External trapping of halomethyllithium enabled by flow microreactors

Article abstract of DOI:10.1002/adsc.201400747

This work demonstrates that the accurate control of the reaction parameters realized within microreactor systems allowed for a taming of the reactivity of thermally unstable intermediates such as haloalkyllithiums. The first example of effective external trapping of a reactive carbenoid such as the chloromethyllithium is described. By using microreactor systems, a continuous flow synthesis of chloro alcohols and chloro amines could be achieved with high yields. By controlling the residence time the highly reactive chloromethyllithium could be generated and reacted with electrophiles at temperatures much higher than in batch-mode and without internal quenching. The developed continuous-flow process matches the requirements for sustainability.

Full text of DOI:10.1002/adsc.201400747

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DOI: 10.1002/adsc.201400747
Very Important Publication
External Trapping of Halomethyllithium Enabled by Flow
Microreactors
Leonardo Degennaro,a Flavio Fanelli,a Arianna Giovine,a and Renzo Luisia,*
a
Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, FLAME-Lab – Flow Chemistry and
Microreactor Technology Laboratory, Via E. Orabona 4, I-70125 Bari, Italy
Fax : (+39)-080-544-2739; phone: (+39)-080-544-2762; e-mail: renzo.luisi@uniba.it
Received: August 1, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400747.
Abstract: This work demonstrates that the accurate
control of the reaction parameters realized within
microreactor systems allowed for a taming of the
reactivity of thermally unstable intermediates such
as haloalkyllithiums. The first example of effective
external trapping of a reactive carbenoid such as
the chloromethyllithium is described. By using mi-
croreactor systems, a continuous flow synthesis of
chloro alcohols and chloro amines could be ach-
ieved with high yields. By controlling the residence
time the highly reactive chloromethyllithium could
be generated and reacted with electrophiles at tem-
peratures much higher than in batch-mode and
without internal quenching. The developed continu-
ous-flow process matches the requirements for sus-
tainability.
amines that are precursors of useful building blocks
such as epoxides and aziridines.[10]
Nevertheless, in order to exploit the nucleophilic
reactivity, the generation of halomethyllithiums re-
quires a lithium–halogen exchange reaction under
cryogenic conditions (usually below À788C) in the
presence of the electrophile (Scheme 2).[11] Such ex-
perimental factors are mandatory to reach high con-
version and acceptable yields. The temperature for
the lithium/halogen permutation reaction is a very im-
portant parameter in the use of such carbenoidic spe-
cies. In fact, relatively high temperatures promote
a metal-assisted a-elimination with formation of car-
bene-like species and thus, they preclude the reactivi-
ty as nucleophiles.[12,13] Moreover, to the best of our
knowledge, effective protocols for the external trap-
ping, even at low temperature, of halomethyllithiums
have not been reported. For the sake of argument, we
Keywords: carbenoids; flow chemistry; microreac-
tor technology; organolithiums; sustainable chemis-
try
a-Haloalkyllithiums are often referred to as carbe-
noids because of their dicothomic reactivity (as
nucleoACHTUNGTRENNUNGphiles and electrophiles) that has been exploit-
ed to carry out various fundamental synthetic trans-
formations.[1] Since the seminal works by Kobrich
during the 1960s, the importance of this class of or-
ganometallic reagents in synthetic chemistry has been
widely demonstrated.[2] In fact, reactive species such
as halomethyllithiums, have been thoroughly em-
ployed for homologation-type reactions of various
carbonyl derivatives such as aldehydes,[3] ketones,[4]
imines,[5] acyl halides,[6] esters,[7] Weinreb amides[8] and
isocyanates[9] (Scheme 1). In addition, the direct intro-
duction of a halomethyl unit into carbonyl com-
pounds and imines gives access to b-halo alcohols and
Scheme 1. Synthetic use of halomethyllithiums in homologa-
tion reactions.
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Leonardo Degennaro et al.
activity aimed at developing more sustainable chemi-
cal processes mediated by organolithiums and organo-
catalysts by using flow microreactor tecnology,[17] we
report herein a preliminary study on the external
trapping of CML generated under the flow regime.
For this study, we used a flow microreactor system
consisting in two T-shaped stainless steel micromixers
(M1 and M2), three pre-cooling units (P1, P2 and P3)
and two microtube reactors (R1 and R2) (Figure 1).
