Establishing the NHBoc functionality as ortho-metallating group for furan

Article abstract of DOI:10.1055/s-2006-933132

The ortho-lithiation of N-Boc protected 3-aminofuran was investigated. Directed lithiation followed by quenching with an appropriate electrophile led to new 2,3-disubstituted furans. Halogenated compounds obtained by this methodology represent useful inte

Full text of DOI:10.1055/s-2006-933132

LETTER
789
Establishing the NHBoc Functionality as ortho-Metallating Group for Furan
N
P
HBoc Functi
e
onality as
o
t
rtho-M
e
etallatingG
r
roupfor
FuraStanetty,* Krzystztof Kolodziejczyk, Gheorghe-Doru Roiban, Marko D. Mihovilovic
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)5880115499; E-mail: peter.stanetty@tuwien.ac.at
Received 8 December 2005
We therefore became interested in examining the
Abstract: The ortho-lithiation of N-Boc protected 3-aminofuran
directing metallation power of the NHBoc group and
chose the correspondingly protected 3-amino furan 1
was investigated. Directed lithiation followed by quenching with an
appropriate electrophile led to new 2,3-disubstituted furans. Halo-
genated compounds obtained by this methodology represent useful
intermediates for subsequent cross-coupling reactions.
(
Scheme 1) as model system. The starting material was
prepared in a one-pot reaction from 3-furoic acid via
Curtius degradation.8
Key words: ortho-lithiation, furans, metallation, ketones, Suzuki
cross-coupling reaction
Our investigations started with the determination of
appropriate lithiation conditions. The DMG employed
here formed a monolithiated amide in the presence of one
The directed ortho-functionalization via lithiation is an equivalent of t-BuLi. Action of the second equivalent of
attractive process in homo- and heteroaryl chemistry due t-BuLi led to complex 2, where an oxygen atom is loosely
5
to the wide range of functional groups which can be in- bound to the electron-deficient Li atom. In order to
1
,2
corporated. It is known that polysubstituted furans are achieve comprehensive lithiation, TMEDA was required
frequently encountered structural features and represent as additive and THF as solvent turned out to be beneficial.
an important pharamcophore with interesting pharmaceu- Due to the high reactivity of t-BuLi under such reaction
3
tical properties. In addition, furans can be employed in conditions, the temperature had to be maintained below
synthetic chemistry as building blocks and a multitude of –40 °C to avoid attack of the solvent.9
4
reactions have been reported in the past.
N-tert-Butylcarbamate 1 was subjected to the optimized
The first investigation of the ability of the NHBoc group directed lithiation procedure10 followed by quenching
to act as a directing ortho-metallating group (DMG) for with an appropriate electrophile, yielding 2,3-substituted
phenyl derivatives was carried out by Muchowski. In furans 3a–k as summarized in Table 1.
contrast to homoaryl compounds, heteroaromatic systems
possess an inherent difference in acidity of the aromatic Table 1 Synthesis of 2-Substituted-3-Boc-amino Furans
5
11
protons. Consequently, DMGs can amplify or compensate
Entry Electrophile
E
Product Yield (%)
this intrinsic acidity, as successfully demonstrated in the
6
thiophene series also with NHBoc as directing group. To
1
2
DMF
CHO
COOEt
3a
3b
51
97
91
52
96
96
56
62
65
96
the best of our knowledge, no principal investigation of
this DMG on the furan system has been performed so far.
Only in one example, Sato and co-workers subjected 2-N-
Boc-substituted furan to lithiation conditions for intro-
ClCOOEt
t-BuNCO
ClSiMe3
3
CONHt-Bu 3c
7
4
SiMe3
Me
3d
3e
3f
ducing a cyano group. In this case, no directing effect
into the 3-position was observed, but rather exclusive
introduction of the CN functionality into the intrinsically
acidic 5-position.
5
MeI
6
Cyclohexanone
Benzaldehyde
C H OH
6
10
7
PhCO
3g
O
NHBoc
E
8
p-Chlorobenzaldehyde 4-ClPhCO 3h
NHBoc
i)
ii)
N
9
Hexachloroethane
Cl
3i
3j
OLi
O
O
Li
10
1,2-Dibromotetrachlo- Br
roethane
O
1
2
3a–k
1
1
I2
I
3k
53–72a
Scheme 1 Reagents and conditions: i) t-BuLi (2.5 equiv), TMEDA
2.5equiv), THF, –90 °C to –70 °C, 1–2 h; ii) electrophile (1.2 equiv),
dry THF, temperature increased slowly to r.t. overnight.
a
Overall yield determined after Suzuki coupling reaction.
