Discovery and application of iminotriphenylphosphorane as a formal aromatic primary amine protecting group

Article abstract of DOI:10.1016/j.tetlet.2012.07.106

During our efforts to selectively synthesise N-arylated benzotriazole fragments, we developed a new primary aromatic amine protecting group strategy showing significant advantages over recognised protecting groups.

Full text of DOI:10.1016/j.tetlet.2012.07.106

Tetrahedron Letters 53 (2012) 5380–5384
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Discovery and application of iminotriphenylphosphorane as a formal
aromatic primary amine protecting group
⇑
Bénédicte Delouvrié, Hervé Germain, Craig S. Harris , Maryannick Lamorlette, Honorine Lebraud,
Ha Thi Hoang Nguyen, Anais Noisier, Gilles Ouvry
AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
During our efforts to selectively synthesise N-arylated benzotriazole fragments, we developed a new pri-
mary aromatic amine protecting group strategy showing significant advantages over recognised protect-
ing groups.
Received 27 June 2012
Revised 16 July 2012
Accepted 25 July 2012
Available online 2 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
This letter is dedicated to all the many
talented chemists who have sadly lost
employment at AstraZeneca and are forced
to move on to other career paths.
Keywords:
Iminotriphenylphosphorane
Primary amine protecting group
Regioselective preparation of triazoles and
benzotriazoles
During a recent programme, we identified the novel fragment,
3-(1H-benzotriazol-1-yl)pyrazin-2-amine (1, Table 1), as a key
substructure to acquire. Our first trials using copper-catalysed1
and base-promoted SNAr conditions afforded very poor isolated
yields with the problems of regioselectivity (Table 1, entries 1–
2). To improve yields, we turned our attention to acid-catalysed
conditions and managed to develop an efficient and novel regiose-
lective synthesis of N-1-linked benzotriazole 2-aminopyrazines
under solvent-free conditions.2 These conditions, although very
high yielding, were determined to be unsafe for large-scale opera-
tion by DSC (differential scanning calorimetry).3 Simple dilution of
the reaction mixture with pentan-2-ol offered enough of an energy
sink to make this process operable on a large-scale (Table 1, entry
4). While this process was almost entirely regioselective in the case
of benzotriazole and 4-substituted benzotriazoles affording mod-
erate to excellent yields of A (Table 1, entries 3–5), the process
was not applicable for the synthesis of C-5 or C-6 substituted ben-
zotriazoles leading to inseparable mixtures (Table 1, entry 7).
Therefore, we needed to develop another strategy (Scheme 1).
To attain our targets with total regioselective control, we
focused on constructing the benzotriazole ring from selectively
arylated 1,2-diaminobenzene fragments (7)4 with the regiochem-
istry fixed at the Buchwald-Hartwig amination step with the
appropriate substituted 2-nitroanilines (8).5 In order to carry out
this approach we required to protect the C-2–NH2 group of the
readily-available 2-amino-3-chloropyrazine building block at the
start of the sequence and the protecting group6 would need to be
stable to basic conditions, hydrogenation, nitrosylation and prefer-
ably, be easily removed at the end of the sequence without affect-
ing the R groups (Scheme 1).
Inspection of the literature revealed three recognised aromatic
amine protecting groups6 in: di(Boc) (Table 2, entry 1);7 2,5-
dimethylpyrrole (Table 2, entry 2);8 and the very labile STABASE
group (tetramethyldisliylazacyclopentane) that was excluded.7,9
While these protecting groups have been extensively used in the
past, even in our own laboratories, they can each have compatibil-
ity issues with certain chemistries and functionalities (Table 2).
Herein, we communicate, to our knowledge, the first successful
application of the iminotriphenylphoshporane as a formal aro-
matic primary amine protecting group11 in the regioselective prep-
aration of C3-substituted benzotriazole aminopyrazine fragments,
demonstrating its thermal stability and orthogonality to the Boc
group.
We decided, perhaps courageously in the absence of any real
stability data,10 to employ TPP protection with the knowledge that:
(i) the –N(Boc)2 group cleaves readily to –NHBoc during the
⇑
Corresponding author. Tel.: +33 (0)3 26 61 5912; fax: +33 (0)3 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.106

