The synthesis of 9,10-dihydro-9-,10-(methaniminomethano)anthracene and N-protected derivatives via double reductive amination

Article abstract of DOI:10.1081/SCC-200030972

An efficient synthesis of 9,10-dihydro-9,10-(methaniminomethano)anthracene and several N-protected derivatives is described via the double reductive animation of cis-9,10-dihydro-9,10-dicarboxaldehyde.

Full text of DOI:10.1081/SCC-200030972

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3481–3489, 2004
The Synthesis of 9,10-Dihydro-9,10-
(Methaniminomethano)Anthracene and
N-Protected Derivatives Via Double
Reductive Amination
*
Patrick Stoy, Jenny Rush, and William H. Pearson
Department of Chemistry, University of Michigan, Ann Arbor, Michigan,
USA
ABSTRACT
An efficient synthesis of 9,10-dihydro-9,10-(methaniminomethano)an-
thracene and several N-protected derivatives is described via the double
reductive amination of cis-9,10-dihydro-9,10-dicarboxaldehyde.
Key Words: Anthracene; Bicyclic amine; Double reductive amination;
Heterocycle.
In the course of investigations into the generation of 2-azaallyl anions[1,2]
via cycloreversions of N-metallated nitrogen-containing heterocycles,[3–5] we
*
Correspondence: William H. Pearson, Berry & Associates, Inc., 2434 Bishop Circle
East, Dexter, Michigan 48130, USA; E-mail: wpearson@berryassoc.com.
3481
DOI: 10.1081/SCC-200030972
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Stoy, Rush, and Pearson
had a need to synthesize the secondary amine 1 [9,10-dihydro-9,10-(methani-
minomethano)anthracene] in several protected forms 2–4 (Sch. 1). However,
we discovered only one synthesis of 1 in the literature,[6] proceeding in 3%
yield over four steps from anthracene. We therefore devised a more practical
and efficient route to 1 and several N-protected derivatives thereof through the
double reductive amination of the known[7] cis-dialdehyde 5.
Murdock and coworkers have synthesized the cis-dialdehyde 5 starting with
the Diels-Alder reaction of anthracene and vinylene carbonate.[7] We followed
Murdock’s route with only minor changes (Sch. 2). Murdock reported the for-
mation of carbonate 6 in 95% yield by heating anthracene and vinylene carbon-
ate (10 eq.) at reflux (ꢀ1908C) for 8 h. We employed a smaller excess (5 eq.) of
neat vinylene carbonate with no loss in yield. Newman and Addor first accom-
plished this transformation in 88% yield by heating vinylene carbonate (8 eq.),
anthracene, and benzene in a sealed tube at 160–1708C for 12h.[8] Several vari-
ations on this approach to 6 have since emerged.[9,10] The hydrolysis of 6 to give
the diol 7 using sodium hydroxide or potassium hydroxide in water or aqueous
ethanol has been reported.[7–11] We employed sodium hydroxide in a methanol/
THF/water mixture at room temperature for this transformation. Diol 7 has also
been made from the dihydroxylation of dibenzobicyclo[2.2.2]octatriene by stoi-
chiometric potassium permanganate[12,13] and osmium tetroxide.[13] Repeating
Murdock’s procedure, diol 7 was cleanly oxidized to cis-dialdehyde 5 with
sodium periodate,[7] a transformation also reported using lead tetraacetate as
oxidant.[7,11,14] No trans-dialdehyde 5, previously synthesized by Lin and
coworkers by another route,[15] was detected by 1H NMR or Fourier-transform
infrared (FT-IR) spectroscopy, and the product was used directly without further
purification. Up to this point, no chromatography was necessary.
Double reductive amination of cis-dialdehyde 5 using conditions developed
by Barili et al.[16] for the synthesis of 1-deoxy-D-galactostatin derivatives gave
amine 1 in about 40% yield (Sch. 3). However, the polar nature of 1 made it
difficult to isolate from similarly polar byproducts. Ultimately, it was found
Scheme 1. 9,10-Dihydro-9,10-(methaniminomethano)anthracene and N-protected
derivatives.

