Enantioselective synthesis of protected amines by the catalytic asymmetric addition of hydrazoic acid to ketenes

Article abstract of DOI:10.1002/anie.200700697

(Chemical Equation Presented) A-mine of possibilities: An effective method for the conversion of achiral ketenes into enantioenriched protected amines was developed by tuning the structure and reactivity of a catalyst on the basis of a mechanistic hypothe

Full text of DOI:10.1002/anie.200700697

Angewandte
Chemie
DOI: 10.1002/anie.200700697
Asymmetric Catalysis
Enantioselective Synthesis of Protected Amines by the Catalytic
Asymmetric Addition of Hydrazoic Acid to Ketenes**
Xing Dai, Takashi Nakai, Jan A. C. Romero, and Gregory C. Fu*
We recently described the ability of a planar-chiral derivative
of 4-dimethylaminopyridine (DMAP) 1 to achieve catalytic
asymmetric additions of nitrogen and oxygen nucleophiles to
ketenes to generate amides and esters [Eq. (1)].[1] We believe
À
Scheme 1. Catalytic enantioselective addition of X H to ketenes: A
possible mechanism (Brønsted acid catalysis).
that these reactions likely proceed through the pathway
illustrated in Scheme 1, wherein the protonated catalyst
serves as a chiral Brønsted acid (see A),[2,3] thereby generat-
ing a new stereocenter.
To the best of our knowledge, there are no previous
examples of catalytic asymmetric additions of HN3 to ketenes
to produce acyl azides.[4–6] In view of the acidity of HN3 (pKa =
5),[7] we postulated that this process might be accomplished by
the cycle depicted in Scheme 1. Since acyl azides can be
converted into amine derivatives by a Curtius rearrangement
[Eq. (2)], this sequence would yield a family of compounds
that are distinct from the acyl derivatives generated in our
earlier studies [Eq. (1)]. Of course, as a result of the ubiquity
of chiral amines, the development of enantioselective meth-
ods for their synthesis is an important objective.[8,9]
selectivity (27% ee and 34% yield for phenyl isopropyl
ketene). During our earlier studies of pyrroles and phenols,
we had obtained the highest ee values when the additions
were conducted at low concentrations and in nonpolar
solvents. One rationale for these observations is that the
chiral counterion ([H-catalyst*]+) and achiral HX compete in
the protonation of the enolate of ion pair A [Scheme 1,
Eq. (3)].
Unfortunately, under the conditions that had proved
useful for the addition of pyrroles and phenols to ketenes
[Eq. (1)], the reaction of HN3 proceeded with low enantio-
[*] Dr. X. Dai, T. Nakai, Dr. J. A. C. Romero, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences: R01-GM57034),
Merck Research Laboratories, and Novartis. We thank Dr. P. Mueller
and L. Firmansjah for X-ray analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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4367

