High-load, soluble oligomeric benzenesulfonyl azide: Application to facile diazo-transfer reactions

Article abstract of DOI:10.1016/j.tet.2005.08.120

The development of a high-load, soluble oligomeric sulfonyl azide using ROM polymerization is reported. The utility in diazo transfer reactions with active methylene compounds is demonstrated using an efficient protocol, with most reactions showing completion in 30 min. The sulfonamide byproduct, being insoluble in the reaction solvent, can be completely removed by simple filtration through a silica gel SPE cartridge.

Full text of DOI:10.1016/j.tet.2005.08.120

Tetrahedron 61 (2005) 12093–12099
High-load, soluble oligomeric benzenesulfonyl azide: application
to facile diazo-transfer reactions
Andrew M. Harned,a,b W. Matthew Sherrill,a,b Daniel L. Flynnb, ,† and Paul R. Hansona,b,
*
*
aDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
bKU Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 1501 Wakarusa Drive,
Lawrence, KS 66047, USA
Received 20 June 2005; revised 7 August 2005; accepted 7 August 2005
Available online 2 November 2005
Abstract—The development of a high-load, soluble oligomeric sulfonyl azide using ROM polymerization is reported. The utility in diazo
transfer reactions with active methylene compounds is demonstrated using an efficient protocol, with most reactions showing completion in
30 min. The sulfonamide byproduct, being insoluble in the reaction solvent, can be completely removed by simple filtration through a silica
gel SPE cartridge.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ring-opening metathesis (ROM) polymerization,3,4 has
emerged as a powerful means of generating high-load,
immobilized reagents with tunable properties that circum-
vent many of the problems associated with conventional
immobilized reagents. There are several salient features that
make ROM polymers ideal supports for reagents. First,
ROM polymerization is a very versatile technique in that the
properties of the generated polymers can be readily
modified by the addition of comonomers or cross-linking
agents as well as by changing which catalyst is employed.
Second, because noncrosslinked oligomers are often soluble
in organic solvents, slow reaction kinetics can be avoided.
Third, the ROM polymers are often insoluble in methanol
and do not pass through silica gel columns, thereby
minimizing purification. Lastly, because ROM polymer-
ization is highly functional group tolerant, active polymeric
reagents can often be formed directly from the correspond-
ing monomer, minimizing the need for functionalizing the
polymer itself. Furthermore because each polymerized
monomer contains an active functional group, this technique
has potential to generate very highly loaded polymers. In
addition, ease of monomer production should not be
overlooked, as most monomers are accessible through
Diels–Alder or reductive Heck chemistry. To this end, we
now report the development and utility of a high-load,
soluble oligomeric sulfonyl azide using ROM
polymerization.
The growing demand for facilitated synthesis protocols to
aid in drug discovery has directed efforts aimed at
integrating the sciences of organic synthesis and purifi-
cation. Towards this goal, the production of designer
polymers with tunable properties has become a powerful
technological advancement in the arena of facilitated
synthesis. In this context, an array of polymer-bound
reagents and scavengers1 has appeared, effectively stream-
lining synthetic methods to simple mix, filter and evaporate
protocols. The hallmark of these methods is that they avoid
the use of insoluble polymers during the actual synthesis,
yet retain the virtues of both solution-phase and solid-phase
approaches. Despite advances in this area, limitations in
reaction homogeneity (nonlinear reaction kinetics), low
resin-load capacities, and means of distributing reagents,
continue to warrant the development of new polymers for
library production.
In order to address these limitations, novel soluble polymers
have surfaced as a means of utilizing solution-phase
reaction kinetics with all the advantages of their solid
phase counterparts.2 In the course of these developments,
Keywords: Sulfonyl azide; Ring-opening metathesis polymerization
(ROMP); Diazo transfer; High-load polymer; Soluble polymer; Supported
reagents.
