Reactions of ortho-lithiophenyl (-hetaryl) isocyanides with carbonyl compounds: Rearrangements of 2-metalated 4H-3,1-benzoxazines

Article abstract of DOI:10.1021/jo9004734

(Chemical Equation Presented) ortho-Lithiophenyl (-hetaryl) isocyanides react with aldehydes and ketones providing isocyanoalcohols 8 (36-89%, nine examples), 4H-3,1-benzoxazines 9 (45-78%, six examples) or, after two types of rearrangements, isobenzofura

Full text of DOI:10.1021/jo9004734

Reactions of ortho-Lithiophenyl (-Hetaryl) Isocyanides with
Carbonyl Compounds: Rearrangements of 2-Metalated
4H-3,1-Benzoxazines
Alexander V. Lygin and Armin de Meijere*
Institut fu¨r Organische und Biomolekulare Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, D-37077 Go¨ttingen, Germany
ameijer1@gwdg.de
ReceiVed March 24, 2009
ortho-Lithiophenyl (-hetaryl) isocyanides react with aldehydes and ketones providing isocyanoalcohols
8 (36-89%, nine examples), 4H-3,1-benzoxazines 9 (45-78%, six examples) or, after two types of
rearrangements, isobenzofuran-1(3H)-imines (iminophthalanes) 18 (52-75%, four examples), or indolin-
2-ones 19 (42-79%, two examples), depending on the reaction conditions and substitution patterns.
Isocyanoalcohols 8, in turn, were converted to 9 or 18 under Cu(I) catalysis (66-86%, eight examples).
4H-3,1-Benzoxazin-4-ones 39-Nu and isatoic anhydride 40 were obtained by the reaction of 2 with carbon
dioxide followed by trapping of the lithiated intermediate with iodine and subsequent reactions with
nucleophiles (45-60%, three examples).
Introduction
N-heterocycles,3 and some of them have been used in the total
syntheses of natural products.4 Recently, we reported that ortho-
lithiophenyl isocyanide (2), generated by bromine-lithium
exchange on o-bromophenyl isocyanide, can be employed for
the synthesis of 2-substituted phenyl isocyanides 1 as well as
3H-quinazolin-4-ones and 3H-quinazolin-4-thiones 3 (Scheme
1).5 Here we report our latest results concerning the facile
addition of ortho-lithiophenyl isocyanide (2) as well as ortho-
lithiohetaryl isocyanides to aldehydes, ketones, and carbon
dioxide.
Aryl isocyanides represent valuable starting materials for the
synthesis of quinolines,1 indoles,2 and other benzoannelated
(1) (a) Kobayashi, K.; Yoneda, K.; Mano, M.; Morikawa, O.; Konishi, H.
Chem. Lett. 2003, 32, 76–77. (b) Kobayashi, K.; Yoneda, K.; Miyamoto, K.;
Morikawa, O.; Konishi, H. Tetrahedron 2004, 60, 11639–11645. (c) Ichikawa,
J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki, H. Org. Lett. 2003, 5, 1455–
1458. (d) Mori, T.; Ichikawa, J. Chem. Lett. 2004, 33, 590–591. (e) Ichikawa,
J.; Mori, T.; Miyazaki, H.; Wada, Y. Synlett 2004, 7, 1219–1222. (f) Kobayashi,
K.; Nakashima, T.; Mano, M.; Morikawa, O.; Konishi, H. Chem. Lett. 2001, 7,
602–603. (g) Kobayashi, K.; Yoneda, K.; Mizumoto, T.; Umakoshi, H.;
Morikawa, O.; Konishi, H. Tetrahedron Lett. 2003, 44, 4733–4736. (h)
Kobayashi, K.; Takagoshi, K.; Kondo, S.; Morikawa, O.; Konishi, H. Bull. Chem.
Soc. Jpn. 2004, 77, 553–560. (i) Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875–
1878.
(2) (a) Ito, Y.; Kobayashi, K.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 3532–
3534. (b) Ito, Y.; Kobayashi, K.; Saegusa, T. J. Org. Chem. 1979, 44, 2030–
2032. (c) Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc. Jpn.
1984, 57, 73–84. (d) Jones, W. D.; Kosar, W. P. J. Am. Chem. Soc. 1986, 108,
5640–5641. (e) Tokuyama, H.; Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng,
G.; Fukuyama, T. Synlett 2001, 9, 1403–1406. (f) Rainier, J. D.; Kennedy, A. R.;
Chase, E. Tetrahedron Lett. 1999, 40, 6325–6327. (g) Rainier, J. D.; Kennedy,
A. R. J. Org. Chem. 2000, 65, 6213–6216. (h) Onitsuka, K.; Suzuki, S.;
Takahashi, S. Tetrahedron Lett. 2002, 43, 6197–6199.
