Grignard reagents: Alkoxide-directed iodine-magnesium exchange at sp 3 centers

Article abstract of DOI:10.1021/ol701947y

(Chemical Equation Presented) Sequential addition of i-PrMgCl and BuLi to sp³ hybridized iodoalcohols triggers a facile iodine-metal exchange. Intercepting the resulting cyclic Grignard reagents with a slight excess of an electrophile leads to a diverse range of substituted alcohols. The iodine-magnesium exchange strategy is effective with 3-carbon iodoalcohols bearing alkyl substitutents on the carbinol or adjacent carbons and with the chain-extended homolog 4-iodobutan-1-ol.

Full text of DOI:10.1021/ol701947y

ORGANIC
LETTERS
2
007
Vol. 9, No. 22
507-4509
Grignard Reagents: Alkoxide-Directed
3
4
Iodine−Magnesium Exchange at sp
Centers
Fraser F. Fleming,*,† Subrahmanyam Gudipati, Viet Anh Vu,
Robert J. Mycka, and Paul Knochel
†
†
†
‡
Department of Chemistry and Biochemistry, Duquesne UniVersity,
Pittsburgh, PennsylVania 15282-1530 and Department Chemie,
Ludwig-Maximilians-UniVersit a¨ t, Butenandtstrasse 5-13, 81377, M u¨ nchen, Germany
flemingf@duq.edu
Received August 9, 2007
ABSTRACT
Sequential addition of i-PrMgCl and BuLi to sp3 hybridized iodoalcohols triggers a facile iodine
−metal exchange. Intercepting the resulting
cyclic Grignard reagents with a slight excess of an electrophile leads to a diverse range of substituted alcohols. The iodine
−magnesium
exchange strategy is effective with 3-carbon iodoalcohols bearing alkyl substitutents on the carbinol or adjacent carbons and with the chain-
extended homolog 4-iodobutan-1-ol.
3
Grignard reagents have remained among the most important
organometallic reagents since their discovery over 100 years
ago. The centrality of Grignard reagents stems from their
exchange processes for synthesizing sp hybridized Grignards
5
5
is significantly more challenging. A few ingenious strategies
1
3
have arisen for accessing sp hybridized Grignard reagents,
driven in part by a desire for increased functional group
tolerance and in part by the potential for generating chiral
high reactivity toward a vast array of electrophiles and their
1
facile synthesis through magnesium insertion. Recently, a
6
renaissance in the chemistry of Grignard reagents has ensued
following the discovery of magnesium exchange reactions
Grignard reagents.
3
A conceptually appealing route to sp hybridized Grignard
2
at low temperatures. The significance of this transformation
reagents is via an intramolecular halogen-metal exchange
in which a pendant alkoxy group facilitates reagent delivery.
Related lithium-halogen, -sulfur, and -tellurium ex-
change processes with haloalcohols generate nucleophilic
reagents and avoid the requirement for hydroxyl protection.11
7
lies in providing Grignard reagents capable of incorporating
3
8
9
10
an array of otherwise incompatible functionality.
2
4
Halogen-magnesium and sulfoxide-magnesium ex-
change strategies provide efficient routes to a diverse range
2
of sp hybridized Grignard reagents. By contrast, the use of
(
5) (a) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed.
2
006, 45, 606. (b) Vu, V. A.; Marek, I.; Polborn, K.; Knochel, P. Angew.
†
Duquesne University.
Ludwig-Maximilians-Universit a¨ t.
Chem., Int. Ed. 2002, 41, 351. (c) Inoue, A.; Shinokubo, H.; Oshima, K.
Org. Lett. 2000, 2, 651. (d) Hoffmann, R. W.; H o¨ lzer, B.; Knopff, O.;
Harms, K. Angew. Chem., Int. Ed. 2000, 39, 3072. (e) Schulze, V.;
Hoffmann, R. W. Chem.-Eur. J. 1999, 5, 337. (f) Avolio, S.; Malan, C.;
Marek, I.; Knochel, P. Synlett 1999, 1820. (g) Satoh, T.; Tokano, K.; Ota,
H.; Someya, H.; Matsuda, K.; Koyama, M. Tetrahedron 1998, 54, 5557.
(h) Hoffmann, R. W.; Nell, P. G. Angew. Chem., Int. Ed. 1999, 38, 338.
(6) Hoffmann, R. W. Chem. Soc. ReV. 2003, 32, 225.
(7) For a summary of related functionalized organolithiums, see: Najera,
C.; Yus, M. Curr. Org. Chem. 2003, 7, 867. For a first report of Mg insertion
with pendant magnesium alkoxides, see: Cahiez, G.; Alexakis, A.; Normant,
J. F. Tetrahedron Lett. 1978, 3013.
‡
(
1) (a) Grignard Reagents: New DeVelopments; Richey, H. G., Jr., Ed.;
Wiley: Chichester, 2000. (b) Handbook of Grignard Reagents; G. S.
Silverman, G. S., Rakita, P. E., Eds.; Dekker: New York, 1996.
(
2) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
303.
3) Handbook of Functionalized Organometallics: Applications in
Synthesis; Knochel, P., Ed.; Wiley-VCH: Chichester, 2005.
4) Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.; Koyama,
M. Tetrahedron 1998, 54, 5557.
4
(
(
1
0.1021/ol701947y CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/05/2007

