γ-Selective Vinylogous Aza-Morita-Baylis-Hillman Reaction with N -Carbamoylimines

Article abstract of DOI:10.1055/s-0039-1690787

Vinylogous aza-Morita-Baylis-Hillman (aza-MBH) reactions of a vinylcyclopentenone with N -Boc imines provide the corresponding γ-adducts in high regioselectivity (10 examples). While the corresponding reactions with N -Ts imines give the α-adducts and γ-a

Full text of DOI:10.1055/s-0039-1690787

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
N. Gondo et al.
Letter
Synlett
-Selective Vinylogous Aza-Morita–Baylis–Hillman Reaction with
N-Carbamoylimines
Naruhiro Gondo
Yusuke Tanigaki
Yoshihiro Ueda
O
O
NHTs
Ar
N
N
(DABCO)
O
N
N
(DABCO)
α
PG
α
N
0
0
0
0-0
0
0
2-5
4
8
5-2
7
2
2
NHBoc
Ar
+
γ
Ar
H
Takeo Kawabata*
γ
PG = Ts
PG = Boc
α-adduct
γ-adduct
previous report
this work
Institute for Chemical Research, Kyoto University, Gokasho, Uji,
Kyoto 611-0011, Japan
kawabata@scl.kyoto-u.ac.jp
α/γ = 1/14 to >20 (37–67%)
10 examples
Received: 03.12.2019
Accepted after revision: 12.12.2019
Published online: 03.01.2020
-Int was proposed to be the intermediate responsible for
both the - and -adducts, based on a H/D-exchange exper-
iment.6 The regiochemistry ( or ) of the Mannich-type C–
C bond formation was proposed to be controlled by the na-
ture of Nu (the catalyst) in -Int (Scheme 1, A).
Contrary to this phenomenon, we found that the use of
N-Boc-aldimines provided the -adducts as the major re-
gioisomers in vinylogous aza-MBH reactions, irrespective
of the catalyst (or promoter) (Scheme 1, C). In particular,
the DABCO-promoted vinylogous aza-MBH reactions be-
tween 1 and various N-Boc-aldimines provided the corre-
sponding -adducts almost exclusively. The obtained multi-
functionalized cyclopentenones are potentially useful
building blocks for biologically important cyclopentanone
derivatives.7
DOI: 10.1055/s-0039-1690787; Art ID: st-2019-u0645-l
Abstract Vinylogous aza-Morita–Baylis–Hillman (aza-MBH) reactions
of a vinylcyclopentenone with N-Boc imines provide the corresponding
-adducts in high regioselectivity (10 examples). While the correspond-
ing reactions with N-Ts imines give the -adducts and -adducts de-
pending on the catalyst, those with N-Boc imines proceed in a -selec-
tive manner, irrespective of the promoter. The nature of the protecting
groups on the nitrogen of the aldimines is found to play a key role in the
regiochemical course of vinylogous aza-MBH reactions.
Key words regioselectivity, vinylogous aza-Morita–Baylis–Hillman re-
action, DABCO, N-Boc imine, N-Ts imine
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is
an efficient carbon–carbon bond-forming reaction between
electron-deficient alkenes and aldimines to give functional-
ized allylamines.1 An advanced version of the aza-MBH re-
action using conjugated dienes with electron-withdrawing
groups has also been developed, which is useful for the con-
struction of further densely functionalized molecules.2
While the aza-MBH reaction with activated conjugated
dienes (the vinylogous aza-MBH reaction) can potentially
provide both the -adduct and the -adduct (Scheme 1, A),
it affords the -adduct in most cases.3,4 In the course of our
continuing efforts to study catalyst-controlled regioselec-
tive reactions,5 we previously developed the first example
of a regiodivergent vinylogous aza-MBH reaction in a cata-
lyst-controlled manner (Scheme 1, B).6 Treatment of 3-vi-
nylcyclopentenone 1 with N-Ts imine 2a in the presence of
1,4-diazabicyclo[2,2,2]octane (DABCO) provided -adduct
3a, exclusively. In contrast to the DABCO-catalyzed reaction,
the corresponding reaction catalyzed by N,N-dimethyl-4-
aminopyridine (DMAP) gave -adduct 4a with high regiose-
lectivity (Scheme 1, B). Although -Int and -Int could be
the intermediates for the -adduct (Scheme 1, A), dienolate
We initiated a study on the effect of the imine protect-
ing groups, since the stereochemistry of Mannich-type re-
actions has been known to be affected by the nature of the
protecting group on the imine.8 We found a totally different
regiochemical profile in the vinylogous aza-MBH reaction
of N-Boc imines from that with N-Ts imines. Treatment of 1
with N-Boc imine 2ba in the presence of DABCO in DMF at
20 °C for 24 hours unexpectedly gave the -adduct 4ba in
high regioselectivity (/ = 1:14) in 39% yield (Table 1, entry
1). Various Lewis bases9 were then examined for the reac-
tion in DMF (entries 2–6). DMAP also promoted the reac-
tion in a -selective manner (/ = 1:5), albeit in a low yield
(7%) (entry 2). While 1,8-diazabicyclo[5,4,0]undec-7-ene
(DBU) or tributylphosphine (PBu3) did not promote the vi-
nylogous aza-MBH reaction (entries 3 and 4), bicyclic ter-
tiary amines such as quinuclidine and 3-quinuclidinol pro-
moted the reaction in a -selective manner to afford 4ba as
the major regioisomer (entries 5 and 6).
