Facile Rearrangement of the 6,11-Diphenyldibenzo[b,f][1,4]diazocine Skeleton into a Substituted 2-(2-Aminophenyl)-1,3-diphenylisoindole via Anomalous Carbolithiation or Hydrolithiation: Corroboration of Operative SET Processes

Article abstract of DOI:10.1002/ejoc.201500917

The starting 6,11-diphenyldibenzo[b,f][1,4]diazocine has been individually treated with R-Li reagents in THF, where R = AlH₄, PhCH₂, Ph₂CH, Ph₃C, CH₃, CH₃(CH₂)₃, C₆H₅ or Ph-C≡C, to learn whether an expected 1,2- or 1,4-addition would cleanly occur. Contrary to such an assumption based on nucleophilic attack, this [1,4]diazocine with PhCH₂Li yielded only the enantiomers of (4b,11R)-11-benzyl-4b,11-diphenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]isoindole; with Ph₂CHLi yielded 2-[1-(4-benzhydrylphenyl)-phenyl-2H-isoindol-2-yl]analine; and with LiAlH₄ 2-(2-aminophenyl)-1,3-diphenylisoindole. Finally, individual reactions of the [1,4]diazocine with CH₃Li, nBuLi or PhLi gave 4-5 inseparable products, instead of any simple 1,2 or 1,4 adduct. The anomalous carbolithiations and hydrolithiation observed are irreconcilable with a nucleophilic mechanism but in excellent accord with a SET radical-anion pathway.

Full text of DOI:10.1002/ejoc.201500917

FULL PAPER
DOI: 10.1002/ejoc.201500917
Facile Rearrangement of the 6,11-Diphenyldibenzo[b,f][1,4]diazocine Skeleton
into a Substituted 2-(2-Aminophenyl)-1,3-diphenylisoindole via Anomalous
Carbolithiation or Hydrolithiation: Corroboration of Operative SET
Processes[‡]
John J. Eisch,*[a] Wei Liu,[a][†] Lisheng Zhu,[a][‡‡] and Arnold L. Rheingold[b]
In memory of our late colleague and friend, Wei Liu (1982–2014)
Keywords: Rearrangement / Carbolithiation / Hydrolithiation / SET addition / Nitrogen heterocycles / Lithiation
The starting 6,11-diphenyldibenzo[b,f][1,4]diazocine has
been individually treated with R–Li reagents in THF, where
R = AlH4, PhCH2, Ph2CH, Ph3C, CH3, CH3(CH2)3, C6H5 or
Ph–CϵC, to learn whether an expected 1,2- or 1,4-addition
would cleanly occur. Contrary to such an assumption based
on nucleophilic attack, this [1,4]diazocine with PhCH2Li
yielded only the enantiomers of (4b,11R)-11-benzyl-4b,11-di-
phenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]isoindole;
with Ph2CHLi yielded 2-[1-(4-benzhydrylphenyl)-phenyl-
2H-isoindol-2-yl]analine; and with LiAlH4 2-(2-amino-
phenyl)-1,3-diphenylisoindole. Finally, individual reactions
of the [1,4]diazocine with CH3Li, nBuLi or PhLi gave 4–5 in-
separable products, instead of any simple 1,2 or 1,4 adduct.
The anomalous carbolithiations and hydrolithiation observed
are irreconcilable with a nucleophilic mechanism but in ex-
cellent accord with a SET radical-anion pathway.
out X-ray diffraction and supplemental spectral measure-
Introduction
ments on 3 and 4, as depicted in Figures 2 and 3.[1,9]
Known Diphenyldibenzodiazocine Isomers
Our interest in nitrogen analogs of cyclooctatetraene (1)
has stemmed from the rigid, tub-shape of 1 itself and all
other nitrogen analogs of 1.[2] In our reinvestigation of the
purported 3,4,7,8-tetraphenyl-1,2,5,6-tetraazocine,[3] we de-
termined that no such structure was isolated but that the
putative substance is actually the well-known 2,4,5-tri-
phenylimidazole.[4] Further literature search ascertained
that the three isomers depicted in 2, 3 and 4 have all been
prepared and characterized by spectral, elemental and mo-
lecular mass analyses.[5–7] A single-crystal X-ray diffraction
study on 2 had already been performed,[8] as shown in Fig-
ure 1. In addition, Rheingold’s and our group have carried
Figure 1. 6,7-Diphenyldibenzo[e,g][1,4]diazocine (2).
Figure 2. 6,12-Diphenyldibenzo[b,f][1,5]diazocine (3).
[‡] Cyclic Conjugated Imines, 5. Part 4: Ref.[1]
[a] Department of Chemistry, State University of New York at
Binghamton,
P. O. Box 6000, Binghamton, NY 13902-6000 USA
E-mail: jjeisch@binghamton.edu
[b] Department of Chemistry and Biochemistry, University of
California,
San Diego, La Jolla, CA 29093-0332, USA
E-mail: arheingold@uscd.edu
[†] Deceased, March 3, 2014, in a tragic traffic accident
(cf. Acknowledgments)
Figure 3. 6,11-Diphenyldibenzo[b,f][1,4]diazocine (4).
[‡‡]Postdoctoral Research Associate with Professor John Eisch,
USA
The three-dimensional structures of diazocines 2, 3 and 4
all have a tub-shaped configuration of the eight-membered
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500917.
7384
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394

Rearrangement via Anomalous Carbolithiation or Hydrolithiation
central ring. This brings the transannular C=N groups into or 4 yielded the interesting transannular dihydro isomer 8,
closer proximity.
or the highly unusual rearranged isomer 9, respectively (ac-
tually akin to the rearranged dihydro isomers 7a and 7b
obtained in the reduction of 2, Scheme 1). Likewise, the re-
duction of either 3[8] or 4[1] with alternative one-electron
SET reductants such as Ti(OiPr)2 also yielded such unex-
pected products.
Tub-Shaped Diazocines as Effective Probes of Possible
Aromatic Structures Involved in SET Reactions
Our initial goal in synthesizing efficiently such diazocines
as 2, 3 and 4 was to learn whether these heterocycles would
be capable of adding two electrons to form planar Hückel
aromatic ten pi-electron eight-membered dianions or pro-
tonated dihydrodiazocenes and/or undergoing transannular
reactions typical of the parent cyclooctatetraene (1). To that
end, tub-shaped 2 in THF was treated with an excess of a
suspension of sodium or lithium metal at 25 °C, with the
expectation of generating the salt 5 or upon hydrolysis, neu-
tral 6. However, hydrolytic workup and fractional
recrystallizations provided none of 6 but separate crystals
of the Z- and E-isomers of enamines 7a and 7b, each of
which separated isomers was examined by X-ray crystal-
lography and was found to have the assigned structure.[8]
Clearly, the profound rearrangement of diazocine 2 upon
reduction with sodium must have involved transannular
bonding in the transition state between the asterisked N
and C sites in 2 (Scheme 1). Because of the tub-shape of 2,
reaching such a transition state apparently requires less en-
ergy than attaining the necessary planarity for Hückel aro-
maticity.[10]
Scheme 2.
