Synthesis and kinetic resolution of substituted tetrahydroquinolines by lithiation then electrophilic quench

Article abstract of DOI:10.1039/c7sc04435f

Treatment of N-Boc-2-Aryl-1,2,3,4-Tetrahydroquinolines with n-butyllithium in THF at-78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable temper

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Synthesis and Kinetic Resolution of Substituted
Tetrahydroquinolines by Lithiation then Electrophilic Quench
Received 00th January 20xx,
Accepted 00th January 20xx
Nicholas Carter, Xiabing Li, Lewis Reavey, Anthony J. H. M. Meijer and Iain Coldham*
DOI: 10.1039/x0xx00000x
Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at –78 °C resulted in efficient lithiation
at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable
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temperature NMR spectroscopy gave kinetic data that showed that the rate of tert-butoxycarbonyl (Boc) rotation was fast
‡
(
ꢀG ≈ 45 kJ/mol at –78 °C) and in situ ReactIR spectroscopy showed fast lithiation at –78 °C. By carrying out the lithiation
in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved.
The resulting enantioenriched N-Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without
significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access
tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-
disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand.
Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl
ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies
and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate
organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc
group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with
retention of configuration from the intermediate enantiomerically enriched organolithium species.
reduction of a substituted quinoline and intramolecular
5
trapping with an indole (Scheme 1a). Zhao, Shi and co-
Introduction
workers developed an asymmetric Povarov reaction (Scheme
6
1b). Hopkins and Wolfe reported a palladium catalyzed
The tetrahydroquinoline ring system is of great importance in
1
natural products and medicinal compounds. Substituted
carboamination to give 2,2-dialkyl tetrahydroquinolines
1,2,3,4-tetrahydroquinolines are present in alkaloids such as
4
d
Scheme 1c). Enantioselective intramolecular N-arylation by
(
angustureine, cuspareine, galipinine, martinellic acid,
virantmycin, many with (for example) antiviral, antibacterial,
1
antifungal, antimalarial, or antitumour activities. The majority
Cai and co-workers was found with copper catalysis (Scheme
7
1d). Here we report the use of deprotonation followed by
electrophile trapping as a convenient approach to 2,2-
disubstituted tetrahydroquinolines (Scheme 1e). This strategy
has found only limited use in a racemic sense with 2-
of syntheses of tetrahydroquinolines involve the reduction of
2
3
quinolines or dihydroquinolines, a Povarov type reaction, or
a cyclization process to make one of the bonds in the partially
8
4
saturated ring. This often leads to tetrahydroquinolines that
cyanotetrahydroquinolines. Our research group has been
studying the lithiation then electrophilic quench of N-Boc
9
are monosubstituted at positions in the partially saturated
ring, for example at C-2, rather than 2,2-disubstituted
products. The ability to prepare 2,2-disubstituted
tetrahydroquinolines would be attractive, opening up a
greater diversity of products and exploring more chemical
space. However, there are few examples of their
enantioselective preparation from achiral compounds. You and
co-workers reported an isolated example of an asymmetric
heterocycles, with a particular recent focus on piperidines,
1
0,11
and tetrahydroisoquinolines.
We show in this study that
we can extend our lithiation chemistry with N-Boc-2-aryl-
heterocycles to tetrahydroquinolines. These substrates have
been found to undergo highly enantioselective kinetic
1
2,13
resolution.
78 °C and can be trapped to give 2,2-disubstituted
tetrahydroquinolines with excellent enantioselectivities.
The organolithium is configurationally stable at
–
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ARTICLE
Journal Name
a)
b)
H
N
R
R
NH
1
3
. NaBH CN, AcOH, rt
Ph
Ph
NH
Ts
L*
L*
MeO
NH
R
N
Ar
2. n-BuLi, Boc O, THF
2
N
Ar
N
Hantzsch
ester
N
H
PMPN
O
R
xylene
heat
N
N
H
O
N
Ts
Boc
4
3% dr 4.7:1
N
Bn
N
Bn
er 88.5:11.5
er up to 89:11
1a–e
L* = chiral phosphoric acid
R = H, Ar = Ph
43% 2a
48% 2b
54% 2c
R = H, Ar = C
R = Cl, Ar = Ph
R = H, Ar = C
6
D
5
c)
R
d)
3
,3’-biarylbinol
a
t
CuI
R’X, NaO Bu
R’
R
R
6
H
4
-p-F 72% 2d
42% 2e
2
6
% Pd
2
(dba)
% (S)-Siphos-PE
PhMe, heat
3
N
I
H
Cs CO3
R = H, Ar = 2-Np
O was used
Scheme 2. Preparation of tetrahydroquinolines 2a–e.
