Synthesis of novel azaxanthones derived from N-hydroxyazoles

Article abstract of DOI:10.1016/S0040-4020(02)00034-0

The synthesis of a new class of azaxanthones is presented. The N-O functionality of 1-hydroxypyrazole and 1-hydroxy-1,2,3-triazole was used to direct metalation and subsequently in the new ring systems.

Full text of DOI:10.1016/S0040-4020(02)00034-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 2397±2404
Synthesis of novel azaxanthones derived from N-hydroxyazoles
²
Jesper L. Kristensen, Per Vedsù and Mikael Begtrupp
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Received 11 October 2001; accepted 10 January 2002
AbstractÐThe synthesis of a new class of azaxanthones is presented. The N±O functionality of 1-hydroxypyrazole and 1-hydroxy-1,2,3-
triazole was used to direct metalation and subsequently incorporated in the new ring systems. q 2002 Published by Elsevier Science Ltd.
1. Introduction
The regioselective functionalisation of 1-hydroxypyrazole
and 1-hydroxy-1,2,3-triazole was reported recently.1±4 We
sought to incorporate the N±O functionality in a new and
distinct group of heterocyclic systems using these protocols.
The xanthone is an ubiquitous structural motif found in
numerous natural products, and substituted derivatives
have a broad spectrum of biological activities.5±10 The
azaxanthones 1a and 1b in Scheme 1 were chosen as the
target molecules.
Scheme 2. Retrosynthetical analysis. Routes A and B.
3. Synthesis of 1a and 1bÐroute A
1-(Benzyloxy)pyrazole 2a and 1-benzyloxy-1,2,3-triazole
2b were acylated in 82and 71% yield, respectively via
Scheme 1. The target azaxanthones.
our metalation/transmetalation/cross-coupling protocols,
followed by debenzylation, see Scheme 3. The crucial
ring closure via displacement of the 2-¯uoro substituent
proceeded under very mild conditions: treating 4a and 4b
with 2equiv. K 2CO3 in DMF at 508C for 30 min gave full
conversion to the desired azaxhanthones 1a and 1b.14
2. Retrosynthetical analysis
We speculated that the compounds could be prepared via
two different approaches, see Scheme 2. In route A, the
central ring would be constructed via an intramolecular
nucleophilic aromatic substitution. Route B involves an
anionic intramolecular ring closure, analogous to the
recent synthesis of substituted xanthones reported by
Snieckus.11±13
Suitable crystals of 1b were obtained, and an X-ray structure
con®rmed the structural assignment (Fig. 1).15
Although the synthesis proceeds very smoothly it requires
four individual steps: benzylation, acylation, debenzylation
and ring closure. Thus, a shorter synthesis would be
desirable.
When ortho-lithiated aryl carbamates are warmed to rt an
anionic Fries rearrangement produces the corresponding
salicylamides, see Scheme 4.16 If the lithiated pyrazole 5
depicted in Scheme 4 could be generated, a similar
rearrangement would give 4a, thereby circumventing the
Keywords: azaxanthones; cyclisations; anionic ring closure.
Corresponding author. Tel.: 145-35-30-60-00; fax: 145-35-30-60-40;
p
e-mail: begtrup@dfh.dk
Current address: Novo Nordisk A/S, Medicinal Chemistry Research, DK-
Ê
2760 Malùv, Denmark.
²
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00034-0

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J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
Scheme 3. Synthesis of 1a and 1b via route A.
nucleophilic attack of the base on the ester-carbonyl. A
series of bases were tested (t-BuLi, LDA, LiTMP,
(TMP)2Mg20) but yields were low, 5±25% after subsequent
ring closure to 1a. The isolated yields were slightly higher
when 7a was used instead of 7b.
The best overall yield (25%) was obtained when the three
step sequence 6 to 1a was performed one-pot, using the very
hindered base lithium t-butyltritylamide,21 see Scheme 6.
Although the yield is modest, it represents a very fast way
of accessing 1a.
Figure 1. X-Ray structure of 1b.
tedious benzylation/debenzylation steps required in the ®rst
synthesis.
O-Acylated 1-hydroxypyrazoles have been reported
previously,17,18 and acylation of 6 gave 7a and 7b
isolated in 74 and 69% yield, respectively, see Scheme 5.
1-Hydroxy-1,2,3-triazoles have been reported as very active
analogues of N-hydroxybenzotriazoles in peptide coupling
reactions, so we speculated that the O-acylated triazole
derivatives would be too unstable to be isolated.19
The generation of the anion 5 was hampered by competing
Scheme 6. One-pot synthesis of 1a from 6.
4. Synthesis of 1a and 1bÐroute B
Next, we focused on the development of route B, see
Scheme 2. However, all attempts to prepare the required
O-arylated N-hydroxyazoles using the procedure developed
by Snieckus for the synthesis of diaryl ethers were
unsuccessful.22 Nevertheless, the concept of constructing
the O-aryl bond prior to ring closure remained attractive,
as this would shorten the synthesis. Compounds 8a and 8b
were chosen as substrates for a modi®ed version of the
Snieckus protocol, see Scheme 7.
Scheme 4. Possible anionic Fries rearrangement giving 4a.
The ease with which 2a and 2b is lithiated, suggested that 8a
and 8b could be lithiated in the 5-position under comparably
mild conditions, thus generating the anion required for the
ring closure.
The activating power of the cyano group in nucleophilic
Scheme 5. Synthesis of O-acyl 1-hydroxypyrazoles 7a and 7b.

J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
2399
imin-anion induced precipitation, and all efforts to circum-
vent this problem were unsuccessful.
This precipitation was not observed when a substituent was
present at C-4. The 4-bromo derivative 9, prepared in 99%
from 8a, gave the desired azaxanthone 10 in 89% yield, see
Scheme 9. To avoid halogen±metal exchange, LDA was
used as base in the lithiation/ring closure step.