(3) (a) Ito, Y.; Kobayashi, K.; Saegusa, T. Tetrahedron Lett. 1978, 24, 2087–
2090. (b) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A.
Tetrahedron 1995, 51, 9045–9062. (c) Curran, D. P.; Liu, H.; Josien, H.; Ko,
S.-B. Tetrahedron 1996, 52, 11385–11404. (d) Josien, H.; Ko, S.-B.; Bom, D.;
Curran, D. P. Chem.sEur. J. 1998, 4, 67–83. (e) Kobayashi, K.; Izumi, Y.;
Hayashi, K.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2005, 78, 2171–
2174.
(4) (a) Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 6, 883–886. (b)
Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 1891–
1893. (c) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863–5864. (d)
Isaacson, J.; Loo, M.; Kobayashi, Y. Org. Lett. 2008, 10, 1461–1463. (e) Gilley,
C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631–3634.
(5) Lygin, A. V.; de Meijere, A. Org. Lett. 2009, 11, 389–392.
4554 J. Org. Chem. 2009, 74, 4554–4559
10.1021/jo9004734 CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009

Reactions of ortho-Lithiophenyl (-Hetaryl) Isocyanides
SCHEME 1. Previously Reported Utilizations of
ortho-Lithiophenyl Isocyanide (2)5
FIGURE 1. Five-, seven-, and eight-membered heterocycles previously
obtained by reactions of metalated isocyanides with aldehydes, ketones,
and epoxides.6,7
Results and Discussion
effect,8 which places the alkoxide more closely to the isocyano
group and thus favors the cyclization of 5 to 6. It might also be
due to enhanced thermodynamic stability of the cyclized 6 over
the noncyclized form 5 for the cases with R1,R2 * H. Upon
treatment of 2 with dimethylformamide and subsequent addition
of water, 2-(formylamino)benzaldehyde (7) was isolated in 76%
yield, apparently arising by hydrolysis of the initially formed
4H-3,1-benzoxazine 9j, as has previously been discussed.5
Obviously, in this case, the NMe2 donor group facilitated
cyclization of 5 to 6. Although 2-substituted 4H-3,1-benzox-
azines are well-known compounds, simply accessible from the
respective o-aminophenylcarbinols,9 there is no generally ap-
plicable method for the synthesis of 2-unsubstituted heterocycles
of type 9.10
Treatment of ortho-lithiophenyl isocyanide (2) with aldehydes
(4a-i) at -78 °C and hydrolysis of the reaction mixture at the
same temperature led to ortho-isocyanobenzylalcohols 8 rather
than the corresponding 4H-3,1-benzoxazines 9 (Table 1, entries
1-9). This may be due to a predominance of the initial alkoxide
adduct 5 in the equilibrium with the lithiobenzoxazine 6. The
TABLE 1. Reaction of 1a with Aldehydes and Ketones Succeeded
by Quenching with Water at -78 °C
Yields of the final products 8 and 9, respectively, were high
from all nonenolizable aldehydes and ketones except for 9k from
benzophenone (4k), which has two large substituents that might
sterically encumber the addition of 2 (entry 11). The yields of
8h from isobutyraldehyde (4h) and of 9m from acetone (4m)
were significantly lower, probably because 2 can abstract a
proton from 4h and 4m in competition with adding to them
(entries 8 and 13). The reaction of ortho-lithiophenyl isocyanide
2 with 3-methylbut-2-enal (4i) afforded the 1,2-adduct 8i in 70%
yield without a trace of the 1,4-addition product (entry 9).
Unsaturated alcohols of type 8i, previously prepared by addition
of substituted vinylmagnesium bromides to N-(o-acylphenyl)-
formamides, have been shown to undergo a Lewis acid-catalyzed
cyclization followed by rearrangement to 1-formyl-1,2-dihy-
droquinoline derivatives.11
The adducts of ortho-lithiophenyl isocyanide (2) to carbonyl
compounds 4 can also be trapped with electrophiles other than
water (Table 2). Thus, the initial adduct of 2 to pyridine-4-
carbaldehyde (4d) upon treatment with methyl chloroformate
afforded the acyclic mixed methyl carbonate 8d-CO2Me in 56%
yield (entry 1), while the adduct to 1,1,1-trifluoroacetophenone
(4l) was trapped with methyl chloroformate and ethyl bromoac-
etate to furnish the 2-substituted 4H-3,1-benzoxazines 9l-CO2Me
(45%) and 9l-CH2CO2Et (47%), respectively (entries 2 and 3).
