Transition metal-free α-C(sp3)-H bond functionalization of amines by oxidative cross dehydrogenative coupling reaction: Simple and direct access to C-4-alkylated 3,4-dihydroquinazoline derivatives

Article abstract of DOI:10.1002/adsc.201200679

A transition metal-free catalytic system has been developed for the cross dehydrogenative coupling of amines with nitroalkanes under mild condition employing potassium iodide/tert-butyl hydrogen peroxide catalytic system. This methodology was further extended for the construction of biologically important N-heterocycles, namely, 3,4-dihydroquinazoline derivatives. This novel strategy provides a simple, efficient, and direct access to 4-alkyl-3,4- dihydroquinazoline derivatives. Copyright

Full text of DOI:10.1002/adsc.201200679

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DOI: 10.1002/adsc.201200679
3
À
Transition Metal-Free a-C(sp ) H Bond Functionalization
N
of Amines by Oxidative Cross Dehydrogenative Coupling
Reaction: Simple and Direct Access to C-4-Alkylated
3,4-Dihydroquinazoline Derivatives
R. Arun Kumar,a G. Saidulu,a K. Rajendra Prasad,a G. Sathish Kumar,a
B. Sridhar,b,* and K. Rajender Reddya,*
a
Inorganic and Physical Chemistry Division, CSIR – Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500
607, India
Fax : (+91)-040-2716-0921; e-mail: rajender@iict.res.in or rajenderkallu@yahoo.com
Laboratory of X-ray Crystallography, CSIR – Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 607,
b
India
E-mail: bsridhar@iict.res.in
Received: July 31, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200679.
Abstract: A transition metal-free catalytic system
has been developed for the cross dehydrogenative
coupling of amines with nitroalkanes under mild
condition employing potassium iodide/tert-butyl hy-
drogen peroxide catalytic system. This methodology
was further extended for the construction of biolog-
ically important N-heterocycles, namely, 3,4-dihy-
droquinazoline derivatives. This novel strategy pro-
vides a simple, efficient, and direct access to 4-
alkyl-3,4-dihydroquinazoline derivatives.
termediates and have been widely used for the con-
struction of biologically and pharmaceutically impor-
tant compounds. After the pioneering studies by Mur-
ahashi and Li, several methods have been developed
À
for the transition metal-catalyzed oxidative a-C H
bond functionalization of amines.[2] In the case of
metal free systems, stoichiometric oxidants such as hy-
pervalent iodine compounds,[3a–c] 2,3-dichloro-5,6-di-
cyanohydroquinone (DDQ),[3d] benzoyl peroxide
(BPO)[3e] and tropylium salts[3f] have been used for
À
the a-C H bond functionalization of amines. Very re-
Keywords: C C bond formation; 3,4-dihydroquina-
cently metal (Ru, Ir) complexes,[5a–c] organic dyes[5e–f]
and mesoporous graphitic carbon nitride (mpg-
C3N4)[5g] have successfully been used as visible light
photoredox catalysts for amine functionalizations.
However, the above methods have certain disadvan-
tages, for example, in case of metal catalysts, the use
of expensive metals and separation of metal impuri-
À
zolines; homogenous catalysis; oxidative coupling;
peroxides; potassium iodide
À
The construction of C C bonds from two unactivated ties are major concerns. Similarly, generation of large
C H bonds through an oxidative cross-dehydrogena- amounts of undesired by-products with stoichiometric
À
tive coupling (CDC) reaction is recognized as an ele- oxidants and use of special equipment with expensive
gant and promising strategy in modern organic and synthetically complex dyes in photocatalytic
chemistry, mainly because it avoids prefunctionalized routes seriously limit the practical application of these
substrates prior to coupling reactions and this makes methods. Therefore, the development of an efficient,
the synthetic route shorter and more atom-economi- operationally simple and convenient metal-free cata-
cal.[1] Generally, CDC reactions are accomplished lytic system for the functionalization of amines is
using transition metal catalysts with different oxidants highly desirable.
such as organic peroxide, H2O2, oxygen and so on.[1]
Tetrahydroisoquinoline (THIQ) derivatives are
Among these reactions, activation of sp C H bonds widely present in natural products[6] and have signifi-
(via a reactive iminium ion intermediate) adjacent to cant biological applications.[7] Apart from the conven-
nitrogen atom in heterocycles under oxidative condi- tional synthetic routes,[8] in recent years a large
tions with various pro-nucleophiles has received much number of reports are devoted to the synthesis of
attention, since functionalized amines are versatile in- THIQ derivatives via the CDC approach.[2–5] On the
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Scheme 1. Synthesis of tetrahydroisoquinoline and 3,4-dihydroquinazoline derivatives via the CDC reaction.