Thus no experimental evidence has been found for the
intermediacy of any planar ten-pi-electron dianion or di-
hydro derivative in such SET reductions. Apparently, the X-
ray crystal structures of tub-shaped 3 and 4 hold the trans-
imino groups in such close proximity that the electron den-
sity of the radical anion of the one imino (–C=N–) group
can readily delocalize over the other –C=N– group.
In summary then, despite our failure to achieve the pri-
mary goal of generating ten-pi electron Hückel aromatic
systems such as 6 or 4b, this research has uncovered novel
reductive rearrangements leading to most interesting and
versatile heterocycles, widely useful in synthesis,[6] 7a, 7b, 8
and 9.
Nature of the Carbolithiation Mechanism with Diazocines
Perhaps the most interesting reaction of azaaromatic nu-
clei is their ready carbolithiation by organolithium reagents,
which reaction was discovered accidentally by Karl Ziegler
and co-workers, when they were evaluating pyridine (10) as
a solvent for the polar phenyllithium oligomer (11)
(Scheme 3).[11] Addition of 11 to yield soluble adduct 12 at
20 °C is followed by elimination of LiH in refluxing ether
to produce 2-phenylpyridine (13). Alternatively, direct
hydrolysis of 12 yields the 1,2-dihydro derivative of 13. An
analogous 1,2-carbolithiation of quinoline, isoquinoline
and phenanthridine and a 1,4-addition to the central ring
of acridine have been achieved.[12] Because of the high po-
larity of the C–Li bond (in the extreme, a C–···Li+ ion pair),
it has been proposed that such carbolithiations be consid-
ered as nucleophilic additions.[13]
Scheme 1.
In order to avoid the destabilizing ortho-H repulsions in
5 (bracketed by arrows), we then examined the analogous
electron-transfer reduction of isomers of 2 namely, 6,12-di-
phenyldibenzo[b,f][1,5]diazocine (3) (Figure 2) and 6,11-di-
phenyldibenzo[b,f][1,4]diazocine (4) (Figure 3).
Of the two diazocines 3 and 4, the latter structure 4 ap-
peared more promising because the intermediate sodium
salt 4a puts the negative charge on both N-centers
(Scheme 2). Despite this seemingly favorable structural fea-
ture for 4, neither diazocine 3 or 4 yielded the desired di-
hydro derivative of a planar ten-π-electron Hückel aromatic
system upon reduction with sodium or lithium metal in
THF and subsequently hydrolysis. For example, in
Scheme 2 the expected aromatic dihydro product 4b antici-
pated from 4 was not found. Instead, such reduction of 3 Scheme 3.
Eur. J. Org. Chem. 2015, 7384–7394
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7385

J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold
FULL PAPER
Scheme 4.
Scheme 5.
Therefore, to define the mechanistic nature of such
carbolithiations experimentally, we had set out in the pre-
vious publications[9] to examine the nature and scope of the
reactions of diazocine 3 with a variety of alkyl-, aryl-, 1-
alkynyl- and benzyl-lithium reagents. All of these reagents
except the 1-alkynyllithium, Ph–CϵC–Li (14) underwent
1,2-carbolithiation or 1,4-carbolithiation when allowed to
react in a molar ratio of 3/RLi = 1.0:1.1 at 25 °C in THF
(Scheme 4).
The observed 1,2- and 1,4-carbolithiations summarized
in Scheme 4 can readily be rationalized as taking place via
1,2- or 1,4-nucleophilic addition, but the formation of
indoloindole 8 cannot be the result of any such process. A
further compelling observation was made when diazocine 3
was treated individually with benzyllithium (16a), benz-
hydryllithium (19) and trityllithium (20) in a molar ration
of 3/RLi = 1.0:2.2 in refluxing THF for 24 h. Under such
conditions and after final hydrolysis, all of 3 was converted
into 8 quantitatively and the benzyl, benzhydryl and trityl
groups were converted in high yield into the expected di-
mers, bibenzyl (17a) 1,1,2,2-tetraphenylethane (17b) and (4-
benzhydrylphenyl)triphenylmethane (17c), known to be the
coupling product of trityl radicals (Scheme 5).[9a] The yields
of such dimers (17a–17c) ranged from 90–99% of the
theoretical amount. Clearly, processes other than simple nu-
cleophilic additions must be operative in these transforma-
tions.
Results
Overall Reactions of 6,11-Diphenyldibenzo[b,f][1,4]diazocine
(4) with Various Lithium Reagents
These reactions of diazocine 4, with the same lithium
reagents as chosen for diazocine 3, were performed on the
same scale and under the same reaction conditions: a
2.2:1.0 molar equivalent ratio of RLi/4 on a millimolar
scale in THF for 24 h at 25 °C before hydrolysis. The total
array of organolithium reagents evaluated were the follow-
ing: benzyllithium·TMEDA (16a), benzylhydryllithium
(19), trityllithium (20), methyllithium (16b) n-butyllithium
(16c) phenyllithium (11) and phenylethynyllithium (14). Un-
der these conditions all these organolithiums, except 14, re-
acted with diazocine 4 completely. Neither at 25 °C for 24 h
nor at reflux for 8 h additionally did 14 show any reaction.
Reaction of Diazocine 4 with Benzyllithium (16a)
Diazocine 4 (1 equiv.) was allowed to react with
2.2 equiv. of benzyllithium–TMEDA complex 16a in THF
at room temperature for 24 h (Scheme 6). Upon hydrolytic
workup, (4bS,11R)-11-benzyl-4b,11-diphenyl-4b,11-dihydro-
In order to discern the operative reaction mechanism
more clearly in the present study, we then scrutinized the
reactions of diazocine 4 with the same three benzylic lith-
ium reagents 16a, 19 and 20. Surprisingly, we found that
although all three lithium reagents readily reacted, in no
case did any simple 1,2- or 1,4-addition result but rather
SET reactions involving free radicals predominated in the
product formation.
Scheme 6.
7386
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394

Rearrangement via Anomalous Carbolithiation or Hydrolithiation
5H-benzo[4,5]imidazo[2,1-a]isoindole (21) was formed exclu- Upon workup, (4bS,11S)-11-benzyl-4b,11-diphenyl-4b,11-di-
sively by a kinetically controlled and exo,syn addition of 16a hydro-5H-benzo[4,5]imidazo[2,1-a]isoindole (23), (cf. preced-
transannularily across the eight-membered ring of 4. Com- ing paragraph for X-ray data obtained from one enantiomer
pound 21 was recrystallized from absolute ethanol as color- of the racemic mixture) was produced in 33% yield, along
less crystals, m.p. 174–175 °C (Scheme 6). Bibenzyl (17a) was with starting material, 21. Compound 23 was purified by
also found in 6% yield, apparently by the dimerization of column chromatography and recrystallized from absolute
16a. The expected product from a 1,2-exo,syn-addition of ethanol as colorless crystals, m.p. 164–165 °C. The acid-cata-
benzyllithium (16a) to 4 (cf. ref.[9]), namely 22, was not found. lyzed equilibration of 21 with 23 can be viewed as occurring
1
The H-NMR spectrum of (4bS,11R)-11-benzyl-4b,11-di- via 22a and 22b [Equation (1)]. Isomer 21 is thermodynami-
phenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]isoind- cally more stable than 23 by about 600 kcal/mol.
ole (21) has 26 protons, including a N–H at δ = 2.20 ppm
and CH2 doublets at δ = 3.11 and 3.52 ppm; the 13C-NMR
spectrum has the appropriate number of 13C signals of 28,
including Ph–CH2 at δ = 30.90 ppm, N–CAr2 at δ =
44.73 ppm and N–C–N at δ = 76.58 ppm; the infrared spec-
trum has a N–H stretch at 3408 cm–1. The 3-D X-ray crystal
structure has been determined as 21, which structure shows
that the two phenyl groups are syn to each other (21 in
Scheme 6).
