Combination of lithium chloride and hexafluoroisopropanol for friedel-crafts reactions

Article abstract of DOI:10.1055/s-0028-1087566

A combination of weak Lewis acid (LiCl) and weak Br?nsted acid (hexafluoroisopropanol, HFIP) promotes efficiently the Friedel-Crafts reaction of electron-rich aromatic compounds with ethyl glyoxylate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087566

LETTER
577
Combination of Lithium Chloride and Hexafluoroisopropanol for
Friedel–Crafts Reactions
Lithium Chloride
a
nd H
a
e
xafluoroi
t
soprop
t
a
nol fo
h
r
Friedel–Cra
i
fts Re
e
a
ctions u Willot, JinChun Chen, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 13 October 2008
complex molecules and as ligands in asymmetric synthe-
sis. Consequently, reaction conditions4 including some
that are catalyst- and solvent-free5 have been developed
allowing the synthesis of numerous functionalized aro-
matics. Enantioselective versions have also been reported
using either chiral Lewis acids6 or small organomolecules
as catalysts.7 In connection with our research program
centering on the synthesis of tetrahydroisoquinoline-con-
taining polycyclic alkaloids,8 we found that the combina-
tion of lithium chloride (LiCl) and 1,1,1,3,3,3-hexa-
fluoroisopropanol (HFIP) in toluene is highly efficient for
promoting the Pictet–Spengler reaction of acid-sensitive
substrates.9 We report herein that these conditions are also
very effective for performing the Friedel–Crafts reactions
between electron-rich aromatics and ethyl glyoxylate.
Abstract: A combination of weak Lewis acid (LiCl) and weak
Brønsted acid (hexafluoroisopropanol, HFIP) promotes efficiently
the Friedel–Crafts reaction of electron-rich aromatic compounds
with ethyl glyoxylate.
Key words: Friedel–Crafts reaction, glyoxylate, lithium chloride,
hexafluoroisopropanol, Lewis acid, Brønsted acid
The Friedel–Crafts (F–C) reaction is one of the most im-
portant C–C bond-forming transformations.1 It encom-
passes a wide set of reactions including acylation,2
alkylation,3 and hydroxyalkylation of aromatic com-
pounds. Among them, the latter reactions involving elec-
tron-rich aromatics and glyoxylate or pyruvate derivatives
have attracted recent attention due to the importance of
the resulting adducts as building blocks in the synthesis of
Table 1 Survey of Reaction Conditions between Phenol 1 and Ethyl Glyoxylate (2)
O
OEt
OH
OR
RO
OR
O
HO
O
HO
O
HO
O
+
+
OEt
OH
O
O
O
O
O
OEt
3a R = Bn
3b R = MOM
1a R = Bn
1b R = MOM
2
4
Entry
Acid
Solvent
Temp (°C)
Yield (%) of 3, 4
0, 0b
1a
AcOH
TFA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
r.t.
r.t.
r.t.
r.t.
r.t.
70
40
r.t.
2a
47, 47
0, 0d
3c
Sc(OTf)3
Yb(OTf)3
LiCl
4c
0, 0d
5c
0, 0b
6c
LiCl
toluene–HFIP (16:1)e
toluene–HFIP (6:1)e
toluene–HFIP (4:1)e
55, 0
7c
LiCl
95, 0
8c
LiCl
97, 0
a R = Bn.
b Phenol 1 was recovered.
c R = MOM.
d Ln(OTf)3 (0.1 equiv), phenol 1 decomposed.
e LiCl (2.0 equiv), in the presence of 3 Å MS.
SYNLETT 2009, No. 4, pp 0577–0580
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087566; Art ID: G33008ST
© Georg Thieme Verlag Stuttgart · New York

578
M. Willot et al.
LETTER
The Friedel–Crafts reaction between phenol 1 and ethyl Table 2 Generality of LiCl–HFIP-Promoted Friedel–Crafts Reac-
tionsa
glyoxylate (2) leading to adduct 3 was needed in our syn-
thesis of ecteinascidin 743 (Yondelis®),10 an anticancer
Entry Substrate
Product
Yield
(%)b
drug. As shown in Table 1, neither Brønsted acids
(AcOH, TFA), nor Lewis acids [(Sc(OTf)3, Yb(OTf)3]
were effective for promoting this transformation. As ex-
pected, only starting materials were recovered when a
weak Lewis acid (LiCl) was used as a promoter (entry 5).
