InCl3 catalyzed carbene insertion into O-H bonds: Efficient synthesis of ethers

Article abstract of DOI:10.1016/j.tetlet.2011.04.099

An efficient InCl₃ mediated insertion of the carbene fragment (:CHCO₂Et), generated in situ from ethyl diazoacetate into O-H bond of a series of saturated and unsaturated alcohols under mild conditions has been developed to afford the corresponding ethers as exclusive products in good to high yields (70-95%) and in shorter reaction times. In the case of unsaturated alcohols, the reaction proceeded with unprecedented selectivity resulting in ethers as the only products and in high yields.

Full text of DOI:10.1016/j.tetlet.2011.04.099

Tetrahedron Letters 52 (2011) 3460–3462
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Tetrahedron Letters
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InCl3 catalyzed carbene insertion into O–H bonds: efficient synthesis of ethers
⇑
Palakodety Radha Krishna , Y. Lakshmi Prapurna, Munagala Alivelu
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient InCl3 mediated insertion of the carbene fragment (:CHCO2Et), generated in situ from ethyl
diazoacetate into O–H bond of a series of saturated and unsaturated alcohols under mild conditions
has been developed to afford the corresponding ethers as exclusive products in good to high yields
(70–95%) and in shorter reaction times. In the case of unsaturated alcohols, the reaction proceeded with
unprecedented selectivity resulting in ethers as the only products and in high yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 March 2011
Revised 25 April 2011
Accepted 26 April 2011
Available online 1 May 2011
Keywords:
InCl3
Ethyl diazoacetate
Carbene
Alcohols
Ethers
Transition metal assisted transfer of carbene units through the
decomposition of diazo compounds1 in the presence of hydroxylic
compounds (water, alcohols, phenols or carboxylic acids) to result
in the formation of a new C–O bond, by a formal insertion of the
carbene into the O–H bond, has a great synthetic bearing.2 Thus,
the synthesis of several natural products as well as of cyclic ethers
have been achieved using this methodology at a certain stage of
the synthetic pathway.3 Several metals have been employed to
mediate this transformation such as Rh,4 Ru,5 Cu,6 Ni,7 Sc8 and
Au.9 Some of these metal complex catalysts are not readily avail-
able and need to be prepared through complicated procedure.
operationally simple reaction conditions, yet possibly display rea-
sonable functional group compatibility over an array of substrates.
In recent years, indium(III) chloride14 emerged as a mild Lewis acid
for effecting a variety of chemical transformations in chemo-, re-
gio-, and stereo-selective fashion. Recently we reported facile InCl3
catalyzed C–C coupling of aryl alcohols and TosMIC followed by the
ready access of b-keto-(E)-enamino esters from 1,3-dicarbonyl
InCl3
N2CHCOOEt
EDA
RH2C
O
CH2COOEt
RCH2OH
neat, r.t.
Ether
4
4,6
Although Lewis acids like Rh2(OAc)4 and Cu(OTf)2 reportedly
catalyzed the insertion reaction, both were nonselective towards
the saturated and unsaturated substrates and furnished mixture
of products. Similarly, BF3ÁEt2O10 mediated transformation re-
quired low temperatures and the substrates with acid sensitive
functional groups failed to survive such strong acidic conditions.
Thus far the reports suggest that either the reaction failed com-
pletely in some cases11 or resulted in moderate yield12 in other
cases or was nonselective4,6 or required esoteric catalytic systems.6
Alternatively, the same transformation could be effected by
quenching the base induced oxyanion with ethyl haloacetate under
convention conditions.13 Nevertheless, it is plagued by harsh con-
ditions. Bearing in mind the above limitations as well as given
the importance of this reaction, a simple catalyst, that is, highly
selective for the O–H etherization is warranted. Therefore, we
turned our attention to find a catalyst system that is, mild, offers
Scheme 1. InCl3 catalyzed carbene insertion into O–H bond.
