Chemoselective radical cleavage of Cbz-protected nitrogen compounds

Article abstract of DOI:10.1021/ol027495c

(Matrix presented) Tributylstannyl radicals promote the deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic rings. These radical conditions do not affect N-Cbz derivatives of basic amines.

Full text of DOI:10.1021/ol027495c

ORGANIC
LETTERS
2
003
Vol. 5, No. 4
69-572
Chemoselective Radical Cleavage of
Cbz-Protected Nitrogen Compounds
5
M.-Llu 1ı sa Bennasar,* Tom a` s Roca, and Ariadna Padull e´ s
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
Barcelona 08028, Spain
bennasar@farmacia.far.ub.es
Received December 19, 2002
ABSTRACT
Tributylstannyl radicals promote the deprotection of N-Cbz derivatives of amides and nitrogen-containing heteroaromatic rings. These radical
conditions do not affect N-Cbz derivatives of basic amines.
Protection strategies using the Cbz (benzyloxycarbonyl)
group have received considerable synthetic attention in the
synthesis of nitrogen-containing compounds. This carbamate
conditions for the removal of the N-Cbz group, which are
selective for originally nonbasic nitrogen atoms, both amide
and those contained within a heteroaromatic ring (Figure 1).
1
moiety is easily introduced into the substrate following well
established protocols, usually by reaction with Cbz-Cl or a
2
related reagent. The possibility of removal under orthogonal
conditions, mainly dissolving metal reductions, catalytic
hydrogenation, and acid treatment,1,3 makes this protecting
group particularly attractive. However, the majority of
protection-deprotection schemes involve N-Cbz derivatives
4
of amines rather than amides or nitrogen heteroaromatic
5
rings, and as far as we know, the available deprotection
methods do not discriminate among these different nitrogen
6
functional groups. In this Letter, we describe a novel set of
Figure 1.
(1) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999. (b) Jarowicki, K.; Kocienski,
P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1589-1615. (c) Jarowicki, K.;
Kocienski, P. J. J. Chem. Soc., Perkin Trans. 1 2000, 2495-2527. (d)
Jarowicki, K.; Kocienski, P. J. J. Chem. Soc., Perkin Trans. 1 2001, 2109-
During the course of our studies on the synthesis of
-acylindole compounds through 3-indolylacyl radicals, we
7
3
2
135.
(2) Kociensky, P. J. Protecting Groups; Thieme: Stuttgart, 1994; Chapter
became interested in the reaction of the Cbz-protected phenyl
1
.
(
3) For other procedures, see inter alia: (a) Sakaitani, M.; Ohfune, Y. J.
Org. Chem. 1990, 55, 870-876. (b) Coleman, R. S.; Carpenter, A. J. J.
(6) For a recent example of a chemoselective removal of N-Cbz
heteroaromatic rings, see: Lipshutz, B. H.; Pfeiffer, S. S.; Reed, A. B. Org.
Lett. 2001, 3, 4145-4148.
(7) (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bassa, M.; Bosch, J. J.
Org. Chem. 2002, 67, 6268-6271. See also: (b) Bennasar, M.-L.; Roca,
T.; Griera, R.; Bosch, J. Org. Lett. 2001, 3, 1697-1700.
Org. Chem. 1992, 57, 5813-5815.
(4) (a) Hungate. R. W.; Chen, J. L.; Starbuck, K. E.; Macaluso, S. A.;
Rubino, R. S. Tetrahedron Lett. 1996, 37, 4113-4116. (b) Tsujimoto, T.;
Murai, A. Synlett 2002, 1283-1284.
(5) Weedon, A. C.; Zhang, B. Synthesis 1992, 95-100.
1
0.1021/ol027495c CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003

