The synthesis of 3-aryl-3-azetidinyl acetic acid esters by rhodium(I)-catalysed conjugate addition of organoboron reagents

Article abstract of DOI:10.1016/j.tetlet.2009.04.078

A practical route to 3-aryl-3-azetidinyl acetic acid esters is developed. The key step involves the rhodium(I)-catalysed conjugate addition of an organoboron reagent to an α,β-unsaturated alkene. Elaboration of one conjugate addition product to give a nov

Full text of DOI:10.1016/j.tetlet.2009.04.078

Tetrahedron Letters 50 (2009) 3909–3911
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Tetrahedron Letters
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The synthesis of 3-aryl-3-azetidinyl acetic acid esters by
rhodium(I)-catalysed conjugate addition of organoboron reagents
Philip N. Collier
Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical route to 3-aryl-3-azetidinyl acetic acid esters is developed. The key step involves the rho-
Received 19 March 2009
Revised 8 April 2009
Accepted 17 April 2009
Available online 24 April 2009
dium(I)-catalysed conjugate addition of an organoboron reagent to an a,b-unsaturated alkene. Elabora-
tion of one conjugate addition product to give a novel spiroazetidine ring system is also described.
Ó 2009 Elsevier Ltd. All rights reserved.
R1
R1
R1
Despite their increasing utility in drug discovery, substituted
azetidines have received considerably less attention than their lar-
ger ring pyrrolidine and piperidine analogs.1 This is in large part
due to the greater difficulty associated with the synthesis of this
strained heterocycle.
As part of a kinase inhibitor programme, we required efficient
entry into 3,3-disubstituted azetidines of type 1. These moieties
are traditionally synthesised via reduction of the corresponding
azetidine-2-ones, which in turn are prepared from poorly accessi-
ble 2-aryl-2-cyanoacetates (Scheme 1).2,3 The variety of azetidines
accessible by this route is clearly limited by the highly reactive re-
agents used in a number of the steps.
(i) NaH
(ii) R2CH2X
Raney-Ni
R1
R2
R2
CO2Et
H2N
NC CO2Et
NC CO2Et
R1
CH3MgI
LiAlH4
R2
R2
HN
HN
1
O
Scheme 1. An established method for 3,3-disubstituted azetidine synthesis.
We envisioned a more direct approach into this class of com-
pound that uses the Rh(I)-catalysed boronic acid conjugate addi-
tion protocol pioneered by Hayashi and Miyaura.4,5 This
methodology was predicted to be compatible with a wide range
of aromatic substituents (R1) and provide 3-aryl-3-azetidinyl acetic
acid ester derivatives 2 possessing a valuable ester group for fur-
ther synthetic manipulation (Scheme 2).
R1
R1
CO2Et
CO2Et
B(OH)2
cat. Rh(I)
PGN
PGN
2
Investigations began with the reaction of phenylboronic acid
Scheme 2. Proposed synthesis of 3-aryl-3-azetidinyl acetic acid esters.
with
a,b-unsaturated ester 3, easily prepared by Horner–Wads-
worth–Emmons reaction from N-Boc-3-azetidinone (Scheme 3).6
Encouragingly, the desired conjugate addition adduct 4, was ob-
tained in 85% yield after stirring at room temperature for one hour
in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer.7
Further similar experiments were used to explore the scope and
limitations of the process and the results are summarised in Table
1.8,9 In general, the reactions were carried out under microwave
heating at 100 °C for 5 min.10 The steric bulk of the N-protecting
group in unsaturated ester 3 did not appear to hinder the reaction.
Indeed, the reaction was also successful when the larger diphenyl-
methyl N-protection, a commonly used protecting group for the
azetidine ring, was used (Table 1, entry 2).
(i)
(ii)
O
CO2Et
CO2Et
BocN
BocN
BocN
3
4
Scheme 3. Reagents and conditions: (i) EtO2CCH2P(O)(OEt)2, NaH, THF, rt, 72%; (ii)
PhB(OH)2 (2 equiv), [Rh(cod)Cl]2 (0.03 equiv), 1.5 M KOH (2 equiv), 1,4-dioxane, rt,
1 h, 85%.
