2,2-difunctionalization of alkenes via Pd(II)-catalyzed aza-Wacker reactions

Article abstract of DOI:10.1021/ol102956x

N-Ts and N-Boc derivatives of 1,2-diamines and 1,2-amino alcohols are shown to undergo efficient Pd(II)-catalyzed aza-Wacker reactions with a large range of electron-deficient alkenes. The resulting enamine intermediate generally undergoes cyclization with the second heteroatom to form 1,3-heterocycles. The sequence facilitates the rapid synthesis of saturated oxazolidines, imidazolidines, and their derivatives. Use of N-l-valinol derivatives results in highly diastereoselective reactions, where the net stereochemical outcome diverges between N-Ts and N-Boc.

Full text of DOI:10.1021/ol102956x

ORGANIC
LETTERS
2011
Vol. 13, No. 4
728–731
2,2-Difunctionalization of Alkenes via
Pd(II)-Catalyzed Aza-Wacker Reactions
Luke D. Elliott,† Joe W. Wrigglesworth,† Brian Cox,‡ Guy C. Lloyd-Jones,*,† and
Kevin I. Booker-Milburn*,†
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K., and
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, RH12 5AB, U.K.
guy.lloyd-jones@bris.ac.uk; k.booker-milburn@bristol.ac.uk
Received December 7, 2010
ABSTRACT
N-Ts and N-Boc derivatives of 1,2-diamines and 1,2-amino alcohols are shown to undergo efficient Pd(II)-catalyzed aza-Wacker reactions with a
large range of electron-deficient alkenes. The resulting enamine intermediate generally undergoes cyclization with the second heteroatom to form
1,3-heterocycles. The sequence facilitates the rapid synthesis of saturated oxazolidines, imidazolidines, and their derivatives. Use of N-L-valinol
derivatives results in highly diastereoselective reactions, where the net stereochemical outcome diverges between N-Ts and N-Boc.
Imidazolidines and oxazolidines are prevalent hetero-
cycles in natural products, in pharmaceuticals,1 and in
ligands of use in organometallic catalysis.2 In 2005, we
reported the first Pd(II)-catalyzed 1,2-diamination of dienes,
using ureas as the dinitrogen source.3 In an attempt to effect
an equivalent 1,2-alkoxyamination sequence, we have in-
vestigated the Pd(II)-catalyzed addition of a range of amino-
alcohol sources across a range of dienes and alkenes. The
results we obtained were unexpected, in that 2,2- rather than
1,2-addition was the dominant pathway. The development
of this novel process, which facilitates rapid synthesis of
saturated oxazolidines, imidazolidines, and their derivatives,
forms the subject of the work presented herein.
In initial experiments, we attempted to react 1,3-dienes,
simple alkenes (n-hexene; cyclohexene), and styrenes with
N-Ts-ethanolamine, using 10 mol % Pd(II), under the oxida-
tive conditions (benzoquinone, DME, 60 °C) that we had pre-
viously found successful for 1,2-addition of ureas3 (Scheme 1).
Of these substrates, only the parent styrene reacted to give
oxazolidine 2a, the product of an oxidative geminal functio-
nalization of the terminal alkenyl carbon, in modest yield
(28-36%). To our knowledge, this is the first example of such
an alkoxyamination sequence4,5 with alkenes, and as such, it
merited further investigation and development.
On changing to more electron-deficient alkenes, the reac-
tion proceeded much more readily, affording the corre-
sponding oxazolidines (2) in good yield (Table 1).
For example, N-Ts-ethanolamine (1, R = Ts) coupled
with butyl acrylate 3 (R0=CO2Bu) in under 2 h at 40 °C, to
† University of Bristol.
‡ Novartis Institutes for Biomedical Research.
(1) (a) Regunathan, S.; Reis, D. Annu. Rev. Pharmacol. Toxicol. 1996,
36, 511–544. (b) Tomizawa, M.; Casida, J. E. Annu. Rev. Pharmacol.
Toxicol. 2005, 45, 247–268. (c) Brown, D.; Evans, J. R.; Fletton, R. A.
Chem. Commun. 1979, 6, 282–283.
(2) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem.
Rev. 2000, 100, 2159–2231.
(4) For Pd(II) mediated reactions of alkenes with diols, see: (a)
Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S. J. Org. Chem.
1987, 52, 1758–1764. (b) Hosokawa, T.; Ohta, T.; Murahashi, S. Chem.
Commun. 1983, 15, 848–849.
(3) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308–7309.
(5) For previous synthesis of oxazolidines, see: Sriramurthy, V.;
Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928–12929.
r
10.1021/ol102956x
Published on Web 01/18/2011
2011 American Chemical Society

