Efficient synthesis of acylsilanes using morpholine amides

Article abstract of DOI:10.1021/ol0483854

(Chemical Equation Presented) A general synthesis of acylsilanes from the corresponding morpholine amides and silyllithium species is described. The use of morpholine amides is economical and prevents over-addition by the silyl nucleophile. The procedure cleanly affords acylsilanes in good yields and circumvents the use of stoichiometric copper(I) cyanide typically employed to synthesize these compounds from acid chlorides.

Full text of DOI:10.1021/ol0483854

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3977-3980
Efficient Synthesis of Acylsilanes Using
Morpholine Amides
Christopher T. Clark, Benjamin C. Milgram, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
scheidt@northwestern.edu
Received August 13, 2004
ABSTRACT
A general synthesis of acylsilanes from the corresponding morpholine amides and silyllithium species is described. The use of morpholine
amides is economical and prevents over-addition by the silyl nucleophile. The procedure cleanly affords acylsilanes in good yields and
circumvents the use of stoichiometric copper(I) cyanide typically employed to synthesize these compounds from acid chlorides.
Acylsilanes are valuable compounds in organic synthesis
primarily due to their ability to access the Brook rearrange-
ment manifold upon the addition of a strong nucleophile.
This important 1,2-silyl migration from carbon to oxygen
was initially described by Brook, and subsequent investiga-
tions of this process have firmly established its utility.1 For
example, acylsilanes have been employed in the synthesis
of enolsilanes2 and alcohols3 and provide direct access to
homoenolates upon addition of vinyl or alkynyl organome-
tallic reagents.4 More recently, acylsilanes undergoing the
Brook rearrangement have been the cornerstone for the
development of tandem annulation reactions,5 and the unique
properties of the resulting anions have been exploited in the
development of new catalytic acyl anion addition reactions.6
However, although acylsilanes are useful entities, standard
procedures for accessing these compounds have numerous
limitations such as low overall efficiency and a reliance on
stoichiometric quantities of a transition metal. Herein, we
report an efficient synthesis of acylsilanes (3, Scheme 1) from
the corresponding morpholine amides (1) via tetrahedral
intermediate A. This approach allows for the efficient access
Scheme 1. General Synthesis of Acylsilanes from Morpholine
Amides
(1) (a) Brook, A. G.; LeGrow, G. E.; MacRae, D. M. Can. J. Chem.
1967, 45, 239-253. (b) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84. (c)
Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647-660. (d) Cirillo, P. F.;
Panek, J. S. Org. Prep. Proced. Int. 1992, 24, 553-582. (e) Moser, W. H.
Tetrahedron 2001, 57, 2065-2084.
(2) (a) Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990,
112, 5609-5617. (b) Lefebvre, O.; Brigaud, T.; Portella, C. J. Org. Chem.
2001, 66, 4348-4351.
(3) (a) Buynak, J. D.; Geng, B. L.; Uang, S. N.; Strickland, J. B.
Tetrahedron Lett. 1994, 35, 985-988. (b) Takeda, K.; Ohnishi, Y.; Koizumi,
T. Org. Lett. 1999, 1, 237-239. (c) Patroc´ınio, A. F.; Correˆa, I. R.; Moran,
P. J. S. J. Chem. Soc., Perkin Trans. 1 1999, 3133-3137. (d) Bolm, C.;
Kasyan, A.; Heider, P.; Saladin, S.; Drauz, K.; Gunther, K.; Wagner, C.
Org. Lett. 2002, 4, 2265-2267. (e) Cossrow, J.; Rychnovsky, S. D. Org.
Lett. 2002, 4, 147-150.
(4) (a) Enda, J.; Kuwajima, I. J. Am. Chem. Soc. 1985, 107, 5495-
5501. (b) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 11290-11291 and references therein. (c) Reich, H. J.; Olson, R. E.;
Clark, M. C. J. Am. Chem. Soc. 1980, 102, 1423-1424.
(5) (a) Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705-
3707. (b) Sasaki, M.; Kawanishi, E.; Nakai, Y.; Matsumoto, T.; Yamaguchi,
K.; Takeda, K. J. Org. Chem. 2003, 68, 9330-9339.
(6) (a) Degl’Innocenti, A.; Pike, S.; Walton, D. R. M.; Seconi, G.; Ricci,
A.; Fiorenza, M. J. Chem. Soc., Chem. Commun. 1980, 1201-1202. (b)
Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta, V. Gazz.
Chim. Ital. 1987, 117, 645-648. (c) Xin, L. H.; Johnson, J. S. Angew. Chem.
Int. Ed. 2003, 42, 2534-2536. (d) Mattson, A. E.; Bharadwaj, A. R.; Scheidt,
K. A. J. Am. Chem. Soc. 2004, 126, 2314-2315. (e) Bharadwaj, A. R.;
Scheidt, K. A. Org. Lett. 2004, 6 2465-2468.
10.1021/ol0483854 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/06/2004

