Multicomponent reactions of convertible isonitriles

Article abstract of DOI:10.1021/jo900414n

(Chemical Equation Presented) A new family of unsaturated isonitriles has been prepared by the base-promoted ring-opening of oxazoles, offering an alternative to the conventional formamide dehydration route. These compounds undergo the full complement of multicomponent reactions for which isonitriles are known and offer the desirable trait of giving amide products that readily participate in acyl substitution reactions (hence, they are convertible). Moreover, they do not have the objectionable odors for which isonitriles are typically known, making them more accessible as reagents for organic synthesis. One focus of the work is isonitriles bearing perfluorinated alkyl groups that enable the ready separation of such reagents from nonfluorinated reaction products using the "light" fluorous method of fluorous solid-phase extraction.

Full text of DOI:10.1021/jo900414n

Multicomponent Reactions of Convertible Isonitriles
Michael C. Pirrung,* Subir Ghorai, and Tannya R. Ibarra-Rivera
Department of Chemistry, UniVersity of California, RiVerside, California 92521-0403
michael.pirrung@ucr.edu
ReceiVed February 24, 2009
A new family of unsaturated isonitriles has been prepared by the base-promoted ring-opening of oxazoles,
offering an alternative to the conventional formamide dehydration route. These compounds undergo the
full complement of multicomponent reactions for which isonitriles are known and offer the desirable
trait of giving amide products that readily participate in acyl substitution reactions (hence, they are
convertible). Moreover, they do not have the objectionable odors for which isonitriles are typically known,
making them more accessible as reagents for organic synthesis. One focus of the work is isonitriles
bearing perfluorinated alkyl groups that enable the ready separation of such reagents from nonfluorinated
reaction products using the “light” fluorous method of fluorous solid-phase extraction.
Introduction
‘horrible’, and ‘extremely distressing’”. A qualitative test for
primary amines (sometimes called the carbylamine test) is based
on the Hofmann reaction with dichlorocarbene, which leads to
formation of an isonitrile whose presence is detected by its foul
odor.7 To quote odor theorist Luca Turin, “isonitriles” are just
the Godzilla of smells, you can’t believe how awful they smell,
they make you vomit your guts out instantly.”8 This property
has even prompted the inclusion of isonitriles in nonlethal
weaponry.9
We were attracted by a little-used route to isonitriles based
on the base-promoted ring-opening of heterocycles such as
benzoxazoles or oxazoles to give O-acylated products like 3
(Scheme 1).10 This method has seen use in the preparation of
ortho oxygen-substituted aryl isonitriles used as ligands for metal
complexes.11 This ring-opening process has been closely studied
mechanistically, and NMR spectra have been observed of
R-isocyanoenolates (2) and o-isocyanophenolates with several
counterions.12 The reactions of the R-isocyanoenolates are
complicated by their ambident nature. The simple system 2
eventually gives a ring-closed product 5 upon silylation, but
Isonitriles are versatile functional groups owing to their status
as the longest-known stable divalent carbon derivatives. The
reactions in which they participate are quite varied, including
free radical additions,1 organometallic transformations like the
Pauson-Khand reaction,2 and polymerizations.3 Isonitriles have
also been quite prolific in multicomponent reactions.4 The
attractions of these functional groups are offset by several
disadvantages. Few isonitriles are available from major com-
mercial suppliers, likely for reasons to follow. They are typically
not simple to prepare, the best method being based on the
dehydration of formamides with the dangerous reagent phos-
gene.5 While some alternative syntheses have been reported,6
they are typically not as general. Isonitriles also convey quite
offensive odors. Ugi admits “The development of the chemistry
of isonitriles has probably suffered through the characteristic
odor of volatile isonitriles, which has been described by
Hofmann and Gautier as ‘highly specific, almost overpowering’,
(1) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177.
(2) Dixon, S.; Whitby R. J. In Titanium and Zirconium in Organic Synthesis;
Wiley-VCH: Wienheim, 2003.
(3) Drenth, W.; Nolte, R. J. M. Acc. Chem. Res. 1979, 12, 30.
(4) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b) Zhu,
J.; Bienayme´, H. Multicomponent Reactions; Wiley-VCH: Wienheim, 2005. (c)
Do¨mling, A. Chem. ReV. 2006, 106, 17. (d) Akritopoulou-Zanze, I. Curr. Opin.
Chem. Biol. 2008, 12, 324.
(5) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K. Angew.
Chem., Int. Ed. Engl. 1965, 4, 472.
(6) Atkinson, R. S.; Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1974,
2619.
(7) (a) Hofmann, A. W. Ber. Drsch. Chem. Ges. 1870, 3, 767. (b) Norris,
J. F. Experimental Organic Chemistry; McGraw-Hill: New York, 1915; p 87.
(8) Burr, C. The Emperor of Scent: A Story of Perfume, Obsession, and the
Last Mystery of the Senses; Random House: New York, 2002.
(9) Pinney, V. R. Malodorant compositions, related non-lethal weapon
systems, and methods of their use. US Pat. 6 352 032, March 5, 2002.
(10) Whitney, S. E.; Rickborn, B. J. Org. Chem. 1991, 56, 3058.
(11) (a) Tamm, M.; Hahn, F. E. Coord. Chem. ReV. 1999, 182, 175. (b) Hahn,
F. E.; Lu¨gger, T. J. Organomet. Chem. 1994, 481, 189. (c) Kernbach, U.; Lu¨gger,
T.; Hahn, F. E.; Fehlhammer, W. P. J. Organomet. Chem. 1997, 541, 51. (d)
Hahn, F. E.; Imhof, L. Organometallics 1997, 16, 763.
4110 J. Org. Chem. 2009, 74, 4110–4117
10.1021/jo900414n CCC: $40.75 2009 American Chemical Society
Published on Web 05/01/2009

Multicomponent Reactions of ConVertible Isonitriles
SCHEME 1
SCHEME 2
TABLE 1. Preparation of Aromatic Isonitrile-Esters
the O-silylated open chain form 4 is an intermediate.13 Anion
2 reacts with carbonyl electrophiles in the ring-closed form to
give C-hydroxyalkylated products 6.14 The C-4 iodination of
lithiated oxazole is also thought to involve C-iodination of the
ring-opened form 2 followed by ring closure.15
compound 10
acylating agent
yield of isonitrile
odor
a
b
c
d
e
f
AcCl
PivCl
85%
92%
96%
83%
96%
90%
93%
93%
malt
natural rubber
creosote
MeC6H4COCl
Boc2O
MeOC6H4COCl
NCC6H4COCl
C6H5COCl
C8F17C6H4COCl
taffy
We viewed the base-promoted ring-opening of oxazoles as
an attractive entry into functionalized, unsaturated isonitriles
useful in synthesis, and aimed to develop methods to prepare
these materials that would reliably trap the ambident intermedi-
ate on oxygen in the open-chain form. We then showed these
compounds confer attractive reactivity on Ugi reaction products,
making them a novel representative of the family of “convertible
isonitriles”,16 that is, those whose Ugi reaction products are
activated for acyl substitution and related processes. The process
reported here was also foreshadowed by the base-promoted ring-
opening of oxazolines to prepare convertible isonitriles.16e-h
We further discovered that many of the newly prepared
compounds do not exhibit the repugnant odors characteristic
of many other isonitriles. These properties should encourage
the use of this family of reagents in organic synthesis. Parts of
this work have been reported in communication form.17
mild cherry
old wood
mild petroleum
odorless
g
h
SCHEME 3
Under the same reaction conditions, 5-phenyloxazole reacts with
either menthyl chloroformate or O-formyl mandeloyl chloride
to give closed-chain, C2-acylated oxazole products (not shown),
as evidenced by the lack of an isonitrile stretch in their IR
spectra.
