Practical synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole, incorporating efficient protecting group removal by flow-reactor hydrogenolysis

Article abstract of DOI:10.1055/s-2006-939036

A practical, safe, high-yielding and efficient synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole has been developed, which avoids the generation of ammonium azide in the cyclisation step and the use of a 9:1 acetic acid-water mixture as the solvent in the hydrogenation. The previously extended hydrogenolysis reaction time (three days) is now reduced to hours through the use of an H-Cube (a continuous-flow reactor employing a mixed hydrogen-liquid flow stream). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939036

LETTER
889
Practical Synthesis of (S)-Pyrrolidin-2-yl-1H-tetrazole, Incorporating
Efficient Protecting Group Removal by Flow-Reactor Hydrogenolysis
a
a
b
a
a
S
V
ynthesis of
(
S
)-Py
i
rrolidi
l
n-2-yl-
i
1
H
-tetr
u
a
zole s Franckevičius, Kristian Rahbek Knudsen, Mark Ladlow, Deborah A. Longbottom, Steven V. Ley*
a
University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
b
GlaxoSmithKline Cambridge Technology Centre, University of Cambridge, Cambridge, CB2 1EW, UK
Received 6 February 2006
NPMP
CO2Et
1 (5 mol%), CH Cl ,
O
O
NHPMP
Abstract: A practical, safe, high-yielding and efficient synthesis of
(
S)-pyrrolidin-2-yl-1H-tetrazole has been developed, which avoids
R1
R1
CO2Et
A
B
C
the generation of ammonium azide in the cyclisation step and
the use of a 9:1 acetic acid–water mixture as the solvent in the
hydrogenation. The previously extended hydrogenolysis reaction
time (three days) is now reduced to hours through the use of an
2
2
R2
R2
r.t., 24 h
3
4
TM
H-Cube (a continuous-flow reactor employing a mixed hydro-
NO2
gen–liquid flow stream)
R3
R4
O
R3
R4
O2N
R1
O
Key words: tetrazole, asymmetric, synthesis, organocatalysis,
flow, hydrogenation
R1
R2
1 (15 mol%),
R2
CH2Cl2, r.t., 3 d
5
6
(
S)-5-pyrrolidin-2-yl-1H-tetrazole (1, Figure 1) is a new
O
O
O
NHPh
O
N
proline-derived organocatalyst that was developed recent-
Ph
1
,2
3,4
ly by ourselves and others. Since both the S- and R-
enantiomers (1 and 2) may be prepared, the user is provid-
ed with a choice of which product to make for any given
asymmetric reaction process.
R1
R1
1
(5 mol%), CHCl3,
°C, 1 h
R2
R2
0
7
8
Scheme 1 Examples of tetrazole catalyst utility: (A) Mannich reac-
tion; (B) addition of nitroalkanes to enones; (C) a-oxidation
N
N
N
N
N
N
H
H
HN
N
HN
N
Firstly, Cbz-protected L-proline was converted to its pro-
line amide derivative in a straightforward fashion and then
dehydrated in a mild manner by the action of cyanuric
chloride (Scheme 2). Both reactions are scalable (we have
carried out reactions on >20 g scale) and can be carried
out with minimum of purification: passing each crude
reaction mixture through a short pad of silica provides
pure material in high yield for use in the next step.
1
2
Figure 1 Structures of (S)- and (R)-5-pyrrolidin-2-yl-1H-tetrazole
The utility of this catalyst has been demonstrated in
several types of reaction, including the Mannich (A,
Scheme 1) and aldol reactions, addition of ketones to
nitroolefins, nitroalkanes to enones (B) and a-oxidation
C) among others.
1
,2
3,4
5
6
7
,8
9–14
(
i) (Boc)2O, NH4HCO3,
However, existing methods for its safe preparation have
pyridine, MeCN, r.t., 5 h (95%)
OH
1
5,16
suffered from a number of problems.
Firstly, ammoni-
N
N
CN
ii) cyanuric chloride, DMF,
0 °C to r.t., 4 h (97%)
Cbz
Cbz
O
um azide can be generated in the key, tetrazole-forming
step. This shock sensitive compound can sublime onto the
sides of the reaction vessel and as such, is an unacceptable
risk. Furthermore, the usual hydrogenolysis conditions
require the use of a 9:1 acetic acid–water mixture under a
9
10
Scheme 2 Synthesis of (S)-2-cyano-pyrrolidine-1-carboxylic acid
benzyl ester (10)
1
6
hydrogen atmosphere for three days. Herein, we report a
safe and reliable procedure for the synthesis of the tetra-
zole catalyst, incorporating state-of-the-art flow-hydro-
genation technology for the final deprotection step.