(
In a first set of experiments, the principal reactivity of the
lithiated species 2 was determined by conversion with
several carbonyl reagents. Reaction with DMF allowed
the introduction of an aldehyde functionality (3a).
SYNLETT 2006, No. 5, pp 0789–0791
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933132; Art ID: D36905ST
1
7.
0
3.
2
0
0
6
©
Georg Thieme Verlag Stuttgart · New York

7
90
P. Stanetty et al.
LETTER
Carboxylic acid derivatives were prepared by utilizing Table 2 Suzuki Cross-Coupling Reaction of Iodo Derivative 3k
ethyl chloroformate and tert-butylisocyanate as electro-
Entry
R
H
Cl
F
Boronic acid Product
Yield (%)
philes, yielding ester 3b and amide 3c in excellent yields.
Transmetallation was accomplished using TMS chloride
to give the silyl species 3d. Introduction of an aliphatic
carbon center was successfully attempted with methyl
iodide (3e). Evaluation of the scope of the methodology
was continued by applying additional carbonyl electro-
philes. When cyclohexanone was used the corresponding
cyclohexanol derivative 3f was obtained in excellent
yield.
1
2
3
4a
4b
4c
5a
5b
5c
68
53
72
large variety of electrophiles can be used for the synthesis
of 2,3-disubstituted furans. In the case of reaction with
Aromatic aldehydes were also added to the preformed aromatic aldehydes, we observed an oxidation process to
organolithium reagent 2 (entries 7 and 8). While the lithi- exclusively give keto products. Iodo compound 3k was
um alkoxide is expected to give an alcohol after acidic identified as reactive intermediate for cross-coupling
workup, we were surprised to obtain the oxidized prod- reactions and a suitable protocol for this transformation
ucts 3g and 3h almost exclusively. There is precedence in avoiding isolation of 3k was developed. Currently, further
the literature in the thiophene series that such an oxidation elaboration of this methodology is under investigation in
1
2
can occur upon workup. In particular in related fused our laboratory.
homo- and heteroarylic systems aerial oxidations were
utilized in combination with lithiation strategies.13 In
addition, a stabilizing effect on adjacent carbonyl groups
Acknowledgment
by the NHBoc group has been reported in context with We thank Syngenta Crop Protection, Basel, for financial support of
1
4
organometallic transformations, previously.
this project.
Halogenated compounds 3i–k were obtained by reaction
with halogen donors hexachloroethane and 1,2-dibromo- References and Notes
tetrachloroethane or with elementary iodine at –80 °C. It
(
1) (a) Anctil, E. J.-G.; Snieckus, V. Metal-Catalyzed Cross-
should be mentioned that compounds 3i–k displayed a
limited stability, in particular in isolated form. Products 3i
and 3j formed beige solids in pure form, but tend to dark-
en and decompose upon storing at room temperature or in
a refrigerator. Iodo derivative 3k is particularly unstable.
It appears as a transparent pale yellow compound in solu-
tion, but after complete removal of the solvent the product
decomposed within minutes at room temperature in an
exothermic reaction. Because of the instability of 3k, we
avoided the isolation and purification of the compound
and rather used a solution of the product in a Suzuki cross-
coupling protocol as an indirect method to determine its
specific reactivity and also to calculate its yield
Coupling Reactions, 2nd ed., Vol. 2; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, 761.
(b) Hartung, C. G.; Snieckus, V. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002,
330. (c) Snieckus, V. Chem. Rev. 1990, 90, 879; and
references cited therein. (d) Alvarez-Ibarra, C.; Quiroga, M.
L.; Toledano, E. Tetrahedron 1985, 41, 3803.
(
2) (a) Tofi, M.; Georgiou, T.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2005, 7, 3347. (b) Li, Z.;
Ganesan, A. Synlett 1998, 405. (c) Bures, E.; Nieman, J. A.;
Yu, S.; Spinazze, P. G.; Bontront, J. L. J.; Hunt, I. R.; Rauk,
A.; Keay, B. A. J. Org. Chem. 1997, 62, 8750. (d) Perry, P.
J.; Pavlidis, V. H.; Naik, M. Appl. Organomet. Chem. 1996,
10, 389. (e) Yang, Y.; Wong, H. N. C. Chem. Commun.
1992, 1723. (f) Carpenter, A. J.; Chadwick, D. J. J. Org.
(
Scheme 2).
Chem. 1985, 50, 4362.
