Expedient synthesis of tetrahydroquinoline-3-spirohydantoin derivatives: Via the Lewis acid-catalyzed tert -amino effect reaction

Article abstract of DOI:10.1039/c6cc03600g

Magnesium triflate was found to effectively catalyze the tert-amino effect reaction (T-reaction) involving ethyl 3-(2-(dialkylamino)-phenyl)-2-nitroacrylates leading to tetrahydroquinoline nitroester derivatives. These compounds can be readily transformed

Full text of DOI:10.1039/c6cc03600g

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Expedient Synthesis of Tetrahydroquinoline-3-Spirohydantoin
Derivatives via Lewis Acid-Catalyzed tert-Amino Effect Reaction
John F. Briones ab and Gregory S. Basarab*ac
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
generated considerable recent interest due, in part, to the
capability of creating novel heterocyclic architectures.6 As such,
to Rheinhoudt pioneered this T-reaction and presented mechanistic
data supporting a sigmatropic [1,5]-hydride shift, followed by the
Mannich cyclization as outlined in Scheme 3.5d Traditionally, this
reaction has been carried out thermally; however, milder conditions
using Lewis acid catalysis have been recently developed.7
Asymmetric variants of the Lewis acid-catalyzed T-reaction and
similar internal redox reactions have also recently been disclosed.8
The thermally-promoted T-reaction with barbituric acid and the
corresponding morpholinoaldehyde was utilized in the syntheses of
the SPTs of Scheme 2.9 We set out to utilize α-nitroacrylate esters in
Magnesium triflate was found to effectively catalyze the tert-
amino effect reaction (T-reaction) involving ethyl 3-(2-
(dialkylamino)-phenyl)-2-nitroacrylates
leading
tetrahydroquinoline nitroester derivatives. These compounds can
be readily transformed to the corresponding valuable
spirohydantoin derivatives.
Spirohydantoins are important motifs commonly found in
pharmaceuticals and natural products offering attractive cores
for library synthesis due to their wide range of therapeutic
activities including antidiabetic, antiepileptic, antipsychotic,
antidepressant and anxiolytic.1 We were motivated to
synthesize as series of spirohydantoins (Scheme 1) wherein the
spirocycle radiates from a tetrahydroquinoline scaffold as
a
variant of the T-reaction toward the synthesis of novel
tetrahydroquinoline-3-spirohydantoins, thereby expanding the
collection of unique and interesting spirocyclic compounds.
Additionally, we show the synthesis of the two spirohydantoin
diastereomers as analogues of an SPT for comparison of
antibacterial activity.
analogues
spiropyrimidinetriones (SPTs). This SPT class includes Pfizer’s
PNU-286607 ( ) as well as and ETX0914 ( ), the latter two
of
antibacterial
agents
known
as
1
2
3
developed at AstraZeneca R&D Boston (Scheme 2). These
compounds represent a new class of DNA gyrase inhibitor
We began by screening various Lewis acid catalysts to promote
the T-reaction 1,5-hydride transfer on the E/Z mixture of the
Knoevenagel adduct 4, synthesized by the condensation of 2-
(benzyl(methyl)amino)benzaldehyde and ethyl nitroacetate. Though
the T-reaction proceeds under thermal conditions (no Lewis acid
catalysis) for malonate derived Knoevenagel adducts,5c heating of 4
either led to no reaction at lower temperatures or decomposition at
higher (Table 1, entry 19). Heating at 80 oC in the presence of a
Lewis acid catalyst was necessary with no reaction being observed
at room temperature (Table 1, entries 1-11). Common Lewis acids
such as Sc(OTf)3, Gd(OTf)3 and magnesium-based Lewis acids
proved to be effective catalysts with Mg(OTf)2 being optimal and
affording the desired α-nitroester 5 in 98% yield in 0.5 h (Table 1,
entry 14).8b,10 Mg(OTf)2 showed optimal results for all of the
substrates examined and, therefore, became the catalyst of choice.
Finally, triflic acid and other protic acids did not catalyze the
reaction (data not shown).
operating under
a mechanism distinct from that of
fluoroquinolones.2 The tetrahydroquinoline scaffold itself,
commonly found in natural products and pharmaceuticals,3
has a wide range of interesting biological activities. Hence, the
