Unexpected reactivity of o-nitrosophenol with RCH2Br: C-H bond cleavage and annulation to benzoxazoles and benzoxazines (R = Alkynyl)

Article abstract of DOI:10.1021/ol902812q

A one-pot reaction between two molecules of 5-diethylamino-2-nitrosophenol with one molecule of 2-butynyl bromide gave rise to a new heterocyclic compound (structure shown above) consisting of one benzoxazole and one benzoxazine ring. The reaction works equally well with 1-phenyl-3-chloro-1-propyne. It was also found that 5-diethylamino-2-nitrosophenol reacts with R-CH₂Br (R = aryl or vinyl) to give benzoxazoles with good functional group tolerance and high yield.

Full text of DOI:10.1021/ol902812q

ORGANIC
LETTERS
2010
Vol. 12, No. 4
736-738
Unexpected Reactivity of
o-Nitrosophenol with RCH2Br:
C-H Bond Cleavage and Annulation to
Benzoxazoles and Benzoxazines
(R ) Alkynyl)
Wei Yao and Dejian Huang*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmhdj@nus.edu.sg
Received December 8, 2009
ABSTRACT
A one-pot reaction between two molecules of 5-diethylamino-2-nitrosophenol with one molecule of 2-butynyl bromide gave rise to a new
heterocyclic compound (structure shown above) consisting of one benzoxazole and one benzoxazine ring. The reaction works equally well
with 1-phenyl-3-chloro-1-propyne. It was also found that 5-diethylamino-2-nitrosophenol reacts with R-CH2Br (R ) aryl or vinyl) to give
benzoxazoles with good functional group tolerance and high yield.
Nitroso compounds have potential as starting materials for
synthesizing a wide range of heterocyclic compounds owing
to their rich reactivity. Nitrosoarenes undergo cycloaddition
to alkynes to give N-hydroxyindoles.1 The nitroso-ene
reaction is a mild and selective method for the direct allylic
nitrogen functionalization of alkenes.2 Not much other
synthetic applications have been reported for o-nitrosophenol
and its analogues except in the synthesis of dyes such as
Nile blue, Nile red3 and cyanine.4 Reported herein are an
unexpected new reaction pattern of o-nitrosophenol and its
naphthalene analogue toward RCH2Br forming oxazoles
through C-H bond activation and annulation. Compounds
with benzoxazole structural motifs are receiving much
attention as therapeutic agents and optical-electronic materi-
als.5,6
(3) For synthetic methods for Nile blue derivatives, see: (a) Jose, J.;
Ueno, Y.; Burgess, K. Chem.sEur. J. 2009, 15, 418–423. For synthetic
methods for Nile Red derivatives, see: (b) Jose, J.; Burgess, K. J. Org.
Chem. 2006, 71, 7835–7839.
(1) Penoni, A.; Giovanni Palmisano, G.; Yi-Lei Zhao, Y.-L.; Kendall,
N.; Houk, K. N.; Volkman, J.; Nicholas, K. M. J. Am. Chem. Soc. 2009,
131, 653–661.
(4) Shindy, H. A.; El-Maghraby, M. A.; Eissa, F. M. Color. Technol.
2008, 124, 159–164.
(2) Adam, W.; Krebs, O. Chem. ReV. 2003, 103, 4131–4146.
10.1021/ol902812q  2010 American Chemical Society
Published on Web 01/22/2010

