Catalytic phosphorus(V)-mediated nucleophilic substitution reactions: Development of a catalytic appel reaction

Article abstract of DOI:10.1021/jo201085r

Catalytic phosphorus(V)-mediated chlorination and bromination reactions of alcohols have been developed. The new reactions constitute a catalytic version of the classical Appel halogenation reaction. In these new reactions oxalyl chloride is used as a consumable stoichiometric reagent to generate the halophosphonium salts responsible for halogenation from catalytic phosphine oxides. Thus, phosphine oxides have been transformed from stoichiometric waste products into catalysts and a new concept for catalytic phosphorus-based activation and nucleophilic substitution of alcohols has been validated. The present study has focused on a full exploration of the scope and limitations of phosphine oxide catalyzed chlorination reactions as well as the development of the analogous bromination reactions. Further mechanistic studies, including density functional theory calculations on proposed intermediates of the catalytic cycle, are consistent with a catalytic cycle involving halo- and alkoxyphosphonium salts as intermediates.

Full text of DOI:10.1021/jo201085r

ARTICLE
pubs.acs.org/joc
Catalytic Phosphorus(V)-Mediated Nucleophilic Substitution
Reactions: Development of a Catalytic Appel Reaction
Ross M. Denton,†,* Jie An,† Beatrice Adeniran,† Alexander J. Blake,† William Lewis,† and Andrew M. Poulton‡
†School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, United Kingdom
‡AstraZeneca R&D Charnwood, Bakewell Road, Loughorough, United Kingdom
S Supporting Information
b
ABSTRACT: Catalytic phosphorus(V)-mediated chlorination
and bromination reactions of alcohols have been developed.
The new reactions constitute a catalytic version of the classical
Appel halogenation reaction. In these new reactions oxalyl
chloride is used as a consumable stoichiometric reagent to
generate the halophosphonium salts responsible for halogena-
tion from catalytic phosphine oxides. Thus, phosphine oxides
have been transformed from stoichiometric waste products into
catalysts and a new concept for catalytic phosphorus-based activation and nucleophilic substitution of alcohols has been validated.
The present study has focused on a full exploration of the scope and limitations of phosphine oxide catalyzed chlorination reactions
as well as the development of the analogous bromination reactions. Further mechanistic studies, including density functional theory
calculations on proposed intermediates of the catalytic cycle, are consistent with a catalytic cycle involving halo- and alkoxypho-
sphonium salts as intermediates.
Scheme 1. Hypothetical Catalytic Cycles for the Transfor-
mation of a Generic Starting Material (S.M.) into a Product by
a P(V) Reagenta
’ INTRODUCTION
During the past five decades phosphorus-mediated transfor-
mations such as the Wittig,1 Mitsunobu,2 and Appel3 reactions
have found widespread application in chemical synthesis. That
these fundamental reactions have been so widely utilized is a
testament to their reliability and generality as well as their
strategic importance in synthesis.4 However, despite being used
on a daily basis, there remains a major limitation with this family
of chemical reactions, namely, the generation of phosphine
oxides as stoichiometric byproduct. The generation of these
phosphine oxides and the problems inherent in their separation
from the desired products impact heavily on the atom efficiency5
and waste streams6 of phosphorus-mediated transformations.
Over the years many creative strategies have been developed to
remove phosphine oxides from reaction mixtures and thereby
eliminate purification issues.7 However, the fundamental prob-
lem of phosphine oxide generation in this family of reactions
remains. In order to tackle this problem new phosphorus-
mediated reactions that generate the minimum amount of waste
and consume the minimum amount of energy and raw materials8
are required, and therefore, catalysis must be considered.9 The
development of such reactions poses a significant challenge to
catalytic reaction design because the strong phosphorusꢀoxygen
double bond, whose formation drives many of the stoichiometric
reactions,10 must be broken in order to convert the derived
phosphine oxides into phosphorus(V) reagents and achieve turn-
over. Despite this and other difficulties, two potential catalytic
cycles for the conversion of a generic starting material (SM) into
product can be contemplated that differ with respect to how
turnover is achieved (Scheme 1). The first (redox-driven catalysis,
Scheme 1a) is predicated on the fact that most phosphorus(V)
a (a) Redox-driven cycle. (b) Redox-neutral cycle.
reagents are formed in situ from tervalent phosphorus com-
pounds, e.g., phosphines.
Therefore, closure of a catalytic cycle of this type could be
achieved by reduction of the derived phosphine oxide to the
corresponding phosphine. In the alternative strategy (redox-
neutral catalysis, Scheme 1b), turnover is achieved by direct
conversion of the phosphine oxide byproduct into the active
phosphorus(V) reagent. Such an approach depends on the
nontrivial conversion of phosphine oxides into synthetically
useful phosphorus(V) reagents in the presence of starting
materials and products. The redox-neutral strategy was pio-
neered by Marsden, who in 2008 disclosed the first examples
of phosphine oxide-catalyzed aza-Wittig reactions.11 In this work
the catalytic cycle was closed by conversion of the phosphine
oxide byproduct into the iminophosphorane required for the
Received: June 7, 2011
Published: July 12, 2011
r
2011 American Chemical Society
6749
dx.doi.org/10.1021/jo201085r J. Org. Chem. 2011, 76, 6749–6767
|

The Journal of Organic Chemistry
ARTICLE
Scheme 2. Proposed General Catalysis Strategy for P(V)-
Mediated Nucleophilic Substitution Reactions Using Con-
sumable Oxalate Reagents
and nucleophilic substitution of alcohols by varying the Nu group
of the oxalate. The transformation of the phosphine oxide
from stoichiometric waste product to organocatalyst was also
an appealing aspect of this approach. Clearly, the success-
ful implementation of this strategy depends on the conversion
of phosphine oxides into phosphonium salts (e.g., 1 f 4,
Scheme 2); however, phosphine oxides are often regarded
as unreactive due the strength of the phosphorusꢀoxygen
double bond.
Nevertheless some interesting and potentially useful trans-
formations of phosphine oxides have been documented; for
example, the conversion of triphenylphosphine oxide to chlor-
otriphenylphosphonium chloride is possible using phosgene.19
Less well-known and more useful is the analogous reaction with
oxalyl chloride that was reported in the late 1970s.20 This latter
reaction provides a clear opportunity to validate the catalysis
strategy outlined in Scheme 2 (where X = Nu = Cl) and,21
therefore, we investigated the development of catalytic Appel
chlorination reactions in which the pivotal halophosphonium
salts22 are accessed from substoichiometric amounts of phosphine
oxides and stoichiometric oxalyl chloride. We reasoned that this
would be a good starting point for our studies because the
classical Appel reaction (eq 1) is used extensively for the
conversion of alcohols into alkyl halides with inversion of
configuration. These halides are fundamental building blocks in
synthesis23 as well as being valuable end products in their own
right.24 Halogenation of alcohols is most straightforwardly
effected using haloacids; however, in general, these reactions
are limited to alcoholic substrates that afford stabilized carboca-
tions upon protonation and ionization.25 Almost all of the other
methods developed26 rely on either stoichiometric covalent
activation of the alcohol followed by nucleophilic displacement27
or in situ stoichiometric activation.28,29 For these reasons the
development of a catalytic halogenation process of the type
depicted in eq 2 and Scheme 1 was attractive.
aza-Wittig reaction by a metathesis reaction with an isocyanate,
the driving force being provided by the elimination of CO2.12 In
2009 the first example of catalysis in the redox-driven manifold
(Scheme 1a) was reported by O’Brien in the form of the first
phosphine-catalyzed Wittig reaction.13 Catalytic turnover was
achieved by reduction of the phosphine oxide byproduct fol-
lowed by reformation of the required ylide from the derived
phosphine. A further example of catalysis in this manifold
followed from Woerpel, who described phosphine-catalyzed
reductions of silyl peroxides in which turnover was again
achieved via phosphine oxide reduction.14 In this article we
provide a detailed account of our studies on the development
of catalytic phosphorus(V)-mediated nucleophilic substitution
reactions of alcohols to afford alkyl chlorides and bromides.15
Reaction Design. Nucleophilic substitution reactions are
fundamental transformations in organic chemistry and underpin
a great deal of syntheses. Phosphorus-mediated reactions of this
type, such as the Mitsunobu and related Appel halogenation
reactions, are particularly attractive owing to their broad sub-
strate scope and mild reaction conditions; however, their poor
atom efficiency undermines their applicability in certain situations
as mentioned above. The desire for catalytic activation/
nucleophilic substitution reactions of alcohols is clear and has
been well articulated.16 The recent development of new methods
for the activation of alcohols, for example, by Lambert,17 as well
as the catalytic halogenation reactions of alcohols developed
by Stephenson18a along with other catalytic processes18 exem-
plify the current drive toward the realization of efficient atom-
economical catalytic nucleophilic substitution reactions. Our
working plan for the design of catalytic transformations of this
type is depicted in Scheme 2. In contemplating new catalytic
reactions we reasoned that catalysis in a redox-neutral cycle
might be possible if alkoxyphosphonium/nucleophile ion pairs
such as 6, the key intermediates in phosphorus(V)-mediated
substitution reactions, could be accessed catalytically from
phosphine oxides at the expense of a consumable stoichiometric
reagent. The generic oxalate reagent 2 depicted in Scheme 2
contains an activating group X to facilitate the initial reaction
with the phosphine oxide, a latent nucleophile (Nu), and im-
portantly, the driving force to compensate for the cleavage of the
phosphorusꢀoxygen double bond in the form of two carbonyl
groups that will be converted into CO and CO2 upon collapse
of phosphonium salt 3. We were attracted to this strategy because, in
principle, it provides a general method for the catalytic activation
’ RESULTS AND DISCUSSION
Chlorination of Alcohols. We began our investigation by
establishing that the conversion of triphenylphosphine oxide 1 to
the desired chlorophosphonium salt 4a occurred rapidly in
CDCl3. Effervescence began almost immediately upon mixing
of the two reagents and continued for approximately 1.5 min.
Analysis of the crude reaction mixture by NMR spectroscopy
indicated complete conversion to the chlorophosphonium salt
(31P NMR δ 64.6 ppm). We next confirmed that the in situ
generated phosphonium salt was effective in chlorinating decanol
in CDCl3 (eq 4). Again, NMR analysis indicated that the desired
6750
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 1. Optimization of the Catalytic Chlorination of Decanola
entry
Ph3PO, mol %
addition protocol/addition time
5a added to (COCl)2
product (yield, %)
1
2
3
4
5
0
30
25
18
15
9a (78) + 10a (22)b
8a (46) + 9a (44) + 10a (10)b
8a (65)c
9a (41) + 10a (59)b
8a (86)b
5a added to (COCl2)2 + Ph3PO
5a added to (COCl)2 + Ph3PO over 2 h
(COCl)2 added to 5a + Ph3PO over 0.5 h
5a and (COCl)2 added to (COCl)2 + Ph3PO over 7 h
a Chloroform solutions of (COCl)2 and 5a were added simultaneously to a solution of (COCl)2 and Ph3PO in chloroform over the time indicated. The
initial amount of (COCl)2 used was equimolar with the catalyst; 1 equiv of (COCl)2 was used in total. b Yield determined by 1H NMR spectroscopy
using Cl2CHCHCl2 as an internal standard. c Isolated yield after flash chromatography.
chloride was formed in high conversion along with the expected
benzylic, and propargylic alcohols also are excellent substrates for
the chlorination reaction. With regard to stereochemistry, in the
case of entry 3, the specific rotation of the product ([R]22D +33.5,
triphenylphosphine oxide byproduct (31P NMR δ 29.0 ppm).30
c 0.58, CHCl3, lit.31 [R]25 +33.7) indicated that the expected
D
inversion of configuration had occurred. This was confirmed by
GC analysis using a capillary column with a chiral stationary
phase.32 The stereochemical outcome of the chlorination of
cholesterol was interesting: in this instance retention of config-
uration was observed and confirmed via X-ray analysis
(Figure 1)33 and is most likely the result of participation of the
neighboring alkene.34
Because HCl is generated during the formation of the alkox-
yphosphonium salt, we examined the possibility of conducting
the reaction in the presence of base. In this regard both H€unig’s
base and 2,6-di-tert-butylpyridine were evaluated with substrates
5a and 5c, and each case the derived chlorides were obtained
in excellent yield. In terms of substrates containing protected
hydroxyl groups, the benzyl protecting group is tolerated (entry
18), and interesting results were obtained for substrates contain-
ing silyl ethers. For example, triethylsilylethers were unstable
to the reaction conditions and afforded very high yields of
chloride products as a result of in situ deprotection under the
reaction conditions (entries 19 and 20), and a double chlorina-
tion reaction of bis-protected diol 8w proceeded in good yield
(entry 23). This is a useful observation since TES ethers are
commonly used as protecting groups for alcohols and can be
cleanly converted into the corresponding chlorides using this
protocol. In contrast mono TBDPS-protected pentane diol
underwent chlorination with retention of the protecting group
in 60% yield in the presence of a non-nucleophilic pyridine base
(entry 21). The catalytic reaction also proceeded smoothly with
amidoalcohol 5v that contains a potentially nucleophilic amide
group (entry 22). Replacement of chloroform with ethyl acetate
solvent was possible with only a small loss in yield (entries 1 and
13). The substrate limitations of the chlorination reaction are
apparent from the data in Table 2. Sterically demanding alcohols
such as cyclohexanol, menthol, and neopentyl alcohol are all poor
substrates. The major products obtained from attempted chlor-
ination reactions on these substrates are the oxalyl chloride
derived chlorooxalates of type 9. The failure of these substrates
in the catalytic reactions indicates that the Arbuzov collapse
Next we established the extent of the unwanted back-
ground reaction between oxalyl chloride and decanol (entry
1, Table 1). The rapid (<10 min) consumption of starting
material and formation of chlorooxalate 9a and bisester 10a
indicated a significant side reaction that could compete with the
desired chlorination. However, an initial trial of the catalytic
reaction using 30 mol % of triphenylphosphine oxide afforded a
promising 46% of the desired product 8a (entry 2, Table 1)
along with 9a and 10a. Given that triphenylphosphine oxide is
cheap and commercially available, we opted to conduct opti-
mization experiments to suppress the formation of the esters
using this catalyst. Addition of the alcohol to a solution of oxalyl
chloride and triphenylphosphine oxide catalyst over 2 h
afforded a 65% isolated yield of 8a (entry 3, Table 1). However,
addition of the oxalyl chloride to a solution of alcohol and the
triphenylphosphine oxide catalyst over 0.5 h afforded no decyl
chloride (entry 4, Table 1). A further modification involving
simultaneous addition of both 85 mol % oxalyl chloride and
decanol to a solution of 15 mol % catalyst and 15 mol % oxalyl
chloride over 7 h afforded an excellent yield of 8a (entry 5,
Table 1). This protocol was therefore adopted for substrate
screening studies.
The chlorination of a range of alcohols was then investigated
using the optimal conditions indentified above (Table 1). The
data in Table 2 indicate the scope and limitations of the catalytic
chlorination reaction. Aliphatic primary and secondary alcohols
are chlorinated very efficiently. Primary and secondary allylic,
6751
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 2. Catalytic Chlorination of Alcohols under Appel
Conditionsa
Figure 1. X-ray structure of 8l.
entry
substrate
decanol 5a
product
yield 8b (%)
1
8a
8b
8c
8d
8e
8f
94 (85) 91d (80)c (85)f
with bis ester 10a accounting for the majority of the remaining
mass balance, when this was attempted. This initial poor result
combined with the stability and availability issues associated with
oxalyl bromide prompted us to examine an alternative strategy
for bromination based on intercepting an alkoxyphosphonium
chloride with a bromide ion.
2
benzyl alcohol 5b
80 (42)
97 96d 88e (54)
3
(R)-(ꢀ)-2-octanol 5c
(S)-ethyl lactate 5d
3-phenyl-1-propanol 5e
2-deyn-1-ol 5f
4
95 (87)
5
95 (72)
6
85 (82)
7
2-buten-1-ol 5g
8g
8h
8i
70
8
1-octene-3-ol 5h
64
9
cinnamyl alcohol 5i
diphenyl methanol 5j
cyclohexenol 5k
88 (70)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
8j
96
8k
8l
88
For such an approach to be viable, attack by the bromide ion
on the alkoxyphosphonium salt intermediate would have to be
faster than the corresponding chlorination reaction in order
for clean bromination to occur. We therefore examined the
possibility of catalytic bromination using the Ph3PO/(COCl)2
system with hetero- and homogeneous sources of bromide ions
(Table 3).
cholesterol 5l
81 (66)
98 (95) (86)c
1-phenylethyl alcohol 5m
cyclohexanol 5n
8m
8n
8o
8p
8q
8r
7
(()-menthol 5o
0
neopentyl alcohol 5p
tert-butanol 5q
0
37
HO(CH2)5OBn 5r
C10H21OTES 5s
88 (66)
89
Initial experiments involving both sodium and lithium bro-
mide (entries 1 and 2) were disappointing since in the first case
the major product formed was the chloride while in the second it
was the unwanted bis ester 10a. Increasing the amount of oxalyl
chloride to 1.3 equiv (entry 3) resulted in a promising 41% yield
of the bromide and suppressed the formation of 10a, but chloride
8a was now obtained as a byproduct. Further optimization involved
increasing both the amount of LiBr to 2.5 equiv (entry 4) and
the addition time to 5 h (entry 5) and resulted in a decrease of
chloride byproduct and an increase of the desired bromide to
an acceptable 75%. At this juncture, in an attempt to improve
on entry 6, we examined the use of tetrabutylammonium bro-
mide as a homogeneous source of bromide ions (entry 7) with
alcohol 5e.
Our expectations that this would lead to a superior bromina-
tion reaction were not met; rather, a mixture of chloride and
bromide products was obtained. In a direct comparison the
corresponding reaction with lithium bromide (entry 6) produced
no chloride.
These results indicate that, in addition to providing bromide
ions, the lithium bromide is also sequestering chloride ions from
solution through the formation of lithium chloride with the
lattice energy of the latter presumably acting as the driving force.
Given these results, we proceeded to examine the catalytic
bromination of a range of alcohols using lithium bromide as
the source of bromide ions (Table 4). In contrast to the catalytic
chlorination reactions, we found it necessary to perform optimi-
zation reactions on several of the alcohol substrates in order to
suppress the formation of chloride products that were difficult to
separate from the desired bromides.