9,10-Dihydro-9,10-(Methaniminomethano)Anthracene
3483
Scheme 2. Murdock’s route to cis-dialdehyde 5.
that double reductive amination of the cis-dialdehyde 5 with p-methoxybenzy-
lamine (PMB amine) gave the N-PMB derivative 2 in 74% yield. Hydrogenation
of the N-PMB group proved sluggish using various palladium (Pd(OH)2, 10%
Pd-C) and hydrogen sources (H2, HCO2NH4, cyclohexene).[17–19] Treatment
of 2 with DDQ led only to decomposition.[20] However, reaction of 2 with
benzyl chloroformate in refluxing benzene[21] gave the N-carbobenzyloxy
(Cbz)-protected amine 3 in excellent yield (93%). The N-Cbz amine 3 could
be converted to amine 1 by catalytic hydrogenation (H2-Pd/C) in 67%
yield, or directly to the N-Boc derivative 4 in 79% yield when employing
di-tert-butyl dicarbonate[22] in the reaction. Purification of 1 was accomplished
by chromatography on silica gel deactivated with hexamethyldisilazane.a
In summary, we developed an efficient synthesis of 9,10-dihydro-9,10-
(methaniminomethano)anthracene 1 in 41% overall yield from anthracene
using double reductive amination of known cis-dialdehyde 5, a route that
also allows access to N-protected derivatives 2, 3, and 4.
a
˚
Procedure for deactivating silica gel: Silica gel (60 A) was dispersed in a 4:1 mixture
of hexanes and hexamethyldisilazane (HMDS) and the resulting slurry added to a
chromatography column. The column was washed thoroughly with 4:1 hexanes/
ethyl acetate, then again washed thoroughly with hexanes prior to loading the
sample onto the column.

3484
Stoy, Rush, and Pearson
Scheme 3. Synthesis of 1 and N-PMB, N-Cbz, and N-Boc derivatives.
EXPERIMENTAL
9,10-Dihydro-9,10-(methaniminomethano)anthracene (1). Palladium
on carbon (10%, 38 mg) was added to a solution of 3 (70 mg, 0.197 mmol)
in 4:1 MeOH/THF (5 mL) at rt under argon. A balloon of hydrogen was
attached and the reaction mixture was briefly flushed with H2. After 1.5 h at
room temperature (rt), the reaction was diluted with CH2Cl2, filtered
through Celite, and concentrated. The residue was chromatographed (10%
to 20% ethyl acetate/hexanes gradient, deactivateda silica gel) to yield

