Taming chlorine azide: Access to 1,2-azidochlorides from alkenes

Article abstract of DOI:10.1021/acs.joc.5b00009

The in situ preparation and trapping of chlorine azide provided a versatile one-pot method for the azidochlorination of alkenes. Gaseous ClN₃ generated from sodium azide, hypochlorite, and acetic acid can be explosive if isolation is attempted. Instead, we generated the reagent in biphasic media in the presence of olefinic compounds dissolved in the organic layer or evenly emulsified throughout the solution in the absence of organic solvent. Under these conditions, ClN₃ is created slowly and trapped immediately at the aqueous-organic interface. The resulting safe and reliable procedure provided 1,2-azidochloride derivatives of a variety of substrates, with evidence for both polar and radical mechanisms. Minor impurities characterized in the product mixtures indicated the presence of alternative reaction pathways deriving primarily from radical intermediates.

Full text of DOI:10.1021/acs.joc.5b00009

Article
pubs.acs.org/joc
Taming Chlorine Azide: Access to 1,2-Azidochlorides from Alkenes
Roman A. Valiulin,†,‡ Sreeman Mamidyala,‡,§ and M. G. Finn*,†,‡
†School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta, Georgia 30332-0400, United
States
‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: The in situ preparation and trapping of chlorine azide
provided a versatile one-pot method for the azidochlorination of alkenes.
Gaseous ClN3 generated from sodium azide, hypochlorite, and acetic acid
can be explosive if isolation is attempted. Instead, we generated the reagent
in biphasic media in the presence of olefinic compounds dissolved in the
organic layer or evenly emulsified throughout the solution in the absence of
organic solvent. Under these conditions, ClN3 is created slowly and
trapped immediately at the aqueous−organic interface. The resulting safe
and reliable procedure provided 1,2-azidochloride derivatives of a variety of
substrates, with evidence for both polar and radical mechanisms. Minor
impurities characterized in the product mixtures indicated the presence of
alternative reaction pathways deriving primarily from radical intermediates.
precursors [Et4NX−PhI(OAc)2−NaN3, X = I, Br] capable of
promoting azidohalogenation of alkenes.49
INTRODUCTION
■
Since their initial discovery [in 1900 (IN3),1 1908 (ClN3),2
1925 (BrN3),3 and 1942 (FN3)4,5], halogen azides have been
regarded as challenging compounds to work with due to their
extreme chemical reactivity, volatility, and potential toxicity.
However, the extraordinarily useful nature of halogen and azide
substituents in organic chemistry has engendered some
exploration of XN3 reactivity through the years. Figure 1
summarizes most of the known examples of the reactions of
halogen azides or their equivalents and analogues with alkenes,
with particular attention to the methods by which these reactive
compounds were generated.
Consistent with the higher oxidation potential of bromine,
the published chemistry of bromine azide is less extensive than
that of iodine azide. BrN3 was first synthesized from Br2 gas and
solid NaN3,3 which was modified by Hassner [Br2−HCl−
NaN3]10,13,18 into a somewhat hazardous procedure that
nevertheless achieved some subsequent use.50−52 Other
approaches have involved the in situ generation of toxic and
explosive hydrazoic acid [NXS−HN3, X = I, Br];53,54 the use of
Br2 solution in the presence of sodium azide under neutral or
basic conditions55,56 avoids that particular hazard, albeit with
diminished yields and the formation of other side products. The
accessibility and versatility of the technique reported by Krief in
1974 [NBS−NaN3]57,58 was noted by several groups,59−63 and
other recently published protocols still rely on NBS as the most
common bromine source [NBS−TMSN3].64 A few variations
of this reaction conducted in the presence of catalytic amounts
of various metal triflates augmented the regio- and stereo-
selectivity of BrN3 addition to organic substrates,65,66 including
the asymmetric azidobromination of α,β-unsaturated carbonyl
Iodine azide was first synthesized from AgN3 and I2,1 and
methods associated with its preparation and reactivity6 are the
most abundant in the literature. Hassner and co-workers7−18
made significant contributions to the understanding of the
mechanism of halogen azide addition to alkenes, and his
original procedures for the formation of IN3 (from ICl +
19−30
NaN3
or I2 + NaN331−34) became popular among those
disposed to use the reagent for synthetic purposes. Several
alternatives soon followed, including those with thallium
(TlN3) or stannous (Bu3SnN3) reagents as the source of
azide ion,35−37 but these and other methods38 did not find
widespread application. Barluenga et al. found a way to perform
68
compounds.67 Lastly, several sources of Br+ (such as TsNBr2
and PhNMe3Br369) have been used with trimethylsilylazide
(TMSN3) in fast and efficient reactions yielding vicinal
bromoazides under catalyst-free conditions.
39,40
azido-iodination of terpenes using IPy2BF4−TMSN3,
While all halogen azides are highly explosive, their stability is
believed to ascend in the following order: FN3 < IN3 < BrN3 <
ClN3.70 A solution of chlorine azide in organic solvents can be
stored for several days at room temperature,2,70 although we do
not recommend this. From its discovery in 1908 through 1965,
leading to several modified protocols employing more familiar
oxidants (hypervalent iodine,41 periodate,42 oxone,43 and
cerium(VI)44,45). In many of these cases, anti-Markovnikov
products were found, in contrast to earlier reports of the
opposite regiochemistry. Kirsching developed several clever
ways to ameliorate the dangers of IN3, first by creating a
nonexplosive polymer-bound form [of general formula R4NI-
(N3)2],46−48 and then by making stable iodine(III)-based
Received: January 3, 2015
© XXXX American Chemical Society
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Tl(OAc)3−TMSN3, X = Cl, Br, I]77 and [MeCOX−Tl-
(OAc)3−TMSN3, X = Cl, Br].78 In this case, the substitution
of a chlorine (or other halogen) source with 40% HF yielded
1,2-azido-fluorides−the only transformation of this kind to our
knowledge. Furthermore, Zbiral also reported a competitive
azidochlorinating reagent PhI(Cl)(N3) obtained from phenyl-
iodosodiacetate [MeCOCl−PhI(OAc)2−TMSN3].79 The reac-
tion outcome based on this reagent system differs considerably
from ClN3-based protocols, including the potential for alkyne
cleavage if there action is performed in the absence of a
chlorine source.80 It is assumed that the reaction occurs via
azidonium ion formation.
Many of the protocols described above lack selectivity, are
low-yielding, or require toxic or exotic reagents. In a search for
a facile and cost-effective technique, we anticipated that N-
chlorosuccinamide (NCS)-based reactions could be a depend-
able option. We were surprised to find only several examples
reported thus far,81−83 including a number of recent reports of
azidooxygenation or hydroazidation, rather than chloroazida-
tion, of alkenes.84,85 We therefore turned to the original Raschig
conditions, acidification of aqueous sodium azide and sodium
hypochlorite with acetic acid,2 and describe here a convenient
and safe one-pot method and a survey of its application to an
initial panel of various types of alkenes.
Mechanisms of Chlorine Azide Formation and
Degradation. The formation of chlorine azide likely occurs
by azide attack on the hypochlorite bond. It is therefore fastest
at pH 4−6, where significant concentrations of N3− and HOCl
exist (Scheme 1).86 ClN3 is soluble in both aqueous and
Scheme 1. Formation and Decomposition of Chlorine Azide
in Aqueous Solution
Figure 1. Published methods for the formation of vicinal azido-
halogenides from alkenes. (A) 1,2-Azidochlorides (formal addition of
ClN3); (B) 1,2-azidobromides (formal addition of BrN3); (C) 1,2-
azidoiodides (formal addition of IN3). Notes: (a) R′I−N3 = 1-azido-
1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (azidoiodine(III)). (b) ClN3
obtained from [AgN3 + Cl2], [HN3 + HClO], or [NaN3 + Cl2].
organic media,70 giving the solution a characteristic yellow
color. It is quite stable in aqueous solution at room temperature
but can be eliminated from the system either via explosive
decomposition (initiated by heat, for example),87 by reaction
with excess azide or hydroxide in solution, or by productive
addition to unsaturated compounds (Scheme 2). Under acidic
conditions, the formation of (N3)2 and its immediate
rearrangement to 3N2 can be explosively rapid, and is likely
the source of some of the danger associated with this chemistry.
Basic hydrolysis of ClN3 is relatively slow but can be significant;
hydrozidous acid is believed to be the first intermediate, leading
either to the formation of nitrogen gas via (N3)2 or hyponitrous
only several examples of the formation of ClN3 [from HClO−
HN3,2 Cl2−AgN3,71,72 and Cl2−NaN373] were described; none
were generally adopted by synthetic chemists. But some
interesting reports then began to appear, such as the method
by Minisci and co-workers [FeCl3−H2O2−NaN3]74 in which
either two azido groups (related to Pb(OAc)4−TMSN3)75,76 or
an azido group and a chlorine atom were added to an
unsaturated substrate via a radical mechanism. Zbiral reported
several protocols based on thallium(III) acetate: [MX−
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Scheme 2. General Mechanisms of Reactivity of ClN3 with
a
Alkenes
Figure 2. Reaction setup for the formation of 1,2-azidochlorides. (A)
Biphasic conditions in which the olefinic substrate is dissolved in an
organic phase. (B) Solvent-free conditions in which the liquid olefinic
substrate is added without organic solvent. Both conditions involve
vigorous magnetic stirring. (C) Reaction parameters varied in
preliminary optimization studies.
a
(A) Fragmentation pathways for ClN3. (B) Formation of 1,2-
azidochlorides. (C) Formation of byproducts.
introduced into the reaction flask. The resulting mixture was
then vigorously stirred, chlorine azide generation was initiated
by the dropwise addition of acetic acid to the open or vented
flask (typically 1−2 equiv with respect to azide), and ClN3 was
rapidly consumed in situ by the alkene. The amount and rate of
evolution of ClN3 can be controlled by the amount of acetic
acid added. In most cases, NaN3 was used in excess (2−10
mmol), and the amounts of acetic acid (4−15 mmol) and
sodium hypochlorite (1−2 mmol) were varied. Approximate
concentrations were as follows: NaN3, 0.6−2 mM in the
aqueous phase; NaOCl, 0.4−0.6 mM in the aqueous phase;
AcOH, 0.5−2 mM in the combined phases after addition is
complete; alkene, 0.1−0.5 mM in the organic phase. In an
alternative “solvent-free” biphasic procedure (Figure 2B), no
organic solvent was used. Here, the liquid alkene was
distributed as an emulsion in the rapidly stirred mixture,
performing the same trapping function during the reaction.
Water-misicible cosolvents (acetonitrile, THF) can be used, but
provided sluggish reactions and poor yields in the few cases
tested. Each organic substrate required the determination of a
partially optimized set of conditions, varying three key
parameters (Figure 2C and Supporting Information): the
nature of the solvent, the reaction temperature, and the amount
of sodium azide. Caution! Even though these conditions diminish
the hazards of chlorine azide substantially, it is still necessary to use
common sense and care. Furthermore, acidic conditions with azide
ion are always to be used with caution and avoided in workup, since
HN3 is highly volatile, toxic, and explosive. Therefore, the reaction
should be performed only in a well-ventilated fume hood behind a
protective shield or hood sash, and workup should avoid the use of
acid, especially when a large excess of NaN3 is left after the reaction
is complete.
acid (HONNOH). The latter species either undergoes
rearrangement to nitrous oxide (N2O) or reaction with
dissolved oxygen, producing peroxynitrous acid (ONO2H)86
(Scheme 1).
RESULTS AND DISCUSSION
■
NaN3 and NaOCl (4.0−4.99% hypochlorite) can be combined
in dilute aqueous solution without apparent reaction for periods
of at least several hours. Chlorine azide formation can be
initiated by the addition of a weak acid such as acetic acid. The
balanced stoichiometry of this overall transformation is shown
in eq 1. The ClN3 thus produced is a gas and can be isolated by
transfer out of the reaction flask with a gentle stream of
nitrogen, bubbled into an organic solvent placed in a receiving
flask. While we performed this procedure a number of times, it
proved to be occasionally explosive, and we strongly discourage
its practice. Instead, we developed a safe procedure to generate
ClN3 in small quantities in situ and in the presence of an alkene
with which it can immediately react, as shown in Figure 2.
NaOCl + NaN3 + 2AcOH → ClN3 + 2NaOAc + H2O
(1)
Two variants of the procedure were routinely used. In a
biphasic protocol (Figure 2A), an aqueous solution of sodium
azide and sodium hypochlorite was kept either at room
temperature (20 °C) or was cooled to −15 °C. (A small
amount of brine was added to ensure that the solution at −15
°C would not freeze, but the mixture often remained in the
liquid state without added salt.) The alkene of interest (0.5−1.0
mmol) was dissolved in an organic solvent of lower density
than water (toluene, ether, ethyl acetate), and this solution was
C
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Table 1. Vicinal Azidochlorination of Aromatic Alkenes
a
Experimental conditions: A = PhMe, 20 °C; B = PhMe, −15 °C; C = solvent-free, 20 °C; D = solvent-free, −15 °C; E = EtOAc, 20 °C; F = EtOAc,
−15 °C. When multiple procedures are listed, the underlined procedure is the one for which the yield is reported, but all gave comparable results.
b
c
Yields refer to isolated products (or their isolated diastereomeric mixtures), except where noted otherwise. Analysis of crude reaction mixture by
d
NMR. See Supporting Information.
The pioneering studies of Alfred Hassner and co-workers
established that heterolytic cleavage dominates the chemistry of
IN3, such that it reacts predominantly as a source of I+, but
BrN3 and ClN3 can be directed along ionic (heterolytic) or
radical (homolytic) pathways by changing the reaction
conditions.12,17 Polar solvents favor ionic addition for styrenyl
substrates, while nonpolar solvents and the absence of
molecular oxygen were reported to promote radical forma-
tion.12,17 A continuum of reactivity is likely, with polar
components to a radical pathway, and, in principle, the
participation of either chloronium or azidonium cations in
ionic reactions (Scheme 2A). For the purposes of this
introductory report, however, we restrict our mechanistic
discussion to the possibilities of Cl+/N3− or •Cl/•N3 described
by Hassner. Thus, ionic reactions are expected to produce
regioisomers derived from azide capture of the most stable
cationic intermediate(s); for styrenes, this places azide at the
benzylic position (Scheme 2B). Radical reactions are expected
to proceed by addition of •N3 to give the most stable carbon
radical, which captures ClN3 to continue the chain, giving
benzylic chlorides from styrenes (Scheme 2B, termination steps
not shown). Some byproducts derived from radical pathways
were also expected and observed (Scheme 2C).
Substrate Scope and Limitations. Table 1 summarizes a
preliminary survey of the vicinal azidochlorination of aromatic
alkenes. Most of the substrates (1−6, entries 1−7) underwent
anti-Markovnikov type addition, in agreement with Hassner’s
observation that a radical pathway is favored for these
substrates. 3,4-Dimethoxystyrene (1) (entry 1) provided an
exception, presumably because the electron-rich nature of the
aromatic ring favored the formation of a cationic benzylic
intermediate. Only at room temperature in toluene was the
radical pathway competitive. The stereochemistry of 1,2-
addition to styrene derivatives was not well controlled,
consistent with the expected stability of the putative benzylic
radical intermediate. Thus, both cis- and trans-stilbene (4 and
4′) gave the same nearly equimolar mixture of erythro and
threo isomers in excellent yield, although this transformation
required a larger excess of sodium azide and higher temperature
to reach completion than for most substrates. (A significant
amount of unreacted starting material 4 was isolated at lower
temperatures.) Similarly, 1,2-dihydronaphthalene (5) and 1-
phenyl-1-cyclohexene (6) also gave stereochemical mixtures,
with a modest preference for anti-addition (entries 6 and 7).
Hydroxyl (entry 8) and terminal alkyne (entry 9) functional
groups were well tolerated. Substrate 9 showed the α-
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ethoxycarbamate moiety to remain intact, with the anti,syn-
isomer 9a isolated as the major product. The azido-carbonyl
derivative 9b was also obtained by a mechanism that we have
not investigated. In contrast, electron-rich nitrogen heterocycles
underwent chlorination rather than chloroazidation under all
conditions tested. Methylindole-6-carboxylate (10) was con-
verted to the corresponding 3,3-dichlorolactam 10a in excellent
yield, implicating hypochlorite as an oxidant as well as a source
of chloride radical. Similarly, 7-azaindole (11) gave only 3-
chloro-1H-pyrollo[2,3-b]pyridine (11a). Indoles are well-
known to undergo chlorination with hypochlorite,88−90
although oxidation at the 2-position, as observed for 10, is
rare.91−93 In some cases (substrates 2, 5, and 8), other
oxidation products were isolated and characterized, reflecting
the pathways shown in Scheme 2C. These results are provided
in Supporting Information, since only small amounts of these
byproducts were formed.
yet able to explain exactly why the formation of side products is
suppressed.