8a
8c
8u
8v
8w
2-triethylsiloxyoctanol 5t
HO(CH2)5OTBDPS 5u
PhCONH(CH2)2OH 5v
PhCH(OTES)CH2OTES 5w
99
64d (58)d
(63)
(68)b
a Chloroform solutions of the substrate (1 equiv) and (COCl)2
(0.85 or 1.03 equiv) were added simultaneously to a solution of
Ph3PO (0.15 equiv) and (COCl)2 (0.15 or 0.17 equiv) in chloro-
1
form over 7 h at rt. b Yield determined by H NMR spectroscopy
using Cl2CHCHCl2 as an internal standard; isolated yields in
c
parentheses. Ethyl acetate was used as solvent. d 1.8 equiv of 2,6-
di-tert-butylpyridine was added with the alcohol. e 1.8 equiv of
H€unig’s base was added with the alcohol. f 10 mmol of alcohol
substrate was used.
of the alkoxyphosphonium salt (e.g., 6 f 8 + 1, Scheme 3) is
slow and likely to be rate-limiting in these cases (vide infra).
Finally, the repetition of three representative reactions with
substrates 5a, 5b, and 5h in the absence of triphenylpho-
sphine oxide confirmed that the catalyst is required for
chlorination.
Having developed a catalytic chlorination reaction, we exam-
ined the feasibility of the analogous bromination reactions. Given
that stoichiometric bromophosphonium salts generated from
either the Ph3P/CBr4 or Ph3P/NBS systems are used extensively
for this purpose, a bromination reaction catalytic in the phos-
phorus component would clearly offer a substantial improve-
ment in terms of atom efficiency and ease of purification of
products. As suggested in Scheme 2 it appeared that reactions of
this type would be simple to implement by substituting oxalyl
chloride with oxalyl bromide; however, this was not the case
(eq 5), and only a modest yield of decyl bromide was obtained,
The catalytic bromination reactions are effective for aliphatic,
benzylic, and propargylic primary alcohols as well as aliphatic,
benzylic and allylic secondary alcohols. As was the case with the
chlorination reactions, the bromination of cholesterol to afford 9l
6752
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 3. Optimization of Catalytic Bromination Reactionsa
entry
alcohol
(COCl)2, mol %
Br source, mol %
addition time, h
product (yield, %)b
1
2
3
4
5
6
7
5a
5a
5a
5a
5a
5e
5e
100
100
130
130
130
130
130
NaBr, 300
LiBr, 200
LiBr, 200
LiBr, 250
LiBr, 250
LiBr, 230
nBu4NBr, 230
7
2
2
2
5
5
5
11a (5), 8a (44), 9a (21), 10a (30)
11a (11), 10a (43), 9a + 12a 1:2 (41), 13a (5)
11a (41), 8a (19), 9a (33), 13a (7)
11a (43), 8a (7), 9a (33), 10a (8), 13a (6)
11a (74), 9a + 12a ca. 1:1 (21%)
11e (66)
11e (27), 8e (47)
a Chloroform solutions of the alcohol (1 equiv) and (COCl)2 were added simultaneously to a solution of Ph3PO (0.15 equiv), LiBr,
and (COCl)2 in chloroform over the time indicated at rt. b Yield determined by H NMR spectroscopy using Cl2CHCHCl2 as an internal
1
standard.
Scheme 3. Possible Catalytic Cycles for Catalytic Chlorination and Bromination Reactions
took place with retention of configuration, while the bromination
of (R)-(ꢀ)-2-octanol took place with the expected inversion of
configuration, as confirmed by the specific rotation of the
product ([R]22 +38.2, c 0.58, CHCl3, lit.35 [R]25 +40.2,
catalytic cycle as depicted in cycle 1 of Scheme 3 or if an
alternative catalytic cycle, in which the phosphine oxide acts
solely as a nucleophilic catalyst, intervenes (cycle 2, Scheme 3).
In order to do this we studied the relative reactivity of the key
intermediates in both possible catalytic cycles, namely, alkox-
yphosphonium salts of type 6 and oxalylphosphonium salts of
type 14.
We began by looking in more detail at those reactions that had
failed. As can be seen from entries 14ꢀ16, Table 2 and entry 12,
Table 4, sterically demanding substrates are not tolerated. These
unsuccessful reactions provide some insight into the turnover-
limiting step of the catalytic cycle. If we assume that (a) the rate
of reaction between oxalyl chloride and triphenylphosphine
oxide will remain constant regardless of the alcohol substrate
employed and (b) the rate of alkoxyphosphonium salt formation
(4a f 6, Scheme 3) and (c) the rate of the background reaction
between alcohol and oxalyl chloride (5 f 9, Scheme 3) will also
not be particularly sensitive to the steric demands of the alcohol,36
then for successful catalytic reactions, the Arbuzov reaction of the
alkoxyphosphonium salt (6 f 8, Scheme 3, cycle 1) needs to be
D
D
c 5.8) and GC analysis.32 The substrate scope is also similar to
the chlorination reactions, i.e., sterically demanding alcohols do
not undergo efficient catalytic bromination. The new catalytic
protocol provides a valuable atom-economical alternative to the
traditional NBS/triphenylphosphine system for bromination of
unhindered primary and secondary alcohols.
Mechanistic Observations. Having established the substrate
scope and limitations of the newly developed reactions, we
sought a more detailed understanding of the nature of the
catalytic cycle involved. We were particularly interested in
understanding why certain catalytic reactions failed and in
gaining an understanding of which step of the catalytic cycle is
rate-limiting so that improved reactions could be developed in
the future. Furthermore, we wished to probe the role of the
phosphine oxide in the catalytic cycle and establish whether our
catalytic reactions are indeed consistent with the Appel-type
6753
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 4. Catalytic Bromination of Alcohols under Appel Conditionsa
entry
alcohol 5
decanol 5a
product
(COCl)2, mol %
Ph3PO, mol %
LiBr, mol %
time, h
yield 11,b %
1
11a
11g
11e
11b
11f
130
130
130
130
130
130
130
130
130
130
130
130
130
130
15
15
15
15
15
15
25
15
15
15
15
15
0
250
300
230
300
250
150
250
250
300
250
250
250
250
300
5
5
5
5
5
7
7
5
5
5
5
5
5
5
75 (70)c
73
2
2-buten-1-ol 5g
3
3-phenyl-1-propanol 5e
benzyl alcohol 5b
2-decyn-1-ol 5f
67 (58)
71 (49)
75 (49)
77
4
5
6
(R)-(ꢀ)-2-octanol 5c
cholesterol 5l
11c
11l
7
44
8
1-phenylethyl alcohol 5m
cinnamyl alcohol 5i
2-cyclohexenol 5k
tert-butyl alcohol 5q
cyclohexanol 5n
11m
11i
74
9
69 (27)
73 (14)
72
10
11
12
13
14
11k
11q
11n
11a
11b
0
decanol 5a
0
benzyl alcohol 5b
0
0
a Chloroform solutions of the substrate (1 equiv) and (COCl)2 (1.11 equiv) were added simultaneously to a solution of Ph3PO (0.15 equiv), LiBr, and
(COCl)2 (0.20 equiv) in chloroform over the time indicated at rt. b Yield determined by 1H NMR spectroscopy using Cl2CHCHCl2 as an internal
standard; isolated yields in parentheses. c 10 mmol of substrate was used.
relatively fast. We therefore examined the reactivity of alkox-
yphosphonium chlorides derived from neopentyl alcohol, cyclo-
hexanol, and decanol (Scheme 4, Table 5).
1H and 31P NMR for the alkoxyphosphonium salts were ob-
served. At the opposite end of the reactivity scale we attempted to
prepare the alkoxyphosphonium salt derived from decanol. As we
had found previously, stoichiometric chlorination of this sub-
strate is very fast (eq 4), but we were able to observe 6a by NMR
if the spectrum was recorded within ca. 1.5 min. After this time
the chlorination reaction is at 50% conversion and ca. 50% of the
alkoxyphosphonium is visible by NMR. These results are con-
sistent with alkoxyphosphonium salt collapse to product being
turnover-limiting if the reaction proceeds in cycle 1 of Scheme 3.
In a further experiment the catalytic chlorination of decanol was
repeated, and aliquots of the reaction mixture were analyzed at 1,
3, 5, and 6 h intervals by multinuclear NMR. These experiments
revealed that decyl chloride formed steadily over the course of
the addition time along with a small amount of chlorooxalate 9a.
31P NMR analysis indicated the presence of chlorophosphonium
salt 4a and another signal (31P δ 32ꢀ40 ppm) that we tentatively
assign to protonated triphenylphosphine oxide.22 At the end of
the reaction a single peak corresponding to triphenylphosphine
oxide was present in the 31P NMR spectrum. These observations
are consistent with a rapid chlorination reaction that is complete
in the time that it takes to run the NMR spectra of the reaction
mixture aliquot (typically 3ꢀ5 min). However, at this point, we
could not rule out formation of the chloride product in cycle 2 of
Given the failure of catalytic reactions with cyclohexanol and
neopentyl alcohol, we were not surprised to observe that the
derived alkoxyphosphonium salts 6n and 6p were relatively
stable. For example, 6n decomposed over 5 h to a mixture of
chloride and cyclohexene. In the neopentyl case no chloride
product was formed over this time period, and we were able to
obtain X-ray quality crystals of the alkoxyphosphonium salt
(Figure 2).37
With NMR data for 6n and 6p in hand, we examined NMR
spectra taken at the end of failed catalytic reactions on cyclohex-
anol, neopentyl alcohol, and menthol. In each case peaks in the
Scheme 4. Formation and Reactivity of Alkoxyphosphonium
Salts
Table 5. Selected NMR Data and Reactivity of Alkoxyphosphonium Salts
entry
alcohol
product
selected NMR data
time
yield of 8,a %
1
2
3
cyclohexanol
neopentyl alcohol
decanol
8n
8p
8a
31P δ 59.2 ppm, 2JCP = 9.2, 3JHP = 4.4
31P δ 61.9 ppm, 2JCP = 9.2, 3JHP = 8.4
31P δ 61.9 ppm, 2JCP = 9.2
5 h
5 h
14b
0
ca. 1.5 min
50
a The yield was determined by 1H NMR spectroscopy using Cl2CHCHCl2 as an internal standard. b The remainder of the mass balance in this reaction
was cyclohexene (75%).
6754
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Figure 2. X-ray structure of 6p.
Figure 3. Ball and spoke representation of 6r and 14r and predicted
transition structures (hydrogen atoms omitted for clarity).
Scheme 3 from either intermediate 9 or 14, and therefore we
examined the reactivity of these species.
to chloride products 8 is very much more difficult than decom-
position of the analogous alkoxyphosphonium salts.
We note first that the chlorooxalates of type 9 have received
very little attention and oxalyl phosphonium salts of type 14
have not been reported; however, it is known that the former
compounds are significantly more stable than analogous chloro-
formates and chlorosulfinates with respect to decomposition to
chlorides.31 For example, the chlorooxalate derived from oxalyl
chloride and butanol was converted to the corresponding
chloride only by conversion to the corresponding pyridinium
salt and heating to 110 °C for 3 h.31 For the present study we
prepared chlorooxalates from substrates 6a, 6b, and 6h by slow
addition to oxalyl chloride and conducted a series of experi-
ments with triphenylphosphine oxide in which we attempted to
convert the chlorooxalates to chloride products of type 8. The
interested reader is referred to the Supporting Information for
full details of these experiments. To summarize the results: our
attempts to convert the oxalates to the corresponding chlorides
8, either under the conditions used in the catalytic reactions
or more forcing conditions involving stoichiometric amounts
of triphenylphosphine oxide and elevated temperatures, were
unsuccessful. Furthermore, we obtained no evidence for the
formation of oxalyl phosphonium salts of type 14a from
chlorooxalates under the conditions of the catalytic reactions.
In a parallel computational study, we modeled the Arbuzov
reactions of truncated (methyl replaced n-decyl) alkoxypho-
sphonium salts of type 6 and oxalylphosphonium salts of type
14a to chloride products 8 (eqs 6 and 7). Geometry optimizations
on the ion pairs 6x and 14x were performed using the B3LYP
model and 6-31G* basis set (Spartan '08 Macintosh).38,39
We succeeded in locating transition structures for the both
of the Arbuzov reactions using the same theoretical model
(Figure 3).
At this point we summarize the key features of the catalytic
chlorination reactions: (a) The catalytic reactions work very well
for primary and secondary alcohols that are not too sterically
hindered. (b) With sterically demanding substrates the slow step
in the catalytic cycle is the collapse of the alkoxyphosphonium
salt (6 f 8, Scheme 4), which leads to alcohol and oxalyl
chloride buildup in the absence of catalyst and, therefore, to
formation of chlorooxalates of type 9. This is corroborated by
the slow stoichiometric chlorination reactions of problematic
substrates and the observation of the alkoxyphosphonium
salts 6 derived from such substrates at the end of failed
catalytic reactions. (c) Chlorooxalates of type 9 are unreactive
with respect to chloride formation, i.e., 9 f 8 and 14a f 8
(Scheme 4) are not viable under the conditions of the catalytic
reactions (or even under more forcing conditions, see Sup-
porting Information). These data and observations are con-
sistent with chlorination occurring in the “Appel-type” pathway
(cycle 1, Scheme 3).
We now collate the results of similar investigations carried
out on the catalytic bromination reactions described in Table 4.
The interested reader is once again referred to Supporting
Information for full details of the experiments relating to each
of the following key points: (a) Alkyl bromides 11 do not form
from alkyl chlorides and LiBr in chloroform under the reaction
conditions. (b) LiBr is superior to homogeneous sources of
bromide ions such as nBu4Br, suggesting that the former is
involved in counterion metathesis that sequesters chloride ions
from the reaction mixture. (c) The conversion of chloroox-
alates into bromooxalates (9b f 12, Scheme 3) under the
conditions of the catalytic reaction is viable; however, the
bromooxalates 12 are not converted to bromide products 11
in the presence of triphenylphosphine oxide under the condi-
tions of the catalytic reactions. It is, however, possible to obtain
bromide products with activated substrates under more forcing
conditions (e.g., 12b, 1 equiv of Ph3PO, 48 h, ca. 30%).
Therefore, we conclude that the catalytic bromination reac-
tions are also consistent with an “Appel-type” pathway as
depicted in cycle 1, Scheme 3.
Further Optimization Studies. Having developed catalytic
chlorination and bromination reactions for a wide range of
alcohol substrates and having established that the reactions were
consistent with a catalytic cycle involving halo- and alkoxypho-
sphonium salts as intermediates, we began a second series of
Activation energies of 12.3 and 31.8 kcal/mol were obtained
for the reactions depicted in eqs 6 and 7, respectively. These
results indicate that decomposition of oxalylphosphonium salts
6755
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 6. Formation and Reactivity of Chlorophosphonium
Salts 4a
decyl chloride had been produced from the reaction of decanol
with chlorophosphonium salt 4k. Similar results were observed
for salts 4i and 4j. These results indicate that the Arbuzov
reaction is also highly sensitive to the nature of the substituents
attached to phosphorus and that bis- and trialkyl phosphine
oxides cannot be effective catalysts due to the low reactivity of
their derived alkoxyphosphonium salts. The results for the
electron-rich phosphine oxides were also poor: the chlorination
reactions were slow, and therefore these phosphine oxides were
also excluded. More promising were the electron-poor aryl
phosphine oxides 1b and 1c: they gave results similar to those
with triphenylphosphine oxide in the stoichiometric chlorination
reaction, and therefore we took these forward, along with 1a, into
a second optimization study focused on reducing catalyst loading
and addition time. We began by comparing the two new
phosphine oxides to 1a (Table 7) in catalytic chlorination
reactions. The result with the pyridyl phosphine oxide 1b was
a moderate 53% (entry 9).
entry
phosphine oxide
1a R1 = R2 = R3 = Ph
1b R1 = R2 = Ph, R3 = py
1c R1 = R2 = R3 = 4-fluorophenyl
1d R1 = R2 = R3 = 2-furyl
yield 8a, %
1
96a
88b
94c
0a
2
3
4
5
1e R1 = R2 = R3 = 2-tolyl
23d
0b
0a
6
1f R1 = R2 = R3 = 4-methoxyphenyl
1g R1 = R2 = R3 = 2,6-dimethoxyphenyl
1h R1 = R2 = Ph, R3 = Me
7
8
8a
9
1i R1 = R2 = R3 = Me
0a
However, phosphine oxide 1c was identical to 1a in this test
reaction and afforded an excellent 94% yield of product (entry 5).
Therefore, we investigated lowering the loading of catalysts 1a
and 1c to more practical levels with decanol and 2-octanol as
representative nonsterically demanding primary and secondary
alcohol substrates.
10
1j R1 = R2 = R3 = Bu
1k R1 = R2 = 3-methylcyclopentenyl, R3 = Ph
1a
2a
11
a Phosphine oxide (1.2 equiv), (COCl)2 (1.2 equiv), and Cl2CHCHCl2
internal standard were dissolved in CDCl3 and stirred for 5 min. Decanol
(1.0 equiv) was added and stirred for 10 min. b The phosphine oxide and
(COCl)2 were stirred for 10 min. c The phosphine oxide and oxalyl
chloride were stirred for 15 min. d The phosphine oxide, 2,6-di-tert-
butylpyridine (1.2 equiv), and (COCl)2 were dissolved in CDCl3 and
stirred for 30 min.
Lowering the loading of both 1a and 1c decreased the yield,
and in both cases it fell off sharply at 2.5 mol %; however, good
yields were still obtained at 5 mol % with 1a and 1c (entries 3
and 5). We were pleased to observe that 1c, which catalyzed the
chlorination of decanol in 81% yield, was an improvement on
triphenylphosphine oxide. This constitutes a significant improve-
ment to the original conditions described in Table 2. A similar
series of experiments was then undertaken with 2-octanol,
and similar results were obtained. Again, the loading of both
catalyst 1a and 1c could be reduced significantly with only a small
affect on the yield. For example, at 3 mol % 1a and 1c afforded
the product in yields of 82% and 85%, respectively (entries 13
and 17). These results indicate that secondary alcohols are better
substrates for the catalytic reaction than primary. During this
and related work we have observed that alkoxyphosphonium
salts form very rapidly from alcohols and the rate of this reaction
is rather insensitive to the steric demands of the alcohol. On the
other hand secondary alcohols react more slowly than primary
alcohols with oxalyl chloride. This results in a slower back-
ground reaction for these substrates and allows lower catalyst
loadings to be realized. To reach still lower catalyst loading we
examined the TES-protected substrate 5t since the background
reaction here ought to be slower than that of 2-octanol.
Our expectations were met: chlorination was achieved in 93%
yield with 2.5 mol % catalyst and 77% yield with just 1 mol %
of catalyst.
