Ti-mediated chemoselective conversion of cyanoesters and cyanoamides into β-aminoesters and 1-aza-spirolactams bearing a cyclopropane ring

Article abstract of DOI:10.1055/s-2003-36785

α-Cyanoesters or tertiary α-cyanoamides react with Grignard reagents and Ti(i-PrO)₄ to afford respectively β-aminoesters or amides, bearing a cyclopropane ring. Starting from β- or γ-cyanoesters, spirocyclopropanelactams are formed via an in situ cyclopropanation-lactamization sequence.

Full text of DOI:10.1055/s-2003-36785

LETTER
265
Ti-Mediated Chemoselective Conversion of Cyanoesters and Cyanoamides
into b-Aminoesters and 1-Aza-spirolactams Bearing a Cyclopropane Ring.
C
hemoselectiv
h
e
C
onversio
i
of Cy
l
anoest
i
ers and
p
Cyanoamide
p
s
e Bertus, Jan Szymoniak*
Réactions Sélectives et Applications, CNRS and Université de Reims, 51687 Reims Cedex 2, France
Fax +33(326)913431; E-mail: jan.szymoniak@univ-reims.fr
Received 2 December 2002
O
O
Abstract: α-Cyanoesters or tertiary α-cyanoamides react with
Ph
CN
Ph
Grignard reagents and Ti(i-PrO)4 to afford respectively β-amino
esters or amides, bearing a cyclopropane ring. Starting from β- or
γ-cyanoesters, spirocyclopropanelactams are formed via an in situ
cyclopropanation-lactamization sequence.
H
NBn2
NBn2
OEt
OH
1
2
3
Ph
Ph
NH2
H
Key words: cyclizations, cyclopropanes, nitriles, spiro com-
pounds, titanium
4
5
6
4 (60%) + 5 (4%)
4 (59%) + 6 (0%)
(a)
(b)
1 + 2
1 + 3
Recently, we developed a new synthetic method for pre-
paring primary cyclopropylamines from nitriles and Grig-
nard reagents in the presence of Ti(i-PrO)4 (Scheme 1).1,2
The described reaction is somewhat similar to the Kulink-
ovich synthesis of cyclopropanols from carboxylic
esters3,4 or carbonates,5 and the de Meijere reaction which
allows for the preparation of tertiary cyclopropylamines
from N,N-dialkyl carboxamides.6 In the Kulinkovich and
de Meijere reactions the intermediate oxatitanacycle rear-
ranges spontaneously, whereas in our reaction the inter-
mediate azatitanacycle contracts under Lewis acid
activation conditions (Scheme 1). However, despite this
difference, similar reagents and conditions are involved in
all reactions.
Scheme 2 Conditions: Ti(i-PrO)4 1.1 equiv, EtMgBr 2 equiv in
Et2O, then BF3⋅OEt2 2 equiv.
Since the reaction from nitriles had tolerated the presence
of an external ester or amide group, we next carried out a
series of reactions from functionalized nitriles, bearing an
ester, carbonate or amide group. The results are summa-
rized in Table 1.
Starting from α-cyanoesters 7 and 9, the cyclopropane-
derived β-alanine analogues 8 and 10 could be obtained
(entries 1 and 2).9 Similarly, α-cyanoamide 11 was con-
verted into the corresponding amide 12 (entry 3).10 There
is an increasing interest for new synthesis of substituted β-
amino acids.11 Readily available α-cyanoesters or -amides
appear as suitable starting materials for a direct prepara-
tion of β-amino acids bearing a cyclopropane ring.
-
BF3
1) EtMgBr
Ti(i-PrO)4
+
R
N
H2N
R
R
CN
(i-PrO)2Ti
2) BF3·OEt2
As for α-cyanoesters and -amides, the chemoselective cy-
clopropanation reaction also took place with the γ-cyano-
amide 13 to afford the corresponding aminocyclopropane
derivative 14 (entry 4). In contrast, when using cya-
noesters 15, 17 and 19 and carbonate 21 with a 2 or 3 atom
tether between C≡N and C=O groups, subsequent cycliza-
tion reactions occurred, even in the absence of additional
Lewis acid.12 As a result, azaspirocyclic lactams 16, 18
and 20 and oxazolidinone 22 were formed in good yields
(entries 5–8). Thus, starting from β-cyanoester 15, only
16 was obtained in 68% yield, without any trace of the
corresponding aminoester.13,14 Similarly, 17 gave the
corresponding spirocyclic lactam 18 in good yield. Inter-
estingly, the dicyanodiester 19 underwent twofold cyclo-
propanation-lactamization sequence to afford 20 (entry
7). Also the nitrile 21 bearing a carbonate group reacts
only on the cyano moiety giving directly the oxazolidi-
none 22 in 72% yield (entry 8).
Scheme 1
In this context, we attempted to study the chemoselectivi-
ty of the reaction employing nitriles in the presence of an
additional ester or amide groups.
Our investigation began with comparative intermolecular
tests of chemoselectivity. Thus, the reactions employing
nitrile 1, ester 2 and amide 3 were performed as depicted
in Scheme 2. Two reactions (a and b) were carried out in-
volving equimolar amounts of 1 and 2 or 1 and 3, respec-
tively. We noticed that cyclopropylamine 4 was the highly
major (reaction a) or even unique (reaction b) cyclopro-
pane-containing product in these cross experiments.7,8
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2003,0,02,0265,0267,ftx,en;D23202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

