Microwave-assisted solid-phase D?tz benzannulation reaction: A facile synthesis of 2,3-disubstituted-1,4-naphthoquinones

Article abstract of DOI:10.1016/j.tetlet.2005.08.158

A microwave-assisted solid-supported D?tz benzannulation of chromium carbene complexes with various alkynes has been developed. The oxidative cleavage of the resulting resin-bound 1,4-naphthols affords 2,3-disubstituted-1, 4-naphthoquinone derivatives in good to moderate yields with high purities.

Full text of DOI:10.1016/j.tetlet.2005.08.158

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7545–7548
¨
Microwave-assisted solid-phase Dotz benzannulation reaction:
a facile synthesis of 2,3-disubstituted-1,4-naphthoquinones
Muthian Shanmugasundaram, Israel Garcia-Martinez, Qingyi Li, Abril Estrada,
Nancy E. Martinez and Luis E. Martinez*
Department of Chemistry, University of Texas at El Paso, 500 West University Ave., El Paso, TX 79968, USA
Received 22 May 2005; revised 27 August 2005; accepted 30 August 2005
Available online 13 September 2005
Abstract—A microwave-assisted solid-supported Do¨tz benzannulation of chromium carbene complexes with various alkynes has
been developed. The oxidative cleavage of the resulting resin-bound 1,4-naphthols affords 2,3-disubstituted-1,4-naphthoquinone
derivatives in good to moderate yields with high purities.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Transition metal-mediated reactions are extremely
appealing for solid-phase organic synthesis (SPOS) due
to their versatility, wide-ranging functional group com-
patibility and potential for synthesizing biologically ac-
tive lead compounds. Although a wide range of Pd-
mediated coupling reactions and transition metal-cata-
lyzed olefin metathesis reactions have been utilized in
SPOS,1 the development of transition metal carbene
chemistry remains relatively unexplored. Notable
among transition metal carbene chemistry is the Do¨tz
benzannulation of Fischer carbene complexes with
alkynes to form substituted phenols.2–4 While the Do¨tz
benzannulation has been extensively applied to synthe-
size a diverse array of natural products,3 no examples
of its application to combinatorial library synthesis have
yet been reported.
solid-phase peptide synthesis, their application to SPOS
remains unexplored. Herein, we report the first example
of the solid-supported Do¨tz benzannulation reaction
and subsequent oxidative cleavage leading to biologi-
cally active 2,3-disubstituted-1,4-naphthoquinone deriv-
atives in good to moderate yields.
Modifying the method originally developed by Connor
and co-workers,8 the synthesis of polymer-supported
Fischer carbene complex 2 was obtained in four steps
(Scheme 1) from commercially available chromium
hexacarbonyl and phenyllithium by O-acylation of
[tetramethylammonium][(2-phenyl)oxidocarbene]penta-
carbonylchromium 1 with acetyl chloride followed by
_
+
Due to the mechanistic complexity of the reaction, the
product distribution of the Do¨tz benzannulation can
vary among naphthol, indene, furan, and cyclobutanone
products by slightly modifying reaction conditions such
as the solvent, Fischer carbene, and alkyne concentra-
tions and the nature of the alkyne.5 Although there is
precedent for the preparation of solid-supported triphe-
nyl phosphine6 Fischer carbene complexes and the
application of a soluble Fischer carbene complex7 to
OMe4N
1. Cr(CO)6, THF, 0 °C, 2 h
2. Me4NBr, water, 0 °C, 2h
PhLi
Cr(CO)5
1
1. CH3COCl,
DCM, 0 °C, 1 h
O
Cr(CO)5
2. PL-Wang resin,
DCM, rt, 3 h
2
Keywords: Solid-phase synthesis; Microwave; Do¨tz reaction; 1,4-
Naphthoquinones; Fischer carbenes.
=
O
*
Corresponding author. Tel.: +1 915 747 5944; fax: +1 915 747
5748; e-mail: luisem@utep.edu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.158