The X-ray data were obtained from the racemic mixture
21 and are presented for the enantiomer drawn in Figure 4.
1
The H-NMR spectrum of 23 has 26 protons, including
the N–H at δ = 3.76 ppm and CH2 doublets at δ = 3.93
and 4.81 ppm; the 13C-NMR spectrum has the appropriate
Figure 4. Thermal ellipsoid (30%) diagrams for (4bS,11R)-11-
benzyl-4b,11-diphenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]-
isoindole (21). Selected bond lengths (atom separations) [Å] and
bond angles of (4bS,11R)-11-benzyl-4b,11-diphenyl-4b,11-dihydro-
5H-benzo-[4,5]imidazo[2,1-a]isoindole (21) are shown as the follow-
ing: N(1)–C(6) 1.406(2), N(1)–C(7) 1.479(2), N(2)–C(1) 1.413(2),
N(2)–C(20) 1.492(2), N(2)–C(7) 1.494(2), C(7)–C(14) 1.501(2), C(7)–
C(8) 1.533(2), C(14)–C(19) 1.385(2), C(20)–C(28) 1.540(2), C(20)–
C(21) 1.563(2), C(21)–C(22) 1.516(2), C(6)–N(1)–C(7) 106.64(13),
C(1)–N(2)–C(20) 122.05(13), C(1)–N(2)–C(7) 105.97(13), C(20)–
N(2)–C(7) 112.45(12), N(2)–C(7)–C(14) 103.20(13), N(1)–C(7)–C(8)
110.95(13), N(2)–C(7)–C(8) 109.18(13), C(14)–C(7)–C(8) 113.94(14),
N(2)–C(20)–C(19) 101.58(13), N(2)–C(20)–C(21) 113.58(13), C(28)–
C(20)–C(21) 108.91(13), C(22)–C(21)–C(20) 118.18(14).
Figure 5. Thermal ellipsoid (30%) diagrams for (4bS,11S)-11-
benzyl-4b,11-diphenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]-
isoindole (23). Selected bond lengths (atom separations) [Å] and
bond angles of (4bS,11S)-11-benzyl-4b,11-diphenyl-4b,11-dihydro-
5H-benzo[4,5]imidazo[2,1-a]isoindole (23) are shown as the follow-
Isomerization of Benzyllitlhium-Diazocine-4 Adduct (21) in
Silica Gel-Chloroform Slurry under an Air Atmosphere
ing: N(1)–C(13) 1.414(1), N(1)–C(7) 1.495(1), N(1)–C(6) 1.505(1),
N(2)–C(12) 1.401(2), N(2)–C(7) 1.480(1), C(5)–C(6) 1.549(2), C(6)–
C(19) 1.517(2), C(6)–C(26) 1.539(2), C(12)–C(17) 1.383(2), C(12)–
C(13) 1.403(2), C(18)–C(19) 1.382(2), C(19)–C(20) 1.393(2), C(13)–
N(1)–C(7) 105.30(8), C(13)–N(1)–C(6) 119.75(9), C(7)–N(1)–C(6)
111.96(8), C(12)–N(2)–C(7) 106.03(9), N(1)–C(6)–C(19) 101.28(8),
N(1)–C(6)–C(26) 114.21(9), N(1)–C(6)–C(5) 109.54(8), N(2)–C(7)–
N(1) 103.10(8), N(2)–C(7)–C(18) 113.38(9), N(1)–C(7)–C(18)
102.79(8), N(1)–C(7)–C(8) 112.37(9), C(12)–C(13)–N(1) 109.63(10),
Attempted column chromatographic purification of 21 led
to the equilibration of racemic 21 to its diastereomeric race-
mate 23. Thus (4bS,11R)-11-benzyl-4b,11-diphenyl-4b,11-di-
hydro-5H-benzo[4,5]imidazo[2,1-a]isoindole (21) (1.0 mmol)
was mixed with undried chloroform (acidic to litmus) and
silica gel and stirred in open air for 48 h [Equation (1)]. C(18)–C(19)–C(6) 111.99(9), C(20)–C(19)–C(6) 127.68(10).
Eur. J. Org. Chem. 2015, 7384–7394
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7387

J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold
FULL PAPER
number of 13C signals of 26, including the Ph–CH2 at δ = Upon hydrolytic workup, 2-[1-(4-benzhydrylphenyl)-3-
45.20 ppm, the N–CAr2 at δ = 79.01 ppm and the N-C–N at phenyl-2H-isoindol-2-yl]aniline (24) formed in quantitative
δ = 93.92 ppm; and the infrared spectrum has an N–H yield. Compound 24 was recrystallized from absolute ethanol
stretch at 3393 cm–1. The 3-D structure has been determined as yellow crystals, m.p. 236–238 °C. None of possible adduct
by X-ray diffraction, which showing that the two phenyl 25 was found. Also 7% of 19 was dimerized to 1,1,2,2-tetra-
groups are anti to each other (Figure 5).
phenylethane. The crystal structure of compound 24 is
shown in Figure 6.
Reaction of Diazocine 4 with Benzhydryllithium (19)
Oxidation of the Hydrolyzed Benzhydryllithium–Diazocine 4
Adduct 24 by Stirring in Silica Gel/Chloroform under an Air
Atmosphere
Diazocine 4 (1 equiv.) was allowed to react with 2.2 equiv.
of 19 in THF at room temperature for 24 h (Scheme 7).
This oxidative method for converting the unsubstituted di-
azocine 4 directly into the corresponding isoindole 9 was first
discovered and described in ref.[1] Here this method was
found useful in producing 26 from 24 in excellent yield.
The 2-[1-(4-benzhydrylphenyl)-3-phenyl-2H-isoindol-2-yl]
aniline (24) was mixed in undried chloroform with siliga gel
and stirred under reflux in open air for 48 h [Equation (2)].
Upon workup, (5Z,11Z)-6-(4-benzhydrylphenyl)-11-phenyld-
ibenzo[b,f][1,4]diazocine (26) was produced in 96% yield.
Compound 26 was recrystallized from absolute ethanol as
colorless crystals, m.p. 204–205 °C.
Scheme 7.
