Taking advantage of lithium monohalocarbenoid intrinsic α-elimination in 2-MeTHF: controlled epoxide ring-openingen routeto halohydrins

Article abstract of DOI:10.1039/d0ob02407d

The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.

Full text of DOI:10.1039/d0ob02407d

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PAPER
Taking advantage of lithium monohalocarbenoid
intrinsic α-elimination in 2-MeTHF: controlled
epoxide ring-opening en route to halohydrins†
Cite this: Org. Biomol. Chem., 2021,
19, 2038
Laura Ielo, a,d Margherita Miele,a Veronica Pillari,a Raffaele Senatore,a
c
Salvatore Mirabile,b Rosaria Gitto,b Wolfgang Holzer, a Andrés R. Alcántara
*
a,d
and Vittorio Pace
*
The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as
C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward
strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding
β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent
2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabiliz-
ing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the
targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature
of the reagents, no racemization of enantiopure materials is observed.
Received 2nd December 2020,
Accepted 8th January 2021
DOI: 10.1039/d0ob02407d
rsc.li/obc
Lithium monohalocarbenoids (LiCH2X, X = halogen) consti- ide) must be conducted under Barbier conditions to ensure
tute highly versatile C1-synthons for accomplishing homologa- that no degradation takes place; (2) running the process in
tion processes in both nucleophilic and electrophilic regimes, coordinative solvents (THF and diethyl ether) in the presence
the former being the usual mode of action for lithium deriva- of lithium halide salts contributes to attenuating (if not elimi-
tives.1 Accordingly, upon releasing the CH2X unit onto a nating) Kirmse’s α-elimination to a free carbene and a LiX
proper electrophilic manifold, a plethora of useful synthetic species (Scheme 1b).5 Notably, these paradigms represent the
transformations could be designed.2 The coexistence of C–Li
and C–halogen bonds on the same carbon atom promotes an
extremely high tendency to induce degradative Kirmse’s
α-elimination phenomenon, triggered by the strong Li–X
internal coordination, with the final result of making the
carbenoid
unproductive
for
homologation
purposes
(Scheme 1a).1c,3 This constitutive aspect of carbenoid chem-
istry is profoundly reflected in the strict operational details
requested for their correct use in batch mode:1e,4 (1) to over-
come the intrinsic instability, the carbenoid generation event
from a given precursor (dihalomethane, stannane, or sulfox-
aUniversity of Vienna – Department of Pharmaceutical Chemistry, Althanstrasse, 14,
1090 Vienna, Austria. E-mail: vittorio.pace@univie.ac.at, vittorio.pace@unito.it;
http://drugsynthesis.univie.ac.at/
bUniversity of Messina – Department of Chemical, Biological, Pharmaceutical and
Environmental Sciences, Viale Palatucci, 13, 98168 Messina, Italy
cComplutense University of Madrid – Department of Chemistry in Pharmaceutical
Sciences, Plaza de Ramón y Cajal, s/n, Madrid, Spain. E-mail: andalcan@ucm.es;
https://www.ucm.es/qffa/transbiomat
dUniversity of Turin – Department of Chemistry, Via P. Giuria 7, 10125 Turin, Italy
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02407d
Scheme 1 General context of the presented work.
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necessary guidelines for the convenient application of carbe- 2). Some important aspects of the process were deduced by
noid-mediated strategies in synthetic methodologies.6
running the reaction in different solvents: thus, decreasing the
Due to our continued interest in this chemistry over the medium-coordination effect on the carbenoid allowed an
years, we wondered if Kirmse’s elimination could have a syn- increase of the yield of the chlorohydrin, as a consequence of a
thetic significance behind the well-known degradative effect on positive modulating effect on Kirmse’s elimination.
