On the mechanism of the directed ortho and remote metalation reactions of N,N-dialkylbiphenyl 2-carboxamides

Article abstract of DOI:10.1021/ol902268h

"Chemical Equation Presented" A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCI) to afford 6 prevents its equilibration with 7. In the absence of an electrophile,5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).

Full text of DOI:10.1021/ol902268h

ORGANIC
LETTERS
2010
Vol. 12, No. 1
68-71
On the Mechanism of the Directed ortho
and Remote Metalation Reactions of
N,N-Dialkylbiphenyl 2-carboxamides§
David Tilly,† Jian-min Fu,‡ Bao-ping Zhao,‡ Manlio Alessi,‡
Anne-Sophie Castanet,† Victor Snieckus,*,‡ and Jacques Mortier*,†
UniVersite´ du Maine and CNRS, Unite´ de Chimie Organique Mole´culaire and
Macromole´culaire (UMR 6011), Faculte´ des Sciences, aVenue OliVier Messiaen,
72085 Le Mans Cedex 9, France, and Department of Chemistry, Queen’s UniVersity,
Kingston, ON K7L 3N6, Canada
snieckus@chem.queensu.ca; jacques.mortier@uniV-lemans.fr
Received October 9, 2009
ABSTRACT
A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is
reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed
to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to
afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous
cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).
Combined directed ortho (DoM) and remote (DreM) met-
alation-cross-coupling strategies have allowed the development
of new synthetically useful methodologies for general and
regioselective routes to fluorenones, dibenzo[b,d]pyranones,
9-phenanthrols, 9-aminophenanthrenes, acridones, and related
heterocycles1 and have acted as a conduit for the synthesis of
natural products.2 In the original prototype study in this area
concerning N,N-diethyl 2-biphenyl carboxamides (Scheme 1),
metalation of 2a with s-BuLi/TMEDA (1.1 equiv) in THF at
-78 °C followed by the addition of an electrophile was shown
to afford C3-substituted derivatives 13 (DoM process), whereas,
in distinct contrast, when 2a was subjected to LDA (1.1 equiv)
at 0 °C-rt, cyclization was observed to give fluorenone 3
(84%)4 (DreM process).
(1) For leading references, see: MacNeil, S. L.; Wilson, B. J.; Snieckus,
V. Org. Lett. 2006, 8, 1133.
§ To Peter Stanetty, a Laudatio for the 60th Birthday: for dedicated
heterocyclic chemistry including new metalation directions, for joie de vivre,
and for friendship.
(2) For a review, see: Hartung, C. G.; Snieckus, V. Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: New York, 2002; p 330.
(3) (a) Sharp, M. J.; Cheng, W.; Snieckus, V. Tetrahedron Lett. 1987,
28, 5093. (b) Cheng, W.; Snieckus, V. Tetrahedron Lett. 1987, 28, 5097.
† Universite´ du Maine and CNRS.
‡ Queen’s University.
10.1021/ol902268h  2010 American Chemical Society
Published on Web 12/08/2009