In a second series of experiments catalysts 1a and 1c were
examined with varying addition times and different catalyst
loadings (Table 8). As can be seen, decreasing the addition
time resulted in a reduction in yield with both catalysts;
however, catalyst 1c provided superior results. For example,
chlorination of decanol over 3 h with 1a afforded a 77% yield,
while the same reaction with 1c gave a much-improved 95%
(entries 3 and 7). In the case of 2-octanol yields of 48% and
82% were obtained for reactions carried out over 1 h with
catalyst 1a and 1c, respectively (entries 12 and 20). These
results clearly indicate the superiority of catalyst 1c with
respect to reaction addition times.
optimization studies with a view to reducing both the catalyst
loading and the addition time to more practical levels. However,
we were also interested in exploring the reactivity of several other
catalysts and we began with a survey of different phosphine
oxides.
We selected a series of aryl- and alkyl-substituted phosphine
oxides and investigated their reactivity with oxalyl chloride and
the reactivity of the chlorophosphonium salts so obtained with
decanol (Table 6). We were pleased to observe that most of the
phosphine oxides reacted smoothly with oxalyl chloride to afford
the desired chlorophosphonium salts 4. It was immediately
apparent that trialkyl-substituted phosphine oxides (e.g., entries
9ꢀ11) reacted more rapidly than their bi- and triaryl counter-
parts. With regard to the latter, electron-deficient triarylpho-
sphine oxides reacted more slowly than triphenylphosphine
oxide (entries 2 and 3), while those phosphine oxides bearing
electron-rich arenes (entries 5ꢀ7) did not form a single species
upon addition of oxalyl chloride. In the case of trifurylphosphine
oxide (entry 4) no appreciable reaction with oxalyl chloride was
observed after 5 or 10 min. We then reacted each of the derived
chlorophosphonium salts with decanol in order to evaluate the
relative rates of the chlorination reactions. From the studies
described above it is clear that, for a given phosphine oxide to be a
viable catalyst, its derived chlorophosphonium salt 4 must
effect chlorination of the alcohol faster than, or at a similar
rate to, the background reaction between the alcohol and oxalyl
chloride (entry 1, Table 1). If the Arbuzov reaction is slow, for
example, in the case of sterically hindered alcohols, the catalytic
reactions fail.
Upon reaction of the derived chlorophosphonium salts 6 with
decanol, it can be seen that the alkoxyphosphonium salts derived
from aliphatic phosphine oxides underwent very slow Arbuzov
decomposition to product. For example, after 10 min only 2%
6756
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 7. Comparison of Phosphine Oxide Catalysts at Dif-
ferent Loadings in Catalytic Chlorinationa
Table 8. Comparison of Phosphine Oxide Catalysts and
Different Addition Times in Catalytic Chlorinationa
entry substrate
catalyst
1a Ar = Ph
loading, mol % yield of 8, %b
loading,
mol %
addition
time, h
yield
of 8, %b
entry alcohol
catalyst
1a Ar = Ph
1
5a
5a
5a
5a
5a
5a
5a
5a
5a
5c
5c
5c
5c
5c
5c
5c
5c
5t
15
10
5
94
86
74
42
(94)
91
81
45
53
97
93
92
82
94
94
88
85
93
77
2
1a Ar = Ph
1
5a
5a
5a
5a
5a
5a
5a
5a
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
15
15
15
15
15
15
15
15
15
15
15
15
5
7
5
3
1
7
5
3
1
7
5
3
1
7
5
3
1
7
5
3
1
94
86
77
36
94
95
95
49
97
92
85
48
92
74
50
22
94
92
89
82
3
1a Ar = Ph
2
1a Ar = Ph
4
1a Ar = Ph
2.5
3
1a Ar = Ph
5
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1b Ar = 2-pyridyl, Ph, Ph
1a Ar = Ph
15
10
5
4
1a Ar = Ph
6
5
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1a Ar = Ph
7
6
8
2.5
7
9
15
15
10
5
8
10
11
12
13
14
15
16
17
18
19
9
1a Ar = Ph
10
11
12
13
14
15
16
17
18
19
20
1a Ar = Ph
1a Ar = Ph
1a Ar = Ph
1a Ar = Ph
3
1a Ar = Ph
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1a Ar = Ph
15
10
5
1a Ar = Ph
1a Ar = Ph
5
1a Ar = Ph
5
3
1a Ar = Ph
5
2.5
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
15
15
15
15
5t
1a Ar = Ph
1
a Chloroform solutions of the substrate (1 equiv) and (COCl)2 (1.2 ꢁ
[1-catalyst loading] equiv) were added simultaneously to a solution of
Ar3PO (amount indicated) and (COCl)2 (1.2 ꢁ catalyst loading equiv)
in chloroform over 7 h at rt. b Yield determined by 1H NMR spectros-
copy using Cl2CHCHCl2 as an internal standard; isolated yields in
parentheses.
a Chloroform solutions of the substrate (1 equiv) and (COCl)2
(1.2 ꢁ [1-catalyst loading] equiv) were added simultaneously to a
solution of Ar3PO (amount indicated) and (COCl)2 (1.2 ꢁ catalyst
loading equiv) in chloroform over the time indicated at rt. b Yield
determined by 1H NMR spectroscopy using Cl2CHCHCl2 as an
internal standard; isolated yields in parentheses.
Clearly, a low loading and short addition time would be
desirable, and to this end, we examined reactions of 2-octanol
run with 5 mol % 1a with varying addition times. Entry 14
indicates that a good (74%) yield was obtained with a relatively
short addition time and low catalyst loading.
provided a convenient means to screen potential catalysts. the
very slow Arbuzov collapse of alkyl alkoxyphosphonium chlor-
ides rule these species out; however, other triarylphosphine
oxides were identified as viable catalysts. (b) The catalyst load-
ing and the addition time can be lowered compared to the
original protocol, resulting in more practical catalytic reactions.
(c) In most cases the use of catalyst 1c provides higher yields at a
given catalyst loading and addition time for decanol and 2-octa-
nol. (d) The benefits associated with catalyst 1c unfortunately
do not translate to the more complex catalytic bromination
reactions of decanol and 2-octanol. (e) Whereas the Arbuzov
reaction of alkoxyphosphonium chloride 6c is fast, the reaction of
the parent phosphine oxide 1c with oxalyl chloride is significantly
slower than that of triphenylphosphine oxide, and therefore the
rate-limiting step in reactions catalyzed by 1c may be the
conversion of the phosphine oxide into the chlorophosphonium
salt (1c f 4c).
Having developed improved protocols for catalytic chlorina-
tion, we revisited catalytic bromination reactions of decanol and
2-octanol (Table 9) to see if catalyst loading could be decreased
and if improvements could be realized here with catalyst 1c.
In the case of decanol and catalyst 1a we were unable to reduce
the catalyst loading below 15 mol % and maintain an acceptable
yield (entries 2 and 3). However, as expected, the secondary
alcohol was a better substrate, and the loading of 1a could be
decreased to 5 mol % while maintaining a reasonable 60% yield of
bromide product (entry 6). Finally, we evaluated the fluorinated
catalyst 1c in the bromination of decanol at loadings of 15 and
10 mol % (entries 7 and 8). At 15 mol % chloride 8c was formed
in addition to the bromide product, while at 10 mol % no chloride
was formed but the yield of bromide 11c was not acceptable. A
range of other bromination experiments were conducted with
this catalyst; however, in contrast to the chlorination reactions,
we were unable to realize an improved protocol.
’ CONCLUSIONS
We now summarize the results of our studies on catalyst
structure, catalyst loading, and addition time: (a) The Arbuzov
reaction of decanol with stoichiometric chlorophosphonium salts
derived from a variety of alkyl and aryl phosphine oxides
In this article we have outlined a new general strategy for
catalytic phosphorus(V)-based activation and nucleophilic sub-
stitution reactions of alcohols that involves accessing phosphonium
6757
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
Table 9. Catalytic Bromination of Alcohols under Appel
instrument as dilute chloroform solutions. Single crystal X-ray diffrac-
tion was carried out by the X-ray crystallography department at the
University of Nottingham. All solvents and reagents were used as
supplied.
Conditions: Effect of Catalyst Structure and Loadinga
Determination of Yield by 1H NMR. The crude reaction mixture
was dissolved in CDCl3 and transferred to a volumetric flask (two
washings of the original flask were done after transfer) that was
subsequently made up to the correct volume with further CDCl3. To
a 1 mL aliquot of this solution was added 1,1,2,2-tetrachlorethane
entry alcohol
catalyst
1a Ar = Ph
loading, mol % 11 (yield, %)b
1
(accurately approximately 15ꢀ80 mg). The H NMR spectrum was
recorded, and the mass of the product was calculated according to the
equation below:
1
2
3
4
5
6
7
8
5a
5a
5a
5c
5c
5c
5a
5a
15
10
5
11c (75)
1a Ar = Ph
11c (51)
1a Ar = Ph
11c (35)
massproduct
1a Ar = Ph
15
10
5
11c (77)
ꢀ
ꢁꢀ
ꢁ
1a Ar = Ph
11c (66)
areaproduct
areastandard
MWproduct
MWstandard
m
¼
massstandard purityfactorstandard 3
n
3
3
3
purityfactoralcohol
1a Ar = Ph
11c (60)
1c Ar = 4-fluorophenyl
1c Ar = 4-fluorophenyl
15
10
11c (52) 8c (34)
11c (56)
where n corrects for the amount of the crude reaction mixture used,
and m corrects for the number of protons associated with the
resonance used.
a Chloroform solutions of the substrate (1 equiv) and (COCl)2
(1.3 ꢁ [1-catalyst loading] equiv) were added simultaneously to a
solution of Ar3PO (amount indicated), LiBr (2.5 equiv), and (COCl)2
(1.3 ꢁ catalyst loading equiv) in chloroform over the time indicated at rt.
b Yield determined by 1H NMR spectroscopy using Cl2CHCHCl2 as an
internal standard.
General Procedure 1. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in either CHCl3 or CDCl3 (1.5 mL) was added
oxalyl chloride (12.0 μL, 0.142 mmol), and the reaction mixture was
stirred for 5 min. The appropriate alcohol (1.00 equiv) and oxalyl
chloride (73.0 μL, 0.863 mmol) as solutions in either CHCl3 or CDCl3
(1.0 mL) were then added simultaneously over 7 h via syringe pump at
rt. The solvent was removed in vacuo. Purification by flash chromatog-
raphy (silica, 5ꢀ10% Et2O/petroleum ether) gave the pure chlorides.
General Procedure 2. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in either CHCl3 or CDCl3 (1.5 mL) was added
oxalyl chloride (15.0 μL, 0.177 mmol), and the reaction mixture was
stirred for 5 min. The appropriate alcohol (1.00 equiv) and oxalyl
chloride (87.0 μL, 1.03 mmol) as solutions in either CHCl3 or CDCl3
(1.0 mL) were then added simultaneously over 7 h via syringe pump at
rt. The solvent was removed in vacuo. Purification by flash chromatog-
raphy (silica, 5ꢀ100% Et2O/petroleum ether) gave the pure chlorides.
1-Chlorodecane (8a).40 The following reagents were combined in
the amounts and method indicated according to general procedure 2.
Decanol (158 mg, 1.00 mmol), oxalyl chloride (102 μL, 1.21 mmol),
triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8a 166 mg, 94% by
1H NMR. Purification by flash column chromatography (silica, 10%
Et2O/petroleum ether) afforded 8a as a colorless oil (150 mg, 85%). 1H
NMR (400 MHz, CDCl3) δ 3.55 (t, J = 6.8 Hz, 2H, CH2Cl), 1.79 (m,
2H, H2CCH2Cl), 1.50ꢀ1.23 (m, 14H, 7 ꢁ CH2), 0.91 (t, J = 6.8, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 45.1, 32.7, 31.9, 29.5, 29.5, 29.3,
28.9, 26.9, 22.7, 14.1.
salts with established reactivity catalytically at the expense of
consumable oxalate reagents. This new mode of catalysis has
been validated through the development of catalytic Appel
halogenation reactions in which the halophosphonium salts
responsible for chlorination and bromination are derived from
catalytic phosphine oxides and stoichiometric oxalyl chloride.
The new reactions, which take place at rt, represent a highly
efficient and atom-economical alternative to the traditional
PPh3/CX4 system for the chlorination and bromination unhin-
dered primary and secondary alcohols. This work demonstrates
that catalysis of reactions in which phosphine oxides are produced
as byproduct is possible at rt using a cheap and low molecular
weight reagent to induce phosphine oxide turnover. Finally,
this study provides a platform for a range of further catalytic
Mitsunobu-type CꢀC and Cꢀheteroatom bond-forming reac-
tions to be developed by adjusting the structure of the oxalate
reagents used. These studies are currently in progress in our
laboratory.
Benzylchloride (8b).17 The following reagents were combined in
the amounts and method indicated according to general procedure 1.
Benzyl alcohol (108 mg, 1.00 mmol), oxalyl chloride (85 μL, 1.0 mmol),
triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8b 101 mg, 80% by
1H NMR. Purification by flash column chromatography (silica, 5%
Et2O/petroleum ether) afforded 8b as a colorless oil (53 mg, 42%). 1H
NMR (270 MHz, CDCl3) δ 7.30ꢀ7.43 (m, 5H, ArH), 4.62 (s, 2H,
CH2); 13C NMR (67.5 MHz, CDCl3) δ137.6, 128.9, 128.7, 128.5, 46.3.
(S)-2-Chlorooctane (8c).41 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 2. (R)-(ꢀ)-2-Octanol (130 mg, 1.00 mmol), oxalyl chloride
(102 μL, 1.21 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol).
Gave 8c (144 mg, 97%) by 1H NMR. 8c [R]22D +32.8 (c 0.58, CHCl3),
alcohol [R]22D ꢀ7.4 (c 0.97, CHCl3); 1H NMR (400 MHz, CDCl3) δ
4.03 (m, 1H, CHCl), 1.71 (m, 2H, H2CCHCl), 1.51 (d, J = 6.6 Hz, 3H,
ClCHCH3), 1.45ꢀ1.24 (m, 8H, 4 ꢁ CH2), 0.9 (t, J = 6.9 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 59.0, 40.0, 31.8, 28.9, 26.7, 25.4,
22.7, 14.1.
’ EXPERIMENTAL SECTION
General. Glassware was dried in an oven overnight before use. Thin
layer chromatography was carried out on silica-aluminum plates, and
plates were visualized using ultraviolet light (254 nm) and KMnO4
solution. For flash column chromatography silica gel 60, 35ꢀ70 μm was
used. NMR data was collected at either 270 or 400 MHz. All samples
were analyzed in CDCl3 unless otherwise stated. Reference values for
residual solvent was taken as δ = 7.27 (CDCl3) for 1H NMR; δ = 77.1
(CDCl3) for 13C NMR. Multiplicities for coupled signals designated
using the abbreviations s = singlet, d = doublet, t = triplet, q = quartet,
quin = quintet, sex = sextet, br = broad signal, ap = apparent and are
given in Hz. 13C multiplicities were assigned using a DEPT sequence.
Where appropriate, COSY, HMQC, and HMBC experiments were
performed to aid assignment. 31P NMR was recorded with decoupling.
High-resolution mass spectrometric data were quoted to four decimal
places (0.1 mDa) with error limits for acceptance of (5.0 ppm (defined
as calcd/found mass 10-6). Infrared spectra were recorded on a FTIR
6758
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
(R)-2-Chloropropanoic Acid Ethyl Ester (8d).42 The following
reagents were combined in the amounts and method indicated accord-
ing to general procedure 2. Ethyl-(s)-(ꢀ)-lactate (118 mg, 1.00 mmol),
oxalyl chloride (102 μL, 1.21 mmol), triphenylphosphine oxide (42 mg,
0.15 mmol). Gave 8d 130 mg, 95% by 1H NMR. Purification by flash
column chromatography (silica, 100% Et2O) afforded 8d as a colorless
oil (119 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 4.37 (q, J = 7.0 Hz,
1H, ClCH), 4.21 (q, J = 7.2 Hz, 2H, H2CCH3), 1.67 (d, J = 7.0 Hz, 3H,
H3CCHCl), 1.29 (t, J = 7.2 Hz, 2H, H2CCH3); 13C NMR (100 MHz,
CDCl3) δ 170.1, 62.0, 52.6, 21.5, 14.0.
HCCH2Cl), 4.28 (dd, J = 7.2 Hz, 2H, CH2); 13C NMR (100 MHz,
CDCl3) δ 136.4, 134.2, 128.7, 128.5, 126.7, 125.0, 45.5.
Diphenylmethyl Chloride (8j).46 The following reagents were
combined in the amounts and method indicated according to general
procedure 1. Diphenyl methanol (184 mg, 1.00 mmol), oxalyl chloride
(85 μL, 1.0 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol). Gave
8j 195 mg, 96% by 1H NMR. 1H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.29
(m, 6H, ArH), 7.47ꢀ7.42 (m, 4H, ArH), 6.17 (s, 1H, CH); 13C NMR
(100 MHz, CDCl3) δ 141.1, 128.6, 128.1, 127.8, 64.3.
2-Cyclohexenyl Chloride (8k).17 The following reagents were
combined in the amounts and method indicated according to general
procedure 1. Cyclohexanol (98.1 mg, 1.00 mmol), oxalyl chloride (85 μL,
1.0 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8k
103 mg, 88% by 1H NMR. 1H NMR (400 MHz, CDCl3) δ 5.91ꢀ5.85
(m, 1H, HCdCHCHCl), 5.85ꢀ5.79 (m, 1H, HCdCHCHCl), 4.62
(m, 1H, HCdCHCHCl), 2.18ꢀ1.97 (m, 4H, H2CCH2CH2CHdCH),
1.96ꢀ1.85 (m, 1H, H2CCH2CH2CHdCH), 1.70ꢀ1.61 (m, 1H,
H2CCH2CH2CHdCH); 13C NMR (100 MHz, CDCl3) δ 131.4,
128.1, 55.6, 32.5, 24.7, 18,4.
3-Phenylpropylchloride (8e).43 The following reagents were
combined in the amounts and method indicated according to general
procedure 2. 3-Phenyl-1-propanol (136 mg, 1.00 mmol), oxalyl chloride
(102 μL, 1.21 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol).
Gave 8e 147 mg, 95% by 1H NMR. Purification by flash column
chromatography (silica, 5% Et2O/petroleum ether) afforded 8e as a
colorless oil (112 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.28
(m, 2H, ArH), 7.26ꢀ7.19 (m, 3H, ArH), 3.54 (t, 2H, J = 6.4 Hz,
PhCH2CH2CH2Cl), 2.80 (t, J= 6.4 Hz, 2H, PhCH2CH2CH2Cl), 2.10
(m, 2H, PhCH2CH2CH2Cl); 13C NMR (100 MHz, CDCl3) δ 140.7,
128.7, 128.6, 126.2, 44.2, 34.1, 32.8.
