The role of the alcohol and carboxylic acid in directed ruthenium-catalyzed C(sp3)-H α-alkylation of cyclic amines

Article abstract of DOI:10.1002/chem.201201072

A general directed Ru-catalyzed C(sp³)-H α-alkylation protocol for piperidines (less-reactive substrates than the corresponding five-membered cyclic amines) has been developed. The use of a hindered alcohol (2,4-dimethyl-3-pentanol) as the solvent and catalyst activator, and a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve a high conversion to product. This protocol was used to effectively synthesize a number of 2-hexyl- and 2,6-dihexyl piperidines, as well as the alkaloid (±)-solenopsin A. Kinetic studies have revealed that the carboxylic acid additive has a significant effect on catalyst initiation, catalyst longevity, and reverses the reaction selectivity compared with the acid-free reaction (promotes alkylation versus competing alkene reduction). Acid makes the difference! A directed Ru-catalyzed C(sp³)-H α-alkylation protocol for cyclic amines has been developed (see scheme). Kinetic studies revealed that the carboxylic acid aids catalyst activation, increases catalyst longevity, and reverses the reaction selectivity. The alcohol selected as the solvent plays an active role in the catalysis. Copyright

Full text of DOI:10.1002/chem.201201072

FULL PAPER
DOI: 10.1002/chem.201201072
The Role of the Alcohol and Carboxylic Acid in Directed Ruthenium-
3
À
Catalyzed C
N
Sheba D. Bergman,[a] Thomas E. Storr,[a] Hana Prokopcovꢀ,[a] Karel Aelvoet,[a]
Gaston Diels,[b] Lieven Meerpoel,[b] and Bert U. W. Maes*[a]
Abstract: A general directed Ru-cata-
is necessary to achieve a high conver-
sion to product. This protocol was used
to effectively synthesize a number of 2-
hexyl- and 2,6-dihexyl piperidines, as
well as the alkaloid (Æ)-solenopsin A.
Kinetic studies have revealed that the
carboxylic acid additive has a significant
effect on catalyst initiation, catalyst
longevity, and reverses the reaction se-
lectivity compared with the acid-free
reaction (promotes alkylation versus
competing alkene reduction).
3
À
lyzed C
N
for piperidines (less-reactive substrates
than the corresponding five-membered
cyclic amines) has been developed. The
use of a hindered alcohol (2,4-dimeth-
yl-3-pentanol) as the solvent and cata-
lyst activator, and a catalytic amount of
trans-1,2-cyclohexanedicarboxylic acid
À
Keywords: acid effects · C H acti-
vation · piperidines · ruthenium ·
selectivity
Introduction
sults in the field generally do not allow efficient piperidine
functionalization as exemplified by our study on the direct
C2 arylation of piperidines,[5d] in which the reaction condi-
tions developed by Sames for pyrrolidines did not give syn-
thetically useful results on piperidines.[5c] Recently, we per-
formed direct C2 alkylation of piperidines and experienced
a similar problem. Under the reaction conditions developed
by Murai for pyrrolidine alkylation, piperidine substrate 1a
C2-substituted piperidines are highly prevalent structural
motifs in natural products and pharmaceuticals.[1] Therefore,
the development of novel synthetic techniques for the direct
À
C2 H functionalization of piperidines is of paramount im-
portance. Several direct synthetic approaches have been de-
scribed, for example via a C2 radical, anion, or cation inter-
mediate, but these require
a
stoichiometric reagent.[2]
gave a poor conversion in a reaction with 1-hexene
Among these methods, direct C2 lithiation followed by reac-
