Vanadium(V)-mediated rearrangement/halogenation cascade: Synthesis of α-haloenones from propargyl alcohols

Article abstract of DOI:10.1016/j.tet.2016.12.055

A method is described for the oxidative Meyer–Schuster-type rearrangement of propargylic alcohols to (Z)-α-chloro- and α-iodoenones using VOCl₃ as a multifunctional reagent. The vanadium reagent is found to serve as rearrangement promoter as well as an active chlorenium ion donor. Yields are improved when VOCl₃ is employed in conjunction with N-halosuccinimide reagents, giving some insights into the complex mechanism.

Full text of DOI:10.1016/j.tet.2016.12.055

Accepted Manuscript
Vanadium(V)-mediated rearrangement/halogenation cascade: Synthesis of α-
haloenones from propargyl alcohols
Meng Zhao, Justin T. Mohr
PII:
S0040-4020(16)31352-7
10.1016/j.tet.2016.12.055
TET 28347
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 September 2016
Revised Date: 1 December 2016
Accepted Date: 22 December 2016
Please cite this article as: Zhao M, Mohr JT, Vanadium(V)-mediated rearrangement/halogenation
cascade: Synthesis of α-haloenones from propargyl alcohols, Tetrahedron (2017), doi: 10.1016/
j.tet.2016.12.055.
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Vanadium(V)-Mediated
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Rearrangement/Halogenation Cascade:
Synthesis of α-Haloenones from
Propargyl Alcohols
Meng Zhao and Justin T. Mohr*

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ACCEPTED MANUSCRIPT
Tetrahedron Letters
journal homepage: www.elsevier.com
Vanadium(V)-Mediated Rearrangement/Halogenation Cascade: Synthesis of
α-Haloenones from Propargyl Alcohols
Meng Zhao and Justin T. Mohr
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method is described for the oxidative Meyer–Schuster-type rearrangement of propargylic
alcohols to (Z)-α-chloro- and α-iodoenones using VOCl3 as a multifunctional reagent. The
vanadium reagent is found to serve as rearrangement promoter as well as an active chlorenium
ion donor. Yields are improved when VOCl3 is employed in conjunction with N-
halosuccinimide reagents, giving some insights into the complex mechanism.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Vanadium
Halogenation
Rearrangement
Enones
Oxidation
1. Introduction
not well-established. The multiple stable oxidation states of V
lead to a rich array of redox chemistry, and V(II), V(III), V(IV),
The synthetic utility of α-haloenones has been widely
recognized particularly as electrophilic partners in transition
metal-mediated cross-coupling reactions.1 The α-iodoenone
substructure is most commonly used in this role, and is
classically produced from the corresponding enone with an
electrophilic I source in the presence of tertiary amines.2
Protocols for preparing the corresponding α-chloroenones are
considerably less common.3 The α-haloenone moiety is also
present in several bioactive molecules4 and natural products.5 A
particularly notable example is a derivative of the natural product
englerin A that exhibits increased inhibitory potency versus renal
cancer cell growth and differs from the natural compound only
by the presence of a Cl atom in place of a H on the cinnamate
sidechain (Figure 1).4c Together these features attest to the
importance of halogenated compounds in chemical synthesis,
natural products chemistry, and medicine.
and V(V) complexes are commercially available. The reactivity
of these reagents is frequently facilitated by the electrophilicity of
V itself in higher oxidation states and such V complexes are
particularly valuable in cascade reactions involving oxidative
steps.8 Of particular interest are highly efficient allylic oxygen
transposition reactions, such as the Meyer–Schuster
rearrangement,9 that are facilitated by V(V) complexes, although
these do not typically involve oxidation events.10 The relatively
low cost of versatile precursors such as VOCl3 ($39 for 100 g,
Strem Chemicals) adds to the practicality of V-based synthetic
methods.
Propargylic alcohols are attractive synthetic intermediates
since they are readily available through addition of metallated
alkynes to carbonyl compounds. The versatility of these systems
is evident in Meyer–Schuster-type rearrangement reactions
(Scheme 1),9 wherein an internal redox isomerization transforms
the alcohol into a conjugated carbonyl product.11 From a
synthetic perspective, the sequence of alkynylation of carbonyl
compounds
followed by rearrangement
achieves
a
regiocontrolled C–C coupling that may be challenging through
alternative means such as aldol condensation. In addition, the
presumed intermediacy of a nucleophilic allenol or
Figure 1. Bioactive α-chloroenone compounds
Vanadium complexes exhibit diverse reactivity in multiple
manifolds,6 including those that facilitate C–halogen bond
formation,7 although the exact role of V in these specific cases is
———
Scheme 1. The Meyer–Schuster rearrangement
 Corresponding author. E-mail address: jtmohr@uic.edu (J.T. Mohr).

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Tetrahedron
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allenolate intermediate has piqued recent interest in
address this issue, we examined addition of an exogenous
halogen source which could compete with presumed
developing this transformation for the synthesis of α-substituted
a
enones.11 Included in this set are some methods for the formation
intermolecular protonation event, serve to activate the putative V-
based Cl+ source, or potentially regenerate a V(V) complex if the
metal were reduced. Indeed, addition of N-chlorosuccinimide
(NCS) significantly improved yield under similar conditions (Eq.
3). Notably the transformation with NCS as an additive does not
of α-bromo- and α-iodoenones.12,13
However, means of
synthesizing the chloroenone congeners through these strategies
are absent from these reports. These methods are nonetheless an
important component of the growing family of transition metal-
mediated redox isomerization/halogenation cascade reactions.14
Although several of these Meyer–Schuster variants require the
use of strong oxidants such as Cr(VI) salts or hypervalent iodine
reagents or strong Brønsted acids such as HI,12 recent progress
has been made through transition metal catalysis or the use of
alkoxyalkynes which avoid these harsh conditions.13 Given our
ongoing interests in novel halogenation protocols15 and remote
functionalization reactions,16 we sought to investigate
rearrangement cascades that might expand on the scope of this
strategy and impact synthetic design while providing inroads
toward the synthesis of useful α-chloroenones. Herein, we report
the development of a protocol for synthesis of α-chloroenones
from propargylic alcohols using an inexpensive V(V) complex
that serves multiple roles including rearrangement promoter and
halogen donor.
proceed in the absence of VOCl3. With these results in hand, we
embarked upon a detailed optimization of reaction parameters to
develop a synthetically useful protocol.
We first investigated the quantity of VOCl3 in the presence of
NCS (Table 1, entries 2–5).18 Presumably a greater concentration
of VOCl3 would force material through the postulated V-based
halgenation pathway, although in the presence of NCS the V salt
might also be made catalytic. When 60 mol% VOCl3 was
employed, however, the yield of chloroenone 2a was comparable
to the reaction with no NCS (Cf. entries 1 and 2). Greater
quantities of VOCl3 gave significantly improved yield, with only
a small improvement above 1.7 equiv of the V complex.
