Efficient reformatsky conjugate additions to alkylidene malonates and malonamides

Article abstract of DOI:10.1055/s-2007-970756

Conditions for the effective conjugate addition of Reformatsky reagents to activated α,β-unsaturated systems under thermal and microwave irradiation conditions have been identified. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970756

LETTER
733
Efficient Reformatsky Conjugate Additions to Alkylidene Malonates and
Malonamides
R
eformatsky Co
m
njugate
A
dditions
t
i
o
A
lky
l
lidene
i
e
tes
a
nd Malonam
B
ides entz,a Mark G. Moloney,*a Susan M. Westawayb
a
The Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)285002; E-mail: mark.moloney@chem.ox.ac.uk
b
GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 28 December 2006
EtO2C
O
EtO2C
O
R
Abstract: Conditions for the effective conjugate addition of
Reformatsky reagents to activated a,b-unsaturated systems under
thermal and microwave irradiation conditions have been identified.
BrZn
R
N
DMPU, THF,
1 h, r.t., 77%
N
O
O
Key words: organometallic reagents, addition reactions, zinc
Ph
Ph
R = CO2t-Bu, CN
1
Scheme 1
We have recently demonstrated that Reformatsky
reagents add efficiently in a conjugate sense to bicyclic
a,b-unsaturated lactam 1 with high diastereocontrol
(Scheme 1) to give pyroglutamate analogues.1,2 One of
the advantages of these reagents for conjugate addition is
their good nucleophilicity coupled with low basicity. The
success of these reactions prompted a literature search, the
result of which indicated that Reformatsky reagents have
been rarely used for conjugate additions.3,4 Most impor-
tantly, detailed studies by Daviaud5 and Gaudemard et
al.6,7 amongst others4,8–10 showed that conjugate additions
of Reformatsky reagents were sluggish and gave variable
yields (40–70%) depending both on the structure of the
Michael acceptor and the Reformatsky reagent, but for
which no consideration of diastereoselectivity or experi-
mental details were included. This compares with the con-
jugate addition of dialkyl zinc reagents, which is both
efficient and applicable to various a,b-unsaturated sys-
tems with excellent enantiocontrol.11–13 New methodolog-
ical approaches for the conjugate addition of enolates with
and without enantiocontrol has also been reported,14–16
and the application of indium(I)-mediated Reformatsky
reactions have also recently been described.17 Given the
potential synthetic utility of these products, and the cur-
rent interest in the development of novel version of the
Reformatsky reaction,18 it was considered of interest to re-
examine the reactivity of Reformatsky reagents in conju-
gate addition processes, and the results of this study are
reported here.
of the Michael acceptor was required for successful
carbon–carbon bond formation, and so alkylidene
malonate 2 was chosen as test substrate and tert-butyl
bromoacetate as precursor of the Reformatsky reagent
(Scheme 2). After some optimisation, the best results for
conjugate addition leading to the product 3 were obtained
by first preparing the required Reformatsky reagent using
ultrasonic irradiation of tert-butyl bromoacetate with zinc
in THF for 15 minutes, followed by addition of the alkyl-
idene malonate and overnight reflux; the reaction was
then worked up and the product obtained by chromatogra-
phy. The success of these conditions contrasted with the
need for the presence of DMPU which had been observed
in earlier cases.1 Although this reaction was slow and
required forcing conditions, an excellent yield of 87% of
product 3 was nonetheless obtained.19
EtO2C
Me
CO2Et
EtO2C
CO2Et
Me
Br
CO2t-Bu
Zn, THF
87%
CO2t-Bu
2
3
Scheme 2
This encouraging result led us to explore the scope of
the reaction. Malonate acceptors were chosen in which the
b-substituent was either methyl or aromatic groups. tert-
Butyl 2-bromopropionate and 2-bromopropionitrile were
used as precursors of the Reformatsky reagents, with the
reaction conditions as described above, and the results are
detailed below (Scheme 3 and Table 1). Reaction of di-
ethyl ethylidenemalonate with the appropriate Refor-
matsky reagent gave an excellent yield of product 4 (entry
1a) and a good yield of the bromonitrile 5 (entry 2a). In the
case of substituted arylidenemalonates, giving products
6–13, the p-chloro-substituted starting material gave the
best yield (entries 7a and 8a); however, the presence of a
methoxy substituent did not give high-yielding outcomes
Our initial study focused on the attempted addition of the
Reformatsky reagent from tert-butyl bromoacetate to a,b-
unsaturated esters. However, all attempts were unsuccess-
ful, and starting material was returned unreacted. This
contrasted with the high reactivity under these conditions
of the bicyclic a,b-unsaturated lactam 11,2 and of nitro-
styrenes.9 On this basis, it was clear that further activation
SYNLETT 2007, No. 5, pp 0733–0736
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970756; Art ID: D39706ST
© Georg Thieme Verlag Stuttgart · New York