9,10-Dihydro-9,10-(Methaniminomethano)Anthracene
3485
29 mg (67%) amine 1 as a colorless film. No spectroscopic data have been pre-
viously published for this known[6] compound. Rf ¼ 0.33 (50% ethyl acetate/
hexanes on neutral alumina, stained with I2); IR (CH2Cl2) 3351 (w) cm21; 1H
NMR (400 MHz, CDCl3) d 7.28–7.23 (m, 4 H), 7.20–7.16 (m, 4 H), 3.83
(t, J ¼ 3.3 Hz, 2 H), 2.98 (d, J ¼ 3.3 Hz, 4 H), 1.90 (br, 1 H); 13C NMR
(100 MHz, CDCl3) d 142.58, 126.39, 125.73, 49.71, 48.76; MS (EI, 70 eV)
m/z (rel. intensity) 221 (Mþ, 49), 178 ([anthracene]þ, 100); HRMS (EI, 70
eV) calcd for C16H15N (Mþ) 221.12045; found, 221.1205.
12-(p-Methoxyphenyl)methyl)-9,10-dihydro-9,10-(methaniminometha-
no)anthracene (2). p-Methoxybenzylamine (58 mg, 0.42 mmol) and acetic
acid (25 mg, 0.42 mmol) were dissolved in CH2Cl2 (4 mL) and cooled to
2788C. Dialdehyde 5 (100 mg, 0.42 mmol) was added in one portion at
2788C, followed by sodium cyanoborohydride (33 mg, 0.53 mmol). After
1 h at 2788C, a second portion of sodium cyanoborohydride was added
(33 mg, 0.53 mmol) and stirred for one additional hour at 2788C, then
allowed to warm to rt. After 18 h at rt, the reaction was diluted with ethyl
acetate, washed with 10% Na2CO3 (2x) brine, dried (Na2SO4), and concen-
trated. The residue was chromatographed (10% ethyl acetate/hexanes) to
yield 107 mg (74%) of 2 as a yellow oil. Rf ¼ 0.40 (30% ethyl acetate/
1
hexanes, stained with I2); H NMR (400 MHz, CDCl3): d 7.12–7.25 (m, 8
H), 6.79 (d, J ¼ 8.8 Hz, 2 H), 6.72 (d, J ¼ 8.8 Hz, 2 H), 4.00 (t, J ¼ 3.8 Hz,
2 H), 3.75 (s, 3 H), 3.40 (s, 2 H), 2.71 (d, J ¼ 3.8 Hz, 4 H); 13C NMR
(100 MHz, CDCl3): d 158.35, 143.05, 130.59, 129.32, 126.02, 125.11,
113.38, 61.31, 56.07, 55.14, 47.51; MS (EI, 70 eV) m/z (rel. intensity) 341
(Mþ, 5), 221 ([M 2 p-C6H4OCH3]þ, 4), 178 ([anthracene]þ, 27), 135 (p-H2-
NCH2C6H4OCHþ3 , 100), 121 (p-CH2C6H4OCHþ3 , 78); HRMS (EI): m/z
calcd for C24H23NO (Mþ): 341.17796; found, 341.1785.
12-Benzyloxycarbonyl-9,10-dihydro-9,10-(methaniminomethano)an-
thracene (3). A solution of 2 (434 mg, 1.27 mmol) in benzene (15 mL) was
treated with benzyl chloroformate (326 mg, 1.91 mmol) and heated at reflux.
After 6 h, the reaction was cooled to rt and treated with NH4Cl (aq). The
mixture was extracted with ethyl acetate (2x), which was washed with
brine, dried (Na2SO4), and concentrated. The residue was chromatographed
(10% to 30% ethyl acetate/hexanes gradient) to afford 421 mg (93%) of N-
Cbz derivative 3 as a white solid. Melting point (mp) 121–1228C;
Rf ¼ 0.53 (30% ethyl acetate/hexanes); IR (CH2Cl2) 1696 (s) cm21
;
1H
NMR (400 MHz, CDCl3) d 7.34–7.28 (m, 5 H), 7.26–7.22 (m, 2 H), 7.21–
7.15 (m, 4 H), 7.10–7.06 (m, 2 H), 4.80 (s, 2 H), 4.10 (t, J ¼ 3.7 Hz, 1 H),
4.03 (t, J ¼ 3.7 Hz, 1 H), 3.80 (dd, J ¼ 4.0, 5.5 Hz, 4 H); 13C NMR
(100 MHz, CDCl3) d 156.31, 141.91, 141.79, 136.77, 128.34, 127.74,
127.55, 126.73, 126.54, 125.99, 125.73, 66.96, 49.35, 48.87, 47.21; MS (EI,
70 eV) m/z (rel. intensity) 355 (Mþ, 16), 264 ([M 2 PhCH2]þ, 11), 220

3486
Stoy, Rush, and Pearson
([M 2 CO2Bn]þ, 16), 178 ([anthracene]þ, 18), 91 (PhCHþ2 , 100); HRMS (EI,
70 eV) calcd for C24H21NO2 (Mþ) 355.15723; found, 355.1578.
12-tert-Butoxycarbonyl-9,10-dihydro-9,10-(methaniminomethano)an-
thracene (4). Palladium on carbon (10%, 10 mg) was added to a solution of 3
(50.0 mg, 0.141 mmol) and di-tert-butyl dicarbonate (61.5 mg, 0.282 mmol) in
4:1 MeOH/THF (2.5 mL) at rt under argon. A balloon of hydrogen was
attached and the reaction mixture was briefly flushed with H2. After 1.5 h at
rt, the reaction was diluted with CH2Cl2, filtered through Celite, and concen-
trated. The residue was chromatographed (1% to 30% ethyl acetate/hexanes
gradient) to yield 37.6 mg (79%) of N-Boc derivative 7 as a waxy white
solid. Rf ¼ 0.46 (20% ethyl acetate/hexanes); IR (CH2Cl2) 1691 (s) cm21
;
1H NMR (400 MHz, CDCl3) d 7.33–7.29 (m, 2 H), 7.28–7.24 (m, 2 H),
7.20–7.16 (m, 1 H), 4.07 (t, J ¼ 3.7 Hz, 1 H), 4.02 (t, J ¼ 4.0 Hz, 1 H),
3.73 (d, J ¼ 3.7 Hz, 2 H), 3.71 (d, J ¼ 4.0 Hz, 2 H), 1.16 (s, 9 H); 13C
NMR (100 MHz, CDCl3) d 155.40, 142.09, 142.03, 126.54, 126.37, 126.00,
125.67, 79.38, 49.44, 47.85, 47.47, 47.41, 27.97; MS (EI, 70 eV) m/z (rel.
intensity) 321 (Mþ, 20), 265 ([M 2 tBu]þ, 77), 220 ([M 2 COt2Bu]þ, 44),
178 ([anthracene]þ, 56), 57 (tBuþ, 100); HRMS (EI, 70 eV) calcd for
C21H23NO2 (Mþ) 321.172879; found, 321.1726.
cis-9,10-Dihydroanthracene-9,10-dicarboxaldehyde (5). The known
title compound was prepared from diol 7 by the method of Murdock and
coworkers.[7] The material was homogeneous by 1H NMR, matched reported
values,[7] and was used without further purification. Complete spectral data
have not previously been published for this compound. IR (CH2Cl2): 2689
1
(w), 1722 (s) cm21; H NMR (300 MHz, CDCl3): d 9.45 (d, J ¼ 0.8 Hz, 2
H), 7.44 (s, 8 H), 4.97 (d, J ¼ 0.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3): d
196.61, 130.54, 129.84, 128.90, 60.24.
cis-3a,4,9, 9a-Tetrahydro-4,9[10,20]-benzenonaphtho[2,3-d]-1,3-dioxol-
2-one (6). The known title compound (also known as cis-9,10-dihydro-
9,10-ethanoanthracene-11,12-diol carbonate) was prepared from anthracene
and vinylene carbonate according to the procedure of Murdock and co-
workers,[7] except that five equivalents of vinylene carbonate were employed
rather than 10 equivalents with no loss in yield. This material was homo-
1
geneous by H NMR, matched reported values,[9,23] and was used without
further purification. Complete spectral data have not previously been pub-
lished for this compound.b IR (CH2Cl2): 1793 (s) cm21
;
1H NMR
(400 MHz, DMSO-D6): d 7.46 (app dd, J ¼ 5.6, 3.6 Hz, 2 H), 7.43 (app dd,
1
bThe H NMR spectra for compounds 6 and 7 in CDCl3 have recently been reported
1
(see Refs. 9 and 25), but without H-1H coupling constants or mention of the spec-
trometer field strength.