The 1H-NMR spectrum of 26 has 28 protons, including a
C–H singlet at δ = 5.53 ppm; the 13C-NMR spectrum has
the appropriate number of 13C signals of 27, including two
Figure 6. Thermal ellipsoid (30%) diagrams for 2-[1-(4-benz-
hydrylphenyl)-2-phenyl-2H-isoindol-2-yl]aniline (24). Selected
bond lengths (atom separations) [Å] and bond angles of 2-[1-(4- lected bond lengths (atom separations) [Å] and bond angles
Figure 7. Thermal ellipsoid (30%) diagrams for (5Z,11Z)-6-(4-
benzhydrylphenyl)-11-phenyldibenzo [b,f][1,4]diazocine (26). Se-
benzhydrylphenyl)-3-phenyl-2H-isoindol-2-yl]aniline
shown in the following: N(1)–C(8) 1.381(2), N(1)–C(1) 1.389(2),
(24)
are
of (5Z,11Z)-6-(4-benzhydrylphenyl)-11-phenyldibenzo[b,f][1,4]di-
azocine (26) are shown in the following: N(1)–C(7) 1.280(2), N(1)–
N(1)–C(15) 1.442(2), N(2)–C(16) 1.335(2), C(1)–C(2) 1.403(2), C(6) 1.420(2), N(2)–C(10) 1.281(2), N(2)–C(1) 1.424(2), C(7)–C(21)
C(1)–C(21) 1.469(2), C(2)–C(3) 1.425(2), C(2)–C(7) 1.437(2),C(3)– 1.483(2), C(7)–C(8) 1.502(2), C(8)–C(9) 1.400(2), C(10)–C(15)
C(4) 1.370(2), C(4)–C(5) 1.427(2), C(7)–C(8) 1.395(2), C(24)–C(27) 1.490(2), C(22)–C(23) 1.383(2), C(24)–C(27) 1.533(2), C(27)–C(28)
1.525(2), C(27)–C(28) 1.524(2), N(1)–N(2) 2.833(3), N(2)–C(1) 1.528(2), N(1)–N(2) 2.911(1), N(1)–C(10) 3.162(1), N(2)–C(7)
3.823(3), N(2)–C(8) 3.092(3), C(8)–N(1)–C(1) 110.84(11), C(8)– 3.185(2), C(7)–C(10) 2.896(2), C(7)–N(1)–C(6) 120.10(10), C(10)–
N(1)–C(15) 124.04(11), C(1)–N(1)–C(15) 124.93(11), N(1)–C(1)– N(2)–C(1) 118.77(10), N(1)–C(7)–C(21) 118.42(10), N(1)–C(7)–
C(2) 106.58(11), N(1)–C(1)–C(21) 124.75(12), N(1)–C(8)–C(7) C(8) 122.80(10), N(2)–C(10)–C(15) 119.51(10), N(2)–C(10)–C(9)
107.50(11), N(1)–C(8)–C(9) 124.41(12).
122.98(10), C(28)–C(27)–C(24) 110.49(9).
7388
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394

Rearrangement via Anomalous Carbolithiation or Hydrolithiation
C=N at 169.74 and 169.56 ppm, and an H–CAr3 group at δ Attempted Reactions of Diazocine 4 with Organolithium
= 56.71 ppm; and the infrared spectrum has two C=N Reagents
stretches at 1631 and 1620 cm–1. The 3-D structure has been
determined by X-ray diffraction (Figure 7).
Two equivalents of methyllithium (28) was allowed to re-
act with diazocine 4 (1 equiv.) in THF at –78 °C for 2 h and
at room temperature for 24 h. Upon hydrolytic workup, defi-
nitely no signals of remaining diazocine 4 or generated iso-
1
indole 9 were found in the H- and 13C-NMR spectra. No
Reaction of Diazocene 4 with Trityllithium (20)
pure products could be separated from the intractable crude
Diazocine 4 (1 equiv.) was allowed to react with trityl-
lithium (20) in THF under 3 sets of conditions: 1) 10 h at
–78 °C; 2) room temp. for 48 h; and 3) refluxing THF for
10 h. Upon hydrolysis, the resulting product compositions
were very similar: the diazocine 4 was partially recovered un-
changed and the Ullmann–Borsum hydrocarbon (17c) was
formed in 15% yield, as was 1-butanol (5%). But no iso-
indole 8 whatsoever was detected, as was corroborated by
mixture, either by fractional crystallizations or column
chromatography. The TLC analysis on silica gel revealed
about 4 to 5 components as closely spaced spots. These spots
were assumed to be adducts of 4 and CH3Li but no adduct
was formed with any high selectivity. When n-butyllithium
(16c) and phenyllithium (11) were employed under similar
reaction conditions, a very similar outcome was obtained.
Apparent reasons for the complexity of these reactions are
considered in the Discussion section.
1
the absence of H and 13C-NMR peaks characteristic of 8.
These results can be interpreted in terms of 4 accepting elec-
trons to give 27 from two equivalents of Ph3–Li and then
forming 17c from the known coupling trityl radicals (path a)
and the lithium salt of 27 transferring electrons to THF with
rupture of the ring (path b) to yield 28 upon hydrolysis
(Scheme 8).[14]
Reductive Rearrangement of Diazocine 4 into Isoindole 9 via
Treatment with LiAlH4 (29) in THF and Subsequent
Hydrolysis
Preliminary to our attempts to hydrometallate the imino-
linkages of diazocine 3, we took notice of prior work with
LiAlH4 in ether achieving the bis-hydrometallation of 4 into
a 3:1 mixture of the 6,12-diphenyl-trans(29)/cis isomers
[Equation (3)].[15]
Accordingly, diazocine 4 (150 mg, 0.42 mmol, 1.0 mo-
lar equiv.) dissolved in 10.0 mL of dry THF under anhydrous
argon was mixed with 0.50 mL of 2 m LiAlH4 in THF
(0.92 mmol, 1.0 molar equiv.) at –78 °C for 10 min. After be-
ing warmed to room temp. the brown mixture was stirred
for 18 h. Hydrolytic workup (gas evolution) gave an organic
residue of almost pure isoindole 9 by TLC and NMR criteria
[Equation (4)].
Scheme 8.
Reactions of Diazocine 4 with Phenylethynyllithium (14)
Phenylethynyllithium (14) (2 equiv.) was allowed to react
with diazocine 4 (1 equiv.) in THF at –78 °C for 2 h and at
room temperature for 24 h. Upon hydrolytic workup, defi-
nitely no isoindole 9 and no diphenyldiacetylene were pro-
1
duced and no new signals in the H and 13C-NMR spectra
were found. When the reaction was carried out under reflux
for 8 h, the same result was obtained.
Discussion
To try to enhance the dissociation of the C–Li bond of
14, hexamethylphosphoramide (2 equiv.) was mixed with
Extreme Mechanistic Pathways under Discussion for the 1,2-
Carbolithiation of Diazocines 3 and 4
phenylethynyllithium (14) (2 equiv.). Then diazocine
4
(1 equiv.) was added and the reaction mixture was refluxed
1,2-Nucleophilic carbolithiation of an imino linkage in di-
for 8 h. Upon workup again, neither isoindole 8 nor diphen- azocine 3 and 4 could be depicted as in Equation (3), where
yldiacetylene were produced. In addition, no new signals in the complex of the imino group with R–Li (30 solvated with
1
the H- and 13C-NMR spectra were found.
THF) rearranges via a bridging transition state into the exo,
Eur. J. Org. Chem. 2015, 7384–7394
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7389

J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold
FULL PAPER
syn-carbolithiation adduct 31 [Equation (5)]. No electrons pling could occur at carbon in 34a, 34b and with rearrange-
become unpaired and the R and Li groupings never become ment, in 34c and 34d. These radicals might well be inter-
separated during the process.
related as high-energy isomers, rather than resonance struc-
tures.
In our carbolithiations of diazocine 4 with benzylic lith-
ium reagents, we have found that PhCH2Li adds to the N
center and radical 34c (21 in Scheme 6), trans to the 11-
phenyl group. The Ph2CHLi adds to the N center and radical
34d with unknown stereochemistry (24 in Scheme 7).