Scheme 1
Table 1. Synthesis of Benzoxazolesa
In an attempt to prepare fluorescence dye, a Nile red
derivative with CH2Br functionality via a known ring-closing
reaction,3 we did not obtain the expected red color product
upon heating 5-diethylamino-2-nitrosophenol with 2-bro-
momethyl-1-naphthol in DMF. Instead, a bright yellow
benzoxazole 1 was isolated in 85% yield (Scheme 1). The
structure of 1 is solved by single-crystal X-ray diffraction.
The bond length of the CdN (1.3019(19) Å) and C-O
(1.3721(18) Å) of the oxazole falls within the normal range
as predicted. The proton of the HO group is pointed toward
the N for an intramolecular hydrogen bond. This is further
corroborated by the short N(1) to O(1) distance of 2.626 Å.
The two conjugated ring systems are nearly coplanar. The
structure is consistent with collective spectral data. We
further investigated the scope of the reaction with a number
of RCH2Br. In most cases, the reaction gave good to excellent
yield as shown in Table 1. The R- group includes naphthyl,
phenyl (entry 1), allyl (entry 2), and pyridyl (entry 3).
However, the reaction did not work for 2-bromobutane.
Apparently, a conjugated R- group is essential for the
reaction. It is remarkable that the reaction has good functional
group tolerance toward phenol (compound 1), pyridine (entry
3), carboxylic acid (entry 4), ester (entry 5), halogen (entries
7, 8) and nitryl (entry 9). The electronic effects of the
substituent on the aryl ring are negligible as both electron-
donating (CH3) and electron-withdrawing (F, Cl, NO2) groups
gave comparable yields (entries 6-9).
1-Nitroso-2-naphthol also reacts with RCH2Br to give
similar product (entries 10, 11). The annulation reaction can
be carried out in aprotic solvents including DMF, THF, and
acetone in the presence of either acid or base without much
a Typical conditions: THF, K2CO3, reflux, 6 h. b 1-Nitroso-2-naphthol
was used.
(5) (a) Aiello, S.; Geoffrey Wells, G.; Stone, E. L.; Kadri, H.; Bazzi,
R.; David, R.; Bell, D. R.; Malcolm, F. G.; Stevens, M. F. G.; Matthews,
C. S.; Bradshaw, T. D.; Andrew, D.; Westwell, A. D. J. Med. Chem. 2008,
51, 5135–5139. (b) Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman,
R. L.; Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang,
K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Angew. Chem., Int.
Ed. 2003, 42, 2758–2761.
impact on the yield. We propose a working mechanism
shown in Scheme 2. Phenol reacts with RCH2Br to yield an
aryl ether intermediate, which undergoes an intramolecular
hydrogen atom transfer reaction to give an unobserved
biradical intermediate. The intramolecular radical coupling
closes the ring. Subsequently, dehydration leads to the final
(6) (a) Taki, M.; Wolford, J. L.; O’Halloran, T. V. J. Am. Chem. Soc.
2004, 126, 712–713. (b) Seo, J.; Kim, S.; Park, S. Y. J. Am. Chem. Soc.
2004, 126, 11154–11155. (c) Ohshima, A.; Momotake, A.; Nagahata, R.;
Arai, T. J. Phys. Chem. A 2005, 109, 9731–9736.
Org. Lett., Vol. 12, No. 4, 2010
737

Scheme 2a
a (HAT ) Hydrogen atom transfer).
Figure 1. ORTEP drawing of one (S) of the two independent
complexes (S and R) presented in the crystals of 13.
product. Alkyl bromide could not work because the formed
carbon radical does not gain stabilization through conjuga-
tion.
13. We found that o-nitrosophenol did not react with
CH3CtCCH2OH under the same conditions, indicating that
an electron-withdrawing group on alkyne (“dienophile”) is
needed for the cyclization reaction to occur. 1-Nitroso-2-
naphthol reacted with PhCCCH2Cl but gave low yield. The
full scope of the R group of reaction 2 is being investigated.
To gain some insight into the reaction, we prepared benzyl
ether intermediate A and converted it to 2 cleaningly in
solution or eVen in the solid state by heating to 65 °C (eq
1). Addition of a radical scavenger, Trolox, did not slow
down the reaction. The purported intramolecular radical
coupling could be too fast to be trapped by radical scaven-
gers. We did not observe any reaction intermediates by the
NMR spectrum, and addition of water did not slow down
the reaction. This indicates that the elimination of water was
an irreversible and fast reaction. It is thus likely that the
hydrogen atom transfer is the rate-limiting step.
Scheme 3
In summary, this is the first reported such reaction pattern
of o-nitrosophenol with alkynes. Nitrosoarenes and alkynes
underwent cycloaddition to form N-hydroxyindoles as the
main products, and the hydroxyl group could be reduced by
hydrogenation (H2/Pd-C) to give indoles.1 In our case, the
presence of an ortho-phenol group alters the reaction pathway
completely. The new reactions described herein are attractive
synthetic methods because they occurred under mild condi-
tions, with good functional group tolerance and without
catalysts required as is the case in a few reported procedures.7
When we expanded the R-CH2X to include alkynes such
as CH3CtCCH2Br or PhCtCCH2Cl, we isolated new
compounds 13 and 14 in good yield (eq 2). X-ray crystal
structural analysis demonstrated that 13 contains benzoxazole
and benzoxazine rings (Figure 1). There is a chiral carbon
in C7, and the unit cell contains both optical isomers. We
proposed a formation mechanism of 13 and 14 as shown in
Scheme 3. The first o-nitrosophenol reacts with R-CH2X to
afford the benzoxazole. The alkynyl moiety in the benzox-
azole intermediate reacts with a second o-nitrosophenol
through Diels-Alder reaction to form a benzoxazine inter-
mediate with OH on the nitrogen. Rearrangement of the HO
group occurred under the basic reaction conditions to give
Acknowledgment. The authors thank the Science and
Engineering Research Council (SERC) of the Agency for
Science, Technology and Research (A*Star) of Singapore
for financial support (Grant number: 072-101-0015).
Supporting Information Available: General procedures
and characterization for representative compounds. CIF for
1 and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
(7) (a) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411–
6413. (b) Chen, Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem.,
Int. Ed. 2008, 47, 9330–9333. (c) Marsden, S. P.; McGonagle, A. E.;
McKeever-Abbas, B. Org. Lett. 2008, 10, 2589–2591.
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