the chemical integrity of these C1-synthons. The current state- Accordingly, the formation of (S)-2 increased when using Et2O,
of-the-art of carbenoid-guided processes, clearly evidences that CPME,17 and TBME (entries 3–5) and it was maximized in
sp2-hybridized carbon electrophiles are privileged platforms for 2-MeTHF, giving an excellent yield of 93% (entry 6). Some
accomplishing homologation-type transformations, as well as additional points merit mention: (a) decreasing the loading of
various heteroatoms (e.g. B,7 Sn,8 inter alia). Unfortunately, the carbenoid to 2.0 equiv. has practically no effect (91% yield),
corresponding sp3-hybridized carbon electrophiles remain thus suggesting that it is optimal in terms of efficiency-costs
elusive materials for accomplishing homologations with (entries 7 and 8); (b) the presence of the additive TMEDA did
LiCH2X, as documented in the seminal work by Huisgen9 and not improve the process (entry 9); (c) the reaction conducted in
Hahn (Scheme 1c).10 In this context, our group very recently toluene considerably lowered the yield (entry 10); (d) by
documented the formal homologation of C–X functionalities running the process at higher temperatures (−40 °C and
through a sequential installation of the carbenoid into a carbo- −10 °C), the effectiveness decreased, probably because of the
nyl group followed by Si–H-mediated deoxygenation.11
non-optimal generation of the carbenoid (prior to its
Herein, we report the controlled ring-opening of epoxides decomposition, entries 11 and 12); (e) the process is indepen-
with the lithium halide liberated during Kirmse’s α-elimination dent of the pro-carbenoid source, as evidenced using a stan-
for obtaining a high-yield of β-halohydrins (Scheme 1d). Pivotal nane or a sulfoxide for accomplishing the corresponding
for the success of the method is the generation and rapid degra- metal exchange (entries 13 and 14), though the procedure on
dation of the carbenoid in 2-MeTHF12 (a green solvent increas- ICH2Cl afforded the best results; (f) the other Kirmse’s elimin-
ingly becoming more useful in classical organic chemistry and ation product, CH2 (free carbene), had no effect on the whole
biotransformations, as well as for polymerization or extractive transformation (vide infra); and (g) the adoption of non-
purposes),13 therefore leading to the degradation of the mono- Barbier-type conditions for forming the carbenoid did not
halolithium. We anticipate the genuine regioselectivity of the provide any material because of the inadequate formation of
transformation harnessed on the formation of LiX which plays the carbenoid (entry 15). Collectively, these results confirmed
the dual role of Lewis acid (facilitating the C–O cleavage) and the previous evidence that LiCH2Cl is not a competent nucleo-
source of the attacking halide.14
phile for C-sp3 hybridized electrophiles.
We selected the enantiomerically pure epoxide-containing
Having established the reaction conditions, we then
phthalimide (S)-1 as the starting material to gather, addition- studied the scope of the reaction (Scheme 2). The use of the
ally, information on the stereochemical outcome of the other enantiomer of 1, i.e. [(R)-1], afforded the corresponding
process. LiCH2Cl was generated under our previously estab- epimeric halohydrin (R)-2 with analogous efficiency and enan-
lished reaction conditions6d from ICH2Cl (3.0 equiv.) and tiomeric purity. This aspect was further evidenced in the case
MeLi–LiBr (2.8 equiv.) in THF at −78 °C (Table 1). Surprisingly, of different halocarbenoids, such as LiCH2Br [(S)-3 and (R)-3]
no attack of the nucleophile leading to the homologated and LiCH2I [(S)-4 and (R)-4], thus indicating the flexibility of
adduct (S)-1a was observed, but rather a mixture of two enan- the methodology. The procedure was then extended to rac-1
tiopure halohydrins [(S)-(2) and (S)-(3)] was recovered in an with the three different carbenoids confirming the average
84 : 16 ratio (entry 1). The subsequent HPLC analysis of both yields obtained with the chiral platform. Unfortunately, the
reaction products indicated the full preservation of the stereo- methodology could not be applied for the LiF ring-opening en