otherhand no such methods have been reported for free (KI/aq. TBHP) catalytic system for the synthesis
3,4-dihydroquinazoline derivatives. 3,4-Dihydroquina- of tetrahydroisoquinoline derivatives through the
zoline derivatives are well known natural alkaloids[9] CDC reaction and an unprecedented one-pot synthe-
and they have been used as a trypanothione reductase sis of 3,4-dihydroquinazoline via an oxidative CDC
(TryR) inhibitor,[10] BACE-1 inhibitor,[11] T-type calci- reaction (Scheme 1).
um channel blocking agent,[12] and especially as
To begin our study, 2-phenyl-1,2,3,4-tetrahydroiso-
cancer treatment agent.[13] Several multi-step ap- quinoline 1a was chosen as a model substrate and
proaches are known for the synthesis of 3,4-dihydro- treated with nitromethane 2a (2 mL) using KI as cata-
quinazoline derivatives using harmful carbodiimide, lyst and aq. TBHP as an external oxidant. It was
isocyanate, azide and isocyanide derivatives.[14] The found that 5 mol% of KI, in the presence of 1.5
limitations of these methods for synthesizing such al- equivalents of aq. TBHP in 2 mL of nitromethane at
kaloids heavily impede their biological studies. 508C were the best conditions for the conversion of
Hence, the discovery of novel and more direct ap- 1a to 3a (see the Supporting Information for details).
proaches for the synthesis of such compounds from Under the optimized reaction conditions, different ni-
simple starting material is highly welcome.
troalkanes were used to react with various THIQ de-
For the last few years, we have been focusing on rivatives and representative results are listed in
metal-free catalytic systems for oxidative organic Table 1. THIQ derivatives gave excellent yields of the
transformation,s particularly with halogens and deriv- desired CDC products (Table 1, compounds 3a–3q).
atives. In this regard, we have demonstrated a variety
We have shown previously that 1,2,3,4-tetrahydro-
of oxidative organic transformations using catalytic quinazoline derivatives 7 (Scheme 1) (which were ob-
amounts of potassium iodide (KI) in thze presence of tained from the condensation of 1,3-diamines and al-
70 wt% of tert-butyl hydroperoxide in water (aq. dehydes in ethanol) could be transformed to quinazo-
TBHP) as an external oxidant.[15]
linones[15d] and quinazolines[16] under oxidative condi-
Recently, we have also demonstrated the construc- tions. Inspired by this work as well as the present re-
À
tion of N-heterocycles like 2-quinazolines and 4H- sults where we could achieve the a-C H bond
benzo[d][1,3]oxazines through cross dehydrogenative functionalization adjacent to the nitrogen atom in
G
coupling using commercially available sodium hypo- THIQ under transition metal-free conditions, we
chlorite (NaOCl).[16] To the best our knowledge, there planned to functionalize the analogous C-4 carbon of
À
is no report on KI-catalyzed oxidative a-C H bond cyclic 1,2,3,4-tetrahydroquinazoline derivatives with
functionalization of amines in the presence aq. TBHP different pro-nucleophiles under the CDC approach.
as an oxidant. Herein, we wish to describe a highly ef- Our attempts to activate the C-4 carbon of cyclic
ficient, operationally simple and convenient metal- product 7a directly with nitromethane as pro-nucleo-
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Transition Metal-Free a-CACTHNUGRTENUNG(sp ) H Bond Functionalization of Amines
Table 1. CDC reaction of tetrahydroisoquinoline with nitro-
treated with KI/aq. TBHP and nitroalkanes to obtain
the desired products and some representative results
are summarized in Table 2. Irrespective of the substi-
tution on the aromatic rings, the desired products
were obtained in good yields (Table 2, compounds
10a–10j). When isovaleraldehyde used as the alde-
hyde the corresponding product was obtained in
lower yield (Table 2, compound 10k).
alkanes catalyzed by potassium iodide.[a]
After this success in the one-pot synthesis of 4-(ni-
troalkyl)-2,3-substituted-3,4-dihydroquinazolines, we
planned to examine other nucleophiles for the synthe-
sis of 3,4-dihydroquinazoline derivatives through this
novel strategy. So we decided to employ the dialkyl
malonate as a nucleophile in place of nitroalkane for
the synthesis dialkyl 2-(2,3-diphenyl-3,4-dihydroquina-
zolin-4-yl)malonate. For this, the peroxy intermediate
8a was prepared by the previous procedure and then
treated with 3 equivalents of dimethyl malonate at
508C in CH3CN for 24 h. The desired product 12a
was obtained in 65% isolated yield. Under the same
conditions, various dialkyl 2-(2,3-diphenyl-3,4-dihy-
droquinazolin-4-yl)malonate derivatives were generat-
ed in moderate yields (Table 3, compounds 12a–12f).