Exploring the viability of an alkoxide-directed halogen-
magnesium exchange employed iodopropanol as a prototype
because of the proven utility of the resulting nucleophiles.
Table 1. Sequential Mg-I Exchange and Alkylation of
1
2
3-Iodopropan-1-ol
Screening numerous organolithium and Grignard reagent
combinations revealed a distinct benefit in first generating
the magnesium alkoxide 2 (Scheme 1) rather than the
3
Scheme 1. Intramolecular Exchange Route to sp Hybridized
Grignard Reagents
corresponding lithium alkoxide. Apparently, the magnesium
alkoxide is less succeptable toward cyclization to the oxetane
than the corresponding lithium alkoxide. Intensive optimiza-
tion led to a procedure in which addition of i-PrMgCl to a
-
78 °C THF solution of iodopropanol is followed by 2 equiv
of butyllithium, by far the most effective organolithium
13
reagent for promoting the halogen-metal exchange (Scheme
). Intercepting the resulting organometallic reagent 3a with
1
a slight excess (1.4 equiv) of cyclohexanone provided the
diol 4a in 71% yield. Remarkably, the clean reaction is
accompanied by only a small amount of the alcohol 5
resulting from resulting from butyl addition. The selective
nucleophilic addition of the alkoxypropyl group is consistent
with formation of the cyclic Grignard reagent 3a.
Intercepting the Grignard reagent 3a with a variety of
electrophiles effectively provides a diverse array of func-
tionalized alcohols (Table 1). Aliphatic and aromatic ketones
and aldehydes smoothly react with 3a to afford the corre-
sponding diols (Table 1, entries 1-5) with ethyl 2-methyl-
a
Accompanied by 41% of 1-phenylpentan-1-ol resulting from butyl
addition. b Required 2.5 equiv of PhSO2SPh.
3
-oxobutyrate generating the alcohol 4b resulting from
selective addition to the more electrophilic ketone carbonyl
Table 1, entry 2). Sulfenylation of the intermediate Grignard
is the only case requiring an excess of the electrophile,
affording the corresponding sulfide 4g and phenylbutyl
sulfide (Table 1, entry 6). An efficient and selective conjugate
addition ensues in the reaction of 3a with benzylidene
malononitrile to afford 4g (Table 1, entry 7).
(
The intramolecular iodine-magnesium exchange strategy
is equally applicable in generating several homologous sp3
hybridized Grignard reagents (Table 2). Iodine-magnesium
exchange with the chain-extended 4-carbon iodoalcohol 5a
provides an intermediate capable of effectively intercepting
carbon and sulfur electrophiles (Table 2, entries 1-3).
Substituents are tolerated within the propanol scaffold at the
carbinol carbon or on the adjacent carbon, although the
efficiency of the reaction is diminished relative to the
unsubstituted parent system (compare Table 2, entries 4-7
with Table 1, entries 1, 5, and 6). Control experiments
indicate that substituents facilitate internal iodide displace-
(
8) (a) Barluenga, J.; Montserrat, J. M.; Florez, J. J. Org. Chem. 1993,
8, 5976. (b) Barluenga, J.; Rubiera, C.; Fernandez, J. R.; Florez, J.; Yus,
M. Synthesis 1987, 819. (c) Barluenga, J.; Florez, J.; Yus, M. Synthesis
983, 378.
9) (a) Mudryk, B.; Cohen, T. J. Org. Chem. 1991, 56, 5760. (b) Mudryk,
B.; Cohen, T. J. Am. Chem. Soc. 1991, 113, 1866.
10) (a) Dos Santos, A. A.; Princival, J. L.; Comasseto, J. V.; de Barros,
5
1
(
(
S. M. G.; Brainer, Neto, J. E. Tetrahedron 2007, 63, 5167. (b) Princival, J.
L.; de Barros, S. M. G.; Comasseto, J. V.; Dos Santos, A. A. Tetrahedron
Lett. 2005, 46, 4423.
2
(11) Several recent protocols describe the formation of sp hybridized
organometallics containing hydroxyl or carboxyl functionality: (a) Kopp,
F.; Wunderlich, S.; Knochel, P. Chem. Commun. 2007, 2075. (b) Uchiyama,
M.; Furuyama, T.; Kobayashi, M.; Matsumoto, Y.; Tanaka, K. J. Am. Chem.
Soc. 2006, 128, 8404. (c) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem.
Commun. 2004, 2288. (d) Kato, S.; Nonoyama, N.; Tomimoto, K.; Mase,
T. Tetrahedron Lett. 2002, 43, 7315.
1
4
ment to oxiranes and oxetanes, consistent with the known
(
12) Oshima, K. Sci. Synth. 2004, 7, 573.
15
propensity of alkyl substitution to promote cyclization.
(13) Phenyllithium and MeLi are unable to promote the reaction whereas
EtLi and t-BuLi were significantly inferior to the use of BuLi. Employing
equiv of ethylhexyllithium, trimethylsilylmethyllithium, or hexyllithium
or 1 equiv and an additional equivalent of BuLi and alkylating with
2
(14) Sequential deprotonation and protonation of 1, 5b, and 5c at -78
°C leads to diminishing recovery with 1-iodo-2,2,4-trimethylpentan-3-ol
affording only 2-isopropyl-3,3-dimethyloxetane.
cyclohexanone as a test electrophile affords 4a in 34-50% yield.
4508
Org. Lett., Vol. 9, No. 22, 2007