Results
Initial studies focused on oxazoles. Adapting Hodges’
method,14 oxazole was treated with n-BuLi at -78 °C in THF,
followed by addition of an acylating agent and warming to room
temperature for 2 h. Compound 3 was obtained in >80% yield
using this method, as was derivative 7 that incorporates an
O-formyl mandelate as a potential chiral auxiliary. In these
reactions of metalated oxazole with acetyl and O-formyl
mandeloyl chlorides, no trace could be found of C-acylation to
give the closed-chain form. Attempts to extend this chemistry
to another commercially available oxazole gave poor results.
An Ugi reaction of 3 in methanol gives product 8 in 74%
yield (Scheme 2). Compound 7 could be successfully used in a
similar Ugi reaction, but it provided no diastereoselectivity. As
an enamide, 8 resembles the N-cyclohexenyl amides used by
Armstrong for the conversion of Ugi reaction products to other
acyl derivatives. We therefore examined reactions of 8 under
Armstrong’s conditions, anhydrous HCl in methanol at 55 °C
for 3 h. Methyl ester 9 was obtained in quantitative yield.
We then investigated conversion of benzoxazole to the
corresponding isonitrile by trapping of the ring-opened phenolate
intermediate. Under similar conditions, using n-BuLi at low
temperature in THF followed by addition of acid chlorides or
anhydrides and warming to room temperature, a variety of ortho-
substituted phenylisonitrile derivatives 10 were obtained. The
results are summarized in Table 1.
The conversion reaction of a simple Ugi product 11 derived
from isonitrile 10c in 90% yield was examined under the same
conditions used with 8, and 9 was obtained in quantitative yield
(Scheme 3). For the conversion reaction of 8, a product derived
from the enamide fragment could not be isolated/identified (but
it is presumably an aminoacetaldehyde derivative). With Ugi
product 11, the greater mass of the isonitrile-derived portion of
(12) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.; Tre´court,
F.; Que´guiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R. J. Org.
Chem. 2005, 70, 5190.
(13) Dondoni, A.; Dall’Occo, T.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Chem. Soc., Chem. Commun. 1984, 258.
(14) Hodges, J. C.; Patt, W. C.; Connolly, C. J. J. Org. Chem. 1991, 56,
449.
(15) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011.
(16) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117,
7842. (b) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
(c) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631. (d)
Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2008, 73, 4198. (e) Lindhorst, T.;
Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411. (f) Linderman, R. J.; Binet, S.;
Petrich, S. R. J. Org. Chem. 1999, 64, 336. (g) Kennedy, A. L.; Fryer, A. M.;
Josey, J. A. Org. Lett. 2002, 4, 1167. (h) Rikimaru, K.; Yanagisawa, A.; Kan,
T.; Fukuyama, T. A. Synlett 2004, 41. (i) Kreye, O.; Westermann, B.;
Wessjohann, L. A. Synlett 2007, 3188.
(17) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128, 11772.
J. Org. Chem. Vol. 74, No. 11, 2009 4111

Pirrung et al.
SCHEME 4
SCHEME 6
SCHEME 5
SCHEME 7
the molecule was expected to allow the other conversion product
to be isolated. This other product proved to be aryl benzoxazole
12. A similar Ugi product 13 was prepared from isonitrile 10b,
and its conversion to the methyl ester 9 using Armstrong’s
conditions was accompanied by the formation of 14.
We considered several possible mechanisms for this acyl
substitution process; one is delineated above (Scheme 4).
Cyclization of the amide nitrogen onto the ester gives the
tetrahedral intermediate 15. Upon OH protonation and loss of
water, a stabilized cation 16 could be formed that should be a
quite reactive acylating agent. Nucleophilic acyl substitution
would give the Ugi conversion product and the observed
benzoxazole.
To further probe this mechanism and perhaps provide
evidence concerning the rate-limiting step of the process, we
examined the effect of aromatic substitution on the conversion.
The initial cyclization step would presumably be faster with a
more electron-deficient ester carbonyl group (engendered by an
electron-withdrawing R substituent), whereas an electron-
donating R substituent should promote either the protonation
of the ester carbonyl or the ionization step to cation 16.
Isonitriles 10e, 10f, and 10g provide a means to examine this
question. They were used in standard Ugi reactions to give
products 17, which were subjected to the conversion reaction
with HCl/MeOH. Notably, all of these reactions occur readily
at room temperature, rather than the 55 °C used for cyclohex-
enamides. The time for the reaction to reach completion at room
temperature is dependent on the aromatic substituent, with the
electron-rich benzoate giving 18 fastest. These results support
the mechanistic pathway in Scheme 4 and suggest that the rate-
determining step is formation of the cation 16. However, an
anomalous observation that confuses the issue is that rather than
17e and 17g giving the benzoxazoles, the open-chain aniline-
esters 19 were obtained.
mu¨nchnones in the conversion reactions under study here. Two
pathways of acyl substitution are possible following the genera-
tion of 20. One involves direct reaction with a nucleophile (path
a), and the other proceeds via the intermediacy of 21, formed by
an intramolecular nucleophilic substitution that should compete
effectively with intermolecular processes (path b). Evidence on the
pathway followed was gained by treatment of Ugi product 22 under
Armstrong’s dipolar cycloaddition conditions. Pyrrole 23 was
obtained in 59% yield, essentially the same outcome observed when
Armstrong prepared this pyrrole from the corresponding cyclo-
hexenamide Ugi product. Naturally, benzoxazole 12 is also formed
(72% isolated yield). This result shows that generation of a
mu¨nchnone from o-(acyloxy)phenylisonitrile Ugi reaction products
is possible, and that this pathway may be followed in conversion
reactions. These mechanistic views do not bear on the conversion
of the products of oxazole-derived isonitriles (such as 8), because
they have a readily available mechanism for cis-trans isomeriza-
tion, which would preclude reforming the oxazole.
