Mechanism of acylation of lithium phenylacetylide with a Weinreb amide

Article abstract of DOI:10.1021/jo061223w

Additions of lithium phenylacetylide to a Weinreb amide are described. Dimeric lithium acetylide reacts via a monosolvated monomer-based transition structure. The robust tetrahedral intermediate forms sequentially a C ₁ 2:2 mixed tetramer with

Full text of DOI:10.1021/jo061223w

Mechanism of Acylation of Lithium
Phenylacetylide with a Weinreb Amide
monomer-based mechanism. A pronounced autoinhibition is
traced to a mixed tetramer composed of intermediate 2 with
4
lithium phenylacetylide (PhCCLi).
Bo Qu and David B. Collum*
Contribution from the Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
dbc6@cornell.edu
Monitoring the addition of PhCCLi to Weinreb amide 1 using
in situ IR spectroscopy provides qualitative insights. Amide
5
ReceiVed June 14, 2006
6
1
does not appreciably complex PhCCLi in all THF/pentane
mixtures studied, as evidenced by the absence of a shift in the
carbonyl absorbance. Reaction of 1.0 equiv of PhCCLi with 1
at -50 °C stalls at 50% conversion. The absence of a new
carbonyl absorbance is consistent with a stable tetrahedral
intermediate. Warming to 20 °C results in the slow consumption
of the starting carboxamide. In contrast, g2.0 equiv of PhCCLi
in 3.0 M THF/pentane causes complete consumption of 1 at
Additions of lithium phenylacetylide to a Weinreb amide
are described. Dimeric lithium acetylide reacts via a mono-
solvated monomer-based transition structure. The robust
-
50 °C within 1.0 h, affording ketone 3 in 90-95% yield.
-1
Under no conditions is ketone 3 (1671 cm ) detectable in the
IR spectrum before quenching, nor is the tertiary alcohol
resulting from double addition detected after quenching.
The source of the apparent autoinhibition was ascertained
1
tetrahedral intermediate forms sequentially a C 2:2 mixed
tetramer with the excess lithium acetylide and a 1:3 (alkox-
ide-rich) mixed tetramer. The stabilities of the mixed
tetramers are consistent with a pronounced autoinhibition.
6
13
using Li and C NMR spectroscopy. Broadband-decoupled
6
6
13
Li NMR spectra recorded on mixtures of 1 and excess [ Li, C]-
7
PhCCLi reveal the resonances corresponding to dimeric
6
13
7,8
[
Li, C]PhCCLi (4) along with four new resonances in a 1:1:
Acylations of organolithiums and organomagnesium reagents
13
1
:1 ratio (Figure 1). C NMR spectra reveal the resonance of
1
to form ketones is of central importance in organic synthesis.
4
along with two new complex multiplets (1:1) corresponding
Among the many acylating reagents, the so-called Weinreb
to the labeled C1 of the PhCCLi fragments. Deconvolution of
2
amides (1) have moved to center stage. Although it seems likely
6
13
1
6
13
the complex Li- C coupling using J( Li, C)-resolved NMR
that the methoxy moiety facilitates the nucleophilic attack both
inductively and through chelation, the mechanism of acylation
is largely unknown. Suggestions that putative tetrahedral
8
spectroscopy (Figure 1) aided by single-frequency decouplings
revealed Li-C connectivities consistent with the 2:2 mixed
tetramer 5 with C1 symmetry (Supporting Information).
1
,3
intermediate (2) are supported by limited indirect evidence.
We show herein that the acylation in eq 1 proceeds via a
(
1) For excellent leading references to acylations in synthesis and a
detailed discussion of putative tetrahedral intermediates in acylation reactions
including a discussion of addition to Weinreb amides), see: Adler, M.;
Adler, S.; Boche, G. J. Phys. Org. Chem. 2005, 18, 193.
2) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Review: Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000,
42, 340. (c) For representative acylations of lithium acetylides using
(
(
3
Weinreb amides, see: Bagley, M. C.; Chapaneri, K.; Dale, J. W.; Xiong,
X.; Bower, J. J. Org. Chem. 2005, 70, 1389; Shin, Y.; Fournier, J.-H.; Fukui,
Y.; Br u¨ ckner, A. M.; Curran, D. P. Angew. Chem., Int. Ed. 2004, 43, 4634;
Masi, S.; Top, S.; Boubekeur, L.; Jaouen, G.; Mundwiler, S.; Spingler, B.;
Alberto, R. Eur. J. Inorg. Chem. 2004, 2013; Schwartz, B. D.; Hayes, P.
Y.; Kitching, W.; De Voss, J. J. J. Org. Chem. 2005, 70, 3054.
(
3) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
1
10, 2506; Jeong, I. H.; Jeon, S. L.; Min, Y. K.; Kim, B. T. Tetrahedron
Lett. 2002, 43, 7171; Jeong, I. H.; Jeon, S. L.; Kim, M. S.; Kim, B. T. J.
Fluorine Chem. 2004, 125, 1629; Sibi, M. P.; Marvin, M.; Sharma, R. J.
Org. Chem. 1995, 60, 5016; Jackson, M. M.; Levett, C.; Toczko, J. F.;
Roberts, J. C. J. Org. Chem. 2002, 67, 5032.
(5) Rein, A. J.; Donahue, S. M.; Pavlosky, M. A. Curr. Opin. Drug
DiscoV. DeV. 2000, 3, 734.
(4) (a) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E.
J. J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028. (b)
Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten, G. Angew. Chem., Int.
Ed. 2005, 44, 1448. (c) Tchoubar, B.; Loupy, A. Salt Effects in Organic
and Organometallic Chemistry; VCH: New York, 1992; Chapters 4, 5,
and 7. (d) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (e)
Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem.-Eur. J. 2003, 9,
(6) The absorbance of 1 is solvent dependent in the absence of lithium
-
1
-1
salts, varying from 1681 cm in neat pentane to 1663 cm in neat THF.
(7) (a) Fraenkel, G.; Stier, M. Prepr. Pap.-Am. Chem. Soc., DiV. Fuel
Chem. 1985, 30, 586. (b) Jackman, L. M.; Scarmoutzos, L. M.; DeBrosse,
C. W. J. Am. Chem. Soc. 1987, 109, 5355.
(8) Briggs, T. F.; Winemiller, M. D.; Collum, D. B.; Parsons, R. L., Jr.;
Davulcu, A. K.; Harris, G. D.; Fortunak, J. D.; Confalone, P. N. J. Am.
Chem. Soc. 2004, 126, 6291.
5
70. (f) Hsieh, H. L.; Quirk, R. P. Anionic Polymerization: Principles and
Practical Applications; Marcel Dekker: New York, 1996.
1
0.1021/jo061223w CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/02/2006
J. Org. Chem. 2006, 71, 7117-7119
7117

