N-methyl azidonation of N,N-dimethylarylamines with the iodosylbenzene /trimethylsilylazide reagent combination and some reactions of α- azidomethylamines

Article abstract of DOI:10.1055/s-1998-5922

Treatment of N-N-dimethylarylamines with iodosylbenzene/trimethylsilylazide results in functionalization of one of the methyl groups to give the N-azidomethyl derivative. Excess reagent produces the bis-azidomethyl adduct. The azidomethyl group can be hydrolyzed, resulting in overall demethylation. Alternatively, the azide group can be replaced by an alkyl or aryl residue thus providing a new route to unsymmetrical N,N-methylalkylarylamines from a symmetrical starting material.

Full text of DOI:10.1055/s-1998-5922

April 1998
SYNTHESIS
547
N-Methyl Azidonation of N,N-Dimethylarylamines with the Iodosylbenzene/Trimethyl-
silylazide Reagent Combination and some Reactions of α-Azidomethylamines
Philip Magnus,* Jérôme Lacour, Wolfgang Weber
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA
Fax +1(512)4717839; E-mail: p.magnus@mail.utexas.edu
Received 27 May 1997
Abstract: Treatment of N,N-dimethylarylamines with iodosyl-
benzene/trimethylsilylazide results in functionalization of one of
the methyl groups to give the N-azidomethyl derivative. Excess
reagent produces the bis-azidomethyl adduct. The azidomethyl
group can be hydrolyzed, resulting in overall demethylation.
Alternatively, the azide group can be replaced by an alkyl or aryl
residue thus providing a new route to unsymmetrical N,N-methyl-
alkylarylamines from a symmetrical starting material.
5 minutes. Even 4-N,N-dimethylaminopyridine 11 (DMAP)
(entry 3) is converted into azidomethylene adduct 12, al-
though the reaction requires twice the amount of PhIO/
TMSN . Only in the case of p-bis-N,N-dimethylami-
3
nobenzene 19 (entry 7) was the more normal electrophilic
4
substitution to give 20 observed. During the conversion
of 19 into 20 a fleeting blue color was observed (which
changed to yellow), and is most probably the aminium
radical-cation, Würsters salt. While the azidomethylene
Key words: azidonation, iodosylbenzene, Mannich reaction,
trimethylsilylazide, N-azidomethylene
5
adducts were stable enough to be used in subsequent reac-
tions, in general they were too labile to be purified by
While examining the scope of the β-azidonation reaction chromatography. Secondary aromatic amines reacted
(
Scheme 1, 1 into 2) we treated 3 with PhIO/TMSN with with PhIO/TMSN to give a complex mixture of products.
3
3
the expectation of producing 5, and subsequently exposed Subsequent to this work Zhdankin has reported the direct
6,7
the crude reaction mixture to Me AlCl/allyltri-n-butyl- methylamidation of ArNMe using amidoiodanes.
stannane, anticipating that 6 would result. Surprisingly,
(60%) was the only isolated product! This implies that
2
2
1
–3
4
oxidation of the -NMe group in 3 had taken place, and
2
subsequent ionization to an iminium ion followed by trap-
ping with allyltri-n-butylstannane results in 4. To assess
the scope of this reaction and to identify the intermediate
oxidation product we have treated a variety of simple aro-
matic N,N-dimethylamines with PhIO/TMSN3.
Scheme 1
Following the reaction of 7 with PhIO/TMSN /CDCl by
3
3
1
H NMR we observed the rapid formation of the amino-
methylene azide 8, iodobenzene and (TMS) O in a very
2
clean transformation. The Table lists the results for a num-
ber of electron-rich N,N-dimethylarylamines (entries 1,2
and 4–6), and in all cases the N-methyl group is converted
into the N-azidomethylene functionality in high yield
1
13
(
> 95%) as judged by NMR [ H, δ 4.85 (2H, s) and C δ
70.5 ppm]. All of the conversions are complete within

5
48
Papers
SYNTHESIS
Azidonation of the unsymmetrical substrate 21 gave 22 Reactions of Mono- and Bis-Azidomethyl Amines
and 23 in a 1:2 ratio, and likewise 24 gave 25 and 26
(
1.8:1). Also the trideuteriomethyl substrate 27 gave a While the α-azidomethylamines are too labile to permit
mixture of 28 and 29 in a ratio of 1:4.1 in CDCl , and 1:3.6 ready isolation, they are generated in the presence of mod-
3
in THF. In CDCl a first order kinetic isotope effect (k / erately innocuous byproducts (PhI and TMS O), and
3
H
2
kD = 4.1) is thus observed, and in tetrahydrofuran, a simi- therefore can be subjected to further transformations in
lar ratio is obtained (k /k = 3.6). Therefore, hydride ab- situ. For example, conversion of 13 into 14 followed by
H
D
straction is the rate determining step and the fairly low workup with aqueous sodium bicarbonate gave 32 (88%).
value of the isotope effect indicates that the transition This is to be contrasted with an acidic workup which gave
8
state is not symmetrical. The above results also provide a complex mixture of products, although if zinc chloride
circumstantial evidence for a direct hydride abstraction in diethyl ether was used a low yield of 33 (15%) was ob-
from the least hindered position rather than hydrogen tained (Scheme 4). The formation of 33 is clearly indica-
atom abstraction by N3
ical (Scheme 2).