As before, a two-step mechanism with attack on a radical (or
ionic) intermediate seemed to determine the stereochemistry of
1,2-addition. anti-Chloroazides predominated for cycloheptene
and cholesterol (15 and 17, entries 4 and 7); no stereo-
selectivity was observed for trans-1,4-butenediol (16, entry 5);
and syn-endo products were modestly favored from bridged
bicyclic substrates 13 and 14 (entries 2 and 3). Studies of the
reaction of 13 with variation of solvent and the addition of a
radical trapping agent, described in Supporting Information,
support the assignment of a primarily radical pathway using this
substrate. The isopropenyl group of (S)-(+)-carvone (18)
participated in dual reactivity depending on the reaction
conditions (entries 8, 9). At low temperatures in EtOAc as the
organic solvent, only allylic chlorination (18a) was observed,
whereas reaction in the less polar toluene at room temperature
gave rise to the azidochloride 18b in modest yield (23%), which
could be increased to 42% with the use of a higher
concentration of NaN3 in the aqueous phase. In both cases, a
significant amount of starting material 18 remained in the
mixture; all other attempts to drive the reaction to completion
resulted in the formation of more 18a as a byproduct.
The X-ray structures of a representative azidochloride (13a),
an unusual byproduct azide (9b) and a product of radical
chlorination (10a) are shown in Figure 3. In general, however,
The existence of radical chlorination as an alternative
reaction was further demonstrated by the fate of three other
substrates. Anthracene (19, entry 10) gave both 9-azido (19a)
and 9-azido-10-chloro (19b) derivatives; one possible pathway
is shown in Scheme 3. The expected addition of azide radical to
C-9 followed by trapping with ClN3 provides intermediate 19c,
with the observed products deriving from either base-mediated
chloride elimination or oxidative aromatization. (Interestingly,
phenanthrene was completely resistant to the biphasic reaction
conditions.) N-Allylaniline (20, entry 11) underwent radical
chlorination of the aromatic ring at −15 °C, leaving the
pendant olefin untouched. Complex mixtures of products were
formed at warmer temperatures; comparable outcomes were
observed for colchicine and other aromatic compounds with
electron-rich aromatic rings (not shown). Lastly, 2′-amino-
ethylcyclohexene (21, entry 12) was converted to a single
product tentatively assigned as structure 21a, which after
chromatographic purification possessed the pungent bleach-like
odor characteristic of N-chloramines.
While clean azidochlorination of olefins requires that the
substrate contain neither electron-rich aromatic rings nor
unfunctionalized amines, the alkene also must not be too
electron-deficient. This is indicated by the lack of reactivity at
the enone moiety of substrate 18 and of the resistance of trans-
4-phenyl-3-buten-2-one (benzylideneacetone) to reaction with
ClN3 under standard biphasic conditions (not shown).
Remarkably, the diacetate of allylic diol 16 was also completely
unreactive (Table 2, entry 6). The addition of Lewis acids
[Y(OTf)3, Sc(OTf)3], iodobenzene (PhI), iodosobenzene
(PhIO), and diacetyliodobenzene [PhI(OAc)2] failed to
promote reaction in this case, returning starting material 16-
(OAc)2 in each case after prolonged exposure. Similarly, the
introduction of a nitrogen into each ring of stilbene (trans-1,2-
di(4-pyridyl)ethylene) gave an unreactive substrate.
Figure 3. ORTEP representations of X-ray crystallographic analyses of
an azidochloride and two byproducts, each from a different alkene.
the structures and stereochemical assignments of the products
were established by conversion of the isolated azides to the
corresponding 1,2,3-triazoles by thermal reaction with
dimethylacetylenedicarboxylate (DMAD). This allowed for
bond connectivities to be established by two-dimensional
NMR techniques, and for five cases, by crystallization and X-ray
analysis. Complete details of all structural assignments are given
in the Experimental Section and Supporting Information.
Table 2 shows the results of ClN3 reactions with unsaturated
aliphatic olefins. A radical pathway was indicated by the
formation of the secondary chloride from 4-allylanisole (12,
entry 1). In this case, radical-derived byproducts were observed
with substantial variation in identity and relative amounts as the
solvent, temperature, reagent stoichiometry, and NaOCl
concentration were changed (see Supporting Information).
Switching to the solvent-free protocol at room temperature
addressed this complication, giving 12a in a consistent and
efficient manner. This procedure (at 20 or −15 °C) proved to
be superior for substrates which remained liquid under the
reaction conditions (Table 1, entries 2, 7; Table 2, entries 1, 4).
In these cases, the interface between the aqueous medium
where ClN3 is generated and the substrate is much different
(droplet size, reactant density and interfacial organization, etc.)
than when the substrate is dissolved in a hydrophobic solvent.
It is therefore not surprising that the reaction proceeds
differently under these two conditions, although we are not
Early in our studies, we used solutions of ClN3 isolated in
organic solvent by the procedure mentioned at the beginning of
the Results section. In these cases, several additional substrates
were found to react cleanly, although the stereo- and
regiochemical outcomes were not firmly established (Support-
ing Information Table S7). These substrates included several
E
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Table 2. Vicinal Azidochlorination of Aliphatic Alkenes
a
Experimental conditions: A = PhMe, 20 °C; B = PhMe, −15 °C; C = solvent-free, 20 °C; D = solvent-free, −15 °C; E = EtOAc, 20 °C; F = EtOAc,
−15 °C. When multiple procedures are listed, the underlined procedure is the one for which the yield is reported, but all gave comparable results.
b
c
d
Yields refer to isolated products (or their isolated diastereomeric mixtures). See Supporting Information. Diethyl ether (Et2O) was used instead
e
f
of toluene. A trace amount of the azidochloride, 18b, was observed in the product mixture. A larger excess of NaN3 than usual (18 vs 10 equiv) was
used.
toluene97 reacted with ClN3 under our standard conditions to
Scheme 3. Vicinal Azidochlorination of Anthracene Showing
give an azide-containing fullerene derivative in good yield
(Supporting Information); further characterization of this
transformation and those involving related substrates are in
progress.
a Potential Pathway for the Formation of 19a and 19b
CONCLUSIONS
■
We describe here a simple, reliable, inexpensive, and safe
method for the generation of ClN3 and its use for the
preparation of 1,2-azidochlorides from olefins. Its success relies
on the slow generation and rapid capture of ClN3, both of
which are enabled by the use of biphasic reaction conditions,
preventing the buildup of the explosive oxidant. Aryl, alcohol,
alkyne, ester, and ether functional groups are well tolerated;
others will be tested in due course. The method is not presently
applicable to molecules containing electron-rich aromatic rings
or free amines, which undergo radical chlorination faster than
chloroazidation. 1,2-Azidochlorides are expected to be a very
useful class of organic compounds suitable for further
derivatization by a variety of processes, including 1,3-dipolar
cycloaddition, SN2 or anchimerically assisted substitution,
reduction, aziridine and azirine formation, elimination, etc.
While we focused on small organic molecules here, including a
natural product and a fullerene, we believe these methods (or
allyl ethers, an allyl ester, and a glycal vinyl ether. Ester and
epoxide groups were found to be undisturbed, while a tert-
butyldiphenylsilyl ether did not survive.
Several recent reports have appeared of azide modification of
graphene,94 carbon surfaces,95 and fullerene,96 most using gas-
phase reactions of iodine azide. Akhmetov and co-workers96
employed several methodologies developed previously65,67 to
prepare new 1-halo-2-azidofullerenes which were characterized
by NMR, IR, and MALDI-TOF. None of these reported
examples were based on vicinal azidochlorination. We were
encouraged to find that solutions of C60 in chlorobenzene or
F
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bicarbonate solution,86 and (like diazomethane) by letting the mixture
stir open to air in the fume hood to allow ClN3 to evaporate.
variations thereof) will be equally useful for the functionaliza-
tion of polymeric materials and surfaces.
(E). Structure Elucidation. Since the chemical shifts of protons
attached to C−N3 and C−Cl centers are very similar, the
determination of the 1,2-azidochloride regio- and stereochemistry
requires some care. We employed the convenient and reliable thermal
[3 + 2] cycloaddition of organic azides with an excess of
dimethylacetylene dicarboxylate (DMAD)99 to make the correspond-
ing 1,2,3-triazoles of many of the compounds reported above (Tables
S8 and S9), and characterized these products extensively by 1D and
2D NMR techniques and X-ray crystallographic analysis (Figures S2
and S3). Further details can be found in Supporting Information.
(F). Reactions and Characterization Data. 4-(2-Azido-1-
chloroethyl)-1,2-dimethoxybenzene (1a). Compound 1a was ob-
tained as a crude mixture together with 1b (1a:1b ≈ 1.3:1 ratio based
on the NMR spectroscopic analysis) from 0.1 mL of 3,4-
dimethoxystyrene (1) (0.675 mmol), 150 mg of NaN3 (2.31 mmol),
4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of AcOH (4.54
mmol) (procedure I; PhMe; 20 °C; 0.5 h). 1a: Rf = 0.23 (silica gel,
EXPERIMENTAL SECTION
■
Representative and detailed procedures for azidochlorination of olefins
are described below; the largest scale employed for these procedures
was 2 mmol of alkene.
(A). General Biphasic Procedure. Sodium azide (150 mg, 2.31
mmol) was added to a mixture of aqueous sodium hypochlorite
(4.00−4.99% obtained from Sigma-Aldrich, 3.5 mL, 2.06 mmol) and 2
mL of an organic solvent (PhMe, EtOAc, or Et2O, unless otherwise
stated). The mixture was stirred briefly to dissolve the NaN3. An
organic substrate (13) (88 mg, 0.61 mmol) was added to the resulting
heterogeneous mixture, allowed to dissolve in the organic media, and
the resulting biphasic mixture was either kept at room temperature (20
°C) or cooled to −15 °C. With continuous vigorous magnetic stirring,
a solution of glacial acetic acid (0.25 mL, 4.37 mmol) in 2 mL of the
organic solvent was added in dropwise fashion with a syringe over a
period of 15 min to 1 h. After the addition was complete, the mixture
was stirred at 20 °C for an additional 30 min to 2 h (or, if initially
carried out at −15 °C, the reaction was allowed to warm to room
temperature over a period of 30 min to 2 h).
(B). General Solvent-Free Procedure. Sodium azide (350 mg,
5.38 mmol) was dissolved in aqueous sodium hypochlorite (4.00−
4.99% obtained from Sigma-Aldrich, 4 mL, 2.36 mmol) immediately
prior to use, and the resulting solution was cooled to −15 °C if
desired. An organic substrate (5) (as a neat liquid, 0.1 mL, 0.63 mmol)
was added to the resulting aqueous solution, which was either kept at
room temperature (20 °C) or cooled to −15 °C. A solution of glacial
acetic acid (0.26 mL, 4.54 mmol) in 2 mL of water was added
dropwise with a syringe over the period of 15 min to 1 h to the
vigorously stirred mixture. After the addition was complete, the
resulting reaction mixture was stirred at 20 °C for an additional 30 min
to 2 h (or allowed to warm to room temperature over a period of 30
min to 2 h if it had been initially cooled).
1
hexanes/EtOAc 10:1); H NMR (500 MHz, CDCl3) δ = 6.94−6.81
(m, 3H), 4.92 (dd, J ≈ 6.9, 6.9 Hz, 1H; in DMSO-d6, apparent t or dd,
J = 8.0, 5.9 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.74 (dd, J = 12.9, 7.5
Hz, 1H), 3.67 (dd, J = 12.9, 6.4 Hz, 1H).
Dimethyl 1-(2-chloro-2-(3,4-dimethoxyphenyl)ethyl)-1H-1,2,3-tri-
azole-4,5-dicarboxylate (1a′). Compound 1a′ was isolated in 25%
yield (64 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 1:1) from
163 mg (0.674 mmol) of 1a:1b mixture (1b′ was isolated in 13% yield,
33 mg) and 0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65
°C; 16 h). 1a′: Rf = 0.33 (silica gel, hexanes/EtOAc 1:1); IR (film)
νmax 2956, 1737, 1727, 1514, 1462, 1263, 1221, 1141, 1024, 729 =
1
cm−1; H NMR (500 MHz, CDCl3) δ = 6.84 (d, J = 2.0 Hz, 1H),
6.82−6.80 (m, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5.28 (dd, J = 6.6, 8.1 Hz,
1H), 5.16 (dd, J = 13.9, 8.2 Hz, 1H), 5.04 (dd, J = 13.9, 6.6 Hz, 1H),
3.93 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H); 13C NMR (125
MHz, CDCl3) δ = 160.4, 159.1, 150.1, 149.5, 139.9, 130.6, 128.9,
120.2, 111.2, 110.1, 60.6, 56.3, 56.17, 56.16, 53.6, 53.0; HRMS (ESI-
TOF) calcd for C16H18ClN3O6 [M + Na+] 406.0782, found 406.0806.
4-(1-Azido-2-chloroethyl)-1,2-dimethoxybenzene (1b). Com-
pound 1b was obtained in 85% yield (138 mg) after PTLC (silica
gel, hexanes/EtOAc = 10:1) from 0.1 mL of 3,4-dimethoxystyrene (1)
(0.675 mmol), 350 mg of NaN3 (5.38 mmol), 4.0 mL of NaOCl
solution (2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure
I; neat; 20 °C; 2 h). Alternatively, 1b can be obtained quantitatively
(∼163 mg) after FCC (silica gel, hexanes/EtOAc = 10:1) from 0.1 mL
of 3,4-dimethoxystyrene (1) (0.675 mmol), 150 mg of NaN3 (2.31
mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (with or without 1.0 mL of brine) (procedure I;
PhMe or EtOAc; −15 °C → 20 °C; 2 h). 1b: Rf = 0.30 (silica gel,
hexanes/EtOAc 10:1); IR (film) νmax = 3000−2800, 2102, 1514, 1262,
1138, 1023, 763, 715 cm−1; 1H NMR (500 MHz, CDCl3) δ = 6.86 (m,
2H), 6.80 (m, 1H), 4.66 (dd, J = 7.3, 6.3 Hz, 1H or dd, J = 8.1, 5.4 Hz,
1H in DMSO-d6), 3.88 (s, 3H), 3.86 (s, 3H), 3.66 (d, J = 1.4 Hz, 1H),
3.64 (s, 1H); 13C NMR (125 MHz, CDCl3) δ = 149.7, 149.5, 129.0,
119.7, 111.3, 109.8, 67.0, 56.1, 56.0, 47.7; HRMS (ESI-TOF) calcd for
C10H12ClN3O2 [M + Na+] 264.0516, found 264.0495.
(C). Workup. For each of the above procedures, the completed
reaction (monitored by TLC) was quenched by the slow addition of
saturated aq. NaHCO3 (5 mL) at 20 °C, during which the evolution of
CO2 ceased, followed by stirring for 5−10 min. The biphasic mixture
was extracted with EtOAc (3 × 5 mL), the combined organic layers
were dried over anhydrous MgSO4, the resulting solution was
concentrated by rotary evaporation, and the crude product was
purified by flash chromatography or preparative thin-layer chromatog-
raphy (silica gel, hexanes/EtOAc).
(D). Important Notes. (1) The solvent-free conditions should be
used only if the alkene remains in the liquid state throughout the
process (in other words, does not freeze if the reaction is cooled; true
here for compounds 1−3, 5, 6, 8, 12, 15, 16, 18, 20, 21). (2) Brine can
be added if the reaction is performed at −15 °C to prevent the
aqueous medium (solution of NaOCl, NaN3, and AcOH) from
solidifying. (3) Caution! Even though these conditions diminish the
hazards of chlorine azide substantially, it is still necessary to use common
sense and care. The addition of glacial acetic acid is an exothermic reaction
accompanied by rapid gas evolution (ClN3, and possibly N2, Cl2, HN3). It
is important to add the acetic acid solution slowly (dropwise), and to make
sure the flask is open or vented to relieve pressure. Furthermore, acidic
conditions with azide ion are always to be used with caution and avoided
in workup, since HN3 is highly volatile, toxic, and explosive. Therefore, the
reaction should be performed only in a well-ventilated fume hood behind a
protective shield or hood sash, and workup should avoid the use of acid,
especially when a large excess of NaN3 is left after the reaction is complete.