3β-Chloro-5-cholestene (8l).47 The following reagents were
combined in the amounts and method indicated according to general
procedure 1. Cholesterin (193 mg, 0.499 mmol), oxalyl chloride (42 μL,
0.50 mmol), triphenylphosphine oxide (21 mg, 0.075 mmol). Gave 8l
(156 mg, 81%) by 1H NMR. Purification by flash column chromatog-
raphy (silica, 5% Et2O/petroleum ether) followed by recrystallization
(EtOAc/petroleum ether) afforded 8l as a white solid (128 mg, 66%).
1H NMR (400 MHz, CDCl3) δ 5.38 (m, 1H), 3.77 (m, 1H), 2.62ꢀ2.46
(m, 2H), 2.11ꢀ1.79 (m, 6H), 1.64ꢀ0.83 (m, 32H), 0.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 140.9, 122.6, 60.5, 56.9, 56.8, 50.2, 43.6,
42.5, 39.9,39.7, 39.2, 36.5, 36.3, 36.0, 33.5, 32.0, 31.9, 28.4, 28.1, 24.4,
24.0, 23.0, 22.7, 21.1, 19.4, 18.9, 12.0.
1-Chloro-2-decyne (8f).43 The following reagents were combined
in the amounts and method indicated according to general procedure 2.
2-Deyn-1-ol (154 mg, 1.00 mmol), oxalyl chloride (102 μL, 1.21 mmol),
triphenylphosphine oxide (42.0 mg, 0.15 mmol). Gave 8f 147 mg, 85%
1
by H NMR. Purification by flash column chromatography (silica, 5%
Et2O/petroleum ether) afforded 8f as a colorless oil (142 mg, 82%). 1H
NMR (400 MHz, CDCl3) δ 4.15 (t, J = 2.4 Hz, 2H, CCCH2Cl), 2.22
(m, 2H, H2CCH2CC), 1.50 (m, 2H, H2CCH2CH2CC), 1.44ꢀ1.22 (m,
8H, 4 ꢁ CH2), 0.91 (t, J = 6.8 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 87.8, 75.0, 31.8, 31.4, 28.9, 28.9, 28.5, 22.7, 18.9, 14.2.
1-Chloro-2-butene (8g).44 The following reagents were combined
in the amounts and method indicated according to general procedure 1.
2-buten-1-ol (72 mg, 1.00 mmol), oxalyl chloride (85 μL, 1.0 mmol),
triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8g 64 mg, 70%
(1-Chloroethyl)benzene (8m).17 The following reagents were
combined in the amounts and method indicated according to general
procedure 2. 1-Phenylethyl alcohol (122 mg, 1.00 mmol,) oxalyl chloride-
(102 μL, 1.21 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol).
Gave 8m 138 mg, 98% by 1H NMR. Purification by flash column
chromatography (silica, 5% Et2O/petroleum ether) afforded 8m as a
colorless oil (134 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.47ꢀ7.30
(m, 5H, ArH), 5.12 (q, J = 6.7 Hz, 1H, CHCl), 1.88 (d, J = 6.7 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3); δ 142.9, 128.7, 128.3, 126.6,
58.8, 26.6.
1
1
by H NMR. H NMR (400 MHz, CDCl3) δ 5.80 (m, 1H, H3C-
CHCHCH2Cl), 5.64 (m, 1H, H3CCHCHCH2Cl), 4.02 (dt, J = 7.0 and
0.9 Hz, 2H, CH2Cl), 1.73 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ 130.1, 129.1, 45.4, 17.7.
2-Chloro-1-octene (8h).45 The following reagents were combined
in the amounts and method indicated according to general procedure 1.
1-Octene-3-ol (128 mg, 1.00 mmol), oxalyl chloride (85 μL, 1.0 mmol),
triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8h (94 mg, 64%)
by 1H NMR. 1H NMR (400 MHz, CDCl3) δ 5.89 (ddd, J =17.0 Hz, 10.1
and 7.3 Hz, 1H, H2CCHCHCl), 5.26 (d, J = 17.0 Hz, 1H, H2CC-
HCHCl), 5.13 (d, J = 10.1 Hz, 1H, H2CCHCHCl), 4.34 (m, 1H,
ClCH), 1.87ꢀ1.74 (m, 2H, ClCHCH2CH2), 1.61ꢀ1.10 (m, 6H,
3 ꢁ CH2), 0.91 (t, J = 6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ 141.4, 114.4, 63.2, 45.5, 31.2, 26.1, 22.6, 14.0. Also gave 1-chloro-2-
octene (25 mg, 17%) by 1H NMR. 1H NMR (400 MHz, CDCl3) δ 5.78
(dt, J = 15.2 and 7.1 Hz, 1H, ClCH2CH), 5.62 (m, 1H, ClCH2CHCH),
4.04 (dd, J = 7.1 and 0.8 Hz, 2H, ClCH2CH), 2.06 (dt, J = 7.1 and 6.8 Hz,
2H, ClCH2CHCHCH2), 1.42ꢀ1.28 (m, 6H, CH2CH2CH2CH3), 0.88
(t, J = 6.4 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ 136.4, 125.9,
45.6, 32.1, 31.4, 28.6, 22.6, 14.0.
(R)-(1-Chloroethyl)benzene (8m).17 To a solution of triphenyl-
phosphine oxide (42 mg, 0.15 mmol) in EtOAc (1.5 mL) was added
oxalyl chloride (15.0 μL, 0.177 mmol), and the reaction mixture was
stirred for 5 min. (S)-1-Phenylethyl alcohol (122 mg, 1.00 mmol) and
oxalyl chloride (87.0 μL, 1.03 mmol) as solutions in EtOAc (1.0 mL)
were then added simultaneously over 7 h via syringe pump at rt. The
solvent was removed in vacuo. Gave 8m 121 mg, 86% by 1H NMR.
tert-Butyl Chloride (8q).48 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 1. tert-Butyl chloride (74.1 mg, 1.00 mmol), oxalyl chloride
(85 μL, 1.0 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol). Gave
1
1
8q (34 mg, 37%) by H NMR. H NMR (400 MHz, CDCl3) δ 1.62
(s, 9H, CCl(CH3)3); 13C NMR (100 MHz, CDCl3) δ 67.6, 34.5.
5-(Benzyloxy)pentan-1-ol (5r).49 A solution of pentane-1,5-diol
(1.57 mL, 15.0 mmol) in THF (5 mL) was added dropwise to a
suspension of NaH (600 mg, 15.0 mmol, 60% in oil) in THF
(15 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then
a solution of benzyl chloride (0.584 mL, 5.00 mmol) in THF (5 mL) was
added dropwise, and the mixture was stirred at rt for 16 h. The reaction
mixture was diluted with EtOAc (60 mL). The organic layer was washed
with water (5 ꢁ 30 mL), brine (2 ꢁ 30 mL), dried over MgSO4, and
filtered. The solvent was removed in vacuo. Purification by flash column
chromatography (silica, 40% EtOAc/petroleum ether) afforded 5r as a
Cinnamylchloride (8i).17 The following reagents were combined
in the amounts and method indicated according to general procedure 1.
Cinnamyl alcohol (134 mg, 1.00 mmol), oxalyl chloride (85 μL,
1.0 mmol), triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 8i
134 mg, 88% by 1H NMR. Purification by flash column chromatography
(silica, 5% Et2O/petroleum ether) afforded 8i as a colorless oil (106 mg,
70%). 1H NMR (400 MHz, CDCl3) δ 7.30ꢀ7.49 (m, 5H, ArH), 6.69 (d,
J = 15.6 Hz, 1H, PhCHCH), 6.36 (dt, J = 15.6 and 7.2 Hz, 1H,
6759
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
colorless oil (463 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.41ꢀ7.28
(m, 5H, ArH), 4.54 (s, 2H, CH2Ph), 3.66 (t, J = 6.5 Hz, 2H, CH2OH),
3.52 (t, J = 6.5 Hz, 2H, CH2OCHPh), 1.73ꢀ1.57 (m, 4H,
OHCH2CH2CH2), 1.53ꢀ1.44 (m, 2H, CH2CH2OCH2Ph); 13C
NMR (100 MHz, CDCl3) δ 138.6, 128.4, 127.7, 127.6, 73.0, 70.4,
62.8, 32.6, 29.5, 22.5.
mixture was warmed to 0 °C and stirred for 6 h. The reaction mixture
was diluted with Et2O (50 mL), washed with water (6 ꢁ 50 mL), dried
over MgSO4, and filtered. The solvent was removed in vacuo. Purifica-
tion by flash chromatography (silica, 33% EtOAc/petroleum ether) gave
1
5u as colorless oil (1.75 g, 51%). H NMR (400 MHz, CDCl3) δ
7.71ꢀ7.65 (m, 4H, ArH), 7.46ꢀ7.36 (m, 6H, ArH), 3.69 (t, J = 6.4 Hz,
2H, CH2OH), 3.63 (t, J = 6.4 Hz, 2H, CH2OTBDPS), 1.65ꢀ1.52 (m,
4H, CH2CH2CH2CH2CH2), 1.48ꢀ1.39 (m, 2H, CH2CH2CH2-
CH2CH2), 1.06 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ
135.7, 134.2, 129.6, 127.7, 63.9, 63.1, 32.5, 32.3, 27.0, 22.1, 19.3.
tert-Butyl (5-Chloropentyloxy)diphenylsilane (8u).54 To a
solution of triphenylphosphine oxide (42 mg, 0.15 mmol) in CDCl3
(1.5 mL) was added oxalyl chloride (15.0 μL, 0.177 mmol), and the
reaction mixture was stirred for 5 min. Then 1.0 mL of a solution of
5-(tert-butyldiphenylsilyloxy)pentan-1-ol 5u (343 mg, 1.00 mmol) and
2,6-di-tert-butyl pyridine (344 mg, 1.80 mmol) in CDCl3 and 1.0 mL of a
solution of oxalyl chloride (87.0 μL, 1.03 mmol) in CDCl3 were added
via syringe pump over 7 h at rt. The solvent was removed in vacuo. Gave
((5-Chloropentyloxy)methyl)benzene (8r).50 To a solution of
triphenylphosphine oxide (21 mg, 0.075 mmol) in CDCl3 (0.75 mL)
was added oxalyl chloride (7.5 μL, 0.089 mmol), and the reaction
mixture was stirred for 5 min. 5r (97 mg, 0.050 mmol) and oxalyl
chloride (43.5 μL, 0.514 mmol) as solutions in CDCl3 (0.5 mL) were
then added simultaneously over 7 h via syringe pump at rt. The solvent
was removed in vacuo. Gave 8r 94 mg, 88% by 1H NMR. Purification by
flash chromatography (silica, 10% Et2O/petroleum ether) afforded 8r as
a white solid (70 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.26
(m, 5H, ArH), 4.52 (s, 2H, CH2Ph), 3.55 (t, J = 6.7 Hz, 2H, CH2Cl),
3.50 (t, J = 6.3 Hz, 2H, CH2OCHPh), 1.86ꢀ1.77 (m, 2H, ClCH2-
CH2CH2), 1.71ꢀ1.62 (m, 2H, ClCH2CH2CH2CH2), 1.61ꢀ1.50
(m, 2H, ClCH2CH2CH2); 13C NMR (100 MHz, CDCl3) δ 138.6,
128.4, 127.7, 127.6, 73.0, 70.1, 45.0, 32.5, 29.1, 23.7.
1
8u 231 mg, 64% by H NMR. Purification by flash chromatography
(silica, 17% Et2O/petroleum ether) gave 8u as a colorless oil (208 mg,
58%). 1H NMR (400 MHz, CDCl3) δ 7.73ꢀ7.69 (m, 4H, ArH),
7.49ꢀ7.39 (m, 6H, ArH), 3.71 (t, J = 6.1 Hz, 2H, CH2Cl), 3.54
(t, J = 6.7 Hz, 2H, CH2OTBDPS), 1.79 (m, 2H, ClCH2CH2-
CH2CH2CH2), 1.66ꢀ1.51 (m, 2H, ClCH2CH2CH2CH2CH2), 1.10
(s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 135.6, 134.1, 129.6,
127.7, 63.6, 45.1, 32.4, 31.8, 27.0, 23.3, 19.3.
Decyloxytriethylsilane (5s).51 To a solution of decanol (791 mg,
5.00 mmol) in DCM (25 mL) at 0 °C was added imidazole (1.36 g,
20.0 mmol), followed by TESCl (1.70 mL, 10.0 mmol). The mixture was
stirred for 1.5 h at 0 °C and 1 h at rt. Then Et2O (100 mL) was added,
and the organic layer was washed with water (3 ꢁ 50 mL) and brine
(50 mL), dried over MgSO4, and filtered. The solvent was removed in
vacuo. Purification by flash chromatography (silica, 10% EtOAc/petro-
leum ether) gave 5s as a colorless oil (1.03 g, 76%). 1H NMR (400 MHz,
CDCl3) δ 3.60 (t, J = 6.8 Hz, 2H, CH2OTES), 1.53 (m, 2H,
H2CCH2OTES), 1.37ꢀ1.20 (m, 14H, 7 ꢁ CH2), 0.97 (t, J = 7.9 Hz,
9H, Si(CH2CH3)3), 0.89 (t, J = 6.9 Hz, 3H, CH3), 0.61 (q, J = 7.9 Hz,
6H, Si(CH2CH3)3); 13C NMR (100 MHz, CDCl3) δ 63.1, 33.1, 32.0,
29.8, 29.7, 29.6, 29.4, 25.9, 22.8, 14.2, 6.9, 4.5.
N-(2-hydroxyethyl)benzamide (5v).55 To a solution of etha-
nolamine (4.55 mL, 75.0 mmol) and triethylamine (15.7 mL, 113
mmol) in DCM (75 mL) was added benzoyl chloride (4.35 mL, 37.5
mmol) via syringe pump over 1 h, and the mixture was stirred at rt for
another 0.5 h. The reaction mixture was then hydrolyzed with water
(50 mL), and the aqueous phase was extracted with DCM (3 ꢁ 50 mL).
The combined organic phase was dried over MgSO4 and filtered. The
solvent was removed in vacuo, and the crude product was crystallized
(EtOAc/Et2O), affording 5v as a white crystal (4.82 g, 78%). 1H NMR
(400 MHz, CDCl3) δ 7.80ꢀ7.74 (m, 2H, ArH), 7.52ꢀ7.46 (m, 1H,
ArH), 7.43ꢀ7.37 (m, 2H, ArH), 6.90 (br, 1H, NH), 3.84ꢀ3.77 (m, 2H,
CH2NH), 3.64ꢀ3.56 (m, 2H, CH2OH), 3.00 (br, 1H, OH); 13C NMR
(100 MHz, CDCl3) δ 168.8, 134.2, 131.7, 128.6, 127.1, 62.2, 42.9.
N-(2-chloroethyl) Benzamide (8v).56 The following reagents
were combined in the amounts and method indicated according
to general procedure 1. N-(2-Hydroxyethyl)benzamide 5v (165 mg,
0.995 mmol), oxalyl chloride (85.0 μL, 1.00 mmol), triphenylphosphine
oxide (42 mg, 0.15 mmol). Purification by flash column chromatography
(silica, 50% EtOaC/petroleum ether) afforded 8v as a white solid
1-Chlorodecane (8a).40 To a solution of triphenylphosphine
oxide (7.0 mg, 0.025 mmol) in CDCl3 (0.75 mL) was added oxalyl
chloride (3.0 μL, 0.035 mmol), and the reaction mixture was stirred for
5 min. Decyloxytriethylsilane 5s (136 mg, 0.499 mmol) and oxalyl
chloride (48.0 μL, 0.567 mmol) as solutions in CDCl3 (0.5 mL) were
then added simultaneously over 7 h via syringe pump at rt. Gave 8a
79 mg, 89% by 1H NMR.
Triethyl(octan-2-yloxy)silane (5t).52 To a solution of 2-octanol
(651 mg, 5.00 mmol) in DCM (25 mL) at 0 °C was added imidazole
(1.36 g, 20.0 mmol), followed by TESCl (1.70 mL, 10.0 mmol). The
mixture was stirred for 1.0 h at 0 °C and 16 h at rt. Then Et2O (100 mL)
was added, and the organic layer was washed with water (3 ꢁ 50 mL)
and brine (50 mL), dried over MgSO4, and filtered. The solvent was
removed in vacuo. Purification by flash chromatography (silica, 10%
1
(115 mg, 63%). H NMR (400 MHz, CDCl3) δ 7.83ꢀ7.77 (m, 2H,
ArH), 7.55ꢀ7.49 (m, 1H, ArH), 7.48ꢀ7.41 (m, 2H, ArH), 6.70 (br, 1H,
1
NH), 3.84ꢀ3.77 (m, 2H, CH2NH), 3.76ꢀ3.71 (m, 2H, CH2Cl); 13
C
EtOAc/petroleum ether) gave 5t as a colorless oil (0.91 g, 75%). H
NMR (400 MHz, CDCl3) δ 3.78 (m, 1H, CHOTES), 1.52ꢀ1.20 (m,
10H, 5 ꢁ CH2), 1.14 (d, J = 6.1 Hz, 3H, ClCHCH3), 0.97 (t, J = 7.9 Hz,
9H, Si(CH2CH3)3), 0.89 (t, J = 6.8 Hz, 3H, CH3), 0.60 (q, J = 7.9 Hz,
6H, Si(CH2CH3)3; 13C NMR (100 MHz, CDCl3) δ 68.6, 39.9, 32.0,
29.5, 25.9, 23.9, 22.7, 14.2, 7.0, 5.0
NMR (100 MHz, CDCl3) δ 167.7, 134.2, 131.9, 128.7, 127.0, 44.3, 41.7.
(S)-3,3,8,8-Tetraethyl-5-phenyl-4,7-dioxa-3,8-disiladecane
(5w). Styrene (573 μL, 5.00 mmol) was added to a cooled (0 °C)
suspension of AD-mix-R (7.00 g) in tBuOH/H2O (25 mL/25 mL) at
once, and the heterogeneous slurry was stirred vigorously at 0 °C for 6 h.
While the mixture was stirred at 0 °C, solid sodium sulfite (7.5 g) was
added, and the mixture was allowed to warm to room temperature and
stirred for 16 h. Ethyl acetate (50 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous phase was further
extracted with ethyl acetate (3 ꢁ 25 mL). The combined organic
extracts were dried over MgSO4 and filtered. The solvent was removed
in vacuo. Purification by flash chromatography (silica, 50% EtOAc/
petroleum ether) gave (S)-1-phenylethane-1,2-diol as a white solid
(()-2-Chlorooctane (8c).43 To a solution of triphenylphosphine
oxide (14 mg, 0.50 mmol) in CDCl3 (1.5 mL) was added oxalyl chloride
(5.0 μL, 0.059 mmol), and the reaction mixture was stirred for 5 min.
