Addition of ureas to arynes: Straightforward synthesis of benzodiazepine and benzodiazepine derivatives

Article abstract of DOI:10.1002/1521-3773(20020902)41:17<3247::AID-ANIE3247>3.0.CO;2-P

Seven- and eight-membered heterocycles are formed straightforwardly, in modest to high yields in this novel addition reaction of ureas to arynes (see scheme; R = alkoxy, alkyl, aryl). The reaction of a meta-substituted aryne affords the product with perfect regioselectivity, whereas a para-substituted aryne gives a mixture of regioisomers.

Full text of DOI:10.1002/1521-3773(20020902)41:17<3247::AID-ANIE3247>3.0.CO;2-P

COMMUNICATIONS
The novel synthetic reaction was discovered when we
generated arynes by treatment of precursors 2 with cesium
fluoride in 1,3-dimethyl-2-imidazolidinone (DMI, 1a)
[Eq. (1)].
Addition of Ureas to Arynes: Straightforward
Synthesis of Benzodiazepine and
Benzodiazocine Derivatives**
Hiroto Yoshida, Eiji Shirakawa,* Yuki Honda, and
Tamejiro Hiyama*
O
TMS
OTf
O
CsF
+
NR2
NR2
R'
ð1Þ
R'
The reaction of arynes with nucleophiles is a unique,
straightforward method for the synthesis of substituted
arenes.[1] Owing to the marked electrophilicity of arynes,
even neutral nucleophiles that are inert toward alkynes are
applicable to such a reaction. In most cases, however, an
initially formed zwitterion abstracts a proton from the
surroundings, which results in the formation of a monosub-
stituted arene (Scheme 1a). Although insertion of an aryne
into a single bond between a nucleophile and an electrophile
20 °C
R2N
NR2
1
2
3
For example, treatment of 1a, 2-(trimethylsilyl)phenyl
triflate (2a),[6,7] and CsF at 208C for 2 h gave 1,4-dimethyl-
2,3,4,5-tetrahydro-(1H)-1,4-benzodiazepin-5-one (3a) in 62%
yield (Table 1, entry 1).[8] Worthy of note is the perfect
regioselectivity observed in the reaction of 3-substituted
ꢀ
(Nu E) should be more beneficial from the standpoint of
Table 1. Reaction of arynes with DMI.[a]
organic synthesis (Scheme 1b), examples of this are limited to
Entry
1
2
Product(s)
t [h] Yield [%][b]
[2a]
[2b]
[2c]
ꢀ
ꢀ
ꢀ
ꢀ
such activated species as Te Te, S S, C Si, and C
Sn[2d] bonds.
1
1a
2a
2b
2c
3a
3b
2
3
62
77
2
3
3c 15 66
Scheme 1. The reaction of arynes with nucleophiles.
ꢀ
Herein we report that an N CO bond of ureas 1 readily
4
5
6
2d
2e
2 f
3d
3d
7
5
89
73
adds to arynes to provide, in one step, a wide variety of 1-
amino-2-(aminocarbonyl)arenes, including 1,4-benzodiaze-
pine and 1,5-benzodiazocine derivatives. These heterocycles
are an important group of therapeutic agents: 1,4-benzodia-
zepines, for example, diazepam and flurazepam, have been
used as antianxiety drugs, sedatives, anticonvulsants, or
hypnotics, whereas 1,5-benzodiazocines have attracted much
interest as homologues of 1,4-benzodiazepine drugs.[3a,b]
Furthermore, some of the products exhibited characteristic
fluorescence comparable to that of anthranilic acid deriva-
tives, which are well-known fluorophores.[4,5]
3e 17 73
3 f
[a] The reaction was carried out in 1a (0.75 mL) at 208C using 2 (0.34 mmol) and
CsF (0.69 mmol). [b] Yield of isolated product, based on 2.
[*] Prof. Dr. E. Shirakawa
Graduate School of Materials Science
Japan Advanced Institute of Science and Technology
Asahidai, Tatsunokuchi, Ishikawa 923-1292 (Japan)
Fax : (þ 81)761-51-1631
benzynes. Thus, the 3-methoxybenzyne derived from 2b or
3-phenylbenzyne from 2c reacted smoothly with 1a, giving 3b
or 3c as a single isomer, respectively (entries 2 and 3). The
reaction of 1-(trimethylsilyl)-2-naphthyl triflate (2d), a 1,2-
naphthalyne precursor, proceeded regioselectively to afford
solely 3d in 89% yield (entry 4). Exclusive formation of 3d
was also observed in the reaction of 2-(trimethylsilyl)-1-
naphthyl triflate (2e; entry 5), which indicates that both
reactions proceed through the 1,2-naphthalyne intermediate.
