A Sequential Homologation of Alkynes and Aldehydes for Chain Elongation with Optional 13C-Labeling

Article abstract of DOI:10.1002/chem.201504248

Terminal alkynes (RCCH) are homologated by a sequence of ruthenium-catalyzed anti-Markovnikov hydration of alkyne to aldehyde (RCH₂CHO), followed by Bestmann-Ohira alkynylation of aldehyde to chain-elongated alkyne (RCH₂CCH). Inverting the sequence by starting from aldehyde brings about the reciprocal homologation of aldehydes instead. The use of ¹³C-labeled Bestmann-Ohira reagent (dimethyl ((1-¹³C)-1-diazo-2-oxopropyl)phosphonate) for alkynylation provides straightforward access to singly or, through additional homologation, multiply ¹³C-labeled alkynes. The labeled alkynes serve as synthetic platform for accessing a multitude of specifically ¹³C-labeled products. Terminal alkynes with one or two ¹³C-labels in the alkyne unit have been submitted to alkyne-azide click reactions; the copper-catalyzed version (CuAAC) was found to display a regioselectivity of >50 000:1 for the 1,4- over the 1,5-triazine isomer, as shown analytically by ¹³C NMR spectroscopy.

Full text of DOI:10.1002/chem.201504248

DOI: 10.1002/chem.201504248
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Synthetic Methods |Hot Paper|
A Sequential Homologation of Alkynes and Aldehydes for Chain
Elongation with Optional 13C-Labeling
Andreas Brunner and Lukas Hintermann*[a]
Dedicated to Professor Antonio Togni on the occasion of his 60th birthday
Abstract: Terminal alkynes (RCCH) are homologated by a se-
quence of ruthenium-catalyzed anti-Markovnikov hydration
of alkyne to aldehyde (RCH2CHO), followed by Bestmann–
Ohira alkynylation of aldehyde to chain-elongated alkyne
(RCH2CCH). Inverting the sequence by starting from alde-
hyde brings about the reciprocal homologation of aldehydes
instead. The use of 13C-labeled Bestmann–Ohira reagent (di-
methyl ((1-13C)-1-diazo-2-oxopropyl)phosphonate) for alkyny-
lation provides straightforward access to singly or, through
additional homologation, multiply 13C-labeled alkynes. The
labeled alkynes serve as synthetic platform for accessing
a multitude of specifically 13C-labeled products. Terminal al-
kynes with one or two 13C-labels in the alkyne unit have
been submitted to alkyne–azide click reactions; the copper-
catalyzed version (CuAAC) was found to display a regioselec-
tivity of >50000:1 for the 1,4- over the 1,5-triazine isomer,
as shown analytically by 13C NMR spectroscopy.
Introduction
Homology is a fundamental concept in organic chemistry. The
identification of homologous series (Gerhardt, 1843/44) of the
formula H-(CH2)n-X (X=functional group; n=1, 2, 3,..) created
a basis for the development of structural theory.[1] Homologa-
tion, that is, the transformation of a starting material R(CH2)nX
into its next higher[2] homolog R(CH2)n+1X, is an important syn-
thetic transformation that introduces flexibility in synthetic
planning towards complex structures.[3] It also provides
straightforward access to structural analogues of specific tar-
gets in structure–activity studies.[4,5] In the chemistry of al-
kynes, an important group of reactions named after Colvin–
Seyferth–Gilbert,[6] Corey–Fuchs,[7] or Bestmann–Ohira[8,9] con-
verts aldehydes RCHO into terminal alkynes RCꢀCH,[9] provid-
ing a simple means of 1-carbon chain elongation (Scheme 1).
