Effective syntheses of 2-trimethylsilylmethyl-3-trimethylsilyl-1-propene and its 1,1-d2- and 1,1,1',1',3,3-d6-isotopomers

Article abstract of DOI:10.1002/jlcr.511

New and effective routes to synthesize 2-trimethylsilylmethyl-3-trimethylsilyl-1-propene and its 1,1-d₂- and 1,1,1',1',3,3-d₆-isotopomers have been developed, using the displacement reaction of lithium trimethylsilylcyanocuprate with

Full text of DOI:10.1002/jlcr.511

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 987–992.
DOI: 10.1002/jlcr.511
Research Article
Effective syntheses of 2-trimethylsilylmethyl-
3-trimethylsilyl-1-propene and its 1,1-d2- and
1,1,10,10,3,3- d6-isotopomersy
Jun Hu* and Robert R. Squires{
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Summary
New and effective routes to synthesize 2-trimethylsilylmethyl-3-trimethylsilyl-
1-propene and its 1,1-d2- and 1,1,10,10,3,3-d6-isotopomers have been developed,
using the displacement reaction of lithium trimethylsilylcyanocuprate with
allylic halides and tosylates. These compounds are pivotal precursors for the
gas-phase synthesis and characterization of the trimethylenemethane anion,
and for negative ion photoelectron spectroscopic investigations of the singlet–
triplet splitting in trimethylenemethane. Copyright # 2001 John Wiley &
Sons, Ltd.
Key Words: 2-trimethylsilylmethyl-3-trimethylsilyl-1-propene; trimethylsilyl-
methyl-2-propen-1-ol; trimethylenemethane; regiospecific deuterium label
Introduction
2-Trimethylsilylmethyl-3-trimethylsilyl-1-propene (1) is a necessary
precursor for the gas-phase synthesis of the negative ion of trimethy-
lenemethane.1 This ion is required for measurements of the electronic
affinity and singlet–triplet splitting of trimethylenemethane by negative
ion photoelectron spectroscopy. In order to elucidate the regioselectivity
*Correspondence to: J. Hu, Department of Chemistry, the University of Akron, Akron, Ohio, OH
44325 U.S.A.
{ Deceased
y Adapted from the Ph.D. thesis of the corresponding author who was supervised by Prof. Robert
R. Squires, Purdue University, West Lafayette, IN 47907, USA, 1997.
Copyright # 2001 John Wiley & Sons, Ltd.
Received 4 May 2001
Revised 16 July 2001
Accepted 24 July 2001