(4) The procedures described here were optimized using only the
4.00−4.99% solution of sodium hypochlorite available from Sigma-
Aldrich. Higher concentrations of sodium hypochlorite were not
exhaustively tested, but preliminary experiments showed a greater
propensity for runaway reactions at higher active concentrations of
NaOCl. (5) Remaining unreacted chlorine azide and any HN3 ion
were neutralized and quenched by the added saturated sodium
Dimethyl 1-(2-chloro-1-(3,4-dimethoxyphenyl)ethyl)-1H-1,2,3-tri-
azole-4,5-dicarboxylate (1b′). Compound 1b′ was isolated in 90%
yield (286 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 1:1)
from 200 mg of 1b (0.828 mmol) and 0.2 mL of DMAD (1.63 mmol)
(procedure II; C6H6; 65 °C; 14 h). 1b′: Rf = 0.10 (silica gel, hexanes/
EtOAc 5:1) or 0.60 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax
=
2956, 1737, 1728, 1515, 1450, 1263, 1214, 1142, 1024, 727 cm−1; H
NMR (500 MHz, CDCl3) δ = 6.95−6.93 (m, 2H), 6.79 (d, J = 8.1 Hz,
1H), 6.18 (dd, J = 10.2, 4.9 Hz, 1H), 4.63 (dd, J = 11.6, 10.3 Hz, 1H),
4.04 (dd, J = 11.7, 4.9 Hz, 1H), 3.91 (s, 3H) overlaps with 3.91 (s,
3H), 3.81 (s, 3H) overlaps with 3.81 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ = 160.6, 159.0, 150.1, 149.5, 140.3, 130.3, 127.6, 120.5,
111.3, 110.3, 66.1, 56.11, 56.06, 53.6, 52.9, 45.5; HRMS (ESI-TOF)
calcd for C16H18ClN3O6 [M + H+] 384.0962, found 384.0960; [M +
Na+] 406.0782, found 406.0779.
1
G
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-(2-Azido-1-chloroethyl)-3-nitrobenzene (2a). Compound 2a was
obtained in 97% yield (206 mg) after FCC (silica gel, hexanes/EtOAc
= 5:1) from 0.15 mL of 3-nitrostyrene (2) (1.08 mmol), 150 mg of
NaN3 (2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26
mL of AcOH (4.54 mmol) (procedure I; PhMe; 20 °C; from 0.5 to 1
4-(2-Azido-1-chloroethyl)benzonitrile (3a). Compound 3a was
obtained in 83% yield (141 mg) after FCC (silica gel, hexanes/EtOAc
= 10:1 → 5:1) from 0.1 mL of 4-cyanostyrene (3) (0.774 mmol), 150
mg of NaN3 (2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol),
and 0.26 mL of AcOH (4.54 mmol) (procedure I; PhMe; 20 °C; 1.5
h). 3a: Rf = 0.45 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax
=
h). 2a: Rf = 0.35 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax
=
2230, 2104, 1307, 1258, 836, 559 cm−1; 1H NMR (500 MHz, CDCl3)
δ = 7.67 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 4.97 (t, J = 6.6
Hz, 1H), 3.76 (dd, J = 12.9, 6.9 Hz, 1H), 3.67 (dd, J = 13.0, 6.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ = 143.2, 132.8, 128.3, 118.3,
113.1, 59.9, 57.6; HRMS (ESI-TOF) calcd for C9H7ClN4 [M + H+]
207.0437, found 207.0401.
2104, 1530, 1350, 1310, 1260, 731, 687 cm−1; H NMR (500 MHz,
CDCl3) δ = 8.29 (t, J = 2.0 Hz, 1H), 8.22 (ddd, J = 8.2, 2.2, 1.0 Hz,
1H), 7.75 (ddd, J = 7.7, 1.3, 1.3 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 5.03
(t, J = 6.7 Hz, 1H or dd, J = 7.4, 5.7 Hz, 1H in DMSO-d6), 3.82 (dd, J
= 13.0, 6.8 Hz, 1H), 3.73 (dd, J = 13.0, 6.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ = 148.7, 140.4, 133.6, 130.2, 124.3, 122.7, 59.6, 57.8.
Dimethyl 1-(2-chloro-2-(3-nitrophenyl)ethyl)-1H-1,2,3-triazole-
4,5-dicarboxylate (2a′). Compound 2a′ was isolated in 78% yield
(127 mg) (together with 13% of 2b′, 21 mg) after FCC (silica gel,
hexanes/EtOAc = 5:1 → 3:1) from 100 mg of 2a (0.441 mmol) and
0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65 °C; 15 h).
2a′: Rf = 0.15 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2956,
1
Dimethyl 1-(2-chloro-2-(4-cyanophenyl)ethyl)-1H-1,2,3-triazole-
4,5-dicarboxylate (3a′). Compound 3a′ was isolated in 42% yield
(81 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1) from 114
mg of 3a (0.552 mmol) and 0.1 mL of DMAD (0.813 mmol)
(procedure II; C6H6; 65 °C; 15 h). 3a′: Rf = 0.27 (silica gel, hexanes/
EtOAc 2:1); IR (film) νmax = 2956, 2231, 1737, 1726, 1221, 1062, 825,
731 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.64 (d, J = 8.4 Hz, 2H),
7.48 (d, J = 8.4 Hz, 2H), 5.40 (dd, J = 8.4, 6.1 Hz, 1H), 5.14 (dd, J =
14.0, 8.4 Hz, 1H), 5.02 (dd, J = 14.0, 6.2 Hz, 1H), 3.92 (s, 3H)
overlaps with 3.92 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 160.3,
158.9, 141.7, 140.2, 133.0, 130.1, 128.3, 118.1, 113.6, 59.1, 56.0, 53.7,
53.0; HRMS (ESI-TOF) calcd for C15H13ClN4O4 [M + H+] 349.0704,
found 349.0702; [M + Na+] 371.0523, found 371.0520.
1
1737, 1726, 1530, 1350, 1219, 1061, 732, 683 cm−1; H NMR (500
MHz, CDCl3) δ = 8.28 (t, J = 2.0 Hz, 1H), 8.20 (ddd, J = 8.2, 2.2, 1.0
Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 5.49 (dd, J
= 8.4, 6.2 Hz, 1H), 5.19 (dd, J = 14.1, 8.4 Hz, 1H), 5.08 (dd, J = 14.1,
6.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ = 160.3, 159.0, 148.7, 140.3, 138.9, 133.5, 130.4, 130.2, 124.6, 122.6,
58.8, 56.1, 53.8, 53.0; HRMS (ESI-TOF) calcd for C14H13ClN4O6 [M
+ H+] 369.0601, found 369.0605; [M + Na+] 391.0421, found
391.0417.
4-(2-Azidoacetyl)benzonitrile (3c). Compound 3c was obtained in
27% yield (41 mg) (together with 71 mg of 3a, 42%) after FCC (silica
gel, hexanes/EtOAc = 10:1 → 5:1) from 0.1 mL of 4-cyanostyrene (3)
(0.774 mmol), 150 mg of NaN3 (2.31 mmol), 4.0 mL of NaOCl
solution (2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure
I; EtOAc; −15 °C → 20 °C; 3 h). 3c: Rf = 0.36 (silica gel, hexanes/
Dimethyl 1-(2-chloro-1-(3-nitrophenyl)ethyl)-1H-1,2,3-triazole-
4,5-dicarboxylate (2b′). Compound 2b′ was isolated in 13% yield
(21 mg) (together with 78% of 2a′, 127 mg) after FCC (silica gel,
hexanes/EtOAc = 5:1 → 3:1) from 100 mg of 2a (0.441 mmol) and
0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65 °C; 15 h).
2b′: Rf = 0.24 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 2956,
1
EtOAc 5:1); IR (film) νmax = 2232, 2105, 1694, 1217, 833 cm−1; H
NMR (500 MHz, CDCl3) δ = 7.99 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.6
Hz, 2H), 4.55 (s, 2H); 13C NMR (125 MHz, CDCl3) δ = 192.4, 137.5,
133.0, 128.7, 117.8, 117.7, 55.3; HRMS (ESI-TOF) calcd for
C9H6N4O [M + Na+] 209.0439, found 209.0408.
1
1737, 1727, 1530, 1351, 1282, 1221, 727 cm−1; H NMR (500 MHz,
CDCl3) δ = 8.34 (t, J = 2.0 Hz, 1H), 8.23 (ddd, J = 8.3, 2.2, 1.0 Hz,
1H), 7.81 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 6.42 (dd, J =
9.4, 5.7 Hz, 1H), 4.63 (dd, J = 11.7, 9.5 Hz, 1H), 4.18 (dd, J = 11.6, 5.7
Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =
160.1, 158.5, 148.4, 140.4, 136.8, 133.5, 130.3, 129.7, 124.5, 122.9,
64.7, 53.5, 52.8, 44.7; HRMS (ESI-TOF) calcd for C14H13ClN4O6 [M
+ H+] 369.0601, found 369.0597; [M + Na+] 391.0421, found
391.0415.
Mixture of syn- and anti-1-Azido-2-chloroethane-1,2-diyl)-
dibenzene (4a:4b). Compounds 4a:4b were obtained as a mixture
of diastereomers in 86% yield (123 mg) after FCC (silica gel, hexanes/
EtOAc = 20:1 → 15:1) from 100 mg of trans-stilbene (4) (0.555
mmol), 400 mg of NaN3 (6.15 mmol), 3.0 mL of NaOCl solution
(1.77 mmol), 0.85 mL of AcOH (14.8 mmol), and 1.0 mL of brine
(procedure I; EtOAc; 20 °C; 3 h). 4a:4b: Rf = 0.51 (silica gel,
hexanes/EtOAc 15:1 or 20:1); IR (film) νmax = 3032, 2101, 1254, 727,
693 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.39−7.35 (m), 7.27 (m),
7.23−7.20 (m), 7.16 (m), 7.07 (m), 5.00 (d, J = 7.8 Hz, 1H) overlaps
with 5.00 (d, J = 8.6 Hz, 1H), 4.95 (d, J = 7.8 Hz, 1H), 4.88 (d, J = 8.6
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 137.7, 137.6, 136.4, 136.2,
129.14, 129.12, 128.9, 128.82, 128.79, 128.7, 128.6, 128.5, 128.4,
128.1, 128.0, 127.8, 72.5, 71.6, 67.0, 64.9.
Dimethyl 1-(2-(3-nitrophenyl)-2-oxoethyl)-1H-1,2,3-triazole-4,5-
dicarboxylate (2c′). Compound 2c′ was isolated in 56% yield (34
mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 1:1) from 36 mg of
2c (0.175 mmol, small amounts 0−24% usually formed at 0 °C in
PhMe) and 0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65
°C; 21 h). 2c′: Rf = 0.35 (silica gel, hexanes/EtOAc 1:1); IR (film)
νmax = 2956, 1737−1712, 1531, 1352, 1278, 1223, 1064, 735 cm−1; 1H
NMR (500 MHz, CDCl3) δ = 8.80 (t, J = 1.8 Hz, 1H), 8.51 (d, J = 8.1
Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 6.21 (s,
2H), 3.97 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =
188.0, 160.5, 159.1, 148.8, 140.6, 135.1, 133.8, 130.8, 130.1, 129.0,
123.2, 56.7, 53.7, 53.1; HRMS (ESI-TOF) calcd for C14H12N4O7 [M +
H+] 349.0784, found 349.0781; [M + Na+] 371.0604, found 371.0600.
2-Chloro-1-(3-nitrophenyl)ethan-1-ol (2d). Compound 2d was
obtained in 57% yield (82 mg) (together with 2a) after FCC (silica
gel, hexanes/EtOAc = 5:1 → 1:1) from 0.1 mL of 3-nitrostyrene (2)
(0.717 mmol), 150 mg of NaN3 (2.31 mmol), 4.0 mL of NaOCl
solution (2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure
I; EtOAc; −15 °C → 20 °C; 1.5 h). 2d: Rf = 0.15 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 3425 (broad), 1524, 1519, 1346, 1068,
(1R,2R)-2-Azido-1-chloro-1,2,3,4-tetrahydronaphthalene +
Enantiomer (5a). Compound 5a was obtained in 67% yield (107
mg) (together with 26% of 5b (42 mg); and ∼10% of 5c (∼14 mg))
after PTLC (silica gel, hexanes/EtOAc = 20:1) from 0.1 mL of 1,2-
dihydronaphthalene (5) (0.766 mmol), 350 mg of NaN3 (5.38 mmol),
4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of AcOH (4.54
mmol) (procedure I; PhMe; −15 °C → 20 °C; 3 h). 5a: Rf = 0.80
(silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 2937, 2093, 1259,
1
739 cm−1; H NMR (500 MHz, CDCl3) δ = 7.43 (m, 1H), 7.22 (m,
2H), 7.10 (m, 1H), 5.04 (d, J = 5.3 Hz, 1H), 4.12 (ddd, J = 7.6, 5.3, 2.9
Hz, 1H), 2.97−2.84 (m, 2H), 2.39 (dddd, J = 13.9, 8.6, 5.9, 2.8 Hz,
1H), 1.96 (m, 1H); 13C NMR (125 MHz, CDCl3) δ = 135.5, 133.5,
130.7, 129.0, 128.8, 126.9, 63.4, 59.5, 25.5, 24.4; HRMS (ESI-TOF)
calcd for C10H10ClN3 [M + H+] 208.0642, found 208.0627.
1
729, 676 cm−1; H NMR (500 MHz, CDCl3) δ = 8.27 (t, J = 2.0 Hz,
1H), 8.16 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.55
(t, J = 8.0 Hz, 1H), 5.02 (m, 1H), 3.78 (dd, J = 11.4, 3.6 Hz, 1H), 3.65
(dd, J = 11.4, 8.1 Hz, 1H), 2.89 (br s, OH); 13C NMR (125 MHz,
CDCl3) δ = 148.6, 142.2, 132.4, 129.9, 123.5, 121.4, 73.1, 50.5; HRMS
(ESI-TOF) calcd for C8H8ClNO3 [M + H+] 202.0270, found
202.0287.
anti-Dimethyl-1-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-
1,2,3-triazole-4,5-dicarboxylate (5a′). Compound 5a′ was isolated in
75% yield (167 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 →
2:1) from 132 mg of 5a (0.636 mmol) and 0.2 mL of DMAD (1.63
mmol) (procedure II; C6H6; 65 °C; 15 h). 5a′: Rf = 0.22 (silica gel,
hexanes/EtOAc 5:1); IR (film) νmax = 2954, 1737, 1731, 1453, 1286,
H
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1223, 743 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.59 (m, 1H), 7.25
(m, 2H), 7.14 (m, 1H), 5.77 (d, J = 9.4 Hz, 1H), 5.33 (ddd, J = 12.1,
9.4, 3.4 Hz, 1H), 3.98 (s, 3H), 3.97 (s, 3H), 3.16 (ddd, J = 17.1, 12.0,
5.3 Hz, 1H), 3.02 (ddd, J = 17.1, 5.0, 3.1 Hz, 1H), 2.64 (dddd, J =
13.2, 12.1, 12.1, 5.2 Hz, 1H), 2.46 (dddd, J = 13.2, 5.3, 3.2, 3.2 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ = 160.7, 159.5, 139.6, 135.4,
134.0, 131.5, 129.8, 128.7 overlaps with 128.7, 127.2, 64.7, 61.8, 53.8,
52.9, 29.7, 28.7; HRMS (ESI-TOF) calcd for C16H16ClN3O4 [M +
H+] 350.0908, found 350.0906; [M + Na+] 372.0728, found 372.0725.
