The preparation of three new partially deuterated hexadecanethiols for applications in surface chemistry

Article abstract of DOI:10.1002/jlcr.1541

The synthesis of three partially deuterated hexadecanethiols has been achieved. Thiols CH₃(CH₂)₇(CD₂) ₈SH, CD₃(CD₂)₇(CH₂) ₈SH and CD₃(CH₂)₁₅SH were targeted, as these compounds, after formation of self-assembled monolayers on Au(1 1 1) or Au nanoparticles, can provide mechanistic information pertaining to reactive atom migrations within the assembly. The syntheses of each of these compounds called upon Grignard coupling chemistry, which was activated by Li ₂CuCl₄. Applicable deuterium containing fragments were either commercially obtained or constructed from by way of an inexpensive and efficient ring opening, protection and dimerization of THF-d₈. Sulfur incorporation was by thiolacetate substitution or addition reactions. The protocols presented possess general applicability in a number of syntheses requiring block-deuterated fattyalkyl sections. Copyright

Full text of DOI:10.1002/jlcr.1541

Research Article
Received 18 June 2008,
Revised 29 July 2008,
Accepted 17 August 2008
Published online 7 October 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1541
The preparation of three new partially
deuterated hexadecanethiols for applications
in surface chemistry
Ã
Erin E. Sheepwash, Paul A. Rowntree, and Adrian L. Schwan
The synthesis of three partially deuterated hexadecanethiols has been achieved. Thiols CH3(CH2)7(CD2)8SH,
CD3(CD2)7(CH2)8SH and CD3(CH2)15SH were targeted, as these compounds, after formation of self-assembled monolayers
on Au(1 1 1) or Au nanoparticles, can provide mechanistic information pertaining to reactive atom migrations within the
assembly. The syntheses of each of these compounds called upon Grignard coupling chemistry, which was activated by
Li2CuCl4. Applicable deuterium containing fragments were either commercially obtained or constructed from by way of an
inexpensive and efficient ring opening, protection and dimerization of THF-d8. Sulfur incorporation was by thiolacetate
substitution or addition reactions. The protocols presented possess general applicability in a number of syntheses requiring
block-deuterated fattyalkyl sections.
Keywords: grignard reaction; self-assembled monolayers; thiol; deuterium
dimensional film,4 and thus clarify the nature of the overall
spectrum.
Introduction
Ordered monolayer-thick organic films present highly structured
interfaces by which to protect metallic and inorganic supports,
provide protein binding sites with controlled topographies and
compositions, and function as controlled resist films for electron
and photon-driven lithography and surface modifications.1 In
addition, the structured nature of these systems makes them
ideal model systems for the study of molecular dynamics,
condensed phase phenomena and energy transfer processes.
These films can be prepared using Langmuir–Blodgett techni-
ques for physisorbed films and self-assembly for covalently
bound monolayers (i.e. SAMs). Much of the interest in these
systems stems from the relative ease with which the composi-
tion of the film can be modified to fulfill specific physical or
chemical design objectives. In this work we will describe the
synthesis of three partially deuterated alkanethiol species that
are designed to provide information related to both of these
objectives for SAM systems.
Alkanethiols adsorbed onto gold substrates constitute the
most studied family of systems in the vast literature on SAMs.
Deuteration of an otherwise perhydrogenated molecule can be
used to distinguish the vibrational properties and ordering
characteristics at specific sites along the chain axis without
significantly perturbing the van der Waals forces that provide
the film’s stability. Previous theoretical2 and experimental
work3,4 has shown that isotopic segregation is not expected
for these systems, and as such mixtures of hydrogenated and
deuterated species can be considered as thermodynamically
ideal solutions and adsorbed films. By diluting deuterated
components within fully hydrogenated isotopomers it has been
possible to identify and quantify the dynamic intermolecular
and intramolecular coupling of the vibrational modes of two
Selective deuteration of n-alkanethiol SAMs can also be used to
explore the chemical consequences of the highly ordered
condensed phase environment of the SAM. We have recently
used perdeuterated alkanethiols to explore the mechanisms of
molecular hydrogen formation when SAMs are exposed to low-
energy (0–15eV) electron beams.3 By measuring the relative
yields of HD and D2 formed as the mole fraction of perdeuterated
thiolates was varied, we have shown that the reaction is
bimolecular in nature, with a primary hydrogen (deuterium)
fragment produced by electron impact, and the molecular
hydrogen being produced by the reactive encounters of these
fragments with adjacent molecules; by unambiguously showing
that the unimolecular fragmentation channels5 has negligible
probabilities, the interpretation of electron-beam induced chem-
istry in lithographic processes becomes more reliable.
The current series of partially deuterated target alkanethiols,
compounds 1, 2 and 3, are designed to further our ability to
study the physical and chemical implications of SAM structure.
The films composed of these species present significantly
simplified infrared spectra (e.g. with fully resolved spectral
regions associated with the methyl and methylene vibrational
modes), and have been used to observe the subtle bands
associated with the a and b methylene sites6,7 (relative to the
methyl termination) as the films are thermally disordered. They
have also been used to estimate effective range of the electron-
Department of Chemistry, University of Guelph, Guelph, Ont., Canada N1G 2W1
*Correspondence to: A. L. Schwan, Department of Chemistry, University of
Guelph, Guelph, Ont., Canada N1G 2W1.
E-mail: schwan@uoguelph.ca
J. Label Compd. Radiopharm 2008, 51 391–398
Copyright r 2008 John Wiley & Sons, Ltd.

