Organocatalytic synthesis of methylene-bridged N-heterobiaryls

Article abstract of DOI:10.1021/acs.orglett.6b02719

A one-step synthesis of 1,1′- and 2,2′-methylene-bridged N-heterobiaryls directly from the corresponding N-heterocycles in a reaction with methylmagnesium chloride in the presence of catalytic amounts of N,N,N′,N′-tetramethylethylenediamine under thermal and microwave conditions is reported. The split-and-merge methylenation of 2,2′-N-heterobiaryls and the direct ortho-alkylation of quinoline and isoquinoline with Grignard reagents have also been developed. Mechanistic studies identified several intermediates and provided insight into the formation and roles of magnesium hydride species in the process.

Full text of DOI:10.1021/acs.orglett.6b02719

Letter
pubs.acs.org/OrgLett
Organocatalytic Synthesis of Methylene-Bridged N‑Heterobiaryls
David E. Stephens, Vu T. Nguyen, Bhuwan Chhetri, Emily R. Clark, Hadi D. Arman,
and Oleg V. Larionov*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: A one-step synthesis of 1,1′- and 2,2′-methylene-bridged N-
heterobiaryls directly from the corresponding N-heterocycles in a reaction with
methylmagnesium chloride in the presence of catalytic amounts of N,N,N′,N′-
tetramethylethylenediamine under thermal and microwave conditions is
reported. The split-and-merge methylenation of 2,2′-N-heterobiaryls and the
direct ortho-alkylation of quinoline and isoquinoline with Grignard reagents have also been developed. Mechanistic studies
identified several intermediates and provided insight into the formation and roles of magnesium hydride species in the process.
o-Methylene-bridged N-heterobiaryls 1 are an important class
of nitrogenous heterocycles with applications in drug
discovery,1 catalyst and ligand design,2 and materials science.3
Previously, they were synthesized in several steps2b or at very
high temperatures.4 We hypothesized that 1 could be accessed
directly from the corresponding N-heterocycles 2 by a reaction
with methylmagnesium halide (Scheme 1). In this case,
We report herein that the scalable synthesis of o-methylene-
bridged N-heterobiaryls 1 can be accomplished directly from
the corresponding N-heterocycles in the presence of catalytic
amounts of TMEDA (N,N,N′,N′-tetramethylethylenediamine).
Initial experiments showed that di(isoquinolin-1-yl)methane
(9) is produced in 7% yield on treatment of isoquinoline (8)
with MeMgCl in hexane at 120 °C (Table 1, entry 1). Addition
of TMEDA led to a significant improvement of the yield
(entries 2 and 3).
Scheme 1. Direct Synthesis of o-Methylene-Bridged N-
Heterobiaryls from N-Heterocycles
The optimal temperature range was 120−140 °C, and hexane
and toluene were both suitable solvents. Other amines were
inferior to TMEDA (entries 4−6), and the starting material
Table 1. Reaction Conditions for the Synthesis of o-
a
Methylene-Bridged N-Heterobiaryls
time
(h)
temp
yield
(%)
entry amine (equiv)
1
X
solvent
(°C)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
hexane
toluene
hexane
hexane
hexane
hexane
toluene
toluene
toluene
2
2
120
120
120
120
120
120
140
140
140
7
93
78
7
2
3
4
5
6
7
8
9
TMEDA (1.3)
TMEDA (1.3)
DABCO (1.3)
PMDTA (1.3)
DMEDA (1.3)
TMEDA (0.2)
TMEDA (0.1)
TMEDA (0.1)
2
2
2
15
0
2
14
14
14
95
97
65
b
b
addition of the Grignard reagent to 2 would produce
intermediate 3 that could undergo elimination of HMgX.
Disproportionation of MgHX produces magnesium hydride
and magnesium halide, as previously observed in Singaram
pinacol boronate ester synthesis.5,6 Deprotonation of 2-
methylazine 4 would produce anionic species 5 that can add
to 2 to give chelate 6. Subsequent elimination of HMgX and
deprotonation of the methylene group would furnish
intermediate 7 that would produce o-methylene-bridged N-
heterobiaryl 1 upon aqueous workup.
a
Isoquinoline (2 mmol), MeMgX (3 equiv), solvent (2 mL). 1,4-
Dimethoxybenzene was used as an internal standard added prior to
b
workup. 1 mL of toluene was used. PMDTA = N,N,N′,N″,N″-
pentamethyldiethylenetriamine. DMEDA = N,N′-dimethylethylenedi-
amine.
Received: September 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02719
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Organic Letters
Letter
remained largely unconsumed. Further experiments showed
that the reaction can be carried out efficiently with catalytic
amounts of TMEDA (entries 7 and 8). Both methylmagnesium
chloride and bromide worked well, while a lower yield was
observed for MeMgI (entries 7−9).
