First zinc bromide promoted annulative domino reactions between enamines and cyclic Morita-Baylis-Hillman alcohols: Synthesis of N, O-ketals

Article abstract of DOI:10.1055/s-0040-1707467

A new efficient ZnBr ₂-mediated annulative domino reaction between enamines and cyclic Morita-Baylis-Hillman (MBH) alcohols is disclosed. The process involves a tandem sequence (intermolecular conjugate addition of enamines to MBH alcohols and intramolecular nucleophilic addition of the hydroxyl moiety to the transiently generated iminium ion), affording the corresponding N, O -ketals diastereoselectively in good yields.

Full text of DOI:10.1055/s-0040-1707467

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
G. Bouhalleb et al.
Letter
Synlett
First Zinc Bromide Promoted Annulative Domino Reactions
between Enamines and Cyclic Morita–Baylis–Hillman Alcohols:
Synthesis of N,O-Ketals
Ghalia Bouhalleba
( )n
Ahmed Meddeba
Noura Fakhar Bourguibaa
Julien Legrosb
Giovanni Polic
Farhat Rezgui*a
( )n
ZnBr2 (3 equiv)
N
+
O
HO
O
CH2Cl2, reflux
N
O
R
O
R
O
Annulative domino process
55–90% yield
12 examples
n =1, 2; R = H, Me, Ph
a Université de Tunis El Manar, Faculté des Sciences de Tunis,
Laboratoire de Chimie Organique Structurale LR99ES14,
Campus Universitaire, 2092 Tunis, Tunisia
farhat.rezgui@fst.utm.tn
b Université de Rouen 1, Laboratoire COBRA UMR CNRS 6014
IRCOF, rue Lucien Tesnière 76821 Mont Saint-Aignan, France
c Sorbonne Université, Faculté des Sciences et Ingénierie,
CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 4 place
Jussieu, 75005 Paris, France
Received: 24.02.2020
Accepted after revision: 13.03.2020
Published online: 06.04.2020
alcohol moiety. The reaction involves an intermolecular
1,4-addition of the enamine to the enone moiety, followed
by a spontaneous intramolecular addition of the hydroxyl
group to the transiently generated iminium ion. Following
exposure to air, the resulting adducts were oxidized to the
corresponding aminonaphthopyran diones (Scheme 1).
DOI: 10.1055/s-0040-1707467; Art ID: st-2020-d0105-l
Abstract A new efficient ZnBr2-mediated annulative domino reaction
between enamines and cyclic Morita–Baylis–Hillman (MBH) alcohols is
disclosed. The process involves a tandem sequence (intermolecular con-
jugate addition of enamines to MBH alcohols and intramolecular nucle-
ophilic addition of the hydroxyl moiety to the transiently generated
iminium ion), affording the corresponding N,O-ketals diastereoselec-
tively in good yields.
O
R
O
R
a. toluene, Ar, rt
b. air oxidation
R1
N
R1 R2
N
O
OH
+
R2
R4
Ref. 17–19
R3
R3
O
R4
Key words MBH alcohol, conjugate addition, enamines, domino reac-
tions, zinc bromide, N,O-ketals
O
Scheme 1 Reactions of enamines with naphthoquinone derivatives
Enamines are versatile synthetic intermediates1,2 that
are commonly involved in the chemistry of natural prod-
ucts such as terpenes, steroids, alkaloids and pharmaceuti-
cals.3 After the pioneering work of Stork4 in the fifties, the
nucleophilic behavior of this functional group has been
successfully exploited in a number of conjugate additions to
electron-poor alkenes such as ,-unsaturated enones,5,6 al-
lenyl ketones and esters,7 as well as methyl acrylate,8 2-
formylcyclohexenones,9 and 2-acetyl-1,4-naphthoqui-
nones.10
Moreover, enamines are capable of undergoing palladi-
um- as well as iridium-catalyzed SN2 and/or SN2′ C-allyla-
tions in the presence of allylic acetates,11,12 phenyl ethers,13
benzotriazoles,14 carbonates,15 and even allylic alcohols.16
In particular, Kobayashi and co-workers17–19 have stud-
ied the coupling reaction between enamines and -(1-hy-
droxyalkyl)-1,4-naphthoquinones, as bifunctional sub-
strates bearing an enone function juxtaposed to an allylic
Recently, our group20 reported a ZnBr2 promoted21–23
palladium-catalyzed allylation of ketoenamines with MBH
adducts bearing good leaving groups such as acetates and
ethers. We now report a new reactivity, taking place be-
tween these ketoenamines and unprotected Morita–Baylis–
Hillman (MBH) alcohols carrying a poor leaving group (OH).
