A survey of enoldiazo nucleophilicity in selective C-C bond forming reactions for the synthesis of natural product-like frameworks

Article abstract of DOI:10.1039/c4ob00709c

A survey of in situ, catalytically generated carbocations for coupling with enoldiazoacetate nucleophiles was performed. These couplings facilitate the rapid assembly of complex organodiazo compounds that provide a template for the synthesis of a variety of carbocyclic and heterocyclic ring systems.

Full text of DOI:10.1039/c4ob00709c

Organic &
Biomolecular Chemistry
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A survey of enoldiazo nucleophilicity in selective
C–C bond forming reactions for the synthesis of
natural product-like frameworks†
Cite this: Org. Biomol. Chem., 2014,
12, 5227
Yuxiao Liu,a,b Yu Liu,a Charles S. Shanahan,a Xichen Xua and Michael P. Doyle*a
Received 3rd April 2014,
Accepted 30th May 2014
A survey of in situ, catalytically generated carbocations for coupling with enoldiazoacetate nucleophiles
was performed. These couplings facilitate the rapid assembly of complex organodiazo compounds that
provide a template for the synthesis of a variety of carbocyclic and heterocyclic ring systems.
DOI: 10.1039/c4ob00709c
www.rsc.org/obc
Complex organodiazo templates 2 have shown great potential
as platforms for syntheses (Scheme 1), but methods for their
preparation have been limited. Recently our group,1a–d and
others,1e,f have endeavoured to unlock the full synthetic poten-
tial of enoldiazo reagents 1 as a way to prepare these complex
organodiazo templates. In addition to their dirhodium(II)-cata-
lyzed dinitrogen extrusion reactions,2 enoldiazo compounds 1
can serve as a general nucleophile in substitution,1a aldol,1b
Michael,1c and Mannich1d reactions whereby the diazo
functionality is retained. These nucleophilic transformations
provide complex organodiazo templates 2 that have long been
of interest in organic synthesis.
Recent explorations of the couplings of enoldiazo com-
pounds 1 (Z = COOR, SO2Ar, COPh, and H) with propargylic
carbocations 3 have revealed the great potential of SN1-like
couplings with 1 to construct complex alkynyl tethered diazo-
ketones 4 via selective C–C bond formation (Scheme 2).1a
Organodiazo compounds 4 were in turn shown to be versatile
synthetic templates for constructing a diverse array of poly-
functionalized carbo- and heterocyclic products. From the per-
spective of Diversity Oriented Synthesis (DOS),3 intermediates
derived from carbocationic couplings of 1 provide organodiazo
templates 2 that offer a range of possibilities for accessing
diverse libraries of small molecules and makes enoldiazo
chemistry a promising platform for drug discovery. SN1-like
couplings place substituents at the δ-position of diazoaceto-
acetates that is most advantageous for catalytic intramolecular
reactions of the diazo ester. Herein we report a generalization
of this electrophilic addition process exemplified by selective
C–C bond forming reactions of methyl enoldiazoacetate 1a
Scheme 1 General coupling strategy.
Scheme 2 Enoldiazoacetate coupling with propargyl acetates (Z =
COOR, SO2Ar, COPh, and H).
(Z = COOMe) with a broad series of carbocation structures. In
addition, we have explored the potential of complex organo-
diazo frameworks such as 4 to prepare unique carbocyclic and
heterocyclic scaffolds bearing natural product-like features.
The reactions of methyl enoldiazoacetate 1a with in situ
generated benzylic, allylic and oxonium carbocations were sur-
veyed. Carbocation generation was designed to occur under
mild conditions using a Lewis acid catalyst. In prior efforts1a,4
zinc triflate and scandium triflate had both been found to be
aDepartment of Chemistry and Biochemistry, University of Maryland, College Park,
Maryland 20742, USA. E-mail: mdoyle3@umd.edu; Tel: +1-301-405-1788
bSchool of Pharmacy, East China University of Science and Technology,
Meilong Road 130, Shanghai 200237, China
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00709c
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Table 1 Optimization of the reaction conditionsa
benzylic substrates. The results from these investigations are
given in Scheme 3. Benzhydryl acetates 6a–i reacted with enol-
diazoacetate 1a to give the corresponding coupling products in
moderate to good yields. These reactions were limited only
when the benzhydryl framework was substituted with the
strongly electron-withdrawing nitro group. A methoxy substi-
tuted in the ortho position significantly decreased product
yield, and m-methoxybenzhydryl acetate was less reactive than
the para-isomer. However, a chloride substituent para on the
benzene ring 6g afforded 7g in good yield. The reaction of
enoldiazoacetate 1a with 1,3-diphenylallyl acetate 8 occurred to
form the corresponding coupling product methyl 2-diazo-3-
Entry Catalyst (mol%) Solvent Temperature (°C) Yield 7ab (%)
1
Zn(OTf)2 (2)
Sc(OTf)3 (1)
Sc(OTf)3 (1)
AgOTf (2)
In(OTf)3 (2)
Cu(OTf)2 (2)
Sc(OTf)3 (1)
Sc(OTf)3 (1)
Sc(OTf)3 (3)
Sc(OTf)3 (5)
Sc(OTf)3 (3)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
8
53
59
Trace
Trace
38
21
50
2c
3
4
5
6
7
8
9
10
11
oxo-5,7-diphenylhept-6-enoate
9 in moderate yield (62%).
