Exploiting the dual reactivity of o-isocyanobenzamide: Three-component synthesis of 4-imino-4H-3,1-benzoxazines

Article abstract of DOI:10.1021/ol052239w

(Chemical Equation Presented) A multicomponent synthesis of 4-imino-4H-3,1-benzoxazines is developed. Heating a toluene solution of an aldehyde (6), an amine (7), and an isonitrile (5) in the presence of a stoichiometric amount of ammonium chloride at 60°C for 12 h produces the title compound in good to excellent yields.

Full text of DOI:10.1021/ol052239w

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5285-5288
Exploiting the Dual Reactivity of
o-Isocyanobenzamide:
Three-Component Synthesis of
4-Imino-4H-3,1-benzoxazines
Damien Bonne,† Mouloud Dekhane,‡ and Jieping Zhu*,†
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex,
France, and AstraZeneca, PR & D, Macclesfield, Cheshire, SK10 2NA, U.K.
zhu@icsn.cnrs-gif.fr
Received September 15, 2005
ABSTRACT
A multicomponent synthesis of 4-imino-4H-3,1-benzoxazines is developed. Heating a toluene solution of an aldehyde (6), an amine (7), and an
isonitrile (5) in the presence of a stoichiometric amount of ammonium chloride at 60
excellent yields.
°C for 12 h produces the title compound in good to
A multicomponent reaction (MCR) is a process in which
three or more reactants are combined in a single reaction
flask to produce a product that incorporates substantial
portions of all starting materials. By saving synthetic
operations while maximizing the buildup of structural and
functional complexity, these highly step-economic reactions
are particularly appealing in the context of diversity,1 as well
as target-oriented syntheses.2
Indeed, isonitrile is one of the key components of the well-
known Passerini three-component reaction (P-3CR)3 and Ugi
four-component reaction (U-4CR).4 Although there are four
diversity points in the U-4CR, the scaffolds that are acces-
sible by the original process are limited. To enlarge the
structural diversity accessible by this multicomponent reac-
tion, the tethering principle by using bifunctional starting
materials and the combination of U-4CR with another
efficient post-condensation transformations have been de-
veloped.5
The ability of isonitrile to undergo facile R-addition with
a nucleophile and an electrophile under mild conditions made
it a popular reactant for the development of novel MCRs.
A number of isonitriles bearing additional functionalities
are known. Among them, R-isocyano acetate (1, Figure 1)6
† Institut de Chimie des Substances Naturelles.
‡ AstraZeneca.
(1) For recent reviews, see: (b) Weber, L. Curr. Med. Chem. 2002, 9,
2085-2093. (c) Do¨mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306-313.
(d) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (e) Orru, R.
V. A.; De Greef, M. Synthesis 2003, 1471-1499. (f) Balme, G.; Bossharth,
E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101-4111. (g) Jacobi von
Wangelin, A.; Neumann, H.; Go¨rdes, D.; Klaus, S.; Stru¨bing, D.; Beller,
M. Chem. Eur. J. 2003, 9, 4286-4294. (h) Murakami, M. Angew. Chem.,
Int. Ed. 2003, 42, 718-720. (i) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu,
S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003,
36, 899-907. (j) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (k) Simon,
C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957-4980.
(2) Toure´, B. B.; Hall, D. G. Multicomponent Reactions in the Total
Synthesis of Natural Products; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, 2005; pp 342-397.
(3) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126-129. (b) Passerini,
M. Gazz. Chim. Ital. 1921, 51, 181-189. (c) Passerini, M. Gazz. Chim.
Ital. 1922, 52, 432-435. For a review, see: (d) Banfi, L.; Riva, R. Org.
React. 2005, 65, 1-140.
(4) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbru¨ckner, C. Angew. Chem.
1959, 71, 386. (b) Ugi, I.; Steinbru¨ckner, C. Angew. Chem. 1960, 72, 267.
For a review, see: (c) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168-3210.
(5) Marcaccini, S.; Torroba, T. Post-condensation Modifications of the
Passerini and Ugi Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, 2005; pp 33-75.
(6) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789-804. (c)
Scho¨llkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 339-348. (c)
Marcaccini, S.; Torroba, T. Org. Prep. Proc. Int. 1993, 25, 141-208.
10.1021/ol052239w CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/15/2005