On the one hand, an enamine bears a nucleophilic site at
the -carbon, while an electrophilic site at the -carbon is
generated in the initial product of its C-allylation. On the
other hand, an MBH adduct bears an electrophilic site at the
-position to the carbonyl group as well as a nucleophilic
hydroxyl moiety. We thus reasoned that if the first interac-
tion between these reaction components involved the con-
jugate addition of the enamine to the MBH alcohol, under
appropriate reactions conditions, we might be able to ac-
complish an annulative domino reaction, as shown in
Scheme 2.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
G. Bouhalleb et al.
Letter
Synlett
ditions as ZnBr2 (3 equiv), CH2Cl2, reflux. Under these con-
ditions, the reaction between MBH alcohol 3a (1 equiv) and
enamine 2a (5 equiv) afforded the desired annulated N,O-
ketal 4a within 3 h (entry 4) in 90% yield as a single diaste-
reoisomer (Scheme 3, see below).
Nu
( )n
( )n
E
α
β
β
E
1,4-addition
MXn
α
+
HO
N
O
N
X
HO
Nu
R
O
R
O
O
MX(n-1)
Table 2 Optimization of the Reaction Conditions for the Synthesis of 4aa
annulative
domino process
intramolecular
addition
– HX
O
O
O
enolate
hydrolysis
( )n
O
( )n
O
N
OH
+
N
N
N
O
O
O
O
2a
3a
R
O
4a
R
O
MX(n-1)
Time (h) Yield 4a (%)b
Scheme 2 Annulative domino reactions of enamines and MBH alcohols
Entry Additive
Solvent
T (°C)
1
2
3
4
none
none
none
none
r.t. → 40
r.t.
24
24
24
3
none
none
none
90
The enamines 2a–c were prepared by the reaction be-
tween the corresponding ketones 1a–c and morpholine un-
der conventional reaction conditions20,24 (Table 1).
CH2Cl2
CH2Cl2
CH2Cl2
reflux
reflux
ZnBr2 (3 equiv)
a Reagents and condition for optimized conditions: cyclic MBH alcohol 3a
(1.5 mmol, 1 equiv), enamine 2b (5 equiv) ZnBr2 (3 equiv), CH2Cl2, reflux.
b Isolated yield.
Table 1 Synthesis of Enamines 2a–c from the Reaction of Ketones 1a–
c with Morpholinea
O
We believe that the mechanism of this reaction involves
the initial conjugate addition of enamine 2a to the ZnBr2-
activated MBH adduct 3a to afford the corresponding imini-
um intermediate I, followed by intramolecular addition25,26
of the zinc alkoxide function to the transiently formed
iminium ion to give the N,O-ketal zinc enolate II. Final hy-
drolytic quench affords the N,O-ketal 4a18,27 (Scheme 3, Ta-
ble 2, entry 4). From a mechanistic viewpoint, it is worth
noting that the role of ZnBr2 in the present reaction is dif-
ferent from that of our previous study.20 Indeed, while in
our previous study ZnBr2 triggered the generation of a η3-
allyl palladium complex, in this study it is expected to be
involved in the conjugate addition step as well as the subse-
quent cyclization onto the iminium ion.