(1R,2S)-2-Azido-1-chloro-1,2,3,4-tetrahydronaphthalene + Enan-
tiomer (5b). Compound 5b was obtained in 26% yield (42 mg)
(together with 67% of 5a (107 mg); and ∼10% of 5c (∼14 mg)) after
PTLC (silica gel, hexanes/EtOAc = 20:1) from 0.1 mL of 1,2-
dihydronaphthalene (5) (0.766 mmol), 350 mg of NaN3 (5.38 mmol),
4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of AcOH (4.54
mmol) (procedure I; PhMe; −15 °C → 20 °C; 3 h). 5b: Rf = 0.72
(silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 2939, 2094, 1258,
731 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.31 (d, J = 7.5 Hz, 1H),
7.24−7.19 (m, 2H), 7.12 (d, J = 7.5 Hz, 1H), 5.26 (dd, J = 3.4, 1.3 Hz,
1H), 3.90 (ddd, J = 11.8, 3.4, 3.4 Hz, 1H), 3.08 (ddd, J = 17.5, 6.3, 2.7
Hz, 1H), 2.93 (ddd, J = 17.5, 11.2, 6.4 Hz, 1H), 2.39 (dddd, J = 13.0,
11.5, 11.5, 6.3 Hz, 1H), 2.07 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
= 134.8, 134.6, 130.5, 129.3, 129.2, 126.9, 61.8, 60.2, 27.8, 22.6.
syn-Dimethyl-1-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-
1,2,3-triazole-4,5-dicarboxylate (5b′). Compound 5b′ was isolated in
48% yield (40 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1)
from 49 mg of 5b (0.236 mmol) and 0.1 mL of DMAD (0.813 mmol)
(procedure II; C6H6; 65 °C; 15 h). 5b′: Rf = 0.20 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2923, 2853, 1742, 1737, 1726, 1450,
19.4; HRMS (ESI-TOF) calcd for C12H14ClN3 [M + H+] 236.0955,
found 236.0961.
Dimethyl 1-((1R,2S)-2-chloro-2-phenylcyclohexyl)-1H-1,2,3-tria-
zole-4,5-dicarboxylate + Enantiomer (6a′). Compound 6a′ was
isolated in 56% yield (18 mg) after FCC (silica gel, hexanes/EtOAc =
5:1 → 1:1) from 20 mg of 6a (0.085 mmol) and 0.1 mL of DMAD
(0.813 mmol) (procedure II; C6H6; 65 °C; 17 h). 6a′: Rf = 0.20 (silica
gel, hexanes/EtOAc 5:1); IR (film) νmax = 2952, 1737, 1727, 1446,
1
1278, 1214, 753, 735, 697 cm−1; H NMR (500 MHz, CDCl3) δ =
7.28 (m, 2H), 7.16−7.10 (m, 3H), 5.62 (ddd, J = 4.8, 2.4, 2.4 Hz, 1H),
3.85 (s, 3H), 3.82 (s, 3H), 3.30 (m, 1H), 2.71 (m, 1H), 2.24 (m, 1H),
2.19−2.08 (m, 2H), 2.02 (m, 1H), 1.96 (m, 1H), 1.70 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ = 160.5, 159.3, 141.5, 138.5, 131.2, 128.6,
128.4, 126.3, 73.6, 64.1, 53.5, 52.7, 33.0, 27.6, 21.4, 19.1; HRMS (ESI-
TOF) calcd for C18H20ClN3O4 [M + H+] 378.1215, found 378.1219;
[M + Na+] 400.1035, found 400.1035.
((1S,2S)-2-Azido-1-chlorocyclohexyl)benzene + Enantiomer (6b).
Compound 6b was obtained as a mixture of 6b plus two other
unidentified products in 8% yield (12 mg) (together with 61% of 6a,
91 mg) after PTLC (silica gel, hexanes/EtOAc = 20:1) from 0.1 mL of
1-phenyl-1-cyclohexene (6) (0.628 mmol), 350 mg of NaN3 (5.38
mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (procedure I; neat; −15 °C → 20 °C; 2 h). 6b: Rf
= 0.70 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 2942, 2865,
1
2100, 1446, 1262, 751, 694 cm−1; H NMR (500 MHz, CDCl3 − a
mixture of three products) δ = 7.68 (m, 2H), 7.61 (m, 2H), 7.53−7.26
(m, 11H), 4.88 (m, 1H), 4.49 (m, 1H), 4.28 (dd, J = 10.9, 4.8 Hz,
1H), 3.77 (dd, J = 11.2, 4.3 Hz, 1H), 2.55 (m, 1H), 2.34 (m, 1H),
2.24−2.08 (m, 7H), 2.05−1.86 (m, 8H), 1.70−1.64 (m, 4H), 1.50−
1.40 (m, 2H); HRMS (ESI-TOF) calcd for C12H14ClN3 [M + H+]
236.0955, found 236.0966.
1
1220, 1062, 730 cm−1; H NMR (500 MHz, CDCl3) δ = 7.32 (d, J =
7.8 Hz, 1H), 7.29 (ddd, J = 7.4, 7.4, 1.5 Hz, 1H), 7.23 (t, J = 7.3 Hz,
1H), 7.18 (d, J = 7.6 Hz, 1H), 5.54 (dd, J = 3.3, 1.4 Hz, 1H), 5.39
(ddd, J = 12.4, 3.2, 3.2 Hz, 1H), 3.97 (s, 6H), 3.23−3.14 (m, 2H), 3.06
(m, 1H), 2.48 (m, 1H); 13C NMR (125 MHz, CDCl3) δ = 160.9,
159.6, 140.9, 134.7, 134.1, 130.9, 129.63, 129.57, 129.4, 127.1, 61.4,
60.0, 53.8, 53.0, 28.8, 22.4; HRMS (ESI-TOF) calcd for
C16H16ClN3O4 [M + H+] 350.0908, found 350.0910; [M + Na+]
372.0728, found 372.0724. 5d′: HRMS (ESI-TOF) calcd for
C16H16ClN3O4 [M + H+] 350.0908, found 350.0907; [M + Na+]
372.0728, found 372.0726.
2-Azido-3,4-dihydronaphthalen-1(2H)-one (5c). Compound 5c
was obtained in 10% yield (14 mg) (together with 67% of 5a (107
mg); and 26% of 5b (42 mg)) after PTLC (silica gel, hexanes/EtOAc
= 20:1) from 0.1 mL of 1,2-dihydronaphthalene (5) (0.766 mmol),
350 mg of NaN3 (5.38 mmol), 4.0 mL of NaOCl solution (2.36
mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I; PhMe; −15
°C → 20 °C; 3 h). 5c: Rf = 0.50 (silica gel, hexanes/EtOAc 10:1); IR
(film) νmax = 2933, 2100, 1692, 1682, 1601, 1264, 1228, 745 cm−1; 1H
NMR (500 MHz, CDCl3) δ = 8.05 (dd, J = 7.8, 1.2 Hz, 1H), 7.50
(ddd, J = 7.5, 7.5, 1.4 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6
Hz, 1H), 4.21 (dd, J = 12.1, 4.7 Hz, 1H), 3.06 (dd, J = 7.8, 4.5 Hz,
2H), 2.36 (dddd, J = 13.3, 4.5, 4.5, 4.5 Hz, 1H), 2.16−2.08 (m, 1H);
13C NMR (125 MHz, CDCl3) δ = 194.0, 143.6, 134.4, 131.3, 128.9,
128.2, 127.3, 64.5, 29.6, 27.8; HRMS (ESI-TOF) calcd for C10H9N3O
[M + Na+] 210.0643, found 210.0638.
((1S,2R)-2-Azido-1-chlorocyclohexyl)benzene + Enantiomer (6a).
Compound 6a was obtained in 61% yield (91 mg) (together with 8%
of 6b, 12 mg) after PTLC (silica gel, hexanes/EtOAc = 20:1) from 0.1
mL of 1-phenyl-1-cyclohexene (6) (0.628 mmol), 350 mg of NaN3
(5.38 mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (procedure I; neat; −15 °C → 20 °C; 2 h). 6a: Rf
= 0.80 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 2939, 2866,
2101, 1446, 1267, 751, 694, 658 cm−1; 1H NMR (500 MHz, CDCl3) δ
= 7.58 (m, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 4.22
(m, 1H), 2.53 (ddd, J = 13.9, 12.4, 4.1 Hz, 1H), 2.38 (dddd, J = 14.3,
13.0, 4.6, 2.9 Hz, 1H), 2.22 (ddddd, J = 13.9, 3.3, 3.3, 1.5, 1.5 Hz, 1H),
1.95 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 1.60 (m, 1H) overlaps with
1.55 (dddd, J = 13.2, 13.2, 4.0, 4.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ = 143.6, 128.7, 128.5, 126.8, 73.1, 67.4, 32.4, 27.0, 21.5,
Dimethyl 1-((1S,2S)-2-chloro-2-phenylcyclohexyl)-1H-1,2,3-tria-
zole-4,5-dicarboxylate + Enantiomer (6b′). Compound 6b′ was
isolated in 62% yield (52 mg) after FCC (silica gel, hexanes/EtOAc =
5:1 → 1:1) from 52 mg of 6b (0.221 mmol) and 0.1 mL of DMAD
(0.813 mmol) (procedure II; C6H6; 65 °C; 16 h). 6b′: Rf = 0.17 (silica
gel, hexanes/EtOAc 1:1); IR (film) νmax = 2951, 1737, 1726, 1445,
1
1285, 1214, 1061, 734, 697 cm−1; H NMR (500 MHz, CDCl3) δ =
7.22−7.16 (m, 3H), 7.19−7.14 (m, 2H), 5.19 (dd, J = 12.0, 3.5 Hz,
1H), 3.86 (s, 3H), 3.52 (s, 3H), 3.01 (m, 1H), 2.55 (ddd, J = 14.1,
12.4, 3.9 Hz, 1H), 2.29 (m, 1H), 2.17 (ddddd, J = 13.1, 13.1, 13.1, 3.7,
3.7 Hz, 1H) overlaps with 2.09 (m, 2H), 1.84 (m, 1H), 1.61 (m, 1H);
13C NMR (125 MHz, CDCl3) δ = 160.7, 159.2, 140.9, 138.5, 131.3,
128.6, 128.4, 126.9, 76.3, 67.4, 53.1, 52.7, 40.2, 29.1, 25.3 21.6; HRMS
(ESI-TOF) calcd for C18H20ClN3O4 [M + H+] 378.1221, found
378.1226; [M + Na+] 400.1040, found 400.1037.
Mixture of syn- and anti-2-Azido-3-chloro-3-phenylpropan-1-ol
(7a:7b). Compounds 7a:7b were obtained as an inseparable mixture in
71% yield (112 mg) after PTLC (silica gel, hexanes/EtOAc = 5:1)
from 100 mg of cinnamyl alcohol (7) (0.745 mmol), 150 mg of NaN3
(2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol), 0.26 mL of
AcOH (4.54 mmol), and 1.0 mL of brine (procedure I; PhMe; 20 °C;
1 h). Alternatively, 7a:7b can be obtained (together with 35% of other
region-isomers; 78% combined yield) from 100 mg of 7 (0.745
mmol), 350 mg of NaN3 (5.38 mmol), 4.0 mL of NaOCl solution
(2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I;
PhMe; −15 °C → 20 °C; 2.5 h). 7a:7b: Rf = 0.28 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 3363 (broad), 2102, 1265, 1057, 733,
1
697, 550 cm−1; H NMR (500 MHz, CDCl3) δ = 7.45−7.32 (m,
10H), 5.01 (d, J = 7.8 Hz, 1H), 4.93 (d, J = 8.2 Hz, 1H), 3.96−3.83
(m, 4H), 3.61 (dd, J = 11.6, 3.8 Hz, 1H), 3.40 (dd, J = 11.5, 6.2 Hz,
1H), 2.05 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ = 137.9, 137.8,
129.4, 129.3, 129.12, 129.06, 128.2, 127.7, 69.8, 69.0, 63.8, 63.0, 62.9,
60.7.
Mixture of syn- and anti-2-Azido-3-chloro-3-phenylpropyl
acetate (7a′:7b′). A mixture of 7a:7b (110 mg, 0.520 mmol) and
Et3N (0.2 mL, 1.43 mmol) in 5 mL of dry DCM was treated with
acetyl chloride (0.07 mL, 0.984 mmol) at 0 °C for 0.5 h. Excess DCM
was removed in vacuo. After FCC (silica gel, hexanes/EtOAc = 5:1)
78% of pure 7a′:7b′ (103 mg) was isolated. 7a′:7b′: Rf = 0.55 (silica
I
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
gel, hexanes/EtOAc 5:1); IR (film) νmax = 2106, 1753−1732, 1221,
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 138.0, 129.2, 129.0, 127.8,
78.9, 75.5, 69.7, 67.1, 63.0, 58.9.
1
1044, 697 cm−1; H NMR (500 MHz, CDCl3) δ = 7.43−7.32 (m,
Mixture of syn- and anti-Dimethyl-1-chloro-1-phenyl-3-(prop-2-
yn-1-yloxy)propan-2-yl)-1H-1,2,3-triazole-4,5-dicarboxylate
(8a′:8b′). Compounds 8a′:8b′ were isolated in 52% yield (41 mg)
after FCC (silica gel, hexanes/EtOAc = 5:1 → 3:1) from 50 mg of
8a:8b (0.200 mmol) and 0.15 mL of DMAD (1.22 mmol) (procedure
II; C6H6; 65 °C; 18 h). 8a′:8b′: Rf = 0.18 (silica gel, hexanes/EtOAc
5:1); IR (film) νmax = 3286, 2954, 1737, 1727, 1453, 1275, 1217, 1099,
10H), 4.92 (d, J = 7.1 Hz, 1H), 4.88 (d, J = 7.9 Hz, 1H), 4.43 (dd, J =
11.7, 3.4 Hz, 1H), 4.25 (dd, J = 11.7, 6.9 Hz, 1H), 4.15 (dd, J = 11.5,
3.7 Hz, 1H), 4.04 (ddd, J = 7.9, 6.9, 3.4 Hz, 1H) overlaps with 4.01
(ddd, J = 7.2, 7.2, 3.6 Hz, 1H), 3.91 (dd, J = 11.5, 7.2 Hz, 1H), 2.10 (s,
3H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 170.6, 170.5,
137.4, 137.3, 129.49, 129.47, 129.2, 129.1, 128.1, 127.6, 66.3, 65.7,
64.3, 64.2, 63.0, 60.9, 20.9, 20.8; HRMS (ESI-TOF) calcd for
C11H12ClN3O2 [M + Na+] 276.0515, found 276.0550.
1
699 cm−1; H NMR (500 MHz, CDCl3) δ = 7.43−7.33 (m, 5H),
7.22−7.18 (m, 5H), 5.72 (m, 1H) overlaps with 5.69 (m, 1H), 5.53 (d,
J = 9.9 Hz, 1H), 5.45 (d, J = 10.0 Hz, 1H), 4.45 (dd, J = 10.1, 3.5 Hz,
1H), 4.27 (dd, J = 10.1, 9.0 Hz, 1H), 4.09 (m, 2H), 3.96 (s, 3H), 3.95
(s, 3H), 3.91 (m, 2H), 3.89 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.60
(dd, J = 10.1, 3.8 Hz, 1H), 2.42 (t, J = 2.4 Hz, 1H), 2.27 (t, J = 2.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ = 160.7, 160.4, 159.3, 159.0,
139.8, 139.3, 137.0, 136.4, 132.1, 131.7, 129.8, 129.5, 129.4, 129.3,
128.9, 128.7, 127.74, 127.69, 78.6, 78.3, 75.62, 75.58, 69.6, 68.9, 61.7,
59.9, 58.7, 58.6, 53.6, 53.5, 52.9, 52.8; HRMS (ESI-TOF) calcd for
C18H18ClN3O5 [M + H+] 392.1013, found 392.1036; [M + Na+]
414.0833, found 414.0832.