*
Corresponding authors. Tel.: C1 785 864 3094; fax: C1 785 864 5396;
e-mail: phanson@ku.edu
Diazo compounds are important intermediates in organic
synthesis.5 Of particular interest is the rich chemistry
associated with their transition metal-catalyzed reactions.6
† Present address: Deciphera Pharmaceuticals, LLC, 4950 Research Park
Way, Lawrence, KS 66047.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.120

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A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
Scheme 1.
While many methods exist for synthesizing these com-
pounds,7 one of the most popular is through the reaction of
an enolate or active methylene compound with a sulfonyl
azide, typically tosyl azide (Scheme 1). While these
methods have proven to be very reliable, at times they
can be problematic due to stoichiometric amounts of
p-toluenesulfonamide that are produced.
via construction from cheap, readily available materials,
thereby allowing for use in large-scale reactions. It was our
belief that a ROM polymer-based sulfonyl azide would
satisfy all of these requirements. We describe herein our
development of such a reagent and its utility in diazo
transfer reaction with active methylene compounds.
Several researchers have attempted to solve these problems
by developing alternatives to p-toluenesulfonyl azide8 or to
generate the reagent in situ.9 However, all of these
approaches have been designed with an eye towards
‘large scale’ synthesis and still require purification of the
diazo compound away from the sulfonamide byproduct.
Surprisingly there have only been a few scattered reports on
the use of polymeric sulfonyl azides,10,11 a potentially useful
strategy for parallel synthesis that would limit purification to
a simple filtration step. These examples have focused on the
use of insoluble polystyrene-based polymers. To the best of
our knowledge, there are no examples of using soluble,
high-load polymers to eliminate impurities from diazo
transfer reactions. We felt that one way to facilitate the
purification of these compounds would be through
construction of a polymeric sulfonyl azide. Ideally, such a
polymeric reagent would possess the following attributes:
(1) high-load capacity, (2) broad solubility profile, allowing
for delivery of the reagent via cannula, (3) facile removal
from the reaction products, and (4) convenient availability
2. Results and discussion
Our initial approach to an oligomeric sulfonyl azide began
with a reductive Heck reaction12 between norbornadiene (1)
and sodium p-bromobenzenesulfonate (2),13 followed by
chlorination of the resulting sulfonate 3 (Scheme 2). While
the reductive Heck reaction proceeded smoothly, problems
were encountered in attempting to convert sulfonate 3 into
sulfonyl chloride 4. Various standard reaction conditions
were attempted, but all resulted in general decomposition of
sulfonate 3. We attribute this to adverse reactions occurring
with the norbornene ring system.
In order to circumvent this problem, we decided to employ a
Diels–Alder reaction to construct the requisite norbornenyl-
tagged sulfonyl chloride. To this end, commercially
available sodium 4-styrenesulfonate (5) was treated
with SOCl2 to form sulfonyl chloride 6 (Scheme 3).14
Initial attempts at reacting purified sulfonyl chloride 6 with
cyclopentadiene were unsuccessful as this compound
Scheme 2.
Scheme 3.

A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
12095
spontaneously polymerizes when concentrated and purified.14
However, we found that when 6 was utilized directly after its
formation, it smoothly reacted with cyclopentadiene to form
Diels–Alder adduct7. Byusing thismethod, we couldproduce
7 on a multi-gram scale with an 8:1 exo/endo mixture as
determined by 1H NMR of the isolated material.
subsequently found that reacting 8 with NaN3 in THF, in the
presence of 2 mol% Hex4NCl,19 cleanly produced the desired
sulfonyl azide 9. This oligomeric sulfonyl azide (2GOSA30)20
has a theoretical yield of 3.6 mmol/g, and was found to be
soluble in CH2Cl2, CHCl3 (partially), THF, and DMF, but
insoluble in heptane, methanol, acetonitrile, benzene, ethyl
acetate, and Et2O. We found that while OSA could be
produced on O1 g scale, it underwent slow, nonviolent
decomposition even if kept in the refrigerator. Best results
were obtained if the polymer was used within 1–2 weeks of
preparation. We believe this instability is due to the trace Ru
impurities in oligomer 8.18 Several alternative purification
methods were attempted to further purify oligomer 8 but were
abandoned due to cost (large scale size exclusion chromato-
graphy) or decomposition during extended periods in solution
(dialysis in THF or CH2Cl2 over several days).