5. Synthesis of functionalised derivatives of 1a
Inspired by our previously reported synthesis of 4-substi-
tuted 1-(benzyloxy)pyrazoles via iodine-magnesium
exchange of 4-iodo-1-(benzyloxy)pyrazole, we investigated
the synthesis of substituted derivatives of 1a.3 The 4-iodo-
pyrazole 11 was obtained in 82% yield over two steps from
6. Iodine±magnesium exchange with iPr-MgCl at 2788C
and quenching with CH3OD after 30 min gave 8a with
,95% deuterium incorporation at C-4. A small series of
electrophiles was introduced using this protocol, see
Table 1.
Scheme 7. Proposed new anionic ring closure.
aromatic substitution is well documented.23±25 Conse-
quently, stirring the Na-salt of 6 with 2-¯uorobenzonitrile
in DMF for 3 h at 708C gave 8a in 94% yield. Surprisingly,
1-hydroxy-1,2,3-triazole failed to give the desired product
8b under similar conditions.
Treating 8a with 1.1 equiv. n-butyllithium in THF at 2788C
for 10 min, followed by quench with CH3OD gave 8c with
.95% deuterium incorporation at C-5, see Scheme 8. This
showed that the required anion could be generated, and the
ring closure was attempted.
When the magnesiated intermediate was treated with
methyl-, ethyl-, benzyl chloroformate or with diethyl
glyoxylate complex mixtures were obtained and the isolated
yields were low. Addition of copper- or manganese salts did
not improve the yields. Methyl cyanoformate is an effective
reagent for the C-acylation of lithium enolates.26 Using this
reagent as electrophile, the desired compound was isolated
in 94% yield. In the synthesis of 12d the use of PhSO2SPh
was crucial, as the isolated yield dropped below 30% with
PhSSPh as electrophile. TMS-Cl and TBDMS-Cl did not
react even after prolonged stirring at rt.
After lithiation at 2788C, the reaction was warmed to rt.
Judged from TLC, full conversion of 8a to a single more
polar compound had occurred. Addition of 4N HCl
produced the desired compound 1a, but the hydrolysis
was accompanied by the formation of an insoluble precipi-
tate and the isolated yield of 1a was low. Repeated efforts
using different bases and work up procedures gave isolated
yields around 20%. Simply adding water to the presumed
The cyclisations of the functionalized compounds were met
with mixed success. Pyrazoles 12a and 12b gave complex
mixtures, whereas 12c and 12d yielded the desired 4-substi-
tuted azaxanthones 13c and 13d in 82and 79% yield,
respectively. The intermediate Ph2P-derivative 12e was
very sensitive to oxygen, and it was found that the sequence
11!12e!13e could be performed one-pot giving 13e in
excellent yield. Performing the sequence 11!12c!13c
and 11!12d!13d in a similar one-pot fashion gave
lower overall yields.
Extension of this approach to the synthesis of aryl-substi-
tuted analogous was examined. Transmetalation of the
magnesiated intermediate with ZnCl2 and subsequent
Pd(0) catalyzed cross-coupling with 4-iodotoluene gave
the desired compound 14 in 80% after 18 h at rt, see
Scheme 10. The following ring closure produced 15 in
91% yield. In the coupling of 11 to 14 an appreciable
amount of 2-hydroxybenzonitrile was also formed, presum-
ably via cleavage of the N±O bond in either 11 or 14. Efforts
toward synthesizing other 4-aryl-substituted derivatives
were plagued by this side reaction, thus the reaction is of
limited scope. Moreover, efforts to synthesize 14 via
Suzuki±Miyaura cross-coupling27 of either 9 or 11 with
4-tolylboronic acid gave low yields of 14, and also led to
the formation of 2-hydroxybenzonitrileÐclearly indicating
the sensitive nature of the N±O bond.
Scheme 8. Lithiation and ring closure of 8a.
Scheme 9. Ring closure of 9 to 10.

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J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
Table 1. Introduction of electrophiles followed by ring closure
Entry
1
Electrophile
DMF
E
Compound
Yield (%)
65
Compound
Yield (%)
a,b
12a
13a
±
b,d
2NCCOOCH
12b
94c
13b
±
3
3
4
TsCN
12c
12d
86
93
13c
13d
82
79
5
CllP(Ph)2
12e
Not isolated
13e
98 over 2steps
a
3 equiv. LDA was used.
b
c
d
Very complex mixture as judged from TLC and 1H NMR. No attempt to isolate any product was made.
Isolated as a 15:1 mixture of 12b and 8a after FC.
LiTMP was used instead of LDA.
Scheme 10. Negishi cross-coupling followed by ring closure.
6. Conclusion
otherwise noted. The multiplicity of 13C signals are assigned
based on APT spectra, and ppm values are given relative to
the solvent peak (CDCl3ˆ76.9 ppm).
A novel anionic ring closure to construct a new class of
azaxanthones has been described. We are currently investi-
gating the scope of this reaction for the preparation of other
heteroaryl- and arylxanthones.
7.1.1. 5-(2-Fluorobenzoyl)-1-(benzyloxy)pyrazole (3a).
Prepared form 1-(benzyloxy)pyrazole (2a) and 2-¯uoro-
benzoyl chloride as described in Ref. 2. 400 mg 2a yielded
556 mg (82%) 3a as a colourless oil, Rf (heptane/EtOAc
1
7. Experimental
7.1. General
5:1) 0.38. H NMR (CDCl3): 5.40 (s, 2H), 6.39 (d, 1H,
Jˆ2.4 Hz), 7.28±7.46 (m, 10H). 13C NMR (CDCl3): 81.3
(t), 110.2(d(d), JC±Fˆ2Hz), 116.4 (d(d), JC±Fˆ22 Hz),
124.0 (d(d), JC±Fˆ4 Hz), 126.4 (s(d), JC±Fˆ13 Hz), 128.5
(d), 129.3 (d), 130.0 (d), 130.7 (d(d), JC±Fˆ2Hz), 132.2(d),
132.9 (s), 133.6 (s), 134.0 (d(d), JC±Fˆ9 Hz), 160.4 (s(d),
JC±Fˆ256 Hz), 180.2 (s). Anal. calcd for C17H13FN2O2: C,
68.91; H, 4.42; N, 9.45. Found: C, 68.95; H, 4.45, N, 9.36.