3
Table 2. Mg-I Exchange and Alkylation of Substituted
Scheme 2. I-Mg Exchange of sp Hybridized Alkyliodides
Iodoalcohols
18
exchange to afford the organolithium 9 prior to reorganiza-
1
7
tion to the magnesium ate complex 10.
Conceptually, the more basic butyl group in the ate
complex 10 might be selectively consumed by engaging the
co-generated butyliodide in an E elimination. Alternatively,
2
an equilibrium between the magnesiate 10 and cyclic
Grignard 3a might be displaced in favor of 3a by consump-
tion of iodobutane by the butyllithium released from the ate
complex. Intercepting the intermediate Grignard reagents
with electrophiles is, in some cases, compromised by
competitive butyl addition to the electrophile (Table 1, entries
5
and 6, and Table 2, entries 2, 3, 5, and 6), suggesting
incomplete consumption of butyllithium prior to alkylation
with the electrophile (Scheme 2). The use of only 1 equiv
of BuLi leads to incomplete iodine-metal exchange.
Alkoxide-directed iodine-magnesium exchange of iodo-
alchohols provides a valuable strategy for accessing sp3
hybridized Grignard reagents. The exchange proceeds rapidly
at -78 °C affording cyclic alkylmagnesium alkoxides that
selectively intercept a range of electrophiles to afford
functionalized alcohols. Conceptually, the alkoxide-directed
a
Required 2.5 equiv of electrophile. b Accompanied by 33% of 1-phen-
exchange strategy provides a valuable synthesis of sp3
c
ylpentan-1-ol resulting from butyl addition. Accompanied by 31% of
-butylcyclohexanol resulting from butyl addition.
1
hybridized Grignard reagents of direct relevance in synthe-
sizing functionalized and chiral Grignard reagents.
Mechanistically the exchange is envisaged to proceed
Acknowledgment. Financial support from the National
Science Foundation (CHE 0515715, 0421252 HRMS, and
0614785 for NMR facilities) is gratefully acknowledged.
through the magnesium alkoxide 2 (Scheme 2). Sequential
chlorine-butyl exchange16 and butyl addition could afford
the electron rich magnesiate 8 from which an iodine-butyl
17
Supporting Information Available: Experimental pro-
exchange would directly generate the cyclic magnesiate 10.
1
13
cedures and H NMR and C NMR spectra for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Alternatively, iodide activation through internal complexation
to magnesium could facilitate a directed iodine-lithium
(
15) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735.
OL701947Y
(16) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc.
1
990, 112, 9393.
17) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed.
006, 45, 159.
(
(18) (a) Klumpp, G. W. Recl. TraV. Chim. Pays-Bas 1986, 105, 1. (b)
Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106, 3693.
2
Org. Lett., Vol. 9, No. 22, 2007
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