Interestingly, 1,1′-biisoquinoline and 2,2′-biquinoline under-
went a C−C bond cleavage with subsequent formation of the
methylene-bridged products 9 and 10 in excellent yields,
indicating that an unusual and facile C-nucleophile/C-
nucleofuge displacement takes place under the reaction
conditions (Scheme 3). Since substituted 1,1′-biisoquinolines
The reaction tolerates a number of functional groups (Figure
1). Quinolines and isoquinolines with substituents in the 3, 4, 5,
Scheme 3. Split and Merge Synthesis of o-Methylene-
Bridged N-Heterobiaryls from 2,2′-Biquinoline and 1,1′-
Biisoquinoline
and 2,2′-biquinolines can be prepared in a scalable manner
from the corresponding N-oxides,7 this route offers additional
flexibility in the synthesis of o-methylene-bridged N-hetero-
biaryls.
We have further investigated the reactions of quinoline and
isoquinoline with other alkylmagnesium halides (Figure 2). The
Figure 1. Organocatalytic synthesis of o-methylene-bridged N-
heterobiaryls.
6, and 7 positions have produced the corresponding o-
methylene-bridged biquinolines and biisoquinolines (8, 10−
21) in good to excellent yields. The reaction was also
successfully carried out under microwave irradiation. Further,
products 9 and 10 were synthesized on a preparative scale (6.3
and 1.9 g, respectively).
Quinolines reacted regioselectively at the C2 position, while
isoquinolines produced the 1,1′-methylene-bridged products.
C2-methylene-bridged bipyridines were not observed when
pyridines were subjected to the standard reaction conditions.
4,4′-Methylene-bridged biquinoline 22 was readily obtained
by a reaction of 4-chloroquinoline 23 with MeMgCl in the
presence of TMEDA (Scheme 2). 4-Hydroxyquinolne (24)
also produced 4,4′-methylene-bridged biquinoline 22, indicat-
ing that 4-hydroxy group can be readily displaced by a Grignard
reagent under these conditions.
Figure 2. Synthesis of 2-alkylquinolines and 2-alkylisoquinolines.
reactions did not produce o-methylene-bridged N-heterobiaryls
but instead afforded the corresponding 2-alkylquinolines (25
and 26) and 1-isopropylisoquinoline (27). These results are in
agreement with the observation of TMEDA-catalyzed arylation
of azines with arylmagnesium bromides reported by Da et al.8
No functionalization of the distal positions9 was observed for
quinolines and isoquinoline. This direct alkylation reaction is
complementary to the deoxygenative ortho-alkylation of
heterocyclic N-oxides.10
Several experiments were carried out to clarify the
mechanism of the reaction. First, monitoring of the reaction
of isoquinoline with methylmagnesium chloride in the presence
of TMEDA in C6D6 at 50 °C by means of 1H NMR
spectroscopy identified several intermediates along the reaction
pathway (Scheme 4). Formation of the Grignard addition
product 28, as well as 1-methylisoquinoline (29) that arises
from the loss of HMgX, was observed. Further, magnesiated
di(isoquinolin-1-yl)methane intermediate 30 was also detected.
Scheme 2. Synthesis of 4,4′-Methylene-Bridged N-
Heterobiaryls
B
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Letter
Scheme 4. Intermediates in the Reaction of Methylmagnesium Chloride with Isoquinoline
Interestingly, formation of 1,2-dihydroisoquinoline intermedi-
ate 31 was also observed. Addition of magnesium hydride
species to pyridines is a reversible process.11 Indeed, when
Scheme 5. Oxidation of the Methylene Group in
Diquinolinylmethanes 16 and 17
12
isoquinoline-1-d1 was heated with 25 mol % MgH2 in the
presence of TMEDA (1 equiv) in toluene-d8 for 2 h at 110 °C,
20% H/D exchange (40% after 21 h) took place in the C1
position of isoquinoline, indicating that magnesium hydride
addition to isoquinoline is reversible under the reaction
conditions. Intermediate 31 may serve as a pool of soluble
magnesium hydride species in solution. It is also possible that a
hydride transfer takes place directly to isoquinoline from 1,2-
dihydroisoquinoline intermediates 28 and 32,13 facilitating their
aromatization. In order to further investigate the formation and
roles of magnesium hydride species in the methylenation
process, the amount of hydrogen produced in the reaction of
quinoline with methylmagnesium chloride in the presence of
TMEDA in hexane at 120 °C was determined by means of gas
chromatography.
biaryls. The methylene bridge in the products of methylenation
can be readily oxidized by air in the presence of potassium tert-
butoxide.