A
2. Results and Discussion
solvent screen found dichloromethane to be the preferred solvent
(entries 5–10). Modifying the amount of NCS additive did not
affect the yield substantially, but yield remained highest when 2
equiv of this reagent were present (entries 11–16).19 A survey of
other potential electrophilic Cl sources found no improvements
Our initial discovery occurred when we observed an
unexpected product when attempting a rearrangement/homoaldol
cascade reaction mediated by VOCl3 instead of a more typical
vanadyl ester reagent.10 Under these conditions the aldol product
was not observed and spectral data indicated that a significant
proportion of the product mixture had incorporated a Cl atom
(Eq. 1). Another unanticipated finding was that the Cl was
over NCS,
although 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH) did deliver comparable results (entries 17–20).20
Multiple heterogeneous bases are comparably competent in
quantities as low as 1.8 equiv, but variation with this parameter
were relatively small.21
Collectively, when weighing the
quantities of reagents needed and overall yield, we selected the
protocol employing 1.7 equiv of VOCl3 (entry 3) for exploration
of the scope of the transformation.
Using our optimized reaction conditions, a variety of aryl
alkynyl carbinols were examined in our halogenative
rearrangement reaction (Table 2). Halogenated arenes perform
well in the reaction, although the variance in yield suggests
sensitivity to the electronic nature of the aryl fragment (entries 2–
4). Both para- and meta-alkyl substituted arenes rearrange
introduced at the α-carbon of the enone moiety, suggesting that
VOCl3 had behaved as a source of electrophilic Cl. In addition,
only the Z-chloroenone was observed suggesting a significant
stereocontrol effect.17
Halogenation protocols using V(V)
complexes as oxidants with halide salts have been reported, but
frequently these involve halide anions or the formation of an
electrophilic halenium donor through oxidation of halide anions.7
In one instance a similar α-chloroenone side product was
observed in very small quantities by Carrillo-Hermosilla and
García-Álvarez and co-workers,10i but to our knowledge neither
the direct reactivity of VOCl3 as a halenium donor nor the
optimization of the chlorination pathway in V-mediated Meyer–
Schuster rearrangement have been reported. Control experiments
indicated that VOCl3 is not capable of chlorinating enone systems
under our reaction conditions (vide infra), suggesting that an
intermediate along the reaction pathway, perhaps the putative
allenolate nucleophile, is responsible for the observed reactivity.
Seeking to improve the selectivity for the halogenative
transformation, we considered the addition of a stoichiometric
base to mitigate the formation of HCl which might serve as a
competing electrophile for a putative allenolate intermediate.
Pretreatment of the alcohol with NaH (1 equiv) did indeed reduce
the quantity of protonated product, but the yield of the
halogenated material increased only modestly (Eq. 2). To
Table 1. Optimization of reaction conditionsa
a
NMR yield from reaction of 0.3 mmol of substrate 1a,
VOCl3, additive, and 10 equiv of K2CO3, in CH2Cl2 (0.1 M in 1a)
at 22 ºC for 8 h. b Reaction with no K2CO3 added.

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pathway,11 a propargyl vanadyl ester (A, Scheme 2a) is formed
Table 2. Scope of chloroenone synthesisa
initially, and a subsequent [3,3]-sigmatropic rearrangement leads
to the key allenolate-type intermediate B. This nucleophile could
then react with a chlorovanadium complex in either an intra- or
intermolecular halogenation event (red arrows shown) leading to
product 2. When VOCl3 is used alone, either pathway would
presumably lead to a reduced V(III) intermediate (C), which
would likely conproportionate in the presence of V(V) to form a
more stable V(IV) oxo complex such as D, which may explain
the poor performance under catalytic conditions.
In the presence of NCS, the external transfer pathway is the
likely point of intervention for the alternative Cl+ donor.
Whereas chlorination with chlorovanadyl complexes is unusual,
we suspected that the internal pathway may be relatively slow
and therefore the improved yield in the presence of NCS would
be explained by providing an alternative pathway. We cannot,
however, exclude the possibility that NCS serves as an activator
for the internal pathway, aggregates with the Lewis acidic V
center for a directed Cl transfer, or regenerates an active V(V)
complex from a reduced form (e.g., C or D) and thus increases
the effective concentration of active V-based chlorenium donor.
Whereas the external pathway would regenerate a V(V)
complex that could be capable of catalysis, the low yields under
catalytic conditions would appear to favor one of these latter
possibilities.
We considered interrogating this notion by
employing a different halenium donor to gain additional
information regarding the nature of the active intermediate.
Accordingly, we substitute N-iodosuccinimide (NIS) for NCS in
our optimized protocol and we were pleased to find the (Z)-α-
iodoenone as the major products, but invariably observed the α-
chloroenone as a chromatographically separable side product
(Table 3).13c,d The combined yield of the haloenone products
range from fair to good across several substrates, and thus the
protocol is a reasonable means of forming the iodo analogues
from readily available propargylic alcohols. Curiously, similar
reactivity is not observed when NBS is used and instead an as yet
unidentified product is formed. From a mechanistic perspective,
a
Isolated yield from reaction of 0.3 mmol of substrate 1, 1.7
equiv of VOCl3, 2.0 equiv of NCS, and 1.8 equiv of NaHCO3 in
CH2Cl2 (0.1 M in 1a) from 0 to 22 ºC for 8 h.
cleanly to the chloroenones in fair to good yields (entries 5–7).
An ortho-brominated carbinol was rearranged in comparable
yield to the para-bromo analogue, indicating that steric effects of
this moiety are not a substantial factor in reactivity (entry 8).
Modification of the alkyne terminus with a sterically demanding
tert-butyl substituent did not negate reactivity and the tert-butyl
ketone forms in reasonable yield (entry 9). Elongation of the
alkyl chain on the alkyne moiety gave a comparable result as well
(entry 10).
The presence of strong electron donating or electron
withdrawing groups on the aromatic portion greatly impact the
efficiency of the reaction and remaining unreacted starting
materials and nonspecific decomposition products are observed.
The transformation does not proceed comparably when tertiary
alcohols, aliphatic alkynyl carbinols, alkenyl alkynyl carbinols,
carbinols derived from phenylacetylene, or terminal alkynes are
employed. The origins of these limitations are unknown at this
point and are objectives for further research.
3. Mechanistic Considerations and Iodoenone Synthesis
Some mechanistic possibilities are shown in Scheme 2.
Scheme 2. Potential mechanisms for haloenone formation
Following
a
typical oxometal-mediated Meyer–Schuster

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Tetrahedron
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Table 3. Iodoenone synthesisa
Table 4. Control experiments with a model enone
cannot confidently assert that the effect of halosuccinimide in our
protocol is simply a secondary process since any active halenium
donor may also intercept the putative allenolate intermediate
which is presumed to be the strongest available nucleophile.
Further studies to differentiate these mechanistic possibilities are
ongoing. It does appear, however, that there are likely multiple
pathways capable of generating the observed products and the
key factors to negating any one of these pathways has not been
determined at this stage.
a
Isolated yield (average of two runs) of iodoenone from
reaction of 0.3 mmol of substrate 1, 1.7 equiv of VOCl3, 2.0
equiv of NIS, and 1.8 equiv of NaHCO3 in CH2Cl2 (0.1 M in 1a)
from 0 to 22 ºC for 8 h. The ratio of haloenones (2:3) was
determined by GC.
these results cannot provide definitive information regarding the
reaction pathway and may, in fact, support the idea that there are
multiple competing pathways leading to the products. We found
that even in the presence of greater quantities of NIS the
chloroenones are still produced in comparable quantities. This
would be consistent with an intramolecular chlorenium transfer
process from V complex B that is difficult to outcompete with
halogen donors that operate through an intermolecular reaction or
a higher order intramolecular pathway. The heterogeneous
nature of the reaction mixture may also limit the ability to
compete with alternative halogen donors, although we noted that
even reagents containing a greater density of active electrophilic
Cl did not improve the reaction (see Table 1, entries 18 and 19).