The diastereomeric mixture was not separated, and was found
to polymerize readily with 1.6 (60-mer), 2.0 (50-mer), and
3.3 mol% (30-mer) using the second generation Grubbs
catalyst [(IMesH2)(PCy3)(Cl)2RuZCHPh; cat-2G].15 Sub-
sequent quenching with ethyl vinyl ether (EVE), and
precipitation from heptane, yielded the oligomeric sulfonyl
chloride (OSC) 816,17 as a free-flowing, light grey solid.18 This
oligomer was found to have a diverse solubility profile, as it
was soluble in CH2Cl2, THF, and DMF while remaining
insoluble in benzene, heptane, ether, acetone, and acetonitrile.
Interestingly, the solubility in CHCl3 could be altered simply
by altering the length of the polymer formed (i.e., by changing
the amount of catalyst). Oligomers produced with 3.3 mol%
cat-2G were completely soluble in CHCl3, while those
produced with 1.6 and 2.0 mol% cat-2G were insoluble.
Despite the absence of long-term stability, oligomer 9 was
found to efficiently participate in diazo transfer reactions with
various active methylene substrates (Table 1). Most reactions
were found to be complete within 30 min as judged by TLC.
We were pleased to find that product 11 (entry 1) could be
produced in high yield and purity,21 even on 200 mg scale.
Thisdiazo phosphonate has proven to be a usefulalternative to
the Seyferth–Gilbert reagent in the conversion of aldehydes to
terminal alkynes.22,23
Initial attempts at forming sulfonyl azide 9 centered on
reacting 8 with NaN3 in DMF. While this method did form the
desired sulfonyl azide, we observed inconsistent results
when subsequent diazo transfer reactions were attempted.
This may be due to reaction between DMF and polymer 8;
forming a Wilsmeyer–Haack-type product. However, it was
In practice, 9 was added as a solid to a CH2Cl2 solution of
the substrate and KOtBu. Because the diazo transfer in this
Table 1.
Entry
1
Product
Time (min)
120
Yielda (%)
Purityb (%)
97c
O95d
2
3
30
30
88
75
O95
O95
4
5
30
30
74
90
O95e
O90
a All reactions performed on 0.2–0.26 mmol scale, with addition of 1.5 equiv 9 as a solid, unless otherwise noted.
1
b Purity by H NMR of crude isolated products.
c Performed on 1 mmol scale.
d Contained 5% diethyl diazomethylphosphonate.
e Contained 7% starting material.

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A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
Scheme 4.
addition, changing base to Et3N), but to no avail. It is
interesting to note that this was not observed in the case of
5,5-dimethyl-1,3-cyclohexanedione (dimedone) (Table 1,
entry 5). Perhaps there is a steric effect involved with the
enolates derived from 16a,b that is not felt with the flat
enolate generated from dimedone.
Figure 1. Silica gel SPE cartridge affixed to SPE manifold before filtering
reaction (left), and after filtration (right).
3. Conclusion
system is so efficient, the polymeric sulfonyl azide is rapidly
converted into polymeric primary sulfonamide 10, which is
not soluble in CH2Cl2. Due to this insolubility issue, the
sulfonamide byproduct could be completely removed from
the reaction products simply by filtering through a silica gel
solid-phase extraction (SPE) cartridge and washing with
EtOAc. As can be seen in Figure 1, the SPE cartridge retains
all precipitated polymer, while the isolated filtrate is
completely clear. Using this simple workup, all diazo
products were isolated in high yield and excellent purity as
judged by GC and 1H NMR, which indicated an absence of
any polymeric material (Fig. 2).