E. E. Sheepwash et al.
impact produced fragment prior to the second reactive 51% of compound 6 over two steps. The deacetylization of 6 to
encounter with a nearby chain.
afford labelled thiol 1 was performed by treating the thiolacetate
These synthetic methods outlined here may find further use in with one equivalent of LAH in THF for 15 min15 producing thiol
the syntheses of partially and/or fully deuterated alkyl chains for cleanly in 70% yield without disulfide contamination.
introduction into lipids which have already been be utilized for
studies of chain dynamics in phospholipid bilayers.8 Solid-state Synthesis of 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(hexadecyldeuter-
2H NMR techniques have also been used to observe the
io)hexadecane-1-thiol (2)
temperature-dependent chain librations using selectively deut-
The synthesis of 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(hexadecyldeuter-
erated alkanethiols bound to gold nanoparticles,9 and quantify
io)hexadecane-1-thiol (2) proved much more difficult, as it
the progressive disordering of these quasi-spherical systems as
required a fully deuterated eight carbon chain with orthogonal
the temperature is increased.
functionality permitting the coupling of bromooctane to one
end while conserving the other end for a thiol. A procedure16
Results and discussions
has been described for the synthesis of (hexadecyldeuterio)-1,8-
octanediol starting from THF-d8 (Scheme 2). This procedure
involves the ring opening of THF-d8 with TMSBr and TMSI
Synthesis of 9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,
16-(heptadecyldeuterio) hexadecane-1-thiol (1)
to form the silyl protected a-bromo-o-alcohol
8 and
The principal tool adopted for the constructions of all
deuterated targets was Grignard coupling reactions. Tamura
and Kochi10 first investigated the use of dilithium tetrachlor-
ocuprate for coupling of alkyl halides with Grignard reagents.
This provided a selective catalyst to couple alkyl, aryl and vinyl
Grignard reagents with primary alkyl halides. Johnson11
demonstrated that in the presence of Li2CuCl4, alkyl Grignard
reagents couple with only one bromide of an alkyl dibromide,
with formation of the dicoupled product possible at higher
temperatures and longer reaction time. Based on this and
other precedents,12–14 the Grignard reagent of commercially
available perdeuterated bromooctane (4) was prepared and
coupled to dibromooctane as the starting point for 9,9,10,10,
11,11,12,12,13,13,14,14,15,15,16,16,16-(heptadecyldeuterio)hex-
adecanethiol-d17 (1, Scheme 1).
The perdeuterated bromooctane Grignard reagent was
reproducibly obtained in refluxing THF in the presence of
ether-rinsed magnesium turnings and an I2 initiator. To ensure
the production of significant monocoupled product, two
equivalents of dibromooctane were reacted with the Grignard
reagent in the presence of a catalytic amount of freshly
prepared Li2CuCl4 (Scheme 1).
a-iodo-o-alcohol 9, respectively. THP protection precedes
magnesiobromide coupling to THP protected iodide 11
using Li2CuCl4.
Given the cost of the TMSX reagents and the eventual need to
differentiate the termini of the symmetric deuterated 8-carbon
backbone, we sought a different approach, one that called on
an iterative construction of the deuterated target 2. Specifically,
we wished to couple the THP-protected bromide 10 (or iodide
11) to an eight carbon bromide through Grignard chemistry,
then connect this to another molecule of bromide 10 (or iodide
11) to give the 16 carbon, partially deuterated chain.
Furthermore, we hoped to adapt a new protocol for opening
THF17,18 and apply it to the perdeuterated manifold, thus
circumventing expensive TMSX reagents. The alternative proce-
dure uses sodium borohydride and iodine in THF over 2 h to ring
open THF (Scheme 3). Targeting the fully deuterated version, an
alternative solvent had to be used as using THF-d8 is not
D
D
O
D
D
TMSBr
or
TMSI
8, X = Br
9, X = I
X
(CD2)4 OTMS
D
D
D
D
This reaction produced an inseparable mixture of the desired
bromohexadecane 5 and leftover dibromooctane. Analysis of the
NMR and mass spectral data indicated a 35% conversion with
65% starting material left over and o2% of the dicoupled
product. The addition of potassium thioacetate to this crude
mixture produced thiolacetate 6, which was easily separated
from doubly functionalized 7 by flash chromatography to yield
DHP, p-TsOH
(CD2)4 OTHP
for X = Br
Mg, Et2O/THF
X
THPO(CD2)8OTHP
(74%)
then 11, Li2CuCl4
10, X = Br, (83%)
11, X = I, (53%)
Scheme 2.
1. Mg, THF, I 2
CD3(CD2)7Br
CD3(CD2)7(CH2)8Br + Br(CH2)8Br
2. Br(CH2)8Br, Li2CuCl4
4
5
KSC(O)Me
CH3CN
O
O
O
LAH
THF, 0ºC
+
CD3(CD2)7(CH2)8SH
CD3(CD2)7(CH2)8S
6 (51% over 2 steps)
S(CH2)8S
1 (70%)
7
Scheme 1.
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E. E. Sheepwash et al.
DHP, pTsOH
D
D
O
CH2Cl2
NaBH4
D
D
I
(CD2)4 OY
I
(CD2)4 OH
or
I2
D
D
D
TBDPSCl
Im, CH2Cl2
toluene
D
11, Y = THP, (79% 2 steps)
14, Y = TBDPS (79% 2 steps)
12
11 or 14
NBS, PPh3
DMF
CH3(CH2)7(CD2)4Br
CH3(CH2)7MgBr
CH3(CH2)7(CD2)4OY
Li2CuCl4, THF
18 (87%)
15, Y = THP, (64%)
16, Y = TBDPS (86%)
AcCl, MeOH
1. Mg, THF
2. 14, LiCuCl4
THF
17, Y = H (90%)
HSC(O)Me
DIAD, PPh3
CH3(CH2)7(CD2)8SY
CH3(CH2)7(CD2)8OY
21, Y = Ac (80%)
2, Y = H (69%)
19, Y = TBDPS (77%)
20, Y = H (80%)
HCl,
MeOH
AcCl,
MeOH
Scheme 3.
economically viable. A variety of solvents were evaluated using (17). The resulting alcohol was then converted to bromide 18
hydrogenated THF and it was found that 1 equivalent of NaBH4 using NBS/Ph3P in DMF.20 Addition of another perdeuterated 4
and 2 equivalents of I2 in toluene for 3 days at room carbon chain was accomplished using the identical Grignard
temperature gave efficient formation of 4-iodobutanol, which coupling conditions affording 16-carbon compound 19, which
could readily be converted to a THP protected iodoalcohol in was readily deprotected to afford alcohol 20 for eventual
74% overall yield.
conversion to thiolacetate 21 (Mitsunobu conditions: PPh3,
These same procedures were carried out for the THF-d8 DIAD, AcSH, 80%).21 The release of thiol 2 was effected in this
substrate. Secondary isotope effects resulted in a longer case with HCl in refluxing methanol to give hexadecanethiol
reaction time of 6 days giving 96% yield of the crude alcohol, with deuterium incorporation on carbons 1–8 (2) in 17% overall
which was carried through to THP protection to yield 79% of the yield over nine steps.
protected perdeuterated compound 11. To our knowledge, this
is the first use of the NaBH4/I2 conditions17 for the preparation of
perdeuterio-4-iodobutan-1-ol and it is recommended as a
Synthesis of 16,16,16-(trideuterio)hexadecane-1-thiol
A number of synthetic schemes were considered for introduc-
tion of deuterium at the terminal methyl group of an
alkanethiol. Long chain alkyl bromides with d3-terminal methyl
groups are commercially available in 4, 6, 8 and 10 carbon
lengths. It was recognized from previous reactions that
one of these could be converted to the Grignard reagent and
coupled to an appropriate length a-halo-o-olefin as outlined in
Scheme 4.