Further efforts to solve this issue and broaden the scope of
electrophile are ongoing in our lab.
Literature reports of formation of electrophilic halogenating
agents from halide salts and V(V) suggest a potential alternative
mechanism (Scheme 2b).7f–i Although the nature of the active
halogenating agent is unknown in these systems, the scope does
include dihalogenations of alkynes. If this were to occur with a
propargylic alcohol (1), then the resulting allylic alcohol E would
be poised for V-mediated rearrangement via vanadate ester F to
form chlorohydrin-type intermediate G. Decomposition of this
species would regenerate VOCl3 and liberate product 2.
Although plausible, it is difficult to reconcile the results of the
iodination reaction (Table 3) since the point of C–halogen bond
formation at the central carbon of the propargylic system would
likely be affected by concentration of NIS.
4. Conclusion
In conclusion, we have developed a useful protocol for
halogenative rearrangement of propargylic alcohols to
haloenones mediated by commercially available VOCl3. In
tandem with succinimide-based halogen donors, good yields are
realized and promising results are achieved for introduction of
iodine substituents by modification of the succinimide. The
transformation is stereoselective and delivers only the (Z)-
haloenone isomers. These product compounds are poised for
further functionalization utilizing the diverse reactivity of the
complex functional group. Efforts to build on these methods and
to employ this transformation in target-directed synthesis are
underway.
5. Experimental section
5.1. General remarks
Reactions were performed in oven-dried glassware under N2
atmosphere using dry, deoxygenated solvents.
dichloromethane and THF were purchased from Fisher Scientific,
degassed with argon, and dried using Pure Process
Anhydrous
a
Technologies solvent drying system. VOCl3 was purchased from
Alfa Aesar and used as received. Thin-layer chromatography
(TLC) was performed using Silicycle silica gel 60 F254
precoated plates (0.25 mm) and visualized by UV fluorescence
A series of control experiments using a model des-haloenone
are suggestive of a third potential pathway (Table 4 and Scheme
2c). Treatment of chalcone with either NCS or VOCl3 under
basic conditions did not lead to halogenation and the combination
of VOCl3 and NCS produced only trace amounts of the α-
chloroenone (Table 4). However, the mixture of VOCl3, NCS,
and base did indeed cause halogenation to occur. These results
suggest that the aggregation of VOCl3 and NCS is either
facilitated by base or involves the base directly, and leads to a
chlorenium donor that is more active than either component
individually. Taking the result at face value, it is tempting to
posit that V-mediated rearrangement occurs to give an initial
mixture of chloroenone and des-chloroenone similar to that
shown in Eq. 1, presumably through a classical oxometal Meyer–
Schuster mechanism where the des-chloroproduct results from
competitive protonation of the allenolate intermediate. The
remaining des-chloroenone may then be processed into the
chloroenone through a secondary process involving an activated
form of NCS (Scheme 2c). This would be consistent with the
iodination results as well, since the proportion of chloroenone
would be independent of iodinating reagent. However, we
quenching or staining with KMnO4 solution.
Flash
chromatography was performed using Silicycle SiliaFlashR P60
silica gel (40–63 μm particle size). Deuterated chloroform
(CDCl3, 99.9%, extra dry) was purchased from Cambridge
Isotope Laboratories, Inc. and used without further purification.
1H and 13C NMR spectra were recorded on a Bruker Avance
DRX-500 (at 500 and 126 MHz, respectively) and chemical
1
shifts are reported relative to Me4Si (δ 0.0 ppm). Data for H
NMR spectra are reported as follows: chemical shift (δ ppm)
(multiplicity, coupling constant (Hz), integration). Multiplicities
are reported as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. Data for 13C NMR spectra are reported in
terms of chemical shift relative to Me4Si (δ 0.0 ppm). Infrared
(IR) spectra were recorded on a Nicolet iS5 FTIR spectrometer
and reported in frequency of absorption (cm–1). GC/MS analyses
were performed on a Hewlett Packard Model 6890 gas
chromatograph interfaced to a Hewlett Packard Model 5973 mass
selective detector (15 m x 0.25 mm capillary column, HP-5MS).
5.2. General procedure for the synthesis of propargylic alcohols
and their spectral data

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To a solution of the alkyne (1 equiv) in THF (1 M in alkyne)
was added n-BuLi (2.5 M soln in hexanes, 1 equiv) at 0 °C and
the solution was stirred at this temperature for 1 h. The
corresponding aldehyde (1 equiv) was added dropwise and the
resulting solution was stirred overnight. Saturated NH4Cl
solution (1 mL per mmol of alkyne) was added and the aqueous
phase was extracted with dichloromethane (3 times, 1 mL per
mmol of alkyne). The combined organic phases were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Purification via column chromatography yielded the
corresponding products.
chromatography (10:1 hexanes:ethyl acetate), this compound
was isolated as a colorless liquid (4.845 g, 91% yield). TLC
(SiO2) Rf = 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3)
7.48 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.39 (s, 1H),
2.40 (d, J = 3.5 Hz, 1H), 2.26 (td, J = 7.0, 1.7 Hz, 2H), 1.52
(app.t, J = 7.1 Hz, 2H), 1.41 (app.t, J = 7.2 Hz, 2H), 0.91 (t, J =
7.3 Hz, 3H); C (126 MHz, CDCl3) 140.3, 131.6, 128.3, 122.1,
88.0, 79.5, 64.1, 30.6, 22.0, 18.5, 13.6; IR (neat, cm–1) 3338,
2956, 2931, 2871, 2358, 2223, 1705, 1591, 1484, 1465, 1428,
1399, 1378, 1326, 1263, 1188, 1134, 1101, 1069, 1009, 943, 907,
886, 847, 818, 772, 735, 657; GC/MS (m/z, intensity) 266.0
(12%), 223.0 (6%), 208.9 (8%), 187.1 (100%), 169.0 (8%), 157.0
(25%), 145.0 (29%), 127.0 (23%), 115.1 (47%), 91.0 (7%), 77.0
(30%), 50.0 (20%).
5.2.1. 1-phenylhept-2-yn-1-ol (1a)
Prepared using benzaldehyde (5.1 mL, 50.0 mmol) and 1-
hexyne (5.8 mL, 50.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (8.643 g, 91% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.55–
7.54 (d, J = 7.2 Hz, 2H), 7.40–7.37 (t, J = 7.3 Hz, 2H), 7.34–7.30
(m, 1H), 5.46–5.45 (d, J = 6.2 Hz, 1H), 2.28 (dt, J = 7.0, 1.9 Hz,
2H), 2.24 (d, J = 2.1 Hz, 1H), 1.58–1.50 (m, 2H), 1.48–1.38 (m,
2H), 0.93 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 141.3, 128.5,
128.2, 126.6, 87.7, 79.9, 64.8, 30.6, 22.0, 18.5, 13.6; IR (neat,
cm–1) 3354, 3030, 2956, 2931, 2871, 2226, 1602, 1493, 1453,
1429, 1378, 1327, 1274, 1191, 1133, 1075, 1000, 916, 825, 724,
696, 633; GC/MS (m/z, intensity) 188.1 (100%), 170.1 (4%),
155.1 (5%), 145.1 (82%), 131.1 (60%), 115.1 (56%), 105.1
(44%), 91.1 (36%), 77.1 (50%), 67.1 (12%), 51.1 (17%).
