Chemoselective N-acylation of indoles and oxazolidinones with carbonylazoles

Article abstract of DOI:10.1002/anie.201203976

Unique reactivity: In the presence of more reactive amine and alcohol functional groups and of carboxylic acids, the chemoselective N-acylation of indoles (see scheme) and oxazolidinones is achieved by taking advantage of the unique reactivity of carbonylazole acylating agents with catalytic amounts of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Copyright

Full text of DOI:10.1002/anie.201203976

Angewandte
Chemie
DOI: 10.1002/anie.201203976
Acylation
Chemoselective N-Acylation of Indoles and Oxazolidinones with
Carbonylazoles**
Stephen T. Heller, Erica E. Schultz, and Richmond Sarpong*
The chemoselective acylation of molecules with multiple
reactive sites is a long-standing problem in organic synthesis.
A variety of reagents and reaction conditions have been
developed to overcome this challenge. For example, influ-
enced by the importance of carbohydrates, many methods to
selectively functionalize sterically differentiated hydroxy
groups have been developed.[1] More recently, progress in
this area has exploited novel oligopeptides,[2] metal clusters,[3]
fine-tuned organometallic complexes,[4] and organocatalysts[5]
that achieve high levels of chemo- or regioselectivity. The
emergence of methods to selectively O-acylate amino alco-
hols[6] led us to question whether novel selectivity for the
functionalization of heteropolyfunctional molecules could be
achieved.
Bearing in mind the dual challenges of chemoselectivity
Scheme 1. Mechanistic hypothesis.
and operational simplicity, we sought to develop new methods
for chemoselective acylation of heteropolyfunctional mole-
cules at their inherently least nucleophilic site. Specifically, we
wondered whether common non-nucleophilic (at nitrogen
atom) azacycles, such as indoles, pyrroles, and oxazolidinones,
could be N-acylated in the presence of stronger nucleophiles,
such as amine or hydroxy groups. The ability to selectively N-
functionalize heterocycles with multiple reactive sites would
significantly simplify the preparation of pharmaceuticals,
functional materials, and complex natural products by obvi-
ating protecting groups.[7]
Non-nucleophilic nitrogen atoms in heterocycles are
typically acylated by quantitative deprotonation followed by
treatment with reactive electrophiles, such as chloroformates
or acid chlorides. However, the use of strong bases for the
deprotonation step limits the functional-group tolerance of
this approach. Alternatively, a wide variety of heterocyclic
amines react with pyrocarbonates in the presence of 4-
dimethylaminopyridine (DMAP) to afford carbamates. In all
of these cases, the acylation reagent engages the most
nucleophilic site first.[8]
might react with a nucleophilic catalyst (e.g., DMAP) to give
ion pair 2, we anticipated that the imidazolide counteranion
would be in the appropriate basicity range to deprotonate, for
example, indole.[10] This would then lead to ion pair 3, which
could rapidly react to afford the desired product (4).
We anticipated that selective acylation could be achieved
by matching the basicity of the counteranion in 2 (imidazo-
lide) with the acidity of the group targeted for functionaliza-
tion (e.g., the indole nitrogen atom in Scheme 1). Therefore,
a scenario would develop in which an anionic nucleophile
(i.e., the indole anion) competes for the acyl electrophile with
neutral groups that are not acidic enough to be deprotonated.
In most cases, this disparity should allow selective acylation of
the more acidic group (i.e., the indole nitrogen atom), which
is selectively deprotonated.
On the other hand, substrates with multiple acidic
pronucleophiles might be selectively acylated by exploiting
the reversibility of the acyl transfer reaction from imidazole
carbamates (i.e., 1) and the target functional group. Indeed,
Birman has demonstrated that azolides are highly efficacious
catalysts for acylation reactions with vinyl or aryl acetates as
acyl donors, presumably through the generation of an
acylazole intermediate.[11] On the basis of trends of pKa
values, it was expected that indole could be N-acylated in
the presence of groups such as phenols, as the resulting indole
carbamate would be much more stable under the reaction
conditions than competing aryl carbonate by-products.
Our overall reasoning led us to investigate whether mildly
reactive carbonylazole acyl transfer reagents could selectively
engage indoles or other acidic non-nucleophilic amines in the
presence of more nucleophilic groups. Our studies com-
menced with the attempted acylation of 5-fluoroindole (5)
We envisioned a conceptually novel approach that
leveraged our previous studies using carbonylimidazole
derivatives in esterification and amidation reactions.[9] By
postulating that imidazole carbamates (e.g., 1, Scheme 1)
[*] S. T. Heller, E. E. Schultz, Prof. R. Sarpong
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
E-mail: rsarpong@berkeley.edu
[**] This work was supported by a CAREER award (0643264) from the
National Science Foundation (USA) (NSF). S.T.H. and E.E.S. are
grateful to the NSF for graduate fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203976.