Mixture of syn- and anti-Dimethyl-3-acetoxy-1-chloro-1-phenyl-
propan-2-yl)-1H-1,2,3-triazole-4,5-dicarboxylate (7a″:7b″). Com-
pounds 7a″:7b″ were isolated in 57% yield (89 mg) after FCC (silica
gel, hexanes/EtOAc = 5:1 → 1:1) from 100 mg of 7a′:7b′ (0.394
mmol) and 0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65
°C; 15 h). 7a″:7b″: Rf = 0.15 (silica gel, hexanes/EtOAc 5:1) or 0.68
(silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 1753−1728, 1453,
1
1214, 1077, 1047, 731, 699 cm−1; H NMR (500 MHz, CDCl3) δ =
7.45−7.34 (m, 5H), 7.18 (m, 5H), 5.73 (ddd, J = 10.2, 8.1, 4.4 Hz,
1H), 5.65 (ddd, J = 10.2, 9.0, 3.3 Hz, 1H), 5.50 (d, J = 10.2 Hz, 1H),
5.43 (d, J = 10.2 Hz, 1H), 5.16 (dd, J = 11.8, 3.3 Hz, 1H), 4.72 (dd, J =
11.8, 9.1 Hz, 1H), 4.34−4.25 (m, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.86
(s, 3H), 3.85 (s, 3H), 1.95 (s, 3H), 1.87 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ = 170.3, 170.2, 160.6, 160.2, 159.2, 158.8, 139.7, 139.3,
136.4, 136.1, 132.1, 131.4, 130.2, 129.62, 129.58, 129.0, 127.7, 127.5,
65.1, 64.6, 63.8, 63.3, 62.0, 59.8, 53.8, 53.6, 53.0, 52.9, 20.7, 20.6;
HRMS (ESI-TOF) calcd for C17H18ClN3O6 [M + H+] 396.0962,
found 396.0976; [M + Na+] 418.0782, found 418.0778.
2-Azido-1-phenyl-3-(prop-2-yn-1-yloxy)propan-1-one (8c). Com-
pound 8c was obtained (together with 98 mg of 8a:8b, 68%) in 10%
yield (13 mg) after PTLC (silica gel, hexanes/EtOAc = 20:1) from 0.1
mL of 8 (0.581 mmol), 350 mg of NaN3 (5.38 mmol), 4.0 mL of
NaOCl solution (2.36 mmol), and 0.26 mL of AcOH (4.54 mmol)
(procedure I; EtOAc; 20 °C; 1 h). 8c: Rf = 0.44 (silica gel, hexanes/
EtOAc 10:1); IR (film) νmax = 3293, 2916, 2849, 2102, 1702−1682,
1
1270, 1228, 1104, 697 cm−1; H NMR (500 MHz, CDCl3) δ = 7.93
(E)-(3-(Prop-2-yn-1-yloxy)prop-1-en-1-yl)benzene (8). Cinnamyl
alcohol (7) (0.5 g, 3.73 mmol) was dissolved in dry THF (15 mL).
The resulting solution was cooled to 0 °C. Sodium hydride (134 mg,
5.58 mmol, prewashed separately from 60% in mineral oil) was added
in portions over the period of 5 min, the reaction was stirred for
additional 20 min at 0 °C after which propargyl bromide (0.72 mL,
6.68 mmol, 80% solution in toluene) was added dropwise. After the
reaction was completed (monitored by TLC, 0 °C → 20 °C; 3 h) it
was slowly quenched with sat. aq. NH4Cl (10 mL). The biphasic
mixture was extracted with CH2Cl2 (3 × 10 mL), the combined
organic layers were dried over anhydrous Na2SO4 and concentrated in
vacuo. FCC (silica gel, hexanes/EtOAc = 10:1 → 5:1) yielded 76%
(0.49 g) of 8 as a colorless oil. 8: Rf = 0.75 (silica gel, hexanes/EtOAc
5:1); IR (film) νmax = 3290, 3026, 2851, 1356, 1116, 1073, 965, 736,
(d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H),
4.84 (dd, J = 6.9, 4.3 Hz, 1H), 4.20 (d, J = 2.4 Hz, 1H), 4.18 (d, J = 2.4
Hz, 1H), 4.04 (dd, J = 10.2, 4.3 Hz, 1H), 3.94 (dd, J = 10.2, 6.9 Hz,
1H), 2.41 (t, J = 2.4 Hz, 1H).
Dimethyl 1-(1-oxo-1-phenyl-3-(prop-2-yn-1-yloxy)propan-2-yl)-
1H-1,2,3-triazole-4,5-dicarboxylate (8c′). Compound 8c′ was iso-
lated in 48% yield (10 mg) after FCC (silica gel, hexanes/EtOAc = 5:1
→ 2:1) from 13 mg of 8c (0.057 mmol) and 0.1 mL of DMAD (0.813
mmol) (procedure II; C6H6; 65 °C; 17 h). 8c′: Rf = 0.11 (silica gel,
hexanes/EtOAc 5:1) or 0.50 (silica gel, hexanes/EtOAc 2:1); IR (film)
νmax = 3283, 2955, 1737−1698, 1450, 1285, 1215, 1102, 692 cm−1; 1H
NMR (500 MHz, CDCl3) δ = 7.92 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H),
7.44 (t, J = 7.8 Hz, 2H), 6.71 (dd, J = 9.0, 4.0 Hz, 1H), 4.39 (dd, J =
10.6, 4.0 Hz, 1H), 4.32 (dd, J = 10.6, 9.0 Hz, 1H), 4.14 (dd, J = 16.0,
2.4 Hz, 1H), 4.07 (dd, J = 16.0, 2.4 Hz, 1H), 3.94 (s, 3H) overlaps
with 3.94 (s, 3H), 2.38 (t, J = 2.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ = 190.9, 160.6, 159.6, 140.0, 134.5, 134.4, 131.0, 129.3,
128.8, 78.6, 75.6, 68.4, 64.9, 58.9, 53.7, 53.0.
Ethyl (2S,3R,4R)-3-azido-4-chloro-2-ethoxy-3,4-dihydroquino-
line-1(2H)-carboxylate + Enantiomer (9a). Compound 9a was
obtained in 67% yield (97 mg) (together with 32% of 9b, 37 mg)
after PTLC (silica gel, hexanes/EtOAc = 5:1) from 110 mg of 2-
ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (9) (0.445
mmol), 350 mg of NaN3 (5.38 mmol), 4.0 mL of NaOCl solution
(2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I;
PhMe; −15 °C → 20 °C; 3 h). 9a: Rf = 0.68 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2980, 2106, 1712, 1311, 1274, 1080,
1046 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.62 (d, J = 7.7 Hz, 1H),
7.40 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.25 (ddd, J = 7.6,
7.6, 1.2 Hz, 1H), 5.69 (d, J = 3.8 Hz, 1H), 4.79 (d, J = 9.2 Hz, 1H),
4.32−4.17 (m, 2H), 3.78 (dd, J = 9.1, 3.8 Hz, 1H), 3.73−3.62 (m,
2H), 1.28 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ = 154.6, 134.7, 128.8, 128.7, 126.9, 126.2, 125.8, 86.1,
72.1, 64.3, 62.8, 57.8, 15.1, 14.5; HRMS (ESI-TOF) calcd for
C14H17ClN4O3 [M + Na+] 347.0886, found 347.0886.
1
691, 669, 632 cm−1; H NMR (500 MHz, CDCl3) δ = 7.38 (m, 2H),
7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 16.0 Hz,
1H), 6.26 (ddd, J = 16.0, 6.2, 6.2 Hz, 1H), 4.23 (dd, J = 6.2, 1.4 Hz,
2H), 4.19 (d, J = 2.4 Hz, 2H), 2.45 (t, J = 2.4 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ = 136.7, 133.6, 128.8, 128.0, 126.8, 125.2, 79.9, 74.7,
70.4, 57.2; HRMS (ESI-TOF) calcd for C12H12O [M + H+] 173.0966,
found 173.0949.
Mixture of syn- and anti-2-Azido-1-chloro-3-(prop-2-yn-1-yloxy)-
propyl)benzene (8a:8b). Compounds 8a:8b were obtained in 82%
yield (119 mg) (together with 5% of 8c, 7 mg) after PTLC (silica gel,
hexanes/EtOAc = 20:1) from 0.1 mL of 8 (0.581 mmol), 150 mg of
NaN3 (2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26
mL of AcOH (4.54 mmol) (procedure I; PhMe; 20 °C; 0.5 h). 8a:8b:
Rf = 0.60−0.70 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax
=
3295, 2916, 2105, 1267, 1094, 732, 697, 639, 528 cm−1; H NMR
(500 MHz, CDCl3) δ = 7.48−7.31 (m, 10H), 5.04 (d, J = 6.9 Hz, 1H),
4.99 (d, J = 7.8 Hz, 1H), 4.21 (t, J = 2.6 Hz, 2H), 4.12 (d, J = 2.4 Hz,
2H), 3.97 (m, 1H), 3.87 (m, 1H), 3.82−3.76 (m, 2H), 3.65 (dd, J =
9.9, 4.1 Hz, 1H), 3.42 (dd, J = 9.9, 5.9 Hz, 1H), 2.46 (t, J = 2.4 Hz,
1H), 2.40 (t, J = 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ =
138.0, 137.6, 129.23, 129.15, 129.0, 128.9, 128.2, 127.8, 79.0, 78.9,
75.47, 75.46, 69.6, 69.5, 67.0, 66.4, 63.0, 60.9, 58.9, 58.8. 8a:8b (one of
the diastereomers): Rf = 0.62 (silica gel, hexanes/EtOAc 10:1); IR
1
Dimethyl 1-((2S,3R,4R)-4-chloro-2-ethoxy-1-(ethoxycarbonyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazole-4,5-dicarboxylate
+ Enantiomer (9a′). Compound 9a′ was isolated in 61% yield (125
mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 3:1) from 142 mg
of 9a (0.437 mmol) and 0.15 mL of DMAD (1.22 mmol) (procedure
II; C6H6; 65 °C; 15 h). 9a′: Rf = 0.18 (silica gel, hexanes/EtOAc 5:1)
1
(film) νmax = 3294, 2916, 2104, 1270, 1109, 744, 699, 649 cm−1; H
NMR (500 MHz, CDCl3) δ = 7.43−7.33 (m, 5H), 5.04 (d, J = 6.9 Hz,
1H), 4.12 (d, J = 2.4 Hz, 2H), 3.86 (d, J = 6.8, 5.8, 4.2 Hz, 1H), 3.65
(dd, J = 9.9, 4.1 Hz, 1H), 3.42 (dd, J = 9.9, 5.8 Hz, 1H), 2.39 (t, J = 2.4
J
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
or 0.37 (silica gel, hexanes/EtOAc 3:1); IR (film) νmax = 2954, 1737,
1731, 1453, 1286, 1223, 1069, 743 cm−1; 1H NMR (500 MHz,
CDCl3) δ = 7.64 (t, J = 7.8 Hz, 1H), 7.42−7.37 (m, 2H), 7.30 (ddd, J
= 7.5, 7.5, 1.5 Hz, 1H), 6.16 (d, J = 4.4 Hz, 1H), 5.49 (d, J = 10.8 Hz,
1H), 5.16 (dd, J = 10.8, 4.4 Hz, 1H), 4.30−4.16 (m, 2H), 3.96 (s, 3H),
3.93 (s, 3H), 3.64 (dddd, J = 9.6, 7.1, 7.1, 7.1 Hz, 1H), 3.84 (dddd, J =
9.6, 7.1, 7.1, 7.1 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ = 160.4, 158.8, 154.4, 139.7,
134.9, 132.1, 129.1, 128.8, 126.6, 126.3, 126.2, 86.4, 71.6, 64.3, 63.1,
57.0, 53.8, 52.9, 14.9, 14.5; HRMS (ESI-TOF) calcd for
C20H23ClN4O7 [M + H+] 467.1333, found 467.1334; [M + Na+]
489.1153, found 489.1150.
(2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I; neat;
20 °C; 1 h). Alternatively, 12a can be obtained in 94% yield (138 mg)
after PTLC (silica gel, hexanes/EtOAc = 20:1 → 10:1) from 0.1 mL of
4-allylanisole (12) (0.651 mmol), 500 mg of NaN3 (7.69 mmol), 4.0
mL of NaOCl solution (2.36 mmol), and 0.35 mL of AcOH (6.11
mmol) (procedure I; PhMe; at room temperature or 0 °C → 20 °C; 5
h). NOTE: Larger amounts of NaOCl, older reagents, EtOAc, lower
temperature, lack of the excess of NaN3 usually cause the formation of
other side products (see 12b′ and 12c′). 12a: Rf = 0.65 (silica gel,
hexanes/EtOAc 10:1); IR (film) νmax = 2957, 2837, 2100, 1611, 1513,
1302, 1246, 1178, 1032, 833, 543 cm−1; 1H NMR (500 MHz, CDCl3)
δ = 7.12 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.13 (dddd, J =
7.0, 7.0, 6.0, 4.7 Hz, 1H), 3.78 (s, 3H), 3.50 (dd, J = 13.0, 4.6 Hz, 1H),
3.44 (dd, J = 13.0, 6.0 Hz, 1H), 3.06 (dd, J = 14.2, 7.0 Hz, 1H), 3.00
(dd, J = 14.2, 7.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 158.9,
130.6, 128.7, 114.2, 61.4, 56.0, 55.4, 40.9; HRMS (ESI-TOF) calcd for
C10H12ClN3O [M + Na+] 248.0566, found 248.0558.
Dimethyl 1-(2-chloro-3-(4-methoxyphenyl)propyl)-1H-1,2,3-tria-
zole-4,5-dicarboxylate (12a′). Compound 12a′ was isolated in 72%
yield (162 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1)
from 138 mg of 12a (0.611 mmol) and 0.25 mL of DMAD (2.03
mmol) (procedure II; C6H6; 65 °C; 16 h). 12a′: Rf = 0.10 (silica gel,
hexanes/EtOAc 5:1); IR (film) νmax = 2955, 1737, 1728, 1514, 1462,
1221, 1178, 1062, 1033, 824, 730 cm−1; 1H NMR (500 MHz, CDCl3)
δ = 7.14 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.89−4.80 (m,
2H), 4.48 (dddd, J = 7.9, 7.1, 7.1, 4.8 Hz, 1H), 3.94 (s, 3H) overlaps
with 3.94 (s, 3H), 3.76 (s, 3H), 3.05 (d, J = 1.6 Hz, 1H), 3.04 (d, J =
2.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 160.5, 159.2, 159.1,
139.9, 131.1, 130.6, 127.8, 114.3, 60.5, 55.4, 54.7, 53.7, 52.9, 41.3;
HRMS (ESI-TOF) calcd for C16H18ClN3O5 [M + H+] 368.1013,
found 368.1038; [M + Na+] 390.0832, found 390.0833.
Mixture of syn- and anti-Dimethyl-1,3-dichloro-1-(4-
methoxyphenyl)propan-2-yl)-1H-1,2,3-triazole-4,5-dicarboxylate
(12b′) plus syn- and anti-Dimethyl-2,3-dichloro-1-(4-
methoxyphenyl)propyl)-1H-1,2,3-triazole-4,5-dicarboxylate (12c′).
Compounds 12b′:12c′ were isolated in various yields after FCC
(silica gel, hexanes/EtOAc = 5:1 → 2:1) from various amounts of 12a
(crude mixture obtained at −15 °C and in EtOAc) and 0.1 mL of
DMAD (0.813 mmol) (procedure II; C6H6; 65 °C; 15 h). 12b′:12c′:
Rf = 0.20 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2956, 1737,
1728, 1514, 1453, 1281, 1256, 1226, 1180, 1154, 1058, 1031, 825
cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.55 (d, J = 8.8 Hz, 2H), 7.47
(d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H) overlaps with 6.87 (d, J =
8.8 Hz, 2H), 6.34 (d, J = 10.1 Hz, 1H) overlaps with 6.32 (d, J = 9.4
Hz, 1H), 5.37 (m, 1H), 5.29 (ddd, J = 9.8, 3.6, 3.1 Hz, 1H), 3.98 (s,
3H), 3.94 (s, 3H), 3.93 (s, 3H) overlaps with 3.93 (s, 3H), 3.84 (dd, J
= 12.7, 3.0 Hz, 1H), 3.79 (dd, J = 12.5, 2.8 Hz, 1H), 3.78 (s, 3H)
overlaps with 3.77 (s, 3H), 3.61 (dd, J = 12.7, 3.7 Hz, 1H), 3.51 (dd, J
= 12.5, 3.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 161.0, 160.8,
160.6, 160.5, 159.0, 158.8, 140.24, 140.15, 130.1, 130.0, 129.1, 129.0,
126.6, 125.6, 114.9, 114.5, 67.3, 65.0, 61.6, 60.5, 55.6, 55.5, 53.8, 53.7,
53.1, 53.0, 47.2, 46.9; HRMS (ESI-TOF) calcd for C16H17Cl2N3O5 [M
+ H+] 402.0623, found 402.0621; [M + Na+] 424.0442, found
424.0439.