In conclusion, we have constructed a high-load, oligomeric
sulfonyl azide and demonstrated its utility in diazo transfer
reactions with active methylene compounds. This system is
extremely efficient with most reactions showing completion
in 30 min. The sulfonamide byproduct, being insoluble in
the reaction solvent, can be completely removed by a simple
filtration through a silica gel SPE cartridge. Application of
this reagent in the synthesis of synthetically relevant diazo
compounds, as well as in other reaction types are being
investigated and will be reported in due course.
4. Experimental
Interestingly, with dibenzoylmethane (16a) and 1-benzoyl-
acetone (16b), the reaction took a different course
(Scheme 4). In these cases, an ‘azo coupling’ reaction
took place to generate azo compounds 18a,b. This type of
reaction has been reported by Regitz and Stadler by utilizing
0.5 equiv of TsN3.24 Various attempts were made to
circumvent these spurious results (changing order of
4.1. General methods
All air and moisture sensitive reactions were carried out
in flame- or oven-dried glassware under argon using
standard gas-tight syringes, cannulas, and septa. CH2Cl2,
Figure 2. 1H NMR spectrum of crude 11.

A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
12097
THF, Et2O, CH3CN, and toluene were purified by passage
through a Solv-Tek (www.solvtek.com) purification system
employing activated Al2O3 (Pangborn, A. B.; Giardello,
M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518). Benzene was purified by
distillation over CaH2. Et3N was purified by passage
through a column of basic alumina and stored over KOH.
The second-generation Grubbs metathesis catalyst was
obtained from Materia, Inc. and used without further
purification. Thin layer chromatography was performed on
silica gel 60F254 plates (EM-5717, Merck). Visualization of
TLC spots was effected using KMnO4 stain. Flash column
chromatography was performed with Merck silica gel (EM-
9385-9, 230–400 mesh). Deuterochloroform (CDCl3) was
resubjected to flash chromatography] afforded 7 (24.52 g,
71%) as a slightly yellow solid (8:1 endo/exo mixture). TLC
(5:1 heptane/EtOAc) Rf 0.11; IR (thin film) 3059, 2968,
1589, 1375, 1175 cmK1
.
Major endo isomer: 1H NMR (400 MHz, CDCl3) 7.87
(d, 2H, JZ8.1 Hz), 7.35 (d, 2H, JZ8.5 Hz), 6.32 (dd, 1H,
JZ5.6, 3.1 Hz), 5.76 (dd, 1H, JZ5.6, 2.8 Hz), 3.49 (ddd,
1H, JZ8.6, 4.0, 4.0 Hz), 3.12 (br s, 1H), 3.02 (br s, 1H),
2.26 (ddd, 1H, JZ12.7, 9.4, 3.8 Hz), 1.56 (br d, 1H, JZ
8.3 Hz), 1.51 (br d, 1H, JZ8.1 Hz), 1.33 (ddd, 1H, JZ11.9,
4.4, 2.5 Hz); 13C NMR (100 MHz, CDCl3) 154.0, 141.4,
138.0, 132.1, 129.2, 126.4, 50.3, 48.8, 44.0, 43.2, 33.0.
purchased from Cambridge Isotope Laboratories and stored
over molecular sieves (4 A) at rt. H and 13C NMR spectra
˚
Minor exo isomer: 1H NMR (400 MHz, CDCl3) 7.94 (d, 2H,
JZ8.0 Hz), 7.49 (d, 2H, JZ8.5 Hz), 6.27 (dd, 1H, JZ5.6,
3.0 Hz), 6.22 (dd, 1H, JZ5.8, 2.8 Hz), 3.02 (br s, 1H), 2.97
(br s, 1H), 2.81 (dd, 1H, JZ7.4, 7.4 Hz), 2.26 (ddd, 1H, JZ
12.7, 9.4, 3.8 Hz), 1.56 (br d, 1H, JZ8.3 Hz), 1.51 (br d, 1H,
JZ8.1 Hz), 1.33 (ddd, 1H, JZ11.9, 4.4, 2.5 Hz); 13C NMR
(100 MHz, CDCl3) 155.2, 141.3, 137.7, 136.8, 128.7, 126.9,
47.8, 45.7, 44.1, 42.3, 33.9.
