Electrophilic amination of diorganozinc reagents by oxaziridines

Article abstract of DOI:10.1016/j.tetlet.2008.10.049

Electrophilic amination of organozinc reagents by oxaziridines has been studied. Diorganozinc reagents R₂Zn (R = alkyl or aryl) react with N-Boc oxaziridine to afford N-Boc protected primary amines BocNHR in moderate to good yields. No additive

Full text of DOI:10.1016/j.tetlet.2008.10.049

Tetrahedron Letters 49 (2008) 7383–7385
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Electrophilic amination of diorganozinc reagents by oxaziridines
*
Mohammed Ghoraf, Joëlle Vidal
Université de Rennes 1, CNRS UMR 6510, Laboratoire de Chimie et Photonique Moléculaires, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrophilic amination of organozinc reagents by oxaziridines has been studied. Diorganozinc reagents
R2Zn (R = alkyl or aryl) react with N-Boc oxaziridine to afford N-Boc protected primary amines BocNHR in
moderate to good yields. No additives are needed in this reaction, which proceeds at 0 °C. We suggest that
the presence of two heteroatoms in oxaziridine allows Lewis base activation of the diorganozinc reagent.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 19 September 2008
Revised 8 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
Electrophilic amination
Oxaziridine
Diorganozinc reagent
Numerous amination methods have been developed for the
synthesis of amines, which are of fundamental interest in many
fields of chemistry.1 Electrophilic amination is an attractive meth-
OH
O
H
N
R1
R2
O
R1
+
R1
R2
M
N
+
R
Boc
Boc
R
+
R
R2
2
3
1
4
5
od for the C–N bond construction since organometallic reagents
þ
a: R1 = H, R2 = 4-CNC6H4, b: R1 = H, R2 = CCl3, c: R1 = R2 = CO2Et
(carbanionic reagents) are widely used and thus, several [NH2
]
synthons have been developed (Scheme 1).2
Among them, correctly N-substituted oxaziridines 1 (R3 = H,
COR, CO2R, CONRR’) behave as useful aminating reagents,3 and
we previously reported that N-alkoxycarbonyl oxaziridines 1
(R3 = CO2R) transferred their N-alkoxycarbonyl group to amines
very efficiently in order to synthesize N-protected hydrazines in
high yields and mild conditions.4 Only a few examples of oxaziri-
dine-mediated organometallic amination have been reported. Sta-
bilized alkali enolates have been aminated by N–H oxaziridines 1
(R3 = H) to give, depending on the nature of the R1 and R2 substit-
uents, either the free amine or the corresponding R1COR2 imine.3b,5
Moreover, nitrile or ester substituents in the substrate were hydro-
lyzed and sometimes, in the case of ester, further decarboxylation
occurred. N-Alkoxycarbonyl oxaziridines were also used to ami-
nate alkali enolates or carbanions.4a,b,6 Although useful stable N-
Scheme 2. Electrophilic amination of organometallic reagents
oxaziridines 1.
2 with N-Boc
few minutes at ꢀ78 °C, yields were low (16–39%) due to competing
aldol reaction producing 5 from the co-product 4 and the starting
enolate (Scheme 2). Extensive studies of the reaction conditions
and modifications of the oxaziridine structure resulted in slight
improvement of the yields.6b–d
We reasoned that the use of organozinc reagents 2, known for
their low reactivity towards aldehydes or ketones,7 would avoid
the formation of by-product 5. Herein we report that N-Boc oxaz-
iridine 1a reacts with diorganozinc reagents 2 (M = ½Zn) to afford
N-Boc protected primary amines 3 in moderate to good yields
(Scheme 2). No catalyst is needed in this reaction, which proceeds
at 0 °C.