chemical information embodied, thereby confirming our pre- route to a fluorohydrin. Considering the key role of the solvent
vious findings on the retention of configuration in reactions in generating LiCH2F,6b,c,18 the use of the optimal mixture
involving basic α-substituted methyllithiums.2a,12k,15 This THF : Et2O (1 : 1 v/v) was tested as an alternative to the herein
initial experiment was indicative of the ring-opening of the employed 2-MeTHF, without observing the formation of the
epoxide with a LiX salt.16 On the other hand, the simultaneous desired compound. Therefore, regardless of the proper gene-
presence of the chloro (S)-(2) and bromo-(S)-(3) derivatives ration of the unstable carbenoid, the degradation salt LiF may
points towards a ring-opening mediated by two different not be efficient in promoting the ring opening.19 Epoxides
species, namely LiCl and LiBr. Presumably, LiCl was formed derived from aldehydes could also be subjected to the reaction
during Kirmse’s α-elimination of the carbenoid, thus yielding conditions leading to decorated aromatic β-chlorohydrins
the chlorohydrin, whereas LiBr, complexing the metalating (5–6). Analogously, disubstituted epoxides (derived from
agent MeLi (i.e. MeLi-LiBr complex in Et2O), directly furnished ketones) easily underwent the ring-opening despite the substi-
bromohydrin (S)-3. To ascertain this hypothesis, LiX-free MeLi tution pattern on the aromatic ring. Notably, the carbenoid
(MeLi in Et2O) was employed for generating the carbenoid formation was not affected by the presence of functionalities
under identical conditions: exclusively the chlorohydrin (S)-2 sensitive to the organolithium environment. Thus, bromo-(7),
was formed, thus confirming that LiCl (carbenoid degradation iodo-(8), fluoro-(9, 11, 12), chloro-(10) and trifluoromethyl-(13)
product) was responsible for the attack on the oxirane (entry β-chlorohydrins were smoothly prepared in 2-MeTHF. The
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Table 1 Reaction optimization
LiCH2Cl
(equiv)
Yield of (S)-2b
Ratio 2/3 a (%)
Entry Solvent
er of (S)-2
1c
2
3
4
5
6
7
8
THF
THF
Et2O
CPME
TBME
2-MeTHF 2.8
2-MeTHF 1.8
2-MeTHF 1.5
2-MeTHF 2.0
2.8
2.8
2.8
2.8
2.8
84 : 16
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
—
66
74
78
81
85
93
91
77
87
61
67
48
85
79
—
>99 : 1
>99 : 1
>99 : 1
98 : 2
97 : 3
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
—
9d
10
11e
12f
13g
14h
15i
Toluene
2.0
2-MeTHF 2.0
2-MeTHF 2.0
2-MeTHF 2.0
2-MeTHF 2.0
2-MeTHF 2.0
Unless otherwise stated, the carbenoid was generated under Barbier-
type conditions starting from ICH2Cl and MeLi (Et2O solution 1.6 M)
in THF at −78 °C. a The ratio has been calculated by 1H-NMR analysis
using 1,3,5-trimethylbenzene as an internal standard. b Isolated yield.
c MeLi–LiBr complex (Et2O solution 1.5 M) was used; compound (S)-3
was obtained in 12% yield and >99 : 1 er. d TMEDA (2.0 equiv.) was
added. e Reaction was run at −40 °C. f Reaction was run at −10 °C.
g The carbenoid was prepared from (n-Bu)3SnCH2Cl. h The carbenoid
was prepared from PhS(O)CH2Cl. i The carbenoid was generated under
non-Barbier conditions.
additional presence of an acidic aromatic alcohol did not con-
stitute a limitation for the method when deprotonation (with
the same MeLi) was carried out prior to carbenoid formation
(14). Epoxides formally derived from benzo- or acetophenones
were amenable substrates for the reaction furnishing deriva-
tives 15–16 and 17–18, respectively, in high yields. The use of
an α-trifluoromethyl-epoxide enabled the straightforward for-
mation of analogue 19, while, much to our delight, even a
labile ester group was tolerated during the carbenoid gene-
ration–degradation sequence, giving compound 20. The instal-
lation of unsaturated fragments (alkyne and alkene) on the
epoxide core was particularly attractive not only for the syn-
thetic importance of the so-obtained halohydrins (21–22) but,
more importantly, for constituting unambiguous proof of the
lack of reactivity of the free carbene generated during the car-
benoid degradation.18b,20 No cyclopropanation-like process
was detected, as judged by NMR analysis of the crude product,
thus confirming the initial hypothesis of the higher reactivity
of the lithium halide salt.
Scheme 2 Scope of the reaction.
