Formation of DPM ethers using O-diphenylmethyl trichloroacetimidate under thermal conditions

Article abstract of DOI:10.1039/c5ob02455b

Alcohols are effectively converted to their corresponding diphenylmethyl (DPM) ethers by reaction with O-diphenylmethyl trichloroacetimidate in refluxing toluene without the requirement of a catalyst or other additives. A number of acid and base sensitive substrates were protected in excellent yield using this new method without disturbing the pre-existing functionality present in these molecules. This reaction is the first example of the formation of an ether from stoichiometric amounts of a trichloroacetimidate and an alcohol without the addition of a Br?nsted or Lewis acid catalyst.

Full text of DOI:10.1039/c5ob02455b

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Formation of DPM ethers using O-diphenylmethyl
trichloroacetimidate under thermal conditions†
Cite this: DOI: 10.1039/c5ob02455b
Kyle T. Howard, Brian C. Duffy, Matthew R. Linaburg and John D. Chisholm*
Alcohols are effectively converted to their corresponding diphenylmethyl (DPM) ethers by reaction with
O-diphenylmethyl trichloroacetimidate in refluxing toluene without the requirement of a catalyst or other
additives. A number of acid and base sensitive substrates were protected in excellent yield using this new
method without disturbing the pre-existing functionality present in these molecules. This reaction is the
first example of the formation of an ether from stoichiometric amounts of a trichloroacetimidate and an
alcohol without the addition of a Brønsted or Lewis acid catalyst.
Received 1st December 2015,
Accepted 16th December 2015
DOI: 10.1039/c5ob02455b
www.rsc.org/obc
In addition, given the high toxicity and shock sensitive nature
of diazo compounds,10 care must be taken in their use,
Introduction
Diphenylmethyl (DPM) ethers (also known as benzhydryl especially on a large scale.
ethers) are commonly employed as protecting groups for alco-
Schmidt and co-workers have previously described the syn-
hols.1 DPM ethers may be cleaved either by hydrogenation2 thesis of O-diphenylmethyl trichloroacetimidate, which was
(making them a good surrogate for benzyl ethers) or under employed in the synthesis of DPM ethers.11 Traditionally
acidic conditions3 (where they can substitute for PMB or MOM trichloroacetimidates have been used to protect alcohols as
ethers). This flexibility in the removal of DPM ethers is ethers by utilizing Brønsted or Lewis acid catalysts,12 with the
especially beneficial in complex molecules containing delicate DPM ethers being no exception, providing excellent yields
functionality where it can be difficult to predict the best under mild conditions when a catalytic amount of TMSOTf
means of deprotection a priori. The large size of the DPM was employed. These conditions may be problematic for acid-
ether has also been proven advantageous in some enantio- sensitive substrates, however. For example, etherification of
selective transformations where the bulk provided by the DPM β-trimethylsilylethanol has been reported to be incompatible
ether provides a steric bias, increasing the selectivity in certain with acidic trichloroacetimidate protection conditions.13 The
substrates.4 The DPM ether has also been employed in medici- development of new imidate-based reagents has been an active
nal chemistry to incorporate a large hydrophobic group into field, with similar systems based on a triazine scaffold having
biologically active molecules, increasing the lipophilicity.5
recently been introduced for the introduction of benzyl14 and
Typically DPM ethers are formed under acidic conditions PMB ethers.15 New trifluoroacetimidate16 and phosphinimi-
from benzhydryl alcohol using protic or Lewis acids.3 These date-based17 reagents for etherification have also been
conditions are often harsh, and usually require high acid cata- advanced, however, all these systems require activation with
lyst loadings and elevated temperatures.6 Metal catalysts such TMSOTf or another acid catalyst.