Addition of iodine to the same reaction mixture from 2 and 4l
and subsequent aqueous workup gave the oxo derivative 13l
(77% yield, entry 4). The initially formed 2-iodo-4-phenyl-4-
(trifluoromethyl)-4H-benzo[1,3]oxazine (9l-I) apparently un-
dergoes rapid nucleophilic substitution by water and enol to
ketone tautomerization during the workup procedure and/or
Carbonyl
Entry Compound 4
Yielda
R1
R2 Product (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Ph
H
H
H
H
H
H
8a
8b
8c
8d
8e
8f
84
83
89
82
78
88
80
36
70
76
48
78
52
4-MeOC6H4
4-ClC6H4
4-pyridyl
2-(5-methylthienyl)
2-(5-methylfuryl)
tBu
iPr
H
H
H
8g
8h
8i
9
1-(2-methyl-2-butene-1-yl)
10
11
12
13
j
k
l
Me2N
Ph
Ph
H
7
Ph
CF3
Me
9k
9l
9m
m
Me
a Yields of isolated products.
same behavior was observed upon addition of R-metalated
isocyanides and ortho-(lithiomethyl)phenyl isocyanides to car-
bonyl compounds and epoxides, which produced the respective
acyclic isocyanoalcohols rather than corresponding five-, seven-,
or eight-membered heterocycles 10,6 11, and 12, respectively
(Figure 1),7 upon hydrolysis of the reaction mixture at low
temperature. The reaction of 2 with ketones (4k-m), however,
after hydrolysis of the reaction mixture at -78 °C, led to 4,4-
disubstituted 4H-3,1-benzoxazines 9 in all cases (entries 11-13).
This may be caused by the Thorpe-Ingold conformational
(8) For reviews, see: (a) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735–
1766. (b) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205–1222.
(9) For a review, see: (a) Gromachevskaya, E. V.; Kvitkovskii, F. V.;
Kosulina, T. P.; Kul’nevich, V. G. Chem. Heterocycl. Compd. 2003, 39, 137–
155.
(10) For a few examples of such compounds published to date, see: (a)
Fleming, I.; Loreto, M. A.; Wallace, I. H. M. J. Chem. Soc., Perkin Trans. 1
1986, 349–359. (b) Gataullin, R. R.; Afonkin, I. S.; Fatykhov, A. A.; Spirikhin,
L. V.; Tal’vinskii, E. V.; Abdrakhmanov, I. B. Russ. Chem. Bull. 2001, 50, 659–
664.
(6) (a) Scho¨llkopf, U.; Gerhart, F.; Hoppe, I.; Harms, R.; Hantke, K.;
Scheunemann, K.-H.; Eilers, E.; Blume, E. Justus Liebigs Ann. Chem. 1976,
183–202. (b) Bo¨ll, W A.; Gerhart, A.; Nu¨rrenbach, A.; Scho¨llkopf, U. Angew.
Chem. 1970, 82, 482-483; Angew. Chem., Int. Ed. Engl. 1970, 9, 458-459. (c)
Scho¨llkopf, U.; Bo¨hmes, P. Angew. Chem. 1971, 83, 490-491; Angew. Chem.,
Int. Ed. Engl. 1971, 10, 491-492.
(7) Ito, Y.; Kobayashi, K.; Saegusa, T. Tetrahedron Lett. 1978, 24, 2087–
2090.
(11) Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H.
Chem. Lett. 1995, 24, 575–576.
J. Org. Chem. Vol. 74, No. 12, 2009 4555

Lygin and de Meijere
TABLE 2. Reaction of 2 with Carbonyl Compounds 4 and
Trapping of the Metalated Intermediates with Electrophiles Other
than Water
TABLE 3. Cu2O-Catalyzed Cyclization of Isocyanobenzylalcohols 8
a Total yield for addition and subsequent cyclization, the crude
isocyanoalcohol 16d was used for the transformation without purification.
and indolin-2-ones 19 were also formed upon warming to
ambient temperature of the reaction mixtures after the addition
of ortho-lithiophenyl isocyanide (2) and ortho-lithiohetaryl
isocyanides 21 and 24 to various carbonyl compounds (Table
4). The latter two organolithium reagents were generated with
equal ease as 2 from the corresponding bromohetaryl isocyanides.