However, 1-phenyl-2-propenyl acetate, which would produce
an unsymmetrical allyl cation intermediate, gave a mixture of
regioisomers in reactions with methyl enoldiazoacetate 1a.
The sensitivity of the benzhydryl system to substituent effects
was expected and suggests the limitation of this methodology
– under the conditions employed in this study benzyl acetates
and simple allyl acetates did not undergo coupling with
methyl enoldiazoacetate 1a, but we can anticipate that the use
of more Lewis acidic catalysts and/or stronger leaving groups
would broaden the scope of this transformation.
DCM
MeCN
MeCN
MeCN
79
82
79
a Reaction conditions:
a mixture of methyl enoldiazoacetate (1.2
equiv.), benzhydryl acetate (1.0 equiv.), molecular sieves (100 mg
mmol−1) and catalyst (1–5 mol%) in freshly distilled solvent (0.5 M)
was stirred at the specified temperature for 16 hours. b Isolated yields.
c Reaction without molecular sieves.
optimal; and they were evaluated along with several other
Lewis acids in this study. Optimization was performed with
benzhydryl acetate 6a which formed 2-diazo-3-oxo-5,5-diphenyl
pentanoate 7a when reactions were performed under anhy-
drous conditions for 16 h. The results reported in Table 1
describe the influence of catalyst, catalyst loading, solvent and
temperature on the yield of the diazoacetoacetate product.
Initially we found that the reaction of 1a with 6a was
sluggish when catalyzed by 2 mol% of anhydrous Zn(OTf)2
(Table 1, entry 1), but the yield of 7a was dramatically
improved to a moderate yield of 53% when 1 mol% of anhy-
drous Sc(OTf)3 was the catalyst (entry 2). An increase in yield
of 7a to 59% was observed when molecular sieve was used
(entry 3). Further optimization by changing the Lewis acid
catalyst (entries 4–6) did not result in any improvement over
that provided by Sc(OTf)3. Although DCM was used in earlier
investigations of electrophilic addition reactions with enoldiazo-
acetates,1b–d as found in reactions with propargyl acetates,1a
dipolar aprotic acetonitrile was the optimum solvent for these
reactions; lower yields of the desired product were found in
reactions performed in THF and DCM (entries 7 and 8).
Increasing the catalyst loading from 1% to 3 mol% improved
product yield from 59% to 79% with little further change
occurring with an increase in catalyst loading to 5 mol% Sc-
(OTf)3 (entries 3, 9 and 10). However, although the effect of
increasing catalyst loading often suggests a sluggish reaction,
heating the reaction mixture at 40 °C did not increase the yield
of 7a (entry 11). The major operational concern with this reac-
tion is hydrolysis of 1a to methyl diazoacetoacetate and,
because of this, a 20% excess of the enoldiazoacetate was
employed.
Orthoesters are a convenient source of relatively stable
carbocations suitable for reactions with diazo compounds,5
and with their use we have observed couplings with enoldiazo-
acetate 1a that form acetal- and ketal-tethered diazoacetoacetates5
in good to excellent yields (Scheme 3). Use of zinc triflate in
DCM gave lower product yields (65% for R = Me; 62% for R =
Et; 56% for R = i-Pr) than did scandium triflate in acetonitrile,
but catalyst loadings for both zinc and scandium triflates at
only 0.5 mol% were adequate (see the ESI† for details). Other
Lewis acids, including La(OTf)3, Yb(OTf)3, Sn(OTf)2, and
copper(II) catalysts were also used, but without improvement.
Changing the R2 substituent of orthoformates from isopropyl
10a to methyl 10b had no effect on product yield (82% and
83%, respectively), and neither did increasing the number of
equivalents of orthoformate. In addition to orthoformates (R1
= H) this coupling reaction could be extended to orthoesters
with R1 = methyl, n-butyl and phenyl. However, with trimethyl
orthovalerate 10d, the initially formed ketal underwent elimin-
ation of methanol under even these mild catalytic conditions
to form enonediazoacetate 11d in only the (E)-configuration,
as confirmed by NOE experiments; complete conversion to 11d
was facilitated by treatment with trifluoroacetic acid. Further-
more, trimethyl orthobenzoate 11e, which does not undergo
coupling with 1a in DCM catalyzed by Zn(OTf)2, formed 11e in
moderate yield (46%) from reactions in acetonitrile catalyzed
by Sc(OTf)3, albeit with higher catalyst loading. At long reac-
tion times these couplings are sensitive to the presence of
trace amounts of water that cause conversion of the orthoester
to the corresponding ester and alcohol causing a subsequent
cascade in loss of orthoester reactant.
To exemplify the utility of this general methodology we
have investigated catalytic intramolecular reactions of these
δ-substituted diazoacetoacetates. The products from conden-
With the optimized protocol in hand, we explored the scope
and limitations of the reaction process with respect to various
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Scheme 4 Benzylation to access β-tetralone derivatives.