NHPMP
R
CO
2
Me
2
N
H
2
CO Me
2
N
PMP
a
KR, up to 50% yield
er up to 98.5:1.5
Boc-ON rather than Boc
2
R = Me, Et
er up to 96:4
e) This study:
KR
Ar
BuLi
R
N
N
Ar
E
+
N
Ar
Boc
Boc
Boc
er up to 97:3
er up to 98:2
Scheme 1. Asymmetric methods to 2,2-disubstituted tetrahydroquinolines.
Results and discussion
We needed access to N-Boc-2-aryltetrahydroquinolines to test
our lithiation chemistry. These were prepared from the
quinolines 1a
in acetic acid using a known method, followed by Boc
protection of the amine to give the novel products 2a
–e by reduction with sodium cyanoborohydride
1
4
–
e
Fig. 1. In situ IR spectroscopy of the deprotonation of 2a with n-BuLi, THF at –78
–1
°
C with time in h:min:sec. with n-BuLi added at time 8 min (
ν
c=o 2a 1705 cm ,
–
1
(Scheme 2).
νc=o lithiated 2a 1641 cm ).
We were aware from earlier studies that the rate of
9
lithiation is dependent on the orientation of the Boc group.
d
n-BuLi, THF, –78 °C
Therefore we probed the rate of rotation of the Boc group in
6 min then E+
Ph
N
compound 2a by using VT-NMR spectroscopy (see ESI) and
‡
N
Ph
E
found activation parameters for Boc rotation, giving
ꢀ
G
≈
47
Boc
Boc
kJ/mol at –78 °C for each rotamer. This suggests that the Boc
group rotates quickly (t1/2 1 sec) even at –78 °C. This was
2a
3a–i
≈
confirmed by ReactIR spectroscopy, which showed rapid
lithiation (within a few minutes) at this temperature (Fig. 1 and
ESI).
Ph
CO Me
Ph
N
Ph
N
N
2
CO
2
Et
D
Boc
Boc
Boc
3c 95%
E+ = D
The intermediate organolithium could be quenched with a
selection of electrophiles to give the 2,2-disubstituted
3a
90%
E+ = MeOCOCl
3b 71%
E+ = EtOCOCl
2
O
tetrahydroquinoline products 3a–i (Scheme 3). Generally good
yields of the products were obtained. The only exception to
this was the use of the electrophile methyl cyanoformate,
Ph
SnBu
Ph
Me
Ph
N
N
N
which gave the product
4
rather than the expected product 3a
.
3
Boc
Boc
Boc
This is discussed further below.
3d
72%
SnCl
3e 87%
E+ = MeI
3f 78%
Kinetic resolution of the tetrahydroquinoline 2a was
E+ = Bu
E+ = allyl bromide
3
studied using (–)-sparteine as the chiral ligand in PhMe and
1
5
adding n-BuLi to this mixture. Moderately good enantiomer
ratios of the recovered tetrahydroquinoline 2a and the
product 3a were obtained by this method. However improved
results were found by pre-mixing the n-BuLi and (–)-sparteine
before adding the tetrahydroquinoline 2a (Scheme 4). The
deprotonation was relatively slow under these conditions and
despite being a kinetic resolution, it was best to use 1.2 equiv.
n-BuLi to achieve a suitable rate of reaction. The recovered
tetrahydroquinoline 2a was isolated with high enantiomer
Ph
CO Me
Ph
Ph
Ph
N
N
N
2
Boc
Boc
Boc
3g
63%
E+ = BrCH
3h 75%
E+ = PhCH
3i 63%
E+ = 4-BrC
H CH Br
6 4 2
Br
2
CO
2
Me
2
Br
CO
2
Me
N
Boc
ratio (er 97:3) and this equates to a selectivity factor s (k ) =
rel
4
62%
E+ = MeOCOCN
Scheme 3. Lithiation–trapping of tetrahydroquinoline 2a
20.
.
2
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iodomethane as the electrophile, possibly as this reacts more
slowly allowing some racemization on warming prior to
16b
1
1
.2 equiv. n-BuLi
.3 equiv. (–)-sp
2a
+
quench. The tetrahydroquinoline 3g was recrystallised and
Ph
CO Me
PhMe, –78 °C
.5 h then MeOCOCl
N
Ph
N
2
2
its absolute configuration was confirmed by single crystal X-ray
analysis. The major diastereomer of the oxazolidinones 10 was
confirmed by X-ray analysis. For X-ray data, see ESI.