Interestingly, hydrogen was formed even before the reaction
mixture was quenched with methanol (0.45 mmol H2 per 1
mmol of quinoline), indicating that magnesium hydride
participates in the deprotonation of intermediates 9 and 29
en route to magnesiated species 30 and 33. Addition of
methanol after the reaction led to generation of 0.7 mmol of
hydrogen per 1 mmol of quinoline, in agreement with the
observed 73% conversion of quinoline.
o-Methylene-bridged N-heterobiaryls 1 can be readily
oxidized to the corresponding ketones that are useful bidentate
chelators.14 For example, diquinolinylmethanes 16 and 17 were
oxidized by air in the presence of potassium tert-butoxide to
give ketones 34 and 35 in 95% and 78% yields, respectively
(Scheme 5).
In conclusion, a simple, one-step synthesis of o-methylene-
bridged biquinolines and biisoquinolines has been developed.
The reaction is catalyzed by an organic base (TMEDA).
Furthermore, the efficient split and merge methylenation of
biquinolines and biisoquinolines by methylmagnesium chloride
in the presence of TMEDA as a catalyst has also been
described. ortho-Alkylation of quinoline and isoquinoline has
been observed with other alkylmagnesium reagents. Mecha-
nistic studies point to a reversible elimination of magnesium
hydride species en route to o-methylene-bridged N-hetero-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02719.
■
S
Experimental and spectral details for all new compounds
and all reactions (PDF)
X-ray crystallographic data for compound 35 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: oleg.larionov@utsa.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Welch Foundation (AX-1788),
NIGMS (SC3GM105579), UTSA, and the NSF (CHE-
1455061) is gratefully acknowledged. Mass spectroscopic
analysis was supported by a grant from the NIMHD
(G12MD007591). We thank Prof. Donald M. Kurtz, Jr.
(UTSA) for access to a gas chromatograph in his laboratory.
C
DOI: 10.1021/acs.orglett.6b02719
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E.; Jennings, M. C.; Puddephatt, R. J. Organometallics 2006, 25, 1583.
(c) Deraeve, C.; Boldron, C.; Maraval, A.; Mazarguil, H.; Gornitzka,
H.; Vendier, L.; Pitie, M.; Meunier, B. Chem. - Eur. J. 2008, 14, 682.
REFERENCES
■
(1) (a) Bold, G.; Altmann, K.-H.; Frei, J.; Lang, M.; Manley, P. W.;
Traxler, P.; Wietfeld, B.; Brueggen, J.; Buchdunger, E.; Cozens, R.;
Ferrari, S.; Furet, P.; Hofmann, F.; Martiny-Baron, G.; Mestan, J.;
Roesel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss, E.; Emmenegger,
R.; Laesser, L.; Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss,
D.; Wood, J. M. J. Med. Chem. 2000, 43, 2310. (b) Whitnall, M.;
Howard, J.; Ponka, P.; Richardson, D. R. Proc. Natl. Acad. Sci. U. S. A.
2006, 103, 14901. (c) Richardson, D. R.; Sharpe, P. C.; Lovejoy, D. B.;
Senaratne, D.; Kalinowski, D. S.; Islam, M.; Bernhardt, P. V. J. Med.
Chem. 2006, 49, 6510.
(2) (a) Najera, C.; Gil-Molto, J.; Karlstroem, S.; Falvello, L. R. Org.
Lett. 2003, 5, 1451. (b) Burns, C. T.; Jordan, R. F. Organometallics
2007, 26, 6737. (c) Karunadasa, H. I.; Montalvo, E.; Sun, Y.; Majda,
M.; Long, J. R.; Chang, C. J. Science 2012, 335, 698.
(3) (a) Boudalis, A. K.; Donnadieu, B.; Nastopoulos, V.; Clemente-
Juan, J. M.; Mari, A.; Sanakis, Y.; Tuchagues, J.-P.; Perlepes, S. P.
Angew. Chem., Int. Ed. 2004, 43, 2266. (b) Lutz, B. R.; Dentinger, C.
E.; Nguyen, L. N.; Sun, L.; Zhang, J.; Allen, A. N.; Chan, S.; Knudsen,
B. S. ACS Nano 2008, 2, 2306. (c) Kubota, Y.; Tsuzuki, T.; Funabiki,
K.; Ebihara, M.; Matsui, M. Org. Lett. 2010, 12, 4010. (d) Lin, Y.-D.;
Ke, B.-Y.; Chang, Y. J.; Chou, P.-T.; Liau, K.-L.; Liu, C.-Y.; Chow, T. J.
J. Mater. Chem. A 2015, 3, 16831.
(4) Pagani, G. A.; Rzepa, H.; Stoppa, F.; Abbotto, A.; Bradamante, S.