becomes prohibitive. As an alternate approach, Fleming and
co-workers first noted that the addition of silyl anions to
amides afforded acylsilanes, but this process was not
adequately explored as an efficient and less toxic strategy
to construct acylsilanes.17
We were prompted to reexamine various acylsilane
syntheses when trying to prepare acylsilane 3a (Scheme 2).
Scheme 2. Dithiane Deprotection Complications and
Conversion of Amide 1a to Acylsilane 3aa
Figure 1. Survey of various acylsilane syntheses.
of acylsilanes in one step from the corresponding amide and
an easily prepared silyl anion.
There are numerous synthetic approaches to construct the
carbonyl carbon-silicon bond (Figure 1).7 Unconventional
approaches include the conversion of R,R-dibromobenzyl-
silanes (4) to acylsilanes on silica gel8 and the hydroboration
of silylalkynes (5).9 The trapping of deprotonated dithianes
with chlorosilanes has been employed for decades, but this
strategy always requires the unmasking of the R-silyl dithiane
(6), which is not always compatible with the substrate (vide
infra).10 Additionally, benzotriazol-1-yl phenoxyalkanes are
useful precursors to a variety of acylsilane structures.11 Not
surprisingly, many of these processes are potentially difficult
due to the unavailability of starting materials or their lack
of atom economy.12 R,â-Unsaturated acylsilanes can be
prepared either by a Horner-Wadsworth-Emmons reaction
of R-(phosphonoacyl)-silanes13 or the silyl-Wittig rearrange-
ment of allylic alcohols followed by oxidation.14 Interest-
ingly, the palladium-catalyzed conversion of aryl acid
chlorides to aryl acylsilanes has been reported, but this
reaction is limited to the trimethylsilyl group and undergoes
decarbonylation with electron-deficient aromatic systems.15
a Conditions: 1) (NH4)2Ce(NO3)6, aq. NaHCO3, MeCN/CH2Cl2,
-30 °C, 5 min; 2) PhI(OTFA)2, aq. NaHCO3, THF/MeCN, 0 °C,
15 min.
The conventional dithiane approach allowed for the prepara-
tion of gram quantities of dithiane 8, but we were unable to
convert this material to 3a without destroying the terminal
alkene. We wanted to avoid using mercury(II) chloride, due
to the toxicity of mercury and the possible interactions of
the metal with the olefin. A search of the literature yielded
only two reagents for the deprotection of dithianes in the
presence of terminal olefins: ceric ammonium nitrate18 and
[bis(trifluoroacetoxy)-iodo]benzene.19 Unfortunately, the use
of either of these reagents under various conditions did not
afford the desired acylsilane.
We envisioned that a morpholine amide 1a would be a
better acylsilane precursor for 3a and that this approach
would be applicable toward many other acylsilanes. The
direct addition of organometallic reagents to morpholine
amides without over-addition has been reported,20 and this
process is more economical than the corresponding Weinreb
amides.21 Gratifyingly, the addition of 1.5 equiv of dimeth-
ylphenylsilyllithium to a -78 °C solution of morpholine
amide 1a in THF for 90 min followed by the addition of
aqueous ammonium chloride affords the desired acylsilane
3a in 72% yield.22 To probe the scope of this reaction, the
The addition of anionic silyl nucleophiles to acid chlorides
is typically the most direct method for the synthesis of
acylsilanes, but this method requires at least 2 equiv of the
silyllithium reagent and suffers largely from stoichiometric
copper(I) cyanide required for the reaction to proceed in high
yield.16 Unfortunately, on a preparative scale, this process
(7) (a) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic
Press: London, 1988. (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem.
Soc. ReV. 1990, 19, 147-195.
(8) Degl’Innocenti, A.; Walton, D. R. M.; Seconi, G.; Pirazzini, G.
Tetrahedron Lett. 1980, 21, 3927-3928.
(9) (a) Miller, J. A.; Zweifel, G. J. Am. Chem. Soc. 1981, 103, 6217-
6219. (b) Miller, J. A.; Zweifel, G. Synthesis 1981, 288-289.
(10) (a) Brook, A. G.; Duff, J. M.; Jones, P. F.; Davis, N. R. J. Am.
Chem. Soc. 1967, 89, 431-434. (b) Corey, E. J.; Seebach, D.; Freedman,
R. J. Am. Chem. Soc. 1967, 89, 434-436.
(11) (a) Katritzky, A. R.; Yang, Z. J.; Hong, Q. M. J. Org. Chem. 1994,
59, 5097-5099. (b) Katritzky, A. R.; Wang, Z. Q.; Lang, H. Y. Organo-
metallics 1996, 15, 486-490. (c) Katritzky, A. R.; Lang, H. Y.; Wang, Z.
Q.; Lie, Z. J. Org. Chem. 1996, 61, 7551-7557.
(12) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(13) Nowick, J. S.; Danheiser, R. L. J. Org. Chem. 1989, 54, 2798-
2802.
(14) Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y. M.; Szczepanski,
S. W. J. Org. Chem. 1985, 50, 5393-5396.
(15) (a) Picard, J. P.; Calas, R.; Dunogues, J.; Duffaut, N.; Gerval, J.;
Lapouyade, P. J. Org. Chem. 1979, 44, 420-424. (b) Rich, J. D. J. Am.
Chem. Soc. 1989, 111, 5886-5893.
(16) (a) Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Ricci, A.;
Dembech, P.; Seconi, G. J. Org. Chem. 1988, 53, 3612-3614. (b) Bonini,
B. F.; Comes-Franchini, M.; Mazzanti, G.; Passamonti, U.; Ricci, A.; Zani,
P. Synthesis 1995, 92-96.
(17) Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257-
262.
(18) Chuang, T.-H.; Fang, J.-M.; Jiaang, W.-T.; Tsai, Y.-M. J. Org.
Chem. 1996, 61, 1794-1805.
(19) Jiaang, W.-T.; Lin, H.-C.; Tang, K.-H.; Chang, L.-B.; Tsai, Y.-M.
J. Org. Chem. 1999, 64, 618-628.
(20) (a) Mart´ın, R.; Romea, P.; Tey, C.; Urp´ı, F.; Vilarrasa, J. Synlett
1997, 1414-1416. (b) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A.
Tetrahedron Lett. 2000, 41, 37-40.
(21) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Sigma-Aldrich pricing: N,O-dimethylhydroxylamine‚HCl costs
$195/mol, while morpholine is only $13/mol (calculation based on 100 g
bottles).
3978
Org. Lett., Vol. 6, No. 22, 2004