Scheme 1
Scheme 2
In a parallel study aimed to enhance the synthetic utility
of the metalation chemistry of unprotected benzoic acids,5
reaction of 2-biphenyl carboxylic acid (2b) with n-BuLi/t-
BuOK (Lochmann-Schlosser base) was shown to occur in a
nonregioselective fashion to also give 3.6 To expand practical
synthetic utility for this important anionic aromatic chemistry,1,7
we have aimed at understanding and controlling the DoM/
DreM regioselectivity of these processes. Herein we report
results that lead to the first mechanistic proposal concerning
the metalation of N,N-dialkyl-2-biphenyl carboxamides.
In examination of the overall proposed general mechanism,
delineated in Scheme 2, we posed a number of questions.
To answer the question of relative stabilities and potential
interconversion of the ortho- and remote lithiated species 5
and 7, formed from 4 via complex C as generally accepted
(complex induced proximity effect, CIPE),8,9 the following
experiments were carried out (Scheme 3). First, it was
demonstrated that carboxamide 4a does not undergo depro-
tonation at -78 °C, as evidenced by its recovery upon
sequential treatment at -78 °C with 1.1 equiv of LDA in
THF and MeI or TMSCl (external quench).4 However, when
LDA (4 equiv) and TMSCl (4 equiv) were premixed in THF
solution (-78 °C) prior to addition of 4a (in situ quench
conditions),10 N,N-diethyl 3-(trimethylsilyl)biphenyl-2-car-
boxamide (6) was formed exclusively (65%).11 This experi-
ment suggests greater kinetic over thermodynamic acidity
of C-3 H compared to C-2′ H in 4a. The reaction of 5 with
TMSCl leading to 6 is faster than its equilibration to 7, which
if it had occurred, should have been evidenced in the
cyclization to 3 (k4 > k3). To fortify this result, a second
experiment was carried out in which the anion 5, prepared
by reaction of 4a with s-BuLi/TMEDA (2.2 equiv) at -78
°C,3 was allowed to warm to rt (Scheme 3). Addition of
dimethyl disulfide (external quench experiment) at this
temperature afforded N,N-diethyl 3-(methylthio)biphenyl-2-
carboxamide (9) as the sole product in 81% yield.
Scheme 3
(4) (a) Fu, J.-m.; Zhao, B.-P.; Sharp, M. J.; Snieckus, V. J. Org. Chem.
1991, 56, 1683. (b) Fu, J.-M. Ph.D. thesis, University of Waterloo, 1990.
(5) (a) Gohier, F.; Castanet, A.-S.; Mortier, J. J. Org. Chem. 2005, 70,
1501. (b) Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.;
Mortier, J. Org. Lett. 2005, 7, 2445. (c) Nguyen, T. H.; Castanet, A.-S.;
Mortier, J. Org. Lett. 2006, 8, 765.
(6) (a) Tilly, D.; Samanta, S. S.; De, A.; Castanet, A.-S.; Mortier, J.
Org. Lett. 2005, 7, 827. (b) Tilly, D.; Samanta, S. S.; Castanet, A.-S.; De,
A.; Mortier, J. Eur. J. Org. Chem. 2006, 174.
(7) Substituted biaryls are of high current interest in the development
of ligands for transition metal catalyzed reactions. For a superb compre-
hensive review, see: Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008,
41, 1461
.
(8) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b)
Whisler, M. N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int.
Ed. 2004, 43, 2206
.
(9) Riggs, J. C.; Singh, K. J.; Yun, M.; Collum, D. B. J. Am. Chem.
Soc. 2008, 130, 13709, and references therein.
(10) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155.
(11) When this reaction was carried out between 0 °C and rt with 2
equiv of LDA/TMSCl, the yield of 6 decreased to 11% yield with 85%
recovery of starting material. At 0 °C, LDA partly destroys in situ TMSCl.
However, even at this temperature, metalation of 4a leading to 5 by the
remaining LDA is competitive in rate.
Org. Lett., Vol. 12, No. 1, 2010
69

