A broadly applicable copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides and bromides

Article abstract of DOI:10.1002/anie.201100633

(Chemical Presented) Well compatible: The trifluoromethylations and perfluoroalkylations of aryl iodides and some aryl bromides with trifluoromethyl and perfluoroalkylcopper(I) phenanthroline complexes occur with broad scope at 25-50 8C (see scheme). The trifluoromethyl complex is prepared from inexpensive reagents and can be used in situ or isolated. The reactions tolerate a range of substituents and also occur with heteroaromatic systems.

Full text of DOI:10.1002/anie.201100633

DOI: 10.1002/anie.201100633
Trifluoromethylation
A Broadly Applicable Copper Reagent for Trifluoromethylations and
Perfluoroalkylations of Aryl Iodides and Bromides**
Hiroyuki Morimoto, Tetsu Tsubogo, Nichole D. Litvinas, and John F. Hartwig*
A large number of recently launched pharmaceuticals and
pharmaceutical candidates contain perfluoroalkyl groups
because these moieties affect the physical properties and
biological processing of organic molecules, while being stable
to degradation.[1] For this reason, the introduction of trifluo-
romethyl groups into aryl halides by simple laboratory
procedures is a major synthetic goal. Despite much effort to
develop reactions that introduce trifluoromethyl groups into
arene substrates, current methods are limited by some
combination of high temperatures, high catalyst loadings,
expensive reagents, catalysts, and ligands, low reactivity with
electron-rich aromatic groups, and intolerance toward protic
and electrophilic functional groups.[2–6] Methods to introduce
longer perfluoroalkyl groups into aryl halides are even more
limited.[7,8]
Recently, Amii and co-workers published a seminal report
on copper-catalyzed trifluoromethylation of electron-defi-
cient aryl iodides with triethyl(trifluoromethyl)silane
(TESCF3) as reagent.[3] They suggested that the reaction
proceeds through the phenanthroline-ligated copper(I) com-
plex [(phen)CuCF3], but this complex had not been generated
previously and was not isolated or detected spectroscopically
in the catalytic system. The reaction was shown to occur with
electron-poor aryl iodides, but no product was observed from
reactions with electron-rich aryl iodides and the reaction of
electron-neutral 4-butyl iodobenzene occurred in less than
50% yield. Furthermore, we found (see below) that the same
reaction conducted with superstoichiometric amounts of
copper and ligand gave the same modest yield of product
from trifluoromethylation of 4-butyl iodobenzene.
discrete species toward electron-poor and electron-rich
iodoarenes. We report two routes to form [(phen)CuCF3]
(1) and its higher perfluoroalkyl homologue [(phen)-
CuCF2CF2CF3] (2) in high yield, one route that forms these
two complexes as pure, isolated species and one that forms
them in high yield in DMF. Most striking, isolated 1 and 2
react in high yield at room temperature with not only
electron-poor iodoarenes, but also electron-neutral and
electron-rich iodoarenes that possess a wide range of func-
tional groups. Because these complexes are prepared from
inexpensive reagents, complexes 1 and 2 represent practical
reagents for the perfluoroalkylation of iodoarenes and
selected bromoarenes. Mechanistic studies show that these
complexes react without the intermediacy of aryl radicals.
Phen-ligated trifluoromethylcopper complex 1 was pre-
[10]
pared by the reaction of [CuOtBu]4 with 1,10-phenanthro-
line, followed by the addition of TMSCF3. From this process,
complex 1 was isolated as an orange-red solid in 96% yield.
Perfluoropropylcopper complex 2 was synthesized in 97%
yield by an analogous reaction starting with commercially
available (perfluoropropyl)trimethylsilane (Scheme 1). Both
Scheme 1. Synthesis of 1,10-phenanthroline-ligated (perfluoroalkyl)cop-
per(I) complexes 1 and 2.
As part of our studies on the structures and reactions of
isolated copper complexes that are potential intermediates in
cross-coupling reactions,[9] we sought to determine the
structure and stability of the proposed [(phen)CuCF3] (1)
and to determine the relative reactivity of this complex as a
complexes were characterized by 1H, 13C, and 19F NMR
spectroscopy and elemental analysis. The only previously
isolated trifluoromethyl complex was the NHC-ligated com-
plex reported by Vicic et al.[11,12] No isolated higher perfluo-
roalkyl complexes have been reported.