Table 1
Optimization of reaction conditionsa
Entry
Lewis acid
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
ZrCl4
FeCl3
CH2Cl2
CH2Cl2
CH3CN
THF
Neat
Neat
0.5
1
2
4
0.5
1
80
92
70
40
90
94
c
CH2Cl2
CH2Cl2
6
3
—
70
a
Reaction conditions: benzyl alcohol (1.5 mmol), ethyl diazoacetate (1 mmol)
and catalyst (0.2 mmol) stirred at rt for 0.5–6 h in solvents or as neat to give
product in 40–94% yield.
b
Isolated yields after purification by column chromatography.
No conversion.
⇑
Corresponding author. Tel.: +91 40 27193158.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
c
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.099

P. Radha Krishna et al. / Tetrahedron Letters 52 (2011) 3460–3462
3461
Table 2
source in CH2Cl2 and pleased to find the insertion product 1a in
92% yield in 1 h reaction time. Gratifyingly, carbene dimeric or
oligomeric products like diethyl fumarate and maleate were not
observed in the above transformation.4 In the presence of InCl3,
generation of carbene takes place via the decomposition of ethyl
diazoacetate, which on subsequent transfer to alcohols16 afforded
ethers as products.
InCl3 catalyzed insertion of EDA into various alcoholsa
Entry Substrate
Product
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
PhCH2OH
PhCH2OCH2CO2Et
1
94
95
92
91
90
80
1
1a
PhCH2CH2OH
PhCH2CH2OCH2CO2Et
0.5
1.5
1
2
2a
Next, the reaction optimization studies were performed be-
tween 1 and EDA using different solvents and Lewis acids (Table
1). After screening, InCl3 was found to furnish the optimum prod-
uct under solvent-free conditions. The reaction stoichiometry was
checked using different equivalents of InCl3 and the optimum
product yield was obtained with 0.2 equiv of the catalyst.
In order to test the generality of this reaction, a series of
saturated and unsaturated alcohols were studied towards the
etherification reaction under the standardized reaction conditions
(Table 2). Expectedly, all the alcohols 2–10 resulted in complete
conversion to afford the corresponding ethers 2a–10a in high
yields.17,18 In all the cases, no amount of residual EDA was detected
after completion of the reaction. It is noteworthy to mention that
the O–H insertion of unsaturated alcohols (Table 2, entries 7 and
8) proceeded with unprecedented selectivity resulting in exclusive
ethers as products, that is, olefin cyclopropanation did not occur.
Earlier, Reed and Katzenellenbogen11 attempted the O–H inser-
tion on the propargylic alcohol 11 using the carbene precursor
CH3OH
CH3OCH2CO2Et
3
3a
C2H5OH
C2H5OCH2CO2Et
4
4a
C4H9OH
C4H9OCH2CO2Et
1.5
1.5
5
5a
CH3(CH2)8CH2OH
6
CH3(CH2)8CH2OCH2CO2Et
6a
CH2OH
CH2OCH2CO2Et
7a
7
0.5
95
7
OH
OCH2CO2Et
8
9
0.5
1
95
82
80
8
8a
p-NO2C6H4CH2OH
p-NO2C6H4CH2OCH2CO2Et
9
9a
(C6H5)2CHOH
10
(C6H5)2CHOCH2CO2Et
10a
2
10
a
Reaction conditions: Alcohol (1.5 mmol), ethyl diazoacetate(1 mmol) and InCl3
(0.2 mmol) were stirred at room temperature under neat conditions.
b
Isolated yields after purification by column chromatography.
ethyl
a-diazoisovalerate with three different Lewis acid catalysts
(rhodium tetraacetate, copper(I) triflate, and boron trifluoride
etherate) but failed to obtain the expected product. The starting
material decomposed under those conditions. Interestingly, the
same substrate underwent a facile O–H insertion to furnish the
corresponding product 11a in 80% yield under the present reaction
conditions.
compounds and TosMIC.15 Both these transformations inspired us
to initiate a systematic study of InCl3 catalyzed carbene insertion
reaction. Herein, we report for the first time, the InCl3 catalyzed
insertion of :CHCO2Et into hydroxyl bonds to afford the corre-
sponding ethers as exclusive products in high yields (Scheme 1).
