Synthesis of 3-halo-2,5-disubstituted furans via CuX mediated cyclization-halogenation reactions

Article abstract of DOI:10.1016/j.tetlet.2011.01.120

The Cu(I) halide (X = I, Br, Cl) mediated reactions of Cbz-protected cis-2-phenylethenyl-3-hydroxypyrrolidine gave novel 3-halo-2,5-trisubstituted furans in good yields, via a cyclization-halogenation, ring-opening reaction sequence. In contrast, the reac

Full text of DOI:10.1016/j.tetlet.2011.01.120

Tetrahedron Letters 52 (2011) 1398–1400
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Tetrahedron Letters
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Synthesis of 3-halo-2,5-disubstituted furans via CuX mediated
cyclization–halogenation reactions
⇑
Arife Yazici, Stephen G. Pyne
School of Chemistry, University of Wollongong, New South Wales 2522, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The Cu(I) halide (X = I, Br, Cl) mediated reactions of Cbz-protected cis-2-phenylethenyl-3-hydroxypyrrol-
Received 19 December 2010
Revised 17 January 2011
Accepted 25 January 2011
Available online 1 February 2011
idine gave novel 3-halo-2,5-trisubstituted furans in good yields, via
a cyclization-halogenation,
ring-opening reaction sequence. In contrast, the reactions with CuCN gave mainly the corresponding
3-cyanofuro[3,2-b]pyrrole formed from a cyclization–cyanation reaction.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Cyclization–halogenation
Cyclization–cyanation
Cu(I) salts
2,3,5-Trisubstituted furans
We recently reported the CuX (X = I, Br, Cl, CN) mediated cycli-
zation–halogenation and cyclization–cyanation reactions of
b-hydroxyalkynes 1 (R = H, Ph) to give 3-halo-(X = Cl, Br, I) and
3-cyanofuro[3,2-b]pyrroles 2 (X = CN), respectively (Fig. 1).1 These
reactions were also extended to ortho-alkynyl phenol and aniline
derivatives which gave rise to 3-iodo, 3-bromo and 3-cya-
nobenzofurans and 3-cyanoindoles, respectively.2 As an extension
of this work we have examined the reaction of the related
b-hydroxyalkyne 3 with CuX. We report here that the reactions
using Cu(I) halides under an oxygen atmosphere give rise to novel
3-halo-2,5-trisubstituted furans 6 (X = halogen) in good yields, via
a cyclization-halogenation, ring-opening reaction sequence.3 In
contrast, the reactions with CuCN gave mainly the corresponding
3-cyanofuro[3,2-b]pyrrole 5 (X = CN) formed from a cyclization–
cyanation reaction.
dihydroxypyrrolidine with potassium phenylacetylenetrifluorobo-
rate.1 Initially the reaction of 3 with CuI was tested. The use of
1 equiv of CuI in DMF at 80 °C under a nitrogen atmosphere re-
sulted in formation of the products 4 and 5 in 55% and 20% yields,
respectively (Table 1, entry 1). Increasing the amount of CuI to
three equiv. yielded 4 and 5 in respective yields of 19% and 52%
(Table 1, entry 2). However the use of 6 equiv of CuI afforded only
Table 1
Reactions of 3 with Cu(I) salts under an N2 atmosphere (compounds 3 and 5 are
racemic)
OH
O
Ph
CuX, DMF
N2, 80 o
16 h
2
CbzHN
N
Cbz
3
Racemic N-Cbz protected cis-2-alkynyl-3-hydroxypyrrolidine 3
was prepared by treatment of the known compound N-Cbz-4,5-
C
Ph
4
O
OH
Ph
O
1
R
O
6a
6
Ph
3
CuX
+
2
3a
5
+
CbzHN
O
O
N
Cbz
X
N
Bn
1
N
Bn
2
X
R
X
5
6
Entry
X (equiv)
Yield (%) of 4
Yield (%) of 5
Yield (%) of 6
X = Cl, Br, I, CN
R = H, Ph
1
2
3
4
5
6
I (1.0)
I (3.0)
I (6.0)
Br (6.0)
Cl (6.0)
CN (6.0)
55
19
0
25
61
26
20
52
65
0
0
30
0
0
0
Figure 1. Reactions of b-hydroxyalkynes with Cu(I) salts.