Boc
Boc
2a
43% er 97:3
3a 56% er 81:19
Scheme 4. Kinetic resolution of tetrahydroquinoline 2a with (–)-sparteine.
Another electrophile that we were interested in testing
was a trialkylborane, as this could result in a borate
The opposite enantiomer of the recovered starting material 2a
could be obtained by using (+)-sparteine in the kinetic
resolution (Scheme 5). Several runs were conducted, all with
very good enantioselectivities. Recrystallisation of the product
1
7
intermediate that should be prone to rearrange. However we
found that, instead of quenching the organolithium, addition
of triethylborane promoted Boc group migration to give the
1
8
tetrahydroquinoline 11 (Scheme 8).
The absolute
3
a
from run 1 gave material that was suitable for single crystal
X-ray analysis. This confirmed the absolute configuration to be
R)-3a as indicated (see ESI), and as expected based on
configuration of the product 11 was confirmed by single crystal
X-ray analysis showing that the rearrangement occurred with
(
retention of configuration starting with the highly
5,16 enantioenriched tetrahydroquinoline 2a. We speculate that
previous findings of the stereoselectivity preference for
1
BuLi·sparteine in the deprotonation of N-Boc-piperidines.
the borane coordinates to the carbonyl oxygen atom to effect
the migration and this must be preferable to direct reaction of
The kinetic resolution was extended to the
tetrahydroquinolines 2c–e (Scheme 6). High enantiomer ratios
the organolithium on the boron atom. The same reaction
occurred with BEt as a catalyst (0.2 equiv. gave product 11
9% yield), or even in the absence of any catalyst (42% yield of
on using BuLi then warming without any BEt ). We were
of the recovered tetrahydroquinolines were obtained in each
case, particularly if more than just a slight excess of sparteine
was added to the reaction mixture. The quenched products
could be separated from the recovered starting material to
3
,
5
1
1
3
able to remove the Boc group from the nitrogen atom in the
products by using trifluoroacetic acid (TFA), for example from
compound 3g to give the secondary amine 12 with only
minimal loss of enantiopurity.
give the desired tetrahydroquinolines (S)-2c–e.
1.2 equiv. n-BuLi
1
.3 equiv. (+)-sp
2a
+
Ph
CO Me
PhMe, –78 °C
.5 h then MeOCOCl
N
Ph
N
2
2
R
R
Boc
Boc
n-BuLi, THF, –78 °C
min then E+
Run 1 2a 45% er 92:8
Run 2 43% er 98:2
Scheme 5. Kinetic resolution of tetrahydroquinoline 2a with (+)-sparteine.
3a 42% er 93:7
6
Ar
54% er 82:18
N
Ar
N
E
Boc
Boc
(
(
R)-2a er 97:3 R = H, Ar = Ph
S)-2a er 92:8 R = H, Ar = Ph
0
.8–1.0 equiv.
n-BuLi
.3–1.7 equiv. Cl
+)-sp
(S)-2c er 92:8 R = Cl, Ar = Ph
(S)-2d er 94:6 R = H, Ar = C H -p-F
(S)-2e er 96:4 R = H, Ar = 2-Np
6
4
1
(
Cl
2c–e
+
Ph
PhMe, –78 °C
.25–1.5 h then
MeOCOCl
N
N
Ph
CO2Me
1
Boc
Boc
Ph
CO Me
2
Ph
CO Et
2
Ph
Me
N
N
N
2c
41% er 92:8
5
42% er 86:14
Boc
Boc
Boc
3
E
a
90% er 97:3
= MeOCOCl
3b 78% er 97:3
3e 91% er 94:6
+
+
+
+
F
E
= EtOCOCl
E
= MeI
C6H4-p-F
CO2Me
N
N
Cl
Boc
Boc
2
d
36% er 94:6
6
7
42% er 85:15
Ph
N
Ph
Me
6 4
C H -p-F
CO Et
2
N
N
CO
2
Me
Boc
Boc
Boc
3
E
g
71% er 92:8
8
69% er 87:13
9
89% er 93:7
+
+
E+ = MeI
E+ = EtOCOCl
= BrCH
2
CO
2
Me
2
-Np
N
N
CO2Me
Boc
Boc
2e
39% er 96:4
12% er 78:22
2-Np
Ph
2-Np
Ph
Scheme 6. Kinetic resolution of tetrahydroquinolines 2c
–
e
with (+)-sparteine.