Accordingly, first we performed the InCl3 catalyzed test reaction
with benzyl alcohol 1 and ethyl diazoacetate (EDA) as the carbene
The next task was to study the functional group tolerance under
these reaction conditions. Accordingly, various substrates having
Table 3
InCl3 catalyzed insertion of EDA into substrates posessing acid sensitive protecting groups
Entry
Substrate
Product
Time (h)
Yield (%)
80
OH
OCH2CO2Et
TMS
N
N
1
2
Boc
Boc
11a
11
TMS
OH
OH
OCH2CO2Et
TBSO
THPO
TBSO
THPO
2
3
2
3
75
80
12a
13a
12
OCH2CO2Et
3
3
13
MOMO
MOMO
BocN
BocN
O
O
HO
EtO2CH2CO
4
5
4
2
70
70
14
OMOM
OMOM
14a
N
N
Boc
OH
15
OCH2CO2Et
15a
Boc
O
O
O
O
O
O
6
4
72
O
O
HO
EtO2CH2CO
16a
O
O
16

3462
P. Radha Krishna et al. / Tetrahedron Letters 52 (2011) 3460–3462
Mini-Rev. Org. Chem. 2004, 1, 1–7; (d) Zhang, Z.-H. Synlett 2005, 711–712; (e)
Zhang, Y.; Li, P.; Wang, M.; Wang, L. J. Org. Chem. 2009, 74, 4364–4367.
15. (a) Radha Krishna, P.; Raja Sekhar, E.; Prapurna, Y. L. Tetrahedron Lett. 2007, 48,
9048–9050; (b) Radha Krishna, P.; Raja Sekhar, E. Adv. Synth. Catal. 2008, 350,
2871–2876.
16. (a) Kirmse, W.; Loosen, K.; Sluma, H.-D. J. Am. Chem. Soc. 1981, 103, 5935–5937;
(b) Tomioka, H.; Hayashi, N.; Sugiura, T.; Izawa, Y. J. Chem. Soc., Chem. Commun.
1986, 1364–1366.
different functional groups were tested for InCl3 catalyzed O–H
insertion reaction (Table 3). To our delight, all the alcohols 11–16
are efficiently converted into their respective ethers 11a–16a17,18
in good yields and in shorter reaction time. In most of the cases,
the BF3ÁOEt2 failed to catalyze the reaction, excepting the prolinol
derivative 15. Acid sensitive groups like Boc, C-TMS, O-Silyl,
MOM–ethers, acetonide groups remained unscathed during this
transformation.
In summary, we have demonstrated a facile InCl3 catalyzed
insertion of :CHCO2Et fragment (from EDA) into the O–H bond un-
der solvent-free conditions with remarkable chemoselectivity
(high yielding ethers) and in case of unsaturated alcohols high reg-
ioselectivity (only insertion products were obtained) to afford the
corresponding ethers. Furthermore, this methodology proved bet-
ter than the reported ones, was general, and displayed good func-
tional group tolerance and versatility. Overall, a facile synthesis of
ethers from alcohols has been accomplished that may find varied
applications in synthetic organic chemistry.3
17. General experimental procedure: To a mixture of alcohol (1.5 mmol) and EDA
(1.0 mmol), InCl3 (0.2 mmol) was added and stirred under neat at ambient
temperature until the completion of the reaction as indicated by TLC. To the
reaction mixture, water (5.0 mL) was added and the product was extracted
with ethyl acetate (2 Â 10 mL). The combined organic layers were washed with
brine (10 mL), dried (Na2SO4) and purified by column chromatography (Silica
gel, 60–120 mesh, EtOAc:n-hexane, 1:9–2:8) to afford products.
18. Analytical and spectral data of selected compounds: Compound 2a: 1H NMR
(300 MHz, CDCl3): d 7.28–7.14 (m, 5H, Ar–H), 4.17 (q, 2H, J = 6.86 Hz, O–CH2),
4.00 (s, 2H, O–CH2), 3.72 (t, 2H, J = 6.86 Hz, O–CH2), 2.91 (t, 2H, J = 6.86 Hz,
CH2), 1.27 (t, 3H, J = 7.84 Hz, CH3). 13C NMR (100 MHz, CDCl3): d = 170.2, 138.2,
128.8, 128.2, 126.1, 72.4, 68.3, 60.9, 36.0, 13.9. IR (neat): 3440, 2930, 1750,
1260, 1157, 1055, 810, 775 cmÀ1 ESI–MS: 231 [M+Na]+. Anal. Calcd for
.