41
0
0
⇑
Corresponding author. Tel.: +61 2 42213511; fax: +61 2 42214287.
E-mail address: spyne@uow.edu.au (S.G. Pyne).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.01.120

A. Yazici, S. G. Pyne / Tetrahedron Letters 52 (2011) 1398–1400
1399
the 3-iodofuro[3,2-b]pyrrole 5 (X = I) in 65% yield (Table 1, entry
3).4
Attempts to prepare independently the product 5 from the reac-
O
Ph
O
CuI (1.1 eq.), O2
Ph
2
CbzHN
DMF, 80 oC, 16 h
90%
N
Cbz
I
tion of 3 and I2 or NIS produced a complex mixture of products.1
We next focused on the CuBr and CuCl mediated reactions of 3
with the aim of preparing the corresponding 3-bromo- and 3-
chloro-furo[3,2-b]pyrroles 5 (X = Br, Cl). Treatment of 3 with
6 equiv of CuBr under the same experimental conditions as de-
scribed above resulted in a mixture of the 2,5-disubstituted furan
4 and the 3-bromofuran product 6 (X = Br) in 25% and 41% yields,
respectively (Table 1, entry 4). Treatment of 3 with CuCl afforded
only the furan 4 in 61% yield (Table 1, entry 5). The reaction of 3
with CuCN (6 equiv) yielded products 4 and 5 (X = CN) in yields
of 26% and 30%, respectively (Table 1, entry 6).
I
5
6
Scheme 2. Reaction of 5 (X = I) with CuI/O2.
O
O
Ph
Ph
(i)
2
2
CbzHN
CbzHN
Br
R
7a
7b
6
62% R = C6H5-
55% R = 4-[(CH3)2N]C6H4-
We proposed that product 4 is formed by protonation of the
RCu(I) intermediate 7 (M = Cu(I), m = 0) to give intermediate 8
which then undergoes a base-catalysed ring-opening reaction as
shown in Scheme 1. Oxidation of the intermediate 7 (M = Cu(I),
m = 0) with CuX gives the corresponding Cu(II)X intermediate 7
(M = Cu(II), m = 1) which upon reductive elimination would give
product 5.1
i) RB(OH)2 (1.5 eq), Pd(OAc)2 (0.15 eq), PPh3 (0.15 eq)
Na2CO3 (1.5 eq), EtOH/H2O, 100 oC, MW
Scheme 3. Suzuki reactions of 6 (X = Br).
We speculated that if we enhanced the rate of oxidation of the
Cu(I) intermediate 7 to the corresponding Cu(II) intermediate in
situ, then we would increase the yield of the halogenated and cya-
nated products. This might also allow us to use lesser amounts of
copper salts. We thus repeated these reactions under an oxygen
atmosphere. The reaction of 3 with 1.1 equiv of CuI in DMF at
80 °C under an oxygen atmosphere for 16 h yielded the 3-iodofu-
ran 6 (X = I) in 74% yield and furan 4 in 5% yield (Table 2, entry
1).5 The relative ratio of these compounds was 91:9 from 1H
NMR analysis of the crude reaction mixture. The reactions using
CuBr and CuCl worked equally well to give the 3-bromo and 3-
chlorofurans 6 (X = Br, Cl) in 68% and 78% yields, respectively (Ta-
ble 2, entries 2 and 3). Treatment of 3 with CuCN under similar
conditions provided the 3-cyanofuro[3,2-b]pyrrole 5 (X = CN) in
40% yield and furan 4 in 35% yield (Table 2, entry 4).
The formation of 3-halofurans 6 (X = I, Br, Cl), rather than the 3-
halofuro[3,2-b]pyrroles 5 (X = I, Br, Cl), when these reactions were
performed under an oxygen atmosphere, could be due to the for-
mation of CuO from the reaction between Cu(I) and O2. CuO could
act as a base to catalyse the ring-opening reaction of the 3-halof-
uro[3,2-b]pyrroles 5 (X = I, Br, Cl) to give 3-halogenated furans 6
(X = I, Br, Cl) (compare with the transformation of 8 into 4 in
Scheme 1). Support for this proposal came from the reaction of 5
(X = I) with CuI/O2 which yielded the corresponding iodofuran 6
(X = I) in 90% yield (Scheme 2).