tion with electrophiles, pioneered by Beak,[3] has recently re-
ceived significant renewed interest.[4] To date, examples of
(Scheme 1).[5b] The reaction yielded only 17% of the 2-hexy-
À
direct C2 H functionalization of piperidines by transition-
metal catalysis are still rare.[5a–d,f] The direct functionaliza-
tion studies published thus far have focused on pyrrolidines
and only show (if any) a limited number of piperidine exam-
ples.[5] This is not surprising when the inherently lower reac-
tivity of the six-membered ring system is considered relative
to its five-membered counterpart. These important initial re-
[a] Dr. S. D. Bergman, Dr. T. E. Storr, Dr. H. Prokopcovꢀ,
Dr. K. Aelvoet, Prof. Dr. B. U. W. Maes
Organic Synthesis
Scheme 1. C2 hexylation of 1 f and 1a under Muraiꢁs reaction condi-
Department of Chemistry
University of Antwerp
tions.[5b]
Groenenborgerlaan 171
2020 Antwerp (Belgium)
Fax : (+32)032653233
E-mail: bert.maes@ua.ac.be
lated product 2a, in addition to 17% of ketal-cleaved 2b
and 48% of recovered 1a (Scheme 1). Surprisingly, GC-MS
analysis of the crude reaction mixture at the end of the reac-
tion revealed that 52% of the initial amount of hexene was
converted to hexane and only 3.4% to alkylated products
(2a and 2b). Acetone was also observed in the reaction mix-
ture, which clearly indicated that the isopropanol solvent
acts as a hydrogen-transfer agent in this process.[6] There-
[b] G. Diels, Dr. L. Meerpoel
Janssen Research & Development
Janssen Pharmaceutica N.V.
Turnhoutseweg 30
2340 Beerse (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201072.
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fore, identification of efficient alkylation conditions requires
tuning of the two competitive reactions (alkylation versus
reduction). Herein, we report that a catalytic amount of
a carboxylic acid additive can be used to achieve this goal.
of 2,4-dimethyl-3-pentanol were taken as the optimal alco-
hol stoichiometry.
To further optimize the alkylation reaction, the effect of
additives was investigated (Table 2). Interestingly, carboxylic
acids tended to further increase the conversion to alkylated
Results and Discussion
Table 2. The effect of additive on the hexylation of 1a.
As the alcohol acts as a reagent in competitive reduction re-
actions, we tested tBuOH as a solvent that cannot act as
a hydrogen transfer agent. However, very little substrate
consumption was observed (Table 1, entry 4), which points
Table 1. The effect of the alcohol structure and loading on the hexylation
of 1a.
Entry
Additive
pKa
1a[a]
2a[a]
3a[a,b]
1
2
3
–
–
3.58
5.01
4.18, 5.93
4.34, 6.76
4.53
4.20
4.14
3.46
1.60
2.98, 5.28
1.99
5.21
10.75
–
–
38
18
26
7
54
63
60
65
64
60
61
62
59
60
10
40
47
46
35
16
8
19
14
28
19
15
16
21
30
15
0
AcOH
PivOH
trans-1,2-CyACTHUNRGTNEUNG(COOH)2
4[c,d]
5
cis-1,2-Cy
(4-MeO)C6H4COOH
PhCOOH
(4-F)C6H4COOH
(COOH)2
17
25
23
17
11
25
90
57
46
48
62
83
6
7
8
9
10
11
12
13
14
15
16
ACHTUNGTRENNUNG
T
(3,4,5-tri-F)C6H2COOH
C6F5COOH
phthalic acid
p-TsOH
Py·HCl
Et3N·HCl
Entry Alcohol
X
1a[a] 2a[a] 3a[a,b] 1b[a] 2b[a]
3
7
6
3
1
2
3
4
5
6
7
8
nBuOH
iPrOH
26
26
26
26
53
61
57
90
71
45
38
40
23
39
10
27
49
54
45
0
0
4
0
2
6
8
5
2
7
0
0
0
0
0
0
5
9
0
0
0
0
0
0
AcOK
(3,4,5-tri-F)C6H2COOK
2,4-dimethyl-3-pentanol
tBuOH
1
2,4-dimethyl-3-pentanol[c] 10
[a] Corrected GC-FID conversion. [b] Compound 3a is a mixture of dia-
stereoisomers. [c] An experiment without [Ru3(CO)12] catalyst under oth-
erwise identical reaction conditions showed no conversion to product.
