Protective group-free synthesis of new chiral diamines via direct azidation of 1,1-diaryl-2-aminoethanols

Article abstract of DOI:10.1039/c3ra23205k

A direct azidation of tertiary alcohols using sodium azide-sulfuric acid is described; the present method provides an efficient and practical path for the synthesis of new chiral diamines from unmasked 1,1-diaryl-2-aminoethanols derived from natural amino

Full text of DOI:10.1039/c3ra23205k

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Protective group-free synthesis of new chiral diamines
via direct azidation of 1,1-diaryl-2-aminoethanols3
Cite this: RSC Advances, 2013, 3, 3526
Harendra Nath Roy,a Arigala Pitchaiah,a Miri Kim,b In Taek Hwanga and Kee-In Lee*ab
Received 13th September 2012,
Accepted 18th January 2013
DOI: 10.1039/c3ra23205k
www.rsc.org/advances
A direct azidation of tertiary alcohols using sodium azide–sulfuric
acid is described; the present method provides an efficient and
practical path for the synthesis of new chiral diamines from
unmasked 1,1-diaryl-2-aminoethanols derived from natural
amino acids.
hydroxyl group activating reagents along with different azide
sources, namely, HN3/Mitsunobu conditions,11a,b diphenyl or
bis(p-nitrophenyl) phosphorazidate/DBU,11c,d NaN3/N-(p-toluene-
sulfonyl)imidazole/tetrabutylammonium iodide11e or 2-azido-1,3-
dimethylimidazolinium hexafluorophosphate/DBU.11f However,
the direct azidation of nonracemic tertiary alcohols has not been
much explored to date, presumably due to preparative difficulties.
Previously, optically active 1,1-diaryl-1,2-ethylenediamines have
been prepared by Grignard addition to N-diphenylphosphinyl
ketimines, which requires multi-step and often elaborating
synthetic sequences to introduce the necessary two aryl groups.12
It is anticipated that a direct substitution of the hydroxyl group of
1,1-diaryl-2-aminoethanols with azide under acidic conditions
would be a low cost and eco-friendly way of securing 2,2-diaryl-2-
azidoamines. Surprisingly, the synthesis of such 1,1,2-trisubsti-
tuted diamines have only been scantly demonstrated as coopera-
tive ligands during the preparation of catalysts, and their
application has been rather limited to N-protected valinol and
prolinol.13 Thus, there is a need for the development of more
flexible strategies that will accommodate a range of structural
diversity. We became interested in the preparation of such
compounds from natural amino acids, since the derivatives
seemed to be quite promising in the field of asymmetric catalysis.
We herein report a simple and practical method for the
preparation of 1,1-diaryl-1,2-ethylenediamines through the direct
azidation of 1,1-diaryl-2-aminoethanols using sodium azide–
sulfuric acid.
Initially, we examined the direct azidation of diarylmethanol
derivatives (1a and 1b) as model substrates with in situ prepared
hydrazoic acid for immediate use via the treatment of sodium
azide with sulfuric acid.14 It has been shown that the use of excess
hydrazoic acid (5–7 equiv.) is optimal and toluene is the best
choice of solvent. It was apparent that the azidation of the
hydroxyl group associated with the diaryl group proceeded readily
to give the corresponding azide in good yield.
We next focused on the direct azidation of 1,2-aminoalcohols.
1,2-Aminoalcohol derivatives have been previously prepared by
Grignard addition to amino acid esters or their N-protected
forms,15 and most of them are now commercially available. With
Amino alcohols are one of the most common structural motifs
frequently found in many complex natural products and
pharmaceuticals, chiral auxiliaries, asymmetric catalysts, and are
used in various organic transformations.1 In particular, trisub-
stituted 1,2-aminoalcohols derived from amino acids are of great
importance as the privileged structures in asymmetric synthesis.
The bulky amino alcohols are perhaps best exemplified by
oxazolidinone auxiliaries,2 bisoxazoline ligands,3 and oxazaboroli-
dine catalysts.4 Furthermore, these structures can be used to
design new catalytic systems, which may include a,a-diarylproli-
nols5 and N-heterocyclic carbenes6 in organocatalysis and their
asymmetric variants with optimized properties.7 It has been
recognized that when two geminal aryl groups are incorporated in
chiral auxiliaries and metal ligands, they are diastereotopic and
might make a great contribution to an enhanced facial selectivity
due to their own characteristics.8 However, in turn the correspond-
ing nonracemic diamines have received only scant attention and
were ignored in the evolution of asymmetric molecular catalysis.