1-Chloro-3-(4-methoxyphenyl)propan-2-ol (12d). Compound
12d was obtained in 24% yield (32 mg) (together with 66% of 12a
(97 mg) and other side-products (see 12b′ and 12c′) usually formed
at −15 °C) after FCC (silica gel, hexanes/EtOAc = 20:1 → 5:1) from
0.1 mL of 4-allylanisole (12) (0.651 mmol), 300 mg of NaN3 (4.61
mmol), 8.0 mL of NaOCl solution (4.72 mmol), and 0.52 mL of
AcOH (9.08 mmol) (procedure I; EtOAc; −15 °C; 2.5 h). 12d: Rf =
0.20 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 3410 (broad),
2955−2836, 1513, 1246, 1178, 1034, 810 cm−1; 1H NMR (500 MHz,
CDCl3) δ = 7.18 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.03
(dddd, J = 6.5, 6.5, 6.5, 3.8 Hz, 1H), 3.82 (s, 3H), 3.64 (dd, J = 11.1,
3.9 Hz, 1H), 3.52 (d, J = 11.1, 6.2 Hz, 1H), 2.86 (d, J = 6.6 Hz, 2H),
2.12 (br s, OH); 13C NMR (125 MHz, CDCl3) δ = 158.7, 130.5,
129.1, 114.3, 72.5, 55.5, 49.4, 39.9.
Ethyl 3-azido-4-oxoquinoline-1(4H)-carboxylate (9b). Compound
9b was obtained in 32% yield (37 mg) (together with 67% of 9a, 97
mg) after PTLC (silica gel, hexanes/EtOAc = 5:1) from 110 mg of 2-
ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (9) (0.445
mmol), 350 mg of NaN3 (5.38 mmol), 4.0 mL of NaOCl solution
(2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I;
PhMe; −15 °C → 20 °C; 3 h). 9b: Rf = 0.55 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2982, 2122, 1759, 1630, 1327, 1275,
1
1212, 1189, 1032, 765 cm−1; H NMR (500 MHz, CDCl3) δ = 8.68
(d, J = 8.9 Hz, 1H), 8.37 (dd, J = 8.1, 1.7 Hz, 1H), 8.19 (s, 1H), 7.68
(ddd, J = 8.9, 7.1, 1.8 Hz, 1H), 7.45 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H),
4.52 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ = 175.0, 151.2, 137.8, 133.3, 127.2, 126.6, 125.8,
125.2, 123.6, 120.1, 65.7, 14.4; HRMS (ESI-TOF) calcd for
C12H10N4O3 [M + H+] 259.0831, found 259.0822; [M + Na+]
281.0650, found 281.0642.
Dimethyl 1-(1-(ethoxycarbonyl)-4-oxo-1,4-dihydroquinolin-3-yl)-
1H-1,2,3-triazole-4,5-dicarboxylate (9b′). Compound 9b′ was
isolated in 39% yield (14 mg) after FCC (silica gel, hexanes/EtOAc
= 5:1 → 2:1) from 23 mg of 9b (0.089 mmol) and 0.1 mL of DMAD
(0.813 mmol) (procedure II; C6H6; 65 °C; 18 h). 9b′: Rf = 0.08 (silica
gel, hexanes/EtOAc 5:1) or 0.19 (silica gel, hexanes/EtOAc 2:1); IR
(film) νmax = 1760−1728, 1656−1644, 1475−1453, 1279, 1206, 1026,
1
865, 764, 733 cm−1; H NMR (500 MHz, CDCl3) δ = 9.03 (s, 1H),
8.74 (d, J = 8.9 Hz, 1H), 8.42 (dd, J = 8.0, 1.7 Hz, 1H), 7.78 (ddd, J =
8.9, 7.1, 1.7 Hz, 1H), 7.52 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 4.59 (q, J =
7.1 Hz, 2H), 3.99 (s, 3H), 3.92 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ = 171.6, 160.3, 159.1, 150.6, 139.0, 138.1,
136.1, 134.3, 133.4, 127.4, 126.7, 126.3, 120.9, 120.4, 66.5, 53.8, 53.0,
14.4; HRMS (ESI-TOF) calcd for C18H16N4O7 [M + H+] 401.1098,
found 401.1091; [M + Na+] 423.0917, found 423.0915.
Methyl 3,3-dichloro-2-oxoindoline-6-carboxylate (10a). Com-
pound 10a was obtained in 89% yield (159 mg) after FCC (silica
gel, hexanes/EtOAc = 5:1) from 120 mg of methylindole-6-
carboxylate (10) (0.685 mmol), 150 mg of NaN3 (2.31 mmol), 4.0
mL of NaOCl solution (2.36 mmol), and 0.26 mL of AcOH (4.54
mmol) (procedure I; EtOAc; 20 °C; 1.5 h). 10a: Rf = 0.25 (silica gel,
hexanes/EtOAc 5:1); IR (film) νmax = 3214, 1747, 1715, 1450, 1278,
1221, 1090, 768, 729 cm−1; 1H NMR (500 MHz, CDCl3) δ = 9.09 (br
s, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.69−7.67 (m, 2H), 3.93 (s,
3H); 13C NMR (125 MHz, CDCl3) δ = 170.7, 165.9, 138.3, 134.0,
133.8, 126.1, 125.3, 112.4, 73.9, 52.9; HRMS (ESI-TOF) calcd for
C10H7Cl2NO3 [M + H+] 259.9881, found 259.9877.
3-Chloro-1H-pyrrolo[2,3-b]pyridine (11a). Compound 11a was
obtained in 91% yield (118 mg) after FCC (silica gel, hexanes/EtOAc
= 1:1) from 100 mg of 7-azaindole (11) (0.846 mmol), 150 mg of
NaN3 (2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26
mL of AcOH (4.54 mmol) (procedure I; PhMe; 20 °C; 0.5 h). 11a: Rf
= 0.29 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 3077−2821
1
(br), 1590, 1414, 1291, 1001, 787, 761, 662 cm−1; H NMR (500
MHz, CD3OD) δ = 8.24 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (dd, J = 7.9,
1.5 Hz, 1H), 7.39 (s, 1H), 7.15 (dd, J = 7.9, 4.8 Hz, 1H); 13C NMR
(125 MHz, CD3OD) δ = 147.6, 144.5, 127.9, 123.8, 119.7, 117.2,
104.8.
1-(3-Azido-2-chloropropyl)-4-methoxybenzene (12a). Compound
12a was obtained in 87% yield (128 mg) after PTLC (silica gel,
hexanes/EtOAc = 20:1) from 0.1 mL of 4-allylanisole (12) (0.651
mmol), 500 mg of NaN3 (7.69 mmol), 4.0 mL of NaOCl solution
Dimethyl 1-(2-chloro-3-phenylpropyl)-1H-1,2,3-triazole-4,5-di-
carboxylate (12e′). Compound 12e′ was isolated in 42% yield (29
K
DOI: 10.1021/acs.joc.5b00009
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The Journal of Organic Chemistry
Article
mg) (together with 17% of 12f′, 13 mg) after FCC (silica gel,
hexanes/EtOAc = 5:1 → 3:1) from 40 mg of 12e (0.204 mmol) and
0.1 mL of DMAD (0.813 mmol) (procedure II; C6H6; 65 °C; 16 h).
12e′: Rf = 0.15 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2955,
Dimethyl 1-((1R,2R,3S,4S)-3-chloro-1,2,3,4-tetrahydro-1,4-epoxy-
naphthalen-2-yl)-1H-1,2,3-triazole-4,5-dicarboxylate + Enantiomer
(13b′). Compound 13b′ was isolated in 65% yield (29 mg) after FCC
(silica gel, hexanes/EtOAc = 5:1 → 2:1) from 27 mg of 13b (0.122
mmol) and 0.15 mL of DMAD (1.22 mmol) (procedure II; C6H6; 65
°C; 16 h). 13b′: Rf = 0.05 (silica gel, hexanes/EtOAc 5:1); IR (film)
νmax = 1737, 1726, 1450, 1282, 1220, 1155, 1067, 912, 853, 839, 765,
1
1737, 1728, 1454, 1273, 1217, 1145, 1061, 825, 737, 700 cm−1; H
NMR (500 MHz, CDCl3) δ = 7.32 (m, 2H), 7.27 (m, 1H), 7.23 (m,
2H), 4.91−4.83 (m, 2H), 4.54 (dddd, J = 7.2, 7.2, 7.2, 5.3 Hz, 1H),
3.95 (s, 3H) overlaps with 3.95 (s, 3H), 3.15−3.08 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ = 160.5, 159.2, 140.0, 135.9, 131.2, 129.5, 129.0,
127.7, 60.2, 54.9, 53.7, 53.0, 42.2; HRMS (ESI-TOF) calcd for
C15H16ClN3O4 [M + H+] 338.0907, found 338.0945; [M + Na+]
360.0727, found 360.0725.
1
732, 630, 584 cm−1; H NMR (500 MHz, CDCl3) δ = 7.47 (m, 2H),
7.33 (m, 2H), 5.57 (d, J = 4.8 Hz, 1H), 5.52 (s, 1H), 5.38 (dd, J = 4.8,
3.1 Hz, 1H), 4.82 (d, J = 3.1 Hz, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ = 160.5, 159.3, 141.5, 141.3, 140.9, 130.7,
128.7, 128.3, 123.6, 120.5, 85.5, 82.5, 71.8, 56.3, 53.9, 53.0; HRMS
(ESI-TOF) calcd for C16H14ClN3O5 [M + H+] 364.0700, found
364.0709; [M + Na+] 386.0520, found 386.0516.
Mixture of syn- and anti-Dimethyl-1,3-dichloro-1-phenylpropan-
2-yl)-1H-1,2,3-triazole-4,5-dicarboxylate (12f′). Compound 12f′ was
isolated in 17% yield (13 mg) (together with 42% of 12e′, 29 mg)
after FCC (silica gel, hexanes/EtOAc = 5:1 → 3:1) from 40 mg of 12e
(0.204 mmol, crude mixture) and 0.1 mL of DMAD (0.813 mmol)
(procedure II; C6H6; 65 °C; 16 h). 12f′: Rf = 0.25 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2955, 1742, 1737, 1731, 1454, 1281,
Mixture of (1S,2R,3S,4R)-2-Azido-3-chlorobicyclo[2.2.1]heptane
+ Enantiomer (14a) and (1S,2R,3R,4R)-2-Azido-3-chlorobicyclo-
[2.2.1]heptane + Enantiomer (14b). Compounds 14a:14b (a mixture
of diastereomers) were obtained in 95% yield (225 mg) from 130 mg
of bicyclo[2.2.1]hept-2-ene (14) (1.38 mmol), 350 mg of NaN3 (5.38
mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (procedure I; Et2O; 20 °C; 1 h). The product was
extracted with Et2O and used without further purification. 14a:14b: IR
(film) νmax = 2967, 2877, 2098, 1335, 1311, 1252, 947, 810, 769, 644,
553 cm−1; 1H NMR (500 MHz, CDCl3) δ = 4.05 (dd, J = 6.5, 1.9 Hz,
1H), 3.89 (m, 1H), 3.58 (dd, J = 6.5, 1.5 Hz, 1H), 3.38 (t, J = 2.7 Hz,
1H), 2.48−2.38 (m, 2H), 2.33 (m, 1H), 2.29 (d, J = 4.9 Hz, 1H), 1.90
(m, 1H), 1.69−1.54 (m, 4H), 1.46−1.39 (m, 2H), 1.35−1.17 (m, 5H).
Dimethyl 1-((1S,2R,3S,4R)-3-chlorobicyclo[2.2.1]heptan-2-yl)-1H-
1,2,3-triazole-4,5-dicarboxylate + Enantiomer (14a′). Compound
14a′ was isolated in 45% yield (165 mg) (together with 19% of 14b′,
70 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1) from 200
mg of 14a:14b (1.17 mmol) and 0.15 mL of DMAD (1.22 mmol)
(procedure II; C6H6; 65 °C; 16 h). 14a′: Rf = 0.18 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2955, 1737−1726, 1450, 1286, 1216,
1066, 947−764, 730, 684 cm−1; 1H NMR (500 MHz, CDCl3) δ = 4.89
(dd, J = 6.8, 1.1 Hz, 1H), 4.27 (dd, J = 6.8, 1.7 Hz, 1H), 3.91 (s, 3H)
overlaps with 3.91 (s, 3H), 3.21 (m, 1H), 2.52 (m, 1H), 2.43 (m, J1 =
10.8 Hz, 1H), 1.80−1.67 (m, 2H), 1.48 (m, J1 = 10.8 Hz, 1H), 1.37−
1.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 160.9, 159.3, 140.0,
130.1, 67.5, 65.2, 53.4, 52.8, 46.4, 41.6, 35.6, 27.7, 26.4; HRMS (ESI-
TOF) calcd for C13H16ClN3O4 [M + H+] 314.0907, found 314.0944;
[M + Na+] 336.0728, found 336.0726.
1
1228, 1076, 701 cm−1; H NMR (500 MHz, CDCl3) δ = 7.47 (m,
4H), 7.27−7.21 (m, 6H), 5.89 (ddd, J = 9.9, 9.9, 3.7 Hz, 1H), 5.80
(ddd, J = 10.2, 10.2, 3.3 Hz, 1H), 5.50 (d, J = 9.8 Hz, 1H), 5.43 (d, J =
10.0 Hz, 1H), 4.57 (dd, J = 11.8, 3.3 Hz, 1H), 4.39 (d, J = 11.7, 10.3
Hz, 1H), 4.03 (m, 1H) overlaps with 4.03 (s, 3H) overlaps with 4.03
(s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.61 (d, J = 11.8, 3.7 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ = 160.7, 160.2, 159.2, 158.6, 140.1, 139.6,
136.4, 135.9, 131.9, 131.4, 130.3, 129.8, 129.7, 129.0, 127.7, 127.6,
67.3, 67.1, 62.6, 61.5, 53.7, 53.6, 53.1, 52.9, 44.5, 43.7; HRMS (ESI-
TOF) calcd for C15H15Cl2N3O4 [M + H+] 372.0517, found 372.0525;
[M + Na+] 394.0338, found 394.0334.
(1R,2R,3R,4S)-2-Azido-3-chloro-1,2,3,4-tetrahydro-1,4-epoxy-
naphthalene + Enantiomer (13a). Compound 13a was obtained in
64% yield (86 mg) (together with 27% of 13b, 36 mg) after PTLC
(silica gel, hexanes/EtOAc = 10:1) from 88 mg of 1,4-epoxy-1,4-
dihydronaphthalene (13) (0.610 mmol), 350 mg of NaN3 (5.38
mmol), 2.5 mL of NaOCl solution (1.47 mmol), and 0.85 mL of
AcOH (14.8 mmol) (with or without 1.0 mL of brine) (procedure I;
PhMe; −15 °C → 20 °C; 3 h). Alternatively, 13a can be obtained in
56% yield (75 mg) (together with 24% of 13b, 32 mg) after PTLC
(silica gel, hexanes/EtOAc = 10:1) from 88 mg of 1,4-epoxy-1,4-
dihydronaphthalene (13) (0.610 mmol), 150 mg of NaN3 (2.31
mmol), 3.5 mL of NaOCl solution (2.06 mmol), and 0.25 mL of
AcOH (4.37 mmol) (procedure I; PhMe; −15 °C → 20 °C; 1 h). 13a:
Rf = 0.45 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 3013,
2100, 1257, 1230, 917, 847, 769, 756, 715, 646, 626, 551, 528 cm−1;
1H NMR (500 MHz, CDCl3) δ = 7.31 (m, 2H), 7.23 (m, 2H), 5.38 (s,
Dimethyl 1-((1S,2R,3R,4R)-3-chlorobicyclo[2.2.1]heptan-2-yl)-1H-
1,2,3-triazole-4,5-dicarboxylate + Enantiomer (14b′). Compound
14b′ was isolated in 19% yield (70 mg) (together with 45% of 14a′,
165 mg) after FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1) from 200
mg of 14a:14b (1.17 mmol) and 0.15 mL of DMAD (1.22 mmol)
(procedure II; C6H6; 65 °C; 16 h). 14b′: Rf = 0.29 (silica gel, hexanes/
EtOAc 5:1); IR (film) νmax = 2956, 1737, 1728, 1450, 1285, 1213,
2H), 4.26 (d, J = 6.2 Hz, 1H), 3.62 (d, J = 6.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ = 142.8, 142.2, 128.6, 128.5, 120.73, 120.65,
86.7, 84.2, 63.3, 62.8; HRMS (ESI-TOF) calcd for C10H8ClN3O [M +
Na+] 244.0253, found 244.0246.