Interestingly, by adding hexafluoroisopropanol (HFIP)11
as co-solvent (toluene–HFIP = 16:1 by volume), the de-
sired alkylation took place at 70 °C, although conversion
remained incomplete, to afford 3 in 55% yield (entry 6).
Increasing the amount of HFIP allowed the reaction to
take place at lower temperature and under optimized con-
ditions: LiCl (2 equiv), toluene–HFIP = 4:1, 3 Å MS, r.t.),
the reaction between phenol 1b and 2 proceeded smoothly
to afford single regioisomer 3 in 97% yield.12 It is interest-
ing to note that the same reaction performed in the pres-
ence of trifluoroacetic acid provided two regioisomers 3
and 4 in a 1:1 ratio (entry 2).
OH
OH OH
COOEt
1
MeO
90
MeO
O
Me
O
Me
Si
Si
1c
3c
OH
OH OH
COOEt
2
3
4
82
90
57
O
O
O
O
1d
3d
OH OH
OH
COOEt
The generality of these conditions were next examined
varying the nature of aromatic compounds and the results
are summarized in Table 2. The reaction took place exclu-
sively at the position ortho to the phenol group (entries 1–
4) or at the para position if the ortho position is occupied
(compound 3b, Table 1). However, the presence of a free
hydroxy group is not an obligation since 1,3-dimethoxy-
benzene (1g) was converted to adduct 3g in 69% yield
(entry 5). In accordance with the literature precedents, the
hydroxyalkylation of N,N-dimethylaniline (1h) occurred
at the para position to furnish 3h in 73% yield (entry 6).
As expected, indole (1i) participated in the reaction to af-
ford 3i in 74% yield (entry 7). However, double F–C reac-
tion occurred in these two cases to furnish bisadducts 5
and 6 in 26% and 27% yields, respectively.13 Finally, un-
activated pyrrole 1j was also transformed to the corre-
sponding F–C adduct 3j in 38% yield (entry 8), together
with a 2,5-bisalkylated product 7 (37%, Figure 1).
MeO
MeO
OMe
OH
OMe
1e
3e
OH
OH
OH
OH
COOEt
COOEt
1f
3f
OMe OH
OMe
5
6
69
73
MeO
MeO
1g
3g
OH
COOEt
NMe2
Me2N
EtOOC
1h
COOEt
3h
NH
HO
COOEt
N
7
8
74
38
Me2N
NMe2
H
N
H
5
6
N
H
1i
1j
OH
COOEt
HO
3i
N
OH
Me
EtOOC
7
N
N
COOEt
Me
Me
Figure 1 Bis-Friedel–Crafts adducts
3j
a General conditions: 1 (1.0 equiv), 2 (1.5 equiv), LiCl (2.0 equiv),
toluene–HFIP = 4:1, c 0.9 M, r.t.
Although the exact role of HFIP was unclear, the syner-
getic effect of LiCl and HFIP in promoting the present
Friedel–Crafts reaction is evident. The weak Brønsted
b Yield of chromatographically pure compound.
acidity (pKa = 9.3), strong ionizing power,14 and hydrogen- was replaced by EtOH or 2,2,2-trifluroethanol (TFE),16 al-
bond donor ability15 may be relevant to its unique role in though the dielectric constant of these two polar protic
this transformation. The polarity effect might not be im- solvents [e (EtOH) = 24.3; e (TFE) = 26.7] is higher than
portant in this case since no reaction occurred when HFIP HFIP (e = 16.7).15a
Synlett 2009, No. 4, 577–580 © Thieme Stuttgart · New York

LETTER
Lithium Chloride and Hexafluoroisopropanol for Friedel–Crafts Reactions
579
K. J. Org. Chem. 2004, 69, 146. (g) Zhao, J.-L.; Sui, Y.;
Liu, Y.-L.; Wang, D.; Chen, Y.-J. Org. Lett. 2006, 8, 6127.
