Oxaziridine-mediated amination of primary amines: Scope and application to a one-pot pyrazole synthesis

Article abstract of DOI:10.1021/ol0474507

(Chemical Equation Presented) Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines.

Full text of DOI:10.1021/ol0474507

ORGANIC
LETTERS
2005
Vol. 7, No. 4
713-716
Oxaziridine-Mediated Amination of
Primary Amines: Scope and Application
to a One-Pot Pyrazole Synthesis
Alan Armstrong,*,† Lyn H. Jones,‡ Jamie D. Knight,† and Richard D. Kelsey†
Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, U.K., and Pfizer Global R&D, Department of DiscoVery Chemistry,
Sandwich, Kent CT13 9NJ, U.K.
a.armstrong@imperial.ac.uk
Received December 13, 2004
ABSTRACT
Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the
corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines.
Electrophilic amination provides a conceptually powerful
means for the incorporation of nitrogen into molecular
frameworks.1 Pioneering work by Collet and co-workers has
established that aldehyde-derived N-Boc-oxaziridines such
as 1 and 2 can effect electrophilic amination of various
nucleophiles.2 However, oxidation often competes with
amination in their reaction with heteroatom nucleophiles.
They cleanly convert secondary amines to the corresponding
protected hydrazines,3 but low yields are observed with
primary amines since these undergo competitive imine
formation with the aldehyde released when the oxaziridines
effect amination.2 Recently we have reported the novel
N-Boc-oxaziridine 3 as an extremely effective nitrogen
transfer reagent for the electrophilic amination of a range of
allylic and propargylic sulfides which subsequently under-
went [2,3]-sigmatropic rearrangement.4 We reasoned that 3
may effect efficient amination of primary amines since the
byproduct of amination is a ketone, diethyl ketomalonate.
The product N-protected alkyl hydrazines are potentially
highly useful for the construction of a large range of valuable
heterocycles,5 but very few are commercially available,
providing a strong stimulus for the investigation of this
chemistry.6 Here we report our successful studies in this area,
and the development of a one-pot synthesis of pyrazoles from
primary amines.
‡ Pfizer Global R&D.
† Imperial College London.
(1) Reviews: (a) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947-1980.
(b) Greck, C.; Genet, J. P. Synlett 1997, 741-748. (c) Mulzer, J.; Altenbach,
H. -J. Organic Synthesis Highlights; VCH: Weinheim, Germany, 1991; p
45-53. (d) Dembach, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6, 1281-
1286. (e) Genet, J. P.; Greck, C.; Lavergne, D. In Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Weinham, Germany, 2000; pp 65-
102.
(2) (a) Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.-C.; Aubry A.;
Collet, A. Chem. Eur. J. 1997, 3, 1691-1709.(b) Vidal, J.; Hannachi, J.-
C.; Hourdin, G.; Mulatier J.-C.; Collet, A. Tetrahedron Lett. 1998, 39,
8845-8848.
(3) (a) Vidal, J.; Drouin, J.; Collet, A. J. Chem. Soc. Chem. Commun.
1991, 435-437. (b) Vidal, J.; Guy, L.; Ste´rin, S.; Collet, A. J. Org. Chem.
1993, 58, 4791-4793. (c) Vidal, J.; Damestoy, S.; Collet, A. Tetrahedron
Lett. 1995, 36, 1439-1442. (d) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.;
Collet, A. J. Org. Chem. 2004, 69, 2367-2373.
(4) (a) Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904-905.
(b) Armstrong, A.; Cooke, R. S.; Shanahan, S. E. Org. Biomol. Chem. 2003,
1, 3142-3143.
(5) Monosubstituted hydrazines are important intermediates en route to
the synthesis of, for example, pyrazoles: (a) Stauffer, S. R.; Huang, Y. R.;
Aron, Z. D.; Coletta, C. J.; Sun, J.; Katzenellenbogen, B. S.; Katzenellen-
bogen, J. A. Bioorg. Med. Chem. 2001, 9, 151-161. Indazoles (b)
Boudreault, N.; Leblanc, Y. Org. Synth. 1996, 74, 241-247. Imidazolinones
(c) Bozzini, S.; Nitti, P.; Pitacco, G.; Pizzioli, A.; Russo, C. J. Heterocycl.
Chem. 1996, 33, 1217-1221. Cinnolines (d) Wunsch, B.; Nerdinger, S.;
Hofner, G. Liebigs Ann. 1995, 1303-1312.
10.1021/ol0474507 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/20/2005