7546
M. Shanmugasundaram et al. / Tetrahedron Letters 46 (2005) 7545–7548
reaction with PL-Wang resin (Polymer Laboratories, 1%
crosslinked 1.7 mmol/g) to produce resin-bound Fischer
carbene complex 2 in 95% loading as determined by ele-
mental analysis.9 Resin loading of the carbene complex
can be easily monitored qualitatively by colorimetric
analysis, the beads turn to a dark red color. The appear-
ance of characteristic Cr–CO stretches at 2061 and
1944 cmÀ1 in the IR spectrum of 2 corresponds to CO
stretches found in analogous aryl carbene complexes.10
naphthols 4a–l (Scheme 2).12 Table 2 illustrates that var-
ious aryl and alkyl substituted alkynes produce 1,4-
naphthoquinones 5a–i in moderate to good yields (en-
tries 1–9) with aryl substituted acetylenes producing
2,3-disubstituted-1,4-naphthoquinones in slightly higher
yields than alkyl substituted acetylenes. In contrast to
the solution-phase benzannulations, the solid-supported
Do¨tz benzannulation reaction cleanly produces the qui-
none product without the indene, indenone, or cyclobu-
tenone side products typically seen in these reactions as
evidenced by GC, 1H NMR, and mass data. An oxidized
product of unreacted resin-bound Fischer carbene com-
plex 2, benzoic acid, was the only side product.13
The reaction of 2 with 1-octyne (3e), followed by the
oxidative cleavage of the resulting resin-bound phenol
4e using cerium(IV) ammonium nitrate (CAN), provides
a useful model system for reaction optimization of the
solid-supported Do¨tz benzannulation reaction (Table
1). In contrast to traditional thermal and a recently re-
ported microwave-assisted11 Do¨tz benzannulation with
soluble Fischer carbene complexes, CH2Cl2 was the
optimal solvent affording 5e in 63% yield (entry 1).
While other solvents, such as acetonitrile, THF, toluene,
and heptane, were also effective for the exclusive forma-
tion of 5e under microwave conditions (entries 2–5), the
use of butyl ether or DMF was less effective (entries 6
and 7). A brief examination of the effect of temperature
on the reaction revealed that 85 ꢁC was found to be the
optimum temperature (entry 1 and entries 8–10) and
extending the reaction time had little influence on the
yield of 5e (entry 1 and entries 11–13). The same reac-
tion can be carried out under traditional thermal condi-
tions with comparable yields (5e, 58% yield: entry 14);
however, there is substantial 6-fold shortening of reac-
tion times for the microwave conditions over traditional
thermal conditions.
The present solid-supported Do¨tz reaction tolerates
alcohol and ester functionality on the alkyne (entries
10 and 11) and produces the corresponding 1,4-naph-
thoquinones in moderate yield. It is noteworthy that 5j
serves as a key intermediate for the synthesis of pyrano-
naphthoquinone, which has significant antitumor activ-
ity.14 To further explore the synthetic scope of the
reaction, the reaction was extended to conjugated
diynes. In contrast to the solution-phase Do¨tz benzann-
ulation with conjugated diynes,15 the reaction of 1,4-
diphenyl butadiyne (3l) with 2 under our standard
conditions cleanly afforded the mono benzannulation
product 2-phenyl-3-phenylethynyl-[1,4]naphthoquinone
O
R1
O
R1
CH2Cl2, MW
Cr(CO)5 +
R2
Cr(CO)3
85 °C, 20 min
R2
Under optimized conditions, the Do¨tz benzannulation
of 2 was performed with various alkynes 3a–l followed
by the oxidative cleavage of the resulting resin-bound
OH
O
2
3a-l
CAN, CH2Cl2/H2O
rt, 12 h
4a-l
R1
Table 1. Effects of solvent, temperature, and time on the solid-
supported Do¨tz benzannulation reaction of 2 with 1-octyne (3e),
followed by the oxidative cleavage of resin-bound intermediate 4ea
R2
O
5a-l
Entry Solvent
Temp (ꢁC) Time (min) Yield of 5e (%)b
Scheme 2.
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
THF
Toluene
Heptane
Butylether
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
85
85
85
85
85
85
85
135
110
60
20
20
20
20
20
20
20
20
20
20
50
30
10
120
63
61
58
56
55
40
35
50
35
50
61
61
57
58
Table 2. Results of the microwave-assisted solid-phase Do¨tz benzan-
nulation of 2 with various alkynes 3a–l, followed by the oxidative
cleavage using CAN
Entry
Alkyne
Product
R1
R2
Yield (%)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
Ph
H
Me
H
H
Ph
Ph
Ph
76 (99)
67 (98)
62 (99)
58 (97)
63 (97)
62 (97)
55 (96)
50 (96)
57 (99)
50 (93)
42 (98)
68 (95)
9
10
11
12
13
14c
85
85
85
85
C5H11
C6H13
C7H15
C3H7
C6H7
C3H7
C3H6OH
CO2Et
C„CPh
H
3g
3h
3i
5g
5h
5i
C3H7
Me
C2H5
H
C2H5
Ph
a Reactions of 2 (0.115 mmol) with 1-octyne (0.575 mmol) were carried
out in the microwave at the specified temp for the specified time in
2.00 mL of the specified solvent followed by the oxidative cleavage of
the resin using CAN (0.575 mmol).
9
10
11
12
3j
5j
3k
3l
5k
5l
b Isolated overall yields were calculated based on the loading of PL-
Wang (1.7 mmol/g) by the supplier. Purity is >95% as determined by
1H NMR spectroscopy.
a Isolated overall yields were calculated based on the loading of PL-
Wang (1.7 mmol/g) by the supplier. Values given in parentheses
represent purity of products as determined by GC.
c No microwave irradiation was employed.