Products 3b 3d contain the amide moiety at the more
sterically hindered position.[9] In contrast, 4-methylbenzyne
prepared from 2 f gave almost equal amounts of regioisomeric
E-mail: shira@jaist.ac.jp
Prof. Dr. T. Hiyama, Dr. H. Yoshida, Y. Honda
Department of Material Chemistry
Graduate School of Engineering, Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (þ 81)75-753-5555
E-mail: thiyama@npc05.kuic.kyoto-u.ac.jp
[**] This work was supported by the Grant-in-Aids for COE Research on
Elements Science, No. 12CE2005 from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 17
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3247 $ 20.00+.50/0
3247

COMMUNICATIONS
products 3e and 3 f,[10] which suggests that a substituent at the
4-position of the benzyne exerts little influence on the
regioselectivity (entry 6).
N,N’-Dimethylpropyleneurea (DMPU, 1b) also reacted
readily with 2a to give 1,5-dimethyl-1,2,3,4,5,6-hexahydro-
1,5-benzodiazocin-6-one (3g) in 62% yield (Scheme 2). As
Scheme 3. A plausible mechanism for the reaction of arynes with ureas.
nucleophilic addition to benzyne at the sterically less con-
gested dimethylamino moiety.[15]
Seven- or eight-membered products derived from DMI or
DMPU, respectively, showed fluorescence in solution. The
excitation and emission wavelengths and fluorescence quan-
tum yields are summarized in Table 2. For example, the
benzodiazepine derivative 3a emitted fluorescence (lex ¼
324 nm; lem ¼ 436 nm) with a quantum yield (Ff) of 0.07 in
MeOH (entry 1, Table 2). In contrast, the fluorescence of
TMU-derived products was hardly detectable. Detailed
investigation of the relationship between fluorescence behav-
ior and structure is underway.
Table 2. Fluorescence properties of products 3, recorded in MeOH.
Entry
Product
lex [nm]
lem [nm]
Ff[a]
1
2
3
4
3a
3c
3d
3g
324
325
355
326
436
430
427
421
0.07
0.02
0.07
0.03
Scheme 2. Products of the reaction of arynes with ureas.
[a] Measured relative to quinine sulfate in H2SO4.
was the case with 1a, the reaction of 1b with 2b or 2d
produced the corresponding 1,5-benzodiazocine deriva-
tives 3h or 3i as a single isomer. In addition to cyclic ureas,
an acyclic urea, N,N,N’,N’-tetramethylurea (TMU; 1c), also
reacted with the formed arynes, which gave 2-aminobenza-
mides 3j and 3k, and 2-amino-1-naphthamide 3l.[11] An
unsymmetrical urea, N,N-diethyl-N’,N’-dimethylurea (1d),
reacted with 2a to afford N,N-diethyl-2-(dimethylamino)ben-
zamide (3m) as the sole insertion product.[12]
Although the mechanism of the reaction is not clear at
present, the susceptibility of arynes to addition of nucleophilic
heteroatoms[1] prompted us to consider a plausible mecha-
nism, depicted in Scheme 3. A urea nitrogen atom adds to an
aryne to give the zwitterion 4, which furnishes the product by
the intramolecular nucleophilic substitution at the carbonyl
carbon atom.[13] The perfect regioselectivities observed in the
reaction of 2b 2d can be rationally explained by steric
considerations: a urea molecule attacks the aryne carbon
atom meta to the substituent R’, which avoids steric repul-
sion.[14] On the other hand, steric effects would be less
pronounced in the addition of a urea to 4-methylbenzyne,
resulting in the formation of a mixture of regioisomers (entry
6, Table 1). Exclusive formation of 3m, which was observed in
the reaction of 1d, can be attributed to the regioselective
In conclusion, a general and efficient approach to 1,4-
benzodiazepines, 1,5-benzodiazocines, and 2-aminobenza-
mides has been developed, based upon the novel reaction of
arynes with ureas. 1,4-Benzodiazepines and 1,5-benzodiazo-
cines prepared in this study, which are hardly accessible by
conventional methods, would be valuable for their fluores-
cence properties as well as for their potential for pharma-
ceutical application. Further studies on the synthetic applica-
tion of the reaction and details of the reaction mechanism are
in progress.
