Generation of nucleophilic chromium acetylides from gem-trichloroalkanes and chromium Chloride: Synthesis of propargyl alcohols

Article abstract of DOI:10.1002/ejoc.200901476

Nucleophilic mixed chromium(II) and chromium(III) acetylides are generated from the smooth reduction of primary 1,1,1-trichloroalkanes with chromium(II) chloride in the presence of an excess amount of triethylamine at room temperature. These species arise from chrornium(III) vinylidene carbenoids. It has been demonstrated that uncommon low-valent Cr^II acetylides are formed by C-H insertion of Cr^IICl₂ into terminal alkynes, formed in situ through the FritschButtenberg-Wiechell (FBW) rearrangement, whereas Cr^III acetylides are concomitantly generated by HCl elimination from the chromium(III) vinylidene carbenoid, Both divergent pathways result, overall, in the formation of nucleophilic acetylides. In situ trapping with electrophilic aldehydes afforded propargyl alcohols. Furthermore, deuteration experiments and the use of deuterium labeled 1,1,1-trichloroalkane substrates demonstrated the prevalence of low-valent Cr¹¹ acetylides, potentially useful, yet highly elusive synthetic intermediates.

Full text of DOI:10.1002/ejoc.200901476

FULL PAPER
DOI: 10.1002/ejoc.200901476
Generation of Nucleophilic Chromium Acetylides from gem-Trichloroalkanes
and Chromium Chloride: Synthesis of Propargyl Alcohols
Dhurke Kashinath,[a] Steve Tisserand,[a] Narender Puli,[b] John R. Falck,*[b] and
Rachid Baati*[a]
Dedicated to the memory of Dr. Charles Mioskowski
Keywords: Chromium / Carbenoids / Rearrangement / Alkynes / Alcohols
Nucleophilic mixed chromium(II) and chromium(III) acet-
ylides are generated from the smooth reduction of primary
1,1,1-trichloroalkanes with chromium(II) chloride in the pres-
ence of an excess amount of triethylamine at room tempera-
ture. These species arise from chromium(III) vinylidene carb-
enoids. It has been demonstrated that uncommon low-valent
CrII acetylides are formed by C–H insertion of CrIICl2 into
terminal alkynes, formed in situ through the Fritsch–
Buttenberg–Wiechell (FBW) rearrangement, whereas CrIII
acetylides are concomitantly generated by HCl elimination
from the chromium(III) vinylidene carbenoid. Both divergent
pathways result, overall, in the formation of nucleophilic ace-
tylides. In situ trapping with electrophilic aldehydes afforded
propargyl alcohols. Furthermore, deuteration experiments
and the use of deuterium labeled 1,1,1-trichloroalkane sub-
strates demonstrated the prevalence of low-valent CrII ace-
tylides, potentially useful, yet highly elusive synthetic inter-
mediates.
of triethylamine (TEA) induces the smooth formation of
alkynylchromium reagents in high yields under exception-
ally mild reaction conditions. Interception of the alk-
ynylchromium intermediates with electrophilic aldehydes
provides convenient access to functionalized propargyl
alcohols (Scheme 1).[12]
Introduction
Since their discovery in 1957, organochromium reagents
have been the focus of constant development and innova-
tions.[1] Due to their unique combination of chemical fea-
tures and remarkable compatibility with a wide range of
functional groups, these reagents have become indispens-
able tools for advanced organic synthesis and for natural
product synthesis.[2] The last 10 years, in particular, have
witnessed an enormous growth in terms of new reagents
and reaction modalities.[3–11] For instance, our laboratories
and others have described several new chromium intermedi-
ates including chromium vinylidene carbenoids,[4] haloge-
nated chromium enolates,[6] chromium Fischer halocarb-
enes,[5,7,11] and carbynes.[9] In continuation of our harvest
of novel intermediates with unusual reactivities formed
through the chromium-mediated reduction of 1,1,1-tri-
haloalkanes, we report herein that the reduction of 1,1,1-
trichloroalkanes by chromium(II) chloride in the presence
Scheme 1. Generation of mixed chromium acetylides from 1,1,1-
trichloroalkanes and in situ reaction with aldehydes.
