Synthesis of 1,2,3,4-tetrahydroisoquinolines by microreactor-mediated thermal isomerization of laterally lithiated arylaziridines

Article abstract of DOI:10.1002/chem.201203533

Flow chemistry: A flow-microreactor-mediated synthesis of 1,2,3,4-tetrahydroisoquinolines (THIQs) is reported (see scheme). Starting from a laterally lithiated aziridine, a tetrahydroisoquinoline lithiated at C4 was generated by thermally induced isomerization. Because the reaction temperature is a crucial parameter, the exquisite thermal control possible in a flow-microreactor system allowed for fast, efficient, and highly reproducible synthesis of functionalized aziridines or THIQs. Copyright

Full text of DOI:10.1002/chem.201203533

COMMUNICATION
DOI: 10.1002/chem.201203533
Synthesis of 1,2,3,4-TetrahydroisoACTHNUTRGENUGNquinolines by Microreactor-Mediated
Thermal Isomerization of Laterally Lithiated Arylaziridines
Arianna Giovine,[a] Biagia Musio,[a] Leonardo Degennaro,[a] Aurelia Falcicchio,[b]
Aiichiro Nagaki,[c] Jun-ichi Yoshida,*[c] and Renzo Luisi*[a]
Chem. Eur. J. 2013, 00, 0 – 0
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Nitrogen-containing heterocycles are ubiquitous in natural
products, as well as in drugs and drug candidates.[1,2] Among
nitrogenous
heterocycles,
the
tetrahydroisoquinoline
(THIQ) core represents a relevant structural motif frequent-
ly found in natural products and biologically active com-
pounds.[3] Of the various synthetic approaches to nitroge-
nous heterocycles, the use of organometallic compounds has
recently emerged as a particularly robust methodology.[4]
Our recent studies on the chemistry of lithiated three-mem-
bered nitrogenous heterocycles[5] demonstrated the impor-
tance of this methodology to the preparation of other nitro-
gen-containing heterocycles, such as piperazines,[6] phtha-
lanes,[7] and isochromanes.[8]
Herein, we report a new synthetic strategy for the prepa-
ration of C4-functionalized 1,2,3,4-tetrahydroisoquinolines,
which exploits the chemistry of lithiated aziridines and the
advantages of flow-microreactor technology.[9] It is worth
mentioning that, because of their biological relevance, new
synthetic routes to substituted THIQs are desired.[10]
During previous work evaluating the reactivity of laterally
lithiated 1-methyl-2-(ortho-tolyl)aziridine, we reported the
solvent-dependent stereochemical outcome of the lithiation
reaction. In fact, when enantioenriched (e.r.>99:1) aziridine
(S)-1a was subjected to a lithiation–electrophilic-trapping
protocol in THF at À788C, racemic (Æ)-[D1]-1a was ob-
tained upon quenching with a deuterium source. In striking
contrast, in a less polar solvent, such as hexane or toluene,
Scheme 1. Solvent dependent lithiation–deuteration of 1-methyl-2-(ortho-
tolyl)aziridine.
caused by the instability of 2-Li with respect to 1-Li. Never-
theless, assuming the presence of the equilibrium depicted
in Scheme 2, we reasoned that the nucleophilic nitrogen
highly
enantioenriched
(S)-[D1]-1a
was
recovered
(Scheme 1). This result could be ascribed to the effect of the
solvent on the nature and aggregation state of the lithiated
intermediate.[11]
It has been proposed that a more polar solvent, such as
THF, could promote an aziridine ring opening with the for-
mation of the ortho-quinodimethane intermediate, 2-Li. This
intermediate promptly undergoes a reclosing reaction on
either enantiotopic face of the double bond, leading to the
observed epimerization (Scheme 1).[12] With the aim of dem-
onstrating the intermediacy of the ortho-quinodimethane, 2-
Li, strong dienophiles, such as maleic anhydride and tetra-
cyanoethylene, were added to the reaction mixture as trap-
ping agents, but without any satisfactory outcome. The in-
ability of a strong dienophile to trap 2-Li is likely to be
Scheme 2. Reaction pathways for laterally lithiated aziridine 1-Li.
À
(N Li) could attack either Cb, leading to 1-Li, or Ca, giving
access to 3-Li, a tetrahydroisoquinoline scaffold lithiated at
C4 (Scheme 2).[13] This strategy would allow, starting from
the same parent aziridine, the preparation of either func-
tionalized aziridines 4 or THIQs 5 upon electrophilic trap-
ping.