1
were recorded in CDCl3 (unless otherwise mentioned) on
either a Bruker DRX-400 MHz spectrometer operating at
400 and 100 MHz, respectively; or a Bruker Avance-
500 MHz spectrometer operating at 500 and 126 MHz,
respectively, and references to residual CHCl3 peaks (7.26
and 77.0 ppm for 1H and 13C, respectively). High resolution
mass spectrometry (HRMS) and FAB spectra were
performed by the Mass Spectrometry Laboratory at the
University of Kansas using a VG Instrument ZAB double-
focusing mass spectrometer. Inductively coupled plasma
mass spectrometry (ICPMS) was performed using a VG
PlasmaQuad IICXS inductively coupled plasma mass
spectrometer and run against calibration standards (1, 5,
10, 50 and 100 ppb) which were made from commercial Ru
stock solution (provided in 10% HCl) by diluting with
distilled 6 N nitric acid to the same acid strength as the
samples. Prior to analysis, samples were weighed (w5 mg)
into screw-top glass vials and 0.3 mL 4:1 H2SO4/35% aq
H2O2 was added. Caution: this mixture is extremely
corrosive. The 35% aq H2O2 should be added extremely
slowly with the temperature of the mixture not allowed to
rise above 50–60 8C. Once dissolution was complete
(1–2 days), the samples were dissolved in 3 mL of distilled
6 N HNO3 acid, capped, and placed on a 50 8C hot plate for
1–2 days. The samples were then cooled and transferred to
acid-cleaned high-density polyethylene bottles, sonicated
for one hour, and diluted to a total volume of approximately
100 mL with distilled acid and distilled-deionized water to a
final acid concentration of about 2%.
4.1.2. Formation of oligomeric sulfonyl chloride (8). A
flask was charged with 7 (8.5814 g, 31.9 mmol) and CH2Cl2
(100 mL) was added. The mixture was degassed with argon
for 20 min. Catalyst 2G was added (895 mg, 1.05 mmol)
and the solution was heated to 50 8C. The reaction was
monitored by TLC (8:1 heptane/EtOAc) and upon
completion (about 30 min), the solution was cooled to rt
and 20 mL ethyl vinyl ether (EVE) was added. The mixture
was stirred for 1 h and then added to 3 L heptane via cannula
with stirring. The precipitate was allowed to settle and the
supernatant was then decanted through a fritted glass funnel.
The precipitate was washed with three 500 mL portions of
10:1 heptane/CHCl3 followed by heptane. Oligomer 8
(8.6396 g, 99%) was collected as a free-flowing, light grey
solid: IR (thin film) 3059, 2943, 1589, 1411, 1373, 1173,
1084, 972, and 837 cmK1
.
4.1.3. Formation of oligomeric sulfonyl azide (9). To a
mixture of 8 (1.0124 g, 3.77 mmol) and Hex4NCl (35.9 mg,
0.0826 mmol) in THF (10 mL), was added NaN3 (394.3 mg,
6.07 mmol). Caution: NaN3 should not be measured out
with metal utensils. The end of a glass pipette was always
used to weigh the necessary amount. The heterogeneous
mixture was stirred at rt for 15 h. The reaction was then
added to a stirred mixture of H2O/MeOH (70 mL/30 mL).
