On the two-component microwave-mediated reaction of isonitriles with carboxylic acids: Regarding alleged formimidate carboxylate mixed anhydrides

Article abstract of DOI:10.1021/ja8047078

Microwave induced two-component coupling (2CC) reaction of carboxylic acids with isonitriles gives rise to various N-formylamides. The formimidate carboxylate mixed anhydride (FCMA) is proposed as the reactive intermediate, which undergoes 1,3-O→N acyl tr

Full text of DOI:10.1021/ja8047078

Published on Web 09/11/2008
On the Two-Component Microwave-Mediated Reaction of Isonitriles with
Carboxylic Acids: Regarding Alleged Formimidate Carboxylate Mixed
Anhydrides
Xuechen Li,† Yu Yuan,† William F. Berkowitz,†,# Louis J. Todaro,‡ and Samuel J. Danishefsky*,†,§
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York,
New York 10065, Department of Chemistry, Hunter College of City UniVersity of New York, 695 Park AVenue,
New York, New York 10065, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027
Received June 30, 2008; E-mail: s-danishefsky@ski.mskcc.org
Recently we reported on the microwave-induced coupling of
carboxylic acids with isonitriles, giving rise to various N-formyl-
amides (cf. 4, Scheme 1).1 We suggested the term two-component
coupling (2CC) to differentiate this work from earlier studies.2 As
we discussed previously, one likely mechanistic interpretation of
the 2CC reaction is that 4 arises from a 1,3-OfN acyl transfer
within 3.3,4 The latter comes about from a protonation-addition
sequence in the joining of 1 and 2. To the best of our knowledge,
no structure corresponding to a formimidate carboxylate mixed
anhydride 3 (hereafter referred to in this paper as a FCMA), had
been documented in a convincing way, let alone fully character-
ized.5-7 Our thoughts and experiences in this area led us to suppose
that a generic FCMA, 3, would be a highly reactive acyl donor.
Accordingly, a recent report5a to the effect that FCMA 7 is produced
at room temperature as a crystalline product from the reaction of
acid 5 and isonitrile 6 in water provoked our curiosity. Moreover,
we noted that the spectroscopic properties of the alleged 7
(particularly its reported IR spectrum)8 do not correspond to what
would be expected from such a structure.9
Figure 1
Fortunately, it proved possible to obtain some diffraction-worthy
crystals from the product of the reaction of 5 and 6. Crystallographic
analysis of the sample revealed the structure to be 10, a stable
complex (fascinating in its own right!) between N-formylcyclo-
hexylamine 9 and m-nitrobenzoic acid 5 (see Figure 1).10 Appar-
ently, the fragile molecular association between 5 and 9 unravels
upon dissolution in chloroform. Thus, the claim that the reaction
of 5 and 6 produces FCMA 7 is not correct.
Also noteworthy was a report, in the same paper, describing a
high yielding formation of amides (cf. 11, Scheme 2) from reactions
of various benzoic acids (cf. 5) and isonitriles (cf. 6) conducted in
methanol at room temperature.5a Our previous work,1 admittedly
conducted in chloroform, showed virtually no reaction between
acids and isonitriles at room temperature. Moreover we suspected
Scheme 1
Scheme 2
In our hands, the reaction of 5 and 6 in water did indeed produce,
as reported by the authors,5a a crystalline product, mp 69-71 °C.
Surprisingly at the time, microwave heating of this solid in
chloroform failed to produce any discernible amounts of what would
have been the expected product, 8, given the claimed structure 7.1
Adding to the puzzle, it was found that the crystalline product could
not be retrieved after it had been dissolved in chloroform, even
without thermolysis (i.e., at room temperature). Instead, evaporation
of the solvent leaves a residue which does not have the properties
of its precursor, allegedly 7. The residue from chloroform could
be separated into components 5 and 9 by exploiting their differing
acidic and neutral solubility properties, respectively.
† Sloan-Kettering Institute for Cancer Research.
‡ City University of New York.
§ Columbia University.
# Professor Emeritus, Queen’s College, City University of New York.
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10.1021/ja8047078 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
that if a FCMA (cf. 3) intermediate were produced, it would have
suffered conversion to the corresponding methyl ester. Accordingly,
we repeated the reaction under the authors’ conditions, that is,
methanol as the solvent, at room temperature. As before, we had
no difficulty in duplicating the published gross observations but
we were not in agreement on the assignments. However, the
assignments of simple amidic structures to the resultant crystalline
products are not correct. First, several of the alleged amides had
actually been previously reported in the literature.11 In each case
that could be checked, there was a large discrepancy in melting
points between the alleged “amides” reported from the isonitrile-
based coupling reactions and those previously reported. In each
case the melting points of the purported amides reported5a were
much higher than those previously reported for the authentic amides.
