Synthesis of acyclic ketones by catalytic, bidirectional homologation of formaldehyde with nonstabilized diazoalkanes. Application of a chiral diazomethyl(pyrrolidine) in total syntheses of erythroxylon alkaloids

Article abstract of DOI:10.1021/jo401377a

This work offers a catalytic approach to convergent ketone assembly based upon formal and tandem C-H insertion of diazoalkanes in the presence of limiting amounts of monomeric formaldehyde, which is easily generated as a gas by thermolysis of the inexpensive and abundant paraformaldehyde (～30 USD/kg). The method forms di-, tri-, and even tetrasubstituted acetones with high efficiency, and it has streamlined a synthesis of (-)-dihydrocuscohygrine in which the absolute stereochemistry of a proline-based starting material is preserved. Assisted by the advent of new protocols for hydrazone oxidation, we also provide full details on handling non-carbonyl-stabilized diazo compounds.

Full text of DOI:10.1021/jo401377a

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pubs.acs.org/joc
Synthesis of Acyclic Ketones by Catalytic, Bidirectional
Homologation of Formaldehyde with Nonstabilized Diazoalkanes.
Application of a Chiral Diazomethyl(pyrrolidine) in Total Syntheses
of Erythroxylon Alkaloids
Andrew J. Wommack and Jason S. Kingsbury*,†
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: This work offers a catalytic approach to convergent ketone assembly based upon formal and tandem C−H
insertion of diazoalkanes in the presence of limiting amounts of monomeric formaldehyde, which is easily generated as a gas by
thermolysis of the inexpensive and abundant paraformaldehyde (∼30 USD/kg). The method forms di-, tri-, and even tetra-
substituted acetones with high efficiency, and it has streamlined a synthesis of (−)-dihydrocuscohygrine in which the absolute
stereochemistry of a proline-based starting material is preserved. Assisted by the advent of new protocols for hydrazone
oxidation, we also provide full details on handling non-carbonyl-stabilized diazo compounds.
and acyclic ketones (c) from cycloalkanone and aldehyde electro-
philes, respectively.11−13 More recently, we recorded the first
examples of enantioselective medium ring aryl ketone synthesis
by ligating bis- and tris(oxazolines) to the Sc(OTf)3 catalyst in
situ.14,15 The mild diazoalkane−carbonyl homologation reac-
tion16−18 offers the strategic benefit of a ring expansion or chain
extension, giving two new bonds to carbon with dinitrogen as
the only stoichiometric byproduct.
As shown herein, the substituted diazomethanes (a) can be
readily prepared from the corresponding aldehyde or ketone.
This suggests that iterative applications of diazoalkane−carbonyl
homologation can lead to even greater product diversity. For
those carbonyl compounds that cannot be purchased or easily
synthesized by alternative routes, some permutations on struc-
ture may be harder to derive from simple pairings of diazoalkane
and acceptor. In a move toward full modularity, we considered
using paraformaldehydean inexpensive and widely available
carbon sourceas a means to prepare any starting material
required for the methodology. On the basis of symmetry pre-
sent in several small natural products and pharmaceutical agents
(see Chart 1),19−24 we chose to begin our investigation by
studying the catalysis of double25−28 diazoalkyl carbon insertion
events with formaldehyde as a 1-C feedstock (a→d, Scheme 1).
In this article, we report efficient access to a number of materials-
and biologically relevant ketones that were formerly unknown
or quite difficult to prepare. Given pervasive concerns about the
toxicity and instability of diazo compounds in general, we also
INTRODUCTION
■
Nucleophilic attack on the carbonyl group remains a standard
practice for building C−C bonds. Acyclic ketones, for instance,
are routinely prepared by organometal addition and reoxida-
tion. Methods that render the event catalytic in a metal and do
not require later readjustment of the oxidation state at the electro-
philic carbon are highly desirable. One transformation with
these features is the Lewis-acid-catalyzed Roskamp synthesis of
β-keto esters from alkyl diazoacetates and aldehydes,1−3 and a
substituted asymmetric variant was recently reported.4 A reliance
on diazoacetate nucleophiles, however, brings limitations to the
types of products one can prepare. α-Alkyl-β-keto esters give
simple alkanones upon hydrolysis and decarboxylation, but not
those with a stereogenic center at the α or α′ carbon.
In an effort to uncover general and direct strategies for prepar-
ing substituted carbonyl compounds, our laboratory is explor-
ing the use of non-carbonyl-stabilized5−7 diazoalkanes8−10 (a)
as carbon nucleophiles for organic synthesis. As shown in Scheme 1,
we have developed catalytic entries to both α-chiral cyclic (b)
Scheme 1. Varied Strategies for Ketone Synthesis by the
Diazoalkane−Carbonyl Homologation Reaction
Received: June 25, 2013
© XXXX American Chemical Society
A
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addition and subsequent heterocyclization. If 3-phenylpropion-
aldehyde is exposed to standard conditions for hydrazone forma-
tion (excess hydrazine hydrate, no solvent, 80 °C), 5-phenyl-
1H-pyrazole can be isolated in an unoptimized 72% yield by
simple extraction (Scheme 2). In stark contrast, mild treatment
Chart 1. Synthetic and Naturally Occurring Medicinal
Agents for Which a Symmetrical 1,3-Disubstituted
Propanone Is a Key Structural Feature
Scheme 2. Divergent Reaction Outcomes in Condensation
with Distinct Hydrazine Reagents
with TIPSNHNH2 and 4 Å molecular sieves (THF, 0 °C) affords
the target TIPS-hydrazone in quantitative yield, and it can be
stored indefinitely below 4 °C under nitrogen. Additional attri-
butes of the monosilyl hydrazine include the fact that (1) it is
readily synthesized and distilled in quantity from a mixture
triisopropylsilyl chloride and hydrazine33 and (2) compared to
bis(tert-butyldimethylsilyl)hydrazine,30,32 it removes the need
for Lewis acid catalysis of the condensation and prevents
coproduction of a high molecular weight silanol that must be
removed from the sample by prolonged warming under high
vacuum.
disclose procedures for their safe manipulation as pure, low-
temperature organic solutions.
RESULTS AND DISCUSSION
■
At the outset, our program benefited from three outstanding
protocols for nonstabilized diazoalkane synthesis,29−31 all of
which rely on oxidation of the corresponding hydrazone. The
most recent, discovered by Brewer, involves dehydrogenation
with the Swern reagent.29 Under optimal conditions of solvent
and stoichiometry, pure monoaryl, diaryl, and mixed alkyl−aryl
diazomethanes are obtained in high yield by simple filtration of
triethylammonium chloride from the reaction mixture. With the
exception of p-methoxyphenyldiazomethane (19b), all aryl
and heteroaryl nucleophiles reported herein were synthesized
by Brewer’s approach directly from unprotected hydrazones.
Regrettably, this entry is less effective for mono- and dialkyl
diazomethanes, perhaps because of lability in the presence of
dimethyl sulfide, a nucleophilic coproduct of the oxidation. It is
here, however, that alternative methods offer a solution. Myers
has oxidized N-tert-butyldimethylsilylhydrazones with (difluoroiodo)-
benzene as a means to furnish diazoalkanes in situ for acid esteri-
fication reactions that are wide in scope.30 This clever applica-
tion of the bulky N-silyl group renders the intermediate
hydrazones bench-stable and shields them against dimerization
to the corresponding azines.32 A third innovation provided by
Shechter31 concerns Pb(OAc)4/tetramethylguanidine/DMF as
a reagent trio for hydrazone oxidation beneficial for another
reason: the choice of DMF as cosolvent permits clean and near
quantitative extraction of the diazo compound from the
reaction mixture upon addition of cold hexane or pentane.
Anticipating the great advantage that high-purity diazoalkane
solutions would offer in the context of reaction development
and catalyst discovery, we captured the essential features in
each of the latter two methods to develop a “hybrid” protocol
for preparative access to the more challenging aliphatic and
α,β-unsaturated nucleophiles.
Further optimization of the carbonyl-to-diazo interchange was
carried out with (S)-citronellal as a model aliphatic aldehyde
(Scheme 3). Treatment with TIPSNHNH2 (1 equiv, THF,
Scheme 3. Efficient Two-Pot Diazoalkane Synthesis from
(S)-Citronellal
23 °C, 4 Å MS) gave rapid conversion to silylhydrazone 1,
albeit with 5−8% contamination by azine (1H NMR analysis).
The impurity can derive from adventitious desilylation32 of the
reagent by the water of condensation. Azine formation is
avoided by cooling the mixture (0 °C), switching to pulverized
or powdered 4 Å sieves, and adding the reagent slowly (2−4 h,
syringe pump) to better control release of water during the
reaction. With these modifications, 1 is obtained in >98% yield
and purity by filtration and solvent removal. The blocking
group is then cleaved by exposure to a commercial solution of
TBAF (THF, 0 °C, 5 min), and after a solvent switch (to 0.1 M
DMF/tetramethylguanidine), the free hydrazone is treated with
1.1 equiv of oxidant34 at −45 °C. Subsequent washing of the
mixture with three equal-volume portions of cold pentane and
siphoning31 of the organic layers by syringe gives a bright
yellow hydrocarbon extract laden with 2. After washing the
solution with 30% KOH at −30 °C to remove any traces of
DMF in the extract, the diazoalkane is directly titrated for use
or redissolved in a less volatile solvent (e.g., toluene) for storage
and dispensing as a stock solution. The 60% yield reported here
corresponds to purified (S)-citronellal benzoyl esterobtained
by acidic quench of an aliquot (benzoic acid, THF, −45 °C),
Time and much experimentation point to triisopropylsilyl-
hydrazine33 as a superior reagent for initial condensation with
the ketone or aldehyde. Propargylic carbonyls perhaps best
illustrate this fact since they are especially prone to Michael
B
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aqueous workup, and chromatography. The yield is a conserva-
tive estimate of the preparative efficiency for three distinct
operations (four steps total, the first two of which are effected
without purification).
Table 1. Diazoalkane Benzoylations Secure the Active Titers
in Solution
The lower diazoalkanes are acutely toxic, explosive gases at
room temperature.35,36 Indeed, this was the principal deterrent
to industrial use of diazomethane for almost a century despite
its wide and demonstrated utility.37 However, recent develop-
ments allow for diazomethane production at levels of 50−60 metric
tons per year.38 Furthermore, anecdotal evidence suggests that
nearly39 all diazomethane explosions have occurred during its
solvent-free distillation, and controlled detonation studies
confirm that the hazard is a close function of the reagent’s
volatility.38 Substituents at the diazoalkyl carbon atom add
molecular weight and stability, and the protocol in Scheme 3
has now safely been applied to a wide range of nonvolatile
derivatives that are brightly colored viscous oils or crystalline
solids at or below 23 °C (Figure 1). Importantly, the two-pot
Figure 1. Toluene stock solutions of substituted diazomethanes show
longevity upon prolonged storage at or below −20 °C and are readily
assayed for the active nucleophile by esterification with benzoic acid.
Alkyldiazoalkanes are yellow to orange in color; conjugated species are
deep red or violet in comparison.
sequence does not require isolation, purification, or even warm-
ing of the potentially hazardous diazo compounds. All required
manipulations, including titration, are carried out in solution at
low temperature. Diazoalkane 2 has characteristic signals in both
its 1H NMR (δ 3.33 ppm, triplet, J = 6.4 Hz) and IR (2025 cm−1)
spectra. Regarding longevity in solution, the half-life of 2 is
approximately 18 h at 23 °C in benchtop CDCl3. Prolonged
stability can be achieved with recourse to a basic additive such as
Et3N, and no measurable drop in titer is observed for solutions of
2 prepared from rigorously air-free, purified solvent. A control
reaction with phenyldiazomethane (undertaken to preclude
protic catalysis of homologation by hydrates of Sc(OTf)3)
shows that in the presence of 1 mol % of TfOH, the primary
byproduct is stilbene (∼1:1 E:Z). By contrast, the main
pathway for decomposition with 1 mol % of Sc(OTf)3 (in the
absence of a carboxylic acid or carbonyl electrophile) is azine
formation, for which there is ample precedent.40
The aforementioned quench with benzoic acid serves to
accurately titrate any given stock solution prior to its use in a
catalytic homologation reaction. It also permits a quantitative
assessment of hydrazone synthesis and oxidation efficiencies
across a broad range of carbonyl precursors. Table 1 provides
representative results for small-scale benzoylations of stock
solution aliquots; yields correspond to chromatographically
pure ester and are based on the starting ketone or aldehyde.
a
Four-step yield for chromatographically pure benzoate based on the
starting ketone or aldehyde (TIPS-hydrazone formation, desilylation,
Pb(IV) oxidation/extraction, and esterification). Three-step yield for
pure ester by oxidation of the free hydrazone with the Swern reagent.
b
Some critical ramifications of this data set include the following:
(1) Aliphatic mono- and disubstituted diazomethanes are
obtained in moderate four-step yields that are routinely lower
than their aryl and α,β-unsaturated counterparts (entries 1−5).
This trend derives from their heightened sensitivity relative to
vinylic examples (entries 6−8) and mechanical losses implicit
to their isolation from DMF/pentane bilayers. (2) Good to
excellent esterification yields are observed for both terminal and
internal aryl diazomethanes (entries 9−12) because of the
C
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simplicity of Brewer’s Swern dehydrogenation29 method and
the universally robust nature of benzylic hydrazones. Here, the
overall step count is necessarily lower since temporary N-silyl
protection of the hydrazone is not needed. (3) The time invest-
ment in running an ester synthesis and purifying the reaction
mixturejust for the sake of knowing with certainty the active
nucleophilic titercan be dramatically reduced by choosing
2-fluorobenzoic acid for the formal OH insertion. In results
communicated previously,41 our group has devised a convenient
19F NMR-based method that requires <15 min of experi-
mental time and can be performed with micromolar quantities
of diazoalkane. A key advantage to the procedure is that
conversion, and ultimately diazoalkane concentration, is
calculated based on integration of the only two observable
expulsion of CO; see eq 1). The latter materials are now of
great theoretical and practical importance in nanoscience.46
Hughes has communicated nice advances in dibenzyl ketone
synthesis,47,48 but stoichiometric amounts of either the Collman
(Na2Fe(CO)4) or van Leusen (tosyl methylisocyanide) reagent
are needed, and ketone yields are only moderate for electron-poor
benzylic bromides. We were motivated to improve the
shortcomings of existing methods in order to facilitate studies
aimed at a controlled synthesis of carbon nanotube end-caps.49−51
Opening experiments with p-butylphenyldiazomethane
(19a) identified a preferred means for delivering monomeric
formaldehyde to a mixture of the catalyst and nucleophile.
Attempts to use a titrated solution of formaldehyde52,53 or to
depolymerize trioxane with the Sc(OTf)3 catalyst in situ54 were
thwarted by repolymerization and lower yields, respectively.