All reactions involving air- and moisture sensitive reagents
were performed under N2 using syringe-septum cap tech-
nique. All glassware was ¯ame-dried under vacuum prior
to use. THF was distilled from Na/Benzophenone. DMF
Ê
was sequentially dried and stored over 3 A sieves. All
other chemicals were used as received from commercial
suppliers. 1-Hydroxypyrazole 6 was prepared as previously
described.28 Melting points are uncorrected. NMR spectra
were recorded on a 300 MHz Varian instrument using
CDCl3 as solvent with TMS as internal standard, unless
7.1.2. 5-(2-Fluorobenzoyl)-1-hydroxypyrazole (4a). 3a
(374 mg, 1.26 mmol) was suspended in 37% HCl (5 mL)
and heated to 708C for 5 h. The mixture was cooled to rt
and transferred to a separating funnel using 37% HCl
(3£1 mL). Toluene (1 mL) was added, and the separating

J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
2401
funnel was shaken vigorously. The phases were separated
and the toluene phase was extracted once with 37% HCl
(3 mL). The combined HCl phase was cooled to 08C and
33% NaOH (6 mL) was added cautiously. Water (10 mL)
was added to dissolve the formed precipitate and the
aqueous phase was extracted with Et2O (3£30 mL).
The combined organic phases were dried (MgSO4) and the
solvent was evaporated giving 258 mg (99%) 4a as white
(DMSO-d6): 7.36±7.42 (m, 2H), 7.63±7.76 (m, 2H), 8.24
(s, 1H). 13C NMR (DMSO-d6): 116.7 (d(d), JC±Fˆ22 Hz),
125.2 (d(d), JC±Fˆ3 Hz), 125.9 (s(d), JC±Fˆ12Hz), 129.1
(s), 131.0 (d(d), JC±Fˆ2Hz), 135.4 (d(d), JC±Fˆ9 Hz), 136.4
(s), 160.3 (s(d), JC±Fˆ253 Hz), 179.7 (s). Anal. calcd for
C9H6FN3O2: C, 52.18; H, 2.92; N, 20.28. Found: C, 51.92;
H, 3.12, N, 20.07.
1
crystals, mp 1168C (heptane/EtOAc), Rf (EtOAc) 0.37. H
7.1.6. 9-Oxa-1,2,9a-triaza-cyclopenta[b]naphthalen-4-
one (1b). Procedure, see 4a to 1a above. 73 mg 4b gave
65 mg (98%) 1b as white crystals, mp 159±1608C (heptane/
NMR (Acetone-d6): 6.69 (t, 1H, Jˆ2.4 Hz), 7.21±7.28 (m,
2H), 7.33 (td, 1H, Jˆ7.6, 1.1 Hz), 7.64 (dddd, 1H, Jˆ15.8,
8.4, 5.1, 1.8 Hz), 7.68±7.74 (m, 2H). 13C NMR (Acetone-
d6): 109.1 (d(d), JC±Fˆ2Hz), 115.5 (d(d), JC±Fˆ22 Hz),
123.8 (d(d), JC±Fˆ4 Hz), 125.8 (s(d), JC±Fˆ14 Hz), 129.8
(d(d), JC±Fˆ2Hz), 130.3 (d), 131.0 (s), 133.5 (d(d),
JC±Fˆ9 Hz), 159.4 (s(d), JC±Fˆ253 Hz), 180.5 (s). Anal.
calcd for C10H7FN2O2: C, 58.26; H, 3.42; N, 13.59.
Found: C, 58.49; H, 3.62, N, 13.59
1
EtOAc), Rf (heptane/EtOAc 1:1) 0.55. H NMR (CDCl3):
7.51±7.59 (m, 2H), 7.90 (ddd, 1H, Jˆ9.0, 7.2, 1.8 Hz), 8.31
(dd, 1H, Jˆ7.2, 1.8 Hz), 8.44 (s, 1H). 13C NMR (CDCl3):
114.7 (dddd, JC±Hˆ167, 8, 2, 1 Hz), 118.2 (dd, JC±Hˆ8,
4 Hz), 124.8 (d, JC±Hˆ15 Hz), 126.1 (dd, JC±Hˆ165,
8 Hz), 127.0 (ddd, JC±Hˆ168, 8, 1 Hz), 131.8 (d,
JC±Hˆ204 Hz), 136.8 (ddd, JC±Hˆ163, 9, 2Hz), 156.6
(ddt, JC±Hˆ11, 4, 1 Hz), 168.3 (dd, JC±Hˆ4.0, 1.4 Hz).
Anal. calcd for C9H5N3O2: C, 57.76; H, 2.69; N, 22.45.
Found: C, 58.04; H, 2.80, N, 22.22.
7.1.3. 9-Oxa-1,9a-diaza-cyclopenta[b]naphthalen-4-one
(1a). 4a (310 mg, 1.50 mmol) and freshly ground K2CO3
(414 mg, 3.00 mmol) was suspended in DMF (8 mL) and
heated to 508C for 30 min. Brine (10 mL) and water
(10 mL) was added, and the mixture was extracted with
Et2O (3£30 mL). The combined organic phase was washed
once with brine (10 mL), dried (MgSO4) and evaporation of
the solvent gave 273 mg (97%) 1a as white crystals, mp
7.1.7. 1-(2-Chlorobenzoyloxy)-pyrazole (7a). 6 (988 mg,
11.8 mmol) was dissolved in Et2O (30 mL) under N2 and
cooled to 08C before NaH (60% in mineral oil, 520 mg,
12.9 mmol) was added in small portions. Stirring was
continued at 08C until the evolution of H2 ceased
(,10 min). 2-Chlorobenzoyl chloride was added and the
icebath was removed. Stirring was continued at rt for
30 min, before quenching with sat. NaHCO3 (30 mL).