Complexes 1 and 2 are soluble in polar, aprotic solvents,
such as DMF and DMSO, partially soluble in THF and
CH2Cl2, and insoluble in less polar solvents, such as benzene
and Et2O. Conductivity experiments on 1 indicate that this
species adopts the ionic form [(phen)2Cu][Cu(CF3)2] in DMF
(See Supporting Information for details of these measure-
ments). The 19F NMR spectrum of 1 in DMF clearly shows
two species; one component [(phen)2Cu][Cu(CF3)2] resonates
at d = À30.8 ppm, and the second component [(phen)CuCF3]
resonates at d = À22.6 ppm.[2e] Isolated 1 and 2 were stable at
room temperature under nitrogen atmosphere for over one
month without decomposition.
[*] Dr. H. Morimoto, T. Tsubogo, Dr. N. D. Litvinas,
Prof. Dr. J. F. Hartwig
Department of Chemistry
University of Illinois at Urbana-Champaign
600 South Mathews Avenue, Urbana, IL 61801 (USA)
Fax: (+1)217-244-9248
E-mail: jhartwig@illinois.edu
[**] The authors thank the NIH (GM-58108 to J.F.H. and 1F32M093540-
01 to N.D.L.) and JSPS for a postdoctoral fellowship to H.M. We
thank Dr. Ramesh Giri for reagents, and Dr. Vera V. Mainz for helpful
discussion concerning NMR experiments. T.T. was supported in
part by Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), MEXT (Japan).
In contrast to the catalytic reactions proposed to occur
through complex 1, isolated 1 reacts in high yields with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100633.
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Communications
electron-neutral and electron-rich aryl iodides. Complex 1
the previously reported catalytic reactions or that this
complex is formed in only very small quantities under those
reaction conditions.[3]
also reacts in high yield with aryl iodides containing a wide
range of potentially reactive functional groups. The reactions
of isolated 1 with excess aryl iodides and bromides are shown
in Schemes 2 and 3. The reaction of 1 with 3a–3n gave
Results of reactions of iodoarenes containing typically
reactive functional groups, such as amino, alkoxy, hydroxy-
alkyl, halo, keto, and formyl groups, are also displayed in
Scheme 2. Bromo- and chloro-substituted iodoarenes 3h and
3k reacted selectively at the iodide. In addition to the
reactions of electron-rich iodoarenes noted above, the
reactions with haloarenes containing aldehyde, alcohol, and
ketone functionalities (3e, 3 f, and 3g) are particularly
striking. Substrates containing these functional groups were
not reported to undergo palladium- or copper-catalyzed
trifluoromethylation reactions,[2a,c,3,4,6] but they do react with
1 to form the trifluoromethylarenes in high yield.
The reactivity of 1 with substrates 3e and 3g containing
formyl and acetyl groups also contrasts with the reaction of
these substrates groups with CF3 anions generated from
Ruppertꢀs reagent in the presence of fluoride activators.[13]
For example, conditions reported by Fuchikami and co-
workers for the copper-mediated trifluoromethylation with-
out added ligand (CuI + TESCF3 + KF) led to reaction of
aryl iodide 3g to give a mixture of the desired cross-coupled
product 4g and trifluoromethyl carbinols from nucleophilic
addition to the ketone function.[8] In contrast, isolated 1
reacted with 3e and 3g to form the corresponding trifluoro-
methylarenes in high yield.
As shown in Scheme 3, reactions of electron-deficient
bromides 5 also gave trifluoromethylarene products in good
yield. Like reactions of aryl iodides, the reactions of aryl
bromides tolerated electrophilic functional groups, such as
ester, aldehyde, and nitrile moieties.
Scheme 2. Reactivity of complex 1 with 5 equivalents aryl iodide 3 at
room temperature. Yield was determined by 19F NMR analysis with 4-
CF3OC6H4OMe as internal standard. The yield was reported as an
average of two runs. Yield of 4b in parentheses was obtained from the
reaction with complex 1 stored over 1 month under nitrogen atmos-
phere.