As expected, the reaction worked well with a range of boronic
acids that incorporated both electron-donating and electron-with-
drawing groups. Boronic esters are equally competent partners in
the coupling reaction (entry 14). We obtained a poor yield of 36%
in the coupling reaction with 3-nitrophenylboronic acid under
E-mail address: philip_collier@vrtx.com
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.078

3910
P. N. Collier / Tetrahedron Letters 50 (2009) 3909–3911
Table 1 (continued)
Table 1
Rhodium-catalysed coupling of alkene 3 or 5 with aromatic boronic acids/esters
Entry Alkene Boronic acid/ester Product
Methoda Yieldb
(%)
ArB(OR)2
Ar
PGN
CO2Et
CO2Et
cat. [(Rh(cod)Cl]2
conditions
O
PGN
O
12
13
14
3
3
3
A
A
A
83
74
74
CO2Et
4,6-18
PG = Boc, 3
B(OH)2
PG = Ph2CH, 5
17
BocN
Entry
Alkene
Boronic acid/ester Product
Methoda Yieldb
H
N
H
N
(%)
CO2Et
CO2Et
MeO
MeO
B(OH)2
O
18
4
CO2Et
BocN
1
3
A
90
B(OH)2
6
BocN
B
MeO
Ph
O
BocN
CO2Et
MeO
2
3
4
5
6
7
8
9
5
3
3
3
3
3
3
3
A
73
80
88
73
83
73
79
65
7
N
B(OH)2
B(OH)2
a
Ph
Method A: ArB(OH)2 (2 equiv), [Rh(cod)Cl]2 (0.03 equiv), 1.5 M KOH (2 equiv),
1,4-dioxane, microwave (300 W, CEM Discover), 100 °C, 5 min. Method B:
ArB(OH)2 (3 equiv), [Rh(cod)Cl]2 (0.03 equiv), K2CO3 (3 equiv), 2-propanol
(3 equiv), THF, 60 °C, conventional heating, 2 h.
Isolated yields based on alkene 3 or 5.
Carried out at rt, overnight.
5 equiv of boronic acid used.
% Conversion based on LC–MS (AUC).
H2N
H2N
HO
b
c
CO2Et
A
8
BocN
d
e
HO
A
CO2Et
B(OH)2
our standard coupling conditions (Table 1, method A). However, it
is known that rhodium-catalysed protodeboronation of the boronic
acid can be a significant competing side reaction when employing
certain electron-deficient boronic acids.11–14 This yield was im-
proved from 36% to 73% by adopting conditions similar to those re-
ported by Parker (entry 5).11 Here, the replacement of water with
iso-propanol, minimizes the water-assisted protodeboronation. In
our studies, we found that three equivalents of the boronic acid
were still necessary to consume the starting material.
We were pleased to observe smooth coupling with a sterically
hindered boronic acid (entry 7) in light of the poorer results re-
ported with ortho-substituted boronic acids by Iyer et al. in their
related studies.10 The anhydrous Parker conditions did not provide
any advantage in this case with respect to reducing the amount of
boronic acid used. The reaction is highly functional group tolerant.
Boronic acids containing a bromine atom (entry 8) and unpro-
tected aniline, phenol and ketone functionalities (entries 3, 4 and
6) were all coupled smoothly and in high yield. Remarkably, 3-bro-
momethylphenylboronic acid (entry 9) was also a suitable cou-
pling partner, furnishing the desired conjugate addition product
14 in 65% isolated yield.
To the best of our knowledge, reaction conditions that inhibit
the fast competing protodeboronation observed when employing
pyridine boronic acids have yet to be developed.15 Therefore the
low yield for entry 10 (Table 1) was expected. Despite this problem
with pyridines, certain 3-heteroaryl-3-alkyl azetidines can be pre-
pared in good yield from heteroaromatic boronic acids possessing
heteroatoms further removed from the boron atom (entries 11–
13).