Based on the experimental evidence we would like
to propose a plausible mechanism for the formation
of THIQ and 3,4-dihydroquinazoline derivatives as
shown in Scheme 3. In the case of 2-phenyltetrahy-
droisoquinoline the first step involves the oxidation of
KI with TBHP to generate molecular iodine and po-
tassium hydroxide,[15d] which subsequently oxidizes 1a
to iminium ion intermediate In1.[17] The intermediate
could be transformed into product 3a via a peroxy in-
termediate 4a or directly with the azinic acid tauto-
mer of nitromethane 2a as shown in the mechanism.
Recently Klussmann and co-workers have shown the
formation of both iminium ion In1 and peroxy inter-
mediates 4a in copper-catalyzed oxidative coupling re-
actions.[2w] They have clearly stated that the iminium
ion intermediate could be observed under aerobic ox-
idtion but not with TBHP. Similarly under the present
TBHP conditions we could not isolate the iminium
ion intermediate In1. This was further supported by
NMR analysis, where the reaction of 1a with KI
(10 mol%) in presence of aq. TBHP (2 equiv.) in eth-
anol without nitromethane showed the exclusive for-
mation of peroxy intermediate 4a without any signal
[a]
Reaction conditions: amine (0.5 mmol), KI (5 mol%), aq.
TBHP (1.5 equiv.), nitroalkane (2 mL), 508C, 6 h.
Numbers in parentheses are the yields [%] of the product
by NMR analysis.
[b]
phile were not successful (Scheme 2, path a). Howev- corresponding to the iminium ion In1. Furthermore,
er, the desired product 10a was obtained in good peroxy intermediate 4a was isolated by column chro-
yield, when we added the reagents in a step-wise matography and subsequently reacted with nitrome-
manner through the formation of a-amino peroxy in- thane to afford the product 3a quantitatively.[18]
termediate 8a, which was prepared by our earlier pro-
cedure using the KI/aq. TBHP catalytic system[15d] anticipate a similar mechanism where in situ generat-
(Scheme 2, path b). ed molecular iodine and potassium hydroxide from
Similarly, in the case of 3,4-dihydroquinazoline, we
Under the same reaction conditions, various struc- the KI/aq. TBHP system oxidize the cyclic compound
turally diverse aromatic and aliphatic aldehydes 6 7a to iminium ion In3 through In2. Subsequently imi-
were coupled with 1,3-diamine derivatives 5 to yield nium ion In3 is trapped by TBHP converting to the
cyclocondensation products which were subsequenly corresponding 4-tert-butylperoxy-2,3-diphenyl quina-
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Scheme 2. One-pot synthesis of 4-(nitromethyl)-2,3-diphenyl-3,4-dihydroquinazoline via CDC reaction using the KI/aq.
TBHP catalytic system. Reagents and conditions (Path a): (i) EtOH, room temperature, 3 h; (ii) nitromethane (2 mL), KI
(20 mol%), aq. TBHP (4 equiv.), 508C, overnight. Reaction conditions (Path b): (i) EtOH (2 mL), room temperature, 3 h; (ii)
KI (20 mol%), aq. TBHP (4 equiv.), room temperature, overnight (iii) nitromethane (2 mL), 508C, 8 h.
Scheme 3. Plausible mechanism for the formation of tetrahydroisoquinoline and 3,4-dihydroquinazoline derivatives.
zoline 8a. Interestingly, the formation of 2,3-diphenyl- the peroxy 8a and hydroxy 9a species seem to be key
3,4-dihydroquinazolin-4-ol 9a as a minor product was intermediates/precursors which could be transformed
also observed, which was isolated and characterized to product 10a by nitromethane 2a without the influ-
by single crystal X-ray analysis (Figure 1).[19,20] Both ence of catalyst. This was further confirmed by NMR
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Transition Metal-Free a-CACTHNUGRTENUNG(sp ) H Bond Functionalization of Amines
Table 2. One-pot synthesis of 4-(nitroalkyl)-2,3-substituted-
3,4-dihydroquinazoline via the CDC reaction using KI/aq.