Communications
On the basis of this analysis, we hypothesized that higher
ee values might be achieved by an increase in the acidity of
the [H-catalyst*]+ (that is, attenuation of the Brønsted
basicity of the catalyst). We therefore decided to examine
the use of planar-chiral pyridines that lack a strong electron-
donating group in the 4-position. We were pleased to
determine that catalyst 2, a relative of 1 with lower Brønsted
basicity, effected the addition of HN3 to phenyl isopropyl
ketene with excellent enantioselectivity (Table 1, entry 1;
under identical conditions, catalyst 1 gave < 5% ee).[10]
Table 1: Catalytic enantioselective addition of HN3 to ketenes.[a]
We believe that these enantioselective additions of HN3 to
ketenes proceed by a chiral Brønsted acid catalyzed pathway,
as illustrated in Scheme 1 (X = N3), wherein protonated 2 is a
key intermediate. Some of the observations that we have
made that are consistent with this mechanism and generally
less well accommodated by a nucleophilic catalysis pathway
(Scheme 2; X = N3)[12] include: 1) treatment of 2 with HN3 led
Entry
R
R1
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Ph
iPr
iPr
iPr
iPr
93
90
94
92
92
93
94
89
93
90
92
90
96
92
97
94
96
96
76
4
94
80
55
70
p-ClC6H4
p-(MeO)C6H4
3-thienyl
Ph
Ph
Ph
Ph
o-tol
o-tol
p-(MeO)C6H4
o-(MeO)C6H4
cyclohexyl
cyclopentyl
tBu
Et
Et
Me
Et
Me
9
10
11
12
[a] All data are the average of two experiments. The reactions in
entries 1–7 and entries 8–12 were carried out at À788C and À908C,
respectively.
À
Scheme 2. Catalytic enantioselective addition of X H to ketenes: A
potential alternative mechanism (nucleophilic catalysis).
We have established that the use of more electron-rich
aromatic substituents led to higher ee values (Table 1,
entries 1–3). Heteroaryl-substituted ketenes proved to be
suitable substrates (entry 4), as were aryl cycloalkyl ketenes
(entries 5 and 6). The planar-chiral pyridine derivative 2 also
could catalyze enantioselective additions of HN3 to highly
hindered ketenes, although a more modest ee value was
observed (entry 7). Unfortunately, in the case of phenyl ethyl
ketene, nearly racemic product was obtained (entry 8);
control experiments revealed that, for unhindered ketenes,
the uncatalyzed addition of HN3 was rapid even at low
temperature.[11] However, if the aryl group was ortho-sub-
stituted, the background reaction was found to be much
slower, thus allowing the enantioselective process catalyzed
by 2 to prevail (Table 1, entry 9). Entry 10 illustrates that this
strategy is even useful for an aryl methyl ketene. Similarly, the
presence of an electron-rich aromatic group diminished the
rate of the uncatalyzed addition and permitted the formation
of the carbamate from an unhindered ketene to proceed with
significant ee values (Table 1, entries 11 and 12).
to protonation of the catalyst [Eq. (6)]; 2) catalyst 2, which
lacks an electron-donating 4-dialkylamino group, proved to
be effective even at very low temperature; 3) higher ee values
were obtained in less-polar solvents, at lower concentrations,
with slower addition of HN3, and with a catalyst of lower
Brønsted basicity; 4) the sense of stereoselectivity was the
same as for the addition of pyrroles and phenols to ketenes
[Table 1 versus Eq. (1)].
As expected, the isocyanate that was produced through a
Curtius rearrangement of the acyl azide could be converted
not only into a methyl carbamate, but also into other
protected amines, as well as the free amine [for example,
Eq. (4) and Eq. (5); Bn = benzyl, tol = tolyl].
In conclusion, on the basis of a mechanistic hypothesis, we
have tuned the structure and reactivity of a chiral catalyst and
thereby developed the first effective method for the catalytic
asymmetric addition of hydrazoic acid to ketenes. Through a
Curtius rearrangement of the resulting acyl azide, this
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Chem. 1996, 108, 2726 – 2748; Angew. Chem. Int. Ed. Engl. 1996,
35, 2566 – 2587.
approach provides a novel route to enantioenriched amine
derivatives. We anticipate that, for a range of chiral Brønsted
acid catalyzed (as opposed to nucleophile-catalyzed) process-
es, these new planar-chiral pyridines may prove to be more
useful than their DMAP-derived relatives.
[4] For leading references on the chemistry of acyl azides, see:
a) H. W. Moore, D. M. Goldish in The Chemistry of Halides,
Pseudo-Halides, and Azides, Vol. 1 (Eds.: S. Patai, Z. Rappoport,
Wiley, New York, 1983, pp. 321 – 368; b) W. Lwowski in Azides
and Nitrenes (Ed.: E. F. V. Scriven), Academic, New York, 1984,
pp. 205 – 246.
Received: February 14, 2007
Published online: April 30, 2007
[5] For an overview of the chemistry of ketenes, see: T. T. Tidwell,
Ketenes, Wiley-Interscience, New York, 2006.
[6] For examples of other catalytic asymmetric reactions of HN3,
see: a) M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N.
Jacobsen, J. Am. Chem. Soc. 2005, 127, 1313 – 1317; b) J. K.
Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959 – 8960.
[7] For a discussion of the chemistry of HN3, including its toxicity,
see: G. W. Breton, P. J. Kropp in Encyclopedia of Reagents for
Organic Synthesis (Ed.: L. A. Paquette), Wiley, New York, 1995,
pp. 2685 – 2688.
Keywords: amines · asymmetric catalysis ·
homogeneous catalysis · ketenes · rearrangement
.
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[10] Consistent with expectations, it is advantageous to add the HN3
by syringe pump over 1–2 h, rather than all at once.
[11] In contrast, under our standard reaction conditions, HN3 does
not add to phenyl isopropyl ketene at an appreciable rate in the
absence of a catalyst.
[2] For reviews, see: a) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth.
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enolates, see: a) A. Yanagisawa in Comprehensive Asymmetric
Catalysis (Supplement 2); (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, New York, 2004, pp. 125 – 132; b) A.
Yanagisawa, H. Yamamoto in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
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sooriya, Tetrahedron: Asymmetry 2001, 12, 1 – 24; d) C. Fehr in
Chirality in Industry II (Eds.: A. N. Collins, G. N. Sheldrake, J.
Crosby), Wiley, New York, 1997, chap. 16; e) C. Fehr, Angew.
[12] For an additional discussion, see reference [1].
Angew. Chem. Int. Ed. 2007, 46, 4367 –4369
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