After a thorough screening of the reaction parameters, we
were happy to find evidence of the presence of 3-Li by
warming a sample of 1-Li, generated in toluene at À788C,
to a temperature in the range À30 to À408C. With ClSiMe3
as the electrophile, the trapping product 5a was obtained in
modest yield.[14] However, this optimization study furnished
evidence of the intermediacy of 2-Li, as well as demonstrat-
ing the crucial role of the temperature for reproducibility of
the reaction outcome.
[a] Dr. A. Giovine, Dr. B. Musio, Dr. L. Degennaro, Prof. R. Luisi
Department of Pharmacy, University of Bari “Aldo Moro”
Via E. Orabona 4, 70125 Bari (Italy)
Fax : (+39)080-5442539
E-mail: renzo.luisi@uniba.it
[b] Dr. A. Falcicchio
Istituto di Cristallografia (IC-CNR)
Via Amendola 122/o, 70125 Bari (Italy)
[c] Dr. A. Nagaki, Prof. J.-i. Yoshida
The critical importance of reaction temperature to the
outcome of the reaction prompted us to investigate this
process by using the microreactor technology. The main ad-
vantages of flow microreactor procedures are exquisite ther-
mal control and efficient heat transfer derived from the in-
creased surface-to-volume ratio possible on the microscale.
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, University of Kyoto
Nishikyo-ku, Kyoto, 615-8510 (Japan)
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203533.
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Thermal Isomerization of Laterally Lithiated Arylaziridines
COMMUNICATION
Table 1. Flow-microreactor system for the lateral-lithiation–electrophilic-
trapping sequence of 1a.
It is also noteworthy that residence time in the reactor can
be precisely adapted to achieve maximum yield and selectiv-
ity.[15] These features have made flow-microreactor systems
excellent alternatives to traditional batch chemistry, even in
the case of moisture sensitive, unstable, and highly reactive
organometallic intermediates such as oxiranylACTHNUTRGNElUNG ithiums and
aziridinyllithiums.[16] The reaction of an intermediate can
also be switched by precise control of residence time and
temperature in the flow-microreactor system.[17] The lateral-
lithiation–isomerization reaction of 1a was optimized in a
flow-microreactor system consisting of two T-shaped micro-
mixers (M1 and M2), two tube reactors (R1 and R2) and
three precooling units (P1, P2 and P3) with ClSiMe3 as the
electrophile.[18] As shown in Figure 1, at T<À488C the main
Product 4[a]
Electrophile
Yield [%][b]
d.r.[c]
4a
4b
4c
4d
4e
SiMe3Cl
90
–
–
cyclohexanone
propiophenone
tBuCHO
48
77[c]
70
82:18
70:30
–
2,6-(CH3)2-C6H3NCO
58
[a] See the Supporting Information for full technical details. Reaction
conditions: tR =20.9 s; flow rates: aziridine 1a 3, sBuLi 1.5, electrophile
1.5 mLminÀ1. [b] Yields of the isolated product. [c] Diastereoisomeric
ratio calculated on the basis of 1H NMR spectra of the crude reaction
mixtures. [d] Only the major diastereoisomer was isolated.
pounds, the lithiation–trapping sequence worked quite well,
giving yields comparable to or even better than those ob-
tained from batch procedures.[8] In addition, the reactions
occurred faster and at higher temperature (À488C vs.
À788C).
The one-pot lateral-lithiation–isomerization process was
then investigated by using a flow-microreactor system con-
sisting of a T-shaped micromixer M1 and a tube reactor R1
(tR1 =20.9 s) cooled to À488C, and a second tube reactor R2
(tR2 =41.9 s), an additional micromixer M2 and a tube reac-
tor R3 (tR3 =15.7 s) operating at 08C (Table 2). The tube re-
actor R1 allowed for the generation of 1-Li, whereas in R2
the isomerization process took place leading to 3-Li. The re-
sults for this microreactor-mediated lithiation–isomeriza-
tion–electrophile-trapping sequence, leading to THIQs 5a–j
functionalized at C4, are summarized in Table 2. It is worth
noting that the generation of THIQs lithiated at C4 is not a
simple task and, to the best of our knowledge, only two ex-
amples of direct lithiation of THIQs, although with modest
yields and at lower temperature (À788C), are reported in
the literature.[19]
Figure 1. Flow microreactor for optimization of lateral lithiation and
isomACHTUNGTRENNUNG
erization of 1a. Reaction conditions: tR =23.56 s; flow rates: aziri-
[18]
dine 1a 3, sBuLi 1, electrophile 2 mLminÀ1
.
