Assessing the utility of HAlCl2 derived vinylalanes for Michael addition

Article abstract of DOI:10.1016/j.tetlet.2014.01.105

Rare alkenylalanes are prepared by Cp₂TiCl₂ or Cp*₂ZrCl₂ (Cp = η-C₅H₅; Cp* = η-C₅Me₅) catalysed addition of HAlCl ₂·(THF)₂ to terminal alkynes (R

Full text of DOI:10.1016/j.tetlet.2014.01.105

Tetrahedron Letters 55 (2014) 1720–1721
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Assessing the utility of HAlCl2 derived vinylalanes for Michael
addition
Darren Willcox a, Humaira Gondal b, Marc Garcia Civit a, Simon Woodward a,
⇑
a School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
b Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
Rare alkenylalanes are prepared by Cp2TiCl2 or Cp*2ZrCl2 (Cp =
g-C5H5; Cp* = g-C5Me5) catalysed addi-
tion of HAlCl2Á(THF)2 to terminal alkynes (R1C„CH; R1 = alkyl). Use of minimum head-volume sealed
vials maximises the hydroalumination yields of volatile alkynes. Facile 1,4-addition of the resultant
alkenylalanes to unsaturated malonates R2CH@C(CO2R3)2 (R2 = alkyl, aryl, R3 = alkyl) is observed provid-
ing rapid and convenient access to the addition products.
Received 25 October 2013
Revised 9 January 2014
Accepted 22 January 2014
Available online 31 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Hydroalumination
Conjugate addition
Alkenes
Michael reaction
Malonate
Dichlorovinylalanes (1) are rare, but potentially quite useful,
organometallics the past application of which is limited to only
four publications covering the transformations shown in
Scheme 1.1–4 First prepared in 19611 by the reaction of
CH2@CHMgCl with AlCl3 they have lain dormant in the literature
for over 50 years. This was largely due to the fact that their only
selective preparation was by AlCl3 addition to Cp2Zr(alkenyl)Cl
Ar
AllylX
cat. Pd
ArX
R
R
cat. Pd
AlCl2
(Cp =
g
-C5H5).2 As the latter are simple Schwartz alkyne hydrozirc-
R
onation products5 already of high utility in subsequent couplings,
the additional transmetallation was deemed pointless by most
potential users. Recently, we have far easier access to 1 through
terminal alkyne hydroalumination with HAlCl2Á(THF)2 under either
AcCl
1
O
D
D2O
R
R
Cp2TiCl2 or Cp*2ZrCl2 (Cp* =
g
-C5Me5) catalysis (2–5 mol %).4 As
Scheme 1. Only known reactivity of dichloroalkenylalanes 1 (1961–2013) prior to
HAlCl2Á(THF)2 is readily available on at least 50 g scale (and has
the useful feature that it can be handled in air for brief periods),
alanes 1 warrant further investigation in their own right.
this study.
Our success in cross-coupling4 using 1 caused us to consider
other potential metal-promoted transformations, in particular
1,4-additions to Michael acceptors. In the absence of any prior
literature we considered additions to alkylidene malonates 2 as
initial substrates to screen alkenylalane additions, especially those
derived from more problematic volatile alkynes (Scheme 2). Alkyl-
idene malonates are powerful acceptors for (among other
reagents) allyl organometallics6 and cyclopentadienyl anions.7
AlCl2
Conditions 1
HAlCl2
+
5 mol%
Cp2TiCl2
or Cp*2ZrCl2
R1
R1
1
R3O2C
R2
CO2R3
CO2R3
CO2R3
Conditions 2
R2
R1
2
⇑
Corresponding author. Tel.: +44 (0)115 9513541; fax: +44 (0)115 9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
Scheme 2. Hydroalumination–Michael chemistry of this study.
http://dx.doi.org/10.1016/j.tetlet.2014.01.105
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

