Suppressing the anionic fries rearrangement of aryl dialkylcarbamates; the isolation of a crystalline ortho-deprotonated carbamate

Article abstract of DOI:10.1002/ejoc.200701096

In the presence of organolithium bases phenyl dialkylcarbamates have previously been shown to undergo facile rearrangement to yield the corresponding salicylamides. However, heterometallic lithium diethyl(2,2,6,6- tetramethylpiperidido)zincate achieves th

Full text of DOI:10.1002/ejoc.200701096

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200701096
Suppressing the Anionic Fries Rearrangement of Aryl Dialkylcarbamates;
the Isolation of a Crystalline ortho-Deprotonated Carbamate
Felipe García,[a] Mary McPartlin,[a] James V. Morey,[a] Daisuke Nobuto,[b]
Yoshinori Kondo,[c] Hiroshi Naka,[c] Masanobu Uchiyama,*[d,e] and
Andrew E. H. Wheatley*[a]
Keywords: Carbamates / Directed ortho-metalation / Lithium / Zincates
In the presence of organolithium bases phenyl dialkylcarb-
NMe2}{Zn(µ-TMP)Et}Li]2 having been structurally charac-
amates have previously been shown to undergo facile re- terized. DFT studies point to a stepwise deprotonative
arrangement to yield the corresponding salicylamides. How-
ever, heterometallic lithium diethyl(2,2,6,6-tetramethylpiper-
idido)zincate achieves the clean directed ortho-metallation
(DoM) of phenyl dialkylcarbamates, with [C6H4{OC(O)-
mechanism in which the zincate reagent exhibits kinetic
amido basicity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Strategies aimed at achieving directed ortho-metalation Whilst our understanding of these systems has, therefore,
(DoM) have been developed over a number of years,[1] and increased, it is nonetheless apparent that structural studies
now represent a core tool in the elaboration of complex on ortho-zincation have so far focused on systems in which
aromatic compounds. While organolithium reagents have ortho deprotonation is also achievable using organolithium
historically been used to achieve this chemistry, their nu- reagents (e.g., tertiary amides, anisoles).[4,5] We therefore
cleophilicity has brought with it the risk of competing reac- considered that we might harness the recorded stability of
tions at the directing group. The need to circumvent this intermediary aromatic zincates (relative to their lithium an-
issue has led to the design of the heterometallic bases alogues) and utilise their documented ability to form
R2Zn(TMP)Li [R = Et, tBu (1); TMP = 2,2,6,6-tetrameth- cleanly and without complications from subsequent re-
ylpiperidide]. These have been successfully used to elaborate arrangement[6] or side-reactions[7] to achieve DoM in a sys-
functionalised aromatic compounds incorporating directing tem where the isolation of an ortho-lithiated intermediate
groups normally susceptible to nucleophilic degradation.[2] was not viable.
Moreover, initial questions over whether these bases effect
alkyl or amido basicity[3] appear to have now been resolved,
with recent density functional theory (DFT) work establish-
ing the view that they exhibit a kinetic preference for amido
ligand exchange[4] according to a stepwise reaction mecha-
nism.[4c] We have also used this idea to explain the experi-
mentally observed polybasicity of 1 (R = Et, tBu).[4c,5]
DoM involving amide-type functional groups (e.g., sec-
ondary and tertiary amides, carbamates and oxazolines) has
revolutionised the synthesis of aromatic compounds. More-
over, the amide-type directing groups mentioned are among
the best directors of reaction; and carboxylic amide and
oxazoline DoM has recently undergone structural study in
the context of deprotonation by organolithium reagents.[8]
However, spontaneous anionic Fries rearrangement of the
ortho-lithiate (Scheme 1) means that the same cannot be
said of carbamate DoM.[9] Hence, whilst aryl dialkylcarb-
amates are the most effective directors of lithiation, the
N,N-dimethyl analogue undergoes facile rearrangement at
–78 °C to yield the corresponding salicylamide.[10] While
this may be controlled by employing diethylcarbamates at
–78 °C, carbamoyl rearrangement still occurs on warm-
ing.[1a,10] Further manipulation of the rearrangement pro-
cess can be effected by utilizing bulky NR2 groups. How-
ever, this makes subsequent deprotection more de-
manding.[9] Overall, the carbamoyl translocation is so ubi-
quitous, that synthetic applications of aryl carbamates have
focused on tandem ortho-lithiation/anionic Fries rearrange-
[a] Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, U.K.
E-mail: aehw2@cam.ac.uk
[b] Graduate School of Pharmaceutical Sciences, The University of
Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
[c] Graduate School of Pharmaceutical Sciences, Tohoku Univer-
sity,
Aramaki Aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan
[d] Advanced Elements Chemistry Laboratory, RIKEN,
2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
E-mail: uchi_yama@riken.jp
[e] School of Biomedical Science, Tokyo Medical and Dental Uni-
versity,
2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
644
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 644–647