as palladium(II) chloride7 and gold(I) salts8 have also been
Of late there has been a surge of research activity in the
used to install DPM ethers under more mild conditions, with development of new reagents for the protection of alcohols as
the caveat that these catalysts are more expensive. Attempts to substituted benzyl ethers under mild conditions that do not
find more mild reaction conditions to form DPM ethers have disturb any sensitive functionality in complex molecules.
led to the use of diphenyldiazomethane.9 While these con- Exemplifying these reagents, Dudley has reported the benzyla-
ditions are quite mild, diazo compounds are inherently tion of alcohols using benzyloxy pyridinium triflates in reflux-
unstable, typically requiring fresh preparation for good yields. ing α,α,α-trifluorotoluene.13,18 Similar systems have also been
developed for the formation of PMB ethers utilizing a lepidine
derivative as the benzyl transfer reagent.19 The quaternary pyri-
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse
dinium salts may also be generated in situ by the addition of
University, Syracuse, New York 13244, USA. E-mail: jdchisho@syr.edu;
methyl triflate to an appropriately functionalized pyridine or
Fax: +1 (315)-443-4070; Tel: +1 (315)-443-6894
quinoline system.19b,20 Recent additions to these reagents
†Electronic supplementary information (ESI) available: Full experimental
details, tabulated characterization data, 1H and 13C NMR spectra, and chiral
HPLC traces. See DOI: 10.1039/c5ob02455b
include triazinylammonium salts developed by the Kunishima
group which install benzyl ethers at room temperature.21 Both
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corresponding DPM ether (Fig. 1). This reaction would provide
a mild entry into DPM ethers under near neutral conditions,
where the strongest base present is the trichloroacetamide
anion (the pKa of trichloroacetamide has been reported as 11.2
(ref. 27)). Furthermore, DPM trichloroacetimidate 1 is a white
solid that is easy to handle and can be stored for long periods
of time (several months in a refrigerator22a) without decompo-
sition. Therefore imidate 1 has many of the elements desired
in an excellent etherification reagent. Given its high reactivity,
DPM imidate 1 was chosen as a test case for additive-free ether
formation, with some exploratory reaction screening per-
formed to determine the viability of the process.
Initial experiments were conducted with 1-octadecanol 8.
When alcohol 8 and 1.2 equivalents of imidate 1 were dis-
solved in toluene and heated to 50 °C for 24 hours, a 24%
yield of the desired ether 9 along with a significant amount of
unreacted starting materials was obtained. Warming the reac-
tion to reflux in toluene led to a more useful 85% isolated
yield. Other solvents were less effective, even when heated to
temperatures near that of refluxing toluene (1,4-dioxane,
α,α,α-trifluorotoluene, DMF). Removal of the trichloroacet-
amide by-product 6 from the nonpolar ether product 9 was
accomplished by washing the crude reaction mixture with
aqueous 2 M sodium hydroxide solution, greatly facilitating
purification. As needed, additional purification by chromato-
graphy removed trace amounts of the dimeric DPM ether 10
and, occasionally, small amounts of trichloroacetamide 4
(Table 1).
Fig. 1 Intercepting the DPM cation with an alcohol.
the Dudley and Kunishima systems function optimally with
the addition of an additive such as MgO, which functions as a
mild base and a desiccant to scavenge adventitious acid and/
or trace amounts of water.
Our recent experiences with the reactivity of trichloroacet-
imidates in the formation of esters22 and sulfides23 without an
added catalyst led us to consider the direct formation of ethers
from an alcohol and a trichloroacetimidate without the use of
any additive. In our earlier studies22a we have noted that DPM
imidate 1 would rearrange to the corresponding acetamide 4
when heated in refluxing toluene (Fig. 1). Allylic trichloroacet-
imidates are known to rearrange through a concerted [3,3]-
sigmatropic rearrangement (the Overman rearrangement24), but
this mechanism is not available to imidate 1. There have been
previous reports of benzylic imidates undergoing rearrange-
ment in the presence of a strong acid,25 likely through a
cationic pathway. Due to the stability of the diphenylmethyl
cation, we therefore hypothesized that the imidate ionizes
under thermal conditions to form the cation 3 and the tri-
chloroacetamide anion 2, a weak base and a poor nucleophile.