•
radicals or an iodine centered rad- tive of the potential of α-azidomethylamines to be
precursors to Mannich-type chemistry.9
Scheme 2
Interestingly, when the quantities of PhIO and TMSN are
3
doubled, a second azidonation takes place on the remain-
ing NMe group resulting in the bis(N,N-azidomethyl) de-
rivatives. For example, 7 was converted into 30, and 13 Scheme 4
into 31 (Scheme 3). The compounds 30 and 31 are ex-
tremely unstable with respect to hydrolysis but can be In a “one pot” sequence 7 was treated with PhIO/TMSN3
used in situ for further transformations (see Scheme 5). and the intermediate 8 directly exposed to PhMgBr to give
The bis-azidonation reaction does not take place in THF 34 (75%). Similarly, treatment of 13 with PhIO/TMSN3
and stops at the mono-azidonation product. The regio- followed by exposure to MeMgBr and separately PhMgBr
chemistry of the second azidonation is in agreement with gave 35 (90%) and 36 (98%), respectively.1
0,11
a hydride abstraction mechanism rather than a hydrogen
The same type of transformation can be achieved using al-
atom (radical) abstraction process.
lylstannane chemistry (Scheme 5). Treatment of 7 with
PhIO/TMSN3 followed by allyl tri-n-butylstannane/
Me AlCl gave 37 (45%). Likewise, except zinc chloride
2
was employed as the Lewis acid, 13 was converted into 38
(
93%). If the amount of PhIO/TMSN is approximately
3
doubled, 13 can be converted into 39 in modest yield
27%).
(
The α-azidomethylamines also react with ethyl vinyl
ether to give tetrahydroquinolines (Scheme 6).12 Treat-
ment of in situ generated 14 with ethylvinyl ether/
Me AlCl/CH Cl at 0°C gave the adducts 40 (17%) and
2
2
2
Scheme 3
41 (58%). Prolonged reaction slowly converted 41 into

April 1998
SYNTHESIS
549
1
3
C NMR (75 MHz, CDCl ) δ = 160.7, 148.7, 130.0, 106.8, 104.1,
3
1
00.8, 70.5, 55.2, 39.0.
In general the adducts 8–20 are too unstable to permit chromatograph-
ic purification, but can be used in situ. Attempts to obtain mass spec-
tral data were unsuccessful. All the azides exhibited a characteristic
–
1
strong infrared absorption at 2100 cm .
N-Azidomethyl-N-methylaniline (10):
Procedure 1: Compound 9 (131 mg, 1.0 mmol), iodosylbenzene
(
264 mg, 1.2 mmol) and trimethylsilylazide (172 µL, 1.3 mmol).
1
H NMR (300 MHz, CDCl ) δ = 7.29–7.23 (2H, m), 6.87–6.84
3
(3H,m), 4.85 (2H, s), 3.09 (3H, s).
4
-N-Azidomethyl-N-methylaminopyridine (12):
Procedure 1: Compound 11 (64 mg, 0.50 mmol), iodosylbenzene
204 mg, 1.2 mmol) and trimethylsilylazide (172 µL, 1.3 mmol).
(
1
H NMR (300 MHz, CDCl ) δ = 8.22 (2H, dd, J = 1.4, 5.3 Hz), 6.66
3
(2H, dd, J = 1.2, 5.3 Hz), 4.82 (2H, s), 3.13 (3H, s).
Scheme 5
1
-N-Azidomethyl-N-methylnaphthylamine (14):
Procedure 1: Compound 13 (171 mg, 1 mmol), iodosylbenzene
396 mg, 1.8 mmol) and trimethylsilylazide (310 µL, 2.3 mmol).
4
0. Treatment of 7 with PhIO/TMSN , followed by the
3
(
TBS-enol ether derived from acetophenone in the pres-
1
H NMR (300 MHz, CDCl ) δ = 8.12–8.08 (1H, m), 7.83–7.79 (1H,
3
ence of LiBPh gave 42 (47%) and 43 (8%). The overall
m), 7.62–7.03 (5H, m), 4.78 (2H, s), 3.04 (3H, s).
4
conversion of 7 into 42 and 43 takes place under excep-
tionally mild reaction conditions.