Experimental Section
3a: To a solution of CsF (0.11 g, 0.69 mmol) in 1a (0.75 mL) was added 2a
(0.10 g, 0.34 mmol); the mixture was stirred for 2 h at 208C before dilution
with ethyl acetate. The resulting mixture was filtered through a celite plug
and evaporated. Bulb-to-bulb distillation to remove the excess urea,
followed by gel-permeation chromatography, gave 3a as a colorless oil
(0.040 g, 62% yield); 1H NMR (270 MHz, CDCl3, 20 8C): d ¼ 2.83 (s, 3H),
3.21 (s, 3H), 3.31 (t, J ¼ 5.5 Hz, 2H), 3.43 (t, J ¼ 5.5 Hz, 2H), 6.87 (d, J ¼
8.3 Hz, 1H), 6.99 (t, J ¼ 7.6 Hz, 1H), 7.37 (t, J ¼ 8.3 Hz, 1H), 7.63 ppm (dd,
J ¼ 7.6, 1.3 Hz, 1H); 13C NMR (67.8 MHz, CDCl3, 20 8C): d ¼ 34.5, 40.0,
48.1, 58.0, 117.4, 121.0, 129.2, 130.0, 131.7, 146.7, 170.5 ppm; elemental
analysis (%) calcd for C11H14N2O: C 69.45, H 7.42; found: C 69.26, H 7.43.
Received: May 15, 2002 [Z19303]
3248
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3248 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 17

COMMUNICATIONS
[1] Review: S. V. Kessar in Comprehensive Organic Synthesis,Vol. 4
(Eds.: B. M. Trost, I. Fleming, C. H. Heathcock), Pergamon, Oxford,
1991, pp. 483 515.
[2] a) N. Petragnani, V. G. Toscano, Chem. Ber. 1970, 103, 1652 1653;
b) J. Nakayama, T. Tajiri, M. Hoshino, Bull. Chem. Soc. Jpn. 1986, 59,
2907 2908; c) Y. Sato, Y. Kobayashi, M. Sugiura, H. Shirai, J. Org.
Chem. 1978, 43, 199 202; d) H. Yoshida, Y. Honda, E. Shirakawa, T.
Hiyama, Chem. Commun. 2001, 1880 1881.
[3] a) T. Howard in Comprehensive Heterocyclic Chemistry II,Vol. 7
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon, New
York, 1996, pp. 151 182; b) K. M. Doxsee in Comprehensive Hetero-
cyclic Chemistry II,Vol. 7 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V.
Scriven), Pergamon, New York, 1996, pp. 591 649.
Pyrazolate Coordination Continues To
Amaze–The New m-h2:h1 Binding Mode and
the First Case of Unidentate Coordination to a
Rare Earth Metal**
Glen B. Deacon,* Craig M. Forsyth, Alex Gitlits,
Rita Harika, Peter C. Junk, Brian W. Skelton, and
Allan H. White
Despite the recent transformations of pyrazolate coordina-
tion chemistry by the discovery of a range of new binding
[4] T. Yoshida, Igaku Kenkyu 1957, 27, 443 455.
[5] Fluorescence properties of representative compounds: Anthranilic
4]
modes[1
and by extension of h2-bonding from f-block
elements[5] to early[6] and mid[7] d-block transition elements
and main group metals,[8] surprising discoveries are still
possible. Thus, we now report the preparation of [Sc2(Ph2pz)6]
(1; Ph2pz ¼ 3,5-diphenylpyrazolate) with the new pyrazolate
coordination mode, m-h2:h1, which is intermediate between
the common m-h1:h1[9] and the recently reported m-h2:h2[2,3a]
ligation, and the first example of h1(N) coordination of a
pyrazolate to a lanthanoid ion in [Nd(h2-Me2pz)2( h1-Me2pz)-
(Me2pzH)2py)] (2; Me2pz ¼ 3,5-dimethylpyrazolate; py ¼ pyr-
idine). Normally and expectedly, the large size and high Lewis
acidity of Ln3þ favor chelation (h2) and/or double bridging (m-
h1:h1, m-h2:h2, m-h2:h5 etc.).[2,3a,9]
acid (lex ¼ 327 nm; lem ¼ 392 nm; Ff ¼ 0.01); ethyl anthranilate (lex
¼
339 nm; lem ¼ 404 nm; Ff ¼ 0.11).
[6] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211
1214.
[7] The aryne precursors used in this study are readily available from the
corresponding 2-halophenols or phenols. For detailed procedures, see
Supporting Information.