Apparently, the lithiated intermediates of type 6 can undergo
ring contraction to form the lithiated precursors of 18 or 19
upon warming to ambient temperature of the reaction mixture
obtained after addition of lithiated isocyanides 17 to carbonyl
compounds. All three compounds of type 6 with trifluoromethyl
substituents obviously rearranged to iminophthalanes 14o and
its heteroanalogues 23l and 25l, respectively (Table 4). The other
examples only furnished indolin-2-ones 20n,k and 22k, respec-
tively. Compound 20n was isolated after the reaction of 2 with
pyridine-2-carbaldehyde (4n) and subsequent treatment of the
reaction mixture with water at -78 °C. In this case, the
coordination of lithium by the pyridyl nitrogen may have played
a crucial role in shifting the equillibrium from 5 to 6 and
facilitate the rearrangement to the lithiated precursor of 19.
Indolin-2-ones (2-oxoindoles) of type 20 represent an important
class of heterocycles with a wide range of biological activities,12
a Aqueous workup procedure. b Morpholine was added before aqueous
workup.
column chromatography on silica gel. The analogous 2-chloro
derivative (9l-Cl), generated by treatment of the adduct of 2 to
4l with N-chlorosuccinimide as an electrophile, also could not
be isolated and afforded 13l. The same reaction mixture from
2, 4l, and iodine upon treatment with morpholine prior to the
aqueous workup afforded 2-morpholinylbenzoxazine 9l-morph
in 55% yield (entry 5).
The isocyanobenzylalcohols 8 with R2 ) H obtained from 2
and aldehydes were found to undergo cyclization to the
corresponding 4H-3,1-benzoxazines 9 under Cu2O catalysis in
high yields (Table 3, entries 1-5) in the same way, as it had
previously been demonstrated for the synthesis of 4,5-dihydro-
3,1-benzoxazepines 11 and 4H-5,6-dihydro-3,1-benzoxazocines
12.7 Treatment of the isocyanobenzylalcohols 8 with bases such
as DBU and KOtBu was less effective, although it also led to
the target 4H-3,1-benzoxazines 9. Such 2-unsubstituted com-
pounds turned out to be unstable in acidic as well as in basic
media but could be isolated by flash chromatography on silica
gel pretreated with triethylamine. In the cases of the isocy-
anobenzylalcohols 8f, 8h, and 16d (the latter was used in the
cyclization step directly after its formation from 3-isocyano-2-
lithiothiophene (21) and pyridine-4-carbaldehyde (4d) without
purification by column chromatography), the arene-annelated
tetrahydrofuranimines 14f,h and 15d, respectively, were ob-
tained unexpectedly as the sole products. Products of this type
(12) (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang,
S. J. Med. Chem. 2006, 49, 3432–3435. (b) Jiang, T.; Kuhen, K. L.; Wolff, K.;
Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 2105–2108. (c) Luk, K. C.; So, S. S.; Zhang, J.;
Zhang, Z. (F. Hoffman-LaRoche AG), WO 2006/136606 A3, 2006. (d)
Hewawasam, P.; Gribkoff, V. K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.;
Martinez, E.; Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram,
K.; Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone, R.; Starrett, J. E., Jr. Bioorg. Med.
Chem. Lett. 2002, 12, 1023–1026. (e) Sarges, R.; Howard, H. R.; Koe, K.;
Weissman, A. J. Med. Chem. 1989, 32, 437–444.
4556 J. Org. Chem. Vol. 74, No. 12, 2009

Reactions of ortho-Lithiophenyl (-Hetaryl) Isocyanides
TABLE 4. Addition of ortho-Lithioaryl Isocyanides to Aldehydes
and Ketones with Subsequent Rearrangement
SCHEME 2. Known Ring Contraction of
2,4-Diaryl-3,1-benzoxazines14 and Proposed Mechanism for
the Reaction of 2 with Ketones
carbanion center have been known for quite some time as
Wittig15 and Stevens rearrangements,16 respectively. Yet, the
stereoelectronic requirements make such [1,2]-migrations un-
likely in the case of 6. More probably, the intermediate 6
undergoes a pericyclic ring opening to yield 29, which by
intramolecular 1,4-addition would furnish the lithiated indolin-
2-one 31 or by intramolecular 1,2-addition and subsequent 6π-
pericyclic reaction of the resulting 30 provide the lithiated
isobenzofuranimines 32 (Scheme 2).17
On the other hand, in the Cu2O-catalyzed transformations of
isocyanobenzylalcohols 8 to 9 and 14, the process starts with
the coordination of an isocyano group to the Cu(I) species, and
this is succeeded by nucleophilic addition of the hydroxyl group
to the thus activated isocyano group in 33 to yield, after
deprotonation, the metalated 4H-3,1-benzoxazine 34 (Scheme
3). The latter rearranges just like 6 to provide the deprotonated
isobenzofuran-1(3H)-imine 35 which, by protonation, gives 14.