5.2.5. 1-(4-methylphenyl)hept-2-yn-1-ol (1e)
Prepared using p-methylbenzaldehyde (2.4 mL, 20.0 mmol)
and 1-hexyne (2.3 mL, 20.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (2.489 g, 62% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.44 (d,
J = 7.8 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 5.41 (s, 1H), 2.62 (s,
1H), 2.38 (s, 3H), 2.29 (dt, J = 7.0, 3.4 Hz, 2H), 1.56 (app.t, J =
7.0 Hz, 2H), 1.46 (app.t, J = 7.1 Hz, 2H), 0.96 (t, J = 7.3 Hz,
3H); C (126 MHz, CDCl3) 138.6, 137.8, 129.2, 126.7, 87.3,
80.3, 64.6, 30.7, 22.0, 21.2, 18.5, 13.6; IR (neat, cm–1) 3363,
2956, 2930, 2871, 2358, 2223, 1614, 1512, 1455, 1429, 1378,
1327, 1299, 1272, 1193, 1178, 1132, 1109, 993, 943, 909, 819,
757, 734, 591, 561; GC/MS (m/z, intensity) 202.1 (45%), 187.1
(100%), 159.1 (23%), 145.1 (66%), 128.1 (34%), 115.1 (55%),
105.1 (34%), 91.1 (91%), 77.1 (25%), 65.1 (29%), 53.1 (22%).
5.2.2. 1-(4-fluorophenyl)hept-2-yn-1-ol (1b)
Prepared using p-flourobenzaldehyde (0.806 g, 6.5 mmol) and
1-hexyne (1.2 mL, 9.8 mmol). After purification by flash
chromatography (15:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (0.801 g, 60% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.51 (dd,
J = 8.2, 5.6 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 5.43 (s, 1H), 2.29–
2.26 (m, 2H), 2.18 (s, 1H), 1.53 (app.t, J = 7.1 Hz, 2H), 1.42
(app.t, J = 7.1 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); C (126 MHz,
CDCl3) 162.6 (d, J = 246.5 Hz), 137.1 (d, J = 2.5 Hz), 128.4 (d, J
= 8.2 Hz), 115.3 (d, J = 21.6 Hz), 87.9, 79.7, 64.1, 30.6, 22.0,
18.5, 13.6; IR (neat, cm–1) 3337, 2958, 2932, 2872, 2222, 1603,
1506, 1465, 1429, 1378, 1326, 1295, 1222, 1189, 1156, 1133,
1094, 993, 938, 887, 838, 769, 738, 687, 589, 559; GC/MS (m/z,
intensity) 206.1 (81%), 190.0 (4%), 177.0 (5%), 163.0 (82%),
149.0 (58%), 133.0 (57%), 123.0 (100%), 109.0 (94%), 95.0
(76%), 83.0 (11%), 75.0 (33%), 67.0 (30%), 53.0 (25%).
5.2.6. 1-(4-(tert-butyl)phenyl)hept-2-yn-1-ol (1f)
Prepared using 4-tert-butylbenzaldehyde (0.7 mL, 4.0 mmol)
and 1-hexyne (0.7 mL, 6.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (0.840 g, 86% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.49 (d,
J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 2.29 (dt, J
= 7.1, 3.6 Hz, 2H), 2.17 (d, J = 4.8 Hz, 1H), 1.55 (app.t, J = 7.1
Hz, 2H), 1.45 (app.t, J = 7.1 Hz, 2H), 1.34 (s, 9H), 0.94 (t, J =
7.3 Hz, 3H); C (126 MHz, CDCl3) 151.2, 138.4, 126.4, 125.5,
87.4, 80.0, 64.6, 34.6, 31.3, 30.7, 22.0, 18.5, 13.6; IR (neat, cm–1)
3357, 2957, 2932, 2869, 2203, 1644, 1604, 1567, 1509, 1462,
1408, 1378, 1362, 1326, 1299, 1268, 1202, 1186, 1135, 1118,
1106, 992, 912, 840, 787, 765, 728, 695, 589, 570; GC/MS (m/z,
intensity) 244.2 (3%), 229.1 (6%), 213.1 (4%), 187.1 (100%),
162.1 (8%), 147.1 (34%), 131.0 (13%), 115.0 (17%), 91.1 (32%),
57.1 (26%).
5.2.3. 1-(4-chlorophenyl)hept-2-yn-1-ol (1c)
Prepared using p-chlorobenzaldehyde (2.811 g, 20.0 mmol)
and 1-hexyne (2.3 mL, 20.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (3.855 g, 86% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.46 (d,
J = 8 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.41 (s, 1H), 2.32 (d, J =
5.7 Hz, 1H) 2.27 (t, J = 6.7 Hz, 2H), 1.56–1.47 (m, 2H), 1.42
(app.t, J = 7.0 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H); C (126 MHz,
CDCl3) 139.8, 133.9, 128.6, 128.0, 128.5, 88.0, 79.6, 64.0, 30.6,
22.0, 18.5, 13.6; IR (neat, cm–1)3349, 2957, 2931, 2871, 2224,
1712, 1595, 1578, 1488, 1465, 1407, 1378, 1326, 1264, 1190,
1134, 1089, 1013, 944, 907, 823, 777, 735, 668; GC/MS (m/z,
intensity) 222.0 (22%), 187.1 (100%), 165.0 (22%), 149.0 (15%),
139.0 (84%), 127.0 (50%), 115.0 (80%), 105.0 (20%), 89.0
(15%), 77.0 (73%), 67.0 (43%), 53.0 (50%).
5.2.7. 1-(m-tolyl)hept-2-yn-1-ol (1g)
Prepared using 3-methylbenzaldehyde (0.5 mL, 4.0 mmol)
and 1-hexyne (0.7 mL, 6.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (0.684 g, 85% yield). TLC (SiO2) Rf
= 0.3 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.36–
7.33 (m, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H),
5.41 (s, 1H), 2.38 (s, 3H), 2.28 (t, J = 6.9 Hz, 2H), 2.17 (s, 1H),
1.54 (app.t, J = 7.0 Hz, 2H), 1.44 (dt, J = 14.7, 7.2 Hz, 2H), 0.93
(t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 141.2, 138.2, 128.9,
128.4, 127.3, 123.7, 87.5, 80.0, 64.9, 30.6, 22.0, 21.4, 18.5, 13.6;
IR (neat, cm–1) 3354, 2956, 2930, 2871, 2359, 2340, 2225, 1644,
1607, 1487, 1455, 1430, 1378, 1273, 1196, 1156, 1130, 1093,
1000, 903, 882, 786, 733, 700, 668, 645, 588, 566; GC/MS (m/z,
intensity) 202.1 (65%), 187.1 (94%), 159.1 (32%), 145.0 (71%),
128.0 (35%), 115.0 (58%), 105.0 (30%), 91.1 (100%), 77.0
(25%), 65.0 (32%), 53.0 (23%).