FIGURE 3. Plot of kobsd vs [PhCCLi] for acylation of PhCCLi with 1
0.005 M) in 6.0 M THF and pentane cosolvent at -50 °C. The curve
(
b
depicts an unweighted least-squares fit to kobsd ) a[PhCCLi] [a )
(
6
13
FIGURE 1. J( Li, C)-resolved NMR spectrum recorded on 0.05 M
-3
3.5 ( 0.2) × 10 , b ) 0.53 ( 0.04].
6
13
[
Li, C]PhCCLi and 0.05 M 1 in 9.60 M THF/pentane at -110 °C
after warming to -40 °C.
q
FIGURE 4. [(CH
3 2
C(dO)NMe(OMe)(PhCCLi)(Me O)] calculated
with density functional theory (B3LYP method and 6-31G* basis set).
q
∆
2 2 4
G ) 28 kcal/mol from (PhCCLi) (Me O) as the reference state.
and half-order PhCCLi dependence (Figures 2 and 3) afford
the idealized rate law in eq 2, consistent with a monosolvated
q
monomer-based transition structure, [(PhCCLi)(THF)(1)] . Den-
FIGURE 2. Plot of kobsd vs [THF] for acylation of PhCCLi (0.10 M)
with 1 (0.005 M) in pentane cosolvent at -50 °C. The curve depicts
sity functional theory computations (B3LYP method and 6-31G*
10
n
basis set) using a simplified model system afforded a transition
an unweighted least-squares fit to kobsd ) a[THF] [a ) (8.5 ( 0.9) ×
-
3
3
1
0
, n ) -1.22 ( 0.06].
structure akin to that proposed by Weinreb with an η -
coordinated substrate (Figure 4). The mechanism of additions
deriving from the mixed-aggregates is unknown.
Although we were somewhat surprised that the C2V isomer
6) was not formed, both the C1 and the C2V isomers have been
(
1
/2
-1
1
observed for structurally similar lithium acetylide-lithium amino
alkoxide mixed aggregates.8 Failure to resolve diastereomers
resulting from the stereogenic centers within the chelates is not
surprising. Further warming to 0 °C converted 2:2 mixed
-d[1]/dt ) k[PhCCLitotal] [THF] [1]
(2)
,9
Autoinhibition due to highly stabilized mixed aggregates
4
appears to be prevalent, which explains why so many orga-
6
tetramer 5 into a new species displaying three Li doublets and
nolithium reactions require excess organolithium reagent.
Conversely, mixed aggregation might also stabilize tetrahedral
intermediate 2, precluding formation of tertiary alcohol resulting
from double addition. We close with a caveat: The results
described above may be generalswe suspect that they ares
but they currently apply to a single substrate-organolithium-
solvent combination: Structural and mechanistic diversity are
the norm within organolithium chemistry.
a singlet (1:1:1:1), consistent with mixed tetramer 7.
Rate studies were carried out under pseudo-first-order condi-
tions using Weinreb amide 1 at low (0.005 M) concentrations.
The PhCCLi and THF were maintained at high, yet adjustable,
concentrations with pentane as the cosolvent. PhCCLi is dimeric
under all conditions used.7 The loss of 1 was monitored using
in situ IR spectroscopy. An inVerse-first-order THF dependence
,8
(
9) Parsons, R. L., Jr.; Fortunak, J. M.; Dorow, R. L.; Harris, G. D.;
Experimental Section
Kauffman, G. S.; Nugent, W. A.; Winemiller, M. D.; Briggs, T. F.; Xiang,
6
6
13
B.; Collum, D. B. J. Am. Chem. Soc. 2001, 123, 9135.
NMR Spectroscopic Analyses. [ Li]PhCCLi and [ Li, C]-
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
PhCCLi were prepared and recrystallized in pentane using recrys-
tallized [ Li]LiHMDS and commercially available phenylacetylene
and [ C-1]phenylacetylene. All samples were prepared under
helium using stock solutions, sealed under partial vacuum, and
stored in a liquid nitrogen bath prior to analysis. Standard Li and
C NMR spectra were recorded on a 500 MHz spectrometer at
3.7 and 125.0 Hz, respectively. The Li resonances were referenced
to 0.3 M [ Li]LiCl/MeOH at -90 °C (0.0 ppm). The spectra were
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh,
PA, 1998.
6
11
13
6
1
3
6
7
6
(11) Romesberg, F. E.; Bernstein, M. P.; Gilchrist, J. H.; Harrison, A.
T.; Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1993, 115, 3475.
7
118 J. Org. Chem., Vol. 71, No. 18, 2006