Alternatively, the intermediate 34 can be protonated directly to
yield the 4H-3,1-benzoxazine 9 as was also observed experi-
mentally. The transformation of 33 to 34 should not be regarded
as an isocyanide insertion into an O-H bond18 because the
product of such a process, the 4H-3,1-benzoxazine 9, is not
converted to 14 under the same reaction conditions, as was
confirmed by a control experiment.19 Interestingly, the pre-
dominant formation of 9 or 14 from 8 is intricately controlled
by the type of substitution. Thus, 8h (R1 ) iPr, R2 ) H) gave
the isobenzofuran-1-(3H)-imine 14h, while 8g (R1 ) tBu, R2
a Reaction mixture was treated with H2O at -78 °C.
while only a few isobenzofuran-1(3H)-imines (iminophthalanes)
of type 14 have been described previously.13
The only known ring contraction of 2,4-diaryl-substituted 4H-
3,1-benzoxazines with formation of 3H-indol-3-ols proceeds in
strongly basic media and was rationalized mechanistically as
an intramolecular nucleophilic addition of 4-deprotonated ben-
zoxazine 26 followed by epoxide opening (Scheme 2).14
However, the above-mentioned benzotetrahydrofuranimines and
indolin-2-ones obviously cannot be formed in such a way.
Formally, the isobenzofuranimine of type 14 and the indolin-
2-one of type 20, respectively, could arise from the initially
formed 2-lithium 4H-3,1-benzoxazine of type 6 by a [1,2]-
migration of the aryl group next to nitrogen or of the alkyl group
next to the oxygen atom and subsequent protonation.
(15) For reviews on [1,2]-Wittig rearrangement, see: (a) Tomooka, K.;
Yamamoto, H.; Nakai, T. Liebigs Ann./Recueil 1997, 1275–1281. (b) Tomooka,
K. In The Chemistry of OrganolithiumCompounds; Rappoport, Z., Marek, I.,
Eds.; Wiley: London, 2004; Vol. 2, pp 749-828.
(16) For reviews, see: (a) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron
2006, 62, 1043–1062. (b) Marko´, I. E., Trost, B. M., Fleming, I., Eds.
ComprehensiVe Organic Synthesis; Pergamon: Oxford, 1991; Vol. 3, pp 913-
973.
Rearrangements with [1,2]-migration of an alkyl group from
an oxygen and from a quaternary nitrogen atom to an adjacent
(13) For some syntheses of iminophthalanes, see: (a) Sato, R.; Ohmori, M.;
Kaitani, F.; Kurosawa, A.; Senzaki, T.; Goto, T.; Saito, M. Bull. Chem. Soc.
Jpn. 1988, 61, 2481–2485. (b) Suzuki, H.; Koge, M.; Inoue, A.; Hanafusa, T.
Bull. Chem. Soc. Jpn. 1978, 51, 1168–1171. (c) Suzuki, H.; Koge, M.; Hanafusa,
T. J. Chem. Soc., Chem. Commun. 1977, 341–342.
(14) (a) Lednicer, D.; Emmert, E. D. J. Heterocycl. Chem. 1970, 7, 575–
581. (b) Schmidt, R. R.; Beitzke, B. Chem. Ber. 1983, 116, 2115–2135.
(17) The authors are grateful to one of the reviewers who pointed out this
possibility.
(18) (a) Saegusa, T.; Ito, Y. Synthesis 1975, 291–300. (b) Saegusa, T.; Ito,
Y.; Takeda, N.; Hirota, K. Tetrahedron Lett. 1967, 8, 1273–1275. (c) Saegusa,
T.; Ito, Y.; Kobayashi, S.; Hirota, K. Tetrahedron Lett. 1967, 8, 521–524.
(19) A mixture of 9l in benzene with 10 mol % of Cu2O was heated under
reflux for 1 h. No changes were detected according to TLC.