These experiments allow the conclusion that the ortho-
lithiated species 5 generated under these conditions is formed
efficiently, does not undergo self-condensation with starting
4a to form a benzophenone product as is the case for the
ortho-lithiated N,N-dialkyl benzamide12 and, significantly,
is stable to room temperature and does not equilibrate with
7 (k2 > k3).
Scheme 4
In contrast, when LDA deprotonation of 4b was carried
out at -20 °C,13 followed by addition of MeI or TMSCl at
this temperature, 10a and 10b were not formed and only
fluorenone (3) was isolated. This experiment suggests a slow
remote deprotonation step occurs to give 7, which has a short
lifetime and undergoes cyclization to 3 in a fast and
irreversible step. To corroborate this proposal and determine
the behavior of anion 7 directly, N,N-diisopropyl 2-(2′-
bromophenyl)benzamide (11) was subjected to metal-halogen
exchange (1.1 equiv of n-BuLi, THF, -78 °C, 5 min)
followed by CD3OD quench. Formation of 2′-deuterated 10c
was not observed and undeuterated fluorenone (3) was
obtained exclusively (89% yield).14 Combined, the above
results show that (1) the conversion of 5 to 7 does not occur
under the RLi/TMEDA and in situ LDA/TMSCl conditions
and (2) the LDA-mediated cyclization of independently
generated 7 to 3 is faster than the isomerization of 7 to 5 (k4
> k-3).
To demonstrate that the kinetically deprotonated anion 5
may be converted into the thermodynamically favored
carbinolamine oxide 8 through proton transfer involving DIA/
LDA, we adopted the poignant experiments of Seebach.15
Thus, biarylamide 4a was treated first with s-BuLi/TMEDA
(1.1 equiv) at -78 °C to form the stable ortho-lithiated
species 5 (Vide supra). Stirring at -78 °C was maintained
for 1 h, and 10 mol % of DIA was then added. After warming
to room temperature and normal workup, 3 was isolated in
30% yield with 70% recovery of starting material. This result
is consistent with reprotonation of 5 by DIA affording 4a,
which in turn can be deprotonated by the generated residual
LDA and give, either directly or via the postulated complex
C, remote metalated species 7. The subsequent cyclization
of 7 leading to 8 is fast and irreversible, and the LDA-
mediated equilibrium 5 h 7 is shifted toward the formation
of 7.
of alkyllithium bases to the generated 3.16 If, however, only
8 is present in solution, expectation that peri-metalated
species 12 will be formed with excess base is inferred from
our previous observations of the formation of the analogous
trianion 15a arising from 2-biphenyl carboxylic acid (2b)
using an excess of n-BuLi/t-BuOK6 to give products 16 and,
from the results of Demeter, for the closer related carbino-
lamine oxide 15b resulting from sequential reaction of 3 with
lithio N-methylpiperazide and n-BuLi followed by quench
with B(OBun)3 to afford 17 (Scheme 4).17 In the event,
reaction of 4a with 3 equiv of LDA at 0 °C followed by
addition of D2O provided the undeuterated fluorenone 3 in
an improved yield (92%) compared with that obtained in
the original experiments.4 Furthermore, when 2-4 equiv of
n-BuLi, s-BuLi, or s-BuLi/TMEDA were added to the
reaction mixture following the treatment with LDA, undeu-
terated fluorenone was also obtained in >90% yields.
The modest DMG power of the carbinolamine oxide
C(OLi)(NR2),18 as suggested by the vigorous conditions
(refluxing benzene) necessary to generate the analogous
species 15b, was considered to be the reason for the lack of
formation of peri-deuterated fluorenone 13 under our condi-
tions (3 equiv of LDA/0 °C/D2O quench). To provide further
evidence for the intermediacy of 15b and thus indirect
evidence for 12, the metalation conditions of Demeter were
reproduced, but the reaction was quenched with D2O.
1-Deutero-9H-fluoren-9-one (13) was obtained in 77% yield
and >95% d1-incorporation.14b Although conclusive evidence
has not been obtained here, we note that corroborative
support for carbinol amine intermediates in these DreM
We now sought to address the nature of the organometallic
species in the reaction mixture prior to hydrolysis. The
carbinolamine oxide 8 is potentially present in equilibrium
with fluorenone (3) by addition-elimination of LiNEt2
(Scheme 4). If this is the case, the formation of 9-butyl-9H-
fluoren-9-ol (14) is expected to some extent by the addition
(12) Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823.
(13) Tilly, D. Ph.D. thesis, Universite´ du Maine, 2004.
(14) (a) Additionally, metalation of N,N-diethyl 3-deuterio-2-biphenyl
carboxamide (d0:d1 1:99) with LDA (3 equiv) at 0 °C followed by quench
with 2 M HCl furnished, in addition to unreacted starting material (8%,
d0:d1 1:99), 1-d1-fluorenone (d0:d1 78:22, 83% yield), indicative of some
erosion of d1-content due to a KIE. 4a-3d1 was prepared by amidation of
3-deutero-2-biphenyl carboxylic acid.6b (b) Isotope ratios were determined
(16) In a separate experiment, treatment of 3 with n-BuLi (1.1 equiv)
in THF at rt afforded 14 (51% yield) as expected.
(17) Demeter, A.; Tima´ri, G.; Kotschy, A.; Be´rces, T. Tetrahedron Lett.
1997, 38, 5219.
1
by H NMR and FIMS. The error is approximated to be (5%.
(18) (a) Comins, D. L. Synlett 1992, 615. (b) For the complexity of
lithio carbinolamine oxide solid-state structures, see: Clegg, W.; Liddle,
S. T.; Snaith, R.; Wheatley, A. E. H. New J. Chem. 1998, 1323, and
references therein.
(15) (a) Laube, T.; Dunitz, J. D.; Seebach, D. HelV. Chim. Acta 1985,
68, 1373. (b) For a review, see: Seebach, D. Angew. Chem., Int. Ed. Engl.
1988, 27, 1624.
70
Org. Lett., Vol. 12, No. 1, 2010

