Magnesiated unsaturated silylated cyanohydrins as synthetic equivalents of aromatic and heterocyclic Grignard reagents bearing a ketone or an aldehyde

Article abstract of DOI:10.1021/ol052792d

The preparation of iodo-substituted aryl, heteroaryl, or cycloalkenyl ketones as silylated cyanohydrins allows the smooth performance of an l/Mg-exchange using i-PrMgCl·LiCl. A facile deprotection of the resulting functionalized products obtained by a rea

Full text of DOI:10.1021/ol052792d

ORGANIC
LETTERS
2006
Vol. 8, No. 4
617-619
Magnesiated Unsaturated Silylated
Cyanohydrins as Synthetic Equivalents
of Aromatic and Heterocyclic Grignard
Reagents Bearing a Ketone or an
Aldehyde
Ching-Yuan Liu, Hongjun Ren, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received November 18, 2005
ABSTRACT
The preparation of iodo-substituted aryl, heteroaryl, or cycloalkenyl ketones as silylated cyanohydrins allows the smooth performance of an
I/Mg-exchange using i-PrMgCl LiCl. A facile deprotection of the resulting functionalized products obtained by a reaction with electrophiles
‚
(acid chlorides, allylic bromide, benzylidene-p-toluenesulfonamide, and 3-iodocyclohexenone) produces polyfunctional ketones in good overall
yields. This sequence can be extended to aromatic iodoaldehydes. In these cases, the deprotection of the silylated cyanohydrin functionality
is best performed with aqueous CuSO4 under basic conditions.
The preparation of Grignard reagents bearing functional
groups has become very convenient by the use of the mixed
magnesium-lithium complex i-PrMgCl‚LiCl, which under-
goes rapidly a Br/Mg exchange on numerous unsaturated
bromides.1 The preparation of aromatic organomagnesium
reagents bearing a reactive functionality such as a ketone2
or an aldehyde is rather difficult to achieve in the absence
of a protecting group.3 As potential protecting group for
iodoketones of type 1, we envisioned using silylated cyano-
hydrins4 of type 2, which are available by a CsF-catalyzed
silylcyanation with trimethylsilyl cyanide (Scheme 1 and
Table 1).
Scheme 1. General Reaction Sequence
(1) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
(c) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 2288.
(d) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543. (e)
Liu, C.-Y.; Knochel, P. Org. Lett. 2005, 7, 2543. (f) Kopp, F.; Sklute, G.;
Polborn, K.; Marek, J.; Knochel, P. Org. Lett. 2005, 7, 3789.
(2) Kneisel, F. F.; Knochel, P. Synlett 2002, 179.
(3) ProtectiVe Groups in Organic Synthesis, 3rd ed.; Greene, T. W., Wuts,
P. G. M., Eds.; John Wiley & Sons, Inc.: New York, 1999; pp 293-369.
Herein, we wish to report that the conversion of the
silylated cyanohydrins 2 to the corresponding Grignard
reagent 3 proceeds well by using the powerful exchange
reagent i-PrMgCl‚LiCl (4).1
10.1021/ol052792d CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/26/2006