To the best our knowledge, only DAIPEN [1,1-bis(4-methoxyphe-
nyl)-3-methyl-1,2-butanediamine] has been used extensively for the
ruthenium-catalyzed asymmetric hydrogenation of a wide range of
aromatic and amino ketones.9
Organic azides have been widely used for the introduction of
primary amino groups, in the construction of heterocyclic
structures, and especially for the ‘click chemistry’ of 1,3-dipolar
azide-alkyne cycloaddition.10 In general, the direct conversion of
alcohols to azides has been achieved mainly by employing
aGreen Chemistry Division, Korea Research Institute of Chemical Technology, Taejon
305-600, Korea. E-mail: kilee@krict.re.kr; Fax: +82 42 8607034; Tel: +82 42 8607186
bGreen Chemistry and Environmental Biotechnology Major, University of Science &
Technology, Taejon 305-333, Korea
Electronic supplementary information (ESI) available: Experimental data and
3
copies of the 1H and 13C NMR spectra. See DOI: 10.1039/c3ra23205k
3526 | RSC Adv., 2013, 3, 3526–3530
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Table 1 Direct azidation and consecutive hydrogenation of diarylmethanol derivatives
Entry
a
Alcohol (1)
Azide (2)
Yield (%)
79
Amine (3)
Yield (%)
a
-
a
b
c
81
83
-
75
82
d
e
79
70
74
f
57
63
90b
g
81
h
66
68c
i
69
83
a
b
Not determined. Adams’ catalyst was used under 50 psi of hydrogen using a Parr hydrogenation apparatus. When 10% Pd/C was used, no
c
reaction was observed until 24 h. LAH used.
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Table 2 Practical synthesis of 1,1-diaryl-1,2-ethylenediamines from unmasked 2-aminoethanols
Entry
a
Aminoalcohol (4)
Azidoamine (5)
Yield (%)
75
Ethylenediamine (6)
Yield (%)
83
b
c
74
78
83
72
d
e
73
75
62
84
f
76a
73b
a
b
For azidation of 4f, CHCl3 was used because of solubility problem. Staudinger reduction of 5f was carried out.
the substrates in hand, we firstly examined the azidation of 1c
with sodium azide–sulfuric acid at ambient temperature. As
anticipated, the azidation of 1c worked well to give the desired
2-azidoamine 2c in 83% isolated yield within 15 min of the
reaction time (Table 1, entry c). This practice is highly effective
since the protonation and dehydration process of a tertiary alcohol
is expected to take place more readily under acidic conditions.
Thus we needed to examine the feasibility of this process for a
variety of N-protected aminoalcohol derivatives containing benzy-
loxycarbonyl (Cbz), trifluoroacetyl, and p-toluenesulfonyl (Ts)
groups. It was found that the amino alcohols were uniformly
converted to the corresponding 2-azidoamine derivatives (2d–2i) in
good yield, as shown in Table 1. The chiral azides prepared could
be isolated by column chromatography on silica gel, and were fully
characterized by spectral and analytical means. A general
procedure employing hydrogenation over 10% Pd/C even with a
hydrogen balloon was routinely applied for the conversion of these
azides to amines. In particular cases, Adams’ catalyst (Pt2O) was
used instead of 10% Pd/C when trifluoroacetyl was the masking
group (entry f), and lithium aluminium hydride (LAH) reduction
was carried out when required (entry h). Thus, we achieved the
facile synthesis of new and valuable chiral diamines via the direct
azidation of 1,1-diaryl-2-aminoethanols derived from natural
amino acids.
Protecting group-free synthesis is highly desirable in the
practice of green and sustainable chemistry, reducing the costs
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reduced pressure to give a residue. The crude residue was purified
by flash silica gel chromatography (15–20% EtOAc–hexane) to
afford 5.
from additional reagents and waste disposal, and at the same
time, environmentally benign.16 However, there are only a few
reports describing access to such diamines through the direct
azidation of unmasked aminoalcohols.11a,17 The most common
aminoalcohols derived from valine, phenylglycine, phenylalanine,
and proline, were selected as unmasked substrates and reacted
and observed in the same way. The reaction profiles were quite
similar to those obtained by the use of N-protected 1,1-diaryl-2-
aminoethanols. For example, (S)-1,1,2-triphenyl-2-aminoethanol 4c
was readily converted to the corresponding azide 5c by treatment
with sodium azide–sulfuric acid in toluene within 15 min without
any problems (Table 2, entry c). In an analogous manner,
2-piperidino-1,1,2-triphenylethanol 4d, one of the most active
catalysts for the asymmetric addition of dialkylzincs to aldehydes,
also smoothly converted to 5d (entry d). In all cases, the azidation
of a,a-diarylethanols took place with an equal efficiency regardless
of the protection as illustrated in Table 2. However, no azidation
was observed when an a,a-dimethyl analog of 4b was employed.18
As usual, the reduction of azidoamines to ethylenediamines
could be accomplished by employing catalytic hydrogenation over
10% Pd/C. For example, the hydrogenation of 5a proceeded
smoothly to furnish the amine 6a in 83% yield.12 However, neither
catalytic hydrogenation nor LAH reduction of 5f gave the desired
amine, but merely delivered unidentified products, presumably
pyrrolidine ring-opened products. The reason is unclear; however,
we speculated that an azide radical species, possibly generated
during the hydrogenation of the azide, might be responsible for
pyrrolidine ring-opening.19 This problem was solved when mild
Staudinger azide reduction (PPh3, H2O, toluene) was applied, and
it produced 2-aminomethylpyrrolidine 6f in 73% yield. Overall,
this protocol is quite effective for unmasked aminoalcohols giving
the corresponding diamines in good yield.