The thiol could be incorporated through a radical reaction of
thiolacetic acid with the double bond and subsequent
deprotection of the thiolacetate to yield the thiol. Although
this scheme seems feasible, the commercially available choices
of (x1y) = 13 proved expensive and in view of this, other
synthetic routes were explored. A previous synthesis developed
for the synthesis of 12,12,12-(trideuterio)-dodecane-1-thiol by
Qin,22 demonstrates the reduction of an unsaturated 11 carbon
convenient, high yielding and inexpensive protocol for the ring
opening of THF-d8.
The synthesis was continued with coupling of compound 11
to the prepared octylmagnesium bromide. This resulted in THP
protected 15 with deuterium incorporation on carbons 1–4.
However, NMR analysis of 15 indicated some protium introduc-
tion a to the OTHP group. Adjusting reaction conditions did not
remedy this, and subsequently a new oxygen-protecting group
was sought for this chemistry.
Accordingly, TBDPS ether 14 was prepared from the
corresponding alcohol in good yield using imidazole and
TBDPSCl.17 Freshly prepared octylmagnesium bromide was then
connected to 14 affording 12-carbon protected alcohol 16,
which did not succumb to any undesirable deuterium–hydrogen
exchange. Substrate 16 was efficiently deprotected19 (AcCl,
MeOH, 90%) to provide 1,1,2,2,3,3,4,4-(octadeuterio)dodeca-1-ol
1. Mg
CD3(CH2)xBr
CD3(CH2)x+yCH=CH2
2. CH2=CH(CH2)yX,
Li2CuCl4
LiAlH4
x + y = 8
O
OTs
CD3
OH
CD3
TsCl
[H]
CD3MgI
CO2H
8
H
8
8
8
22
Scheme 4.
J. Label Compd. Radiopharm 2008, 51 391–398
Copyright r 2008 John Wiley & Sons, Ltd.
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E. E. Sheepwash et al.
acid and reaction of the resulting aldehyde with d3-methylmag- regarding the mechanism of molecular hydrogen formation
nesium iodide (Scheme 4). The secondary alcohol (22) was during low-energy (10 eV) electron irradiation of hexadeca-
reduced through conversion to a tosylate and LAH reduction. nethiol SAM’s.
Placement of the thiol at the double bond was accomplished as
indicated above.
In addition to the construction of new useful compounds 1–3,
the methods adopted herein offer improvements over some
For a final chain length of 16 carbons, a 15 carbon o- existing protocols. We have demonstrated
a facile and
unsaturated alcohol would have to be made. Following a inexpensive approach to perdeuterated 4-iodobutan-1-ol. We
procedure by Christoffers,23 15-bromopentadecene was made have applied a more expeditious conversion of primary tosylate
from the Grignard reaction of allylmagnesium chloride and 1,12- to alkane circumventing the partial reduction protocol of a
dibromododecane. This produced an inseparable mixture of the carboxylic acid. We have established that the TBDPS group
product 23, 1,12-dibromododecane and possibly 1,17-octadeca- suitably protects alcohols during Grignard reactions while
diene. This crude mixture was taken directly to the next step to maintaining the isotopic integrity of the substrate. Finally, we
convert the bromide to alcohol 24,24 by first displacing bromides have demonstrated an iterative method for the incorporation of
with acetates and then hydrolyzing all acetates. Purification by C4D8 units into organic molecules. In principle, numerous
flash chromatography afforded 24 in 21% yield over three steps. deuterated targets can be assembled with this chemistry.
At this point we were able to expedite CD3 incorporation
compared with the synthesis of Scheme 4. It has been shown that
methyl group incorporation can be accomplished by reaction of a
Experimental methods
primary tosyl group with methyllithium25,26 or methylmagnesium
General methods
chloride27 in the presence of copper (I) iodide.28 The methyl-
lithium was first attempted with tosylate 25, which was prepared
in 71% yield by the reaction of alcohol 24 with TsCl. While methyl
incorporation was accomplished with MeLi in only 20%, the same
The general procedures have been published elsewhere.29 UV
irradiation was performed with a Hanovia 200 W immersion
lamp light source. Deuterium-labelled compounds were pur-
chased from C-D-N isotopes. A 0.1 M solution of Li2CuCl4 in THF
reaction with methylmagnesium bromide was significantly more
was prepared by drying LiCl and CuCl2ꢀ2H2O under vacuum for
4 h at 1201C.
efficient, proceeding in 77% yield. Thus, by circumventing alcohol
oxidation as required by Scheme 4, d3-alkene 26 was obtained
directly from primary tosylate 25 in 87% yield.
9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,16-(Heptadecyldeuter-
The addition of thiolacetic acid to the double bond of this
io)-1-bromohexadecane (5)
alkene 21 was accomplished through a radical chain addition
assisted by photoinitiated AIBN. Specifically, alkene 26,
thioacetic acid and AIBN in toluene exposed to UV irradiation
for 5 h, and after chromatography, afforded addition product
27 in 84% yield. Deprotection of this thiolacetate was
accomplished in 50% whether using LiAlH4 or acidic methanol
(75 mg scale). (Scheme 5).