To gain insight into the differences between the reactivity
of isolated 1 and the catalytic reactions proposed to occur
through 1, we submitted several of the substrates in Scheme 2
to the recently reported catalytic reaction conditions.[3] In
each case, we found that less than half the yield of the reaction
of isolated 1 was observed from the reactions with catalytic
amounts of 1.[14] In addition, the reaction of benzaldehyde 3e
under published conditions involving catalytic amounts of
phen and CuI formed the trifluoromethyl carbinol without
any of the desired trifluoromethylarene, and reaction of
acetophenone 3g under these conditions gave low conversion
to a 1:1:2 mixture of 1-(4-(trifluoromethyl)phenyl)ethanone
(4g), 1,1,1-trifluoro-2-(4-(trifluoromethyl)phenyl)propan-2-
ol, and 1,1,1-trifluoro-2-(4-iodophenyl)propan-2-ol. This mix-
ture of products is the same as that observed by Fuchikami
and co-workers by copper-mediated trifluoromethylation
without added ligand.[8] Moreover, reactions conducted with
a copper and ligand loading of 100% under conditions
otherwise identical to the catalytic conditions did not give
product yields comparable to those observed with complex 1.
Thus, the milder conditions and broader scope we observe for
the reactions of complex 1 likely stems from the generation of
1 as a discrete species in high yield.
Scheme 3. Reactivity of complex 1 with 5 equivalents aryl bromide 5 at
1108C.
trifluoromethylarenes 4a–4n in good yield. The reaction of
3a and 3b shows that compound 1 converts electron-neutral
iodoarenes to trifluoromethylarenes in nearly quantitative
yields, and the reactions of 3c and 3d show that this
compound also converts electron-rich iodoarenes to trifluo-
romethylarenes in equally high yields. The reactions of 1 also
tolerate a significant degree of steric hindrance. The combi-
nation of 1 and even 2,6-disubstituted aryl iodides 3l and 3m
formed 4l and 4m in good yield. These results imply that
iodoarenes react with an intermediate other than complex 1 in
The unprecedented substrate scope displayed by 1 and the
facile synthesis of this complex led us to appreciate that
complex 1 itself represents a practical reagent for trifluoro-
methylation. For this complex to be useful, it must react with
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iodoarenes when the ratio of iodoarenes and copper complex
1 is nearly 1:1 and the iodoarene is the limiting reagent.
Indeed, simply reducing the concentration of iodoarenes led
to reactions of aryl iodides 3c, 3e, and 3g with 1.5 equiv
compound 1 in yields similar to those obtained when using the
copper complex as limiting reagent (Scheme 4). Simple aryl
iodides, like 3t and 3q, and functionalized aryl iodides
containing amide (3r), ester (3o and 3u), aldehyde (3u),
bromide (3v), and heterocyclic (3w, 3x, 3y) functionality
reacted with 1 to give trifluoromethylarenes 4 in good yields.
Quinoline 3x containing an exposed basic nitrogen was
converted to the corresponding trifluoromethyl heteroarene
in greater than 90% yield at room temperature, and similar
results were obtained for the purine and indole derivatives 3w
and 3y. The functionalized aryl iodide 3z, which is available
by metalation with Knochelꢀs LiCl-(TMP)MgX reagent and
iodination of the arylmagnesium intermediate,[15] also gave
product 4z in good yield. Finally, trifluoromethylation of the
3,3’-diiodo-binol derivative 3aa gave the MOM-protected
3,3’-(CF3)2-binol 4aa under mild conditions. Previous synthe-
ses of 3,3’-(CF3)2-binol have required superstoichiometric
amounts of Burtonꢀs CuCF3 reagent or generate stoichiomet-
ric amounts of SO2 and MeI.[16,17]
Complex 1 that was stored for long periods under nitrogen
displayed reactivity that is similar to that of freshly prepared
complex. The reaction of 3b with 1 stored in glove box over
one month gave 4b in 83% yield, which is comparable to the
result with freshly prepared 1. Moreover, a glove box is
unnecessary for conducting these reactions. The reaction of p-
phenyl iodoarenes 3t with 1 that was weighed quickly in air
formed the trifluoromethylarene product in 92% yield. Vinyl
iodide 3bb reacted with 1 to afford the trifluoromethylalkene
4bb in 99% yield.