reactions for species of the type 8 has been achieved by a
irrevesible formation of carbinolamine oxide 8, which
constitutes the thermodynamic driving force and the basis
for the success of the DreM reaction; (5) although direct
evidence for 8, most likely existing as a dimer or larger
associated complex species,21 was not obtained, the formation
of this species bearing a weak DMG prior to hydrolysis was
inferred by evidence for the generation of an analogous peri-
metalated species 15b and a React IR study on a related
biaryl 2-amide.
We believe that this mechanistic study which leads to an
advanced understanding of the ortho and remote metalation
of birarylamides will warrant a reappraisal of other known
analogous processes, provide a foundation for rational design
of new DoM and DreM reactions, and thereby may contribute
to further progress in the field of carbanionic synthetic
aromatic chemistry.
React IR study.19
In summary, the first study concerning the mechanism of
the DoM and DreM reactions of biaryl-2-carboxamide
derivatives has been carried out (Scheme 2), which allows
the following comments and conclusions: (1) the initial
generation of complex C in a fast process representative of
the well accepted CIPE8,20 is assumed; (2) ortho-lithiated
species 5, generated under s-BuLi/TMEDA or in situ LDA/
TMSCl conditions, does not undergo equilibration with 7
as evidenced by the formation of 3-substituted products 6
and 9 (Scheme 3); remote-metalated species 7, generated
independently by metal-halogen exchange of 11, does not
undergo equilibration with 5 but rather rapid cyclization to
give fluorenone (3) via the tetrahedral intermediate 8; (3)
the equilibrium between 5 and 7 via 4a is established by
generation of residual LDA (by addition of DIA) in the
solution of independently generated 5; (4) the inability to
trap 7, independently generated under typical LDA condi-
tions, by electrophiles (including D2O) and its resulting
formation of fluorenone (3) is consistent with fast and
Acknowledgment. This research was supported by the
CNRS, Universite´ du Maine, Institut Universitaire de France,
NSERC Canada (Discovery Grant), and the Government of
China (BpZ). D.T. thanks CNRS and “Re´gion Pays-de-la-
Loire” (France) for a doctoral research grant. We thank
Professors Peter Beak (University of Illinois), Stan Brown
(Queen’s University), and Marek Majewski (University of
Saskatchewan) for constructive criticism.
(19) Treatment of N,N-diethyl 4-(3-methoxy-phenyl)-nicotinamide with
LDA leads to the gradual disappearance of the amide absorption band (CdO,
ν ) 1632 cm-1) and, only after quench with MeOH, the appearance of the
azafluorenone band (CdO, ν 1718 cm-1); see: Alessi, M.; Larkin, A. L.;
Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. J. Org. Chem.
2007, 72, 1588.
Supporting Information Available: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) All reactions, whether conducted with RLi bases or LDA bases,
may proceed via CIPE. The structures of the complexes will have different
geometries and therefore different possible access to transition state
deprotonation. For example, different stoichiometries of (s-BuLi)n-
(TMEDA)m complexes can be involved in similar deprotonation reactions;
see: Hay, D. R.; Song, Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc. 1988,
OL902268H
(21) Zhao, P.; Condo, A.; Keresztes, I.; Collum, D. B. J. Am. Chem.
Soc. 2004, 126, 3113.
110, 8145
.
Org. Lett., Vol. 12, No. 1, 2010
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