To a flame dried RBF was added scratched magnesium turnings
(348 mg, 1.43 mmol), a crystal of iodine and THF (5 mL). 1-
Bromooctane-d17 (1.00 g, 4.76 mmol) was added dropwise and
the reaction was stirred under reflux until complete formation of
Grignard reagent was indicated by GC analysis (3.5 h). To
another flame dried RBF was added 1,8-dibromooctane (2.59 g,
9.52 mmol), a freshly prepared 0.1 M solution of Li2CuCl4
(0.952 mL) and THF (5 mL). This mixture was cooled to 01C and
the prepared Grignard reagent was added dropwise. During
addition, the reaction turned from orange to dark purple to clear
and then remained dark purple. The reaction was stirred
overnight at 01C and was then quenched with 1 M HCl (30 mL)
and extracted with diethyl ether (3 Â 20 mL). The combined
organic layers were washed with brine, dried over MgSO4 and
Summary
This paper outlines the preparation of three heretofore
unknown hexadecanethiols with different sections of perdeu-
teration. In studies to be submitted elsewhere two of the
compounds have been used to secure valuable information
THF
Br
MgCl
Br
+
+
Br
Br
23
Br
13
Li2CuCl4
11
11
+ -OAc
K
1.
2. KOH, MeOH
TsCl, py
CH2Cl2
OH
CD3MgI, CuI
THF
+
HO
HO
13
TsO
D3C
13
13
11
26 (87%)
25 (71%)
24
(21% over 3 steps)
AcSH, AIBN
hν, PhMe
CD3(CH2)15SAc
27 (84%)
HCl, MeOH
CD3(CH2)15SH
3 (50%)
Scheme 5.
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Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 391–398

E. E. Sheepwash et al.
concentrated to yield an inseparable mixture of 1,8-dibromooc- combined organics were washed with brine, dried over MgSO4
tane and the product 9,9,10,10,11,11,12,12,13,13,14,14,15,15, and concentrated. The mixture was purified by flash chromato-
16,16,16-(heptadecyldeuterio)-bromohexadecane (5) (2.81 g total graphy on silica gel (5% EtOAc/hexanes) to yield pure 11 (2.68 g,
mass). Characterization data for 5:1H NMR (CDCl3)d3.38 (t, 62%). 1H NMR (CDCl3)d4.55 (m, 1H), 3.88–3.81 (m, 1H), 3.74–3.66
2
J = 6.8 Hz, 2H), 1.83 (p, J = 7.1 Hz, 2H), 1.42–1.23 (m, 4H). H NMR (m, 1H), 3.50–3.45 (m, 1H), 3.39–3.31 (m, 1H), 1.83 (m, 8H),
(CHCl3)d1.17 (s, 14H), 0.80 (s, 3H). 13C NMR (CDCl3)d34.0, 33.9, 1.2–1.3 (m, 18H), 0.85 (t, J = 6.5 Hz, 3H). 2H NMR (CHCl3)d3.71
32.9, 32.7, 29.6, 29.4, 28.8, 28.5, 28.2, 28.0. IR (cmÀ1): 2928, 2855, (1 H), 3.37 (1H), 3.19 (2H), 1.87 (2H), 1.63 (2H). 13C NMR
2196, 2095, 1464. MS (EI), m/z (%):323 (M1 81Br, 6), 321 (M1 79Br, (CDCl3)d98.9, 67.7, 62.3, 31.9, 30.8, 29.8, 29.6, 29.5, 29.3, 26.2,
6), 242 (12), 165 (3), 163 (3), 151 (22), 149 (22), 137 (98), 135 (100). 25.5, 22.7, 19.7, 14.1. MS (CI, NH3), m/z (%): 288 ((M1NH4)1, 25),
186 (43), 169 (23), 102 (100), 85 (10), 53 (2).
9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16-(Heptadecyldeuterio)-
hexadecyl-1-thiolacetate (6)
1,1,2,2,3,3,4,4-(Octyldeuterio)-4-iodobutan-1-ol (12)
The crude mixture of 1,8-dibromooctane and bromohexade-
cane-d17 (2.81 g) was dissolved in CH3CN (40 mL) to which was
added potassium thiolacetate (2.18 g, 19.1 mmol). The mixture
was stirred at room temperature until complete by TLC (3 h). The
reaction was quenched with H2O (40 mL), the layers were
separated and the aqueous layer was extracted with pentanes
(3 Â 30 mL). Combined organic layers were washed with brine,
dried over MgSO4 and concentrated. The mixture was purified
by flash chromatography on silica gel (2% EtOAc/hexanes) to
yield the pure 6 (767 mg, 51% over two steps). 1H NMR
(CDCl3)d2.84 (t, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.53 (m, 2H), 1.23 (m,
12H). 2H NMR (CHCl3)d1.17 (s, 14H), 0.80 (s, 3H). 13C NMR
(CDCl3)d195.5, 30.6, 29.6, 29.5, 29.4, 29.1, 28.8. IR (cmÀ1): 2917,
2851, 2191, 2090, 1687, 1469. MS (EI), m/z (%): 317 (M1, 9), 274
(100), 257 (21), 241 (18).
To a solution of sodium borohydride (1.89 g, 50.0 mmol) and
THF-d8 (4.00 g, 50.0 mmol) was added dropwise a solution of
iodine (25.4 g, 100 mmol) in toluene (130 mL). The mixture was
stirred for 6 days in the dark, cooled to 01C and slowly quenched
with H2O (80 mL). The layers were separated and the aqueous
layer was extracted with ether (3 Â 50 mL). The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated. Crude 12 (10.0 g, 96%) was protected without
further purification. 2H NMR (CHCl3)d3.49 (s, 2D), 3.10 (s, 2D),
1.75 (s, 2D), 1.50 (s, 2D). 13C NMR (CDCl3)d60.5 (m), 32.0 (m), 28.7
(m), 6.9 (m). IR (cmÀ1): 3346, 2212, 2098.