Triethyl(octan-2-yloxy)silane 5t (244 mg, 0.998 mmol) and oxalyl
chloride (97.0 μL, 1.15 mmol) as solutions in CDCl3 (1.0 mL) were
then added simultaneously over 7 h via syringe pump at rt. Gave 8c 147
mg, 99% by 1H NMR.
5-(tert-Butyldiphenylsilyloxy)pentan-1-ol (5u).53 TBDPSCl
(2.60 mL, 10.0 mmol) was added to a cooled (ꢀ25 °C) solution of
pentane-1,5-diol (2.62 mL, 25.0 mmol) and imidazole (1.36 g,
20.0 mmol) in DMF (10 mL) over 1 h via syringe pump. Then the
1
(658 mg, 95%). H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.29 (m, 5H,
ArH), 4.84 (dd, J = 8.1 and 3.6 Hz, 1H, PhCHOH), 3.79 (dd, J = 11.3
and 3.6 Hz, 1H, CH2OH), 3.68 (dd, J = 11.3 and 8.1 Hz, 1H, CH2OH);
6760
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
13C NMR (100 MHz, CDCl3). δ 140.6, 128.7, 128.1, 126.1, 74.8, 68.2.
To a solution of (S)-1-phenylethane-1,2-diol (207 mg, 1.50 mmol) in
DCM (5 mL) at 0 °C was added imidazole (613 mg, 9.00 mmol),
followed by TESCl (766 μL, 4.50 mmol). The mixture was stirred for 2.0
h at 0 °C and 16 h at rt. Then Et2O (20 mL) was added, and the organic
layer was washed with water (4 ꢁ 10 mL) and brine (10 mL), dried over
MgSO4, and filtered. The solvent was removed in vacuo. Purification by
flash chromatography (silica, 10% EtOAc/petroleum ether) gave 5w as a
colorless oil (502 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.22
(m, 5H, ArH), 4.72 (dd, J = 7.1 and 5.1 Hz, 1H, PhCHOTES), 3.69 (dd,
J = 10.2 and 7.1 Hz, 1H, CH2OTES), 3.57 (dd, J = 10.2 and 5.1 Hz, 1H,
CH2OTES), 0.95ꢀ0.88 (m, 18H, 2 ꢁ Si(CH2CH3)3), 0.61ꢀ0.51 (m.
12H, 2 ꢁ Si(CH2CH3)3); 13C NMR (100 MHz, CDCl3). δ 142.9,
128.0, 127.3, 126.5, 76.0, 69.6, 6.8, 6.8, 4.9, 4.4; IR vmax (CHCl3) 2957,
2912, 2877, 1492, 1241, 1124, 1098, 1075, 1006, 962 cmꢀ1; HRMS
(EI+) C20H38NaO2Si2 calcd 389.2303, found 389.2302.
2H, H2CCH2Br),1.48ꢀ1.20 (m,14 H, 7 ꢁ CH2), 0.89 (t, J = 6.9 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 34.0, 32.9, 31.9, 29.5, 29.5, 29.3,
28.8,28.2, 22.7, 14.1.
1-Bromodecane (11a).58 The following reagents were combined
in the amounts and method indicated according to general procedure 3.
Decanol (158 mg, 1.00 mmol), oxalyl chloride (110 μL, 1.30 mmol),
LiBr (217 mg, 2.50 mmol), triphenylphosphine oxide (42 mg,
0.15 mmol). Gave 11a 166 mg, 75% by 1H NMR. Purification by flash
column chromatography (silica, 5% Et2O/petroleum ether) afforded
11a as a colorless oil (135 mg, 61%).
1-Bromomethylbenzene (11b).59 The following reagents were
combined in the amounts and method indicated according to general
procedure 3. Benzyl alcohol (108 mg, 1.00 mmol), oxalyl chloride
(110 μL, 1.30 mmol), LiBr (261 mg, 3.01 mmol), triphenylphosphine
oxide (42 mg, 0.15 mmol). Gave 11b 121 mg, 71% by 1H NMR.
Purification by flash column chromatography (silica, 5% Et2O/petro-
(R)-(1,2-Dichloroethyl)benzene (8w).15 To a solution of tri-
phenylphosphine oxide (21 mg, 0.075 mmol) in CDCl3 (0.75 mL) was
added oxalyl chloride (8.0 μL, 0.095 mmol), and the reaction mixture
was stirred for 5 min. 5w (183 mg, 0.499 mmol) and oxalyl chloride
(94.0 μL, 1.11 mmol) as solutions in CDCl3 (0.5 mL) were then added
simultaneously over 7 h via syringe pump at rt. Gave 8w 60 mg, 68% by
1
leum ether) afforded 11b as a colorless oil (84 mg, 49%). H NMR
(400 MHz, CDCl3) δ 7.45ꢀ7.30 (m, 5H, ArH), 4.52 (s,2H, CH2); 13
NMR (100 MHz, CDCl3) δ 137.9, 129.1, 128.9, 128.5, 33.6.
C
(S)-2-Bromooctane (11c).59 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 3 (the alcohol and oxalyl chloride was added over 7 h).
(R)-(ꢀ)-2-Octanol (130 mg, 1.00 mmol), oxalyl chloride (110 μL, 1.30
1
1H NMR. H NMR (400 MHz, CDCl3) δ 7.46ꢀ7.35 (m, 5H, ArH),
5.02 (dd, J = 7.9 and 6.5 Hz, 1H, PhCHCl), 4.01 (dd, J = 11.3 and 6.5 Hz,
1H, CH2Cl), 3.94 (dd, J = 11.3 and 7.9 Hz, 1H, CH2Cl); 13C NMR
(100 MHz, CDCl3). δ 138.1, 129.2, 128.9, 127.5, 61.8, 48.4.
1,8-Dichlorooctane (8x).57 To a solution of triphenylphosphine
oxide (42 mg, 0.15 mmol) in CDCl3 (1.5 mL) was added oxalyl chloride
(15.0 μL, 0.177 mmol), and the reaction mixture was stirred for 5 min.
5x (73 mg, 0.499 mmol) as a solution in THF (1.0 mL) and oxalyl
chloride (87.0 μL, 1.03 mmol) as solution in CDCl3 (1.0 mL) were then
added simultaneously over 7 h via syringe pump at rt. The solvent was
removed in vacuo. Purification by flash chromatography (silica, 100%
petroleum ether) afforded 8x as a colorless oil (65 mg, 71%). 1H NMR
(400 MHz, CDCl3) δ 3.54 (t, J = 6.8 Hz, 4H, 2 ꢁ CH2Cl), 1.78 (m, 4H,
2 ꢁ ClCH2CH2), 1.45 (m, 4H, 2 ꢁ ClCH2CH2CH2), 1.34 (m, 4H, 2 ꢁ
ClCH2CH2CH2CH2); 13C NMR (100 MHz, CDCl3). δ 45.2, 32.6,
28.8, 26.8.
mmol), LiBr (127 mg, 1.46 mmol), triphenylphosphine oxide (42 mg,
1
0.15 mmol). Gave 11c 149 mg, 77% by H NMR. 11c [R]22 +38.2
D
(c 0.58, CHCl3), alcohol [R]22 ꢀ7.42, (c 0.97, CHCl3); H NMR
1
D
(400 MHz, CDCl3) δ 4.14 (m, 1H, ClCH), 1.89ꢀ1.73 (m, 2H,
H2CCHCl), 1.71 (d, J = 6.6 Hz,3H, CH3), 1.57ꢀ1.24 (m, 8H, 4 ꢁ
CH2CH3), 0.90 (t, J = 6.7 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ 52.1, 41.3, 31.8, 28.7, 27.8, 26.5, 22.7, 14.1.
3-Phenyl-1-bromopropane (11e).60 The following reagents
were combined in the amounts and method indicated according to
general procedure 3. 3-Phenyl-1-propanol (136 mg, 1.00 mmol), oxalyl
chloride (110 μL, 1.30 mmol), LiBr (200 mg, 2.30 mmol), triphenylpho-
sphine oxide (42 mg, 0.15 mmol). Gave 11e 133 mg, 67% by 1H NMR.
Purification by flash column chromatography (silica, 5% Et2O/petroleum
ether) afforded 11e as a colorless oil (116 mg, 58%). 1H NMR (400 MHz,
CDCl3) δ 7.36ꢀ7.30 (m, 2H, ArH), 7.27ꢀ7.20 (m, 3H, ArH), 3.43
(t, J = 6.5 Hz, 2H, PhCH2CH2CH2Cl), 2.82 (t, J = 7.3 Hz, 2H,
PhCH2CH2CH2Cl), 2.21 (m, 2H, PhCH2CH2CH2Cl); 13C NMR
(100 MHz, CDCl3) δ 140.6, 128.6, 128.6, 126.2, 34.2, 34.0, 33.1.
1-Bromodec-2-yne (11f).61 The following reagents were combined
in the amounts and method indicated according to general procedure 3.
2-Deyn-1-ol (154 mg, 1.00 mmol), oxalyl chloride (110 μL, 1.30 mmol),
LiBr (217 mg, 2.50 mmol), triphenylphosphine oxide (42 mg,
0.15 mmol). Gave 11f 163 mg, 75% by 1H NMR. Purification by flash
column chromatography (silica, 5% Et2O/petroleum ether) afforded
Synthesis of Bromides
General Procedure 3. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in either CHCl3 or CDCl3 (1.5 mL) were added
oxalylchloride (16.5μL, 0.195 mmol) and LiBr(130ꢀ304 mg, 1.50ꢀ3.50
mmol), and the reaction mixture stirred for 5 min. The appropriate
alcohol (1.00 equiv) and oxalyl chloride (93.5 μL, 1.11 mmol) as
solutions in either CHCl3 or CDCl3 (1.0 mL) were then added
simultaneously over 5 h via syringe pump at rt. The reaction mixture
was filtered. The solvent was removed in vacuo. Further purification by
flash chromatography (silica, 5ꢀ10% Et2O/petroleum ether) gave the
pure bromides.
1
11f as a colorless oil (106 mg, 49%). H NMR (400 MHz, CDCl3) δ
3.93 (t, J = 2.3 Hz, 2H, CCCH2Cl), 2.24 (m, 2H, H2CCH2CC), 1.51
(m, 2H, H2CCH2CH2CC), 1.41ꢀ1.24 (m, 8H, 4 ꢁ CH2CH3), 0.89
(t, J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 88.4, 75.3,
31.7, 28.8, 28.8, 28.4, 22.7, 19.0, 15.9, 14.1.
General Procedure 4. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in either CHCl3 or CDCl3 (1.5 mL) was added
oxalyl bromide (14 μL, 0.15 mmol), and the reaction mixture stirred for
5 min. The appropriate alcohol (1.00 equiv) and oxalyl bromide (80 μL,
0.85 mmol) as solutions in either CHCl3 or CDCl3 (1.0 mL) were then
added simultaneously over 7 h via syringe pump at rt. The solvent was
removed in vacuo. Further purification by flash chromatography (silica,
5ꢀ10% Et2O/petroleum ether) gave the pure bromides.
1-Bromo-2-butene (11g).62 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 3. 2-Buten-1-ol (72 mg, 1.0 mmol), oxalyl chloride (110 μL,
1.30 mmol), LiBr (261 mg, 3.01 mmol), triphenylphosphine oxide
1
1
(42 mg, 0.15 mmol). Gave 11g 100 mg, 73% by H NMR. H NMR
(400 MHz, CDCl3) δ 5.85ꢀ5.61 (m, 2H, HCdCH), 3.95 (d, J = 7.4 Hz,
2H, BrCH2), 1.74 (d, J = 5.9 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 131.5, 127.6, 33.6, 17.7.
1-Bromodecane (11a).58 The following reagents were combined
in the amounts and method indicated according to general procedure 4.
Decanol (158 mg, 1.00 mmol), oxalyl bromide (94 μL, 1.0 mmol),
triphenylphosphine oxide (42 mg, 0.15 mmol). Gave 11a 106 mg, 48%
Cinnamyl Bromide (11i).63 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 3. Cinnamyl alcohol (134 mg, 1.00 mmol), oxalyl chloride
(110 μL, 1.30 mmol), LiBr (261 mg, 3.01 mmol), triphenylphosphine
1
by H NMR. Purification by flash column chromatography (silica, 5%
Et2O/petroleum ether) afforded 11a as a colorless oil (52 mg, 24%). 1H
NMR (400 MHz, CDCl3) δ 3.40 (t, J = 6.9 Hz, 2H, BrCH2), 1.86 (m,
6761
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
oxide (42 mg, 0.15 mmol). Gave 11i 136 mg, 69% by 1H NMR. 1H NMR
(400 MHz, CDCl3) δ 7.46ꢀ7.28 (m, 5H, ArH), 6.68 (d, J = 15.5 Hz, 1H,
PhCHCH), 6.44 (dt, J = 15.5 and 7.7 Hz, 1H, HCCH2Cl), 4.19
(d, J =7.7 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ 135.5,
134.3, 128.4, 123.1, 126.5, 124.9, 33.4.
CDCl3) δ 7.90ꢀ7.84 (m, 3H, ArH), 7.79ꢀ7.68 (m, 12H, ArH), 3.89 (d,
3JHP = 4.4 Hz, 2H, OCH2), 0.95 (s, 9H, CO(CH3)3); 13C NMR (100
MHz, CDCl3) δ 136.6 (d, J = 3.1 Hz), 133.3 (d, J = 11.5 Hz), 130.7 (d, J
= 13.8 Hz), 118.5 (d, J = 106.6 Hz), 80.6 (d, J = 9.2 Hz), 32.8 (d, J = 6.9
Hz), 25.9; 31P NMR (162 MHz, CDCl3) δ 61.9.
Bromocyclohexene (11k).64 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 3. Cyclohexanol (98.1 mg, 1.00 mmol), oxalyl chloride
(110 μL, 1.30 mmol), LiBr (217 mg, 2.50 mmol), triphenylphosphine
Decyl 2-Chloro-2-oxoacetate (9a). To a solution of oxalyl
chloride (127 mg, 1.00 mmol) in CHCl3 (1.5 mL) was added decanol
(158 mg, 1.00 mmol) as a solution in CHCl3 (1.0 mL) via syringe pump
over 0.5 h. The solvent was removed in vacuo, affording chlorooxalate 9a
(229 mg, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.35
(t, J = 6.8 Hz, 2H, H2CO), 1.76 (m, 2H, H2CCH2O), 1.44ꢀ1.20 (m,
14H, 7 ꢁ CH2), 0.88 (t, J= 6.4 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 161.2, 155.9, 69.2, 31.9, 29.5, 29.5, 29.3, 29.1, 28.3, 25.7, 22.7,
1
1
oxide (42 mg, 0.15 mmol). Gave 11k 118 mg, 73% by H NMR. H
NMR (400 MHz, CDCl3) δ 5.95ꢀ5.89 (m, 1H, HCdCHCHCBr),
5.85ꢀ5.79 (m, 1H, HCdCHCHBr), 4.85 (m, 1H, HCdCHCHBr),
2.28ꢀ1.61 (m, 6H, CH2CH2CH2CHdCH); 13C NMR (100 MHz,
CDCl3) δ 131.1, 128.9, 49.1, 32.7, 24.7, 18.6.
14.1; IR vmax (CDCl3) 2909 (CH), 1780 (CO), 1467, 1378 cmꢀ1
;
3β-Bromo-5-cholestene (11l).47 To a solution of triphenylpho-
sphine oxide (35 mg, 0.13 mmol) in CHCl3 were added oxalyl chloride
(14 μL, 0.17 mmol) and LiBr (109 mg, 1.26 mmol), and the reaction
mixture was stirred for 5 min. Cholesterin (193 mg, 0.499 mmol) and
oxalyl chloride (41 μL, 0.49 mmol) as solutions in CHCl3 (1.0 mL) were
then added simultaneously over 7 h via syringe pump at rt. The reaction
mixture was filtered. The solvent was removed in vacuo. Gave 11l 99 mg,
44% by 1H NMR. 1H NMR (400 MHz, CDCl3) δ 5.37 (m, 1H), 3.92
(m, 1H), 2.75 (m,1H), 2.58 (m,1H), 2.20ꢀ0.85 (m, 38H), 0.68 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 141.6, 122.4, 56.7, 56.2, 52.6, 50.2, 44.3,
42.3, 40.4, 39.7, 39.6, 36.4, 36.2, 35.8, 34.4, 31.8, 31.8, 28.3, 28.0, 24.3,
23.9, 22.9, 22.6, 20.9, 19.3, 18.8, 11.9.
HRMS (EI+) (of the CH3OH derived methylesters) C13H24NaO4 calcd
267.1567, found 267.1560.
Didecyl Oxalate (10a). To asolution ofoxalylchloride (63mg, 0.50
mmol) in CHCl3 (2.5 mL) was added decanol (158 mg, 1.00 mmol). The
reaction mixture was stirred at rt for 2 h. The solvent was removed in
vacuo, affording oxalate 10a (175 mg, 94%) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 4.30 (t, J = 6.8 Hz, 2H, H2CO), 1.75 (m, 2H,
H2CCH2O), 1.23ꢀ1.49 (m, 14H, 7 ꢁ CH2), 0.90 (t, J = 6.9 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 158.1, 67.2, 31.9, 29.6, 29.5,
29.3, 29.2, 28.3, 25.8, 22.7, 14.2; IR vmax (CDCl3) 2928 (CH), 1763
(CO), 1739, (CO), 1467, 1318, 1185 cmꢀ1; HRMS (EI+) C22H42O4
calcd 370.3083, found 370.3077.
Decyl 2-Bromo-2-oxoacetate (12a). To a solution of oxalyl
bromide (94 μL, 1.0 mmol) in CHCl3 (1.5 mL) was added decanol
(158 mg, 1.00 mmol) as a solution in CHCl3 (1.0 mL) via syringe pump
over 0.5 h. The solvent was removed in vacuo, affording 12a (249 mg,
85%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 4.35 (t, J = 6.7 Hz,
2H, H2CO), 1.76 (m, 2H, H2CCH2O), 1.44ꢀ1.21 (m, 14H, 7 ꢁ CH2),
0.88 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 157.8,
155.8, 69.3, 31.9, 29.5, 29.4, 29.3, 29.1, 28.2, 25.6, 22.7, 14.1; IR vmax
(CHCl3) 2928 (CH), 1793 (CO), 1755 (CO),1466, 1261 cmꢀ1; HRMS
(EI+) (of the CH3OH derived methylester) C13H24NaO4 calcd
267.1567, found 267.1560.
1-Bromoethyl Benzene (11m).65 The following reagents were
combined in the amounts and method indicated according to general
procedure 3. 1-Phenylethyl alcohol (122 mg, 1.00 mmol, oxalyl chloride
(110 μL, 1.30 mmol), LiBr (217 mg, 2.50 mmol), triphenylphosphine
1
oxide (42 mg, 0.15 mmol). Gave 11m 137 mg, 74% by H NMR.