[d] When [Ru3(CO)12] (4 mol%) and trans-1,2-CyACHTUNTRGNE(NUG COOH)2 (4 mol%)
were used a conversion of 2:59:39 (1a/2a/3a) was observed.
2,4-dimethyl-3-pentanol
2,4-dimethyl-3-pentanol
2,4-dimethyl-3-pentanol
10
5
2.5 50
[a] Corrected GC-FID conversions. [b] Compound 3a is a mixture of dia-
stereoisomers. [c] Reaction volume increased to 1.82 mL by addition of
tBuOH (volume when iPrOH (26 equiv) is used, see entry 2).
products. Carboxylates are known to facilitate a number of
2
À
different transition-metal catalyzed C
(sp ) H functionaliza-
towards an active role of the alcohol in the alkylation reac-
tion mechanism. Primary alcohol nBuOH gave a slightly
better conversion to the desired reaction products than
iPrOH (Table 1, entry 1 versus 2). Interestingly, the use of
2,4-dimethyl-3-pentanol (a more sterically hindered secon-
dary alcohol that is harder to oxidize) gave more of the de-
sired alkylated products and completely suppressed the
ketal reduction (Table 1, entry 3).[7] Therefore, this alcohol
was selected as the solvent for further studies. The reaction
with 2,4-dimethyl-3-pentanol (10 equiv), in which the
“inert” solvent tBuOH was used to make up the difference
in volume relative to the standard experiment, showed a de-
crease in substrate conversion (Table 1, entry 5 versus 3).
This result further supports the active role of the alcohol in
the alkylation reaction. Reduction of the amount of alcohol
(26 to 10 to 5 equiv) led to an increase in the conversion of
1a into 2a and 3a (Table 1, entries 6 and 7), presumably
due to a concentration effect. Further decrease of the alco-
hol content appears to be detrimental as less substrate con-
sumption was observed (Table 1, entry 8), thus, 5 equivalents
tions,[8] but only in rare cases do these reactions occur under
acidic conditions.[9] The use of trans-1,2-Cy
ACTHUNTRGNE(UGN COOH)2 (Cy=
cyclohexane; Table 2, entry 4) was found to be particularly
effective and led to 93% conversion. The lower conversion
and inhibition observed with cis-1,2-CyACTHNURGTNEUNG(COOH)2 and
phthalic acid, respectively, indicates the importance of spa-
tial arrangement when dicarboxylic acids are used (Table 2,
entries 5 and 11). Benzoic acid additives generally give good
conversion, but when the acidity becomes too high the con-
version ultimately drops (Table 2, entries 6–10). The best
result was obtained with 3,4,5-trifluorobenzoic acid, which
led to a conversion of 89% (Table 2, entry 9).[10] In contrast,
when the reaction was performed with other types of acid it
was significantly inhibited in comparison to the additive-free
reaction (Table 2, entries 12–14 versus 1). Surprisingly, the
use of potassium carboxylates provided lower conversions
than those obtained with the corresponding carboxylic acids
(Table 2, entries 15 and 16 versus 2 and 9). These results
clearly demonstrate the necessity for the additive to possess
both a carboxylate structural entity and an acidic proton.