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Table 1: Optimization of indole acylation.
and 11). In all cases, the only by-product was free imidazole,
which was easily removed upon aqueous workup.
Carbamylimidazoles and acylimidazoles were also found
to be competent reagents for the N-functionalization of
indoles. However, the optimized reaction conditions varied
significantly in these cases. For instance, while carbamylindole
16 can be prepared from the corresponding carbamylimida-
zole, a longer reaction time and a higher catalyst loading was
required. Similarly, 18 may be prepared from indole and N-
tosylimidazole, but in this case, heating to 508C was required.
With the effectiveness of the indole N-acylation estab-
lished, we turned our attention to the selective acylation of
molecules with multiple reactive sites. Gratifyingly, ethoxy-
carbonyl, Boc, benzoyl, and propionyl groups could be
introduced at the indole nitrogen atom with excellent
selectivity in the presence of other nucleophilic groups
(Scheme 3). For example, the N-acylated product 19a was
obtained in greater than 20:1 selectivity. Similarly, acylation
of the indole nitrogen atom could be efficiently accomplished
(10:1 selectivity) in the presence of an amino group (see 20a/
b).[14,15] Moreover, acylation of the aniline group was not
observed when 1-(tert-butoxycarbonyl)imidazole was
employed as an acyl donor (see 21a). Acidic functional
groups, such as carboxylic acids, were tolerated in the N-
acylation of the indole core (see 23).
We then sought to further explore the scope of this mild
acylation reaction by using a variety of functionalized indole
substrates and ethyl imidazole carbamate (1) as the acylation
reagent. Notably, groups, such as mono-protected amines
(26a/b), alkyl halides (26c), acidic esters (27), and terminal
alkynes (25b), were tolerated. The indole nitrogen atom of
Boc-Trp-OMe (Trp = tryptophan) could be protected with
a benzyloxycarbonyl (Cbz) group without loss of optical
activity (see 24).[16] C2- and C3-alkylated indoles reacted
efficiently to afford the desired N-acylated indoles (see 30 and
29, respectively). However, large groups at C2 (31) or C7 (see
32) were found to impede acylation. Pyrrole could also be
acylated with ethyl imidazole carbamate (33) and a stoichio-
metric quantity of DBU, but substituted pyrroles were poor
substrates (34).[17]
Entry
Catalyst
Mol%
Time [h]
Conversion [%][a]
1
2
3
4
5
6
Et3N
PBu3
MPO
DMAP
DABCO
DBU
100
20
20
20
20
20
24
24
24
24
2.5
1
n.r.
trace
trace
10
52
>95
[a] Conversion determined by integration of 19F NMR resonances.
DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMAP=4-(dimethylamino)pyridine, MPO=4-
methoxypyridine N-oxide, n.r.=no reaction.
with 1 (Table 1). Classical nucleophilic catalysts, such as
tributylphosphine and 4-methoxypyridine N-oxide (MPO),
led only to trace amounts of products (Table 1, entries 2 and
3). However, consistent with our hypothesis, a small amount
of 6 was obtained when DMAP was employed as a catalyst
(entry 4). DABCO catalysis led to 52% conversion in less
than three hours at 238C (entry 5). Moreover, employment of
DBU, which has recently been recognized as an excellent
nucleophilic catalyst,[12] led to rapid and efficient acylation of
5 (entry 6).
Several imidazole carbamates were then explored as acyl
donors, and were found to cleanly afford the corresponding
N-acylated indoles in excellent yield (Scheme 2). Primary,
secondary, and even tertiary alkoxy-bearing imidazole carba-
mates were competent electrophiles (see 7, 8 and 9). How-
ever, for the formation of 9, the reaction was discernably
slower. Imidazole carbamates that are known to effect N-
alkylation[13] afforded only the N-acylated products (i.e., 7
In line with our hypothesis that selective acylation of
indoles was thermodynamically controlled for substrates that
contain highly acidic functional groups, we thought it might be
possible to selectively acylate electronically unperturbed
indole derivatives in the presence of relatively acidic hetero-
cycles, such as 5-nitroindole [35, Eq. (1); pKa = 14.6 in
H2O].[18] In this case, readily reversible acylation of the
more acidic nitroindole species would be expected. Indeed,
the reversible acylation of 35 in the presence of 1 was
observed by 1H NMR analysis.[19] Finally, competition
between indole and 35 for acylation led to a 10:1 mixture of
Scheme 2. Scope of the imidazole-based electrophile. [a] Reaction
performed at 508C and with 50 mol% DBU. Yields in parentheses are
for isolated compounds. Bn=benzyl, Ts=toluene-4-sulfonyl.