Crystalline ortho-Deprotonated Carbamate
ment.[11] However, by utilizing a heterometallic base de-
signed to target intermediary aromatic metalates resistant
to subsequent rearrangement, we can now report the first
structural investigation of ortho-metalated aryl dialkyl-
carbamates that resist anionic Fries rearrangement at room
temperature.
Scheme 1.
Figure 1. The crystallographic dimer (3)2 shown at 40% probability
and with lattice toluene and hydrogen atoms omitted. Selected pa-
rameters [Å, °]: C10–Zn1 2.008(5), C16–Zn1 2.055(4), N1–Zn1
2.033(4), N1–Li1 2.057(8), O1–Li1 2.003(8), O1A–Li1 1.940(7);
Zn1–C16–C15 126.6(3), N1–Zn1–C16 110.33(15), Zn1–N1–Li1
85.6(2), N1–Li1–O1 128.5(4), N1–Li1–O1A 139.6(4), C16–C15–
O2–C14 83.13(46).
The treatment of HTMP with nBuLi and Et2Zn in THF
at –78 °C under N2 yielded 1Et (= 1; R = Et) in situ. Injec-
tion of phenyl dimethylcarbamate (2) afforded a solution
that was warmed to room temperature and stirred for 2 h
to give a red emulsion. This was concentrated to give an oil
that was taken up in toluene and stored at –30 °C to yield
crystals (Scheme 2). Analysis of this material by X-ray dif-
fraction revealed a dimer of [C6H4{OC(O)NMe2}{Zn(µ-
TMP)Et}-2]Li (3) (there resided one molecule of disordered
lattice toluene per dimer).[12] We were pleased to observe
that, in contrast to previous reports on the rearrangement
of aryl dialkylcarbamates, employment of 1Et allowed reten-
tion of the directing group in spite of the use of an N,N-
dimethylated system. The carbamate unit is twisted nearly
perpendicular to the aryl moiety [C16–C15–O2–C14
83.13(46)°, Figure 1], the ortho position of which is zincated
[2.055(4) Å] to give an dialkyl(aryl)zincate ion. The alkali
metal ion is coordinated both by the carbamoyl O-center
[2.003(8) Å] and the bridging TMP ligand [N1–Zn1
2.033(4) Å, N1–Li1 2.057(8) Å]. Unlike in sodium complex
[C6H4{C(O)NMe2}{Zn(TMP)(tBu)}-2]Na·TMEDA, where
a polydentate Lewis base precludes association,[5] further
support of the Li+ ion in 3 comes from dimerization [Li1–
O1A 1.940(7) Å in (3)2]. Moreover, the structure of 3 con-
trasts with those of previously noted ortho-lithiated aro-
matic amides[8a,8c] in that external solvent is excluded, pre-
sumably by virtue of the crowding effects of TMP and the
NMe2 groups. Instead, and consistent with previous obser-
vation,[2c] weak support of the alkali metal is provided by
the zincated aromatic carbon atom [2.600(8) Å]. We are not
