Stereoselective Pd(0) catalysed five component cascade synthesis of complex Z,Z-bisallylamines

Article abstract of DOI:10.1039/c3cc00067b

Catalytic 5-component cascade chemistry provides an effective stereo- and regioselective route to novel multi-functional Z,Z-bisallylamines. The process, which is capable of considerable further extension, utilises ammonium tartrate as a novel ammonia source which avoids the use of ammonia gas or aqueous ammonia. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc00067b

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Stereoselective Pd(0) catalysed five component
cascade synthesis of complex Z,Z-bisallylamines†
Ronald Grigg,*a Sunisa Akkarasamiyo,ab Nutthawat Chuanopparat,ab
Elghareeb E. Elboray,ac Moustafa F. Aly,c Hussien H. Abbas-Temirek,c
Boonsong Kongkathipb and Ngampong Kongkathipb
Cite this: Chem. Commun., 2013,
49, 2007
Received 4th January 2013,
Accepted 29th January 2013
DOI: 10.1039/c3cc00067b
www.rsc.org/chemcomm
Catalytic 5-component cascade chemistry provides an effective
stereo- and regioselective route to novel multi-functional
Z,Z-bisallylamines. The process, which is capable of considerable
further extension, utilises ammonium tartrate as a novel ammonia
source which avoids the use of ammonia gas or aqueous ammonia.
Scheme 1 Products arising from allylic aminations.
Both ammonia and non-gaseous ammonia equivalents are well
known participants in catalytic cross-coupling amination reac-
tions with aryl/heteroaryl halides.1a–d For example NH4OAc and PtII catalyzed direct amination of allylic alcohols with aqueous
(NH4)2CO3 are well known ammonia sources.2a–h Methods ammonia.7b
employing ammonia include the Cu2O catalysed reaction of
In the PtII catalyzed amination the use of aqueous ammonia
ammonia with aryl/heteroaryl halides to afford primary and a triple solvent mixture (H2O, dioxane, MeOH) are essential
amines,3a and the reaction of aromatic halides with ammonia for delivering selective monoallylation whilst high concen-
(80 psi) plus Pd–Josiphos which produces a mixture of mono tration of ammonia cause partial deactivation of the catalyst.
and di-arylamines in a 17 : 1 to 50 : 1 ratio.3b Interestingly There are potentially three outcomes of the established allylic
Stradiotto et al. report aryl tosylates react at room temperature amination reactions (Scheme 1). Our interest in this area arose
to afford primary amines with their Pd/P–N catalyst system.3c from the potential of replacing the normal 2- and 3-component
The use of CuII or Pd0 catalysts can also give rise to indoles process, employing allylic substrates with a variable leaving
under appropriate conditions4a,b whilst CuII catalysts promote group (Scheme 1), by a 5-component allene cascade. This
amination of aryl halides5a and terpinic chlorides5b in water. A generates no leaving group and allows a significant increase
further sub-set of reactions attracting significant attention are in molecular complexity for exploiting biochemical space by
catalytic allylic aminations. Kobayashi and Nagano, employing concomitant installation of variety of aromatic/heteroaromatic
a Pd(PPh3)4 catalyst, reported the first successful use of aqueous substituents. A recent paper by our group reported 3- and
NH3 in asymmetric allylic amination.6a Hartwig’s group6b–f and 9-component cascades exploiting adamantane as a versatile
others have employed iridium catalysts with both ammonia and organic tecton.8
ammonia surrogates. Recently Ghorai et al.7a reported the allylic
We selected ammonium carbonate, tartrate and citrate as
substitution of alcohols by an electron deficient ammonia ammonium surrogates for our studies. To our knowledge the
surrogate catalysed by Re2O7 and Ohshima et al. disclosed the latter two have not been evaluated as ammonia surrogates. We
selected a panel of allenes (Chart 1) based on purine 1,
quinazolinone 2 and 3, thymidine 4 and uridine 5 cores,
chosen to illustrate the significant increase in molecular
a Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre,
School of Chemistry, University of Leeds, Leeds, LS6 9JT, UK.
complexity delivered by the cascade chemistry, together with
a panel of aryl/heteroaryl iodides (Chart 1). Initial optimization
E-mail: r.grigg@leeds.ac.uk; Fax: +44 (0)113 343 6501; Tel: +44 (0)113 343 6401
b Natural Products and Organic Synthesis Research Unit (NPOS), Department of
Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
c Department of Chemistry, Faculty of Science at Qena, South Valley University,
Qena, Egypt
with
1 and 6a (Scheme 2, Table 1) using Pd2dba3
(tris(dibenzylideneacetone)palladium (0)) and TFP (tri(2-furyl)-
phosphine)9 surveyed toluene, MeCN and dioxane as solvents
in the presence of ammonium carbonate at 80 1C. No reaction
occurred in toluene and dioxane whilst MeCN gave low yields
† Electronic supplementary information (ESI) available: Full characterisation of
all new compounds. See DOI: 10.1039/c3cc00067b
c
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Scheme 3 Plausible mechanism for Z,Z-bisallylamine synthesis.
Chart 1 Allene–aryl iodide cascade components.
of ammonia. Neither the tartrate carboxylate anion or the
alcoholic OH groups reacted as nucleophiles under these
conditions. The ability of urea to engineer transfer of dimethyl-