M. Shanmugasundaram et al. / Tetrahedron Letters 46 (2005) 7545–7548
7547
(5l) in 68% yield (entry 12) without any intermolecular
double benzannulation or cyclobutenone product
formed.
dilute base or by passage through a basic solid-phase
extraction (SPE) column. Third, in contrast to the solu-
tion-phase Do¨tz benzannulation, the purification proce-
dure for the present solid-supported methodology is
quite simple and requires no column chromatography.
The 1,4-naphthoquinone derivatives display a broad
spectrum of biological activities16 and preliminary
screening of these compounds in our laboratories has
showed significant cyctotoxic17 and antimycobacterial
activities.18
To understand the regioselectivity of the solid-supported
Do¨tz benzannulation, the reaction with o-methoxyphe-
nyl Fischer carbene complex 8, synthesized as described
in Scheme 3, was investigated. Under our standard con-
ditions (Scheme 4), the reactions of 8 with unsymmetri-
cal acetylenes 1-pentyne (3k) and phenylacetylene (3b)
were highly regioselective and the regiochemistry was
same as that of the solution-phase chemistry, affording
the corresponding 2-substituted 1,4-naphthoquinone as
the sole product by GC (9a: 70% yield—98% purity,
9b: 80% yield—97% purity).5b
In summary, we have developed a new resin-bound
Fischer carbene of chromium complexes. The solid-sup-
ported Do¨tz benzannulation reaction followed by CAN
cleavage allows an efficient synthesis of various 1,4-
naphthoquinone derivatives in good to moderate yields.
Further work in our laboratories is to utilize this meth-
odology for the preparation of libraries of structurally
diverse compounds, including natural products, and
the screening of these compounds against a variety of
biological targets is currently underway.
Several interesting features are noteworthy from this
study. First, the present solid-supported Do¨tz reaction
is highly insensitive to the nature of the solvents (Table
1, entries 1–7). Irrespective of the solvent under our
standard conditions, the reaction afforded the single
1,4-naphthoquinone product and no other product
was seen in the 1H NMR spectrum. This is in sharp con-
trast to the solution-phase chemistry in which the Do¨tz
reaction is highly solvent dependent. For example, the
solution-phase reaction of phenyl Fischer carbene
complex with diphenyl acetylene using heptane as the
solvent at 80 ꢁC for 30 min followed by the CAN
oxidation afforded four different products,5b whereas
the present solid-phase reaction of 2 with diphenyl acet-
ylene using heptane as the solvent under microwave as
well as thermal conditions afforded single product 5a
with 98% purity in 60% and 63% yields, respectively.
Second, the only side product, benzoic acid, can be eas-
ily removed from the reaction mixture by washing with
Acknowledgments
This work was supported by the National Institute of
Health (MBRS-SCORE 2S06 GM-801233 and NIAID
U54 Al057156), the Robert A. Welch Foundation, a Re-
search Corporation Cottrell College Science Award, and
the UTEP University Research Institute. Q.L. was sup-
ported by a UTEP Border Health Research Grant and a
Graduate School Award of UTEP. A.E. was supported
by a MARC U*STAR grant (5T34 GM-8048).
References and notes
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_
+
1. n-BuLi, THF, 0 0C, 2h
OMe OMe4N
OMe
2. Cr(CO)6, THF, 0 0C, 2 h
Cr(CO)5
Br
3. Me4NBr, water, 0 0C, 2h
6
7
1. CH3COCl,
O
DCM, 0 0C, 1 h
Cr(CO)5
OMe
2. PL-Wang resin,
DCM, rt, 3 h
8
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O
OMe O
O
R1
1. DCM, MW,
R1
R2
85 0C, 20 min
Cr(CO)5
+
2. CAN, CH2Cl2/H2O,
rt, 12 h
OMe
R2
8
3
9a,b
9a: R1 = H, R2 = C3H7 70%
9b: R1 = H, R2 = Ph
80%
Scheme 4.

