Dual Bronsted acid/nucleophilic activation of carbonylimidazole derivatives

Article abstract of DOI:10.1021/ol300339q

Carbonylimidazole derivatives have been found to be highly active acylation reagents for esterification and amidation in the presence of pyridinium salts. These reactions are thought to involve both Bronsted acid and nucleophilic catalysis. This mode of activation has been applied to the synthesis of difficult to access oxazolidinones, as well as esters and amides. Finally, the use of pyridinium salts has been shown to accelerate the esterification of carboxylic acids with imidazole carbamates.

Full text of DOI:10.1021/ol300339q

ORGANIC
LETTERS
2012
Vol. 14, No. 8
1970–1973
Dual Brønsted Acid/Nucleophilic Activation
of Carbonylimidazole Derivatives
Stephen T. Heller, Tingting Fu, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
rsarpong@berkeley.edu
Received February 10, 2012
ABSTRACT
Carbonylimidazole derivatives have been found to be highly active acylation reagents for esterification and amidation in the presence of
pyridinium salts. These reactions are thought to involve both Brønsted acid and nucleophilic catalysis. This mode of activation has been applied
to the synthesis of difficult to access oxazolidinones, as well as esters and amides. Finally, the use of pyridinium salts has been shown to
accelerate the esterification of carboxylic acids with imidazole carbamates.
Carbonylimidazole derivatives constitute an important
and versatile class of acylation reagents, particularly in the
preparation of esters and amides.1 Recently we, as well as
Batey, haveexplored the chemistryof imidazolecarbamate
and carbamylimidazole derivatives as acylating reagents
that obviate the need to preform an acylimidazole.2 Like
their parent compound, 1,10-carbonylimidazole (CDI),
carbonylimidazole derivatives are attractive reagents be-
cause of their enhanced stability relative to acid halides.3
This property has led to their rapid adoption in industrial
chemistry for a variety of applications.4
However, because of their reduced reactivity relative to
carbonyl halides, carbonylimidazole derivatives are often
used in conjunction with an activating reagent. For in-
stance, Staabobservedthatmostalcoholsdo notreact with
acylimidazoles at room temperature but rapidly yield
esters in the presence of catalytic amounts of alkoxide.5
The carbonylimidazole group can also be activated by
engaging with electrophiles such as NBS6 or by alkylating
at the distal nitrogen of the imidazole nucleus.7 Alterna-
tively, displacement of the imidazole by coupling reagents
such as HOBt has been explored in the context of
amidation.8 Finally, we and others have investigated acti-
vation of these species through nitrogen protonation.9
However, the weak basicity of most carbonylimidazoles
makes Brønsted acid activation challenging. Keeping each
of the aforementioned activation strategies and their at-
tendant limitations in mind, we sought to develop alter-
native methods for the activation of carbonylimidazole
derivatives that would be mild, selective, and general.
As an entry into new activation paradigms, we chose to
study the synthesis of sterically encumbered oxazolidi-
nones that are inaccessible through simple treatment of
(1) (a) Staab, K. M.; Bauer, H.; Schneider, K. M. Azolides in Organic
Synthesis and Biochemistry; Wiley-VCH: Weinheim, 1998. (b) Armstrong,
A. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley & Sons: Chichester, UK, 1995; Vol. 2, p 1006.
(2) (a) For synthesis of esters from imidazole carbamates, see: Heller,
S. T.; Sarpong, R. Org. Lett. 2010, 12, 4572. (b) For the synthesis of
amides from carbamylimidazoles, see: Grzyb, J. A.; Shen, M.; Yoshina-
Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A. Tetrahedron 2005, 61,
7153and references therein.
(5) Staab, H. A.; Mannschreck, A. Chem. Ber 1962, 95, 1284.
(6) Katsuki, T. Bull. Chem. Soc. Jpn. 1976, 49, 2019.
(7) (a) Esters from 1-acyl-3-alkylimidazolium salts: Kamijo, T.;
Harada, H.; Iizuka, K. Chem. Pharm. Bull. 1984, 32, 5044. (b) Ureas and
carbamates from carbamylimidazolium salts: Grzyb, J. A.; Batey, R. A.
Tetrahedron Lett. 2008, 52, 5279. (c) Carbamates from imidazolium
carboxylates: Ballatore, C.; Aspland, S. E.; Castillo, R.; Desharnais, J.;
Eustaquio, T.; Sun, C.; Castellino, A. J.; Smith, A. B. Bioorg. Med. Chem.
Lett. 2005, 15, 2477. (d) CDI can be activated using MeOTf: Saha, A. K.;
Rapoport, H.; Schultz, P. J. Am. Chem. Soc. 1989, 111, 4856.
(8) Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Org.
Process Res. Dev. 2003, 7, 244.
(9) (a) See ref 2a. (b) Heller, S. T.; Sarpong, R. Tetrahedron 2011, 67,
8851. (c) Oakenfull, D. G.; Salvesen, K.; Jencks, W. P. J. Am. Chem. Soc.
1971, 93, 188. (d) Wolfenden, R.; Jencks, W. P. J. Am. Chem. Soc. 1961,
83, 4390. (e) Woodman, E. K.; Chaffey, J. G. K.; Hopes, P. A.; Hose,
D. R. J.; Gilday, J. P. Org. Process Res. Dev. 2009, 13, 106.
ꢀ
(3) Larrivee-Aboussafy, C.; Jones, B. P.; Price, K. E.; Hardink,
M. A.; McLaughlin, R. W.; Lillie, B. M.; Hawkins, J. L.; Vaidyanathan,
R. Org. Lett. 2010, 12, 324.
(4) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2004, 4, 2337. (b) Dunn, P. J.; Hoffmann, W.; Kang, Y.;
Mitchell, J. C.; Snowden, M. J. Org. Process Res. Dev. 2005, 9, 956.
(c) Dale, D. J.; Dunn, P. J.; Golighty, C.; Hughes, M. L.; Levett, P. C.;
Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res.
Dev. 2000, 4, 17.
r
10.1021/ol300339q
Published on Web 04/02/2012
2012 American Chemical Society

