Ruthenium-catalyzed cascade N- and C(3)-dialkylation of cyclic amines with alcohols involving hydrogen autotransfer processes

Article abstract of DOI:10.1002/adsc.201000546

An unprecented N- and C(3)-dialkylation of unactivated amines by a cascade reaction via borrowing hydrogen methodology using new (arene)ruthenium(II) complexes featuring phosphinosulfonate ligands is described. This reaction is highly regioselective and produces water as the only side product. Copyright

Full text of DOI:10.1002/adsc.201000546

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DOI: 10.1002/adsc.201000546
Ruthenium-Catalyzed Cascade N- and C(3)-Dialkylation of
Cyclic Amines with Alcohols Involving Hydrogen Autotransfer
Processes
Basker Sundararaju,a Zhou Tang,a Mathieu Achard,a Gangavaram V. M. Sharma,b
Loꢀc Toupet,c and Christian Bruneaua,*
a
UMR6226 CNRS – Universitꢁ de Rennes, Sciences chimiques de Rennes, Catalyse et Organomꢁtalliques, Campus de
Beaulieu, 35042 Rennes Cedex, France
Fax : (+33)-2-2323-6939; e-mail: christian.bruneau@univ-rennes1.fr
Organic Chemistry Division III, D 211, Discovery Laboratory, Indian Institute of Chemical Technology (CSIR),
b
Hyderabad – 500007, India
c
UMR 6251 CNRS – Universitꢁ de Rennes, Institut de Physique de Rennes, Campus de Beaulieu, 35042 Rennes Cedex,
France
Received: July 12, 2010; Revised: September 10, 2010; Published online: December 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000546.
Abstract: An unprecented N- and C(3)-dialkylation
of unactivated amines by a cascade reaction via bor-
rowing hydrogen methodology using new (arene)ru-
thenium(II) complexes featuring phosphinosulfo-
nate ligands is described. This reaction is highly re-
gioselective and produces water as the only side
product.
ed products arising from alcohols,[11–14] a one-step pro-
cess for the simultaneous alkylation of both the N
atom and the unactivated C(3) carbon of secondary
amines is so far unknown and corresponds to a formal
À
C H activation for the later. Such modifications are
of a great interest and would afford new routes to get
access to functionalized amines of known biological
interest[15] which usually require multistep synthe-
ses.[16]
Herein, we report an unprecedented N- and C(3)-
dialkylation of unactivated cyclic amines in the pres-
ence of new ruthenium precatalysts based on phos-
Keywords: borrowing hydrogen; homogeneous cat-
alysis; hydrogen autotransfer; P,O chelates; rutheni-
um
AHCTUNGTREGpNNNU hinosulfonate ligands acting as P,O chelates, involv-
ing the borrowing hydrogen methodology. During the
course of our studies on the applications of N,O- and
The N-alkylation of amines with alcohols via a hydro- P,O-chelating ligands in ruthenium-catalyzedreac-
gen autotransfer strategy using homogeneous or het- tions,[17] we synthesized in good yields the new
erogeneous ruthenium,[1,2] iridium,[3,4] copper,[5] plati-
ACHTUNGTREN(NUNG arene)ruthenium(II) complexes A and B featuring
num,[6] nickel,[7] rhodium,[1b,8] or iron[9] catalysts has phosphinobenzenesulfonate ligands 1a and 1b starting
[10]
À
become a powerful tool for N C bond formation.
from [RuACTHGUNTRENNU(G p-cymene)Cl2]2 (Scheme 1). Crystal struc-
À
Likewise, C C bond formation reactions have also
been investigated starting from carbonucleophiles or
ylides with alcohols by a similar strategy.[11–14] This
transformation involves the conversion of alcohols
into aldehydes or ketones as transient intermediates
via an oxidative hydrogen elimination. The in situ
generated carbonyl groups are reactive towards nucle-
ophiles such as amines and lead to the formation of
iminium cationic species or imines, affording the ex-
pected N-alkylated amines after reduction, with water
as sole side product. Although several examples
adopting this strategy have been documented for the
construction of N-alkylated amines,[1–10] and C-alkylat- Scheme 1. Preparation of complexes A and B.