Optimization experiments were carried out feeding
the microflow system with a 0.073M THF solution of
chloroiodomethane 1, a commercially available solu-
tion of methyllithium in diethyl ether/THF 0.073M,
and a 0.1M THF solution of benzaldehyde (Figure 1).
The reactants were introduced into the microreactor
Scheme 2. Genesis and reactivity of halomethyllithiums.
reinvestigated the external trapping reaction of system by using syringe pumps. The residence times
chloro
ACHTUNGTRENNUNG
chloroiodomethane 1 with MeLi at À988C and length of the microtube reactor R1 (see the Support-
À408C (Scheme 2). Attempts at trapping with neat ing Information) and the flow rates. In the search for
benzaldehyde after only 1 second failed in both cases. the optimal reaction conditions, equimolar amounts
Only traces of chlorohydrin 2a were detected by GC- of 1 and MeLi were used and the stoichiometric ratio
MS analysis.
between CML and the electrophile (PhCHO) was
For this reason, we have taken into consideration kept at 2 equiv. to 1 equiv., respectively. With the aim
the possibility to use the advantages of microreactor to tame the thermal instability of CML, the most im-
technology, in order to control the thermal (and portant parameters varied in the optimization study
chemical) instability of CML, to avoid decomposition were the temperature and the residence time. The re-
and pursuing its external quenching in a more sustain- sults obtained are summarized in the plot in Figure 2.
able way. Seminal works by Yoshida and co-workers,
We were pleased to find that CML could be effec-
demonstrated that flow microreactors enable reac- tively trapped with benzaldehyde working at low tem-
tions involving highly unstable organolithiums even in peratures (below À608C) in a wide range of residence
the presence of sensitive functional groups (i.e., car- times (i.e., 0.18–1.31 s). In fact, adduct 2a was formed
bonyl, ester, nitro groups).[14]
in high yields (>93%) under these reaction condi-
The same author introduced the concept of flash tions. In addition, from these data we could speculate
chemistry that is defined as a field of chemical synthe- that the lithium/halogen exchange reaction is a very
sis where extremely fast reactions are conducted in fast process and that CML could survive long enough
a highly controlled manner to produce the desired to allow its external trapping. In fact, high yields were
compounds with high selectivity.[15]
observed with either 0.18 s or 1.31 s as residence time.
The main advantages of microreactors and continu- Conducting the reaction using longer residence times
ous flow systems lie in the improved heat and mass resulted in a drop of the yields. The thermal instabili-
transfer, short residence times, precise reaction con- ty was faced by conducting the process at higher tem-
trol, with possibility to automate the process, higher perature. Working at À408C, it was possible to get
safety in using reactive and hazardous materials and higher yields of 2a only by using shorter residence
more sustainability.[16] In continuation of a research times (0.18–0.31 s). Longer residence times were dele-
Figure 1. Flow microreactor system employed for the external trapping of chloromethyllithium.
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External Trapping of Halomethyllithium
Figure 2. External quenching of CML: effect of temperature and residence time on the yields. All the experiments were con-
ducted using 2 equiv. of 1, 2 equiv. of MeLi and 1 equiv. of PhCHO.
terious for the yields. The reactions were conducted
With the aim to minimize degradative a-elimina-
even at À208C and 08C. In both conditions, the trap- tion of CML, according to pioneering studies by Vil-
ping product 2a was observed, with moderate yields lieras,[19] and recent findings by Pace and co-work-
using very short residence time (0.18 s). Nevertheless, ers,[8–9] the use of the complex MeLi·LiBr was also
using 0.18 s as the residence time allows for the exter- considered (Table 2). The use of the microflow system
nal trapping of CML at 08C leading to 2a with 28% in Figure 1, with 0.31 s and 0.65 s of residence time at
yield. These observations are quite surprising and
prove the potential of microreactor systems. In fact,
Table 1. Evaluation of the amount of lithiating agent.
external trapping of CML at 08C in batch conditions
was practically impossible.[18] However, we attempted
the external trapping of CML at À208C after 1 sec
and 5 sec (Scheme 3) but only adduct 3, deriving from
the nucleophilic attack of MeLi to benzaldehyde, was
recovered together with unreacted aldehyde.
The amount of the lithiating agent was investigated
next. The flow microreactor system depicted in
1 (equiv.)
MeLi (equiv.)
2a[a]
3[a]
PhCHO[a]
Table 1, was fed with variable amounts of 1 and MeLi
by using a residence time of 0.18 sec and working at
À408C. The results reported in Table 1 show how
yields and conversions are dependent on the ratio of
1 and MeLi. Maximum conversion and selectivity
could be obtained using 2 equiv. of 1 and 2 equiv. of
MeLi.