aware of any structural data in the literature on ortho-de-
protonated aryl carbamates, though oxidative addition has
afforded the bis(PPh3) solvate of ortho-metalated ArPdI
{Ar = C6H4[OC(O)N(Me)(CH2CH=CH2)]}.[13]
As in recent examples of the employment of zincate ba-
ses[3,4c] DoM has occurred with overall alkane elimination.
Based on theoretical work that points to a stepwise depro-
tonative mechanism whereby amine elimination is followed
by re-coordination at the alkali metal atom with subsequent
alkane loss,[4c] we considered that both electronic and steric
effects must influence the composition of any isolated orga-
nometallic compound. This prompted us to extend our re-
cent calculations on directed metallation[4c] to also consider
the relative favourabilities of external solvation of the
monomer (e.g. 3·sol) versus dimerisation (viz. 32).[12]
The competition between ligand transfer preferences was
investigated, the conversions of reagents (RT) into pre-reac-
tion complexes (CP) and products (PD) being optimized at
the B3LYP/631SVPs level (Scheme 3).[14] Modeling of direct
bridging-alkyl transfer and the conversion of MeZn(Me)-
(NMe2)Li·OMe2 (RT1) into MeZn(Ar)(NMe2)Li·OMe2
[PD1; ArH = PhOC(=O)NMe2] revealed an exothermic
(∆G = –23.6 kcal/mol) profile with a high activation barrier
(∆G‡ = +41.4 kcal/mol). In contrast, stepwise amido ligand
exchange (CP2 Ǟ TS2) followed by coordination of gener-
ated HNMe2 (PD4) at the Li+ ion in Me2Zn(Ar)Li·OMe2
(PD3), with subsequent alkane loss affording PD1, showed
a low activation barrier for the initial deprotonation (∆G‡
= +23.2 kcal/mol). While this process was nominally endo-
thermic (∆G = +0.6 kcal/mol), it was clearly kinetically pre-
ferred to direct alkyl exchange. Moreover, and consistent
with the observation of 3, the recombination of PD3 and
PD4 was significantly exothermic (∆G = –24.1 kcal/mol,
∆G‡ = +19.5 kcal/mol).
The formation of a dibasic structure type, synonymous
with that recently noted for RZn(µ-Ar)2Li·2L [R = tBu, Ar
= C6H4C(O)N(iPr)2-2, L = 0.5(TMEDA) (4a); R = Et, Ar
= C10H6C(O)N(iPr)2-2, L = THF (4b)][4c,5] was computed
by modeling the reaction of PD1 with PhOC(=O)NMe2.
The data revealed a kinetically plausible (∆G‡ = +13.3 kcal/
mol) but significantly endothermic process (∆G = +9.5 kcal/
mol).[12] In line with this, experimental observation tells us
Scheme 2.
Eur. J. Org. Chem. 2008, 644–647
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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645