B. Delouvrié et al. / Tetrahedron Letters 53 (2012) 5380–5384
5381
Table 1
Results obtained for the displacement of 2-amino-3-chloropyrazine with a substituted benzotriazoles under differenct conditions
R
R
N
N
N
N
N
Cl
N
N
N
N
N
N
N
Conditions
N
R
N
+
+
N
H
NH2
NH2
NH2
A
B
Entry
Compd
R
Conditions
Ratio (A/B)
Isolated yield (%)
1
2
3
4
5
6
7
1
1
1
1
2
3
4
H
H
H
H
4-CH3
4-F
CuI, TBAF, DMF, 140 °C, 16 h
CsF, DMSO, 120 °C, 16 h
Solvent-free, 140 °C, 1 h
Pentan-2-ol (3 vols), reflux, 16 h
Solvent-free, 150 °C, 1 h
Solvent-free, 140 °C, 5 h
Melt conditions
80/20
80/20
100/0
100/0
100/0
80a/20
100b/0
14
34
95
82
52
11
65
5-CH3
a
Separable 70/30 mixture of C-4 and C-8–F benzotriazole isomers.
b
Inseparable 1:1 mixture of C-5 and C-6 methylbenzotriazole isomers obtained as determined by 1H NMR.
R
R
R
R
NO2
NH2
N
N
N
N
N
N
N
Cl
N
N
X
Pd catalysed
amination
N
N
NH
Protection
N
N
N
NH
N
N
N
Deprotection
Cyclisation
Reduction
N
NH2
NH2
Commercially
available
N(PG)
N(PG)
N(PG)
N(PG)
5
7
9
6
8
Scheme 1. Retrosynthetic analysis of target 5 (PG = protecting group, X = suitable leaving group (i.e., Cl/Br/I).
Table 2
Table showing a comparison of the common protecting groups employed for aromatic amines
Buchwald-Hartwig amination step leading to selectivity issues and
poor yields; and (ii) the 2,5-dimethylpyrrole group is known to be
difficult to remove at the end of the sequence. To our satisfaction,
the TPP group was stable to each step and finally easily removed by
hydrolysis. After installation of the TPP group under basic condi-
tions (Ph3P, C2Cl6, TEA, toluene, 80 °C, 2 h)11 or acidic conditions
(Ph3P, Cl3CCN, toluene, À15 to 80 °C, 16 h), 12 was obtained in
excellent yields as the free base or hydrochloride salt, respectively.
The Buchwald-Hartwig step with substituted 2-nitroanilines5 (13)
worked efficiently affording isolated yields of 14 consistently
above 60 %. We postulated that the TPP group would actually sit
orthogonally to the plane of the pyrazine ring, leaving the C-3–Cl
position relatively unhindered for the approach of the (L)nPd (0)
species and this was confirmed by X-ray diffraction studies
(Fig. 1). We also cannot exclude the possibility that the C2-N@PPh3
group could act as a transient ligand12 itself explaining the high
yields for the amination step. Hydrogenation of 14 afforded the
ortho-diamine intermediates 15 in good isolated yields. Finally,
ring closure4 followed by hydrolysis13 of the C-2–N@PPh3 group
gave our desired fragments (17) in satisfactory to excellent overall
yields (Scheme 2).
After having successfully employed the TPP protecting group to
synthesise our benzotriazole fragments with total regiocontrol, we
turned our attention to its suitability for the regioselective synthe-

5382
B. Delouvrié et al. / Tetrahedron Letters 53 (2012) 5380–5384
Figure 1. X-ray analysis of 12. The C-2–N@PPh3 group is sitting below the C-3–Cl bond, orthogonal to the plane of the pyrazine ring.
R
R
R
R
NO2
NH2
(c)
R
N
N
Cl
N
N
N
N
NH
N
N
NH
N
N
N
(a)
N
N
N
(b)
47-100%
N
(d)
N
+
NO2
63-100%
N
P
60-99%
N
P
75-100%
N
P
N
P
NH2
NH2
13
Ph
12
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
17 a-g
Ph
14 a-g
Ph
16 a-g
15 a-g
Scheme 2. Regioselective preparation of N-1-arylated benzotriazole fragments. Reagents and conditions: (a) Pd(OAc)2, xantphos, Cs2CO3, toluene, 100 °C, 16 h; (b) H2, Pd-C,
EtOAc, rt, 16 h or H2 (15 psi), PtO2, EtOAc–EtOH, rt; (c) isoamylnitrite, AcOH, rt; (d) 2 N HCl, MeOH, 80 °C, 2 h, 75%-quant (where R is: (a) 4-OCH3; (b) 5-OCH3; (c) 6-OCH3; (d)
5-CH3; (e) 6-CH3; (f) 5-F; (g) 6-F).
R
R
+ N
N
N
N
N
Cl
N
N
N
N
N
N
N
N
N
NH2
(a)
N
N
N
N
(b)
(c)
N
+
N
P
N
P
.HCl
Ph
R
N
P
N
P
NH2
21 a-b
Ph
Ph
18
Ph
Ph
Ph
Ph
Ph
Ph
12.HCl
Ph
Ph
19 a-b
Ph
20
Scheme 3. Regioselective preparation of N-1-arylated triazole fragments. Reagents and conditions: (a) NaN3, DMSO, 90 °C, 16 h, 96%; (b) CuI, toluene, 50 °C, 16 h, R = Ph (19a,
55%) R = t-Bu (19b, 45%); (c) 2 N HCl (aq), MeOH, 80 °C, 2 h R = Ph (21a, 74%), R = t-Bu (21b, 85%).
H
NH2
H
N
N
O
O
N
N
N
N
N
N
O
N
N
N
O
(a)
(b)
N
P
Ph
N
P
NH2
Ph
Ph
Ph
Ph
23 e
Ph
22 e
24
Scheme 4. Orthogonality of the TPP to the Boc group. Reagents and conditions: (a) TFA–DCM (80/20), 0 °C-rt, 78%; (b) AcOH–H2O (80/20), 90 °C, 5 h, 89%.

