Mild reaction conditions for the terminal deuteration of alkynes

Article abstract of DOI:10.1021/ol2029178

Routinely employed syntheses of terminally deuterated alkynes often utilize strong bases (i.e., LDA, n-BuLi, or Grignard reagents) or low (i.e., -78 °C) or elevated (i.e., 56 °C) reaction temperatures; furthermore many of these procedures afford average y

Full text of DOI:10.1021/ol2029178

ORGANIC
LETTERS
2012
Vol. 14, No. 2
456–459
Mild Reaction Conditions for the Terminal
Deuteration of Alkynes
Sean P. Bew,* Glyn D. Hiatt-Gipson, Jenny. A. Lovell, and Christophe Poullain
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich,
U.K., NR4 7TJ
s.bew@uea.ac.uk
Received October 28, 2011
ABSTRACT
Routinely employed syntheses of terminally deuterated alkynes often utilize strong bases (i.e., LDA, n-BuLi, or Grignard reagents) or low
(i.e., À78 °C) or elevated (i.e., 56 °C) reaction temperatures; furthermore many of these procedures afford average yields and in some cases less
than optimum deuterium incorporation. Herein we report the application of alternative extremely mild reaction conditions that readily afford
quantitative yields of terminally deuterated alkynes in a matter of minutes with exceptional isotope incorporation at ambient temperature.
The development of protocols that afford high value,
deuterated molecules in high yields and, importantly, with
excellent levels of deuterium incorporation is very impor-
tant to academia and biotechnology, medicinal, analytical,
pharmaceutical, and agrochemical industries.
Protocols for deuterated alkyne synthesis employ either
elevated6 or subambient reaction conditions;7 extended,
often hour-long reaction times;8 or strong bases, i.e.
n-BuLi,9 Grignard reagents10 (Scheme 1), or LDA;11 or
an expensive transition metal salt,12 a consequence of
which is the requirement that anhydrous reaction condi-
tions and solvents be maintained at all times.
2H-alkynes are valuable, synthetically useful entities1
capable of being used for the synthesis of additional
deuterated molecules; e.g., 2H-alkyne hydrogenation gen-
2
erates cis- or trans-2H-alkenes2 or H-alkanes.3 Alterna-
tively aqueous gold salts4 afford 2H-ketones, and
2H-alkyne cyclotrimerization affords 2H-aromatics.5
Scheme 1. Synthesis of Deuterated Alkyne 2 from 1
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r
10.1021/ol2029178
Published on Web 01/11/2012
2012 American Chemical Society