However, as shown in entry 1 of Table 2, 20a is isolated in 88%
yield by “cracking” paraformaldehyde with a heat gun and
1
19F signals. Attempts to apply H NMR spectroscopy to other
substituted benzoic acid derivatives is often successful, but it
does not prove to be a universal solution because of problems
with overlapping resonances. To conclude, two of the esters in
Table 1 (entries 2 and 4) are ortho-fluorobenzoates that served
to corroborate yields obtained with our more rapid and direct
assay based on quantitative 19F NMR spectroscopy.41
An even greater benefit to practicality could follow work
aimed at consuming the nucleophiles the instant they are pro-
duced by the application of flow42,43 or in situ5,30 techniques.
Nonetheless, we have been fortunate to identify inexpensive
scandium(III) salts as uniquely effective catalysts for diazoalkane−
carbonyl homologation, a discovery that may not have been
possible without access to high-purity diazoalkane solutions.
As illustrated by the homologation products shown in Chart 2,
Table 2. Symmetric Ketones by Catalytic Chain Elongation
a
with CH2O
Chart 2. Representative Diazoalkane−Carbonyl
Homologation Products
the catalytic carbon insertion methods we have reported toler-
ate severe steric crowding in the diazoalkane, giving congested
quaternary carbon atoms in excellent yield (96% of 15).11
Noteworthy is that disubstituted (internal) diazo compounds react
smoothly with unstrained electrophiles, and the procedures are
scalable. An excellent demonstration of preparative utility is given
by the synthesis of 16 in 97% yield from 1 g (5 mmol) of cyclo-
hexanone.11 This and other spirocycles cannot be easily pre-
pared by enolate (or metalloenamine) alkylation or even
α-vinylation protocols.44 The 74% recovery of benzaldehyde ho-
mologation product 17 shows compatibility with common halogen
groups as well as complexity in the nucleophile.12 Finally, severe
steric bulk is also tolerated in the electrophile; reaction of
pivaldehyde with a citral-based diazoalkane gives neither stereo-
mutation of the starting olefin nor isomerization into conjugation
with the carbonyl group (→18, 88% yield).12
Armed with confidence that the high reaction efficiencies
would translate well to the desired two-directional carbo-
functionalization of formaldehyde, we turned our attention to
the synthesis of 1,3-diarylacetones as a proof of concept. Their
Knoevenagel condensations with diarylethanediones e give first
tetraarylcyclopentadienones f and then hexarylbenzenes g
(following Diels−Alder cycloaddition45 with diarylethynes and
a
b
For the conditions above with flash pyrolysis (CH2O)n·H2O. Over
c
three steps based on 19F NMR titration with o-FC6H5CO2H. Isolated
yield after column chromatography. Run with Sc(tmhd)3. See text.
d
e
D
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passing the gas through a warm steel cannula55 into a toluene
suspension of dry Sc(OTf)3 with simultaneous addition of 19a
at −20 °C. Reactions are complete in less than 10 min, and
efficiency stays high with representative electron-donating
(20b, entry 2) and -withdrawing groups (20c,d, entries 3 and 4).
The product of entry 5 (20e) is noteworthy because the alkyne
substituents are suitable handles for accessing larger phenylene
oligomers and dendrimers.46 As shown in entry 6 of Table 2,
ester groups are also tolerated. LiOH hydrolysis of 22a gives
22b, a diacid natural product found in the bark of Cerbera
manghas that may exert a role in the plant’s analgesic, anticon-
vulsant, cardiotonic, and hypotensive properties.24 Hetereoar-
omatic (23 and 25, entries 7 and 8) and aliphatic nucleophiles
(27) are also viable. The product of entry 9 is a novel tetrasub-
stituted acetone which exhibits a preference for Sc(tmhd)3
(tmhd = 2,2,6,6-tetramethyl-3,5-heptanedianato, or t-butyl-
(acac)) as the catalyst, consistent with other reactions involving
dialkyl diazomethanes.11 The lower 55% yield recorded for 28
is still respectable given the double β-branching present in
diazoalkyl component 27.
Scheme 4. Rates for the Tandem C−H Insertion Process
Decrease with Bulky Diazo Compounds, Permitting Access
to Dissymmetric Ketones
Scheme 5. Bis(pyrrolidine) Alkaloids Result from a
Divergence in the Biosynthetic Pathway That Gives Tropane
Alkaloids Such as Cocaine
Lastly, the bis(arylated) propan-2-ones 30 and 32 are now
structures available to our colleagues for the elaboration of
bowl-shaped polyarenes and carbon nanotube end-caps.56,57
Previous methodologies48 produce these ketones only with
difficulty or not at all, but the double homologation reactions
(entries 10 and 11) proceed in workable yield and add insight
concerning steric hindrance in the diazoalkane. The yield of
product from bromonaphthyldiazomethane 29 is 74%, just 10%
lower than that for 2-bromophenyldiazomethane (data not
shown). However, with bromophenanthryldiazomethane 31,
the predominant product (85% yield) is the arylacetaldehyde.
Presumably, the greater steric bulk in the reactant diminishes
the rate of the second formal C−H insertion. The reported
67% yield for 32 is based on two steps in which the
arylacetaldehyde has been resubjected to the reaction
conditions (without formaldehyde) after filtration through a
pad of silica.
Scheme 6. Short Enantiospecific Synthesis of Erythroxylon
Alkaloids by Two-Stage Carbon Insertion with a Chiral
Diazomethyl(pyrrolidine)
The predominance of a monoinsertion product observed
with a doubly o-substituted reagent like 31 (entry 11) derives
from the fact that thermal cracking of paraformaldehyde invariably
introduces an excess of monomeric electrophile as the reaction
takes place. This further suggests that successful bidirectional
syntheses with the less hindered nucleophiles (entries 1−10)
may benefit from low solubility of the gaseous formaldehyde
under the reaction conditions (toluene, −20 °C). In any event,
we now find that other bulky diazoalkanes show a similar
reluctance toward bidirectional product formation, and this
permits a straightforward entry to nonsymmetrical ketones.
For instance, as shown in Scheme 4, diphenyl and dicyclohexyl
diazomethane give rise to the corresponding disubstituted
acetaldehydes 33 and 36 in 79 and 91% yield under the former
conditions of Table 2. Succeeding mergers with two different
diazo compounds (34 and 37) then provide dissymmetric
alkanones 35 and 38 in good yield. Additional experimentation
will be needed to establish the full scope of α-substituted
aldehyde and acyclic ketone synthesis based on tandem
formaldehyde homologation, but such opening results certainly
underscore the advantages of its implicit modularity.
hygrine (see 44, Scheme 6) was identified in the same plant and
in members of the Erythroxylaceae family.60−62 Labeling studies
confirm that the metabolites are byproducts of tropane alkaloid
biosynthesis, and they often coextract with other Solanaceae
alkaloids.63 Specifically, ornithine gives rise to N-methyl-Δ1-
pyrrolinium 39, affording hygrine-1-carboxylic acid (40) upon
its reaction with acetoacetic acid.63 Whereas dehydrogenation
and internal C−C bond formation afford the tropane skeleton,
decarboxylation of 40 and condensation with a second equi-
valent of 39 gives cuscohygrine. Along with bioactivity studies,64,65
two total syntheses66,67 of dihydrocuscohygrine have appeared
in which absolute configuration is secured by the use of a chiral
auxiliary or enzyme catalysis.
A more concise path of synthesis for the natural products
features two-directional formaldehyde homologation and is
shown in Scheme 6. We had planned to begin the sequence
with commercially available N-methyl prolinol, as this would
furnish the target molecules without the need for a protecting
group. However, upon oxidation, the amino aldehyde 41b was
unstable and difficult to isolate in pure form. The more hin-
dered N-benzyl aldehyde 41a proved to be more robust and
was easily prepared from (S)-proline on gram scale by the
As a demonstration of utility for the double homologation
method, we targeted a pair of bis(pyrrolidine) alkaloids found
in the leaves of Erythroxylon coca. Structure elucidation58,59 of
C2-symmetric cuscohygrine (Scheme 5) was first reported in
1889, long before its reduction product (−)-dihydrocusco-
E
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sequence: Fisher esterification, N-benzylation, reduction, and
Swern reoxidation. The needed aldehyde→diazomethyl con-
version was then achieved as described above (Scheme 3) with
temporary N-TIPS protection to prevent the formation of
azine.30,32 In two flasks over the three steps of condensation,
desilylation, and Swern oxidation,29 (diazomethyl)pyrrolidine
42a forms in 36% yield based on the purified o-fluorobenzoate
43. 19F NMR analysis of the esterification reaction serves to
establish a titer for the solution of diazoalkane, which is not
concentrated or even warmed. Notably, chiral SFC analysis of
ester 43 shows that it forms in >98% enantiomeric excess,
confirming that no racemization occurs during diazotization.
We thus turned our attention to the key diazoalkyl insertion
step. Under our standard conditions (Table 1), a di-N-benzyl
ketone was recovered in an unoptimized 60% yield after silica
gel chromatography. However, due to growing concern that
this sensitive material might racemize or epimerize upon expo-
sure to mild acid (vide infra), the homologation product
(>98% ee by SFC analysis) was taken on without purification.
We were delighted to find that debenzylation and subsequent
methylation68 in the same pot gives (−)-dihydrocuscohygrine
(44) in 43% yield from 42a. The seven resonances visible in its
13C NMR spectrum are a signature of the C2-symmetry and
indicate that 44 was prepared free of a meso contaminant. In
addition, the target was formed in 98% ee on the basis of chiral
alkaloid (−)-dihydrocuscohygrine starting from (S)-N-benzyl
prolinol. Noteworthy is that sensitive, α-chiral aldehydes are
transformed to the corresponding diazo compounds for use in
esterification or homologation reactions with no racemization.
EXPERIMENTAL SECTION
■
General. Any synthetic chemist who wishes to repeat or adapt
experiments reported herein should exercise caution and recognize
that all diazoalkanes are likely toxic and shock-sensitive. Although
these materials can be assayed in neat form by both NMR and IR
spectroscopy, our procedures do not call for isolation, distillation, or
even warming of the potentially hazardous diazo compounds. All
transfers and manipulations, including reagent storage, are carried out
in solution at low temperature, and the active titer for a given diazo
compound is conveniently obtained by acidic quench of a stock
solution aliquot with 2-fluorobenzoic or benzoic acid. In cases where a
volatile diazoalkane is being prepared or a large-scale (>1 g) experi-
ment is desirable, adequate precautions should be taken, such as the
use of a safety shield. Gloves must be worn at all times when handling
diazoalkane solutions and vessels.
IR spectra were recorded on a FT-IR spectrophotometer, νmax in
1
cm−1. H NMR spectra were recorded on a 400 MHz spectrometer
with chemical shifts reported in parts per million from TMS with the
solvent resonance as the internal standard (CHCl3: δ 7.26). 13C NMR
spectra were recorded on the same instrument (100 MHz) with
complete proton decoupling. Chemical shifts are reported in parts per
million from TMS with solvent as the internal standard (CDCl3:
δ 77.23). High-resolution mass spectra were obtained with a TOF
detector using Data Acquisition in Real Time (DART) or with
ESI-TOF in positive ion mode. The enantiomer ratio for 43 was
determined by supercritical fluid chromatography (SFC) with a
Chiralcel OD-H column (0.46 cm ϕ × 25 cm). Enantiopurity for 44
was determined by chiral GLC analysis on a Chiraldex BDM column
(30 m × 0.25 mm) with the injection inlet, column, and detector all
set to a constant temperature of 250 °C.
Unless stated otherwise, all reactions were carried out in flame-dried
glassware under an atmosphere of nitrogen in dry, degassed solvents
using standard Schlenk or vacuum-line techniques. THF, Et2O,
toluene, CH2Cl2, DMF, pentane, and hexanes were dispensed from a
multiport, inert solvent purification system under a positive pressure
stream of high-purity argon. Triisopropylsilylhydrazine was prepared
as formerly described.33 4-Butylbenzaldehyde and 1,1,3,3-tetramethyl-
guanidine were vacuum distilled over calcium hydride. 4-Methoxy-
benzaldehyde, 4-formylbenzonitrile, 4-((trimethylsilyl)ethynyl)benzal-
dehyde, methyl 3-formylbenzoate, furfural, thiophene-2-carboxaldehyde,
dicyclopropylmethanone, dicyclohexylmethanone, and 3,4-dihydro-
naphthalen-1(2H)-one were vacuum distilled. 4-Nitrobenzaldehyde
was recrystallized from water−isopropyl alcohol. Pb(OAc)4, after
dissolution in minimal hot glacial acetic acid, deposited as bright white
needles upon cooling. The crystals were washed in a fritted Schlenk
filter with dry pentane, dried under high vacuum, and then stored in a
glovebox at −20 °C. Sc(OTf)3 (99%) was finely powdered and dried
at 200 °C over P2O5 for 24 h under vacuum (approximately 0.1 mm of Hg).
2-Fluorobenzoic acid was sublimed at 100 °C under vacuum and dried
over P2O5. Hydrazine hydrate, TBAF, 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-
acetaldehyde, 9-bromophenanthrene, 1-bromo-2-methylnaphthalene,
benzophenone, powdered 4 Å molecular sieves, (S)-1-methyl-2-pyrroli-
dinemethanol, benzoic acid, and Sc(tmhd)3 were obtained commer-
cially and used as received. The procedure below for preparing an
unprotected arylhydrazone is based on one reported previously.71
Flash column chromatography was carried out with silica gel 60 and
driven with compressed air. Analytical TLC was performed with
250 μm silica gel 60 F254 plates and either a ceric ammonium molybdate,
potassium permanganate, ninhydrin, or dinitrophenylhydrazine stain
for spot visualization.
GC analysis ([α]D = −102, c 0.76, acetone; lit.34 [α]D
=
23
23
−105, c 2.05 acetone).
Success in this route can be attributed to a fortuitous reduc-
tion of the central carbonyl group under the conditions of
hydrogenolysis. In this manner, (−)-dihydrocuscohygrine is
prepared without the intermediacy of cuscohygrine, which is
yet to be obtained in optically active form.60,66 This results
from facile stereomutation, presumably by a retro-Mannich or
retro-Michael (β-elimination) pathway.69 The existence of
related isomerizations within the oxindole family of alkaloids
for structures like horsfiline,70 which lack an α-hydrogen atom,
would appear to point to the former as the operative mechanism.
By analogy to studies by Stapper and Blechert, we failed to find
conditions for mild, efficient oxidation of 44 to cuscohygrine
(45).66 Jones oxidation affords the ketone in 81% yield as a
racemate (step e, Scheme 6), but other reagents give incomplete
conversion or decomposition of the material. Despite the
instability of amine carboxaldehyde 41b, its corresponding
diazo compound 42b could be prepared in 23% yield over four
steps by careful handling of the aldehyde. In a final attempt to
access homochiral cuscohygrine, 42b was treated with form-
aldehyde and Sc(OTf)3, and the mixture was filtered through
neutral alumina. The natural product is formed cleanly in low
yield, but 1H NMR analysis still shows it to be indistinguishable
from both synthetic and naturally occurring cuscohygrine, again
implying that the meso and D,L forms are interconverting even
under neutral conditions.60,66
CONCLUSIONS
■
In conclusion, we report an efficient catalytic approach to
ketones by a two-stage coupling event between monomeric
formaldehyde and non-carbonyl-stabilized diazo compounds.
