A direct approach to orthogonally protected α-amino aldehydes

Article abstract of DOI:10.1021/acs.orglett.9b02237

O-Neopentyl-xanthate 19 bearing a masked α-amino aldehyde, with the two functional groups orthogonally protected, reacts cleanly with many functional alkenes. The radical addition-transfer furnishes densely functionalized adducts that can be further transformed into an array of amino-substituted carbocycles and heteroaromatics. They are also easily converted into imidazolones.

Full text of DOI:10.1021/acs.orglett.9b02237

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Direct Approach to Orthogonally Protected α‑Amino Aldehydes
Richard Lamb, Vincent L. Revil-Baudard, and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652, Ecole Polytechnique, 91128 Palaiseau Cedex, France
S
* Supporting Information
ABSTRACT: O-Neopentyl-xanthate 19 bearing a masked α-
amino aldehyde, with the two functional groups orthogonally
protected, reacts cleanly with many functional alkenes. The
radical addition−transfer furnishes densely functionalized
adducts that can be further transformed into an array of
amino-substituted carbocycles and heteroaromatics. They are
also easily converted into imidazolones.
ultifunctional building blocks are of central importance
to organic synthesis. In this respect, structures bearing
Scheme 1. Main Routes to α-Amino Aldehydes
M
both nucleophilic and electrophilic centers, termed amphoteric
molecules by Yudin,1 offer unique opportunities as far as new
bond formation and the rapid construction of cyclic scaffolds
are concerned. Latent amino carbonyl derivatives, such as
orthogonally protected amino ketones and amino aldehydes,
are prominent examples of such amphoteric molecules because
they can undergo a vast array of useful transformations. α-
Amino aldehydes 1 constitute a particularly interesting
subclass, in view of the rich chemistry associated with the
aldehyde and amine functions.2
The main route to α-amino aldehydes relies on the
controlled reduction of protected α-amino acid esters 3
using DIBAH or on the complete reduction to α-amino
alcohol 4 followed by oxidation of the primary alcohol group
to the aldehyde (Scheme 1).3 The advantage of this approach
is the commercial availability of a number of optically pure α-
amino acids 2, which allows access to enantiomerically pure α-
amino aldehydes, even if care must be exercised to avoid partial
racemization because of the lability of the α-proton. The
protection of the aldehyde group by conversion into an
aminonitrile 5 allows synthetic manipulation of the masked α-
amino aldehydes without fear of racemization.4 Other
strategies involve the addition of formaldehyde anion
equivalents, namely, metalated dithiane 6 and thiazole 8,5 to
imines and nitrones, followed by unmasking of the aldehyde
motif from the respective adducts 7 and 9. More recently, the
conceptually analogous addition of the dioxolanyl radical to an
imine has been reported.6 Nucleophilic addition to imines
derived from monoprotected glyoxal 10 to give adducts 11 is
another useful strategy.7 The radical addition of carbamyl
radicals to chiral enamines 12 using photoredox catalysis also
leads to protected α-amino aldehydes 1.8 The enamines are
generated in situ using catalytic amounts of a chiral cyclic
amine. Finally, an interesting rearrangement of α-haloimines
13 upon exposure to alkoxide was found by De Kimpe and co-
workers to produce α-amino aldehydes, where the aldehyde is
protected as the corresponding acetal 11′.9 In this sequence,
the alkoxide adds to the imine and the buildup of negative
charge on the nitrogen induces substitution of the halide to
give an intermediate alkoxy aziridine (not shown), which
rapidly opens with addition of a second alkoxy group to give
the observed acetal 11′ (note the position of the hydrogen in
blue). We now describe a direct route to such acetal-protected
α-amino aldehydes, which complements existing methods. It
involves the design of a synthetic equivalent to amino aldehyde
radical 14 and hinges on the ability of xanthates to undergo
radical additions, even to unactivated alkenes, while tolerating
the presence of polar functional groups.10
The first obstacle to overcome was the synthesis of the
requisite xanthate 18 from readily available acetal 15 (Scheme
Received: June 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02237
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
2).11 Treatment with trimethylsilyl triflate and DIPEA
triggered the elimination of one ethoxy group and furnished
= lauroyl peroxide). The addition occurred as expected to give
adduct 20 accompanied by a small amount of dexanthylated
starting material 15. The formation of the latter is puzzling and
could be the result of hydrogen abstraction from the solvent;
however, its formation could not be suppressed in this case by
switching from ethyl acetate to benzene. Indeed, in the latter
solvent, the proportion of the reduced side product increased
to 20%. Furthermore, the use of deuterated benzene did not
lead to the formation of deuterated 15.