C
12H16O3: C, 69.21, H, 7.74. Found: 69.19, H, 7.70. Compound 6a: 1H NMR
(300 MHz, CDCl3): d 4.21 (q, 2H, J = 7.18 Hz, O–CH2), 3.99 (s, 2H, O–CH2), 3.48
(t, 2H, J = 6.61 Hz, O–CH2), 1.35–1.26 (m, 19H), 0.88 (t, 3H, J = 6.42 Hz, CH3). 13
NMR (100 MHz, CDCl3): d 170.6, 71.9, 68.3, 64.9, 31.9, 29.5, 29.4, 29.3, 29.2,
28.5, 25.9,25.8, 22.6, 14.1. IR (neat): 3440, 2930, 1690, 1510, 1257, 1036 cmÀ1
C
.
Acknowledgements
ESI–MS: 267 [M+Na]+. Anal. Calcd for C14H28O3: C, 68.81, H, 11.55. Found:
68.84, H, 11.51. Compound 9a: 1H NMR (300 MHz, CDCl3): d 8.20 (d, 2H,
J = 7.18 Hz, Ar–H), 7.51 (d, 2H, J = 8.31 Hz, Ar–H), 4.71 (s, 2H, O–CH2), 4.21 (q,
2H, J = 7.55 Hz, O–CH2), 4.13 (s, 2H, CH2), 1.31 (t, 3H, J = 7.55 Hz, CH3). 13C NMR
(100 MHz, CDCl3): d 169.8, 147.3, 144.8, 127.8, 123.4, 71.8, 67.7, 60.9, 14.0. IR
(neat): 3450, 2830, 1690, 1410, 1257, 1036, 850, 770 cmÀ1. ESI–MS: 262
[M+Na]+. Anal. Calcd for C11H13NO5: C, 55.23, H, 5.48, N, 5.86. Found: 55.21, H,
5.52, N, 5.83. Compound 10a: 1H NMR (300 MHz, CDCl3): d 7.34–7.15 (m, 10H,
Ar–H), 5.54 (s, 1H, CH), 4.18 (q, 2H, J = 6.80 Hz, O–CH2), 4.04 (s, 2H, O–CH2),
1.28 (t, 3H, J = 7.55 Hz, CH3). 13C NMR (75 MHz, CDCl3): d 170.5, 141.0, 128.3,
127.7, 127.2, 83.4, 65.9, 60.7, 14.1. IR (neat): 3450, 2830, 1695, 1250, 1157,
1050, 834, 776 cmÀ1. ESI–MS: 293 [M+Na]+. Anal. Calcd for C17H18O3: C, 75.53,
H, 6.71. Found: 75.55, H, 6.75. Compound 11a: 1H NMR (300 MHz, CDCl3): d
4.70 (d, 1H, J = 2.26 Hz, O–CH), 4.28–4.11 (m, 4H, 2 Â O–CH2), 3.54–3.24 (m,
3H), 2.26–1.65 (m, 4H, 2 Â CH2), 1.45 (s, 9H, 3 Â CH3), 1.28 (t, 3H, J = 6.79 Hz,
CH3), d = 0.16 (s, 9H, 3 Â CH3). 13C NMR (75MHz, CDCl3): d 169.5, 168.6, 102.3,
96.2, 79.1, 70.8, 65.9, 60.5, 60.4, 47.0, 28.2, 26.0, 24.5, 14.4, À0.26. IR (neat):
3451, 2856, 1739, 1254, 1040, 700 cmÀ1. ESI–MS: m/z 407 [M+Na]+. Anal. Calcd
for C19H34NO5Si: C, 59.34, H, 8.91, N, 3.64. Found: C, 59.36, H, 8.94, N, 3.66.