The reaction is quite suitable for preparing 1,3-diarylacetone
building blocks for materials science, and well-established
methods for the synthesis and handling of diazoalkane stock
solutions are provided herein. The mild reaction conditions,
together with the brevity ensured by a bidirectional strategy, have
facilitated an enantiospecific synthesis of the bis(pyrrolidine)
Representative Procedure for Synthesis and Handling of
Aliphatic Diazoalkanes (Benzoic Acid Quench). (S)-(−)-Citro-
nellal N-(Triisopropylsilyl)hydrazone (1). A 50 mL round-bottom
flask equipped with a Teflon-coated stir bar and a jointed vacuum
F
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The Journal of Organic Chemistry
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adapter was charged with powdered 4 Å molecular sieves (4 g) and
then flame-dried under high vacuum. After backfilling with nitrogen, the
vacuum adapter was swapped for a rubber septum, and (S)-(−)-citronellal
(1.70 g, 11.0 mmol, 1.0 equiv) and THF (22 mL) were added
successively with stirring. The suspension was cooled to 0 °C, and
triisopropylsilylhydrazine (2.08 g, 11.0 mmol, measured by mass
difference into a gastight syringe) was slowly added dropwise over 2 h
with a syringe pump. After 30 min of additional stirring, the mixture
was filtered through a pad of Celite in a sintered glass Schlenk filter
into a dry 100 mL round-bottom flask cooled to 0 °C. The original
flask, molecular sieves, and Celite were washed with two additional
10 mL portions of cold Et2O. The resulting homogeneous filtrate was
concentrated on a rotovap equipped with an oil-free diaphragm pump
(3−10 Torr), affording 3.57 g (11.0 mmol, >98%) of 1 as a colorless
CDCl3): δ 8.04 (dd, J = 8.4, 1.3 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.44
(m, 2H), 5.10 (t, J = 6.6 Hz, 1H), 4.36 (m, 2H), 2.01 (m, 2H), 1.86−
1.21 (m, 5H), 1.67 (s, 3H), 1.60 (s, 3H), 0.97 (d, J = 6.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 167.0, 132.9, 129.6, 128.4, 124.7, 117.1,
63.6, 37.2, 35.7, 35.6, 29.7, 25.9, 25.6, 19.7, 17.8. HRMS (ESI+) calcd
+
for C17H25O2 [M + H]+: 261.1855; found 261.1856.
1-(2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethylidene)-2-(triisopropyl-
silyl)hydrazone. 2-(2,2-Dimethyl-1,3-dioxolan-4-yl)acetaldehyde
(0.166 g, 1.15 mmol), THF (2.5 mL), and triisopropylsilylhydrazine
(0.216 g, 1.15 mmol, 1.0 equiv) were combined with powdered 4 Å
molecular sieves exactly as described above for structure 1. Filtration
and concentration provided 0.362 g (1.15 mmol, >98%) of product as
1
a colorless oil (∼3:2 E:Z mixture, >98% pure by H NMR analysis).
Alternative Procedure for Diazoalkane Synthesis and
Manipulation (2-Fluorobenzoic Acid Quench). 4-(2-Diazo-
ethyl)-2,2-dimethyl-1,3-dioxolane. A 50 mL round-bottom flask
equipped with a large Teflon-coated stir bar was charged with 1-(2-
(2,2-dimethyl-1,3-dioxolan-4-yl)ethylidene)-2-(triisopropylsilyl)-
hydrazone (362 mg, 1.15 mmol) and 10 mL of THF. After cooling
the colorless solution to 0 °C, 1.15 mL of TBAF (1.0 M in THF,
1.15 mmol, 1.0 equiv) was added by syringe, at which point a bright
orange discoloration immediately occurred. The solution was stirred
for 10 min and then concentrated under low vacuum on a rotovap.
Without purification and in the same flask, the crude hydrazone
was freed of residual solvent under high vacuum, backfilled with
nitrogen, and redissolved in 7.6 mL of DMF and 2.88 mL of 1,1,3,3-
tetramethylguanidine (23.0 mmol, 20 equiv). The resulting light pink
solution was cooled to −45 °C (dry ice/1:1 ethanol−ethylene
glycol),72 and Pb(OAc)4, finely powdered and weighed into a vial in a
glovebox (561 mg, 1.26 mmol, 1.1 equiv), was added in a single portion.
After 45 min of stirring at −45 °C, 50 mL of ice cold pentane was added
and the mixture was transferred to a separatory funnel. Upon removing
the colored organic layer, the DMF layer was washed three times with
25 mL of cold pentane and discarded as waste. The combined extracts
were quickly washed twice with cold 25 mL volumes of saturated
ammonium chloride and once with 25 mL of cold (−20 °C) 30%
aqueous potassium hydroxide.31 The diazoalkane solution was then
dried over potassium carbonate, filtered with a sintered glass fritted
filter, and concentrated under high vacuum at −45 °C to afford 4-(2-
diazoethyl)-2,2-dimethyl-1,3-dioxolane as an orange oil. The oil was
immediately dissolved in toluene and transferred (quantitatively, with
rinsing) by cannula to a 1.00 mL volumetric flask. The active titer was
assayed by esterification with 2-fluorobenzoic acid.41 Thus, 100 μL of
the stock solution was added dropwise by syringe to a cold (−45 °C)
flask containing a 1.0 M Et2O solution of 2-fluorobenzoic acid (16 mg,
0.115 mmol, 1.0 equiv based on theoretical). Upon warming from
−45 °C, the reaction mixture became colorless and nitrogen evolution
was observed. The solvent was removed under reduced pressure,
and the contents of the flask were dissolved in CDCl3 for 19F NMR
analysis. Based on integration of the unreacted 2-fluorobenzoic acid
to the newly formed benzoate ester (1.44:1), the active titer for the
diazoalkane stock solution in toluene was obtained (0.47 M, 41% yield).
Representative Procedure for the Preparation of an
Unprotected Arylhydrazone. 4-Nitrobenzaldehyde Hydrazone.
In a 2 dram glass vial containing a Teflon-coated stir bar, 4-nitrobenz-
aldehyde (0.453 g, 3.00 mmol) was suspended in 2.0 mL of hydrazine
hydrate. After sealing the vial with a Teflon-lined screw cap, the hetero-
geneous mixture was stirred rapidly with heating at 100 °C. After 6 h, the
mixture was cooled to 23 °C and the product was extracted with three
2 mL volumes of CH2Cl2. The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated under reduced pre-
ssure to provide 0.479 g (2.90 mmol, 96%) of an oil. The material was
1
oil (∼9:1 E:Z mixture, >98% pure by H NMR analysis). If not used
directly in a subsequent oxidation reaction, this material was stored
under nitrogen at −20 °C.
(S)-3,7-Dimethyl-1-diazooct-6-ene (2). A flame-dried 50 mL
round-bottom flask with an oversized Teflon-coated stir bar was charged
with 1 (490 mg, 1.5 mmol, 1.0 equiv) and 10 mL of THF. After
cooling the colorless solution to 0 °C, 1.51 mL of TBAF (1.0 M in
THF, 1.51 mmol, 1.0 equiv) was added by syringe, at which time a
yellow-orange discoloration was observed. The solution was stirred for
10 min and then concentrated with a nitrogen purge. Without purifica-
tion and in the same vessel, the crude hydrazone was freed of residual
solvent under vacuum, purged with nitrogen, and redissolved in 15 mL
of DMF and 3 mL of 1,1,3,3-tetramethylguanidine (36.0 mmol,
24 equiv). The resulting yellow solution was cooled to −45 °C (dry
ice/acetonitrile bath) and Pb(OAc)4, finely powdered and weighed
into a large vial in a glovebox (736 mg, 1.66 mmol, 1.1 equiv), was
added in a single portion. After 45 min of stirring at −45 °C, 15 mL of
precooled pentane was added and the mixture was stirred very
vigorously for 1 min. The upper, bright yellow pentane layer was removed
by syringe and transferred to a 100 mL pear-shaped flask and cooled to
−78 °C. Extraction was repeated two to three more times (15 mL of
pentane) until the extract was no longer visibly colored. The organic
layers were washed twice with 15 mL of saturated ammonium chloride
and once with 15 mL of 30% aqueous potassium hydroxide.31 In each
case, prolonged (>30 s) vigorous stirring was allowed, the aqueous
layer was removed by syringe, and warming above the freezing point
(−20 °C) was required for miscibility; these washes serve (respectively)
to remove residual tetramethylguanidine and DMF from the organic
extracta prerequisite for efficient catalytic carbon insertion but not
simple esterification.
(S)-3,7-Dimethyloct-6-en-1-yl Benzoate (3). The solution of
diazoalkane 2 was transferred with rinsing (freezing the final aqueous
wash is most convenient) to a 100 mL round-bottom flask and concen-
trated under high vacuum at −45 °C to give 2 as a yellow oil. The
NMR data that follow represent direct assay of this material without
further purification. 1H NMR (400 MHz, CDCl3): δ 3.32 (t, J =
6.4 Hz, 1H), 2.32−2.23 (m, 2H), 1.92−1.83 (m, 2H), 1.59 (s, 3H),
1.51 (s, 2H), 1.46−1.07 (m, 4H), 0.89 (d, J = 6.8 Hz, 3H). Typically,
the diazoalkane is kept cold, immediately redissolved in toluene, and
transferred (quantitatively, with rinsing) by cannula to a 1.00 mL
volumetric flask. The active titer can be determined by esterification
with benzoic acid. Thus, 100 μL of the stock solution was diluted with
1 mL of THF in a 5 mL round-bottom flask, cooled to −45 °C, and
treated with benzoic acid dropwise by syringe (166 μL of a 1.0 M
solution in THF, 0.166 mmol, 1.1 equiv based on theoretical). Upon
slow warming from −45 °C, the reaction mixture became colorless and
nitrogen evolution was observed. The mixture was diluted with Et2O
(25 mL) and saturated sodium bicarbonate (25 mL) and transferred to
a separatory funnel. The aqueous layer was washed with two additional
10 mL volumes of Et2O. The combined organic layers were dried over
magnesium sulfate and concentrated to a light yellow oil. Purification
by silica gel chromatography (TLC Rf = 0.28 in 25:1 hexanes/ethyl
acetate) afforded 23.6 mg of benzoate ester 3 (60% yield, indicative of
a 0.91 M stock solution of diazoalkane 2). IR (thin film): 2860 (w),
2913 (w), 1719 (s), 1451 (w), 1379 (w), 1314 (w), 1270 (s), 1175
1
>98% pure by H NMR spectroscopy and proved to be a >98:2 E:Z
mixture.
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl 2-Fluorobenzoate (4).
4-(2-Diazoethyl)-2,2-dimethyl-1,3-dioxolane was prepared in 41%
yield as a 0.47 M solution in toluene from 0.362 g (1.15 mmol) of
(E)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylidene)-2-(triisopropyl-
silyl)hydrazine based on esterification to give 2-(2,2-dimethyl-1,3-
dioxolan-4-yl)ethyl 2-fluorobenzoate (4). Purification by flash
1
(w), 1110 (m), 1070 (w), 1026 (w), 709 (s). H NMR (400 MHz,
G
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chromatography (TLC Rf = 0.35 in 97.5:2.5 hexanes/ethyl acetate)
delivered the ester as a colorless oil. IR (thin film): 2400 (w), 1717 (s),
1613 (w), 1457 (w), 1372 (w), 1159 (m), 1034 (w). 1H NMR
(400 MHz, CDCl3): δ 7.92 (dt, J = 7.4, 1.9 Hz, 1H), 7.55−7.47
(m, 1H), 7.19 (dt, J = 7.8, 1.1 Hz, 1H), 7.15−7.09 (m, 1H), 4.54−4.23
(m, 3H), 4.10 (dd, J = 8.1, 6.0 Hz, 1H), 3.63 (dd, J = 8.1, 7.0 Hz, 1H),
2.11−1.94 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 164.5 (d, J = 2.9 Hz), 162.1 (d, J = 206.8 Hz), 134.7 (d, J =
7.3 Hz), 132.3, 124.1 (d, J = 3.0 Hz), 118.8 (d, J = 7.9 Hz), 117.2 (d,
J = 14.0 Hz), 109.1, 73.4 (d, J = 2.0 Hz), 69.5 (d, J = 3.9 Hz), 62.4,
32.9, 27.1, 25.8. 19F NMR (376 MHz, CDCl3): δ 109.8. HRMS (ESI+)
gel chromatography (TLC Rf = 0.35 in 95:5 hexanes/ethyl acetate)
gave the ester as a colorless oil. IR (thin film): 3019 (w), 2399 (w),
1717 (s), 1496 (w), 1476 (w), 1377 (w), 1118 (m), 1097 (w).
1H NMR (400 MHz, CDCl3): δ 8.11−8.08 (m, 2H), 7.60−7.54 (m,
1H), 7.48−7.41 (m, 4H), 7.37−7.24 (m, 3H), 6.75 (d, J = 15.9 Hz,
1H), 6.41 ppm (dt, J = 15.9, 6.4 Hz, 1H), 4.99 (dd, J = 6.4, 1.3 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 166.5, 145.8, 136.3, 134.4,
133.1, 129.8, 128.7, 128.5, 128.2, 126.8, 123.4, 65.7. HRMS (ESI+)
+
calcd for C16H18NO2 [M + NH4]+: 256.1338; found 256.1325.
Cyclohex-2-en-1-yl Benzoate (10). 3-Diazocyclohex-1-ene was
prepared in 66% yield as a 0.62 M solution in toluene from 0.402 g
(1.51 mmol) of (E)-1-(cyclohex-2-en-1-ylidene)-2-(triisopropylsilyl)-
hydrazine based on reaction to give cyclohex-2-en-1-yl benzoate (10).
Purification by silica gel chromatography (TLC Rf = 0.4 in 95:5
hexanes/ethyl acetate) gave the ester as a clear oil. IR (thin film): 2869
(w), 1709 (s), 1602 (w), 1521 (w), 1428 (w), 1274 (m), 1177 (w),
1116 (w). 1H NMR (400 MHz, CDCl3): δ 8.07−8.06 (m, 2H),
7.55−7.51 (m, 1H), 7.44−7.40 (m, 2H), 6.01−5.99 (m, 1H), 5.87−
5.83 (m, 1H), 5.54−5.51 (m, 1H), 2.15−2.11 (m, 1H), 2.07−1.93 (m,
2H), 1.90−1.81 (m, 2H), 1.71−1.68 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 166.2, 132.8, 132.8, 130.8, 129.6, 128.3, 125.7, 68.6, 28.4,
+
calcd for C14H18FO4 [M + H]+: 269.1189; found 269.1198.