Concerning the 1,3-dipolar cycloadditon reaction which
constitutes the next step in the synthesis, we used a varia-
17
tion of an existing method, which avoids the generation
of shock-sensitive ammonium azide. Thus, treatment of
the nitrile 10, formed in the previous step, with triethyl-
amine hydrochloride and sodium azide in toluene at a con-
centration of 1 M results in clean formation of the desired
cyclised tetrazole product (Scheme 3).
SYNLETT 2006, No. 6, pp 0889–0892
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939036; Art ID: G04906ST
©
Georg Thieme Verlag Stuttgart · New York

8
90
V. Franckevičius et al.
LETTER
NaN3 (1.3 equiv), Et3N·HCl
N
N
N
CN
toluene, 95 °C, 24 h (95%)
N
Cbz
Cbz
HN
N
10
11
Scheme 3 Synthesis of (S)-2-(1H-tetrazol-5-yl)-pyrrolidin-1-car-
boxylic acid benzyl ester (11)
The excess azide in the reaction is quenched in the follow-
ing way (Equation 1). Sodium nitrite and sulfuric acid
react together to give sodium sulfate and nitric acid. Nitric
acid then reacts (quite vigorously) with hydrazoic acid,
with rapid evolution of both nitrogen and nitrous oxide
gases and concurrent production of water. Thus, the
highly toxic hydrazoic acid side-product is completely
and safely quenched under these conditions.
Figure 2 H-CubeTM flow hydrogenator
test the capacity of the technology and ultimately, suc-
cessfully hydrogenated 3 g of material in just 3.5 hours,
compared to 3 days under standard conditions. No purifi-
cation was needed as simple evaporation of the solvent
afforded pure product 1 in 98% yield.
2
NaNO2 (aq) + H2SO4 (aq)
HNO2 (aq) + HN3 (aq)
Na2SO4 (aq) + 2HNO2 (aq)
N2 (g) + N2O (g) + H2O
Equation 1 Quenching of hydrazoic acid
N
N
N
1
0% Pd/C,
flow hydrogenation
98%)
N
The final step remaining in the catalyst synthesis is the
deprotection, namely removal of the carboxybenzoyl
protecting group. Previously, this had caused problems:
reaction times in the solvent of choice for this reaction,
acetic acid–water (9:1), are extended (3 d), the solvent is
not especially volatile and the reaction work-up can there-
HN
N
N
N
H
O
O
HN
N
(
11
1
Scheme 4 Hydrogenation of (S)-2-(1H-tetrazol-5-yl)-pyrrolidine-
-carboxylic acid benzyl ester (11)
1
1
5,16
fore be time consuming.
We thought that the use of a continuous flow reactor could
remove the protecting group in a mild and efficient man-
In conclusion, we have developed a practical and safe syn-
thesis of (S)-5-pyrrolidin-2-yl-1H-tetrazole (1). The new
method avoids the generation of ammonium azide, and
protection group removal has been facilitated by employ-
ing a flow-hydrogenation method, thereby eliminating the
hazardous and time-consuming aspects of performing
hydrogenation reactions on a preparatively useful scale.
1
8–20
ner.
These flow processes, both on a microfluidic and
mesofluidic scale, are receiving increased attention and
offer a number of potential advantages over existing batch
techniques. For example, reaction conditions (flow rate,
stoichiometry, temperature and pressure) can be indepen-
dently varied and precisely controlled. This leads to a high
level of reproducibility, greatly facilitating the reaction
optimisation process, whereby a range of different condi-
tions can be rapidly investigated.