Water was added until two clear phases appeared. The
phases were separated, and the aqueous phase was extracted
with Et2O (3£50 mL), drying (MgSO4) and evaporation of
the solvent gave the crude product which was puri®ed by FC
giving a clear colourless oil. Crystallization from Et2O/
hetane gave 1.92g (74%) 7a as white crystals, mp 56±
1
1358C (heptane/EtOAc), Rf (heptane/EtOAc 3:1) 0.41. H
NMR (CDCl3): 7.08 (d, 1H, Jˆ2.4 Hz), 7.41±7.49 (m, 2H),
7.57 (d, 1H, Jˆ2.4 Hz), 7.79 (ddd, 1H, Jˆ8.4, 7.2, 1.5 Hz),
8.30 (dd, 1H, Jˆ7.8, 1.5 Hz). 13C NMR (CDCl3): 103.2(dd,
JC±Hˆ185, 10 Hz), 114.4 (dddd, JC±Hˆ166, 8, 3, 1 Hz),
117.8 (dd, JC±Hˆ9, 5 Hz), 124.9 (dd, JC±Hˆ164, 8 Hz),
126.7 (ddd, JC±Hˆ167, 8, 1 Hz), 129.1 (dd, JC±Hˆ9,
5 Hz), 132.4 (dd, JC±Hˆ194, 4 Hz), 135.5 (ddd, JC±Hˆ162,
10, 3 Hz), 156.6 (dddd, JC±Hˆ8.9, 8.6, 4, 2Hz), 169.5 (d,
JC±Hˆ4 Hz). Anal. calcd for C10H6N2O2: C, 64.52; H, 3.25;
N, 15.05. Found: C, 64.66; H, 3.35, N, 15.07.
1
588C. H NMR (CDCl3): 6.41 (t, 1H, Jˆ2.4 Hz), 7.40±
7.47 (m, 2H), 7.49 (dd, 1H, Jˆ2.4, 1.0 Hz), 7.56±7.59 (m,
2H), 8.10 (ddd, 1H, Jˆ7.8, 1.5, 0.6 Hz). 13C NMR (CDCl3):
104.8 (d), 124.1 (d), 124.9 (s), 126.8 (d), 131.5 (d), 132.0
(d), 134.4 (d), 134.5 (d), 135.1 (s), 162.6 (s). Anal. calcd for
C10H7ClN2O2: C, 53.95; H, 3.17; N, 12.58. Found: C, 54.20;
H, 3.24, N, 12.53.
7.1.4.
5-(2-Fluorobenzoyl)-1-benzyloxy-1,2,3-triazole
(3b). Prepared form 1-benzyloxy-1,2,3-triazole (2b) and
2-¯uorobenzoyl chloride as described in Ref. 4. 337 mg
2b yielded 405 mg (71%) 3b as white crystals, mp 66±
1
678C (heptane/EtOAc), Rf (heptane/EtOAc 1:1) 0.60. H
NMR (CDCl3): 5.53 (s, 2H), 7.18 (ddd, 1H, Jˆ10.5, 8.7,
0.9 Hz), 7.28 (td, 1H, Jˆ7.5, 1.2Hz), 7.34±7.42(m, 5H),
7.49±7.55 (m, 1H), 7.61 (dddd, 1H, Jˆ8.4, 7.2, 5.1, 1.8 Hz),
7.88 (d, 1H, Jˆ1.5 Hz). 13C NMR (CDCl3): 83.5 (t), 116.7
(d(d), JC±Fˆ22 Hz), 124.4 (d(d), JC±Fˆ4 Hz), 125.3 (s(d),
JC±Fˆ12 Hz), 128.7 (d), 129.77 (s), 129.84 (d), 130.2 (d),
130.8 (d(d), JC±Fˆ2Hz), 131.8 (s), 135.1 (d(d), JC±Fˆ9 Hz),
136.6 (d(d), JC±Fˆ3 Hz), 160.6 (s(d), JC±Fˆ257 Hz), 178.5
(s). Anal. calcd for C16H12FN3O2: C, 64.64; H, 4.07; N,
14.13. Found: C, 64.87; H, 4.14; N, 14.26.
7.1.8. 1-(2-Fluorobenzoyloxy)-pyrazole (7b). 7b was
prepared using an identical procedure with 2-¯uorobenzoyl
chloride. 460 mg 6 gave 1.11 g (69%) 7b as white crystals,
1
mp 61±638C. H NMR (CDCl3): 6.38 (t, 1H, Jˆ2.4 Hz),
7.22 (ddd, 1H, Jˆ10.7, 8.4, 1.1 Hz), 7.29 (td, 1H, Jˆ7.7,
1.1 Hz), 7.44 (dd, 1H, Jˆ2.3, 1.1 Hz), 7.47 (dd, 1H, Jˆ2.5,
1.0 Hz), 7.66 (dddd, 1H, Jˆ8.4, 7.4, 4.9, 1.8 Hz), 8.07 (ddd,
1H, Jˆ7.6, 7.0, 1.8 Hz). 13C NMR (CDCl3): 104.7 (d), 114.0
(s(d), JC±Fˆ10 Hz), 117.2(d(d), JC±Fˆ22 Hz), 124.1 (d),
124.4 (d(d), JC±Fˆ4 Hz), 132.3 (d), 134.3 (d), 136.6 (d(d),
JC±Fˆ9 Hz), 161.7 (s(d), JC±Fˆ4 Hz), 162.2 (s(d),
JC±Fˆ264 Hz). Anal. calcd for C10H7FN2O2: C, 58.26; H,
3.42; N, 13.59. Found: C, 58.21; H, 3.42, N, 13.57.