Scheme 2. Synthesis of the Protected α-Amino Aldehyde
Xanthate 19
Despite this unexpected complication, we examined the
extension to other alkenes. The results are displayed in Scheme
4. The addition exhibited good tolerance to various polar
Scheme 4. Further Examples of Additions of Xanthate 19
enol ether 16 as a 2:1 mixture of the Z and E isomers in 96%
yield.12 Bromination with NBS in ethanol as the solvent
afforded bromide 17 in 97% yield. In contrast to these smooth
and highly efficient first two steps, the substitution of the
hindered bromine with potassium O-ethyl xanthate proved to
be problematic. Under the various conditions that were
examined, the product, 18, appeared to be decomposing as
fast as it was being formed. It is known that O-alkyl xanthates
(especially methyl and ethyl) can be subject to nucleophilic
substitution on the carbon attached to the oxygen atom in the
O-alkyl group, resulting in the formation of various side
products depending on the experimental conditions.13 To slow
such unwanted reaction pathways, potassium O-ethyl xanthate
was replaced with sodium O-neopentyl xanthate. The neo-
pentyl group is much less susceptible to nucleophilic attack,
and the product, 19, is significantly more resistant to ionic
degradation. Indeed, after screening various experimental
conditions, we found that heating bromide 17 with the
neopentyl xanthate salt in DMF at 70 °C furnished the desired
xanthate in 68% yield. Pleasingly, this xanthate required no
purification by column chromatography and could be easily
recrystallized from ethanol. The sequence could be carried out
on a multigram scale (5 g in a single pass) in a 63% overall
yield. The choice of the phthalimide group in the reagent is
based on an observation we made earlier, which indicated that
imides and related structures provided an extra stabilization to
an adjacent radical.14 In the degenerative addition−transfer of
xanthates, it is important that the initial radical derived from
the starting xanthate, 19 in this case, be more stable than the
radical generated upon addition to the alkene.10
functional groups, namely, esters (22, 34, and 40), ketones (31
and 36), acetals (29), free alcohols (24), boronates (27),
protected amines and anilines (33 and 39), and phosphonate
(30), in addition to the cyanide group present in the first
example, 20. All of the products were essentially 1:1 mixtures
of diastereoisomers that were simplified in a few cases by
reductively removing the xanthate group using hypophorous
salts, according to the Barton method.15 The formation of
reduced side product 15 was significant in a couple of
instances, namely, in the syntheses of adducts 25 and 27. In
the other cases, the radical addition was more in line with our
previous experience and premature reduction was almost
insignificant. The reasons for this delinquent behavior are still
not clear.