Experimental Protocols
(
S)-2-Amidopyrrolidine-1-carboxylic Acid Benzyl Ester
We recently reported on the reduction of imines by flow
An oven-dried, single-neck, 1-L round-bottomed flask
1
8
hydrogenation, and this method has been extended here equipped with stirring bar was charged with Cbz-L-proline (20.0 g,
for the use in larger scale Cbz deprotection. Using this 80.3 mmol, 1.0 equiv), di-tert-butyl dicarbonate (22.7 g, 104 mmol,
1
.3 equiv), NH HCO (7.60 g, 96.2 mmol, 1.2 equiv) and MeCN
4 3
flow procedure, the hydrogen is generated by electrolysis
of water in situ and there is at no time more than 8 mL of
hydrogen present in the system. Consequently, this make-
and-use concept, producing a reagent in situ and using it
(400 mL) under an argon atmosphere. Anhyd pyridine (3.89 mL,
4
8.1 mmol, 0.6 equiv) was added in one portion via syringe and the
reaction stirred for 5 h at r.t. After complete consumption of starting
material, the solvent was removed under reduced pressure until
immediately, is attractive in the handling of potentially 100 mL remained. Then, EtOAc (200 mL) and H O (200 mL) were
2
hazardous substances.
added and the organic phase separated. The aqueous phase was ex-
tracted further with EtOAc (2 × 200 mL) and the combined organic
Thus, a 0.05 M solution of the protected proline derivative
phase washed with brine (200 mL), dried (MgSO ) and concentrat-
4
1
1 was prepared with EtOH–EtOAc–AcOH (1:1:1) as the
ed under reduced pressure to give a white crystalline solid. Suction
filtration through a pad of silica gel, eluting with EtOAc, afforded
TM
solvent and passed through the H-Cube flow hydro-
2
1
genator (Figure 2, Scheme 4). In just 10 minutes, 70 mg 19.0 g (96%) of the desired amide as a white crystalline solid.
2
5
of tetrazole was successfully hydrogenated, dramatically
reducing the reaction time and demonstrating strongly the
utility of this new flow technology in solving the depro-
tection problem. Encouraged by this result, we decided to
R
(
(
f
= 0.26 (EtOAc); [a]
D
–82.8 (c 0.50, CHCl ); mp 90–92 °C. IR
3
–
1 1
film): nmax = 3386, 3196, 2952, 1693, 1673, 1502 cm . H NMR
500 MHz, CDCl , mixture of rotamers): d = 7.39–7.26 (5 H, m,
ArH), 6.70 (app s), 5.99 (app s), 5.81–5.49 (m, 2 H, NH ), 5.16
3
2
(
1 H, d, J = 12.3 Hz, ArCHH¢), 5.12 (1 H, d, J = 12.4 Hz, ArCHH¢),
Synlett 2006, No. 6, 889–892 © Thieme Stuttgart · New York

LETTER
Synthesis of (S)-Pyrrolidin-2-yl-1H-tetrazole
891
–
1 1
4
2
.40–4.25 (1 H, m, NCH), 3.59–3.37 (2 H, m, NCH ), 2.32 (app s),
1694, 1443, 1404, 1132 cm . H NMR (600 MHz, CDCl ): d =
2
3
1
3
.16 (app s), 2.05–1.84 (m, 4 H, CH CH ). C NMR (125 MHz,
7.36–7.20 (5 H, m, ArH), 5.21 (1 H, d, J = 12.3 Hz, ArCHH¢), 5.17–
5.10 (2 H, m, ArCHH¢, NCH), 3.64–3.56 (1 H, m, NCHH¢), 3.56–
3.50 (1 H, m, NCHH¢), 2.76–2.68 (1 H, m, NCHCHH¢), 2.37–2.28
2
2
CDCl , mixture of rotamers): d = 175.1, 174.1 [C(O)NH ], 156.1,
1
3
2
55.1 [C(O)O], 136.3 (Ar), 128.5 (Ar), 128.1 (Ar), 127.9 (Ar), 67.4
(
(
ArCH ), 60.6, 60.1 (NCH), 47.5, 47.0 (NCH ), 31.1, 28.3
NCHCH ), 24.5, 23.6 (NCH CH ). MS (ESI): m/z calcd for
(1 H, m, NCHCHH¢), 2.28–2.16 (1 H, m, NCH CHH¢), 2.11–2.02
2
2
2
1
3
(1 H, m, NCH CHH¢). C NMR (150 MHz, CDCl ): d = 156.4,
2
2
+
2
2
3
+
C H N O : 249.1239 [M + H] ; found: 249.1239 [M + H] .