J. Org. Chem. Vol. 74, No. 12, 2009 4557

Lygin and de Meijere
SCHEME 3. Mechanism of the Cu2O-Catalyzed Cyclization
of Isocyanobenzylalcohols 8
Experimental Section
General Procedure for the Reaction of ortho-Lithiophenyl
(-Hetaryl) Isocyanides with Aldehydes and Ketones (GP1). To a
solution of o-bromophenyl (-hetaryl) isocyanide (2 mmol) in
anhydrous tetrahydrofuran (20 mL), kept in an oven-dried 25 mL
Schlenk flask under an atmosphere of dry nitrogen, was added
dropwise with stirring a 2.5 M solution of n-BuLi in hexane (0.8
mL, 2 mmol) at -78 °C over a period of 10 min. The mixture was
stirred at -78 °C for another 10 min, before the respective aldehyde
(ketone) (2 mmol) in anhydrous THF (2 mL) was added dropwise.
The mixture was stirred at -78 °C for 3 h and was then treated in
three different ways (variants A-C).
(A) The reaction was quenched with water (2 mL) at -78 °C.
(B) The mixture was gradually warmed to 0 °C within 2 h, and
then the reaction was quenched with water (2 mL) at 0 °C.
(C) The mixture was treated with the solution of an electrophile
in THF (2 mL) at -78 °C, and the resulting mixture was stirred at
the same temperature for 2 h and warmed to rt overnight.
Then the mixture was diluted with diethyl ether (50 mL), washed
with water (2 × 10 mL) and brine (20 mL), and dried over
anhydrous Na2SO4. The solvents were removed under reduced
pressure to give a crude product, which was purified by column
chromatography on silica gel or by Kugelrohr distillation.
(2-Isocyanophenyl)(phenyl)methanol (8a). The isocyanide 8a
(350 mg, 84%) was obtained from o-bromophenyl isocyanide (364
mg, 2 mmol) and benzaldehyde (4a) (212 mg, 2 mmol) following
GP1 (A) and after column chromatography (hexane/ethyl acetate
) H) provided the corresponding benzoxazine 9g exclusively.
The isocyanobenzylalcohols 8f and 16d with furyl and thienyl
moieties afforded selectively isobenzofuran-1-(3H)-imine 14f
and thiophene-annelated tetrahydrofuranimine 15d, respectively,
whereas all the other aryl-substituted isocyanobenzylalcohols
8a-8d gave the corresponding 4H-3,1-benzoxazines 9.
ortho-Lithiophenyl isocyanide 2 also reacts with carbon
dioxide at -78 °C to initially yield lithium ortho-isocyanoben-
zoate 36, which equilibrates with the 2-lithiobenzoxazin-4-one
37. The latter reacts with iodine to furnish 2-iodobenzoxazin-
4-one (38) which readily undergoes in situ substitution by added
nucleophiles such as water, morpholine, and aziridine to provide
the correspondingly substituted 4-H-benzo[3,1]oxazin-4-ones20,21
39-Nu and isatoic anhydride 40 in a one-pot four-step procedure
in moderate yields (Scheme 4).
1
4:1, Rf ) 0.27) as a yellow oil: H NMR (300 MHz, CDCl3) δ
7.74 (d, J ) 7.9 Hz, 1 H, Ar-H), 7.47-7.25 (m, 8 H, Ar-H),
6.18 (s, 1 H, CH), 2.51 (s, 1 H, OH); 13C NMR (75.5 MHz, CDCl3,
APT) δ 167.6 (C), 141.6 (C), 139.9 (C), 129.7 (CH), 128.7 (2 CH),
128.3 (CH), 128.2 (CH), 127.0 (2 CH), 126.9 (2 CH), 124.4 (C),
71.9 (CH); IR (film) 3393 (br, OH), 3064, 3031, 2896, 2120 (NC),
1483, 1453, 1188, 1035, 1024, 761, 699 cm-1; MS (EI) m/z (%)
209 (46) [M+], 180 (100), 77 (34); HRMS (EI) calcd for C14H11NO+
[M]+ 209.0841, found 209.0839.
SCHEME 4. Synthesis of 2-Substituted
4H-Benzo[d][1,3]oxazin-4-ones (39-Nu) and Isatoic
Anhydride 40
3-(Trifluoromethyl)-3-methylisobenzofuran-1(3H)-imine (14o).