One drawback of the conversion reaction is that it requires
chromatographic separation of the desired acyl substitution
product from the benzoxazole. To make this process more
convenient, a “light” fluorous convertible isonitrile was prepared.
The fluorous acid chloride 24 required was prepared by a known
route from p-iodobenzoic acid.18 The initial coupling step was
significantly improved by using microwave heating, which gives
p-perfluorooctylbenzoic acid in 87% yield in 2 h compared to
the reported 44% yield in 16 h with conventional heating.
There are further questions to be answered about the mechanism
of the acyl substitution step. Armstrong implicated oxazolone (or
mu¨nchnone) intermediates (Scheme 6) in the acyl substitution of
cyclohexenamide Ugi products by trapping them in dipolar
cycloaddition reactions (when the R1 substituent is aromatic) to
give pyrroles.16b We therefore considered the involvement of
4112 J. Org. Chem. Vol. 74, No. 11, 2009

Multicomponent Reactions of ConVertible Isonitriles
SCHEME 8
CHART 1
Benzoxazole was metalated as before and acylated with 24,
giving 10h in excellent yield. It can be used in a fluorous Ugi
process based on earlier work from the Pittsburgh group,19
modified for “light” fluorous technology using fluorous solid-
phase extraction (SPE).20 The isonitrile 10h is used as the
limiting reagent, and the other reagents used in excess are readily
removed following the reaction. They flow through fluorous
silica gel when it is eluted with MeOH/H2O, whereas product
25 is retained and then eluted with THF. Compound 25 was
subjected to the conversion process under Armstrong’s condi-
tions. Ester 9 is eluted in 98% yield with MeOH/H2O, and the
benzoxazole 26 is eluted in 97% yield with THF.
SCHEME 9
A different application of fluorous technology was investi-
gated to elaborate the Ugi reaction products of these function-
alized phenylisonitriles. Benzoxazole was metalated and the
resulting phenolate was sulfonylated with a light fluorous
sulfonyl halide, giving 27 (Scheme 8). This isonitrile was used
in two example Ugi reactions, and the resulting products 28
and 29 were again readily purified by fluorous SPE. These
compounds participate in conventional organometallic trans-
formations such as the Suzuki (30-31), Sonogashira (32-35),
and Stille (36-37) coupling reactions, as fluorous aryl sulfonates
have reactivity similar to triflates,21 giving an array of products
(Chart 1) in overall excellent yields. The ability to separate these
products from 28 and 29 by fluorous SPE significantly eases
the cleanup of these reactions.
Few limitations to the known chemistry of isonitriles have
been discerned in the reactions of compounds 10. For example,
10b and 10d undergo straightforward Ugi reactions with
thiocarboxylic acids to give thioamides 38-40 (Scheme 9).
It did not prove possible to use 10a in Ugi reactions because
its aryl acetate competitively acylates the amine. However, other
isonitriles in this family readily give Passerini, Gro¨bcke,22 and
Ugi-Smiles23 reaction products 41-43, respectively (Scheme
10).
reactions of cyclobutanone.24 For that purpose, we investigated
a model reaction of convertible isonitrile 10c, which unfortu-
nately gives a low conversion to 44. As an alternative, we
examined the corresponding reaction with isocyanocyclohexene,
which gives a far better outcome (Scheme 11). Aiming to exploit
some of our recent results on the aqueous acceleration of Ugi
reactions,25 a similar reaction was investigated in water using
convertible isonitrile 10b, but no reaction was observed.
Likewise, isocyanocyclohexene could be used in an Ugi reaction
with a protected aspartic acid derivative to give 46 in moderate
yield, but when 10b was used instead, the yield was only 16%.
These results suggest that isocyanocyclohexene is more reactive
than these o-(acyloxy)phenylisonitriles. Scant data is available
on the relative nucleophilicity of isonitriles, with only a recent
report on a few isonitriles, none of them convertible.26
We have been interested in the synthesis of a peptide that
includes a C-terminal cyclobutane amino acid based on Ugi
(18) Paciorek, K. J. L.; Masuda, S. R.; Shih, J. G.; Nakahara, J. H. J. Fluorine
Chem. 1991, 53, 233.
(19) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62,
2917.
(20) (a) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866. (b)
Curran, D. P. Synlett 2001, 1488. (c) Matsugi, M.; Curran, D. P. Org. Lett. 2004,
6, 2717.
(21) (a) Lu, Y.; Zhang, W. QSAR Comb. Sci. 2004, 23, 827. (b) Zhang, W.;
Nagashima, T.; Lu, Y.; Chen, C. H-T. Tetrahedron Lett. 2004, 45, 4611. (c)
Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473. (d)
Zhang, W.; Chen, C. H.-T. Tetrahedron Lett. 2005, 46, 1807. (e) Zhang, W.;
Nagashima, T. J. Fluorine Chem. 2006, 127, 588.
(22) (a) Gro¨bcke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661. (b) Lu, Y.;
Zhang, W. QSAR Comb. Sci. 2004, 23, 827.
(23) El Ka¨ım, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,
4019.
The acyloxy group in these isonitrile derivatives can offer
several benefits such as facilitating the conversion reaction and
permitting fluorous purification. Its asymmetric induction was
also explored. For example, isonitrile 47 bearing a menthyl
(24) (a) Wang, J. PhD Thesis, Duke University, 2007. (b) Pirrung, M. C.;
Wang, J. J. Org. Chem. 2009, 74, 2958.
(25) Pirrung, M. C.; Das Sarma, K.; Wang, J. J. Org. Chem. 2008, 73, 8723.
(26) Tumanov, V. V.; Tishkov, A. A.; Mayr, H. Angew. Chem., Int. Ed. 2007,
46, 3563.
J. Org. Chem. Vol. 74, No. 11, 2009 4113

Pirrung et al.
SCHEME 10
emerged from these organoleptic measures is included in the
final column in Table 1.
Discussion
The factors that control whether the ambident anion derived
from metalating oxazoles is acylated in the open-chain or closed-
chain form are not fully understood. Examples from the literature
favor acylation in the closed-chain form by converting the initial
lithium reagents to less electropositive metals,27 but there are
no systematic means known to favor the O-acylation product.
The influence of oxazole substituents (e.g., 5-phenyl vs 5-H)
on the acylation site is also inscrutable.
Investigations of the mechanism of the conversion process
produced a dilemma. All observations suggested that the
conversion involves the formation of an intermediate 16, its
cyclization to a mu¨nchnone, and its reaction with a nucleophile,
until 19e and 19g were isolated as the byproduct of conversion
reactions. It is very difficult to understand the dependence of
the reaction on the aromatic substituent without the intermediacy
of a species like 20, and yet its ring must be opened to give the
observed products 19.
The ease of the conduct of Ugi reactions with these isonitriles
and the subsequent reactions of the Ugi products (both acyl
substitution/conversion reactions and organometallic couplings)
was significantly facilitated by the use of light fluorous
technology. The solid-phase extraction method for product
purification/separation is less of a chromatography and more
of a filtration, with no question about the separability of desired
targets from other reagents.