Having established a method to prepare 1 in isolated
form, we sought a method to generate 1 as a discrete species
in situ prior to addition of the iodoarenes to enable the use of
1 on larger scales. We prepared [(phen)CuOtBu] in situ in
DMF from commercially available copper chloride, potas-
sium tert-butoxide, and 1,10-phenanthroline, which were all
weighed outside of the glove box. The solution of [(phen)-
CuOtBu] was then treated with Ruppertꢀs reagent to afford
phen-ligated trifluoromethylcopper 1. Subsequent addition of
aryl iodides 3 to the mixture provided trifluoromethylarenes 4
in 83 to 99% yield. The use of copper chloride and potassium
tert-butoxide, as well as formation of complex 1 prior to the
addition of the aryl halide was important to achieve these high
yields.
The results of reactions conducted under these conditions
that generate 1 in situ are shown in Scheme 5. These reactions
include those of aryl halides containing electron-donating
groups, electron-withdrawing groups, potentially reactive
functional groups, and both electron-rich and electron-poor
heterocyclic compounds. Each of these reactions occurred in
yields that were comparable to those of reactions of these
iodoarenes with isolated 1. In addition, the reaction of
benzyloxy-substituted 3q on a 10 mmol scale formed the
trifluoromethylarene in quantitative yield after 24 h to give
2.5 g of the product 4q. Thus, the reactions of complex 1
generated in situ represent a procedure for trifluoromethyl-
ation of aryl iodides that occurs under mild conditions from
inexpensive, commercially available reagents. The total cost
of the reagents to generate 1 in situ is less than $1/mmol.
Prior to this work, one of the most general copper-
mediated methods for arene trifluoromethylation involved
the combination of catalytic CuI with methyl fluorosulfonyl-
difluoroacetate FSO2CF2CO2Me. We compared the scope of
this trifluoromethylation reaction under the reported con-
ditions, but with the aryl halide as limiting reagent, to our
method with complex 1 (Scheme 6).[18] An electron-rich and
an electron-neutral aryl iodide were chosen to compare the
reaction conditions. The yields of trifluoromethylarene prod-
ucts, as determined by 19F NMR analysis using 4-
CF3OC6H4OMe as internal standard, were much higher
under the reaction conditions with 1.5 equiv phen-ligated 1
than with catalytic CuI and 2.5 equiv FSO2CF2CO2Me.
Scheme 4. Copper-mediated trifluoromethylation with isolated (trifluo-
romethyl)copper(I) complex 1. The reactions were conducted with
0.50 mmol aryl iodide 3 and 0.75 mmol 1 in DMF (0.25m) at 508C;
yields of isolated products are reported unless otherwise noted. The
reactions of 3c, 3e and 3bb were run on a 0.10 mmol scale. [a] The
yield was determined by 19F NMR spectroscopy with 4-CF3OC6H4OMe
as internal standard. [b] The reaction was performed with 1 that was
weighted in air. [c] The reaction was performed at room temperature.
[d] The reaction was performed with 1.2 equivalents 1 at room temper-
ature. [e] 3.0 equivalents 1 was used.
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Scheme 8. Perfluoroalkylation of aryl iodides 3. The reaction was
performed with 1.5 equivalents 2 at 508C unless otherwise noted.
[a] The reaction was conducted at 808C with perfluoropropylcopper
complex 2 prepared in situ under the same conditions as for reactions
in Scheme 5. [b] The reaction was performed at room temperature.
Scheme 5. Copper-mediated trifluoromethylation with (trifluoro-
methyl)copper complex 1 generated in situ. All reactions were per-
formed with 0.50 mmol haloarene as limiting agent without the use of
a glove box unless otherwise noted. [a] The reaction was conducted
with 1.5 equivalents 1 prepared in situ. [b] The reaction was conducted
with 10 mmol iodoarene for 24 h. [c] The yield was determined by
19F NMR spectroscopy with 4-CF3OC6H4OMe as internal standard.
kylation of iodoarenes with perfluoropropylcopper complex 2
formed perfluoropropylarenes 6 in good yields under mild
conditions. These reactions occurred with electron-rich and
electron-poor iodoarenes, as well as iodoarenes containing
potentially reactive quinoline and nitroarene units. The yield
of nitro-substituted 6c (88%) from the reaction of complex 2
was higher than that reported previously with the combina-
tion of CuI, KF, and TMSCF2CF2CF3 (41%).[8] The reaction
of complex 2 prepared in situ outside of the glove box gave
the product 6a in 79% yield after 18 h at 808C. This
transformation is milder and occurs in higher yields than
previous perfluoroalkylations conducted by reductively cou-
pling aryl iodides with perfluoroalkyl iodides.[7]
Scheme 6. Comparison of the reactions of aryl iodides 3. The yields
were determined by 19F NMR spectroscopy with 4-CF3OC6H4OMe as
internal standard.
