Iron-catalysed alkylation of 2-methyl and 4-methyl azaarenes with alcoholsviaC-H bond activation

Article abstract of DOI:10.1039/d0cc01593h

The first Fe-catalysed alkylation of 2-methyl and 4-methyl-azaarenes with a series of alkyl and hetero-aryl alcohols is reported (>39 examples and up to 95% yield). Multi-functionalisation of pyrazines and synthesis of anti-malarial drug (±) Angustureine significantly broaden the scope of this methodology. Preliminary mechanistic investigation, deuterium labeling and kinetic experiments including trapping of the enamine intermediate1a'are of special importance.

Full text of DOI:10.1039/d0cc01593h

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DOI: 10.1039/D0CC01593H
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Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Iron-Catalysed Alkylation of 2-Methyl and 4-Methyl
azaarenes with Alcohols via C-H Bond Activation
Lalit Mohan Kabadwal, Sourajit Bera and Debasis Banerjee*
The first Fe-catalysed alkylation of 2-methyl and 4-methyl- is the key for success. Importantly, such processes are
azaarenes with a series of alkyl and hetero-aryl alcohols is reported expensive and required multi-step ligand synthesis (Scheme
(>39 examples and up to 95% yield). Multi-functionalisation of 1a). However, to the best of our knowledge iron-catalysed
pyrazines and synthesis of anti-malarial drug (±) Angustureine alkylation of primary alcohols with 2-methyl or 4-methyl N-
significantly broadens the scope of this methodology. Preliminary heteroaromatics yet not established.8 Notably, iron is non-toxic,
mechanistic investigation, deuterium labeling and kinetic most earth-abundant, inexpensive metal and found in variable
experiments including trapping of the enamine intermediate 1a’ biological systems. Therefore, application of iron-catalysts for
are of special highlights.
crucial organic transformations fascinated significantly.9
a) Previous work
[M] = Ir, Ru, Pt, Co, Ni etc.
multi-step ligand synthesis
only 2-alkyl N-heterocycles
N-Heteroaromatics and their derivatives are ubiquitous in
various important pharmaceuticals, bioactive compounds and
significantly used as lifesaving drugs.1 Therefore, metal-
catalysed functionalization of C(sp3)-H bond in such azaarenes
enables access to valuable N-hetero aromatics.2 Nevertheless,
conventional pre-functionalised alkyl halides, carbonates and
esters are utilised for such alkylation of N-heteroaromatics and
generates undesired side waste. In general, selective
functionalization of C(sp3)-H bond associated with high energy
barriers. Thus, often metal-catalysed alkylation of such C-H
bonds were performed involving directing group assistance in
combination with activated olefins or related derivatives.3
Hence, development of an atom-economic alkylation process
for C(sp3)-H bond in N-heteroaromatics following sustainable
technology is a challenging goal.4 Notably, in terms of
sustainability, recent years witnessed the applications of bio-
mass derived renewable alcohols as a promising coupling
partner for alkylation process. Such metal-catalysed hydrogen
borrowing (HB) approach has been well documented for the
construction the new C-X (X = C, N etc.) bonds and generates
water as sole by-product.5
Pioneering study by Kempe on Ir-catalysed alkylation of methyl
N-heteroaromatics using alcohols is noteworthy.6a Thereafter,
other precious metal-based catalysts have been explored for
such alkylation (Ir-, Ru-, and Pt).6b-h Thus, replacement of
precious and expensive metal-base catalysts with earth
abundant and inexpensive metals attracted significant
attention in catalytic research.7 Recently, a few examples based
on non-precious metal catalysts were reported for alkylation of
2-methyl N-heteroaromatics using alcohols.8 Nevertheless,
often applications of pincer-based PN5P or NNN-ligands system
[M]
Het
Het
HO
R
R
b) This work: Fe-catalysed alkylation of methyl heteroarenes with alcohols
Fe(OAc)2 (5 mol%)
Phen (10 mol%)
Het
N
Het
R
N
H
N
N
H2O
R
OH
N
N
Me
Me
(±) Angustureine
(Antimalarial drug)
>39 examples; 95 % yield
R
N
R
Scope with aryl, heteroaryl and aliphatic alcohols
Non-precious metal-catalyst
gram scale synthesis
(iso)quinaldine, lepidine, pyrazine and pyridine derivatives
multi-functionalization/durg synthesis
Mechanistic studies
c) Mechanistic rationale for Fe-catalysed alkylation of methyl heteroarenes
overall transformations
R
OH
N
R
2a
3a
Fe
dehydrogenation
Hydrogenation
H2
Fe[H]
Detected using
GC-MS and 1H-NMR
R
O
base
2a'
N
R
H2O
1a
3a'
Base
D2O
D
N
N
N
1a
H
1a-d1
1a'
dearomatization
Detected using GC-MS (m/z = 144)
and 1H NMR
Scheme 1: (a) Previous reports. (b) Proposed Fe-catalysed alkylation of N-
heteroarenes with alcohols. (c) Mechanistic proposal.