selenoester 1 with alkene acceptors (e.g., methyl acrylate,
Scheme 1). As we had previously observed with other indoles
temperature seemed to be a critical factor, but the use of
polar solvents (diglyme or DMF) with boiling points similar
to ethylbenzene was unsuccessful. As a confirmation of the
radical nature of the process, no reaction occurred without
8
AIBN.
Scheme 1
A possible rationale for the above results is as follows
(Scheme 2). Reversible addition of a tributylstannyl radical
Scheme 2
substituted at the nitrogen by an electron-withdrawing group,
the use of standard reductive conditions (n-Bu SnH-AIBN,
3
benzene, 80 °C) resulted in the isolation of the expected
adduct 2 in only moderate yields (40-50%). However, a
closer examination of reaction mixtures revealed an interest-
ing result: trace amounts of the deprotected adduct 3 had
been formed, particularly in one assay in which the reaction
temperature was accidentally increased. This fortuitous
observation prompted us to investigate the possibility of
developing a novel deprotection strategy for the N-Cbz group
based on radical technology.
We set out to examine several experimental conditions to
achieve the desired transformation using N-Cbz indole 4 as
a model substrate, which was allowed to react with 1.5 equiv
3
of n-Bu SnH and catalytic amounts of AIBN at the reflux
temperature of different solvents (Table 1). Following the
to the carbonyl oxygen would produce the intermediate
carbon-centered radical A, which would undergo, if the
temperature was appropriate, fragmentation into a stabilized
radical (benzyl, B) and a tin carbamate (C). Reduction of
the former by the hydride would give a new stannyl radical
to propagate the chain. Complete deprotection is probably
accomplished by hydrolysis of carbamate C during the
workup. This reaction pathway closely resembles the one
9
first proposed by Khoo and Lee for the deoxygenation of
Table 1. Reaction of Indole Carbamates 4-7 with
benzyl and allyl alcohols via the corresponding benzoates.
More recently, Zard reported a similar stannane addition-
SnH-AIBNa
10
n-Bu
3
fragmentation process for the generation of several nitrogen-
centered radicals from oxime esters and hydroxamic acid
1
1
derivatives.
In full accordance with the proposed mechanism, indole
carbamates 5 or 6, able to produce a stabilized (tert-butyl or
allyl) radical after the fragmentation step (eq 2), could also
entry indole
solvent
benzene
reaction time conversion (%)
be deprotected under the n-Bu SnH-AIBN conditions,
3
1
2
3
4
5
6
7
8
9
4
4
4
5
5
6
6
7
7
2 h
2 h
1.5 h
2 h
<5%
35
100
0
toluene
although a higher temperature was required (Table 1).
Complete removal of the Boc moiety of 5 occurred when
the reaction was performed at the reflux temperature of
ethylbenzene
ethylbenzene
p-cymene
ethylbenzene
p-cymene
1 h
2 h
100
0
12
p-cymene (178 °C, entry 5). A similar result was obtained
from N-Alloc indole 6, although in this case the reaction
was slower, probably due to the interference of the allyl
3.5 h
2 h
75
0
ethylbenzene
p-cymene
2 h
0
(8) n-Bu3SnH efficiently participates as a hydride donor in the palladium-
a
catalyzed deprotection of allyl carbamates: Dangles, O.; Guib e´ , F.;
Balavoine, G.; Lavielle, S.; Marquet, A. J. Org. Chem. 1987, 52, 4984-
4993.
Indoles 4-7 (0.6 mmol), n-Bu3SnH (0.9 mmol), and AIBN (0.06 mmol)
in the solvent (6 mL) were heated (reflux). Additional AIBN (0.06 mmol)
was added every 30 min.
(
9) (a) Khoo, L. E.; Lee, H. H. Tetrahedron Lett. 1968, 4351-4354.
See also: (b) Dolan, S. C.; MacMillan, J. J. Chem. Soc., Chem. Commun.
985, 1588-1589.
10) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Schiano, A.-
M.; Zard, S. Z. Tetrahedron 1995, 51, 6517-6528.
11) Addition of a stannyl radical to a thiocarbonyl group followed by
1
(
first unsuccessful attempts using benzene (entry 1), we were
pleased to find that the reaction proceeded to completion
over a period of 1.5 h in ethylbenzene (136 °C, entry 3).
The deprotection in toluene was considerably slower, requir-
ing 2 h to reach 35% conversion (entry 2). The reaction
(
fragmentation constitutes the first step of the powerful Barton-McCombie
deoxygenation reaction. For a review, see: Motherwell, W. B.; Crich, D.
Free Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1992; Chapter 3.
570
Org. Lett., Vol. 5, No. 4, 2003