7.1.5. 1-(2-Fluorobenzoyl)-1-hydroxy-1,2,3-triazole (4b).
3b (305 mg, 1.03 mmol) and 10% Pd(C) (32mg) was
dissolved in MeOH (10 mL) and cooled to 08C. The ¯ask
was ®tted with a H2-ballon and stirring was continued at 08C
for 30 min. The mixture was ®ltrated through a plug of
celite and the solvent was evaporated, giving 212 mg
(100%) 4b as slightly yellow crystals. Recrystallization
7.1.9. One-pot synthesis of 1a from 6. 6 (120 mg,
1.43 mmol) was dissolved in THF (4 mL) under N2 and
cooled to 08C before NaH (washed three times with dry
pentane immediately prior to use, 38 mg, 1.6 mmol) was
added and stirring was continued at 08C for 10 min before
1
from MeOH gave white crystals, mp 66±678C. H NMR

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J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
2-chlorobenzoyl chloride (200 mL, 1.57 mmol) was added.
After 45 min at 08C, the mixture was cooled to 2788C and a
freshly prepared solution of lithium t-butyltritylamide
(1.72mmol in 3 mL THF) was added. 21 15 min later the
cooling bath was removed and the mixture was warmed to
rt. At rt, freshly grinded K2CO3 (300 mg, 2.15 mmol) and
DMF (2mL) was added and the mixture was heated to
1008C for 12h. Cooling to rt and work up as described for
4a to 1a gave the crude product which was puri®ed by FC
giving 67 mg (25%) 1a as white crystals, identical to the
material described above.
(1 M, 100 mL) and HCl (4N, 20 mL), and extracted with
CH2Cl2 (3£100 mL). The combined organic phase was
dried (MgSO4) and the solvent was evaporated giving the
crude product as orange crystals. FC (heptane/EtOAc)
yielded 7.98 g (82%) 11 as slightly yellow crystals.
Recrystallization from heptane/EtOAc gave 7.08 g (73%)
colourless crystals, mp 94±958C, Rf (heptane/EtOAc 3:1)
0.35 1H NMR (CDCl3): 6.63 (ddd, 1H, Jˆ8.6, 1.0,
0.4 Hz), 7.27 (td, 1H, Jˆ7.6, 1.0 Hz), 7.49 (d, 1H,
Jˆ1.0 Hz), 7.55 (ddd, 1H, Jˆ8.6, 7.6, 1.7 Hz), 7.64 (d,
1H, Jˆ1.0 Hz), 7.70 (ddd, 1H, Jˆ7.7, 1.7, 0.4 Hz). 13C
NMR (CDCl3): 55.5 (s), 100.5 (s), 113.8 (d), 114.2(s),
125.1 (d), 127.3 (d), 133.9 (d), 134.7 (d), 139.7 (d), 160.2
(s). Anal. calcd for C10H6N3OI: C 38.61, H 1.94, N 13.51.
Found: C 38.87, H 2.01, N 13.50.
7.1.10. 2-(Pyrazol-1-yloxy)-benzonitrile (8a). NaH (60%
in mineral oil, 870 mg, 21.7 mmol) was suspended in DMF
(18 mL) under N2 at rt. 1-Hydroxypyrazole (6) (1.52g,
18.1 mmol) was added in small portions over 5 min. Stirring
was continued at rt for 15 min before 2-¯uorobenzonitrile
(2.16 mL, 19.9 mmol) was added, and the mixture was
heated to 708C. After 3 h, the mixture was cooled to rt
and quenched carefully with sat NH4Cl (20 mL), water
(20 mL) was added and the mixture was extracted with
Et2O (4£25 mL). The combined organic phase was dried
(MgSO4) and the solvent was evaporated. FC (heptane/
EtOAc) yielded 3.14 g (94%) of 8a as a colourless thick
oil that crystallized upon standing, mp 40±418C (heptane/
Et2O), Rf (heptane/EtOAc 3:1) 0.30. 1H NMR (CDCl3): 6.40
(t, 1H, Jˆ2.4 Hz), 6.53 (dd, 1H, Jˆ8.7, 0.6 Hz), 7.23 (td,
1H, Jˆ7.6, 1.0 Hz), 7.45 (dd, 1H, Jˆ2.4, 1.0 Hz), 7.52 (ddd,
1H, Jˆ8.7, 7.6, 1.7 Hz), 7.57 (dd, 1H, Jˆ2.4, 1.0 Hz), 7.69
(dd, 1H, Jˆ7.7, 1.7 Hz). 13C NMR (CDCl3): 100.0 (s), 105.0
(d), 113.4 (d), 114.4 (s), 123.2 (d), 124.6 (d), 133.7 (d),
134.5 (d), 134.5 (d), 160.7 (s). Anal. calcd for C10H7N3O:
C 64.86, H 3.81, N 22.69. Found: C 65.08, H 3.95, N 22.81
7.2. General procedure for I±Mg exchange (11!12a±d)
To at solution of 11 (1 mmol) in THF (4 mL) at 2788C,
iPrMgCl (2.0 M in THF, 0.65 mL, 1.3 mmol) was added
over 1 min. Stirring was continued for 30 min at 2788C
before the electrophile (1.5 mmol) was added. After
15 min the cooling bath was removed and the mixture was
warmed to rt and quenched with sat NH4Cl (10 mL).
Extraction with CH2Cl2 (3£25 mL), drying of the organic
phase (MgSO4) and removal of the solvent in vacuo gave the
crude product, which was puri®ed by FC using heptane/
EtOAc as eluent.
7.2.1. 2-(4-Formylpyrazol-1-yloxy)-benzonitrile (12a).
Following the general procedure with DMF as electrophile.