5.2.4. 1-(4-bromophenyl)hept-2-yn-1-ol (1d)
Prepared using p-bromobenzaldehyde (3.700 g, 20.0 mmol)
and 1-hexyne (2.3 mL, 20.0 mmol). After purification by flash

6
Tetrahedron
ACCEPTED MANUSCRIPT
5.2.8. 1-(2-bromophenyl)hept-2-yn-1-ol (1h)
5.3.1. (Z)-2-chloro-1-phenylhept-1-en-3-one (2a)
Prepared using o-bromobenzaldehyde (0.7 mL, 6.0 mmol) and
Prepared using 1-phenylhept-2-yn-1-ol (56 mg, 0.3 mmol), N-
chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45 mg, 0.54
mmol) and VOCl3 (0.05 mL, 0.5 mmol) in dichloromethane (3
mL). After purification by flash chromatography (15:1
hexanes:ether), this compound was isolated as a pale yellow solid
(1st run: 49 mg, 2nd run: 48 mg, 72% yield). TLC (SiO2) Rf = 0.4
(10:1 hexanes:diethyl ether); H (500 MHz, CDCl3) 7.86–7.84
(m, 2H), 7.76 (s, 1H), 7.45–7.41 (m, 3H), 2.89 (t, J = 7.4 Hz,
2H), 1.68 (app.t, J = 7.5 Hz, 2H), 1.40 (app.t, J = 7.4 Hz, 2H),
0.96 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 195.9, 134.8,
133.0, 130.8, 130.2, 130.1, 128.6, 38.4, 26.4, 22.3, 13.9; IR (neat,
cm–1) 3055, 3016, 2948, 2923, 2865, 1687, 1592, 1571, 1492,
1464, 1446, 1399, 1374, 1345, 1278, 1261, 1192, 1141, 1085,
1073, 1030, 1020, 999, 991, 977, 944, 925, 902, 801, 753, 733,
721, 687, 667, 574, 557; GC/MS (m/z, intensity) 222.1 (15%),
180.0 (51%), 165.0 (51%), 145.1 (100%), 129.0 (9%), 115.1
(11%), 102.0 (62%), 85.1 (9%), 75.0 (13%), 57.1 (27%).
1-hexyne (1.2 mL, 9.8 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (1.329 g, 83% yield). TLC (SiO2) Rf
= 0.4 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.77 (dd,
J = 7.7, 1.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.5 Hz,
1H), 7.17 (td, J = 7.7, 1.6 Hz, 1H), 5.76 (s, 1H), 2.48 (s, 1H),
2.26 (td, J = 7.1, 1.9 Hz, 2H), 1.52 (app.t, J = 7.0 Hz, 2H), 1.41
(app.t, J = 14.2, 7.1 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H); C (126
MHz, CDCl3) 140.1, 132.9, 129.7, 128.5, 127.8, 122.8, 87.9,
78.8, 64.3, 30.6, 22.0, 18.5, 13.6; IR (neat, cm–1) 3337, 2956,
2930, 2870, 2225, 1590, 1569, 1465, 1439, 1377, 1325, 1250,
1191, 1134, 1046, 1014, 946, 887, 819, 749, 677, 625; GC/MS
(m/z, intensity) 266.0 (5%), 237.0 (10%), 223.0 (20%), 187.1
(76%), 169.0 (20%), 157.0 (26%), 145.1 (100%), 131.1 (44%),
115.1 (80%), 77.1 (37%), 63.1 (10%), 51.1 (16%).
5.2.9. 4,4-dimethyl-1-phenylpent-2-yn-1-ol (1i)
5.3.2. (Z)-2-chloro-1-(4-fluorophenyl)hept-1-en-3-
one (2b)
Prepared using benzaldehyde (0.2 mL, 1.6 mmol) and 3,3-
dimethylbut-1-yne (0.3 mL, 2.4 mmol). After purification by
flash chromatography (10:1 hexanes:ethyl acetate), this
compound was isolated as a colorless liquid (0.268 g, 89% yield).
TLC (SiO2) Rf = 0.4 (6:1 hexanes:ethyl acetate); H (500 MHz,
CDCl3) 7.55 (d, J = 7.4 Hz, 2H), 7.38 (app. t, J = 7.4 Hz, 2H),
7.32 (app. t, J = 7.3 Hz, 1H), 5.45 (s, 1H), 1.27 (s, 9H); C (126
MHz, CDCl3) 141.3, 128.5, 128.1, 126.7, 95.8, 78.3, 64.7, 30.9,
27.5; IR (neat, cm–1) 3354, 3031, 2967, 2867, 2359, 2234, 1602,
1493, 1454, 1362, 1261, 1202, 1060, 1029, 980, 916, 851, 817,
746, 697, 626; GC/MS (m/z, intensity) 188.1 (100%), 173.1
(14%), 158.1 (24%), 145.1 (19%), 131.0 (50%), 115.1 (27%),
105.0 (41%), 91.1 (27%), 77.1 (46%), 67.1 (15%), 57.1 (21%),
50.1 (6%).
Prepared using 1-(4-fluorophenyl)hept-2-yn-1-ol (62 mg, 0.3
mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 50 mg, 2nd run: 49 mg,
70% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.87 (dd, J = 8.2, 5.5 Hz, 2H), 7.72 (s, 1H),
7.12 (t, J = 8.5 Hz, 3H), 2.87 (t, J = 7.3 Hz, 2H), 1.67 (app.t, J =
7.4 Hz, 2H), 1.40 (app.t, J = 7.2 Hz, 2H), 0.95 (t, J = 7.3 Hz,
3H); C (126 MHz, CDCl3) 195.8, 163.5 (d, J = 252.8 Hz), 133.4,
133.0 (d, J = 8.5 Hz), 129.4 (d, J = 63.8 Hz), 115.8 (d, J = 21.7
Hz), 38.4, 26.4, 22.3, 13.9; IR (neat, cm–1) 3008, 2958, 2928,
2863, 1686, 1594, 1582, 1507, 1465, 1455, 1412, 1398, 1381,
1348, 1325, 1280, 1240, 1164, 1139, 1107,1080, 1021, 1013,
973, 955, 934, 916, 901, 848, 836, 821, 784, 734, 716, 708, 672,
618, 572; GC/MS (m/z, intensity) 240.0 (6%), 198.0 (34%), 183.0
(36%), 163.0 (100%), 147.0 (8%), 135.0 (14%), 120.0 (79%),
109.0 (4%), 99.0 (11%), 85.0 (12%), 75.0 (8%), 57.1 (49%).