TBHP.[a]
Table 3. One-pot synthesis of dialkyl 2-(2,3-diaryl-3,4-dihy-
droquinazolin-4-yl)malonates via the CDC reaction using
KI/aq. TBHP.[a]
[a]
Reaction conditions: (i) 1,3-diamine (0.5 mmol), aldehyde
(0.5 mmol), EtOH (2 mL), room temperature, 3 h; (ii) KI
(0.2 mmol), aq. TBHP (4 equiv.), room temperature,
overnight; (iii) Dialkyl malonate (3 equiv.), CH3CN
(2 mL), 508C, 24 h.
[b]
Numbers in parentheses are yields [%] of pure products
after column chromatography.
[a]
Reaction conditions: (i) 1,3-diamine (0.5 mmol), aldehyde
(0.5 mmol), EtOH (2 mL), room temperature, 3 h; (ii) KI
(0.2 mmol), aq. TBHP (4 equiv.), room temperature,
overnight; (iii) nitroalkane (2 mL), 508C, 8 h.
[b]
Numbers in parentheses are isolated yields [%] of pure
products after column chromatography.
experiments, where the formation of product 10a was
observed with intermediates 8a, 9a, which were isolat-
ed by column chromatography and treated with nitro-
methane.[18] In a similar manner, dimethyl malonate
can react with 8a, 9a to generate 12a.
In summary, we have demonstrated a highly effi-
cient, operationally simple and metal-free catalytic
method for the synthesis of tetrahydroisoquinoline
derivatives through a cross-dehydrogenative coupling
(CDC) reaction, employing potassium iodide as cata-
lyst and aq. TBHP as an external oxidant. This CDC
methodology was further explored for the first time
towards the synthesis of biologically important 3,4-di-
Figure 1. ORTEP drawing of compound 9a (CCDC 887280).
Atoms are represented by displacement ellipsoids at the
hydroquinazoline derivatives from simple aldehydes 30% probability level.[20]
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(0.2 mmol) and 0.25 mL of 70 wt% TBHP in H2O (4 equiva-
lents) were added dropwise for 5 min and stirred at room
temperature overnight. The solvent (EtOH) was removed
under reduced pressure. Then residue was treated with di-
and 1,3-diamine derivatives using the same catalytic
system (KI/aq. TBHP). Further research on the de-
tailed mechanistic elucidation, as well as application
of this methodology to the synthesis of biologically
important molecules having tetrahydroisoquinoline
and 3,4-dihydroquinazoline as a core structure are on-
going in our laboratory.
AHCTUNGTERGNUNaN lkyl malonates (3 equivalents) in CH3CN 2 mL. The mix-
ture was heated to 508C for 24 h. The progress of the reac-
tion was monitored by TLC. After cooling to room tempera-
ture, the solvent (CH3CN) was removed under vacuum. The
product was isolated by column chromatography using
hexane/ethyl acetate mixture as eluent and was analyzed by
1H NMR, 13C NMR, IR, ESI-MS and ESI-HR-MS.
Experimental Section
For full experimental and spectral details see Supporting In-
formation.
Acknowledgements
R.A.K., K R P., and G.S.K, thank the Council of Scientific
and Industrial Research (CSIR) and G.S thanks the Universi-
ty Grants Commission (UGC) for the award of research fel-
lowships.
General Procedure for Synthesis of Tetrahydro-
isoquinoline Derivatives using KI/aq. TBHP
To
a
solution of 2-aryl-1,2,3,4-tetrahydroisoquinoline
(0.5 mmol) and potassium iodide (5 mol%) in 2 mL of nitro-
alkane, 0.1 mL of 70 wt% aqueous TBHP (1.5 equivalent)
was added dropwise with stirring over a period of 5 min.
The reaction mixture was stirred at room temperature
before the reaction temperature was increased to 508C.The
reaction mixture was stirred at this temperature (508C) for
another six hours. Reaction progress was monitored by
TLC. After cooling to room temperature, removal of the
solvent under vacuum afforded the crude product. The
crude product was extracted with ethyl acetate and washing
with saturated sodium thiosulphate (Na2S2O3) solution,
water and brine solution. The organic layer was collected
and dried over Na2SO4. The solvent was removed under re-
duced pressure. The crude compounds were used for spec-
tral analysis.
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General Procedure for One-Pot Synthesis of Dialkyl
2-(2,3-Diaryl-3,4-dihydroquinazolin-4-yl)malonates
via CDC Reaction using KI/aq. TBHP
To a solution of 1,3-diamine (0.5 mmol) in 2 mL of ethanol,
the aldehyde (0.5 mmol) was added and the mixture stirred
at room temperature for 3 h. To the same solution, KI
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