protected
a
-amino ketones were obtained in one step within a
At first, we studied amination of three classes of organozinc re-
agents 2: organozinc halides (M = ZnX), diorganozincs (M = ½Zn)
and lithium triorganozincates (M = 1/3ZnLi).7b,7c Only a few elec-
trophilic aminating reagents have been reacted so far with these
organozinc reagents. A former publication described sluggish ami-
nation of diethylzinc with chloramines in 46% yield.8 No catalyst
was needed to react di-tert-butyl azodicarboxylate (BocN@NBoc)
with organozinc halides or functionalized arylazotosylates
(ArN@NSO2Ar) with organozinc halides and diorganozincs to give
the corresponding hydrazines.9,10 A further in situ cleavage of the
N–NSO2Ar bond led to secondary amines in 45–79% overall
O
R1
R3
N
C
N
C
+
N
R2
1
Scheme 1. C–N bond formation by an electrophilic amination reaction and
oxaziridine general formula.
* Corresponding author. Tel.: +33 2 23 23 57 33; fax: +33 2 23 23 69 78.
E-mail address: joelle.vidal@univ-rennes1.fr (J. Vidal).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.049

7384
M. Ghoraf, J. Vidal / Tetrahedron Letters 49 (2008) 7383–7385
Table 1
Table 3
Reactivity of organometallic reagent
2
(R = nBu, M = ZnI, ½Zn, 1/3ZnLi, Li) with
Amination of R2Zn with oxaziridine 1a in 1:4 Et2O/hexane mixture at 0 °C
oxaziridine 1a (R3 = Boc)
Entry
R
Reaction time (min)
Yield of 3 (%)
Entry
1
Organometallic
reagent 2
Solvent
Et2O
Conditions
rt, 20 h
Yield
3 (%)
Yield
5a (%)
1
2
3
4
nBu
sBu
tBu
Cyclohexyl
40
60
60
71
28
21
40
nBuZnI
No
reaction
57
120
2
3
nBu2Zn
nBu3ZnLi
Et2O/hexane 5:1
THF/ Et2O/
hexane 6:1:2
THF/hexane 4:1
0 °C, 35 min
0 °C, 30 min
—
27
CH2
16
5
330
39a
4
nBuLi
ꢀ78 °C, 10 min
15
35
6
7
Phenyl
4-Methoxyphenyl
120
90
43
29
yields.10 With other electrophilic aminating agents, O-acyl-N-
substituted hydroxylamines (RR0N–OCOR00) or acetone-O-aryl-
sulfonyloxime (Me2C@N–OSO2Ar), copper catalysis was needed
to allow for the preparation of, respectively, a wide range of sec-
ondary and tertiary amines from diorganozinc reagents (43–98%
yields),11 or aryl and benzyl primary amines from organozinc
halides, diorganozincs and bromomagnesium triorganozincates
(30–95% yields).12 Our work began by studying the reactivity of
organozinc reagents 2 (M = ZnI, ½Zn, 1/3ZnLi) with commercially
available oxaziridine 1a.4a,b Results are reported in Table 1.
Butylzinc iodide, pre-prepared from BuI and activated Zn,7b,c did
not react at room temperature (entry 1). Dibutylzinc was pre-
formed from nBuLi in hexanes and freshly fused anhydrous ZnCl2
(0.5 equiv) in anhydrous ether (entry 2).7b,c We were pleased to
find that reaction with oxaziridine 1a (molar ratio 1:1) was com-
plete within a few minutes (30 min) at 0 °C, without any additive.
Moreover, alcohol 5a was not detected by TLC. After acidic work-
up and purification by chromatography, N-protected butylamine
3 was isolated in 57% yield. Reaction of Bu3ZnLi, pre-prepared from
BuLi in hexanes and anhydrous ZnCl2 (0.33 equiv) in THF,7b,c with
1a (molar ratio 1:1) occurred in a short time at 0 °C (entry 3). How-
ever, N-Boc butylamine was isolated in a low yield, along with
alcohol 5a. The use of nBuLi, which reacted with 1a at ꢀ78 °C, gave
yields of 3 and 5a similar to those obtained with the lithium zin-
cate reagent (entry 4).