1
1069, 948, 825−732 cm−1; H NMR (500 MHz, CDCl3) δ = 4.89
(ddd, J = 4.2, 4.2, 1.5 Hz, 1H), 4.58 (dd, J = 4.2, 2.1 Hz, 1H), 3.96 (s,
3H), 3.92 (s, 3H), 2.62 (m, 1H), 2.50 (d, J = 4.5 Hz, 1H), 2.19 (m, J1
= 10.9 Hz, 1H), 2.00 (m, 1H), 1.75 (dddd, J = 12.3, 12.3, 4.7, 4.7 Hz,
1H), 1.57 (dddd, J = 12.8, 4.3, 4.3, 1.8 Hz, 1H), 1.54−1.47 (m, 2H);
13C NMR (125 MHz, CDCl3) δ = 160.6, 159.2, 140.1, 130.7, 72.6,
(1R,2R,3S,4S)-2-Azido-3-chloro-1,2,3,4-tetrahydro-1,4-epoxy-
naphthalene + Enantiomer (13b). Compound 13b was obtained in
27% yield (36 mg) (together with 64% of 13a, 86 mg) after PTLC
(silica gel, hexanes/EtOAc = 10:1) from 88 mg of 1,4-epoxy-1,4-
dihydronaphthalene (13) (0.610 mmol), 350 mg of NaN3 (5.38
mmol), 2.5 mL of NaOCl solution (1.47 mmol), and 0.85 mL of
AcOH (14.8 mmol) (with or without 1.0 mL of brine) (procedure I;
PhMe; −15 °C → 20 °C; 3 h). Alternatively, 13b can be obtained in
24% yield (32 mg) (together with 56% of 13a, 75 mg) after PTLC
(silica gel, hexanes/EtOAc = 10:1) from 88 mg of 1,4-epoxy-1,4-
dihydronaphthalene (13) (0.610 mmol), 150 mg of NaN3 (2.31
mmol), 3.5 mL of NaOCl solution (2.06 mmol), and 0.25 mL of
AcOH (4.37 mmol) (procedure I; PhMe; −15 °C → 20 °C; 1 h). 13b:
Rf = 0.60 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax = 2916,
2093, 1240, 952, 937, 859, 849, 835, 785, 754, 637, 585, 543 cm−1; 1H
NMR (500 MHz, CDCl3) δ = 7.40 (m, 1H), 7.34 (m, 1H), 7.28 (m,
2H), 5.41 (d, J = 4.7 Hz, 1H), 5.33 (s, 1H), 4.29 (ddd, J = 4.7, 2.3, 0.5
Hz, 1H), 3.42 (d, J = 2.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ =
141.7, 141.5, 128.4, 127.9, 123.4, 120.2, 84.9, 82.2, 70.7, 58.5.
64.8, 53.7, 52.9, 45.3, 43.8, 35.8, 27.9, 21.4; HRMS (ESI-TOF) calcd
for C13H16ClN3O4 [M + H+] 314.0907, found 314.0958; [M + Na+]
336.0728, found 336.0724.
anti-1-Azido-2-chlorocycloheptane (15a) with Trace Amount of
syn-1-Azido-2-chlorocycloheptane (15b). Compound 15a (with
trace amount of 15b) was obtained in 98% yield (219 mg) from
0.15 mL of cycloheptene (15) (1.285 mmol), 350 mg of NaN3 (5.38
mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (procedure I; neat; 20 °C; 1 h). The product was
used without further purification. 15a: IR (film) νmax = 2933, 2862,
1
2093, 1461−1445, 1258, 954, 876, 724 cm−1; H NMR (500 MHz,
CDCl3) δ = 3.93 (ddd, J = 8.1, 8.1, 3.5 Hz, 1H), 3.64 (ddd, J = 8.6, 8.1,
3.2 Hz, 1H), 2.09 (m, 1H), 1.99−1.91 (m, 2H), 1.79−1.65 (m, 3H),
1.59−1.48 (m, 4H); 13C NMR (125 MHz, CDCl3) δ = 70.6, 66.4,
35.0, 30.9, 27.6, 23.6, 23.4.
L
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
anti-Dimethyl-2-chlorocycloheptyl)-1H-1,2,3-triazole-4,5-dicar-
boxylate (15a′). Compound 15a′ was isolated in 55% yield (149 mg)
(together with 13% of 15b′, 36 mg) after FCC (silica gel, hexanes/
EtOAc = 5:1 → 2:1) from 150 mg of 15a (0.864 mmol) and 0.15 mL
of DMAD (1.22 mmol) (procedure II; C6H6; 65 °C; 16 h). 15a′: Rf =
0.30 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2939, 1737,
3H), 0.85 (d, J = 2.1 Hz, 3H), 0.83 (d, J = 2.1 Hz, 3H), 0.72 (s, 3H);
13C NMR (125 MHz, CDCl3) δ = 160.6, 160.4, 139.1, 132.7, 83.5,
67.6, 64.0, 56.4, 56.3, 53.9, 52.9, 46.1, 43.1, 41.3, 40.6, 40.0, 39.7, 36.4,
36.0, 34.6, 32.5, 31.5, 30.4, 28.5, 28.2, 24.1, 24.0, 23.0, 22.8, 21.6, 18.9,
17.7, 12.6; HRMS (ESI-TOF) calcd for C33H52ClN3O5 [M + H+]
606.3674, found 606.3666; [M + Na+] 628.3494, found 628.3485.
(3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-Azido-5-chloro-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-
cyclopenta[a]phenanthren-3-ol (17b). Compound 17b was obtained
in 8% yield (26 mg) (together with 47% of 17a, 148 mg) after PTLC
(silica gel, hexanes/EtOAc = 5:1 → 3:1) from 261 mg of cholesterol
(17) (0.675 mmol), 400 mg of NaN3 (6.15 mmol), 2.5 mL of NaOCl
solution (1.47 mmol), 0.85 mL of AcOH (14.8 mmol), and 1.0 mL of
brine (procedure I; PhMe; 20 °C; 2.5 h). 17b: Rf = 0.43 (silica gel,
hexanes/EtOAc 3:1) or 0.06 (silica gel, hexanes/EtOAc 5:1); IR (film)
νmax = 3348 (broad), 2936, 2867, 2097, 1467−1445, 1382−1366,
1
1728, 1461, 1453, 1278, 1211, 1179, 1151, 1062, 825, 731 cm−1; H
NMR (500 MHz, CDCl3) δ = 4.98 (ddd, J = 9.7, 9.7, 3.2 Hz, 1H),
4.60 (ddd, J = 9.7, 8.4, 3.8 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 2.29−
2.18 (m, 2H), 2.08−2.00 (m, 2H), 1.94 (m, 1H), 1.81 (m, 1H), 1.71−
1.55 (m, 4H); 13C NMR (125 MHz, CDCl3) δ = 160.7, 159.6, 139.1,
130.8, 69.5, 65.1, 53.6, 52.8, 35.6, 32.9, 27.3, 24.6, 23.3; HRMS (ESI-
TOF) calcd for C13H18ClN3O4 [M + H+] 316.1064, found 316.1092;
[M + Na+] 338.0883, found 338.0881.
syn-Dimethyl-2-chlorocycloheptyl)-1H-1,2,3-triazole-4,5-dicar-
boxylate (15b′). Compound 15b′ was isolated in 13% yield (36 mg)
(together with 55% of 15a′, 149 mg) after FCC (silica gel, hexanes/
EtOAc = 5:1 → 2:1) from 150 mg of 15a (0.864 mmol) and 0.15 mL
of DMAD (1.22 mmol) (procedure II; C6H6; 65 °C; 16 h). 15b′: Rf =
0.18 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2937, 1742,
1
1240, 1059−1028, 907, 734 cm−1; H NMR (500 MHz, CDCl3) δ =
4.22 (dddd, J = 10.8, 10.8, 5.3, 5.3 Hz, 1H), 3.43 (dd, J = 11.4, 5.0 Hz,
1H), 2.53 (ddd, J = 13.7, 5.1, 1.8 Hz, 1H), 1.97 (m, 1H), 1.89−1.65
(m, 7H), 1.63−1.45 (m, 6H), 1.41 (m, 1H), 1.37−1.27 (m, 3H),
1.26−1.08 (m, 9H), 1.07 (s, 3H), 0.97 (m, 1H), 0.88 (d, J = 6.5 Hz,
3H), 0.85 (d, J = 2.4 Hz, 3H), 0.83 (d, J = 2.4 Hz, 3H), 0.63 (s, 3H).
Dimethyl 1-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-5-chloro-3-hy-
droxy-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-
1H-cyclopenta[a]phenanthren-6-yl)-1H-1,2,3-triazole-4,5-dicarbox-
ylate (17b′). Compound 17b′ was isolated in 68% yield (23 mg) after
FCC (silica gel, hexanes/EtOAc = 5:1 → 1:1) from 26 mg of 17b
(0.056 mmol) and 0.1 mL of DMAD (0.813 mmol) (procedure II;
C6H6; 65 °C; 15 h). 17b′: Rf = 0.04 (silica gel, hexanes/EtOAc 5:1) or
0.25 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 3340 (broad),
2950, 2868, 1742−1728, 1450, 1279, 1223, 1066, 735 cm−1; 1H NMR
(500 MHz, CDCl3) δ = 5.48 (dd, J = 12.5, 3.7 Hz, 1H), 4.08 (dddd, J
= 10.8, 10.8, 5.2, 5.2 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.70 (q, J =
12.5 Hz, 1H), 2.00 (m, 1H), 1.87−1.79 (m, 4H), 1.77−1.64 (m, 3H),
1.60−1.45 (m, 6H), 1.39−1.19 (m, 8H) overlaps with 1.24 (s, 3H),
1.15−0.95 (m, 6H), 0.88 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 2.5 Hz, 3H),
0.83 (d, J = 2.5 Hz, 3H), 0.66 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
= 161.1, 160.0, 140.0, 130.6, 82.6, 67.0, 62.7, 56.2, 55.4, 53.7, 53.0,
46.0, 43.0, 42.5, 40.4, 39.8, 39.7, 36.3, 36.0, 35.1, 32.8, 32.2, 29.9, 28.3,
28.2, 24.1, 24.0, 23.0, 22.8, 21.7, 18.8, 16.9, 12.4; HRMS (ESI-TOF)
calcd for C33H52ClN3O5 [M + H+] 606.3674, found 606.3664; [M +
Na+] 628.3494, found 628.3482.
1
1737, 1726, 1450, 1346, 1279, 1214, 1179, 1063, 825 cm−1; H NMR
(500 MHz, CDCl3) δ = 5.23 (ddd, J = 10.4, 4.9, 2.9 Hz, 1H), 4.48
(ddd, J = 7.5, 2.9, 2.9 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.68 (dddd,
J = 14.3, 10.2, 10.2, 4.0 Hz, 1H), 2.33−2.23 (m, 2H), 2.03 (dddd, J =
15.1, 9.3, 3.1, 3.1 Hz, 1H), 1.95−1.87 (m, 2H), 1.77−1.53 (m, 4H);
13C NMR (125 MHz, CDCl3) δ = 161.0, 159.8, 140.0, 130.1, 65.1,
64.1, 53.7, 52.9, 34.5, 29.6, 27.1, 24.17, 24.16; HRMS (ESI-TOF) calcd
for C13H18ClN3O4 [M + H+] 316.1064, found 316.1095; [M + Na+]
338.0883, found 338.0886.
syn- and anti-2-Azido-3-chlorobutane-1,4-diol (16a). Com-
pounds 16a:16b were obtained as a mixture of diastereomers in
94% yield (189 mg) from 0.1 mL of cis-2-butene-1,4-diol (16) (1.22
mmol), 150 mg of NaN3 (2.31 mmol), 4.0 mL of NaOCl solution
(2.36 mmol), and 0.26 mL of AcOH (4.54 mmol) (procedure I;
PhMe; 20 °C; 1.5 h). The product was used without further
purification. 16a:16b: Rf = 0.19 (silica gel, hexanes/EtOAc 2:1); IR
(film) νmax = 3338 (broad), 2942, 2104, 1259, 1034, 550 cm−1.
(3S,5R,6R,8S,9S,10R,13R,14S,17R)-6-Azido-5-chloro-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-
cyclopenta[a]phenanthren-3-ol (17a). Compound 17a was obtained
in 47% yield (148 mg) (together with 8% of 17b, 26 mg) after PTLC
(silica gel, hexanes/EtOAc = 5:1 → 3:1) from 261 mg of cholesterol
(17) (0.675 mmol), 400 mg of NaN3 (6.15 mmol), 2.5 mL of NaOCl
solution (1.47 mmol), 0.85 mL of AcOH (14.8 mmol), and 1.0 mL of
brine (procedure I; PhMe; 20 °C; 2.5 h). 17a: Rf = 0.51 (silica gel,
hexanes/EtOAc 3:1) or 0.15 (silica gel, hexanes/EtOAc 5:1); IR (film)
νmax = 3331 (broad), 2943, 2868, 2100, 1467, 1381, 1267, 1038, 905,
735 cm−1; 1H NMR (500 MHz, CDCl3) δ = 4.28 (dddd, J = 10.8, 10.8,
5.4, 5.4 Hz, 1H), 3.80 (dd, J = 3.8, 2.3 Hz, 1H), 2.29 (dd, J = 13.4, 10.4
Hz, 1H), 2.07−1.95 (m, 3H), 1.88 (m, 1H), 1.82 (m, 1H), 1.71 (ddd, J
= 14.5, 4.2, 2.3 Hz, 1H), 1.66−1.44 (m, 8H), 1.40−1.23 (m, 6H), 1.21
(s, 3H), 1.18−1.04 (m, 7H), 0.97 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H),
0.85 (d, J = 2.3 Hz, 3H), 0.83 (d, J = 2.3 Hz, 3H), 0.65 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ = 83.9, 67.8, 67.1, 56.3, 55.7, 46.1, 42.9,
42.3, 40.4, 39.9, 39.7, 36.4, 36.0, 33.8, 31.2, 31.1, 30.6, 28.4, 28.2, 24.2,
24.0, 23.0, 22.8, 21.4, 18.9, 18.1, 12.4.
((S)-5-(3-Chloroprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one
(18a). Compound 18a was obtained in 65% yield (77 mg) (together
with trace amount of 18b and 18) after PTLC (silica gel, hexanes/
EtOAc = 10:1) from 0.1 mL of (S)-(+)-carvone (18) (0.639 mmol),
350 mg of NaN3 (5.38 mmol), 2.5 mL of NaOCl solution (1.47
mmol), and 0.85 mL of AcOH (14.8 mmol), and 1.0 mL of brine
(procedure I; EtOAc; −15 °C → 20 °C; 0.5 h). 18a: Rf = 0.37 (silica
gel, hexanes/EtOAc 10:1); IR (film) νmax = 2923, 1677−1667, 1366,
1253, 1108, 902, 750 cm−1; 1H NMR (500 MHz, CDCl3) δ = 6.73 (m,
1H), 5.24 (s, 1H), 5.04 (s, 1H), 4.07 (m, 2H), 2.96 (m, 1H), 2.64
(ddd, J = 16.1, 3.7, 1.3 Hz, 1H), 2.54 (m, 1H), 2.37 (dd, J = 16.1, 13.1
Hz, 1H) overlaps with 2.30 (m, 1H), 1.77 (s, 3H); 13C NMR (125
MHz, CDCl3) δ = 199.1, 146.8, 144.2, 135.9, 115.4, 47.2, 43.3, 38.1,
31.6, 15.9; HRMS (ESI-TOF) calcd for C10H13ClO [M + H+]
185.0733, found 185.0732; [M + Na+] 207.0552, found 207.0551.