(
(
3) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Dean, F.
M. In Advances in Heterocyclic Chemistry, Vol. 30;
Katritzky, A. R., Ed.; Academic Press: New York, 1982.
(c) Natural Products Chemistry, Vol. 1-3; Nakanishi, K.;
Goto, T.; Ito, S.; Natori, S.; Nozoe, S., Eds.; Kodansha:
Tokyo, 1974. (d) Dean, F. A. Naturally Occurring Oxygen
Ring Compounds; Butterworth: London, 1963.
NHBoc
NHBoc
(HO)2B
+
O
I
R
O
R
3
k
4a–c
5a–c
4) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. O.; Lo, T.
H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54,
Scheme 2 Suzuki coupling reaction for compound 3k.
1
955; and references cited therein.
5) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45,
798.
6) (a) Brugier, D.; Outurquin, F.; Paulmier, C. J. Chem. Soc.,
Perkin Trans. 1 2001, 37. (b) Galvez, C.; Garcia, F.; Garcia,
J. J. Chem. Res., Synop. 1985, 296.
(
(
The iodo compound 3k was submitted to cross-coupling
4
1
5
reaction conditions using (4-substituted) phenylboronic
1
6
acids 4a–c to yield derivatives 5a–c as summarized in
Table 2. The resulting products were stable and separated
by column chromatography.
(7) Sato, N.; Yue, Q. Tetrahedron 2003, 59, 5831.
(
8) (a) Campbell, M. M.; Kaye, A. D.; Sainsbury, M.
Tetrahedron 1982, 38, 2783. (b) Shioiri, T.; Ninomiya, K.;
Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203.
In summary we have established the ortho-directing
properties of the NHBoc group on the furan system. A
Synlett 2006, No. 5, 789–791 © Thieme Stuttgart · New York

LETTER
NHBoc Functionality as ortho-Metallating Group for Furan
791
(
9) (a) Stanetty, P.; Mihovilovic, M. D. J. Org. Chem. 1997, 62,
514. (b) Stanetty, P.; Koller, H.; Mihovilovic, M. D. J. Org.
Chem. 1992, 57, 6833.
(CDCl ): d = 27.3 [q, C(CH ) ], 80.0 [q, C(CH ) ], 107.6 (s,
C3), 118.9 (d, C4), 129.6 (s, C2), 139.5 (d, C5), 151.6 (s,
NHCO).
3
3 3
3 3
1
(
10) General Procedure for the Lithiation Reaction.
N-(2-Bromo-3-furyl)carbamic Acid tert-Butyl Ester (3j).
Beige solid which decomposed upon storage (96%). H
1
To a cooled (–90 °C to –70 °C), stirred solution of compound
1
(1.64 mmol) in dry Et O or preferable dry THF (25 mL)
NMR (CDCl ): d = 1.43 [s, 9 H, C(CH ) ], 6.23 (br s, 1 H,
2
3
3 3
3
and TMEDA (4.1 mmol) under argon, a solution of t-BuLi
in pentane (1.6 M, 4.1 mmol) was added dropwise. The
mixture was then stirred for 1–2 h while raising the
NH), 6.83 (br s, 1 H, H4), 7.26 (d, 1 H, H5, J = 2.0 Hz).
(12) Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1985, 41,
3803.
temperature from –90 °C to –40 °C. After addition of an
electrophile (1.97 mmol; as solution in THF if solid) the
reaction mixture was stirred for 6 h or overnight with a slow
increase of the temperature to r.t. The reaction mixture was
(13) (a) Watanabe, M.; Snieckus, V. J. Am. Chem. Soc. 1980,
102, 1457. (b) Sammes, P. G.; Dodsworth, D. J. J. Chem.
Soc., Chem. Commun. 1979, 33. (c) De Silva, S. O.;
Watanabe, M.; Snieckus, V. J. Org. Chem. 1979, 44, 4802.
(d) Slocum, D. W.; Gierer, P. L. J. Org. Chem. 1976, 41,
3668.
then quenched with an excess of aq sat. NaHCO (40 mL),
3
and extracted with CH Cl (6 × 25 mL). The collected
2
2
organic layers were dried over Na SO and the solvent was
(14) Zhang, P.; Terefenko, E. A.; Slavin, J. Tetrahedron Lett.
2001, 42, 2097.
(15) General Procedure for the Suzuki Cross-Coupling
Reaction.
2
4
evaporated (not completely), under 400–500 mbar at 30–35
C. The obtained solution was then purified by filtration
through a column of silica gel, using CH Cl as an eluent.