Adv. Synth. Catal. 2010, 352, 3141 – 3146
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Figure 1. Structures of A and B·2CH2Cl2 at 50% probability ellipsoids. All hydrogen atoms and solvent are omitted for clari-
À
À
À
À
ty. Selected bond lengths [ꢃ] and angles [8]. Complex A: Ru(1) Cl(1) 2.399, Ru(1) P(1) 2.357, Ru(1) O(3) 2.118, P(1)
À
À
À
À
À
À
À
Ru(1) O(3) 90.71, O(3) Ru(1) Cl(1) 80.85. Complex B: Ru(1) Cl(1) 2.401, Ru(1) P(4) 2.368, Ru(1) O(1) 2.127, P(4)
À
À
À
Ru(1) O(1) 79.92, O(1) Ru(1) Cl(1) 89.35.
tures of these complexes revealed that the phosphino-
The results from the initial evaluation of the preca-
sulfonate coordinates as a bidentate ligand through talysts A and B in the N-alkylation of amines are pre-
the phosphine and one oxygen atom (Figure 1).[18]
sented in Table 1. Reaction of 1 equivalent of benzyl
alcohol 2a with pyrrolidine 3a in the presence of
Table 1. N-alkylation and N- and C(3)-dibenzylation of pyrrolidine 3a with benzyl alcohol 2a.[a]
Entry
Catalyst
Additive[b]
Solvent
4a/5a
Conversion[c]
1
A
A
B
B
B
B
B
B
B
B
B
none
none
none
none
toluene
neat
toluene
water
97/3
100/0
93/7
65%
95% (92)
80%
85%
93%
99%
99%
99%
99%
2[d]
3
4
5
100/0
83/17
40/60
37/63
31/69
25/75
12/88
25/32
none
neat
6[e]
7[e]
8[e]
9[e]
10[e]
11[e]
CSA (10)
CSA (15)
CSA (20)
CSA (30)
CSA (40)
CSA (100)
toluene
toluene
toluene
toluene
toluene
toluene
99% (80)
15%
[a]
Reactions were carried out at 0.9M concentration (except entries 2 and 4) with 2a/3a/precatalyst in a 1/1.1/0.025 molar
ratio under an inert atmosphere using a thermostated oil bath at 1508C (except entry 2).
Amount of additive in mol%.
[b]
[c]
Conversion based on GC analysis (tetradecane as internal standard), number in parentheses is isolated yield of the major
compound (4a in entry 2 and 5a in entry 10).
[d]
[e]
Reaction performed with 2a/3a/A in a 1.05/1.0/0.010 molar ratio at 1008C.
Reaction performed with 2a/3a/B in a 2.5/1.0/0.015 molar ratio at 1508C, CSA=camphorsulfonic acid (mol% with respect
to 3a).
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Ruthenium-Catalyzed Cascade N- and C(3)-Dialkylation of Cyclic Amines with Alcohols
2.5 mol% of A and B (entries 1 and 3) in toluene at formation of the ammonium sulfonate in order to
1508C for 16 h afforded the N-alkylated amine 4a in achieve complete conversion, and possibly to inhibit
good conversion with complex B, featuring an elec- protonation of the phosphine leading to the formation
tron-rich phosphine, while modest conversion was ob- of unchelated inactive ruthenium species. Finally,
tained with A. The side-product that was observed in 40 mol% of CSA was found to afford 5a in 80% iso-
both reactions was identified as the N- and C(3)-di- lated yield after purification by silica gel chromatog-
benzylated amine 5a. This result presents the first ex- raphy (entry 10). Increased amounts of CSA did not
ample, although in very poor yield, for the N- and C- improve the selectivity towards 5a, while the conver-
dialkylation of an unactivated amine involving ruthe- sion drastically dropped (entry 11). Having estab-
nium-catalyzed hydrogen autotransfer strategy. It is lished the best reaction conditions for N- and C(3)-di-
noteworthy that the exclusive formation of 4a, with benzylation, the general applicability of this cascade
no traces of 5a under neat conditions at 1008C pro- reaction was next evaluated (Table 2).