Should no competing nucleophile be present, the trichloroacet-
amide anion adds to the cation and the corresponding acet-
amide 4 is formed. However, in the presence of an external
nucleophile like an alcohol, we reasoned that it may be possi-
ble to intercept cation 3, leading to the direct formation of
ether 7 and trichloroacetamide 6. A search of the literature
found a single example of the uncatalyzed formation of an
ether from a trichloroacetimidate reported by Schmidt and co-
workers.26 This reaction involved the solvolysis of an O-gluco-
pyranosyl trichloroacetimidate with methanol. Attempts to dis-
place the same imidate with more complex alcohols were
reported to provide no ether products under similar solvolysis
conditions.
With the conditions in hand, a number of simple substrates
were tested in this new etherification process (Table 2). The
reaction proceeded very well for primary benzyl alcohols as
Table 1 Etherification with imidate 1 under thermal conditions
Entry
Solvent
Temperature
Yielda
1
2
3
4
5
6
7
8
9
Toluene
Toluene
50 °C
111 °C
102 °C
83 °C
40 °C
66 °C
101 °C
82 °C
110 °C
24%
85%
62%
66%
18%
36%
60%
28%
33%
α,α,α-Trifluorotoluene
1,2-Dichloroethane
Dichloromethane
THF
1,4-Dioxane
Acetonitrile
DMF
Results and discussion
The more reactive DPM imidate 1 may be able to capture a stoi-
chiometric amount of an alcohol nucleophile to form the
a Isolated yield.
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Table 2 Etherification of simple alcohols using DPM imidate 1
Table 3 Etherification of complex alcohols and phenols using DPM
imidate 1
Entry
1
DPM ether
Yielda
85%
Entry
1
DPM ether
Yielda
65%
2
3
94%
71%
2
3
79%
80%
4
5
88%
88%
4
5
6
91%b
73%
80%
6
7
97%
93%
8
92%
9
85%
92%
7
96%
10
a Isolated yield.
8
9
90%
shown in entries 2–4 (Table 2). Interestingly cinnamyl alcohol
(entry 5), which is a challenging substrate for some etherifica-
tion reagents,18d gave an 88% yield of the corresponding ether
14. Propargyl alcohol also proved to be an excellent substrate,
and gave the corresponding ether 15 in 97% yield. Simple
secondary alcohols were also successively etherified with DPM
imidate as shown in entries 7 and 8 (Table 2). Entries 9 and 10
demonstrate that tertiary alcohols may be protected with DPM
imidate in high yields.
In addition to the simple substrates shown in Table 2, a
number of more complex examples were subjected to the
etherification conditions with DPM imidate 1 (Table 3).
Sensitive substrates like the epoxide containing ether 20 were
successfully formed in good yields (entry 1, Table 3). Etherifi-
84%b
10
11
12
91%
61%
53%
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tain a stock of the reagent. This procedure provides a general
method for the protection of alcohols as DPM ethers, and
should facilitate the protection of sensitive substrates and
popularize the use of DPM ethers in synthetic applications.
Table 3 (Contd.)
Experimental section
Representative procedures for the formation of DPM ethers
Entry
13
DPM ether
Yielda
74%
with DPM trichloroacetimidate (1) under thermal conditions
Octadecyloxydiphenylmethane (8). 1-Octadecanol (200 mg,
0.739 mmol) was placed in a flame dried round bottom flask
and dissolved in anhydrous toluene to a concentration of
0.25 M (3 mL). Trichloroacetimidate 1 (291 mg, 0.887 mmol,
1.2 equiv.) was added and the reaction was warmed to reflux.