Heretofore, the generation of metal acetylides under mild
conditions compatible with various functional groups has
[a] University of Strasbourg, Faculty of Pharmacy CNRS/UMR long been an unresolved synthetic challenge.[13] Classical
7199, Laboratory of Functional Chemosystems
methods have mainly exploited the relatively high acidity of
74, route du rhin, B. P. 60024, 67401 Illkirch, France
terminal acetylenic C–H bonds to form metal alkynylides,
either by direct metalation using strong bases, such as n-
butyllithium or lithium diisopropylamide at low tempera-
ture (–100 to –80 °C),[14] or upon treatment with tertiary
amines in the presence of a stoichiometric or catalytic
amount of the metal salt of interest (Figure 1, route a).[15]
Lithium and silver acetylides prepared by this approach are
Fax: +33-3-68854306
E-mail: baati@bioorga.u-strasbg.fr
[b] University of Texas Southwestern Medical Center, Department
of Biochemistry
5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA
Fax: +1-214-648-6455
E-mail: j.falck@utsouthwestern.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901476.
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FULL PAPER
also utilized for the preparation of other acetylides by nickel(II) additives, polar solvents, and/or high reaction
transmetalation with magnesium, zinc, cerium, and other temperatures.[1c] In sharp contrast, we have discovered that
metals (Figure 1, route b).[16–20] Alternatively, lithium acet- alkynylchromiums can be easily synthesized from the re-
ylides can also be prepared through the Fritsch– duction of gem-1,1,1-trihaloalkanes by using 6 equiv. of
Buttenberg–Wiechell (FBW) rearrangement/metalation of CrCl2 and 10 equiv. of TEA (Figure 1, route f; Scheme 2).
1,1-dibromoolefins when treated with an excess amount of
The postulated mechanism for the formation of chro-
n-butyllithium (Figure 1, route d).[20,21] An in situ met- mium acetylides likely proceeds through a comparatively
alation/desilylation strategy has recently been applied suc- stable chromium(III) vinylidene carbenoid 6, generated
cessfully to the preparation of highly stable ruthenium acet- through the syn-β-elimination of chromium hydride from
ylides of interest for their electronic properties (Figure 1, the unstable 1-chloro-1,1-bis-chromium alkane carbenoid 5,
route c).[22]
initially formed by the reduction of two C–Cl bonds in
1,1,1-trichloralkane 4 (Scheme 2).[4a] Subsequent β-elimi-
nation of hydrogen chloride induced by Et3N abstraction of
the vinylic proton of 6 gives rise to chromium(III) acetylide
7 (Scheme 2, path a).
Surprisingly, whereas DBU, pyridine, 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD), and DABCO were completely inac-
tive and even inhibited the reduction of trichloroalkane 4,
TEA was unique amongst the common organic bases and
did not interfere with the overall transformations of gem-
1,1,1-trichloroalkanes. The role of TEA is not known yet,
although it is assumed that the dramatic decrease in the
pKa of the carbenoid vinylic proton can be ascribed to the
concerted metal-assisted ionization phenomenon (MAI),[27]
which triggers the formation of chromium(III) acetylide 7
as shown in postulated binuclear complex 13 (Scheme 3).
Figure 1. General approaches for the generation of metalated acet-
ylides.
Chromium(III) acetylides, that are mainly generated by
reduction of alkynyl halides with chromium(II) chloride
(Figure 1, route e),[23] or more recently by transmetalation
of lithium acetylides (Figure 1, route b),[24] have received
scant attention, in spite of their demonstrated synthetic util-
ity in a great number of natural product total syntheses[25]
and for their interesting electronic properties.[26]
Scheme 3. Possible intermediate for the abstraction of HCl and
FBW rearrangement of dinuclear chromium vinylidene carbenoid
13.
Hydrogen abstraction from 13 (Scheme 2, path a) is as-
sumed to be kinetically competitive with the FBW re-
arrangement that leads to terminal alkyne 9 (Scheme 2,
path b).[28] We postulate that this unprecedented reactivity
Results and Discussion
The generation of alkynylchromium(III) reagents by the of chromium vinylidene carbenoids is a result of coordina-
most widely used reductive route (Figure 1, route e) is, how- tion of the σ-donor lone pair of the basic nitrogen to chro-
ever, plagued by drawbacks, inter alia, dependency upon mium(III), yielding chromium(III) acetylides 7. This mech-
Scheme 2. Postulated mechanism for the formation of mixed chromium acetylides.