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3
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Directed Ruthenium-Catalyzed CACTHNUTRGNE(UNG sp ) H a-Alkylation of Cyclic Amines
FULL PAPER
The [Ru3(CO)12] loading could be reduced to 4 mol% with-
out sacrificing conversion (Table 2, entry 4). The catalyst/
carboxylic acid ratio was screened for the two best perform-
was observed, which is a result of the catalyst isomerizing
the 1-undecene reagent to yield a mixture of nine undecenes
in comparison with five in the 1-hexene case. Hence, the
longer the chain, the more challenging the coupling, due to
a lower concentration of the reactive terminal alkene. The
use of the 1:1 [Ru3(CO)12]/3,4,5-trifluorobenzoic acid
(8 mol%) catalyst system over 48 h was found to be optimal
for C6 undecylation of 4 (see the Supporting Informa-
tion).[12] Piperidine 5 was isolated in 78 % yield as a 5:3
(trans/cis) diasteriomeric ratio (Scheme 2). Hydrogenation
of the pyridine ring of trans-5 with Rh/C under H2 pressure
allowed efficient directing group removal in a single step to
provide 65% of (Æ)-solenopsin A (Scheme 2).
ing acid additives, trans-1,2-CyACHTNUGTRENUNG(COOH)2 and 3,4,5-trifluoro-
benzoic acid. In general, good conversion can be achieved
by using a 1:1 ratio of catalyst to additive, but higher load-
ings of acid inhibited the reaction (see the Supporting Infor-
mation).
With the optimized conditions in hand (1a (1 equiv), 2,4-
dimethyl-3-pentanol
(5 equiv),
1-hexene
(10 equiv),
[Ru3(CO)12] (4 mol%), trans-1,2-CyAHCTUNGTRE(UNNNG COOH)2 (4 mol%),
1408C , 24 h), the substrate scope was assessed. Under these
reaction conditions, both unsubstituted piperidine 1b and
C4-substituted piperidines 1a, 1c, and 1d were hexylated ef-
ficiently to deliver good yields of mono- and dialkylated
products 2 and 3 (Table 3, entries 1–4). Piperidine 1e proved
Table 3. Hexylation of cyclic amines 1 under the optimized reaction con-
ditions.
Scheme 2. Synthesis of (Æ)-solenopsin A (6).
Entry
1
R
2
Yield
[%][a]
3
Yield
[%][a]
To rationalize the effect of the carboxylic acid on the rate
of the catalysis, we analyzed the conversion of substrate 1a
into products 2a and 3a as a function of time, both in the
1
2
3
1a
1b
1c
2a
2b
2c
48
3a
3b
3c
43[b]
43[c]
47[e]
26
absence and presence of trans-1,2-CyACTHNUTRGEN(UNG COOH)2 (Figures 1a
39[d]
and b). Comparison of the kinetic profiles confirmed
a faster reaction in the presence of the acid, and also re-
vealed that without acid the reaction onset was much slower
(>1 h induction period; Figure 1a). Additionally, in the ab-
sence of acid catalyst deactivation is observed after 6 h and
conversion reaches a plateau after 10 h (Figure 1a). In con-
trast, the reaction in the presence of a catalytic amount of
4
1d
2d
32[f]
3d
53[g]
5
6
1e
1 f
2e
2 f
–
3e
3 f
76[h]
70[i]
(pyrrolidine)
26
[a] Isolated yield. [b] Trans/cis ratio=1:1, compound 1a (2%) was also
isolated. [c] Trans/cis ratio=2:1. [d] Trans/cis ratio=1:1. [e] Diastereo-
meric ratio (d.r.)=9:3:1. [f] Trans/cis ratio=1:3. [g] d.r.=4:1:1, com-
pound 1d (12%) was also isolated. [h] d.r. 2:6:1, [Ru3(CO)12] (8 mol%)
and trans-1,2-CyACHTUNGTRENNUNG(COOH)2 (8 mol%) were used; compound 1e (9%) was
also isolated. [i] Trans/cis ratio=5:3.
trans-1,2-CyACHTNUTRGNEUNG(COOH)2 showed essentially no initiation
period and sustained conversion to alkylated products was
observed over the full 24 h reaction time (Figure 1b). This
implies that the acid additive is involved in the catalyst acti-
vation process and, moreover, increases catalyst longevity.