(Z)-Oct-5-en-1-yl Benzoate (5). (Z)-8-Diazooct-3-ene was prepared
in 42% yield as a 0.48 M solution in toluene from 0.62 g (2.09 mmol)
of (E)-1-((Z)-oct-5-en-1-ylidene)-2-(triisopropylsilyl)hydrazine based
on esterification to afford (Z)-oct-5-en-1-yl benzoate (5). Purification
by silica gel chromatography (TLC Rf = 0.4 in 97.5:2.5 hexanes/ethyl
acetate) gave the ester as a colorless oil. IR (thin film): 2779 (w), 1714
1
(s), 1558 (w), 1502 (w), 1488 (w), 1182 (w), 1157 (w). H NMR
(400 MHz, CDCl3): δ 8.07−8.03 (m, 2H), 7.59−7.53 (m, 1H) 7.47−
7.41 (m, 2H), 5.42−5.28 (m, 2H), 4.32 (t, J = 6.7 Hz, 2H), 2.09−1.99
(m, 4H), 1.82−1.73 (m, 2H), 1.47−1.42 (m, 4H), 0.95 (t, J = 7.5 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 166.9, 133.0, 132.1, 130.7,
129.7, 129.0, 128.5, 65.3, 29.6, 28.8, 27.2, 25.9, 20.7, 14.6. HRMS (ESI+)
+
25.0, 19.0. HRMS (ESI+) calcd for C13H15O2 [M + H]+: 203.1072;
found 203.1101.
1-Phenylpropyl Benzoate (11). (1-Diazopropyl)benzene was
prepared in 88% yield as a 1.33 M solution in toluene from 0.351 g
(2.37 mmol) of (E)-(1-phenyl-propylidene)hydrazine based on esterifica-
tion to give 1-phenylpropyl benzoate (11). Purification by flash chromato-
graphy (TLC Rf = 0.35 in 95:5 hexanes/ethyl acetate) afforded the ester
as a colorless oil. IR (thin film): 2433 (w), 1714 (s), 1601 (w), 1520
+
calcd for C15H21O2 [M + H]+: 233.1542; found 233.1535.
1-Methylpiperidin-4-yl 2-Fluorobenzoate (6). 4-Diazo-1-methyl-
piperidine was made in 37% yield as a 0.61 M solution in toluene from
0.25 g (0.88 mmol) of 1-methyl-4-(2-(triisopropylsilyl)hydrazono)-
piperidine based on reaction to give 1-methylpiperidin-4-yl 2-fluoro-
benzoate (6). Purification by chromatography (TLC Rf = 0.30 in 90:10
hexanes/ethyl acetate) gave ester 6 as an oil. IR (thin film): 2388 (w),
1
(w), 1451 (w), 1423 (m), 1274 (w), 1177 (w), 1081 (w). H NMR
(400 MHz, CDCl3): δ 8.12−8.08 (m, 2H), 7.59−7.53 (m, 1H), 7.45−
7.28 (m, 7H), 5.93 (t, J = 6.4 Hz, 1H), 2.17−1.86 (m, 2H), 0.97 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.1, 140.9, 133.2,
130.8, 129.9, 128.7, 128.6, 128.1, 126.7, 78.2, 29.8, 10.2. HRMS (ESI+)
calcd for C16H20NO2+ [M + NH4]+: 258.1494; found 258.1470.
1-(o-Tolyl)ethyl Benzoate (12). 1-(1-Diazoethyl)-2-methylbenzene
was made in 82% yield as a 1.45 M solution in toluene from 1.60 g
(10.8 mmol) of (E)-(1-(o-tolyl)ethylidene)hydrazine based on
reaction to afford 1-(o-tolyl)ethyl benzoate (12). Purification by silica
gel chromatography (TLC Rf = 0.35 in 95:5 hexanes/ethyl acetate)
gave the ester as a colorless oil. IR (thin film): 2979 (w), 2897 (w),
1712 (s), 1584 (w), 1476 (w), 1391 (w), 1276 (m), 1174 (w), 1114
1
1717 (s), 1613 (w), 1585 (w), 1520 (w), 1475 (m), 1301 (w). H
NMR (400 MHz, CDCl3): δ 7.93 (dt, J = 1.9, 7.5 Hz, 1H), 7.56−7.48
(m, 1H), 7.20 (dt, J = 1.1, 7.6 Hz, 1H), 7.13 (ddd, J = 1.1, 8.3, 10.9 Hz,
1H), 4.39−4.35 (m, 3H), 3.63−3.58 (m, 3H), 2.02−1.90 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 164.7 (d, J = 2.9 Hz), 162.1 (d, J = 206.7
Hz), 134.7 (d, J = 7.2 Hz), 132.3 (d, J = 0.7 Hz), 124.2 (d, J = 3.0 Hz),
118.9 (d, J = 7.2 Hz), 117.2 (d, J = 17.8 Hz), 64.7, 44.7, 29.4, 26.3. 19F
NMR (376 MHz, CDCl3): δ 111.6. HRMS (ESI+) calcd for
+
C13H20FN2O2 [M + NH4]+: 255.1509; found 255.1529.
1-Cyclopropylethyl Benzoate (7). (1-Diazoethyl)cyclopropane
was made in 44% yield as a 1.12 M solution in toluene from 1.06 g
(10.8 mmol) of (E)-(1-cyclopropylethylidene)hydrazine based on
esterification to afford 1-cyclopropylethyl benzoate (7). Purification by
silica gel chromatography (TLC Rf = 0.35 in 97.5:2.5 hexanes/ethyl
acetate) provided the ester as a colorless oil. IR (thin film): 2321 (w),
1707 (s), 1601 (w), 1469 (w), 1451 (w), 1378 (m), 1338 (w), 1276
(m), 1216 (w), 1070 (w). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J =
8.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 4.60
(qd, J = 6.3, 2.1 Hz, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.16−1.11 (m, 1H),
0.62−0.46 (m, 3H), 0.35−0.30 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 166.3, 132.8, 131.1, 129.7, 128.4, 75.9, 20.1, 16.6, 3.8.
HRMS (ESI+) calcd for C12H15O2+ [M + H]+: 191.1072; found 191.1067.
(E)-Hex-2-en-1-yl Benzoate (8). (E)-1-Diazohex-2-ene was pre-
pared in 52% yield as a 0.44 M solution in toluene from 0.173 g
(0.644 mmol) of (E)-1-((E)-hex-2-en-1-ylidene)-2-(triisopropylsilyl)-
hydrazine based on reaction to give (E)-hex-2-en-1-yl benzoate (8).
Purification by flash chromatography (TLC Rf = 0.4 in 95:5 hexanes/
ethyl acetate) gave the ester as a colorless oil. IR (thin film): 2433 (w),
1714 (s), 1521 (w), 1424 (w), 1315 (w), 1114 (m), 1070 (w).
1H NMR (400 MHz, CDCl3): δ 8.08−8.05 (m, 2H), 7.57−7.53 (m, 1H),
7.46−7.42 (m, 2H), 5.90−5.83 (m, 1H), 5.72−5.66 (m, 1H), 4.76 (dd,
J = 6.4, 0.9 Hz, 2H), 2.09−2.04 (m, 2H), 1.46 (qt, J = 7.4, 7.4 Hz, 2H),
0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.6, 136.6,
133.0, 130.6, 129.8, 128.5, 124.1, 66.0, 34.6, 22.3, 13.9. HRMS (ESI+)
1
(w), 1069 (w). H NMR (400 MHz, CDCl3): δ 8.12−8.09 (m, 2H),
7.60−7.51 (m, 2H), 7.48−7.42 (m, 2H), 7.28−7.16 (m, 3H), 6.34 (q,
J = 6.5 Hz, 1H), 2.46 ppm (s, 3H), 1.66 (d, J = 6.5 ppm, 3H). 13C
NMR (100 MHz, CDCl3): δ 165.9, 140.3, 134.9, 133.0, 130.60, 130.59,
129.7, 128.5, 127.8, 126.5, 125.4, 70.1, 21.7, 19.3. HRMS (ESI+) calcd for
C16H17O2+ [M + H]+: 241.1229; found 241.1212.
1,2,3,4-Tetrahydronaphthalen-1-yl Benzoate (13). 1-Diazo-
1,2,3,4-tetrahydronaphthalene was prepared in 80% yield as a 1.40 M
solution in toluene from 0.54 g (3.37 mmol) of (E)-(3,4-dihydro-
naphthalen-1(2H)-ylidene)hydrazine based on reaction to give 1,2,3,4-
tetrahydronaphthalen-1-yl benzoate (13). Purification by flash chroma-
tography (TLC Rf = 0.40 in 95:5 hexanes/ethyl acetate) gave the ester
as a colorless oil. IR (thin film): 2253 (w), 1709 (s), 1584 (w),
1350 (w), 1269 (w), 1211 (m), 1155 (w), 1070 (w), 1026 (w), 1002
1
(w). H NMR (400 MHz, CDCl3): δ 8.11 (dd, J = 8.4, 1.3 Hz, 2H),
7.57 (dt, J = 7.4, 1.3 Hz, 1H), 7.47−7.41 (m, 3H), 7.31−7.27
(m, 1H), 7.24−7.20 (m, 2H) 6.32 (t, J = 4.4 Hz, 1H), 3.00−2.94
(m, 1H), 2.88−2.83 (m, 1H), 2.18−2.09 (m, 3H), 1.96−1.91 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 166.5, 138.3, 134.9, 133.1, 130.9,
129.9, 129.8, 129.3, 128.5, 128.4, 126.3, 70.9, 29.5, 29.4, 19.4.
+
HRMS (ESI+) calcd for C17H17O2 [M + H]+: 253.1229; found
253.1219.
(10-Bromophenanthren-9-yl)methyl Benzoate (14). 9-Bromo-10-
(diazomethyl)phenanthrene was prepared in 81% yield as a 0.28 M
solution in toluene from 0.122 g (0.408 mmol) of (E)-((10-bromo-
phenanthren-9-yl)methylene)hydrazine based on reaction to afford
(10-bromophenanthren-9-yl)methyl benzoate (14). Purification by
flash chromatography (TLC Rf = 0.35 in 95:5 hexanes/ethyl acetate)
+
calcd for C13H20NO2 [M + NH4]+: 222.1494; found 222.1496.
Cinnamyl Benzoate (9). (E)-(3-Diazoprop-1-en-1-yl)benzene was
prepared in 59% yield as a 0.80 M solution in toluene from 0.351 g
(1.16 mmol) of (E)-1-((E)-3-phenylallylidene)-2-(triisopropylsilyl)hydrazine
based on reaction to give cinnamyl benzoate (9). Purification by silica
H
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gave the ester as a colorless, crystalline solid; mp = 135−136 °C. IR
(thin film): 2976 (m), 1716 (s), 1521 (w), 1476 (w), 1423 (w), 1271
(m), 1113 (w). H NMR (400 MHz, CDCl3): δ 8.76−8.70 (m, 2H),
4-(Diazomethyl)benzonitrile (19d). Prepared as a 0.271 M toluene
solution in 82% yield from 0.240 g of 4-(hydrazonomethyl)benzo-
nitrile (1.65 mmol) by the known procedure.29 Used in a reaction
immediately after its preparation, otherwise stored cold at −78 °C.
4,4′-(2-Oxopropane-1,3-diyl)dibenzonitrile (20d). Prepared ac-
cording to the representative procedure given above from 0.136
mmol of 19d (0.502 mL of a 0.271 M solution in toluene, 1.0 equiv)
and 6.6 mg of Sc(OTf)3 (0.013 mmol, 0.10 equiv). Product 20d was
isolated as a white solid (15.2 mg, 86% yield). Characterization data
for this material have been reported previously.74
((4-(Diazomethyl)phenyl)ethynyl)trimethylsilane (19e). Prepared
as a 1.98 M toluene solution in 84% yield from 0.266 g of (4-((trimethyl-
silyl)ethynyl)benzylidene)hydrazone (1.23 mmol) by the known pro-
cedure.29 Used in a reaction immediately after its preparation, other-
wise stored cold at −78 °C.
1
8.59−8.56 (m, 1H), 8.21−8.18 (m, 1H), 8.04−8.01 (m, 2H), 7.75−
7.63 (m, 4H), 7.55−7.50 (m, 1H), 7.41−7.35 (m, 2H), 6.20 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 166.7, 133.2, 131.8, 131.4, 130.4,
130.12, 131.10, 130.05, 129.98, 129.95, 129.7, 128.5, 128.3, 127.95,
127.94, 127.3, 125.1, 123.4, 122.8, 65.4. HRMS (ESI+) calcd for
+
C22H16BrO2 [M + H]+: 391.0334; found 391.0360.
1-Butyl-4-(diazomethyl)benzene (19a). Prepared as a 1.23 M
solution in 82% yield from 0.574 g of (4-butylbenzylidene)hydrazone
(3.00 mmol) by the known procedure.29 Used in a reaction with
formaldehyde immediately after its preparation, otherwise stored cold
at −78 °C.
Representative Procedure for the Bidirectional Synthesis of
Ketones. 1,3-Bis(4-butylphenyl)propan-2-one (20a). In a glovebox,
Sc(OTf)3 (35 mg, 0.071 mmol, 0.095 equiv) was added to a 25 mL
round-bottom flask containing a Teflon-coated stir bar. The flask was
sealed with a rubber septum, removed from the glovebox, and taken to
a fume hood. Under positive nitrogen pressure, the Sc(OTf)3 was
suspended in toluene (7.5 mL, 0.10 M) and the flask was cooled to
−20 °C (ethylene glycol−ethanol/dry ice bath).72 Monomeric
formaldehyde was then introduced by “cracking” solid paraformalde-
hyde (thermal depolymerization, >150 °C) in a separate flask and
allowing the gas generated to pass through a steel wide bore (16 gauge)
cannula into the suspension of Sc(OTf)3 in toluene. Typically,
30 equiv of the polymer was dispensed for multiple reactions so that
the amount of formaldehyde consumed could be determined by mass
difference (in this case ∼100 mg, 3.3 mmol, 4.4 equiv). While the
formaldehyde gas was bubbling through the reaction mixture, a
solution of 19a (0.61 mL of a 1.23 M solution in toluene, 0.75 mmol,
1.0 equiv) was added dropwise over 5 min. At the end of the addition,
the bubbling of formaldehyde gas was stopped and the reaction was
stirred at −20 °C for 10 min. The reaction then mixture was poured
into a separatory funnel, diluted with 20 mL of Et2O, and washed with
40 mL portions of water and saturated sodium chloride. After
collecting the organic layer, it was dried over sodium sulfate, filtered,
and concentrated to a light yellow oil that was purified by silica gel
chromatography (TLC Rf = 0.30 in 97.5:2.5 hexanes/ethyl acetate).
These operations delivered 106 mg (0.33 mmol, 88% yield) of 20a as a
colorless oil. IR (thin film): 2928 (m), 2857 (m), 1702 (s), 1606 (w),
1512 (w), 1457 (w), 1276 (w), 1103 (m), 823 (w) 650 (w), 537 (w).
1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.1 Hz, 4H), 7.05 (d, J =
8.0 Hz, 4H), 3.67 (s, 4H), 2.85 (t, J = 6.4 Hz, 4H), 1.59 (dt, J = 6.8,
4.6 Hz, 4H), 1.35 (dd, J = 15.0, 7.4 Hz, 4H), 0.92 (t, J = 7.3 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 206.4, 141.9, 131.4, 129.6, 129.0,
48.9, 35.5, 33.8, 22.6, 14.2. HRMS (ESI+) calcd for C23H31O+
[M + H]+: 323.2375; found 323.2357.