Interestingly, the term homologation has been applied to
some of those conversions, and apparently to any kind of
carbon framework extending reactions,[10] even though they
provide products with different functionality than the starting
material, i.e., heterologs, in Gerhardt’s terms. With the discovery
of[11] and recent advances in catalytic anti-Markovnikov hydra-
tion of terminal alkynes to aldehydes,[12,13] terminal alkynes can
now be regarded as synthetic equivalents or masked forms of
aldehydes.[14] As a consequence, it should now be possible to
Scheme 1. Important chain elongation methodology for converting alde-
hydes into terminal alkynes.
realize true homologations of alkynes (in Gerhardt’s sense) by
applying a sequence of catalytic anti-Markovnikov hydration
and either one of the aldehyde alkynylation methodologies
mentioned (Scheme 1), and indeed, a single example has al-
ready been reported.[15,16]
Here, we present a generally applicable process for the ho-
mologation of terminal alkynes that profits from very fast anti-
Markovnikov hydration conditions (15–30 min). The potential
of this synthetic methodology is reinforced by numerous ex-
amples of homologation and heterologation, and by its exten-
sion to a new approach of synthesizing specifically 13C-labeled
building blocks. The 13C-labeled alkynes have also been used
in click reactions (“13Click”), for which it was shown that the
13C-label is a unique probe for quantitative analysis of even
minor reaction products.
[a] Dr. A. Brunner, Prof. Dr. L. Hintermann
Department Chemie, Technische Universität München
Lichtenbergstr. 4, 85748 Garching bei München (Germany)
E-mail: lukas.hintermann@tum.de
Supporting information and ORCID from the corresponding author for this
article are available on the WWW under http://dx.doi.org/10.1002/
chem.201504248.
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Results and Discussion
Table 1. Substrate scope of the homologation of terminal alkynes.[a,b]
The catalytic anti-Markovnikov hydration of a terminal alkyne
yields an aldehyde. The reaction of an aldehyde with a suitable
alkynylation reagent (Scheme 1) should give a product that is
the next higher homolog of the original alkyne. If the homolo-
gous alkyne is again hydrated to an aldehyde, the latter is a ho-
molog of the previous aldehyde; the methodology thus realiz-
es reciprocal homologation for both alkynes and aldehydes
(Scheme 2).[17]
Entry
1
Substrate
Steps[a,b]
Product
Yield
[%]
H
MW +A1
75
1 (n=1)
2 (n=2)
2 (n=1)
3 (n=2)
2
3
H
MW +A1
MW +A1
69
71
3 (n=3)
H
4 (n=3)
For a proof of concept, 4-phenyl-1-butyne (1) was hydrated
by a catalyst formed in situ from CpRuCl(PPh3)2 and ISIPHOS,[18]
4
HT +A1
92
5 (n=8)
6 (n=9)
7 (n=10)
6 (n=8)
7 (n=9)
8 (n=10)
5
6
7
HT +A1
78
80
85
H
MW +A1
MW +A1
H
9
10
12
14
Scheme 2. Reciprocal homologation of alkynes and aldehydes by sequential
anti-Markovnikov hydration of terminal alkynes and alkynylation of alde-
hydes.
8
9
H
MW +A1
76
70
11
13
HMW[c] +A1
with heating either in an oil-bath (HT), or by microwave irradia-
tion (HMW, Scheme 3).[12f] The intermediary aldehyde 1a was al-
kynylated, without prior purification, by means of the Best-
mann–Ohira protocol (Step A) to give homo-alkyne 2. Micro-
wave heating (HMW) accelerates the hydration step considera-
bly, rendering this two-step homologation a convenient 1 day
operation.
10
HMW[c] +A1
80
15
16
11
12
H
MW +A2
65
72
The generality of alkyne homologation by the HMW/A-se-
quence was explored on a range of variably functionalized
substrates, as shown in Table 1. The process is sufficiently relia-
17 (R=nPr)
19 (R=tBu)
18 (R=nPr)
20 (R=tBu)
H
MW +A2
[a] Conditions for anti-Markovnikov hydration (step H): CpRuCl(PPh3)2
(2 mol%), ISIPHOS (2 mol%), acetone/H2O (4:1). HMW: microwave heating,
1608C, 15 min. HT: thermal heating, 658C, 4–19 h. [b] Conditions for alky-
nylation: Method A1: BOR (1.2 equiv), K2CO3 (2 equiv), MeOH, rt, over-
night; Method A2: BOR (1.2 equiv), NaOMe (1.2 equiv), THF, À788C,
20 min, addition of aldehyde, 5 min at À788C, 30 min at rt. [c] Catalyst
loading 4 mol%.