Thus, it was found that N-Boc imine 2ba underwent the
vinylogous aza-MBH reaction with 1 in a -selective man-
ner, irrespective of the Lewis base, while the regiochemical
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. Gondo et al.
Letter
Synlett
(vide infra). N-Boc-3-pyridylimine 2bi and N-Boc-2-naph-
thylimine 2bj also underwent vinylogous aza-MBH reac-
tions with 1 in a highly -selective manner. The reactions of
2bf, 2bh and 2bi with compound 1 proceeded in higher
yields in DMSO than those in DMF.
The effects of the benzaldimine nitrogen protecting
groups on the regioselectivity of the DABCO-promoted vi-
nylogous aza-MBH reactions of 1 are highlighted in Table 2.
In addition to the above-mentioned properties of N-Ts
imine 2aa and N-Boc imine 2ba (entries 1 and 2), N-Cbz
imine 2ca was found to show high -selectivity in the viny-
logous aza-MBH reaction (/=1/>20) (entry 3). The carba-
mate functionality seems to be essential for the -selectivi-
ty. Neither the -adduct or -adduct was obtained in the re-
A. General Scheme of the Vinylogous Aza-MBH Reaction
PG
H
O
O
NHPG
R
N
α
α
β
R
R
R
Nu
O
β-Int
α
α-adduct
R
+ catalyst (Nu)
γ
β
O
O
PG
H
δ
N
R
NHPG
R
starting material
B. Previous Work
γ
R
γ
R
δ
Nu
γ-adduct
δ-Int
O
Ts
N
+
Ar
H
action of
1
with benzaldimine 2da with
a
2a
1
diphenylphosphinyl (Dpp) group, probably due to the low
electrophilicity of this substrate.10 Thus, the nitrogen pro-
tecting group was found to play a key role on the reaction
path of the vinylogous aza-MBH reaction.
O
O
NHTs
α
Ar
NMe2
NHTs
Ar
γ
N
N
N
3a
only α
4a
(DABCO)
(DMAP)
O
α/γ = 1/7 to >20
C. This Work
Table 1 Optimization of the Conditions for the -Selective Vinylogous
Aza-MBH Reaction with N-Boc Imine 2ba
O
Boc
N
+
DABCO
NHBoc
Ar
γ
O
O
Ar
H
NHBoc
Ph
O
α
Lewis base
(1.0 equiv)
1
2b
4b
Boc
H
N
α/γ = 1/14 to >20
NHBoc
Ph
+
+
γ
solvent
20 °C, 24 h
Ph
Scheme 1 (A) The aza-MBH reaction of activated conjugated dienes.
(B) Catalyst-controlled regiodivergent vinylogous aza-MBH reaction. (C)
-Selective vinylogous aza-MBH reaction with N-Boc imine 2b
1
3ba
4ba
2ba
(2.0 equiv)
Entry
Lewis base
Solventa
Yield of 4ba (%)b /
1
2
DABCO
DMAP
DMF
39
1:14
course of the reaction of N-Ts imine 2a was dependent on
the Lewis base. Solvent effects were also examined in the
DABCO-promoted reaction (Table 1, entries 7–12). A strong
solvent dependency for the promotion of the reaction was
observed, and DMF and DMSO were found to be suitable
solvents (entries 1 and 12). The use of three equivalents of
2ba in DMF at an elevated temperature (50 °C) for a longer
reaction time (36 h) improved the yield of 4ba, retaining
the high -selectivity (entry 13, 52% yield, / = 1/14). An
attempt to use a catalytic amount (20 mol%) of DABCO re-
sulted in a very sluggish reaction (entry 14).