SCHEME 11
These isonitriles have a few limitations that should be not
be overlooked. They do not seem as reactive as some other
isonitriles, convertible or not. We were also disappointed by
our inability to use chiral versions that were readily preparable
from conventional chiral auxiliaries to promote asymmetric
multicomponent reactions, processes considered the final frontier
in this field.28
Conclusion
carbonate chiral auxiliary was prepared using the conventional
route, and 7 was available as described earlier. However, their
multicomponent reactions were completely nondiastereoselec-
tive, giving 1:1 mixtures. Evidently, conformational flexibility
and the distance between the stereogenic carbon in the auxiliary
and the isonitrile carbon are too great for effective asymmetric
induction.
A novel family of convertible isonitriles has been prepared
and examined in a number of the classical multicomponent
reactions. The preparation of related reagents along similar lines
should be a straightforward extension of this methodology, and
all of these reagents should be applicable to other isonitrile-
based multicomponent reactions (including newer versions such
as the Passerini-Smiles, etc.). Considering the role played by
isonitriles as acyl anion equivalents in the Ugi reaction, simple
and mild methods such as this one to convert the products to
other carboxylic acid derivatives will broaden the structural
diversity of end-products accessible via multicomponent pro-
cesses. The ability to work with these reagents without the
accompanying pungent aroma around the lab, in the equipment,
and on the researcher should also encourage their use. This virtue
may apply particularly to polymer and radical chemistry, where
the advantages of the conversion reaction may not be as
significant. The fluorous properties of select members of the
family can also be exploited more broadly.
Having worked with isonitriles for some time, we quickly
realized that members of this family do not exhibit the usual
offensive odors to which we were accustomed. We aimed to
classify their odors, and did so by an empirical jury protocol.
Samples of each compound were spotted onto tissues, and all
members of the laboratory were asked to smell each of them
and provide a subjective description. The consensus that
(27) Pippel, D. J.; Mapes, C. M.; Mani, N. S. J. Org. Chem. 2007, 72, 5828.
(28) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
4114 J. Org. Chem. Vol. 74, No. 11, 2009

Multicomponent Reactions of ConVertible Isonitriles
a known compound31 that exhibits spectral properties consistent
with this structure. The standard procedure for compounds 18 was
as follows. To a solution of Ugi product (0.06 mmol) in methanol
(0.1 mL) was added a solution of acetyl chloride (0.3 mmol) in
methanol (0.5 mL) in one portion. The resulting solution was stirred
at room temperature until the starting material disappeared. The
solvent was removed in Vacuo and purified by flash column
chromatography on silica gel, eluting with hexanes to 7:3 hexanes/
ethyl acetate gradient to provide the methyl ester 18 as a colorless
liquid. When 17g was used the reactant, ester 18 was produced in
quantitative yield and 2-aminophenyl benzoate (19g) was produced
in 95% yield. It gave spectral properties identical to the known
compound.32 When 17e was used as a reactant, the ester 18 was
produced in quantitative yield and 2-aminophenyl 4-methoxyben-
zoate (19e) was produced in 94% yield. It gave spectral properties
identical to the known compound.33
Dimethyl 1-(4-methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrole-
3,4-dicarboxylate (23). The amide 22 (0.052 g, 0.10 mmol) was
azeotropically dried with toluene, and then dissolved in toluene (2
mL). The dimethyl acetylenedicarboxylate (0.062 mL, 0.50 mmol)
was added to the reaction mixture followed by HCl (1.0 M solution
in anhydrous ether, 0.3 mL, 0.30 mmol). The flask was then capped
and heated at 100 °C for 4 h. After cooling the reaction mixture
solvent was evaporated and the residue was taken up in CH2Cl2
and filtered. The soluble portion was purified by flash column
chromatography on silica gel, eluting with CH2Cl2 to 19:1 CH2Cl2/
methanol gradient to provide the title compound 23 (0.023 g, 59%)
as a white solid. This compound is known from Armstrong’s work
and our product showed identical spectral properties.16
Experimental Section
Experimental descriptions for compounds 7-9, 10a-g, 11, 17,
18, 22, 41b, and 42 are available in the Supporting Information
for our communication on this work.17
2-Isocyanophenyl 4-Perfluorooctylbenzoate (10h). A 50 mL
round-bottom flask equipped with a magnetic stir bar and charged
with benzoxazole (0.900 g, 7.56 mmol) and THF (18 mL) are
allowed to cool to -78 °C for 5 min prior to addition of n-BuLi
(1.6 M solution in hexanes, 4.96 mL, 7.94 mmol). The reaction
mixture was allowed to stir at the same temperature for 1.5 h. The
acid chloride 2429 (4.44 g, 7.94 mmol) was dissolved in 4 mL THF
and added dropwise to the solution. The solution was allowed to
warm to room temperature and stirred for 2 h. The reaction mixture
was poured onto a mixture of ether (100 mL) and saturated aqueous
NaHCO3 (50 mL). The organic layer was washed with water (2 ×
50 mL), dried, and concentrated in vacuo. The resulting residue
was purified by silica gel flash column chromatography and the
organics concentrated in vacuo to provide the title compound (4.51
g, 93%). 1H NMR (300 MHz, CDCl3): δ 8.39 (d, J ) 8.1 Hz, 2H),
7.79 (d, J ) 8.4 Hz, 2H), 7.50 (t, J ) 7.5 Hz, 2H), 7.42-7.32 (m,
2H). 19F NMR (282 MHz, CDCl3): δ -81.3, -111.7, -111.8,
-121.6, -122.1, -122.3, -123.1, -126.6. 13C NMR (75 MHz,
CDCl3): δ 169.9, 163.0, 146.4, 134.5 (t, JC-F ) 24.0 Hz), 132.1,
130.8, 130.7, 127.9, 127.7 (t, JC-F ) 6.0 Hz), 127.1, 123.6, 120.4,
119.3-106.8 (m, C8F17). IR (film): 2124, 1748, 1490, 1454, 1413,
1371, 1332, 1298, 1262, 1198, 1143, 1115, 1104, 1093, 1068, 1048,
1017 cm-1. MS (CI): m/z 659 (M + NH4), 523. HRMS (ESI):
Calcd. for C22H9F17NO2 [MH]+, 642.0356; Found, 642.0351.
p-Perfluorooctylbenzoic Acid. To a solution of 4-iodobenzoic
acid (0.248 g, 1.00 mmol) and perfluorooctyl iodide (0.29 mL, 1.10
mmol) in DMSO (2.5 mL) was added Cu powder (0.191 g, 3.00
mmol). The reaction mixture and a magnetic stir bar were sealed
in the reaction vessel of a Discover monomode microwave apparatus
(CEM) and irradiated for 2 h at 130 °C. Temperature was monitored
with the IR temperature monitoring feature of the Discover reactor.