t-Butyl-(1,1,2,2,3,3,4,4-(octyldeuterio)-4-iodobutoxy)diphenylsilane
(14)
This protocol was adapted from a previous method.17 To a flame
dried RBF was added a solution of crude 4-iodobutan-1-ol-d8
(12, 6.80 g, 32.7 mmol), imidazole (5.57 g, 81.8 mmol) and CH2Cl2
(100 mL). t-Butylchlorodiphenylsilane (10.1 mL, 39.2 mmol) was
9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16-(Heptadecyldeuterio)-
hexadecane-1-thiol (1)
To a flame dried RBF was added LiAlH4 (23.9 mg, 0.630 mmol) added dropwise at 01C. The mixture was warmed slowly to room
and THF (0.5 mL). This mixture was cooled to 01C and a mixture temperature and stirred in the dark overnight. The reaction was
of hexadecanethiolacetate-d17 (6, 200 mg, 0.630 mmol) in THF quenched with saturated NH4Cl solution (40 mL), the layers were
(1.5 mL) was added dropwise. Reaction was stirred at this separated and the aqueous layer was extracted with CH2Cl2
temperature for 30 min. The reaction quenched slowly with H2O (3 Â 30 mL). The combined organics were washed with brine,
(5 mL) and the aluminum salts were filtered off and washed with dried over MgSO4 and concentrated. Product was purified by
CH2Cl2. The filtrate layers were separated and the aqueous layer flash chromatography on silica gel (10% EtOAc/hexanes) to yield
1
was extracted with CH2Cl2 (3 Â 5 mL). The combined organic pure 14 (11.5 g, 79%). H NMR (CDCl3)d7.67 (dd, J = 7.7, 1.5 Hz,
2
layers were washed with brine, dried over MgSO4 and 4H), 7.42–7.36 (m, 6H), 1.04 (s, 9H). H NMR (CHCl3)d3.63 (s, 2H),
concentrated. The mixture was isolated by flash chromatogra- 3.15 (s, 2H), 1.88 (s, 2H), 1.59 (s, 2H). 13C NMR (CDCl3)d135.5,
phy on silica gel (100% hexanes) to yield pure 1 (122 mg, 70%). 133.8, 129.6, 127.6, 26.8, 19.2. IR (cmÀ1): 3070, 2929, 2856, 2198,
1H NMR (CDCl3)d2.50 (q, J = 7.4 Hz, 2H), 1.58 (m, 2H), 1.36–1.22 2084, 1727, 1427, 1265, 1111, 1047. MS (CI, NH3), m/z (%): 464
(m, 13H). 2H NMR (CHCl3)d1.18 (s, 14H), 0.82 (s, 3H). 13C NMR ((M1NH4)1, 100), 447 (8), 406 (19), 386 (5), 326 (1), 191 (6).
(CDCl3)d34.1, 29.6, 29.5, 29.1, 29.4, 24.7. IR (cmÀ1): 2924, 2853,
2195, 2095, 1465, 1087. MS (EI), m/z (%): 275 (M1, 100), 240 (49),
1,1,2,2,3,3,4,4-(Octyldeuterio)-(tetrahydropyranyloxy)dodecane
212 (10), 152 (4), 121 (9), 101 (20), 83 (32), 55 (41). HRMS (EI): (15)
Calc’d for C16H17D17S, 275.3348; Found, 275.3443.
This protocol was adapted from a previous method.16 To a flame
dried RBF was added scratched magnesium turnings (189 mg,
7.77 mmol), a crystal of iodine and THF (3 mL). 1-bromooctane
(500 mg, 2.59 mmol) was added dropwise and the reaction was
stirred under reflux until complete formation of the Grignard
reagent was indicated by GC analysis (3.5 h). To another flame
dried RBF was added 1,1,2,2,3,3,4,4-(octyldeuterio)-4-iodo-1-
(tetrahydropyranyloxy)butane (14, 380 mg, 1.30 mmol), a freshly
prepared 0.1 M solution of Li2CuCl4 (0.260 mL) and THF (2 mL).
This mixture was cooled to 01C and the prepared Grignard
reagent was added dropwise. The reaction was stirred at this
temperature overnight and was quenched with 1 M HCl (5 mL)
and then extracted with diethyl ether (3 Â 5 mL). The combined
organic layers were washed with brine, dried over MgSO4 and
1,1,2,2,3,3,4,4-(octyldeuterio)-4-iodo-1-(Tetrahydropyranyloxy)bu-
tane (11)
This protocol was adapted from a previous method.30 To a flame
dried RBF was added 1,1,2,2,3,3,4,4-(octyldeuterio)-4-iodobutan-
1-ol (12, 3.10 g, 14.9 mmol), p-toluenesulfonic acid (567 mg,
2.98 mmol) and CH2Cl2 (20 mL). The mixture cooled to 01C and
3,4-dihydro-2H-pyran (3.41 mL, 37.3 mmol) added dropwise. The
reaction was warmed to room temperature and stirred in the
dark until TLC indicated completion (4 h). The reaction was
quenched with H2O (20 mL), the layers were separated and
aqueous layer was extracted with ether (3 Â 15 mL). The
J. Label Compd. Radiopharm 2008, 51 391–398
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E. E. Sheepwash et al.
concentrated. The mixture was purified by flash chromatogra- to destroy excess reagent. The reaction was extracted with ether
1
phy on silica gel (100% hexanes) to yield 15 (230 mg, 64%). H (3 Â 10 mL) and combined organic layers were washed with 1 M
NMR (CDCl3)d4.56–4.55 (m, 1H), 3.87–3.82 (m, 1H), 3.74–3.66 (m, HCl (16 mL), brine, dried over MgSO4 and concentrated. The
0.2H), 3.50–3.48 (m, 1H), 3.37–3.31 (m, 0.2H), 1.83–1.81 (m, 1H), mixture was purified by flash chromatography on silica gel
1.80–1.67 (m, 1H), 1.59–1.48 (m, 6H), 1.30–1.24 (m, 12H), 0.86 (t, (100% hexanes) to yield pure 18 (1.70 g, 87%). 1H NMR
2
J = 6.9 Hz, 3H). H NMR (CHCl3)d3.68 (s, 0.9H), 3.32 (s, 0.9H), 1.52 (CDCl3)d1.24 (s, 14H), 0.86 (t, J = 6.8 Hz, 3H). 2H NMR (CHCl3)d3.36
(s, 2H), 1.25 (s, 4H). 13C NMR (CDCl3)d98.8, 67.7, 62.3, 31.9, 31.8, (s, 2H), 1.78 (s, 2H), 1.35 (s, 2H), 1.24 (s, 2H). 13C NMR
30.8, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 26.2, 25.5, 22.7, 19.7, (CDCl3)d31.9, 29.6, 29.5, 29.3, 29.2, 22.7, 14.1. IR (cmÀ1): 2924,
14.1. IR (cmÀ1): 3449, 2924, 2854, 1466, 1028. MS (CI, NH3), m/z 2853, 2197, 2099, 1466, 991. MS (EI), m/z (%): 258 (M1 81Br, 3),
(%): 296 ((M1NH4)1, 43), 277 (5), 102 (100), 85 (10).