an amino alcohol with CDI. Instead, imidazole carba-
mates such as 1 (Table 1) are produced. Treatment of 1
with bases or nucleophilic additives did not effect ring
closure to 2 (Table 1, entries 1ꢀ4), whereas acids promoted
the formation of the desired oxazolidinone (2, entries
5ꢀ16). In these cases, a strong correlation between con-
version and the pKa of the acid activator was noted.10,11
reaction (entries 12, 14, and 15), but we elected to use
pyridinium chloride (entries 11 and 12) because of its low
cost and availability as an industrial waste product.12
Further optimization revealed conditions that led to com-
plete conversion of 1 to 2 using 2 equiv of pyridinium
chloride at 40 °C (entry 16).13 In cases where the chloride
salt was ineffective, we generally found success by employ-
ing pyridinium triflate (see Schemes 3 and 4).
Following the identification of optimal conditions for
oxazolidinone formation (Table 1, entry 16), we investi-
gated the substrate scope of the oxazolidinone synthesis
(Scheme 1). Both sterically encumbered (see the corre-
sponding products, i.e., 2 and 3) and electronically deac-
tivated aniline derivatives (see 4) can be acylatedtoprovide
the corresponding oxazolidinones in good to excellent
yields. We also investigated the use of polyfunctional
substrates, finding that oxazolidinone formation occurred
in preference to displacement of a primary chloride (see 5)
or benzoyl group migration (see 7). Similarly, R-tertiary
anilines can be transformed to the corresponding spiro-
cyclic oxazolidinones (8).
Table 1. Initial Investigation of Imidazole Carbamate Activation
a
entry
activator
pKa equiv % conversionb
c
1
2
0
TEA
1
1
1
1
0
3
imidazole
DMAP
AcOH
0
4
0
5
12.3
0
7
AcOH-d4
imidazole HCld
12.3 ∼85e
49
trace
48f
33
53
20
36
38
63
76
>95g
6
7.0
3.5
2.5
1.6
3.4
3.4
3.4
3.4
3.4
3.4
2
1
2
1
1
2
1
2
2
2
3
8
TFA
Scheme 1. Scope of Oxazolidinone Synthesisa
9
N,N-dimethylaniline HOTs
3
10
11
12
13
14
15
16
(þ)-CSA
pyridine HCl
3
3
3
3
3
3
pyridine HCl
pyridine HOTs
pyridine HOTs
pyridine HOTf
pyridine HCl
a In DMSO, see ref 10. b Conversions determined by integration of
resonances in 1H NMR. c Compound 1 was heated to 130 °C in DMF-d7.
d The reaction was run in DMSO-d6. e AcOH-d4 was used as solvent.
f 2.5:1 ratio of 2 to trifluoroacetylation products obtained. g The reaction
was run at 40 °C for 24 h.
Surprisingly, PPTS (entries 13 and 14), which is less
acidic than N,N-dimethylanilinium tosylate (entry 9), was
a superior acid source for the activation of 1. This result
suggested that pyridinium salts may be unique activators
for carbonylimidazole derivatives. Accordingly, we were
drawn to these mild acid sources, as they would allow for
greater functional group compatibility than could be
achieved using strong acids such as TFA or CSA (entries
8 and 10).
a Yields are for isolated compounds. b Reaction performed at 40 °C.
c >90% conversion to 4 observed by 1H NMR.
The observation that the facility of oxazolidinone for-
mation was not strictly dependent on the pKa of the
activating agent (Table 1, compare entries 9 and 14) led
us to further investigate the seemingly special role of
pyridinium salts. Specifically, we wondered whether pyr-
idine generated from an acidꢀbase reaction of a carbony-
limidazole derivative with pyridinium chloride could be
acting as a nucleophilic catalyst.14
Our initial results with pyridinium salts demonstrated
thatlesscoordinating counteranionswerebeneficial forthe
(10) (a) pKas in DMSO: Bordwell, F. G. Acc. Chem. Res. 1988, 21,
456. (b) pKa of imidazolium = 7.0 in DMSO: Kozak, A.; Czaja, M.;
Chmurzynski, L. J. Chem. Thermodyn. 2006, 38, 599.
(11) The reaction of 1 with trifluoroacetic acid likely proceeds
through the generation of a mixed anhydride intermediate, which gives
rise to esterification products as well as 2 (see ref 9b).
(12) (a) For instance, in the synthesis of Tamiflu: Rohloff, J. C.; Kent,
K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.;
Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu,
R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545. (b) On Feb 9, 2012,
pyridine hydrochloride could be purchased from Sigma-Aldrich (SKU:
243086) for 0.26 $/g, or 30.1 $/mol.
(13) See the Supporting Information for reaction optimization de-
tails. Reactions performed with dried pyridinium chloride were gener-
ally slightly higher yielding as no product arising from
carbonylimidazole hydrolysis was observed. This side product was
typically obtained as a 3ꢀ5% impurity in reactions run with commercial
pyridinium chloride.
€
(14) (a) Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. 1969, 8, 981.
€
€
(b) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. 1978,
17, 569. (c) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk SSSR
Ser. Khim. 1967, 176, 97. (d) Denmark, S. E.; Beutner, G. L. Angew.
Chem., Int. Ed. 2008, 47, 1560 and references cited therein.
Org. Lett., Vol. 14, No. 8, 2012
1971