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Synthesis of Propargyl Alcohols
anistic pathway was partially corroborated by the fact that
(Z)-2-chloroalk-2-en-1-ols 14 were formed in low amounts
(4–10%) as byproducts when the reaction was performed
under Barbier conditions in the presence of various alde-
hydes (Scheme 4).
were well tolerated and afforded expected adducts 3a–
d[30,31] and 3g–i[32] in good to excellent yields (Table 1, En-
tries 1–4, 7–9). Similarly, an α,β-unsaturated aldehyde like
(E)-cinnamaldehyde (12f) reacted smoothly and delivered
cleanly the corresponding propargyl allyl alcohol 3f[30] in a
good isolated yield of 63% (Table 1, Entry 6). In sharp con-
trast, the use of an enolizable aliphatic aldehyde like dihy-
drocinnamaldehyde (12e) under the same conditions was
problematic, and the yield of addition product 3e[33] was
drastically decreased to 22% because of competitive cross-
aldol as well as elimination. (Table 1, Entry 5).[34] Primary
1,1,1-trichloroalkanes 1c reacted moderately and resulted in
the formation of 3j[35] in reasonable isolated yield (56%)
when benzaldehyde (12j) was used as the electrophile
(Table 1, Entry 10). It is worth mentioning that the use of
allylic 1,1,1-trichloroalkane 1d offered the opportunity to
extend the scope of this transformation in generating useful
enyn–alcohol 3k[36] in excellent yield (Table 1, Entry 11).
Scheme 4. Application to the synthesis of propargyl alcohols.
The high yield of propargyl alcohol 3, combined with the
ready availability of 1,1,1-trichloroalkanes 1a–d, make this
methodology very attractive for the preparation of a large
panel of propargyl alcohols (Table 1).[29] Aromatic alde-
hydes 12a–d and 12g–i bearing diverse, sensitive functional
groups such as bromo, cyano, acetoxy, methoxy, and fluoro, Attempts to reduce the amount of chromium reagent by
Table 1. Synthesis of different propargyl alcohols.
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FULL PAPER
Scheme 5. Generation of alkynylating chromium agents from phenylacetylene (11).
using multicomponent redox system for chromium recycl- um(II) and chromium(III) acetylides through two divergent
ing [CrCl2 (10 mol-%)/Mn0/TMSCl][37] and TEA (10 equiv.) pathways from chromium(III) vinylidene carbenoid 6
in THF at room temperature for 12 h were not satisfactory (Scheme 2). To further distinguish the prevalence of one
as a result of limited conversion of the starting 1,1,1-tri- pathway with respect to the other, we examined the re-
chloroalkanes (Ͻ10%). This result suggests, most likely, duction of deuterated substrate 17 and performed ad-
that the initial generation of key vinylidene carbenoid 6 ditional deuteration experiments (Scheme 6). Substrate 17
(Scheme 2) might be the rate-limiting step of the process was first treated with 4 equiv. of CrCl2 under the same ex-
under these specific conditions.
perimental conditions as those outlined for compounds 1.
Mechanistically, to determine whether terminal alkyne 9, Quenching the reaction with H2O afforded a 2:3 mixture of
generated by FBW rearrangement from 6, could eventually protonated terminal alkyne 18 and its deuterated analogue
be an intermediate in the overall transformation (Scheme 2, 19 (FBW product) as determined by quantitative GC–MS
path b), we examined the reactivity of terminal alkynes with analysis.
chromium(III) and chromium(II) chloride in the presence
or absence of TEA. Notably, as a control experiment, 1-
phenylacetylene (11) does not react with chromium(III)
chloride in the presence or in the absence of TEA in THF
under the same conditions as 1, thus excluding pathway a
in the formation of chromium(III) acetylide 7a (Scheme 5).
However, we were surprised by the fact that CrIICl2 re-
acted smoothly with 11 in the presence of TEA (Scheme 5,
path b), as evidenced by the formation of a minimum of
60% of adduct 16 when the organometallic species was
trapped with benzaldehyde under Barbier conditions. Be-
cause the direct insertion of chromium(III) into the C–H
bond of terminal alkynes is excluded for the formation of Scheme 6. Mechanistic deuteration experiments.
chromium(III) acetylide 7a, these results suggest strongly
that the nucleophilic metalated acetylide is the uncommon
low-valent chromium(II) acetylide 15. This result might be
Interestingly, this result was corroborated by the re-
explained by ligand exchange of CrII, allowing nucleophilic duction of 1a with 4 equiv. of CrCl2,[4a] in the presence of
substitution of labile ligands (e.g., Cl) to give nucleophilic an excess amount of TEA, and subsequent deuteration with
chromium(II) acetylide 15. Indeed, like ZnII, CuI, or AuI DCl in D2O, which yielded 30–35% of [D1]phenylacetylene
acetylides that are generated in situ from terminal alkynes (20), along with 70–65% of 11. These observations demon-
at room temperature upon treatment with an organic base strated unambiguously the propensity of vinylidene car-
(TEA, iPr2NnPr, or NH4OH)[13,15c,15d,29] by ligand ex- benoids 6, prepared in the presence of TEA, to undergo
change, this substitution reaction occurs for CrII. This FBW rearrangement predominantly and, therefore, the pre-
mechanism is supported by kinetic studies reported by Mer- valence of pathway b that leads to CrII acetylides 10
bach, who showed that this ligand exchange is kinetically (Scheme 2). The smooth generation of low-valent chromi-
very fast and favored for CrII, whereas CrIII is known to be um(II) acetylides from 1,1,1-trihaloalkanes and CrCl2 as
extremely resistant to this process.[38] Indeed, the exchange well as the reactivity of such organometallic species as new
ligand rates are ca. 15 orders of magnitude higher for CrII alkynylating agents have not been studied earlier. Although
than CrIII [39]
The synthesis of end-bound acetylide ligands their nucleophilic behavior has been shown by trapping
.