The conjugate addition adducts can be easily converted into
simple 3-aryl-3-alkyl azetidines. For example, treatment of the
aldehyde derived from ester 13 with Wilkinson’s catalyst gave
3-(3-bromophenyl)-3-methylazetidine 19 after N-Boc deprotection
(Scheme 4).
9
BocN
O2N
O2N
O
CO2Et
B
B(OH)2
10
BocN
O
A
CO2Et
11
B(OH)2
BocN
Ac,d
CO2Et
B(OH)2
12
BocN
Br
Br
CO2Et
13
A
B(OH)2
B(OH)2
BocN
Br
Br
N
Ac
CO2Et
14
BocN
N
10
11
3
3
A
A
7e
CO2Et
CO2Et
B(OH)2
15
16
BocN
N
N
75
The conjugate addition adducts could also be of interest in the
area of Diversity Oriented Synthesis.16,17 For example, cyclisation
of the acid derivative of adduct 20 gave the previously unreported
spiroazetidine 21 in protected form (Scheme 5).
B(OH)2
BocN

P. N. Collier / Tetrahedron Letters 50 (2009) 3909–3911
3911
M.; Muller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M.
Angew. Chem., Int. Ed. 2006, 45, 7736–7739.
Br
Br
(i)-(iii)
8. General procedure, method A (for compound 6): To a solution of [Rh(cod)Cl]2
(6.1 mg, 0.012 mmol) in 1,4-dioxane (1 mL) was added aqueous KOH (1.5 M,
0.553 mmol, 0.829 mmol). After stirring for 5 min, 3-methoxyphenylboronic
acid (126 mg, 0.829 mmol) and then alkene 3 (100 mg, 0.414 mmol) in THF
(1.5 mL) were added in rapid succession. The reaction mixture was irradiated
with microwaves (300 W) at 100 °C for 5 min, then diluted with water and
extracted with EtOAc (2 Â 20 mL). The combined organics were dried
(magnesium sulfate), filtered and concentrated. Purification by column
chromatography (3:1, petroleum ether/EtOAc) gave adduct 6 (130 mg, 90%)
as a colourless oil. General procedure, method B (for compound 10): To a solution
CO2Et
BocN
HN
19
13
Scheme 4. Reagents and conditions: (i) DIBAL-H, DCM, À78 °C, 1 h, 81%; (ii)
ClRh(PPh3)3, toluene, 4 h, reflux; (iii) TFA, Et3SiH, DCM, 44% (two steps).
of alkene
1.24 mmol) and K2CO3 (172 mg, 1.24 mmol) in THF (4 mL) and 2-propanol
(75 mg, 1.24 mmol) was added solution of [Rh(cod)Cl]2 (10.1 mg,
0.021 mmol) in THF (1.5 mL) under nitrogen. The reaction was heated at
60 °C for 2 h and then worked-up as in method A. Purification by column
chromatography (3:1, petroleum ether/EtOAc) gave adduct 10 (110 mg, 73%) as
a colourless oil.