2
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equimolar ratio of 36 and 1 remained in the DBU-mediated
equilibration described in Equation (1) suggested that carba-
mate reactivity might be easily approximated by the pKa
value of the free heterocycle to which the carbonyl group is
attached. On this basis, we investigated the acylation of
nitroindole 35 with 1,2,4-triazole carbamates (Scheme 4;
pKa = 10.3 in H2O for 1,2,4-triazole).[21] Nearly quantitative
conversion of 35 to 36 or 37 was observed.[22] The use of
carbonyltriazoles as acylation reagents for highly acidic
azacycles appears to be general (see 38–40). Importantly,
ketone and aldehyde groups were generally well-tolerated in
these reactions.[23,24]
Scheme 4. Acylation of acidic heteroaromatic compounds with carbon-
yltriazoles. Yields in parentheses are of isolated compounds.
Because the pKa value of the pronucleophile appeared to
correlate strongly with its selective acylation (i.e., indole NH),
we reasoned that other nitrogen atoms with a similar pKa
value might be efficiently acylated. To that end, we inves-
tigated whether oxazolidinones (pKa ꢀ 20 in DMSO)[25] could
be acylated under our established conditions. Indeed, a variety
of carbonylimidazoles have been found to acylate both the
parent oxazolidinone (see 46, Scheme 5), as well as several
commonly used chiral auxiliaries (see 41–43). Furthermore,
Scheme 3. Nucleophile scope of chemoselective acylation. [a] Reaction
performed with 50 mol% DBU. [b] Reaction performed at 508C with
50 mol% DBU. [c] 22 was obtained as a 11:1 inseparable mixture with
the starting material. [d] 120 mol% DBU used. [e] No racemization
was observed (see the Supporting Information). [f] 100 mol% DBU
used. Ratios reflect acylation of indole nitrogen atom versus compet-
ing nucleophile. Yields in parentheses are of isolated products.
Boc=tert-butoxylcarbonyl.
4 to 36 [Eq. (2)]. These observations strongly support
a thermodynamically controlled acylation process.
The fact that 5-nitroindole has a pKa value similar to that
of imidazole (14.6 versus 14.5 in H2O)[20] and that a nearly
Scheme 5. N-acylation of oxazolidinones.
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oxazolidinones can be acylated in the presence of phenol (44)
and aniline (45) groups.
ylimidazoles.[33] Conversely, functional groups or azacycles
that are more acidic than imidazole will be rapidly acylated
because they can be easily deprotonated by imidazolide.
However, if the product of this acylation is less or similarly
stable relative to the imidazole carbamate, the acylation may
be readily reversible.[34] As a consequence, there is a functional
lower limit to the pKa value of the pronucleophile, which we
tentatively assign to be approximately 19 (in DMSO).
In conclusion, we have demonstrated that DBU reacts
with a series of carbonylazoles[35] to generate an ion pair with
azolide as the counteranion. The basicity of the azolide allows
the chemoselective N-acylation of pronucleophiles, such as
indoles and oxazolidinones, in a certain pKa range ( ꢀ 19–23
for carbonylimidazoles) in the presence of carboxylic acids,
phenols, and anilines—a selectivity that has never before been
observed in acylation reactions.
Acyloxazolidinones are typically prepared by quantitative
deprotonation of the free oxazolidinone with strong base, thus
contrasting sharply with the mild and rapid reaction at room
temperature reported here.[26,27] Therefore, these mild acyla-
tion conditions should find widespread use in the exploitation
of these important auxiliaries.[28]
Preliminary mechanistic investigations have been directed
toward elucidating the role of DBU in these acylation
reactions. Rather than simply acting as a base, we postulated
that DBU might instead react as a nucleophilic catalyst
(analogous to DMAP; Scheme 1) to produce imidazolide.[29]
When 13 and 47 (Scheme 6, top) were treated with DBU, slow
acyl group exchange was observed, thus suggesting that
imidazolide was indeed generated directly from 47. Even
though this observation provided direct evidence that DBU
could act as a nucleophilic catalyst toward carbonylimidazole
derivatives, we could not rule out the possibility that DBU
serves as a Brønsted base toward indole nitrogen groups
bearing an acidic hydrogen.