Having identified that dibutylzinc is the best reagent for elec-
trophilic amination by oxaziridine 1a, optimization of the reaction
conditions was conducted using commercial diethylzinc in hex-
anes (Table 2). Diethylzinc and oxaziridine 1a (1:1 ratio) in a 5:1
mixture of Et2O and hexane gave within 30 min at 0 °C N-Boc eth-
ylamine in 67% isolated yield (entry 1). Other N-Boc oxaziridines,
1b4c and 1c,13 were used since kinetics of their reaction with nitro-
gen nucleophiles is known to greatly depend on the R1 and R2 sub-
stitutents.4a–c As expected, reaction with oxaziridine 1b took place
at ꢀ50 °C overnight (entry 2). However, pure N-Boc ethylamine
could not be obtained after chromatography on silica gel because
of the presence of chloral 4b. The use of oxaziridine 1c did not im-
prove the yield (entry 3). Nevertheless, its high aminating ability
allowed reaction with BuZnI in ether (0 °C, 1 h) to give N-Boc butyl-
amine in 38% yield (data not shown, see also Table 1, entry 1). An
experiment using a 0.5:1 ratio of Et2Zn and 1a showed that only
one ethyl residue of diethyl zinc could be aminated at 0 °C (entry
a
New compound: [
a
]
D
ꢀ10.5 (c 1, MeOH), mp = 60 °C.
4). Increasing hexane content of the solvent resulted in a better
yield (entry 5).
These optimized reaction conditions (0 °C, hexane as the major
solvent constituent, oxaziridine 1a) allowed us to synthesize sev-
eral N-Boc primary amines in 21–71% yields (Table 3).14 The yield
of N-Boc butylamine was increased under these conditions (entry 1
and Table 1, entry 2). Steric hindrance of dialkylzincs, pre-prepared
from corresponding organolithium and anhydrous ZnCl2 in
ether,7b,c resulted in longer reaction times and reduced yields (en-
tries 2–4).
Optically active N-Boc cis-pinan-2-ylmethyl amine was ob-
tained in 39% yield from the corresponding enantiopure chiral
diorganozinc reagent prepared from (ꢀ)-b-pinene (entry 5).15 Ami-
nation of diarylzinc reagents, pre-prepared from the corresponding
Grignard reagent, proceeded in fair yields even in the absence of
magnesium salts which were precipitated in dioxane and then fil-
tered (entries 6–7).7b,c In the case of diphenylzinc, solvent compo-
sition proved to be essential since reaction at 0 °C in ether/dioxane
resulted in a very complex mixture from which unexpected N-Boc
amine 6 was isolated in 35% yield (Scheme 3).16
Depending on the nature of the nucleophile (amine, phosphine
or sulfide) and of the solvent, oxaziridine 1a was shown to behave
as an aminating reagent and also as an oxidant (Scheme 3).4b Par-
allel oxidation of Ph2Zn by 1a producing N-Boc imine 7 may have
occurred in ethereal solvent. As 7 is an excellent Michael accep-
tor,17 its further trapping by diphenylzinc may be postulated to ex-
plain isolation of 6.
The presence of two heteroatoms and a weak N–O bond in
oxaziridine 1a seems to be essential to explain its high reactivity
towards diorganozinc reagents (Scheme 4). We propose that the
Nu
Nu
N
O
Boc + 4
amination
Nu + 1a
oxidation
Ph
Boc
Ar
N
H
Boc
6
+ Ar
N
Ar = 4-CNC6H4
7
Scheme 3. Compound
nucleophile Nu by N-Boc oxaziridine 1a.
6 formula and competitive amination or oxidation of
Table 2
Amination of diethylzinc with oxaziridines 1a–c (R3 = Boc)
Entry Oxaziridine Solvent Et2O/ Et2Zn:
T (°C) Reaction Yield of
hexane
1 ratio
time
EtNHBoc (%)
R
R
Zn
+
1
2
3
4
5
1a
1b
1c
1a
1a
5:1
5:1
5:1
5:1
1:4
1:1
1:1
1:1
0.5:1
1:1
0
30 min
22 h
105 min
60 min
30 min
67
Zn
R
Zn
H+
ꢀ50
Impure
34
R
R
N
3
O
0
O
O
N
nda
74
Ar
Ar
Ar
Boc
0
0
Boc
N
Boc
R
H
4
9
H
8
H
nd: not determined. 1H NMR analysis of the crude product indicated a 1:1
a
mixture of EtNHBoc and 2a.