After cooling to room temperature, CH2Cl2 was added to the
reaction mixture and the inorganic salts were filtered and washed
with more CH2Cl2. The combined solution was then washed with
water, dried and concentrated in Vacuo. The crude product was
purified by crystallization from ethanol gives the title compound
(0.47 g, 87%) as a white solid. This compound is known and the
properties of this material were consistent with that report.18
General Procedure for Fluorous Ugi Reactions. To a solution
of amine (1.0 mmol) in methanol (2.0 mL) was added aldehyde
(1.0 mmol), and the reaction mixture was stirred at room temper-
ature for 10 min. To this solution was added carboxylic acid (1.0
mmol), and the reaction mixture was stirred for 5 min, and isonitrile
(1.0 mmol) was added. The resulting mixture was stirred at room
temperature until the reaction was determined to be complete by
TLC. The resulting solution was concentrated in vacuo and purified
by fluoroflash silica gel flash column chromatography (solvents
noted) to provide the title compounds.
2-(2-(N-Benzylpropionamido)-3-methylbutanamido)phenyl Piv-
alate (13). To a solution of benzylamine (0.11 mL, 1.00 mmol) in
methanol (2.0 mL) was added isobutyraldehyde (0.091 mL, 1.00
mmol), and the reaction mixture was stirred at room temperature
for 10 min. To this solution was added propionic acid (0.075 mL,
1.00 mmol), and the reaction mixture was stirred for 5 min, then
2-isocyanophenyl pivalate (10b) (0.203 g, 1.00 mmol) was added.
The resulting mixture was stirred at room temperature for 18 h
and after that resulting solution was concentrated in Vacuo. The
resulting residue was purified by flash column chromatography on
silica gel, eluting with CH2Cl2 to 11:1 CH2Cl2/methanol gradient
to provide the title compound 13 (0.385 g, 88%) as a colorless
liquid. 1H NMR (300 MHz, CDCl3): δ 8.47 (br s, 1H), 7.99 (dd, J
) 7.2, 1.8 Hz, 1H), 7.22-7.02 (m, 8H), 4.62 (s, 2H), 4.57 (d, J )
11.1 Hz, 1H), 2.59-2.51 (m, 1H), 2.43-2.20 (m, 2H), 1.47 (s,
9H), 1.09 (t, J ) 6.9 Hz, 3H), 1.00 (d, J ) 6.6 Hz, 3H), 0.88 (d,
J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 176.9, 176.7,
168.7, 140.7, 137.1, 130.5, 129.0, 127.5, 126.3, 126.2, 124.4, 122.1,
66.7, 53.7, 49.5, 39.7, 27.5, 27.4, 26.6, 20.2, 19.1, 9.8; IR (film):
3190, 2970, 2875, 1757, 1696, 1635, 1607, 1526, 1479, 1451, 1414,
1369, 1309, 1275, 1251, 1230, 1180, 1097, 1028 cm-1. MS (FAB):
m/z 439 (M + H), 246. HRMS: Calcd. for C26H35N2O4 [MH]+,
439.2597; Found, 439.2602.
Conversion Reactions. The procedure for compounds 11 and
13 was as follows. To a solution of Ugi product (0.3 mmol) in
methanol (2.5 mL) was added acetyl chloride (1.5 mmol) in one
portion. The flask was equipped with a reflux condenser and heated
to 55 °C for 3 h. The reaction was cooled to room temperature and
the solvent was removed in Vacuo. The resulting residue was
purified by flash column chromatography on silica gel, eluting with
hexanes to 19:1 hexanes/ethyl acetate gradient to provide ester 9
as a colorless liquid. The other products were: 2-p-tolylbenzo[d]ox-
azole (12), a known compound30 that exhibits spectral properties
consistent with this structure, and 2-tert-butylbenzo[d]oxazole (14),
2-(2-(N-benzylpropionamido)-3-methylbutanamido)phenyl
4-Perfluorooctylbenzoate (25). Prepared according to the general
procedure for 15 h to provide title compound as a colorless liquid
(78%) after purification by flash column chromatography on
fluoroflash silica gel, eluting with 80% MeOH/H2O followed by
THF. The title compound exists as a two rotamers in 4:1 ratio at
1
room temperature in chloroform. H NMR (300 MHz, CDCl3): δ
9.63 (br s, 0.2H), 9.38 (br s, 0.8H), 8.45 (d, J ) 8.4 Hz, 1.6H),
(31) (a) Tauer, E.; Grellmann, K. H. J. Org. Chem. 1981, 46, 4252. (b)
DeLuca, M. R.; Kerwin, S. M. Tetrahedron 1997, 53, 457. (c) Yoshida, Y.;
Hamada, Y.; Umezu, K.; Tabuchi, F. Org. Proc. Res. DeV. 2004, 8, 958. (d)
Altenhoff, G.; Glorius, F. AdV. Synth. Cat. 2004, 346, 1661.
(29) Matsui, M.; Tanka, N.; Nakaya, K.; Funabiki, K.; Shibata, K.; Mura-
matsu, H.; Abe, Y.; Kaneko, M. Liq. Cryst. 1997, 23, 217.
(30) (a) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org. Lett.
2003, 5, 3713. (b) Derridj, F.; Djebbar, S.; Benali-Baitich, O.; Doucet, H. J.
Organomet. Chem. 2008, 693, 135.
(32) (a) So, Y.-H.; Heeschen, J. P. J. Org. Chem. 1997, 62, 3552. (c) Marshall,
F. J.; Sigal, M. V., Jr.; Sullivan, H. R.; Cesnik, C.; Root, M. A. J. Med. Chem.
1963, 6, 60.
(33) Jan, T.; Floner, D.; Moinet, C. Electrochim. Acta 1997, 42, 2073.
J. Org. Chem. Vol. 74, No. 11, 2009 4115

Pirrung et al.