Interestingly, further analysis of the kinetic data revealed
that the selectivity for alkylation versus reduction is re-
versed. Without the acid additive the rate of hexene reduc-
tion is far greater than that of the alkylation reaction (ca.
ꢃ5), whereas in the presence of acid the alkylation reaction
becomes the major reaction pathway (Figure 1c). This is in
accordance with a reduced rate of alcohol oxidation to
to be less reactive, therefore a double catalyst and acid load-
ing (8 mol%) was used, in this case only the dihexylated
product 3e was obtained (Table 3, entry 5). Gratifyingly, the
standard reaction conditions also proved suitable for pyrroli-
dine 1 f (Table 3, entry 6). Compared with the original
Murai conditions (Scheme 1), our reaction conditions re-
quire half of the original catalyst loading and a reaction
time of 24 h rather than 60 h.
To further showcase the potential of the newly developed
alkylation procedure, we devised a new route to (Æ)-sole-
nopsin A (6) starting from 2-methyl-(1-pyridin-2-yl)piperi-
dine (4).[11] A slow conversion to undecylated product (5)
ketone found in the presence of trans-1,2-CyACTHNURGTNEUNG(COOH)2 (Fig-
ure 1d).
To further understand the reaction dependence upon re-
agent stoichiometry, a number of kinetic analyses in the
presence of acid additive were performed by alteration of
the quantities of 1-hexene and 2,4-dimethyl-3-pentanol used.
The overall reaction concentration was maintained by keep-
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B. U. W. Maes et al.
ing the total volume equal by the addition of dodecane.
When the reaction was performed with varying amounts of
olefin the rate of the reaction, under the optimized reaction
conditions, increased with the number of equivalents of 1-
hexene (5, 10, and 15 equiv; see the Supporting Informa-
tion) used. The kobsd was found to exhibit a pseudo-first-
order dependence with respect to the hexene concentration
(see the Supporting Information). The conversion of sub-
strate as a function of time in the presence of trans-1,2-Cy-
AHCTUNGTERG(NNUN COOH)2 with various concentrations of alcohol (see the
Supporting Information) revealed no significant overall rate
effect. In the presence of more alcohol (10 equiv relative to
5 or 2.5 equiv), the reaction showed a short induction
period, similar to what was observed when no acid was
added. However, the conversion was almost complete after
24 h, which indicates that the catalyst remains active
throughout the course of the reaction when acid is present.
It is important to note that in the absence of Ru acid alone
does not allow catalysis to occur; no conversion was ob-
tained (Table 2, entry 4). Reactions performed 1) without
2,4-dimethyl-3-pentanol and 2) with tBuOH to replace 2,4-
dimethyl-3-pentanol, both in the presence of trans-1,2-Cy-
AHCTUNGTERG(NUNN COOH)2, gave little alkylation product (see the Supporting
Information). Conversions of 1a to 2a were only 10 and
14%, respectively, and 3a was not present. These experi-
ments indicate that when there is no acid present, the alco-
hol is solely responsible for the catalyst activation. However,
in the presence of acid, both the acid and the alcohol are in-
volved in the catalyst activation process. These results can
be rationalized based on competitive binding of the acid and
alcohol to Ru0. This is also in accordance with the results
obtained when a higher trans-1,2-CyACHTUNRGTENN(UG COOH)2/ACHTUTGNERN[NUGN Ru3(CO)12]
ratio was used; catalysis was inhibited when the same
amount of alcohol was present (see the Supporting Informa-
tion).
Based on the experimental data, a mechanistic proposal
3
À
for directed Ru-catalyzed C
G
Scheme 3.[13] Hydrogen bonding between the hydroxyl
groups of the carboxylic acid and the alcohol bound to Ru0
(C)[14] facilitates oxidative addition of the alcohol. The
bound carboxylic acid can release the alcohol by protona-
tion to yield H Ru OOCR (E), which is the catalytically
active species. Subsequent alkene insertion, which is the
rate-limiting step based on the observed rate dependence on
the concentration of the alkene, provides F. Upon coordina-
tion of substrate 1, the ruthenium-bound carboxylate assists
II
À
À
À
in the C H activation step by a concerted metalation–de-
protonation (CMD) type mechanism to reform the carboxyl-
ic acid.[15] Reductive elimination finally yields alkylated
compound 2 (and after a second cycle, compound 3) and re-
generates Ru0.