289 mg 11 gave 129 mg (65%) 12a as a colourless oil, that
solidi®ed upon standing. Crystallization from heptane/
EtOAc gave colourless crystals, mp 918C, Rf (heptane/
EtOAc 1:1) 0.44. 1H NMR (CDCl3): 6.72(d, 1H,
Jˆ8.6 Hz), 7.33 (td, 1H, Jˆ7.6, 1.0 Hz), 7.59 (ddd, 1H,
Jˆ8.6, 7.6, 1.7 Hz), 7.74 (dd, 1H, Jˆ7.7, 1.7 Hz), 7.95 (d,
1H, Jˆ1.0 Hz), 8.15 (d, 1H, Jˆ1.0 Hz), 9.93 (s, 1H). 13C
NMR (CDCl3): 100.9 (s), 114.0 (s), 114.2 (d), 122.1 (s),
125.6 (d), 126.4 (d), 134.0 (d), 134.8 (d), 135.9 (d), 159.5
(s), 183.3 (d). Anal. calcd for C11H7N3O2: C, 61.97; H, 3.31;
N, 19.71. Found: C, 61.80; H, 3.54, N, 19.47.
7.1.11. 2-(4-Bromopyrazol-1-yloxy)-benzonitrile (9). To a
solution of 8a (647 mg, 3.49 mmol) and freshly ground
K2CO3 (720 mg, 5.2 mmol) in CH2Cl2 (10 mL) at 2788C,
Br2 (0.36 mL, 6.98 mmol) was added dropwise. Stirring was
continued for 5 min before the cooling bath was removed.
At rt stirring was continued for 30 min before 1N Na2SO3
(20 mL) was added. Extraction with CH2Cl2 (3£20 mL),
drying of the organic phase (MgSO4) and removal of the
solvent gave 913 mg (99%) 9 as colourless crystals, mp
1
878C (heptane/EtOAc), Rf (heptane/EtOAc 3:1) 0.35. H
7.2.2.
2-(4-Methoxycarbonylpyrazol-1-yloxy)-benzo-
NMR (CDCl3): 6.64 (ddd, 1H, Jˆ8.6, 1.0, 0.4 Hz), 7.28
(td, 1H, Jˆ7.6, 1.0 Hz), 7.43 (d, 1H, Jˆ1.0 Hz), 7.56
(ddd, 1H, Jˆ8.6, 7.6, 1.7 Hz), 7.64 (d, 1H, Jˆ1.0 Hz),
7.70 (ddd, 1H, Jˆ7.7, 1.7, 0.4 Hz). 13C NMR (CDCl3):
92.8 (s), 100.5 (s), 113.8 (d), 114.2 (s), 123.5 (d), 125.2
(d), 133.9 (d), 134.7 (d), 135.3 (d), 160.2(s). Anal. calcd
for C10H6BrN3O: C, 45.48; H, 2.29; N, 15.91. Found: C,
45.77; H, 2.45, N, 16.01.
nitrile (12b). Following the general procedure with
NCCOOCH3 as electrophile. 305 mg 11 gave 239 mg of a
15:1 mixture of 12b and 8a after FC, corresponding to an
isolated yield of 94%. Crystallization from EtOAc/heptane
gave analytically pure 12b as colourless crystals, mp 116±
1
78C, Rf (heptane/EtOAc 3:1) 0.27. H NMR (CDCl3): 3.88
(s, 3H), 6.65 (d, 1H, Jˆ8.6 Hz), 7.26±7.33 (m, 1H), 7.53±
7.60 (m, 1H), 7.72(dd, 1H, Jˆ7.7, 1.7 Hz), 7.88 (d, 1H,
Jˆ1.0 Hz), 8.08 (d, 1H, Jˆ1.0 Hz). 13C NMR (CDCl3): 51.7
(q), 100.8 (s), 113.7 (s), 113.9 (d), 114.1 (s), 125.4 (d), 126.4
(d), 134.0 (d), 134.7 (d), 136.4 (d), 159.9 (s), 162.2 (s). Anal.
calcd for C12H9N3O3: C, 59.26; H, 3.73; N, 17.28. Found: C,
59.29; H, 3.89, N, 17.10.
7.1.12. 2-(4-Iodopyrazol-1-yloxy)-benzonitrile (11). The
procedure described for the preparation of 8a using NaH
(1.50 g,
37.5 mmol),
1-hydroxypyrazole
(2.63 g,
31.3 mmol) and DMF (30 mL) was followed. The crude
product was dissolved in CH2Cl2 (50 mL) and freshly
ground K2CO3 (8.6 g, 62.6 mmol) was added. ICl (10.8 g,
66.3 mmol) dissolved in CH2Cl2 (30 mL) was added to the
mixture. The ¯ask was wrapped in alufoil, ®tted with a
condenser and heated to re¯ux for 1 h (oil bath at 608C).
After cooling to rt the mixture was quenched with Na2SO3
7.2.3. 2-(4-Cyanopyrazol-1-yloxy)-benzonitrile (12c).
Following the general procedure with TsCN (dissolved in
1 mL THF) as electrophile. 563 mg 11 gave 328 mg (86%)
12c as white crystals, mp 1408C (heptane/EtOAc), Rf
1
(heptane/EtOAc 1:1) 0.61. H NMR (CDCl3): 6.74 (br d,

J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
2403
1H, Jˆ8.6 Hz), 7.35 (td, 1H, Jˆ7.6, 1.0 Hz), 7.60 (ddd, 1H,
Jˆ8.6, 7.6, 1.7 Hz), 7.75 (dd, 1H, Jˆ7.7, 1.7 Hz), 7.78 (d,
1H, Jˆ1.0 Hz), 8.08 (d, 1H, Jˆ1.0 Hz). 13C NMR (CDCl3):
92.3 (s), 101.4 (s), 111.7 (s), 113.9 (s), 114.6 (d), 126.1 (d),
128.3 (d), 134.2 (d), 134.8 (d), 138.0 (d), 159.3 (s). Anal.
calcd for C11H6N4O: C, 62.86; H, 2.88; N, 26.65. Found: C,
62.67; H, 3.05, N, 26.52.