With optimized reaction conditions in hand, we next in-
vestigated the substrate scope (Scheme 2). N-Boc aromatic
aldimines with para-, meta-, and ortho-substituents 2bb–
bh underwent vinylogous aza-MBH reactions to give the -
adducts 4bb–bh in high regioselectivities (/ = 1/14 to >20)
and moderate yields (39–60%). N-Boc aromatic aldimines
with electron-withdrawing groups (2bb, 2bc, 2bd, and 2bg)
showed similar reactivity to those with electron-donating
groups (2be, 2bf, and 2bh). This observation may suggest a
mechanistic implication in which Mannich-type C–C bond
formation may not be involved in the rate-determining step
DMF
7
1:5
–
3
DBU
DMF
trace
trace
32
4
PBu3
DMF
–
5
quinuclidine
3-quinuclidinol
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMF
1:12
1:6
–
6
DMF
19
7
MeOH
acetone
MeCN
CH2Cl2
DMA
DMSO
DMF
trace
trace
trace
trace
26
8
–
9
–
10
11
12
13c
14e
–
1:10
1:17
1:14
1:8
45
52 (46)d
12
DMF
a Anhydrous solvents were used.
b Yield determined by 1H NMR analysis with 1,3-dinitrobenzene as an inter-
nal standard.
c Run with 3.0 equivalents of 2ba at 50 °C for 36 hours.
d Yield of isolated product.
e Run with 20 mol% of 2ba at 50 °C for 12 hours in the presence of 20 mol%
of DABCO.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
N. Gondo et al.
Letter
Synlett
The kinetic isotope effects in the vinylogous aza-MBH
reaction were also investigated (Figure 1). The reaction
rates were measured under pseudo-first order conditions
employing 10 equivalents of N-Boc imine 2ba. The reac-
tions of 1 with N-Boc imine 2ba in the presence of DABCO
proceeded with the rate: kH = 5.5 × 10–2 h–1. On the other
hand, deuterated substrate 1-,′,′,-d4 underwent the re-
O
O
Boc
H
N
NHBoc
γ
X
DABCO (1.0 equiv)
+
X
DMF (0.25 M)
50 °C, 36 h
2bb–bj
(3.0 equiv)
1
4bb–bj
O
O
O
action under the same conditions with the rate: kD
=
2.3 × 10–2 h–1. The estimated KIE value (kH/kD = 2.4) indi-
cates that the -C–H bond cleavage is involved in the rate-
determining step in the -selective vinylogous aza-MBH re-
action. The substrate scope shown in Scheme 2 suggests
that the electronic properties of the imines do not affect the
reaction paths, indicating that the Mannich-type C–C bond-
forming step is not expected to be involved in the rate-de-
termining step. These experimental data as well as reported
mechanistic studies11 suggest that the rate-determining
step of the present vinylogous aza-MBH reaction seems to
be the elimination step of the Lewis base via deprotonation
of the -C–H bond. However, the regio-determining step is
not yet clear. The marked difference in the regiochemical
course between the reactions with N-Boc imines and those
NHBoc
NHBoc
NHBoc
CF3
Cl
Br
4bb
4bc
4bd
57% (α/γ = 1/>20)
54% (α/γ = 1/>20)
48% (α/γ = 1/>20)
O
O
O
NHBoc
NHBoc
NHBoc
Cl
Me
OMe
49% (α/γ = 1/>20)a
4be
4bf
4bg
49% (α/γ = 1/14)
60% (α/γ = 1/>20)
O
O
O
NHBoc
Me
Table 2 The Effects of Different Protecting Groups on the Aldimines
NHBoc
N
NHBoc
O
O
NHPG
Ph
O
α
4bh
PG
H
4bi
4bj
N
39% (α/γ = 1/>20)a
NHPG
Ph
37% (α/γ = 1/>20)a
+
γ
DABCO (1.0 equiv)
67% (α/γ = 1/19)
+
Ph
DMF (0.25 M)
50 °C, 36 h
Scheme 2 Substrate scope of the -selective vinylogous aza-MBH re-
action. The yield indicates the isolated pure -isomer. a Run in DMSO.
2aa–da
(3.0 equiv)
α-adduct
3aa–da
γ-adduct
4aa–da
1
Entry
1b,c
Imine (PG)
Major product (yield)a
/
In order to gain mechanistic insights, the retro-Mannich
processes were examined (Scheme 3). Treatment of -ad-
duct 3ba under the conditions for the -selective vinylo-
gous aza-MBH reaction, except for the absence of the imine,
did not give -adduct 4ba, only recovery of 3ba (Scheme 3,
A). Similarly, conversion from -adduct 4ba into 3ba was
not observed (Scheme 3, B). These results indicate that a
retro-Mannich process was not involved in the vinylogous
aza-MBH reaction.