7548
M. Shanmugasundaram et al. / Tetrahedron Letters 46 (2005) 7545–7548
Do¨tz, K. H.; Assenmacher, W.; Hoffbauer, W.; Husing,
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N.; Nieger, M.; Pfeiffer, J.; Popall, M.; Schubert, U.;
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none derivatives 5a–l. To a microwave process vial
(10.0 mL), resin 2 (100 mg, 0.115 mmol) was added and
the vial was sealed with an aluminum/Teflon crimp top.
Then, a solution of alkyne 3 (0.575 mmol) in dry CH2Cl2
(2.0 mL) was added under Nitrogen atmosphere. The
reaction mixture was subjected to microwave irradiation
(Biotage EmrysTM Optimizer—300 W maximum power) at
80 ꢁC for 20 min. The reaction mixture was filtered and the
resin was washed sequentially with CH2Cl2 (2 · 50 mL),
THF (1 · 25 mL), and CH2Cl2 (1 · 25 mL) and dried
under vacuum for 1 h to afford resin-bound naphthols 4a–
l. Resin-bound naphthols 4a–l (0.115 mmol) were sus-
pended in a mixture of 3.0 mL of CH2Cl2 and ceric
ammonium nitrate (0.315 g, 0.575 mmol) in 1.0 mL of
water. The resulting suspension was stirred for 12 h and
then filtered through a fritted glass funnel. The resin was
washed with water (5.0 mL) and CH2Cl2 (5.0 mL). The
resulting clear solution was washed with 10% NaOH
(2 · 5 mL) and water (10.0 mL). The organic layer was
dried over MgSO4 and filtered. The solvent was removed
under vacuum to afford pure 1,4-naphthoquinones 5a–l.
13. Bernasconi, C. F.; Flores, F. X.; Kittredge, K. W. J. Am.
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9. Preparation of resin-bound Fischer carbene complex 2:
Chromium hexacarbonyl (3.00 g, 13.6 mmol) and dry
THF (20.0 mL) were placed in a 100 mL two-necked
round bottom flask under N2 atmosphere. The flask was
cooled to 0 ꢁC and
a solution of phenyllithium
(20.5 mmol, 1.9 M in cyclohexane-ether, 10.8 mL) was
slowly added over a period of 20 min and allowed to stir
for 2 h. The solvent was removed under vacuum and the
resulting orange red residue was added to a solution of
tetramethyl ammonium bromide (4.19 g, 27.2 mmol) in
20.0 mL of oxygen-free water. The reaction mixture was
allowed to stir at 0 ꢁC for 2 h. The product was extracted
with dry CH2Cl2 (2 · 50 mL) and the combined organic
extracts were dried over anhydrous magnesium sulfate.
The solvent was concentrated under vacuum to afford
4.64 g (92%) of crude 1 as a red solid. To a stirred solution
of crude red solid 1 (4.64 g, 12.5 mmol) in 10.0 mL of
CH2Cl2 at 0 ꢁC, acetyl chloride (1.27 g, 16.3 mmol) was
added. After stirring at 0 ꢁC for 1 h, the reaction mixture
was allowed to warm to room temperature immediately.
The solvent and the unreacted acetyl chloride were
removed under reduced pressure. The bright red
solid was diluted with 20.0 mL of CH2Cl2 and this
solution was transferred via cannula to a 50.0 mL fritted
funnel (solid-phase peptide synthesizer) containing poly-
styrene PL-Wang resin (1.47 g, 2.5 mmol–1.7 mmol/g
specified by manufacturer). The reaction mixture was
shaken on a wrist shaker at room temperature for 3 h,
after which the mixture was filtered and the resin was
washed sequentially with CH2Cl2 (2 · 50 mL), THF
(1 · 25 mL), and CH2Cl2 (1 · 25 mL) and dried under
vacuum to constant weight to give 2.17 g resin-bound
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complex 2 as a red solid. IR (KBr) 2061, 1944 cmÀ1
.
(Found: Cr, 5.67%. 95% loading @ 1.7 mmol/g requires
Cr, 5.99%).
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