Large-scale preparation of long-chain ADMET synthons

Article abstract of DOI:10.1080/00397911.2014.899606

We report a convenient process with minimal purification to produce large quantities of α,ω-alkenyl alcohols. These reagents are indispensable precursors in ADMET chemistry. Icos-19-en-1-ol, nonacos-28-en-1-ol, and octatriacont-37-en-1-ol were produced effortlessly in large quantities (up to 45 g in a single batch) from undec-10-en-1-ol. By extension of the method, any desired methylene run length in the ADMET precursor can be achieved. Copyright

Full text of DOI:10.1080/00397911.2014.899606

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Large-Scale Preparation of Long-Chain
ADMET Synthons
Nicolas F. Sauty a , Hong Li a , Lucas Caire da Silva a & Kenneth B.
Wagener a
a George and Josephine Butler Polymer Research Laboratory,
Department of Chemistry and Center for Macromolecular Science
and Engineering , University of Florida , Gainesville , Florida , USA
Accepted author version posted online: 05 May 2014.Published
online: 01 Jul 2014.
To cite this article: Nicolas F. Sauty , Hong Li , Lucas Caire da Silva & Kenneth B. Wagener
(2014) Large-Scale Preparation of Long-Chain ADMET Synthons, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:16, 2409-2415,
DOI: 10.1080/00397911.2014.899606
To link to this article: http://dx.doi.org/10.1080/00397911.2014.899606
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Synthetic Communications1, 44: 2409–2415, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.899606
LARGE-SCALE PREPARATION OF LONG-CHAIN
ADMET SYNTHONS
Nicolas F. Sauty, Hong Li, Lucas Caire da Silva, and
Kenneth B. Wagener
George and Josephine Butler Polymer Research Laboratory, Department of
Chemistry and Center for Macromolecular Science and Engineering,
University of Florida, Gainesville, Florida, USA
GRAPHICAL ABSTRACT
Abstract We report a convenient process with minimal purification to produce large
quantities of a,x-alkenyl alcohols. These reagents are indispensable precursors in ADMET
chemistry. Icos-19-en-1-ol, nonacos-28-en-1-ol, and octatriacont-37-en-1-ol were produced
effortlessly in large quantities (up to 45 g in a single batch) from undec-10-en-1-ol. By
extension of the method, any desired methylene run length in the ADMET precursor can
be achieved.
Keywords ADMET; alkenyl synthons; homologation; precision polymers
INTRODUCTION
Acyclic diene metathesis (ADMET) polymerization, first reported in 1991 by
the Wagener research group,[1] has been extensively studied since then[2] as a versatile
tool to access precision polyolefins.[3–5] These polymers feature a functionality
positioned at unequivocal intervals along a polymer chain and display enhanced
properties as compared to their random counterparts. For instance, in the precision
butyl-branched polyethylene, a linear relationship between the branch frequency and
fusion temperature of the polymer was reported.[6]
Precision polyolefins are synthesized from their corresponding symmetrical
a,x-diene monomers. The olefin moiety and the desired number of methylene spacers
are in many instances introduced with the use of a,x-alkenyl bromides[7–9] or with
a,x-alkenyl alcohols.[10] Reducing the functionality frequency along the chain in
precision polymers correlates with augmenting the methylene run length in the
Received January 20, 2014.
Address correspondence to Kenneth B. Wagener, George and Josephine Butler Polymer Research
Laboratory, Department of Chemistry and Center for Macromolecular Science and Engineering,
University of Florida, Gainesville, FL 32611-7200, USA. E-mail: wagener@chem.ufl.edu
2409