8.38 (d, J ) 8.4 Hz, 0.4H), 8.24 (d, J ) 8.1 Hz, 0.2H), 8.19 (d, J
) 8.1 Hz, 0.8H), 7.78 (d, J ) 8.4 Hz, 1.6H), 7.66 (d, J ) 8.4 Hz,
0.4H), 7.43 (d, J ) 8.1 Hz, 0.4H), 7.30-7.05 (m, 7.2H), 6.85 (d,
J ) 6.3 Hz, 0.4H), 4.54 (d, J ) 15.6 Hz, 0.2H), 4.53 (s, 1.6H),
4.41 (d, J ) 15.6 Hz, 0.2H), 4.16 (br m, 1H), 2.86-2.73 (m, 0.2H),
2.65-2.53 (m, 0.8H), 2.25-2.01 (m, 2H), 1.06 (d, J ) 6.3 Hz,
0.6H), 1.03 (d, J ) 6.3 Hz, 0.6H), 0.97 (d, J ) 6.3 Hz, 2.4H), 0.80
(d, J ) 6.3 Hz, 2.4H), 0.71 (t, J ) 7.2 Hz, 3H). 19F NMR (282
MHz, CDCl3): δ -81.2, -81.3, -111.5, -111.6, -121.5, -122.1,
-122.3, -123.1, -126.5. 13C NMR (75 MHz, CDCl3): δ 177.1,
173.3, 169.1, 168.5, 164.2, 164.0, 140.2, 139.6, 136.6, 135.7, 133.9
(t, JC-F ) 24.0 Hz), 132.9, 131.0, 130.0, 129.0, 128.9, 128.0, 127.8,
127.4 (t, JC-F ) 6.0 Hz), 127.2, 127.0, 126.6, 124.5, 124.4, 122.3,
122.2, 122.1, 119.3-106.8 (m, C8F17), 69.7, 51.0, 27.5, 26.6, 26.5,
20.2, 19.6, 19.3, 9.0. IR (film): 3266, 2971, 1747, 1693, 1630, 1610,
1533, 1498, 1454, 1413, 1369, 1238, 1199, 1146, 1105, 1068, 1030,
1018 cm-1. MS (FAB): m/z 915 (M + K), 899 (M + Na). HRMS
(ESI): Calcd. for C36H30F17N2O4[MH]+, 877.1929; Found, 877.1926.
General Procedure for Fluorous Conversion Reactions.
2-(p-Perfluorooctyl)benzo[d]oxazole (26). To a solution of fluorous
Ugi product 25 (0.263 g, 0.3 mmol) in methanol (2.5 mL) was
added acetyl chloride (0.107 mL, 1.5 mmol) in one portion. The
flask was equipped with a reflux condenser and heated to 55 °C
for 3 h. The reaction was cooled to room temperature and the
solvent was removed in Vacuo. The resulting residue was purified
by flash column chromatography on fluoroflash silica gel, eluting
with 80% MeOH/H2O to give methyl ester 9 followed by THF to
give the title compound 26 (0.178 g, 97%) as a white solid. mp:
155.5-156.8 °C. 1H NMR (300 MHz, CDCl3): δ 8.40 (d, J ) 8.1
Hz, 2H), 7.83-7.80 (m, 1H), 7.77 (d, J ) 8.1 Hz, 2H), 7.65-7.60
(m, 1H), 7.44-7.37 (m, 2H). 19F NMR (282 MHz, CDCl3): δ
-81.2, -111.47, -111.53, -121.5, -122.1, -122.2, -123.1,
-126.5. 13C NMR (75 MHz, CDCl3): δ 161.7, 151.1, 142.2, 131.7
(t, JC-F ) 24.0 Hz), 130.9, 127.9, 127.8 (t, JC-F ) 6.0 Hz), 126.1,
125.2, 120.7, 119.3-106.8 (m, C8F17), 111.1. IR (film): 2927, 1609,
1558, 1506, 1473, 1455, 1416, 1371, 1334, 1299, 1196, 1143, 1111,
1093, 1059, 1046, 1017, 1002 cm-1. MS (CI): m/z 631 (M + NH4).
Anal. Calcd. for C21H8F17NO: C, 41.13; H, 1.31; N, 2.28; Found:
C, 41.41; H, 1.68; N, 2.25. HRMS (ESI): Calcd. for
C21H9F17NO[MH]+, 614.0407; Found, 614.0409.
2-Isocyanophenyl Perfluorooctanesulfonate (27). A 50 mL
round-bottom flask equipped with a magnetic stir bar and charged
with benzoxazole (1.00 g, 8.39 mmol) and THF (20 mL) are
allowed to cool to -78 °C for 5 min prior to addition of n-BuLi
(1.6 M solution in hexanes, 5.50 mL, 8.80 mmol). The reaction
mixture was allowed to stir at the same temperature for 1.5 h. The
perfluoro-1-octanesulfonyl fluoride (2.43 mL, 8.81 mmol) was
added dropwise to the solution. The solution was allowed to warm
to room temperature and stirred for 2 h. The reaction mixture was
poured onto a mixture of ether (100 mL) and saturated aqueous
NaHCO3 (50 mL). The organic layer was washed with water (2 ×
50 mL), dried, and concentrated in vacuo. The resulting residue
was purified by silica gel flash column chromatography eluting with
hexanes to a 24:1 hexanes/ethyl acetate gradient to provide the title
compound 27 (4.34 g, 86%). 1H NMR (300 MHz, CDCl3): δ
7.57-7.51 (m, 1H), 7.50-7.42 (m, 3H). 13C NMR (75 MHz,
CDCl3): δ 173.1, 144.5, 131.1, 129.3, 129.0, 122.9, 120.4,
119.2-106.8 (m, C8F17). 19F NMR (282 MHz, CDCl3): δ -72.2,
-81.1, -108.9, -119.9, -121.7, -122.0, -122.2, -123.1, -126.5.
IR (film): 2127, 1489, 1433, 1371, 1332, 1198, 1150, 1096, 1062,
1037 cm-1. MS (CI): m/z 619 (M + NH4), 602 (M + H). Anal.
Calcd. for C15H4F17NO3S: C, 29.97; H, 0.67; N, 2.33; Found: C,
29.94; H, 0.78; N, 2.36.
g, 0.177 mmol) was added and the mixture was purged with argon
followed by stirring at 80 °C for 8 h. Once the reaction was
complete, water was added to the reaction mixture, and it was
extracted with CH2Cl2. The combined organic layers were washed
with water, dried and concentrated in vacuo affording a brownish
liquid, which was purified by flash column chromatography on silica
gel, eluting with hexanes to 11:1 hexanes/ethyl acetate gradient
afforded the title compound (0.029 g, 79%) as a colorless liquid.
1H NMR (300 MHz, CDCl3): δ 8.28 (br s, 1H), 7.82 (d, J ) 8.4
Hz, 1H), 7.48-7.09 (m, 13H), 4.65 (d, J ) 17.4 Hz, 1H), 4.52 (d,
J ) 17.4 Hz, 1H), 4.36 (d, J ) 11.1 Hz, 1H), 2.53-2.40 (m, 1H),
2.32-2.04 (m, 1H), 0.98 (t, J ) 7.5 Hz, 3H), 0.95 (d, J ) 6.6 Hz,
3H), 0.80 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
176.2, 168.9, 138.4, 137.5, 134.7, 134.0, 130.4, 129.5, 129.1, 128.9,
128.2, 128.1, 127.5, 126.5, 124.9, 122.9, 66.9, 49.6, 27.5, 26.9,
20.1, 19.1, 9.6. IR (film): 3261, 3030, 2965, 2873, 1684, 1633,
1584, 1519, 1495, 1448, 1437, 1416, 1370, 1302, 1272, 1229, 1206,
1167, 1129, 1074, 1030, 1010 cm-1. MS (FAB): m/z 415 (M +
H), 246. HRMS (ESI): Calcd. for C27H31N2O2 [MH]+, 415.2380;
Found, 415.2382.