(h) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao,
W.-J. Adv. Synth. Catal. 2007, 349, 1597. (i) Major, J.;
Kwiatkowski Jurczak, J. Org. Lett. 2008, 10, 2955. (j) For
a review, see: Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem. Int. Ed. 2004, 43, 550.
In summary, we demonstrated that a combination of a
weak Lewis acid (LiCl) and a weak Brønsted acid (HFIP)
is effective for promoting the Friedel–Crafts reactions be-
tween electron-rich aromatics and glyoxylate. The utility
of these conditions is readily seen as one of the adduct 1b
has been employed as a key building block in our total
synthesis of ecteinascidin 743.10
(7) Organocatalysis: (a) Török, B.; Abid, M.; London, G.;
Esquibel, J.; Török, M.; Mhadgut, S. C.; Yan, P.; Prakash,
G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086. (b) Li, H.;
Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063. (c) Zhao,
J.-L.; Liu, L.; Gu, C.-L.; Wang, D.; Chen, Y.-J. Tetrahedron
Lett. 2008, 49, 1476.
(8) (a) Chen, J.; Chen, X.; Willot, M.; Zhu, J. Angew. Chem. Int.
Ed. 2006, 45, 8028. (b) Chen, X.; Zhu, J. Angew. Chem. Int.
Ed. 2007, 46, 3962. (c) Wu, Y.-C.; Liron, M.; Zhu, J. J. Am.
Chem. Soc. 2008, 130, 7148. (d) For an excellent review,
see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669.
General Procedure
To a round-bottom flask containing dried LiCl (84.8 mg, 2.0 mmol,
2.0 equiv) and 3 Å MS (100.1 mg), a solution of compound 1b–j
(1.0 mmol) in dry toluene (1.8 mL), freshly distilled ethyl glyoxy-
late (2, 50% solution in toluene, 268 mL, 1.5 mmol, 1.5 equiv), and
hexafluoroisopropanol (0.45 mL) were added successively. The
reaction mixture was stirred at r.t. under argon atmosphere until the
complete consumption of the starting phenol (7–36 h). The solution
was then filtered, washed with CH2Cl2, and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (SiO2, EtOAc in heptane) to afford compounds
3b–j.
(9) (a) De Paolis, M.; Chiaroni, A.; Zhu, J. Chem. Commun.
2003, 2896. (b) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J.
J. Org. Chem. 2005, 70, 4397.
(10) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2006, 128, 87.
(11) Selected recent references on HFIP-assisted
transformations: (a) Cativirla, C.; García, J. I.; Majoral,
J. A.; Salvatella, L. Can. J. Chem. 1994, 72, 308.
(b) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T.
J. Org. Chem. 1995, 60, 2320. (c) Das, U.; Crousse, B.;
Kesavan, V.; Bonnet-Delpon, D.; Bégué, J.-P. J. Org. Chem.
2000, 65, 6749. (d) Takita, R.; Oshima, T.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 4661. (e) Neimann, K.;
Neumann, R. Org. Lett. 2000, 2, 2861. (f) Snider, B. B.;
O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455.
(g) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson,
B.; Pinto, B. M. J. Am. Chem. Soc. 2002, 124, 8245.
(h) Yagi, H.; Ramesha, A. R.; Kalena, G.; Sayer, J. M.;
Kumar, S.; Jerina, D. M. J. Org. Chem. 2002, 67, 6678.
(i) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005,
7, 175. (j) For a review, see: Bégué, J.-P.; Bonnet-Delpon,
D.; Crousse, B. Synlett 2004, 18.
Acknowledgment
Financial supports from CNRS and this institute are gratefully ack-
nowledged.
References and Notes
(1) Olah, G. A.; Krishnamurti, R.; Surya Prakash, G. K.
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I., Eds.; Pergamon: New York, 1991, 293–339.
(2) Selected examples: (a) Kawada, A.; Mitamura, S.;
Kobayashi, S. Synlett 1994, 545. (b) Répichet, S.; Le Roux,
C.; Dubac, J.; Desmurs, J.-R. Eur. J. Org. Chem. 1998,
2743. (c) Kobayashi, S.; Komoto, I. Tetrahedron 2000, 56,
6463.