Table 1. Amination of 2-Phenylethylamine 8a Using
Oxaziridine 3a
Our original reported synthesis of oxaziridine 34a involved
aza-Wittig reaction of diethyl ketomalonate with an imino-
phosphorane derived from (potentially hazardous) N-Boc-
azide, followed by oxidation of the resulting imine with
mCPBA/BuLi. An early aim was to develop an improved
synthesis. We developed a novel route to 3 that is amenable
to large-scale synthesis (Scheme 1).
entry
solvent
9a (%)
10a (%)
3 (%)
1
2
3
4
5
6
7
8
9b
CH2Cl2
Et2O
THF
Acetone
Petrol
PhCH3
CH3CN
EtOH
41
45
48
52
54
62
37
50
75
8
15
19
18
22
<5
<5
<5
8
25
10
10
7
<5
20
40
30
-
Scheme 1. Novel Route to Oxaziridine 3a
CH2Cl2
a Oxaziridine (0.7 equiv), amine (1.0 equiv), solvent (0.12 M in amine),
rt under nitrogen, 24 h. The yields quoted are isolated yields based on
oxaziridine 3. b Amine/oxaziridine ratio 2:1, 24 h.
diaminated product 10a was also isolated, and this was a
significant side product in several other solvents (entries
2-5). Highest yield was obtained using toluene as solvent
(entry 6). Overall yields based on aminating agent were good,
indicating that 3 is an efficient nitrogen transfer reagent.
Imine byproducts were not detected. To minimize the amount
of diamination product 10a, we repeated the reaction in CH2-
Cl2 using 2.0 equiv of amine relative to oxaziridine (entry
9). This resulted in an improved yield of 75% 9a (based on
oxaziridine) and may offer a useful strategy when relatively
cheap amines are used as substrates.
While the above study suggested toluene to be the
optimum solvent, we considered that use of CH2Cl2 would
have practical advantages, particularly if the method was to
be applied to parallel synthesis. We therefore investigated a
wider range of substrates using both solvents and a 1:1 ratio
of amine/oxaziridine (Table 2).9 In some cases, small
amounts of imine byproduct 11 were observed. Table 2
reveals excellent amination for a range of unbranched and
branched aliphatic amines (entries 1-4), with use of toluene
as solvent offering superior yields. For aromatic amines
(entries 5-7), higher yields of 9 were obtained in CH2Cl2.
A higher proportion of diamination product 10 was obtained
with the electron rich substrate 8f (compare entries 6 to 5,
7). The use of nonaromatic aliphatic amines, cyclopropyl-
amine, cyclohexylamine and heptylamine afforded poor to
modest yields of the corresponding hydrazine products in
both solvent systems (entries 8-10). However, gratifyingly
the methodology tolerates the use of amino acid derivatives
and heteroaromatics to afford promising quantities of the
monoaminated products (entries 11-13).
Thus, amination of triphenylphosphine with hydroxy-
lamine-O-sulfonic acid and subsequent N-protection via the
acyl imidazolide 5 afforded iminophosphorane 6.7 Following
aza-Wittig reaction with diethyl ketomalonate, we were able
to effect oxidation of imine 7 with aqueous Oxone in CH3-
CN/H2O.8
With quantities of 3 in hand, we tested its reaction with a
sample primary amine, 2-phenylethylamine 8a, in a range
of solvents (Table 1). Initial reaction in CH2Cl2 afforded a
moderate yield of desired product 9a, with unreacted
oxaziridine 3 also recovered (entry 1). Interestingly, the novel
(6) An alternative synthetic approach involves reductive amination of
aldehydes with hydrazates. Recent examples in the literature include, for
example: (a) Weber, D.; Berger, C.; Eickelmann, P.; Antel, J.; Kessler, H.
J. Med. Chem. 2003, 46, 1918-1930. (b) Xu, Z.; Singh, J.; Swinden, M.
D.; Zheng, B.; Kissick, T. P.; Patel, B.; Humora, M. J., Quiroz, F.; Dong,
L.; Hsieh, D. -M.; Heikes, J. E.; Pudipeddi, M.; Lindrud, M. D.; Srivastava,
S. K.; Kronenthal, D. R.; Mueller, R. H. Org. Process Res. DeV. 2002, 6,
323-328. (c) Kruse, L. I.; Kaiser, C.; DeWolf, W. E.; Finkelstein, J. A.;
Frazee, J. S.; Hilbert, E. L.; Ross, S. T.; Flaim, K. E.; Sawyer, J. L. J.
Med. Chem. 1990, 33, 781-789. However, this approach has not been used
to prepare hydrazines with a stereocenter R-to nitrogen. A more recent
approach which does provide hydrazines with a stereocenter R-to nitrogen
involves the hydrohydrazination reaction of olefins with azodicarboxylates
see Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676-5677.
However, the products were all prepared as their racemates.
(7) Tomcufcik, A. S.; Emma, J. E.; Eudy, N. H.; Marsico, J. W.;
Newman, H. US Patent No. 4767749, 1988; Chem. Abstr. 1988, 109,
231197.
(9) DSC testing on oxaziridine 3 showed a broad exotherm at 100 °C.
We therefore recommend that this reagent is not heated above room
temperature and that it is kept in the freezer when not in use. TSU testing
on benzylamine 8b as substrate with oxaziridine 3 in CH2Cl2 showed no
exotherm or pressure buildup; therefore no thermal hazards are expected
from the normal reaction at room temperature.
(8) Armstrong, A.; Draffan, A. G. J. Chem. Soc., Perkin Trans. 1 2001,
2861-2873.
714
Org. Lett., Vol. 7, No. 4, 2005