Recently, we have started a program to explore the potential role of
non-precious metal-catalysts (Ni-, Mn-, and Fe-) for sustainable
organic transformations.10 In this direction, we have studied Ni-, and
Fe-catalysed synthesis of E-selective olefins involving alkyl N-
heteroarenes with primary alcohols.11 Notably, during mechanistic
studies for the Ni-catalysed alkylation of N-heteroarenes with
alcohols, we envisioned the potential role of the Ni-H species for the
hydrogenation of the intermediate 3a’ (Scheme 1c). Therefore, 10
mol % NiBr2 and excess (50 mol %) 1,10-phenanthroline was the key
for selective alkylation.12 Again, we witnessed the diminished
reactivity for heteroaryl alcohols, cyclic alkyl alcohols, and even with
Department of Chemistry, Laboratory of Catalysis and Organic Synthesis, Indian
Institute of Technology Roorkee, Roorkee-247667, Uttarakhand, India.
E-mail: debasis.banerjee@cy.iitr.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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lepidine derivatives.12 Interestingly, the present strategy report the alcohol 2c and 1-naphthylmethanol 2g reacted smoothly with 1a, 3c
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first example of inexpensive Fe-catalysed route (5 mol % cat. and 10 and 3g were obtained in 85-89% isolated yields respectively.
DOI: 10.1039/D0CC01593H
mol % ligand) for chemo-selective alkylation of methyl N-hetero
aromatics, such as, quinaldine, lepidine, pyridines, pyrazines,
Scheme 2: Synthesis of chain-elongated heteroarenesa
isoquinolines including benzimidazole and quinoxaline with a series
Fe(OAc)2 / Phen
R
OH
2a-2v
of alkyl and hetero-aryl alcohols (Scheme 1b).