Furthermore, in several cases, we prepared authentic amide samples
ourselves by standard (cf. DCC) coupling methods. The NMR
spectra of the authentic amides were very different from those of
the amides claimed as arising from the isonitrile method.5a
In pursuing the matter, it became clear that the product of the
reaction of 5 + 6 in methanol is not the amide 11 but rather the
salt 13, arising from the neutralization of the acid 5 and cyclohexyl
amine 12. Indeed, the same material as that synthesized by the
authors (cf. 13) was generated by simply mixing equivalent amounts
of 5 and 12. It is likely that 12 arises from a well-precedented,
though mechanistically unclear, methanol-mediated conversion of
isonitriles to amines.12 Neutralization of the amine 12 provides the
actual product, salt 13.
While this uncertainty remains to be sorted out, it is clear that
the published assertions which claimed the formation and
survival of labile FCMA systems in the presence of putative
acyl acceptors (for instance, methanol or water as solvents) are
not correct.18 In addition to the cases studied above, there may
well be other instances where such claims warrant re-
examination.5e
Motivated by the results described above, we asked whether a
relatively weak nucleophile, such as methanol, could compete with
1,3-OfN acyl transfer in the context of a microwave mediated
2CC experiment (Scheme 4). Under these near stoichiometric
conditions, substantial methanol-induced conversion of isonitrile
to amine12 would hopefully be attenuated. We started by studying
the reaction of ca. 1:1:1 equiv of acid 19, isonitrile 6, and methanol
under the usual microwave-mediated thermolysis. In the event, there
was obtained ca. 38% yield of methyl ester 20, the expected two-
component coupling product 21 (30%), and traces of the amide 22
(4%). Separately, it was demonstrated that amide 22 does not arise
from methanolytic deformylation of 21 under closely simulated
methanol conditions. It is likely that 22 comes about from small
amounts of cyclohexylamine (12) or its equivalent arising from 6.
Thus, acylation of 12 by FCMA 23 could lead to 22.
Scheme 5
Another earlier paper by Gloede et al. on the reaction of
isonitriles and carboxylic acids (Scheme 3) provoked skepticism
on our part.5b,c It was reported that the reaction of p-nitrobenzoic
acid 14 and cyclohexylisonitrile 6, when conducted in methanol
under reflux, gave rise to FCMA 15, mp 174-176 °C. Again,
for obvious reasons,13 we wondered whether such a FCMA could
have persisted in methanol. Accordingly, we repeated the
experiment and obtained, exactly as reported, a crystalline
compound, mp 173-175 °C (in addition to varying quantities
of methyl ester 16). However, it was soon found that the high
melting product is actually 17, the p-nitrobenzoic acid salt of
1,3-dicyclohexylamidine 18.14 This structure was confirmed by
spectroscopic analysis of the product formed from mixing 2 equiv
14 and 1 equiv 18.15 Furthermore, removal of p-nitrobenzoic
acid by basic workup afforded amidine 18 as the product. While
the definition of a specific pathway for formation of 17 from
among several obvious possibilities is not available from our
data, qualitatively, it must involve, in some form, the metha-
nolytic progression of 6 toward cyclohexylamine 12 as discussed
above. The formation of the amidine 18 may well reflect an
addition reaction of cyclohexylamine with 616 or an acid-mediated
condensation between N-cyclohexylformamide 9 (or its equiva-
lent) and cyclohexylamine 12 (or its functional equivalent).17
Finally, it was of interest to study the possibility of a 2CC
reaction between phthaloyl glycine 24 and serine isonitrile benzyl
ester 25 as a model for interdiction by an intramolecular hydroxyl
group (Scheme 5). Remarkably, even at room temperature, the 2CC
reaction does occur, giving rise to 26, although in only ca. 25%
yield. In an important control experiment, it was shown that
hydroxyl protected serine isonitrile derivative 2719 seemingly does
not react with 24 at all at room temperature.
Scheme 6
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C O M M U N I C A T I O N S
656. Actually, it is not clear whether the FCMA structure claimed in
the paper is correct (see figure below) (personal communication from
Dr. M. Isaka).