4
-N-Azidomethyl-N-methyltoluidine (16):
Procedure 2. To a suspension of iodosylbenzene (freshly prepared,
28 mg, 2.4 mmol) and 15 (270 mg, 2.0 mmol) in THF (10 mL) at 0˚C
was added trimethylsilylazide (400 µL, 3.0 mmol). After 2 min the
mixture was quenched with H O (10 mL) and Et O (10 mL). The
5
2
2
phases were separated and the organic layer washed with brine
(
10 mL). The combined aqueous layers were extracted with Et O
2
(
2 × 10 mL), dried (Na SO ), filtered, and evaporated in vacuo. The
2
4
1
H NMR spectrum shows only iodobenzene, TMS O and 16.
2
1
H NMR (300 MHz, CDCl ) δ = 7.10 (2H, d, J = 8.5 Hz), 6.81 (2H,
3
d, J = 8.5 Hz), 4.87 (2H, s), 3.08 (3H, s), 2.28 (3H, s).
1
-N-Azidomethyl-N-methylamino-2,4,6-trimethylbenzene (18):
Procedure 1: Compound 17 (163 mg, 1 mmol), iodosylbenzene
264 mg, 1.2 mmol) and trimethylsilylazide (200 µL, 1.5 mmol). The
(
1
H NMR spectroscopic data shows only iodobenzene, TMS O and
8.
2
1
1
H NMR (300 MHz, CDCl ) δ = 6.86 (2H, s), 4.60 (2H, s), 2.94 (3H,
3
s), 2.29 (6H, s), 2.25 (3H, s).
2
-Azido-1,4-(N,N-tetramethylbisamino)benzene (20):
Procedure 1: Compound 19 (82 mg, 0.5 mmol), iodosylbenzene
132 mg, 0.6 mmol) and trimethylsilylazide (100 µL, 0.75 mmol). As
Scheme 6
(
soon as the trimethylsilylazide was added, the color of the solution be-
came deep blue. After 5 min the color became yellow. H NMR data
1
The ability to selectively functionalize ArNMe groups
2
under very mild conditions, and subsequently conduct
Mannich-type chemistry on the NCH N group, has po-
tential applications to the synthesis of heterocycles.
shows only iodobenzene, TMS O and 20. The product was purified
by chromatography over silica gel eluting with CH2Cl2 to give 20 (91
2
2
3
mg, 89%).
–
1
IR (film): ν = 2937, 2860, 2825, 2014, 1615 cm .
1
H NMR (300 MHz, CDCl ) δ = 6.94 (1H, d, J = 8.75 Hz), 6.46 (1H,
3
Important Cautionary Information: Reactions involving TMSN3
are capable of being violently explosive. It is important to make cer-
tain that the evolution of dinitrogen is complete before workup. The
reactions must not be allowed to run dry and should be conducted be-
hind a safety shield.
dd, J = 8.75, 2.8 Hz), 6.40 (1H, d, J = 2.8 Hz), 2.89 (6H, s), 2.66 (6H, s).
1
3
C NMR (75 MHz, CDCl ) δ = 147.6, 137.7, 133.8, 120.7, 109.7,
3
103.8, 44.5, 40.7.
HRMS (M ) calcd for C H N 205.133. Found 205.133.
+
1
0 15 5
N,N-Bis(azidomethyl)-3-methoxyaniline (30):
3
-Methoxy-N-azidomethyl-N-methylaniline (8):
Procedure 1: To a suspension of iodosylbenzene (freshly prepared,
64 mg, 1.2 mmol) and 7 (151 mg, 1.0 mmol) in CDCl (6 mL) at 0˚C
Procedure 1: Compound 7 (85.6 mg, 0.50 mmol), doubling the quan-
tity of the reagents, iodosylbenzene (418 mg, 1.9 mmol) and trimeth-
1
2
ylsilylazide (266 µL, 2.0 mmol) in CDCl3 (12 mL). H NMR
3
was added trimethylsilylazide (200 µL, 1.5 mmol). After 5 min the
suspension became a yellow solution, which was warmed to 25˚C.
The crude mixture was directly analyzed by H and C NMR spec-
indicates a mixture of 30 and 8 (1:2.1).
1
H NMR (300 MHz, CDCl ) δ = 7.15–7.10 (1H, m), 6.30–6.20 (3H,
3
1
13
m), 4.84 (4H, s), 3.78 (3H, s).
troscopy and showed only iodobenzene, TMS O and 8. This reaction
2
can also be performed in CH Cl or THF.
1-N,N-Bis(azidomethyl)naphthylamine (31):
Procedure 1: Compound 13 (85.6 mg, 0.50 mmol), doubling the quan-
tity of the reagents, iodosylbenzene (418 mg, 1.9 mmol) and trimeth-
2
2
1
H NMR (300 MHz, CDCl ) δ = 7.18 (1H, t, J = 8.1 Hz), 6.50–6.41
3H, m), 4.85 (2H, s), 3.78 (3H, s), 3.09 (3H, s).
3
(

5
50
Papers
SYNTHESIS
ylsilylazide (266 µL, 2.0 mmol) in CDCl (12 mL) to give 31 as the
major product. When the reaction was carried out in THF, only 14
purified by flash chromatography over silica gel eluting with hexanes
3
followed by hexanes/EtOAc (19:1) to give 36 (243 mg, 98%).