t-BuOK 1,4-dioxane,
N
R
N
Table 1. Fe-catalysed alkylation of 2-methylquinoline with alcohola
140 °C, 24 h
3, 4, 5
1a-1j
Fe(OAc)2 (5 mol%)
L1 (6 mol%)
A. Scope of quinaldine, methyl-pyrazine and lepidine with aryl alcohols
Ph
OH
KOH (1.0 equiv)
toluene, 140 °C, 24 h
From Quinaldine (1a)
Ar = Ph, 3a, 91%
Ar = 4-EtPh, 3d, 79%
N
N
Ph
N
Ph
2a
1a
72%, (gram scale)
Ar = 4-i-PrPh, 3e, 62%
Ar = 4-OMePh, 3f, 87%
Ar = 1-Naphthyl, 3g, 89%
3a
3a'
Ar = 4-MePh, 3b, 85%
Ar = 2-MePh, 3c, 75%f
Entry Deviation from the above
Conv. (%)b
N
Ar
3a
71
6
3a’
29
0
1
-
3i, 56%b
O
S
N
2
Fe(acac)3
Fe2(CO)9
FeCl2
N
3h, 42%b
3c
4
16
10
10
40
75
76
21
35
70
55
60
25
14
11
3
N
From 2-methylpyrazine (1b)
Ar = 4-OMePh, 3l, 72%c
Ar = 1-Naphthyl, 3m, 57%c
Ar = Ph, 3j, 76%c
Ar = 4-MePh, 3k, 52%c
5
6
7
8
L3 instead of L1
L5 instead of L1
1,4-dioxane
1,4-dioxane, t-BuOK
1,4-dioxane, t-BuONa
1,4-dioxane, t-BuOK, L1 (10 mol%) 93 (91)
no Fe-cat., no L1, t-BuOK, 1,4-dioxane
N
N
Ar
Ar = Ph, 3n, 88%d
N
Ar = 4-MePh, 3o, 82%d
Ar = 4-i-PrPh, 3p, 92%d
Ar = 4-OMePh, 3q, 37%d
O
Ar
9
From Lepidine
3r, 56%b
10
11
12
(1c)
2
0
-
-
B. Scope of Substituted N-methyl heteroaromatics with alkyl alcohols
R1
no base, 1,4-dioxane
Reaction conditions: a1a (0.25 mmol), 2a (0.50 mmol), Fe(OAc)2 (0.0125 mmol),
phen (0.025 mmol), t-BuOK (0.25 mmol) in 1,4-dioxane (1.0 mL) in a pressure tube
Ph
4d, 95%
N
Ph
4c, 53%
N
Ph
under N2 atmosphere at 140 °C (oil bath) for 24 h. bIsolated yield, Fe2(CO)9 (2.5
c
O
R2
N
mol%), phen (3.0 mol%) were used. L1 = 1,10-phenanthroline. L2 = 2,9-dimethyl
1,10- phenanthroline. L3 = bipyridine. L4 = 4,4’ -dimethylbipyridine. L5 = 2,2’-
biquinoline. Conversions were calculated based on 1a.
R1= H, R2= OMe, 4a, 92%
R1= OMe, R2= H, 4b, 30%e
N
Ar = Ph, 4e, 76%
Ar = 3,4 -(Methylenedioxy)Ph, 4f, 82%b
Ar = 4-ClPh, 4g, 12%b,h (4e, 16%)
Ar = 4-BrPh, 4h, 4%b,h (4e, 14%)
Ar = 4-CF3Ph, 4i, ndb,h (4i', 35%)
Ar = 4-CNPh, 4j, ndb,h
Primarily, we systematically investigated the model reaction
involving 2-methylquinoline (1a) with benzyl alcohol (2a) using
different Fe-catalysts (Table 1, entries 1-4). To our delight, Fe(II)
acetate (5 mol%) and 1,10-phenanthroline L1 (6 mol%) gave 71%
isolated yield of 3a, when using KOH (1.0 equiv.) as a base.
Interestingly, olefin 3a’ was also detected in the GC-MS analysis
(Table 1, entry 1 and SI Table S1). Further, to improve the product
yields and selectivity of 3a, electronically different nitrogen-based
ligands L2-L5 were tested and proved less efficient (Table 1, entries
5-6 and SI Table S2). Next, influence of different non-polar or polar
solvents (p-xylene, 1,4-dioxane, N, N-dimethyl acetamide and t-amyl
alcohol) were examined and found 1,4-dioxane as promising solvent
for the alkylation process (Table 1, entry 7 and SI Table S3).
Thereafter, application of different bases (t-BuOK, t-BuONa, NaOH,
KOH and K2CO3) in 1,4-dioxane resulted in up to 76% conversion to
3a (Table 1, entries 8-9 and SI Table S4). At this point, we realized the
potential role of the ligand L1 to control the product selectivity. As
expected, an increment to 10 mol% of L1 gave almost quantitative
yield of 3a (Table 1, entry 10 and SI Table S5). Alkylation reaction
using lower catalyst loading resulted albeit with poor product yield.
