Facile synthesis of vicinal diamines via oxidation of N-phenyltetrahydroisoquinolines with DDQ

Article abstract of DOI:10.1016/j.tetlet.2008.12.101

The oxidation of N-phenyltetrahydroisoquinolines occurs rapidly with DDQ. Under ambient conditions and in the presence of nitromethane, the corresponding β-nitroamine derivatives are isolated in good to excellent yields. Variation in the electronic nature of the isoquinoline and the N-phenyl substituent showed that a broad range of substituents are tolerated, with electronic communication between the isoquinoline aromatic ring and the C1 carbon being stronger than with the N-aryl ring. Reduction of the β-nitroamines to the corresponding novel chiral vicinal diamines are straightforward. Examination of the reaction by ¹H NMR spectroscopy suggested that the reaction proceeds via an iminium ion, which then reacts with nitromethane upon work-up. This information was used to shorten the required reaction time.

Full text of DOI:10.1016/j.tetlet.2008.12.101

Tetrahedron Letters 50 (2009) 1199–1202
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of vicinal diamines via oxidation
of N-phenyltetrahydroisoquinolines with DDQ
*
Althea S.-K. Tsang, Matthew H. Todd
School of Chemistry, University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation of N-phenyltetrahydroisoquinolines occurs rapidly with DDQ. Under ambient conditions
and in the presence of nitromethane, the corresponding b-nitroamine derivatives are isolated in good
to excellent yields. Variation in the electronic nature of the isoquinoline and the N-phenyl substituent
showed that a broad range of substituents are tolerated, with electronic communication between the
isoquinoline aromatic ring and the C1 carbon being stronger than with the N-aryl ring. Reduction of
the b-nitroamines to the corresponding novel chiral vicinal diamines are straightforward. Examination
of the reaction by 1H NMR spectroscopy suggested that the reaction proceeds via an iminium ion, which
then reacts with nitromethane upon work-up. This information was used to shorten the required reaction
time.
Received 4 November 2008
Revised 17 December 2008
Accepted 22 December 2008
Available online 7 January 2009
Dedicated to Professor Max Crossley on the
occasion of his 60th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
There has been a great deal of recent interest in direct C–H bond
activation at sp3 centres adjacent to heteroatoms, frequently cata-
lysed by metal complexes.1 Li has developed a powerful ‘Cross-
Dehydrogenative Coupling’ in which unfunctionalised sp3 centres
can be coupled via copper(I) catalysis.2 The method gives high
yields, and is catalytic, using a copper catalyst in addition to the
stoichiometric oxidant. Fu has reported a similar procedure that
is capable of amidation of sp3 C–H bonds adjacent to nitrogen.3
We wondered whether mild reaction conditions could be found
for this important bond formation, which do not require the pres-
ence of a metal catalyst. DDQ4 was an attractive candidate reagent
since it is an inexpensive, stable crystalline solid that is easy to
handle, and has been used in the oxidative formation of C–C
bonds.5
To the best of our knowledge, such a DDQ-effected transforma-
tion has never been attempted with nitromethane as the
(pro)nucleophile. In the course of our studies towards an enantio-
selective synthesis of the important pharmaceutical praziquantel,6
we were interested in the efficient synthesis of the key diamine 1
(Scheme 1). An oxidative coupling, of the kind demonstrated by Li,
would permit the generation of the key b-nitroamine precursor 2
from tetrahydroisoquinoline 3 and nitromethane. The C–C bond
forming step would in effect be an aza-Henry reaction without
pre-formation of either nitronate or iminium ion. Oxidation of 4
to the iminium ion 5 would be followed by nucleophilic attack
by the azinic acid tautomer of nitromethane 6. Such a scheme
would access diverse b-nitroamines, which could be reduced to
valuable chiral vicinal diamines, molecules of wide use in chemis-
try and biology.7 Since 1-nitromethyl-1,2,3,4-tetrahydroisoquino-
line (2, R = H) is unstable with respect to starting materials,8 we
chose to employ N-phenylated tetrahydroisoquinolines for this
study, with a view to a later deprotection that would allow us to
liberate the diamine 1.
A screen of several available reagents confirmed that DDQ is
able to oxidise N-phenyltetrahydroisoquinoline (4a, R = Ph)9 in
good yield in a range of solvents (e.g., EtOAc, EtOH and MeOH).
The conversion was particularly efficient when nitromethane itself
was used as solvent. The reaction conditions initially identified
were mild (ca. 1 equiv DDQ, non-dried solvent, open to air, room
temperature, 3 h). The procedure involved a very simple aqueous
work-up followed by filtration through a plug of silica to yield
the product, 2a (R = Ph), in ca. 50% yield, pure by 1H NMR
spectroscopy.
Variation in the number of equivalents of DDQ was then as-
sayed. Starting material was reclaimed when less than 1 equiv of
DDQ was used, and use of more than 1.2 equiv of DDQ gave rise
to other products according to monitoring by TLC (presumably
through over-oxidation to the corresponding isoquinolinium ions).
While one equivalent of DDQ gave good results, it was found that
the use of 1.1 equiv gave a significantly faster conversion. When
the concentration of the reaction mixture was varied (between
0.48 and 0.024 M starting material) it was found that the best com-
bination of rate and ease of handling (low viscosity and low dilu-
tion) was at
a concentration of approximately 0.15 M (e.g.,
100 mg starting material in 5 mL MeNO2).
We then turned to variation of the substrate. If the mechanism
of this oxidation is hydride abstraction by DDQ, then the reaction
should be sensitive to electronic variation of the substrate.
N-Aryltetrahydroisoquinolines 4a–c,e were synthesised via
* Corresponding author. Tel.: +61 2 9351 2180; fax: +61 2 9351 3329.
E-mail address: m.todd@chem.usyd.edu.au (M.H. Todd).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.101