Table 2. Conversion of Primary Amines 8 to N-Boc Hydrazines 9a
(i) PhCH3
(ii) CH2Cl2
entry
amine 8
R1
9 (%)
10 (%)
3 (%)
9 (%)
10 (%)
3 (%)
1
2
3
a
b
c
d
e
f
g
h
i
PhCH2CH2
PhCH2
PhCH(Me)
PhCH(Ph)
67
75
75
80
55
45
60
34e
45
11
65
50
35f
13
<2
4
2
45
52b
32
54
71
51
70
29e
43
<5
53
44
42f
5
10
30
5
4c
5
Ph
10d
19
8
5
5d
10
6
5
6c
7
4-OMe-C6H4
4-CN-C6H4
cyclopropyl
cyclohexyl
8
9
10
11
12
13
28
20
<5
16
8
25
23
<5
20
9
5d
35
6d
41
j
k
l
n-heptyl
PhCH2CH(CO2Et)
(CH3)2CHCH(CO2Et)
3-NH2CH2C5H5N
15
15
15
12
m
20
20
a Oxaziridine (1.0 equiv), amine (1.0 equiv), solvent (0.17 M in amine), rt under nitrogen, 72 h. The yields quoted are isolated yields. b Reaction worked
up after 25.5 h. c For entry 4: (i) <5% 11, (ii) 23% 11. For entry 6: (i) 13% 11, (ii) 10% 11. d Inseparable mixture of bisaminated material and oxaziridine
3. e Reactions worked up after 48 h. f Amination occurs on the benzylic primary amine of 3-(aminomethyl)pyridine. This was confirmed by a downfield shift
1
of the signals in the corresponding H and 13C spectra at positions 2 and 6 of the pyridine ring for the bisaminated product 10.
We next turned our attention to the application of our
amination methodology to heterocyclic synthesis. Since
unprotected alkyl hydrazines can be unstable,10 their in situ
generation and reaction with electrophiles offered an attrac-
tive possibility for investigation. We elected to study the
synthesis of 1,3,5-trisubstituted pyrazoles since these are key
components of a number of important biological compounds
that have attracted considerable industrial attention.11 Initially
we took the hydrazine products 9a,b and 9e as representative
examples for screening with a symmetrical 1,3-diketone,
hepta-3,5-dione, to avoid issues of regioisomerism in the final
pyrazole products. The respective hydrazines were dissolved
in dichloromethane and treated with TFA for 0.5 h, followed
by the addition of hepta-3,5-dione (1.0 equiv). The reactions
were left to stir for 24 h and monitored by TLC. Removal
of the solvent in vacuo and purification by flash column
chromatography gratifyingly afforded the desired pyrazole
products in quantitative yields. With a view to developing
this chemistry into a one-pot pyrazole synthesis, we felt that
it would be advantageous to be able to remove the diethyl
ketomalonate side product from the initial electrophilic
amination by aqueous extraction. This should facilitate a
cleaner, more efficient synthesis of the desired pyrazole