O
NHTs
O
O
α
S
N
Ph
>20:1
Ph
Ph
H
2aa (Ts)
3aa (68%)
O
O
N
O
2
NHBoc
1:14
γ
H
Ph
4ba (52%)
2ba (Boc)
O
A.
O
O
O
NHBoc
Ph
NHBoc
Ph
O
DABCO
(1.0 equiv)
α
α
N
O
+
+
NHCbz
3
4
1:>20
NHBoc
Ph
γ
γ
DMF
50 °C, 36 h
Ph
Ph
H
Ph
4ca (37%)
2ca (Cbz)
3ba
3ba (87%)
4ba (0%)
O
B.
O
O
O
Ph
Ph
NHBoc
P
DABCO
(1.0 equiv)
N
α
no adducts
–
Ph
NHBoc
Ph
NHBoc
H
γ
γ
DMF
50 °C, 36 h
2da (Dpp)
Ph
4ba (91%)
a Yield of isolated pure regioisomer.
3ba (0%)
4ba
b The reaction was carried out with 2.0 equivalents of 2aa at 20 °C for 9 h.
c Data quoted from reference 6.
Scheme 3 Examination of the retro-Mannich process
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
N. Gondo et al.
Letter
Synlett
(2) (a) Back, T. G.; Rankic, D. A.; Sorbetti, J. M.; Wulff, J. E. Org. Lett.
2005, 7, 2377. (b) Sorbetti, J. M.; Clary, K. N.; Rankic, D. A.;
Wulff, J. E.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3326.
(c) Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62, 461. (d) Clary, K. N.;
Back, T. G. Synlett 2007, 2995. (e) Duvvuru, D.; Betzer, J.-F.;
Retailleau, P.; Frison, G.; Marinetti, A. Adv. Synth. Catal. 2011,
353, 483. (f) Shuler, M.; Duvvuru, D.; Rateilleau, P.; Betzer, J.-F.;
Marinetti, A. Org. Lett. 2009, 11, 4406.
O
O
α’
α
H/D
Boc
H
D/H
D/H
H/D
NHBoc
N
DABCO (1.0 equiv)
+
γ
γ
H/D
Ph
DMSO-d6 (0.16 M)
2ba
20 °C
Ph
(10 equiv)
1 or 1-α,α’,α’,γ-d4
(1.0 equiv)
γ-adduct
4ba or 4ba-α,α’,α’-d3
(3) It was reported that the -adduct of an ,,,-unsaturated
lactone (a 4-alkenylcoumarin derivative) was obtained under
aza-MBH conditions with concomitant reduction of the ,-
double bond, see: Duvvuru, D.; Retailleau, P.; Betzer, J.-F.;
Marinetti, A. Eur. J. Org. Chem. 2012, 897.
(4) -Selective MBH reactions of ,-dialkylallenoates have been
reported, see: Selig, P.; Turočkin, A.; Raven, W. Synlett 2013, 24,
2535.
(5) Ueda, Y.; Kawabata, T. Top. Curr. Chem. 2015, 372, 203.
(6) Hyakutake, R.; Gondo, N.; Ueda, Y.; Yoshimura, T.; Furuta, T.;
Kawabata, T. Tetrahedron Lett. 2016, 57, 1321.
(7) (a) Heasley, B. Eur. J. Org. Chem. 2009, 1477. (b) Parr, B. T.;
Davies, H. M. L. Nat. Commun. 2014, 5, 4455.
Figure 1 Kinetic isotope effects in vinylogous aza-MBH reactions
(8) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev.
2011, 111, 2626.
with N-Ts imines is also unclear. Theoretical calculations to
aid in answering these questions are currently underway.
In summary, we have found that the nature of the pro-
tecting groups on the nitrogen of aldimines plays a key role
in the regiochemical course of vinylogous aza-MBH reac-
tions. While the reactions of vinylcyclopentenone 1 with N-
Ts imines in the presence of DABCO provided the -adducts
exclusively, those with N-Boc imines afforded the -ad-
ducts12 with high regioselectivity.
(9) Mayer, H.; Lakhdar, S.; Maji, B.; Ofial, A. R. Beilstein J. Org. Chem.
2012, 8, 1458.
(10) Appel, R.; Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240.
(11) (a) Buskens, P.; Klankermayer, J.; Leitner, W. J. Am. Chem. Soc.