2-(N-Benzylpropionamido)-3-methyl-N-(2-(phenylethynyl)phe-
nyl)butanamide (32). Compound 29 (0.071 g, 0.0.085 mmol) was
added to a flask and dissolved in 0.7 mL of DMF. LiCl (0.011 g,
0.26 mmol), Pd(PPh3)2Cl2 (3 mg, 4.4 nmol), and CuI (1 mg, 5.3
nmol) were added to the flask. After 0.9 mL of Et3N was added,
the mixture was stirred at room temperature for 2 min. Phenyl
acetylene (0.014 mL, 0.127 mmol) was added and the reaction
mixture was purged with argon followed by stirring at 80 °C for
8 h. Once complete the reaction, water was added to the reaction
mixture and extracted with CH2Cl2. The combined organic layers
were washed with water, dried and concentrated in vacuo affording
a brownish liquid, which was purified by flash column chroma-
tography on silica gel, eluting with hexanes to 14:1 hexanes/ethyl
acetate gradient afforded the title compound (0.036 g, 98%) as a
1
brownish liquid. H NMR (300 MHz, CDCl3): δ 8.91 (br s, 1H),
8.08 (d, J ) 9.0 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 2H), 7.51 (d, J )
7.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.25-7.13 (m, 6H), 7.04 (t, J )
7.8 Hz, 1H), 4.90 (d, J ) 10.5 Hz, 1H), 4.64 (s, 2H), 2.63-2.46
(m, 1H), 2.44-2.31 (m, 1H), 2.27-2.14 (m, 1H), 1.06 (m, 6H),
0.90 (d, J ) 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 176.4,
168.8, 138.9, 137.2, 132.2, 129.4, 128.8, 128.6, 127.3, 126.2, 123.7,
122.9, 120.2, 113.1, 96.9, 84.3, 65.4, 48.7, 27.3, 26.6, 20.2, 18.9,
9.6. IR (film): 3291, 3063, 2965, 2874, 2209, 1698, 1636, 1605,
1578, 1519, 1492, 1445, 1413, 1371, 1359, 1301, 1227, 1203, 1166,
1127, 1073, 1029 cm-1. MS (FAB): m/z 461 (M + Na), 439 (M +
H), 246. HRMS (ESI): Calcd. for C29H31N2O2[MH]+, 439.2380;
Found, 439.2383.
2-(N-Cyclopropylacetamido)-3-methyl-N-(2-((trimethylsilyl)-
ethynyl)phenyl) Butanamide (35). Prepared according to the above
procedure from 28 by using trimethylsilyl acetylene (1.5 equiv)
for 8 h to provide title compound as a brownish liquid (92%) after
purification by flash column chromatography on silica gel, eluting
with hexanes to 19:1 hexanes/ethyl acetate gradient. 1H NMR (300
MHz, CDCl3): δ 9.43 (br s, 1H), 8.30 (d, J ) 8.1 Hz, 1H), 7.41
(dd, J ) 7.8, 1.2 Hz, 1H), 7.27 (td, J ) 7.8, 1.8 Hz, 1H), 6.98 (td,
J ) 7.8, 1.2 Hz, 1H), 4.15 (d, J ) 11.1 Hz, 1H), 2.89-2.76 (m,
1H), 2.74-2.67 (m, 1H), 2.27 (s, 3H), 1.17-1.09 (m, 1H), 1.06
(d, J ) 6.3 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 0.93-0.80 (m, 3H),
0.31 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 174.7, 170.2, 140.0,
132.6, 129.6, 123.4, 120.0, 113.2, 102.2, 100.0, 71.2, 32.0, 29.9,
27.0, 23.4, 20.5, 20.0, 9.5, 0.1. IR (film): 3281, 2964, 2156, 1697,
1684, 1646, 1602, 1577, 1521, 1447, 1386, 1324, 1300, 1248, 1200,
1187, 1136, 1116, 1104, 1035 cm-1. MS (CI): m/z 371 (M + H),
182. HRMS (ESI): Calcd. for C21H31N2O2Si [M]+, 371.2149; Found,
371.2151.
2-(N-Benzylpropionamido)-N-(biphenyl-2-yl)-3-methylbutan-
amide (30). Compound 29 (0.074 g, 0.088 mmol) was added to a
flask and dissolved in 1 mL of DMF. LiCl (0.011 g, 0.26 mmol)
was added followed by Pd(PPh3)2Cl2 (3 mg, 4.4 nmol). Aqueous
Na2CO3 (2M, 0.132 mL, 0.26 mmol) was added and the reaction
stirred at room temperature for 5 min. Phenyl boronic acid (0.022
2-(N-Benzylpropionamido)-3-methyl-N-(2-vinylphenyl)bu-
tanamide (36). Compound 29 (0.089 g, 0.106 mmol) was added
to a flask and dissolved in 0.8 mL of DMF. The tributylvinyl tin
(0.038 mL, 0.128 mmol) was added followed by LiCl (0.023 g,
4116 J. Org. Chem. Vol. 74, No. 11, 2009

Multicomponent Reactions of ConVertible Isonitriles
0.532 mmol) and Pd(PPh3)2Cl2 (0.004 g, 0.005 mmol). The reaction
mixture was purged with argon and stirred at 125 °C for 24 h.
Once complete the reaction, water was added to the reaction mixture
and extracted with CH2Cl2. The combined organic layers were
washed with water, dried and concentrated in vacuo affording a
colorless liquid, which was purified by flash column chromatog-
raphy on silica gel, eluting with hexanes to 11:1 hexanes/ethyl
acetate gradient afforded the title compound 36 (0.028 g, 72%) as
a colorless liquid. 1H NMR (300 MHz, CDCl3): δ 8.84 (br s, 1H),
7.68 (d, J ) 8.1 Hz, 1H), 7.45 (d, J ) 7.8 Hz, 1H), 7.35-7.11 (m,
7H), 6.87 (dd, J ) 17.1, 11.1 Hz, 1H), 5.69 (d, J ) 17.1 Hz, 1H),
5.42 (d, J ) 11.1 Hz, 1H), 4.70 (d, J ) 17.1 Hz, 1H), 4.61 (d, J )
17.1 Hz, 1H), 4.37 (d, J ) 9.3 Hz, 1H), 2.70-2.65 (m, 1H),
2.47-2.26 (m, 2H), 1.13 (t, J ) 7.2 Hz, 3H), 1.03 (d, J ) 6.3 Hz,
3H), 0.89 (d, J ) 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
177.1, 169.0, 137.0, 134.7, 132.1, 130.1, 129.0, 128.5, 127.7, 126.7,
125.2, 123.2, 117.9, 68.9. 50.8, 27.8, 27.0, 20.2, 19.4, 9.8. IR (film):
3253, 2966, 2936, 2874, 1684, 1627, 1581, 1520, 1496, 1451, 1416,
1360, 1297, 1232, 1207, 1168, 1127, 1074, 1029 cm-1. MS (FAB):
m/z 387 (M + Na), 246. HRMS (ESI): Calcd. for C23H29N2O2 [M]+,
365.2224; Found, 365.2220.