3 (100 mg, 0.414 mmol), 3-nitrophenylboronic acid (207 mg,
H
H
N
N
a
(i)
(ii), (iii)
CO2Et
CO2Et
N
Ph
O
N
N
Ph
Ph
Ph
Ph
9. NMR data of some representative compounds: compound 3: 1H NMR (400 MHz,
CDCl3): d 1.30 (3H, t, J = 9.2 Hz), 1.48 (9H, s), 4.20 (2H, q, J = 9.2 Hz), 4.60–4.63
(2H, m), 4.82–4.86 (2H, m), 5.77–5.79 (1H, m); 13C NMR (100 MHz, CDCl3): d
14.7, 28.7 (3C), 58.3 (2C), 60.8, 80.6, 114.1, 152.9, 156.7, 165.7; Compound 6: 1H
NMR (400 MHz, CDCl3): d 1.15 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 2.96 (2H, s), 3.82
(3H, s), 4.03 (2H, q, J = 7.0 Hz), 4.21 (2H, d, J = 9.0 Hz), 4.27 (2H, d, J = 9.0 Hz),
6.74 (1H, s), 6.78–6.81 (2H, m), 7.25–7.29 (1H, m); 13C NMR (100 MHz, CDCl3):
d 14.5, 28.8 (3C), 40.1, 46.1, 55.6, 60.0 (2C, br s), 60.8, 80.0, 112.3, 112.7, 118.7,
129.9, 146.0, 156.8, 160.0, 170.8; Compound 10: 1H NMR (400 MHz, CDCl3): d
1.08 (3H, t, J = 7.2 Hz), 1.39 (9H, s), 2.97 (2H, s), 3.95 (2H, q, J = 7.2 Hz), 4.16 (2H,
d, J = 8.8 Hz), 4.21 (2H, d, J = 8.8 Hz), 7.44–7.53 (2H, m), 8.00–8.06 (2H, m); 13C
NMR (100 MHz, CDCl3): d 14.4, 28.7 (3C), 39.9, 45.6, 60.5 (2C, br s), 61.2, 80.5,
121.8, 122.4, 130.0, 133.0, 146.5, 148.7, 156.6, 170.3; Compound 12: 1H NMR
(400 MHz, CDCl3): d 1.10 (3H, t, J = 7.2 Hz), 1.46 (9H, s), 2.22 (3H, s), 2.97 (2H,
s), 3.98 (2H, q, J = 7.2 Hz), 4.23–4.25 (2H, m), 4.33 (2H, d, J = 8.4 Hz), 7.04–7.07
(1H, m), 7.14–7.18 (3H, m); 13C NMR (100 MHz, CDCl3): d 14.4, 20.0, 28.8 (3C),
41.1, 44.2, 59.9 (2C, br s), 60.8, 80.1, 126.2, 127.6, 128.0, 131.8, 135.3, 141.1,
157.1, 170.9; Compound 19: 1H NMR (400 MHz, DMSO): d 1.51 (3H, br s), 3.21–
3.85 (4H, br m), 7.23 (1H, d, J = 7.5 Hz), 7.29 (1H, t, J = 7.5 Hz), 7.38–7.41 (2H,
m); 13C NMR (100 MHz, DMSO): d 16.9, 28.9, 59.4 (2C, br s), 122.2, 124.7, 127.7,
128.4, 129.0, 130.9; Compound 21: 1H NMR (400 MHz, DMSO): d 3.21 (2H, d,
J = 7.2 Hz), 3.30 (2H, d, J = 7.2 Hz), 3.39 (2H, s), 4.61 (1H, s), 7.17 (2H, t,
J = 7.2 Hz), 7.24–7.40 (6H, m), 7.49 (4H, d, J = 7.2 Hz), 7.59 (1H, d, J = 6.4 Hz),
7.92 (1H, s), 12.13 (1H, br s); 13C NMR (100 MHz, DMSO): d 39.7, 51.9, 65.1,
76.5, 110.7, 113.4, 116.5, 124.2, 125.5, 127.3, 127.5, 128.5, 128.8, 134.0 (2C),
142.8, 191.4.
Ph
5
20
21
Scheme 5. Reagents and conditions: (i) indole-4-boronic acid, cat. [Rh(cod)Cl]2, aq
KOH, dioxane, 100 °C, microwave, 84%; (ii) 5 M KOH, 1,4-dioxane, reflux; (iii)
polyphosphoric acid, 100 °C, 47% (two steps).
In summary, we have developed a practical and efficient route
to 3-aryl-3-azetidinyl acetic acid esters by rhodium-catalysed con-
jugate addition of organoboron reagents to a,b-unsaturated esters
derived from N-protected-3-azetidinone. The wide scope of the
procedure allowed for the preparation of a range of 3,3-disubsti-
tuted azetidines for biological testing in our research programmes.
Acknowledgements
I would like to thank Drs. J. Golec, S. Young and J.-M. Jimenez for
helpful discussions.
References and notes
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