amine from DMF to the p-allyl intermediate in the cascade was
also briefly explored (Table 1, entry 9) and resulted in the
formation of 12aa (Scheme 2), a protected form of (B)
(Scheme 3), in 79% yield after 4 h.7b,10a,b Our hydroxylamine
cascades also deliver protected forms of (B).11 In all other cases
the cascade delivered the Z,Z-bisallylamine 12a (see ESI†).
We selected dibasic ammonium tartrate (3–6 mole
equivalents) in 5 : 1 dioxane–DMF for an in depth cascade
survey (Table 2), generating 30 products in yields ranging from
52–99%. Cascades employing 4-iodonitrobenzene gave, in
general, the quickest reactions (Table 2, compounds 12b, 13a,
14a and 15a, 57–82%), albeit that excess ammonium tartrate
was employed to generate products 12b and 15a. Reactions
employing 3-iodopyridine also worked well (Table 2, compounds
13e, 14d, 15f, 16c and 16e, 52–78%) despite the potential for
sequestration of the catalyst by the product. 2-Iodothiophene also
gave moderate to good yields (Table 2, compounds 12j and 13f,
66 and 65%, respectively).
Scheme 2 Cascade synthesis of complex Z,Z-bisallylamine 12a.
Table 1 Optimization of reaction conditions for cascade synthesis of complex
Z,Z-bisallylaminesa
Ammonium
Entry salt (equiv.)
Solvent
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
Carbonate (6) DMF–water (2 : 1)
Carbonate (6) DMF–water (1 : 2)
Carbonate (6) Dioxane–water (2 : 1)
3
7
8
58b
24b
65c
75
Tartrate (3)
Dioxane–water (5 : 1) 40
Carbonate (6) Dioxane–DMF (5 : 1)
24
22
22
23
4
63c
80
Tartrate (6)
Tartrate (3)
Citrate (6)
Urea (12)
Dioxane–DMF (5 : 1)
Dioxane–DMF (5 : 1)
Dioxane–DMF (5 : 1)
DMF–water (2 : 1)
Table 2 5-Component cascade synthesis of complex Z,Z-bisallylaminesa
77
77
79d
a
Allene (1 mmol), aryl iodide (1.2 mmol), Pd2dba3 (2.5 mol%), TFP
(10 mol%), K2CO3 (2 mmol), 100 1C (for tartrate and citrate), 80 1C
b
c
(for carbonate and urea). Reaction without K2CO3. Reaction with
d
K2CO3 or without K2CO3 gave the same results. Product 12aa.
and very slow reactions. Mixed solvents were more effective.
Reactions with ammonium carbonate (6 equiv.) in 2 : 1 DMF–
water or 1 : 2 DMF–water gave moderate to low yields of 12a
(Table 1, entries 1 and 2). Both ammonium carbonate (6 equiv.)
in 2 : 1 dioxane–water and dibasic ammonium tartrate
(3 equiv.) in 5 : 1 dioxane–water gave improved yields
(Table 1, entries 3 and 4). Ammonium carbonate, tartrate and
tribasic ammonium citrate in the presence of K2CO3 in 5 : 1
dioxane–DMF furnished good yields of 12a albeit with longer
reaction times (entries 5–8).
Table 1 indicates that when ammonium carbonate was
employed the addition of K2CO3 was unnecessary due to the
lower thermal stability of ammonium carbonate and the faster
liberation of ammonia under the reaction conditions (entries
1–3 and 5). In contrast reactions employing ammonium tartrate,
which has a high thermal stability compared to ammonium
carbonate, required addition of K2CO3 to enhance the liberation
c
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Table 2 (continued )
calculated pKa’s using the ACD/I-Lab web service give pKa’s
for the mono-allyl amine conjugate acids of 8.58–9.67 and 9.24
for ammonia.12
In summary, we have developed a facile and efficient five
component stereoselective cascade synthesis of complex
Z,Z-bisallylamines employing ammonium tartrate as a novel
ammonia surrogate. Our protocol displays broad functional
group compatibility, effects a substantial increase in molecular
complexity and the products offer multivalent tunable probes.
We acknowledge support from the Egyptian Government,
South Valley University, Leeds University, Thailand Research
Fund (TRF), Royal Golden Jubilee Program, the Center of
Excellence for Innovation in Chemistry (PERCH-CIC), Commission
on Higher Education, Ministry of Education and Kasetsart
University Research and Development Institute (KURDI).
Notes and references
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a
A mixture of allene (1 mmol), aryl iodide (1.2 mmol), Pd2dba3
(2.5 mol%), TFP (10 mol%), ammonium tartrate (3 mmol) and K2CO3
(2 mmol) in the presence of (5 : 1) dioxane : DMF (24 mL) at 100 1C.
b
Ammonium tartrate (6 equiv.) was used.
A plausible mechanism for the cascade (Scheme 3) starts
normally with oxidative addition followed by allene coordina-
tion and migratory insertion to furnish the p-allyl complex (A)
which is attacked by the generated ammonia to afford a mono-
allyl amine intermediate (B) which attacks the p-complex (A)
faster than ammonia to give the desired Z,Z-bisallylamine.
The created H–PdII–I species regenerates Pd0 via reductive
elimination in the presence of K2CO3. The mechanism requires
the intermediate allyl amine (B) to be more nucleophilic
than ammonia. This has already been commented on by
Hartwig1a,6b,c for Ir-catalysed allylic amination whilst Kobayashi
and Nagano6a reported optimization of a Pd-catalysed process
for mono-allylic aminations. We note, en passant, that the
9 V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585–9595.
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11 E. E. Elboray, C. Gao and R. Grigg, Tetrahedron, 2012, 68, 3103–3111
and references therein.
12 Predicted pKa values of the conjugate acids were calculated using
the ACD/I-Lab web service (ACD/pKa 12.0).
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2007--2009 2009