734
E. Bentz et al.
LETTER
Table 1 Yields for Conjugate Addition of Reformatsky Reagents to Alkylidene and Arylidene Malonate Esters According to Scheme 3
Entry
R1
R2
Product
Conditionsa
Time
Yield (%)
1a
1b
2a
2b
Me
CO2t-Bu
4
reflux
microwave
reflux
overnight
15 min
overnight
12 min
99
99+
76
Me
CN
5
microwave
99+
3a
3b
4a
4b
Ph
Ph
CO2t-Bu
6
7
reflux
microwave
reflux
overnight
20 min
overnight
20 min
77
47
77
90
CN
microwave
5a
5b
6a
6b
p-MeOC6H4
p-MeOC6H4
CO2t-Bu
8
9
reflux
microwave
reflux
overnight
35 min
overnight
20 min
57
34
68
99+
CN
microwave
7a
7b
8a
8b
p-ClC6H4
p-ClC6H4
CO2t-Bu
10
11
reflux
microwave
reflux
overnight
20 min
overnight
20 min
82
92
76
91
CN
microwave
9a
9b
10a
10b
p-NO2C6H4
p-NO2C6H4
CO2t-Bu
12
13
reflux
microwave
reflux
overnight
20 min
overnight
20 min
47
b
CN
34
b
microwave
a Thermal reaction in refluxing THF; microwave with CEM Explorer Microwave with irradiation power set to achieve a temperature of 100 °C
for 10 min.
b Only degradation products obtained.
(entries 5a and 6a), and a p-nitro group significantly be responsible for its high reactivity. However, instead of
impeded the reaction (entries 9a and 10a). In the former simple addition products, the reaction between ethyl 2-
case, this may be due to electronic deactivation, and in (benzylcarbamoyl)-3-phenylacrylate [(E)-14] and the
the latter, competitive reduction of the nitro function. In Reformatsky reagent from tert-butyl 2-bromopropionate
these reactions, all the products were obtained as a mix- led to compound 15 (yield 36%, Figure 1) as a result of
ture of two diastereoisomers in approximately a 1:1 ratio, intramolecular cyclisation of the first formed addition
as shown by 13C NMR analysis; the lack of diastereoselec- product (Scheme 4). In this case, only the all-trans diaste-
tivity may be a result of the forcing conditions (extended reoisomer was isolated, as established by NOE analysis
reflux in THF) required to achieve the addition. In the (Figure 2). The same product was obtained when either
case of compound 11, isolation and crystallisation of one E- or Z-alkylidene 14a or 14b was used, and in similar
of the diastereomers permitted unequivocal structural yields (Z, 37%; E, 36%). This trifunctionalised glutarim-
characterisation by single-crystal X-ray analysis.20
ide (piperidine-2,6-dione) is a structural motif present in
many compounds with biological activities such as cyclo-
heximide (antibiotic) and thalidomide (treatment of
AIDS). The conjugate addition reaction of the Refor-
matsky reagent derived from bromoacetonitrile was much
less successful, giving multiple products, including a low
yield of the conjugate adducts 16 (37%) and as a mixture
of diastereomers. The addition of both of the Reformatsky
reagents derived from tert-butyl 2-bromopropionate and
bromoacetonitrile to ethyl 2-(benzylcarbamoyl)pent-2-
enoate (17) gave a mixture of 18, 19, and 20, respectively,
each as a complex mixture of diastereomers as determined
by NMR spectroscopic and mass spectrometric analysis.
R2
Me
Br
EtO2C
R1
CO2Et
Me
EtO2C
CO2Et
R1
R2 = CO2t-Bu, CN
Zn, THF
R2
R1 = Me, Ph, p-MeOC6H4,
see Table 1
p-ClC6H4, p-NO2C6H4
4–13
Scheme 3
In order to understand the large difference in reactivity of
bicyclic lactam 1 (Scheme 1) compared to the alkylidene
malonates shown in Scheme 3, it was of interest to pre-
pare the acyclic analogue 14 and examine its reaction with
Reformatsky reagents (Scheme 4). In this case also, the
reaction still required overnight reflux to be completed,
indicating that the ring strain of lactam 1 is most likely to
Given our recent success in promoting novel Zn(II)-medi-
ated reactions under microwave irradiation,21 and of
microwave accelerated processes in general,22–25 it was
considered to be worthwhile to examine conjugate addi-
tions of Reformatsky reactions under similar conditions.
When the addition of the Reformatsky reagent from tert-
Synlett 2007, No. 5, 733–736 © Thieme Stuttgart · New York