266
P. Bertus, J. Szymoniak
LETTER
More substituted cyclopropanes can also be obtained by
employing higher Grignard reagents. As an example, eth-
yl-substituted cyclopropane 23 was obtained by using n-
BuMgBr instead of EtMgBr (entry 9 vs. 5).
Table 1 Reaction of Grignard Reagents with Cyanoesters, Cyano-
amides and Carbonates Mediated by Ti(i-PrO)4
Entry Nitrile
Product
Yielda
O
O
O
O
In summary, by using the title reaction, we have presented
a new and easy access to cyclopropane-containing β-ami-
no acid derivatives and azaspirolactams.
NC
NC
1
35%
OEt
O
OEt
OEt
N
7
8
References
(1) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792.
(2) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965.
(3) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.;
Pritytskaja, T. S. Russ. J. Org. Chem. 1989, 25, 2027.
(b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.
Synthesis 1991, 234.
(4) For reviews, see: (a) de Meijere, A.; Kozhushkov, S. I.;
Savchenko, A. I. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002,
390. (b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
2000, 100, 2789.
2
51%
NC
H2N
OEt
9
10
O
O
NC
3
4
40%
H2N
N
11
12
(5) Lee, J.; Kim, Y. G.; Bae, J. G.; Cha, J. K. J. Org. Chem.
1996, 61, 4878.
O
46%b
NC
( )3
( )3
(6) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed.
Engl. 1996, 35, 413. (b) Lee, J.; Cha, J. K. J. Org. Chem.
1997, 62, 1584.
(7) Carboxylic esters have been demonstrated to be generally
more reactive towards the cyclopropanation reaction than
the corresponding amides, see: Cho, S. Y.; Lee, J.; Lammi,
R. K.; Cha, J. K. J. Org. Chem. 1997, 62, 8235.
(8) Under the same cyclopropanation conditions, the ester 2
alone or the amide 3 alone give cyclopropanol 5 (66% yield)
or cyclopropylamine 6 (40%) respectively, irrespective of
the addition of BF3⋅OEt2.
(9) No cyclopropane-containing product was obtained from
ethyl cyanoacetate, probably due to the presence of acidic
hydrogens.
NEt2
O
H2N
NEt2
13
14
5
6
68%c
63%c
O
O
N
NC
OEt
H
15
16
18
O
NC
( )3
OEt
N
H
17
(10) Typical procedure for the synthesis of 8, 10, 12 and 14: Ethyl
1′-aminobicyclopropyl-1-carboxylate 10: To a solution of
nitrile 9 (139 mg, 1 mmol) and Ti(i-PrO)4 (0.33 mL, 1.1
mmol) in anhydrous Et2O (5 mL), was added dropwise at
room temperature a solution of EtMgBr in Et2O (2 mmol).
After the mixture was stirred for 1 h, BF3·OEt2 (0.25 mL, 2
mmol) was added. After additional stirring for 30 min, water
(1 mL) was added, followed by 10% aq HCl (10 mL) and
CH2Cl2 (20 mL). A 10% aq NaOH 10% solution was added
to the resulting clear mixture until the pH became basic. The
product was extracted with CH2Cl2 (2 × 20 mL). The
combined organic extracts were dried (Na2SO4). After
evaporation of the solvent, the product was purified by flash