1200
A. S.-K. Tsang, M. H. Todd / Tetrahedron Letters 50 (2009) 1199–1202
Scheme 1. Proposed synthesis of chiral vicinal diamine 1 using an oxidative coupling of tetrahydroisoquinolines and nitromethane, via iminium ion 5.
the optimised procedure involved extraction with several portions
of CH2Cl2, and washing with saturated sodium bicarbonate solu-
tion, followed by loading the residual nitromethane solution (after
removal of the volatiles) directly onto a short silica gel flash
column.13
It can be seen from these data that the reaction is more influ-
enced by changes in R2 than R1: yields are generally lower when
R2 = OMe, whereas there are no clear trends for variation in yield
Scheme 2. Reduction of N-phenyl-b-nitroamines, and attempted cleavage of the
N-p-methoxyphenyl protecting group in 8b.
with variation in R1. We were able to obtain a crystal structure
of one of the precursor compounds (4e, Fig. 1),14 which clearly
showed the C-1 carbon (the site of reaction) to be coplanar with
the isoquinoline aromatic ring, but non-coplanar with the N-phe-
nyl ring. These results suggest electronic communication between
the C-1 position and the isoquinoline aromatic ring is more effi-
cient (and influential) than with the N-phenyl ring.
copper(I)-catalysed coupling of aryl iodides and the relevant tetra-
hydroisoquinoline.9 The NO2-substituted derivatives, 4d and 4h,
were more troublesome and attempted synthesis using the same
procedure was unsuccessful. We found that N-phenylation could
be achieved in these cases by a copper(II)-catalysed coupling reac-
tion10 with the p-nitrophenylboronic ester,11 furnishing 4d and 4h
in 10% and 13% yields, respectively. The low yields are due, in part,
to formation of the dinitrobiphenyl byproduct, during the coupling
reaction. Compounds 4f and 4g were synthesised through a similar
coupling reaction, but with the relevant boronic acids.12
We examined the reaction between N-phenyltetrahydroiso-
quinoline (4a) and DDQ in deuterated nitromethane over time by
1H NMR spectroscopy. The product of this reaction was isolated
in 66% yield on a preparative scale. When the reaction was run
in the NMR tube, a simple conversion of starting material to prod-
uct was not seen, and instead a number of broad signals were ob-
served that were neither starting material nor product. The
reaction appeared to halt after approximately 20 min, giving a
spectrum containing only small signals corresponding to the ex-
Subjecting these substrates to the standard reaction conditions
gave most products in good to excellent yield (Table 1). It was
found that correct work-up of the reactions was very important:
Table 1
Yields for oxidative coupling of substituted N-phenyltetrahydroisoquinolines and nitromethane with DDQ
Product 2
R1
R2
Yield (%)
a
b
c
d
e
f
H
H
H
H
H
OMe
OMe
OMe
OMe
95
80
69
58
71
52
30
68
OMe
Me
NO2
H
OMe
Me
NO2
g
h