General procedure for the reduction of 5
To a solution of 5 (~150 mg) in a mixture of EtOH–EtOAc (2 : 1, 9
mL) was added 10% Pd/C (15 mg) under an argon atmosphere.
Then the flask was fitted tightly with a balloon filled with
hydrogen gas. The mixture was stirred at room temperature for 2
h. The reaction mixture was filtered through a pad of Celite and
the solvents were evaporated under reduced pressure to give a
residue. The crude residue was purified by flash silica gel
chromatography (5–15% MeOH–CHCl3) to afford 6.
Acknowledgements
This paper was studied with the support of the Nanocatalyst
Platform Technology Program (SI-1201) from the Ministry of
Knowledge Economy, and the Brain Pool fellowship to H. N.
Roy (121S-1-2-0232) from the Korean Federation of Science and
Technology Societies, Republic of Korea.
References
1 (a) D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96,
835; (b) G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 25,
117; (c) E. Juraristi, D. Quintana and J. Escalante, Aldrichimica
Acta, 1994, 27, 3; (d) D. C. Cole, Tetrahedron, 1994, 50, 9517; (e)
F. D. Klingler, Acc. Chem. Res., 2007, 40, 1367.
2 (a) S. G. Bull, S. G. Davies, S. Jones, M. E. C. Polywka, R.
S. Prasad and H. J. Sangance, Synlett, 1998, 519; (b) S.
P. Beaumont, E. A. Ilardi, L. R. Monroe and A. Zakarian, J.
Am. Chem. Soc., 2010, 132, 1482; (c) J. K. Nunnery, T. L. Suyama,
R. G. Linington and W. H. Gerwick, Tetrahedron Lett., 2011, 52,
2929.
In summary, we developed an efficient and practical method
for the direct azidation of tertiary alcohols using sodium azide–
sulfuric acid in toluene (Caution: Hydrazoic acid is extremely
dangerous due to its explosive nature and high toxicity and the
reaction must be conducted with extreme caution). This protocol
provides an economically viable procedure to deliver new chiral
diamines from unmasked 1,1-diaryl-2-aminoethanols derived
from natural amino acids. These diamines are currently being
investigated as potential molecular catalysts.
3 S. Hong, S. Tian, M. V. Metz and T. J. Marks, J. Am. Chem. Soc.,
2003, 125, 14768.
4 E. J. Corey and C. J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1986.
´
5 (a) J. Franzen, M. Marigo, D. Fielenbach, T. C. Wabnitz,
A. Kjærsgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127,
18296; (b) I. Ibrahem, R. Rios, J. Vesely, P. Hammar,
´
L. Eriksson, F. Himo and A. Cordova, Angew. Chem., Int. Ed.,
2007, 46, 4507; (c) D. Enders, M. R. M. Hu¨ttl, C. Grondal and
G. Raabe, Science, 2006, 441, 861.
´
6 (a) C. Concellon, N. Duguet and A. D. Smith, Adv. Synth. Catal.,
Experimental
¨
2009, 351, 3001; (b) F. Liu, X. Bugaut, M. Schedler, R. Frohlich
and F. Glorius, Angew. Chem., Int. Ed., 2011, 50, 12626; (c) C.
D. Campbell, C. Concellon and A. D. Smith, Tetrahedron:
Asymmetry, 2011, 22, 797.