(3) (a) Mine, N.; Fujiwara, Y.; Taniguchi, H. Chem. Lett. 1986,
357. (b) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa,
S. J. Org. Chem. 1997, 62, 6997. (c) Shiina, I.; Suzuki, M.
Tetrahedron Lett. 2002, 43, 6391. (d) Noji, M.; Ohno, T.;
Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem.
2003, 68, 9340. (e) Mantri, K.; Komura, K.; Kubota, Y.;
Sugi, Y. J. Mol. Catal. A: Chem. 2005, 236, 168. (f) Jiang,
B.; Huang, Z. G. Synthesis 2005, 2198.
(4) (a) Hao, J.; Taktak, S.; Aikawa, K.; Yusa, Y.; Hatano, M.;
Mikami, K. Synlett 2001, 1443. (b) Prakash, G. K. S.; Yan,
P.; Török, B.; Olah, G. A. Synlett 2003, 527. (c) Ding, H.;
Zhang, H. B.; Chen, Y. J.; Lu, L.; Wang, D.; Li, C. J. Synlett
2004, 555. (d) Soueidan, M.; Collin, J.; Gil, R. Tetrahedron
Lett. 2006, 47, 5467.
(5) (a) Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett.
2001, 42, 2545. (b) Zhao, J.-L.; Liu, L.; Zhang, H. B.; Wu,
Y.-C.; Wang, D.; Chen, Y.-J. Tetrahedron Lett. 2006, 47,
2511. (c) Zhao, J.-L.; Liu, L.; Zhang, H. B.; Wu, Y.-C.;
Wang, D.; Chen, Y.-J. Synlett 2006, 96.
(12) Analytical Data
Compound 3b: IR (neat): 3428, 2904, 1734, 1654, 1499,
1461, 1370, 1215, 1046, 994, 931 cm–1. 1H NMR (300 MHz,
CDCl3, 293 K): d = 6.54 (s, 1 H), 6.26 (br s, 1 H), 5.96 (d,
J = 1.1 Hz, 1 H), 5.91 (d, J = 1.1 Hz, 1 H), 5.12 (s, 1 H), 5.05
(s, 2 H), 4.23 (dq, J = 10.2, 7.2 Hz, 1 H), 4.18 (dq, J = 10.2,
7.2 Hz, 1 H), 3.49 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3, 293 K): d = 173.0, 142.3, 141.5,
134.4, 132.3, 110.7, 108.3, 102.1, 97.6, 68.3, 62.2, 56.5, 14.0
ppm. HRMS (ESI+): m/z [M + Na]+ calcd for C13H16O8:
323.0743; found: 323.0745.
Compound 3c: IR (neat): 3386, 2930, 2857, 1731, 1482,
1335, 1251, 1126, 1006 cm–1. 1H NMR (300 MHz, CDCl3,
293 K): d (mixture of two diastereomers) = 6.89 (2 s, 1 H),
6.55 (s, 1 H), 5.18 (d, J = 3.1 Hz, 1 H), 4.30 (dq, J = 10.7, 7.2
Hz, 1 H), 4.20 (dq, J = 10.7, 7.2 Hz, 1 H), 3.74 (s, 3 H), 3.45
(d, J = 3.1 Hz, 1 H), 2.15 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H),
1.01 (s, 9 H), 0.96 (2 t, J = 7.6 Hz, 3 H), 0.72 (m, 2 H), 0.16
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 293 K): d = 173.2,
150.4, 148.1, 142.1, 120.9, 117.7, 117.1, 72.7, 62.6, 60.1,
26.3 (3 C), 18.8, 14.1, 9.2, 7.5, 4.8, –6.5 ppm. MS (ESI+):
m/z = 791.3 [2 M + Na]+, 407.1 [M + Na]+, 367.2 [M – H2O
+ H]+. HRMS (ESI+): m/z [M + Na]+ calcd for C19H32O6Si:
407.1866; found: 407.1862.
(6) Lewis acid catalysis: (a) Bigi, F.; Casiraghi, G.; Casnati, G.;
Sartori, G.; Fava, G. G.; Belicchi, M. F. J. Org. Chem. 1985,
50, 5018. (b) Erker, G.; Van de Zeijden, A. A. H. Angew
Chem., Int. Ed. Engl. 1990, 29, 512. (c) Isshi, A.;
Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65,
1597. (d) Gathergood, N.; Zhuang, W.; Jørgensen, K. A.