A. S.-K. Tsang, M. H. Todd / Tetrahedron Letters 50 (2009) 1199–1202
1201
Figure 1. X-Ray crystal structure of 4e. Regular view (left) and view showing lack of coplanarity of the N-phenyl aromatic ring with position C-1 (right).
pected reaction product. By comparison with an internal standard
(1,1,2,2-tetrachloroethane), the yield of product was seen to be
approximately 10%, despite giving a far higher yield after work-
up. A large resonance could clearly be observed downfield at
9 ppm. We postulate that this downfield signal, and others ob-
served in the 1H NMR spectrum, arise from the iminium ion 5, pos-
sibly trapped as an ion pair with the phenolate 7 derived from
DDQ.15 Support for this was obtained from monitoring the reaction
by 13C NMR spectroscopy, where a broad signal appeared at
approximately 170 ppm, presumably arising from the C-1 carbon
of the iminium ion 5 in 7. The reaction between 4a and nitrometh-
ane with DDQ was not inhibited by the initial presence of 2.2 equiv
of TEMPO suggesting that the reaction does not proceed via a rad-
ical mechanism. By allowing the reaction to stand, following reac-
tion with DDQ, and adding no external nucleophile, a yellow
precipitate was formed. Isolation and dissolution in acetone-d6
gave a 1H NMR spectrum identical to that observed at the end of
the reaction. Further characterisation of this solid, presumed to
be the salt 7, is ongoing.
tween a nitrogen atom and its p-methoxyphenyl substituent is
known to be possible using ceric ammonium nitrate.18 When this
was attempted, disappearance of starting material was observed
by TLC, but adequate purification of this key diamine (which would
constitute a new formal synthesis of praziquantel) has not so far
been possible.
In summary, we have described a novel, operationally simple
method for the synthesis of chiral vicinal diamines based on a
DDQ-mediated coupling between tetrahydroisoquinolines and
nitromethane. NMR monitoring of this reaction suggests that the
DDQ oxidation is fast, and gives an intermediate iminium ion,
probably as a salt, that may be isolated. Reaction with nitrometh-
ane appears to occur during basic work-up. We used this informa-
tion to reduce the reaction time of the process to 30 min, providing
rapid access to these potentially useful structures.
Acknowledgement
We thank the University of Sydney for funding.
References and notes
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Chem. Soc. 2006, 128, 5648–5649; (e) North, M. Angew. Chem., Int. Ed. 2004, 43,
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Am. Chem. Soc. 2003, 125, 6462–6468; (g) Doye, S. Angew. Chem., Int. Ed. 2001,
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26, 1229–1232.
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Green Chem. 2007, 9, 1047–1050.
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Y.-C.; Kohlman, D. T.; Liang, S. X.; Erikkson, C. Org. Lett. 1999, 1, 1599–1602; (c)
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6. (a) Mansour, W.; El-Fayyoumy, S.; Todd, M. H. Tetrahedron Lett. 2006, 47, 1287–
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8. Thirukkumaran, T.; Muneer, A.; Leung, W.-Y.; Milewska, M.; Jensen, P.;
Schroers, J.; Todd, M. H., in preparation.
9. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–584.
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These NMR studies suggested that the reaction was essentially com-
plete after 20–30 min, and that the attachment of the nitromethane
was presumably occurring during the work-up with aqueous base.
When the reaction was re-run using a shorter reaction time of
30 min with substrate 4a, we were delighted to be able to isolate
the expected product in 95% yield. The role of the base is under
study; one could envisage roles in dissociation of the ions in 7 or
deprotonation of nitromethane (i.e., the attacking species is a nitr-
onate, not an azinic acid tautomer). It is notable that this procedure
does not require slow addition of DDQ to give high yields of prod-
ucts, unlike some related DDQ-based reactions.5f
Reduction of these b-nitroamines has never been reported.16
We found that reduction of 2a to the novel corresponding diamine
8a (Scheme 2) could not be achieved with Pd/C (starting material
reclaimed) or LiAlH4 (complex mixture) but could be achieved with
Raney nickel in an unoptimised 42% yield. The product was puri-
fied by column chromatography using 90:9:1 CH2Cl2/MeOH/aq
NH3 as eluent.17 These conditions were also found to be very effec-
tive for the reduction of 2b (66%) and 2c (86%) to the correspond-
ing novel diamines. Dephenylation of the diamines involves
oxidative removal of the phenyl group. Cleavage of the bond be-
12. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400.
13. Representative procedure: To 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(0.120 g, 0.53 mmol, 1.1 equiv) in nitromethane (5 mL) was added 2-phenyl-