synthesis of 4-imino-4H-3,1-benzoxazine (8) involving an
aldehyde 6, an amine 7, and isonitrile 5 (Scheme 1). 4-Imino-
Scheme 1
Figure 1. Functionalized isocyanides.
4H-3,1-benzoxazines have previously been prepared by
dehydrative cyclization of N-acylanthranilamides16 and are
readily rearranged to the quinazolin-4-one, a privileged
structure in medicinal chemistry.17-21 Although little is know
about the biological activity of iminobenzoxazine, a recent
patent dealing with the application of 4-imino-4H-3,1-
benzoxazine (8) in crop science to control invertebrate pests
is noteworthy.22
and toluenesulfonylmethyl isocyanide (2, TosMIC),7 devel-
oped by Scho¨llkopf and Van Leusen, respectively, are notable
examples and have found wide applications in the synthesis
of diverse class of heterocycles. Reaction sequences utilizing
these two synthons are in general initiated by the nucleophilic
addition of the R-carbanion, rather than the divalent carbon
of the isonitrile as in the P-3CR and U-4CR, onto the
respective electrophiles.8
Using isonitrile 5a (X ) H, R1 ) n-Bu), heptanal 6a, and
morphiline 7a as test substrates (Scheme 2), we performed
We have been working on the chemistry of R-isocyano
acetamide (3)9 and R-isocyanoacetic acid (4).10 On the basis
of the unique reactivities of these two synthons, a number
of multicomponent reactions have since been developed for
syntheses of polyheterocycles11,12 and macrocycles13 and for
conducting the functional group transformations.14 In all of
these transformations, the reaction sequence based on 3 and
4 is triggered by the nucleophilicity of the isonitrile carbon
that differentiates them from compounds 1 and 2. As a logical
extension of this work and in conjuction with our interests
in the synthesis of benzofused heterocycles, we started
investigating the chemical reactivity of unknown 2-isocyano
benzamide (5)15 and report herein a new three-component
Scheme 2
(7) Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57, 417-
666.
a survey of the reaction conditions. In the event, stirring a
toluene solution of 5a, 6a, and 7a in the presence of
ammonium chloride at room temperature for 8 h resulted in
the formation of iminobenzoxazine 8a (R1 ) n-Bu, R2 )
n-C6H13, NR3R4 ) morpholinyl) in 78% yield. Heating the
reaction to 60 °C increased the reaction rate and conversion
(8) For examples, see: (a) Suzuki, M.; Nunami, K.-I.; Moriya, T.;
Matsumoto, K.; Yoneda, N. J. Org. Chem. 1978, 26, 4933-4935. (b) Bon,
R. S.; Van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; De Kanter, F. J. J.;
Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru, R. V.
A. J. Org. Chem. 2005, 70, 3542-3553 and references therein.
(9) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.; Zhu, J. Org. Lett. 2001,
3, 877-880. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem.
Soc. 2002, 124, 2560-2567. (c) Fayol, A.; Housseman, C.; Sun, X.; Janvier,
P.; Bienayme´, H.; Zhu, J. Synthesis 2005, 161-165.
(15) We cannot find this isonitrile from SciFinder and Beilstein databases.
We prepared it by dehydration of N-formylanthranilamide (POCl3, CH2Cl2,
0 °C; see Supporting Information).
(16) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973-980.
(17) Molina, p.; Alajarin, M.; Vidal, A.; Foces-Foces, M.; Cano, F. H.
Tetrahedron 1989, 45, 4263-4286.
(18) (a) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432-2433.
(b) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022-1030. (c) Wang,
H.; Ganesan, A. J. Comb. Chem. 2000, 2, 186-194.
(19) (a) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397-1399. (b)
Snide, B. B.; Zeng, H. Heterocycles 2003, 61, 173-182.
(20) (a) Freed, J. D.; Hart, D. J.; Magomedov, N. A. J. Org. Chem. 2001,
66, 839-852. (b) Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001,
123, 5892-5899.
(21) Liu, J.-F.; Lee, J. Dalton, A. M.; Bi, G.; Baldino, C. M.; MCElory,
E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241-1244. (b) Liu, J.-F.; Ye,
P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J.
Org. Chem. 2005, 70, 6339-6345.
(22) Selby, T. P.; Birch, L. D. WO Patent 03/032731 A1, 2003; Chem
Abstr. 2003, 138:316207.
(10) (a) Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2004, 6, 4771-
4774. See also: (b) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis
1994, 672-674.
(11) (a) Gonza´lez-Zamora, E.; Fayol, A.; Bois-Choussy, M.; Chiaroni,
A.; Zhu, J. J. Chem. Soc., Chem. Commun. 2001, 1684-1685. (b) Ga´mez-
Montan˜o, R.; Zhu, J. J. Chem. Soc., Chem. Commun. 2002, 2448-2449.
(c) Janvier, P.; Bienayme´, H.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41,
4291-4294. (d) Ga´mez-Montan˜o, R.; Gonza´lez-Zamora, E.; Potier, P.; Zhu,
J. Tetrahedron 2002, 58, 6351-6358. (e) Fayol, A.; Zhu, J. Angew. Chem.,
Int. Ed. 2002, 41, 3633-3635. (f) Fayol, A.; Zhu, J. Org. Lett. 2004, 6,
115-118. (g) Fayol, A.; Zhu, J. Org. Lett. 2005, 7, 239-242. (h) Tron, G.
C.; Zhu, J. Synlett 2005, 532-534.
(12) Wang, Q.; Xia, Q.; Ganem, B. Tetrahedron Lett. 2003, 44, 6825-
6827. (b) Wang, Q.; Ganem, B. Tetrahedron Lett. 2003, 44, 6829-6832.
(13) (a) Zhao, G.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem. Soc.
2001, 123, 6700-6701. (b) Janvier, P.; Bois-Choussy, M.; Bienayme´, H.;
Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811-814.
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6926-6927.
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Org. Lett., Vol. 7, No. 23, 2005