156.3 (NCO, NCN), 135.7 (Ar), 128.6 (Ar), 128.3 (Ar), 127.8 (Ar),
8.0 (ArCH ), 51.4 (NCH), 47.0 (NCH ), 29.5 (NCHCH ), 24.6
1
3
16
2
3
6
2
2
2
Note: i) Prior to reaction workup, there is a UV-active impurity;
following workup it is no longer present; ii) It was found that dis-
solving the crude product in CH Cl to load it onto the silica is the
(
NCH CH ). MS (ESI): m/z calcd for C H N O : 296.1123 [M +
2 2 13 15 5 2
+
+
Na] ; found: 296.1113 [M + Na] .
2
2
most successful protocol.
Note: Three layers form in the reaction vessel when this reaction is
complete.
(
S)-2-Cyanopyrrolidine-1-carboxylic Acid Benzyl Ester (10)
An oven-dried, single-neck, 1-L round-bottomed flask equipped
with stirring bar was charged with (S)-2-amido-pyrrolidine-1-car-
boxylic acid benzyl ester (20.0 g, 80.6 mmol, 1.0 equiv) and N,N-
dimethylformamide (240 mL) under an argon atmosphere. The so-
lution was cooled in an ice–water bath for 30 min and cyanuric chlo-
ride (9.62 g, 52.3 mmol, 0.65 equiv) was then added in one portion.
The reaction mixture was stirred at this temperature for 1 h, at which
point the ice bath was removed and it was stirred at r.t. for a further
(2S)-5-Pyrrolidin-2-yl-1H-tetrazole (1)
A solution of 11 (3.0 g, 11.0 mmol) as a 0.05 M solution in EtOAc–
AcOH–EtOH (1:1:1, 220 mL) was pumped through the H-Cube
flow hydrogenator fitted with a 10 mol% Pd/C catalyst cartridge
heated to 80 °C at 1 bar with the full hydrogen option enabled.
The flow rate was set at 1 mL/min. The catalyst was pre-saturated
with hydrogen gas for 5 min before passing the substrate through.
The solvent was evaporated, toluene (200 mL) was added and evap-
TM
3
h. After complete consumption of starting material, distilled H O
orated, yielding 1.50 g of product 1 (98%) as a white solid. R = 0.25
2
f
2
5
(
(
200 mL) was added and the aqueous extracted with EtOAc
3 × 200 mL). The combined organic phases were washed with LiCl
[n-BuOH–H O –CH CO H (3:3:1)]; [a] –10.5 (c 0.63, CHCl ).
2 3 2 D 3
–1 1
IR (film): nmax = 3676, 2972, 2588, 2457, 1629 cm . H NMR
solution (10 wt% in distilled H O, 3 × 200 mL), dried (MgSO ) and
concentrated under reduced pressure to give a yellow oil. Suction
filtration through a pad of silica, eluting with CH Cl , afforded
(500 MHz, DMSO-d ): d = 9.19 (1 H, br s, NH), 4.78 (1 H, dd,
2
4
6
J = 8.2, 7.3 Hz, NHCH), 3.38 (1 H, br s, NH), 3.32–3.19 (2 H, m,
NHCH ), 2.38–2.30 (1 H, m, NHCHCHH¢), 2.20–1.95 (3 H, m,
2
2
2
1
3
1
8.0 g (97%) of 10 as a pale-yellow crystalline solid. R = 0.29
NHCHCHH¢CH2). C NMR (125 MHz, DMSO-d ): d = 171.1
(NHCHC), 54.2 (NHCH), 44.3 (NHCH ), 29.9 (NHCHCH ), 23.2
f
6
25
(
CH Cl ); [a] –89.0 (c 1.00, CHCl ); mp 37–39 °C. IR (film):
2
2
D
3
1 1
2
2
–
nmax = 2959, 2888, 2343, 1701 cm . H NMR (600 MHz, CDCl ,
(NHCH CH ). MS (ESI): m/z calcd for C H N : 162.0756 [M +
3
2 2 5 9 5
+
+
mixture of rotamers): d = 7.43–7.30 (5 H, m, ArH), 5.24–5.13 (2 H,
Na] ; found: 162.0748 [M + Na] .
m, ArCH ), 4.62 (d, J = 6.1 Hz), 4.55 (1 H, d, J = 6.2 Hz, NCHCN),
2
3
2
.64–3.52 (1 H, m, NCHH¢), 3.49–3.36 (1 H, m, NCHH¢), 2.34–
13
Acknowledgment
.00 (4 H, m, CH CH ). C NMR (150 MHz, CDCl , mixture of
2
2
3
rotamers): d = 154.2, 153.6 (NCO), 136.0, 135.9 (Ar), 128.5 (Ar),
We thank the Cambridge European Trust and the EPSRC (V.F.), the
Carlsberg foundation (K.R.K.), the EPSRC and Trinity College
1
4
2
28.2 (Ar), 128.1 (Ar), 118.8, 118.6 (NCHCN), 67.7, 67.6 (ArCH2),
7.5, 46.9 (NCH), 46.3, 45.9 (NCH ), 31.7, 30.7 (NCHCH ), 24.6,
2
2
(
D.A.L.) and Novartis (S.V.L.) for financial support.