The reversal of preference for alkylation versus reduction
in the presence of acid can be rationalized by analysis of the
mechanism of hexane formation in the absence of acid
(Scheme 4). Ruthenium alkoxide (I), formed by oxidative
addition of an alcohol, can produce a ruthenium dihydride
species (J), which yields the undesired alkane upon alkene
Figure 1. Kinetic profiles for the reaction of 1a (0.5 mmol) with 1-hexene
(5 mmol) in 2,4-dimethyl-3-pentanol (2.5 mmol) in the presence of
[Ru3(CO)12] (4 mol%): a) in the absence of acid additive, b) in the pres-
ence of trans-1,2-Cy
(hexane formationꢀ[hexane]) versus alkylation (formation of 2a and
3aꢀ[2a]+2[3a]) in the absence or presence of trans-1,2-Cy(COOH)2
(4 mol%). d) Oxidation of 2,4-dimethyl-3-pentanol to 2,4-dimethyl-3-
ACHTUNGTRENNUNG(COOH)2 (4 mol%). c) Selectivity of reduction
A
ACHTUNGTRENNUNG
pentanone in the absence or presence of trans-1,2-CyACTHNUTRGNEUNG(COOH)2
(4 mol%).
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À
Directed Ruthenium-Catalyzed CACTHNUTRGNE(UNG sp ) H a-Alkylation of Cyclic Amines
FULL PAPER
Scheme 3. Plausible mechanism for alkylation in the presence of a carboxylic acid additive.
Scheme 4. Plausible mechanisms for alkylation (minor) and alkene reduction (major) in the absence of a carboxylic acid additive.
insertion and subsequent reductive elimination (via K). This
process can be slowed through protonation of the alkoxide
by bound carboxylic acid, which is in accordance with the
reduced amount of alkene reduction (less alkane and
ketone formation) and increased rate of alkylation observed
in the presence of a carboxylic acid additive. When no car-
boxylic acid is added, b-hydride elimination, which leads to
alkene reduction, is not inhibited and is, therefore, more
complex M through a four-membered transition state that
involves bound alkoxide in place of carboxylate.
Conclusion
We have discovered that carboxylic acid additives improve
3
À
the directed ruthenium-catalyzed C
G
3
À
pronounced versus the C
U
cyclic amines with alkenes. For less-reactive ring sizes (pi-
peridine) the acid additive is crucial to achieve full conver-
À
In the absence of acid, the C H activation step occurs in
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B. U. W. Maes et al.
[6] a) Ruthenium in Organic Synthesis (Eds.: S.-I. Murahashi, N.
Komiya), Wiley-VCH, Weinheim, 2004; b) R. A. T. M. Abbenhuis, J.
Boersma, G. van Koten, J. Org. Chem. 1998, 63, 4282–4290; c) S.
Horn, M. Albrecht, Chem. Commun. 2011, 47, 8802–8804.
[7] For the use of 2,4-dimethyl-3-pentanol in Ru-catalyzed racemiza-
tions of amines to avoid side reactions, see: O. Pꢄmies, A. H. ꢅll,
J. S. M. Samec, N. Hermanns, J.-E. J. Bꢆckvall, Tetrahedron Lett.
2002, 43, 4699–4702.
sion of substrate. Carboxylic acid improves catalyst activa-
tion, catalyst longevity, and induces a profound selectivity
shift (undesired alkene reduction versus desired alkylation).