Heterocycles 1995, 40, 757.
(5) Clary, J. W.; Rettenmaier, T. J.; Snelling, R.; Bryks, W.; Banwell,
J.; Wipke, W. T.; Singaram, B. J. Org. Chem. 2011, 76, 9602.
(6) (a) Dymova, T. N.; Eliseeva, N. G. Russ. J. Inorg. Chem. 1963, 8,
820. (b) Ashby, E. C.; Goel, A. B. J. Am. Chem. Soc. 1977, 99, 310.
(7) Stephens, D. E.; Lakey-Beitia, J.; Burch, J. E.; Arman, H. D.;
Larionov, O. V. Chem. Commun. 2016, 52, 9945.
(8) Zhuo, F.-F.; Xie, W.-W.; Yang, Y.-X.; Zhang, L.; Wang, P.; Yuan,
R.; Da, C.-S. J. Org. Chem. 2013, 78, 3243.
(9) For examples of distal functionalization of azines, see: (a) Chen,
Q.; Mollat du Jourdin, X.; Knochel, P. J. Am. Chem. Soc. 2013, 135,
4958. (b) Stephens, D. E.; Lakey-Beitia, J.; Chavez, G.; Ilie, C.; Arman,
H. D.; Larionov, O. V. Chem. Commun. 2015, 51, 9507. (c) Stephens,
D. E.; Lakey-Beitia, J.; Atesin, A. C.; Atesi̧ n, T. A.; Chavez, G.; Arman,
H. D.; Larionov, O. V. ACS Catal. 2015, 5, 167. (d) Stephens, D. E.;
Larionov, O. V. Tetrahedron 2015, 71, 8683.
(10) (a) Andersson, H.; Sainte-Luce Banchelin, T.; Das, S.; Olsson,
R.; Almqvist, F. Chem. Commun. 2010, 46, 3384. (b) Larionov, O. V.;
Stephens, D.; Mfuh, A.; Chavez, G. Org. Lett. 2014, 16, 864.
(c) Stephens, D. E.; Chavez, G.; Valdes, M.; Dovalina, M.; Arman, H.
D.; Larionov, O. V. Org. Biomol. Chem. 2014, 12, 6190. See also:
(d) Armitage, M. A.; Mitchell, M. B. J. Chem. Soc., Perkin Trans. 1
1990, 10, 2848. (e) Fakhfakh, M. A.; Franck, X.; Fournet, A.;
Hocquemiller, R.; Figadere, B. Tetrahedron Lett. 2001, 42, 3847.
(f) Anzai, K.; Fukumoto, H.; Yamamoto, T. Chem. Lett. 2004, 33, 252.
(g) Zhang, F.; Zhang, S.; Duan, X.-F. Org. Lett. 2012, 14, 5618.
(h) Zhang, S.; Liao, L.-Y.; Zhang, F.; Duan, X.-F. J. Org. Chem. 2013,
78, 2720.
(11) (a) de Koning, A. J.; Boersma, J.; van der Kerk, G. J. M. J.
Organomet. Chem. 1980, 186, 159. (b) de Koning, A. J.; Budzelaar, P.
H. M.; van Aarssen, B. G. K.; Boersma, J.; van der Kerk, G. J. M. J.
Organomet. Chem. 1981, 217, C1. (c) Hill, M. S.; MacDougall, D. J.;
Mahon, M. F. Dalton Trans. 2010, 39, 11129. (d) Arrowsmith, M.;
Hill, M. S.; Hadlington, T.; Kociok-Kohn, G. Organometallics 2011, 30,
̈
5556. (e) Hill, M. S.; Kociok-Kohn, G.; MacDougall, D. J.; Mahon, M.
̈
F.; Weetman, C. Dalton Trans. 2011, 40, 12500. (f) McSkimming, A.;
Colbran, S. B. Chem. Soc. Rev. 2013, 42, 5439.
(12) Michalczyk, M. J. Organometallics 1992, 11, 2307.
(13) (a) de Koning, A. J.; Budzelaar, P. H. M.; Boersma, J.; van der
Kerk, G. J. M. J. Organomet. Chem. 1980, 199, 153. (b) de Koning, A.
J.; Boersma, J.; van der Kerk, G. J. M. J. Organomet. Chem. 1980, 186,
173.
(14) (a) Puscasu, I.; Mock, C.; Rauterkus, M.; Rondigs, A.; Tallen,
G.; Gangopadhyay, S.; Wolff, J. E. A.; Krebs, B. Z. Anorg. Allg. Chem.
2001, 627, 1292. (b) Zhang, F.; Prokopchuk, E. M.; Broczkowski, M.
D
DOI: 10.1021/acs.orglett.6b02719
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