5.2.10. 1-phenylundec-2-yn-1-ol (1j)
Prepared using benzaldehyde (4.0 mL, 4.0 mmol) and 1-
decyne (1.1 mL, 6.0 mmol). After purification by flash
chromatography (10:1 hexanes:ethyl acetate), this compound was
isolated as a colorless liquid (0.763 g, 78% yield). TLC (SiO2) Rf
= 0.4 (6:1 hexanes:ethyl acetate); H (500 MHz, CDCl3) 7.55 (d,
J = 7.2 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.32 (dd, J = 8.3, 6.3
Hz, 1H), 5.45 (s, 1H), 2.27 (td, J = 7.2, 1.9 Hz, 2H), 1.55 (app.t, J
= 7.3 Hz, 2H), 1.45–1.36 (m, 2H), 1.33–1.29 (m, 8H), 0.90 (t, J =
6.9 Hz, 3H); C (126 MHz, CDCl3) 141.3, 128.5, 128.2, 126.6,
87.7, 80.0, 64.8, 31.8, 29.2, 29.1, 28.9, 28.6, 22.7, 18.8, 14.1; IR
(neat, cm–1) 3353, 3030, 2924, 2854, 2360, 1602, 1493, 1454,
1377, 1328, 1269, 1190, 1134, 994, 916, 721, 696, 634; GC/MS
(m/z, intensity) 244.2 (100%), 226.1 (3%), 207.0 (4%), 185.0
(2%), 171.0 (3%), 159.0 (7%), 145.0 (54%), 131.0 (50%), 105.0
(65%), 91.1 (25%), 77.0 (56%), 55.1 (24%).
5.3.3. (Z)-2-chloro-1-(4-chlorophenyl)hept-1-en-3-
one (2c)
Prepared using 1-(4-chlorophenyl)hept-2-yn-1-ol (67 mg, 0.3
mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 43 mg, 2nd run: 41 mg,
55% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.79 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.40
(d, J = 8.4 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 1.67 (app.t, J = 7.4
Hz, 2H), 1.40 (app.t, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3, 3H); C
(126 MHz, CDCl3) 195.7, 136.2, 133.2, 132.0, 131.4, 130.5,
128.9, 38.5, 26.3, 22.3, 13.9; IR (neat, cm–1) 2954, 2936, 2865,
2358, 1688, 1596, 1562, 1490, 1463, 1403, 1376, 1345, 1275,
1209, 1184, 1144, 1117, 1084, 1014, 953, 909, 820, 731, 707,
684, 616; GC/MS (m/z, intensity) 256.0 (6%), 214.0 (20%), 199.0
(27%), 179.0 (100%), 136.0 (54%), 115.0 (8%), 101.0 (12.5%),
85.1 (10%), 75.0 (12%), 57.1 (27%).
5.3. General procedure for the synthesis of α-chloroenones and
their spectral data
To a stirred suspension of N-chlorosuccinimide (0.6 mmol,
2.0 equiv) and NaHCO3 (1.8 equiv) in dichloromethane (3 mL)
was added propargylic alcohol (0.3 mmol, 1.0 equiv). The
mixture was cooled to 0 C and stirred for 15 min. Then neat
VOCl3 (0.5 mmol, 1.7 equiv) was added to the mixture and the
reaction was stirred for 8 h. Water (3 mL) was added to quench
the reaction. The mixture was extracted with dichloromethane (3
x 5 mL) and the combined organic layers were washed with brine
(1 x 5 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification via column
5.3.4. (Z)-2-chloro-1-(4-bromophenyl)hept-1-en-3-
one (2d)
Prepared using 1-(4-bromophenyl)hept-2-yn-1-ol (80 mg, 0.3
mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography yielded the chloroenone product.
Enone
geometry was determined by comparison of NMR data to those
of closely related compounds in the literature.12,13,17

7
ACCEPTED MANUSCRIPT
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 48 mg, 2nd run: 48 mg,
53% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.72–7.68 (m, 3H), 7.56 (d, J = 8.3 Hz, 2H),
2.87 (t, J = 7.3 Hz, 2H), 1.67 (app.t, J = 7.4 Hz, 2H), 1.39 (app.t,
J = 7.2 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3)
195.7, 133.3, 132.2, 131.8, 130.6, 124.6, 38.5, 26.3, 22.3, 13.9;
IR (neat, cm–1) 2952, 2934, 2868, 2360, 1688, 1595, 1582, 1559,
1487, 1463, 1399, 1375, 1345, 1275, 1266, 1208, 1185, 1144,
1116, 1085, 1073, 1010, 952, 907, 817, 724, 703, 680; GC/MS
(m/z, intensity) 301.9 (9%), 259.9 (22%), 244.9 (13%), 222.9
(7%), 208.9 (6%), 179.0 (100%), 164.0 (54%), 136.0 (62%),
115.0 (18%), 101.0 (32%), 75.0 (21%), 57.1 (44%).
133.0, 131.5, 131.1, 130.0, 128.4, 127.9, 38.4, 26.5, 22.3, 21.4,
13.9; IR (neat, cm–1) 3018, 2952, 2925, 2861, 1686, 1602, 1591,
1480, 1463, 1451, 1398, 1374, 1344, 1316, 1278, 1263, 1166,
1137, 1081, 1017, 998, 966, 942, 923, 906, 898, 801, 789, 766,
733, 706, 691, 666, 565; GC/MS (m/z, intensity) 236.1 (19%),
221.1 (29%), 194.0 (24%), 179.0 (67%), 159.1 (51%), 143.0
(9%), 128.0 (6%), 115.0 (100%), 89.0 (11%), 57.1 (28%).
5.3.8. (Z)-1-(2-bromophenyl)-2-chlorohept-1-en-3-
one (2h)
Prepared using 1-(2-bromophenyl)hept-2-yn-1-ol (80 mg, 0.3
mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 43 mg, 2nd run: 47 mg,
50% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.95 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.64 (d,
J = 8.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H),
2.90 (t, J = 7.4 Hz, 2H), 1.71 (app.t, J = 7.4 Hz, 2H), 1.41 (app.t,
J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3)
195.2, 134.6, 133.4, 132.9, 132.6, 130.9, 130.9, 127.1, 125.1,
38.5, 26.5, 22.3, 13.9; IR (neat, cm–1) 2957, 2931, 2871, 1693,
1606, 1560, 1462, 1433, 1378, 1317, 1262, 1204, 1143, 1081,
1046, 1026, 979, 954, 902, 880, 856, 751, 719, 664, 593; GC/MS
(m/z, intensity) 302.0 (3%), 259.9 (10%), 221.1 (100%), 179.0
(39%), 164.0 (44%), 136.0 (78%), 115.1 (18%), 101.0 (31%),
75.0 (22%), 57.1 (47%).
5.3.5. (Z)-2-chloro-1-(p-tolyl)hept-1-en-3-one (2e)
Prepared using 1-(4-methylphenyl)hept-2-yn-1-ol (60 mg, 0.3
mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 47 mg, 2nd run: 47 mg,
67% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.77 (d, J = 7.9 Hz, 2H), 7.74 (s, 1H), 7.24 (d,
J = 7.9 Hz, 2H) 2.88 (t, J = 7.3 Hz, 2H), 2.39 (s, 3H), 1.68 (app.t,
J = 7.4 Hz, 2H), 1.40 (app.t, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz,
3H); C (126 MHz, CDCl3) 195.9, 140.8, 134.9, 130.9, 130.2,
129.3, 38.4, 26.5, 22.3, 21.5, 13.9; IR (neat, cm–1) 3036, 2953,
2927, 2868, 1789, 1683, 1596, 1566, 1509, 1464, 1454, 1411,
1370, 1336, 1277, 1265, 1206, 1187, 1158, 1097, 1183, 1017,
952, 896, 887, 813, 776, 742, 709, 697, 684, 628; GC/MS (m/z,
intensity) 236.1 (12%), 221.0 (15%), 194.0 (21%), 179.0 (100%),
159.1 (28%), 145.0 (50%), 128.0 (7%), 115.0 (89%), 102.0 (4%),
91.0 (11%), 77.0 (3%), 57.1 (19%).