2410
N. F. SAUTY ET AL.
Figure 1. Precision butyl-branched polyethylene with alkyl branch every 75th carbon.
monomer, and therefore in alkenyl synthons. These intermediates are commercially
available or can be synthesized[11] for methylene run lengths up to 10; however, no
convenient methodology to produce long-chain a,x-alkenyl synthons has been
reported thus far, although there is a synthesis to prepare an a,x-alkenyl bromide
precursor containing 36 methylene spacers, with 4 leading to a butyl branch on every
75th carbon (Fig. 1).
Nonetheless, onerous purification processes were precluded from yielding more
than milligrams of the polymer of interest, supplementary work exploiting such
lengthy spacers has been pursued. This small-scale limitation has also confined pre-
cision polymers to spectral and morphologic characterization only. Larger scales are
strongly desired for further analyses and mechanical studies, leading to the evident
need for a convenient synthetic route to access ADMET precursors with lengthy
spacers in large quantities. This is the object of the research, a result never achieved
before. We report a dependable synthesis based on a series of well-established reac-
tions, for an iterative and tunable n-carbon homologation of a,x-alkenyl alcohols on
the multidecagram scale, thereby offering an easy route to alkenyl synthons of any
desired methylene run length.
RESULTS AND DISCUSSION
Preparation of nonisomerized alkenyl synthons is paramount in the design of
flawless precision polymers. While internal olefins would remain active toward most
metathesis catalysts,[12] albeit at a lower conversion rate,[13] an ill-defined material
with a statistical distribution of methylene run lengths would result from the use
of an isomerized reagent, thereby destroying the precision character. Detectable
isomerization by 1H NMR or infrared (IR) inevitably disqualifies any starting
material. Commercially available synthons must be tested prior to use as some lots
may contain up to 5% isomerized reagent, based on our experience. Our new
methodology avoids isomerization completely. The synthesis relies on two building
blocks: the parent a,x-alkenyl alcohol to be homologated by n carbons, and an
a,x-bromoalcohol containing n methylene spacers as a homologation agent. We
are interested in synthesizing alkenyl synthons containing 18, 27, and 36 methylene
spacers. 9-Bromo-1-nonanol[14] (1) is the sole homologation reagent utilized in this
report.
The methodology for the homologation of a,x-alkenyl alcohols is presented in
Scheme 1. To simplify our presentation, a,x-alkenyl alcohols containing X methyl-
ene spacers are abbreviated XspOH. Initial investigations were conducted on a gram
scale and all the intermediates shown in the sequence were isolated while establishing
the methodology. Step-to-step purifications were not necessary.
tert-Butyldimethylsilyl chloride was chosen to protect 1 for its excellent stab-
ility in most environments and facile cleavage.[15–18] Following a recently published

LONG-CHAIN ADMET SYNTHONS
2411
Scheme 1. Synthesis of icos-19-en-1-ol. Reagents and conditions: (a) 1-methylimidazole, I2, TBDMSCl,
CH2Cl2, rt, 10 min (98%); (b) PCC, CH2Cl2, rt, 2 h (90%); (c) (9-((tert-butyldimethylsilyl)oxy)nonyl)
magnesium bromide, Et2O, 35 ꢀC, overnight (96%); (d) (i) NaH, imidazole, THF, 0 ꢀC to rt, 2 h; (ii)
CS2, 0 ꢀC to rt, overnight; (iii) MeI, 0 ꢀC to rt, 4 h (93%); (e) TEA, H3PO2, AIBN, dioxane, reflux, 3 h
(77%); (f) CuCl2 ꢁ 2H2O, acetone=water (95:5), reflux, 2 h (98%).
high-yield protection procedure by Stawinski and coworkers,[19] the corresponding
silyl ether 2 was obtained in 98% yield in only 10 min. Batches as large as 150 g could
be purified using simple silica plugs. Commercially available aldehyde 3 can shorten
the synthesis although lots containing detectable levels of isomerization must be dis-
carded. Compound 3 was also synthesized by oxidation of undec-10-en-1-ol (9spOH)
with pyridinium chlorochromate, affording the desired intermediate in 90% yield.
Silyl ether 2 was treated with magnesium, and the corresponding Grignard reagent
was reacted with the previously prepared aldehyde 3, affording secondary alcohol
4 in 96% yield. Xanthate 5 was obtained by treatment of 4 with sodium hydride, car-
bon disulfide, and methyl iodide at 0 ꢀC to attenuate the formation of undesired pro-
ducts.[20] Reductive deoxygenation of the xanthate was first attempted under
standard Barton–McCombie conditions,[21] but an unidentified by-product had to
be arduously removed from deoxygenated intermediate 6.
As the occurrence mentioned previously would have most certainly precluded
scale up, an alternative deoxygenation procedure was done. Using hypophosphorous
acid[22] instead of tributyltin hydride successfully promoted 6 and alleviated our puri-
fication concerns. The presence of free radicals may induce olefin isomerization;[23]
1
however, no detectable levels of isomerization by H NMR resulted from this reac-
tion. Typically, NMR experiments with concentrated samples (400 mmol=mL
CDCl3) and large number of transients (512 or more) enable the detection of low
levels isomerization (0.5% and above). Subsequent deprotection of the resulting
deoxygenated compound was done by refluxing an acetone–water mixture contain-
ing 5 mol% of copper(II) chloride dihydrate, as demonstrated by Tan et al.[24]
18spOH was isolated as white flakes with limited solubility with an overall yield
of 59% for the first homologation.
The synthesis was repeated on a large scale with no systematic purification
after each step. No systematic purification is key to the success we report herein.