ketones of type 5 in good yields (Scheme 1 and Table 1).
Thus, the silylated cyanohydrins were readily prepared by
using TMSCN (1.2 equiv) and CsF (20 mol %) in CH3CN
(room temperature, 2 h), starting from the corresponding
ketones.4
Table 1. Polyfunctional Ketones Obtained by the Reaction of
the Silylated Cyanohydrins 2 with i-PrMgCl‚LiCl, Leading to
Functionalized Gignard Reagents 3, Followed by
Transmetalation with CuCN‚2LiCl and Reaction with an
Electrophile and Deprotection
The reaction of the silylated cyanohydrins 2a with
i-PrMgCl‚LiCl (4; -20 °C, 1 h) provides the intermediate
arylmagnesium reagent 3a, which is stable at low temper-
ature.6 Its transmetalation with CuCN‚2LiCl allows a smooth
cross-coupling with 3-iodocyclohexenone, leading to the
diketone 5a in 83% yield (entry 1). The removal of the
transient silylated cyanohydrin is carried out by adding TBAF
(1.5 equiv, 1 M solution in THF). After 0.5 h, a 2 M HCl
solution is added, and the reaction mixture is stirred for 2 h.
Alternatively, the Grignard reagent 3a reacts after trans-
metalation with CuCN‚2LiCl with furoyl chloride, furnishing
the diketone 3b in 85% yield (entry 2). The same behavior
is observed with the silylated cyanohydrin 2b derived from
3-iodoacetophenone. After a copper-mediated acylation with
1-naphthoyl chloride, the expected diketone 5c is isolated
after deprotection in 72% yield (entry 3). Heterocyclic
ketones can be used as well. Thus, the resulting silylated
cyanohydrin 2c is converted at -40 °C to the corresponding
heteroarylmagnesium derivative 3c. Acylation with various
acid chlorides furnishes the diketones 5e,f in 71-72% yield
(entries 4 and 5). Unsaturated 3-iodocyclohexenones can be
readily converted to the expected silylated cyanohydrins 2d,e
in almost quantitative yield. Their reactions with i-PrMgCl‚
LiCl (4) in THF at -40 °C for 1 h produce the Grignard
reagents 3d,e in high yields. Copper(Ι)-catalyzed acylation
with furoyl chloride affords after standard deprotection
(TBAF, 2 M HCl) the unsaturated diketones 5g and 5h in
81-87% yield (entries 6 and 7). A similar reactivity pattern
is observed with the silylated cyanohydrin 2f that reacts with
3-iodocyclohexenone or PhCOCl, leading to diketones 5i,j
in 71-76% yield (entries 8 and 9).
Interestingly, the silylated cyanohydrin 2e reacts after
magnesiation with PhCOCl, leading to the ketone 6, which
after Wittig olefination and deprotection furnishes dienic
ketone 7 in 83% yield. The treatment of the functionalized
diene 7 with BF3‚OEt2 (5 equiv; 0 to 40 °C, 7 h) triggers an
intramolecular Michael addition, providing the annelated
spiroketone 8 in 83% yield (Scheme 2).7
Starting from the silylated cyanohydrin 2d, we performed
after magnesiation a Negishi cross-coupling with methyl
2-iodoacrylate. The usual deprotection led to the dienic
ketone 9 in 81% yield. A solution of 9 in mesitylene was
heated (220 °C, 72 h) and underwent an electrocyclic ring
closing followed by a double bond isomerization, affording
the tricyclic ketone 10 in 85% yield (Scheme 3).
a Reaction conditions for performing the I/Mg exchange. b Overall yield
(being from the cyanohydrin) after reaction with an electrophile and
deprotection.
A direct reaction of 3 with various electrophiles (E+) or
in the presence of CuCN‚2LiCl5 provides a range of silylated
cyanohydrins that are readily converted to the polyfunctional
The use of silylated cyanohydrins as protecting group can
be also successfully applied to aldehydes. Thus, the mag-
nesiation of the silylated cyanohydrins 11a,b occurs rapidly
with i-PrMgCl‚LiCl (4) at -78 °C (0.5 h). In the presence
(4) (a) Kim, S. S.; Rajagopal, G.; Song, D. H. J. Organomet. Chem.
2004, 689, 1734. (b) North, M. Synlett 1993, 807. (c) Deng, H.; Ister, M.
P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2002, 41, 3333.
(d) Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. (e) Hayashi,
M.; Miyamoto, Y.; Inoue, S.; Oguni, N. J. Org. Chem. 1993, 58, 1515. (f)
Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 537. (g)
Hanashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805. (h) Tian, S. K.; Hong, R.; Deng, L. J. Am.
Chem. Soc. 2003, 125, 9900.
(6) (a) Fleming, F. F.; Gudipati, V.; Steward, O. W. Org. Lett. 2002, 4,
659. (b) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. Org. Lett.
2002, 4, 2493.
(5) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(7) Lomberget, T.; Bentz, E.; Bouyssi, D.; Balme, G. Org. Lett. 2003,
5, 2055.
618
Org. Lett., Vol. 8, No. 4, 2006