Scheme 3
to afford 8a in 90%. It is worth noting that this three-
component reaction took place even in the absence of
ammonium chloride albeit with slight decreased yield. When
the same reaction was performed in MeOH, a classic solvent
for Ugi-type reaction, imidate (9a) was produced (12%)
together with 8a (62%). Prolonged heating in methanol led
to the exclusive formation of 9a (85%) at the expense of
8a. Control experiment indicated that 9a was produced from
8a, most probably by nucleophilic addition of methanol onto
the C-4 carbon of 8a followed by fragmentation. Compound
8a is stable in basic or neutral conditions and can be easily
purified by flash chromatography on alumina support.
A plausible reaction scenario that accounts for the forma-
tion of 8 is shown in Scheme 3. Thus, condenstion of an
aldehyde 6 and an amine 7 would give the iminium 10, which
Figure 3. Structure of 4-imino-4H-3,1-benzoxazines. (a) Two
separable diastereoisomers were obtained.
would react with isonitrile 5 to afford the nitrilium interme-
diate 11. Trapping of the latter by the internal amide oxygen
would produce the 4-iminobenzoxazine 8. Formation of
quinazolin-4-one (12), which could result from the nucleo-
philic addition of amide nitrogen to the nitrilium intermediate
was not observed.
The following conditions, toluene (0.2 M), NH4Cl, 60 °C,
12 h, were used to evaluate the scope of this novel three-
Figure 2. Structures of amines, aldehydes, and isonitriles.
Org. Lett., Vol. 7, No. 23, 2005
5287