with monovalent and divalent octahedral chromium(II) has with electrophiles such as aldehydes, these reagents could be
been recently reported; however, to the best of our knowl- eventually used either in one-pot, metal (Pd, Ni, Fe) cross-
edge, there is no report that accounts for their reactivity coupling reactions or engaged in situ in [3+2]-Huisgen di-
towards C–C bond-forming reactions.[26] At this point in polar cycloaddition with azides.[40] The optimization as well
our investigation, we provided evidence that the reduction as the scope and the potential applications of these synthet-
of 1,1,1-trichloroalkanes with chromium(II) chloride in the ically useful reagents are underway in our laboratories and
presence of TEA affords unprecedented mixed chromi- will be disclose elsewhere.
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Eur. J. Org. Chem. 2010, 1869–1874

Synthesis of Propargyl Alcohols
1-(4-Methoxyphenyl)-3-(p-tolyl)prop-2-yn-1-ol (3g): Yield: 164 mg
(65%), light-yellow-colored viscous solid. 1H NMR (400 MHz,
CDCl3): δ = 7.48–7.45 (m, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.05 (d,
J = 8 Hz, 2 H), 6.84–6.86 (m, 2 H), 5.56 (d, J = 5.6 Hz, 1 H), 3.75
(s, 3 H), 2.27 (s, 3 H), 2.12 (d, J = 6 Hz, 1 H) ppm. 13CNMR
(100 MHz, CDCl3): δ = 159.7, 138.7, 131.6, 133.1, 129.2, 129.0,
128.9, 128.1, 128.0, 119.4, 114.0, 88.2, 86.6, 64.8, 55.3, 21.5 ppm.
Conclusions
In summary, we have found that the reduction of 1,1,1-
trichloroalkanes with an excess amount of chromium(II)
provides direct access to mixed nucleophilic chromium(II)
and chromium(III) acetylides. Both species are formed
through divergent pathways, from chromium(III) vinylidene
carbenoids, which favor the formation of uncommon low-
valent chromium(II) acetylides, generated through the FBW
route. We have demonstrated that in situ generated mixed
chromium acetylides react smoothly with electrophilic alde-
hydes, providing access to propargyl alcohols, complement-
ing other known strategies. Further promising develop-
ments using this new reductive/oxidation reaction of 1,1,1-
trichloroalkanes by CrCl2 are expected to emerge and will
be disseminated shortly.
IR (film): ν = 3400, 2921, 2835, 2197, 1608, 1508, 1245, 1170, 1029,
˜
814 cm–1. HRMS (EI): calcd. for C17H16NaO2 [M
275.1042; found 275.1053.
+
Na]+
1-{4-[1-hydroxy-3-(4-methylphenyl)prop-2-ynyl]phenyl}ethanone
(3h): Yield: 239 mg (79%), colorless sticky solid. 1H NMR
(400 MHz, CDCl3): δ = 7.53–7.51 (m, 2 H), 7.27–7.25 (m, 2 H),
7.03–7.00 (m, 4 H), 5.56 (br. s, 1 H), 2.51 (br. s, 1 H), 2.25 (s, 3 H),
2.20 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.5, 150.5,
138.8, 138.4, 131.6, 129.1, 127.9, 121.7, 119.2, 87.9, 86.9, 64.5, 21.5,
21.3, 21.1 ppm. IR (film): ν = 3432, 3043, 2931, 2195, 1754, 1505,
˜
1194, 1163, 1012, 815, 734 cm–1. HRMS(EI): calcd. for
C18H16NaO3 [M + Na]+ 303.0991; found 303.1000.