988
J. HU AND R. R. SQUIRES
and mechanism of ion formation, the 1,1-d2-2-trimethylsilylmethyl-3-
trimethylsilyl-1-propene (d2-1) has been produced and used in generat-
ing 1,1-d2-trimethylenemethane anion. The 1,1,10,10,3,3-d6-2-trimethyl-
silylmethyl-3-trimethylsilyl-1-propene (d6-1) is also needed for aid in the
interpretation of vibrational fine structures in the negative ion
photoelectron spectrum of the trimethylenemethane anion.2, z The
significance of these compounds is not limited to our purposes alone.
Allylsilanes are versatile syntheticreagents and trimethylenemethane is
an important syntheticbuilding block in many synthetictransforma-
tions.3–9 Isotopically labelled compounds of this type may be useful as
spectroscopic and mechanistic probes.10,11 Herein, we report the
syntheses of 1 and its 1,1-d2- and 1,1,10,103,3,-d6-isotopomers.
Results and discussion
Miginiacreported a straightforward synthesis of 1 by disilylation of
isobutene dianion.3 However, we encountered several problems when
using this method. First, trace amounts (4–5% by GC-MS) of (E)- and
(Z)-2-trimethylsilylmethyl-1-trimethylsilyl-propenes are produced as
by-products in the synthesis. These impurities are very difficult to
remove by distillation, and they may produce isomers of trimethylene-
methane anion in subsequent gas-phase reactions. In addition, we found
a significant amount of deuterium/hydrogen exchange between d8-
isobutene and the hydrocarbon solvent during dianion formation,
which led to about 15% deuterium loss (by mass spectrometry) in the
labelled product.
We sought an alternative synthesis of 1 that can also be adapted to
synthesize the deuterium labelled compounds, d2- and d6-1, with high
isotopic purity. We found that lithium trimethylsilylcyanocuprate
readily reacts with commercially available 2-chloromethyl-3-chloro-1-
propene to give 1 in excellent yield (Equation (I)).12, } The mild reaction
z The mass spectrometric nature of these experiments requires complete isomeric purity of the
neutral precursors. The limited sensitivity and mass resolving power of the instruments require a
few grams of the samples and greater than 98% isotopicincorporation.
} A slightly modified procedure was used. To a solution of hexamethyldisilane (4.0 g, 27.0 mmol) in
16.0 ml hexamethylphosphoramide (HMPA) at 08C was added dropwise a solution of halogen-free
methyllithium (17.0 ml, 1.6 M in ethyl ether, 27.2 mmol). The solution was stirred under nitrogen
atmosphere at À5–08C for 15 min. Then, it was cooled to À508C and a suspension of copper(I)
cyanide (1.7 g, 19.0 mmol) in 50 ml THF was added via a Teflon1 cannula under nitrogen. The
reaction mixture was vigorously stirred at À40 Æ 58C for an hour, then cooled to À788C, and
3-chloro-2-chloromethyl-1-propene (1.2 ml, neat, 8.9 mmol) was added. The resulting reaction
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EFFECTIVE SYNTHESES
989
conditions used for this procedure permitted the efficient syntheses of
the deuterium labelled compounds of 1, as shown in Schemes 1 and 2.
ð1Þ
For the synthesis of d2-1, 2-trimethylsilylmethyl-2-propen-1-ol (2)13
was first oxidized in two steps with manganese dioxide to methyl 2-
trimethylsilylmethylacrylate 3.14 Deuterium was then introduced into
the molecule by reduction with LiAlD4. The product, 1,1-d2-2-
trimethylsilyl-2-propen-1-ol (4), was then converted to the correspond-
ing tosylate 5 and reacted with lithium trimethylsilylcyanocuprate to
give the desired product d2-1 in 54% isolated yield. This displacement
reaction may proceed through an SN20 reaction to give d2-1a or an SN2
pathway to give d2-1b. Similar to the non-deuterated compound 1, the
1H-NMR spectrum for d2-1 displays three resonance signals at 0.1, 1.44,
and 4.36 ppm, which were assigned, respectively, to the trimethylsilyl-
group, allylic, and vinylic hydrogens. The allylic hydrogen peak in the
1H-NMR of d2-1 is noticeably sharpened compared to that of 1, due to
the smaller vinyl-allylicD–H coupling. Integrations of the peaks at 1.44
and 4.36 ppm gave a ratio of 189/24, which indicated that, the SN20
reaction is favored by 3.4 to 1. To our knowledge, this is the first
deuterium labelling study that evaluates the competing SN20 and SN2
reactivity of the lithium trimethylsilylcyanocuprate reagent.
For the synthesis of d6À1, the deuterium labelled 2-hydroxymethyl-2-
nitro-1,3-propanediol (6) was obtained from a triple-condensation of
commercially available perdeuterated p-formaldehyde with nitro-