The compound 14o (250 mg, 58%) was obtained from o-
bromophenyl isocyanide (364 mg, 2 mmol) and 1,1,1-trifluoroac-
etone (4o) (224 mg, 2 mmol) following GP1 (B) and after Kugelrohr
distillation (0.1 Torr, 85-95 °C) as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 7.39 (td, J ) 7.2, 1.9 Hz, 1 H, Ar-H), 7.30-7.21
(m, 3 H, Ar-H), 7.15 (s, 1 H, NH), 1.87 (s, 3 H, CH3); 13C NMR
(125 MHz, CDCl3, APT) δ 148.4 (C), 136.7 (C), 130.7 (CH), 127.9
(CH), 125.8 (CH), 125.3 (CH), 124.1 (q, JCF ) 287 Hz, C), 121.4
(C), 77.2 (q, J2CF ) 31 Hz, C), 22.0 (CH3); MS (EI) m/z (%) 215.0
(39) [M+], 146.0 (100); IR (KBr) 3304 (br) (NH), 1676, 1636, 1456,
1295, 1225, 1179, 1096, 769 cm-1. Anal. Calcd for C10H8F3NO:
C, 55.82; H, 3.75; N, 6.51. Found: C, 55.74; H, 3.51; N, 6.30.
Methyl 4-(Trifluoromethyl)-4-phenyl-4H-3,1-benzoxazine-2-car-
boxylate (9l-CO2Me). Compound 9l-CO2Me (302 mg, 45%) was
obtained from o-bromophenyl isocyanide (376 mg, 2 mmol), 1,1,1-
trifluoroacetophenone (4l) (348 mg, 2 mmol), and methyl chloro-
formate (189 mg, 2 mmol) following GP1 (C) and after column
chromatography on silica gel (hexane/ethyl acetate 4:1, Rf ) 0.26)
In conclusion, the reactions of ortho-lithiophenyl isocyanide
and other ortho-lithiohetaryl isocyanides with aldehydes, ke-
tones, and carbon dioxide furnish, apart from the expected
isocyanobenzylalcohols 8, 4H-3,1-benzoxazines 9, and 4H-
benzoxazin-4-ones 39-Nu, iminophthalanes of type 18 or
indolin-2-ones of type 19, respectively, by two novel rearrange-
ments of the intermediate 2-lithio-4H-3,1-benzoxazines.
1
as a yellow oil: H NMR (300 MHz, CDCl3) δ 7.50 (m, 4 H,
Ar-H), 7.39 (m, 5 H, Ar-H), 3.98 (s, 3 H, CH3); 13C NMR (125
MHz, CDCl3, APT) δ 159.3 (C), 145.6 (C), 137.0 (C), 135.0 (C),
130.7 (CH), 129.7 (CH), 129.3 (CH), 128.4 (CH), 127.4 (CH), 127.3
(CH), 126.1 (q, J ) 2.3 Hz, CH), 123.4 (q, J ) 285.4 Hz, C),
121.1 (C), 83.0 (q, J ) 30.8 Hz, C), 53.8 (CH3); MS (EI) m/z (%)
335 (16) [M+], 266 (88), 43 (100); IR (KBr) 2955, 1745, 1647,
1601, 1327, 1293, 1211, 1180, 990, 767, 702 cm-1; HRMS (ESI)
calcd for C17H12NF3O3Na+ [M + Na+] 358.0661, found 358.0666.
General Procedure for the Cu2O-Catalyzed Cyclization of
(2-Isocyanophenyl)methanols 8 (GP2). To a solution of isocy-
anobenzylalcohol 8 (2 mmol) in benzene (10 mL) was added Cu2O
(14.4 mg, 5 mol %), and the resulting mixture was heated under
(20) For examples of naturally occurring 4H-3,1-benzoxazin-4-ones, see: (a)
Mason, J. J.; Bergman, J.; Janosik, T. J. Nat. Prod. 2008, 71, 1447–1450. (b)
Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432–2433.
(21) (a) Fenton, G.; Newton, C. G.; Wyman, B. M.; Bagge, P.; Dron, D. I.;
Riddell, D.; Jones, G. D. J. Med. Chem. 1989, 32, 265–272. (b) Hedstrom, L.;
Moorman, A. R.; Dobbs, J.; Abeles, R. H. Biochemistry 1984, 23, 1753–1759.
For reviews on 4H-3,1-benzoxazin-4-ones, see: (c) Coppola, G. M. J. Heterocycl.
Chem. 1999, 36, 563–588. (d) Coppola, G. M. J. Heterocycl. Chem. 2000, 37,
1369–1388.
4558 J. Org. Chem. Vol. 74, No. 12, 2009

Reactions of ortho-Lithiophenyl (-Hetaryl) Isocyanides
reflux for 1 h. Then, the mixture was cooled to rt, the solvent was
removed under reduced pressure, and the product was purified by
column chromatography on silica gel.
diluted with diethyl ether (50 mL), washed with Na2S2O5 solution
(20 mL), water (10 mL), and brine (20 mL), and dried over
anhydrous Na2SO4. The solvents were removed under reduced
pressure, and the crude product was purified by column chroma-
tography on silica gel.