products and make the final chromatographic purification a
simple filtration. Pleasingly, it was discovered that washing
with saturated aqueous sodium hydrogencarbonate resulted
Scheme 2. One-Pot Synthesis of 1,3,5-Trisubstituted
Pyrazolesa
(10) Krivis, A. F.; Supp, G. R. Prepr. Papers, Am. Chem. Soc., DiV.
Fuel Chem. 1967, 11, 137-141.
(11) For example, Celecoxib: Schnitzer, T. J.; Kong, S. X.; Mitchell, J.
M.; Mavros, P.; Watson, D. J.; Pellissier, J. M.; Straus, W. L. Clin. Ther.
2003, 25, 3162-3172. Tartrazine: Shah, K. M. Handbook of Synthetic Dyes
and Pigments; Multi-tech Publishing Co.: India, 1998. Sildenafil (Via-
gra): Moreland, R. B.; Goldstein, I; Kim, N. N.; Traish, A. Trends
Endocrinol. Metab. 1999, 10, 97-104. Martell, A. M.; Graul, A.; Rabasseda,
X.; Castaner, R. Drugs Fut. 1997, 22, 138-143. Terrett, N. K.; Bell, A. S.;
Brown, D.; Ellis, P. Biorg. Med. Chem. Lett. 1996, 6, 1819-1824. Boolell,
M.; Allen, M. J.; Ballard, S. A.; Gepi-Attee, S.; Muirhead, G. J.; Naylor,
A. M.; Osterloh, I. H.; Gingell, C. Int. J. Urol. Res. 1996, 8, 47-52.
Org. Lett., Vol. 7, No. 4, 2005
715

in almost complete removal of diethyl ketomalonate from a
CH2Cl2 solution. Armed with this knowledge we therefore
screened a selection of amines 8 in a novel one-pot approach
as outlined in Scheme 2. Thus, the amination reaction mixture
was washed with saturated aqueous NaHCO3 and the aqueous
layer removed by pipet before sequential addition of solid
MgSO4, TFA and the 1,3-diketone. Evaporation of the
reaction mixture and filtration on silica then afforded the
pyrazole in acceptable overall yield.
develop a one-pot synthesis of functionalized pyrazoles from
primary amines which has potential for application to library
synthesis. Further development of the amination technology
and extension of the approach to a wider range of valuable
nitrogen heterocycles is underway.
Acknowledgment. We thank Pfizer for the support of
this work, in particular Ian Marsh, David Hoople, and Andy
Bell.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization information for
all novel compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have reported a simple and efficient
procedure for the electrophilic amination of primary amines
under metal free conditions, affording synthetically versatile,
mono-Boc-protected hydrazines. Additionally, easy removal
of the byproduct in the amination step has allowed us to
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Org. Lett., Vol. 7, No. 4, 2005