General procedure for the azidation of 4
To a suspension of NaN3 (228 mg, 3.5 mmol) in toluene (5 mL)
was added concentrated sulfuric acid (0.19 mL, 3.5 mmol) drop-
wise for 10 min using a syringe pump and the mixture was stirred
for 15 min at room temperature. To this mixture, a solution of 4
(0.5 mmol) in toluene (5 mL) was added via syringe at ice-cold
temperature and the resulting mixture was stirred vigorously for 5–
10 min at room temperature. The reaction mixture was quenched
with an aqueous solution of NaHCO3 (15 mL, until pH 10), then
the organic layer was extracted with EtOAc (3 6 10 mL). The
combined organic extracts were washed with brine (10 mL) and
dried over anhydrous MgSO4. The solvents were removed under
7 (a) B. M. Trost and L. R. Terrell, J. Am. Chem. Soc., 2003, 125,
´
`
338; (b) N. Garcia-Delgado, K. S. Reddy, L. Sola, A. Riera, M.
`
A. Pericas and X. Verdaguer, J. Org. Chem., 2005, 70, 7426; (c)
Y. Li, X. Liu, Y. Yang and G. Zhao, J. Org. Chem., 2007, 72, 288.
8 M. Braun, Angew. Chem., Int. Ed., 2012, 51, 2550.
9 (a) H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa,
E. Katayama, A. F. England, T. Ikariya and R. Noyori, Angew.
Chem., Int. Ed., 1998, 37, 1703; (b) T. Ohkuma, D. Ishii,
H. Takeno and R. Noyori, J. Am. Chem. Soc., 2000, 122, 6510; (c)
C.-Y. Chen, R. A. Reamer, J. R. Chilenski and C. J. McWilliams,
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 3526–3530 | 3529

View Article Online
Communication
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Org. Lett., 2003, 5, 5039; (d) J. F. McGarrity and A. Zanotti-
Gerosa, Tetrahedron: Asymmetry, 2010, 21, 2479.
10 (a) E. F. V. Scriven and R. Turnbull, Chem. Rev., 1988, 88, 297;
14 Caution: Hydrazoic acid vapor is highly toxic and explosive, and
should be handled with extreme care in a well-ventilated fume
hood with a safety shield.
15 (a) P. Delair, C. Einhorn, J. Einhorn and J. L. Luche, J. Org.
Chem., 1994, 59, 4680; (b) C. L. Gibson, K. Gillon and S. Cook,
Tetrahedron Lett., 1998, 39, 6733; (c) L. Cai, H. Mahmoud and
Y. Han, Tetrahedron: Asymmetry, 1999, 10, 411; (d) T.
E. Kristensen, K. Vestli, F. K Hansen and T. Hansen, Eur. J.
Org. Chem., 2009, 5185.
16 I. S. Young and P. S. Baran, Nat. Chem., 2009, 1, 193.
17 (a) D. Uraguchi, S. Sakaki and T. Ooi, J. Am. Chem. Soc., 2007,
129, 12392; (b) D. Uraguchi, S. Sakaki, Y. Ueki, T. Ito and T. Ooi,
Heterocycles, 2008, 76, 1081.
¨
(b) S. Brase, C. Gil, K. Knepper and V. Zimmermann, Angew.
Chem., Int. Ed., 2005, 44, 5188.
11 (a) H. Brunner, P. Hankofer and B. Treittinger, Chem. Ber.,
1990, 123, 1029; (b) G. E. Green, D. M. Bender, S. Jackson, M.
J. O’Donnell and J. M. McCarthy, Org. Lett., 2009, 11, 807; (c) A.
S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J. Mathre
and E. J. J. Grabowski, J. Org. Chem., 1993, 58, 5886; (d)
M. Mizuno and T. Shioiri, Chem. Commun., 1997, 2165; (e) M.
N. S. Rad, S. Behrouz and A. Khalafi-Nezhad, Tetrahedron Lett.,
2007, 48, 3445; (f) M. Kitamura, T. Koga, M. Yano and
T. Okauchi, Synthesis, 2012, 23, 1335.
12 Y. Kohmura and T. Mase, J. Org. Chem., 2004, 69, 6329.
13 (a) S.-J. Wey, K. J. O’Connor and C. J. Burrows, Tetrahedron Lett.,
1993, 34, 1905; (b) J. L. Olivares-Romero and E. Juaristi,
Tetrahedron, 2008, 64, 9992.
18 M. Achmatowicz, J. Chan, P. Wheeler, L. Liu and M. M. Faul,
Tetrahedron Lett., 2007, 48, 4825.
ˇ
19 (a) S. Hayakawa, M. Hashimoto, H. Matsubara and F. Turecek,
J. Am. Chem. Soc., 2007, 129, 7936; (b) L. Chomicz, J. Rak,
P. Paneth, M. Sevilla, Y. J. Ko, H. Wang and K. H. Bowen, J.
Chem. Phys., 2011, 135, 114301.
3530 | RSC Adv., 2013, 3, 3526–3530
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