To further demonstrate the strength of this microreactor-
mediated methodology for the synthesis of THIQs, the re-
AHCTUNGTREGaNNNU ctivity of the most challenging aziridine 1b, bearing an
product was the laterally substituted aziridine 4a, whereas
the silylated tetrahydroisoquinoline 5a, likely derived from
the isomerization of 1-Li, was obtained as the main product
when the reaction was run at 08C. Reduced yields were ob-
served at higher temperatures. Starting from the reaction
conditions described in Figure 1, aziridine 1a was lithiated
at À488C in M1 (250 mm) and, after a residence time of 20.9
seconds in R1, 1-Li was successfully trapped with several
electrophiles in M2 (500 mm) to furnish aziridines 4a–e
(Table 1).
ortho-allyl substituent, was investigated (Scheme 3).[20] The
ortho-allyl substituted aziridine 1b was first lithiated in a
macrobatch reactor at À788C with sBuLi in 5 min, and the
corresponding lithiated intermediate 1b-Li was trapped with
a deuterium source to furnish a mixture of two regioisomers,
6 and 7, in a 4:1 ratio, respectively. The thermally induced
isomACTHUNRTGNEUNGerization was more difficult for this system and only
upon warming of 1b-Li to 08C for 2.5 h was a 30% yield of
THIQ 8 obtained, along with derivatives 6 and 7 and several
byproducts. Longer reaction times or higher temperatures
Regardless of the diastereomeric ratio of the products ob-
served from the reactions with prochiral carbonyl com-
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J.-i. Yoshida, R. Luisi et al.
Table 2. Flow-microreactor system for the one-pot lateral-lithiation–ther-
Table 3. Flow-microreactor system for the lateral-lithiation–electrophilic-
mal isomerization reaction of aziridine 1a.
trapping sequence of 1b.
Product 5[a]
Electrophile
Yield [%][b]
d.r.[c]
5a
5b
5c
5d
5e
5 f
5g
5h
5i
SiMe3Cl
60
58
54
95
75
63
90
60
73
95
–
–
Products 6,7[a]
Electrophile
Yield [%][b]
6/7 ratio
cyclohexanone
p-CF3-C6H4CHO
PhCHO
acetophenone
2,4,6-(CH3)3C6H2CHO
tBuCHO
Ph2CO
C6H11NCS
2,6-(CH3)2C6H3NCO
45:55[d]
45:55
52:48
70:30
82:18
–
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6 f, 7 f
CD3OD
EtI
acetone
iPrI
Ph2CO
SiMe3Cl
98
80:20
62:38
65:35
93:7
10:90
5:95
90[c]
86
53[c]
74
68
–
–
[a] See the Supporting Information for full technical details. Reaction
conditions: tR =5.24 s; flow rates: aziridine 1a 3, sBuLi 1.5, electrophile
1.5 mLminÀ1. [b] Overall yields of the isolated product. [c] Inseparable
mixture of regioisomers.
5j
[a] See the Supporting Information for full technical details. Reaction
conditions: tR1 =20.9 s; tR2 =41.9 s; flow rates: aziridine 1a 3, sBuLi 1.5,
electrophile 1.5 mLminÀ1. [b] Overall yields of the isolated products.
[c] Diastereoisomeric ratio calculated on the basis of 1H NMR spectra of
the crude reaction mixtures. [d] Structure and stereochemistry confirmed
by X-ray analysis (see the Supporting Information).
using a flow-microreactor system. We were happy to find
that the isomerization occurred in a microtube reactor R2 of
100 cm working at 608C with good yields of the THIQs 8a–f
after electrophilic quenching (Table 4). It is also worth
noting that all attempts to reproduce this transformation in
a macrobatch reactor gave unsatisfactory results.
resulted in complex reaction mixtures and only traces of the
desired THIQ.
Notwithstanding the above mentioned difficulties, this
process was transferred to a microreactor system with the
aim of improving the regioselectivity of the lateral-lithia-
tion–electrophilic-trapping sequence, and inducing the isom-
In summary, a new synthesis of THIQs has been devel-
oped starting from laterally lithiated aziridines by a thermal-
ly induced isomerization reaction. The use of flow-micro-
reactor technology allowed for precise temperature control,
which seems to be crucial for this transformation. Interest-
ingly, a lithiated isoquinoline could be efficiently generated
and trapped even at 608C. Such conditions were prohibitive
in macrobatch reactions. Further work is underway to
expand the synthetic applications and control the stereo-
chemistry of this process.