1.1[b]
1.5[c]
2[d]
1.1[b]
1.5[c]
2[d]
66%
75%
>98%
>98%
>98%
17%
15%
–
–
–
17%
10%
2.5[e]
3[f]
2.5[e]
3[f]
[a]
1
Yields calculated by H NMR.
[b]
[c]
[d]
[e]
[f]
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
PhCHO=3 mLminÀ1.
;
;
;
;
;
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
PhCHO=2.2 mLminÀ1.
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
PhCHO=1.65 mLminÀ1.
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
PhCHO=1.32 mLminÀ1.
Scheme 3. External quenching of chloromethyllithium
(CML) in batch conditions.
Flow rate: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
PhCHO=1.1 mLminÀ1.
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Table 2. Evaluation of the complex MeLi·LiBr as lithiating agent.
tR (s)
Temp. [8C]
2a[a]
3[a]
Note
0.31[b]
0.31[b]
0.31[b]
0.65[c]
0.65[c]
0.65[c]
0
–
–
0
–
–
–
–
clogging
–
–
clogging
–
–
À20
À40
0
>98%
>98%
–
74%
84%
[d]
À20
[e]
À40
[a]
1
Yields calculated by H NMR.
[b]
[c]
[d]
[e]
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1; PhCHO=3 mLminÀ1.
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1; PhCHO=2.2 mLminÀ1.
26% of unreacted PhCHO.
16% of unreacted PhCHO.
À408C and À208C allowed to obtain 2a with good
The developed process was further tested in the
yields. However, even if CML could survive slightly presence of a chiral ligand such as (À)-sparteine.[21]
longer times at higher temperature, the microflow Yoshida reported recently on the possibility to control
system was found to be more subject to clogging the stereochemistry of lithiated intermediates in the
problems. Such problems hampered the use of the mi- presence of this chiral ligand and in a microflow
croflow systems at 08C. For these reasons we decided system.[22] The microflow system reported in Table 4
to use the microflow system in Figure 1 in the pres- was fed with a solution containing an equimolar
ence of MeLi.
amount of 1 and (À)-sparteine and a solution of
After assessing the optimal conditions to perform MeLi. The reaction was conducted at several temper-
the generation and trapping of CML in a microflow atures and with a fixed residence time of 0.31 s. Ac-
system, the scope of the methodology was probed cording to the results obtained in the absence of the
(Table 3). The reactions were conducted at À408C chiral ligand (vide infra), good yields of adduct 2a
using 0.18 s as residence time. We were pleased to were observed at temperatures below À408C. Never-
find that the CML could be effectively trapped with theless, the effect of the chiral ligand was negligible,
several electrophilic entities in very good to excellent the sample of 2a always being racemic.
yields. The reaction occurred smoothly with carbonyl
The performance of the process was also evaluated
compounds (aldehydes and ketones) leading to chlor- by running the microflow system in Figure 1, under
oa lcohols 2b–l (Table 3, entries 1–11) The reaction the optimized conditions, for 4 h without any prob-
proceeded with excellent results even with notorious- lem. Chlorohydrins 2a and 2e were prepared with
ly difficult carbonyl derivatives such as enolizable ke- a productivity of 1–1.5 ghÀ1. This aspect is important
tones (entries 9, 11) or nitro-substituted aromatic al- considering the interest in the use of lithium halocar-
dehyde (entry 5).[20] The microflow system proved to benoids for continuous flow synthesis.[23]
be successful for trapping of CML even with hindered
In conclusion, this work tries to harness the role
or heterosubstituted aldehydes (entries 4 and 6). The and potentials of microflow systems in modern syn-
microflow system allows also the reaction of CML thetic chemistry. We have demonstrated that the accu-
with imines leading to chloro amines 2m–p in good rate control of the reaction parameters, in a microreac-
yields and without traces of aziridines deriving from tor system, allowed for a taming of the reactivity of
an intramolecular cyclization (Table 3, entries 12– thermally unstable intermediates such as haloalkyl-
15).[5a,b] The process has been effectively applied also lithiums. Controlling the residence time, the highly re-
to a Weinreb amide and an isocyanate obtaining adducts active chloromethyllithium could be generated and
2q and 2r, respectively (Table 3, entries 16 and 17).
reacted with electrophiles at temperatures much
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Table 3. Scope of the generation and external trapping of
CML in a microflow system.