3.7 (NCH CH ). MS (ESI): m/z calcd for C H N O : 231.1134
2
2
13 14
2
2
+
+
[
M + H] ; found: 231.1124 [M + H] .
Note: Following filtration of the product through the silica pad, References and Notes
there is a minor impurity present, which runs just above the desired
(
1) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558.
product by TLC; this is no longer present when the product has been
(2) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
1
under vacuum for several hours and cannot be seen in the H NMR
spectrum at any time.
(
(
(
(
3) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem. Int. Ed. 2004, 43, 1983.
4) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
(
S)-2-(1H-Tetrazol-5-yl)pyrrolidine-1-carboxylic Acid Benzyl
Ester (11)
2004, 15, 1831.
An oven-dried, single-neck 250-mL flask was charged with (S)-2-
cyano-pyrrolidine-1-carboxylic acid benzyl ester (10, 16.4 g,
5) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V.
Chem. Commun. 2004, 1808.
7
1.3 mmol, 1.0 equiv), NaN (6.03 g, 92.8 mmol, 1.3 equiv),
3
6) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346.
7) Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577.
8) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5374.
Et N·HCl (12.81 g, 92.8 mmol, 1.3 equiv) and toluene (70 mL),
3
under an atmosphere of argon. The reaction mixture was heated to
(
(
9
5 °C for 24 h and after complete consumption of starting material,
H O (100 mL) was added and the organic layer separated off. The
2
organic layer was further extracted with H O (50 mL) and the com-
2
(
9) Suri, J. T.; Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005,
bined aqueous fractions cooled to 0 °C with stirring, in a round-bot-
7
, 1383.
10) Thayumanavan, N. R.; Tanaka, F.; Barbas, C. F. Org. Lett.
004, 3541.
11) Chowdari, N. S.; Barbas, C. F. Org. Lett. 2005, 7, 867.
12) Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem.
Commun. 2006, 66.
13) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V.
Org. Lett. 2005, 7, 4189.
14) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, in
press.
tomed flask. Then, NaNO solution (20 wt% aq, 21 mL) was added
3
(
in one portion, followed by dropwise addition of H SO (20 wt% aq,
2
4
2
1
5 mL) until no more gas was evolved, the solution was acidic and
(
(
a sticky orange solid was formed. This aqueous mixture was then
further extracted with EtOAc (3 × 50 mL), taking care that all the
orange solid had dissolved completely. The organic fractions were
(
(
then combined, dried (MgSO ) and the solvent removed under re-
4
duced pressure to yield 18.5 g of the crude product 11 (95%) as an
orange foam, which was then used directly in the next step.
2
5
R = 0.28 [toluene–EtOAc–CH CO H (20:20:1); [a]
–91.3 (c
.27, CHCl ); mp 84–86 °C. IR (NaCl plate): n = 3000–2400,
f
3
2
D
1
3
max
Synlett 2006, No. 6, 889–892 © Thieme Stuttgart · New York

8
92
V. Franckevičius et al.
LETTER
(
(
(
(
15) Almquist, R. G.; Chao, W. R.; Jennings-White, C. J. Med.
Chem. 1985, 28, 1067.
16) Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005,
(19) Jones, R. V.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge, L.;
Darvas, F. J. Comb. Chem. 2006, 8, 110.
(20) Desai, B.; Kappe, O. J. Comb. Chem. 2005, 7, 641.
(21) For further details, please refer to the product details on the
company website: http://www.thalesnano.com. Address:
Thales Nanotechnology, 1031 Budapest, Záhony ucta 7
(Graphisoft Park), Hungary. Fax: +36(1)6666190; Tel:
+36(1)6666100.
4
287.
17) Koguru, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998,
10.
9
18) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem.
Commun. 2005, 2909.
Synlett 2006, No. 6, 889–892 © Thieme Stuttgart · New York