With a good supply of the requisite reagent in hand, we
proceeded to examine its behavior in radical additions to allyl
cyanide, a typical unactivated terminal alkene (Scheme 3; DLP
Scheme 3. First Example of Addition of Xanthate 19
B
DOI: 10.1021/acs.orglett.9b02237
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Sulfanilide adduct 39 could be made to cyclize into indoline
43 by further reaction with the peroxide (Scheme 5). However,
Scheme 6. Access to Aminocyclohexenes
Scheme 5. Additions to Aromatics and Heteroaromatics
promotes a more efficient cyclization, presumably by exerting a
beneficial Thorpe−Ingold effect. The presence of the xanthate
group in cyclohexenone 53 can be exploited to further enrich
the structure through application of the numerous radical or
ionic reactions associated with sulfur. Thus, a xanthate is
readily cleaved by nucleophiles, and especially primary and
secondary amines, to give the corresponding thiol, which can
then be transformed into a sulfide, a sulfoxide, or a sulfone; it
can be converted by various radical processes directly into a
sulfide, an azide, an alcohol, or a bromide or used to create
carbon−carbon bonds through vinylation and allylation
reactions.18
Masked 1,4-keto-aldehydes and 1,4-dialdehydes are also
readily accessible (Scheme 7). Addition−fragmentation on
Scheme 7. Synthesis of Masked 1,4-Dicarbonyls and a
Protected 3-Aminopyrrole
further oxidation to give indole 44 could not be avoided,
presumably because of the presence of the electron-releasing
methoxy substituent, which facilitates the oxidation/aromatiza-
tion step. Direct addition of reagent 19 to certain
heteroaromatics also proved to be possible. Indole 3-
carboxaldehyde reacted cleanly and efficiently to give adduct
45 in high yield. Interestingly, this compound contains two
aldehyde groups, one of which is protected as an acetal. To the
best of our knowledge, this is the first instance of installment of
a latent amino aldehyde motif by a radical reaction with a
heteroaromatic structure. Other examples include addition to
caffeine and to 1,3-dimethyl uracil to give addition products 46
and 47, respectively, in good yields. 2-Chloro-6-methylamino-
pyrazine reacted slightly less efficiently, affording regioselec-
tively compound 48. Such regioselectivities had been noted
before with pyrazine derivatives substituted with electron rich
groups.16 Finally, addition to 2-aminopyrazine 49 gave rise to
two main products, normal adduct 50 and fused tetracyclic
derivative 51, where the primary amino group condensed with
the phthalimide motif. This latter compound belongs to a
hitherto unknown structural family. Exposure of the former to
trifluoroacetic acid liberated the aldehyde function and
resulted in the formation of phthalimido diazaindole 52.
While such diazaindoles17(or, more systematically, 5H-pyrrolo-
[2,3-b]pyrazine) are well documented, those substituted with a
nitrogen group at position 7 are very rare and mostly confined
to the patent literature.
enol ether 55 leads initially to enol ether adduct 56,19 which is
not isolated but exposed gently to a selective acid hydrolysis to
give ketone 57 in a useful overall yield. While this product is a
1,4-ketoaldehyde, with the aldehyde group protected, the
addition product 40 to vinyl acetate is a masked 1,4-dialdehyde
with the two aldehyde groups protected differently.20 Contact
with formic acid cleaves selectively the acetal motif but does
not affect the terminus geminally substituted by both the
acetoxy and xanthate groups. Nevertheless, compound 58 thus
produced undergoes condensation with methylamine to
furnish 3-phthalimido pyrrole 59 by what may be viewed as
a variation on the venerable Paal−Knorr synthesis.21 Free
aminopyrroles are highly sensitive to oxidation and are
generally not isolated. They are most commonly obtained by
reduction of 3-nitropyrroles, which are not readily available
starting materials.22 This approach provides a practical
preparation of 3-aminopyrroles in a conveniently protected
form, where the substituent on the nitrogen can be modified in
principle by simply varying the amine partner.
The densely functionalized protected α-amino aldehydes
that can be accessed by this approach offer numerous
possibilities for postmodifications. For example, both initial
adduct 31 and its reductively dexanthylated congener 32
undergo a Robinson-type annulation to give cyclohexenones
53 and 54, respectively, upon exposure to toluenesulfonic acid
in refluxing toluene (Scheme 6). It is interesting to note that
the xanthate group in 31 survives the acidic conditions and
The geminal arrangement of the protected amine and
aldehyde allows the synthesis of various heterocyclic structures.
One illustration displayed in Scheme 8 is the formation of
imidazolones 60 and 61 starting with dexanthylated adduct 26
and the addition of product 46 to caffeine. Removal of the
C
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Scheme 8. Synthesis of Imidazolones
ACKNOWLEDGMENTS
■
The authors thank Ecole Polytechnique and Bayer S. A. S. for
financial support of R.L. and V.L.R.-B. and Mrs. Sophie
Bourcier and Mr. Vincent Jactel (both at Ecole Polytechnique)
for HRMS measurements.
DEDICATION
■
This article is dedicated with respect and admiration to
Professor David A. Evans (Harvard University).
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(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samir.zard@polytechnique.edu.
ORCID
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(20) Quiclet-Sire, B.; Zard, S. Z. Xanthates and Vinyl Esters, a
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DOI: 10.1021/acs.orglett.9b02237
Org. Lett. XXXX, XXX, XXX−XXX