2412
N. F. SAUTY ET AL.
Scheme 2. Synthesis of nonacos-28-en-1-ol. Reagents and conditions: (a) (i) PCC, CH2Cl2, reflux, 2 h
(88%); (b) crude, (9-((tert-butyldimethylsilyl)oxy)nonyl)magnesium bromide, Et2O, 35 ꢀC, overnight
(94%); (c) (i) NaH, imidazole, THF, 0 ꢀC to rt, 2 h; (ii) CS2, 0 ꢀC to rt, overnight; (iii) MeI, 0 ꢀC to rt,
4 h; (iv) crude, TEA, H3PO2, AIBN, dioxane, reflux, 3 h; (v) crude, CuCl2 ꢁ 2H2O, acetone=water (95:5),
reflux, 2 h (66%).
In fact, each subsequent reaction was performed using the crude product of the
former, with the exception of 3 and 4, which were refined by distillation and flash
column chromatography respectively. The desired homologated alcohol 18spOH
was obtained pure after recrystallization in pentane (about 5 mL pentane per gram
of 18spOH). The synthetic sequence afforded approximately 45 g of 18spOH from
45 g of 9spOH, equivalent to an overall 58% yield.
With the intention of producing 27spOH, the synthetic sequence was similarly
repeated with limited purifications (Scheme 2). Compounds 7 and 8 were both pur-
ified by flash column chromatography, and 27spOH was recrystallized from hexanes.
A yield of 20 g of the latter resulted from 26 g of 18spOH, corresponding to 55%
overall yield for the second homologation.
Likewise, 36spOH, which in our previous work was especially difficult to make,
was produced with only two purification steps (Scheme 3). Purification of 7 was
performed by flash column chromatography using near boiling eluent mixtures
(50–55 ꢀC) to circumvent the lower solubility of the intermediate. The subsequent
xanthate was formed at higher temperatures and reduced concentration as 7 was
not soluble in tetrahydrofuran (THF) at 0 ꢀC. As for the deprotection, twice as much
solvent (in comparison with the deprotection of 6) as well as addition of heptane was
necessary to solubilize the parent silyl ether of 36spOH. The unprotected alcohol
Scheme 3. Synthesis of octatriacont-37-en-1-ol. Reagents and conditions: (a) (i) PCC, CH2Cl2, reflux, 2 h;
(ii) crude, (9-((tert-butyldimethylsilyl)oxy)nonyl)magnesium bromide, Et2O, 35 ꢀC, overnight (79%); (b) (i)
NaH, imidazole, THF, rt to 40 ꢀC, 2 h; (ii) CS2, rt, overnight; (iii) MeI, rt, 4 h; (iv) crude, TEA, H3PO2,
AIBN, dioxane, reflux, 3 h; (v) crude, CuCl2 ꢁ 2H2O, acetone=water=heptane (90:5:5), reflux, 2 h (60%).

LONG-CHAIN ADMET SYNTHONS
2413
Scheme 4. Synthesis of precision polymers from alkenyl alcohols.
precipitated as the reaction proceeded, and fully crystallized as white pure flakes
upon cooling of the reaction mixture. Nearly 10 g of 36spOH were obtained from
16 g of 27spOH corresponding to 48% overall yield for the third homologation.
The reduced overall yield was attributed to the limited solubility of the intermedi-
ates, not to the actual chemistry at hand. In most instances, a diminished conversion
of the starting materials was observed. 36spOH was synthesized from 10-undecen-1-
ol after three consecutive 9-carbon homologations. Based on our reported yields,
48 g of 36spOH could be prepared from 100 g of 9spOH.
CONCLUSION
To conclude, we report a successful, convenient, and reliable synthetic route to
prepare large quantities of lengthy a,x-alkenyl alcohols without isomerization of the
olefin moiety. We effectively prepared alkenyl alcohols containing 18, 27, and 36
methylene units. The alkenyl alcohols can be transformed straightforwardly to their
corresponding alkenyl bromides counterparts, building blocks of precision polymers
(Scheme 4).
We are convinced that the straightforward and limited number of purifications
can indubitably promote a fast production of alkenyl synthons on a much greater
scale than we described in this report. Virtually any methylene run length can be
accessed by tuning the homologating agent.
EXPERIMENTAL
Icos-19-en-1-ol (18spOH)
In a 1-L, flame-dried, three-necked, round-bottom flask, 4 (97.2 g, 227.8 mmol)
and THF (300 mL) were added. The solution was cooled to 0 ꢀC and sodium hydride
60% in mineral oil (15.1 g, 378.1 mmol) was carefully added. After 30 min, the mix-
ture was allowed to slowly warm up to room temperature. After 2 h, the reaction was
cooled to 0 ꢀC, and carbon disulfide (52.0 g, 683.2 mmol) was added dropwise. After
3 h, the mixture was allowed to slowly warm to room temperature. Eight h later, the
reaction was cooled to 0 ꢀC, and methyl iodide (48.4 g, 341.6 mmol) was added drop-
wise to the reaction. After 1 h, the reaction was allowed to slowly warm to room tem-
perature, after which the mixture became more viscous. Four h later, the reaction
was cooled to 0 ꢀC and was carefully quenched with a saturated ammonium chloride
solution. Diethyl ether was added, and aqueous phase was extracted with diethyl
ether. The combined organic layers were washed with brine and dried over sodium
sulfate. Removal of the solvents in vacuo afforded an impure orange oil (124.3 g).
Triethylamine (350 mL, 2.51 mol) and a hypophosphorous acid solution in water