°
2
2
First fractions containing the desired product were collected
and the solvent evaporated under reduced pressure (30–35
To a solution of dioxane–water (4:1) in a three-necked
round-bottom flask (150 mL) equipped with condenser,
thermometer and argon inlet, a solution of 3k (ca. 10.0
mmol; estimated from 1) in THF was added. Boronic acids
4a–c (12.1 mmol) and K CO (22.0 mmol) were added to the
system. The flask was flushed with argon and then Pd(PPh3)4
(0.272 mmol) was added (2.2 mol%). The reaction mixture
was heated at 70–80 °C keeping the inert atmosphere until
the TLC showed complete reaction (usually 17–56 h) then
°C, 400–500 mbar). In the case of the unstable compound 3k
the solvent was not evaporated completely and its yield was
calculated indirectly after the subsequent Suzuki coupling
reaction.
2
3
(
11) N-(2-Formyl-3-furyl)carbamic Acid tert-Butyl Ester
(
3a).
1
Pale yellow crystals (51%); mp 58–61 °C. H NMR
(
7
CDCl ): d = 1.44 [s, 9 H, C(CH ) ], 7.16 (br s, 1 H, H4),
the obtained mixture was quenched with aq sat. NaHCO (40
3
3 3
3
3
5
.39 (dd, 1 H, H5, J = 2.0 Hz, J = 0.6 Hz), 8.56 (br s, 1 H,
mL), extracted with CH Cl (4 × 100 mL), and the organic
2
2
5
13
NH), 9.64 (d, 1 H, CHO, J = 0.8 Hz). C NMR (CDCl3):
d = 27.2 [q, C(CH ) ], 80.9 [q, C(CH ) ], 105.6 (d, C4),
1
layers were dried over Na SO . After solvent evaporation the
2 4
residue was purified by flash column chromatography using
PE–EtOAc (10:1) as eluent. The products 5a–c were
obtained in an overall yield varying between 53–72%,
calculated from compound 1.
3
3
3 3
36.0 (s, C3), 137.9 (s, C2), 147.2 (d, C5), 151.2 (s, NHCO),
78.8 (d, CHO).
1
N-[2-(1-Hydroxy)cyclohexyl-3-furyl]carbamic Acid tert-
Butyl Ester (3f).
Transparent colorless oil (96%). H NMR (CDCl ): d = 1.43
(16) N-(2-Phenyl-3-furyl)carbamic Acid tert-Butyl Ester (5a).
1
1
Yellow oil (68%). H NMR (CDCl ): d = 1.41 [s, 9 H,
3
3
3
[
s, 9 H, C(CH ) ], 1.53–1.70 (m, 6 H, H3¢, H4¢, H5¢), 2.09–
C(CH ) ], 6.27 (d, 1 H, H4, J = 2.0 Hz), 6.76 (br s, 1 H,
3
3
3 3
3
2.19 (m, 2 H, H2¢), 2.24–2.34 (m, 2 H, H6¢), 5.94 (br s, 1 H,
NH), 7.10–7.18 (m, 1 H, H4¢), 7.23 (d, 1 H, H5, J = 2.0 Hz),
3
OH), 6.08 (br s, 1 H, NH), 6.72 (br s, 1 H, H4), 7.11 (d, 1 H,
7.24–7.33 (m, 2 H, H3¢, H5¢), 7.49 (d, 2 H, H2¢, H6¢, J = 9.0
3
13
H5, J = 2.0 Hz).
Hz). C NMR (CDCl ): d = 27.2 [q, C(CH ) ], 79.7 [q,
3
3 3
N-(2-Benzoyl-3-furyl)carbamic Acid tert-Butyl Ester
C(CH ) ], 108.4 (d, C4), 119.7 (s, C3), 122.7 (s, C1¢), 123.7
3 3
(
3g).
(d, C2¢, C6¢), 126.1 (d, C4¢), 127.8 (d, C3¢, C5¢), 129.5 (s,
C2), 139.7 (d, C5), 152.4 (s, NHCO).
1
Pale yellow oil (56%). H NMR (CDCl ): d = 1.43 [s, 9 H,
3
C(CH ) ], 7.23 (br s, 1 H, H4), 7.33–7.44 (m, 4 H, H2¢, H3¢,
N-[2-(4-Chlorophenyl)-3-furyl]carbamic Acid tert-Butyl
3
3
3
H5¢, H6¢), 8.00 (d, 1 H, H5, J = 2.0 Hz), 8.04 (d, 1 H, H4¢,
Ester (5b).