ble to allow for iterative sequential homologations of alkynes:
thus, starting 4-phenyl-1-butyne (1) was extended consecutive-
ly by three CH2-units to give 7-phenyl-1-heptyne (4) in 36%
yield over six steps (entries 1–3), with some losses arising from
the volatility of the materials. Another threefold iteration of al-
kynol 5 to 8 (entries 4–6) proceeds in 57% over six steps, with
isolation of each alkynol. The homologation proceeded un-
eventfully with simple hydrocarbons (entries 1–3 and 7), and
tolerated a range of functionality, including alcohol (entries 4–
6), carboxylic acid (entry 8), nitrile (entry 9), TBS-ether
(entry 10), or arene (entries 1–3, 11, and 12). Nitriles are known
to reversibly inhibit the hydration catalyst,[12f] but substrate 13
could be successfully homologated in the usual short time by
Scheme 3. Realization of an alkyne–aldehyde–alkyne homologation. Reac-
tion conditions for individual reaction steps, and structures of required re-
agents.
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applying a slightly higher catalyst loading, and microwave
heating conditions (entry 9).
Plain homologation of alkynes is valuable in its own right,
but we wished to extend its synthetic potential further by in-
troducing 13C-labeled Bestmann–Ohira reagent (13C-BOR) for
the chain-elongation step, which should give straightforward
access to terminally 13C-labeled alkynes.[19] The reagent 13C-BOR
was prepared from 13CH3I through Michaelis–Arbuzov reac-
tion,[20] Claisen-type phosphonate acylation,[21] and diazo-trans-
fer (pTsN3, NaH),[22] by following procedures optimized with
nonlabeled reagents (Scheme 4).
Use of 13C-BOR in the direct synthesis of a terminally 13C-la-
beled alkyne was first tested with a commercially available al-
dehyde as starting material (Table 2, entry 1). The labeling tech-
nique was next incorporated into the homologation sequence
Scheme 4. Synthesis of (1-13C)-diethyl (1-diazo-2-oxopropyl)phosphonate.
where it indeed provided versatile access to a variety of 1-13C-
labeled alkynes (Table 2, entries 2–9).
The iterative approach allows for inclusion of additional 13C-
labels into the growing alkyl chain; this was explored for non-
functionalized alkyne 1 as well as for alkynol 5, which were
both taken through a threefold iterative hydration–alkynyla-
tion–sequence to give either mono-labeled 2 or 6, di-labeled 3
or 7, and finally tri-labeled 4 or 8, respectively (entries 2–4, or
5–7, respectively). A region of a 13C{1H} NMR spectrum of
a triply labeled alkyne from a threefold iteration sequence with
13C-BOR, displaying characteristic ABC-coupling patterns is
shown in Figure 1.
Table 2. Synthesis of 13C labeled targets through homologation with 13C-
BOR.[a]
Entry
1
Substrate
Steps[a]
Product
Yield
[%]
A1
80
21
1
22
2
3
H
H
MW +A1
79
81
(1-13C)-2
MW +A1
(1-13C)-2
(1,2-13C2)-3
4
5
6
H
H
H
MW +A1
MW +A1
MW +A1
76
92
91
Figure 1. Two regions from the 13C{1H} NMR spectrum (CDCl3, 91 MHz) of
(1,2,3-13C3)-4.
(1,2-13C2)-3
(1,2,3-13C3)-4
(12-13C)-6
With the straightforward and general access to 13C-labeled
alkynes, a versatile synthetic platform for obtaining specifically
labeled products of variable functionality can be established,
as exemplified by the selected catalytic follow-up functionaliza-
tion reactions of labeled alkynes presented in Scheme 5:
5
(12-13C)-6
(12,13-13C2)-7
7
H
H
MW +A1
74
(12,13-13C2)-7
(12,13,14-13C3)-8
(1-13C)-10
8
9
MW +A1
78
69
9
HMW+A1
11
(12-13C)-12
Scheme 5. Labeled alkynes as synthetic platforms: a) Table 2; b) TsN3, CuI
(cat.), NEt3, H2O, CHCl3;[23] c) NaAuCl4 (cat.), MeOH/H2O (10:1);[24] d) Table 2.
[a] See Table 1 for definition of the reaction conditions.
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tion as neat substance on millimolar scale was not attempted.