(1, R = Ts; Boc) both proceeded well under the standard
conditions with a range of monosubstituted electron-defi-
cient alkenes (entries 6-22).6 When the sulfonamide or
carbamate moieties were changed to the less NH-acidic
N-acyl derivative (entry 24) there was no reaction.
Scheme 1. 2,2-Alkoxyamination of Styrene
Table 2. Effect of Chain Length in the Aminoalcohol Derivatives
give oxazolidine 2b in 82% yield (Table 1, entry 1); indeed,
the reaction even proceeded at ambient temperature, with as
little as 2 mol % Pd, in under 18 h (entries 2-4). Attempts to
adopt lower catalyst loadings as optimal conditions resulted
in inconsistent yields, and as a result 10% catalyst loading
was used throughout the study. Interestingly, the alkoxy-
amination sequence was specific for monosubstituted alkenes
as no reaction was observed with methacrylates, crotonates,
or cycloalkenones.
entry
R
R0
n
5
yield (%)
1
2
Ts
CO2Bu
CO2Bu
CO2tBu
CO2Me
CO2H
1
1
1
1
1
1
2
2
2
2
5a
5b
5c
5d
5e
5f
83
17
39
71
32
37
13
30
9
Boc
Ts
3
4
Ts
A control reaction conducted in the absence of catalyst
(entry 5) confirmed the key role of Pd in the process. The
reactions of N-Ts-ethanolamine and N-Boc-ethanolamine
5
Ts
6
Boc
Ts
CO2H
7
CO2Bu
CO2Bu
CO2H
5g
5h
5i
8
Boc
Ts
9
10
Boc
CO2H
5i
14
Table 1. Oxyamination of Electron-Deficient Alkenes with
Ethanolamine Derivatives
We then explored the use of homologous reagents (4, n =
1, 2) to assess the scope for formation of six- and seven-
membered heterocycles (Table 2). With N-Ts propanol-
amine, good yields of 1,3-oxazinane 5 (R = Ts, n = 1) were
obtained with simple acrylates (entries 1 and 4). However, the
outcome with N-Boc propanolamine (entries 2 and 6) was
less clear-cut, with uncyclized Wacker-type products7 being
formed, in addition to 5 (R = Boc, n = 1). Yields of seven-
membered heterocycles 5 (R = Ts, Boc, n = 2) were gen-
erally poorer (entries 7-10) possibly due to the greater entro-
pic cost in cyclization.
Finally, we explored 2,2-diamination of electron-deficient
alkenes using N,N0-derivatized 1,2-ethylenediamine sources.
In general, the Boc disubstituted ethylenediamines gave
the best results. Overall, however, the reactions proved to
be less selective than with ethanolamines, since mixtures of
the imidazolidines 7 and the aza-Wacker products 8 were
obtained in moderate to good overall yield (Table 3).
Palladium-catalyzed intermolecular aza-Wacker addi-
tions to alkenes have been extensively studied by Stahl8
and others. We envisage an analogous aza-Wacker se-
quence (Scheme 2) for the first stage of the 2,2-alkoxyami-
nation reaction, with an off-cycle conjugate addition
leading to the final product (2). In this model, activation
of the electron-deficient alkene by coordination to Pd(II) is
entry
R
R0
product
yield (%)
1
Ts
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
2b
2b
2b
2b
2b
2c
2d
2e
2f
82a
75b
73c
78d
0e
2
Ts
3
Ts
4
Ts
5
Ts
6
Boc
Ts
60f
54f
69 f
39 f
67f
65g
26g
79f
72f
82f
63f
52f
62f
38f
53f
57f
18f
77f
0 f
7
CONMe(OMe)
CONMe(OMe)
CO(morpholinyl)
CO(morpholinyl)
SO2Ph
8
Boc
Ts
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Boc
Ts
2g
2h
2i
Boc
Ts
SO2Ph
CO2Me
2j
Ts
CO2tBu
2k
2l
Ts
CO2H
Boc
Ts
CO2H
2m
2n
2o
2p
2q
2r
2s
2t
CON(Me)2
CON(Me)2
CONHiPr
COMe
Boc
Ts
Ts
Boc
Ts
COMe
(6) In general the yields were moderate to good. In the case of the
lower yielding examples in Table 1, increasing the amount of alkene and/
or benzoquinone did not significantly improve overall yields.
(7) For example, see 13 in the Supporting Information.
CN
pNs
Ac
CO2Bu
CO2Bu
2u
(8) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
2003, 125, 12996–12997. (b) Brice, J. L.; Harang, J. E.; Timokhin, V. I.;
Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868–2869. (c)
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888–17893.
(d) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (e) Liu,
X.; Hii, K. K. Eur. J. Org. Chem. 2010, 27, 5181–5189.
a Catalyst loading: 10 mol %, 40 °C, 2 h. b Catalyst loading: 10 mol %,
21 °C, 18 h. c Catalyst loading: 5 mol %, 21 °C, 18 h. d Catalyst loading:
2mol%, 21°C, 18 h. e Catalyst loading: 0 mol %, 21 °C, 48 h. f Catalyst load-
ing: 10 mol %, 40 °C, 18 h. g Catalyst loading: 10 mol %, 60 °C, 18 h.
Org. Lett., Vol. 13, No. 4, 2011
729