chromatography on silica gel (Et2O, then acetone) to afford
83 mg (49%) of 10 as a pale yellow oil. IR (KBr): 3373,
1719, 1311 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.35–
0.39 (m, 2 H), 0.60–0.69 (m, 4 H), 1.15–1.21 (m, 2 H), 1.26
(t, J = 7.1 Hz, 3 H), 2.15 (s, 2 H), 4.15 (q, J = 7.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 13.1, 14.2, 14.7, 30.5,
34.9, 60.5, 174.8. MS (EI, 70 eV), m/z (%): 169 (4, M+),154
(18), 140 (34), 123 (60), 112 (78), 94 (100).
O
O
CN
OEt
7d
60%b,c
EtO
NC
HN
NH
O
O
O
19
20
Et
Et
O
O
8
72%c
NC
O
OEt
N
21
H
22
Et
9e
15
74%c,f
O
N
H
23
a Isolated yields.
b Reaction performed in THF.
c Lewis acid is not required.
(11) For recent reviews on the use and preparation of β-amino
acids, see: (a) Steer, D. A.; Lew, R. A.; Perlmutter, P.;
Smith, A. I.; Aguilar, M. I. Curr. Med. Chem. 2002, 9, 811.
(b) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
d 2 equiv of Ti(i-PrO)4 and 4 equiv of EtMgBr were used.
e n-BuMgBr was used instead of EtMgBr.
f Diastereoisomeric ratio 82:18.
Synlett 2003, No. 2, 265–267 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Chemoselective Conversion of Cyanoesters and Cyanoamides
267
(12) Typical procedure for the synthesis of 16, 18, 20 and 22: 4-
Azaspiro[2.5]octan-5-one 18: To a solution of nitrile 17
(141 mg, 1 mmol) and Ti(i-PrO)4 (0.33 mL, 1.1 mmol) in
anhydrous Et2O (5 mL), was added dropwise at room
temperature a solution of EtMgBr in Et2O (2 mmol). After
the mixture was stirred for 1 h, water (1 mL) was added,
followed by CH2Cl2 (20 mL). The resulting precipitate was
removed and washed with CH2Cl2 (2 × 10 mL). The
(m, 2 H), 1.61–1.67 (m, 2 H), 1.83–1.95 (m, 2 H), 2.37 (t,
J = 6.7 Hz, 2 H), 7.08 (s, 1 H). 13C NMR (63 MHz, CDCl3):
δ = 12.8, 20.0, 30.9, 31.1, 35.8, 173.5. MS (EI, 70 eV), m/z
(%): 125 (38, M+), 96 (48), 82 (100).
(13) These spirocyclopropanelactams cannot be directly prepared
from cyclic imides using the same procedure (Grignard
reagent and titanium isopropoxide), since the resulting
titanaoxacyclopentanes do not lead to cyclopropane
formation. See: Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem.
Soc. 1997, 119, 8127.
(14) The spirolactam 16, being a γ-aminobutyric acid (GABA)
analogue, has already been prepared, in several steps. See:
Kordes, M.; Winsel, H.; de Meijere, A. Eur. J. Org. Chem.
2000, 3235.
combined organic extracts were dried (Na2SO4). After
evaporation of the solvent, the product was purified by flash
chromatography on silica gel (Et2O, then Et2O–MeOH,
95:5) to afford 80 mg (63%) of 18 as a white solid, mp 124–
125 °C. IR (KBr): 3183, 3058, 2951, 1655, 1404 cm–1. 1H
NMR (250 MHz, CDCl3): δ = 0.58–0.66 (m, 2 H), 0.69–0.76
Synlett 2003, No. 2, 265–267 ISSN 0936-5214 © Thieme Stuttgart · New York