–1
was formed.
IR (film): ν = 3048, 2951, 2846, 2794, 1574 cm .
1
1
H NMR (300 MHz, CDCl ) δ = 8.10–7.00 (7H, m), 4.83 (4H, s).
H NMR (300 MHz, CDCl ) δ = 8.45–8.41 (1H, m), 7.91–7.87 (1H, m),
3
3
7
.62–7.33 (9H, m), 7.15 (1H, d, J = 7.3 Hz), 4.33 (2H, s), 2.83 (3H, s).
1
3
N-Methyl-1-naphthylamine (32):
Trimethylsilylazide (1.0 mL, 7.6 mmol, 1.9 eq) was added to a sus-
pension of iodosylbenzene (1.58 g, 7.2 mmol, 1.8 eq) and 13 (685 mg,
C NMR (75 MHz, CDCl ) δ = 150.1, 138.7, 134.8, 129.1, 128.3,
3
1
28.2, 127.0, 125.8, 125.7, 125.3, 123.7, 115.5, 61.4, 41.6.
+
HRMS (M ) calcd for C H N 247.136. Found 247.136.
1
8 17
4
.0 mmol, 1 eq) at 0˚C in THF (30 mL). After 10 min, Et O (20 mL)
2
and sat. aq. NaHCO (20 mL) were added, and the organic phase
washed with sat. aq NaHCO (15 mL) and brine (15 mL). The aque-
ous phase was extracted with Et O (2 × 15 mL), and the extracts dried
3
N-(But-3-enyl)-3-methoxy-N-methylaniline (37):
3
Using the procedure described below, 7 (151 mg, 1.0 mmol), iodosyl-
benzene (264 mg, 1.2 mmol), trimethylsilylazide (172 µL, 1.3 mmol),
and allyl tri-n-butylstannane (372 µL, 1.2 mmol). The reaction was
2
(Na SO ), and evaporated in vacuo. The product was purified by
2 4
chromatography over silica gel eluting with hexanes/EtOAc (17:3) to
carried out in CH Cl (5 mL), and with Me AlCl (1.05 mL, 1.0 M in
2
2
2
give 32 (554 mg, 88%).
hexane, 1.05 mmol). The product was purified by flash chromatogra-
phy over silica gel eluting with hexanes followed by hexanes/EtOAc
1
,1-Bis(4-N-methylaminonaphthalene)methane (33):
(
23:2) to give 37 (86.0 mg, 45%).
IR (film): ν = 3076, 2943, 2835, 1641, 1612 cm .
H NMR (300 MHz, CDCl ) δ = 7.14 (1H, t, J = 8.0 Hz), 6.35–6.24
Trimethylsilylazide (250 µL, 1.9 mmol) was added to a suspension of
iodosylbenzene (396 mg, 1.8 mmol, 1.8 eq) and 13 (171 mg, 1.00 mmol,
–1
1
3
1
1
eq) in THF (5 mL) at 0 ˚C. After 5 min ZnCl (1.0 mL, 1.0 M in Et O
2 2
(3H, m), 5.89–5.75 (1H, m), 5.13–5.02 (2H, m), 3.81 (3H, s), 3.38
.0 eq) was added. After 17 h the mixture was quenched with Et O
2
(2H, t, J = 7.5 Hz), 2.92 (3H, s), 2.36–2.29 (2H, q, J = 7.3 Hz).
(5 mL) and sat. aq NaHCO (10 mL). The organic phase was washed
13
3
C NMR (75 MHz, CDCl ) δ = 160.7, 150.4, 135.9, 129.8, 116.4,
3
with sat. aq NaHCO (15 mL) and brine (15 mL). The aqueous phase
was extracted with Et O (15 mL) and EtOAc (15 mL). The extracts were
combined, dried (Na SO ), and evaporated in vacuo. The residue was
purified by flash chromatography over silica gel eluting with hexanes
3
105.3, 100.7, 98.7, 55.1, 52.4, 38.4, 31.1.
HRMS (MH ) calcd for C H NO 192.139. Found 192.138.
+
2
1
2 18
2
4
N-(But-3-enyl)-1-N-methylnaphthylamine (38):
followed by hexanes/EtOAc (19:1) to give 33 (21 mg, 15%).
Trimethylsilylazide (250 µL, 1.9 mmol) was added to a suspension of
iodosylbenzene (396 mg, 1.8 mmol, 1.8 eq) and 13 (171 mg,
1.00 mmol, 1 eq) in THF (5 mL). After 5 min allyl tri-n-butylstannane
–
1
IR (CHCl ) ν = 3453, 3073, 3009, 2906, 2812, 1654 cm .
