst introduced. Thus, the bulk of the azide remains in the
more stable TMSN3 form, and the disproportionation appears to be initiated
by Et3N.
(
cyclic and acyclic R,â-unsaturated ketones proved to be
excellent substrates for these reactions. In addition to
cyclohexenone (entry 1), cyclopentenone 3 was transformed
9) Numbered products were characterized by H NMR, 13C NMR, and
1
IR spectra, TLC Rf , and combustion analysis. Supporting Information for
this Letter is available.
1108
Org. Lett., Vol. 1, No. 7, 1999

to the corresponding azidoketone 4 in reasonable yield (70%,
entry 2). 4,4-Dimethylcyclohexenone (5) was transformed
to the corresponding azide 6 in 87% yield, demonstrating
that steric hindrance in the allylic position does not present
any inherent problem (entry 3). Likewise, the tert-butyl-
substituted ketone 7 proved to be an excellent substrate,
undergoing transformation to azide 8 in 90% yield (entry
ester 16 can be converted to â-azidoester 17 in 83% yield,
employing the conditions above (Scheme 1). Subsequently,
Scheme 1
4). Trisubstituted cyclohexenones present a perhaps nonob-
vious reactivity profile. Whereas 3-methylcyclohexenone (9)
underwent transformation to the corresponding quaternary
azide 10 in 20% isolated yield under the standard conditions
(entry 5), the 2-methyl variant 11 was inert under these
reaction conditions (entry 6). While the reasons for this
reactivity are not completely clear at this time, it is important
to note that access to compounds with quaternary amine-
functionalized centers may be possible with the present
method. In addition, substrates other than ketones also
function in the present reaction. For example, the crotonate
derivative of 2-oxazolidinone (12) is processed under the
conditions reported above to afford azide 13 in 95% yield
a two-step sequence transforms 17 into N-BOC-â-amino acid
1
8. Thus, subjection of compound 17 to catalytic hydrogena-
tion in the presence of BOC O (H , Pd/C, BOC O, MeOH,
5 °C, 3 h) afforded the intermediate protected aminoester
77%). Subsequent hydrolysis (LiOH, THF/MeOH/H O, 25
C, 12 h) produced the protected amino acid 18 (recrystal-
2
2
2
2
(
°
(entry 7).
In the process of exploring other R,â-unsaturated carbonyl
2
derivatives that might serve as suitable substrates for the
conjugate addition, we found that ethyl crotonate did not
undergo reaction under the above conditions, or even in the
presence of a stoichiometric amount of amine base (eq 2);
1
3
lized yield, 59%).
In summary, we have reported a facile transformation of
a range of R,â-unsaturated carbonyl compounds to the
corresponding â-azidocarbonyl compounds. The reaction
proceeds through catalysis by substoichiometric quantities
of a tertiary amine base. While reactivity is excellent with
ketones and oxazolidinone substrates, esters are less reactive
unless a tertiary amine is incorporated as a component of
the substrate. Finally, the successful application of intramo-
lecular bases, as well as external bases bound to solid
supports, bodes well for the development of chiral auxiliary
processes and combinatorial screening of chiral bases for
asymmetric catalysis, respectively. Current efforts are focused
on these approaches.
instead, complete recovery of the ester was observed. In
contrast, the N,N-dimethylaminoethanol derivative 14 un-
derwent a clean reaction to produce azide 15 in 58% isolated
yield (eq 3), even when the external amine catalyst was
omitted. The prospect of intramolecular activation represents
a potential strategy for asymmetric versions of these pro-
cesses employing chiral aminoester substrates.
Acknowledgment. This research is supported by the
National Institutes of Health (GM-57595). We are also
grateful to the National Science Foundation for generous
support in the form of a CAREER Award (CHE-9874963).
In addition we thank Research Corporation (RIA-116) for
generous research support. Acknowledgment is also made
to the donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support. S.J.M.
is a Cottrell Scholar of Research Corporation. In addition,
we thank James Jewell for the preparation of substrate 7.
Finally, â-azido carbonyl compounds represent useful
surrogates for â-amino acids. For example, R,â-unsaturated
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds synthe-
sized for this paper. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Caution: Organic azides are potentially explosive compounds and
should be handled with great care. We encountered no explosive behavior
during these studies, however. In addition, differential scanning calorimetry
OL9909076
(DSC) was performed on compounds 2, 6, and 13 at Science Resources,
Inc. (Evansville, IN). In each case, the thermochemical transitions occurred
at g130 °C. Full details of these measurements are reported in the
Supporting Information (pp SI-9-SI-13).
(12) For the preparation of this catalyst, see: Copeland, G. T.; Jarvo, E.
R.; Miller, S. J. J. Org. Chem. 1998, 63, 6784-6785.
(13) R-Azido ketones may also be converted to an R-amino acid. For
example, see: Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa,
S. J. Chem. Soc., Chem. Commun. 1994, 111-113.
(
11) ) For a discussion of the hazards associated with HN3 and related
azides, see: Bretherick, L. Handbook of ReactiVe Chemical Hazards;
Butterworth: London, 1975; pp 775-776.
Org. Lett., Vol. 1, No. 7, 1999
1109