With the aim to gather useful insights into the mechanistic
aspects of the transformation, a 1 : 1 molar mixture of epoxide
rac-1 and an aromatic aldehyde was reacted with LiCH2Cl (1.8 fact can be rationalized taking into account the higher electro-
equiv.) in 2-MeTHF (Scheme 3a). Two halohydrins were philicity of the carbonyl group compared to that of the
obtained upon the attack of the carbenoid on the aldehyde epoxide: although not optimal for stabilizing LiCH2Cl, the car-
(major compound, 5) and the attack of the degradation bonyl nucleophilic addition still takes place, as the predomi-
product (LiCl) on the epoxide (minor compound, rac-2). This nant process, in 2-MeTHF. Concomitantly, the epoxide ring-
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equiv.). After 2 min, an ethereal solution of MeLi (1.8 equiv.,
1.6 M) was added dropwise, using a syringe pump (flow:
0.200 mL min−1). The resulting solution was stirred for one
hour at −78 °C. A saturated solution of NH4Cl was added
(2 mL mmol−1 substrate), and then extracted with Et2O (2 ×
5 mL) and washed with water (5 mL) and brine (10 mL). The
organic phase was dried over anhydrous Na2SO4, filtered and,
after removal of the solvent under reduced pressure, the so-
obtained crude mixture was subjected to chromatography on
silica gel to afford pure compounds.
2-(3-Chloro-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione
(rac-2). By following the general procedure 1, starting from
2-[(oxiran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (203 mg,
1.0 mmol, 1.0 equiv.), ICH2Cl (353 mg, 0.15 mL, 2.0 mmol, 2.0
equiv.), MeLi (1.6 M, 1.1 mL, 1.8 mmol, 1.8 equiv.) and
2-MeTHF (3 mL), the desired product was obtained in 91%
yield (218 mg) as a white solid (m.p.: 95 °C) after chromato-
graphy on silica gel (50 : 50 v/v, n-hexane/diethyl ether). 1H
NMR (400 MHz, CDCl3) δ: 7.81 (m, 2H, Phthal H-4,7), 7.70 (m,
Scheme 3 Additional mechanistic proof.
opening product was observed, though in a lesser yield (21%
yield of rac-2), promoting itself the degradation of the carbe-
noid. Notably, when only 1 equiv. of LiCH2Cl was used, no sig-
nificant differences in the ratio of rac-2 and 5 were observed,
probably indicating that, due to its short life, the carbenoid
reacted (again) with the more activated substrate (aldehyde)
before the decomposition took place, so that the degradation
product (LiCl) attacked the epoxide. However, when the reac-
tion was carried out in the carbenoid stabilizing THF, the
attack of 1 equiv. of LiCH2Cl on the aldehyde was a practically
uniquely occurring phenomenon, since no significant
Kirmse’s elimination took place. Finally, as an additional
proof of the formation of LiX, we carried out an experiment
using the labelled carbenoid LiCD2I (formed upon treatment
of CD2I2 with MeLi),6d observing the iodohydrin rac-4, as the
sole product (Scheme 3b). This could be explained considering
that Kirmse’s elimination of LiCD2I provided CD2 (unreactive)
and LiI, responsible for the oxirane opening.
In summary, we have developed a straightforward prepa-
ration of different β-halohydrins (chloro, bromo, and iodo)
through boosted Kirmse’s elimination of the corresponding
lithium monohalocarbenoids starting from epoxide. The
degradative process – usually conceived as problematic in
canonical homologation chemistry – is herein implemented in
the eco-friendly and non-coordinating solvent 2-MeTHF.
Accordingly, the controlled formation of LiX salts is triggered,
leading ultimately to the ring-opening of the epoxides. The
uniformly high-yield, the full preservation of the embodied
stereochemical information and the high chemocontrol –
deduced by selectively preparing variously decorated motifs –
further document the potential of this operationally simple
and intuitive methodology.
2H, Phthal H-5,6), 4.16 (brs, 1H, CH̲OH), 3.91 (dd, J = 14.3, 7.4
Hz, 1H, NCH2), 3.83 (dd, J = 14.3, 4.4 Hz, 1H, NCH2), 3.64 (dd,
J = 11.5, 4.7 Hz, 1H, CH2Cl), 3.59 (dd, J = 11.5, 5.5 Hz, 1H,
CH2Cl), 3.18 (brs, 1H, OH). 13C NMR (100 MHz, CDCl3) δ:
168.6 (Phthal C-1,3), 134.2 (Phthal C-5,6), 131.7 (Phthal
C-3a,7a), 123.4 (Phthal C-4,7), 69.5 (CHOH), 47.2 (CH2Cl) 41.5
+
(NCH2). HRMS (ESI), m/z: calcd for C11H11ClNO3 : 240.0422
[M + H]+; found: 240.0426.