N
N
O
O
O
O
1
0a
= PhCHO
er 95:5 62% 2 : 1 10b
er 95:5
The enantioenriched 2-aryltetrahydroquinolines 2a and
were treated with n-BuLi in THF at –78 °C and the
resulting organolithiums were found to be configurationally
stable. After electrophilic quench, the products 3a 3e 3g
and 10 were obtained with high enantiomer ratios (Scheme
). A slight loss of enantioselectivity was noticeable on using
+
E
Scheme 7. Lithiation–quench of enantioenriched tetrahydroquinolines 2a, 2c–e.
2c–e
–b
,
,
,
8
–
7
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Calculations (using DFT/B3LYP-GD3BJ/6-311G**; see
Computational methods below) initially focused on Boc
rotation of tetrahydroquinoline 2a, for which we found an
activation Gibbs energy of 48.7 kJ/mol in fair agreement with
the experimental value of about 44 kJ/mol at 298 K.
Subsequent calculations focused on the structures of the
intermediate organolithium. In particular, we studied the
complexation of the intermediate lithiated species with
MeOCOCl and MeOCOCN. This gave insight into the potential
reason for the change in regioselectivity. The minimised
structures had the lithium atom coordinated to the carbonyl
oxygen atom and close to C-2 when coordinated to THF or
n-BuLi, THF
78 °C, 6 min
–
CO t
Ph
Bu
then BEt
3
2
N
Ph
N
H
Boc
(
S)-2a er 98:2
71% 11 er 98:2
TFA
Ph
CO
CH2Cl2
Ph
N
N
H
2
Me
2
CO Me
Boc
3g
er 92:8
Scheme 8. Formation of secondary amine products.
69% 12 er 88:12
MeOCOCl (Fig. 2a–b). On the other hand, there was clearly an
3
We were surprised to find that the electrophile methyl
cyanoformate gave the product rather than the expected
product 3a. We were concerned that there may have been
η
co-ordination of the lithium atom when MeOCOCN was
4
bound (Fig. 2c). An alternative explanation could be that
released cyanide could affect the regiochemistry, however an
experiment in which MeOCOCl was added to the
organolithium after addition of one equivalent of NaCN
returned only the alpha-substituted product 3a. Thus, we
surmise that a change in structure of the organolithium on
complexing the different electrophiles (MeOCOCl or
MeOCOCN) must be influencing the regiochemistry on
reaction with the electrophile, although the precise way that
1
9
competitive ortho lithiation, although this would be contrary
to the formation of the products 3a . We recently uncovered
an example of such an unusual change in regioselectivity with
–
i
1
1c
a benzylic organolithium on changing the electrophile, and
wanted to probe this reactivity further. Treatment of the
deuterated tetrahydroquinoline 3c under the same conditions
(1.2 equiv. n-BuLi in THF) followed by addition of MeOCOCN
returned recovered starting material 3c, indicating a large
21
this happens will be subject to further study.
2
0
kinetic isotope effect. This suggests that the benzylic proton
in 2a is indeed removed and not the ortho proton. Forcing the
deprotonation with 3 equiv. n-BuLi for 1 h before addition of
MeOCOCN still gave predominantly recovered 3c but did give a
(a)
(b)
(c)
O
small amount (8% yield) of the product
4 (no deuterium
Li
O
N
present). Treatment of the tetrahydroquinoline 2b with n-BuLi
then MeOCOCl gave the expected 2,2-disubstituted product 13
O
O
(Scheme 9). However, with MeOCOCN as the electrophile, the
ortho substituted product 14 was obtained in moderate yield
as a mixture in which the major product had deuterium at the
2
-position. Hence the reaction must proceed by initial
deprotonation alpha to the nitrogen atom. Most electrophiles
react at C-2 to give the products 3a . With methyl
O
CH3
O
O
–
i
Li
N
O
cyanoformate, substitution occurs at the ortho position and
then rearomatisation takes place (see ESI). The transfer of the
proton (or deuterium) is likely to occur non-selectively and
indeed on using enantioenriched tetrahydroquinoline 2a (er
Cl
O
92:8, prepared as described below), the product
4 was formed
with low selectivity (er 61:39).
H
O
3
C
O
O
n-BuLi, THF, –78 °C
Li
N
O
CN
6 min then E+
6 5
C D
CO Me
2
N
C
6
D
5
N
O
Boc
Boc
2b
13 81%
E+ = MeOCOCl
CO
D
2
Me
D/H
Fig. 2. Lithiated intermediates by DFT [6-311G(d,p) basis set with B3LYP
functional] and their ChemDraw representations. (a) in THF; (b) with MeOCOCl;
c) with MeOCOCN.