256 (M1 79Br, 3), 159 (19), 157 (19), 143 (100), 145 (97), 104 (6), 90
(11), 76 (19), 57 (41).
t-Butyl-(1,1,2,2,3,3,4,4-(octyldeuterio)-dodecyl)diphenylsilane (16)
t-Butyl-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(hexadecyldeuterio)-hexade-
cyl)diphenylsilane (19)
To a flame dried RBF was added scratched magnesium turnings
(758 mg, 31.2 mmol), a crystal of iodine and THF (10 mL). 1-
bromooctane (2.00 g, 10.4 mmol) was added dropwise and the
reaction was stirred under reflux until complete formation
of Grignard reagent was indicated by GC analysis (3.5 h).
To another flame dried RBF was added t-butyl-(1,1,2,2,3,
3,4,4-(octyldeuterio)-4-iodobutoxy)diphenylsilane (14, 2.31 g,
5.18 mmol), a freshly prepared 0.1 M solution of Li2CuCl4
(2.08 mL) and THF (10 mL). This mixture was cooled to 01C and
the prepared Grignard reagent was added dropwise. Upon
addition of the Grignard, the reaction turned from orange to
dark purple to clear and then remained dark purple. The
reaction stirred overnight at this temperature. Workup and
purification as per 15 yielded pure 16 (1.93 g, 86%). 1H NMR
(CDCl3)d7.66 (d, J = 7.4 Hz, 4H), 7.40–7.24 (m, 6H), 1.29–1.25 (m,
14H), 1.04 (s, 9H), 0.88 (t, J = 5.1 Hz, 3H). 2H NMR (CHCl3)d3.61 (s,
2H), 1.48 (s, 2H), 1.26 (s, 2H), 1.22 (s, 2H). 13C NMR (CDCl3)d135.5,
133.8, 129.6, 127.6, 26.9, 19.2. IR (cmÀ1): 3071, 2926, 2855, 2199,
2087, 1471, 1112, 1075. MS (CI, NH3), m/z (%): 450 ((M1NH4)1,
100), 433 (27), 392 (27), 372 (7), 338 (2), 256 (3).
To a flame dried RBF was added scratched magnesium turnings
(425 mg, 17.5 mmol), a crystal of iodine and THF (8 mL).
1,1,2,2,3,3,4,4-(octyldeuterio)-1-bromododecane (18, 1.50 g,
5.83 mmol) was added dropwise and the reaction was stirred
under reflux until complete formation of Grignard reagent was
indicated by GC analysis (3.5 h). To another flame dried RBF was
added
t-butyl-(1,1,2,2,3,3,4,4-(octyldeuterio)-4-iodobutoxy)di-
phenylsilane (12, 1.30 g, 2.92 mmol), a freshly prepared 0.1 M
solution of Li2CuCl4 (2.33 mL) and THF (8 mL). This mixture was
cooled to 01C and the prepared Grignard reagent was added
dropwise. Upon Grignard addition, the reaction turned from
orange to dark purple to clear and then remained dark purple.
The reaction was stirred overnight at this temperature. Workup
and purification as per 15 yielded pure 19 (1.12 g, 77%). 1H NMR
(CDCl3)d7.72 (d, J = 7.3 Hz, 4H), 7.45–7.39 (m, 6H), 1.31 (s, 14H),
2
1.10 (s, 9H), 0.93 (t, J = 5.3 Hz, 3H). H NMR (CHCl3)d3.61 (s, 2H),
1.48 (s, 2H), 1.17 (s, 12H). 13C NMR (CDCl3)d135.6, 134.2, 129.5,
127.6, 32.0, 29.8, 29.7, 29.5, 29.4, 26.9, 22.7, 19.2, 13.1. IR (cmÀ1):
3071, 2925, 2855, 2197, 2095, 1463, 1427, 1112, 1047, 823. MS
(CI, NH3), m/z (%): 514 ((M1NH4)1, 100), 498 (37) 456 (36), 437
(9), 338 (5), 321 (4), 280 (2), 256 (5).
1,1,2,2,3,3,4,4-(Octyldeuterio)-dodecan-1-ol (17)
This protocol was adapted from a previous method.19 To a flame
dried RBF was added t-butyl-(1,1,2,2,3,3,4,4-(octyldeuterio)-
dodecyl)diphenylsilane (16, 4.24 g, 9.80 mmol) in methanol
(30 mL). The mixture was cooled to 01C and acetyl chloride
(115 mg, 1.47 mmol) was added dropwise. The reaction was
warmed slowly to room temperature and stirred until TLC
indicated completion (5 h). The reaction was diluted with CH2Cl2
(150 mL) and neutralized with 10% NaHCO3 solution (9 mL). The
organic layer was separated and washed with H2O (20 mL),
brine, dried over MgSO4 and concentrated. The mixture was
purified by flash chromatography on silica gel (10% EtOAc/
hexanes) to yield pure 17 (1.71 g, 90%). 1H NMR (CDCl3)d1.24 (s,
14 H), 0.85 (t, J = 6.4 Hz, 3H). 2H NMR (CHCl3)d3.58 (s, 2H), 1.49 (s,
2H), 1.26 (s, 4H). 13C NMR (CDCl3)d31.9, 29.7, 29.6, 29.5, 29.3,
22.6, 14.1. IR (cmÀ1): 3347, 2923, 2853, 2201, 2099, 1466, 1117.
MS (CI, NH3), m/z (%): 212 ((M1NH4)1, 100), 52.4 (16).
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(Hexadecyldeuterio)-hexadecan-1-ol
(20)
This protocol was adapted from a previous method.19 To a flame
dried RBF was added t-butyl-(1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(hex-
adecyldeuterio)-hexadecyl)diphenylsilane (19, 1.00 g, 2.01 mmol)
in methanol (6 mL). The mixture was cooled to 01C and acetyl
chloride (2.37 mg, 0.302 mmol) was added dropwise. The
reaction was warmed slowly to room temperature and stirred
until TLC indicated completion (5 h). Workup and purification as
per compound 17 yielded pure 20 (0.418 g, 80%). 1H NMR
(CDCl3)d1.23 (s, 14H), 0.86 (t, J = 6.8 Hz, 3H). 2H NMR (CHCl3)d3.59
(s, 2H), 1.50 (s, 2H), 1.27 (s, 2H), 1.19 (s, 10H). 13C NMR
(CDCl3)d31.9, 29.7, 29.6, 29.4, 29.3, 22.6, 14.1. IR (cmÀ1): 3293,
2918, 2850, 2194, 2090, 1563, 1265, 908. MS (CI, NH3), m/z (%):
276 ((M1NH4)1, 100), 275 (6), 53 (10).