Received: May 23, 2012
Published online: && &&, &&&&
Keywords: acylation · chemoselectivity · imidazole · indoles ·
.
oxazolidinones
[1] A large quantity of research has been conducted in this area.
Some leading reviews include: a) M. Nahmany, A. Melman, Org.
Biomol. Chem. 2004, 2, 1563; b) W. T. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis, 4th ed., Wiley, New
´
York, 2006; c) M. Miljkovic, Carbohydrates: Synthesis Mecha-
nisms, and Stereoelectronic Effects, 1st ed., Springer, New York,
2010.
[2] a) Kinetic resolution: S. J. Miller, G. T. Copeland, N. Papaioan-
nou, T. E. Horstmann, E. M. Ruel, J. Am. Chem. Soc. 1998, 120,
1629; b) Regioselective acylation: K. S. Griswold, S. J. Miller,
Tetrahedron 2003, 59, 8869.
[3] T. Ohshima, T. Iwasaki, Y. Maegawa, A. Yoshiyama, K.
Mashima, J. Am. Chem. Soc. 2008, 130, 2944.
[4] A. Orita, A. Mitsutome, J. Otera, J. Org. Chem. 1998, 63, 2420.
[5] a) X. Sun, A. D. Worthy, K. L. Tan, Angew. Chem. 2011, 123,
8317; Angew. Chem. Int. Ed. 2011, 50, 8167; b) A. D. Worthy, X.
Sun, K. L. Tan, J. Am. Chem. Soc. 2012, 134, 7321.
Scheme 6. Acyl transfer by nucleophilic catalysis (top) and generation
of equilibrium with imidazolide (bottom).
[6] a) H. Ouchi, Y. Saito, Y. Yamamoto, H. Takahata, Org. Lett.
2002, 4, 585; b) See reference [3].
[7] For recent discussions, see: a) P. S. Baran, T. Maimone, J. M.
Richter, Nature 2007, 446, 404; b) R. W. Hoffmann, Synthesis
2006, 3531.
[8] See Ref. [1b]. Weak bases, such as triethylamine, have been used
with an acyl halide and DMAP.
[9] a) S. T. Heller, R. Sarpong, Org. Lett. 2010, 12, 4572; b) S. T.
Heller, R. Sarpong, Tetrahedron 2011, 67, 8851; c) S. T. Heller, T.
Fu, R. Sarpong, Org. Lett. 2012, 14, 1970.
[10] The pKa values of imidazole and indole are 18.6 and 21.0 in
DMSO, respectively. For imidazole, see: F. G. Bordwell, Acc.
Chem. Res. 1988, 21, 456. For indole, see: F. G. Bordwell, G. E.
Drucker, H. E. Fried, J. Org. Chem. 1981, 46, 632. Trends in pKa
values vary significantly depending on solvent. The publications
listed herein also include a detailed account of trends of pKa
values in non-aqueous solvents.
[11] X. Yang, V. B. Birman, Org. Lett. 2009, 11, 1499.
[12] a) M. Carafa, E. Mesto, E. Quaranta, Eur. J. Org. Chem. 2011,
2458; b) C. Larrivꢀe-Aboussafy, B. P. Jones, K. E. Price, M. A.
Hardink, R. W. McLaughlin, B. M. Lillie, J. M. Hawkins, R.
Vaidyanathan, Org. Lett. 2010, 12, 324; c) W. C. Shieh, S. Dell, O.
However, simple Brønsted catalysis is inconsistent with
the observation that DABCO is a better catalyst compared to
triethylamine or DMAP, even though it is less basic
(Table 1).[30] Rather, this reactivity trend is strongly correlated
with nucleophilicity.[31] It seems likely that DBU, albeit less
nucleophilic, outperforms DABCO as an acylation catalyst
because of its high carbon basicity.[32] That is, with DBU,
a higher concentration of imidazolide could be accessed by
shifting the equilibrium (Scheme 6, bottom) to favor the
formation of 50. Thus, a balance between nucleophilicity and
carbon basicity is important in this strategy for catalysis of
acylations with carbonylimidazoles.
This mechanistic hypothesis accounts for the observation
that pronucleophiles with a pKa value substantially higher
than that of imidazole are not acylated under the conditions
described here; in these cases deprotonation by imidazolide is
inefficient. Therefore, we tentatively propose that pronucleo-
philes with pKa values (in DMSO) greater than 23 will be
relatively inert to the DBU-catalyzed acylation with carbon-
4
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ˇ
Repic, J. Org. Chem. 2002, 67, 2188; d) V. K. Aggarwal, A.