2005, 127, 16762. (b) Raheem, I. T. Adv. Synth. Catal. 2005, 347,
1701. (c) Roy, D.; Patel, C.; Sunoj, R. B. J. Org. Chem. 2009, 74,
6936. (d) Yukawa, T.; Seelig, B.; Xu, Y.; Morimoto, H.;
Matsunaga, S.; Berkessel, A.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 11988. (e) Saunders, L. B.; Cowen, B. J.; Miller, S. J.
Org. Lett. 2010, 12, 4800. (f) Regiani, T.; Santos, V.; Godoi, M. N.;
Vaz, B. G.; Eberlin, M. N.; Coelho, F. Chem. Commun. 2011, 47,
6593. (g) Lindner, C.; Liu, Y.; Karaghiosoff, K.; Maryasin, B.;
Zipse, H. Chem. Eur. J. 2013, 19, 6429. (h) Verma, P.; Verma, P.;
Sunoj, R. B. Org. Biomol. Chem. 2014, 12, 2176.
Funding Information
(12) -Selective Vinylogous Aza-MBH Reaction; General Proce-
dure
This research was financially supported by the Japan Society for the
Promotion of Science (JSPS) [Grants-in-Aid for Scientific Research S
(JP26221301), Scientific Research B (JP18K14866) and Scientific Re-
search on Innovative Areas ‘Middle Molecular Strategy’
(JP18H04405)] and the Sasagawa Scientific Research Grant. N.G. ac-
knowledges financial support from the JSPS Research Fellowships for
DABCO (60 mol, 1.0 equiv) was added to a solution of diene 1
(60 mol, 1.0 equiv) and N-Boc imine 2b (0.18 mmol) in anhy-
drous DMF (0.24 mL) at room temperature and the resulting
mixture was heated to 50 °C. After stirring for 36 h, the reaction
mixture was partitioned between EtOAc and 1 N HCl. The layers
were separated and the aqueous phase was extracted with
EtOAc (×3). The combined organic layer was dried over Na2SO4,
filtered and concentrated in vacuo. The crude residue was puri-
fied by preparative thin-layer chromatography to obtain the
roughly separated product including the - and -adducts. The
ratio of - and -adducts was determined by 1H NMR spectros-
copy. The - and -adducts were separated carefully by prepar-
ative thin-layer chromatography to afford the pure -adduct.
tert-Butyl [2-(3-Oxocyclopent-1-en-1-yl)-1-phenylallyl]car-
bamate (4ba)
Young Scientists (JP19J14988).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690787.
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References and Notes
(1) (a) Wei, W.; Shi, M. Chem. Rev. 2013, 113, 6659. (b) Declerck, V.;
Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1.
Colorless oil; yield: 8.0 mg (46%). IR (neat): 3328, 2978, 2929,
1701, 1681, 1516, 1366, 1246, 1168, 866 cm–1 1H NMR (400
.
MHz, CDCl3):  = 7.35–7.24 (m, 5 H), 5.98 (s, 1 H), 5.90 (s, 1 H),
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
N. Gondo et al.
Letter
Synlett
5.66 (s, 1 H), 5.61 (d, J = 7.6 Hz, 1 H), 4.95–4.87 (m, 1 H), 2.92–
2.73 (m, 2 H), 2.46–2.32 (m, 2 H), 1.44 (s, 9 H). 13C NMR (101
MHz, CDCl3):  = 209.75, 170.79, 154.74, 143.97, 139.49, 129.79,
129.20, 128.35, 127.53, 119.49, 80.32, 57.04, 34.54, 28.57,
28.47. HRMS (ESI): m/z [M + Na]+ calcd for C19H23NO3Na:
336.1570; found: 336.1540.
2978, 1702, 1575, 1492, 1366, 1248, 1167, 888, 732 cm–1 1H
.
NMR (400 MHz, CDCl3):  = 7.35–7.27 (m, 2 H), 7.24–7.17 (m, 2
H), 5.97 (s, 1 H), 5.89 (s, 1 H), 5.60 (s, 2 H), 4.89 (s, 1 H), 2.92–
2.72 (m, 2 H), 2.41 (t, J = 5.1 Hz, 2 H), 1.44 (s, 9 H). 13C NMR (101
MHz, CDCl3):  = 209.52, 170.44, 154.69, 143.81, 138.16, 134.19,
129.84, 129.35, 128.84, 120.13, 80.58, 56.35, 34.55, 28.56,
28.46. HRMS (ESI): m/z [M + Na]+ calcd for C19H22NO3ClNa:
370.1180; found: 370.1182.
tert-Butyl [1-(4-Chlorophenyl)-2-(3-oxocyclopent-1-en-1-
yl)allyl]carbamate (4bb)
White amorphous powder; yield: 12 mg (57%). IR (neat): 3323,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E