Furthermore, we assume that Ph3CLi also carbolithiates as
with 34d, but such a labile adduct redissociates again to yield
17c and 4.
In the case of the reaction of benzhydryllithium with di-
azocine 4, the initial coupling product 35 would then un-
dergoe a base-promoted elimination reaction with further
RLi to produce 35a and then the observed hydrolysis prod-
uct 9 (Scheme 10).
With diazocine 4 and the benzylic lithiums, PhCH2Li
(16a), Ph2CHLi (19) and Ph3CLi, no 1,2-carbolithiation of
an imino group whatsoever was observed. Hence, no 1,2-
or 1,4-nucleophilic carbolithiation could be involved in the
observed reactions (Scheme 6, Schemes 7 and 8). Finally,
neither diazocine 3 nor 4 reacts at all with 1-phenyl-
ethynyllithium (14). Now in reactions with a wide variety of
carbonyl substrates, reagent 14 behaves as an efficient ad-
dend, producing the Grignard-like adducts.[16] Thus simple
nucleophilic addition is unlikely operative in the carbolithi-
ation of either diazocine 3 or diazocine 4.
The alternative mechanism for the carbolithiation of the
imino linkage in these diazocines 3 and 4 would involve elec-
tron transfer in the imino complex of the R–Li(THF)n (30)
[Equation (6)].
Scheme 10.
In this event the two radicals are held in proximity by
dynamic radical caging in the solvent and hence could re-
combine with each other at radical sites on other carbon
centers not adjacent to the imino N (32, solvent omitted).
For example, an R–Li complex with diazocine 4 can undergo
electron transfer to form 34a with radical character delocal-
ized on asterisked carbon centers (Scheme 9). Depending
both on the lifetime and steric demands of R·, radical cou-
With the foregoing results in mind, it is reasonable to sug-
gest that the several (4–5) unknown components formed
from 4 and CH3Li, CH3CH2CH2CH2Li or PhLi in individ-
ual reactions could result from the coupling of radicals 34a–
34d with the group furnished by the R–Li reagent.[18]
Furthermore, such coupling could result in some cases with
the formation of cis- and trans-isomers and/or isomeric nu-
clear skeletons (e.g., with 34c and 34d). Proof that attempted
hydrometalation of 4 can induce skeletal isomerization has
been demonstrated by the outcome shown in Scheme 11,
where an SET pathway for this transformation can readily
be depicted.
Scheme 9.
Scheme 11.
7390
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394

Rearrangement via Anomalous Carbolithiation or Hydrolithiation
Analytical Methods: The IR spectra were recorded with a Perkin–
Elmer instrument, model 457, and samples were measured either as
mineral oil mulls or as KBr films. The NMR spectra (1H and 13C)
were recorded with a Bruker spectrometer, model Avance III 600,
Conclusions
(1) An investigation of a range of organolithium reagents
in THF, containing sp2- and sp3-hybridized carbon atoms
bonded to lithium, namely methyllithium, n-butyllithium, and tetramethylsilane Me4Si was used as the internal standard. The
chemical shifts reported are expressed on the scale in parts per mil-
lion (ppm) from the Me4Si reference signal. Melting points were
determined on a Thomas-Hoover Unimelt capillary melting point
apparatus and are uncorrected.
phenyllithium, benzyllithium, benzhydryllithium and trityl-
lithium indeed do effect the carbometallation of diazocine 4
but in every case yielding a result incompatible with the oper-
ation of simple nucleophilic addition. In a straightforward
nucleophilic addition, such reactions should occur in a selec-
tive 1,2 or 1,4 manner without skeletal change.
(2) In a comparative study of the reactions of diazocine 4
individually with benzyllithium, benzhydryllithium and tri-
tyllithium, it was found that none of the three benzylic lith-
ium reagents underwent a normal 1,2- or 1,4-carbo-
lithiation to the C=N or C=C–C=N functional groups. In-
stead benzyllithium and benzhydryllithium underwent totally
abnormal carbolithiation of the rearranged skeleton of the
diazocine 4 system. Trityllithium executed electron-transfers
with both diazocine 4 and THF to produce the dimer of two
trityl groups, 17c, and the lithium salt of 1-butanol.
1
Authentic H- and 13C-NMR spectra for comparison with those of
all known compounds listed in Supplemental Information and are
accessible from AIST: Integrated Spectral Database System of Or-
ganic Compounds.[19]
Preparation of Known Starting Materials and Products
6,12-Diphenyldibenzo[b,f][1,4]diazocine (4): The requisite o-dibenzo-
ylbenzene was prepared in strict adherence to a published pro-
cedure[20] from phthaloyl chloride and phenylmagnesium bromide in
diethyl ether, in 27% yield and recrystallized from 95% ethanol, m.p.
146–147 °C.
The procedure for preparing o-dibenzoylbenzene has been modified
from that employed by Olliéro and Solladié,[7] namely by condensing
this diketone and o-diaminobenzene in a 1:3 molar ratio in benzene
and heating at reflux for 10 days with p-toluenesulfonic acid mono-
hydrate in a ratio of 1:0.25. Instead, we have conducted the reaction
in refluxing toluene with the condenser attached to a Dean–Stark
trap. With this procedure the expected amount of water was collected
after 12 h. The resulting solution was subjected to rotary evapora-
tion. The dark residue was purified by column chromatography on
silica gel employing a 3:1 by volume hexane/ethyl acetate eluent.
From 5.73 g of the diketone and 6.50 g of the diamine, 6.32 g of 4
(100%) was obtained, yellow crystals, m.p. 197–198 °C (ref.[7] 184–
189 °C). 1H NMR (CDCl3): δ = 7.82 (d, 4 H), 7.43 (t, 2 H), 7.40 (q,
2 H), 7.37 (t, 4 H), 7.16 (q, 2 H), 7.00 (m, 4 H) ppm. 13C NMR
(CDCl3): δ = 169.73, 141.91, 137.8, 136.43, 130.99, 128.97, 128.74,
128.25, 127.11, 124.05, 121.18 ppm.
(3) The individual reactions of diazocine 4 with meth-
yllithium, n-butyllithium and phenyllithium in THF did not
produce selectively the 1,2 or 1,4 adducts expected from sim-
ple nucleophilic addition. Instead, each organolithium gener-
ated four to five hydrolyzed adducts of unknown structure
unattainable through normal carbolithiation.
(4) Phenylethynyllithium in THF, which performs success-
ful nucleophilic additions to a wide variety of carbonyl sub-
strates, is completely unreactive toward diazocine 4 between
–78 °C to +80 °C or in the presence of HMPA. An electronic
rationale for the inertness of this lithium reagent is presented
in ref.[9b] in Table 3. In a proposed SET pathway the neces-
sary radical cluster, 32 in Equation (6), would be too high in
energy with an alkynyl radical (R–CϵC·) to participate.
(5) The observations made concerning the reactions of di-
azocine-4 and organolithiums above under points (2)–(4) are
completely incompatible with the operation of a nucleophilic
carbolithiation. In contrast, all such reaction traits can be
readily accommodated by the stepwise electron-transfer and
radical-coupling process depicted and discussed at Equation
(6) (cf. supra).