(4-Methoxyphenyl)diazomethane (19b). Prepared as a 1.47 M
toluene solution in 78% yield from 0.297 g of (4-methoxybenzyl-
idene)hydrazone (1.97 mmol) by the known procedure.29 Used in a
reaction immediately after its preparation, otherwise stored cold at
−78 °C.
1,3-Bis(4-methoxyphenyl)propan-2-one (20b). Prepared accord-
ing to the representative procedure given above from 0.248 mmol of
19b (0.169 mL of a 1.47 M solution in toluene, 1.0 equiv) and 10 mg
of Sc(OTf)3 (0.02 mmol, 0.08 equiv). Product 20b was recovered as a
colorless oil (27.8 mg, 83% yield). Characterization data for this
material have been reported previously.47
1,3-Bis(4-ethynylphenyl)propan-2-one (20e). Prepared according
to the representative procedure given above from 1.00 mmol of 19e
(0.505 mL of a 1.98 M solution in toluene, 1.0 equiv) and 50.0 mg of
Sc(OTf)3 (0.102 mmol, 0.10 equiv). After purification by flash
chromatography (TLC Rf = 0.33 in 12:1 hexanes/ethyl acetate), which
results in desilylation, 104 mg of 20e was obtained as a white solid in
81% yield; mp = 132 °C. IR (thin film): 3293 (s), 3032 (w), 2889 (w),
1716 (s) 1508 (m), 1414 (m), 1335 (m), 1303 (m), 1108 (w), 1054
1
(m), 1020 (w), 847 (m), 823 (m), 641 (m), 543 (m), 515 (w). H
NMR (400 MHz, CDCl3): δ 7.47−7.42 (m, 1H), 7.12−7.08 (m, 1H),
3.72 (s, 1H), 3.07 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 204.5,
147.1, 134.6, 132.6, 129.6, 121.2, 83.4, 49.2. HRMS (ESI+) calcd for
C19H15O+ [M + H]+: 259.1123; found 259.1124.
Methyl 3-(Diazomethyl)benzoate (21). Prepared as a 0.33 M
toluene solution in 51% yield according to the representative pro-
cedure for the synthesis and handling of aliphatic diazoalkanes from
0.310 g (0.927 mmol) of methyl 3-((2-(triisopropylsilyl)hydrazono)-
methyl)benzoate. Used in a reaction immediately after its preparation,
otherwise stored cold at −78 °C.
Dimethyl 3,3′-(2-Oxopropane-1,3-diyl)dibenzoate (22a). Prepared
according to the representative procedure above from 0.33 mmol of 21
(1.0 mL of a 0.33 M solution in toluene, 1.0 equiv) and 16.2 mg of
Sc(OTf)3 (0.033 mmol, 0.10 equiv). Diester 22a was recovered as a
colorless oil (48.5 mg, 90% yield) after flash chromato-
graphy (TLC Rf = 0.33 in 8:2 hexanes/ethyl acetate). IR (thin film):
2919 (m), 2863 (m), 1722 (m), 1711 (s), 1599 (w), 1562 (w), 1427
1
(w), 1413 (w), 1337 (m), 1309 (w), 1070 (w) 758 (w), 698 (w). H
NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 7.6, 1.4 Hz, 1H), 7.82
(s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 6.1, 1.5 Hz, 1H), 3.91 (s,
3H), 3.81 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 204.4, 166.9, 134.2,
134.1, 130.8, 130.8, 128.9, 128.6, 52.3, 49.1. HRMS (ESI+) calcd for
C19H19O5+ [M + H]+: 327.1232; found 327.1213.
3,3′-(2-Oxopropane-1,3-diyl)dibenzoic Acid (22b). A solution of
22a (27.6 mg, 0.085 mmol) in 1:1 THF−water (0.05 M) was added to
a 10 mL round-bottom flask containing a Teflon-coated stir bar and
treated with LiOH (20.0 mg, 0.858 mmol, 10 equiv) as a solid in one
portion. Upon dissolution of the base, the colorless solution was
stirred for 4 h and diluted with 20 mL of a 1 N HCl solution. The
contents of the reaction vessel were then poured into a separatory
funnel and washed three times with 25 mL of CH2Cl2. The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated to afford a light yellow solid. Purification by silica gel
chromatography (TLC Rf = 0.30 in 9:1 CH2Cl2/methanol) provided
11.6 mg of diacid 22b as a white solid in 42% yield. Spectral data were
in agreement with that reported in the isolation literature.24
(4-Nitrophenyl)diazomethane (19c). Prepared as a 1.51 M toluene
solution in 94% yield from 0.240 g of 4-nitrobenzaldehyde hydrazone
(1.58 mmol) by the known procedure.29 Used in a reaction immediately
after its preparation, otherwise stored cold at −78 °C.
1,3-Bis(4-nitrophenyl)propan-2-one (20c). Prepared according to
the representative procedure given above from 1.51 mmol of 19c
(1.00 mL of a 1.51 M solution in toluene, 1.0 equiv) and 44 mg of
Sc(OTf)3 (0.090 mmol, 0.06 equiv). Product 20c was recovered as a
recovered as a crystalline solid (190 mg, 84% yield). Characterization
data for this material have been reported previously.73
2-(Diazomethyl)furan (23). Prepared as a 1.72 M toluene solution
in 37% yield from 0.451 g of (furan-2-ylmethylene)hydrazone (4.09 mmol)
by the known procedure.29 Used in a reaction immediately after its
preparation, otherwise stored cold at −78 °C.
1,3-Di(furan-2-yl)propan-2-one (24). Prepared according to the
representative procedure above from 0.34 mmol of 2-(diazomethyl)-
furan (23) (0.20 mL of a 1.72 M solution in toluene, 1.0 equiv) and
16.7 mg of Sc(OTf)3 (0.034 mmol, 0.10 equiv). Purification by flash
chromatography (TLC Rf = 0.30 in 92:8 hexanes/ethyl acetate) gave
23.8 mg of a colorless oil (74% yield). IR (thin film): 3121 (w),
I
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2924 (w), 2853 (w), 1726 (s), 1598 (w), 1504 (m), 1384 (w), 1329
(w), 1147 (m), 1074 (w), 1011 (m), 913 (w), 806 (w), 734 (s), 599
(m). H NMR (400 MHz, CDCl3): δ 7.37 (dd, J = 1.9, 0.8 Hz, 2H),
6.34 (dd, J = 3.1, 1.9 Hz, 2H), 6.19 (dd, J = 3.2, 0.7 Hz, 2H), 3.77 (s,
4H). 13C NMR (100 MHz, CDCl3): δ 201.3, 147.8, 142.4, 110.9,
108.7, 41.6. HRMS (ESI+) calcd for C11H11O3+ [M + H]+: 191.0708;
found 191.0725.
((1-Bromonaphthalen-2-yl)methylene)hydrazone. In a 20 mL vial
equipped with a Teflon-coated stir bar, 1-bromo-2-naphthaldehyde
(0.710 g, 3.02 mmol, 1.0 equiv) was suspended in 0.50 mL of
hydrazine hydrate (15 mmol, 5.0 equiv) and 6.0 mL of ethanol (0.50 M).
After sealing the vial with a Teflon-lined screw cap, the heterogeneous
mixture was stirred rapidly at 80 °C. After 2 h, the mixture was cooled
to 23 °C and left stirring for 12 h out of convenience. The product was
then extracted with three 5 mL volumes of CHCl3. The pooled
extracts were dried over sodium sulfate, filtered, and concentrated to
afford 0.479 g (2.90 mmol, 96% yield) of a white solid. The hydrazone
was >98% pure and consisted of a >98:2 E:Z mixture on the basis of
1H NMR analysis.
1-Bromo-2-(diazomethyl)naphthalene (29). Prepared as a 0.25 M
toluene solution in 85% yield from 0.252 g of ((1-bromonaphthalen-2-yl)-
methylene)hydrazone (1.01 mmol) by the known procedure.29 Used
in a reaction immediately after its preparation, otherwise stored cold
at −78 °C.
1,3-Bis(1-bromonaphthalen-2-yl)propan-2-one (30). Prepared by
the representative procedure given above from 0.50 mmol of 29
(2.0 mL of a 0.25 M solution in toluene, 1.0 equiv) and 25 mg of
Sc(OTf)3 (0.051 mmol, 0.10 equiv). Purification by flash chromatogra-
phy (TLC Rf = 0.30 in 95:5 hexanes/ethyl acetate) delivered 86.6 mg
of 30 as a white solid in 74% yield; mp = 163 °C. IR (thin film): 3087
(w), 3052 (w), 1716 (s), 1603 (w), 1585 (w), 1488 (w), 1452 (w),
1392 (m), 975 (w), 822 (m), 760 (w). 1H NMR (400 MHz, CDCl3):
δ 8.31 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.77
(d, J = 8.0 Hz, 2H), 7.60 (dd, J = 8.4, 6.9 Hz, 2H), 7.52 (dd, J = 8.4,
6.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.24 (s, 4H). 13C NMR
(100 MHz, CDCl3): δ 203.3, 133.9, 132.8, 132.7, 128.7, 128.3, 128.0,
127.7, 127.6, 126.6, 125.3, 51.3. HRMS (ESI+) calcd for C23H17Br2O+
[M + H]+: 466.9646; found 466.9625.
9-Methylphenanthrene. A solution of 5.00 g of 9-bromo-
phenanthrene (19.4 mmol) in Et2O (100 mL, 0.20 M) at 0 °C was
treated with 10.7 mL of n-BuLi (2.0 M in hexanes, 21.4 mmol,
1.1 equiv) dropwise over 10 min. After the solution was warmed to
23 °C for 10 min and recooled to 0 °C, 3.52 mL of dimethyl sulfate
(36.9 mmol, 1.9 equiv) was added dropwise over a 30 min period. The
reaction mixture was then heated to reflux for 5 h. After being cooled
to 23 °C, the reaction was quenched with 40 mL of ammonium
hydroxide and transferred to a separatory funnel. The organic layer
was washed three times with 50 mL of saturated sodium chloride and
then collected, dried over sodium sulfate, filtered, and concentrated.
The resulting solid was crystallized from hexanes to give 3.59 g of
colorless needles (72% yield). Characterization data for this material
have been reported previously.76
9-Bromo-10-methylphenanthrene. A 100 mL round-bottom flask
equipped with a Teflon-coated stir bar and covered with aluminum foil
to exclude light was charged with 2.44 g (12.7 mmol) of 9-methyl-
phenanthrene and 2.71 g of N-bromosuccinimide (15.2 mmol, 1.2
equiv). The flask was flushed with nitrogen and sealed with a rubber
septum. The reactants were dissolved in acetonitrile (21.2 mL, 0.6 M)
for 24 h of stirring at 23 °C. At the end of the reaction period, 20 mL
of 1 N sodium hydroxide was added with 10 min of stirring.
The mixture was poured into a separatory funnel and extracted with
three 25 mL volumes of CH2Cl2. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated to give 3.10 g
(90% yield) of bromide that was used directly in the next reaction
without purification. Characterization data for this material have been
reported previously.76
9-Bromo-10-(bromomethyl)phenanthrene. A 250 mL flask
containing a Teflon-coated stir bar was charged with 3.10 g of
9-bromo-10-methylphenanthrene (11.4 mmol), 4.27 g of N-bromo-
succinimide (24.0 mmol, 2.1 equiv), and 0.280 g of azobisisobutyro-
nitrile (1.71 mmol, 0.15 equiv). The flask was outfitted with a reflux
condenser, evacuated, and purged with nitrogen. The reactants were
dissolved in benzene (60 mL, 0.2 M) and stirred at reflux for 24 h.
The reaction mixture was then cooled to 23 °C, transferred to a
separatory funnel, and washed three times with 50 mL of saturated
sodium bisulfite. In each case, the aqueous wash was back-extracted
with 15 mL of CH2Cl2, and this rinse fraction was added to the organic
1
2-(Diazomethyl)thiophene (25). Prepared as a 0.35 M toluene
solution in 45% yield from 0.353 g of (thiophen-2-ylmethylene)hydra-
zone (3.150 mmol) by the known procedure.29 Used in a reaction
immediately after its preparation, otherwise stored cold at −78 °C.
1,3-Di(thiophen-2-yl)propan-2-one (26). Prepared according to
the representative procedure above from 0.14 mmol of 2-(diazo-
methyl)thiophene (0.40 mL of a 0.35 M solution in toluene, 1.0 equiv)
and 8.0 mg of Sc(OTf)3 (0.016 mmol, 0.12 equiv). Purification by
flash chromatography (TLC Rf = 0.30 in 95:5 hexanes/ethyl acetate)
provided 11.9 mg of a colorless oil (76% yield). IR (thin film): 3105
(w), 2921 (w), 2898 (w), 2854 (w), 1721 (s), 1612 (w), 1532 (w),
1435 (w), 1401 (w), 1317 (w), 1211 (w), 1079 (m), 851 (w), 696 (s),
1
537 (w). H NMR (400 MHz, CDCl3): δ 7.22 (dd, J = 5.2, 1.2 Hz,
2H), 6.96 (dd, J = 5.2, 3.5 Hz, 2H), 6.87 (d, J = 3.5 Hz, 2H), 3.96 (d,
J = 0.7 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 202.8, 134.9, 127.3,
127.2, 125.5, 42.6. HRMS (ESI+) calcd for C11H11S2O+ [M + H]+:
223.0251; found 223.0272.
(Diazomethylene)dicyclopropane (27). Prepared as a 0.63 M
toluene solution in 28% yield according to the representative procedure
for the synthesis and handling of aliphatic diazoalkanes from 0.516 g of
(dicyclopropylmethylene)hydrazine (4.15 mmol). Used in a reaction
immediately after its preparation, otherwise stored cold at −78 °C.
1,1,3,3-Tetracyclopropylpropan-2-one (28). Prepared according to
the representative procedure above from 0.186 mmol of 27 (0.295 mL
of a 0.63 M solution in toluene, 1.0 equiv) and 11.1 mg of Sc(tmhd)3
(0.019 mmol, 0.10 equiv). Purification by flash chromatography (TLC
Rf = 0.30 in 97.5:2.5 hexanes/ethyl acetate) gave 11.2 mg of 28 as a
colorless oil (55% yield). IR (thin film): 3080 (w), 3006 (w), 2924
(m), 2854 (w), 1731 (s), 1463 (m), 1377 (w), 1272 (w), 1098 (m),
1
1020 (w), 998 (w), 958 (w), 932 (w), 856 (w), 820 (m). H NMR
(400 MHz, CDCl3): δ 2.53 (t, J = 7.6 Hz, 2H), 0.94 (qt, J = 8.2, 5.1
Hz, 4H), 0.51−0.40 (m, 8H), 0.36−0.29 (m, 4H), 0.25−0.18 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 210.9, 27.10, 20.8, 10.7. HRMS (ESI+)
calcd for C15H23O+ [M + H]+: 219.1749; found 219.1744.