J. Am. Chem. Soc. 2000, 122, 12517. (e) Zhuang, W.;
Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2001, 66, 1009. (f) Yuan, Y.; Wang, X.; Li, X.; Ding,
Compound 3d: IR (neat): 3349, 2983, 2903, 1722, 1628,
1485, 1442, 1169, 1033, 930 cm–1. 1H NMR (500 MHz,
Synlett 2009, No. 4, 577–580 © Thieme Stuttgart · New York

580
M. Willot et al.
LETTER
CDCl3, 293 K): d = 6.64 (s, 1 H), 6.42 (s, 1 H), 5.90 (s, 1 H),
5.89 (s, 1 H), 5.19 (s, 1 H), 4.28 (dq, J = 10.8, 7.1 Hz, 1 H),
4.21 (dq, J = 10.8, 7.1 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3, 293 K): d = 173.3, 150.4,
148.7, 141.5, 114.6, 107.8, 101.4, 99.8, 72.1, 62.7, 14.2 ppm.
MS (ESI+): m/z = 263.0 [M + Na]+, 245.0 [M – H2O + Na]+,
223.1 [M – H2O + H]+. HRMS (ESI+): m/z [M + Na]+ calcd
for C11H12O6: 263.0532; found: 263.0497.
Hz, 2 H), 5.06 (s, 1 H), 4.26 (dq, J = 10.9, 7.0 Hz, 1 H), 4.16
(dq, J = 10.9, 7.0 Hz, 1 H), 3.27 (br s, 1 H), 2.95 (s, 6 H),
1.23 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
293 K): d = 174.3, 150.8, 127.7 (2 C), 126.3, 112.5 (2 C),
72.9, 62.0, 40.6 (2 C), 14.2 ppm. MS (ESI+): m/z = 246.1
[M + Na]+, 224.1 [M + H]+, 206.1 [M – H2O + H]+. HRMS
(ESI+): m/z [M + H]+ calcd for C12H17NO3: 224.1287; found:
224.1270.
Compound 3e: IR (neat): 3414, 2937, 2837, 1729, 1616,
1515, 1451, 1417, 1197, 1109, 997 cm–1. 1H NMR (500
MHz, CDCl3, 293 K): d = 7.21 (br s, 1 H), 6.67 (s, 1 H), 6.42
(s, 1 H), 5.22 (s, 1 H), 4.22 (dq, J = 10.8, 7.1 Hz, 1 H), 4.17
(dq, J = 10.8, 7.1 Hz, 1 H), 4.00 (s, 1 H), 3.79 (s, 3 H), 3.77
(s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3, 293 K): d = 173.3, 150.2, 149.3, 142.7, 113.6, 111.9,
101.9, 71.8, 62.4, 56.6, 55.9, 14.1 ppm. MS (ESI+): m/z =
279.1 [M + Na]+. HRMS (ESI+): m/z [M + Na]+ calcd for
C12H16O6: 279.0845; found: 279.0840.
Compound 3f: IR (neat): 3418, 2961, 2871, 1724, 1625,
1460, 1368, 1222, 1059, 1024, 935 cm–1. 1H NMR (500
MHz, CDCl3, 293 K): d = 7.63 (br s, 1 H), 6.77 (d, J = 8.2
Hz, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 5.72 (br s, 1 H), 5.30 (s,
1 H), 4.33 (dq, J = 10.7, 7.1 Hz, 1 H), 4.24 (dq, J = 10.7, 7.1
Hz, 1 H), 3.39 (br s, 1 H), 3.27 (hept, J = 7.0 Hz, 1 H), 1.29
(t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.23 (t, J = 7.0
Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 293 K):
Compound 3i: IR (neat): 3399, 2981, 1724, 1548, 1457,
1423, 1198, 1077, 1037, 743 cm–1. 1H NMR (500 MHz,
CDCl3, 293 K): d = 8.40 (br s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H),
7.29 (d, J = 8.2 Hz, 1 H), 7.20 (ddd, J = 8.2, 7.0, 1.0 Hz, 1
H), 7.14 (ddd, J = 8.2, 7.0, 0.9 Hz, 1 H), 7.08 (d, J = 2.3 Hz,
1 H), 5.46 (d, J = 5.5 Hz, 1 H), 4.28 (dq, J = 10.8, 7.0 Hz, 1
H), 4.16 (dq, J = 10.8, 7.0 Hz, 1 H), 3.51 (m, 1 H), 1.20 (t,
J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 293 K):
d = 174.1, 136.5, 125.4, 123.5, 122.5, 120.1, 119.4, 113.6,
111.6, 67.4, 62.1, 14.1 ppm. MS (ESI+): m/z = 242.1 [M +
Na]+, 202.1 [M – H2O + H]+. HRMS (ESI+): m/z [M + Na]+
calcd for C12H13NO3: 242.0793; found: 242.0805.