After 18 hours, the reaction was allowed to cool to room temp-
erature and concentrated under reduced pressure. The residue
was pre-adsorbed on silica gel and purified by silica gel
column chromatography (1% ethyl acetate/hexanes) to provide
0.273 g (85%) of octadecyloxydiphenylmethane (8) as a white
solid. Mp = 47–48 °C; TLC Rf = 0.80 (10% ethyl acetate/
hexanes); IR (thin film from CH2Cl2) 3027, 2923, 2852, 1493,
a Isolated yield. b The reaction was allowed to proceed for 48 hours,
and a second equiv. of DPM imidate was added after 24 h.
cation of β-trimethylsilylethanol was also readily accomplished
(entry 2, Table 3) in 79% yield. This result is notable as protec-
tion of β-silyl alcohols is complicated by rapid Peterson elimi-
nation28 under acidic or basic conditions, complicating the
etherification. As discussed above, the protection of β-tri-
methylsilylethanol has been reported to be incompatible with
acid-catalyzed imidate etherification reactions.13 The base sen-
sitive N-hydroxyphthalimide also provided a high yield of the
DPM ether 22. Other sensitive substrates also performed well,
resulting in the formation of β-alkoxyester 26 and α-alkoxyester
27 in yields of 96% and 90% respectively.
No racemization was observed in the formation of serine
ether 23, lactate DPM ether 27 or threonine ether 28 as deter-
mined by chiral HPLC (for 23 and 27) and 1H NMR analysis
(28). A number of phenol and phenol-like substrates were also
etherified with this methodology (entries 10–13, Table 3).
These reactions demonstrate that DPM ethers can be formed
under neutral conditions in the presence of a sensitive func-
tionality utilizing only the DPM trichloroacetimidate.
1453, 1097 cm−1 1H NMR (300 MHz, CDCl3) δ 7.21–7.37 (m,
;
10H), 5.33 (s, 1H), 3.44 (t, J = 6.6 Hz, 2H), 1.60–1.67 (m, 2H),
1.26 (m, 30H), 0.88 (t, J = 6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 142.9, 128.5, 127.5, 127.2, 83.8, 69.4, 32.2, 30.1, 29.94,
29.91, 29.87, 29.85, 29.7, 29.6, 26.5, 22.9, 14.3 (several signals
in the aliphatic region were not resolved). Anal calcd for
C31H48O: C, 85.26; H, 11.08. Found: C, 85.18; H, 11.13.
1-(Benzhydryloxy)adamantane (19). 1-Adamantanol (200 mg,
1.313 mmol) was placed in a flame dried round bottom flask
and dissolved in anhydrous toluene to a concentration of
0.25 M (5 mL). Trichloroacetimidate 1 (515 mg, 1.576 mmol,
1.2 equiv.) was added and the reaction was warmed to reflux.
After 18 hours, the reaction was cooled to room temperature
and concentrated under reduced pressure. The residue was
pre-adsorbed on silica gel and purified by silica gel column
chromatography (1% ethyl acetate/hexanes) to provide 0.383 g
(92%) of 1-(benzhydryloxy)adamantane (19) as an orange solid.
Mp = 64–66 °C; TLC Rf = 0.71 (10% ethyl acetate/hexanes);
Conclusions
In summary, a mild method for protecting primary, secondary IR (thin film from CH2Cl2) 3025, 2905, 2850, 1492, 1451, 1354,
1
and tertiary alcohols in high yields using diphenylmethyl 1082 cm−1; H NMR (300 MHz, CDCl3) δ 7.20–7.39 (m, 10H),
trichloroacetimidate 1 under thermal conditions has been 5.80 (s, 1H), 2.14 (s, 3H), 1.83 (bs, 6H), 1.62 (bs, 6H); 13C NMR
demonstrated. In contrast to other conditions more commonly (100 MHz, CDCl3) δ 145.3, 128.2, 127.2, 126.9, 74.4, 73.8, 43.0,
advanced, these thermal protection conditions do not require 36.6, 30.8. Anal calcd for C23H26O: C, 86.75; H, 8.23. Found:
the use of an acid catalyst or other additives. Indeed, this study C, 86.72; H, 8.18.