2-(2-Aminophenyl)-1,3-diphenylisoindole (9): According to a pub-
lished procedure,[7] an intimate mixture of 5.73 g (20 mmol) of o-
dibenzoylbenzene, 2.16 g (20 mmol) of o-diaminobenzene and 1.0 g
(5.3 mmol) of p-toluenesulfonic acid monohydrate was heated in an
oil bath at 200 °CϮ5 °C for 2 h, whereupon it became a viscous
melt. Although the authors claim they obtained a quantitative yield,
the operative steps and criteria are not given. In our procedure the
reaction mixture was stirred with a water/ethyl ether slurry and the
organic layer was separated and dried with anhydrous Na2SO4. Fil-
tration of the dried solution and evaporation of the solvent left a
dark residue of crude 9 and other amino components. Column
chromatography on silica gel with a 3:1 v/v hexane/ethyl acetate elu-
Experimental Section
General Experimental Procedures
1
ent yielded 4.18 g (85%) of 9, 10% of phenazine (by H NMR and
General Reaction and Hydrolytic Workup Procedures: All reactions
were carried out under a positive pressure of anhydrous, oxygen-free
argon. All solvents employed with organometallic compounds were
dried and distilled from a sodium metal-benzophenone ketyl mixture
prior to use.[18]
TLC) and ≈ 5% of other amines: 9 from 95% ethanol, yellow crys-
tals, m.p. 212–213 °C (ref.[7] 201–202 °C). 1H NMR (CDCl3): δ =
773 (q, 2 H), 7.30 (d, 3 H), 7.25 (m, 4 H), 7.17 (t, 2 H), 7.08 (t, 1
H), 7.04 (m, 2 H), 6.96 (d, 1 H), 6.62 (t, 1 H), 6.58 (d, 1 H), 3.47
(b, 2 H) ppm. 13C NMR (CDCl3): δ = 143.17, 131.78, 130.16, 129.59,
129.54, 128.13, 126.45, 124.47, 124.41, 123.12, 122.5, 119.88, 118.29,
115.97 ppm.
Routinely, the organometallic reaction mixtures were hydrolyzed
with deoxygenated water. Ether was added to the hydrolysate, the
organic layer was separated and the organic layer then dried with
Preparation and Analysis of Organolithium Reagents
1
anhydrous Na2SO4. The volatile solvent was removed and H- and
13C-NMR spectra and TLC were recorded on the crude organic
products. Where preparative yields were to be corroborated, column
chromatographic separation of products on silica gel with a hexane/
ethyl acetate eluent was carried out.
n-Butyllithium (2.5 m in hexane) was used as received from the Ald-
rich Chemical Company, with all transfers being made under dry,
oxygen-free argon with argon-flushed gastight syringes. Likewise, the
benzylic lithium reagents were prepared, as described in the follow-
Eur. J. Org. Chem. 2015, 7384–7394
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7391

J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold
FULL PAPER
ing paragraphs, transferred and allowed to react under an argon
atmosphere.[17]
When keeping other conditions the same, but using only 1.1 mmol
of benzyllithium–TMEDA complex 16a, 57% of 21 was obtained.
1H NMR (CDCl3): δ = 8.01 (d, 2 H), 7.55 (d, 2 H), 7.51 (q, 3 H),
7.40 (t, 2 H), 7.33 (t, 1 H), 7.21 (t, 2 H), 7.16 (t, 1 H), 7.11 (d, 1 H),
7.01 (q, 2 H), 6.92 (m, 2 H), 6.80 (t, 2 H), 6.63 (d, 1 H), 5.96 (d, 2
H), 3.82 (d,1 H), 3.52 (d, 1 H), 3.11 (d, 1 H), 2.20 (s,1 H) ppm. 13C
NMR (CDCl3): δ = 147.01, 146.86, 146.48, 145.76, 142.04, 140.78,
136.08, 130.67, 128.63, 128.50, 128.25, 127.72, 127.12, 127.09,
127.04, 126.92, 126.70, 125.91, 124.85, 123.71, 122.88, 122.49,
116.07, 114.78, 93.36, 76.58, 44.73, 30.90 ppm.
Benzyllithium (16a), Prepared as Needed by Two Separate Pro-
cedures: (1) In THF by the cleavage of benzyl methyl ether by lithium
metal pieces in THF at –10 °C and then analyzed by the Gilman
double titration method.[17] (2) In toluene as the 1:1 complex with
TMEDA by treatment of 1.0 equiv. of TMEDA in toluene with
1.0 equiv. of n-butyllithium in hexane and with subsequent analysis
by adduction of an aliquot of 16a with benzophenone.
Benzhydryllithium(diphenylmethyllithium) (19) was prepared by treat-
ing a solution of diphenylmethane (505 mg, 3.0 mmol, 1.0 equiv.) in
THF (25 mL) with n-butyllithium in hexane (1.32 mL, 3.29 mmol,
1.1 equiv.) at room temperature. After 2 h the blood-red solution was
analyzed by treating an aliquot with D2O (100%), separating the
organic layer after addition of ethyl ether, drying the organic layer,
Reaction of Diazocine 4 with Diphenylmethyllithium (19): Diazocine
4 (360 mg, 1 mmol.) was added to diphenylmethyllithium (19)
(2 mmol) in 20 mL THF and stirred at room temperature for 24 h.
After workup 4 was completely converted into the 2-[1-(4-benz-
hydrylphenyl)-3-phenyl-2H-isoindol-2-yl]aniline (24). 1,1,2,2-Tetra-
phenylethane was also generated by dimerization of 19 in 7% yield.
Compound 24 was purified by column chromatography (eluent: hex-
anes/ethyl acetate, 3:1) in quantitative yield as yellow crystals, m.p.
236–238 °C. 1H NMR (CDCl3): δ = 7.74 (m, 2 H), 7.40–7.15 (m, 12
H), 7.15–6.90 (m, 10 H), 6.61 (m, 2 H), 5.50 (s, 1 H), 3.45 (br., 2 H)
ppm. 13C NMR (CDCl3): δ = 143.91, 143.222, 141.89, 131.82,
130.21, 129.84, 129.63, 129.50, 129.36, 129.18, 128.31, 128.13, 126.43
126.33, 124.55, 124.03, 123.11, 122.50, 122.38, 120.04, 119.88,
118.24, 115.91, 56.59 ppm.
1
and removing volatiles and recording the H-NMR spectrum of the
organic residue. The relative integrated intensities of the phenyl pro-
tons to the methyl protons, which had been 10.0 to 2.0 in the starting
diphenylmethane, were now 10.0 to 1.2, indicating 80% deuteriation
at the CH2 group and thus an 80% yield of 19. The 1H-NMR spec-
trum showed no trace of 5,5-diphenyl-1-pentanol, the product of the
attack of 19 on THF at higher temperatures.
Trityllithium(triphenylmethyllithium) (20) was similarly prepared by
treating
a solution of triphenylmethane (180 mg, 0.75 mmol,
Reactions of Diazocine 4 with Triphenylmethyllithium (20) and Reac-
tion Variants: Diazocine 4 (360 mg, 1 mmol) was added to triphenyl-
methyllithium (20) (2 mmol) in 20 mL THF and stirred at room tem-
perature for 24 h. After workup, triphenylmethane (84%), the
Ullmann–Borsum hydrocarbon (17c) (14%), triphenylmethanol
(1%) and 1-butanol (1%) were found in the crude hydrolysate.