[24] Competition experiments between 5-nitroindole and either 4-
Mereu, Chem. Commun. 1999, 2311.
[13] Allyl imidazole carbamate is known to mediate imidazole N-
allylation. See Ref. [9b].
[14] Though it has been reported that DBU catalyzes the acylation of
anilines by acylimidazoles at high temperature (Ref. [12b]), we
did not observe any reaction between 1 and 4-fluoroaniline in
the presence of DBU at room temperature after two days.
Addition of indole to this mixture leads to rapid acylation of
indole.
fluorophenol or 4-fluoroaniline demonstrated that even with the
more reactive carbonyltriazole acylating reagents, the indole
nitrogen atom was selectively functionalized over other nucle-
ophilic groups [Eq. (3)].
[15] Carbonates are not competent acyl donors in the absence of
imidazole. For example, treatment of methyl phenyl carbonate
with 4-fluoroaniline and DBU did not affect acyl transfer to the
aniline amine group.
[25] F. G. Bordwell, H. E. Fried, J. Org. Chem. 1991, 56, 4218.
[26] J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 83.
[27] Recent work by Carreira demonstrated that acyl fluorides could
react with oxazolidinones in the presence of weak bases.
However, acylimidazoles are substantially more stable, as well
as easier and safer to prepare than acyl fluorides: C. S. Schindler,
P. M. Forster, E. M. Carreira, Org. Lett. 2010, 12, 4102. See
references therein for other mild methods for oxazolidinone N-
acylation.
[28] D. J. Ager, I. Prakesh, D. R. Schaad, Chem. Rev. 1996, 96, 835.
[29] a) For a previous report of dual nucleophilic catalysis with
DABCO, see: W. C. Shieh, S. Dell, A. Bach, O. Repic, T. J.
Blacklock, J. Org. Chem. 2003, 68, 1954; b) see Ref. [12b] for
a similar proposal.
[30] Conjugate acid pKa values in H2O: NEt3 = 10.8, DMAP = 9.2,
and DABCO = 8.8 (J. March, Advanced Organic Chemistry,
4th ed., Wiley, New York, 1992).
[31] M. Baidya, S. Kobayashi, F. Brotzel, U. Schmidhammer, E.
Riedle, H. Mayr, Angew. Chem. 2007, 119, 6288; Angew. Chem.
Int. Ed. 2007, 46, 6176.
[16] If the reaction is allowed to run for long periods of time (i.e.,
24 h), some loss of optical activity is noted. However, installation
of the Cbz group requires only one hour.
[17] 2,4-Dimethylpyrrole was not acylated, even when exposed to
1 and DBU at 808C.
[18] M. A. MuÇoz, P. Guardado, J. Hidalgo, C. Carmona, M. Balꢁn,
Tetrahedron 1992, 48, 5901.
[19] Evaluation of both sides of the equilibrium outlined in
Equation (1) showed that the observed product distribution
was path-independent.
[20] H. Walba, R. W. Isensee, J. Org. Chem. 1961, 26, 2789.
[21] C. F. Krçger, W. Freiberg, Z. Chem. 1965, 5, 381.
[22] Lower catalyst loadings resulted in incomplete reactions because
of competitive protonation of DBU by free triazole.
[23] A small amount of a triazole adduct (see below) was observed
when 5-indolecarboxaldehyde was used as a substrate.
[32] M. Baidya, H. Mayr, Chem. Commun. 2008, 1792.
[33] Compounds that are sufficiently nucleophilic as neutral species
may violate these guidelines. Therefore, we cannot recommend
the use of this acylation system in the presence of unprotected
aliphatic amines or alcohols at this time.
1
[34] The acetyl group of phenyl acetate was observed (by H NMR
spectroscopy) to transfer to the nitrogen atom of indole in the
presence of DBU and imidazole.
[35] A range of these carbonylazoles are commercially available
from Aldrich Chemicals (Product numbers: 424013, 752886,
748773, 748730, 748765, 748811, 748781, 748838).
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Communications
Acylation
S. T. Heller, E. E. Schultz,
R. Sarpong*
&&&& — &&&&
Chemoselective N-Acylation of Indoles
and Oxazolidinones with Carbonylazoles
Unique reactivity: In the presence of
more reactive amine and alcohol func-
tional groups and of carboxylic acids, the
chemoselective N-acylation of indoles
(see scheme) and oxazolidinones is ach-
ieved by taking advantage of the unique
reactivity of carbonylazole acylating
agents with catalytic amounts of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU).
6
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