4
13
1
J = 1.6 Hz), 9.39 (br s, 1 H, NH). C NMR (CDCl ): d =
Pale yellow solid (53%); mp 89–93 °C. H NMR (CDCl ):
3
3
2
6.2 [q, C(CH ) ], 79.3 [q, C(CH ) ], 104.4 (d, C4), 125.5
d = 1.42 [s, 9 H, C(CH ) ], 6.15 (br s, 1 H, NH), 6.73 (br s, 1
3
3
3 3
3 3
(
d, C3¢, C5¢), 127.2 (d, C2¢, C6¢), 130.3 (d, C4¢), 134.7 (s,
H, H4), 7.26 (d, 1 H, H5), 7.25–7.32 (d, 2 H, H3¢, H5¢,
3
J = 9.0 Hz), 7.43–7.47 (d, 2 H, H2¢, H6¢, J = 9.0 Hz). 13C
3
C3), 135.6 (s, C1¢), 137.1 (s, C2), 144.2 (d, C5), 150.4 (s,
NHCO), 180.5 (s, CO).
NMR (CDCl ): d = 27.2 [q, C(CH ) ], 79.9 [q, C(CH ) ],
3
3 3
3 3
N-[2-(4-Chlorobenzoyl)-3-furyl]carbamic Acid tert-
108.9 (d, C4), 119.2 (s, C1¢), 120.0 (s, C3), 124.8 (d, C2¢,
C6¢), 127.9 (d, C3¢, C5¢), 129.0 (s, C2), 131.7 (s, C4¢), 140.0
(d, C5), 152.4 (s, NHCO).
Butyl Ester (3h).
Colorless crystals (62%); mp 52–55 °C. H NMR (CDCl ):
d = 1.53 [s, 9 H, C(CH ) ], 7.34 (br d, 1 H, H4, J = 2.0 Hz),
1
3
3
N-[2-(4-Fluorophenyl)-3-furyl]carbamic Acid tert-Butyl
Ester (5c).
3
3
3
3
7
.47 (d, 2 H, H3¢, H5¢, J = 9 Hz), 7.48 (dd, 1 H, H5, J = 2.0
5
3
1
Hz, J = 0.6 Hz), 8.10 (d, 2 H, H2¢, H6¢, J = 9.0 Hz), 9.44
Pale yellow crystals (72%), mp 68–71 °C. H NMR
1
3
(br s, 1 H, NH). C NMR (CDCl ): d = 27.1 [q, C(CH ) ],
(CDCl ): d = 1.41 [s, 9 H, C(CH ) ], 6.18 (br s, 1 H, NH),
3
3 3
3
3 3
3
8
0.5 [q, C(CH ) ], 105.5 (d, C4), 127.6 (d, C3¢, C5¢), 129.7
6.69 (br s, 1 H, H4), 7.00 (d, 2 H, H2¢, H6¢, J = 9.0 Hz), 7.23
(d, 1 H, H5, J = 2.0 Hz), 7.48 (dd, 2 H, H3¢, H5¢, J = 9.0
3
3
3
3
(
1
d, C2¢, C6¢), 134.0 (s, C3), 136.4 (s, C1¢), 137.8 (s, C2),
38.5 (s, C4¢), 145.4 (d, C5), 151.3 (s, NHCO), 179.8 (s,
3
13
Hz, J = 3.5 Hz). C NMR (CDCl ): d = 28.2 [q,
H–F 3
CO).
C(CH ) ], 80.8 [q, C(CH ) ], 109.8 (d, C4), 115.8 (d, C3¢,
3 3 3 3
2
N-(2-Chloro-3-furyl)carbamic Acid tert-Butyl Ester (3i).
Beige solid which decomposed on storage (65%). H NMR
C5¢, J = 21.6 Hz), 120.2 (s, C2), 122.2 (s, C3), 126.4 (d,
C–F
1
3
4
C2¢, C6¢, J = 13.1 Hz), 126.7 (s, C1¢, J = 4.1 Hz),
C–F C–F
140.6 (d, C5), 153.6 (s, NHCO), 161.8 (d, C4¢, J = 247.4
1
(CDCl ): d = 1.43 [s, 9 H, C(CH ) ], 6.14 (br s, 1 H, NH),
3
3 3
C–F
3
13
6.82 (br s, 1 H, H4), 7.12 (d, 1 H, H5, J = 2.0 Hz). C NMR
Hz).
Synlett 2006, No. 5, 789–791 © Thieme Stuttgart · New York