Compound 3j: IR (neat): 3369, 2981, 1730, 1492, 1368,
1299, 1203, 1052, 1018, 714 cm–1. 1H NMR (500 MHz,
CDCl3, 293 K): d = 6.61 (t, J = 2.1 Hz, 1 H), 6.05 (d, J = 2.1
Hz, 2 H), 5.20 (d, J = 7.0 Hz, 1 H), 4.31 (dq, J = 10.9, 7.0
Hz, 1 H), 4.27 (dq, J = 10.9, 7.0 Hz, 1 H), 3.66 (s, 3 H), 3.15
(d, J = 7.0 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 293 K): d = 172.9, 129.2, 124.1, 108.5,
107.0, 66.4, 62.1, 34.1, 14.2 ppm. MS (ESI+): m/z = 206.1
[M + Na]+, 166.1 [M – H2O + H]+. HRMS (ESI+): m/z [M +
Na]+ calcd for C9H13NO3: 206.0793; found: 206.0791.
(13) Formation of bisindolylalkanes, see for examples:
(a) Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem.
2005, 3, 4043. (b) Nair, V.; Abhilash, K. G.; Vidya, N. Org.
Lett. 2005, 7, 5857.
d = 173.4, 143.0, 141.8, 135.5, 119.9, 118.8, 118.0, 72.7,
62.9, 27.3, 22.5, 22.4, 14.1 ppm. MS (ESI+): m/z = 277.1 [M
+ Na]+. HRMS (ESI+): m/z [M + Na]+ calcd for C13H18O5:
277.1052; found: 277.1034.
Compound 3g: IR (neat): 3482, 2939, 2839, 1731, 1612,
1589, 1507, 1207, 1157, 1065, 1030 cm–1. 1H NMR (500
MHz, CDCl3, 293 K): d = 7.15 (d, J = 8.5 Hz, 1 H), 6.45 (m,
2 H), 5.19 (d, J = 5.8 Hz, 1 H), 4.19 (dq, J = 10.8, 7.1 Hz,
1 H), 4.18 (dq, J = 10.8, 7.1 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s,
3 H), 3.53 (d, J = 5.8 Hz, 1 H), 1.19 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3, 293 K): d = 174.0, 161.2, 158.3,
130.2, 119.9, 104.4, 99.0, 69.8, 61.7, 55.5, 55.4, 14.1 ppm.
MS (ESI+): m/z = 263.1 [M + Na]+. HRMS (ESI+): m/z [M +
Na]+ calcd for C12H16O5: 263.0895; found: 263.0893.
Compound 3h: IR (neat): 3442, 2891, 1727, 1614, 1523,
1354, 1180, 1074, 1012, 800 cm–1. 1H NMR (500 MHz,
CDCl3, 293 K): d = 7.25 (d, J = 8.7 Hz, 2 H), 6.70 (d, J = 8.7
(14) Schadt, F. L.; Bentley, T. W.; Schleyer, P.v.R.. J. Am. Chem.
Soc. 1976, 98, 7667.
(15) (a) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F.
Chem. Commun. 1996, 2105. (b) Berkessel, A.; Adrio,
A. A.; Hüttenhain, D.; Neudörfl, J. M. J. Am. Chem. Soc.
2006, 128, 8421.
(16) We thank one of the referees for bringing up this important
point.
Synlett 2009, No. 4, 577–580 © Thieme Stuttgart · New York

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