hexanes/ethyl acetate gradient afforded the title compound 43 (0.377
g, 72%) as a colorless liquid. H NMR (300 MHz, CDCl3): δ
1
8.18-8.13 (m, 3H), 7.74 e 7.65 (m, 2H), 0.756-7.51 (m, 2H),
7.29-7.09 (m, 10H), 6.88-6.83 (m, 1H), 4.42 (d, J ) 16.0 Hz,
1H), 4.41 (d, J ) 16.0, 1H), 3.30 (d, J ) 9.0 Hz), 2.43 (sextuplet,
J ) 7.2 Hz, 1H), 1.07 (d, J ) 7.2 Hz, 3H), 0.90 (d, J ) 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 168.9, 164.6, 146.8, 141.8,
141.2, 136.8, 134.2, 132.2, 130.6, 129.7, 128.9, 128.8, 128.6, 128.5,
127.39, 126.6, 126.4, 125.2, 124.6, 124.3, 123.0, 122.7, 74.5, 52.6,
28.3, 19.5, 19.3. IR (film): 2962, 1743, 1690, 1519, 1450, 1261,
1175, 1104, 1056, 706 cm-1. HRMS (ESI): Calcd. for C31H30N3O5,
524.2185; Found, 524.2189.
2-Isocyanophenyl (1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl
Carbonate (47). A 50 mL round-bottom flask equipped with a
magnetic stir bar and charged with benzoxazole (1.00 g, 8.39 mmol)
and THF (20 mL) are allowed to cool to -78 °C for 5 min prior
to addition of n-BuLi (1.6 M solution in hexanes, 5.50 mL, 8.80
mmol). The reaction mixture was allowed to stir at the same
temperature for 1.5 h. The (1S)-(+)-menthyl chloroformate (1.87
mL, 8.81 mmol) was added dropwise to the solution. The solution
was allowed to warm to room temperature and stirred for 2 h. The
reaction mixture was poured onto a mixture of ether (100 mL) and
saturated aqueous NaHCO3 (50 mL). The organic layer was washed
with water (2 × 50 mL), dried, and concentrated in vacuo. The
resulting residue was purified by flash column chromatography on
silica gel, eluting with hexanes to 32:1 hexanes/ethyl acetate
gradient afforded the title compound 47 (1.97 g, 78%) as a colorless
liquid. 1H NMR (300 MHz, CDCl3): δ 7.46-7.40 (m, 2H),
7.30-7.25 (m, 2H), 4.67 (td, J ) 10.5, 4.8 Hz, 1H), 2.22-2.18
(m, 1H), 2.13-2.03 (m, 1H), 1.77-1.69 (m, 2H), 1.58-1.44 (m,
2H), 1.25-1.03 (m, 2H), 0.95 (d, J ) 6.6 Hz, 6H), 0.91-0.88 (m,
1H), 0.85 (d, J ) 6.9 Hz, 3H). IR (film): 2960, 2925, 2868, 2851,
2122, 1754, 1490, 1454, 1389, 1370, 1279, 1258, 1226, 1176, 1152,
1096, 1080, 1039, 1028, 1006 cm-1. MS (FAB): m/z 302 (M +
H). HRMS (ESI): Calcd. for C18H24NO3 [MH]+, 302.1756; Found,
302.1747.
2-(3-Methyl-2-(propionyloxy)butanamido)phenyl 4-Methyl-
benzoate (41c). To a solution of 2-isocyanophenyl 4-methylben-
zoate (10c) (0.152 g, 0.64 mmol) in CH2Cl2 (1.5 mL) were added
isobutyraldehyde (0.058 mL, 0.64 mmol) followed by propionic
acid (0.048 mL, 0.64 mmol), and the reaction mixture was stirred
at room temperature for 18 h. After completion of the reaction,
solvent was removed in Vacuo, and the residue was purified by
flash column chromatography on silica gel, eluting with hexanes
to 10:1 hexanes/ethyl acetate gradient afforded the title compound
1
41c (0.181 g, 74%) as a pale-yellow liquid. H NMR (300 MHz,
CDCl3): δ 8.23 (d, J ) 8.1 Hz, 1H), 8.11 (d, J ) 8.1 Hz, 2H), 8.01
(br s, 1H), 7.35 (d, J ) 8.1 Hz, 2H), 7.33-7.16 (m, 3H), 5.22 (d,
J ) 3.6 Hz, 1H), 2.47 (s, 3H), 2.41-2.28 (m, 1H), 2.19-1.94 (m,
2H), 0.94 (t, J ) 7.8 Hz, 3H), 0.92 (d, J ) 7.2 Hz, 3H), 0.91 (d,
J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 172.9, 167.9,
164.7, 145.5, 141.2, 130.5, 129.8, 129.6, 126.9, 126.0, 125.5, 123.1,
122.5, 77.9, 31.1, 27.4, 22.0, 18.9, 16.9, 9.1. IR (film): 3425, 2968,
1740, 1697, 1609, 1524, 1480, 1453, 1265, 1239, 1173, 1104, 1057,
1017 cm-1. MS (FAB): m/z 384 (M + H), 119. HRMS (ESI): Calcd.
for C22H26NO5[MH]+, 384.1806; Found, 384.1811.
2-(2-(Benzyl(2-nitrophenyl)amino)-3-methylbutanamido)phe-
nyl Benzoate (43). Benzylamine (0.11 mL, 1.00 mmol), o-
nitrophenol (0.139 g, 1.00 mmol), and isobutyraldehyde (0.091 mL,
1.00 mmol) were added to a solution of 2-isocyanophenyl benzoate
(10g) (0.223 g, 1.00 mmol) in methanol (1.0 mL). The resulting
mixture was stirred at 50 °C under an inert atmosphere for 16 h
and concentrated in Vacuo. The crude product was purified by flash
column chromatography on silica gel, eluting with hexanes to 2:1
Acknowledgment. Fellowship support from UC-MEXUS
(TI-R) is appreciated. The image in the graphical abstract is
used by permission of the American Rhinologic Society.
1
Supporting Information Available: H NMR spectra for
10h, 13, 25-40, 41c, and 43-47. 13C NMR spectra for 10h,
13, 26-38, 40,41c, and 43-46. Experimental procedures for
the preparation of 28, 29, 31, 33, 34, 37-40, 41b, 42, and
44-46. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900414N
J. Org. Chem. Vol. 74, No. 11, 2009 4117