Furthermore many afford subquantitative yields of
product with reduced levels of deuterium incorporation
or employ multistep procedures requiring presynthesized
bespoke ‘not off the shelf’ reagents, i.e. 5 (Scheme 2),13 or
hazardous to handle alkali metals.14
sample was added potassium carbonate (1 eqn) in D2O.
Interestingly the deuteration of methyl propiolate was
2
extremely fast, complete within minutes affording H-6
in >99% (Supporting Information (SI)).
Buoyed by this result we undertook a study using pro-
pargyl alcohol, propargyl bromide, monotri(isopropyl)-
silylacetylene, and propiolic acid (Scheme 4). Using
1H NMR as an efficient, sensitive ‘real time investigative
probe’ we established terminal alkyne deuteration was,
again, fast and complete within minutes.
Scheme 2. Synthesis of Deuterated Alkyne 4 from 3 Using 5
Scheme 4. Deuteration of Alkynes Monitored via 1H NMR
A mild, quick, and efficient protocol capable of generat-
2
ing terminal H-6 was required (Scheme 3). Our initial
thoughts focused on reacting methyl propiolate with so-
dium deuteroxide/D2O mixtures; however significant ester
hydrolysis was observed. Using less basic reaction condi-
tions, the weaker base potassium carbonate was probed;
furthermore using a water ether biphasic reaction medium
we envisaged may negate the ester hydrolysis problem,
affording high yields of 2H-6. After methyl propiolate was
dissolved in ether, it was stirred with a 1 M aqueous (D2O)
This limited substrate scope indicated our isotope ex-
change reaction tolerated a range of functionality that
included the relatively base labile propargyl bromide, as
well as propargyl alcohol, TIPS-acetylene (TMS-acetylene
did not survive the reaction15), and electron-poor sub-
strates such as propiolic acid. This simple protocol af-
2
potassium carbonate solution. H-6 was generated in an
averageyieldwithrelativelypoor(25%) 2H-incorporation.
Gratifyingly it seemed these less basic reaction conditions
mediated significantly less ester hydrolysis but at the
expense of lower deuterium incorporation. A solvent study
using dichloromethane, toluene, 1,2-dichloroethane, tert-
butylmethyl ether, ethyl acetate, hexane, toluene, and
1,1,1-trichloroethane and employing the same reaction
conditions again generated 2H-6, but the yields were
2
forded 2H-7À H-10 via a straightforward process and with
excellent levels of 2H-incorporation (see SI).
Confident our protocol was robust, we subjected dodec-
1-yne to terminal deuteration. 2H-11 was generated in both
2
quantitative yield and H-incorporation (judged by the
2
unacceptable and purification of H-6 from methyl pro-
piolate was tedious and time-consuming.
disappearance of the terminal alkyne triplet at 1.93 ppm).
Similarly ethynylbenzene as well as 1- and 2-ethynyl-
naphthalenes afforded 2H-12, 2H-13, and 2H-14 in quanti-
tative yields. Gratifyingly performing a one-pot double
deuteration on(Z)-hexa-3-en-1,5-diyne generated2H-15in
Aqueous potassium carbonate had negated the ester
hydrolysis problem; however the efficiency of the reaction,
i.e. conversion of methyl propiolate to 2H-6, was poor. We
considered that part of the problem lies in the biphasic
nature of the reaction system. Mindful that switching
to water miscible acetonitrile and aqueous potassium
carbonate would result in extensive ester hydrolysis, we
2
a quantitative yield and with >95% H-incorporation.
Using 1H NMR as our investigative tool no (Z)-2H-15 to
(E)-2H-15 isomerization was observed.16
Using ethynylbenzene (12) we investigated, indepen-
dently, water miscible dioxane and THF as possible alter-
2
natives to acetonitrile. Both afforded H-12 with >99%
2
were delighted to observe the formation of H-6 in both
quantitative yield and 2H-incorporation (Scheme 3).
deuterium incorporation and essentially quantitative
yields (K2CO3, rt, 1 h). To probe alternative inorganic or
organic bases, the synthesis of 2H-12 was attempted using
cesium carbonate, sodium carbonate, sodium hydrogen
carbonate, triethylamine, and polystyrene bound trisa-
Scheme 3. Mild Synthesis of Deuterated Propiolate Ester 2H-6
2
mine (all 1 eqn). All the inorganic bases afforded H-12
in excellent yield and deuterium incorporation, i.e. >99%.
Triethylamine and immobilized trisamine afforded 2H-12
in good yields; however the 2H-incorporation was slightly
lower, i.e. 95%.
Probing the rate of the reaction, we dissolved methyl
propiolate in CD3CN and ran the 1H NMR. To the same
(15) Diederich, F.; Stang, P. J. Metal Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Chichester, 1998.
(16) McMahon, R. J.; Halter, R. J.; Fimmen, R. L.; Wilson, R. J.;
Peebles, S. A.; Kuczkowski, R. L.; Stanton, J. F. J. Am. Chem. Soc. 2000,
122, 939–949.
(13) Cintrat, J. C.; Pillion, F.; Rousseau, B. Tetrahedron Lett. 2001,
42, 5001.
(14) Sirokan, G.; Molnar, A.; Bartok, M. J. Labelled Compds. Radio-
pharm. 1989, 27, 439.
Org. Lett., Vol. 14, No. 2, 2012
457

