A facile synthesis of 2,3-azaisoindoline

Article abstract of DOI:10.1016/j.tetlet.2010.08.091

2,3-Azaisoindoline (4) was prepared via reaction of dichloride 11 with 2,4-dimethoxybenzyl amine followed by deprotection with trifluoroacetic acid and triethylsilane. Isolation of the unstable 2,3-azaisoindoline 4 was facilitated by conversion to the bis-HCl salt.

Full text of DOI:10.1016/j.tetlet.2010.08.091

Tetrahedron Letters 51 (2010) 5859–5860
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of 2,3-azaisoindoline
Subas M. Sakya a, , Michel Van Den Berg b, Kees Pouwer b, John M. Humphrey a, Christopher J. Helal a,
⇑
Christopher J. O’Donnell a
a Pfizer Global Research and Development, Neuroscience Medicinal Chemistry, Groton, CT 06355, USA
b Syncom BV, Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3-Azaisoindoline (4) was prepared via reaction of dichloride 11 with 2,4-dimethoxybenzyl amine fol-
lowed by deprotection with trifluoroacetic acid and triethylsilane. Isolation of the unstable 2,3-azaisoind-
oline 4 was facilitated by conversion to the bis-HCl salt.
Received 14 July 2010
Revised 27 August 2010
Accepted 30 August 2010
Available online 6 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
2,3-Azaisoindoline is an important intermediate used in the
synthesis of pharmaceutical analogs to obtain desired properties
of the target molecule.1 Although it is available commercially, it
is prohibitively expensive ($540–650/g). For our medicinal chemis-
try program, we required a synthetic route amenable to a large
scale (50–1000 g) preparation of 2,3-azaisoindoline 4. Compound
4 has been made on a small scale using the literature intramolec-
ular Diels–Alder route shown in Scheme 1.1b,c However, route A
was limited by the cost of starting material 1a ($520–742/g) and
route B gave isomeric products (4 and 5) in moderate yields.
An additional literature-based route looked attractive due to its
simplicity and readily available starting materials (Scheme 2).2 In
addition, pthalimide had been shown to be easily reduced to the
isoindoline with borane in moderate yield.3 Thus, for our initial ef-
forts, we prepared both the azapthalimide 6 and it is benzyl deriv-
ative 7 via literature-reported conditions (Scheme 2).4
Attempted reduction of benzyl azapthalimide 6 with either LAH2
or borane3 resulted in over-reduction and/or incomplete reduction,
resulting in variable yields (5–20%). Multiple attempts to repeat lit-
erature conditions used to reduce pthalimide failed to provide the
desired product 4.2 Use of alane as the reducing agent (diethylether,
room temp) gave about 20% yield of the corresponding benzyl-
protected azaisoindoline intermediate. Unfortunately, the use of
hydrogenolysis or carbamate exchange conditions with refluxing
1-chloro-ethyl chloroformate (ACE-Cl) failed to give pure azaisoind-
oline 4. The catalytic hydrogenation conditions proceeded very
slowly even upon heating and high pressure. Initial preparation of
the mono hydrochloride salt of 7 not only helped the reduction pro-
gress but also led to side products resulting from reduction of the
pyridine ring.
Cl
N
NHCO2Et
N
Y
NCO2Et
N
As an alternate, we pursued a route where the removal of the
protecting group could be facilitated with an acid so the product
could be isolated as a stable salt. For this approach, we envisioned
preparing a suitably protected 2-azaisoindoline via the dimesylate
10 or the dichloride 11 intermediate6 (Scheme 3).
X
A
1a,
2
X=N, Y=CH
1b, X=CH, Y=N
A
NHCO2Et
Thus the commercially available, inexpensive diester 8 ($7.96/g
for 25 g and $2.28/g for 2.5 kg) was reduced with sodium borohy-
N
N
NCO2Et
NH.2HCl
O
N
N
B
NH
3
4
5
LAH
O
O
N
N
NH.2HCl
6
NH.2HCl
N
4
NBn
Scheme 1. Literature Diels–Alder approaches to 4.
1. LAH, borane or alane
2. Pd/C or ACECl
O
7
⇑
Corresponding author. Tel.: +1 860 715 0425; fax: +1 860 715 7312.
E-mail address: subas.m.sakya@pfizer.com (S.M. Sakya).
Scheme 2. Azapthalimide route to prepare 4.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.091