Preliminary data on the mechanism of the trifluoro-
methylation have been gained. To assess whether the reaction
proceeds by free aryl radical intermediates,[21] we conducted
the trifluoromethylation of 2-(allyloxy)iodobenzene 3cc. The
aryl radical derived from this haloarene cyclizes with a rate
constant of 1010 sÀ1.[22,23] Thus, if the trifluoromethylation
occurs through an aryl radical, then cyclized product 7 should
be observed (Scheme 9).[9b,c] Instead, the trifluoro-
The reactivity of 1 with aryl bromides as the limiting
reagent was also examined and compared to the reaction of
CuI and 5 equiv FSO2CF2CO2Me. (Scheme 7). Electron-poor
aryl bromides, including those with nitro, cyano, and ethoxy-
carbonyl groups, reacted with 1 to give high yields of trifluo-
romethylarene products. In contrast, the reactions of these
haloarenes with the combination of FSO2CF2CO2Me and CuI
occurred in low yield.
Finally, these protocols were extended to the perfluoro-
alkylation[19,20] of iodoarenes to install fluoroalkyl groups that
are longer than a per fluoromethyl group (Scheme 8). Similar
to the trifluoromethylation described above, the perfluoroal-
Scheme 9. Trifluoromethylation of 2-(allyloxy)iodobenzene. Trifluoro-
methylarene 4cc was obtained in 91% yield; cyclized product 7 was
not detected by GC-MS analysis.
methylarene 4cc was obtained in 91% yield, and cyclized
product 7 was not detected by GC/MS analysis. This result
implies that the copper-mediated trifluoromethylation reac-
tion proceeds without the intermediacy of an aryl radical from
electron transfer and expulsion of iodide.[24–26]
Scheme 7. Comparison of the reactions of aryl bromides 5. The yields
were determined by 19F NMR spectroscopy with 4-CF3OC6H4OMe as
internal standard.
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stirred at 508C for 18 h, then cooled, diluted with Et2O and filtered
through a pad of Celite. The Celite pad was washed with Et2O and the
combined organic layer was washed with 1m aqueous HCl, saturated
aqueous NaHCO3 solution and brine, and dried over Na2SO4. After
filtration and evaporation of the solvent, the crude mixture was
purified by flash silica gel column chromatography using pentane/
Et2O as eluent to give ArCF3 4.
In summary, we have isolated a trifluoromethylcopper(I)
reagent ligated by 1,10-phenanthroline that reacts with
unprecedented range of aryl halides at room temperature to
508C. In comparison to current alternative methods for
trifluoromethylation of aryl halides, this system reacts under
much milder conditions, tolerates a wider range of functional
groups, tolerates basic heterocycles, reacts with more hin-
dered substrates, can be extended to perfluoroalkylation, and
occurs with a low total cost of goods. On a more fundamental
level, the high reactivity of complexes 1 and 2 with a broad
range of iodoarenes demonstrates that a general catalytic
perfluoroalkylation of aryl iodides is not limited by the
reactivity of the trifluoromethylcopper intermediate.
Received: January 25, 2011
Published online: March 25, 2011
Keywords: aryl halide · copper · cross coupling ·
.
trifluoromethylation
[1] S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320 – 330.
Experimental Section
[2] For approaches to trifluoromethylation of aryl halides, see the
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1679 – 1681; b) V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc.
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[3] M. Oishi, H. Kondo, H. Amii, Chem. Commun. 2009, 1909 –
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[4] For recent developments in trifluoromethylation of arenes, see:
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2010, 132, 2878 – 2879; b) X. S. Wang, L. Truesdale, J. Q. Yu, J.
Am. Chem. Soc. 2010, 132, 3648 – 3649.