1,1,2,2,3,3,4,4-(Octyldeuterio)-1-bromododecane (18)
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(Hexadecyldeuterio)-hexadecyl-1-thio-
lacetate (21)
This protocol was adapted from a previous method.20 To a flame
dried RBF was added 1,1,2,2,3,3,4,4-(octyldeuterio)-dodecan-1-ol
(17, 1.47 g, 7.56 mmol), PPh3 (3.96 g, 15.1 mmol) and DMF
(15 mL). N-bromosuccinimide (2.69 g, 15.1 mmol) was added
slowly to the mixture and the reaction was stirred at 501C for
15 min. The reaction was cooled to room temperature and
methanol (9 mL) was added and stirred for an additional 5 min
This protocol was adapted from a previous method.21 To a flame
dried RBF was added PPh3 (780 mg, 2.70 mmol) and THF (6 mL).
The mixture was cooled to 01C and diisopropylazodicarboxylate
(546 mg, 2.70 mmol) was added dropwise. After the mixture
was stirred at 01C for 30 min, a solution of 1,1,2,2,3,3,4,4,5,5,
6,6,7,7,8,8-(hexadecyldeuterio)-hexadecan-1-ol (20, 0.349 mg,
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 391–398

E. E. Sheepwash et al.
1.35 mmol) and thiolacetic acid (195 mg, 2.70 mmol) in THF 1H), 4.90 (d, J = 10.5 Hz, 1H), 3.62 (t, J = 6.6 Hz, 2H) 2.02 (q,
(4 mL) was added at 01C. The reaction was stirred at 01C for 1 h J = 6.9 Hz, 2H), 1.56–1.50 (m, 2H), 1.24 (m, 20H). 13C NMR
then warmed to room temperature and stirred until TLC (CDCl3)d179.0, 139.3, 114.1, 63.1, 33.8, 32.8, 29.6, 29.5, 29.4, 29.1,
indicated completion (1.5 h). The solvent was evaporated 28.9, 25.7.
and the mixture was purified by flash chromatography
on silica gel (5% EtOAc/hexanes) to yield pure 21 (305 mg,
71%). 1H NMR (CDCl3)d2.29 (s, 3H), 1.23 (s, 14H), 0.85
Pentadec-14-en-1-yl tosylate (25)
2
Pentadec-14-en-1-ol (24, 713 mg, 3.15 mmol) and p-toluenesul-
fonyl chloride (901 mg, 4.73 mmol) were dissolved in
CH2Cl2 (3 mL) in a flame dried RBF and a catalytic amount of
pyridine (0.510 mL) was added. The reaction was stirred
at room temperature until TLC indicated completion (5 h). The
reaction was diluted with CH2Cl2 (10 mL) and quenched
with H2O (10 mL). The layers were separated and the organic
layer was washed with 1 M HCl (10 mL), saturated NaHCO3
(10 mL), brine, dried over MgSO4 and concentrated. The mixture
(t, J = 6.8 Hz, 3H). H NMR (CHCl3)d2.81 (s, 2H), 1.26 (s, 2H), 1.17
(s, 2H). 13C NMR (CDCl3)d196.0, 31.9, 30.6, 29.7, 29.6, 29.4,
29.3, 22.7, 14.1. IR (cmÀ1): 2923, 2853, 2196, 2096, 1695, 1467,
1353, 1132, 957. MS (EI), m/z (%): 316 (M1, 13), 273 (100), 252
(17), 239 (15).
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(Hexadecyldeuterio)-hexadecane-1-
thiol (2)
This protocol was adapted from a previous method.22 To a flame was purified by flash chromatography on silica gel
dried RBF was added 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-(hexadecyldeu- (50% toluene/hexanes) to yield pure 25 (850 mg, 71%). 1H
terio)-hexadecyl-1-thiolacetate (21, 54 mg, 0.170 mmol) and NMR (CDCl3)d7.77 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H),
MeOH (2.5 mL). 1 drop of concentrated HCl was added to the 5.86–4.89 (m, 1H), 4.97 (d, J = 20.7 Hz, 1H), 4.93 (d, J = 10.2 Hz,
reaction mixture and the reaction was refluxed overnight. The 1H), 4.00 (t, J = 6.5 Hz, 2H) 2.43 (s, 3H), 2.02 (q, J = 7.0 Hz, 2H), 1.61
solvent was evaporated and the residue was dissolved in EtOAc (p, J = 6.9 Hz, 2H), 1.35–1.20 (m, 20H). 13C NMR (CDCl3)d144.5,
(10 mL). The solution was washed with water (2 Â 10 mL), brine, 139.2, 133.3, 129.7, 127.8, 114.0, 70.6, 33.8, 29.6, 29.5, 29.4, 29.3,
dried over MgSO4 and concentrated. Purification by flash 29.0, 28.9, 28.8, 25.3, 21.6. IR (cmÀ1): 3074, 2925, 2854, 1640,
chromatography (100% hexanes) yielded pure 2 (32 mg, 69%). 1599, 1466, 1364, 1189, 1178. MS (CI, NH3), m/z (%): 398 ((M1
1H NMR (CDCl3)d1.27–1.24 (m, 15H), 0.86 (t, J = 6.6 Hz, 3H). 2H NH4)1, 100), 356 (3), 316 (3).
NMR (CHCl3)d2.47 (2H), 1.53 (2H), 1.30 (2H), 1.19 (10H). 13C NMR
(CDCl3)d31.9, 29.7, 29.4, 29.3, 22.7, 14.1. IR (cmÀ1): 2956, 2922,
16,16,16-(Trideuterio)-hexadec-1-ene (26)
2853, 2196, 2094, 1466. MS (EI), m/z (%): 274 (M1, 100), 239 (40),
207 (8), 104 (14), 90 (20), 74 (20), 62 (27). HRMS (EI): Calc’d for
C16H18D16S, 274.3386; Found, 274.3386.