3
1
H NMR (300 MHz, CDCl ) δ = 8.05–8.01 (2H, m), 7.87–7.94 (2H,
m), 7.49–7.44 (4H, m), 6.99 (2H, J = 7.75 Hz), 6.47 (2H, d, J =
3
(
372 µL, 1.2 mmol) and ZnCl (1.0 mL, 1.0 M in Et O, 1.0 eq) were
2 2
7
.75 Hz), 4.68 (2H, s), 4.35 (2H, br), 2.97 (6H, s).
added, and after 30 min the mixture was quenched with Et O (5 mL)
and sat. aq NaHCO (10 mL). The organic phase was washed with sat.
aq NaHCO (15 mL) and brine (15 mL). The aqueous phases were ex-
tracted with Et O (15 mL) and EtOAc (15 mL). The extracts were
combined, dried (Na SO ), and evaporated in vacuo. The product was
purified by flash chromatography over silica gel eluting with hexanes
1
3
2
C NMR (75 MHz, CDCl ) δ = 143.3, 132.8, 127.7, 125.8, 125.5,
3
3
1
24.9, 124.4, 124.0, 120.4, 103.8, 34.9, 31.1.
+
3
HRMS (M ) calcd for C H N 326.178. Found 326.177.
2
3
22
2
2
2
4
N-Benzyl-3-methoxy-N-methylaniline (34):
Using the procedure described below 7 (302 mg, 2.0 mmol), iodosyl-
benzene (528 mg, 2.4 mmol), trimethylsilylazide (400 µL, 3.0 mmol),
and PhMgBr (8.0 mL, 1.0 M in THF, 4 eq) gave 34. The crude product
was purified by flash chromatography over silica gel eluting with hex-
anes followed by hexanes/EtOAc (9:1) to give 34 (170 mg, 75%).
followed by hexanes/EtOAc (19:1) to give 38 (196 mg, 93%).
–1
IR (film): ν = 3050, 2977, 2953, 2849, 2796, 1640 cm .
H NMR (300 MHz, CDCl ) δ = 8.34 (1H, dd, J = 2.4, 7.1 Hz), 7.89
1
3
(
1H, dd, J = 2.8, 6.8 Hz), 7.62–7.44 (4H, m), 7.18 (1H, d, J = 0.6,
7.3 Hz), 6.00–5.86 (1H, m), 5.18–5.07 (2H, m), 3.24 (2H, t, J =
.6 Hz), 2.95 (3H, s), 2.46 (2H, q, J = 7.3 Hz).
–
1
IR (film): ν = 3061, 3028, 2936, 2834, 1614 cm .
H NMR (300 MHz, CDCl ) δ = 7.38–7.28 (5H, m), 7.20 (1H, t, J =
7
1
13
3
C NMR (75 MHz, CDCl ) δ = 150.1, 136.3, 134.8, 129.6, 128.2,
3
8
.1 Hz), 6.45 (1H, dd, J = 8.1 Hz, 1.7 Hz), 6.39–6.35 (2H, m), 4.59
125.7, 125.6, 125.1, 124.0, 123.1, 115.8, 115.7, 56.4, 42.3, 31.9.
(
2H, s), 3.82 (3H, s), 3.07 (3H, s).
+
1
3
HRMS (M ) calcd for C H N 211.136. Found 211.135.
15 17
C NMR (75 MHz, CDCl ) δ = 160.7, 151.0, 138.9, 129.8, 128.5,
3
1
26.8, 126.6, 105.4, 101.2, 98.8, 56.4, 54.9, 38.5.
+
1-N,N-Bis(but-3-enyl)naphthylamine (39):
HRMS (M ) calcd for C H NO 227.131. Found 227.130.
1
5 17
Using the above procedure from 13 (171 mg, 1.0 mmol), iodosylben-
zene (836 mg, 3.8 mmol), trimethylsilylazide (532 µL, 4.0 mmol),
and allyl tri-n-butylstannane (930 µL, 3.0 mmol). The reaction was
carried out in CH Cl (20 mL) and with Me AlCl (2.5 mL, 1.0 M in
N-Ethyl-1-N-methylnaphthylamine (35):
Trimethylsilylazide (250 µL, 1.9 mmol) was added to a suspension of io-
dosylbenzene (396 mg, 1.8 mmol, 1.8 eq) and 13 (171 mg, 1.00 mmol,
2
2
2
hexane, 2.5 mmol). The crude product was purified by flash chroma-
tography over silica gel eluting with hexanes, followed by hexanes/
EtOAc (49:1) to give 39 (67.0 mg, 27%).
1
eq) in THF (5 mL) at 0 ˚C. After 10 min MeMgBr (1.34 mL, 3.0 M in
Et O, 4.0 eq) was added to the mixture, and after 30 min the mixture was
2
quenched with Et O (5 mL) and sat. aq NaHCO (10 mL). The organic
2
3
–1
IR (film): ν = 3075, 3047, 2975, 2926, 2823, 1640 cm .
phase was washed with sat. aq NaHCO (15 mL) and brine (15 mL). The
3
1
H NMR (300 MHz, CDCl ) δ = 8.31–8.28 (1H, m), 7.82–7.79 (1H,
m), 7.55 (1H, dd, J = 8.2 Hz), 7.46–7.36 (3H, m), 7.18 (1H, d, J =
aqueous phase was extracted with Et O (15 mL) and EtOAc (15 mL).