Table 4. Attempts for microflow-enabled enantioselective
addition of CML.
tR
Temp. [8C][a] 2a [%][b] PhCHO [%][b] er (2a)[c]
0.31 s À20
0.31 s À40
0.31 s À60
0.31 s À80
25
82
98
98
75
18
2
50:50
50:50
50:50
50:50
2
Flow rates: 1=4.5 mLminÀ1, MeLi=4.5 mLminÀ1
;
[a]
PhCHO=3 mLminÀ1.
[b]
[c]
1
Yields calculated by H NMR.
Ascertained by chiral HPLC analysis.
higher than in batch-mode and without internal
quenching. Under the microflow conditions, the reac-
tion of chloromethyllithium with a broad variety of
electrophiles has been accomplished. The process has
also elements of sustainability. To the best of our
knowledge, this work represents the first example of
the effective external trapping of a reactive carbenoid
such as the chloromethyllithium.
Experimental Section
Procedure
The employed flow microreactor system consists of two
stainless steel T-shaped micromixers, M1 (ø=250 mm) and
M2 (ø=500 mm), two stainless steel microtube reactors, R1
(inner diameter ø=1000 mm, length L=3.5 cm), and R2
(inner diameter ø=1000 mm, length L=100 cm), and three
stainless steel tubes as pre-cooling units, P1 (inner diameter
ø=1000 mm, length L=100 cm), P2 (inner diameter ø=
1000 mm, length L=100 cm) and P3 (inner diameter ø=
1000 mm, length L=50 cm). The microreactor was dipped in
a cooling bath at À408C. A solution of ClCH2I 1 (0.073M)
in THF (flow rate: 4.50 mLminÀ1) and a solution of MeLi
(0.073M) in THF (flow rate: 4.5 mLminÀ1) were introduced
into M1 by syringe pumps. The resulting solution was passed
through R1 and was mixed with a solution of electrophile
(0.1M) in THF (flow rate: 1.65 mLminÀ1) in M2. The result-
ing solution was passed through R2. After a steady state
had been reached, the product solution was collected for
[a]
Yields of isolated products.
A mixture of diastereomers was isolated, dr: 60:40.
A mixture of diastereomers was isolated, dr: 50:50.
[b]
[c]
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60 s or longer while being quenched with NH4Cl (saturated
aqueous solution, 1 mL). The reaction mixture was poured
into water (10 mL) and extracted with Et2O (3ꢁ10 mL).
The combined organic layers were dried (Na2SO4), filtered
and concentrated under vacuum. Flash chromatography on
the crude afforded the chloromethyl-substituted products
2a–r.
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Acknowledgements
We thank National Project “FIRB - Futuro in Ricerca”
(code: CINECA RBFR083M5N), Regional Project “Reti di
Laboratori Pubblici di Ricerca” (Project. Code 20), “Labora-
torio SISTEMA” code PONa300369 financed by Italian
MIUR, and Interuniversity Consortium CINMPIS for finan-
cial support. We are grateful to Prof. J.-i. Yoshida and Prof.
A. Nagaki for their precious help in the beginning of this re-
search theme.
[11] An isolated work reports the generation and in-situ
trapping of CML at À158C under sonochemical condi-
tions by using lithium metal, see: C. Einhorn, C. Alla-
vena, J.-L. Luche, J. Chem. Soc. Chem. Commun. 1988,
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[12] A tactic to prolong the life-time of carbenoids consists
in the introduction of anion-stabilizing groups, for ex-
amples, see: a) S. Florio, V. Capriati, R. Luisi, Curr.
Org. Chem. 2004, 8, 1529; b) X. Sun, P. R. Blakemore,
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therein.
[13] Examples of “stabilized” chloro carbenoids stable at
room temperature have been recently reported, see: C.
Kupper, S. Molitor, V. H. Gessner, Organometallics
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We were aware that at higher temperature the expect-
ed chlorohydrin could cyclize giving the corresponding
1
epoxide. However, H NMR analysis of the crude reac-
tion mixture revealed the presence of benzaldehyde
and traces of adduct 3.
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Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
8 External Trapping of Halomethyllithium Enabled by Flow
Microreactors
Adv. Synth. Catal. 2014, 356, 1 – 8
Leonardo Degennaro, Flavio Fanelli, Arianna Giovine,
Renzo Luisi*
8
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!