electivity in the cyclization when the ethanolamine backbone
is appropriately substituted. To probe this issue we reacted
N-Ts- and N-Boc-L-valinol (10a and 10b) with butyl acrylate
and found complementary stereogenic outcomes (Figure 1).
Table 3. Diamination of Electron-Deficient Alkenes
entry
R
R0
7 (%)
8 (%)
1
Ts
CO2Bu
CO2Bu
7a (46)
7b (57)
7c (24)
7d (63)
7e (10)
7f (63)
7g (34)
7h (0)
8a (11)
8b (10)
8c (12)
8d (13)
8e (29)
8f (16)
8g (4)
2
Boc
Ts
3
CONMe(OMe)
CONMe(OMe)
CO(morpholinyl)
CO(morpholinyl)
SO2Ph
4
Boc
Ts
5
6
Boc
Ts
7a
8b
Boc
SO2Ph
8h (17)
a 70 °C, 48 h. b 60 °C, 48 h.
followed by amino-palladation leading to the σ-Pd(II) spe-
cies II. β-Hydride elimination leads to the enamide III and
Pd(0) which is then reoxidized by BQ to the active Pd(II)
catalyst. In the majority of cases, the final cyclization (IIIf2)
is efficient under the reaction conditions, such that no III or
IV accumulates. However, during a larger scale reaction
(Table 1, entry 10, 5 mmol of 3, 1% Pd), we were able to
isolate enamide 9. This proved to be stable on heating, but on
addition of 10 mol % (MeCN)2PdCl2 with no added BQ, it
underwent efficient cyclization to 2g. Similar reasults were
then observed with TsOH and BF3•Et2O. This suggests
Lewis or Bronsted acid catalysis for this step (IIIf2) under
the reaction conditions. A separate experiment showed
hydroquinone, a reaction coproduct, to be insufficiently
acidic in catalyzing the cyclization of 9 to 2g.
Figure 1. Oxyamination with N-L-valinol derivatives.
Analysis of the evolution of two reactions during the first
10 min revealed a constant 9/1 selectivity for the formation
of the anti isomer 12a, when R = Boc. The anti isomer was
also favored when R = Ts (12b), albeit with lower selectivity
(krel = 2). However, in contrast to 12a, the anti isomer 12b
epimerized, via pseudo-first-order equilibrium kinetics, to
eventually give almost pure syn-11b (Keq > 98). No enamide
(III) or enol ether (IV) intermediates were detected, and
neither (MeCN)2PdCl2 (10 mol %) nor hydroquinone
(1 equiv) had any effect on reference samples of anti-12b/
syn-11b in DME. However, under the reaction conditions
(Figure 1) the rate of epimerization of 12b to 11b was found
to be inversely dependent on the stoichiometry of the benzo-
quinone. This suggested that increasing the efficiency of
Pd-reoxidation ([Pd(0)] þ BQ þ 2 HCl f [Pd(II)]Cl2 þ
hydroquinone) reduces the concentration of free HCl and
thus the rate of epimerization via a ring-opened oxonium
intermediate. This conclusion was supported by the observa-
tion of a rapid increase in the rate of epimerization when 10
mol % anhydrous HCl was added to the reaction.
The prochiral nature of intermediate III raises interesting
questions concerning kinetic and thermodynamic diastereos-
Scheme 2. Proposed Pd(II)-Catalyzed Aza-Wacker Mechanism
and Acid-Catalyzed Cyclization of 9
In summary, we report an oxidative aza-Wacker meth-
odology for the conversion of electron-deficient alkenes into
functionalized, saturated heterocycles. The reaction has
broad scope for a range of amino-alcohol and diamine
nucleophiles. Reactions with valinol nucleophiles show an
interesting switch in diastereoselectivity, and further studies
on the mechanism of this process, including other amino acid
derived substrates, will be reported in full in due course.
730
Org. Lett., Vol. 13, No. 4, 2011

Acknowledgment. We thank Novartis for provision of a
PhD studentship to J.W.W. and EPSRC for funding (EP/
E061575/1). G.C.L.J. is a Royal Society Wolfson Research
Merit Award Holder.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
731