Instead, precursor 34 was desilylated in hot methanolic
sodium hydroxide and the solution thus obtained was neutral-
ized with aqueous acid. After removal of silylated side-prod-
ucts by extraction with hexane, the concentration of product
(3-13C)-32 was determined by 1H NMR spectroscopic analysis
against an internal standard. The stock solution was then kept
and used directly for further experiments.
Having access to 13C-labeled terminal alkynes inspired us to
use them in 1,3-dipolar cycloadditions of the CuAAC[27] and
RuAAC[28] type “13Click” chemistry,[29] so to speak (Scheme 8).[30]
Scheme 6. Use of 1-13C-labeled aldehydes as synthetic platform.
a) NH2OH·HCl, NaOAc, EtOH/H2O. b) 2,4-Dinitrophenylhydrazine, pTsOH,
CH2Cl2. c) KCN, AcOH, MeOH. d) HCl conc. aq, 5 h, 1158C. e) NiCl2·6H2O,
NaBH4, MeOH, Ac2O or Boc2O.[25] Boc=tBuOCO.
Among the products, 13C-labeled aldehydes (Scheme 5, d)
can serve as starting materials in a whole array of follow-up re-
actions. Examples of variously functionalized labeled products,
which have thus been obtained, are presented in Scheme 6.
The starting aldehydes in Scheme 6 were derived from mi-
crowave catalytic anti-Markovnikov hydration (HMW) of the cor-
responding alkyne in less than 30 min and used in the next
steps without purification. This procedure considerably extends
the range of products available from the synthetic platform
based on labeled or nonlabeled alkynes.
As is now established, reactions of aldehydes with 13C-BOR
to give 13C-labeled terminal alkynes (cf. Table 2) render the
latter readily available products. The starting aldehydes in such
syntheses may come from various other sources besides anti-
Markovnikov hydration of alkynes. For a specific project, in
which a propargyl alcohol-derived alkyne linker was desired,
we planned to access the previously unknown, specifically la-
beled (3-13C)-propargyl alcohol ((3-13C)-32). An evaluation of
the synthetic options pointed to alkynylation of aldehyde 33[26]
as the most convenient access pathway (Scheme 7).
Scheme 8. 13Click reactions. Reaction conditions: a) toluene, 115 8C, 120 h;
performed with unlabeled alkynol 5. b) CuI (2 mol%), iPr2NEt (4 mol%),
AcOH (4 mol%), CH2Cl2, rt, 2 d.[31] c) Cp*RuCl(PPh3)2 (3 mol%), dioxane, 608C,
17 h.[28]
Thermal cycloaddition of alkynol 5 to benzyl azide proceed-
ed slowly even upon heating, to give a mixture of regioisomers
35a/b in roughly equal amounts. The reaction of alkynol (12-
13C)-6 with benzyl azide in the presence of a copper catalyst[31]
produced an almost quantitative yield of 1,4-substituted 1,2,3-
triazole 36a at room temperature, whereas ruthenium catalysis
gave 1,5-substituted triazole 36b in high, albeit imperfect re-
gioselectivity (Scheme 8).[32] Metal-catalyzed click reactions
were also performed with doubly labeled starting material
(12,13-13C2)-7 to give (13C2)-37a or (13C2)-37b, depending on
the catalyst used. Labeled click adducts could be suitable ma-
terials for use in mass-spectrometric tagging, or as internal
standards in SIM-GC-MS. The 13C-label also allows for specific
and sensitive detection by NMR spectroscopy. As a first appli-
cation example thereof, we analyzed the regioselectivity of
click reactions quantitatively: monitoring of the minor regioiso-
mer 36a of the RuAAC reaction mixture next to the major
component 36b was particularly simple by 13C{1H} NMR spec-
troscopy, for which the isomers display well-resolved, sharp
Scheme 7. Synthesis of (3-13C)-propargyl alcohol ((3-13C)-32).