OH
B
H
N
O
Ph
Ph
Cbz
3
4
N
Cbz
H
-H+
MXn
m = 0, 1
H+
8
O
Ph
MXm
O
N
Cbz
m = 1
Ph
7
N
Cbz
5
1. oxidation of
Cu(I) to Cu(II)
2. reductive
elimination
X
The 3-iodo- and 3-bromo-furans 6 (X = I, Br) are potentially
useful scaffolds for the synthesis of libraries of novel 2,3,5-trisub-
stituted furans. For example, the Suzuki coupling reactions of the
Scheme 1. Proposed mechanisms for the formation of products 4 and 5.
3-bromofuran
6 (X = Br) with phenylboronic acid or 4-dim-
ethylaminophenylboronic acid gave the desired cross-coupling
products 7a and 7b in yields of 62% and 55%, respectively
(Scheme 3).6
Table 2
Reactions of 3 with Cu(I) salts under an O2 atmosphere (compounds 3 and 5 are
racemic)
In summary, an efficient synthesis of 2,3,5-trisubstituted furans
has been developed using copper-mediated reactions. Such deriva-
tives would be difficult to prepare in a regioselective fashion using
more conventional methods.
OH
O
Ph
CuX, DMF
O2, 80 oC
16 h
2
CbzHN
N
Ph
O
Cbz
4
3
Acknowledgements
Ph
O
Ph
We thank the Australian Research Council and the University of
Wollongong for financial support.
+
2
+
CbzHN
N
X
X
Cbz
5
6
References and notes
Entry
X (1.1 equiv)
Yield (%) of 4
Yield (%) of 5
Yield (%) of 6
1. Jury, J. C.; Swamy, N. K.; Yazici, A.; Willis, A.; Pyne, S. G. J. Org. Chem. 2009, 74,
5523–5527.
2. Nalivela, K. S.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412–3419.
3. For the synthesis of substituted furans, see: (a) Marshall, J. A.; Robinson, E. D. J.
Org. Chem. 1990, 55, 3450–3451; (b) Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl.
1995, 34, 1581–1583; (c) Hashmi, A. S. K.; Lothar, S.; Ji-Hyun, C.; Frost, T. M.
1
2
3
4
I
5
4
6
0
0
0
74
68
78
0
Br
Cl
CN
35
40

1400
A. Yazici, S. G. Pyne / Tetrahedron Letters 52 (2011) 1398–1400
Angew. Chem., Int. Ed. 2000, 39, 2285–2288; (d) Yao, T.; Zhang, X.; Larock, R. C. J.
Am. Chem. Soc. 2004, 126, 11164–11165.
7.31 (8H, m, ArH), 7.25 (1H, d, J = 7.0 Hz, ArH), 6.27 (1H, s, H4), 5.10 (2H, s,
CH2Ph), 4.90 (1H, br s, NH), 3.54 (2H, dd, J = 7.0, 13.0 Hz, CH2NH), 2.90 (2H, t,
J = 7.0 Hz, CH2CH2).13C NMR (CDCl3, 125 MHz) d 156.4 (CO), 151.6 (ArC), 136.4
(ArC), 130.3 (ArC), 128.7 (ArC), 128.6 (ArCH), 128.4 (ArCH), 128.2 (ArCH), 127.8
(ArC), 127.1 (ArC), 126.2 (ArCH), 117.6 (C4), 67.0 (CH2Ph), 61.4 (C3), 39.6
(CH2NH), 28.8 (CH2CH2). EIMS m/z 447 (M+, 50%); HREIMS calculated for
4. General procedure for the CuX mediated reactions of 3 under an N2 atmosphere:
To a suspension of CuI (0.077 g, 0.411 mmol) in DMF (4 mL) was added 3
(0.022 g, 0.068 mmol) and the resulting mixture was heated at 80 °C for 16 h
under a nitrogen atmosphere. The reaction mixture was then cooled to rt, H2O
(10 mL) was added and the aqueous layer was extracted with Et2O (3 Â 10 mL).
The combined organic extracts were dried (MgSO4), filtered and concentrated in
vacuo to give the crude product. Column chromatography (CH2Cl2 as eluent) of
C
20H18NO3I (M+Å) 447.0320, found 447.0331.