1H NMR (400 MHz, CDCl3) δ 7.48ꢀ7.28 (m, 5H, ArH), 5.25
(q, J = 6.9 Hz, 1H, ClCH), 2.08 (d, J = 6.9 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 143.3, 128.7, 128.4, 126.9, 49.6, 26.9.
tert-Butyl Bromide (11q).59 The following reagents were com-
bined in the amounts and method indicated according to general
procedure 3. tert-Butyl chloride (74.1 mg, 1.00 mmol), oxalyl chloride
(110 μL, 1.30 mmol), LiBr (217 mg, 2.50 mmmol), triphenylphosphine
oxide (42 mg, 0.15 mmol). Gave 11q 99 mg, 72% by 1H NMR. 1H NMR
(400 MHz, CDCl3) δ 1.80 (s, 9H, CBr(CH3)3); 13C NMR (100 MHz,
CDCl3) δ 63.0, 36.5.
2-(Decyloxy)-2-oxoacetic Acid (13a). To a solution of oxalyl
chloride (127 mg, 1.00 mmol) in CHCl3 (1.5 mL) was added decanol
(158 mg, 1.00 mmol) as a solution in CHCl3 (1.0 mL) via syringe pump
over 0.5 h. Water (100 μL) was then added, and the reaction mixture
was stirred for 2 h. The solvent was removed in vacuo, affording 13a
Synthesis of Intermediates and Oxalates
Alkoxyphosphonium Salt (6a). To a solution of triphenylpho-
sphine oxide (28 mg, 0.10 mmol) in CDCl3 (0.35 mL) was added oxalyl
chloride (8.8 μL, 0.10 mmol), and the reaction mixture was stirred for
5 min. Decanol (16 mg, 0.10 mmol) was then added. The NMR
spectrum was acquired <2 min. 31P NMR (162 MHz, CDCl3) δ 61.7.
Alkoxyphosphonium Salt (6n). To a solution of triphenylpho-
sphine oxide (139 mg, 0.499 mmol) in CDCl3 (2.0 mL) was added
oxalyl chloride (0.0423 mL, 0.500 mmol), and the reaction mixture was
stirred for 5 min. Cyclohexanol (50.0 mg, 0.499 mmol) was then added,
1
1
(184 mg, 80%) by H NMR. H NMR (400 MHz, CDCl3) δ 4.29
(t, J = 6.8 Hz, 2H, H2CO), 1.72 (m, 2H, H2CCH2O), 1.41ꢀ1.17
(m, 14H, 7 ꢁ CH2), 0.86 (t, J= 7.2 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 159.1, 158.2, 68.0, 31.9, 29.5, 29.4, 29.3, 29.1, 28.2, 25.6, 22.7,
14.1; IR vmax (CHCl3) 2922 (CH), 1732 (CO), 1755 (CO),1466,
1377 cmꢀ1; HRMS (EI+) (of the CH3OH derived methylester)
C13H24NaO4 calcd 267.1567, found 267.1560.
Benzyl 2-Chloro-2-oxoacetate (9b).67 To a solution of oxalyl
chloride (85 μL, 1.0 mmol) in CHCl3 (1.5 mL) was added benzyl
alcohol (108 mg, 1.00 mmol) as a solution in CHCl3 (1.0 mL) via
syringe pump over 0.5 h. The solvent was removed in vacuo, affording
chlorooxalate 9b (146 mg, 79%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.45ꢀ7.36 (m, 5H, ArH), 5.38 (s, 2H, CH2O); 13C NMR
(100 MHz, CDCl3) δ 161.0, 155.6, 133.4, 129.4, 129.0, 128.8, 70.4.
Dibenzyl Oxalate (10b)68. To a solution of oxalyl chloride
(0.042 mL, 0.50 mmol) in CHCl3 (2.5 mL) was added benzyl alcohol
(108 mg, 1.00 mmol). The reaction mixture was stirred at rt for 2 h. The
solvent was removed in vacuo, affording oxalate 10b (214 mg, 79%). 1H
NMR (400 MHz, CDCl3) δ 7.46ꢀ7.36 (m, 10H, ArH), 5.32 (s, 4H,
H2COCOCOOCH2); 13C NMR (100 MHz, CDCl3) δ 157.6, 134.2,
128.9, 128.8, 128.7, 68.7.
1
and the reaction mixture was stirred for 2 min. H NMR (400 MHz,
3
CDCl3) δ 7.89ꢀ7.69 (m, 15H, ArH), 4.58 (m, JHP = 8.0 Hz, 1H,
HCO), 1.95ꢀ1.20 (m, 10H, 5 ꢁ CH2), 13C NMR (100 MHz, CDCl3) δ
136.4 (d, J = 3.1 Hz), 133.2 (d, J = 11.5 Hz), 130.6 (d, J = 13.8 Hz), 119.5
(d, J = 106.6 Hz), 84.3 (d, J = 9.2 Hz), 33.2 (d, J = 3.1 Hz), 24.2, 23.1; 31P
NMR (162 MHz, CDCl3) δ 59.2.
Alkoxyphosphonium Salt (6p).66 To a solution of triphenylpho-
sphine oxide (278 mg, 1.00 mmol) in CDCl3 (3.0 mL) was added oxalyl
chloride (85 μL, 1.0 mmol), and the reaction mixture was stirred for 5
min. Neopentanol (88.1 mg, 1.00 mmol) was added, and the reaction
mixture was stirred for 5 min. The crude reaction mixture was
concentrated in vacuo, and the crude product was crystallized
1
(MeCN/Et2O), affording 4p as white crystals. H NMR (400 MHz,
6762
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
2-(Benzyloxy)-2-oxoacetic Acid (13b).69 To a solution of
oxalyl chloride (102 μL, 1.21 mmol) in CDCl3 (1.0 mL) was added
benzyl alcohol (108 mg, 1.00 mmol) as a solution in CDCl3 (1.0 mL) via
syringe pump over 0.5 h. Water (100 μL) was then added, and the
reaction mixture was stirred for 16 h. The organic phase was separated,
affording 13b (168 mg, 93%). 1H NMR (400 MHz, CDCl3) δ8.16 (br,
1H, COOH), 7.44ꢀ7.33 (m, 5H, ArH), 5.31 (s, 2H, CH2O); 13C NMR
(100 MHz, CDCl3) δ158.7, 157.9, 133.7, 129.1, 128.9, 128.8, 69.3.
Benzyl 2-Bromo-2-oxoacetate (12b). To a solution of oxalyl
bromide (113 μL, 1.20 mmol) in CHCl3 (1.5 mL) was added benzyl
alcohol (108 mg, 1.00 mmol) as a solution in CHCl3 (1.0 mL) via
syringe pump over 0.5 h. The solvent was removed in vacuo, affording
bromooxalate 12b (208 mg, 91%) as an orange oil. 1H NMR (400 MHz,
CDCl3) δ 7.47ꢀ7.40 (m, 5H, ArH), 5.38 (s, 2H, H2CO); 13C NMR
(100 MHz, CDCl3) δ 157.7, 155.6, 133.3, 129.4, 129.0, 128.8, 70.6; IR
another 2 h. The THF was removed in vacuo. The reaction mixture was
diluted with water and extracted with EtOAc. The extract was dried over
MgSO4 and filtered. The solvent was removed in vacuo. Give pure
phosphine oxide.
2-(Diphenylphosphoryl)pyridine (1b).70 The following re-
agents were combined in the amounts and method indicated according
to general procedure 5. Diphenyl-2-pyridyl-phosphine (1.32 g,
5.01 mmol), H2O2 (7.08 mL, 25.0 mmol, 12% in water). Gave 1b
1.22 g, 88%. 1H NMR (400 MHz, CDCl3) δ 8.78 (m, 1H, ArH), 8.31
(m, 1H, ArH), 7.93ꢀ7.83 (m, 5H, ArH), 7.56ꢀ7.37 (m,7H, ArH); 13
C
NMR (100 MHz, CDCl3) δ 156.3 (d, J = 131.9 Hz), 150.2 (d, J = 19.9
Hz), 136.3 (d, J = 9.2 Hz), 132.2 (d, J = 9.2 Hz), 132.0 (d, J = 2.3 Hz),
132.0 (d, J = 103.6 Hz), 128.6, 128.5 (d, J = 12.3 Hz), 125.4 (d,
J = 3.1 Hz); 31P NMR (162 MHz, CDCl3) δ 21.4.
Tris(4-fluorophenyl)phosphine Oxide (1c).71 The following
reagents were combined in the amounts and method indicated accord-
ing to general procedure 5. Tris(4-fluorophenyl)phosphine (1.00 g,
3.16 mmol), H2O2 (4.48 mL, 15.8 mmol, 12% in water). Gave 1c 909
vmax (CHCl3) 1786 (CO), 1758 (CO),1456, 1263 cmꢀ1
.
Oct-1-en-3-yl 2-Chloro-2-oxoacetate (9h). To a solution of
oxalyl chloride (102 μL, 1.19 mmol) in CHCl3 (1.5 mL) was added
1-octen-3-ol (128 mg, 1.00 mmol) as a solution in CHCl3(1.0 mL)
via syringe pump over 0.5 h. The solvent was removed in vacuo,
affording chlorooxalate 9h (146 mg, 79%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 5.82 (ddd, J = 17.1 Hz, 10.5 Hz and 7.2 Hz, 1H,
H2CCHCHO), 5.41ꢀ5.28 (m, 3H, H2CCHCHO), 1.86ꢀ1.66 (m, 2H,
OCHCH2), 1.43ꢀ1.24 (m, 6H, 3 ꢁ CH2), 0.89 (t, J = 6.7, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 161.2, 155.2, 134.3, 119.5, 80.9, 33.8,
31.4, 24.6, 22.5, 14.0; IR vmax (CHCl3) 1791 (CO), 1754 (CO),1467,
1267 cmꢀ1. We were unable to determine the HRMS of either 9h or its
derived methyl ester.
5-(tert-Butyldiphenylsilyloxy)pentyl 2-Chloro-2-oxoace-
tate (9u). To a solution of oxalyl chloride (32.0 μL, 0.378 mmol) in
CHCl3 (0.75 mL) was added 5-(tert-butyldiphenylsilyloxy)pentan-1-ol
5u (100 mg, 0.292 mmol) as a solution in CHCl3 (0.75 mL) via syringe
pump over 1 h. The solvent was removed in vacuo, affording 9u (119 mg,
95%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.72ꢀ7.66 (m,
4H, ArH), 7.48ꢀ7.38 (m, 6H, ArH), 4.36 (t, J = 6.7 Hz, 2H, CH2OCO),
3.71 (t, J = 6.1 Hz, 2H, CH2OTBDPS), 1.78 (m, 2H, OCOCH2-
CH2CH2CH2CH2), 1.67ꢀ1.58 (m, 2H, OCOCH2CH2CH2CH2CH2),
1.57ꢀ1.47 (m, 2H, OCOCH2CH2CH2CH2CH2), 1.08 (s, 9H, C-
(CH3)3); 13C NMR (100 MHz, CDCl3) δ 161.1, 155.8, 135.6, 134.0,
129.7, 127.7, 69.0, 63.4, 31.9, 28.0, 26.9, 22.1, 19.3; IR vmax (CHCl3)
3011, 1788 (CO), 1758 (CO), 1272, 1111, 989 cmꢀ1. HRMS was
obtained on the corresponding acid (ESIꢀ) C23H29O5Si1 [M ꢀ 1]ꢀ
calcd 413.1790, found 413.1808.
2-(5-(tert-Butyldiphenylsilyloxy)pentyloxy)-2-oxoacetic
Acid (13u). To a solution of oxalyl chloride (32.0 μL, 0.378 mmol) in
CHCl3 (0.75 mL) was added 5-(tert-butyldiphenylsilyloxy)pentan-1-ol
5u (100 mg, 0.292 mmol) as a solution in CHCl3 (0.75 mL) via syringe
pump over 0.5 h. Water (1.00 mL) was then added, and the reaction
mixture was stirred for 2 h. The reaction mixture was diluted with EtOAc
(10 mL), washed with brine (10 mL), dried over MgSO4, and filtered,
The solvent was removed in vacuo. Gave 13u as a white solid (89.6 mg,
75%). 1H NMR (400 MHz, CDCl3) δ 7.70ꢀ7.65 (m, 4H, ArH),
7.46ꢀ7.36 (m, 6H, ArH), 4.31 (t, J = 6.7 Hz, 2H, CH2OCO), 3.68
(t, J = 6.2 Hz, 2H, CH2OTBDPS), 1.75 (m, 2H, OCOCH2CH2-
CH2CH2CH2), 1.65ꢀ1.56 (m, 2H, OCOCH2CH2CH2CH2CH2),
1.53ꢀ1.43 (m, 2H, OCOCH2CH2CH2CH2CH2), 1.06 (s, 9H, C-
(CH3)3); 13C NMR (100 MHz, CDCl3) δ 158.6, 158.3, 135.6, 134.0,
129.7, 127.7, 68.0, 63.6, 32.0, 28.0, 26.9, 22.1, 19.3; IR vmax (CHCl3) 3446,
2933 (CH), 1802 (CO), 1737 (CO), 1187, 1111, 909 cmꢀ1; HRMS
(ESIꢀ) C23H29O5Si1 [M ꢀ 1]ꢀ calcd 413.1790, found 413.1808.
Synthesis of Phosphine Oxides
1
mg, 87%. H NMR (400 MHz, CDCl3) δ 7.65 (m, 6H, ArH), 7.18
(m, 6H, ArH); 13C NMR (100 MHz, CDCl3) δ 134.6 (d, J = 8.4 Hz),
134.5 (d, J = 8.4 Hz), 116.3 (d, J = 13.0 Hz), 116.1 (d, J = 13 Hz); 31P
NMR (162 MHz, CDCl3) δ 26.9.
Tri-2-furylphosphine Oxide (1d).72 The following reagents
were combined in the amounts and method indicated according to
general procedure 5. Tri(2-furyl)phosphine (1.00 g, 4.31 mmol), H2O2
(6.12 mL, 21.6 mmol, 12% in water). Gave 1d 884 mg, 83%. 1H NMR
(400 MHz, CDCl3) δ 7.74 (m, 1H, CHCHCHO), 7.18 (m, 1H,
CHCHCHO), 6.56 (m, 1H, CHCHCHO); 13C NMR (100 MHz,
CDCl3) δ 149.0 (d, J = 9.2 Hz), 145.9 (d, J = 145.9 Hz), 123.7
(d, J = 22.1 Hz), 111.2 (d, J = 9.2 Hz); 31P NMR (162 MHz, CDCl3)
δ ꢀ11.4.
Tri(o-tolyl)phosphine Oxide (1e).73 The following reagents
were combined in the amounts and method indicated according to
general procedure 5. Tri(o-tolyl)phosphine (2.44 g, 8.02 mmol), H2O2
1
(11.3 mL, 39.9 mmol, 12% in water). Gave 1e 2.54 g, 99%. H NMR
(400 MHz, CDCl3) δ 7.48ꢀ7.41 (m, 3H, ArH), 7.35ꢀ7.30 (m, 3H,
ArH), 7.21ꢀ7.06 (m, 6H, ArH), 2.50 (s, 9H, 3 ꢁ CH3); 13C NMR
(100 MHz, CDCl3) δ 143.6 (d, J = 7.7 Hz), 133.0 (d, J = 13.0 Hz), 132.1
(d, J = 10.7 Hz), 132.0 (d, J = 2.3 Hz), 130.5 (d, J = 101.4 Hz), 125.6
(d, J = 12.3 Hz), 22.1 (d, J = 3.8 Hz); 31P NMR (162 MHz, CDCl3)
δ 37.6.
Tris(4-methoxyphenyl)phosphine Oxide (1f).74 The follow-
ing reagents were combined in the amounts and method indicated
according to general procedure 5. Tris(4-methoxyphenyl)phosphine
(2.82 g, 8.00 mmol), H2O2 (11.3 mL, 39.9 mmol, 12% in water). Gave 1f
2.84 g, 96%. 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 6H, ArH), 6.95
(m, 6H, ArH), 3.83 (s, 9H, 3 ꢁ CH3); 13C NMR (100 MHz, CDCl3) δ
162.5 (d, J = 2.3 Hz), 134.0 (d, J = 11.5 Hz), 124.2 (d, J = 111.2 Hz),
114.1 (d, J = 13.8 Hz), 55.4; 31P NMR (162 MHz, CDCl3) δ 29.9.
Tris(2,6-dimethoxyphenyl)phosphine Oxide (1g).74 The
following reagents were combined in the amounts and method indicated
according to general procedure 5. Tris (2,6-dimethoxyphenyl)pho-
sphine (2.21 g, 4.99 mmol), H2O2 (7.08 mL, 25.0 mmol, 12% in water).
Gave 1g 2.07 g, 90%. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 8.3 Hz,
3H, ArH), 6.50 (dd, J = 8.4 and 4.9 Hz, 6H, ArH), 3.52 (s, 18H,
6 ꢁ CH3); 13C NMR (100 MHz, CDCl3) δ 162.4, 132.5, 113.6
(d, J = 113.6), 104.5 (d, J = 6.9 Hz), 55.9; 31P NMR (162 MHz, CDCl3)
δ 17.0.
Diphenylmethylphosphine Oxide (1h).75 The following re-
agents were combined in the amounts and method indicated according
to general procedure 5. Tri(2-furyl)phosphine (0.963 g, 4.81 mmol),
H2O2 (6.80 mL, 24.0 mmol, 12% in water). Gave 1h 777 mg, 75%. 1H
NMR (400 MHz, CDCl3) δ 7.77ꢀ7.70 (m, 4H, ArH), 7.56ꢀ7.44
(m, 6H, ArH), 2.03 (d, J = 13.2 Hz, CH3); 13C NMR (100 MHz,
General Procedure 5. To a solution of phosphine (1.00 equiv) in
THF (5 mL/1 mmol phosphine) was added H2O2 (5.00 equiv, 12% in
water) via syringe pump over 30 min, and the mixture was stirred for
6763
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
CDCl3) δ 134.0 (d, J = 101.6 Hz), 131.9 (d, J = 3.1 Hz), 130.6
(d, J = 10.0 Hz), 128.7 (d, J = 11.5 Hz), 16.6 (d, J = 73.2 Hz); 31P NMR
(162 MHz, CDCl3) δ 30.2.