vided the best reaction conditions to produce 4a in
Accordingly, reaction of 3a with para- and ortho-
92% isolated yield with precatalyst A (entry 2). The substituted benzylic alcohols 2b–2f afforded N- and
reaction in water in the presence of complex B also C(3)-dialkylated amines 5b–5f in 58–80% isolated
presents an interesting potential (entry 4). However, yield, respectively. Piperidine 3b with diverse benzylic
the 83/17 4a/5a ratio with 93% conversion under sol- alcohols 2a–2e, 2g gave amines 6a–6e, 6g in 52–71%
vent-free conditions with B (entry 5), prompted us to yields. Furthermore, the reaction of azepane 3c with
optimize the reaction conditions to selectively form 2a allowed the formation of the disubstituted azepane
5a employing precatalyst B. Thus, reaction with 7a in 68% yield but with lower amount of CSA
10 mol% of camphorsulfonic acid (CSA) as additive (20 mol%). It is important to note that attempts to
with 2a (2.5 equiv.) and 3a led to full conversion of 3a react the 4-membered cyclic amine azetidine in the
and afforded the disubstituted amine 5a together with presence of benzyl alcohol were unsuccessful, presum-
4a in a 40/60 4a/5a ratio (entry 6). In addition to ably due to hydrolysis of the iminium intermediate
CSA, the order of addition of the substrates was and ring opening. Analysis of these results (Table 2)
found to be crucial. Thus, reaction of 3a with CSA amply demonstrates that the influence of either elec-
before catalyst addition was essential to ensure the
Table 2. General applicability of the reaction.[a]
[a]
Yields in parentheses are of isolated products.
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Basker Sundararaju et al.
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via nucleophilic substitution of 2a or aldol-type reac-
tion on 8a[3h,14] to the iminium species IV which, in
turn, would afford the expected dialkylated amine 5a
after reduction in the presence of the ruthenium hy-
dride species. It is noteworthy that under the present
reaction conditions, in the absence of any amine, 2a
gave dibenzyl ether as the exclusive product, while in
contrast, without CSA, benzyl benzoate[22] was ob-
tained as the major product. These results suggest
Scheme 2. Dialkylation of 3a with hexan-1-ol.
tron-withdrawing or electron-releasing groups is mini- that the nucleophilic substitution on 2a with III
mal. cannot be ruled out. The unsuccessful attempts to
We showed that the methodology could be extend- react N-alkylated amine 4a to afford the amine 5a fur-
ed to aliphatic alcohols. Indeed, pyrrolidine reacted ther consolidates that 4a is not involved in the catalyt-
with n-hexan-1-ol at 1708C in the presence of ic cycle and supports the proposed mechanism. At
1.5 mol% of B to give the dialkylated pyrrolidine 5g this stage, we were unable to extend the reaction to
in 50% isolated yield. This reactivity reveals that aliphatic acyclic amines such as dipropylamine 9. In
C(3)-alkylation took place only at the cyclic carbon of contrast to cyclic amines, the formation of aldehyde
the amine and not at the aliphatic side chain intro- products resulting from the hydrolysis of the iminium
duced during the first step as confirmed by NMR ion is not reversible under these conditions. Thus,
analyses (Scheme 2).[19]
during the reaction of 9 in the presence of benzyl al-
A plausible mechanism based on an autotandem cohol 2a an N-dealkylation–N-benzylation cascade oc-
catalytic cycle[20] is depicted in Scheme 3. Benzyl alco- curred affording a mixture of di- and tri-benzylamines
hol 2a is converted into aldehyde 8a along with the 10 and 11 with full conversion (Scheme 4).[23]
generation of the ruthenium hydride species accord-
In conclusion, we have designed and prepared new
ing to a well-accepted mechanism.[10] The in situ gen- (arene)Ru(II) complexes. Complex B is very efficient
erated 8a reacts with the amine to form the iminium
ion I which, in the absence of acidic additive, under-
goes reduction and gives 4a. However, in the presence
of sulfonic acid, as reported earlier by Williams and
Beller in the case of indole derivatives,[21] I might re-
arrange into the iminium ion II via a [1,3] hydride
shift. Deprotonation of II might lead to the formation
of enamine III as key intermediate. Thus, we also
assume that the presence of CSA facilitates the equili-
bration of the two iminium ions and thereby lowers
the formation of 4a resulting from the reduction of
iminium ions I or II. Finally, enamine III, would lead Scheme 4. Dealkylation benzylation cascade.