1202
A. S.-K. Tsang, M. H. Todd / Tetrahedron Letters 50 (2009) 1199–1202
1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.48 mmol, 1.0 equiv). The reaction
17. (a) Representative procedure: To 1-(nitromethyl)-2-(p-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (0.519 g, 1.71 mmol) in methanol (100 mL) were added
25% of aqueous ammonia (20 mL) and Raney Nickel (10 mL). The reaction
mixture was stirred at room temperature under H2 (100 psi) for 24 h. The
reaction mixture was filtered, concentrated under reduced pressure and
extracted into ethyl acetate (100 mL). The organic phase was dried (MgSO4)
and purified by flash column chromatography (1:9:90 aq ammonia/methanol/
dichloromethane) to give the diamine 8b as a brown oil (0.272 g, 66%). 1H NMR
(MeOD 300 MHz): d 2.53 (1H, ddd, J 16.5, 7.5, 3.6, H-4), 2.75–2.97 (3H, m, H-4,
H-3), 3.47 (2H, dd, J 7.9, 3.9, CH2NH2), 3.66 (3H, s, Me), 4.46 (1H, dd, J 8.7, 5.1,
CHN), 6.76 (2H, d, J 9.0, Ar), 6.92 (2H, d, J 9.0, Ar), 7.02-7.18 (4H, m, Ar). 13C
NMR (MeOD 75 MHz): d 26.4, 44.6, 47.0, 55.9, 62.8, 115.5, 120.5, 127.1, 127.2,
mixture was stirred at room temperature for 30 min, diluted with saturated
NaHCO3 solution (50 mL) and extracted with dichloromethane (3 ꢀ 50 mL).
The organic phases were combined, washed with saturated NaHCO3 solution
(50 mL), dried (MgSO4) and concentrated under reduced pressure to give a red
liquid. The residue was purified by flash column chromatography (5:1 hexane/
ethyl acetate) to give the tetrahydroisoquinoline 2a as a pale yellow, crystalline
solid (0.121 g, 95%). mp 87–88 °C. 1H NMR (CDCl3 300 MHz): d 2.79 (1H, ddd, J
16.3, 10.1, 4.9, H-4), 3.09 (1H, ddd, J 16.3, 14.3, 7.1, H-4), 3.65 (2H, m, H-3), 4.56
(1H, dd, J 12.0, 8.0, CHHNO2), 4.87 (1H, dd, J 12.0, 8.0, CHHNO2), 5.55 (1H, dd, J
8.0, 8.0, H-1), 6.85 (1H, dd, J 7.2, 7.2, H-40), 6.97 (2H, d, J 8.1), 7.06–7.31 (6H, m).
IR (CHCl3)
m
max/cmꢁ1 1596, 1550, 1380, 1496. m/z (ESI) 208.3 ([MꢁCH2NO2]+,
100%). Spectral data matched those reported, see Refs.2a,b
14. CCDC number 707604.
.
128.2, 130.0, 136.7, 137.4, 146.1, 155.1. IR (CHCl3) m
max/cmꢁ1 2401, 1506, 1261,
1095. m/z (ESI) 269.0 (MH+, 90%), 252.1 ([MꢁNH2]+, 63%), 238.1
([MꢁCH2NH2]+, 100%). HRMS (ESI) 269.16464 (MH+); calcd for C17H21N2O
(MH+) 269.16484. 2-(p-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was
also obtained (0.052 g, 10%); (b) Lázár, L.; Kivelä, H.; Pihlaja, K.; Fülöp, F.
Tetrahedron Lett. 2004, 45, 6199–6201.
15. For discussion on the possible nature of the intermediate in DDQ reactions, see:
(a) Xu, Y.-C.; Lebeau, E.; Attardo, G.; Myers, P. L.; Gillard, J. W. J. Org. Chem.
1994, 59, 4868–4874; (b) Wang, W.; Li, T.; Attardo, G. J. Org. Chem. 1997, 62,
6598–6602.
16. For
a
recent solution to the difficulties that may be encountered in the
18. (a) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47, 2765–2768;
(b) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry 1999, 10,
221–223.
reduction of related b-nitroamines see: Anderson, J. C.; Chapman, H. A.
Synthesis 2006, 3309–3315.