Our data do not allow us to distinguish between several obvious
variations of the general scheme suggested in Scheme 6. Globally,
the teaching seems to be that an otherwise unfavorable formation
of a FCMA can be driven to product 26 through neighboring
hydroxyl participation to enable the 1,3-OfN acyl transfer at room
temperature.18
The formation of 26 points to an eventual approach to serine
ligation.20 In the succeeding paper, we probe subtle but important
mechanistic issues as well as new directions for the 2CC reac-
tion.
For cyclic structures of formimidate-carboxylate mixed anhydride, see:
(f) Black, D. S. C.; Boscacci, A. B. Aus. J. Chem. 1977, 30, 1109. (g)
Kobayashi, S.; Tsukamoto, Y.; Saegusa, T. Macromolecules 1990, 23, 2608.
(h) Reed, P. E.; Katzenellenbogen, J. A. J. Med. Chem. 1991, 34, 1162. (i)
Gomory, A.; Somogyi, A.; Tamas, J.; Stajer, G.; Bernath, G.; Komaromi,
I. Int. J. Mass Spec. Ion Proc. 1991, 107, 225.
Acknowledgment. Support for this research was provided by
the National Institutes of Health (CA28824 to S.J.D.). This
investigation was supported by a “Research Centers in Minority
Institutions” award, RR-03037 (to L.J.T.), from the National
Center for Research Resources, National Institutes of Health.
Special thanks go to Rebecca Wilson for editorial consultation
and Dana Ryan for assistance with the preparation of the
manuscript. We thank Dr. Jianglong Zhu and Dr. Brendan
Crowley for their helpful discussions. We thank Dr. George
Sukenick for NMR spectroscopic assistance, and Ms. Hui Fang
and Ms. Sylvi Rusli for mass spectrometric assistance. We also
thank Prof. Shaabani for supplying experimental details regarding
ref 5a and Dr. Isaka for a personal communication regarding
ref 5e.
(6) In some instances, spectroscopic suggestion of such an intermediate has
been described, for example: (a) Hou, J-L.; Ajami, D.; Rebek, J., Jr J. Am.
Chem. Soc. 2008, 130, 7810. (b) Restorp, P.; Rebek, J., Jr J. Am. Soc.
Chem. 2008, 130, 11850.
(7) Greater progress in characterization has been achieved with related mixed
anhydrides which are not in the formimidate series. cf. inter alia: (a)
Kawasaki, K.; Tsumura, S.; Katsuki, T. Synlett. 1995, 12, 1245. (b) Schwarz,
J. S. P. J. Org. Chem. 1972, 37, 2906. (c) Cambie, R. C.; Hayward, R. C.;
Roberts, J. L.; Rutledge, P. S. J. Chem. Soc., Perkin Transc. 1 1974, 15,
1858.
(8) The authors reported absorptions at 1687 and 1598 cm-1 for the alleged
mixed anhydride 7.
(9) Typical IR absorptions reported for a nonformimidate mixed anhydride of
the type 7 are ca. 1710-1660 cm-1; see ref 7.
(10) The NMR spectrum of the diffraction worthy crystal is the same as that of
the bulk material. For a crystal structure based on a hydrogen-bonded
complex between two “small molecules”, see: Leiserowitz, L.; Nader, F.
Acta Crystallogr. 1977, B33, 2719.
(11) (a) Atta-ur-Rahman; Basha, A.; Waheed, N. Tetrahedron Lett. 1976, 3,
219. (b) Cooley, J. H.; Stone, D. M.; Oguri, H. J. Org. Chem. 1977, 42,
3096. (c) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1989, 54, 1144.
(d) Rigby, J. H.; Laurent, S. J. Org. Chem. 1998, 63, 6742. (e) Fernholz,
H.; Schmidt, H. J. Angew. Chem., Int. Ed. 1969, 8, 521. (f) Callens, E.;
Burton, A. J.; Barrett, A. G. M. Tetrahedron Lett. 2006, 47, 8699. (g)
Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210. (h)
Shrestha-Dawadi, P. B.; Jochims, J. C. Synthesis 1993, 4, 426. (i)
Siebenmann, C.; Schnitzer, R. J. J. Am. Chem. Soc. 1943, 65, 2126.
(12) (a) Gassman, P. G.; Haberman, L. M. Tetrahedron Lett. 1985, 26, 4971.