9,10-Dihydro-9,10-(Methaniminomethano)Anthracene
3487
J ¼ 5.6, 3.2 Hz, 2 H), 7.24 (app dd, J ¼ 4.8, 2.8 Hz, 4 H), 5.03 (t, J ¼ 2.2 Hz, 2
H), 4.87 (t, J ¼ 1.8 Hz, 2 H); 13C NMR (100 MHz, DMSO-D6): d 153.89,
138.06, 137.22, 127.27, 126.93, 126.33, 125.65, 75.94, 46.37; MS (CI-NH4)
m/z (rel. intensity): 282 ([M þ NH4]þ, 100), 178 ([anthracene]þ, 32).
cis-9,10-Dihydro-9,10-ethanoanthracene-11,12-diol (7). By a new
procedure for this known compound,[7–11,23] methanol (20 mL), THF
(20 mL), and 3 M NaOH (20 mL) were added to cyclic carbonate 6 (1.37 g,
5.17 mmol) and the dispersion was stirred for 20 h at rt. The reaction was
diluted with water, extracted with ethyl acetate (2x), and the combined
organic phases were washed with brine, dried (Na2SO4), and concentrated
to yield 1.20 g (98%) 7 as a white powder. This material was homogeneous
1
by H NMR, matched reported values,[9,23] and was used without further
purification. Complete spectral data have not previously been published for
b
this compound. Mp 199–2018C (lit.[8] 201.9–202.78C); IR (CH2Cl2): 3380
1
(br s) cm21; H NMR (400 MHz, CDCl3): d 7.39 (app dd, J ¼ 5.5, 3.3 Hz,
2 H), 7.32 (app dd, J ¼ 5.6, 3.3 Hz, 2 H), 7.22 (app dd, J ¼ 5.6, 3.2 Hz, 2
H), 7.26 (app dd, J ¼ 5.2, 3.2 Hz, 2 H), 4.41–4.44 (m, 2 H), 4.06–4.09
(m, 2 H), 2.07–2.10 (m, 2 H); 13C NMR (100 MHz, CDCl3): d 139.89,
138.56, 126.75, 126.54, 124.76, 68.16, 51.33; MS (EI, 70 eV) m/z (rel. inten-
sity): 178 ([anthracene]þ, 100).
ACKNOWLEDGMENTS
We thank Bristol-Myers Squibb for a fellowship for P. Stoy, the National
Science Foundation for a REU undergraduate fellowship (CHE 0097585) for
J. Rush, and the National Institutes of Health for funding (GM 52491).
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Received in the USA June 2, 2004