Scheme 4. Plausible mechanism for dialkylzinc amination by N-Boc oxaziridine 1a.

M. Ghoraf, J. Vidal / Tetrahedron Letters 49 (2008) 7383–7385
7385
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oxygen atom of oxaziridine 1a acts as a Lewis base which coordi-
nates to the zinc atom to form zincate complex 8. So, attack of
the electrophilic nitrogen by the organo moiety R is activated
and followed by fragmentation of the adduct to give 4 and 9. Sim-
ilar activation of intermediate 9 is probably disfavoured because of
a weaker Lewis acidity, so resulting in no transformation of the
second organo moiety R. In order to promote the amination reac-
tion, competing Lewis bases such as ethereal solvent must be
avoided.
In conclusion, we have shown that N-Boc oxaziridine 1a reacts
with diorganozinc reagents 2 (M = ½Zn) without any additives at
0 °C in hexane/ether solvent. We suggest that the presence of
two heteroatoms in oxaziridine 1a allows Lewis base activation
of this reaction. Furthermore, N-Boc protected primary amines
are obtained in fair to good yields.
Acknowledgements
12. (a) Erdik, E.; Dasßkapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139–3142; (b)
Université de Rennes 1 and CNRS (UMR 6510) are acknowl-
edged for financial support. M.G. thanks the Ministère de l’enseign-
ement supérieur et de la recherche for a doctoral fellowship. We
gratefully acknowledge Nicolas Richy for technical help and Dr.
Émilie Genin for critical reading of the manuscript.
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14. Typical experimental procedure: Under argon, commercial nBuLi in hexanes
(1.6 M, 1.5 mL, 2.4 mmol) was added dropwise to a Schlenk tube cooled at 0 °C
and containing ZnCl2 in ether (1 M, 1.2 mL, 1.2 mmol) and anhydrous ether
(3 mL). After 30 min. at 0 °C, the mixture was concentrated in vacuo to ca.
2 mL. This solution was added at 0 °C to a mixture of anhydrous hexane (7 mL),
anhydrous ether (1 mL) and oxaziridine 1a (242 mg, 1 mmol). After 40 min at
0 °C, TLC analysis showed that 1a was consumed. Then aqueous HCl (0.15 M,
10 mL) was added to the reaction mixture. After extraction of the aqueous
phase by ether (2 ꢁ 5 mL), the combined organic phases were successively
washed by aqueous 1 M NaHCO3 and water, then dried over Na2SO4 and
concentrated in vacuo. Flash chromatography on silica gel (15 g, ether/AcOEt
95:5) afforded N-Boc butylamine (123 mg, 71%) as an oil. 1H NMR (300 MHz,
CDCl3) d 0.84 (t, J = 7.2 Hz, 3 H), 1.25–1.41 (m, 13 H), 3.02 (m, 2 H), 4.57 (br s,
1 H); 13C NMR (75 MHz, CDCl3) d 12.7, 18.9, 27.4, 31.2, 39.3, 77.9, 155.0.
15. Langer, F.; Knochel, P. Tetrahedron Lett. 1995, 36, 4591–4594.
16. Compound 6: white solid, mp 106 °C, 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9 H),
5.17 (br s, 1 H), 5.92 (br s, 1 H), 7.19–7.21 (m, 2 H), 7.31–7.36 (m, 3 H), 7.41 (d,
J = 8.3 Hz, 2 H), 7.64 (d, J = 8.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) d 28.3, 80.4,
111.1, 118.7, 127.5, 127.7, 128.1, 129.1, 129.9, 132.4, 132.8, 140.6, 154.9. EI-
HRMS: m/z calcd for C15H12N2O2 [MꢀC4H8]+: 252.0900; found: 252.0891.
17. (a) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008,
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