B. Delouvrié et al. / Tetrahedron Letters 53 (2012) 5380–5384
5383
Table 3
Results obtained from nucelophilic substitution of 12 with a variety of nucleophiles
N
Cl
N
N
Nu
Conditions
N
Nu
AcOH / H2O
90 °C, 12 h
N
N
P
Ph
N
P
N
NH2
Ph
Ph
Ph
Ph
23 a-e
Ph
22 a-e
12
Entry
1
Compd
Nucelophile
Conditions
Conversion/isolated yield (%)
22a
HN
Neat, 160 °C, 5 h
100/87
O
Neat, 160 °C, 5 h
Neat, 170 °C, 16 h
25/NA
88/65
2
22b
H2N
5 equiv, NMP, 130 °C, 16 h
5 equiv, NMP, 160 °C, 16 h
5/NA
95/52
3
4
5
22c
22d
22e
NaO
NaO
5 equiv 130 °C, 2 h
100/87
89/74
O
HN
NHBoc
5 equiv, NMP, 130 °C, 16 h
sis of triazoles using ‘Click’ chemistry (Scheme 3).14 The added
hydrocarbon weight of the TPP group permitted the safe prepara-
tion and manipulation of the C-3 azide intermediate 18. In the ab-
sence of the TPP group, the intermediate azide has 62% nitrogen
content and could be classed as a potential explosive.15 The subse-
quent ‘Click’ reaction proceeded with high regiocontrol as expected
affording satisfactory yields of triazole products (19a, 19b) with
the reduced C-3–NH2 side product (20).16
Finally, although SNAr of C-2-amino-3-chloropyrazine is well
known in the absence of any protecting group, we were curious
to test the thermal stability of this group with the knowledge that
the Boc group undergoes readily thermolysis above 150 °C.17 We
prepared a small library to illustrate the thermal stability of the
C-2–N@PPh3 group to a large excess of oxygen- and nitrogen-based
nucleophiles at very high temperatures for prolonged periods of
time (Table 3). Compound 22e allowed us to illustrate nicely
how Boc and TPP can be deprotected selectively and are stable to
each other’s deprotection conditions. This interesting observation
could be exploited further by using polymer-supported triphenyl-
phosphine in an anchoring strategy (Scheme 4).
References and notes
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192 °C on a 10 g scale over 14 min. The exothermic behaviour did appear to
subside slightly at this point but then accelerated in rate with the test having to
be terminated before damaging temperature/pressure occurred. Maximum
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approximately 270 °C. Residual pressure was approximately 5.1 bar. Significant
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In conclusion, we have discovered a novel aromatic primary
amine protecting group and demonstrated its application to the
regioselective synthesis of 2-amino-3-N-1-linked triazole and ben-
zotriazole pyrazine fragments on multi-gram quantities. We have
also demonstrated the thermal stability and orthogonality of the
TPP to the Boc group and are currently looking at extending the
scope and application of this protecting group system.
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Acknowledgement
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The authors would like to acknowledge Mr. Jonathan Lecoq, Mr.
Antoine Le Griffon, Mme. Françoise Magnien, Mr. Michel Vautier,
Dr. Mark Hoyle, Mr. Patrice Koza, Mr. Christian Delvare and Dr.
Anne Ertan for their large-scale synthetic and analytical support
for this exploration.
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Supplementary data
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and references cited therein.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.106.

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