[5] For recent developments in trifluoromethylation of aryl boronic
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[6] For a copper-catalyzed trifluoromethylation of aryl halides that
appeared during the processing of this manuscript, see: T.
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Preparation of [(phen)CuCF3] (1): To an oven-dried 250 mL round-
bottomed flask equipped with a stir bar were added [CuOtBu]4
(1.094 g, 2.00 mmol, 8.00 mmol for monomeric CuOtBu), 1,10-
phenanthroline (1.442 g, 8.00 mmol, 1.00 equiv), and benzene
(80 mL). The flask was sealed with a septum and the dark purple
mixture was stirred at room temperature for 30 min, then TMSCF3
(1.31 mL, 8.80 mmol, 1.1 equiv) was added dropwise. The mixture was
stirred at room temperature for 18 h to give a red-orange suspension.
The suspension was filtered through a medium fritted funnel, and the
solid was washed with Et2O (50 mL) and dried under vacuum to give 1
as an orange solid (2.397 g, 96% yield). 1H NMR (400 MHz,
[D7]DMF): d = 9.18 (d, J = 4.2 Hz, 2H), 8.89 (d, J = 8.0 Hz, 2H),
8.31 (s, 2H), 8.10 ppm (dd, J = 4.2, 8.0 Hz, 2H). 13C{1H} NMR
(100 MHz, [D7]DMF): d = 150.4, 144.2, 138.3, 130.0, 127.8, 126.5 ppm
(note that a carbon peak for CF3 was not observed due to 1) dynamic
behavior of the complex, 2) broadening the peak through Cu–C
coupling, and 3) splitting of the peak through C–F coupling).
19F NMR (376 MHz, [D7]DMF): d = À22.6 (br), À30.9 ppm (s).
Anal. calcd for C13H8CuN2F3: C 49.92, H 2.58, N 8.96, F 18.22;
found: C 49.74, H 2.52, N 8.99, F 18.17.
General procedure for the reaction of isolated 1 with aryl iodides
3 as limiting agent: To a 20 mL vial equipped with a stir bar was added
ArI 3 (if solid, 0.50 mmol), 1 (235 mg, 0.75 mmol, 1.5 equiv), and
DMF (2.0 mL). Then ArI 3 (if liquid, 0.50 mmol) was added, and the
mixture was stirred at the indicated temperature in Scheme 4 (room
temperature or 508C). After 18 h, the stirring was stopped, and the
reaction mixture was diluted with Et2O and filtered through a pad of
Celite. The Celite pad was washed with Et2O. The combined filtrate
was washed with 1m aqueous HCl, saturated aqueous NaHCO3
solution and brine, and dried over Na2SO4. After filtration and
evaporation of the solvent, the crude mixture was purified by flash
silica gel column chromatography using pentane/Et2O or pentane as
eluent to give ArCF3 4.
General procedure for the reaction of 1 generated in situ.
General procedure outside glove box: To a 20 mL vial equipped with
a stir bar and a Teflon-lined screw cap was added CuCl (99 mg,
1.0 mmol, 2.0 equiv). Then air in the vial was evacuated and dry
nitrogen was refilled (once). KOtBu (112 mg, 1.0 mmol, 2.0 equiv)
and 1,10-phenanthroline (180 mg, 1.0 mmol, 2.0 equiv) were added,
then air in the vial was evacuated and dry nitrogen was refilled
(twice). To the mixture was added DMF (2.0 mL), and the dark red
mixture was stirred at room temperature for 30 min under nitrogen,
then TMSCF3 (0.148 mL, 1.0 mmol, 2.0 equiv) was slowly added. The
resulting mixture was further stirred at room temperature for 1 h and
the stirring was stopped. Then the screw cap was removed and ArI 3
(0.50 mmol) was expeditiously added. While opening the cap, surface
of the vial turned green, implying partial decomposition of the copper
reagent. The cap of the vial was closed tightly and the vial was
evacuated and refilled with dry nitrogen. The resulting mixture was
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[11] For isolation of the only prior ligated copper-trifluoromethyl
compound, see references [2h] and [2i].
[12] Burton and co-workers reported the observation of a ligandless
CuCF3 species by NMR spectroscopy in reference [2e], but this
compound has not been isolated and fully characterized.
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