1.0 equiv.) in THF (20 mL) with n-butyllithium in hexane (0.32 mL,
0.80 mmol, 1.1 equiv.) at room temperature. After 2 h an aliquot of
the resulting deep-red solution was worked up with D2O and ethyl
ether, as in the foregoing procedure. The original aryl to methyne
proton ratio of 15:1.0 for the starting Ph3CH was now 15:0.55, indi-
cating a 45% yield of 20. Neither in this preparation of 20 nor in
the foregoing preparation of 19 was there any sign of remaining n-
butyllithium. Were any such a lithium reagent still present in reac-
tions with diazocine 4, the known butylated adduct would have been
formed. Thus, any nBuLi not consumed by lithiating Ph2CH2 or
Ph3CH must have been destroyed by the known attack of nBuLi on
THF to produce ethylene and CH2=CHOLi.
When such a reaction was carried out in THF either at –78 °C or
under reflux, the same products resulted.
Attempted Reactions of Diazocine 4 with Organolithium Reagents:
Methyllitnium (16b) (0.4 mL, 3 m in diethoxymethane, 1.2 mmol)
was added to diazocine 4 (180 mg, 0.5 mol) in 15 mL THF at –78 °C
for 2 h and then at room temperature for 24 h. After workup defi-
nitely no signals of diazocine 4 or isoindole 24 was found in the
1H- and 13C-NMR spectra. But the complex crude product, which
Phenylethenyllithium (14) was prepared by treating a solution of
phenylacetylene (102 mg, 1.0 mmol, 1.0 equiv.) in 5 mL of THF with
n-butyllithium in hexane (0.44 mL, 1.1 mmol, 1.1 equiv.) at –78 °C displayed by TLC analysis four to five closely spaced fluorescent
for 30 min and then at room temp. for 30 min to give a colorless
solution of 14, which was analyzed by treating an aliquot with D2O
(100%), separating the organic layer after addition of ethyl ether,
drying the organic layer and removing volatiles and recording the
1H-NMR spectrum of the organic residue. The relative integrated
intensities of the phenyl protons to the methylidyne protons, which
had been 5.0 to 1.0 in the starting phenylacetylene, were now 5.0 to
0, indicating 100% deuteriation at the CH group and thus a 100%
yield of 14.
spots, could not be separated either by crystallization or by column
chromatography.
The same outcome resulted when the reaction was carried out with
either n-butyllithium (16c) or phenyllithium (11) under similar reac-
tion conditions.
Attempted Reactions of Diazocine 4 with Phenylethynyllithium (14)
and Reaction Variants: Phenylethynyllithium (14) (1 mmol) was
added to diazocine 4 (180 mg, 0.5 mmol) in 15 mL THF at –78 °C,
then stirred at –78 °C for 2 h and at room temperature for 24 h.
After workup only 4 was recovered. When such a reaction was
heated at reflux for 8 h, the same outcome resulted.
Reactions of 6,11-Diphenyldibenzo[b,f][1,4]diazocine (4) with Organo-
lithium Reagents
Reaction of Diazocine 4 with Benzyllithium and Reaction Variants:
Diazocine 4 (360 mg, 1.0 mmol) was added to the benzyllithium-
TMEDA complex (16a) (2.2 mmol) in 15 mL THF and stirred at
room temperature for 24 h. After workup (4bS,11R)-11-benzyl-
4b,11-diphenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]isoind-
ole (21) was obtained in quantitative yield by the usual hydrolytic
Hexamethylphosphoramide (HMPA) (0.20 mL, 1 mmol) was ad-
mixed with phenylethynyllithium 101 (1 mmol) in 15 mL THF at
–78 °C for 15 min and then [1,4]diazocine 4 (180 mg, 0.5 mmol) was
added. Subsequent reflux for 8 h and usual workup yielded only 4.
Isomerization of the Benzyllithium–Diazocine Adduct (16a) by Stir-
workup. Bibenzyl was also found in this reaction in 6% yield. Crys- ring in Silica Gel/Chloroform: The (4bS,11R)-11-benzyl-4b,11-di-
tals of 21 were obtained by recrystallization from absolute ethanol,
phenyl-4b,11-dihydro-5H-benzo[4,5]imidazo[2,1-a]isoindole
(21)
m.p. 174–175 °C.
(0.45 g, 1.0 mmol) was mixed with 15 mL chloroform and silica gel
7392
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394

Rearrangement via Anomalous Carbolithiation or Hydrolithiation
(5.0 g), and stirred in open in air for 48 h. After workup the Diego, with the help of Dr. Yongxuan Su of the Facility Staff. In
product
(4bS,11S)-11-benzyl-4b,11-diphenyl-4b,11-dihydro-5H- addition, Dr. Kun Yu, who obtained his doctorate with Professor
benzo[4,5]imidazo[2,1-a]isoindole (23) was determined as 33% yield
Eisch in May of 2013, was a most helpful co-worker for Wei Liu
in exploring the synthesis and reactions of such dibenzo[1,4]- and
from the 1H-NMR spectrum of the reaction mixture, along with the
unchanged starting material 21. Compound 23 was purified by col- dibenzo[1,5]diazocenes.[1,9a,9b] – Finally, we, his co-authors, mourn
umn chromatography (eluent: hexanes/ethyl acetate, 20:1) as color- the loss of Dr. Wei Liu, a promising young scientist in lithium bat-
less crystals, m.p. 164–165 °C. 1H NMR (CDCl3): δ = 7.36 (m, 2 H), tery research, who in February 2014 was appointed Research Man-
7.21 (d, 1 H), 7.18 (d, 3 H), 7.09 (m, 4 H), 6.99 (q, 5 H), 6.88 (t, 2
H), 6.75 (d, 2 H), 6.62 (t, 1 H), 6.56 (d, 1 H), 6.38 (t, 1 H), 6.26 (d,
1 H), 4.81 (s, 1 H), 3.93 (d, 1 H), 3.76 (d, 1 H) ppm. 13C NMR
ager for Novel Organic Battery Electrolyte Development at the
Shandong Hairong Power Supply Materials Co., Ltd., Shandong
Province, P. R. China. This article and the previous article[1] are
(CDCl3): δ = 148.15, 145.66, 144.22, 143.38, 142.49, 139.29, 137.18, largely based upon his doctoral dissertation, Novel Aspects of Epime-
131.78, 128.41, 128.35, 127.91, 127.78, 127.37, 126.99, 126.85, talation in Organic Synthesis, completed in October 2013, and super-
125.94, 125.60, 124.54, 123.70, 122.11, 119.50, 116.13, 108.59, 93.92,
79.01, 45.20 ppm.
vised by Professor John Eisch at Binghamton University, Bingham-
ton, New York, USA. Dr. Wei Liu collaborated extensively in the
composition of this article by E-mail exchange after his return to
China.
Oxidation of the Diphenylmethyllithium–Diazocine Adduct 24 by Stir-
ring in Silica Gel/Chloroform: 2-[1-(4-Benzhydrylphenyl)-3-phenyl-
2H-isoindol-2-yl]aniline (24) (0.96 g, 1.8 mmol) was mixed in 25 mL
chloroform and silica gel (10.0 g), then stirred for 48 h in open air.