D. Willcox et al. / Tetrahedron Letters 55 (2014) 1720–1721
1721
Table 1
initial heating can cause significant escape of alkyne leading to
variable yields in normal Schlenk-ware under either Cp2TiCl2 or
Cp*2ZrCl2 catalysis (Table 1, Runs 1 and 2). Reducing the reaction
temperature and using higher concentrations are not effective
(Run 3) and little reaction occurs at room temperature. Fortu-
nately, these difficulties could be overcome using septa equipped
GC vials as minimum headspace ‘microreactors’ (see Supporting
information) (Runs 4 and 7). Optimum results were attained in
THF but slight excesses of HAlCl2 were required (Runs 6 and 7).
Additionally, the GC vial approach worked well for other alkynes
(volatile or otherwise) on 1 mmol scales (>90% yields).
Optimisation of t-BuC„CH hydroalumination (conditions 1)a
Run
Cat.a
Conditionsb
Yield of 1c (%)
Alk.c (%)
1
2
3
4
5
6
7
Ti
Zr
Ti
Ti
Ti
Ti
Ti
THF, 1.0 M, 1.4 Eq. 80 °C, Schk
THF, 1.0 M, 1.4 Eq. 80 °C, Schk
THF, 2.0 M, 1.4 Eq. 50 °C, Schk
Toluene, 1.0 M, 1.4 Eq. 70 °C, vial
DME, 1.0 M, 1.4 Eq. 70 °C, vial
THF, 1.0 M, 1.4 Eq. 70 °C, vial
THF, 1.0 M, 1.1 Eq. 70 °C, vial
34–93d
30–45d
31
2–7
2–3
3
1
2
85
63
94
53
3
6
a
Reactions carried out on 1.00 mmol (distilled) t-BuC„CH in 0.5–1.0 mL solvent;
Ti = Cp2TiCl2 (5 mol %), Zr = Cp*2ZrCl2 (5 mol %).
Additions of
1
(R1 = t-Bu) to diethyl 2-(2-methylpropylid-
b
Data in form: solvent, [alkyne], equivalents HAlCl2 (THF)2, temperature, carried
ene)malonate to afford 2a (R2 = i-Pr, R3 = Et) were used for optimi-
sation (Conditions 2, Table 2). Conversions into 2a were
determined by 1H NMR spectroscopy. Preliminary studies revealed
that ethereal solvents were optimal and chemoselectivity was
optimised at 0 °C (no C@O reduction through the slight excesses
of alane present in 1).
out in either a 5 mL volume Schlenk tube (Schk) or a 1.5 mL vial (vial).
c
Yield of 1 determined by GC after quench (HCl, 0 °C); Alk. = t-BuEt; mass bal-
ance is t-BuC„CH.
d
A range of yields was obtained.
Table 2
The conditions of Tables 1 and 2 were applied to a range of
substrate combinations leading to the isolated yields in Figure 1.
The 1,4-addition products were isolated in moderate to good yields
(16–85%) reflecting the electronic donor/acceptor properties of the
R2 groups. All additions to alkylidene malonates were spontaneous
needing no catalytic copper source, as has been found previously
for the acylcoumarins 3.8 Attempts at enantioselective additions
were not successful with a range of ligands due to these fast
background reactions. Conversely, analogous 1,4-additions to less
activated substrates (cyclohexenone, nonenone, b-nitrostyrene)
only proceeded in the presence of CuI catalysts, but not at practical
yields (<5%) under the present conditions.9
Optimisation of the 1,4-addition (conditions 2)a
Run
Eq. of 1
Time (h)
[Malonate] (M)
Conv. to 2ab (%)
1
2
3
4
5
1.0
1.0
3.0
3.0
2.0
2
2
1
2
2
0.5
0.7
0.5
0.5
0.5
16
61
58
97
98 (84)
a
Reactions carried out on 1 mmol 1 (prepared in THF, 1.0 mL followed by solvent
removal) and subsequent addition of diethyl 2-methylpropylidenemalonate (0.33–
1.0 mmol) in THF (0.5–1 mL).
b
Determined by GC versus internal standard, isolated yield in parentheses.
In summary, these 1,4-additions provide a simple one-pot
approach to addition products 2 as an alternative to palladium-cat-
alysed additions of malonates to allylic electrophiles.10
EtO2C
CO2Et
But
MeO2C
EtO2C
CO2Me
But
CO2Et
But
Acknowledgments
One of us (D.W.) thanks the University of Nottingham for a
studentship. H.G. is grateful for a Commonwealth Fellowship.
2a
84%
2b
2c
68%
64%
EtO2C
CO2Et
MeO2C
EtO2C
CO2Me
C6H13
CO2Et
Supplementary data
C6H13
Supplementary data (full experimental and spectroscopic data
for compounds 2) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
105.
C6H13
2d
73%
2e
2f
76%
85%
MeO2C
CO2Me MeO2C
CO2Me MeO2C
CO2Me
C6H13
Ph
References and notes
4-MeC6H4
But
Ph
But
1. Ramsden, H. E. US Patent 3010985, 1961, pp 7; Chem. Abstr. 1962, 57, 4100.
2. Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1979, 101, 3521–3531.
3. Bumagin, N. A.; Kasatkin, A. N.; Beletskaya, I. P. Izv. Akad. Nauk SSSR, Ser. Khim.
1984, 1858–1865.
2g
65%
2h
2i
48%
63%
4. Andrews, P.; Latham, C. M.; Magre, M.; Willcox, D.; Woodward, S. Chem.
Commun. 2013, 1488–1490.
5. Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910.
6. (a) Yamamoto, Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597–3603; (b) Fallan, C.;
Lam, H. W.; Quigley, P. F. J. Org. Chem. 2011, 76, 4112–4118.
7. (a) Filippini, M.-H.; Rodriguez, J. Synth. Commun. 1995, 25, 245–252; (b) Yang,
Y.; Chan, T. H. J. Am. Chem. Soc. 2000, 122, 402–403.
8. Tang, X.; Blake, A. J.; Lewis, W.; Woodward, S. Tetrahedron: Asymmetry 2009, 20,
1881–1891; Alkylidene malonate additions are limited to: Cahiez, G.; Venegas,
P.; Tucker, C. E.; Majid, T. N.; Knochel, P. Chem. Commun. 1992, 1406–1408.
9. For some improved conditions, see: Willcox, D.; Woodward, S.; Alexakis, A.
Chem. Commun. 2014, 50, 1655–1657. http://dx.doi.org/10.1039/C3CC48191C.
10. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944.
MeO2C
3-CF3C6H4
O
CO2Me
O
MeO2C
CO2Me
Ph
O
used in a
previous
study.
S
But
But
2k 72%
2j 16%
3
Figure 1. Isolated yields of 1,4-addition products (1 mmol scale).
Volatile t-BuC„CH (bp 37 °C) can be capricious under
hydroalumination4 at smaller scales (<5 mmol). Over vigorous