5.3.9. (Z)-2-chloro-4,4-dimethyl-1-phenylpent-1-
en-3-one (2i)
Prepared using 4,4-dimethyl-1-phenylpent-2-yn-1-ol (57 mg,
0.3 mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3
(45 mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 38 mg, 2nd run: 33 mg,
54% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.75 (d, J = 7.3 Hz, 2H), 7.42–7.38 (m, 3H),
7.33 (s, 1H), 1.39 (s, 9H); C (126 MHz, CDCl3) 202.9, 133.3,
133.2, 130.2, 129.5, 128.7, 128.7, 128.4, 44.0, 27.6; IR (neat, cm–
1) 2969, 2871, 1679, 1590, 1573, 1491, 1477, 1461, 1446, 1395,
1366, 1338, 1259, 1110, 1098, 1074, 1018, 1000, 935, 877, 832,
775, 757, 690, 614, 589; GC/MS (m/z, intensity) 222.1 (21%),
165.0 (100%), 137.0 (28%), 128.0 (10%), 102.0 (43%), 75.0
(11%), 57.1 (83%).
5.3.6. (Z)-1-(4-(tert-butyl)phenyl)-2-chlorohept-1-
en-3-one (2f)
Prepared using 1-(4-(tert-butyl)phenyl)hept-2-yn-1-ol (73 mg,
0.3 mmol), N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3
(45 mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow solid (1st run: 52 mg, 2nd run: 49 mg,
60% yield). TLC (SiO2) Rf = 0.4 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 7.83 (d, J = 8.2 Hz, 2H), 7.75 (s, 1H), 7.46 (d,
J = 8.3 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 1.68 (app.t, J = 7.4 Hz,
2H), 1.44–1.38 (m, 2H), 1.34 (s, 9H), 0.96 (t, J = 7.3 Hz, 3H); C
(126 MHz, CDCl3) 195.5, 153.9, 134.8, 130.9, 130.2, 129.4,
125.6, 38.4, 34.9, 31.1, 26.5, 22.3, 13.9; IR (neat, cm–1) 2958,
2870, 2359, 1688, 1594, 1557, 1504, 1464, 1410, 1363, 1329,
1267, 1201, 1159, 1143, 1108, 1082, 1017, 948, 901, 829, 753,
731, 685, 628, 560; GC/MS (m/z, intensity) 278.1 (9%), 263.1
(47%), 221.1 (37%), 179.0 (100%), 165.0 (14%), 143.1 (41%),
128.1 (24%), 115.1 (49%), 103.1 (11%), 91.1 (6%), 77.1 (6%),
57.1 (82%).
5.3.10. (Z)-2-chloro-1-phenylundec-1-en-3-one (2j)
Prepared using 1-phenylundec-2-yn-1-ol (73 mg, 0.3 mmol),
N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45 mg, 0.54
mmol) and VOCl3 (0.05 mL, 0.5 mmol) in dichloromethane (3
mL). After purification by flash chromatography (15:1
hexanes:ether), this compound was isolated as a pale yellow solid
(1st run: 48 mg, 2nd run: 49 mg, 59% yield). TLC (SiO2) Rf = 0.4
(10:1 hexanes:diethyl ether); H (500 MHz, CDCl3) 7.85 (d, J =
7.5 Hz, 2H), 7.76 (s, 1H), 7.45–7.41 (m, 3H), 2.88 (t, J = 7.4 Hz,
2H), 1.69 (app.t, J = 7.3 Hz, 2H), 1.37–1.28 (m, 10H), 0.89 (t, J
= 6.7 Hz, 3H); C (126 MHz, CDCl3) 195.9, 134.7, 133.0, 130.8,
130.2, 130.1, 128.6, 38.8, 31.8, 29.4, 29.2, 29.1, 24.3, 22.7, 14.1;
IR (neat, cm–1) 3053, 2954, 2918, 2850, 1686, 1592, 1572, 1492,
1466, 1455, 1446,1397, 1375, 1343, 1303, 1278, 1259, 1219,
1190, 1138, 1111, 1077, 1055, 1039, 999, 986, 952, 944, 887,
859, 797, 757, 723, 688, 668, 612, 575, 559; GC/MS (m/z,
intensity) 278.1 (7%), 242.2 (8%), 180.0 (56%), 165.0 (27%),
145.1 (100%), 129.1 (8%), 115.1 (7%), 102.1 (31%), 55.1 (9%).
5.3.7. (Z)-2-chloro-1-(m-tolyl)hept-1-en-3-one (2g)
Prepared using 1-(m-tolyl)hept-2-yn-1-ol (61 mg, 0.3 mmol),
N-chlorosuccinimide (80 mg, 0.6 mmol), NaHCO3 (45 mg, 0.54
mmol) and VOCl3 (0.05 mL, 0.5 mmol) in dichloromethane (3
mL). After purification by flash chromatography (15:1
hexanes:ether), this compound was isolated as a pale yellow solid
(1st run: 46 mg, 2nd run: 47 mg, 64% yield). TLC (SiO2) Rf = 0.4
(10:1 hexanes: diethyl ether); H (500 MHz, CDCl3) 7.74 (s, 1H),
7.68 (d, J = 7.7 Hz, 1H), 7.65 (s, 1H), 7.33 (t, J = 7.7 Hz, 1H),
7.23 (d, J = 7.4 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H),
1.68 (app.t, J = 7.4 Hz, 2H), 1.40 (app.t, J = 7.3 Hz, 2H), 0.96 (t,
J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 195.9, 138.2, 135.0,

8
Tetrahedron
ACCEPTED MANUSCRIPT
isolated as a pale yellow oil (1st run: 31 mg, 2nd run: 31 mg, 30%
5.4. General procedure for the synthesis of α-iodoenones and
their spectral data
yield). The chloroenone and iodoenone ratio (37%:63%) is
determined by GC/MS in the crude solution. TLC (SiO2) Rf = 0.3
(10:1 hexanes:diethyl ether); H (500 MHz, CDCl3) 7.95 (s, 1H),
7.72 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 2.97 (t, J = 7.3
Hz, 2H), 1.69 (app.t, J = 7.4 Hz, 2H), 1.39 (app.t, J = 7.4 Hz,
2H), 0.95 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 196.0, 144.9,
136.0, 134.1, 130.9, 128.7, 108.2, 38.0, 27.1, 22.3, 13.9; IR (neat,
cm–1) 2956, 2929, 2870, 2358, 1680, 1589, 1562, 1487, 1463,
1402, 1378, 1338, 1266, 1203, 1147, 1090, 1012, 880, 815, 749,
719, 695, 575; GC/MS (m/z, intensity) 348.0 (17%), 305.9 (10%),
290.9 (70%), 271.0 (27%), 221.1 (28%), 179.0 (22%), 165.0
(17%), 136.0 (100%), 115.0 (11%), 101.0 (26%), 75.0 (16%),
57.1 (31%).