LETTER
Reformatsky Conjugate Additions to Alkylidene Malonates and Malonamides
735
Br
yield of product (entries 3b, 5b, 7). However, the presence
of the nitro group once again led only to degradation prod-
ucts (entries 9b and 10b). When this protocol (microwave
irradiation at 100 °C for 10 min) was used on benzylidene
malonamide (E)-14, the cyclised product 15 was obtained
in 47% yield and 27% of the starting material (E)-14 was
recovered. In this case, the reaction was cleaner, with no
degradation products, making the purification easier and
the overall yield better than with the reflux conditions.
O
O
EtO2C
Ph
(i)
EtO2C
Me
Zn, THF
(ii) heat
CO2t-Bu
NBn
NHBn
O
Ph
Me
14a (E)
14b (Z)
15
Scheme 4
H
H
We have shown that the conjugate addition of simple
Reformatsky reagents from bromoesters and bromo-
nitriles to a,b-unsaturated malonate esters under thermal
and microwave conditions is a viable process, but without
diastereocontrol. This process offers a viable synthetic
alternative to the conjugate addition of an allyl metal
followed by ozonolysis, replacing a two-step process by a
single step.
O
EtO2C
NBn
Ph
Me
H
O
Figure 1 NOESY correlations for 15
O
O
O
EtO2C
Ph
EtO2C
NHBn
CN
EtO2C
NBn
Acknowledgment
NHBn
Et
O
We gratefully acknowledge EPSRC and GSK for a DTA/CASE
award to E.B., EPSRC for funding (GR/T20380/01) and the EPSRC
Chemical Database Service at Daresbury.
Et
17
Me
16
Me
18
O
O
EtO2C
Et
EtO2C
Et
References and Notes
NHBn
Me
NHBn
CN
(1) Dyer, J.; Keeling, S.; Moloney, M. G. Tetrahedron Lett.
1996, 37, 4573.
CO2t-Bu
Me
(2) Brewster, A. G.; Broady, S.; Mills, C. E.; Heightman, T. D.;
Hermitage, S. A.; Hughes, M.; Moloney, M. G.; Woods, G.
A. Org. Biomol. Chem. 2004, 2, 1031.
(3) Moreau, J. L.; Frangin, Y.; Gaudemar, M. Bull. Soc. Chim.
Fr. 1970, 4511.
19
20
Figure 2
(4) Boersma, J. In Comprehensive Organometallic Chemistry,
Vol. 2; Wilkinson, G., Ed.; Pergamon: Oxford, 1982, Chap.
16.
(5) Daviaud, G.; Massy, M.; Migniac, P. Tetrahedron Lett.
1970, 11, 5169.
(6) Goasdoue, N.; Gaudemar, M. J. Organomet. Chem. 1972,
39, 17.
(7) Goasdoue, N. G. M. J. Organomet. Chem. 1971, 28, C9.
(8) Rathke, M. W.; Weipert, P. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, Chap. 1.8.
(9) Menicagli, R.; Samaritani, S. Tetrahedron 1996, 52, 1425.
(10) Ocampo, R.; Dolbier, W. R. Tetrahedron 2004, 60, 9325.
(11) Rimkus, A.; Sewald, N. Synthesis 2004, 135.
(12) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
2002, 1877.
(13) Schuppan, J.; Minnaard, A. J.; Feringa, B. L. Chem.
Commun. 2004, 792.
(14) Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura,
S.; Hashimoto, S. Tetrahedron 2003, 59, 7307.
(15) Bella, M.; Jørgenson, K. A. J. Am. Chem. Soc. 2004, 126,
5672.
butyl bromoacetate to the alkylidene malonate 2 was ex-
amined, a quantitative yield was obtained after optimisa-
tion of time and temperature. Even more interesting was
that simplified conditions proved to be highly effective:
thus, zinc, bromoacetates and alkylidene malonates in
THF were irradiated by microwave for 10 minutes at
100 °C to give, after quenching and purification, the de-
sired product (99+% yield). Under these conditions, the
Reformatsky reagent was formed in situ and reacted readi-
ly with the alkylidene malonate, thereby avoiding the sep-
arate Reformatsky reagent-forming step in the thermal
process. When these conditions were applied to the
previous examples, excellent overall results were ob-
tained (Scheme 3, Table 1), and for most of the reactions,
the yield was improved when compared to the thermal
process. Interestingly, the reaction using bromonitriles
was now better than bromoesters, contrary to the results
obtained under the classical thermal conditions, and this is
likely to be related to the higher dipole moment and lower
dielectric loss factors of nitriles over esters.26 In particu-
lar, the addition of the Reformatsky reagent from bro-
mopropionitrile gave excellent yields with arylidene
malonates independent of the substitution of the aromatic
group (entries 4b, 6b, 8b), whereas the addition of the 2-
bromopropionate needed an activated partner for a good
(16) Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Mañas,
M.; Sebastian, R. M.; Vallribera, A. Tetrahedron 2005, 61,
8598.
(17) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett.
2004, 6, 4475.
(18) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E.
M. Org. Lett. 2005, 7, 3821.
Synlett 2007, No. 5, 733–736 © Thieme Stuttgart · New York