Scheme 5 Prenylation products to synthesize cyclopentanones.
sation with benzhydryl acetates are suitably constructed for
intramolecular cycloaddition or substitution of catalyst-gener-
ated metal carbenes into the aromatic ring.6 Although, the vast
array of intramolecular substitution reactions have been per-
formed with aromatic rings at the γ-position7 and, conversely,
most intramolecular aromatic cycloaddition reactions have
occurred with aromatic rings at the δ-position,8 this system
was examined with the potential that either or both processes
could occur. The reaction of 7a with Rh2(OAc)4 in refluxing
CH2Cl2 gave a mixture of substitution and aromatic cyclo-
addition products that, following treatment with TFA, provided
β-tetralone9 12 in 82% yield (Scheme 4), which bears resem-
blance to biologically active tetralin natural products, such
as the calamenenes,10 and synthetic intermediates used to
prepare drug-like molecules.11 The p-methoxy derivative 7b
afforded the corresponding tetralin derivative in 84% yield.
Diazoacetoacetate 9 provided an opportunity to assess
chemoselectivity in catalytic dinitrogen extrusion reactions. A
prior report from a dirhodium(II) catalysed reaction of a diazo-
ketone showed cyclopropanation to be competitive with
aromatic cycloaddition with rhodium acetate.12 However,
rhodium acetate catalysed reaction of 9 gave only the bicyclic
cyclopentanone 13 through cyclopropanation (Scheme 5), and
products from aromatic cycloaddition or substitution into the
phenyl ring were not observed. In this event, cyclopentanone
13 was produced in 56% yield with 65 : 35 diastereoselectivity
(13a : 13b). Rhodium caprolactamate was also used in refluxing
DCE, but without improvement of diastereoselectivity. Cyclo-
propanes such as 13 have proven to be versatile intermediates
in the synthesis of more complex biologically active
compounds.13
Scheme 3 SN1 reactions of enoldiazoacetates with benzhydryl/allyl
acetates and orthoesters. aReaction conditions: a mixture of enoldiazo-
acetate (1.2 equiv.), substrate (1.0 equiv.), molecular sieve (100 mg
mmol−1) and anhydrous Sc(OTf)3 (3.0 mol%) in freshly distilled aceto-
nitrile (0.5M) was stirred at room temperature for 16 hours. bThe reaction
was catalyzed by 5.0 mol% anhydrous Sc(OTf)3 under the same con-
ditions. cThe reaction was catalyzed by 0.50 mol% anhydrous Sc(OTf)3
under the same conditions. d11d was formed after treating the reaction
mixture with 1.0 equivalent TFA, and its configuration was determined
by 1D NOE experiments. See ESI† for details. eThe reaction was catalyzed
by 1.5 mol% anhydrous Sc(OTf)3.
δ,δ-Dialkoxy-β-keto-α-diazoesters 11b,c allowed divergent
access to interesting compounds based solely on the R-group
used in the couplings of 10b,c with 1a. The placement of an
ether oxygen at the δ-position allows formation of oxonium
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Scheme 8 Activated cyclobutanones to synthesize pyrazoles.
yield, and only the (E)-configuration for 17 was observed as
established by NOE experiments. In this case, a terminal
alkene 16 was formed after migration of the methoxy group,
which then readily tautomerized to β-ketoester 17 by proton
transfer. What is different in this latter case from the ylide
mechanism depicted for the formation of cyclobutanone 14 is
that the enolate anion of the ylide intermediate undergoes
deprotonation at the terminal methyl group instead of under-
going nucleophilic attack.
Scheme 6 Formation of cyclobutanone products from the Mukaiyama-
aldol condensation of 1a with aldehydes.
Based on the known sensitivity of strained cyclobutanones
to cleavage,16 we considered that cleavage of the C–C bond
between the quaternary carbon and tertiary carbon of 14
would be facile and could be applied to synthesis of other
functionalized molecules. Lewis acid catalyzed cycloadditions
of aldehydes and ketones, as well as of imines and allyl-
silanes,17 with 3-alkoxy-2,2-dimethylcyclobutanones have been
reported. Cyclobutanones 14 were investigated as latent 1,4-
dipoles in dipolar cycloaddition reactions with benzaldehyde,
which provided the pyranone compound 15 in 40% yield and
60 : 40 diastereoselectivity (Scheme 7). The final pyranone com-
pound bears remarkable resemblance to the core structure of
the chrolactomycin natural products.18
Scheme 7 Acetal products to prepare cyclobutanones, pyranones and
β-ketoester.
Another application of β-alkoxycyclobutanone compounds
is the synthesis of pyrazoles by reacting for β-alkoxycyclobuta-
none with monosubstituted hydrazines.19 In a one-pot process
methyl 5,5-dimethoxy-3-oxo-2-diazo-pentanoate was sequen-
tially treated with rhodium acetate and without isolation of
methyl 1,2-dimethoxy-4-oxo-cyclobutanecarboxylate 14, 1.0
equivalent of tosylhydrazine and 10 mol% zinc triflate were
added to the reaction solution. The reaction was run at reflux-
ing DCM for 6 h to yield the desired pyrazole product 18 in
55% isolated yield after purification (Scheme 8).
ylide intermediates that can undergo skeletal rearrange-
ments.14 Previously, the coupling products formed catalytic
Mukaiyama-aldol reactions of 1a were shown to form cyclo-
butanone products with good diastereoselectivity (Scheme 6).15
Transformation of the intermediate dirhodium carbene to the
corresponding oxonium ylide formed with the siloxy oxygen
was completed by an internal SN2-type displacement that
resulted in ring closure to the observed cyclobutanone
products.