development of efficient methods to synthesize
tetrahydroquinolines has been of great interest and the
subject of several recent reviews.4
Among the myriad ways to construct the tetrahydroquinoline
core is a variant of the tert-amino effect reaction (T-reaction),
wherein a cyclization cascade ensues from ortho-vinyl substituted
anilines.5 As described, this particular T-reaction is a subset of many
internal redox reactions involving a hydride migration, which have
With the optimized catalyst in hand, we explored the scope
and generality of the reaction (Table 2). The Mg(OTf)2-
catalyzed T-reaction worked well with a variety of N,N-dialkyl
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J. Name., 2013, 00, 1-3 | 1
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substituted phenylnitroacrylates affording the desired nitroacrylate adduct 20 as a
Journal Name
∼
1:1 mixture of E/Z isomers. This
tetrahydroquinoline products in excellent yields (92-98%). mixture was then subjected to the Mg(OTf)2-catalyzed T-
Differential substitution on the aniline nitrogen sets up reaction conditions to provide the tetrahydroquinoline
competition experiments for the T-reaction. Complete nitroester 21, which was directly used for the Zn reduction of
regioselectivity was observed for entries 3 and 4 with exclusive the nitro group affording a diastereomeric mixture of amines.
hydride transfer observed from the ethyl and isopropyl The major diastereomers 22 and epi-C3-22 were separated by
substituents, respectively, over the methyl group.11 The group HPLC and were independently transformed to spirohydantoins
that better stabilizes the developing positive charge 23 and epi-C3-23 in 93 and 95% yields, respectively, over two
dominated steric considerations,12 indicating a late transition steps. The all-equatorial arrangement of substituents around
state for the [1,5]-hydride transfer (Scheme 1). Carbocation the morpholine ring was seen for both of the major isolated
stabilizing π-systems also outcompeted the methyl group as diastereomers 23 and epi-C3-23 (as confirmed by nOe
with the allyl substituent of entry 6 and the benzyl substituent analyses) and paralleled the stereochemistry seen during the
of entries 1, 2 and 8. Diastereoselectivity in the T-reaction was preparation of SPTs.9 Both 23 and epi-C3-23 were assessed for
modest with diastereomeric ratios likely reflecting relative inhibition of DNA gyrase from E. coli,9b but they failed to show
thermodynamic stabilities.9b The major diastereomer from activity at the highest concentration tested (83 µM) and were
entry 1 could be isolated, and its relative stereochemistry was considerably less active than 24 (IC50 = 0.79 µM).
determined by X-ray crystallographic analysis showing the
phenyl substituent trans to the nitro.12 More generally, it
Conclusions
proved difficult to separate the nitro ester diastereomers due
to facile retro-Mannich/re-cyclization leading to epimerization
of the quaternary center, seen for example on contact with
silica gel. However, separation was easily achieved after
reduction of the nitro group to the corresponding amine. The
Mg(OTf)2-catalyzed T-reaction also worked well with pyridines
(entries 7-8). Hydride transfer from even a methyl group
occurred smoothly affording nitroester 11 (entry 7) in 99%
yield. For entry 8 as before, only the benzylic hydride migrated
leading to the tetrahydronaphthyridine product 12 in 92%
yield, 2:1 dr.
In summary, Mg(OTf)2 is an effective catalyst for promoting
the
T-reaction
with
nitroacrylates.
Versatile
and
tetrahydroquinoline-3-nitroesters
tetrahydronaphthyridine-3-nitroesters are easily accessed and
efficiently converted to the corresponding spirohydantoin
derivatives.
Notes and references
1
(a) M. J. Nieto, A. E. Philip, J. H. Poupaert, C. R. McCurdy, J.
Comb. Chem. 2005, , 258.; (b) G. J. T. Kuster, L. W. A. van
Berkom, M. Kalmoua, A. van Loevezijn, L. A. J. M. Sliedregt,
After establishing Mg(OTf)2 as an effective Lewis acid
catalyst for the T-reaction, we then transformed the
tetrahydroquinoline-3-nitroesters into the corresponding
spirohydantoin derivatives, first working out the chemistry
7