[8] Although the reaction of benzyne (from 2a and CsF) with a small
excess of ureas in THFalso gave moderate yields of products (e.g. with
2 equiv of 1a, 208C, 27 h, 41% yield of 3a), we employed ureas as a
solvent, as the yields were considerably improved.
[9] The structure of the products was determined by NOE in 1H NMR
spectra (Scheme 4). Furthermore, the crystal structure of 3b was
determined by an X-ray diffrac-
tion
study.
CCDC-185541
Compound 1 was synthesized by the direct reaction
between scandium metal and 3,5-diphenylpyrazole at 270
3008C [Eq. (1)], and was isolated by extraction with toluene
from which single crystals were obtained.
(3b)contains the supplementary
crystallographic data for this pa-
per. These data can be obtained
free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallo-
graphic Data Centre, 12, Union
Road, Cambridge CB21EZ, UK;
fax: (þ 44)1223-336-033; or de-
posit@ccdc.cam.ac.uk).
2 Sc þ 6 Ph2pzH ! ½Sc2ðPh2pzÞ6ꢁ ð1Þ þ 3 H2
ð1Þ
Scheme 4. Determination of
the structures of 3 by meas-
uring the magnitude of the
NOE denoted by the double-
headed arrow.
On the other hand, 2 was a minor product of the redox
transmetalation/ligand exchange reaction between neodymi-
um metal, Hg(C6F5)2, and 3,5-dimethylpyrazole in pyridine, a
reaction giving [Nd(Me2pz)3(py)] (3) as the main product
[Eq. (2)].
[10] Although the regioisomeric ratio
of 3e and 3 f was elucidated to be
52:48 by 1H NMR, we did not pursue the exact position of the methyl
substituent of each compound, because separation of the regioisomers
was difficult.
py
2 Nd þ 3 HgðC6F5Þ2 þ 6 ðor 8Þ Me2pzH ! 2 3 ðor 2Þ þ 6 C6F5H þ 3 Hg
[11] 2-Amino-1-naphthamide 3l was produced solely, regardless of the
precursor (2d or 2e) employed, which indicates that the reaction of an
acyclic urea also proceeds through an aryne intermediate.
[12] In this reaction, 2-(dimethylcarbamoyl)phenyl triflate, which should
be produced by the reaction of 1d with the aryl anion derived from Ar-
TMS and a fluoride ion, was also formed as a by-product.
[13] Because the urea oxygen atom is often considered to be more
nucleophilic than the urea nitrogen atom, we cannot rule out the
possibility that the reaction proceeds through other pathways,
triggered by the nucleophilic addition of the urea oxygen atom to an
aryne.
ð2Þ
A few single crystals of 2 deposited amidst bulk impure 3
and were separated for structure determination.
The structure of 1[10a] comprises a dimer (Figure 1). Each
scandium center is seven-coordinate with two terminal h2-
Ph2pz ligands and two bridging Ph2pz ligands, one of which
(3n) is h1-bonded by N(32) to Sc(1) and h2-linked through
[14] It is well-known that electronic effects also favor nucleophilic attack at
this m-position (see ref. [1]).
[*] Prof. Dr. G. B. Deacon, Dr. C. M. Forsyth, Dr. A. Gitlits, R. Harika,
Dr. P. C. Junk
[15] The generation of 2-(dimethylcarbamoyl)phenyl triflate (see ref. [12])
may imply that the reaction of 1d proceeds through a pathway which
does not involve an aryne intermediate: The reaction of the primarily
formed aryl anion (from Ar TMS with a fluoride ion) with 1d and
subsequent aromatic nucleophilic substitution at a C OTf moiety with
an amide anion (R2Nꢀ). However, this pathway can be discounted, at
least in the case of 1a, because, according to this pathway, the reaction
of 1a with a 1,2-naphthalyne precursor (2d or 2e) should afford the
corresponding regioisomeric product. This conclusion contrasts with
the results in entries 4 and 5 of Table 1.
School of Chemistry
Monash University
Victoria, 3800 (Australia)
Fax : (þ 61)3-9905-4597
E-mail: glen.deacon@sci.monash.edu.au
Dr. B. W. Skelton, Prof. Dr. A. H. White
Chemistry
University of Western Australia
Crawley WA, 6009 (Australia)
[**] This work was supported by the Australian Research Council and by
Australian Postgraduate Research Awards to A.G. and R.H.; Dr.
Maria Forsyth assisted with the CPMAS spectrum.
Angew. Chem. Int. Ed. 2002, 41, No. 17
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3249 $ 20.00+.50/0
3249