6. Typical procedure for the Suzuki reaction: Compound
0.05 mmol), 4-dimethylaminophenylboronic acid (13 mg, 0.075 mmol),
Pd(OAc)2 (1.7 mg, 7.5 mol), PPh3 (2 mg, 7.5 mol) and Na2CO3 (7.9 mg,
6
(X = Br) (20 mg,
the crude residue furnished product 5 (X = I) (0.020 g, 65%) as a light pink oil. 1
H
l
l
NMR (CDCl3, 500 MHz) d 7.85 (2H, br s, ArH), 7.46–7.25 (8H, m, ArH), 5.46 (1H,
br s, H6a), 5.22 (1H, s, H3a), 5.18 (2H, s, CH2Ph), 3.99 (1H, br s, H5), 3.21 (1H,
ddd, J = 9.5, 9.5, 19.5, Hz, H5), 2.22 (1H, dd, J = 9.5, 19.5 Hz, H6), 2.07 (1H, m, H6).
13C NMR (CDCl3, 125 MHz) d 155.3 (CO), 129.8 (ArC), 129.7 (ArC), 129.3 (ArCH),
128.9 (ArCH), 128.8 (ArCH), 128.4 (ArCH), 128.2 (ArCH), 128.0 (ArCH), 83.3 (C3),
71.7 (C6a), 67.2 (CH2Ph), 56.5 (C3a), 42.8 (C5), 33.1 (C6). EIMS m/z 447 (M+, 40%).
HREIMS calculated for C20H18NO3I (M+Å) 447.0331, found 447.0318.
0.075 mmol) were placed into a microwave reactor tube and H2O/EtOH (2 mL,
1: 1) was added. The reaction mixture was heated to 100 °C over 5 min (100 W,
5 bar, closed vessel) and stirred at this temperature for 10 min in
a CEM
microwave reactor. CH2Cl2 (5 mL) was added to the cooled reaction mixture and
the aqueous layer was extracted with CH2Cl2 (2 Â 3 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude
product was purified by column chromatography (1:9, EtOAc/petrol) to give
compound 7b (12 mg, 55%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) d 7.54 (2H,
d, J = 7.5 Hz, ArH), 7.35–7.25 (10H, m, ArH), 7.22 (2H, d, J = 8.5 Hz, ArH), 6.20
(1H, s, H4), 5.12 (2H, s, CH2Ph), 5.01 (1H, br s, NH), 3.57 (2H, dd, J = 6.0, 13.0 Hz,
CH2NH), 2.98 (6H, s, 2 Â CH3), 2.93–2.90 (2H, t, J = 6 Hz, CH2CH2). 13C NMR
(CDCl3, 125 MHz) d 156.8 (CO), 151.8 (ArC), 149.8 (ArC), 146.8 (ArC), 131.8 (ArC),
129.4 (ArCH), 128.7 (ArCH), 128.6 (ArCH), 128.6 (ArC), 128.5 (ArCH), 128.3
(ArCH), 127.3 (ArC), 127.1 (ArCH), 126.0 (ArCH), 123.3 (ArC), 112.7 (ArCH), 111.3
(C4), 66.9 (CH2Ph), 39.8 (CH2NH), 28.9 (CH2CH2). ESIMS m/z 441 (M+H+, 100%);
HRESIMS calculated for C28H29N2O3 (M+H+) 441.2178, found 441.2180.
5. General procedure for the CuX mediated reactions of 3 under an O2 atmosphere:
To a solution of 3 (0.040 g, 0.125 mmol) in DMF (1.5 mL) under an oxygen
atmosphere (balloon) was added CuI (0.026 g, 0.173 mmol) and the reaction
vessel was placed in a pre-heated oil bath at 80 °C. The mixture was stirred at
this temperature for 16 h. H2O (5 mL) was then added and the aqueous layer
was extracted with EtOAc (3 Â 5 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated in vacuo. The crude product was purified by
column chromatography (1:5, EtOAc/petrol) to give compound 6 (X = I) (0.041 g,
74%) as a pink oil. 1H NMR (CDCl3, 500 MHz) d 7.92 (1H, d, J = 8.0 Hz, ArH), 7.40–