The role of the acid presented here is unprecedented in
3
À
direct transition-metal-catalyzed
C
G
tions and will stimulate new advances in this challenging
field. As an application of the methodology, the alkaloid
(Æ)-solenopsin A was synthesized.
2
À
[8] For representative examples of ruthenium-catalyzed C
N
tionalization reactions that utilize carboxylate additives, see: a) E. F.
Flegeau, C. Bruneau, P. H. Dixneuf, A. Jutand, J. Am. Chem. Soc.
2011, 133, 10161–10170; b) L. Ackermann, M. Mulzer, Org. Lett.
2008, 10, 5043–5045; c) L. Ackermann, P. Novꢀk, Org. Lett. 2009,
11, 4966–4969; d) W. Li, P. B. Arockiam, C. Fischmeister, C. Bru-
neau, P. H. Dixneuf, Green Chem. 2011, 13, 2315–2319; e) B. Li,
C. B. Bheeter, C. Darcel, P. H. Dixneuf, ACS Catal. 2011, 1, 1221–
Experimental Section
General procedure for 2-hexylation of 1-(pyridin-2-yl)piperidines: Two
microwave pressure vials (10 mL) were each charged with the appropri-
ate 1-(pyridin-2-yl)piperidine or 1-(pyridin-2-yl)pyrrolidine (0.5 mmol),
[Ru3(CO)12] (12.8 mg, 0.02 mmol, 4.0 mol%), rac-trans-cyclohexane-1,2-
dicarboxylic acid (3.4 mg, 0.02 mmol, 4 mol%), 2,4-dimethyl-3-pentanol
(350 mL, 2.5 mmol, 5 equiv), and 1-hexene (625 mL, 5.0 mmol, 10 equiv).
The vials were purged with Ar and sealed with crimp caps. Subsequently,
the reaction vials were placed in a preheated oil bath at 1408C for 24 h
(the cap was secured with a vial top clamp). After the allotted reaction
time, the content from both vials were combined in a round-bottomed
flask and reduced in vacuo. The products were isolated by flash chroma-
tography on silica gel.
2
À
1224; for a review on the use of carboxylates in C
G
alizations, see: f) L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.
À
[9] Commonly C H functionalization reactions require the use of stoi-
2
À
chiometric amounts of an inorganic base. For examples of C
U
functionalization under acid conditions, see: a) B. Liꢇgault, D. Lee,
M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org. Chem. 2008, 73,
5022–5028; b) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn, B.
DeBoef, Org. Lett. 2007, 9, 3137–3139; c) H. A. Chiong, Q.-N.
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2
À
sentative examples of ruthenium-catalyzed C
N
Acknowledgements
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This work was financially supported by the University of Antwerp (IOF),
the Hercules foundation, and Janssen Research & Development, a divi-
sion of Janssen Pharmaceutica N.V. The authors would like to thank Phil-
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[10] For the use of 3,4,5-trifluorobenzoic acid in copper-catalyzed direct
2
À
C
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Received: March 30, 2012
Published online: && &&, 2012
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Chem. Eur. J. 0000, 00, 0 – 0
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Directed Ruthenium-Catalyzed CACTHNUTRGNE(UNG sp ) H a-Alkylation of Cyclic Amines
FULL PAPER
À
C H Activation
S. D. Bergman, T. E. Storr,
H. Prokopcovꢀ, K. Aelvoet, G. Diels,
L. Meerpoel,
B. U. W. Maes* ............... &&&& — &&&&
The Role of the Alcohol and Carbox-
ylic Acid in Directed Ruthenium-Cata-
3
À
lyzed C
Amines
G
Acid makes the difference! A directed
aids catalyst activation, increases cata-
lyst longevity, and reverses the reac-
tion selectivity. The alcohol selected as
the solvent plays an active role in the
catalysis.
3
À
Ru-catalyzed C
N
protocol for cyclic amines has been
developed (see scheme). Kinetic stud-
ies revealed that the carboxylic acid
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!