Reaction of 11b with Rh2(OAc)4 (1 mol%) provided cyclo-
butanones 14 via ring contraction of an intermediate oxonium
ylide in excellent yield (80%) and 75 : 25 diastereoselectivity
(Scheme 7). Use of the more electrophilic rhodium perfluoro-
butyrate gave 14 in only 46% yield (dr = 58 : 42), but the steri-
cally bulky rhodium triphenylacetate had little impact on
diastereoselectivity (73% yield, dr = 70 : 30). Under the same
conditions in refluxing DCM, rhodium caprolactamate did not
cause dinitrogen extrusion from 11b. While in refluxing DCE,
rhodium caprolactamate gave 14 in only 28% yield (dr =
70 : 30). As expected, varying the acetal alkyl groups of 11 had
little effect on product yields, but did influence diastereoselec-
tion in cyclobutanone formation (R = Et, 75% yield, dr =
72 : 28; R = i-Pr, 72% yield, dr = 53 : 47). On the other hand, the
reaction of 11c with Rh2(OAc)4 afforded β-ketoester 17 in 82%
Conclusions
In summary, we have developed a general Lewis-acid catalyzed
carbocationic coupling reaction of enoldiazo compounds,
including coupling with benzhydryl, allylic and oxonium carbo-
cations. This report has further demonstrated the utility of
enoldiazo coupling reactions to prepare complex organodiazo
templates, which are useful for the construction of natural
product-like scaffolds. When combined with the array of coup-
ling reactions that have been reported for enoldiazo com-
pounds, the application these reagents presents a unique
opportunity to apply DOS-type strategies to rapidly access large
and diverse libraries of medicinally interesting compounds.
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stirred solution was cooled to −45 °C with an acetonitrile-dry
ice bath. Boron trifluoride etherate (1.0 mmol, 2.0 equiv.) was
then added to the reaction solution. The reaction mixture was
Experimental
General considerations
All reactions were carried out under an inert atmosphere of dry stirred at −45 °C for 1 hour and then at room temperature for
nitrogen with magnetic stirring. All solvents were dried and 1 hour. After the acetonitrile-dry ice bath was removed, the
distilled according to standard procedures. Flash chromato- color of the reaction slowly turned from pale yellow to reddish
graphy was performed with silica gel (32–63 μm) supplied by brown. The reaction was quenched with saturated aqueous
Dynamic Adsorbents and reactions were monitored by thin sodium bicarbonate solution and washed with brine, dried
layer chromatography (TLC) using UV light to visualize the over anhydrous magnesium sulfate, filtered and concentrated.
course of the reactions. 1H NMR spectra were recorded on a The crude product was purified by flash column chromato-
Bruker DRX-400 (400 MHz) spectrometer and chemical shifts graphy, eluting with 1 : 3 EtOAc–hexane to give a pale yellow
were reported in ppm. The peak information was described as: liquid as product.
br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, comp = composite; coupling constant(s) is given in
General procedure for product 18
Hz. 13C NMR spectra were recorded on a Bruker DRX-400 Compound 14 (0.5 mmol) was dissolved in 3 mL CH2Cl2, fol-
(100 MHz). High-resolution mass spectra (HRMS) were per- lowed by addition of p-toluenesulfonyl hydrazide (0.5 mmol,
formed on JEOL AccuTOF-CS mass spectrometer using CsI as 1.0 equiv.) and zinc triflate (0.05 mmol, 0.1 equiv.). The color
the standard.
of the reaction turned from yellow to reddish brown upon
addition of the sulfonyl hydrazide. The reaction was allowed to
reflux for 6 h. The catalyst was then removed by passing the
General procedure for products 7a–i, 9, 11a–e
Molecular sieves (100 mg) was added to the Schlenk tube and resulting solution through a short plug of silica, and the
flame dried under vacuum, then anhydrous Sc(OTf)3 was solvent was removed under reduced pressure. The crude
added and heated (110 °C) under vacuum for 1 h to dehydrate product was purified by flash column chromatography, eluting
the catalyst. After cooling to room temperature the electrophile with 1 : 2 EtOAc–hexanes to give a pale yellow crystalline
precursor (6a–i/8/10a–e: 1.0 mmol) in 3 mL of dry acetonitrile product.
was added, and this mixture was stirred at room temperature
Methyl 2-diazo-3-oxo-5,5-diphenylpentanoate (7a). Yield:
for 5 min. Enoldiazoacetate 1a (1.2 mmol, 1.2 equiv.) was 79%; yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.31–7.29
added via syringe all at once. The bright yellow solution was (comp, 8H), 7.24–7.17 (comp, 2H), 4.74 (t, J = 7.6 Hz, 1H), 3.87
stirred vigorously at room temperature. After 16 h the reaction (s, 3H), 3.70 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
mixture was concentrated under reduced pressure, and the δ 190.9, 162.1, 144.1, 128.8, 128.2, 126.7, 52.5, 46.4, 45.8;
resulting mixture was purified by silica gel chromatography, HRMS (ESI) calcd for C18H19N2O3 [M + H]+ calcd 309.1239;
eluting with 1 : 10 EtOAc–hexane to give the corresponding found 309.1228.
product.