Compound 12a: 1H NMR (300 MHz, CDCl3): d 4.15 (q, 2H, J = 7.18 Hz, O–CH2),
3.98 (s, 2H, O–CH2), 3.59 (t, 2H, J = 6.04 Hz, O–CH2), 3.49 (t, 2H, J = 6.23 Hz, O–
CH2), 1.29–1.16 (m, 4H, 2 Â CH2), 1.26 (t, 3H, J = 7.17 Hz), 0.85 (s, 9H, 3 Â CH3),
0.00 (s, 6H, 2 Â CH3). 13C NMR (100 MHz, CDCl3): d 170.1, 96.2, 71.6, 68.3, 62.8,
29.8, 29.4, 26.1, 22.9, 14.3, À5.1. IR (neat): 3078, 2932, 2858, 1711, 1433, 1254,
1090, 834 cmÀ1. ESI–MS: m/z 313 [M+Na]+. Anal. Calcd for C14H30O4Si: C, 57.89,
H, 10.41. Found: 57.92, H, 10.44. Compound 13a: 1H NMR (300 MHz, CDCl3): d
5.79–5.49 (m, 2H, olefinic), 4.54 (s, 1H, O–CH), 4.18 (m, 2H, O–CH2), 3.99–3.97
(m, 4H, 2 Â O–CH2), 3.82–3.64 (m, 2H, O–CH2), 3.47–3.27 (m, 2H, O–CH2), 2.17
Two of the authors (Y.L.P. and M.A.) acknowledge the financial
support from the UGC and the CSIR, New Delhi in the form of
fellowships.
References and notes
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(t, 2H, J = 6.04 Hz, CH2), 1.82–1.39 (m, 8H, 4 Â CH2), 1.31–1.25 (m, 3H, CH3). 13
C
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NMR (100 MHz, CDCl3): d 170.1, 135.1, 125.5, 98.6, 71.8, 66.6, 66.5, 62.0, 60.5,
30.5, 28.8, 28.7, 25.2, 19.4, 13.9. IR (neat): 3050, 2952, 1720, 1455, 1260,
1065 cmÀ1. ESI–MS: m/z 309 [M+Na]+. Anal. Calcd for C15H26O5: C, 62.91, H,
9.15. Found: 62.93, H, 9.19. Compound 14a: 1H NMR (300 MHz, CDCl3): d 4.80–
4.56 (m, 6H, 3 Â O–CH2), 4.24–4.05 (m, 3H), 4.01 (s, 2H, O–CH2), 3.87 (t, 1H,
J = 7.93 Hz), 3.78–3.55 (m, 3H), 3.33 (s, 3H, O–CH3), 3.33 (s, 3H, O–CH3), 1.41 (d,
15H, J = 8.9 Hz, 5 Â CH3), 1.24 (t, 3H, J = 6.94 Hz, CH3). 13C NMR (75 MHz,
CDCl3): d 169.4, 151.6, 98.2, 95.9, 93.0, 79.6, 71.5, 70.9, 68.3, 63.2, 60.2, 58.5,
57.8, 55.9, 55.3, 28.2, 14.0. IR (neat): 3120, 2965, 2870, 1730, 1460, 1250,
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Perkin Trans. 1 2000, 3015–3019; (b) Fringuelli, F.; Piermatti, O.; Pizzo, F.;
Vaccaro, L. Curr. Org. Chem. 2003, 7, 1661–1689; (c) Frost, C. G.; Hartley, J. P.
1050, cmÀ1. ESI–MS: m/z 481 [M+H]+, 503 [M+Na]+. Anal. Calcd for C22H42NO10
:
C, 54.98, H, 8.81, N, 2.91. Found: C, 54.96, H, 8.78, N, 2.94. Compound 15a: 1H
NMR (300 MHz, CDCl3): d 4.62 (s, 1H), 4.28–4.15 (m, 4H, 2 Â O–CH2), 4.03 (br.
s, 1H), 3.62 (d, J = 6.9 Hz, 1H) 3.31 (br. s, 2H), 2.15–1.82 (m, 4H, 2 Â CH2), 1.45
(s, 9H), 1.29 (t, 3H, J = 6.9 Hz, O–CH3). 13C NMR (75 MHz, CDCl3): d 169.6, 153.8,
78.5, 71.4, 67.9, 63.2, 60.0, 56.0, 46.5, 28.2, 23.5, 13.9. ESI–MS: m/z 288 [M+H]+,
310 [M+Na]+. Anal. Calcd for C14H25NO5: C,58.52, H, 8.77, N, 4.87. Found: C,
58.54, H, 8.75, N, 4.89.