Initial studies into this possibility were conducted by
using sterically encumbered pyridinium salts as activating
agents. In the event, comparison of two pyridinium salts of
nearly equal acidity15 but differing steric profiles (Figure 1,
10 and 11) demonstrated that reduction of the nucleophi-
licity of pyridine led to dramatically decreased reactivity.
This same effect can be observed by comparing 10 and 12,
where the latter is nearly 10 times less acidic but still
outperforms the less nucleophilic 10. The fact that PPTS
(9) is a superior promoter relative to 12, which is much less
acidic but provides a more nucleophilic conjugate base,
suggests that a balance between acidity and nucleophilicity
must be achieved in order to obtain efficient carbonylimi-
dazole activation.
Scheme 2. Proposed Mechanism of Pyridinium Dual Catalysis
nucleophiles. To this end, we first investigated the effect
of pyridinium salts on the reaction of acylimidazoles
with alcohols.
Treatment of benzoylimidazole with a range of alcohols at
room temperature in the presence of pyridinium chloride
typically led to clean production of esters (Scheme 3). More
sterically congested primary alcohols such as neopentyl
alcohol were efficiently esterified at room temperature using
pyridinium triflate (see 18 and 19). Similarly, secondary esters
such as isopropyl 3-phenylpropanoate (26) could be pre-
pared in good yield but generally required mild heating.16
The mild conditions required for acylimidazole esterifi-
cation allowed for a high degree of functional group
tolerance. PMB, TBS, and Boc protecting groups were
all unaffected (see 21, 22, and 24), and even reactive
primary bromides (see 23)17 survived the esterifica-
tion conditions. We did not observe isomerization when
Z-alkenes were used (see 20) or racemization when en-
antioenriched 1-phenylethanol was benzoylated (see 25).18
Although the reaction of acylimidazoles with most
amine nucleophiles need not be catalyzed, anilines can
sometimesbe challengingassubstratesforamide synthesis.
However, the generation of benzamides is greatly acceler-
ated using pyridinium salt activation of the acylimidazole
electrophile. For example, 27 formed nearly instanta-
neously using pyridinium chloride as a promoter. Addi-
tionally, 28 (Scheme 3) could be prepared in 8 h at 40 °C.
In comparison, the use of imidazole hydrochloride as an
activating agent for this purpose was reported to require
heating to 100 °C for 10 h.9e
Figure 1. Pyridinium derivatives as mechanistic probes.
Compound 1 was treated with 2 equiv of the pyridinium salt in
CD3CN for 2 h. Values in parentheses represent conversions determined
by integration of resonances in 1H NMR. pKa values refer to measure-
ments performed in pure MeCN (see ref 15). All compounds are tosylate
salts (anion omitted for clarity).
These observations are consistent with pyridinium salts
(13, Scheme 2) acting as both Brønsted acid and nucleo-
philic catalysts in the acylation reactions of carbonylimi-
dazole derivatives (e.g., 14). Initially, an acidꢀbase
equilibrium develops to generate a carbonylimidazolium
salt (15). This intermediate could then undergo an ex-
change reaction with pyridine (generated in the acidꢀbase
equilibrium) to form a strongly electrophilic acylpyridi-
nium salt (16). Finally, this activated ester species is
engaged by the amine (or alcohol) nucleophile to generate
the desired amide (or ester) linkage (e.g., 17). Even though
we propose that this reaction is formally catalytic in
pyridinium salt, free imidazole formed during the reaction
acts as a terminal base, thereby requiring the use of
stoichiometric amounts of pyridinium salts.
With a mechanistic hypothesis in hand, we reasoned that
this mode of activation should be applicable to any trans-
formation where a carbonylimidazole derivative acts as
an electrophilic acylating reagent. Therefore, we sought
to extend this mode of carbonylimidazole activation
to intermolecular reactions, the most basic of which
is the coupling of acylimidazoles with heteroatomic
The esterification of carboxylic acids with imidazole
carbamates, a reaction we reported recently,2a is also
accelerated by pyridinium salts (Scheme 4) but most
(16) See the Supporting Information for full details on reaction
temperatures and times.
€
(15) pKa of pyridinium salts in MeCN: Kaljurand, I.; Kutt, A.;
(17) Esterification occurs at room temperature with pyridinium
chloride; however, some alkyl chloride is produced as well. The use of
pyridinium tosylate ameliorates this problem.
(18) As expected, this ester was produced with retention of
stereochemistry.
€
€
Soovali, L.; Rodima, T.; Maemets, V.; Leito, I.; Koppel, I. A. J. Org.
Chem. 2005, 70, 1019. The pKa of 11 is apparently unknown in MeCN
using the scale reported in the above reference. However, it is known that
4-picoline is slightly more basic than 2-picoline in organic solvents:
ꢀ
Halle, J.-C.; Lelievre, J.; Terrier, F. Can. J. Chem. 1996, 74, 613.
1972
Org. Lett., Vol. 14, No. 8, 2012