1-(4-Fluorophenyl)-3-(p-tolyl)prop-2-yn-1-ol (3i): Yield: 195 mg
(81%), colorless sticky solid. 1H NMR (400 MHz, CDCl3): δ =
7.52–7.48 (m, 2 H), 7.28–7.26 (m, 2 H), 7.05–6.96 (m, 2 H), 7.04
(d, J = 8 Hz, 2 H), 5.57 (d, J = 5.2 Hz, 1 H), 2.30 (d, J = 6 Hz, 1
H), 2.26 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.9 (d,
1J = 246 Hz, C), 161.4, 138.9, 136.6 (d, 4J = 3 Hz, C), 131.6, 129.1,
Experimental Section
General: All reactions were performed under an argon atmosphere.
The solvent (THF) was distilled from Na and benzophenone. All
commercially available reagents were used without further purifica-
tion. Analytical thin-layer chromatography (TLC) was performed
on glass-backed silica gel plates. Visualization of the developed
chromatogram was performed by using UV absorbance and stain-
ing with a vanillin, phosphomolybdic acid, or cerium sulfate solu-
tion. Flash column chromatography was performed with silica gel
(40–63 µm) according to a standard technique. Nuclear magnetic
resonance spectra (1H, 13C, and 19F) were recorded with a Bruker
400 MHz spectrometer equipped with a BBI or a DUAL probe.
Chemical shifts for 1H and 13C NMR spectra are recorded in parts
per million by using the residual chloroform as an internal standard
(1H, δ = 7.26 ppm; 13C, δ = 77.16 ppm). Multiplicities are indicated
by s (singlet), br. s (broad singlet), d (doublet), t (triplet), and m
(multiplet). Mass spectra were recorded with a MS–MS high-reso-
lution Micromass ZABSpecTOF spectrometry. Infrared spectra
were recorded with an FTIR spectrometer equipped with KRS-5.
3
2
128.6 (d, J = 8 Hz, C), 128.5, 125.5, 119.1, 115.5 (d, J = 22 Hz,
C), 115.3, 115.2, 87.8, 87.0, 64.4, 21.5, 21.3 ppm. 19F NMR
(376.49 MHz, CDCl ): δ = –113.8 (s, 1 F) ppm. IR (film): ν = 3338,
˜
3
2921, 2229, 1604, 1506, 1221, 1156, 1013, 836, 814 cm–1. HRMS
(EI): calcd. for C16H14FO [M + H]+ 241.1023; found 241.1036.
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, and 19F (for 3i) NMR spectra of the original com-
pounds.
Acknowledgments
Les Laboratoires Pierre-Fabre, le Centre National pour la Recher-
che Scientifique (CNRS), and l’Agence National pour la Recherche
(ANR) Proteasome are warmly acknowledged for grants to S. T.
and D. K. J. R. F. and N. P. were supported by the National Insti-
tutes of Health (NIH) (GM31278) and the Robert A. Welch Foun-
dation. The authors are grateful to Cyril Antheaume from the Uni-
versity of Strasbourg for helpful scientific discussions.
General Procedure for the Generation of Chromium Acetylides and
Their Reaction with Aldehydes: All the reactions were performed
on 1-mmol scale of trichloroalkanes 1a–d. To a solution of tri-
chloroalkane 1 (1 equiv.) in THF (15 mL) was added aldehyde 12
(1 equiv.), CrCl2 (6 equiv.), and TEA (10 equiv.) under an inert at-
mosphere. The whole mixture was allowed to stir overnight at room
temperature (10 h). After completion of the reaction (TLC analy-
sis), the mixture was quenched with 1  HCl (5 mL) and extracted
with EtOAc (2ϫ10 mL). The organic layer was washed with water
and brine and dried with Na2SO4. Evaporation of the solvent under
reduced pressure gave the crude product, which was purified by
silica gel column chromatography. Elution with EtOAc/cyclohex-
ane gave desired propargyl alcohol 3 and (Z)-2-chloroalk-2-en-1-ol
(14) as an inseparable mixture.[32]
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1-[4-(1-hydroxy-3-phenylprop-2-ynyl)phenyl]ethanone (3d): Yield:
192 mg (72%), colorless sticky solid. 1H NMR (400 MHz, CDCl3):
δ = 7.54 (d, J = 8.4 Hz, 2 H), 7.37–7.39 (m, 2 H), 7.22–7.24 (m, 3
H), 7.03 (d, J = 8.8 Hz, 2 H), 5.5 (br. s, 1 H), 2.41 (br. s, 1 H), 2.20
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.5, 169.4,
150.6, 138.2, 131.7, 128.3, 127.9, 122.3, 121.7, 88.5, 86.8, 64.5,
21.1 ppm. IR (film): ν = 3414, 3056, 2183, 1753, 1504, 1195, 1164,
˜
1064, 733 cm–1. HRMS (EI): calcd. for C17H14NaO3 [M + Na]+
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Received: December 17, 2009
Published Online: February 23, 2010
1874
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