3
2
The dried (Na SO ) extracts were evaporated in vacuo, and the residue
2
4
7
.3 Hz), 5.83–5.69 (2H, m), 5.00–4.91 (4H, m), 3.22 (4H, t, J =
.3 Hz), 2.22 (4H, q, J = 7.3 Hz).
purified by flash chromatography over silica gel eluting with hexanes fol-
7
lowed by hexanes/EtOAc (9:1) to give 35 (167 mg, 90%).
1
3
–
1
C NMR (75 MHz, CDCl ) δ = 147.7, 136.6, 134.8, 131.1, 128.1,
IR (film): ν = 3048, 2972, 2935, 2869, 1592 cm .
H NMR (300 MHz, CDCl ) δ = 8.30 (1H, dd, J = 2.3, 7.8 Hz), 7.86
3
125.7, 125.5, 125.2, 124.2, 123.7, 118.5, 115.6, 53.8, 31.6.
1
3
+
HRMS (M ) calcd for C H N 251.167. Found 251.167.
(
1H, dd, J = 2.9, 6.5 Hz), 7.59–7.42 (4H, m), 7.14 (1H, d, J = 6.9 Hz),
18 21
3
.19 (2H, q, J = 7.1 Hz), 2.91 (3H, s), 1.26 (3H, t, J = 7.1 Hz).
1
3
4-Ethoxy-N-methyl-1,2,3,4-tetrahydrobenzo[h]quinoline (40)
and N-3-Ethoxyazidopropyl-N-methylnaphthylamine (41):
Trimethylsilylazide (504 µL, 3.8 mmol) was added to a suspension of
iodosylbenzene (796 mg, 3.6 mmol, 1.8 eq) and 13 (342.5 mg, 2.0
mmol, 1 eq) in THF (10 mL) at 0˚C. After 5 min, ethyl vinyl ether
C NMR (75 MHz, CDCl ) δ = 150.3, 134.8, 129.5, 128.2, 125.6 (2),
3
1
25.1, 124.0, 122.9, 115.3, 51.5, 41.2, 12.7.
+
HRMS (M ) calcd for C H N 185.121. Found 185.120.
1
3 15
N-Benzyl-1-N-methylnaphthylamine (36):
Using the procedure described above, 13 (171 mg, 1.0 mmol), iodo-
sylbenzene (792 mg, 3.6 mmol), trimethylsilylazide (500 µL, 3.8
mmol), and PhMgBr (8.0 mL, 1.0 M in THF, 8 eq). The product was
(796 µL, 8.0 mmol, 4.0 eq) and ZnCl2 (2.1 mL, 1.0 M in Et O,
2
1.05 eq) were added. After 15 min, the mixture was quenched with
Et O (5 mL) and sat. aq NaHCO (10 mL). The organic phase was
2
3

April 1998
SYNTHESIS
551
washed with sat. aq NaHCO (15 mL) and brine (15 mL). The aqueous
The National Institutes of Health (GM 32718), National Science
Foundation and the Welch Foundation are thanked for their support
of this research. Rhône Poulenc Rorer are thanked for a graduate fel-
lowship to J.L.
3
phase was extracted with Et O (15 mL) and EtOAc (15 mL). The com-
2
bined extracts were dried (Na SO ), and evaporated in vacuo. The crude
2
4
product was purified by flash chromatography over silica gel eluting with
hexanes/EtOAc (9:1) to give 40 (83 mg, 17%) and 41 (331 mg, 58%).
4
0:
(
1) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme, C.
–
1
IR (CH Cl ) ν = 3049, 2946, 2864, 1568 cm .
2
2
J. Am. Chem. Soc. 1996, 118, 3406.
1
H NMR (300 MHz, CDCl ) δ = 8.19–8.16 (1H, m), 7.80–7.76 (1H,
3
(2) Magnus, P.; Lacour, J. J. Am. Chem. Soc. 1992, 114, 3993.
3) Magnus, P.; Lacour, J.; Weber, W. J. Am. Chem. Soc. 1993,
15, 9347.
m), 7.50–7.39 (4H, m), 4.49 (1H, t, J = 4.2 Hz), 3.83–3.73 (1H, m),
(
3
2
.70–3.60 (1H, m), 3.48–3.39 (1H, m), 3.27 (1H, dt, J = 13.3, 4.3 Hz),
.99 (3H, s), 2.09–2.05 (2H, m), 1.31 (3H, t, J = 7.0 Hz).
C NMR (75 MHz, CDCl ) δ = 145.3, 134.5, 128.1, 127.6, 125.6,
1
Magnus, P.; Hulme, C.; Weber, W. J. Am. Chem. Soc. 1994,
116, 4501.
1
3
3
1
24.8, 124.5, 124.4, 121.9, 72.9, 63.6, 47.7, 44.0, 22.2, 15.7.