Chlorophosphonium Chloride (3j).77 To a solution of tribu-
tylphosphine oxide (109 mg, 0.499 mmol) in CDCl3 (2.0 mL) was
added oxalyl chloride (63 μL, 0.74 mmol), and the reaction mixture was
stirred for 5 min. 1H NMR (400 MHz, CDCl3) δ 3.11 (m, 6H,
P(CH2CH2CH2CH3)3), 1.69ꢀ1.57 (m, 6H, P(CH2CH2CH2CH3)3),
1.47 (m, 6H, P(CH2CH2 CH2CH3)3), 0.90 (t, J = 7.3 Hz, 9H,
P(CH2CH2 CH2CH3)3); 13C NMR (100 MHz, CDCl3) δ 27.1
(d, J = 40.6 Hz), 23.5 (d, J = 6.1 Hz), 23.3 (d, J = 17.6 Hz), 13.3; 31P
NMR (162 MHz, CDCl3) δ 106.6.
Synthesis of Chlorophosphonium Chlorides
Chlorophosphonium Chloride (3a).76 To a solution of triphe-
nylphosphine oxide (139 mg, 0.499 mmol) in CDCl3 (2.0 mL) was
added oxalyl chloride (63 μL, 0.74 mmol), and the reaction mixture was
stirred for 5 min. 1H NMR (400 MHz, CDCl3) δ 7.88ꢀ7.81 (m, 3H,
ArH), 7.76ꢀ7.68 (m, 6H, ArH), 7.67ꢀ7.58 (m, 6H, ArH); 13C NMR
(100 MHz, CDCl3) δ 137.2 (d, J = 3.1 Hz), 133.3 (d, J = 13.0 Hz), 130.8
(d, J = 15.3 Hz), 118.3 (d, J = 93.5 Hz); 31P NMR (162 MHz, CDCl3)
δ 64.5.
Chlorophosphonium Chloride (3k).81 To a solution of tribu-
tylphosphine oxide (109 mg, 0.499 mmol) in CDCl3 (2.0 mL) was
added oxalyl chloride (63 μL, 0.74 mmol), and the reaction mixture was
stirred for 5 min. 1H NMR (400 MHz, CDCl3) δ 8.19ꢀ8.11 (m, 2H,
ArH), 7.74ꢀ7.69 (m, 1H, ArH), 7.66ꢀ7.59 (m, 2H, ArH), 6.54 (m, 1H,
PCHdC), 3.64ꢀ3.56 (m, 2H, PCH2), 3.48ꢀ3.38 (m, 2H, PCH2CH2),
2.33 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 183.6 (d, J = 30.6
Hz), 136.1 (d, J = 3.1 Hz), 132.2 (d, J = 13.8 Hz), 130.2 (d, J = 15.3 Hz),
120.8 (d, J = 91.3 Hz), 109.5 (d, J = 85.9 Hz), 37.3 (d, J = 8.4 Hz), 28.9
(d, J = 52.2 Hz), 22.4 (d, J = 19.9 Hz); 31P NMR (162 MHz, CDCl3)
δ 97.7.
Experimental Details of Control Experiments Tabulated in
Supporting Information. Table 1, entry 1; Table 2 entries 1, 10,
and 11. To CDCl3 (1.5 mL) was added oxalyl chloride (12 μL,
0.14 mmol), and the mixture was stirred for 5 min. Decanol (158 mg,
1.00 mmol) and oxalyl chloride (73 μL, 0.86 mmol) as solutions in
CDCl3 (1.0 mL) were then added simultaneously over 7 h via syringe
pump. Gave 8a (0%), 9a (88%), 10a (12%) by 1H NMR. The material
was used without purification in the next step. Triphenylphosphine
oxide (278 mg, 1.00 mmol) was added, and the reaction mixture was
stirred at rt for 16 h. Gave 8a 0% by 1H NMR. The reaction mixture was
then heated at reflux for a further 2 h. Gave 8a 0% by 1H NMR. Then
CDCl3 was removed in vacuo. The reaction mixture was dissolved in
toluene-d8 (2 mL) and heated at reflux under N2 for 5 h. Gave 8a 0% by
1H NMR.
Table 1, entry 2 and Table 2, entry 2. To CDCl3 (1.5 mL) was added
oxalyl chloride (12 μL, 0.14 mmol), and the mixture was stirred for 5
min. Benzyl alcohol (108 mg, 1.00 mmol) and oxalyl chloride (73 μL,
0.86 mmol) as solutions in CDCl3 (1.0 mL) were then added simulta-
neously over 7 h via syringe pump. Gave 8b (0%), 9b (80%), 10b (20%)
by 1H NMR. The material was used without purification in the next step.
Triphenylphosphine oxide (278 mg, 1.00 mmol) was added. The
reaction mixture was stirred at rt for 16 h. Gave 8b 0% by 1H NMR.
Table 1, entry 3 and Table 2, entry 3. To CDCl3 (1.5 mL) was added
oxalyl chloride (12 μL, 0.14 mmol), and the mixture was stirred for
5 min. 1-Octen-3-ol (128 mg, 1.00 mmol) and oxalyl chloride (73 μL,
0.86 mmol) as solutions in CDCl3 (1.0 mL) were then added simulta-
neously over 7 h via syringe pump. Gave 8h (0%), 9h (100%), 10h (0%)
by 1H NMR. The material was used without purification in the next step.
Triphenylphosphine oxide (278 mg, 1.00 mmol) was added, and the
reaction mixture was stirred at rt for 16 h. Gave 8h (0%) by 1H NMR.
Table 2, entry 4. To a solution of triphenylphosphine oxide (42 mg,
0.15 mmol) in CDCl3 (1.5 mL) were added simultaneously 9a (249 mg,
1.00 mmol) in CDCl3 (1.0 mL) and CDCl3 (1.0 mL) over 7 h via syringe
pump. Gave 8a (0%) by 1H NMR.
Chlorophosphonium Chloride (3b). To a solution of 2--
(diphenylphosphoryl)pyridine (42 mg, 0.15 mmol) in CDCl3 (0.6 mL)
was added oxalyl chloride (44 μL, 0.52 mmol), and the reaction mixture
was stirred for 30 min. 1H NMR (400 MHz, CDCl3) δ 8.96ꢀ8.90 (m, 1H,
ArH), 8.42ꢀ8.26 (m, 2H, ArH), 7.94ꢀ7.81 (m, 7H, ArH), 7.80ꢀ7.72
(m, 4H, ArH); 13C NMR (100 MHz, CDCl3) δ 152.3 (d, J = 24.6 Hz),
143.6 (d, J = 134.2 Hz), 139.5 (d, J = 11.5 Hz), 137.2 (d, J = 3.1 Hz), 133.8
(d, J = 13.0 Hz), 131.6 (d, J = 29.2 Hz), 130.7 (d, J = 15.3 Hz), 129.7
(d, J = 4.6 Hz), 118.3 (d, J = 92.1 Hz); 31P NMR (162 MHz, CDCl3)
δ 51.8.
Chlorophosphonium Chloride (3c).77 To a solution of tris
(4-fluorophenyl)phosphine oxide (66 mg, 0.20 mmol) in CDCl3
(0.8 mL) was added oxalyl chloride (22 μL, 0.26 mmol), and the
reaction mixture was stirred for 20 min. 1H NMR (400 MHz, CDCl3) δ
7.96 (m, 6H, ArH), 7.46 (m, 6H, ArH); 13C NMR (100 MHz, CDCl3) δ
167.7 (dd, J = 263.8 and 3.8 Hz), 137.0 (dd, J = 15.7 and 10.4 Hz), 118.8
(dd, J = 23.0 and 16.8 Hz), 114.9 (dd, J = 102.0 and 3.1 Hz); 31P NMR
(162 MHz, CDCl3) δ 59.9.
Chlorophosphonium Chloride (3e).78 To a solution of tri
(o-tolyl)phosphine oxide (96 mg, 0.30 mmol) and 2,6-di-tert-butylpyr-
idine (101 μL, 0.450 mmol) in CDCl3 (1.0 mL) was added oxalyl
chloride (38 μL, 0.45 mmol), and the reaction mixture was stirred for
2 h. 13C NMR (100 MHz, CDCl3) δ 143.8 (d, J = 10.0 Hz), 137.2
(d, J = 3.1 Hz), 134.4 (d, J = 1.5 Hz), 134.3 (d, J = 2.3 Hz), 127.8
(d, J = 15.3 Hz), 115.8 (d, J = 88.4 Hz), 22.2 (d, J = 5.4 Hz); 31P NMR
(162 MHz, CDCl3) δ 63.5.
Chlorophosphonium Chloride (3f).79 To a solution of tris
(4-methoxyphenyl)phosphine oxide (111 mg, 0.301 mmol) in CDCl3
(1.0 mL) was added oxalyl chloride (38 μL, 0.45 mmol), and the
reaction mixture was stirred for 10 min. 31P NMR (162 MHz, CDCl3)
δ 64.0.
Chlorophosphonium Chloride (3g). To a solution of tris(2,6-
dimethoxyphenyl)phosphine oxide (230 mg, 0.502 mmol) in CDCl3
(2.0 mL) was added oxalyl chloride (42 μL, 0.50 mmol), and the
reaction mixture was stirred for 5 min. Complex mixture of products
formed. See NMR spectrum.
Chlorophosphonium Chloride (3h).77 To a solution of diphe-
nylmethylphosphine oxide (100 mg, 0.499 mmol) in CDCl3 (2.0 mL)
was added oxalyl chloride (63 μL, 0.74 mmol), and the reaction mixture
was stirred for 5 min. 1H NMR (400 MHz, CDCl3) δ 8.14ꢀ8.05 (m, 4H,
ArH), 7.81ꢀ7.75 (m, 2H, ArH), 7.71ꢀ7.64 (m, 4H, ArH), 3.58
(d, J = 12.9 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 136.4
(d, J = 3.1 Hz), 132.5 (d, J = 13.0 Hz), 130.5 (d, J = 15.3 Hz), 120.3
(d, J = 89.7 Hz), 17.2 (d, J = 52.9 Hz); 31P NMR (162 MHz, CDCl3)
δ 71.5.
Table 2, entry 5. To a solution of triphenylphosphine oxide (42 mg,
0.15 mmol) in CDCl3 (1.5 mL) were added simultaneously 9b (199 mg,
1.00 mmol) in CDCl3 (1.0 mL) and CDCl3 (1.0 mL) over 7 h via syringe
pump. Gave 8b (0%) by 1H NMR.
Table 2, entry 6. To a solution of triphenylphosphine oxide (42 mg,
0.15 mmol) in CDCl3 (1.5 mL) were added simultaneously 9h (219 mg,
1.00 mmol) in CDCl3 (1.0 mL) and CDCl3 (1.0 mL) over 7 h via syringe
pump. Gave 8h (0%) by 1H NMR.
Chlorophosphonium Chloride (3i).80 To a solution of tri-
methylphosphine oxide (23 mg, 0.25 mmol) in CD3CN (1.0 mL) was
added oxalyl chloride (28 μL, 0.33 mmol), and the reaction mixture was
stirred for 5 min. 1H NMR (400 MHz, CD3CN) δ 2.5 (d, J = 14.0 Hz,
9H, 3 ꢁ CH3); 13C NMR (100 MHz, CD3CN) δ 17.1 (d, J = 51.4 Hz);
31P NMR (162 MHz, CD3CN) δ 93.7.
Table 2, entry 7. To a solution of triphenylphosphine oxide (42 mg,
0.15 mmol) in CDCl3 (1.5 mL) was added oxalyl chloride (12.0 μL,
6764
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
0.142 mmol), and the reaction mixture was stirred for 5 min. 9a (249 mg,
1.00 mmol) as a solution in CDCl3 (1.0 mL) and CDCl3 (1.0 mL) were
added simultaneously over 7 h via syringe pump. Gave 8a (0%) by1HNMR.
Table 2, entry 8. To a solution of triphenylphosphine oxide (42 mg,
0.15 mmol) in CDCl3 (1.5 mL) was added oxalyl chloride (12 μL,
0.14 mmol), and the reaction mixture was stirred for 5 min. 9b (199 mg,
1.00 mmol) as a solution in CDCl3 (1.0 mL) and CDCl3 (1.0 mL) were
added simultaneously over 7 h via syringe pump. Gave 8b (0%) by
1H NMR.
X-ray crystallographic data in CIF format; and spectral data This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: ross.denton@nottingham.ac.uk.
Equation 1, R1 = C9 . To a solution of 1-chlorodecane 8a (88.0 mg,
H21
’ ACKNOWLEDGMENT
0.500 mmol) in CDCl3 (1.75 mL) was added LiBr (109 mg, 1.26 mmol),
and the reaction mixture stirred for 16 h at rt. Gave 11a (0%) by 1H NMR.
Equation 1, R1 = Ph. To a solution of benzylchloride 8b (63.0 mg,
0.498 mmol) in CDCl3 (1.75 mL) was added LiBr (109 mg, 1.26 mmol),
and the reaction mixture stirred for 16 h at rt. Gave 11 (0%) by 1H NMR.
Table 2, entry 2 and Table 4, entries 2 and 3. To CDCl3 (1.5 mL)
was added oxalyl bromide (13 μL, 0.14 mmol). Benzyl alcohol (108 mg,
1.00 mmol) and oxalyl bromide (81 μL, 0.86 mmol) as solutions in
CDCl3 (1.0 mL) were then added simultaneously over 7 h via syringe
pump. Gave 11b (30%), 10b (69%) by 1H NMR. The material was used
in the next step without purification. Triphenylphosphine oxide (278
mg, 1.00 mmol) was added. The reaction mixture was stirred at rt for 16
Financial support was provided by The University of Nottingham
(New Researcher’s Fund NF5012), The Royal Society (Research
Grant RG090319), and the EPSRC (First Grant EP/H018034/1).
We are grateful to Professor Barry Lygo (University of Nottingham)
and Dr. Damien Webb (Massachusetts Institute of Technology) for
helpful discussions relating to this work.
’ REFERENCES
(1) For reviews, see: (a) Abell, A. D.; Edmonds, M. K. In Organopho-
sphorus Reagents; Murphy, P. J., Ed.; Oxford University Press: Oxford,
U.K., 2004; pp 99ꢀ127. (b) Edmonds, M.; Abell, A. In Modern Carbonyl
Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004;
Chapter 1. (c) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A.
Liebigs Ann. 1997, 7, 1283–1301. (d) Vedejs, E.; Peterson, M. J. Adv.
Carbanion Chem. 1996, 2, 1. (e) Maryanoff, B. E.; Reitz, A. B. Chem. Rev.
1989, 89, 863–927.(f) Bestmann, H. J.; Vostrowsky, O. Top. Curr. Chem.
1983, 109, 85ꢀ163. For mechanistic and stereochemical aspects of the
reaction, see: (g) Robiette, R.; Richardson, J.; Aggarval, V. K.; Harvey,
J. N. J. Am. Chem. Soc. 1996, 128, 2394–2409. (h) Vedejs, E.; Peterson,
M. I. Top. Stereochem. 1994, 21, 1–157.
(2) For a recent review, see: (a) Swamy, K. C. K.; Kumar, N. N. B.;
Balaraman, K. E.; Kumar, K.V.P.P Chem. Rev. 2009, 109, 2551–2651.
(3) The conversion of alcohols to alkyl halides using phosphines and
positive halogen sources is often referred to as the Appel reaction;
however, it was originally described by Downie, Holmes, and Lee. See:
(a) Downie, I. M.; Holmes, J. B.; Lee, J. B. Chem. Ind. (London)
1966, 900. Such reactions are now usually referred to as halogenation
“under Appel conditions”. We are grateful to Professor Declan Gilheany
(University College Dublin) for making us aware of this. For a
review, see:(b) Appel, R. Angew. Chem. 1975, 87, 863.
1
h. Gave 11b (38%), 12b (50%), 13b (13%) by H NMR. Then the
reaction mixture was stirred at rt for 48 h. Gave 11b (63%), 12b (25%),
13b (13%) by 1H NMR.
Table 3, entry 1 and Table 4, entry 1. To CDCl3 (1.5 mL) was added
oxalyl bromide (13 μL, 0.14 mmol). Decanol (158 mg, 1.00 mmol) and
oxalyl bromide (81 μL, 0.86 mmol) as solutions in CDCl3 (1.0 mL) were
then added simultaneously over 7 h via syringe pump. Gave 12a (90%)
by 1H NMR. The material was used in the next step without purification.
Then triphenylphosphine oxide (278 mg, 1.00 mmol) was added. The
reaction mixture was stirred at rt for 16 h. Gave 11a (0%), 12a (15%),
13a (85%) by 1H NMR.
Table 5, entry 1. To CDCl3 (1.5 mL) were added oxalyl chloride
(16.5 μL, 0.20 mmol) and LiBr (217 mg, 2.5 mmol), and the reaction
mixture stirred for 5 min. The decanol (158 mg, 1.00 mmol) and oxalyl
chloride (93.5 μL, 1.11 mmol) as solutions in CDCl3 (1.0 mL) were
then added simultaneously over 5 h via syringe pump. Gave 11a (0%), 9a
and 12a (86%) by 1H NMR.
Table 5, entry 2. To CDCl3 (1.5 mL) were added oxalyl chloride
(16.5 μL, 0.20 mmol) and LiBr (261 mg, 3.01 mmol), and the reaction
mixture stirred for 5 min. The benzyl alcohol (108 mg, 1.00 mmol) and
oxalyl chloride (93.5 μL, 1.11 mmol) as solutions in CDCl3 (1.0 mL)
were then added simultaneously over 5 h via syringe pump. Gave 11b
(0%), 9b and 12b (82%) by 1H NMR.
Equation 2, substrate 9a. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in CDCl3 (1.5 mL) was added LiBr (217 mg, 2.50
mmol) followed by 9a (249 mg, 1.00 mmol) as a solution in CDCl3
(1.0 mL) and CDCl3 (1.0 mL) simultaneously over 5 h via syringe
pump. Gave 11a (0%) by 1H NMR.
(4) For an excellent introduction to organophosphorus reagents in
synthesis, see: Organophosphorus Reagents in Organic Synthesis; Cadogan,
J. I. G., Ed.; Academic Press: London, 1979.
(5) Trost, B. M. Science 1991, 254, 1471–1477.
(6) For a recent summary of green chemistry aspects of chemical
synthesis, see: Li, C. J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 13197–13202.
(7) For chlorination using polymeric halophosphonium salts, see:
(a) Relles, H. M.; Schluenz, R. W. J. Am. Chem. Soc. 1974, 96,
6469–6475. (b) Harrison, C. R.; Hodge, P.; Hunt, B. J.; Khoshdel, E.;
Richardson, G. J. Org. Chem. 1983, 48, 3721–3728. For removal of
phosphine oxides via impurity annihilation, see: (c) Barrett, A. G. M.;
Roberts, R. S.; Schr€oder, J. Org. Lett. 2000, 2, 2999–3001. For a recent
review on phase-switching strategies, see: (d) Arstad, E.; Barrett,
A. G. M.; Hopkins, B. T.; Koebberling, J. Org. Lett. 2002, 4,
1975–1977. (e) Dandapani, S.; Curran, D. Chem.—Eur. J. 2004,
10, 3130. For the use of chemically tagged phosphines, see: (f) Smith,
C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.;
Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562–1568.