The protocol is based on a published method.27 To a flame dried
RBF was added pentadec-14-en-1-yl tosylate (25, 800 mg,
2.10 mmol), copper (I) iodide (80 mg, 0.420 mmol) and
THF (8 mL). The mixture was cooled to 01C and 1.0 M solution
of d3-methylmagnesium iodide in ether (5.25 mL, 5.25 mmol)
was added dropwise by syringe. The reaction was brought
15-Bromo-1-pentadecene (23)
Following an established protocol,23 1,12-dibromododecane
slowly to room temperature and stirred overnight. The
reaction was diluted with diethyl ether (10 mL) and quenched
slowly with 1 M HCl (15 mL). The layers were separated and
aqueous layer was extracted with ether (3 Â 5 mL). The
combined organic layers were washed with brine, dried over
MgSO4 and concentrated. Product was purified by flash
chromatography on silica gel (100% hexanes) to yield pure 26
(416 mg, 87%). 1H NMR (CDCl3)d7.77 (d, J = 8.3 Hz, 2H), 7.32
(d, J = 8.1 Hz, 2H), 5.86–4.89 (m, 1H), 4.97 (d, J = 20.7 Hz, 1H), 4.93
(d, J = 10.2 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H) 2.43 (s, 3H), 2.02
(q, J = 7.0 Hz, 2H), 1.61 (p, J = 6.9 Hz, 2H), 1.35–1.20 (m, 20H).
2H NMR (CDCl3)d0.83. 13C NMR (CDCl3)d139.3, 114.1, 33.9, 31.8,
29.7, 29.5, 29.4, 29.2, 29.0, 22.4. IR (cmÀ1): 3078, 2924, 2854,
2214, 2075, 1641, 1466, 909. MS (EI), m/z (%): 227 (M1, 55), 199
(13), 185 (5), 171 (5), 143 (10), 125 (20), 111 (45), 97 (94), 83 (100),
69 (68), 55 (80).
(10.0 g, 3.05 mmol) was dissolved in a 0.15 M solution of Li2CuCl4
in THF (45 mL). The mixture was cooled to 01C and allylmagne-
sium chloride (2.0 M, 22.8 mL, 4.58 mmol) was added slowly
over a period of 30 min. The reaction was stirred at this
temperature for 1 h and then quenched with 1 M HCl (72 mL)
and stirred for an additional 30 min. The layers were separated
and aqueous layer was extracted with ether (3 Â 50 mL).
The combined organic layers were washed with brine, dried
over MgSO4 and concentrated to give an inseparable mixture of
product 23 and starting 1,12-dibromododecane (7.70 g). This
crude product was carried onto the next step without
purification.
Pentadec-14-en-1-ol (24)
The crude mixture of 15-bromo-1-pentadecene and 1,12-
dibromododecane was dissolved in DMF (50 mL). Potassium
acetate (10.2 g, 104 mmol) was added to the mixture and the
reaction was stirred at 601C for 2 h. After evaporation of the
16,16,16-(Trideuterio)-hexadecyl-1-thiolacetate (27)
solvent, the residue was treated with KOH (5.84 g, 104 mmol) To an oven dried quartz vial was added d3-hexadec-1-ene (26,
and MeOH (60 mL) and stirred at the same temperature for 1.5 h. 750 mg, 3.30 mmol), AIBN (54 mg, 0.330 mmol) thiolacetic acid
The solvent was evaporated and the residue was dissolved in (0.891 mL, 13.2 mmol) and toluene (5 mL). The reaction was
CH2Cl2 (50 mL). The layers were separated and the organic layer irradiated under UV light for 5 h. The reaction was diluted with
was washed with H2O (2 Â 50 mL), brine, dried over MgSO4 and CH2Cl2 (10 mL) and quenched with saturated NaHCO3 until no
concentrated. Purification by flash chromatography on silica gel thiolacetic acid remained. The combined organic layers were
(20% EtOAc/hexanes) yielded pure 2431 (1.51 g, 21% over three washed with brine, dried over MgSO4 and concentrated. The
steps). 1H NMR (CDCl3)d5.83–5.75 (m, 1H), 4.97 (d, J = 17.4 Hz, mixture was purified by flash chromatography on silica gel (5%
J. Label Compd. Radiopharm 2008, 51 391–398
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

E. E. Sheepwash et al.
EtOAc/hexanes) to yield pure 27 (838 mg, 84%). 1 H NMR
(CDCl3)d2.84 (t, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.54 (p, J = 7.5 Hz, 2H),
1.32–1.23 (m, 26H). 2H NMR (CHCl3)d0.83 (s). 13C NMR
(CDCl3)d31.9, 30.6, 29.7, 29.6, 29.4, 29.3, 28.3, 22.7, 14.1. IR
(cmÀ1): 2915, 2850, 2209, 1694, 1471. MS (EI), m/z (%): 303 (M1,
10), 260 (100), 243 (19), 227 (18).
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16,16,16-(Trideuterio)-hexadecane-1-thiol (3)
To a flame dried RBF was added LiAlH4 (75.1 mg, 1.98 mmol) and
THF (2.5 mL). This mixture was cooled to 01C and a solution of
d3-hexadecanethiolacetate (27, 600 mg, 1.98 mmol) in THF
(3.5 mL) was added dropwise. The reaction was stirred at this
temperature for 10 min and then quenched slowly with H2O
(10 mL). The aluminum salts were filtered off and washed with
CH2Cl2. The layers of filtrate were separated and the aqueous
layer was extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were washed with brine, dried and concentrated.
The product was isolated by flash chromatography (100%
hexanes) to yield pure 3 (257 mg, 50%). 1H NMR (CDCl3)d2.49 (q,
J = 7.3 Hz, 2H), 1.59 (m, 2H), 1.35–1.24 (m, 27H). 2H NMR
(CHCl3)d0.84 (s). 13C NMR (CDCl3)d34.1, 31.8, 29.7, 29.5, 29.4,
29.1, 28.4, 24.7, 22.4. IR (cmÀ1): 2923, 2853, 2213, 1465, 1055. MS
(EI), m/z (%): 261 (M1, 100), 227 (70), 199 (22), 125 (17), 111 (36),
97 (75), 83 (87), 69 (64), 55 (63). HRMS (EI): Calc’d for C16H31D3S,
261.2569; Found, 261.2574.
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Acknowledgement
The authors are indebted to the Natural Sciences and
Engineering Research Council for supporting this research. The
authors would also like to thank Dr F.-I. Auzanneau for the use of
a photochemical UV lamp. EES wishes to thank the Ontario
Government for an OGSST scholarship.
[28] CD3MgI was not directly coupled to compound 23 due to
separation issues between 23 and the starting 1,12-dibromodo-
decane.
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