To a stirred suspension of N-iodosuccinimide (0.6 mmol, 2.0
equiv) and NaHCO3 (1.8 equiv) in dichloromethane (3 mL) was
added propargylic alcohol (0.3 mmol, 1.0 equiv). The mixture
was cooled to 0 C and stirred for 15 min. Then neat VOCl3 (0.5
mmol, 1.7 equiv) was added to the mixture and the reaction was
stirred for 8 h. Water (3 mL) was added to quench the reaction.
The mixture was extracted with dichloromethane (3 x 5 mL) and
the combined organic layers were washed with brine (1 x 5 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Purification via column chromatography
yielded the iodoenone product. Enone geometry was determined
by comparison of NMR data to those of closely related
compounds in the literature.12,13,17
5.4.4. (Z)-1-(4-bromophenyl)-2-iodohept-1-en-3-
one (3d)
5.4.1. (Z)-2-iodo-1-phenylhept-1-en-3-one (3a)
Prepared using 1-(4-bromophenyl)hept-2-yn-1-ol (80 mg, 0.3
mmol), N-iodosuccinimide (135 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow oil (1st run: 45 mg, 2nd run: 44 mg, 38%
yield). The chloroenone and iodoenone ratio (35%:65%) is
determined by GC/MS in the crude solution. TLC (SiO2) Rf = 0.4
(10:1 hexanes:diethyl ether); H (500 MHz, CDCl3) 7.93 (s, 1H),
7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 2.96 (t, J = 7.3
Hz, 2H), 1.69 (app.t, J = 7.4 Hz, 2H), 1.39 (app.t, J = 7.3 Hz,
2H), 0.95 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 196.0, 145.0,
134.6, 131.6, 131.0, 124.4, 108.3, 38.0, 27.1, 22.3, 13.9; IR (neat,
cm–1) 2956, 2929, 2870, 2358, 1680, 1583, 1484, 1463, 1398,
1378, 1339, 1265, 1147, 1092, 1071, 1009, 907, 880, 812, 730,
648, 580; GC/MS (m/z, intensity) 391.9 (7%), 334.0 (20%), 256.0
(35%), 209.0 (11%), 180.0 (60%), 144.1 (100%), 128.0 (11%),
101.0 (65%), 75.0 (37%), 57.1 (60%).
Prepared using 1-phenylhept-2-yn-1-ol (56 mg, 0.3 mmol), N-
iodosuccinimide (135 mg, 0.6 mmol), NaHCO3 (45 mg, 0.54
mmol) and VOCl3 (0.05 mL, 0.5 mmol) in dichloromethane (3
mL). After purification by flash chromatography (15:1
hexanes:ether), this compound was isolated as a pale yellow oil
(1st run: 41 mg, 2nd run: 43 mg, 44% yield). The chloroenone and
iodoenone ratio (39:61) is determined by GC/MS in the crude
solution. TLC (SiO2) Rf = 0.3 (10:1 hexanes:diethyl ether); H
(500 MHz, CDCl3) 8.02 (s, 1H), 7.78–7.77 (m, 2H), 7.45–7.44
(m, 3H), 2.98 (t, J = 7.3 Hz, 2H), 1.70 (app.t, J = 7.4 Hz, 2H),
1.40 (app.t, J = 7.3 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H); C (126
MHz, CDCl3) 196.1, 146.4, 135.7, 130.1, 129.6, 128.3, 107.7,
38.0, 27.2, 22.3, 13.9; IR (neat, cm–1) 2955, 2929, 2869, 1678,
1592, 1572, 1492, 1445, 1410, 1378, 1337, 1261, 1204, 1145,
1094, 1070, 1028, 1000, 922, 870, 750, 689, 622, 594; GC/MS
(m/z, intensity) 314.0 (17%), 271.9 (23%), 256.9 (67%), 228.9
(10%), 187.1 (23%), 162.9 (10%), 145.0 (33%), 131.0 (22%),
115.0 (22%), 102.0 (100%), 77.0 (15%), 57.1 (25%).
Acknowledgments
5.4.2. (Z)-1-(4-fluorophenyl)-2-iodohept-1-en-3-
one (3b)
Funding was provided by the UIC Department of Chemistry.
We thank Profs. Vladimir Gevorgyan, Duncan Wardrop, Tom
Driver, Laura Anderson, and Daesung Lee (UIC) for helpful
discussions and use of reagents and equipment.
Prepared using 1-(4-fluorophenyl)hept-2-yn-1-ol (62 mg, 0.3
mmol), N-iodosuccinimide (135 mg, 0.6 mmol), NaHCO3 (45
mg, 0.54 mmol) and VOCl3 (0.05 mL, 0.5 mmol) in
dichloromethane (3 mL). After purification by flash
chromatography (15:1 hexanes:ether), this compound was
isolated as a pale yellow oil (1st run: 39 mg, 2nd run: 40 mg, 40%
yield). The chloroenone and iodoenone ratio (37%:63%) is
determined by GC/MS in the crude solution. TLC (SiO2) Rf = 0.3
(10:1 hexanes:diethyl ether); H (500 MHz, CDCl3) 7.97 (s, 1H),
7.80 (dd, J = 8.2, 5.6 Hz, 2H), 7.14 (t, J = 8.5 Hz, 2H), 2.97 (t, J
= 7.4 Hz, 2H), 1.69 (app.t, J = 7.4 Hz, 2H), 1.39 (app.t, J = 7.3
Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H); C (126 MHz, CDCl3) 195.8,
163.5 (d, J = 252.1 Hz), 145.1, 131.8 (d, J = 8.5 Hz), 131.7 (d, J
= 2.8 Hz), 115.5 (d, J = 21.7 Hz), 107.4, 38.0, 27.2, 22.3, 13.9;
IR (neat, cm–1) 2957, 2930, 2871, 1711, 1678, 1598, 1505, 1464,
1410, 1360, 1230, 1146, 1091, 1071, 1012, 881, 827, 783, 710,
682, 639, 578; GC/MS (m/z, intensity) 332.0 (7%), 290.0 (13%),
275.0 (36%), 246.9 (5%), 205.1 (17.5%), 163.1 (36%), 149.0
(12.5%), 133.0 (10%), 120.0 (100%), 94.0 (10%), 74.0 (5%),
57.1 (25%).
Supplementary Material
Supplementary data associated with this article can be found
in the online version.
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1
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19.A similar trend is observed with 1.7 equiv of VOCl3 with 2 equiv of NCS
being optimal.
20.Despite the greater density of active Cl in DCDMH, no improvements in
yield were observed with further modification of the quantity of this
reagent. This argues against a solubility-limited effect of the halogen
donor. The reaction with NCS is insensitive to overall reaction
concentration, which is also consistent with an effect other than reagent
solubility.
21.Carbonate, bicarbonate, and carboxylate bases delivered higher yields than
phosphates, hydroxides, or sulfates. Tertiary amine bases are not suitable
for this transformation. Yields varied less than 8% when quantity of
K2CO3 varied from 1.2–10 equiv. We selected NaHCO3 for convenience
and slightly higher yield relative to K2CO3.
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