Control experiments, revealed the significant role of the individual
component and poor alkylation product observed in case of lower
catalyst and base loading (entries 11-12, SI Tables S1-S5). Notably,
we observed benzaldehydeformation in 1H-NMR and GC-MS analysis
of the crude reaction mixture (Scheme 1c).
N
Ar
Ar = 4-PhCO2Ph, 4k, ndb,h
Bn
N
N
Ph
4l, 47%g
4m, 35%c
N
Ph
C. Scope of N-methyl heteroaromatics with alkyl alcohols
5a, 57%b
n
N
N
N
5c, n= 5, 44%b
5d, n= 7, 49%b
5e, n= 9, 50%b
5f, n= 11, 53%b
N
5b, 42%b
5g, 57%b
Reaction Conditions: a1a (0.25 mmol), primary alcohol 2a (0.50 mmol), Fe(OAc)2 (0.0125
mmol), phen (0.025 mmol), t-BuOK (0.25 mmol) using 1,4-dioxane (1.0 mL) in pressure
tube under N2 atmosphere at 140 °C in a pre-heated oil bath for 24 h. b2 (0.75 mmol),
c
Fe(OAc)2 (0.025 mmol), phen (0.075 mmol), t-BuOK (0.375 mmol), 36 h. 36 h. dt-BuOK
e
(0.25 mmol), 24 h. t-BuOK (0.375 mmol), 36 h. f 2 (0.75 mmol), Fe(OAc)2 (0.025 mmol),
phen (0.075 mmol), t-BuOK (0.375 mmol), 36 h, 150 °C. g2-methylpyridine N-oxide is used
(0.25 mmol), Fe(OAc)2 (0.025 mmol), phen (0.075 mmol), t-BuOK (0.50 mmol), 36 h. hGC-
MS conversion based on 1h.
Notably, more challenging, furan-2yl-methanol, 2h and thiophene-
2yl-methanol 2i coupled with 1a and transformed into the bis-
heteroarylated alkanes 3h-3i in 42-56% yields (Scheme 2). Further,
when using, 2-methylpyrazine, 1b as coupling partner with
electronically different benzyl alcohols (2a,b and 2f,g), the desired
alkylated pyrazines were obtained in up to 76% yields (3j-3m,
Scheme 2). Remarkably, 4-methylquinoline (lepidine, 1c) also
participated efficiently with different aryl and heteroaryl
alcohols and transformed into the desired 4-alkylatedquinolines
3n-3r, in up to quantitative yields (up to 92%, Scheme 2).
Next, using the standard conditions of (Table 1, entry 10), a series of
primary alcohols were examined with quinaldine, pyrazine and
lepidine in good to excellent yields (Scheme 2). Initially, when 2-
methylquinoline 1a was employed with benzyl alcohols (2b, 2d-f)
bearing p-methyl, p-ethyl, p-iso-propyl and p-methoxy substituents,
resulted the desired alkylated products 3b and 3d-3f in up to 87%
yields (Scheme 2). Importantly, sterically hindered o-methyl benzyl
After having excellent reactivity, we further extended the alkylation
process using electronically different alkyl N-heteroaromatics with
2 | J. Name., 2012, 00, 1-3
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benzyl alcohols (Scheme 2). To our delight, 8-methoxyquinaldine 1d, Remarkably, the current protocol is tolerant to quinalVdieinweA,rtlieclpeiOdninlinee,
afforded almost quantitative yield (91%) to 4a. However, the pyridines, pyrazines, isoquinolines, benzimidazole including
DOI: 10.1039/D0CC01593H
reaction with 6-methoxyquinaldine 1e, was sluggish and resulted quinoxaline. A series of cyclic and acyclic alkyl alcohols, hetero-aryl
acceptable yield to 4b. Whereas, 8-alkoxyquinaldine 1f furnished the alcohols, sterically hindered 2-methylbenzyl alcohols including allylic
alkylated product 4c in moderate yield (53%, Scheme 2). Notably, 1- ether and terminal olefin functionalities participated efficiently.
methylisoquinoline 1g and 2-methylquinoxaline 1h, efficiently However, we observed diminished reactivity in case of benzyl
transformed into the products 4d-4e in 76-95% yield respectively alcohols having halides, nitro and nitrile functionalities including
(Scheme 2). Importantly, 3,4-methylenedioxybenzyl alcohol 2j, gave pyridine motif.
the desired functionalised product 4f in 82% yield (Scheme 2).