With a suitable procedure in hand for the synthesis of
acylsilanes from morpholine amides, we questioned whether
other tertiary amides were equally effective in this transfor-
mation. To explore these possibilities, a small range of
octanoyl amides were treated with dimethylphenylsilyllithium
under our established reaction conditions (Table 2). Surpris-
ingly, only the morpholine, N,N-dimethyl, and piperidyl
Table 1. Synthesis of Acylsilanes from Alkyl Morpholine
Amidesa
Table 2. Synthesis of Acylsilanes from Octanoyl Amidesa
entry
R
yield (%)
1
2
3
4
5
6
morpholine (1b)
NMe2
NEt2
NBn2
piperidine
NMe(OMe)
81
46
0b
0b
10
0b
a All reactions were carried out 0.3 M in substrate in THF with 1.5 equiv
of phenyldimethylsilyllithium for 1.5 h at -78 °C. Reactions were quenched
at -78 °C by the addition of saturated ammonium chloride and stirred for
30 min. Following workup, the residue was purified by silica gel
chromatography. b Complex mixture.
amides gave any acylsilane product under these conditions.
Although the morpholine amide is clearly beneficial for the
overall reaction, its special nature is currently not well
understood.
The extension of this methodology to the use of aromatic
morpholine amides is currently problematic. Straightforward
additions of silyl anions to aromatic amides (10) usually
undergo a Brook rearrangement after formation of the
tetrahedral intermediate (11), presumably due to stabilization
of the resulting carbanion 12 by the aromatic moiety (Scheme
3, path B). Surprisingly, this anion subsequently undergoes
a All reactions were carried out 0.3 M in substrate in THF with 1.5
equivalents of phenyldimethylsilyllithium for 1.5 h at -78 °C. Reactions
were quenched at -78 °C by the addition of saturated aqueous ammonium
chloride and were stirred for 30 min. Following workup, the residue was
purified by silica gel chromatography.
Scheme 3. Rearrangement of Aryl Morpholine Amides
addition of dimethylphenylsilyllithium to a number of
morpholine amides has been examined (Table 1).
The addition of dimethylphenylsilyllithium to morpholine
amides occurs in good yields and is a general process for
the synthesis of alkyl acylsilanes (entries 1-9). Gratifyingly,
no double addition was observed for any of the substrates.
Both linear and branched alkyl morpholine amides are
suitable substrates for the reaction and are efficiently
transformed into alkyl acylsilanes.23
an R-elimination of the silyloxy substituent and the ensuing
carbene either encounters an additional equivalent of the
silyllithium species or dimerizes.24 Not unexpectedly, the use
(22) Dimethylphenylsilyllithium is easily prepared from the incubation
of commercially available dimethylphenylsilyl chloride and finely cut lithium
metal in THF at 0 °C for 40 h. The resulting dark red suspension is used
after titration according to: Fleming, I.; Newton, T. W.; Roessler, F. J.
Chem. Soc., Perkin Trans. 1 1981, 2527-2532.
(23) Table 2, entry 3, has been performed on a 55 mmol scale to yield
acylsilane 3c. See Supporting Information for details.
(24) For the first reported observation of this behavior, see: Fleming,
I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257-262. (b) Buswell,
M.; Fleming, I. Chem. Commun. 2003, 202-203 and references therein.
Org. Lett., Vol. 6, No. 22, 2004
3979