1
signals for the labeled carbons. Even though H NMR spectros-
Alkynylation of 33 under regular conditions (MeOH, K2CO3)[8]
led to extensive desilylation of substrate and product. Howev-
er, alkynylation at low temperature with stoichiometric base[19]
gave the desired silyl ether 34. Propargyl alcohol is a volatile,
water-soluble compound of low molecular weight and its isola-
copy is considerably more sensitive, it proved to be less suita-
ble for analyzing product ratios in a ratio of ꢁ100:1, due to
the narrow spectral range, signal splitting by homonuclear
coupling, and by overlap of minor component signals with 13C
satellites or impurities.
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Inclusion of 13C-labeled Bestmann–Ohira reagent (BOR) into
the alkyne homologation sequence gives direct access to spe-
cifically 13C-labeled alkynes. By suitable synthetic elaboration,
almost any desired 13C-labeled aliphatic chain compound
should be accessible through this route. The 13C-labeled al-
kynes are useful in their own right as tools for mechanistic
studies, or as substrates in 13Click reactions. Those click reac-
tions may prove useful for applications involving tagging tech-
niques in mass-spectrometric analysis.
Experimental Section
Synthesis
Homologation of 19 to 20 is described as an example; general pro-
cedures and complete experimental details with characterization
data and NMR spectra can be found in the Supporting Informa-
tion.
Microwave-assisted anti-Markovnikov hydration of 19, and Best-
mann–Ohira alkynylation to 20: Catalytic anti-Markovnikov hydra-
tion was carried out by using the microwave heating protocol.[12f]
To a 10 mL microwave reaction vessel equipped with a stirring bar,
CpRuCl(PPh3)2 (7.3 mg, 0.01 mmol, 2 mol%), ISIPHOS (4.7 mg,
0.01 mmol, 2 mol%), degassed acetone (1.5 mL), degassed H2O
(375 mL), and alkyne 19 (79.1 mg, 0.50 mmol) were added under
argon. After capping of the vessel, the mixture was heated in the
microwave reactor to 1608C with magnetic stirring for 15 min.
After cooling to RT, the reaction mixture was diluted with Et2O
(30 mL) and saturated aqueous NaCl (30 mL). The phases were sep-
arated, the aqueous phase was extracted with Et2O (3”40 mL), and
the combined organic phases were washed with saturated aque-
ous NaCl (40 mL). After drying (MgSO4), filtration, and evaporation
under reduced pressure, the crude aldehyde was dissolved in THF
(4.0 mL). In a separate Schlenk flask, NaOMe (1.0m in MeOH,
0.60 mL, 1.2 equiv) was added dropwise to a cooled (À788C) solu-
tion of BOR (132 mg, 0.60 mmol, 1.2 equiv) in anhydrous THF
(6.0 mL) under argon. After stirring the mixture for 15 min at
À788C, the aldehyde solution was added slowly to the Schlenk
flask, and the reaction mixture was stirred and warmed from
À788C to RT. After dilution with tBuOMe (10 mL) and saturated
aqueous NH4Cl (10 mL), the aqueous phase was extracted with
tBuOMe (3”15 mL) and the combined organic phases were
washed with saturated aqueous NH4Cl (20 mL). After drying
(MgSO4), filtration, and evaporation under reduced pressure, the
residue was purified by column chromatography (SiO2; pentane) to
Figure 2. Excerpt of the 13C{1H} NMR (cryo-probe, 126 MHz, CDCl3, 1024
scans, d1=4 sec) spectrum of a CuAAC reaction mixture (10 mg). Top:
CuAAC reaction product. Peaks at d=134.05, 131.98 and 130.95 ppm are
from unidentified impurities. Bottom: same sample after spiking with 0.2 mg
(1.3 mm) of 4-13C-36b. The time required for each analysis was 140 min.
The CuAAC reaction is known to be highly regioselective,[27c]
but we are not aware of any experimental detection of the re-
gioisomeric ratio. Analysis of the CuAAC product 36a (10 mg
in 450 mL of CDCl3) by 13C{1H} NMR analysis failed to show
a peak for the labeled carbon of minor regioisomer 36b
(Figure 2, top).[33]
To define practical detection limits, the sample was spiked
with minute amounts of RuAAC-product (4-13C)-36b, and
a clear-cut signal (S/N ratio>4) of the latter could be seen
even after addition of only 0.2 mg of material (Figure 2,
bottom), placing a lower limit for the regioselectivity of the
CuAAC reaction at 50,000:1. Additional spiking was performed
to assure that the signal at 132.70 ppm was indeed due to
36b.[34] Notably, 0.6 nmol of 13Click product was readily detect-
ed under the conditions of this experiment, at a concentration
of 1.3 mm.