736
E. Bentz et al.
LETTER
(19) Typical Procedure for the Reformatsky Reaction
1-tert-Butyl 3,3-Diethyl 2-methylpropane-1,3,3-
tricarboxylate (3)
column chromatography (PE–EtOAc, 70:30) to afford the
desired product 3 (60 mg, 100%). Rf = 0.50 (PE–EtOAc,
70:30). IR (film): nmax = 2980, 2938, 1732 (s), 1369, 1256,
1155 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.00 [3 H, d,
J = 6.8 Hz, C(2)CH3], 1.20 (6 H, t, J = 7.1 Hz, OCH2CH3),
1.39 [9 H, s, C(CH3)], 2.16–2.25 [1 H, m, C(1)H2], 2.41–
2.48 [1 H, m, C(1)H2], 2.65–2.72 [1 H, m, C(2)H], 3.32 [1 H,
d, J = 7.3 Hz, C(3)H], 4.12 (4 H, q, J = 7.1 Hz, OCH2CH3).
13C NMR (100.6 MHz, CDCl3): d = 14.0 (OCH2CH3), 17.2
[C(2)CH3], 27.9, 28.0, 28.1 [C(CH3)], 30.2 [C(2)], 39.9
[C(3)], 56.7 [C(1)], 61.2 (OCH2CH3), 80.4 [C(CH3)], 168.4,
168.4, 171.3 (C=O). MS (ESI+): m/z (%) = 325 (100)[M +
Na)+]. HRMS: m/z calcd for C15H26O6Na: 325.1627; found:
325.1610 [M + Na]+.
Zinc powder was activated by shaking with a sat. solution of
NH4Cl for 5 min, followed by washing with H2O, EtOH,
Et2O and then drying under high vacuum at r.t. for 3 h.
Thermal Conditions
To a suspension of activated zinc (350 mg, 5.4 mmol) in
THF (5 mL) were added a few crystals of iodine, followed
by tert-butyl 2-bromopropionate (520 mL, 3.2 mmol). The
mixture was sonicated at 35–40 °C for 15 min. With stirring,
diethyl ethylidenemalonate (2, 182 mL, 1.1 mmol) was
added and the mixture was sonicated at 35–40 °C for 15 min.
After 18 h at reflux, the mixture was quenched with a
solution of sat. NH4Cl (5 mL) and EtOAc (5 mL). The
organic layer was separated, dried over MgSO4, filtered and
concentrated under vacuum. The crude material was purified
by flash chromatography (PE–EtOAc, 90:10) to afford 1-
tert-butyl 3,3-diethyl 2-methylpropane-1,3,3-tricarboxylate
(3) as a yellow oil (283 mg, 87%).
(20) Crystal data and data collection parameters for compound
11: C17H20ClNO4, T = 150 K, M = 337.80, monoclinic,
a = 33.7267(9), b = 5.6388(2), c = 18.2387(5) Å,
V = 3458.36(18) Å3. Space group C2/c, Z = 8, Dx = 1.297
mg m–3, m = 0.240 mm–1 R = 0.0375, wR = 0.0399. The
compound was crystallised from EtOAc–PE.
Microwave Conditions
(21) Bentz, E.; Moloney, M. G.; Westaway, S. M. Tetrahedron
Lett. 2004, 45, 7395.
(22) Leadbeater, N. E. Tetrahedron 2006, 62, 4633.
(23) Coleman, W. F. J. Chem. Educ. 2006, 83, 621.
(24) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(25) Caddick, S. Tetrahedron 1995, 51, 10403.
(26) Hayes, B. L. Microwave Synthesis; CEM Publishing:
Matthews, NC, 2002.
To a suspension of activated zinc (65 mg, 1.0 mmol) in THF
(2 mL) were added a few crystals of iodine, followed by tert-
butyl 2-bromopropionate (97 mL, 0.6 mmol) and diethyl
ethylidenemalonate (37 mL, 0.2 mmol). The mixture was
placed into the microwave reactor to achieve a temperature
of 100 °C for 10 min. The reaction mixture was quenched
with a sat. solution of NH4Cl (3 mL) and extracted with
EtOAc (4 mL). The organic layer was dried over MgSO4,
filtered and concentrated. The residue was purified by flash
Synlett 2007, No. 5, 733–736 © Thieme Stuttgart · New York

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