Methyl
2-diazo-5,5-bis(4-methoxyphenyl)-3-oxopentanoate
(7b). Yield: 81%; pale yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 7.19–7.06 (comp, 4H), 6.82–6.62 (comp, 4H), 4.56 (t,
General procedure for product 12a–b
A solution of 7a/7b (0.5 mmol) in 2 mL of anhydrous CH2Cl2 J = 7.7 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 6H), 3.56 (d, J = 7.7 Hz,
was added via syringe pump over 2 h to a refluxing solution of 2H); 13C NMR (100 MHz, CDCl3) δ 188.7, 159.7, 155.9, 134.2,
2 mg Rh2(OAc)4 (0.005 mmol) in 1 mL of anhydrous CH2Cl2, 126.6, 111.8, 53.2, 50.2, 43.7, 42.5; HRMS (ESI) for C20H21N2O5
followed by in situ treatment with TFA (0.5 mmol, 1.0 equiv.) [M + H]+ calcd 369.1451; found 369.1457.
for 1 hour. The catalyst was removed by passing the resulting
Methyl 2-diazo-5-(3,4-dimethoxyphenyl)-3-oxo-5-phenyl-
solution through a short plug of silica, and the solvent was pentanoate (7c). Yield: 68%; pale yellow liquid; 1H NMR
removed under reduced pressure to give the corresponding (CDCl3, 400 MHz) δ 7.20–7.18 (comp, 4H), 7.11–7.07 (m, 1H),
product.
6.79–6.65 (comp, 3H), 4.58 (t, J = 7.7 Hz, 1H), 3.76 (s, 3H), 3.75
(s, 3H), 3.74 (s, 3H), 3.65 (dd, J = 16.7, 7.7 Hz, 1H), 3.48 (dd, J =
16.7, 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 190.1, 161.1,
General procedure for products 13, 14, 17
A solution of compound 9/11b/11c (0.5 mmol) in 2 mL of 148.2, 146.9, 143.4, 135.6, 127.9, 127.0, 125.7, 118.9, 110.8,
anhydrous CH2Cl2 was added via syringe pump over 2 h to a 110.5, 55.2, 55.1, 51.6, 45.2, 44.7; HRMS (ESI) for C20H21N2O5
refluxing solution of 2 mg Rh2(OAc)4 (0.005 mmol) in 1 mL of [M + H]+ calcd 369.1451; found 369.1465.
anhydrous CH2Cl2. The catalyst was removed by passing the
resulting solution through a short plug of silica and the ate (7d). Yield: 79%; yellow liquid; H NMR (400 MHz, CDCl3)
solvent was removed under reduced pressure to give the corres- δ 7.20–7.13 (comp, 4H), 7.14–7.03 (comp, 3H), 6.78–6.67
Methyl 2-diazo-5-(4-methoxyphenyl)-3-oxo-5-phenylpentano-
1
ponding product.
(comp, 2H), 4.58 (t, J = 7.2 Hz, 1H), 3.74 (s, 3H), 3.66 (s, 3H),
3.58 (dd, J = 16.1, 7.2 Hz, 1H), 3.53 (dd, J = 16.1, 7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 190.0, 161.1, 157.4, 143.5, 135.3,
General procedure for product 15
Compound 14 (0.5 mmol) was dissolved in 3 mL CH2Cl2, fol- 128.1, 127.9, 127.1, 125.7, 113.2, 54.5, 51.6, 44.9, 44.7; HRMS
lowed by addition of benzaldehyde (0.5 mmol, 1.0 equiv.). The (ESI) for C19H19N2O4 [M + H]+ calcd 339.1345; found 339.1325.
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Methyl 2-diazo-5-(3-methoxyphenyl)-3-oxo-5-phenylpentano- 13C NMR (100 MHz, CDCl3) δ 207.3, 189.4, 162.0, 97.2, 68.8,
1
ate (7e). Yield: 67%; yellow liquid; H NMR (400 MHz, CDCl3) 52.7, 46.5, 31.3, 23.7, 22.8. HRMS (ESI) for C12H20N2O5
δ 7.34–7.28 (comp, 4H), 7.24–7.20 (comp, 2H), 6.94–6.92 (m, [M + H]+ calcd 273.1450; found 273.1461.
1H), 6.89–6.85 (m, 1H), 6.77–6.75 (m, 1H), 4.74 (t, J = 7.6 Hz,
Methyl 5,5-dimethoxy-3-oxo-2-diazopentanoate (11b). Yield:
1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.74 (dd, J = 17.0, 7.6 Hz, 1H), 83%; yellow liquid; 1H NMR (400 MHz, CDCl3) δ 4.95 (t, J =
3.68 (dd, J = 17.0, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 5.7 Hz, 1H), 3.86 (s, 3H), 3.39 (s, 6H), 3.25 (d, J = 5.7 Hz, 2H);
190.5, 161.8, 159.7, 145.4, 143.7, 129.5, 128.6, 127.8, 126.5, 13C NMR (100 MHz, CDCl3) δ 188.8, 161.6, 101.0, 53.5, 52.3,
120.2, 113.9, 111.5, 55.2, 52.3, 46.2, 45.4; HRMS (ESI) for 43.4; HRMS (ESI) for C8H13N2O5 [M + H]+ calcd 217.0824;
C19H19N2O4 [M + H]+ calcd 339.1345; found 339.1325.
found 217.0836.