1-Bromo-2-(dibromomethyl)naphthalene. A 100 mL round-
bottom flask equipped with a Teflon-coated stir bar was charged
with 2.21 g (10.0 mmol) of 1-bromo-2-methylnaphthalene, 4.45 g of
N-bromosuccinimide (25.0 mmol, 2.5 equiv), and 0.33 g of
azobisisobutyronitrile (2.0 mmol, 0.20 equiv). The flask was outfitted
with a reflux condenser, evacuated, and backfilled with nitrogen. The
reactants were dissolved in benzene (35 mL, 0.30 M) and stirred at
reflux for 24 h. The reaction mixture was then cooled to 23 °C,
transferred to a separatory funnel, and washed three times with 25 mL
of saturated sodium bisulfite. In each case, the aqueous wash was back-
extracted with 5 mL of CH2Cl2, and this rinse fraction was added to
the organic layer. After drying over sodium sulfate, filtering, and
concentrating, the crude product was purified by passage through a
pad of silica gel (TLC Rf = 0.35 in 98:2 hexanes/ethyl acetate) to give
3.61 g of the tribromide as a yellow solid (96% yield). Characterization
data for this material have been reported previously.75
1-Bromo-2-naphthaldehyde. A 200 mL round-bottom flask con-
taining a Teflon-coated stir bar was covered with aluminum foil to
exclude light and charged with 3.79 g of 1-bromo-2-(dibromomethyl)-
naphthalene (10.0 mmol) and 3.34 g of silver(I) acetate (20.0 mmol,
2.0 equiv). The solids were dissolved in 16 mL of water, 33 mL of
acetone, and 50 mL of ethanol (0.10 M, 1:2:3 ratio). After 24 h of
stirring at 23 °C, the mixture was placed in a separatory funnel and
washed with 100 mL of Et2O. The organic layer was washed twice with
80 mL of saturated sodium chloride. After collecting the ether layer, it
was dried over sodium sulfate, filtered, and concentrated. Purification
by silica gel chromatography (TLC Rf = 0.33 in 98:2 hexanes/ethyl
acetate) gave 2.21 g of the aryl carboxaldehyde as a solid (95% yield).
Characterization data for this material have been reported previously.75
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layer. The solution was dried over sodium sulfate, filtered, and
concentrated to give 3.91 g (98%) of dibromide that was directly used
in the next reaction without purification. Characterization data for this
material have been reported previously.76
(0.017 mmol, 0.10 equiv) in 1.8 mL of toluene (0.10 M). Purification
by flash chromatography (TLC Rf = 0.35 in 9:1 hexanes/ethyl acetate)
gave 57.8 mg of 32 as a white solid in 67% yield; mp = 249 °C. IR
(thin film): 3073 (w), 2954 (w), 2923 (w), 2852 (w), 1712 (s), 1488
(m), 1444 (m), 1333 (w), 1066 (w), 1050 (w), 901 (w), 749 (s), 718
(10-Bromophenanthren-9-yl)methanol. A 250 mL round-bottom
flask containing a Teflon-coated stir bar and coated with aluminum foil
to exclude light was charged with 4.12 g (11.0 mmol) of 9-bromo-
10-(bromomethyl)phenanthrene, and 4.00 g of silver(I) acetate
(24.2 mmol, 2.2 equiv). After the solids were dissolved in 10 mL of
water, 30 mL of acetone, and 60 mL of ethanol (0.10 M, 1:2:3 ratio),
the solution was stirred at 23 °C for 24 h. The reaction mixture was
then transferred to a separatory funnel and washed with 100 mL of
Et2O. In turn, the organic layer was washed three times with 80 mL of
saturated sodium chloride and dried over sodium sulfate, filtered,
and concentrated. Purification by flash chromatography (TLC Rf =
0.33 in 9:1 hexanes/ethyl acetate) gave 2.94 g of a solid (93%
yield). Characterization data for this material have been reported
previously.76
10-Bromophenanthrene-9-carbaldehyde. A −60 °C solution of
0.22 mL of methyl sulfoxide (3.13 mmol, 1.10 equiv) in THF (20 mL)
was treated with 0.26 mL of oxalyl chloride (2.99 mmol, 1.05 equiv)
dropwise over 5 min. After 15 min of stirring, 0.820 g (2.84 mmol,
1.0 equiv) of (10-bromophenanthren-9-yl)methanol was added in
8 mL of THF. After 15 min, 0.84 mL of triethylamine (5.97 mmol,
2.1 equiv) was added, and the vessel was allowed to slowly warm to
23 °C. The mixture was diluted with 50 mL of water in a separatory
funnel and extracted three times with 20 mL of ethyl acetate. The
combined organic layers were washed three times with 30 mL of
saturated sodium chloride before being dried over sodium sulfate,
filtered, and concentrated. Purification by silica gel chromatography
(TLC Rf = 0.30 in 95:5 hexanes/ethyl acetate) gave 0.72 g of the
benzylic aldehyde as a white solid (88% yield). Characterization data
for this material have been reported previously.76
1
(s). H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 8.2 Hz, 2H), 8.69
(dd, J = 6.4, 3.1 Hz, 2H), 8.48 (dd, J = 7.6, 2.0 Hz, 2H), 7.83 (d, J =
8.4 Hz, 2H), 7.71−7.65 (m, 6H), 7.53 (t, J = 8.3 Hz, 2H), 4.73 (s, 4H).
13C NMR (100 MHz, CDCl3): δ 203.9, 131.7, 131.3, 130.7, 130.5,
130.1, 129.2, 127.9, 127.8, 127.7, 127.2, 127.1, 125.3, 123.5, 122.8,
48.8. HRMS (ESI+) calcd for C31H20Br2ClO− [M + Cl]−: 602.9549;
found 602.9578.
Diphenyl Diazomethane. Prepared as a 0.89 M toluene solution in
85% yield from 1.82 g (10.0 mmol) of benzophenone by the known
procedure.29 Used in a reaction immediately after its preparation,
otherwise stored cold at −78 °C.
2,2-Diphenylacetaldehyde (33). The predominant product if using
the representative procedure given above with 0.178 mmol of diphenyl
diazomethane (0.200 mL of a 0.89 M solution, 1.0 equiv) and 8.9 mg
of Sc(OTf)3 (0.018 mmol, 0.10 equiv). Purification by flash chroma-
tography (TLC Rf = 0.30 in 97.5:2.5 hexanes/ethyl acetate) gave
13.8 mg of monoinsertion product as a colorless oil in 79% yield.
Characterization data for this material have been reported previously.77
1-Diazo-1,2,3,4-tetrahydronaphthalene (34). Prepared as a
0.37 M toluene solution in 80% yield from 55.0 mg (0.343 mmol)
of α-tetralone hydrazone by the known procedure.29 Used in a
reaction immediately after its preparation, otherwise stored cold at
−78 °C.
Representative Procedure for the Synthesis of a Dissym-
metric Ketone from Two Different Diazoalkanes. 2,2-Diphenyl-
1-(1,2,3,4-tetrahydronaphthalen-1-yl)ethanone (35). A stirring
suspension of 38.2 mg (0.195 mmol) of 2,2-diphenylacetaldehyde
and 9.8 mg of Sc(OTf)3 (0.020 mmol, 0.10 equiv) in 2.0 mL toluene
at −78 °C was treated with 0.214 mmol of 1-diazo-1,2,3,4-
tetrahydronaphthalene (0.578 mL of a 0.37 M in solution in toluene,
1.1 equiv). After being stirred for 10 min at −78 °C, the reaction
mixture was diluted with 20 mL of Et2O, poured into a separatory
funnel, and washed three times with 20 mL of water and once with
20 mL of saturated sodium chloride before being dried over sodium
sulfate, filtered, and concentrated. Purification by silica gel chroma-
tography (TLC Rf = 0.33 in 97.5:2.5 hexanes/ethyl acetate) afforded
49.7 mg of 35 as a white solid in 78% yield; mp = 81 °C. IR (thin
film): 3059 (m), 3026 (m), 2936 (m), 2867 (w), 1715 (s), 1658 (m),
1598 (w), 1494 (m), 1448 (m), 1317 (w), 1277 (m), 1075 (w), 1044
(w), 941 (w), 919 (w), 743 (m), 701 (s), 638 (m). 1H NMR
(400 MHz, CDCl3): δ 7.81 (dd, J = 8.2, 1.1 Hz, 2H), 7.60 (t, J = 7.3
Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.33 (dd, J = 9.1, 5.6 Hz, 2H), 7.28
(d, J = 2.3 Hz, 2H), 7.21 (dd, J = 6.4, 4.7 Hz, 2H), 7.12 (d, J = 5.7 Hz,
1H), 7.03 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 5.35 (s, 1H),
4.06 (t, J = 6.3 Hz, 1H), 2.75 (dd, J = 13.7, 6.9 Hz, 2H), 2.11−1.93 (m,
2H), 1.77 (dd, J = 74.1, 4.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
209.4, 139.1, 138.5, 138.1, 137.8, 133.6, 132.6, 130.3, 129.8, 129.6,
129.3, 129.1, 129.0, 128.7, 128.5, 127.5, 127.2, 127.1, 126.0, 62.0, 53.2,
29.3, 26.2, 20.6. HRMS (ESI+) calcd for C24H23O+ [M + H]+:
327.1749; found 327.1775.
((10-Bromophenanthren-9-yl)methylene)hydrazone. In a 2 dram
glass vial equipped with a Teflon-coated stir bar, 0.190 g of 10-bromo-
phenanthrene-9-carbaldehyde was suspended in 0.150 mL of
hydrazine hydrate (3.33 mmol, 5.0 equiv) and ethanol (1.5 mL,
0.50 M). The vial was sealed with a Teflon-lined screw cap, and the
mixture was stirred rapidly with heating at 80 °C. After 2 h, the
mixture was cooled to 23 °C for 12 of stirring. The product was then
extracted with three 5 mL volumes of CHCl3. The combined extracts
were dried over sodium sulfate, filtered, and concentrated under
reduced pressure to afford 0.197 g of a white solid (99% yield). The
hydrazone was >98% pure and consisted of a >98:2 E:Z mixture based
1
on H NMR analysis.
9-Bromo-10-(diazomethyl)phenanthrene (31). Prepared as a
0.42 M toluene solution in 81% yield from 0.200 g of ((10-bromo-
phenanthren-9-yl)methylene)hydrazone (0.668 mmol) by the known
procedure.29 Used in a reaction immediately after its preparation,
otherwise stored cold at −78 °C.
2-(10-Bromophenanthren-9-yl)acetaldehyde. The predominant
product when using the representative procedure given above with
0.110 mmol of 31 (0.262 mL of a 0.42 M solution in toluene,
1.0 equiv) and 5.4 mg of Sc(OTf)3 (0.011 mmol, 0.10 equiv).
Purification by flash chromatography (TLC Rf = 0.35 in 9:1 hexanes/
ethyl acetate) gave 28.0 mg of the product as a white solid in 85%
yield; mp = 198 °C. IR (thin film): 3068 (w), 2923 (w), 2850 (w),
(Diazomethylene)dicyclohexane. Made as a 0.42 M toluene
solution in 48% yield according to the representative procedure for
the synthesis and handling of aliphatic diazoalkanes from 0.510 g
(2.62 mmol) of dicyclohexyl ketone. Used immediately after
preparation, otherwise stored cold at −78 °C.
1
2723 (w), 1721 (s), 1488 (w), 1445 (w), 753 (s), 720 (m). H NMR
(400 MHz, CDCl3): δ 9.73 (t, J = 1.9 Hz, 1H), 8.65 (dd, J = 8.2, 1.4
Hz, 1H), 8.62 (d, J = 9.5 Hz, 1H), 8.41 (dd, J = 7.5, 2.1 Hz, 1H), 7.84
(dd, J = 8.1, 1.0 Hz, 1H), 7.64−7.60 (m, 3H), 7.58−7.53 (m, 1H),
4.52 (d, J = 1.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 198.6,
131.6, 131.3, 130.1, 130.6, 129.2, 128.03, 128.01, 127.9, 127.4, 127.1,
125.00, 123.6, 122.9, 49.1. HRMS (ESI+) calcd for C16H12BrO+
[M + H]+: 299.0072; found 299.0050.
1,3-Bis(10-bromophenanthren-9-yl)propan-2-one (32). Prepared
according to the general procedure given below for the synthesis of
dissymmetric ketones from 45.6 mg of 2-(10-bromophenanthren-9-
yl)acetaldehyde (0.152 mmol) and 0.168 mmol of 31 (0.4 mL of a
0.42 M solution in toluene, 1.10 equiv) with 8.3 mg of Sc(OTf)3
2,2-Dicyclohexylacetaldehyde (36). The predominant product
when the representative procedure above is run with 1.36 mmol
of (diazomethylene)dicyclohexane (3.24 mL of a 0.42 M solution
in toluene, 1.0 equiv) and 66.9 mg of Sc(OTf)3 (0.136 mmol,
0.10 equiv). Purification by flash chromatography (TLC Rf = 0.30 in
98:2 hexanes/ethyl acetate) gave 129 mg of 36 as a colorless oil (91%
yield). IR (thin film): 2923 (s), 2851 (m), 1721 (m), 1447 (w),
1
991 (w). H NMR (400 MHz, CDCl3): δ 9.66 (d, J = 4.6 Hz, 1H),
1.89−1.57 (m, 13H), 1.35−1.07 (m, 6H), 1.10−0.88 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 207.8, 63.2, 35.7, 30.2, 26.7, 26.6.
K
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Featured Article
HRMS (ESI+) calcd for C14H25O+ [M + H]+: 209.1905; found
209.1906.
of 41a (0.530 g, 2.79 mmol) in THF (4.0 mL, 0.7 M) containing
flame-dried 4 Å molecular sieves (0.53 g, 1:1 w/w) at 0 °C. Upon
complete addition, the suspension was warmed to 23 °C and stirred
rapidly under nitrogen for 36 h, at which time an NMR aliquot showed
the absence of starting material. The mixture was filtered through
cotton (with 2 mL of Et2O as a rinse) and concentrated. The resulting
1.00 g of colorless oil (>99% yield) was used immediately without
further purification.
1,1-Dicyclohexyl-4-(2,2-dimethyl-1,3-dioxolan-4-yl)butan-2-one
(38). Prepared according to the general procedure given above for the
synthesis of a dissymmetric ketone from 25.1 mg of 2,2-dicyclohexyl-
acetaldehyde (36) (0.120 mmol), 0.132 mmol of 4-(2-diazoethyl)-2,2-
dimethyl-1,3-dioxolane (0.281 mL of a 0.47 M solution in toluene,
1.1 equiv), 7.1 mg of Sc(tmhd)3 (0.012 mmol, 0.10 equiv), and 1.2 mL
of toluene (0.10 M). Purification by silica gel chromatography (TLC
Rf = 0.30 in 97.5:2.5 hexanes/ethyl acetate) afforded 27.5 mg of 38 as a
colorless oil (68% yield). IR (thin film): 2920 (s), 2874 (m), 1719 (s),
1420 (w), 1347 (w), 1237 (w), 1009 (w), 984 (w), 955 (w), 928 (w).