5860
S. M. Sakya et al. / Tetrahedron Letters 51 (2010) 5859–5860
reaction of the unstable dimesylate with dimethoxybenzylamine
N
CO2Me
CO2Me
N
N
a
OH
OH
did provide 13 in 88% yield. Additionally, in our hands, attempted
reactions with amide or sulfonamide protected amines (BOCNH2,
p-tolSO2NH2) failed to give the desired products (BOCNH2)7 or gave
lower yields (p-tolSO2NH2, 30–40%).1a
8
9
b
c
Attempted removal of the t-butyl group of 12a using TFA or HCl
failed to give any desired product. However, the treatment of the
2,4-dimethoxybenzyl amine derivative 13 with TFA gave the de-
sired product 4 as it is bis TFA salt but was difficult to purify. To
provide clean reactions and facilitate isolation of the product, the
deprotection reaction was performed in the presence of triethylsi-
lane to trap the reactive dimethoxybenzyl cation generated from
the TFA cleavage. This was followed by exchange of the resulting
TFA salt with HCl which resulted in the formation of the desired
product 4 as an easily filtered solid (Scheme 4). This reaction pro-
vided pure 2,3-azaisoindoline bis-hydrochloride 4 in 70% yield.8
In summary, we have demonstrated a four step synthesis of
2,3-azaisoindoline 4 in 25% overall yield. This approach is an
improvement on previous methods as it uses the readily available
and economic starting materials, can be performed on large scale,
and allows facile isolation of the product as stable and easily han-
dled solid.
N
OMs
OMs
Cl
Cl
·HCl
10
11
d
RNH2
N
NR
4
, R = H
12a, R = C(CH3)
12b, R = CPh3
Scheme 3. Reagents and conditions: (a) NaBH4, CaCl2, EtOH, rt, 74%; (b) MsCl,
iPr2NEt, DCM, 48%; (c) SOCl2, toluene, 100 °C, 93–96%; (d) For 12a: tBuNH2, Et3N,
DCM, 30%.
References and notes
OMe
1. (a) Kim, D. Y.; Lee, I. C.; Yoon, G. J. J. Korean Chem. Soc. 1998, 42, 102; b Petersen,
U.; Krebs, A.; Schenke, T.; Grohe, K.; Bremm, K. D.; Endemann, R.; Grohe, K.;
Bremm, K. D.; Endelman, R.; Metzger, K. G.; Zeiller, H. J. EP 92110043, 1992.; (c)
Paget, S. D.; Foleno, B. D.; Boggs, C. M.; Goldschmidt, R. M.; Hlasta, D. J.;
Weidner-Wells, M. A.; Werblood, H. M.; Wira, E.; Bush, K.; Macielag, M. J. Bioorg.
Med. Chem. Lett. 2003, 13, 4173; (d) Paget, S. D.; Boggs, C. M.; Foleno, B. D.;
Goldschmidt, R. M.; Hlasta, D. J.; Weidner-Wells, M. A.; Werblood, H. M.; Bush,
K.; Macielag, M. J. Bioorg. Med. Chem. Lett. 2006, 16, 4537.
N
a
N
Cl
Cl
·HCl
N
OMe
11
13
b
2. Bryans, J. S.; Johnson, P. S.; Roberts, L. R. WO2006123242(A1), 2006.
3. Gawley, R. E.; Chemburkar, S. R.; Smith, A. L.; Anklekar, T. V. J. Org. Chem. 1988,
53, 5381.
N
4. Carpino, L. A.; Xia, J.; El-Faham, A. J. Org. Chem. 2004, 69, 54.
NH·2HCl
5. Wang, Y.-X.; Mabic, S.; Castagnoli, N. Bioorg. Med. Chem. 1998, 6, 143.
6. Grimm, J. S.; Maryanoff, C. A.; Patel, M.; Palmer, D. C.; Sorgi, K. L.; Stefanick, S.;
Webster, R. R. H.; Zhang, X. Org. Proc. Res. Dev. 2002, 6, 938.
4
7. Zwanenburg, D. J.; Wynberg, H. J. Org. Chem. 1969, 34, 333.
8. Preparation of 6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine
(13)
Scheme 4. Reagents and conditions: (a) 1.1 equiv 2,4-dimethoxybenzyl amine,
3.3 equiv iPr2NEt, DCM, rt, 50%; (b) Et3SiH, TFA, HCl/dioxane, 70%.
2,3-Bis(chloromethyl)pyridine hydrochloride (10ÁHCl, 17.89 g, 84.2 mmol) was
placed in a dry flask with dichloromethane (350 ml). The flask was purged with
argon and placed in a water bath (ꢀ15–20 °C. Diisopropylethylamine (46.1 ml,
278.9 mmol) was added dropwise over a 5 min period and the mixture was
stirred for 10 min at room temperature. 2,4-Dimethoxybenzylamine (14 ml,
93.2 mmol) was added dropwise over a 7 min period and the mixture was