recorded with a three-channel probe designed to accommodate
lithium and carbon pulses. The tube was transferred from the liquid
nitrogen bath to a -78 °C bath to thaw the solution and then was
quickly transferred into the spectrometer and shimmed off the proton
spectrum.
30 s for 5 half-lives. The rates of acylation of lithium phenylacetyl-
ide with Weinreb amide 1 were monitored by following the loss
of 1. The disappearance of the amide 1 was fit to the equation y )
bx
ae + c. Term c is a measure of the absorbance remaining at t )
∞, which is typically a positive number at e5% of a.
IR Spectroscopy. IR spectra were recorded using an in situ IR
5
spectrometer fitted with a 30-bounce silicon-tipped probe. The IR
Acknowledgment. We thank the National Science Founda-
tion for direct support of this work as well as Dupont
Pharmaceuticals, Merck Research Laboratories, Pfizer, Sanofi-
Aventis, R. W. Johnson, Schering-Plough, and Boehringer-
Ingelheim for indirect support.
probe was inserted through a nylon adapter and FETFE O-ring seal
into a cylindrical flask fitted with a magnetic stir bar and T-joint.
The T-joint was fitted with a nitrogen line and septum for injections.
The flask was heated under full-vacuum and flushed twice with
nitrogen. PhCCLi was weighted in a glovebox and dissolved in
THF before syringe-transferred to the IR vessel. Pentane was added
to the vessel to make the total volume 10 mL. The solution was
cooled to -50 °C in a thermostated bath for 25 min. A background
spectrum was recorded, followed by addition of 0.05 mL of a 1.0
M stock solution of 1 while stirring. Spectra were recorded every
Supporting Information Available: NMR and IR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO061223W
J. Org. Chem, Vol. 71, No. 18, 2006 7119