double bond (entry 7). As expected, no deprotection was
observed from methyl carbamate 7 (entries 8 and 9).
Having established a functional protocol for the depro-
tection of the indole N-Cbz group, we next studied the scope
(entry 2) as well as of heterocycles 8-11 (entries 3-6) took
place in shorter reaction times (0.5-1 h) than that of simple
indole 4 (entry 1). These differences were tentatively
attributed to the presence of pendant electron-withdrawing
groups or other annular nitrogen atoms that would diminish
the electronic density of the nitrogen carbamate group, thus
increasing the reactivity of the carbonyl unit toward stannyl
radicals (Scheme 2, eq 1).
of the process (Table 2). Thus, the n-Bu SnH-AIBN-
3
Table 2. Cleavage of N-Cbz Carbamates Using
n-Bu
3
SnH-AIBNa
At this point we wondered whether the feasibility of the
radical deprotection of the N-Cbz group could depend on
the basic character of the nitrogen atom, giving opportunities
for a discrimination among different nitrogen-containing
functional groups. With this in mind, several N-Cbz deriva-
tives of originally nonbasic amides and basic amines were
subjected to the above experimental conditions. Our reason-
ing proved to be correct, since N-acyl carbamates 12 (entry
7
a
7
) and 13 (entry 8) cleanly afforded the corresponding
secondary amides, without affecting the enol ether or the
benzyl ester function, respectively. In contrast, carbamates
1
4-16 (Figure 2) did not lead to any detectable amounts of
the corresponding deprotected amines even under forcing
conditions (p-cymene, reflux).
Figure 2.
a
General procedure: A solution of the substrate (0.6 mmol), n-Bu3SnH
0.9 mmol), and AIBN (0.06 mmol) in ethylbenzene (6 mL) was heated
reflux). Additional AIBN (0.06 mmol) was added every 0.5 h. Upon the
(
(
Therefore, deprotection only occurs in those substrates in
which the nitrogen lone pair is less available as a result of
its participation in aromaticity or resonance, i.e., in originally
nonbasic nitrogen compounds. Consequently, the carbamate
carbonyl group is sufficiently reactive toward stannyl radicals
to productively participate in the radical chain depicted in
Scheme 2. On the contrary, the lower reactivity of the
carbamate carbonyl group derived from basic amines would
cause the equilibrium of eq 1 to shift much more to the left,
the overall process being inefficient.
disappearance of the starting material, the reaction mixture was concentrated.
The residue was partitioned between hexanes and acetonitrile, and the polar
layer was washed with hexanes to remove tin compounds. The solvent was
removed, and the crude product was chromatographed on SiO2. b All new
compounds were fully characterized by NMR analysis and gave satisfactory
c
HRMS and/or combustion data. Isolated yields.
ethylbenzene conditions were applied to 3-acylindole 2 and
a variety of N-Cbz derivatives of commercially available
aromatic heterocycles, including benzotriazole, pyrrole,
imidazole, and pyrazole, most of them carrying additional
carbonyl functions. To our delight, the reaction proceeded
efficiently to give the deprotected products in high isolated
yields. As can be observed, deprotection of 3-acylindole 2
However, tryptamine 17 (Figure 2), containing both types
of N-Cbz groups, remained untouched under n-Bu SnH-
3
AIBN-ethylbenzene conditions even after prolonged expo-
sure to the reagents. Similarly, when nonreactiVe carbamate
1
4 was mixed (1:1) with reactiVe carbamates 4 or 12, neither
(
12) We appreciate the suggestion of one of the reviewers, pointing out
substrate showed any loss of the Cbz group. The radical chain
leading to deprotection seems to be somehow inhibited by
the presence of a Cbz group derived from a basic amine.
the possibility of a thermal deprotection (by a retro-ene reaction) competing
with the radical process. However, simple heating of 5 in p-cymene for 1
h only led to a partial (15%) removal of the Boc group.
Org. Lett., Vol. 5, No. 4, 2003
571

We do not have any convincing explanation for this
unexpected observation, which deserves further attention.
In conclusion, an unprecedented radical-mediated depro-
tection of N-Cbz derivatives of amides and nitrogen-
containing heterocycles, which is well tolerated by other
functional groups, has been developed. Further work is
currently underway to more fully establish the scope and
limitations of this novel reaction.
is gratefully acknowledged. We also thank the DURSI
(Generalitat de Catalunya) for Grant 2001SGR00084.
Supporting Information Available: Representative ex-
perimental procedures and characterization data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the “Ministerio
de Ciencia y Tecnolog ´ı a” (Spain, project BQU2000-0785)
OL027495C
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Org. Lett., Vol. 5, No. 4, 2003