1-Chloro-2-(4-iodophenyl)-2-propanol (8). By following the
general procedure 1, starting from 2-(4-iodophenyl)-2-methyl-
oxirane (260 mg, 1.0 mmol, 1.0 equiv.), ICH2Cl (353 mg,
0.15 mL, 2.0 mmol, 2.0 equiv.), MeLi (1.6 M, 1.1 mL, 1.8 mmol,
1.8 equiv.) and 2-MeTHF (3 mL), the desired product was
obtained in 83% yield (246 mg) as a colourless oil after chrom-
atography on silica gel (90 : 10 v/v, n-hexane/diethyl ether). 1H
NMR (400 MHz, CDCl3) δ: 7.70 (m, 2H, Ph H-3,5), 7.21 (m, 2H,
2
Ph H-2,6), 3.79 (A-part of an AB-system, JAB = 11.2 Hz, 1H,
CH2Cl), 3.73 (B-part of an AB-system, 2JAB = 11.2 Hz, 1H, CH2Cl),
2.60 (brs, 1H, OH), 1.60 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3) δ: 144.0 (Ph C-1), 137.5 (Ph C-3,5), 127.1 (Ph C-2,6), 93.2
(Ph C-4), 73.7 (COH), 55.0 (CH2Cl), 27.3 (CH3). HRMS (ESI), m/z:
calcd for C9H11ClIO+: 296.9538 [M + H]+; found: 296.9542.
1-Chloro-2-(2,4,5-trifluorophenyl)-2-propanol (12). By follow-
ing the general procedure 1, starting from 2-methyl-2-(2,4,5-tri-
fluorophenyl)oxirane (188 mg, 1.0 mmol, 1.0 equiv.), ICH2Cl
(353 mg, 0.15 mL, 2.0 mmol, 2.0 equiv.), MeLi (1.6 M, 1.1 mL,
1.8 mmol, 1.8 equiv.) and 2-MeTHF (3 mL), the desired
product was obtained in 91% yield (204 mg) as a colourless oil
after chromatography on silica gel (90 : 10 v/v, n-hexane/diethyl
1
ether). H NMR (400 MHz, CDCl3) δ: 7.52 (ddd, J = 11.5, 9.0,
7.3 Hz, 1H, Ph H-6), 6.91 (m, 1H, Ph H-3), 4.01 (d, J = 11.2 Hz,
1H, CH2Cl), 3.86 (dd, J = 11.2, 1.1 Hz, 1H, CH2Cl), 2.79 (brs,
1H, OH), 1.64 (d, J = 1.2 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3) δ: 153.8 (ddd, J = 244.1, 9.3, 2.9 Hz, Ph C), 149.3 (ddd,
J = 251.5, 14.6, 12.8 Hz, Ph C), 146.8 (ddd, J = 244.6, 12.0,
Experimental part
General procedure 1
To a cooled (−78 °C) solution of the suitable epoxide (1.0 3.4 Hz, Ph C), 127.9 (dt, Jd = 15.0 Hz, Jt = 4.4 Hz, Ph C-1), 116.4
equiv.) in dry 2-MeTHF was added iodochloromethane (2.0 (ddd, J = 21.4, 5.9, 1.3 Hz, Ph C-6), 106.4 (dd, J = 29.9, 21.0 Hz,
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Ph C-3), 72.6 (d, J = 4.7 Hz, COH), 53.4 (d, J = 6.5 Hz, CH2Cl),
25.8 (d, J = 3.5 Hz, CH3). 19F NMR (376 MHz, CDCl3) δ: −141.9
(m, F), −134.7 (m, F), −115.7 (m, F). HRMS (ESI), m/z: calcd for
C9H9ClF3O+: 225.0289 [M + H]+; found: 225.0286.
2016, 55, 7712; (c) S. Molitor and V. H. Gessner, Chem. –
Eur. J., 2013, 19, 11858; (d) C. Kupper, S. Molitor and
V. H. Gessner, Organometallics, 2014, 33, 347; (e) S. Molitor
and V. H. Gessner, Synlett, 2015, 861; (f) F. M. Bickelhaupt,
H. L. Hermann and G. Boche, Angew. Chem., Int. Ed., 2006,
45, 823.
4 S. Monticelli, M. Rui, L. Castoldi, G. Missere and V. Pace,
Monatsh. Chem., 2018, 149, 1285.
5 R. Tarhouni, B. Kirschleger, M. Rambaud and J. Villieras,
Tetrahedron Lett., 1984, 25, 835.