However, benzyl alcohols (2k-2o) bearing chloro, bromo,
Scheme 4: Catalytic and mechanistic studiesa(see SI)
a. Evidence of the 2-styrylquinoline intermediate and catalytic deuteration studies
trifluoromethyl, nitrile and phenyl ester functionalities did not result
standard conditions
93 %
Ph
OH
the desired products (4g-4k) and only de-halogenated products or
intermediated olefin was detected in the GC-MS analysis.
Interestingly, 2-methyl-pyridine did not participate for the alkylation
process under the standard conditions. However, 2-methylpyridine
N-oxide 1i, resulted the deoxygenated alkylated pyridine 4l in
moderate yield (47%, Scheme 2). Again, 2-benzyl-benzo[d]azole 1f,
efficiently participated and resulted the interesting heteroarene 4m
N
Ph
N
Ph
2a
3a
3a'
H/D (33%)
b
D
D
standard conditions
OH
91%
a
Ph
N
Ph
N
Ph
H/D (36%)
3a-d2
2a-d2 (92 % D)
3a'
b. Parallel and competetive experiments
standard conditions
H/D (88%)
D
D
b
t-BuOK (2 eqiv.)
a
(i)
Ph
OH
N
Ph
in 35% yield (Scheme 2).
N
N
N
N
30 %
1a
1a
2a-d2 (92 % D)
H/D (70%)
3a-d2
Scheme 3: Synthetic applications and drug synthesis a (see SI)
standard conditions
t-BuOK (2 eqiv.)
H/D (6%)
N
N
b
a
Ph
OD
Fe(OAc)2 / Phen
(ii)
Me
N
Ph
97 %
Ar
OH
2a-d1 (98 % D)
Ar
3a-d2
t-BuOK 1,4-dioxane,
N
N
Ar
H/D (8%)
140 oC, 36 h
2a,b,f
D
D
6
1k,l
standard conditions
H/D (49%)
Ph
OH
-BuOK (2 eqiv.)
t
b
Multi-functionalization of pyrazines
(iii)
2a-d2 (92 % D)
a
Ar= 4-Ph, 6c, 85%
Ar= 4-MePh, 6d, 70%
Ar= 4-OMePh, 6e, 62%
N
Ph
78 %
N
1a
Ar
N
N
Ph
Ph
OH
OH
KbH/KbD= 1.05
3a-d2
H/D (33%)
2a
2a
standard conditions
t-BuOK (2 eqiv.)
H/D (22%)
Ar
N
Ar
b
a
Ar
(iv)
Ar= Ph, 6a, 77%
Ar= 4-MePh, 6b, 65%
CD3
82 %
Ph
N
1a-d3 (96 % D)
3a-d2
H/D (28%)
B. Synthesis of Antimalarial drug
c. Insitu trapping of enamine intermediate
Ph
standard conditions
5h, 27%
7, 90%
+
NiCl2.6H2O /NaBH4
MeOH, rt, 5 h
1a
3a (17%)
N
N
Ph
N
H
N
N
3a'
1a
Fe(OAc)2 (10 mol%)
Phen (30 mol%)
t-BuOK (1.5 equiv)
1,4-dioxane, 140 °C, 36 h
9 (50%)
MeI/K2CO3
t-BuOK (2.0 equiv.)