Scheme 3. Proposed mechanism.
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Ruthenium-Catalyzed Cascade N- and C(3)-Dialkylation of Cyclic Amines with Alcohols
References
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Interestingly, this methodology would allow the
access of C(3)-substituted cyclic secondary amines by
a simple hydrogenolysis. This C(3)-alkylation of cyclic
amines by an ecofriendly cascade reaction producing
only water as side product, may open new avenues
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Experimental Section
Preparation of [Ru
Complex B
(p-cymene)(k2-o-t-BuPPBS)Cl]
ACHTUNGTRENNUNG
Phosphine 1b (0.652 mmol) and t-BuOK (0.717 mmol) were
added to a 25-mL flame-dried Schlenk tube. The sealed
Schlenk tube was evacuated and filled with argon three
times. Minimum amount of MeOH (degassed by nitrogen
purge for 30 min) was added and the solution was stirred for
30 min. To this solution [RuACHTNUGTRNEG(UN p-cymene)Cl2]2 (0.200 g,
0.326 mmol) was added. After stirring for 14 h, the solvent
was evaporated, and then the crude was dissolved in 30 mL
of dichloromethane. The solution was cannulated to remove
the inorganic salt. The filtrate was reduced to a minimum
amount, and covered with hexane leading to the formation
1
of red crystals of complex B; yield: 0.360 g (93%). H NMR
(500 MHz, CD2Cl2): d=8.05 (t, 2H, J=8.5 Hz), 7.83 (dd,
1H, J=4.3, 7.7 Hz), 7.51–7.41 (m, 4H), 7.20 (t, 1H, J=
8.0 Hz), 7.07 (t, 1H, J=8.9 Hz), 5.97 (d, 1H, J=6.1 Hz),
5.72 (d, 1H, J=6.1 Hz), 5.67ACTHNUTRGNEUGN(m, 2H), 2.24 (sept, 1H, J=
6.8 Hz), 1.54 (d, 9H, J=14.3 Hz), 1.22 (s, 3H), 1.14 (d, 6H,
J=6.8 Hz); 31P (81 MHz, CD2Cl2): d=42.05; 13C NMR
(125 MHz, CD2Cl2): d=151.2, 151.1, 135.0, 133.4, 133.2,
132.9, 131.4, 130.94, 130.93, 129.1, 129.0, 128.6, 128.5, 127.9,
127.8, 126.6, 126.2, 107.9, 94.6, 90.7, 85.3,82.3, 38.4, 38.2,
30.8, 29.8, 29.7, 22.5, 21.2, 16.1; elemental analysis: calcd. for
C26H32ClO3PRuS: C 52.74, H 5.45; found: C 52.70, H 5.46.
General Procedure for Dialkylation
To a stirred solution of amine 3 (0.42 mmol) in 1 mL of tolu-
ene was added d-(+)-camphorsulfonic acid (0.17 mmol).
After stirring for 1 min, alcohol 2 (1.05 mmol) and [Ru] cat-
alyst (0.0063 mmol) were sequentially added. Then the reac-
tion mixture was evacuated by vacuum-argon cycles 5 times
and stirred at 1508C for 16 h. After evaporation of the sol-
vent, the residue was directly purified by column chroma-
tography (EtOAc/PE) to afford the expected dialkylated
amine.
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Adv. Synth. Catal. 2010, 352, 3141 – 3146