O
O
N
p-TSA
( )n
R1
+
( )n
toluene, reflux
N
H
R1
1a: n = 1, R1 = H
1b: n = 2, R1 = H
1c: n = 2, R1 = Me
2a
2b
2c
Entry
1
Enamine 2
Reaction time (days) Yield 2 (%)b
N
O
3
4
1
60
70
65
2a
N
O
2
3
2b
O
N
O
H
O
H
H
H
N
C
A
2c
A
C
A
H
H
ul
B
C
a Reaction conditions: ketone 1a–c (1.0 equiv), morpholine (1.5 equiv), p-
toluenesulfonic acid (2 equiv), toluene.
b Isolated yield.
ZnBr
Br
N
O
O
ZnBr
N
O
O ZnBr
Br
H+
Zn
Br
2a
OZnBr
I
O
O
II
H2O
3aOZnBr(ZnBr2)
We then explored the reaction between MBH alcohol 3a
(1 equiv) and enamine 2a (1 to 5 equiv) as the model reac-
tion. At room temperature, or at 40 °C, under solvent-free
conditions, and without any additive, the starting materials
were always recovered (Table 2, entry 1). The same result
was obtained using CH2Cl2 as the solvent at room tempera-
ture or at reflux for 24 h (entries 2 and 3). Extensive further
experimentation allowed us to establish the optimized con-
H
9b 9a
3a B 5a
H
C
A
H
N
O
O
4a
4a
O
Scheme 3 Proposed mechanism for the domino reaction 2a + 3a to
give 4a and X-ray crystal structure of 4a. Thermal ellipsoids are shown
at 30% probability.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
G. Bouhalleb et al.
Letter
Synlett
The structure of the N,O-ketal 4a as well as the nature of
the A/B and B/C ring junctions were elucidated on the basis
of X-ray diffraction analysis. Notably, the domino reaction
generates, in a single operation, four contiguous stereogenic
centers (3aR*,5aR*,9aS*,9bR*) with complete diastereose-
lection. Such a selectivity is determined in the course of
three separate steps. Indeed, the relative stereochemistry at
C9a/C9b is determined during the 1,4-addition, which takes
place with ul topicity, while center C3a is determined in the
subsequent alkoxide addition to the iminium ion. Finally,
the stereochemistry at C5a is decided during the hydrolytic
enolate quench. The A/B trans junction for compound 4a is
consistent with the work of Alexakis28 on conjugate addi-
tions to -substituted cyclic enones. The observed selectivi-
ty for the cis-fusion of the B/C rings is not surprising, being
the result of a 6-exo-trig-nucleophilic addition on a five-
membered electrophilic substrate. This is also in line with
the work of Kobayashi and co-workers,18 who showed that
the treatment of 2-hydroxymethyl-1,4-naphthoquinone
with morpholine enamines afforded exclusively cis-3-mor-
pholino-3,4-dihydro-1H-naphthopyran-5,10-diones.
To examine the scope of this reaction, a variety of differ-
ently substituted (R2 = H, Me, Ph) six- and five-membered
cyclic MBH alcohols 3a–d were selected and their behavior
towards enamines 2a–c was investigated, under the previ-
ously optimized conditions (ZnBr2 (3 equiv), dichlorometh-
ane, reflux) (Table 3, entries 2–12). Thus, the addition of
enamines 2b and 2c was also successfully performed with
six-membered cyclic alcohol 3a (n = 2, R2 = H), providing 4b
and 4c in 87 and 80% yields, respectively (entries 2 and 3).
Moreover, the reaction of enamines 2a–c with five-mem-
bered cyclic alcohol 3b (n = 1, R2 = H) worked well, furnish-
ing, within 4–5 h, the N,O-ketals 4d–f in 55–58% yields (en-
tries 4–6).
These interesting results prompted us to also investigate
the behavior of -substituted cyclic MBH alcohols 3c,d (n =
2, R2 = Me, Ph) towards enamines 2a–c to elucidate the pos-
sible effect of steric hindrance at the ′-carbon on the
course of the reaction. Under the optimized conditions, we
observed that the optimized protocol still works well, lead-
ing to the N,O-ketals 4g–l in 60–75% yields (entries 7–12).