71 mg 12d gave 56 mg (79%) 13d as a slightly yellow thick
oil. Crystallization from heptane/EtOAc gave colourless
1
crystals, mp 73±748C, Rf (heptane/EtOAc 3:1) 0.39. H
NMR (CDCl3): 7.25±7.50 (m, 8H), 7.77 (ddd, 1H, Jˆ8.5,
7.7, 1.7 Hz), 8.25 (dd, 1H, Jˆ8.3, 1.7 Hz). 13C NMR
(CDCl3): 113.2 (s), 114.3 (d), 118.3 (s), 125.2 (d), 126.8
(d), 127.1 (s), 127.7 (d), 129.3 (d), 131.0 (d), 133.9 (s),
134.1 (d), 135.6 (d), 156.7 (s), 169.1 (s). Anal. calcd for
C16H10N2O2S: C, 65.29; H, 3.42; N, 9.52. Found: C,
65.03; H, 3.37, N, 9.42.
7.2.4. 2-(4-Phenylsulfanylpyrazol-1-yloxy)-benzonitrile
(12d). Following the general procedure with PhSO2SPh as
electrophile. 291 mg 11 gave 255 mg (93%) 12d as a
colourless oil. Crystlallization from heptane/EtOAc gave
colourless crystals, mp 82±838C, Rf (heptane/EtOAc 3:1)
0.32. 1H NMR (CDCl3): 6.67 (dd, 1H, Jˆ8.6, 0.5 Hz),
7.15±7.32(m, 6H), 7.53 (d, 1H, Jˆ1 Hz), 7.53±7.60 (m,
1H), 7.71 (dd, 1H, Jˆ7.7, 1.7 Hz), 7.74 (d, 1H, Jˆ1 Hz).
13C NMR (CDCl3): 100.6 (s), 108.8 (s), 113.8 (d), 114.2(s),
125.1 (d), 126.1 (d), 127.2 (d), 127.6 (d), 129.1 (d), 133.9
(d), 134.7 (d), 137.0 (s), 139.5 (d), 160.2(s). Anal. calcd for
C16H11SN3O: C, 65.51; H, 3.78; N, 14.32. Found: C, 65.37;
H, 3.92, N, 14.24.
7.3.4.
3-Diphenylphosphanyl-9-oxa-1,9a-diaza-cyclo-
penta[b]naphthalen-4-one (13e). One-pot I±Mg-exchange
and ring closure using (Ph)2PCl as electrophile: 11 (182mg,
0.59 mmol) was dissolved in THF (2.5 mL) and cooled to
2788C before iPrMgCl (2.0 M in THF, 0.38 mL,
0.76 mmol) was added over 1 min. Stirring was continued
for 30 min at 2788C before (Ph)2PCl (0.16 mL, 0.88 mmol)
was added. The cooling bath was removed and the mixture
was allowed to warm to rt over 15 min. After the mixture
reached rt it was cooled to 2788C again, before a freshly
prepared solution of LDA (1.18 mmol) in THF (1 mL) was
added and the cooling bath was removed. At rt the mixture
was worked up as described in the general procedure. FC
yielded 212 mg (98%) 13e as ¯uorescent yellow crystals,
mp 1608C (heptane/EtOAc), Rf (heptane/EtOAc 1:1) 0.72.
1H NMR (CDCl3): 6.93 (d, 1H, Jˆ0.9 Hz), 7.34±7.45 (m,
12H), 7.76 (ddd, 1H, Jˆ8.6, 7.2, 1.7 Hz), 8.20 (ddd, 1H,
Jˆ7.9, 1.7, 0.4 Hz). 13C NMR (CDCl3): 114.3 (d), 115.3
(s(d), JC±Pˆ21 Hz), 118.2 (s), 125.1 (d), 126.8 (d), 128.6
(s(d), JC±Pˆ7 Hz), 129.1 (d), 130.0 (s(d), JC±Pˆ24 Hz),
133.4 (d(d), JC±Pˆ21 Hz), 135.5 (d), 135.7 (s(d),
JC±Pˆ10 Hz), 135.9 (d(d) JC±Pˆ2Hz), 156.8 (s), 169.3 (s).
Anal. calcd for C22H15PN2O2: C, 71.35; H, 4.08; N, 7.56.
Found: C, 71.26; H, 4.21, N, 7.54.
7.3. General procedure for the ring closure of 9, 12c, 12d
and 14 with LDA
The substrate (1 mmol) was dissolved in THF (6 mL) under
N2 and cooled to 2788C before a freshly prepared solution
of LDA (1.3 mmol) in THF (1 mL) was added. The cooling
bath was removed, and the mixture was allowed to warm to
rt over 15 min, during which dramatic colour changes took
place depending on the substrate. At rt the mixture was
quenched with 4N HCl (10 mL) and stirring was continued
for 30 min. Water (20 mL) was added before extraction with
CH2Cl2 (3£25 mL), drying of the organic phase (MgSO4)
and removal of the solvent in vacuo gave the crude products,
which were puri®ed by FC using heptane/EtOAc as eluent.