ACHTUNGTRENNUNGerization to THIQ. By using a flow-microreactor system
consisting of two T-shaped micromixers (M1, M2) of 500 mm
inner diameter and two microtube reactors (R1, R2) of 50
and 100 cm length, respectively, the lateral-lithiation–elec-
trophilic-trapping sequence of 1b was optimized. As report-
ed in Table 3, the trapping occurred in good yields, but with
the regioselectivity depending on the electrophile. Subse-
quently, the isomerization reACTHNUGRTNEUNGaction was also optimized by
Acknowledgements
We thank National Project “FIRB -
Futuro in Ricerca” (code: CINECA
RBFR083M5N); Regione Puglia:
“Reti di Laboratori Pubblici di Ricer-
ca” Project code 20; the Grant-in-Aid
for Scientific Research on Innovative
Areas (No. 2015) and a Grant-in-Aid
for Global COE program from
MEXT, Japan. We thank Prof. S.
Florio for the useful suggestions in the
beginning of this work. We thank Dr.
Giuseppe Romanazzi of the DICA-
TECh, Polytechnic of Bari, for provid-
ing HRMS analyses.
Scheme 3. Lateral lithiation–isomerization of 1b.
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Thermal Isomerization of Laterally Lithiated Arylaziridines
COMMUNICATION
Table 4. Flow-microreactor system for the one-pot lateral-lithiation–ther-
mal isomerization reaction of aziridine 1b.
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Product 8[a]
Electrophile
Yield [%][b,c]
d.r.[d]
8a
8b
8c
8d
8e
8 f
SiMe3Cl
MeI
cyclohexanone
acetone
78
50:50
56:44
60:40[f]
50:50
55:45
50:50
57[e]
50
60
C6H5CON
N
(OCH3)
53[e]
51
2,6-(CH3)2-C6H3NCO
[a] See the Supporting Information for full technical details. Reaction
conditions: tR1 =5.24 s; tR2 =10.5 s; flow rates: aziridine 1a 3, sBuLi 1.5,
electrophile 1.5 mLminÀ1. [b] Overall yields of the isolated products.
[c] Relative stereochemistry not assigned. [d] Diastereoisomeric ratio cal-
culated from the 1H NMR spectra of the crude reaction mixtures. [e] In-
separable mixture of stereoisomers. [f] Structure and stereochemistry
confirmed by X-ray analysis (see the Supporting Information).
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[13] The attack at Ca could be considered an irreversible process because
the resulting six-membered heterocycle is not
system like the three-membered aziridine.
a spring-loaded
[14] A preliminary NMR investigation of the process depicted in
Scheme 2 did not give evidence of the presence of 2-Li, but gave
clear signals for 1-Li at low temperature and 3-Li at higher tempera-
ture. This study is still underway.
[15] a) J. Yoshida, Chem. Rec. 2010, 10, 332–341; b) H. Kim, A. Nagaki,
J. Yoshida, Nat. Commun. 2011, 2, 264.
Keywords: aziridines · flow microreactor · heterocycles ·
lithiation · organolithium compounds · stereoselectivity ·
tetrahydroisoquinolines
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[18] All optimization conditions are reported in the Supporting Informa-
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[20] The lithiated intermediate 1b-Li, thanks to the additional effects of
the allylic moiety, was expected to be very stable and hardly prone
to thermal isomerization.
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Received: October 4, 2012
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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J.-i. Yoshida, R. Luisi et al.
Microreactor Chemistry
A. Giovine, B. Musio, L. Degennaro,
A. Falcicchio, A. Nagaki, J.-i. Yoshida,*
R. Luisi* .......................... &&& — &&&
Synthesis of 1,2,3,4-Tetrahydroiso-
ACHTUNGTRENNUNGquinolines by Microreactor-Mediated
Thermal Isomerization of Laterally
Lithiated Arylaziridines
Flow chemistry: A flow-microreactor-
mediated synthesis of 1,2,3,4-tetrahy-
droisoquinolines (THIQs) is reported
(see scheme). Starting from a laterally
lithiated aziridine, a tetrahydroisoquin-
Because the reaction temperature is a
crucial parameter, the exquisite ther-
mal control possible in a flow-micro-
reactor system allowed for fast, effi-
cient, and highly reproducible synthe-
sis of functionalized aziridines or
THIQs.
AHCTUNGTRENNoGUN line lithiated at C4 was generated by
thermally induced isomerization.
Organolithium Compounds
A flow microreactor system consisting of micromixers and
microtube reactors has been used as effective tool for the
generation and reactions either of laterally lithiated aziri-
dines or tetrahydroisoquinoline lithiated at C4, depending
on the reaction temperature. A thermally induced isomeri-
zation process has been tamed by exquisite thermal
control realized in the flow microreactor system. Trapping
with electrophiles of such organolithium intermediates
gave access to functionalized aziridines and tetrahydroiso-
quinolines. Details of these interesting processes are
described in the Communication by J.-i. Yoshida, R. Luisi
and co-workers on page &&ff.
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These are not the final page numbers!