D2O
THF, reflux, 12 h
+
D
N
N
toluene, 140 °C, 12 h
(Antimalarial drug)
1a-d1 (20%)
N
Thereafter, we focused to gain deeper insight into the reaction
mechanism for the alkylation process and a series of deuterium-
labelling and control experiments were performed (Scheme 4). At
the beginning, 2-styrylquinoline 3a’ was employed with 2a and 2a-d2
(92% D) under standard conditions and afforded 3a and 3a-d2 in up
to 93% yield. We observed 33-36% deuterium incorporation at 3a-d2
(Scheme 4a and SI, Scheme S5). Further, alkylation of 1a using 2a-d2
(92% D) or 2a-d1 (98% D), indicated the formation of H/D-scrambled
product 3a-d2 in variable yields (Scheme 4bi-ii, SI, Schemes S1-S2).
However, in case of 2a-d1 only 6-8% deuterium incorporation
indicated the micro-reversible HB process using iron-catalysis.13
Additionally, a competitive experiment using 1:1 mixture of 2a and
2a-d2 with 1a also established the micro-reversible HB
transformations (Scheme 4biii and SI, Scheme S3). Notably, the
alkylation reaction of 1a-d3 with benzyl alcohol 2a resulted the
formation of 3a-d2 in 82% yield and exhibited 22-28% deuterium
incorporation (Scheme 4biv and SI, Scheme S4). These deuterated
experimental findings are in agreement for the D/H exchange
following hydrogen auto-transfer principle (Scheme 4 and SI,
Schemes S1-S5).13a
OH
(±) Angustureine; 8, 86%
N
2w
Me
1a
Next we studied the alkylation of 1a with more challenging cyclic and
acyclic alkyl alcohols (Scheme 2). To our delight, reactions of 1a with
cyclopropylmethanol 2p, and cyclohexylmethanol 2q, converted into
the desired alkylated derivatives 5a-5b in moderate yields (42-53%,
Scheme 2). Gratifyingly, acyclic linear C4-C12 alkyl alcohols, 2r-2u
and 2w smoothly participated with 1a and transformed into the
chain-elongated quinolines in up to 53% isolated yields (5c-5f and 5h,
Schemes 2-3). Similarly, citronellol 2v (a natural acyclic
monoterpenoid) chemo-selectively alkylated with 1a and resulted in
57% yield of 5g without significantly affecting the olefinic double
bond (Scheme 2).
For a practical application, the catalytic protocol was applied for the
one-pot multi-functionalisation of pyrazine derivatives. For instance,
2,6-dimethyl pyrazine 1k, and 2,5-dimethyl pyrazine 1l, employed
with substituted benzyl alcohols (2a-b and 2f) and resulted the
interesting bis-alkylated pyrazines in up to 85% yields (6a-e, Scheme
3). Notably, these bis-functionalised pyrazines widely used in
materials applications.2 A gram scale reaction could be performed
using standard conditions and 72% yield of 3a was obtained (Scheme
2 and ESI, Scheme S8, 1.17 g). For a synthetic application, we made
an attempt for the straightforward synthesis of the anti-malarial drug
(±) Angustureine 8. Ni-catalysed hydrogenation followed by N-
methylation of the alkylated product 5h, resulted the desired drug 8
in excellent yield (Scheme 3).1 These examples highlight the
importance of the present protocol.
Nevertheless, a series of control experiments were performed using
1a with 4-methoxybenzaldehyde 2f’ and 2f in presence and absence
of iron-catalyst, revealed the significant role of the Fe-catalyst for the
alkylation process (Scheme S11). Moreover, alkylation of the model
reaction (Table 1) was monitored using gas chromatography analysis
for 22 h and revealed the constant formation of benzaldehyde 2a’
following dehydrogenation of alcohol 2a (SI, Scheme S7).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Gratifyingly, we have studied the 1H-NMR analysis for the detection (6) (a) B. Blank and R. Kempe, J. Am. Chem. Soc., 2010,V1ie3w2A,r9tic2le4-O9n2lin5e;
of in situ generation of water during alkylation process (SI, Scheme (b) Y. Obora, S. Ogawa and N. Yamamoto, DJ.OOI:r1g0..1C0h3e9m/D.0, C2C010125,9737H,
S10). Finally, to determine the rate and order of the reaction, two 9429-9433; (c) C. Chaudhari, S. M. A. H. Siddiki and K. Shimizu,
sets of kinetics experiments were performed and we observed the Tetrahedron Lett., 2013, 54, 6490-6493; (d) T. Feng, H. Li, D. Young
first order kinetics (SI, Scheme S6).