Scheme 3. Esterification and Amidation of Acylimidazolesa
Scheme 4. Imidazole Carbamate Mediated Esterification Under
Pyridinium Salt Catalysisa
a Yields in parentheses are for isolated compounds. bPyridinium
triflate was used. cPyridinium tosylate was used. d10 min, rt. e8 h, 40 °C.
efficiently by pyridinium triflate. Reactions that proceeded
at 80 °C without a promoter can now be effectively
performed at 40 °C with comparable results (29ꢀ33).
Notably, secondaryimidazolecarbamatescan nowbe used
as esterification reagents at 40 °C (see 31), whereas this
transformation required 48h at 80 °C under our previously
reported conditions.2a
a Yields in parentheses are for isolated compounds. bResults obtained
by preparation of esters by heating imidazole carbamates with car-
boxylic acids at 80 °C for 24ꢀ48 h (refs 2a and 9a).
The scope of this new esterification protocol appears to
be similar to that previously reported. Aryl and heteroaryl
carboxylic acids were well-tolerated (34, 36, and 39), and
acid-sensitive ring systems such as indoles were chemose-
lectively esterified (35). Notably, this method of carbony-
limidazole activation also allowed for sequestration of
imidazole through protonation, which makes possible
the esterification of R-chiral carboxylic acids without
racemization (see 37). This was previously a serious limita-
tion to the use of imidazole carbamates as esterification
reagents.9a Finally, enoates such as 38 could be prepared in
good yield, though we observed small quantities of a side
product arising from the conjugate addition of imidazole
when the esterification of cinnamic acid is monitored by
1H NMR.
less-desirable reagent. Furthermore, this method enables
the preparation of esters from acylimidazoles at room
temperature. Similarly, pyridinium salt additives acceler-
ated the reaction of imidazole carbamates with carboxylic
acids to yield esters. Additional studies on the mechanism
by which these salts activate carbonylimidazole derivatives
and application to new acylation protocols are ongoing.
Acknowledgment. We thank the National Science
Foundation for a Predoctoral Fellowship (S.T.H.) and a
CAREER award (0643264, R.S.), UC Berkeley for a
Undergraduate Research Fellowship (T.F.), and Sigma-
Aldrich for a Graduate Student Innovation Award (S.T.H.)
and the kind gifts of CDI and pyridinium bromide.
In conclusion, we have developed a mild and selective
method for the activation of carbonylimidazole derivatives
using pyridinium salts that is applicable to both intermo-
lecular and intramolecular reactions. This activation mode
was applied to the synthesis of oxazolidinones from amino
alcohols that would be difficult to prepare without the
use of phosgene, thereby providing an alternative to this
Supporting Information Available. Experimental de-
tails and copies of 1H and 13C spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
1973