M. Uchiyama, A. E. H. Wheatley et al.
SHORT COMMUNICATION
Scheme 3. Calculated structures and Gibbs free energy changes [kcal/mol] (B3LYP/631SVPs level) for carbamate ortho-zincation.
that, for 1Et + 2, monobasicity dominates with 3 dimerising major component was non-rearranged 2-iodophenyl di-
instead. Dimerisation was computed to be nominally exo- methylcarbamate (6) (53.5%). The data improved dramati-
thermic (∆G = –0.4 kcal/mol for the aggregation of PD1 cally when 2 was replaced by its analogue, phenyl diethyl-
with the concomitant loss of two Me2O molecules).[12] The carbamate (7). While the ortho-lithiate of 7 is known to con-
ramifications of aggregation appear pronounced; the dual vert cleanly to 2-iodophenyl diethylcarbamate (8) at –78 °C,
action of TMP and the NMe2 groups remove both the elec- it undergoes Fries rearrangement to give 2-hydroxy-N,N-
trostatic need and space for ether solvation (vide supra), diethylbenzamide (9) if allowed to exceed this tempera-
and it also prevents the coordination (at Li+) of unreacted ture.[1a] In contrast, reaction of 7 with 1Et (1 equiv.) at room
carbamate. This prevents initial complex formation (viz. temperature revealed the complete suppression of re-
CP1/2) and suggests that, like the presence of strong Lewis arrangement and gave only non-rearranged 8 (53%) and
base additives,[4c] aggregation acts to limit intermediary starting material 7 (47%). The use of excess zincate reagent
zincate reactivity.
has been shown to encourage higher yields in the past,[2]
1
A H NMR spectroscopic analysis of 3 in [D8]THF re- and in an attempt to encourage reaction we now employed
veals three species in solution at room temperature (labeled 2 equiv. of 1Et, while stirring the reaction mixture at room
#1–#3, see Exp. Sect.).[12] The first of these (#1) is consis- temperature for 6 h. Analysis of the product revealed com-
tent with limited reformation of carbamate 2 on dissol- plete elimination of Fries rearrangement and essentially
ution. This phenomenon, which we have observed before in quantitative conversion of 7 into 8 (Ͼ 99% by NMR spec-
the study of ortho-deprotonated aromatic systems,[8c] could troscopy, Scheme 4).[12]
not be eradicated in spite of repeated spectroscopic exami-
nations. The remaining species (#2, #3) analyze as 3 and
are tentatively attributable to different aggregation states.
Heating of the sample to 50 °C followed by reacquisition of
the spectrum at room temperature reveals that these species
are replaced by a fourth species (#4). These data point to
the Fries rearrangement of ortho-zincate 3 and, consistent
1
with this notion, H NMR spectroscopy on aliquots ob-
Scheme 4.
tained from the hydrolytic workup of solutions of 3 in THF
reveal signals attributable only to 2 and rearranged 2-hy-
In conclusion, we have presented the first structural evi-
droxy-N,N-dimethylbenzamide (5) irrespective of whether dence for an ortho-deprotonated aryl dialkylcarbamate ob-
the solution was exposed to only room temperature or ele- tained by DoM. This has been achieved through the tar-
vated temperatures. We observed consistent behaviour dur- geted use of a heterometallic substrate based on our re-
ing an examination of the reactivity of 3 with iodine.[12] cognition that zincates such as 1Et react selectively with aro-
Combination of 1Et with equimolar amounts of carbamate matic species to give stable intermediates that resist re-
2 in THF at –78 °C gave a mixture that was stirred at room arrangement.[6] The structure reveals ortho-zincation and
temperature for 1 h before being returned to –78 °C and the retention of TMP, the presence of which is consistent
quenched with I2. Washing and concentration gave an oil. with a recently described stepwise deprotonative mecha-
1H NMR spectroscopy showed that this material comprised nism.[4c] Data suggest the significant resistance of 3 to an-
18% rearranged 5 and 28.5% starting material, but that its ionic Fries rearrangement, even after extended periods at
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Eur. J. Org. Chem. 2008, 644–647

Crystalline ortho-Deprotonated Carbamate
[3]
[4]
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[5]
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[7]
[8]
Note Added in Proof (December 11, 2007): The characterization of
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Acknowledgments
This work was supported by the U.K. EPSRC (M. McP., J. V. M.),
Newnham, Trinity and Wolfson Colleges, Cambridge (F. G.), the
Hoansha Foundation, and Grant-in Aid for Young Scientists (A),
Houga, and Priority Area (No. 452 and 459) from the Ministry of
Education, Sports, Science, and Technology, Japan. Computational
resources were partly provided by the RIKEN Advanced Center
for Computing and Communication (RSCC).
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Received: November 20, 2007
Published Online: December 18, 2007
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