and J. Lang, J. Org. Chem., 2017, 82, 4113-4120; For recent selected
Based on our initial mechanistic and control experiments, we examples, see: (e) Z. Tan, H. Jiang and M. Zhang, Chem. Commun.,
proposed a possible catalytic cycle in Scheme 1c.12 Primarily, to 2016, 52, 9359-9362; (f) C.-S. Wang, T. Roisnel, P. H. Dixneuf and J.-
establish the involvement of 1a’, we proposed the base mediated F. Soule, Org. Lett., 2017, 19, 6720-6723; For others closely related
(de)aromatization of quinaldine 1a to 1a’. For instance, in absence of examples, see: (g) Z. Tan, H. Jiang, and M. Zhang, Chem. Commun.,
base, no 3a was formed (Table 1, entry 12), highlighting the essential 2016, 52, 9359-9362; (h) C. Zhou, Z.Tan, H. Jiang and M. Zhang,
role of t-BuOK for (de)aromatization of quinaldine. Additionally, ChemCatChem, 2018, 10, 2887-2892.
(7) (a) R. M. Bullock, Catalysis Without Precious Metals, Wiley-VCH,
Weinheim, 2010; (b) R. J. M. K. Gebbink and M.-E. Moret, Non-Noble
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when 1a was reacted with D2O and t-BuOK at 140 C for 12 h, 1a-d1
was formed in 20% yield (Scheme 4c). Again, to trap the intermediate
1a’, an in situ experiment was performed using 1a with 3a’ and
resulted 9 in 50 % yield (Scheme 4c). These, control experiments
strongly support the participation of enamine 1a’ (SI, Scheme S9). On
the basis of our initial findings and literature report, we anticipated
that, initially, alcohol 2a undergoes dehydrogenation to aldehyde 2a’
catalyzed by iron and transient Fe-H species is formed (Scheme 1c).9
Afterward, aldehyde coupled with enamine 1a’ to the intermediate
3a’. Successive hydrogenation of 3a’ by transient Fe-H species gave
alkylated product 3a with the elimination of water (Scheme 1c).
Notably, chemo-selective alkylation was achieved when 1,4-dioxane
was used as solvent and facilitate the hydrogenation of 3a’ by Fe-H
species.11a Nevertheless, Meerwein-Ponndorf mechanism for such
process is another possibility.13b
In summary, we have reported an operationally simple and cost-
efficient iron-catalysed system for the alkylation of 2-methyl and 4-
methylazaarenes with alcohols. A series of substituted N-hetero-
arenes could efficiently participated with various cyclic and acyclic
alkyl alcohols, hetero-aryl alcohols having allylic and terminal olefin
functionalities. Multi-functionalisation of pyrazines, synthesis of
anti-malarial drug (±) Angustureine including initial mechanistic
investigation, kinetic studies and trapping of the enamine
intermediate 1a’ are of special highlights.
The authors thank DAE-BRNS, India (Young Scientist Research Award
to D. B., 37(2)/20/33/2016-BRNS). IIT Roorkee (SMILE-32) and DST
(FIST) are gratefully acknowledge for providing instrumentation
facilities. L. M. K. and S. B. thank UGC (India) and INSPIRE Fellowship
(DST/2017/IF170766) for financial support.
Conflicts of interest
There are no conflicts to declare.
(12) M. Vellakkaran, J. Das, S. Bera and D. Banerjee, Chem. Commun.
2018, 54, 12369-12372.
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DOI: 10.1039/D0CC01593H
Graphical Abstract:
Iron-catalysed alkylation of methylazaarenes with primary
alcohols is presented. The catalytic protocol is highly
selective for alkylation process and generates water as by-
product.
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