(b) Kotha, S.; Brahmachary, E. Bioorg. Med. Chem. 2002, 10, 2291. (c)
Priestley, E. S.; Decicco, C. P. Org. Lett. 2000, 2, 3095. (d) Kotha, S.;
Screenivasachary, N.; Mohanraja, K.; Durani, S. Bioorg. Med. Chem. Lett.
2001, 11, 1421.
Supporting Information Available: Detailed experimental proce-
dures, copies of all spectral data, full characterization, and a cif file of
X-ray for compound 10. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) (a) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446. (b) Jones,
G. O.; Li, X.; Hayden, A. D.; Houk, K. N.; Danishefsky, S. J. Org. Lett.
Published online August 16, 2008, http://dx.doi.org/10.1021/ol8016287.
(2) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181. (b) Ugi, I.; Meyr, R.;
Fetzer, U.; Steinbru¨ckner, C. Angew. Chem. 1959, 71, 386. For reviews,
see: (c) Banfi, L.; Riva, R. Org. React. 2005, 65, 1. (d) Do¨mling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168. (e) Do¨mling, A. Chem. ReV.
2006, 106, 17.
(3) The reaction described here is a special instance of a Mumm rearrangement
which involves a 1,3-OfN acyl transfer not in the formimidate series.
However, the formimidate context reported here renders this reaction unique.
For literature access to the Mumm reaction, see: (a) Mumm, O.; Hesse,
H.; Volquartz, H. Ber. 1915, 48, 379. (b) Curtin, D. Y.; Miller, L. L. J. Am.
Chem. Soc. 1967, 89, 637. (c) Sheehan, J. C.; Corey, E. J. J. Am. Chem.
Soc. 1952, 74, 4555. (d) Schwarz, J. S. P. J. Org. Chem. 1972, 37, 2906.
(e) Darbeau, R. W.; White, E. H.; Nunez, N.; Coit, B.; Daigle, M. J. Org.
Chem. 2000, 65, 1115.
(4) In our first paper in this series (ref 1), we described a direct pathway to 4, Via
a formal cycloaddition pathway, which does not pass through 3. In this paper,
we focus on the presumed pathway from 3 to 4. However, involvement of the
direct cycloaddition pathway to reach 4 is not ruled out.
(5) (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007,
48, 6137. (b) Gloede, J.; Gross, H. Z. Chem. 1968, 8, 219. (c) Gloede, J.
J. Prakt. Chem. 1982, 324, 667. (d) Shono, T.; Kimura, M.; Ito, Y.;
Nishida, K.; Oda, R. Bull. Chem. Soc. Jpn. 1964, 37, 635. The structure
was presumed on the basis of its infrared spectrum. (e) Isaka, M.;
Boonkhao, B.; Rachtawee, P.; Auncharoen, P. J. Nat. Prod. 2007, 70,
(13) Microwave heating of Gloede’s product (purported 15) in chloroform again
failed to produce the desired N-formylamide.
(14) It should be noted that the elemental analysis, “%N ) 10.45,” (ref 3b) of
Gloede’s product 15 (calcd % N ) 10.14) fits better for compound 17
(calcd. %N ) 10.33) than that concluded by Gloede. As reported by the
authors, the claimed 15 does not react with methanol under reflux
conditions.
(15) Authentic 1,3-dicyclohexylamidine (18) was prepared according to a known
procedure: Taylor, E. C.; Ehrhart, W. A. J. Org. Chem. 1963, 28, 1108.
(16) Simon, J. R. Synthesis 2001, 13, 2011.
(17) (a) Price, C. C.; Roberts, R. M. J. Am. Chem. Soc. 1946, 68, 1255. (b)
Olgu´ın, L. F.; Jime´nez-Estrada, M.; Ba´rzana, E.; Navarro-Ocan˜a, A. Synlett
2005, 2, 340.
(18) This concept was suggested to account for the small amount of amide
formation at room temperature; see ref 1. For cyclization examples that do
not follow Baldwin’s rule, see: Astudillo, M. E. A.; Chokotho, N. C. J.;
Jarvis, T. C.; Johnson, C. D.; Lewis, C. C.; McDonnel, P. D. Tetrahedron
1985, 41, 5919.
(19) Both isonitriles 25 and 27 were prepared in racemic form.
(20) Okamoto, R.; Kajihara, Y. Angew. Chem., Int. Ed. 2008, 47, 5402.
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