component reaction. From six amines, four aldehydes, and
six 2-isocyano benzamides (Figure 2), the 4-imino-4H-3,1-
benzoxazines listed in Figure 3 were synthesized. As is seen,
most of these heterocycles (4) were isolated with good to
excellent yields. Both primary and secondary amines can be
used, although primary amines usually gave lower yields.
When hydrochloride salts of amines were used in the
presence of triethylamine, the reaction took place smoothly
in the absence of ammonium chloride.23 The stoichiometric
amount of Et3N‚HCl generated in situ seems to be able to
promote the 3CR as did the ammonium chloride. No reaction
occurred when aniline (structure not shown) was used as the
amine input. For the aldehyde part, aliphatic aldehydes
including formaldehyde participated well in this transforma-
tion; however, aromatic aldehyde failed to react under these
conditions. As far as 2-isocyano benzamides were concerned,
amide derived from a variety of primary amines including
butylamine, benzylamine, phenethylamine, methyl phenyl-
alanate, and tryptophane methyl ester are well tolerated.
When chiral nonracemic isonitriles 5d and 5e were used,
two enantiomerically pure diastereoisomers were isolated.
As it may be expected, no asymmetric induction was
observed in this multicomponent reaction.
The rearrangement of 4-imino-4H-3,1-benzoxazines
to quinazolin-4-one has been studied in detail since
Mazurkiewicz’s initial report.15 Under basic conditions
developed by Ganesan16 and Snider,17 compound 8h did
rearrange to 13 (Scheme 3). However, we found that, in
accord with previous studies, this rearrangement is quite
substrate-dependent.16,19 In fact, 4-imino-4H-3,1-benzox-
azines derived from secondary amine did not undergo
rearrangement under a variety of conditions varying the
nucleophilic amines (pyrrolodine, piperidine, proline, DBU
with or without silica gel), the temperatures, and the solvents.
We suspected that the steric hindrance around the C-2 of 8
may hamper the nucleophilic addition of amine and hence
the rearrangement. On the other hand, treatment of 8h under
acidic conditions (EtOAc, silical gel, or 1 N HCl) led to the
formation of N-acylanthranilamide resulting from the nu-
cleophilic addition of water onto the C-4 carbon (14, Scheme
4). This two-step sequence (3CR followed by acidic hy-
Scheme 4
drolysis) was an effective alternative route for the construc-
tion of 14 when the amino acid to be incorporated is not
easily available. In fact, the amino acid unit to be attached
to the amino function of anilamide was generated in the
course of the three-component reaction.
In summary, we have developed a three-component
synthesis of 4-imino-4H-3,1-benzoxazine heterocycles based
on the dual reactivity of 2-isocyano benzamide (5). Compli-
mentary to the dehydrative cyclization of N-acylanthranil-
amide, the present methodology has an added advantage in
that it de novo creates the amino acid unit in the course of
the reaction.
Acknowledgment. Financial support from CNRS and a
doctoral fellowship from AstraZeneca to D.B. are gratefully
acknowledged.
(23) Synthesis of 8b is typical. Dimethylamine hydrochloride (14.7 mg,
0.18 mmol, 1.2 equiv) was added to a solution of heptanal (25.0 µL, 0.18
mmol, 1.2 equiv) in dry toluene (1.0 mL). Triethylamine (25 µL, 0.18 mmol,
1.2 equiv) was added to the mixture, which was allowed to stir for 15 min
at room temperature. N-Butyl-2-isocyanobenzamide 5a (30.3 mg, 0.15
mmol) was added, and the reaction was stirred for 12 h at 60 °C. The
reaction was then evaporated to dryness. Purification by flash column
chromatography on Al2O3 (eluent, 30% diethyl ether in heptane) gave pure
1-(4-(butylimino)-4H-benzo[1,3]oxazin-2-yl)-N,N-dimethylheptan-1-
amine 8b as a colourless oil (45 mg, 87%).
Supporting Information Available: Experimental details
and physical data for compounds 8a-o, 9a, 13, and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052239W
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Org. Lett., Vol. 7, No. 23, 2005