of N-benzoylmorpholine as a substrate did not fare better,
yielding no acylsilane. We hypothesized that use of more
electron-donating aryl groups could inhibit the deleterious
Brook rearrangement (path B) and allow for the reaction to
proceed via the desired path A. To investigate this possibility,
we attempted to synthesize acylsilanes from a variety of
electron-rich aryl morpholine amides (Table 3). The place-
ment of a single electron-donating substituent on the phenyl
conditions. Accordingly, amide 1b was reacted under the
optimized conditions with silyl anion 9, except that THF was
replaced with a 2:1 (v/v) mixture of THF/HMPA. In this
event, no acylsilane was recovered, thus determining that
the use of HMPA as a solvent is unsuited for this methodol-
ogy.
In addition, we sought to determine the tolerance of this
reaction to various hydroxyl-protecting groups. To this end,
various O-protected 4-hydroxybutyryl morpholine amides
were synthesized and treated with dimethylphenylsilyllithium
under the optimized reaction conditions. Gratifyingly, alkyl-
or silyl-protected hydroxy amines underwent smooth addition
to yield acylsilanes (18-22) in moderate to high yields
(Table 4).
Table 3. Aryl Morpholine Amides as Electrophilesa
Table 4. Synthesis of Protected Acylsilanesa
entry
R
acylsilane
yield (%)
1
2
3
4
5
PhCH2
MeOCH2OCH2
Ph3C
i-BuPh2Si
i-Pr3Si
18
19
20
21
22
85%
67%
75%
60%
79%
b
a All reactions were carried out 0.3 M in substrate in THF with 1.5 equiv
of phenyldimethylsilyllithium for 1.5 h at -78 °C. Reactions were quenched
at -78 °C by the addition of saturated ammonium chloride and stirred for
30 min. Following workup, the residue was purified by silica gel
chromatography.
a All reactions were carried out 0.3 M in substrate in THF with 1.5
equivalents of phenyldimethylsilyllithium for 5 min at -78 °C. Reactions
were quenched at -78 °C (aq NH4Cl), then purified (SiO2). b Complex
mixture.
In conclusion, a direct and efficient synthesis of acylsilanes
from amides has been described. The use of the morpholine
amide is a key feature since it minimizes over-addition of
the silyl nucleophile and also provides the highest yields of
the amides surveyed. The additions of silyllithium species
to aromatic amides are hampered by a nonproductive Brook
rearrangement. The overall process has been developed to
be highly preparative in nature, avoids the use of transition
metals, and tolerates varied alkyl amide structures, including
various protecting groups. The application of this methodol-
ogy to facilitate investigations into the reactivity and utility
of acylsilanes is in progress in our laboratory.
ring of the amide did not inhibit reaction path B (entries 2
and 3). The use of a 2,4-dimethoxyphenyl amide did allow
for isolation of the desired acylsilane (15), albeit in low yield.
Unexpectedly, the 2-furyl morpholine amide afforded the
corresponding acylsilane in moderate yield (60%, entry 5).25
To further probe the scope of the reaction, we examined
the addition of other silyllithium species to 1b. The addition
of diphenylmethylsilyllithium afforded no acylsilane, possibly
due to complications from a faster Brook rearrangement
facilitated by the additional phenyl group on the silicon.
Surprisingly, the reaction of trimethylsilyllithium26 with 1b
did not yield an acylsilane. In addition, use of 2-methoxy-
phenyldimethylsilyllithium and 2-(5-methylfuryl)dimethyl-
silyllithium27 resulted in no desired products. Interestingly,
the syntheses of these additional silyl anions require hexa-
methylphosphoramide (HMPA), and we questioned whether
this additive was incompatible with our optimized reaction
Acknowledgment. We thank Northwestern University for
support of this work. We are grateful to Wacker Chemical
Co. (Specialties Division, Adrian, MI) for kindly supplying
various organosilicon reagents.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Employing additional 2-substituted aromatic heterocycles (e.g.,
N-methyl pyrroyl, thiophen-2-yl) was not successful using the current
reaction conditions.
(26) Still, W. C. J. Org. Chem. 1976, 41, 3063-3064.
(27) Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337-3339.
OL0483854
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