A terminally deuterated alkyne attached to an optically
active molecule engenders it with synthetic ‘appeal’ espe-
cially if it can be used to synthesize optically active
(deuterated) building blocks or drug-like molecules. Using
an exceptionally mild, one-pot, two-step procedure,
(1R,2S)-ephedrine (27) was N-propargylated using condi-
tions reported17 by Couty et al. (Scheme 6); we were
delighted that, without workup, the introduction of deu-
Scheme 5. Synthesis of 2H-Aliphatic and 2H-Aromatic Species
2
2
terium oxide afforded H-28 with quantitative H-incor-
2
poration. Treatment of H-28 with thionyl chloride and
subsequently sodium azide (D6-DMSO, 110 °C) afforded
>95% incorporated 2H-29 in a 64% yield. No reduction
in 2H-incorporation was observed for this transformation
(cf. >95% for 2H-28). Worthy of note is that this exceeds
Probing the generality of the deuteration process, a
series of structurally diverse heterocyclic and heteroatom
alkynes were investigated. 4-Ethynylpyridine (16), 1-(prop-
2-ynyl)-1H-benzo[d]imidazole (17), ethynyl 2,2,3,3-tetra-
methylcyclopropanecarboxylate (18), 1-ethynyl-4-nitro-
benzene (19), 4-(prop-2-ynyloxy)-1H-isochromen-1-one
(20), 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (21), 2-(prop-
2-ynyl)isoindoline-1,3-dione (22), and 4-(prop-2-ynyl)-
morpholine (23) reacted (standard reaction conditions
2
the 80% H-incorporation reported by Couty et al. for
their low temperature (À78 °C) deprotonation (n-BuLi)
electrophilic quench process using non-2H 28.
Scheme 6. Synthesis of Deuterated Triazole Piperazine 2H-29
2
employed in Scheme 5), within minutes, affording H-
2
16À H-23 in quantitative yields and excellent levels of
deuterium (Figure 1). Incorporating multiple deuterium
atoms into terminal bis- or tetra(alkynes) in quantitative
yield and 2H-incorporation had significant appeal. Subject-
ing diprop-2-ynyl pyridine-2,6-dicarboxylate and diethyl
2,2-di(prop-2-ynyl)malonate to our standard D2O/K2CO3
To further demonstrate the broad scope of this excep-
tionally mild deuteration protocol, its exploitation for the
chemoselective deuteration of an organometallic complex
was sought. Synthesis of ferrocene propargyl acetate 30
(48% yield) was straightforward.18 Gratifyingly, dissol-
ving 30 in acetonitrile, adding deuterium oxide and potas-
2
2
(2.5 eqn) reaction conditions afforded H-24 and H-25
in quantitative yields and, importantly, 100% deuterium
incorporation. To exploit this further, the incorporation
of four deuteriums was attempted using a calix[4]arene
appended with four lower-rim O-propargyl ethers. To our
delight 2H-26 was afforded in a quantitative yield and with
outstanding levels of deuterium incorporation.
2
sium carbonate, allowed the efficient synthesis of H-31
with >95% deuterium incorporation and in an excellent
98% yield (Scheme 7); no evidence of cyclopentadienyl
2
1HÀ H exchange was detected.
Scheme 7. Synthesis of Isotopically Labelled Ferrocene 2H-31
The synthesis of isotopically labeled R-amino acids and
carbohydrates is critically important to (in)organic and
biological mechanism elucidation, probing for kinetic iso-
tope effects, and protein structure analysis. To validate the
extremely mild nature of our protocol, the deuteration of
variously N,C-protected-R-amino acids and O-protected
carbohydrates was investigated. N-Boc-C-tert-butyl-O-
Figure 1. Examples of deuterated molecules 2H-16À H-26.
2
(17) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2004, 45, 3725.
(18) Bew, S. P.; Hiatt-Gipson, G. D. J. Org. Chem. 2010, 75, 3897.
458
Org. Lett., Vol. 14, No. 2, 2012

propargyl-(S)-tyrosine, (S)-prop-2-ynyl-2-(tert-butoxy-
carbonylamino)pent-4-ynoate, N-Boc-C-propargyl-(S)-
phenylalanine, and N-Boc-C-propargyl-(S)-4-fluorophe-
nylglycine (unnatural R-amino acid) were transformed
investigating (immobilized) base, solvent, and temperature
conditions, we were unable to prevent ring-opening.
2
2
(standard conditions) into H-32À H-35 (Figure 2) with
Scheme 8. Synthesis of 2H-O-Propargyltazobactam 2H-43
2
>99% H-incorporation and excellent yields. The term-
inal deuteration (S)-N-Boc-C-propargyl methione, (S)-N-
dansylproline propargyl ester, and N-Bn-38 afforded
2
2H-36À H-38 in excellent yields and, again, levels of
deuterium. Incorporating O-propargylated glucose, bio-
tin, and lactose afforded the corresponding deuterated
2
2
derivatives, H-39À H-41 respectively, in excellent yields
2
Negating this, 3-deutero propargyl bromide H-7 (see
and levels of deuterium incorporation.
Scheme 4) reacted directly with the sodium salt of the
β-lactam tazobactam 42 affording 2H-43 in excellent yield
and >95% 2H-incorporation (Scheme 8). Similarly react-
ing the sodium salt of 44 with 7 at ambient temperature in
DMF afforded the desired 2H-O-propargylcefazolin 45 in
excellent yield and deuterium incorporation (Scheme 9).
Scheme 9. Synthesis of 2H-O-Propargylcefazolin 45
In summary, this is an exceptionally mild, synthetically
versatile, extremely practical protocol that efficiently
transforms terminal alkynes into their deuterated analogs;
is straightforward; does not use low temperature, anhy-
drous solvent, or strong base; is cheap and environmen-
tally friendly; and should prove useful to the organic,
inorganic, medicinal and agrochemist alike.
Figure 2. 2H-alkyne derived R-amino acids and carbohydrates.
Isotopically labeled entities are crucial to the pharma-
ceutical, agrochemical, and biotechnology industries
(ADME and PKME studies); therefore efficient routes
to labeled drug compounds are very important. β-Lactam
antibiotics are very sensitive to β-lactam ring opening
under aqueous basic or acidic conditions. When O-pro-
pargyl tazobactam 42 was subjected to our standard
slightly basic D2O/K2CO3 2H-propargylating reaction
conditions, none of the desired 2H-43 was isolated; instead
as expected extensive decomposition was observed. While
Acknowledgment. The authors would like to acknowl-
edge UEA, Chemistry Innovation and Librarion for
financial support and the Mass Spectroscopy Service at
the University of Wales for MS analysis.
Supporting Information Available. Data for com-
2
2
2
2
pounds H-11À H-41, H-43, and H-45. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 14, No. 2, 2012
459