Scheme 2. Synthesis of Annelated Spiroketone 8
Scheme 4. Preparation of Functionalized Aldehydes via
Magnesiated Silylated Cyanohydrins Derived from Aldehydes
of CuCN‚2LiCl, allylations and acylations proceed smoothly.
We have found that the deprotection of the resulting silylated
cyanohydrins is best performed with CuSO4‚5H2O (1 equiv)
Scheme 3. Electrocyclic Ring Closing of 9
Grignard reagents bearing silylated cyanohydrins under very
mild conditions. Extensions of this methodology are currently
underway in our laboratories.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Boehringer-
Ingelheim (Vienna, Austria) and Chemetall GmbH (Frank-
furt, Germany) for the generous gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052792D
added. After 30 min, HCl (0.45 mL, 2.0 M) was added, and the reaction
mixture was stirred for 2 h before the addition of aqueous NH3 (2 mL).
The aqueous phase was extracted with diethyl ether (2 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by flash chromatography (pentane/
ether ) 2:3) yielded the pure product 5f (135 mg, 87%) as a yellow solid,
mp 79.8-80.4 °C.
and 1 M NaOH (room temperature, 2 h), leading to the
desired aldehydes 12a-d in 71-88% yield (Scheme 4).
In summary, we have prepared polyfunctionalized aryl-,
heteroaryl-, and cycloalkenyl-magnesium derivatives bearing
silylated cyanohydrins as masked ketones and aldehydes.
These functionalized Grignard reagents react with a range
of electrophiles in satisfactory yields, leading to polyfunc-
tional ketones and aldehydes after simple deprotection
procedures. The use of the powerful I/Mg exchange reagent
i-PrMgCl‚LiCl (4)1,8 allows generation of the intermediate
(10) Typical Procedure 2. Preparation of 12c. A dry and argon-flushed
10 mL flask, equipped with a magnetic stirrer and a septum, was charged
with a solution of 11b (196 mg, 0.5 mmol) in dry THF (0.5 mL). i-PrMgCl‚
LiCl (2.0 M in THF, 0.55 mmol) was added slowly at -78 °C, and the
resulting reaction mixture was stirred at this temperature for 0.5 h. A
complete conversion to the Grignard reagent was observed as indicated by
GC analysis of hydrolyzed reaction aliquots. THF (1.0 mL) and the solution
of CuCN‚2LiCl (0.55 mmol, 0.55 mL, 1.0 M in THF) were added at this
temperature and stirred for 15 min. 2-Furoyl chloride (0.75 mmol in 0.5
mL of THF) was added, and the reaction mixture was stirred at -78 °C for
1 h, then warmed to room temperature and stirred for 1 h before it was
quenched with aqueous ammonia (2 mL). The aqueous phase was extracted
with diethyl ether (3 × 20 mL). The organic fractions were washed with
brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The concentrated
organic fraction is dissolved in ethanol (2 mL). An aqueous solution of
NaOH (1 M, 1 mL) and CuSO4‚5H2O (0.5 mmol, 125 mg) were added to
the ethanolic solution, and the reaction mixture was stirred at room
temperature for 2 h. The aqueous phase was extracted with diethyl ether (3
× 20 mL). The organic fractions were washed with brine (10 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by flash chromatography
(eluent, pentane/ether ) 3:1) yielded the pure product 12c (108 mg, 83%)
as a solid, mp 103.6-104.0 °C.
(8) i-PrMgCl‚LiCl is commercially available from Chemetall GmbH,
Frankfurt, Germany.
(9) Typical Procedure 1. Preparation of Diketone 5f. To a solution
of 2d (217 mg, 0.46 mmol) in THF (0.35 mL) was slowly added i-PrMgCl‚
LiCl (0.26 mL, 0.51 mmol, 2.0 M in THF) at -40 °C. The reaction mixture
was stirred at -40 °C for 1 h. A complete conversion to the Grignard reagent
was observed as indicated by GC analysis of hydrolyzed reaction aliquots.
CuCN‚2LiCl (0.45 mmol, 0.45 mL, 1.0 M in THF) was added dropwise at
-40 °C, and then the reaction mixture was slowly warmed to -30 °C over
40 min. Furoyl chloride (92 mg, 0.70 mmol) in THF (0.10 mL) was added,
and the mixture was stirred at -30 °C for 1 h, then warmed to room
temperature, and stirred again for 1 h. TBAF (0.7 mL, 1.0 M in THF) was
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