D
(
N
Boc
D
D
14
46% D/H 2:1
E+ = MeOCOCN
Experimental
Scheme 9. Lithiation–trapping of tetrahydroquinoline 2b
.
4
| Chem. Sci., 20xx, xx, 1-x
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ARTICLE
A representative method for the kinetic resolution of the on the basis of DFT studies, to result from a small change in
tetrahydroquinoline 2a is given below. For further details and the structure of the organolithium intermediate. Excellent
all data, see ESI.
n-BuLi (0.6 mL, 0.39 mmol, 2.5 M in hexane) was added to the presence of the chiral ligand sparteine. This chemistry
freshly distilled (+)-sparteine (106 mg, 0.45 mmol) in PhMe (4 therefore provides new method to prepare highly
mL) at –78 °C. After 30 min, tetrahydroquinoline 2a (101 mg, enantiomerically enriched 2-aryltetrahydroquinolines and
.33 mmol, 0.3 M solution in toluene) was added. After 2.5 h, tetrahydroquinolines that are fully substituted at the 2
enantioselectivities in the kinetic resolution were obtained in
a
0
methyl chloroformate (0.09 mL, 1.15 mmol) was added. The position.
mixture was allowed to warm to room temperature over 16 h
and then MeOH (1 mL) was added. Purification by column
Conflicts of interest
chromatography on silica gel, eluting with petrol−EtOAc (95:5),
gave the recovered tetrahydroquinoline (S)-2a (44 mg, 43%) as There are no conflicts of interest to declare.
an amorphous solid; m.p. 60–61°C; er 98:2, determined by CSP
2
D
3
HPLC with a Cellulose-2 column; [α]
3
–103.9 (0.6, CHCl ); and
in addition the tetrahydroquinoline (R)-3a (65 mg, 54%) as an Acknowledgements
amorphous solid; m.p. 71–74°C; er 82:18, determined by CSP
We acknowledge support from the EPSRC, the China
HPLC.
Scholarship Council (UK-China Scholarships for Excellence), and
the University of Sheffield. We thank Harry Adams and Craig
Robertson for the single crystal X-ray analyses, Sandra van
Meurs and Craig Robertson for help with NMR spectroscopy,
and Ashraf el-Tunsi for further experiments.
Computational methods
All calculations were performed using density functional
2
theory, employing the B3LYP functional as implemented in
2
2
the D.01 version of Gaussian 09. Calculations included
3
2
4
dispersion corrections using the GD3-BJ method. All Notes and references
calculations used the 6-311G(d,p) basis set. Solvent was
2
5
1
V. Sridharan, P. A. Suryavanshi and J. C. Menéndez, Chem.
Rev., 2011, 111, 7157.
2
6
included via the PCM method as implemented in Gaussian
with the default parameters for THF.
2
For example, see: (a) Z. Zhang and H. Du, Org. Lett., 2015, 17
816; (b) Y.-L. Du, Y. Hu, Y.-F. Zhu, X.-F. Tu, Z.-Y. Han and L.-Z.
Gong, J. Org. Chem., 2015, 80, 4754; (c) J. Wen, R. Tan, S. Liu,
Q. Zhao and X. Zhang, Chem. Sci., 2016, , 3047; (d) Y. Wang,
,
2
The starting positions of coordinated solvent and
electrophile molecules were varied to obtain the lowest
energy structures. Frequency calculations were performed on
all optimized structures to confirm that these were true
minima. One transition state calculation was performed, for
which a single imaginary frequency was found, as expected.
For the calculations on 2a no imaginary frequencies were
found. The two complexes presented in Figures 2a & 2b also
showed no imaginary frequencies. The complex presented in
7
Y. Liu, D. Zhang, H. Wei, M. Shi and F. Wang, Angew. Chem.
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For some reviews, see: (a) M. Fochi, L. Caruana and L.
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–
1
Figure 2c showed a single imaginary frequency of –16.5 cm .
Inspection shows this mode is largely a torsional mode of the
ligands around the lithium-ligand bond. Re-running the
(
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015, 17, 4090; (d) B. A. Hopkins and J. P. Wolfe, Chem. Sci.
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calculation with
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optimization convergence led to a structure without imaginary
frequencies. This latter structure is reported in the ESI. All
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5
6
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S.-G. Wang, W. Zhang and S.-L. You, Org. Lett., 2013, 15,
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In conclusion, we have developed a rapid access to 2,2-
disubstituted
tetrahydroquinolines
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2-
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2
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