Methyl 2-diazo-5-(2-methoxyphenyl)-3-oxo-5-phenylpentano-
Methyl 5,5-dimethoxy-3-oxo-2-diazohexanoate (11c). Yield:
1
1
ate (7f). Yield: 24%; yellow liquid; H NMR (400 MHz, CDCl3) 83%; yellow liquid; H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H),
δ 7.25–7.14 (comp, 4H), 7.13–7.04 (comp, 3H), 6.84–6.80 (m, 3.29 (s, 2H), 3.23 (s, 6H), 1.46 (s, 3H); 13C NMR (100 MHz,
1H), 6.77–6.75 (m, 1H), 5.05 (t, J = 7.7 Hz, 1H), 3.76 (s, 3H), CDCl3) δ 188.2, 161.1, 100.0, 51.6, 47.9, 44.1, 21.4; HRMS (ESI)
3.71 (s, 3H), 3.67 (dd, J = 17.3, 7.7 Hz, 1H), 3.49 (dd, J = 17.3, for C9H14N2O5 [M + H]+ calcd 231.0981; found 231.0975.
7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.2, 162.3, 157.3,
Methyl
(E)-2-diazo-5-methoxy-3-oxonon-4-enoate
(11d).
1
144.0, 132.6, 128.7, 128.5, 128.4, 127.9, 126.5, 120.9, 111.2, Yield: 69%; yellow liquid; H NMR (400 MHz, CDCl3) δ 6.45 (s,
55.9, 52.6, 45.0, 39.6; HRMS (ESI) for C19H19N2O4 [M + H]+ 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.73–2.69 (t, J = 7.3 Hz, 2H), 1.51
calcd 339.1345; found 339.1326.
−1.43 (m, 2H), 1.34–1.24 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H); 13C
Methyl 5-(4-chlorophenyl)-2-diazo-3-oxo-5-phenylpentanoate NMR (100 MHz, CDCl3) δ 191.0, 167.3, 161.4, 78.7, 54.0, 50.9,
(7g). Yield: 72%; yellow liquid; 1H NMR (400 MHz, CDCl3) 38.5, 30.3, 28.0, 21.4, 12.8; HRMS (ESI) for C11H18N2O4 [M +
δ 7.23–7.19 (comp, 4H), 7.16–7.09 (comp, 5H), 4.61 (t, J = H]+ calcd 241.1188; found 241.1197.
7.6 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J = 17.0, 7.6 Hz, 1H), 3.53
Methyl 2-diazo-5,5-dimethoxy-3-oxo-5-phenylpentanoate (11e).
(dd, J = 17.0, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 190.3, Yield: 46%; yellow liquid; 1H NMR (400 MHz, CDCl3)
161.7, 143.3, 142.3, 132.2, 129.2, 128.7, 127.7, 126.6, 52.3, 45.5, δ 7.42–7.37 (comp, 2H), 7.27–7.19 (comp, 3H), 3.59 (s, 3H),
45.3; HRMS (ESI) for C18H16ClN2O3 [M + H]+ calcd 343.0849; 3.52 (s, 2H), 3.17 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 188.2,
found 343.0843.
161.6, 140.0, 128.4, 128.1, 127.6, 102.3, 52.4, 49.4, 45.7; HRMS
Methyl 2-diazo-5-(4-nitrophenyl)-3-oxo-5-phenylpentanoate (ESI) for C13H13N2O4 [M + H − CH3OH]+ calcd 261.0875; found
(7h). Yield: 38%; yellow liquid; 1H NMR (400 MHz, CDCl3) 261.0856.
δ 8.17–8.02 (comp, 2H), 7.43–7.34 (comp, 2H), 7.28–7.26
Methyl 2-hydroxy-4-phenyl-3,4-dihydronaphthalene-1-carb-
(comp, 2H), 7.21–7.14 (comp, 3H), 4.77 (t, J = 7.6 Hz, 1H), 3.81 oxylate (12a). Yield: 82%; pale yellow liquid; 1H NMR
(s, 3H), 3.71 (dd, J = 17.3, 7.6 Hz, 1H), 3.60 (dd, J = 17.3, 7.6 (400 MHz, CDCl3) δ 13.18 (s, 1H), 7.70 (dd, J = 8.0, 1.0 Hz, 1H),
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.8, 160.7, 150.4, 7.29–7.18 (comp, 3H), 7.17–7.07 (comp, 3H), 6.99–6.98 (m,
145.5, 141.1, 127.9, 127.7, 126.7, 126.1, 122.8, 51.3, 44.8, 43.9; 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.09 (t, J = 5.9 Hz, 1H), 3.86 (s,
HRMS (ESI) for C18H16N3O5 [M + H]+ calcd 354.1090; found 3H), 2.85 (dd, J = 14.3, 5.9 Hz, 1H), 2.80 (dd, J = 14.3, 5.9 Hz,
354.1074.