It is notable that the isolated yields of adducts 4g–l (60–
75%), using ′-substituted alcohols 3c and 3d (n = 2, R2 =
Me, Ph) (Table 3, entries 7–12) are lower than those of 4a–c
(80–90%), starting from the alcohol 3a (n = 2, R2 = H) (en-
tries 1–3). We believe that the presence of a substituent at
the ′-position of alcohols 3c and 3d may introduce a mod-
erate steric hindrance responsible for the yield decrease in
4g–l.
by an intramolecular addition of the zinc alkoxide to the
iminium ion. Since N,O-ketals are known for their interest-
ing biological activities as well as their use as precursors for
complex molecules,30 in vitro biological activity tests for
the derivatives 4a–l are in progress in our laboratory. More-
over, compounds 4a–l can be regarded as masked 1,5-dike-
tones, the deketalization of which would generate the cor-
responding open 1,4-addition adducts.27 In future work, we
plan to expand the scope of this protocol to include noncy-
clic MBH adducts31 and a variety of enamines using various
catalysts.20,32–34
Table 3 Annulative Domino Reactions of Enamines 2a–c and Cyclic
MBH Alcohols 3a–da
O
R2
O
R2
O
ZnBr2 (3 equiv)
CH2Cl2, reflux
N
O
O
N
OH
+
n
n
n
n
R1
R1
3a–d
2a–c
4a–l
n = 1, 2; R2 = H, Me, Ph; R1 = H, Me
Entry Alcohol Enamine Time N,O-Ketal 4
Yield 4
3
2
(h)
(%)b
O
O
O
N
1
2
3a
3a
2a
2b
3
90
87
4a
4b
O
O
O
N
5
O
O
O
N
3
3a
2c
4
80
4c
O
O
O
N
4
5
3b
3b
2a
2b
5
5
55
57
4d
O
In conclusion, we have described an efficient synthetic
route toward polycyclic functionalized N,O-ketals 4a–l29 via
a ZnBr2-promoted annulation between morpholine enam-
ines and cyclic MBH alcohols. The mechanism of this trans-
formation is proposed to involve an initial conjugate addi-
tion of the enamine to the ,-unsaturated ketone followed
O
O
N
4e
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
G. Bouhalleb et al.
Letter
Synlett
Table 3 (continued)
Funding Information
Entry Alcohol Enamine Time N,O-Ketal 4
Yield 4
The authors thank the DGRST, the Tunisian Ministry of Higher Educa-
tion for financial support.()
3
2
(h)
(%)b
O
O
O
N
Supporting Information
6
3b
2c
4
58
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707467.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
4f
References and notes
O
O
O
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N
7
8
3c
3c
2a
2b
4
6
67
60
4g
4h
O
O
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N
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O
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O
N
9
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4i
O
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O
10
3d
2a
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N
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4j
(18) Kobayashi, K.; Uchida, M.; Uneda, T.; Yoneda, K.; Tanmatsu, M.;
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O
(19) Kobayashi, K.; Kosaku, N.; Toshikazu, O.; Miyuki, T.; Osamu, M.;
Hisatoshi, K. Synthesis 2003, 673.
(20) Bouhalleb, G.; Bouajila, J.; Rezgui, F. C. R. Chim. 2017, 20, 484.
(21) Katritzky, A. R.; Wu, H.; Xie, L.; Rachwal, S.; Rachwal, B.; Jiang,
J.; Zhang, G.; Lang, H. Synthesis 1995, 1315.
O
O
11
3d
2b
6
73
N
4k
(22) Katritzky, A. R.; Chen, J.; Belyakov, S. A. Tetrahedron Lett. 1996,
37, 6631.
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O
(24) Trost, B. M.; Verhoeven, T. R.; Wilkinson, G. (Ed.), Comprehensive
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O
O
12
3d
2c
7
75
N
(25) Golantsov, N. E.; Nguyen, H. M.; Golubenkova, A. S.; Varlamov, A.