methane. The reaction was found to proceed in nearly quantitative
yield when carried out in anhydrous ethanol with a catalytic amount of
potassium hydroxide (3–5 mol%).15 Compound 6 was converted under
standard conditions to the corresponding d6-tris(tosylate) 7, which was
( footnote continued )
mixture was warmed gradually to room temperature over a period of 2 h and quenched with an
aqueous solution of ammonium chloride (40 ml). The aqueous layer was separated and extracted
with ethyl ether. The combined organic layers were washed with brine (3 Â 20 ml) and dried with
anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude product
was purified by vacuum distillation to afford 1.5 g (74–768C/15 Torr, 82% yield) of product as a
colorless liquid: 1H NMR (CDCl3) d 0.10 (s, 18H), 1.43 (s, 4H), 4.37 (s, 2H) ppm; 13C NMR
(CDCl3) d-0.98, 29.94, 130.45, 145.53 ppm; IR (neat): 3086, 2956, 1622, 1420, 1248, 1156, 860,
736 cmÀ1; GC-MS (EI) m/e (intensity) 73(100.00), 84(13.45), 97(5.92), 112(15.95), 185(5.43),
200(3.85).
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J. HU AND R. R. SQUIRES
Scheme 1. (a) (1) MnO2, hexanes; (2) MnO2, NaCN, AcOH, MeOH, 73%
(b) LiAlD4, THF 88%; (c) TsCl, Py, 77%; (d) Me3SiCuCNLi, HMPA, THF,
54% total
Scheme 2. (a) (CD2O)n, KOH, EtOH, 95%; (b) TsCl, Py, CH2Cl2, 86%; (c).
Bu3SnH, 1,10-azobis(cyclohexanecarbonitrile), benzene, 92%; (d) LiBr, acetone,
89%; (e) DBU, THF; (f) Me3SiCuCNLi, HMPA, THF, 70% from 9
selectively reduced to d6-tris(tosylmethyl)methane 8 using tributyltin
hydride as the reducing agent.16, } Our original plan was to synthesize
2-(p-tosyloxymethyl)allyl tosylate by treating 8 with 1,8-diazabicy-
clo[5,4,0]undec-7-ene (DBU), and then to carry out double-silylation
with the product bis(tosylate). The reaction of 8 with DBU proceeded
smoothly even at 08C in methylene chloride; however, we found the
product to be too labile for practical use in the subsequent reaction.
Thus, the d6-tris(tosylate) 8 was converted to the corresponding d6-
tribromide 9 by refluxing in acetone with anhydrous lithium bromide.17
Reaction of d6-tris(bromomethyl)methane with DBU in THF produced
} A modified procedure was used. A degassed solution of 8, 1.2 equivalent tributyltin hydride and
0.05 equivalent 1,10-azobis(cyclohexanecarbonitrile) in benzene was refluxed for 5 h. After removal
of solvent under reduced pressure, the solid residue was chromatographed on silica gel to yield the
pure product.
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EFFECTIVE SYNTHESES
991
d6-2-bromomethyl allylbromide 10, which, in turn, produced d6-1 in
70% yield from 9, upon treatment with lithium trimethyl-
silylcyanocuprate.k
General procedures
All reactions were conducted under Ar atmospheres and monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm E.M. silica
gel plates (60F-254) using UV-light detection or 5% anisaldehyde and
5% sulfuric acid as the visualization reagent. E.M. science silica gel 60
(230–400 mesh ASTM) was used for flash column chromatography.
LiAlD4 (98 at% D) and (CD2O)n (99 at% D), were purchased from
Aldrich Chemical Co. Other common reagents were also purchased
from Aldrich with a few exceptions from other commercial sources.
Tetrahydrofuran and benzene were distilled from sodium benzophenone
ketyl under Ar. Methylene chloride, hexanes, pyridine and diisopropy-
lamine were distilled from calcium hydride under Ar. Other reagents
were purified by literature procedures.18
1 H and 13C NMR spectra were recorded in CDCl3 or C6D6 on a
Varian Gemini-200 and a GE QE-300 NMR spectrometers. IR spectra
were taken on either a Perkin-Elmer 1310 or a Perkin-Elmer 1600 FT-
IR spectrophotometer using sodium chloride plates. GC-MS spectra
were taken with a Finnigan 4000 mass spectrometer.
Conclusions
As demonstrated by the above syntheses, the title compounds can be
conveniently prepared from the displacement reactions of lithium
trimethylsilylcyanocuprate. No detectable isomeric impurities were
found and no loss of deuterium was observed in the course of these
transformations.
Acknowledgements
This manuscript is dedicated to the memory of Professor Robert R.
Squires.
k The compound displays identical TLC and GC behaviors as the non-deuterated 1 and IR (neat):
2956, 2906, 1570, 1248, 968, 910, 842, 736, 690, 650 cmÀ1; GC-MS (EI) m/e (intensity) 73(100.00),
74(15.45), 103(3.61), 116(4.89), 117(8.31), 118(7.30), 191(8.90), 206(6.08).
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J Labelled Cpd Radiopharm 2001; 44: 987–992