1H); 13C NMR (100 MHz, CDCl3) δ 175.8, 171.5, 141.0, 134.9,
Methyl 2-diazo-5-(naphthalen-2-yl)-3-oxo-5-phenylpentano- 130.6, 127.9, 127.4, 126.9, 126.1, 126.0, 125.4, 124.6, 99.3, 51.1,
ate (7i). Yield: 76%; pale yellow solid; 1H NMR (400 MHz, 42.5, 35.9; HRMS (ESI) for C18H19O3 [M + H]+ calcd 281.1177;
CDCl3)
δ
7.73–7.65 (comp, 4H), 7.40–7.29 (comp, 3H), found 281.1177.
Methyl 2-hydroxy-7-methoxy-4-(4-methoxyphenyl)-3,4-dihydro-
7.27–7.20 (comp, 4H), 7.12–7.08 (m, 1H), 4.81 (t, J = 7.6 Hz,
1H), 3.77 (s, 3H), 3.73 (dd, J = 16.9, 7.6 Hz, 1H), 3.66 (dd, J = naphthalene-1-carboxylate (12b). Yield: 84%; pale yellow
1
16.9, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 190.9, 162.2, liquid; H NMR (400 MHz, CDCl3) δ 13.11 (s, 1H), 7.73 (d, J =
144.1, 141.6, 133.9, 132.6, 129.0, 128.6, 128.4, 128.2, 128.0, 8.7, 1H), 7.21–7.04 (comp, 2H), 6.92–6.84 (comp, 2H), 6.81 (dd,
127.2, 126.9, 126.4, 126.2, 125.9, 52.7, 46.6, 45.7; HRMS (ESI) J = 8.7, 2.8 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 4.10 (t, J = 7.4 Hz,
for C22H19N2O3 [M + H]+ calcd 359.1396; found 359.1389.
1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H), 2.87 (d, J = 7.4 Hz,
Methyl 2-diazo-3-oxo-5,7-diphenylhept-6-enoate (9). Yield: 1H), 2.85 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 175.6, 172.6,
62%; yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.25–7.21 158.9, 157.6, 138.4, 134.0, 129.5, 127.6, 124.4, 114.4, 114.3,
(comp, 5H), 7.21–7.08 (comp, 5H), 6.36–6.26 (comp, 2H), 4.09 111.7, 100.1, 55.7, 55.6, 52.2, 43.3, 37.2; HRMS (ESI) for
(dd, J = 13.8, 7.2 Hz, 1H), 3.75 (s, 3H), 3.38–3.30 (m, 2H); 13C C20H21O5 [M + H]+ calcd 341.1389; found 341.1374.
NMR (100 MHz, CDCl3) δ 191.1, 162.2, 143.4, 137.6, 132.7,
Methyl 2-oxo-4,6-diphenylbicyclo[3.1.0]hexane-1-carboxylate
130.4, 129.0, 128.9, 128.2, 127.7, 127.1, 126.7, 52.6, 45.8, 44.8; (13a and 13b). Yield 56%; 13a: yellow liquid; 1H NMR
HRMS (ESI) for C20H19N2O3 [M + H]+ calcd 335.1396; found (400 MHz, CDCl3) δ 7.34–7.20 (comp, 8H), 7.19–7.14 (comp,
335.1376.
2H), 3.57 (d, J = 8.3 Hz, 1H), 3.42 (s, 3H), 3.20 (d, J = 5.5 Hz,
Methyl
5,5-diisopropoxy-3-oxo-2-diazopentanoate
(11a). 1H), 2.99 (d, J = 5.5 Hz, 1H), 2.85 (dd, J = 19.0, 8.3 Hz, 1H),
1
Yield: 82%; yellow liquid; H NMR (400 MHz, CDCl3) δ 5.14 (t, 2.32 (d, J = 19.0, 1H); 13C NMR (100 MHz, CDCl3) δ 204.5,
J = 5.6 Hz, 1H), 3.93–3.90 (comp, 2H), 3.86 (s, 3H), 3.20 (d, J = 164.4, 143.9, 132.6, 128.6, 127.8, 127.8, 127.3, 126.6, 125.7,
5.6 Hz, 2H), 1.21 (d, J = 6.2 Hz, 6H), 1.17 (d, J = 6.2 Hz, 6H); 51.7, 47.8, 42.1, 38.7, 37.2, 37.1, 30.4; HRMS (ESI) for C20H19O3
5232 | Org. Biomol. Chem., 2014, 12, 5227–5234
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[M + H]+ calcd 307.1334; found 307.1342. 13b: pale yellow
liquid; 1H NMR (400 MHz, CDCl3) δ 7.32–7.30 (comp, 2H),
7.29–7.23 (comp, 4H), 7.23–7.18 (comp, 4H), 4.08–3.92 (m,
1H), 3.46 (t, J = 5.4 Hz, 1H), 3.42 (s, 3H), 3.12 (d, J = 5.4 Hz,
1H), 2.76 (dd, J = 18.3, 10.0 Hz, 1H), 2.47 (dd, J = 18.3, 10.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 202.7, 163.8, 139.5, 131.8,
127.6, 127.3, 127.2, 126.7, 125.9, 125.5, 51.0, 47.3, 38.7, 36.6,
35.4, 33.6; HRMS (ESI) for C20H19O3 [M + H]+ calcd 307.1334;
found 307.1340.