1H NMR (400 MHz, CDCl3): δ 4.11−4.09 (m, 1H), 3.64 (dd, J = 8.3,
(S)-1-Benzyl-2-(diazomethyl)pyrrolidine (42a). The following
pilot-scale oxidation and esterification was used to determine if any
loss in enantiopurity occurred during elaboration of 42a from (S)-1-
benzyl-2-pyrrolidinemethanol. Gratifyingly, no racemization of the
proline-derived stereocenter occurs for batches of 42a derived from
either a Swern or Pb(IV)-based oxidation protocol. The former was
chosen for scale-up even though the yield of diazoalkane was
reproducibly 2−3% lower. A THF solution (4.0 mL, 0.040 M) of
(S)-1-benzyl-2-((2-triisopropylsilyl)hydrazono)methyl)pyrrolidine
(0.055 g, 0.154 mmol) was treated with TBAF (0.155 mL of a 1.0 M
solution, 0.155 mmol, 1.0 equiv) at 0 °C with rapid stirring. After
10 min of stirring at 0 °C, the THF was removed under reduced
pressure. Prior to deprotection of the hydrazone, a 1.0 M solution of
(COCl)2 (0.021 mL, 0.23 mmol, 1.5 equiv) in CH2Cl2 was added
dropwise to a stirring solution of DMSO (0.031 mL, 0.46 mmol,
3.0 equiv) in CH2Cl2 (0.3 mL, 1.5 M) at −78 °C. After being stirred at
this temperature for 45 min, the freshly prepared free hydrazone was
slowly introduced over 10 min as a solution in 0.30 mL of CH2Cl2.
The mixture was stirred for 20 min at −78 °C before Et3N (0.86 mL,
0.62 mmol, 4.0 equiv) was added by syringe. After slow warming to
0 °C and 30 min of additional stirring, the reaction mixture was
transferred to a separatory funnel and washed with 5 mL volumes of
saturated NaHCO3 and NaCl. The CH2Cl2 layer was then dried over
Na2SO4, filtered, and concentrated under high vacuum at low
temperature. These operations gave the neat diazoalkane as a yellow
oil. After dissolution in 0.10 mL of toluene and esterification with
2-fluorobenzoic acid as described above, the titer was determined to be
0.50 M, corresponding to a 33% yield from the aldehyde 42a (four
steps). Diazoalkane 42a was also made reliably in 36% yield by the
general procedure above for the synthesis and handling of aliphatic
diazoalkanes with Pb(OAc)4 as the oxidant and starting from 1.35 g
(3.75 mmol) of the TIPS-hydrazone. The diazoalkane was used
immediately after its synthesis, otherwise stored cold at −78 °C.
(S)-(1-Benzylpyrrolidin-2-yl)methyl 2-Fluorobenzoate (43). For an
appreciable amount of the o-fluorobenzoate, the esterification reaction
was conducted as follows. A 400 μL aliquot of the 0.45 M diazoalkane
stock solution (0.18 mmol) was added to a solution of 2-fluorobenzoic
acid (25.2 mg, 0.18 mmol, 1.0 equiv) in Et2O (0.50 mL, 0.36 M) at
−45 °C dropwise by syringe. The cooling bath was removed, and upon
slow warming from −45 °C, the reaction mixture became colorless and
nitrogen evolution was observed. Direct concentration of the reaction
mixture and purification by flash chromatography (TLC Rf = 0.30 in
95:5 hexanes/ethyl acetate) gave 56 mg of the ester as a viscous,
colorless oil (99% yield, >99% ee based on chiral SFC, trace provided
6.0, 1 H), 3.58 (dd, J = 8.3, 6.7, 1H), 2.53−2.66 (m, 2H), 2.38−2.35
(m, 1H), 1.89−1.59 (m, 14H), 1.42 (s, 3H), 1.37 (s, 3H) 1.35−1.07
(m, 6H), 1.12−0.90 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 208.3,
108.8, 69.3, 63.2, 39.8, 35.6, 30.2, 29.9, 27.6, 26.9, 26.7, 26.6, 25.8.
+
HRMS (ESI+) calcd for C21H37O3 [M + H]+: 337.2743; found
337.2743.
(S)-Methyl 1-Benzylpyrrolidine-2-carboxylate. Prepared in accord-
ance with a known procedure78 in which AcCl (9.26 mL, 130 mmol)
was added dropwise with stirring to a 0 °C solution of (S)-proline
(5.00 g, 43.4 mmol) in MeOH (80 mL). Upon addition, the ice bath
was removed and the stirring was continued for 15 h at 23 °C. Volatile
organics were then removed, and the residual oil was redissolved in
dry MeCN (70 mL). Et3N (18.0 mL, 130 mmol) and BnBr (6.20 mL,
52.1 mmol, 1.2 equiv) were added to give a white suspension. After
12 h of stirring at 23 °C, the MeCN was evaporated and the residue
was partitioned between saturated NH4Cl (200 mL) and Et2O
(200 mL) in a separatory funnel. The phases were separated, and the
aqueous layer was washed twice with 40 mL of Et2O. The pooled
organic layers were washed with one volume of saturated NaCl, dried
over MgSO4, and concentrated. Purification by silica gel chromatog-
raphy (TLC Rf = 0.30 in 92:8 hexanes/ethyl acetate) gave 6.37 g of a
colorless oil (69% yield). Spectroscopic data were in full agreement
with values reported previously.79
(S)-1-Benzyl-2-pyrrolidinemethanol. To a solution of LAH (0.570 g,
15.1 mmol, 1.1 equiv) in THF (10 mL) at 0 °C was added (S)-methyl
1-benzylpyrrolidine-2-carboxylate (3.00 g, 13.7 mmol, 1.0 equiv) in
THF (25 mL) dropwise with rapid stirring. After being warmed slowly
to 23 °C and stirred for 6 h, the mixture was diluted with 15 mL of
Et2O, transferred to a separatory funnel, and washed with 50 mL
volumes of saturated NH4Cl and saturated NaCl. Before being
discarded, the aqueous washes were back-extracted with 50 mL of
Et2O. The combined organic layers were dried over Na2SO4, filtered,
and concentrated to afford 2.46 g of a colorless oil (12.9 mmol, 94%
yield). The product’s spectroscopic data were in agreement with that
reported in the literature,80 and it was used without further
purification.
(S)-1-Benzylpyrrolidine-2-carbaldehyde (41a). Prepared in accord-
ance with a known procedure81 by adding a CH2Cl2 solution (11 mL,
1.5 M) of (COCl)2 (1.45 mL, 16.6 mmol, 1.5 equiv) dropwise to a
solution of DMSO (2.18 mL, 32.9 mmol, 3.0 equiv) in CH2Cl2
(22 mL, 1.5 M) at −78 °C. After stirring was continued at this
temperature for 45 min, a CH2Cl2 (18 mL, 0.5 M) solution of (S)-1-
benzyl-2-pyrrolidinemethanol (2.0 mL, 11 mmol) was added slowly
over 10 min. After being stirred for 20 additional min at −78 °C, Et3N
(6.16 mL, 43.9 mmol, 4.0 equiv) was added and the reaction was
allowed to warm slowly to 0 °C and stirred for 2 h. The mixture was
diluted with 50 mL of CH2Cl2, transferred to a separatory funnel, and
washed with 100 mL each of saturated NaHCO3 and NaCl. The
CH2Cl2 layer was dried over Na2SO4, filtered, and directly
concentrated to give 1.89 g of a colorless oil (9.98 mmol, 91%
yield) that proved to be >98% pure by 1H NMR analysis and was used
without further purification. If possible, the compound should be used
promptly as it undergoes slow decomposition in solution at 23 °C.
(S)-1-Benzyl-2-((2-triisopropylsilyl)hydrazono)methyl)pyrrolidine.
Prepared by the representative procedure given above for the synthesis
and handling of aliphatic diazoalkanes involving a slow, 2 h addition of
triisopropylsilylhydrazine (0.780 g, 4.19 mmol, 1.5 equiv) to a solution
23
as Supporting Information). [α]D = −59.6 (c = 0.80 g·cm−3 in
CHCl3). IR (thin film): 2950 (m), 2843 (w), 2779 (m), 1712 (s),
1612 (m), 1488 (m), 1454 (m), 1293 (s), 1247 (s), 1228 (m), 1157
(m), 1124 (m), 1081 (s), 1033 (s), 967 (w), 754 (s), 691 (w), 655
1
(w). H NMR (400 MHz, CDCl3): δ 7.98 (td, J = 7.6, 1.8 Hz, 1H),
7.55−7.49 (m, 1H), 7.38 (d, J = 7.0 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H),
7.26 (t, J = 7.3 Hz, 1H), 7.21 (td, J = 7.7, 1.1 Hz, 1H), 7.15 (ddd,
J = 10.7, 8.4, 1.0 Hz, 1H), 4.37 (qd, J = 11.0, 5.7 Hz, 2H), 4.21 (d, J =
13.1 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 3.06−2.94 (m, 2H), 2.32
(ddd, J = 9.1, 6.0, 2.3 Hz, 1H), 2.12−2.01 (m, 1H), 1.87 (m, 3H). 13C
NMR (100 MHz, CDCl3): δ 164.5 (d, J = 2.9 Hz), 162.1 (d, J = 206.8
Hz), 139.7, 134.5 (d, J = 7.1 Hz), 132.2 (d, J = 2.9 Hz), 128.8, 128.1,
126.9, 124.0 (d, J = 3.2 Hz), 119.0, 118.9, 117.1, 116.9, 68.0, 61.9, 59.5,
54.5, 28.7, 23.0. 19F NMR (376 MHz, CDCl3): δ 110.2. HRMS (ESI+)
+
calcd for C19H21FNO2 [M + H]+: 314.1556; found 314.1564.
1,3-Bis((S)-1-benzylpyrrolidin-2-yl)propan-2-one. Prepared accord-
ing to the representative procedure for the bidirectional synthesis of
ketones from 0.156 mmol of (S)-1-benzyl-2-(diazomethyl)pyrrolidine
L
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The Journal of Organic Chemistry
Featured Article
42a (0.75 mL of a 0.21 M toluene solution). Due to concern that the
ketone might racemize during exposure to silica gel, its enantiopurity
was directly assayed by SFC (>98% ee, trace provided as Supporting
Information), and it was moved onto the natural product as is. Still, in
other experiments, the material was purified to gauge homologation
efficiency. Purification by silica gel chromatography (TLC Rf = 0.30 in
70:30 hexanes/ethyl acetate) gave 31 mg of a colorless oil (58% yield).
[α]23D = −35.2 (c = 1.53 g·cm−3, in CHCl3). IR (thin film): 3086 (m),
3058 (w), 3027 (m), 2966 (m), 2872 (m), 1711 (s), 1601 (m), 1495
(m), 1444 (m), 1370 (w), 1317 (w), 1262 (w), 1221 (w), 1167 (m),
1078 (m), 1043 (w), 1029 (m), 908 (w), 807 (w), 718 (w), 697 (s),
(100 MHz, CDCl3): δ 208.7, 208.6, 62.0, 61.9, 56.8, 48.2, 48.1, 40.6,
40.6, 31.4, 22.2. HRMS (ESI+) calcd for C13H25N2O+ [M + H]+:
225.1967; found 225.1960.
(S)-1-Methylpyrrolidine-2-carbaldehyde (41b). Prepared in ac-
cordance with a known procedure82 by adding (COCl)2 (0.179 mL,
2.05 mmol, 1.03 equiv) dropwise to a stirring solution of DMSO
(0.150 mL, 2.11 mmol, 1.06 equiv) in CH2Cl2 (3.0 mL, 0.70 M) at
−78 °C. After being stirred for 20 min at this temperature, the
homogeneous solution was warmed to −50 °C and a CH2Cl2 (1.0 mL,
2.0 M) solution of (S)-1-methyl-2-pyrrolidinemethanol (230 mg,
2.0 mmol) was added as a gentle stream down the walls of the reaction
flask for adequate precooling. The mixture became turbid after being
stirred for 30 min at −50 °C. The flask was cooled to −78 °C, and
Et3N (0.307 mL, 2.20 mmol, 1.10 equiv) was added dropwise to the
center of the stirring mixture by syringe. After 30 min of stirring at
−60 °C, a cloudy precipitate had formed. Pentane (5.0 mL) was then
added to the reaction mixture for 10 min of stirring. The septum was
then removed in preparation for filtration through Celite with multiple
pentane rinses. The volatiles were then removed under reduced
pressure, giving 0.196 g of a colorless oil (1.73 mmol, 86%). The
material was kept under nitrogen atmosphere at all times and quickly
transformed to its corresponding TIPS-hydrazone without any further
purification. The compound had to be used immediately since it
undergoes slow decomposition in solution at 23 °C.
(S)-1-Methyl-2-((2-triisopropylsilyl)hydrazono)methyl)pyrrolidine.
Prepared by the representative procedure above for synthesis and
handling of aliphatic diazoalkanes involving a 2 h addition of triiso-
propylsilylhydrazine (0.489 g, 2.59 mmol, 1.5 equiv) to a 0 °C solution
of (S)-1-methylpyrrolidine-2-carbaldehyde (0.196 g, 1.73 mmol) in
THF (3.5 mL, 0.5 M) containing flame-dried 4 Å molecular sieves
(0.20 g, 1:1 w/w). Upon completion of the addition, the suspension
was warmed to 23 °C and stirred rapidly under N2 for 36 h, at which
time an NMR aliquot showed the absence of starting material. The
mixture was filtered through cotton (with 2 mL of Et2O as a rinse) and
concentrated. The resulting 0.485 g of colorless oil (99% yield) was
used quickly without further purification.
(S)-1-Methyl-2-(diazomethyl)pyrrolidine (42b). Prepared as a
0.33 M toluene solution in 23% yield by following the general
procedure for the synthesis and handling of aliphatic diazoalkanes with
0.485 g of (S)-1-methyl-2-((2-triisopropylsilyl)hydrazono)methyl)-
pyrrolidine (1.71 mmol). Used in a reaction immediately after its
preparation, otherwise stored cold at −78 °C.
( )-Cuscohygrine. Prepared according to the representative pro-
cedure for the bidirectional synthesis of ketones starting with
0.410 mmol of (S)-1-methyl-2-(diazomethyl)pyrrolidine (1.24 mL of
a 0.33 M solution in toluene) and 19.6 mg of Sc(OTf)3 (0.041 mmol,
0.10 equiv). Purification by column chromatography over neutral
alumina (TLC Rf = 0.31 in 5:4:3 in hexanes/CH2Cl2/Et3N) gave
8.3 mg of a colorless oil (18% yield). Characterization data were
identical to that reported in the literature66 and that obtained above by
Jones oxidation of (−)-dihydrocuscohygrine.