6 For recent work with carbenoids from our group, see:
(a) S. Touqeer, R. Senatore, M. Malik, E. Urban and V. Pace,
Adv. Synth. Catal., 2020, 362, 5056; (b) L. Ielo, L. Castoldi,
S. Touqeer, J. Lombino, A. Roller, C. Prandi, W. Holzer and
V. Pace, Angew. Chem., 2020, 59, 20852; (c) L. Ielo,
S. Touqeer, A. Roller, T. Langer, W. Holzer and V. Pace,
Angew. Chem., Int. Ed., 2019, 58, 2479; (d) V. Pace,
L. Castoldi, E. Mazzeo, M. Rui, T. Langer and W. Holzer,
Angew. Chem., Int. Ed., 2017, 56, 12677.
7 For illuminating examples, see: (a) D. S. Matteson, J. Org.
Chem., 2013, 78, 10009; (b) D. S. Matteson and
D. Majumdar, J. Am. Chem. Soc., 1980, 102, 7588;
(c) S. Balieu, G. E. Hallett, M. Burns, T. Bootwicha,
J. Studley and V. K. Aggarwal, J. Am. Chem. Soc., 2015, 137,
4398; (d) G. Casoni, M. Kucukdisli, J. M. Fordham,
M. Burns, E. L. Myers and V. K. Aggarwal, J. Am. Chem. Soc.,
2017, 139, 11877; (e) J. Wu, P. Lorenzo, S. Zhong, M. Ali,
C. P. Butts, E. L. Myers and V. K. Aggarwal, Nature, 2017,
547, 436; (f) A. Fawcett, A. Murtaza, C. H. U. Gregson and
V. K. Aggarwal, J. Am. Chem. Soc., 2019, 141, 4573.
2-Chloro-1-(4-fluorophenyl)-1-phenylethanol (15). By follow-
ing the general procedure 1, starting from 2-(4-fluorophenyl)-2-
phenyloxirane (214 mg, 1.0 mmol, 1.0 equiv.), ICH2Cl (353 mg,
0.15 mL, 2.0 mmol, 2.0 equiv.), MeLi (1.6 M, 1.1 mL,
1.8 mmol, 1.8 equiv.) and 2-MeTHF (3 mL), the desired
product was obtained in 90% yield (225 mg) as a colourless oil
after chromatography on silica gel (90 : 10 v/v, n-hexane/diethyl
1
ether). H NMR (400 MHz, CDCl3) δ: 7.43 (m, 2H, Ph2 H-2,6),
7.42 (m, 2H, Ph1 H-2,6), 7.36 (m, 2H, Ph2 H-3,5), 7.30 (m, 1H,
Ph2 H-4), 7.03 (m, 2H, Ph1 H-3,5), 4.18 (A-part of an AB-system,
2
2JAB = 11.7 Hz, 1H, CH2Cl), 4.16 (B-part of an AB-system, JAB
=
11.7 Hz, 1H, CH2Cl), 3.17 (brs, 1H, OH). 13C NMR (100 MHz,
CDCl3) δ: 162.2 (d, J = 246.9 Hz, Ph1 C-4), 143.0 (Ph2 C-1), 139.1
(d, J = 3.2 Hz, Ph1 C-1), 128.4 (Ph2 C-3,5), 128.3 (d, J = 8.2 Hz,
Ph1 C-2,6), 127.9 (Ph2 C-4), 126.3 (Ph2 C-2,6), 115.2 (d, J =
21.4 Hz, Ph1 C-3,5), 77.5 (COH), 53.1 (CH2Cl). 19F NMR
(376 MHz, CDCl3) δ: −114.7 (m, F). HRMS (ESI), m/z: calcd for
C14H13ClFO+: 251.0633 [M + H]+; found: 251.0659.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
8 (a) S. Touqeer, L. Castoldi, T. Langer, W. Holzer and
V. Pace, Chem. Commun., 2018, 54, 10112; For analogous
operations leading to stable a-selenomethyl halides, see:
(b) R. Senatore, M. Malik, E. Urban, W. Holzer and V. Pace,
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L. I. and M. M. contributed equally to the work. We thank the
University of Vienna, the University of Turin, the Complutense
University of Madrid and Fondazione RiMed (Palermo, Italy)
for generous support. M. M. acknowledges OEAD for a Blau
grant. V. Pillari thanks the University of Vienna for a Uni:docs
fellowship. S. M. thanks the University of Messina for a visiting
pre-doctoral grant.
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