Catalytic alkylation of methyl-N-heteroaromatics with alcohols

Article abstract of DOI:10.1021/ja9095413

(Chemical Equation Presented) A novel catalytic C-C coupling reaction in which N-heteroaromatic-substituted methyl groups are efficiently alkylated using primary alcohols is introduced. The synthesis protocol is based on iridium catalysts and most likely relies on the borrowing hydrogen or hydrogen autotransfer mechanism. A variety of substrate combinations can readily be employed in this reaction, including pyrimidines, pyrazines, pyridazines, and even fairly activated 2- and 4-picolines. Copyright

Full text of DOI:10.1021/ja9095413

Published on Web 01/04/2010
Catalytic Alkylation of Methyl-N-Heteroaromatics with Alcohols
Benoˆıt Blank and Rhett Kempe*
Anorganische Chemie II, UniVersita¨t Bayreuth, UniVersita¨tsstrasse 30, 95440 Bayreuth, Germany
Received November 17, 2009; E-mail: kempe@uni-bayreuth.de
The so-called “borrowing hydrogen” methodology (Williams et
extensively studied in our group.9 To show the general applicability
of this novel C-alkylation methodology, several alcohols were used
(Table 2).
al.1) or “hydrogen autotransfer” reaction (Yus et al.2) has aroused
great interest in recent years and provides excellent protocols for
the (selective3) alkylation of amines using simple, nontoxic
alcohols4,5 (also under mild conditions).3b Similar (but much less
intensively investigated) methodologies have been used to ac-
complish C-C bond formations1 such as ꢀ-alkylation of secondary
alcohols6 and alkylation of methylketones.2,7 We herein report a
novel iridium-based C-C bond formation reaction, namely, the
catalytic alkylation of methyl-N-heteroaromatics using simple
alcohols.
Table 2. General Application of Several Substituted Benzylic and
Aliphatic Alcoholsa
In the course of amine alkylation studies3 with the P,N-ligand-
stabilized8 iridium catalyst 1 (Scheme 1), we observed C-alkylation
of a methyl group as a side reaction.
Entry
R1
R2
Product
TON
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3a
4a
4b
4c
49
48
45
46
46
47
46
37
39
31
37
43
43
42
41
31
98 (87)
95 (78)
90 (77)
91
92
94
4-OMe-C6H4
4-Me-C6H4
3-Me-C6H4
Scheme 1. Observed N- and C-Alkylation with Alcohols
2-Me-C6H4
2,4,6-Me3-C6H2
4-t-Bu-C6H4
4-SMe-C6H4
3-Cl-C6H4
91
73
78
2-CF3-C6H4
62c
alcohol ) 1-octanol
alcohol ) 1-butanol
Ph
4-OMe-C6H4
3-Me-C6H4
74
86
85d
83d
81d
62e
H
H
H
N-Benzylated 4-methylpyrimidin-2-ylamine (2) was employed
to optimize several reaction parameters for this C-alkylation step
(see the Supporting Information). The results showed that diglyme
is the best solvent and that a reaction temperature of 110 °C is
necessary. Screening of several organic and inorganic bases showed
that the reaction works best with KOtBu, but it can also be
performed with KOH or NaOtBu, albeit with ∼20% lower yields
of the corresponding products. Ligand screening (Table 1) revealed
that the P,N-ligand Py2NP(i-Pr)2 (Py ) pyridinyl, Pr ) propyl)
affords the best results but that the reaction can interestingly also
be performed with [IrCl(cod)]2 (cod ) cycloocta-1,5-diene),
although slightly lower product yields are obtained.
alcohol ) 1-butanol
a Reaction conditions: 1.0 mmol of 2, 1.1 mmol of alcohol, 1 mol %
[IrCl(cod)]2, 2 mol % Py2NP(i-Pr)2, diglyme, 1.1 mmol of KOtBu, 24 h,
110°C. b Isolated yield; yields in parentheses correspond to the reaction
with neat [IrCl(cod)]2. c Using 8 mol % 1. d Using 2.2 mmol of alcohol
and KOtBu. e Using 3.0 mmol of 1-butanol and a reaction time of 48 h.
The presented results show that a multitude of functional groups
are tolerated and that benzylic (entries 1-10) and aliphatic alcohols
(entries 11 and 12) can be employed. The reaction works especially
well with electron-donating substituents in the ortho, meta, and para
positions and even with rather bulky substrates such as 2,4,6-
trimethylbenzylic alcohol. The reaction with electron-withdrawing
substituents is slightly more difficult, and higher catalyst loadings
are necessary in order to obtain high conversions (entry 10). This
is somehow a contradiction to literature results for the condensation
of aldehydes with methylheteroaromatics, where a higher efficiency
was observed for electron-poor aldehydes.10 This implies that the
successive hydrogenation of the formed olefin rather than the
condensation step is hampered by electron-withdrawing substituents.
As determined above, the reaction can also be performed using
neat [IrCl(cod)]2 without the addition of the P,N-ligand, but as
shown for entries 1-3 (the values in parentheses), the expected
products are obtained in 10-20% lower yields in comparison to
those using 1. The simultaneous N- and C-alkylation of 2-amino-
4-methylpyrimidine with alcohols (entries 13-16) can, however,
only be performed with 1, affording products 3a and 4a-c.
Table 1. Ligand Screeninga
Entry
Ligand
TON
Yieldb
1
2
3
4
5
6
7
PPh3
137
243
97
200
0
41
73
29
60
0
Py2NP(i-Pr)2
Ph2PC3H6PPh2
2,2′-bipyridine
1,3-bis(2,6-dimethylphenyl)-4,5-dihydroimidazole
1,3-bis(2,6-diisopropylphenyl)imidazole
none (COD)
0
227
0
68
a Reaction conditions: 1.0 mmol of 2, 1.1 mmol of benzyl alcohol,
0.0015 mmol of [IrCl(cod)]2, 0.003 mmol of ligand, 300 µL of diglyme,
1.1 mmol of KOtBu, 24 h, 110 °C. b Determined by GC analysis with
dodecane as internal standard.
It is possible that the substrate in a deprotonated form could itself
act as an aminopyridinate, a class of ligands that has been
9
924 J. AM. CHEM. SOC. 2010, 132, 924–925
10.1021/ja9095413  2010 American Chemical Society