7.3.5. 2-(4-p-Tolylpyrazol-1-yloxy)-benzonitrile (14). To
a solution of 11 (336 mg, 1.08 mmol) in THF (5 mL) at
2788C, iPrMgCl (2.0 M in THF, 0.70 mL, 1.4 mmol) was
added over 1 min. Stirring was continued for 30 min at
2788C before ZnCl2 (1 M in THF, 3.24 mL, 3.24 mmol)
was added, and the mixture was warmed to rt. At rt,
p-iodotoluene (471 mg, 2.16 mmol) and Pd(PPh3)4 (62mg,
0.054 mmol) in DMF (3.5 mL) was added, and the mixture
was stirred 18 h at rt. Quenching with sat NH4Cl (20 mL)
and extraction with Et2O (4£25 mL), drying of the organic
phases (MgSO4) and removal of the solvent in vacuo gave
the crude product, which was puri®ed by FC using heptane/
EtOAc as eluent giving 239 mg (80%) 14 as colourless
crystals, mp 128±1298C (heptane/EtOAc), Rf (heptane/
7.3.1. 3-Bromo-9-oxa-1,9a-diaza-cyclopenta[b]naphtha-
len-4-one (10). Following the general procedure. 92mg 9
gave 89 mg (89%) 10 as off-white crystals, mp 1878C (hep-
tane/EtOAc), Rf (heptane/EtOAc 3:1) 0.49. 1H NMR
(CDCl3): 7.43 (ddd, 1H, Jˆ8.5, 1.0, 0.5 Hz), 7.46 (ddd,
1H, Jˆ7.9, 7.3, 1.0 Hz), 7.57 (s, 1H), 7.79 (ddd, 1H,
Jˆ8.5, 7.3, 1.7 Hz), 8.28 (ddd, 1H, Jˆ9.7, 1.7, 0.5 Hz).
13C NMR (CDCl3): 92.2 (s), 114.4 (d), 117.9 (s), 125.3
(d), 125.9 (s), 126.8 (d), 133.4 (d), 135.8 (d), 156.6 (s),
168.8 (s). Anal. calcd for C10H5BrN2O2: C, 45.31; H,
1.90; N, 10.57. Found: C, 45.53; H, 2.16, N, 10.28.
7.3.2. 3-Cyano-9-oxa-1,9a-diaza-cyclopenta[b]naphtha-
len-4-one (13c). Following the general procedure. 99 mg
12c gave 82mg (82%) 13c as colourless crystal, mp
1
EtOAc 1:1) 0.71. H NMR (CDCl3): 2.37 (s, 3H), 6.67
(ddd, 1H, Jˆ8.6, 0.9, 0.3 Hz), 7.18±7.23 (m, 2H), 7.24
(td, 1H, Jˆ7.6, 1.0 Hz), 7.37±7.42(m, H2 ), 7.53 (ddd,
1H, Jˆ8.6, 7.6, 1.7 Hz), 7.68 (d, 1H, Jˆ1.2Hz), 7.69
(ddd, 1H, Jˆ7.6, 1.7, 0.4 Hz), 7.78 (d, 1H, Jˆ1.2Hz). 13C
NMR (CDCl3): 20.9 (q), 100.2 (s), 113.7 (d), 114.4 (s),
119.9 (d), 122.3 (s), 124.7 (d), 125.4 (d), 128.1 (s), 129.7
(d), 131.5 (d), 133.8 (d), 134.7 (d), 137.2(s), 160.7 (s). Anal.
calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
73.89; H, 4.62, N, 14.99.
1
2018C (heptane/EtOAc), Rf (heptane/EtOAc 1:1) 0.59. H
NMR (CDCl3): 7.52(d, 1H, Jˆ8.5 Hz), 7.55 (ddd, 1H,
Jˆ8.0, 7.3, 1.0 Hz), 7.89 (ddd, 1H, Jˆ8.6, 7.3, 1.7 Hz),
7.94 (s, 1H), 8.33 (ddd, 1H, Jˆ8.0, 1.7, 0.4 Hz). 13C NMR
(CDCl3): 89.8 (s), 100.9 (s), 114.7 (d), 117.7 (s), 126.2 (d),
126.9 (d), 130.7 (s), 136.7 (d), 137.2 (d), 156.8 (s), 167.3 (s).
Anal. calcd for C11H56N3O2: C, 62.56; H, 2.39; N, 19.90.
Found: C, 62.27; H, 2.42, N, 19.65.
7.3.6. 3-p-Tolyl-9-oxa-1,9a-diaza-cyclopenta[b]naphtha-
len-4-one (15). Following the general procedure. 91 mg
7.3.3. 3-Phenylsulfanyl-9-oxa-1,9a-diaza-cyclopenta[b]-
naphthalen-4-one (13d). Following the general procedure.

2404
J. L. Kristensen et al. / Tetrahedron 58 (2002) 2397±2404
Rampa, A.; Valenti, P.; Palzer, M.; Palusczak, A.; Hartmann,
R. W. J. Med. Chem. 2001, 44, 672±680.
14 gave 78 mg (91%) 15 as colourless crystals, mp 1238C
(heptane/EtOAc), Rf (heptane/EtOAc 3:1) 0.44. H NMR
1
11. Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508±
6509.
(CDCl3): 2.41 (s, 3H), 7.25±7.30 (m, 2H), 7.39±7.45 (m,
2H), 7.68 (s, 1H), 7.72±7.79, m, 3H), 8.25±8.29 (m, 1H).
13C NMR (CDCl3): 21.1 (q), 114.1 (d), 118.4 (s), 122.7 (s),
124.9 (d), 125.3 (s), 126.9 (d), 127.2 (s), 128.8 (d), 129.2
(d), 130.6 (d), 135.4 (d), 138.2(s), 156.3 (s), 169.9 (s). Anal.
calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14. Found:
C, 73.88; H, 4.61, N, 10.15.
12. Familoni, O. B.; Ionica, I.; Bower, J. F.; Snieckus, V. Synlett
1997, 1081±1083.
13. MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.; Snieckus, V.
Synlett 1998, 419±421.
14. A sample of 4b dissolved in DMSO-d6 spontaneously gave 1b
at rt without added base.
15. Crystallographic data (excluding structure factors) for the
structure of 1b have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 171161. Copies of the data can be obtained,
free of charge, on application to CCDC, 12Union Road,
Cambridge, CB21EZ, UK [fax: 144(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We are very grateful to Dr Frederik Krebs at the Danish
Polymer Centre, Risù for obtaining the X-ray structure of
1b.
16. Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935±1937.
17. Freeman, J. P.; Gannon, J. J. J. Org. Chem. 1969, 34, 194±
198.
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