The precipitate was filtered with a coarse glass frit and
washed with H2O, MeOH, and heptane to afford oligomer 9
(1.0745 g, 99%) as a brown solid. Caution: while we have
had no problems with handling oligomer 9, safety shields
should be utilized when handling large quantities: IR (thin
4.1.1. 4-(Bicyclo[2.2.1]hept-5-en-2-yl)benzene-1-sulfonyl
chloride (7). A flask was charged with SOCl2 (85 mL,
891 mmol) and cooled with an ice bath. Sodium 4-styr-
enesulfonate (26.37 g, 128 mmol) was added portion-wise
with heavy stirring over 1 h. DMF (35 mL) was added
slowly and the mixture warmed to RT. After 6 h the flask
was placed in a refrigerator overnight. The cold mixture was
then carefully poured onto w800 mL of ice. The mixture
was extracted with Et2O, and evaporated. The residue was
dissolved in toluene (60 mL), freshly cracked cyclopenta-
diene (w10 mL) was added, and the solution heated to
reflux. Fresh cyclopentadiene was added in 10 mL
increments every hour for 5 h. After the last addition the
mixture was kept at reflux for 2 h. After cooling to RT, the
reaction was concentrated under reduced pressure. Flash
chromatography [heptane (to remove dicyclopentadiene)
and then 10:1 heptane/EtOAc, all mixed fractions were
film) 3051, 2943, 2125, 1593, 1371, 1169, 1088 cmK1
.
4.2. General procedure for diazo transfer reaction
with OSA
An oven-dried vial was charged with the active methylene
compound (1 equiv), and KOt-Bu (1.5 equiv) and dissolved
in CH2Cl2 (0.2 M). Oligomer 9 (1.5–2 equiv) was added
and the mixture stirred at rt and monitored by TLC. When
the reaction was complete, EtOAc (1 mL) was added

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A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
and the mixture filtered through a SPE cartridge containing
w650 mg silica. The cartridge was washed with EtOAc
(4!1 mL). The filtrate was evaporated under reduced
pressure to afford pure diazo compound.
Fund (KU-RDF), the NIH Center of Excellence in Chemical
Methodologies and Library Development (KU-CMLD, NIH
1P50 GM069663-01), the ACS Division of Organic
Chemistry Nelson J. Leonard Fellowship sponsored by
Organic Syntheses, Inc. (A. M. H.), and the NSF-REU (W.
M. S.). The authors thank Materia, Inc. for supplying
catalyst and helpful discussions as well as Dr. Gwen L.
Macpherson, director of the University of Kansas Plasma
Analytical Laboratory in the Department of Geology for
conducting ICPMS measurements.
4.3. Characterization of diazo transfer products 11–15
4.3.1. Diethyl (1-diazo-2-oxopropyl)phosphonate (11).
The general procedure above was followed starting with
diethyl (2-oxopropyl)phosphonate (200 mL, 1.04 mmol),
KOt-Bu (131.4 mg, 1.17 mmol), and
9 (433.5 mg,
1.56 mmol), to afford 11 (224.5 mg, 97%) as an orange oil:
IR (thin film) 2986, 2123, 1659, 1267, 1018 cmK1; 1H NMR
(400 MHz, CDCl3) 4.21 (dq, 4H, JZ7.0, 8.4 Hz), 2.28 (s,
3H), 1.39 (dt, 6H, JZ7.1, 0.6 Hz); 13C NMR (100 MHz,
CDCl3) 190.1 (JCPZ13.8 Hz), 63.4 (JCPZ5.6 Hz), 27.2, 16.1
(JCPZ6.8 Hz); 31P NMR (162 MHz, CDCl3) K12.49.
References and notes
1. (a) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32,
18–26. (b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000,
3815–4195. (c) Kirschning, A.; Monenschein, H.; Wittenberg,
R. Angew. Chem. Int. Ed. 2001, 40, 650–679. (d) Eames, J.;
Watkinson, M. Eur. J. Org. Chem. 2001, 1213–1224.
2. For reviews concerning soluble polymers, see: (a) Gravert,
D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489–509. (b) Toy,
P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546–554. (c)
Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev. 2002,
102, 3325–3344. (d) Haag, R. Chem. Eur. J. 2001, 7, 327–335.
(e) Haag, R.; Sunder, A.; Hebel, A.; Roller, S. J. Comb. Chem.
2002, 4, 112–119. (f) Bergbreiter, D. E. Chem. Rev. 2002, 102,
3345–3384.