P. Magnus, P.; Hulme, C. Tetrahedron Lett. 1994, 35, 8097.
+
HRMS (M ) calcd for C H NO 241.147. Found 241.147.
1
6
19
(4) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T.
Tetrahedron Lett. 1991, 34, 4321.
Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mi-
toh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
(5) Nelsen, S. F. Nitrogen-Centered Radicals in Free-Radicals,
Kochi, J. K. J., Ed.; Wiley: New York 1973.
4
1:
IR (film): ν = 3048, 2976, 2799, 2101, 1622, 1593 cm .
H NMR (300 MHz, CDCl ) δ = 8.24–8.21 (1H, m), 7.84–7.81 (1H,
–
1
1
3
m), 7.57–7.37 (5H, m), 7.13 (1H, d, J = 7.5 Hz), 4.50 (1H, t, J =
6
2
.1 Hz), 3.82–3.76 (1H, m), 3.46–3.40 (1H, m), 3.31–3.20 (2H, m),
.85 (3H, s), 2.03 (2H, q, J = 6.7 Hz), 1.17 (3H, t, J = 7.0 Hz).
C NMR (75 MHz, CDCl ) δ = 149.4, 134.8, 129.6, 128.2, 125.7,
Würster, C.; Sendther, R. Ber. 1879, 12, 1803.
1
3
(6) Zhdankin, V. V.; McSherry, M.; Mismash, B.; Bolz, J. T.;
3
Woodward, J. K.; Arbit, R. M.; Erickson, S. Tetrahedron Lett.
1
25.6, 125.3, 123.6, 123.5, 115.9, 90.9, 64.8, 51.6, 43.3, 32.6, 14.8.
+
1
997, 38, 21.
HRMS (M ) calcd for C H N O 284.164. Found 284.163.
1
6 20 4
•
3
(7) PhI(OAc) /NaN has been proposed as a source of N radicals,
2
3
Fontana, F.; Minisci, F.; Yan, Y. M.; Zhao, L, Tetrahedron Lett.
993, 34, 2517.
For a comprehensive survey of hypervalent iodine chemistry,
Varvoglis, A. The Organic Chemistry of Polycoordinated
Iodine, VCH: New York, 1992.
Electrochemical oxidation of N,N-dimethylanilines, Shono, T.;
Matsumura, Y.; Inoue, K.; Ohmizu, H.; Kashimura, S. J. Am.
Chem. Soc. 1982, 104, 5753.
Chlorine dioxide oxidation of amines, Chen, C-K.; Hortmann,
A. G.; Marzabadi, M. R. J. Am. Chem. Soc. 1988, 110, 4829.
4
-(tert-Butyldimethylsiloxy)-7-methoxy-N-methyl-4-phenylqui-
1
noline (42) and 4-(tert-Butyldimethylsiloxy)-5-methoxy-N-meth-
yl-4-phenylquinoline (43):
Synthesized in an analogous manner to 40 using the above procedure
in CH Cl with LiBPh (299 mg, 0.50 mmol, 1.0 eq) as the Lewis ac-
2
2
4
id, from 7 (76 mg, 0.50 mmol), iodosylbenzene (116 mg, 0.75 mmol),
trimethylsilylazide (100 µL, 0.75 mmol), and 1-t-butyldimethyl-
silyl(oxy) styrene (176 mg, 0.75 mmol). The crude product was puri-
fied by flash chromatography over silica gel eluting with hexanes/
EtOAc (17:3), and Kugelrohr distillation at 110˚C under high vacuum
for 2 h to give 42 (90 mg, 47%) and 43 (15 mg, 8%).
(
Alkylperoxy)iodinane oxidation of amines, Ochiai, M.; Ito, T.;
Masaki, Y.; Shiro, M. J. Am. Chem. Soc. 1992, 114, 6269.
Photoinduced electron transfer, Pandey, G.; Kumaraswamy, G.;
Reddy, P. Y. Tetrahedron, 1992, 48, 8295.
4
2:
IR (film): ν = 3086, 3047, 3026, 2928, 2854, 1620 cm .
H NMR (300 MHz, CDCl ) δ = 7.43 (2H, m), 7.33–7.23 (3H, m),
.73 (1H, d, J = 8.5 Hz), 6.18 (1H, d, J = 2.45 Hz), 6.10 (1H, dd, J =
.5, 2.45 Hz), 3.80 (3H, s), 3.52 (1H, dt, J = 3.6, 11.5 Hz), 3.13 (1H,
–
1
1
6
8
For the oxidation of amines using PhIO, see: Moriarty, R. M.;
Vaid, R. K.; Duncan, M. P.; Ochiai, M.; Inenaga, M.; Nagao, Y.
Tetrahedron Lett. 1988, 29, 6913.
3
dt, J = 11.5, 4.1 Hz), 2.15 (1H, dt, J = 4.3, 13.0 Hz), 2.02 (1H, dt, J =
3.0, 4.3 Hz), 0.97 (9H, s), –0.07 (3H, s), –0.51 (3H, s).