C O M M U N I C A T I O N S
A range of different methyl-substituted heteroaromatic substrates
was also tested in order to show the general applicability of this
novel method (Table 3).
hydrogen” or “hydrogen autotransfer” methodology toward a new
reaction and a new class of substrates. The work indicates the hidden
potential of catalytic reactions using alcohols. Mechanistic studies
and the development of more efficient catalysts are underway.
Table 3. Variation of the Heteroaromatic (Het) Substratea
Acknowledgment. This work was supported by NanoCat, an
International Graduate Program within the Elitenetzwerk Bayern.
B.B. is thankful for a Bavarian Elite Graduation Grant (Gra-
duiertenstipendium nach dem Bayerischen Elitefo¨rderungsgesetz).
Dedicated to Uwe Rosenthal on the occasion of his 60th birthday.
Supporting Information Available: Characterization data and
detailed experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Reaction conditions: 3.0 mmol of heteroaromatic substrate, 1.0
mmol of alcohol, 2.5 mol % [IrCl(cod)]2, 5 mol % Py2NP(i-Pr)2,
diglyme, 1.1 mmol of KOtBu, 48 h, 110°C. b Isolated yield.
As shown in entries 1-5, not only methyl-substituted pyrimidines
but also pyrazines, pyridazines, and even pyridines can be used as
substrates. As expected, with decreasing acidity of the methyl
protons11 from 4-methylpyrimidine and 2-methylpyrazine toward
the chemically similar substrates 3-methylpyridazine12 and 2-pi-
coline, the reaction proceeds less efficiently and affords lower yields
of the C-alkylated products. However, it is interesting that the
alkylation of 2- and 4-picoline with alcohols is still possible, even
though the latter are only poorly activated substrates. Furthermore,
the presence and position of the N atom in the heterocylic ring
plays an important role, since only substrates with N in the 2- or
4-position can be efficiently alkylated, whereas 3-picoline, toluene,
and pentafluorotoluene do not react. A tautomerization of the
heteroaromatic educt into the corresponding enamine seems to be
crucial for the reaction, which is possible neither for 3-picoline
nor toluene derivatives. These findings support our theory that a
“borrowing hydrogen” or “hydrogen autotransfer” mechanism is
operating here, including dehydrogenation of the alcohol and
subsequent condensation of the formed aldehyde with the het-
eroaromatic substrate, which has beforehand been deprotonated by
the strong base (using a stoichiometric amount of the base). This
should lead to the corresponding aldol product, which rapidly
eliminates H2O at elevated temperatures to form an olefinic
substrate, onto which the “borrowed” hydrogen equivalents can be
retransmitted to yield the final alkylation product (see the Supporting
Information).
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In conclusion, we have developed a protocol allowing the
alkylation of methyl groups in N-heteroaromatic substrates using
simple alcohols in a novel catalytic C-C bond formation reaction.
This protocol extends the application scope of the “borrowing
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