4-Phenyl-4H-3,1-benzoxazine (9a). Compound 9a (301 mg, 86%)
was obtained from isocyanobenzylalcohol 8a (350 mg, 1.67 mmol)
following GP2 and after column chromatography on silica gel
(hexane/ethyl acetate/Et3N 5:1:1, Rf ) 0.38) as a slightly yellow
2-(Aziridin-1-yl)-4H-3,1-benzoxazin-4-one (39-azirid). Com-
pound 39-azirid (188 mg, 50%) was obtained following GP3 from
o-bromophenyl isocyanide (364 mg, 2 mmol) and aziridine (86 mg,
2 mmol) and after column chromatography on silica gel (ethyl
acetate, Rf ) 0.26) as a colorless solid: mp 154-155 °C; 1H NMR
(300 MHz, CDCl3) δ 8.15 (dd, J ) 7.5, 1.3 Hz, 1 H, Ar-H), 7.66
(ddd, J ) 8.4, 7.2, 1.6 Hz, 1 H, Ar-H), 7.50 (d, J ) 8.1 Hz, 1 H,
Ar-H), 7.32 (ddd, J ) 8.1, 7.2, 1.3 Hz, 1 H, Ar-H), 4.76 (t, J )
8.4 Hz, 2 H, CH2), 4.37 (t, J ) 8.4 Hz, 2 H, CH2); 13C NMR (75.5
MHz, CDCl3) δ 160.8 (C), 155.4 (C), 148.9 (C), 134.8 (CH), 126.5
(CH), 126.1 (CH), 124.7 (CH), 118.3 (C), 65.8 (CH2), 42.2 (CH2);
MS (EI) m/z (%) 188.1 (100) [M+], 146.1 (86); IR (KBr) 1696,
1640, 1609, 1562, 1473, 1418, 1263, 1135, 1015, 980, 863, 769,
692 cm-1. Anal. Calcd for C10H8N2O2: C, 63.82; H, 4.28; N, 14.89.
Found: C, 63.62; H, 4.21; N, 14.67.
1
solid: mp 62-63 °C; H NMR (300 MHz, CDCl3) δ 7.40-7.22
(m, 7 H, Ar-H), 7.19 (s, 1 H, CHdN), 7.12 (dt, J ) 7.5, 1.5 Hz,
1 H, Ar-H), 6.73 (d, J ) 7.5 Hz, 1 H, Ar-H), 6.29 (s, 1 H, CH);
13C NMR (75.5 MHz, CDCl3) δ 150.4 (CH), 139.8 (C), 137.1 (C),
129.1 (CH), 129.0 (CH), 128.7 (CH), 127.8 (CH), 127.1 (CH), 125.5
(CH), 125.3 (C), 124.8 (CH), 77.4 (CH); MS (EI) m/z (%) 209.0
(56) [M+], 180.0 (100); IR (KBr) 1612, 1601, 1489, 1455, 1219,
1125, 1096, 773 cm-1. Anal. Calcd for C14H11NO: C, 80.36; H,
5.30; N, 6.69. Found: C, 80.71; H, 5.19; N, 6.88.
General Procedure for the Synthesis of 4H-3,1-Benzoxazine-4-
ones 39 and Isatoic Anhydride 40 (GP3). To a solution of
o-bromophenyl isocyanide (364 mg, 2 mmol) in anhydrous THF
(20 mL), kept in an oven-dried 25 mL Schlenk flask under an
atmosphere of dry nitrogen, was added dropwise with stirring a
2.5 M solution of n-BuLi in hexane (0.8 mL, 2 mmol) at -78 °C
over a period of 10 min. The mixture was stirred at -78 °C for 10
min, and CO2 was bubbled through the mixture at -78 °C for 1
min. The mixture was stirred at -78 °C for 1 h, then a solution of
I2 (508 mg, 2 mmol) in anhydrous THF (2 mL) was added dropwise,
and the temperature was allowed to rise to 20 °C over a period of
1 h. Water (for the synthesis of 40) or a solution of the
corresponding amine (2 mmol) and triethylamine (2 mmo) in THF
(2 mL) was added, and the mixture was stirred at rt for 2 h. After
addition of saturated NH4Cl solution (20 mL), the mixture was
Acknowledgment. This work was supported by the Land
Niedersachsen. A.V.L. is indebted to the Degussa-Stiftung
(Evonik Industries AG) for a graduate student fellowship.
Supporting Information Available: Experimental proce-
dures and full characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO9004734
J. Org. Chem. Vol. 74, No. 12, 2009 4559