2414
N. F. SAUTY ET AL.
(50% w=v, 150.3 g, 588.7 mmol) were added to a 2-L flask equipped with a condenser
containing the impure oil and dioxane (770 mL). The mixture was refluxed and an
AIBN solution (7.48 g, 45.55 mmol) in dioxane (100 mL) was added continuously
over 4 h. After disappearance of the starting material by thin-layer chromatography
(TLC) analysis, the solvents were removed in vacuo, and 100 mL of hexanes were
added. The resulting mixture was passed through a silica plug using hexanes=ethyl
acetate (98:2) as the mobile phase. The solvents were removed in vacuo, affording
a slightly yellow oil (68.4 g). Water (82 mL) and copper(II) chloride dihydrate
(1.94 g, 11.39 mmol) were added to a 2-L flask equipped with a condenser containing
the yellow oil and acetone (1.6 L). The green mixture was refluxed for 2 h, after which
the solvents were removed in vacuo. The resulting solid was dissolved in hexanes,
and the solution was filtered over a bed of celite. The solvent was removed in vacuo,
and the crude solid was recrystallized in pentane (250 mL), affording 18spOH as pure
1
white flakes (45.3 g, 67% from 4). Melting point: 56–57 ꢀC; H NMR (300 MHz,
chloroform-d) d (ppm) 5.83 (ddt, J ¼ 17.0, 10.2, 6.6 Hz, 1H, vinyl CH), 5.06–4.89
(m, 2H), 3.65 (t, J ¼ 6.6 Hz), 2.10–1.99 (m, 2H), 1.73–1.18 (m, 32H); 13C NMR
(75 MHz, chloroform-d) d (ppm) 139.5, 114.3, 63.2, 33.0, 32.0, 29.9, 29.9, 29.8,
29.82, 29.80, 29.78, 29.76, 29.73, 29.66, 29.4, 29.2, 26.0; IR tmax ¼ 3272, 3079,
2922, 2849, 1647, 1464 cmꢂ1
C20H40O: 314.3417; found: 314.3428. Elemental analysis, calculated: C, 81.01%; H,
13.60%. Found: C, 80.99%; H, 13.73%.
;
DART=HRMS: [M þ NH4]þ calculated for
Characterization Data of 27spOH
Melting point: 78–79 ꢀC; 1H NMR (300 MHz, chloroform-d) d (ppm) 5.82 (ddt,
J ¼ 17.0, 10.3, 6.7 Hz, 1H), 5.06–4.88 (m, 2H), 3.65 (t, J ¼ 6.6 Hz, 2H), 2.11–1.98 (m,
2H), 1.18–1.62 (m, 50H); 13C NMR (75 MHz, chloroform-d) d (ppm) 139.5, 114.3,
63.3, 34.00, 33.0, 29.93, 29.85, 29.74, 29.66, 29.4, 29.2, 26.0; IR tmax ¼ 3326, 3079,
2922, 2846, 1643, 1464 cmꢂ1
C29H58O: 440.4826; found: 440.4831. Elemental analysis: calculated C, 82.39%; H,
13.83%. Found: C, 82.09%; H, 13.70%.
;
DART=HRMS: [M þ NH4]þ calculated for
Characterization Data of 36spOH
Melting point: 90–92 ꢀC; 1H NMR (300 MHz, chloroform-d) d (ppm) 5.83 (ddt,
J ¼ 17.0, 10.2, 6.6 Hz, 1H), 5.05–4.86 (m, 2H), 3.65 (t, J ¼ 6.6 Hz, 2H), 2.05 (m, 2H),
1.26–1.62 (m, 68H); 13C NMR (125 MHz, chloroform-d, 50 ꢀC) d (ppm) 139.5, 114.3,
63.4, 34.0, 33.1, 29.94, 29.91, 29.86, 29.85, 29.76, 29.70, 29.4, 29.2, 26.0; IR
tmax ¼ 3323, 3079, 2922, 2849, 1643, 1464 cmꢂ1; DART=HRMS: [M þ NH4]þ calcu-
lated for C38H76O: 566.6234; found: 566.6232. Elemental analysis calculated: C,
83.13%; H, 13.95%. Found: C, 83.25%; H, 14.05%.
FUNDING
We gratefully acknowledge the National Science Foundation (DMR-1203136)
and the Army Research Office (W911NF-13-1-0362) for the financial support of this
research.

LONG-CHAIN ADMET SYNTHONS
2415
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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