1
615 (m). H NMR (400 MHz, CDCl3): δ 7.39−7.28 (m, 10H), 3.90
(d, J = 13.1 Hz, 2H), 3.47 (d, J = 13.1 Hz, 2H), 3.01 (dd, J = 8.8, 7.4
Hz, 2H), 2.88−2.80 (m, 2H), 2.48−2.36 (m, 4H), 2.36−2.25 (m, 2H),
2.17−2.04 (m, 2H), 1.92−1.80 (m, 2H), 1.80−1.68 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ 209.5, 138.1, 129.2, 128.5, 127.3, 62.9,
61.5, 56.4, 53.0, 35.1, 25.0. HRMS (ESI+) calcd for C25H33 N2O+
[M + H]+: 377.2593; found 377.2612.
(−)-Dihydrocuscohygrine (44). To a suspension of Pd/C (10% w/w)
in 1.0 mL of MeOH was added unpurified 1,3-bis((S)-1-benzyl-
pyrrolidin-2-yl)propan-2-one (0.156 mmol theoretical) in MeOH (2.6 mL,
0.060 M based on theoretical) through a cannula under N2
atmosphere. The reaction mixture was purged with H2 three times
from a balloon, and the 1 atm environment was maintained for 16 h of
stirring at 23 °C. The catalyst was removed by filtration through a pad
of neutral Al2O3 with two 0.5 mL volumes of MeOH to rinse the filter
cake. The filtrate was directly collected in a 5 mL round-bottom flask
containing a stirring solution of 29.5 μL of formic acid (0.782 mmol,
5.0 equiv) in a 37% formaldehyde solution (0.23 mL, 20 equiv) at
23 °C. The resulting light yellow solution was heated at 80 °C for 6 h.
After cooling to 23 °C, the reaction mixture was diluted with 15 mL of
CHCl3, transferred to a separatory funnel, and washed three times with
15 mL volumes from a cold solution of 1.0 N NaOH. The organic
layer was collected, dried over Na2SO4, filtered, and concentrated to an
oil. Purification by silica gel chromatography (TLC Rf = 0.38 in 5:4:1
hexanes/DCM/Et2NH) afforded 7.6 mg of (−)-dihydrocuscohygrine
(44) as a colorless oil that quickly turns yellow upon standing at 23 °C
(0.034 mmol, 43% yield over three steps). Enantiomeric purity for the
natural product was determined by chiral gas chromatography in
comparison to authentic racemic material (99:1 er in trace provided as
Supporting Information, Chiraldex BDM column, 15 psi, 250 °C).
23
[α]D = −102 (c = 0.76 g·cm−3, acetone). IR (thin film): 3254 (b),
2937 (s), 2839 (m), 2781 (s), 1658 (w), 1547 (w), 1543 (s), 1370
(m), 1352 (w), 1289 (w), 1209 (m), 1110 (m), 1037 (s), 957 (w), 901
1
(m), 827 (m), 745 (w), 700 (w), 575 (w), 459 (w). H NMR (400
MHz, CDCl3): δ 4.12−4.03 (m, 1H), 3.07 (t, J = 7.8 Hz, 2H), 2.41−
2.36 (m, 2H), 2.35 (s, 6H), 2.14 (td, J = 9.4, 7.7 Hz, 2H), 2.00−1.89
(m, 2H), 1.83−1.76 (m, 2H), 1.75−1.65 (m, 4H), 1.63−1.57 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 67.4, 64.5, 57.3, 41.0, 39.4, 30.3, 23.1.
HRMS (ESI+) calcd for C13H27N2O+ [M + H]+: 227.2123; found
227.2134.
( )-Cuscohygrine. Following the procedure of Stapper and
Blechert,66 a solution of (−)-dihydrocuscohygrine (44) (7.0 mg,
0.031 mmol) in acetone (0.20 mL, 0.15 M) was treated with freshly
prepared Jones’ reagent (0.20 g of CrO3, 0.178 mL of H2SO4, and
1.08 mL of water) at 0 °C and stirred for 1 h at this temperature. At
this point, the reaction mixture was quenched with 10 mL of saturated
NaHCO3, transferred to a separatory funnel, and washed three times
with 10 mL of ice cold CHCl3. The pooled organic layers were washed
with 25 mL of a 30% KOH solution precooled to −20 °C, dried over
NasSO4, filtered, and concentrated to an oil. Purification by silica gel
chromatography (TLC Rf = 0.26 in 5:4:1 hexanes/DCM/Et2NH) gave
5.6 mg of cuscohygrine as a colorless oil (0.025 mmol, 81% yield).
This material, which proved to be racemic as a function of a known
epimerization mechanism,69,70 had the following spectral properties.
IR (thin film): 3386 (m), 2924 (s), 2853 (m), 2780 (m), 1712 (s),
1456 (m), 1375 (m) 1210 (w), 1115 (w), 1031 (w), 966 (w), 906 (w).
1H NMR (400 MHz, CDCl3): δ 3.13−3.04 (m, 2H), 2.88−2.79 (m,
2H), 2.68−2.43 (m, 4H), 2.33 (s, 6H), 2.27−2.18 (m, 2H), 2.16−
2.01 (m, 2H), 1.86−1.66 (m, 4H), 1.50−1.37 (m, 2H). 13C NMR
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all new compounds and
analytical SFC or GC traces to validate enantiopurity. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jason.kingsbury@pomona.edu.
■
Present Address
†Department of Chemistry, Pomona College, 645 North
College Avenue, Claremont, CA 91711.
Notes
The authors declare no competing financial interest.
M
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(30) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126,
12222−12223.
ACKNOWLEDGMENTS
■
Generous funding from Boston College and the ACS
Petroleum Research Fund (#5001009) has made this work
possible. We are indebted to Professor Larry T. Scott for his
insight and encouragement, and to Dr.’s David C. Moebius and
Victor L. Rendina for experimental expertise. A.J.W. was a
LaMattina graduate fellow.
(31) Holton, T. L.; Shechter, H. J. Org. Chem. 1995, 60, 4725−4729.
(32) For a thorough discussion on the longstanding complication of
hydrazone instability, see: Furrow, M. E.; Myers, A. G. J. Am. Chem.
Soc. 2004, 126, 5436−5445.
(33) Justo de Pomar, J. C.; Soderquist, J. A. Tetrahedron Lett. 2000,
41, 3285−3288.
(34) PhI(O2CCF3) can be substituted for Pb(OAc)4 with no impact
on the yield of 2, although the extract becomes contaminated with PhI.
(35) Informative details are posted in the Aldrich Technical Bulletin
#AL-180: “Diazald®, MNNG, and Diazomethane Generators.” This
material is available under the ‘Related Information’ tab of the Search
command at http://www.sigma-aldrich.com.
(36) Hudlicky, M. J. Org. Chem. 1980, 45, 5377.
(37) Sammakia, T. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley and Sons: Chichester, U.K., 1995.
(38) Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6, 884−
992.
(39) Explosion of a supersaturated crystallizing solution was once
observed: De Boer, T. J.; Backer, H. J. In Organic Synthesis, Collective;
Rabjohn, N., Ed.; John Wiley and Sons: New York, 1963; Vol. IV, pp
250−252.
(40) Shankar, B. K. R.; Shechter, H. Tetrahedron Lett. 1982, 23,
2277−2279.
(41) Rendina, V. L.; Kingsbury, J. S. J. Org. Chem. 2012, 77, 1181−
1185.
REFERENCES
■
(1) (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258−3260.
(2) Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33,
1131−1134.
(3) Murata, H.; Ishitani, H.; Iwamoto, M. Tetrahedron Lett. 2008, 49,
4788−4791.
(4) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.;
Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532−8533.
(5) Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem.
2005, 1479−1492.
(6) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.;
Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125,
10926−10940.
(7) May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426−
12427.
(42) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675−680.
(43) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38−54.
(44) Alexander, M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 9900−9901.
(8) A review on catalytic carbon C−H insertion reactions based on
α-diazo ester and diazocarbonyl reagents: Doyle, M. P.; Duffy, R.;
Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704−724.
(9) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417−424.
(10) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc.
2008, 130, 2434−2435.
(45) For an early double Knoevenagel−inverse demand Diels−Alder
approach to 9,10-disubstituted fluoranthenes, see: Scott, L. T.;
Hashemi, M. M.; Meyer, D. T.; Warren, H. B. J. Am. Chem. Soc.
1991, 113, 7082−7084.
(11) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009, 131,
878−879.
(46) Grimsdale, A. C.; Mullen, K. Angew. Chem., Int. Ed. 2005, 44,
(12) Wommack, A. J.; Moebius, D. C.; Travis, A. L.; Kingsbury, J. S.
Org. Lett. 2009, 11, 3202−3205.
̈
5592−5629 and references cited therein.
(47) Potter, R. G.; Hughes, T. S. Org. Lett. 2007, 9, 1187−1190.
(48) Potter, R. G.; Hughes, T. S. Chem. Commun. 2007, 4665−4667.
(49) Jackson, E. A.; Steinberg, B. D.; Bancu, M.; Wakamiya, A.; Scott,
L. T. J. Am. Chem. Soc. 2007, 129, 484−485.
(50) Omachi, H.; Segawa, Y.; Itami, K. Acc. Chem. Res. 2012, 45,
1378−1389.
(13) Moebius, D. C.; Dabrowski, J. A.; Wommack, A. J.; Kornahrens,
A. F.; Kingsbury, J. S. Org. Lett. 2010, 12, 3598−3601.
(14) Rendina, V. L.; Moebius, D. C.; Kingsbury, J. S. Org. Lett. 2011,
13, 2004−2007.
(15) Rendina, V. L.; Kaplan, H. Z.; Kingsbury, J. S. Synthesis 2012,
686−693.
(51) Scott, L. T.; Jackson, E. A.; Zhang, Q.; Steinberg, B. D.; Bancu,
M.; Li, B. J. Am. Chem. Soc. 2012, 134, 107−110.
(52) Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
(53) Rodriquez, L.; Lu, N.; Yang, N.-L. Synlett 1990, 227−228.
(54) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M.
T. J. Am. Chem. Soc. 1990, 112, 8215−8216.
(55) Gilman, H.; Catlin, W. E. Org. Synth. 1926, 6, 22.
(56) Reisch, H. A.; Bratcher, M. S.; Scott, L. T. Org. Lett. 2000, 2,
1427−1430.
(57) Andrusyszyn, P. M. Extending the Aryl Radical Cyclization
Approach to Large Geodesic Polyarenes. Ph.D. Thesis, Boston
College, 2002.
(16) Gutsche, C. D. Org. React. 1954, 8, 364−429.
(17) Hauptmann, S.; Hirschberg, K. J. Prakt. Chem. 1966, 34, 272.
(18) Gutsche, C. D.; Redmore, D. In Carbocyclic Ring Expansion
Reactions; Hart, H., Karabatsos, G. J., Eds.; Academic Press: New York,
1968; pp 81−98.
(19) Mullin, S.; Mani, N.; Grossman, T. H. Antimicrob. Agents
Chemother. 2004, 4171−4176.
(20) Minderman, H.; O’Loughlin, K. L.; Pendyala, L.; Baer, M. R.
Clin. Cancer Res. 2004, 10, 1826−1834.
(21) Polydefkis, M.; Sirdofsky, M.; Hauer, P.; Petty, B. G.; Murinson,
B.; McArthur, J. C. Neurology 2006, 66, 259−261.
(22) Cai, M.; Zhou, Y.; Wang, X.; Li, R.; Liao, X.; Ding, L. Rapid
Commun. Mass Spectrom. 2007, 21, 1931−1936.
(23) Wang, X.; Ma, Y.-Y.; Ding, K.-Y.; Ding, L. Chinese Traditional
and Herbal Drugs 2010, 41, 340−342.
(58) Liebermann, C. Ber. 1889, 2, 675.
(59) Liebermann, C.; Cybulski, G. Ber. 1895, 28, 578.
(60) Turner, C. E.; Elsohly, M. A.; Hanus, L.; Elsohly, H. N.
Phytochemistry 1981, 20, 1403−1405.
(24) Zhang, X.-P.; Liu, M.-S.; Zhang, J.-Q.; Kang, S.-L.; Pei, Y.-H. J.
Asian Nat. Prod. Res. 2009, 11, 75−78.
(25) Hoye, T. R.; Suhadolnik, J. C. Tetrahedron 1986, 42, 2855−
2862.
(26) Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett.
1991, 32, 3961−3964.
(27) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9−17.
(28) A review on applications of two-directional strategies in natural
products synthesis: Magnuson, S. R. Tetrahedron 1995, 51, 2167−
2213.
(61) El-Imam, Y. M. A.; Evans, W. C.; Plowman, T. Phytochemistry
1985, 24, 2285−2289.
(62) Christen, P.; Roberts, M. F.; Phillipson, J. D.; Evans, W. C.
Phytochemistry 1995, 38, 1053−1056.
(63) Leete, E. Phytochemistry 1983, 22, 699.
(64) Novak, M.; Salemink, C. A.; Khan, I. J. Ethnopharmacol. 1984,
10, 261−274.
(65) Watson, E. S.; Murphy, J. C.; Elsohly, H. N.; Elsohly, M. A.;
Turner, C. E. Toxicol. Appl. Pharmacol. 1983, 71, 1−13.
(66) Stapper, C.; Blechert, S. J. Org. Chem. 2002, 67, 6456−6460.
(29) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789−1792.
N
dx.doi.org/10.1021/jo401377a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(67) Yamauchi, T.; Hagiwara, S.; Higashiyama, K. J. Org. Chem. 2008,
73, 9784−9787.
(68) Icke, R. N.; Wisegarver, B. B.; Alles, G. A. Org. Synth. 1945, 25,
89.
(69) Brown, R. T. In The Chemistry of Heterocyclic Compounds;
Saxton, J. E., Ed.; Wiley Interscience: New York, 1983; Vol. 25, Part 4,
pp 85−97.
(70) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027−2030.
(71) Pross, A.; Sternhill, S. Aust. J. Chem. 1970, 23, 989−1003.
(72) Lee, D. O.; Jensen, C. M. J. Chem. Educ. 2000, 77, 629.
(73) Potter, R. G.; Hughes, T. S. J. Org. Chem. 2008, 73, 2995−3004.
(74) Inaba, S.; Rieke, R. D. J. Org. Chem. 1985, 50, 1373−1381.
(75) Bongui, J.; Elomri, A.; Cahard, D.; Tillequin, F.; Pfeiffer, B.;
Pierre, A.; Seguin, E. Chem. Pharm. Bull. 2005, 53, 1540−1547.
(76) Lin, S.; Chen, Q.; You, T. Synlett 2007, 13, 2101−2105.
(77) Nagahara, S.; Maruoka, K.; Yamamoto, H. Chem. Lett. 1992, 21,
1193−1196.
(78) Trost, B. M.; Ito, H. Catalytic Compositions and Methods for
Asymmetric Aldol Reactions. U.S. Patent 147367-A1, 2002.
(79) Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442−444.
(80) Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 2737−2743.
(81) Deur, C. J.; Miller, M. W.; Hegedus, L. S. J. Org. Chem. 1996, 61,
2871−2876.
(82) Cannon, J. G.; Milne, L. D. J. Heterocycl. Chem. 1976, 13, 686−
689.
O
dx.doi.org/10.1021/jo401377a | J. Org. Chem. XXXX, XXX, XXX−XXX