After workup, pure (5Z,11Z)-6-(4-benzhydrylphenyl)-11-phenyldib-
enzo[b,f] [1,4]diazocine (26) was obtained in quantitative yield by
filtering off the silica gel and evaporating the volatile solvent. Com-
[1] J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold, Eur. J. Org. Chem.
2014, 7489–7498.
[2] A most recent review of the nitrogen ring-substituted cyclo-
octatetranes, namely azocines, diazocines, benzoazocines and
benzodiazocines, can be found in Part B of the doctoral disser-
tation of Wei Liu, Novel Aspects of Epimetalation in Organic
Synthesis, State University of New York at Binghamton, Octo-
ber 2013, part B, p. 144–162 (Dissertation Abstracts).
[3] J. J. Eisch, T. Y. Chan, J. N. Gitua, Eur. J. Org. Chem. 2008, 392–
397.
1
pound 26 is a colorless solid, m.p. 204–205 °C. H NMR (CDCl3):
δ = 7.69 (d, 2 H), 7.50 (d,1 H), 7.33 (m, 3 H), 7.26 (m, 2 H), 7.07
(m, 5 H), 6.94 (d, 1 H), 6.55 (m, 2 H), 6.34 (t, 1 H), 6.11 (d, 1 H),
6.06 (m, 1 H), 5.19 (d, 1 H), 5.09 (d, 1 H), 4.81 (s, 1 H), 3.39 (m, 1
H), 3.16 (m,1 H) ppm. 13C NMR (CDCl3): δ = 148.79, 146.43,
142.82, 142.25, 141.85, 139.25, 135.64, 128.93, 128.49, 128.27,
127.80, 127.63, 127.32, 126.86, 125.68, 124.30, 123.17, 121.67,
119.69, 118.13, 115.71, 109.38, 93.57, 77.23, 77.14, 65.78, 44.99,
15.24 ppm.
[4] B. Radziszewski, Ber. Dtsch. Chem. Ges. 1882, 15, 1493–1496.
[5]
N. L. Allinger, G. A. Youngdale, J. Org. Chem. 1959, 24, 306–
308.
[6]
W. Metlesics, T. Resnick, G. Silverman, R. Tavares, L. H.
Sternbach, J. Med. Chem. 1966, 9, 633–634.
D. Olliéro, G. Solladié, Synthesis 1975, 246–247.
C. J. Finder, M. G. Newton, N. L. Allinger, J. Chem. Soc. Perkin
Trans. 2 1973, 1929–1932.
a) J. J. Eisch, K. Yu, A. L. Rheingold, Eur. J. Org. Chem. 2012,
3165–3171; b) J. J. Eisch, K. Yu, A. L. Rheingold, Eur. J. Org.
Chem. 2014, 818–832.
Reductive Isomerization of Diazocine 4 to Isoindole 9: A solution of
diazocine 4 (150 mg, 0.42 mmol, 1.0 molar equivalent) formed in
10 mL of dry THF under an atmosphere of anhydrous, deoxygenatd
argon was cooled to –78 °C in a Dry Ice-acetone bath and treated
dropwise (via a gastight syringe) with a 2.0m solution of LiAlH4 in
THF (0.46 mL, 0.92 mmol, 2.2 m equivalents). After ten minutes at
–78 °C the initially pale yellow solution had turned dark brown. The
solution was then brought to room temp. for 12 h and worked up in
the usual manner. The resulting crude product (160 mg) was shown
to be almost pure isoindole 9 (Ͼ 98%) by NMR and TLC analysis,
with traces of 4 and 1-butanol.
[7]
[8]
[9]
[10]
a) The necessary planarity of 2 required for Hückel aromaticity
involves two energy barriers. First, previous research on the bar-
rier to inversion of the optical active derivative of 2 bearing carb-
oxyl groups at the 3- and 10-positions has estimated the mini-
mum repulsion energy of such ortho H groups in a transition of
2 to its planar form at 20 kcal/mol (N. L. Allinger, W. Szkrybalo,
M. A. DaRooge, J. Org. Chem. 1963, 28, 3007–3009). In ad-
dition, the ring strain energy of producing an all-planar eight-
membered ring is assessed at about 23 kcal/mol (A. Streit-
weiser Jr., Molecular Orbital Theory for Organic Chemists, Wiley,
New York, 1962, p. 283); b) Up to 81 kcal/mol, the mean bond
CCDC-956943 (for 21), -956944 (for 23), -956942 (for 24) and
-956945 (for 26) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this article):
Copies of the 1H- and 13C-NMR spectra with fully displayed DEPT
and IR spectra.
3
stabilization energy for the fully formed Csp3–Csp σ-bond be-
tween asterisked N- and C-atoms in 2, see: J. Waser, K. N. True-
blood, C. M. Knobler, Chem. One, McGraw-Hill, New York,
1976.
[11]
K. Ziegler, H. Zeiser, Justus Liebigs Ann. Chem. 1931, 485, 174–
179.
[12]
[13]
[14]
H. Gilman, J. J. Eisch, J. Am. Chem. Soc. 1959, 81, 4000–4003.
J. J. Eisch, H. Gilman, Chem. Rev. 1957, 57, 525–581.
Cf. J. J. Eisch, J. Org. Chem. 1963, 28, 707–710, where the 2:1
lithium-biphenyl adduct in refluxing THF has been shown to
cleave THF to 1-butanol after subsequent hydrolysis.
W. Metlesics, R. Tavares, L. H. Sternbach, J. Org. Chem. 1966,
31, 3356–3362.
O. F. Foote, D. W. Knight, A. C. Low, Y. F. Li, Tetrahedron Lett.
2007, 8, 647–650.
Carbolithiations of diazocine 4 at radical sites depicted in 34a,
34b, 34c and 34d are suggested by the 1,2- and 1,4-additions
Acknowledgments
Our continuing studies on cyclic diimines have been partly supported
by a grant from Dr. John M. Birmingham of the Boulder Scientific
Company, Mead, Colorado. The 1H-NMR and 13C-NMR spectra
reported here were recorded at the regional NMR Facility at Bing-
hamton University on the 600 MHz instrument, obtained from the
US National Science Foundation (NSF) under grant number CHE-
0922815. The NRMS measurements were obtained from the Molec-
ular Mass Spectrometry Faiclity in the University of California, San
[15]
[16]
[17]
Eur. J. Org. Chem. 2015, 7384–7394
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7393

J. J. Eisch, W. Liu, L. Zhu, A. L. Rheingold
FULL PAPER
occurring with diazocine 3 and the anomalous carbolithiations [19] National Institute of Advanced Industrial Science and
observed with diazocine 4 (Schemes 4, 6 and 7).
Technology;
cgi-bin/creindex.cgi.
[20] F. Jensen, J. Org. Chem. 1960, 25, 269.
Received: August 3, 2015
website:
http://riodb01.ibase.aist.go.jp/sdba/
[18] General detailed procedures for purification and drying and
conducting organometallic reactions under an inert atmosphere
are available, see: J. J. Eisch, Organomet. Synth. 1981, 2, 7–25;
J. J. Eisch, Organomet. Synth. 1981, 2, 94–96.
Published Online: October 16, 2015
7394
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7384–7394