V.; Van der Eycken, E. V.; Voskressensky, L. G. Front. Chem. 2019,
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3157.
4l
a Reaction performed using cyclic MBH alcohols 3 (1 equiv), ketoenamine 2
(5equiv), and ZnBr2 (3 equiv), CH2Cl2, reflux.
b Isolated yield.
Thieme. All rights reserved. Synlett 2020, 31, A–E

E
G. Bouhalleb et al.
Letter
Synlett
(28) Germain, N.; Guénée, L.; Mauduit, M.; Alexakis, A. Org. Lett.
2014, 16, 118.
13C NMR (CDCl3, 75 MHz):  = 212.1, 97.1, 67.3, 58.7, 46.8, 45.8,
41.8, 40.9, 39.0, 29.7, 28.3, 26.5, 22.6, 19.8. HRMS: m/z [M + H]+
calcd for C16H25NO3+: 280.1913; found: 280.1913.
(29) Synthesis of N,O-Ketals 4a–l; General Procedure: Under nitro-
gen, a mixture of cyclic MBH alcohols 3 (1.5 mmol), and ZnBr2
(4.5 mmol, 1.013 g) was heated to reflux in CH2Cl2 (10 mL) for
15 min. Then a solution of enamine 2a–c (7.5 mmol) in CH2Cl2
(5 mL) was added, and the reaction mixture was heated to
reflux for 3–6 h. After the evaporation of CH2Cl2, water (10 mL)
and aq NaOH (1 M, 30 mL) were added, and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were washed with a saturated solution of ammonium chloride
(10 mL) and dried over magnesium sulfate. After filtration and
removal of solvent, the residue was subjected to column chro-
matography, eluting with petroleum ether/ether/acetone =
40:40:20, to produce the pure N,O-ketals 4a–l.
4a-Morpholino-6-phenyldecahydro-1H-benzo[c]chromen-
1
7(10bH)-one (4k): Yield: 73%; white solid; mp 153–155 °C. H
NMR (CDCl3, 300 MHz):  = 7.84–7.82 (m, 2 H), 7.55–7.37 (m,
3 H), 4.26 (d, J = 12 Hz, 1 H), 3.64 (t, J = 4.5 Hz, 4 H), 3.16 (tt, J =
3, 6 Hz, 1 H), 2.54–2.35 (m, 4 H), 2.30–2.10 (m, 4 H), 1.88–1.43
(m, 7 H), 1.30–0.86 (m, 5 H). 13C NMR (CDCl3, 75 MHz):  =
209.3, 198.7, 137.9, 132.9, 128.6, 128.1, 67.8, 64.8, 61.9, 42.1,
40.7, 40.4, 26.2, 25.8, 25.5, 25.5, 23.9, 23.8. HRMS: m/z [M + H]+
calcd for C23H31NO3+: 370.2382; found: 370.2381.
(30) Zhu, Y.; Guo, J.; Jin, S.; Guo, J.; Bai, X.; Wang, Q.; Bu, Z. Org.
Biomol. Chem. 2018, 16, 1751.
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4229–4232.
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Angew. Chem. Int. Ed. 2014, 53, 6776.
3a-Morpholinodecahydrocyclopenta[c]isochromen-6(2H)-
one (4a): Yield: 90%; white solid; mp 146–148 °C. 1H NMR
(CDCl3, 300 MHz):  = 4.03 (t, J = 12 Hz, 1 H), 3.69 (t, J = 4.5 Hz,
4 H), 3.62 (dd, J = 6, 3 Hz, 1 H), 2.67–2.55 (m, 2 H), 2.42–227 (m,
5 H), 2.16–2.08 (m, 3 H), 1.81–1.69 (m, 4 H), 1.64–1.47 (m, 5 H).
(34) Ibrahem, I.; Cordova, A. Angew. Chem. Int. Ed. 2006, 45, 1952.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E