B. J. van Steen, C. G. Kruse, F. P. J. T. Rutjes, H. W. Schreen, J.
Comb. Chem. 2006, 8, 85. (c) M. Meusel, M. Gütschow, Org.
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with compound 5a, the major diastereomer of
5 (Scheme 4).
2
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J. A. Schuck, R. Tommasi, G. Walkup and J. V Newman, Sci.
Compound 5a was converted to the spirohydantoin in three
reaction steps: 1) Reduction of the nitro group with excess Zn
dust in acetic acid to afford amine 13; 2) Conversion of the
amine to the urea 14 by acylation with potassium cyanate in
acetic acid; 3) Base-mediated ring closure with sodium
ethoxide in ethanol to the desired spirohydantoin 15 13
Other
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spirohydantoins 17a-k synthesized are shown in Table 3.
Generally, the overall four-step sequence from Knoevenagel
adducts
to
spirohydantoins
required
only
one
3
4
chromatographic purification step carried out either at the
amine stage (Procedure A) or at the spirohydantoin stage
(Procedure B) depending on the ease of chromatographic
separation. The relative stereochemistries of the
spirohydantoin products 17a-k were not assigned.
(a) J. A. Sirvent, F. Foubelo, M. Yus, J. Org. Chem. 2014, 79
,
1356.; (b) K. Mori, K. Ehara, K. Kurihara, T. Akiyama, J. Am.
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Katritzky and A.J. Boulton, 1972, pp 211-278.; (b) G. W.
Visser, W. Verboom, P. H. Benders, D. N. Reinhoudt, J. Chem.
We then set out to synthesize an analogue containing the
spirohydantoin motif (23 and epi-C3-23, Scheme 5) to compare
activity with SPTs that show high DNA gyrase inhibitory
potency and antibacterial activity.9b For ease of synthesis, we
chose the SPT analogue 24 synthesized at Pfizer as the point of
comparison (Scheme 5).14 We began the synthesis of
spirohydantoins 23 by conversion of aldehyde 18 to the
morpholinoaldehyde 19 in 84% yield. Knoevenagel
condensation with ethyl nitroacetate provided the
5
2 | J. Name., 2012, 00, 1-3
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9
For stereochemical details on the transformations see: (a) J.
C. Ruble, A. R. Hurd, T. a Johnson, D. a Sherry, M. R.
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11 Tetrahydroquinoline nitroester
8 degraded to 1-methyl-3-
nitro-3,4-dihydroquinolin-2(1H)-one 25 after prolonged
storage at rt.
12 The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre, deposition number CCDC
1437250.
13 Q. Zhu, Y. Pan, Z. Xu, R. Li, G. Qiu, W. Xu, X. Ke, L. Wu, X. Hu,
Eur. J. Med. Chem. 2009, 44, 296.
14 M. R. Barbachyn, P. J. Dobrowolski, A. Hurd, D. J. McNamara,
J. R. Palmer, A. G. Romero, J. C. Ruble, D. A. Sherry, L. M.
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2004.
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Table 1. Catalyst screening for the T-reaction with ethyl 3-(2-
morpholinophenyl)-2-nitroacrylate 4
Entry
Lewis acid
Time (h)
Yield (%)
Temp (°C)
1
2
FeCl3
InCl3
23
23
23
23
23
23
23
23
80
80
80
80
80
80
80
80
80
12
12
12
12
12
12
12
12
12
12
12
6
0
0
3
AlCl3
0
4
Sc(OTf)3
Mg(OTf)2
Gd(OTf)3
ZnCl2
0
5
0
6
0
7
0
8
FeCl3
0
9
InCl3
0
10
11
12
13
14
15
16
17
AlCl3
0
ZnCl2
0
Gd(OTf)3
Sc(OTf)3
Mg(OTf)2
Mg(ClO4)2
Mg(NTf2)2
LiClO4
92
94
98
91
90
0
12
0.5
2
2
12
18
19
NaOTf
none
80
12
12
0
0
120

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Table 2. Catalyst screening for the T-reaction with ethyl 3-(2-
morpholinophenyl)-2-nitroacrylate 4
Entry
1
Substrate
Products
Yield (%) dr
R’ = H; R’’ = Ph, 5
96
95
3:1
3:1
EtO2C
NO2
2
R’ = H; R’’ = Ar, 6
N
Ar
Ar = 4-F-Ph
3
4
R’ = H; R’’ = Me, 7
95
98
6:1
R’ = H; R’’ = gem-Me2, 8
-
5
R’ = H; R’’ = -(CH2)4, 9
92
3:1
6
7
R’ = H; R’’ = CH=CH2, 10
R’ = H; R’’ = H, 11
95
99
3:1
-
8
R’ = H; R’’ = Ph, 12
92
2:1

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Table 3. Synthesis of spirohydantoins from tetrahydroquinoline
aminoester derivatives 16a-k
O
NH
O
N
H
N
17e, 92% (B) dr 3:1
aProcedure A: separation of diastereomers 16; Procedure B: separation of
diastereomers 17. Yields for Procedure B: for combined diastereomers; dr's
determined by 1H NMR of crude mixtures of spirohydantoins.

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