(S)-5-((R)-1-Azido-2-chloropropan-2-yl)-2-methylcyclohex-2-en-
1-one + (S)-5-((S)-1-Azido-2-chloropropan-2-yl)-2-methylcyclohex-
2-en-1-one (18b). Compound 18b was obtained as a diastereomeric
mixture in 42% yield (60 mg) (together with 16% of 18a (19 mg) and
42% of 18 (42 mg)) after FCC (silica gel, hexanes/EtOAc = 10:1)
from 0.1 mL of (S)-(+)-carvone (18) (0.639 mmol), 770 mg of NaN3
(11.8 mmol), 4.0 mL of NaOCl solution (2.36 mmol), 0.28 mL of
AcOH (4.89 mmol), and 1.0 mL of brine (procedure I; PhMe; 20 °C;
1.5 h). 18b: Rf = 0.25 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax
= 2924, 2100, 1677−1666, 1450, 1383, 1367, 1294, 1256, 1108, 905
Dimethyl 1-((3S,5R,6R,8S,9S,10R,13R,14S,17R)-5-chloro-3-hy-
droxy-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-
1H-cyclopenta[a]phenanthren-6-yl)-1H-1,2,3-triazole-4,5-dicarbox-
ylate (17a′). Compound 17a′ was isolated in 47% yield (30 mg) after
FCC (silica gel, hexanes/EtOAc = 5:1 → 2:1 → 1:1) from 49 mg of
17a (0.106 mmol) and 0.2 mL of DMAD (1.63 mmol) (procedure II;
C6H6; 65 °C; 16 h). 17a′: Rf = 0.10 (silica gel, hexanes/EtOAc 5:1) or
0.50 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 3424 (broad),
1
1737−1731, 1450, 1267, 1228, 1063, 734 cm−1; H NMR (500 MHz,
CDCl3) δ = 5.31 (dd, J = 5.6, 0.9 Hz, 1H), 4.25 (dddd, J = 10.8, 10.8,
5.3, 5.3 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 2.48 (m, 1H), 2.38 (ddd, J
= 14.6, 12.7, 6.4 Hz, 1H), 2.10−1.99 (m, 3H), 1.82 (m, 2H), 1.67 (m,
2H), 1.55−1.43 (m, 5H), 1.40−1.05 (m, 11H) overlaps with 1.23 (s,
3H), 0.98 (s, 3H) overlaps with 0.97 (m, 1H), 0.89 (d, J = 6.5 Hz,
1
cm−1; H NMR (500 MHz, CDCl3) δ = 6.71 (m, 1H), 3.55 (dd, J =
18.1, 12.8 Hz, 1H − one diastereomer) overlaps with 3.53 (dd, J = 16.6,
12.8 Hz, 1H − another diastereomer), 2.59 (m, 1H), 2.50−2.31 (m,
4H), 1.75 (m, 3H), 1.56 (s, 1.5H − one diastereomer) overlaps with
M
DOI: 10.1021/acs.joc.5b00009
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 4. FTIR Spectra of Azidochloro-Fullerene (22a) and Aminochloro-Fullerene (22a′)
a
The number of azide and chloride groups introduced to the fullerene structure was not established.
1.55 (s, 1.5H − another diastereomer); 13C NMR (125 MHz, CDCl3) δ
= 198.59, 198.57, 144.0, 143.8, 135.7, 135.6, 73.46, 73.45, 60.1, 60.0,
42.83, 42.79, 39.5, 39.4, 27.42, 27.35, 25.93, 25.90, 15.72, 15.71;
HRMS (ESI-TOF) calcd for C10H14ClN3O [M + Na+] 250.0723,
found 250.0713.
Dimethyl 1-(anthracen-9-yl)-1H-1,2,3-triazole-4,5-dicarboxylate
(19a′). Compound 19a′ was isolated in 82% yield (149 mg) (together
with trace amount of 19b′, ∼ 18%) after FCC (silica gel, hexanes/
EtOAc = 20:1 → 5:1 → 2:1) from 110 mg of 19a (0.502 mmol) and
0.2 mL of DMAD (1.63 mmol) (procedure II; C6H6; 65 °C; 17 h).
19a′: Rf = 0.41 (silica gel, hexanes/EtOAc 5:1); IR (film) νmax = 2953,
Dimethyl 1-((R*)-2-chloro-2-((S)-4-methyl-5-oxocyclohex-3-en-1-
yl)propyl)-1H-1,2,3-triazole-4,5-dicarboxylate + Diastereomer
(18b′). Compound 18b′ was isolated in 78% yield (42 mg) after
FCC (silica gel, hexanes/EtOAc = 5:1 → 1:1) from 33 mg of 18b
(0.145 mmol) and 0.15 mL of DMAD (1.22 mmol) (procedure II;
C6H6; 65 °C; 17 h). 18b′: Rf = 0.07 (silica gel, hexanes/EtOAc 5:1) or
0.45 (silica gel, hexanes/EtOAc 1:1); IR (film) νmax = 2955, 1737−
1
1737−1731, 1445, 1315, 1289, 1224, 1136, 1064, 908, 733 cm−1; H
NMR (500 MHz, CDCl3) δ = 8.65 (s, 1H), 8.05 (m, 2H), 7.52−7.47
(m, 4H), 7.17 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 160.5,
158.4, 139.1, 135.3, 131.1, 131.0, 128.9, 128.7, 128.59, 128.57, 126.2,
121.6, 53.5, 53.1; HRMS (ESI-TOF) calcd for C20H15N3O4 [M + H+]
362.1140, found 362.1142; [M + Na+] 384.0960, found 384.0955.
Dimethyl 1-(10-chloroanthracen-9-yl)-1H-1,2,3-triazole-4,5-dicarboxy-
late (19b′): 1H NMR (500 MHz, CDCl3) δ = 8.58 (ddd, J = 8.9, 0.9,
0.9 Hz, 2H), 7.63 (ddd, J = 8.9, 6.6, 1.1 Hz, 2H), 7.53 (ddd, J = 8.8,
6.6, 1.1 Hz, 2H), 7.15 (ddd, J = 8.8, 0.9, 0.9 Hz, 2H), 4.07 (s, 3H),
3.52 (s, 3H); HRMS (ESI-TOF) calcd for C20H14ClN3O4 [M + H+]
396.0751, found 396.0747; [M + Na+] 418.0570, found 418.0565.
N-Allyl-2,4-dichloroaniline (20a). Compound 20a was obtained in
67% yield (100 mg) after PTLC (silica gel, hexanes/EtOAc = 20:1)
from 0.1 mL of N-allylaniline (20) (0.737 mmol), 150 mg of NaN3
(2.31 mmol), 4.0 mL of NaOCl solution (2.36 mmol), and 0.26 mL of
AcOH (4.54 mmol) (with or without 1.0 mL of brine) (procedure I;
PhMe; −15 °C → 20 °C; 1 h). 20a: Rf = 0.75 (silica gel, hexanes/
EtOAc 10:1); IR (film) νmax = 3424, 3100−2800 (weak), 1598, 1510,
1503, 1321, 923, 800 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.24 (d,
J = 2.5 Hz, 1H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (d, J = 8.8 Hz,
1H), 5.91 (dddd, J = 17.1, 10.3, 5.2, 5.2 Hz, 1H), 5.26 (dddd, J = 17.1,
1.6, 1.6, 1.6 Hz, 1H), 5.18 (dddd, J = 10.3, 1.5, 1.5, 1.5 Hz, 1H), 4.45
(br s, NH), 3.80 (ddd, J = 5.2, 1.6, 1.6 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ = 142.7, 134.5, 128.9, 127.9, 121.5, 119.6, 116.9, 112.3, 46.3;
HRMS (ESI-TOF) calcd for C9H9Cl2N [M + H+] 202.0190, found
202.0174; [M + Na+] 224.0009, found 224.0005.
1
1728, 1673, 1434, 1352, 1279, 1226, 1112, 1062, 825, 731 cm−1; H
NMR (500 MHz, CDCl3) δ = 6.73 (m, 1H), 5.08 (d, J = 14.4 Hz,
0.5H − one diastereomer) overlaps with 5.07 (d, J = 14.4 Hz, 0.5H −
another diastereomer), 4.81 (d, J = 14.4 Hz, 0.5H − one diastereomer)
overlaps with 4.80 (d, J = 14.4 Hz, 0.5H − another diastereomer), 3.96
(s, 1.5H − one diastereomer) overlaps with 3.96 (s, 1.5H − another
diastereomer), 3.94 (s, 1.5H − one diastereomer) overlaps with 3.94 (s,
1.5H − another diastereomer), 2.75 (m, 1H), 2.66 (m, 1H), 2.49−2.33
(m, 3H), 1.76 (m, 3H), 1.50 (s, 1.5H − one diastereomer), 1.47 (s,
1.5H − another diastereomer); 13C NMR (125 MHz, CDCl3) δ =
197.9, 197.7, 160.36, 160.35, 159.7, 159.6, 143.6, 143.3, 139.52,
139.46, 136.0, 135.8, 132.3, 132.1, 72.71, 72.69, 56.88, 56.82, 53.79,
53.78, 52.95, 52.93, 44.1 (2 overlapping peaks), 39.7, 39.5, 27.61,
27.58, 25.6, 25.5, 15.68, 15.67; HRMS (ESI-TOF) calcd for
C16H20ClN3O5 [M + H+] 370.1169, found 370.1169; [M + Na+]
392.0989, found 392.0976.
9-Azidoanthracene (19a). Compound 19a was obtained in 66%
yield (81 mg) after PTLC (silica gel, hexanes/EtOAc = 20:1) from
100 mg of anthracene (19) (0.561 mmol), 350 mg of NaN3 (5.38
mmol), 2.5 mL of NaOCl solution (1.47 mmol), and 0.7 mL of AcOH
(12.2 mmol) (with or without 1.0 mL of brine) (procedure I; PhMe;
20 °C; 0.5 h). 19a: Rf = 0.78 (silica gel, hexanes/EtOAc 20:1); IR
(film) νmax = 3049, 2097, 1347, 1282, 1242, 1002, 883, 837, 730, 718,
N,N-Dichloro-2-(cyclohex-1-en-1-yl)ethan-1-amine (21a). Pro-
posed compound 21a was obtained in 73% yield (102 mg) after
PTLC (silica gel, hexanes/EtOAc = 10:1 → 5:1) from 0.1 mL of 2-
(cyclohexen-1-yl)ethylamine (21) (0.717 mmol), 350 mg of NaN3
(5.38 mmol), 2.5 mL of NaOCl solution (1.47 mmol), 0.7 mL of
AcOH (12.2 mmol), and 1.0 mL of brine (procedure I; PhMe; 20 °C;
0.5 h). 21a: Rf = 0.79 (silica gel, hexanes/EtOAc 10:1); IR (film) νmax
= 2924, 2857, 2834, 1446, 1439, 1435, 1136, 919, 910, 802, 694, 641,
1
541 cm−1; H NMR (500 MHz, CDCl3) δ = 8.35 (dddd, J = 8.8, 0.9,
0.9, 0.9 Hz, 2H), 8.28 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.55 (ddd, J =
8.7, 6.6, 1.2 Hz, 2H), 7.49 (ddd, J = 8.3, 6.6, 1.2 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ = 132.0, 130.9, 128.9, 126.5, 125.8, 125.7, 125.4,
122.7.
N
DOI: 10.1021/acs.joc.5b00009
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The Journal of Organic Chemistry
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1
576 cm−1; H NMR (500 MHz, CDCl3) δ = 5.47 (m, 1H), 3.67 (m,
(13) Hassner, A.; Boerwinkle, F.; Lavy, A. B. J. Am. Chem. Soc. 1970,
92, 4879−4883.
2H), 2.35 (t, J = 7.5 Hz, 2H), 1.97 (m, 2H), 1.91 (m, 2H), 1.63−1.58
(m, 2H), 1.56−1.50 (m, 2H); 13C NMR (125 MHz, CDCl3) δ =
133.3, 124.1, 74.9, 37.0, 28.8, 25.5, 23.0, 22.4.
(14) Hassner, A.; Teeter, J. S. J. Org. Chem. 1970, 35, 3397−3401.
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C60 Derivatives. The fullerene C60 was subjected to general
procedure I in either chlorobenzene or toluene solvent, resulting in
the complete consumption of starting material and the isolation of a
product (or mixture of products) with good mass recovery (Scheme
4). The presence of the azide group in the product was confirmed by
IR spectroscopy (strong asymmetric stretch at 2094 cm−1, weaker
symmetric stretching band at 1217 cm−1),98 and by reduction with
polymer-bound triphenylphosphine to give the amine derivative 22a′.
The presence of chloride has not been verified, so structures 22a and
22a′ are speculative at present.
(17) L’Abbe,
98−104.
́
G.; Hassner, A. Angew. Chem., Int. Ed. Engl. 1971, 10,
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Azido-chloro-fullerene (22a). Product 22a was obtained in 22 mg
yield as a crude mixture from 20 mg of fullerene (22) (0.028 mmol),
500 mg of NaN3 (7.69 mmol), 8.0 mL of NaOCl solution (4.72
mmol), and 0.52 mL of AcOH (9.08 mmol) (procedure I; PhMe or
PhCl; 20 °C; 1 h). 22a: IR (film) νmax = 2094, 1217 cm−1.
Amino-chloro-fullerene (22a′). Product 22a′ was isolated from 20
mg of 22a and 100 mg of polymer-bound triphenylphosphine (3
mmol/g, 200−400 mesh) (procedure II; C6H6/THF/H2O; 65 °C; 16
h). 22a′: IR (film) νmax = 3362 (broad), 1673−1614, 1119, 722−693
cm−1.
(27) Carmen Cano, M.; Gom
J. R. Tetrahedron 1993, 49, 243−254.
(28) Cano, M. D. C.; Gomez-Contreras, F.; Sanz, A. M.; Yunta, M. J.
R. Can. J. Chem. 1997, 75, 348−355.
́
ez-Contreras, F.; Sanz, A. M.; Yunta, M.
́
ASSOCIATED CONTENT
* Supporting Information
Tables summarizing optimization experiments, details of X-ray
crystallographic analyses (including CIF files), NMR and IR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
■
́
́
(29) Alajarín, M.; Orenes, R.-A.; Vidal, A.; Pastor, A. Synthesis 2003,
1, 49−52.
S
(30) Banert, K.; Ihle, A.; Kuhtz, A.; Penk, E.; Saha, B.; Wurthwein, E.-
U. Tetrahedron 2013, 69, 2501−2508.
̈
(31) Cambie, R. C.; Noall, W. I.; Potter, G. J.; Rutledge, P. S.;
Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1977, 226−230.
(32) Woodgate, P. D.; Lee, H. O. H.; Rutledge, P. S.; Cambie, R. C.
Synthesis 1977, 1977, 462−464.
(33) Ando, T.; Clark, J. H.; Cork, D. G.; Fujita, M.; Kimura, T. J.
Chem. Soc., Chem. Commun. 1987, 1301−1302.
(34) Terent’ev, A. O.; Krylov, I. B.; Kokorekin, V. A.; Nikishin, G. I.
Synth. Commun. 2008, 38, 3797−3809.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mgfinn@gatech.edu.
■
Present Address
§Institute for Molecular Biosciences, The University of
Queensland, St. Lucia QLD 4072, Australia.
(35) Cambie, R. C.; Hayward, R. C.; Rutledge, P. S.; Smith-Palmer,
T.; Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 840−845.
(36) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P.
D. J. Chem. Soc., Perkin Trans. 1 1978, 997−1001.
Notes
The authors declare no competing financial interest.
(37) Woodgate, P. D.; Janssen, S. J.; Rutledge, P. S.; Woodgate, S. D.;
Cambie, R. C. Synthesis 1984, 1984, 1017−1020.
ACKNOWLEDGMENTS
(38) Zefirov, N. S.; Kasumov, T. M.; Koz’min, A. S.; Sorokin, V. D.;
Polishchuk, V. R. Russ. J. Org. Chem. 1994, 30, 341−352.
■
This work was supported by the Skaggs Institute for Chemical
Biology at The Scripps Research Institute, the Georgia Institute
of Technology, and the National Science Foundation (CHE-
1011796). We thank Dr. J. Bacsa and Ms. M. Wieliczko for X-
ray crystallographic assistance.
́
(39) Barluenga, J.; Alvarez-Per
́
ez, M.; Fananas
́
, F. J.; Gonzal
́
ez, J. M.
̃
Adv. Synth. Catal. 2001, 343, 335−337.
(40) Barluenga, J.; Alvarez-Per
́
ez, M.; Rodríguez, F.; Fananas
́
, F. J.;
̃
Cuesta, J. A.; García-Granda, S. J. Org. Chem. 2003, 68, 6583−6586.
(41) Gottam, H.; Vinod, T. K. J. Org. Chem. 2010, 76, 974−977.
(42) Chouthaiwale, P. V.; Karabal, P. U.; Suryavanshi, G.; Sudalai, A.
Synthesis 2010, 2010, 3879−3882.
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