Ochiai, M.; Inenaga, M.; Nagao, Y.; Moriarty, R. M.; Vaid, R.
K.; Duncan, M. P. Tetrahedron Lett. 1988, 29, 6917.
Davis, G. T.; Rosenblatt, D. H. Tetrahedron Lett. 1968, 4085.
Butler, R. N. Chem. Rev. 1984, 84, 249.
Porta, F.; Crotti, C.; Cenini, S.; Palmisano, G. J. Mol. Cat. 1989,
50, 333.
1
1
3
C NMR (75 MHz, CDCl ) δ = 160.6, 149.3, 148.5, 132.0, 127.4,
3
1
1
26.7, 126.2, 119.3, 100.0, 97.1, 75.3, 55.0, 47.4, 40.9, 39.4, 26.2,
8.7, –2.7, –3.9.
+
HRMS (M ) calcd for C H NOSi 383.228. Found 383.227.
2
3 33
These authors report the dehydrogenation of primary and secon-
dary benzylamines with PhIO to give the corresponding imines.
Barton, D. H. R.; Billion, A.; Boivin, J. Tetrahedron Lett. 1985,
4
3:
IR (film): ν = 3052, 2956, 2929, 2884, 2854, 1599 cm .
H NMR (300 MHz, CDCl ) δ = 7.29–7.07 (6H, m), 6.34 (1H, d, J =
–
1
1
3
26, 1229.
8
(
.5 Hz), 6.10 (1H, d, J = 8.1 Hz), 3.40 (1H, dt, J = 4.2, 11.2 Hz), 3.13
3H, s), 3.05–2.94 (1H, m), 2.96 (3H, s), 2.05–1.98 (2H, m), 0.94 (9H,
s), –0.11 (3H, s), –0.46 (3H, s).
(
8) The primary kinetic isotope effect (PKIE) is modest, and similar
to that observed for the classical Hoffmann β-elimination.
Saunders, W. H.; Cockerill, A. F. Elimination Reactions, Wiley:
New York, 1973.
9) For recent and exhaustive reviews on Mannich bases, see:
Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
Heaney, H. The Bimolecular Aromatic Mannich Reaction in
Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I.
Eds.; Vol. 2, 953. Pergamon: New York 1991.
1
3
C NMR (75 MHz, CDCl ) δ = 158.6, 152.2, 149.0, 129.5, 127.1,
3
1
1
24.8, 124.1, 114.5, 105.1, 100.4, 74.0, 53.9, 47.4, 43.8, 40.3, 26.3,
9.0, –3.23, –3.91.
(
+
HRMS (M ) calcd for C H NOSi 383.228. Found 383.228.
2
3 33
Compound 4:
Synthesized in an analogous manner to 37 from 3 (158 mg, 0.39 mmol,
.0 eq). The product was purified by flash chromatography over Florisil
eluting with hexanes/EtOAc (9:1) to give 4 (104 mg, 60%).
1
Grieco, P. A.; Bashas, A. J. Org. Chem. 1987, 52, 1378.
(
(
10) Glacet, C.; Couturier, J. C. Bull. Chim. Soc. Fr. 1962, 2097.
11) For methodology using aminomethylbenzotriazoles: Katritzky,
A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron 1991, 47, 2683.
Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1993,
–
1
IR (film): ν = 2943, 2868, 1664, 1646, 1615 cm .
1
H NMR (300 MHz, C D ) δ = 7.38 (1H, d, J = 8.4 Hz), 6.38 (1H, dd,
6
6
J = 8.4, 2.3 Hz), 6.20 (1H, d, J = 2.3 Hz), 5.72–5.59 (1H, m), 5.15
1H, d, J = 3.4 Hz), 4.99–4.93 (2H, m), 4.30–4.20 (1H, m), 3.47 (3H,
s), 3.15 (2H, t, J = 7.4 Hz), 2.60 (3H, s), 2.22–2.07 (4H, m), 1.77–1.57
3H, m), 1.44–1.35 (1H, m), 1.20–1.02 (21H, m).
(
5
8, 812.
Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J. J. Org.
Chem. 1992, 57, 4932.
(
1
3
C NMR (75 MHz, C D ) δ = 158.2, 152.0, 149.3, 136.4, 129.5,
(12) Shono, T.; Matsumara, Y.; Inoue, K.; Ohmizu, H.; Kashimura,
S. J. Am. Chem. Soc. 1982, 104, 5753.
6
6
1
3
23.7, 116.2, 107.6, 105.2, 96.6, 54.8, 52.9, 38.4, 33.6, 31.5, 31.1,
0.4, 21.7, 18.3, 13.1.
Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855.
Hesse, K.-D. Liebigs Ann. Chem. 1970, 741, 117.
+
HRMS (M ) calcd for C H NO Si 443.322. Found 443.322.
2
7
45
2