4.3.2. t-Butyl 2-diazo-3-oxobutanoate (12). The general
procedure above was followed starting with t-butyl
acetoacetate (45 mg, 0.284 mmol), KOt-Bu (51.6 mg,
0.460 mmol), and 9 (120.4 mg, 0.433 mmol) to afford 12
(46 mg, 88%) as a yellow-orange oil:10c IR (thin film) 2980,
2934, 2131, 1659, 1651 cmK1; 1H NMR (400 MHz, CDCl3)
2.45 (s, 3H), 1.52 (s, 9H); 13C NMR (125 MHz, CDCl3)
190.5, 160.5, 83.1, 28.2, 28.1.
4.3.3. 2-Diazo-5,5-dimethyl-1,3-cyclohexanedione (13).
The general procedure above was followed starting
with 5,5-dimethyl-1,3-cyclohexanedione (33.1 mg,
0.236 mmol), KOt-Bu (45.1 mg, 0.402 mmol), and 9
(99.3 mg, 0.357 mmol) to afford 13 (29.5 mg, 75%) as a
pale yellow solid: mp 103–105 8C (lit.25 105–107 8C), IR
¨
3. (a) Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J. Chem.
Rev. 2002, 102, 3301–3324. (b) Flynn, D. L.; Hanson, P. R.;
Berk, S. C.; Makara, G. M. Curr. Opin. Drug Discov. Devel.
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P. R. The Use of Olefin Metathesis in Combinatorial
Chemistry: Supported and Chromatography-free Synthesis.
In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003, pp 361–402.
1
(thin film) 2962, 2137, 1643, 1312, 1277 cmK1; H NMR
(400 MHz, CDCl3) 2.44 (s, 4H), 1.12 (s, 6H); 13C NMR
(125 MHz, CDCl3) 189.8, 50.5, 31.1, 28.3.
4.3.4. Di-t-butyl 2-diazomalonate (14). The general
procedure above was followed starting with di-t-butyl
malonate (46.3 mg, 0.214 mmol), KOt-Bu (38.8 mg,
0.346 mmol), and 9 (95.9 mg, 0.345 mmol) to afford 14
(38.3 mg, 74% containing 7% starting material) as a yellow-
orange oil: IR (thin film) 2980, 2133, 1747, 1693 cmK1; 1H
NMR (400 MHz, CDCl3) 1.50 (s); 13C NMR (125 MHz,
CDCl3) 160.3, 82.6, 28.2.
4. Harned, A. M.; Zhang, M.; Vedantham, P.; Mukherjee, S.;
Herpel, R. H.; Flynn, D. L.; Hanson, P. R. Aldrichim. Acta
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1821–1839. (b) Kirmse, W. Eur. J. Org. Chem. 2002,
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M. C. B. V.; Cunha, A. C. Quim. Nova 2001, 24, 540–553. (d)
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998. (e) Doyle, M. P.; McKervey, M. A.
J. Chem. Soc., Chem. Commun. 1997, 983–989. (f) Burke,
S. D.; Grieco, P. A. Org. React. 1979, 26, 361–475. (g) The
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4.3.5. Ethyl 2-diazo-3-oxo-3-phenylpropanoate (15). The
general procedure above was followed starting with ethyl
benzoylacetate (39.7 mg, 0.207 mmol), KOt-Bu (43.3 mg,
0.386 mmol), and 9 (99.6 mg, 0.359 mmol) to afford 15
(40.5 mg, 90%) as a yellow-orange oil: IR (thin film) 3061,
2984, 2143, 1728, 1631 cmK1; 1H NMR (400 MHz, CDCl3)
7.66–7.61 (m, 2H), 7.56–7.51 (m, 1H), 7.46–7.40 (m, 2H),
4.24 (q, 4H, JZ7.1 Hz), 1.26 (t, 6H, JZ7.1 Hz); 13C NMR
(125 MHz, CDCl3) 186.9, 161.0, 137.1, 132.2, 128.3, 127.8,
61.6, 14.1.
Acknowledgements
This work was generously supported by partial funds
provided by the National Science Foundation (NSF Career
9984926), the University of Kansas Research Development

A. M. Harned et al. / Tetrahedron 61 (2005) 12093–12099
12099
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