give
1-(tert-butyl)-4-(2-propyn-1-yl)benzene
(20;
62.5 mg,
Conclusion
0.36 mmol, 72%) as a colorless oil. Known compound, CAS 70090–
67–4. Rf =0.47 (Et2O/pentane, 1:50); H NMR (360 MHz, CDCl3): d=
1.31 (s, 9H; tBu), 2.16 (t, J(H,H)=2.7 Hz, 1H; H-1), 3.57 (d, J(H,H)=
2.7 Hz, 2H; H-3), 7.27–7.37 ppm (m, 4H; ArH); 13C NMR (91 MHz,
CDCl3): d=24.5, 31.5, 34.6, 70.3, 82.4, 125.7, 127.7, 133.2,
149.8 ppm.
1
The reciprocal, iterative homologation of alkynes and alde-
hydes has been established as a process of considerable syn-
thetic potential. The majority of preparative examples present-
ed have been carried out as alkyne homologations, rather than
aldehyde homologations, because aldehydes typically have
limited shelf-live and are not preferred intermediates for stor-
age. Nevertheless, the process presents a complementary alter-
native to Levine’s aldehyde homologation with Ph3P=
CHOMe,[17] which requires an enol ether hydrolysis under
strongly acidic conditions.
3
3
Keywords: alkynes · click chemistry · homogeneous catalysis ·
ruthenium · synthetic methods
[1] a) C. Gerhardt, PrØcis de chimie organique, Vol. 1, Fortin et Masson, Paris,
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87, 360.
[2] Reactions leading to the next or second next lower homolog have been
called dehomologation: a) C. E. Harris, L. Y. Lee, H. Dorr, B. Singaram, Tet-
Terminal alkynes RCꢀCH can be considered storable forms
for aldehydes RCH2CHO, because the former are readily con-
verted into the latter in less than 30 min by following the mi-
crowave catalytic anti-Markovnikov hydration protocol.[12f]
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rahedron Lett. 1995, 36, 2921; b) M. Xie, D. A. Berges, M. J. Robins, J.
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[14] Alkynes have earlier been converted into aldehydes, for example, by
hydroboration-oxidation. The methodology has not typically been as
convenient as the catalytic hydration processes: a) H. C. Brown, G. Zwei-
fel, J. Am. Chem. Soc. 1961, 83, 3834; b) R. G. Lewis, D. H. Gustafson,
W. F. Erman, Tetrahedron Lett. 1967, 8, 401; c) E. J. Corey, G. Wess, Y. B.
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[15] Fürstner and co-workers have performed an alkyne–aldehyde–alkyne
homologation through anti-Markovnikov alkyne hydration/Bestmann–
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lide esters, see refs.[13g,h] Our work was started independently: A. Brun-
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[16] For an example of alkyne–aldehyde–alkyne homologation through hy-
droboration/oxidation of alkyne plus Seyferth–Gilbert alkynylation, see:
J. A. Marshall, N. D. Adams, J. Org. Chem. 2002, 67, 733.
[17] For a widely applied aldehyde to aldehyde homologation, see: S. G.
Levine, J. Am. Chem. Soc. 1958, 80, 6150.
[3] Some total syntheses involving true (i.e., not heterologic) homologa-
tions: a) Twistane: H. W. Whitlock, J. Am. Chem. Soc. 1962, 84, 3412;
b) Calcimycin: Y. Nakahara, A. Fujita, K. Beppu, T. Ogawa, Tetrahedron
1986, 42, 6465; c) Quinine: G. Stork, D. Niu, A. Fujimoto, E. R. Kroft, J. M.
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[4] Prominently, Arndt–Eistert homologation gave access to b- and g-
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[5] Arndt–Eistert homologation of carboxylic acids: a) M. J. Fuchter, in
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[33] Only extractive workup was applied to the CuAAC reaction mixture,
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[34] See the Supporting Information for experimental details.
Received: October 21, 2015
Published online on && &&, 0000
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