M. P. Doyle, Org. Lett., 2012, 14, 3608; (c) Y. Liu, Y. Zhang,
N. Jee and M. P. Doyle, Org. Lett., 2008, 10, 1605; (d) X. Xu,
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51, 9829; (e) H. M. L. Davies, D. G. Stafford and T. Hansen,
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2001, 57, 1; (f) D. M. Hodgson, F. Y. T. M. Pierard and
P. A. Stupple, Chem. Soc. Rev., 2001, 30, 50.
3 (a) T. Alzieu, J. Lehmann, A. B. Naidu, R. E. Martin and
R. Britton, Chem. Commun., 2014, 50, 1867;
(b) W. C. Cronk, O. A. Mukhina and A. G. Kutateladze,
J. Org. Chem., 2014, 79, 1235; (c) Y. Zou, A. M. Spokoyny
and B. L. Pentelute, Org. Biomol. Chem., 2014, 12, 566;
(d) J. Zhang, C. Proulx, A. Tomberg and W. D. Lubell,
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S. Karamthulla and L. H. Choudhury, RSC Adv., 2014, 4,
3732.
1,2-Dimethoxy-4-oxocyclobutanecarboxylate (14). Yield: 80%;
1
pale yellow liquid; major isomer: H NMR (400 MHz, CDCl3) δ
4.25 (dd, J = 8.0, 4.0 Hz, 1H), 3.76 (s, 3H), 3.61 (s, 3H), 3.38
−3.46 (m, 1H), 3.42 (s, 3H), 3.06 (dd, J = 18.0, 4.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 199.8, 168.3, 96.2, 73.3, 58.6, 56.7,
1
52.8, 52.5; minor isomer: H NMR (400 MHz, CDCl3) δ 4.06 (t,
J = 8.0 Hz, 1H), 3.79 (s, 3H), 3.53 (s, 3H), 3.37 (s, 3H), 3.21 (dd,
J = 18.0, 8.0 Hz, 1H), 3.11–3.16 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 200.1, 167.0, 99.6, 75.1, 58.5, 55.5, 52.6, 48.9; HRMS
(ESI) for C8H13O5 [M + H]+ calcd 189.0762; found 189.0763.
Methyl
3,4-dihydro-3-methoxy-4-oxo-2-phenyl-2H-pyran-3-
carboxylate (15). Yield: 40%; pale yellow liquid; major isomer:
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H), 7.37–7.44
(comp, 5H), 5.65 (s, 1H), 5.60 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H),
3.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 189.2, 168.4, 164.5,
133.0, 129.5, 128.7, 128.5, 105.1, 85.4, 83.9, 55.1, 52.8; minor
1
isomer: H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H),
4 P. M. Truong, M. D. Mandler, P. Y. Zavalij and M. P. Doyle,
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5 M. A. Calter and P. M. Sugathapala, Tetrahedron Lett., 1998,
39, 8813.
6 M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides, Wiley-Interscience, New York,
1998.
7.37–7.44 (comp, 5H), 5.44 (s, 1H), 5.67 (d, J = 8.0 Hz, 1H), 3.67
(s, 3H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.9, 168.2,
163.8, 129.9, 129.0, 128.6, 127.4, 107.5, 84.3, 82.7, 56.1, 52.8;
HRMS (ESI) for C14H14O5 [M + H]+ calcd 263.0919; found
263.0931.
Methyl (E)-2,5-dimethoxy-3-oxohex-4-enoate (17). Yield:
1
82%; pale yellow liquid; H NMR (400 MHz, CDCl3) δ 5.76 (s,
1H), 4.22 (s, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.40 (s, 3H), 2.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 190.2, 176.3, 167.4, 93.1,
86.4, 57.3, 55.1, 51.7, 19.6; HRMS (ESI) for C9H15O5 [M + H]+
calcd 203.0919; found 203.0932.
7 (a) M. P. Doyle, M. S. Shanklin, H. Q. Pho and
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Methyl 2-methoxy-2-(1-tosyl-1H-pyrazol-3-yl)acetate (18).
Yield: 55%; pale yellow crystalline; H NMR (400 MHz, CDCl3)
8 (a) M. P. Doyle, M. N. Protopopova, C. S. Peterson,
J. P. Vitale, M. A. McKervey and C. F. Garcia, J. Am. Chem.
Soc., 1996, 118, 7865; (b) A. L. Crombie, J. L. Kane Jr.,
K. M. Shea and R. L. Danheiser, J. Org. Chem., 2004, 69,
8652.
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Synthesis of Natural Products, Part B: Bicyclic and Tricyclic
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1
δ 8.06 (d, J = 4.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.32 (d, J =
8.0 Hz, 2H), 6.48 (d, J = 4.0 Hz, 1H), 4.92 (s, 1H), 3.71 (s, 3H),
3.34 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4,
153.8, 146.0, 133.9, 132.5, 130.0, 128.1, 107.3, 76.8, 57.6, 52.5,
21.7; HRMS (ESI) for C14H16N2O5S [M + H]+ calcd 325.0858;
found 325.0850.
Acknowledgements
Support for this research from the National Science Foun- 11 (a) D. M. Tschaen, L. Abramson, D. Cai, R. Desmond,
dation (CHE-1212446) is gratefully acknowledged. Yuxiao Liu
was supported by the China Scholarship Council (CSC).
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Notes and references
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