is the first report of the etherification of an alcohol utilizing a
(S)-Benzyl 3-(benzhydryloxy)-2-(((benzyloxy)carbonyl)amino)
stoichiometric amount of a trichloroacetimidate that proceeds propanoate (23). N-Benzyloxycarbonyl-L-serine benzyl ester
without the addition of an acid catalyst or a promoter. The (200 mg, 0.607 mmol) was placed in a flame dried round
DPM ethers may be formed in high yields in systems contain- bottom flask and dissolved in anhydrous toluene to a concen-
ing both acid and base sensitive functionalities. These mild tration of 0.25 M (2.5 mL). Trichloroacetimidate 1 (239 mg,
reaction conditions have shown compatibility with polyfunc- 0.728 mmol, 1.2 equiv.) was added and the reaction was
tional molecules, and the necessary reagents may be accessed warmed to reflux. After 24 hours the reaction still showed the
from simple, inexpensive starting materials. In addition, the starting material by thin layer chromatography analysis, so
DPM imidate reagent 1 is quite stable, and can be stored for more trichloroacetimidate 1 was added (239 mg, 0.728 mmol,
long periods of time in a refrigerator, making it easy to main- 1.2 equiv.). After another 24 hours at reflux, the reaction was
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allowed to cool to room temperature and concentrated under
reduced pressure. The residue was dissolved in ethyl acetate,
washed with 2 M aq. NaOH (3×), dried (Na2SO4) and concen-
trated (this workup removes the trichloroacetamide by-
product). The residue was pre-adsorbed on silica gel and purified
by silica gel column chromatography (15% ethyl acetate/
hexanes) to provide 0.273 g (91%) of (S)-benzyl 3-(benzhydry-
loxy)-2-(((benzyloxy)carbonyl)amino) propanoate (23) as a clear
oil. [α]2D1.6 −12.5 (c 1.26, CHCl3); TLC Rf = 0.18 (10% ethyl
acetate/hexanes); IR (thin film from CH2Cl2) 3434, 3341, 3062,
2006, 71, 8651; (d) M. B. Andrus and Z. Ye, Tetrahedron
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1
3030, 2949, 2876, 1722, 1498, 1339, 1197, 1067 cm−1; H NMR
(400 MHz, CDCl3) δ 7.07–7.30 (m, 20H), 5.63 (d, J = 12.0 Hz,
1H), 5.19 (s, 1H), 5.12 (d, J = 4.0 Hz, 2H), 5.04 (s, 2H), 4.49 (dt,
J = 2.8 Hz, 1H), 3.84 (dd, J = 9.4, 2.8 Hz, 1H), 3.60 (dd, J = 9.4,
3.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 170.3, 156.1, 141.6,
141.4, 136.4, 135.4, 128.7, 128.65, 128.6, 128.5, 128.4, 128.3,
128.2, 127.7, 127.0, 126.9, 84.2, 69.0, 67.4, 67.2, 54.8 (two
signals in the aromatic region were not resolved). Anal calcd
for C31H29NO5: C, 75.13; H, 5.90; N, 2.83. Found: C, 74.94; H,
5.97; N, 3.00. Chiral HPLC analysis: chiralcel OD (heptane/
2-PrOH = 90/10, 1.0 mL min−1, 254 nm, 25 °C): t(S enantiomer)
16.7 min, t(R enantiomer) = 23.9 min.
=
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Acknowledgements
Financial support was provided by the National Institute of
General Medical Sciences (R15-GM116054). Acknowledgement
is also made to the Donors of the American Chemical Society
Petroleum Research Fund for a New Directions award in
support of this research (54823-ND1). Support for the Syracuse
University NMR facility used in this study was provided by the
National Science Foundation (CHE-1229345), which is grate-
fully acknowledged.
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