For an interesting “waste as catalyst” strategy, see: (g) Cao, J. J.; Zhou, F.;
Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976–4980.
Equation 2, substrate 9b. To a solution of triphenylphosphine oxide
(42 mg, 0.15 mmol) in CDCl3 (1.5 mL) was added LiBr (261 mg, 3.00
mmol) followed by 9b (198 mg, 1.00 mmol) as a solution in CDCl3
(1.0 mL) and CDCl3 (1.0 mL) simultaneously over 7 h via syringe
pump. Gave 11a (0%) by 1H NMR.
Equation 3, substrate 12a. To a solution of triphenylphosphine
oxide (42 mg, 0.15 mmol) in CDCl3 (1.5 mL) was added simultaneously
12a (293 mg, 1.00 mmol) as a solution in CDCl3 (1.0 mL) and CDCl3
(1.0 mL) over 7 h via syringe pump. Gave 11a, 0% by 1H NMR.
’ ASSOCIATED CONTENT
(8) This is important as there is predicted to be a shortage in
phosphate rock, the raw material from which most organophosphorus
compounds are derived; see: Cordell, D.; Drangert, J.-O.; White, S.
Global Env. Change 2009, 19, 292–305.
S
Supporting Information. Experimental procedures for the
b
synthesis and reactions of chlorooxalates; details of computations;
6765
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
(9) Noyori, R. Nat. Chem. 2009, 1, 5–6.
oxychloride/phosphine oxide binary system, see: (d) Kazantseva,
M. V.; Timokhin, B. V.; Rokhin, A. V.; Blazhev, D. G.; Golubin, A. I.;
Rybakova, Y. V. Russ. J. Gen. Chem. 2001, 71, 1233–1235.
(22) For a recent creative application of the Appel reaction for
dynamic resolution of P-stereogenic phosphine oxides, see: (a) Enda,
B.; O’Connor, C. T.; Robinson, S. B.; McGarringle, E. M.; O’Mah-
ony, C. P.; Gilheany, D. G. J. Am. Chem. Soc. 2007, 129, 9566–9567.
(b) Kamalraj, V. R.; Kennedy, L.; Gilheany, D. G. Eur. J. Org. Chem.
2010, 5642–5649. For phosphonium-salt mediated halogenation of
alcohols, see: (c) Firouzabadi, H.; Iranpoor, N.; Ebrahimzadeh, F.
Tetrahedron Lett. 2006, 47, 1771–1775. (d) Appel, R. Angew. Chem.,
Int. Ed. 1975, 14, 801–811. (e) Appel, R.; Halstenberg, M. In
Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G.,
Ed.; Academic Press: London, 1979; Chapter 9. (f) Castro, B.; Selve,
C. Bull. Soc. Chim. Fr. 1971, 2296–2298. (g) Schweizer, E. E.;
Creasey, W. S.; Light, K. K.; Shaffer, E. T. J. Org. Chem. 1968, 34,
2270–2274. (h) Downie, I. M.; Holmes, J. B.; Kee, J. B. Chem. Ind.
(London) 1966, 900–901. (i) Wiley, G. A.; Hershkowitz, R. L.; Rein,
B. M.; Chung, B. C. J. Am. Chem. Soc. 1964, 86, 964–965. (j) Trippett,
S. J. Chem. Soc. 1962, 2337–2340. (k) Hoffmann, L.; Horner, L.;
Wippel, H. G.; Michael, D. Chem. Ber. 1962, 95, 523.
(10) For example, the strength of the PdO bond in triphenylpho-
sphine oxide is 128 kcal/mol. For example, in the context of Appel
chlorination, the CꢀCl bond of an alkyl chloride is about 10 kcal/mol
weaker than the CꢀO bond of an aliphatic alcohol. In the context of the
Wittig reaction the CdC bond of an alkene is approximately 30 kcal/
mol weaker than that of an aldehyde. The formation of the PdO bond
provides enthalpic compenzation for this. For a review on the bonding in
phosphines, phosphine oxides and phosphonium ylides, see: Gilheaney,
D. G. Chem. Rev. 1994, 1339–1374.
(11) McGonagle, A. E.; Marsden, S. P.; McKever-Abbas, B. Org. Lett.
2008, 10, 2589.
(12) Monagle, J. J.; Campbell, T. W.; McShane, H. F. J. Am. Chem.
Soc. 1962, 84, 4288.
(13) For the first Wittig reaction catalytic in phosphorus, see:
(a) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A. L.;
Kunkel, S. R.;Przeworski, K. C.;Chass, C. G. Angew. Chem., Int. Ed. 2009, 48,
6836ꢀ6839. For a review on catalytic olefinations of aldehydes, see: (b)
K€uhn, F. E.; Santos, A. M. Mini-Rev. Org. Chem. 2004, 1, 55–64.
(14) Harris, J. R.; Haynes, M. T., II; Thomas, A. M.; Woerpel, K. A.
J. Org. Chem. 2010, 75, 5083–5091.
(15) For the preliminary communication on catalytic halogenation
under Appel conditions, see: (a) Denton, R. M.; Jie, A.; Adeniran, B.
Chem. Commun. 2010, 46, 3025–3027. For a related 1,2-dichlorination
of epoxides under catalytic Appel conditions, see:Denton, R. M.; Tang,
X.; Przeslak, A. Org. Lett. 2010, 12, 4678–4682.
(16) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manely, J.; Pearlman, B. A.;
Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(17) For the conversion of alcohols to chlorides using
dichlorodiphenylcyclopropene, see: Kelly, B. D.; Lambert, T. H. J. Am.
Chem. Soc. 2009, 131, 13930–13931.
(18) For the conversion of alcohols to bromides or iodides via an
interesting photoredox catalysis approach, see: (a) Dai, C.; Naraya-
nam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2011, 3, 140–145. For
another catalytic system for the chorination of alcohols, see: (b)
Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am. Chem. Soc. 2004,
126, 7186–7187. (c) Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A.
Org. Synth. 2006, 83, 38–44. (d) Yasuda, M.; Shimizu, K.; Yamasaki,
S.; Baba, A. Org. Biomol. Chem. 2008, 6, 2790–2975. For an alter-
native approach to involving catalytic electronic activation of
alcohols, see: (e) Edwards, M. G.; Williams, J. M. J. Angew. Chem.,
Int. Ed. 2002, 41, 4740–4743. (f) Hamid, M. H. S. A.; Slatford, P. A.;
Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555–1575. (g)
Williams, J. M. J. Angew. Chem., Int. Ed. 2002, 41, 4740–4743. (h)
Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc.
2009, 131, 1766–1774.
(23) For reviews on the synthetic utitlity of alkyl chlorides, see: (a)
Larock, R.C. In Comprehensive Organic Transformations, 2nd ed.; John
Wiley & Sons: New York, 1999; pp 689ꢀ702. (b) Bohlmann, R. In
Comprehensive Organic Synthesis; Trost, B., Flemming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 6, pp 203ꢀ223. (c) Hudlicky, M.; Hudlicky, T.
In Chemistry of Functional Groups, Supplement D; Patai, S., Rappoport, Z.,
Eds.; Wiley: New York, 1983; p 1021. (d) Chambers, R. D.; James, S. R. In
Comprehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.;
Pergamon Press: Oxford, 1979; Vol. 1, p 493.
(24) For an introduction to isolation and synthesis aspects of
chlorosulfolipids, see: (a) Bedke, D. K.; Vanderwal, D. Nat. Prod. Rep.
2010, 28, 15ꢀ25. For reviews on halogenated natural products, see: (b)
Gribble, G. W. J. Chem. Ed. 2004, 81, 1441ꢀ1449. (c) Gribble, G. Am.
Sci. 2004, 92, 342–349. (d) Gribble, G. W. Acc. Chem. Res. 1998,
31, 141–152. (e) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353–1395.
(25) (a) Norris, J. F.; Taylor, H. B. J. Am. Chem. Soc. 1907,
38, 627–630. (b) Norris, J. F.; Taylor, H. B. J. Am. Chem. Soc. 1924,
46, 753–756.(c) Norris, J. F.; Olmsted, A. W. Organic Synthesis; Wiley:
New York, 1941; Collect. Vol. I, pp 146ꢀ147.
(26) Fuchs, R.; Cole, L. L. Can. J. Chem. 1975, 53, 3620–3621.
(27) For representative examples, see: (a) Nelson, S. D.; Kouzi, S. A.
J. Org. Chem. 1993, 58, 771–773. (b) Falorni, M.; Lardicci, L. J. Org.
Chem. 1986, 51, 5291–5294. (c) Meyers, A. I.; Collington, E. W. J. Org.
Chem. 1971, 36, 3044–3048.
(28) (a) Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002,
4, 553–555. (b) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 2000, 41, 6049–6052. (c) Benazza, T.; Uzan, R.;
Beaupere, D.; Demailly, G. Tetrahedron Lett. 1992, 33, 4901–4904. (d)
Ireland, R. B.; Norbeck, D. W.; Mandel, G. S.; Mandel, N. S. J. Am. Chem.
Soc. 1985, 107, 3285–3294. (e) Fujisawa, T.; Iida, S.; Sato, T. Chem. Lett.
1984, 1173–1174.
(29) (a) Mukaiyama, T.; Shoda, S. I.; Watanabe, Y. Chem. Lett. 1997,
383–385. (b) Hojo, K.; Mukaiyama, T. Chem. Lett. 1976, 619–622.
(30) Note that the 31P chemical shift of triphenylphosphine oxide
varies in the presence of both Br€onsted and Lewis acids. For example, in
the absence of acid triphenylphosphine oxide resonates at 29 ppm relative
to H3PO4 at 0 ppm. See: (a) Maciel, G. E.; James, R. V. Inorg. Chem. 1964,
3, 1650–1651. (b) Zeldin, M.; Mehta, P.; Vernon, W. D. Inorg. Chem.
1979, 18, 463–466.
(31) Rhoads, S. J.; Michel, R. E. J. Am. Chem. Soc. 1963, 85, 585–591.
(32) Forfull details of theGC conditions, seeSupporting Information.
(33) Cambridge Crystallographic Database deposition number
788124.
(34) (a) Lepore, S. D.; Bhunia, A. K.; Mondal, D.; Cohn, P. C.;
Lefkowitz, C. J. Org. Chem. 2006, 71, 3285–3286. (b) Braddock, D. C.;
Pouwer, R. H.; Burton, J. W.; Broadwith, P. J. Org. Chem. 2009, 74,
6042–6049.
(19) (a) Relles, H. M.; Schluenz, R. W. J. Am. Chem. Soc. 1974,
96, 6469–6475. (b) Senet, J.-P. C. R. Acad. Sci., Ser. IIc:, Chim. 2000,
3, 505–516.(c) Wunsch, G.; Wintersberger, G. Geierhass, G. German
Patent 1247310, 1966, BASF. (d) Appel, R.; Heinzelmann, W. German
Patent 1192205, 1962, BASF.
(20) (a) Yano, T.; Kuroboshi, M.; Tanaka, H. Tetrahedron Lett. 2010,
51, 698–701. (b) Yano, T.; Hoshino, M.; Kuroboshi, M.; Tanaka, H. Synlett
2010, 5, 801–803. (c) Masaki, M.; Fukui, K. Chem. Lett. 1977, 151–152.
(21) Some examples of phosphine oxide-catalyzed chlorination
reactions can be found in the patent literature. For example, thio-
nylchloride can be used as a stoichiometric reagent in conjunction
with catalytic phosphine oxides; see: (a) Rhode, T.; Huttenloch, O.;
Osswald, F. Wissel, K. U.S. Patent App. US 2008/0228016, 2008. In
this work the phosphine oxide most likely catalyzes the decomposi-
tion of the derived chlorosulfinate. Trialkylphosphine oxides catalyze
chlorination of alcohols using phosgene as the stoichiometric
reagent; see: (b) Henklemann, J.; Troetsch-Schaller, I.; Wettling,
T.; Kahl, T. M.; Hupfer, L.; Franzischka, W.; Koehler, H. U.S. Patent
US 5196611, 1993;(c) Dabee, A.; Gauthier, P.; Senet, J. P. U.S. Patent
US 5672770, 1994. For a chlorination using a phosphorus
6766
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767

The Journal of Organic Chemistry
ARTICLE
(35) Gerrard, W.; Hudson, H. R. Nature 1964, 876.
(36) (a) Jones, L. A.; Summer, C. E.; Franzus, B.; Huang, T.T.-S.;
Snyder, E. I. J. Org. Chem. 1978, 43, 2821–2827. (b) Ramos, S.; Rosen,
W. J. Org. Chem. 1981, 46, 3530–3533. (c) Kelly, J. W.; Evans, S. A. J. Org.
Chem. 1986, 51, 5492–5494.
(72) Griffin, C. E.; Peller, R. P.; Martin, K. R.; Peters, J. A. J. Org.
Chem. 1965, 30, 97–101.
(73) Yasui, S.; Tojo, S.; Majima, T. J. Org. Chem. 2005, 70, 1276–1280.
(74) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 3413–3422.
(37) Cambridge Crystallographic Database deposition number 788125
(38) Spartan '08, Wavefunction, Inc. Irvine, C. A.; et al. Phys. Chem.
Chem. Phys. 2006, 8, 3172–3191.
(39) For further details, see Supporting Information.
(40) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128,
5360–5361.
(41) Sellen, M.; Baeckvall, J. E.; Helquist, P. J. Org. Chem. 1991,
56, 835–839.
(42) Stephany, O.; Dron, F.; Tisse, S.; Martinez, A.; Nuzillard, J. M.;
Peulon-Agasse, V.; Cardinael, P.; Bouillon, J. P. J. Chromatogr. A 2009,
1216, 4051–4062.
(43) Kelly, M.; Ross, R., Jr.; Young, D. H. U.S. Patent 9253708, 2009.
(44) Phillion, D. P. WO Patent 3,020,684, 2003.
(45) (a) Fox, R. J.; Lalic, G.; Bergman, R. G. J. Am. Chem. Soc. 2007,
129, 14144–14145. (b) Glueck, S. M.; Fabian, W. M. F.; Faber, K.;
Mayer, S. F. Chem.—Eur. J. 2004, 10, 3467–3478.
(46) Baidya, M.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2010,
132, 4796–4805.
(75) Palacios, F.; Herran, E.; Alonso, C.; Rubiales, G.; Lecea, B.;
Ayerbe, M.; Cossio, F. P. J. Org. Chem. 2006, 71, 6020–6030.
(76) Sonnet, P. E.; Oliver, J. E. J. Org. Chem. 1976, 41, 3279–3283.
(77) Godfrey, S. M.; McAuliffe, C. A.; Pritchard, R. G.; Sheffield,
J. M.; Thompson, G. M. J. Chem. Soc., Dalton Trans. 1997, 4823–4828.
(78) Wells, A. Synth. Commun. 1994, 24, 1715–1719.
(79) Rozinov, V. G.; Grechkin, E. F.; Kalabina, A. V. Izv. Nauchno-
Issled. Inst. Nefte- Uglekhim. Sint. Irkutsk. Univ. 1969, 11, 52–53.
(80) Harris, R. K.; Root, A.; Gates, P. N.; Muir, A. S. Spectrochim.
Acta, Part A 1992, 48A, 1371–1384.
(81) Quin, L. D.; Belmont, S. E.; Mathey, F.; Charrier, C. J. Chem.
Soc., Perkin Trans. 2 1986, 629–633.
(47) Sun, Q.; Cai, S.; Peterson, B. R. Org. Lett. 2009, 11, 567–570.
(48) Villano, S. M.; Eyet, N.; Lineberger, W. C.; Bierbaum, V. M.
J. Am. Chem. Soc. 2009, 131, 8227–8233.
(49) Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73,
5198–5201.
(50) Genzer, J. D.; Huttrer, C. P.; Van Wessem, G. C. J. Am. Chem.
Soc. 1951, 73, 3159–3162.
(51) Ito, H.; Takagi, K.; Miyahara, T.; Sawamura, M. Org. Lett. 2005,
7, 3001–3004.
(52) Biffis, A.; Castello, E.; Zecca, M.; Basato, M. Tetrahedron Lett.
2001, 57, 10391–10394.
(53) Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520–4523.
(54) Aucagne, V.; Leigh, D. A.; Lock, J. S.; Thomson, A. R. J. Am.
Chem. Soc. 2006, 128, 1784–1785.
(55) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
(56) Barluenga, J.; Montserrat, J. M.; Florez, J. J. Org. Chem. 1993,
58, 5976–5980.
(57) Erbas, S.; Gorgulu, A.; Kocakusakogullari, M.; Akkaya, E. U.
Chem. Commun. 2009, 4956–4958.
(58) Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Commun.
2007, 825–827.
(59) Iranpoor, N.; Firouzabadi, H.; Jamalian, A.; Kazemi, F. Tetra-
hedron Lett. 2005, 61, 5699–5704.
(60) Chan, V. S.; Chiu, M.; Bergman, R. G.; Toste, F. D. J. Am. Chem.
Soc. 2009, 131, 6021–6032.
(61) Schelper, M.; De Meijere, A. Eur. J. Org. Chem. 2005, 582–592.
(62) Mixer, R. Y.; Young, W. G. J. Am. Chem. Soc. 1956, 78,
3379–3384.
(63) Jindrich, J.; Tislerova, I. J. Org. Chem. 2005, 70, 9054–9055.
(64) Sellen, M.; Baeckvall, J. E.; Helquist, P. J. Org. Chem. 1991,
56, 835–839.
(65) Egorov, A. M.; Matyukhova, S. A.; Kocherova, I. S.; Novikova,
A. A.; Anisimov, A. V. Russ. J. Gen. Chem. 2009, 79, 444–452.
(66) Slagle, J. D.; Huang, T. T. S.; Franzus, B. J. Org. Chem. 1981,
46, 3526–3530.
(67) Duan, H. F.; Xie, J. H.; Qiao, X. C.; Wang, L. X.; Zhou, Q. L.
Angew. Chem., Int. Ed. 2008, 47, 4351–4353.
(68) Trahanovsky, W. S.; Ong, C. C.; Lawson, J. A. J. Am. Chem. Soc.
1968, 90, 2839–2842.
(69) Bartel, K.; Goosen, A.; Scheffer, A. J. Chem. Soc. C. 1971,
3766–3769.
(70) Carson, E. C.; Lippard, S. J. J. Am. Chem. Soc. 2004, 126,
3412–3413.
(71) Tojo, S.; Yasui, S.; Fujitsuka, M.; Majima, T. J. Org. Chem. 2006,
71, 8227–8232.
6767
dx.doi.org/10.1021/jo201085r |J. Org. Chem. 2011, 76, 6749–6767