stirred for 18 h at room temperature. Water (350 ml) was added and the layers
were separated. The aqueous layer was extracted with dichloromethane
(2 Â 175 ml). The combined organic layer was dried over sodium sulfate, was
filtered, and was concentrated in vacuo yielding 31.22 g of a brown oil. Column
chromatography over silica gel using 5% methanol in dichloromethane as the
eluent gave 11.42 g (50%) of 6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridine (13) as a brown oil. 1H NMR (300 MHz, CDCl3) d 383 (s,
3H, OCH3); 3.84 (s, 3H, OCH3); 3.93 (s, 2H, CH3OCCCH2); 4.02 (s, 2H, NCH2CCN);
4.07 (s, 2H, NCH2CN); 6.48–6.52 (m, 2H, CH3OCCH); 7.07 (dd, J = 7.6 Hz,
J = 5.1 Hz, 1H, NCHCH); 7.30 (d, J = 8.9 Hz, 1H, CH3OCCHCH); 7.46 (d,
J = 6.6 Hz, 1H, NCCCH); 8.37 (d, J = 4.0 Hz, 1H, NCH); 13C NMR (300 MHz,
CDCl3) d 161.87, 160.16, 158.62, 147.83, 133.85, 131.17, 129.92, 121.43, 118.90,
103.95, 98.52, 59.32, 56.95, 55.45, 55.32, 53.16; MS (m/z) 270.10 (M+); HRMS for
dride in the presence of calcium chloride to give the corresponding
diol 9 in 74% yield (Scheme 3). Conversion to the dimesylate 10
proceeded in 48% yield.5 Reaction of the diol with thionyl chloride,
following available procedure,6 gave the dichloride hydrochloride
salt 11 in greater than 90% yield. Low yields with the dimesylate
preparation are attributed to the instability of the dimesylate free
base (formation of baseline by-products) whereas the dichloride is
isolated as a stable salt.
Having secured the key intermediates, the initial idea was to
convert dichloride 11 directly into 2,3-azaisoindoline 4 using
ammonia (Scheme 3). Unfortunately, reaction with ammonia was
rather messy (multiple spots on tlc, no product by LCMS) and did
not yield any desired product. Next, we examined the double dis-
placement of the dichloride with a suitably functionalized amine
in which the substituent on the amine could serve as a protecting
group that could be easily removed under acidic conditions. Reac-
tion between dichloride 11 and t-butylamine or tritylamine gave
the desired t-butyl- and triphenylmethyl azaisoindolines 12a and
12b in 30% and 3% yield, respectively (Scheme 3). We speculated
that the low yields for these reactions were a result of the bulky
amino groups used so we attempted the displacement with a less
sterically demanding amine. To this end, reaction of dichloride 11
with 2,4-dimethoxybenzyl amine gave the suitably protected 2-
azaisoindoline 13 in 50% yield (Scheme 4). It should be noted that
C
16H19N2O2 calcd 271.1441, found 271.1437.
6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (4)
6-(2,4-Dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (13, 9.43 g,
34.9 mmol) was placed in
a dry flask under nitrogen. Trifluoroacetic acid
(27 ml) and triethylsilane (6.0 ml) were added. The mixture was stirred and
heated at 60 °C for 5 h. The volatiles were removed in vacuo resulting in a sticky
oil. HCl (4 M in dioxane, 40 ml) was added to the residue followed by the
addition of ethyl acetate (50 ml). Vigorous stirring at room temperature for ꢀ1 h
resulted in a precipitate. The solids were isolated by filtration and were washed
with ethyl acetate (25 ml) and were dried in vacuo yielding 5.25 g (70%) 6,7-
dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride 4 as pale brown solid: 1H
NMR (300 MHz, CD3OD) d 4.71 (s, 2H, NHCH2CCN); 4.78 (s, 2H, NHCH2CN); 7.6
(t, J = 7.2 Hz, 1H, NCHCH); 8.10 (d, J = 7.6 Hz, 1H, NCCCH); 8.65 (d, J = 5.3 Hz, 1H,
NCH). All other NMR data were compared with known compounds and were
consistent with the structures.