Effect of the substitution pattern on reactions of methoxylated araldehyde 2,4-dimethylpent-3-ylimines with organolithium reagents

Full text of DOI:10.1021/jo9602175

4812
J . Org. Chem. 1996, 61, 4812-4815
Sch em e 1
Effect of th e Su bstitu tion P a tter n on
Rea ction s of Meth oxyla ted Ar a ld eh yd e
2,4-Dim eth ylp en t-3-ylim in es w ith
Or ga n olith iu m Rea gen ts†
Lee A. Flippin,* J acob Berger, J ason S. Parnes,1 and
Mark S. Gudiksen2
Division of Chemical Research and Development,
Roche Bioscience, Palo Alto, California 94304
Received February 1, 1996
In tr od u ction
Araldimines are versatile araldehyde equivalents that
may direct selective aromatic ring metalation,3 lateral
metalation,4 or nucleophilic aromatic substitution (SNAr)5
reactions depending on the choice of imine structure and
reaction conditions. Araldehyde 2,4-dimethylpent-3-
ylimines containing a suitably positioned nucleofugic
group are particularly useful substrates for SNAr reac-
tions with a variety of organolithium reagents;5 however,
it was recently observed that treatment of 2,4,5-tri-
methoxybenzaldehyde 2,4-dimethylpent-3-ylimine, 1, with
n-BuLi or PhLi (ether-hexane; -78 f +20 °C) followed
by workup with aqueous NH4Cl, afforded only unchanged
starting material rather than the expected nucleophilic
aromatic substitution products.6 This result prompted
us to conduct a more detailed study of imine 1 and the
general effect of substitution pattern on the reactions of
methoxylated araldehyde 2,4-dimethylpent-3-ylimines
with selected organolithium reagents.
Ta ble 1. SNAr Rea ction s of Ar a ld im in es w ith n -Bu Li
Resu lts a n d Discu ssion
entry imine
R3
R4
R6
reactiona productb (%)
Closer scrutiny has revealed that imine 1 undergoes
facile ortho-directed lithiation at C-6 with n-BuLi; thus,
reaction of the imine with n-BuLi (ether-hexane) fol-
lowed by a methyl iodide quench to probe for metalation
processes gave, after acid hydrolysis, aldehyde 2 in 83%
isolated yield (eq 1).
1
2
3
4
5
7
9
11
13
15
H
MeO
H
H
H
MeO
H
H
H
H
MeO
H
A
A
B
A
A
8 (70)c
10 (94)c
12 (88)
14 (73)c
16 (69)
H
MeO MeO
a
Method A: (1) n-BuLi (2) H3O+. Method B: (1) n-BuLi, (2)
CH3I (to detect possible metalation), (3) H3O+. Yields are for
b
isolated products. c Reference 5c.
Reaction of imine 3 with n-BuLi (Scheme 1) could
potentially lead to lateral metalation of the C-6 methyl
group, ring metalation at the unsubstituted C-3 position,
or SNAr replacement of the C-2 methoxy substituent. In
an initial experiment to probe this question imine 3
reacted with 1.2 equiv of n-BuLi to give a red solution
which was quenched with excess methyl iodide and
hydrolyzed to give a 4:1 ratio of aldehydes 4 and 6. When
the methyl iodide quench was replaced with a simple
hydrolytic workup the reaction of n-BuLi with imine 3
gave aldehyde 4 exclusively and in high yield. Similarly,
phenyllithium reacted smoothly with imine 3 to give
aldehyde 5. A convenient one-pot SNAr reaction-lateral
metalation-electrophilic capture sequence was demon-
strated using imine 3: Treatment of the imine with 2.5
equiv of n-BuLi gave a deep magenta solution that was
quenched with excess methyl iodide. The crude product
was hydrolyzed and purified by flash chromatography to
give aldehyde 6 in 94% yield (Scheme 1).
Although the C-5 methoxy group might be expected to
attenuate SNAr-reactivity at C-2 of imine 1, it is remark-
able that ring metalation was the exclusive reaction
pathway and occurred only at C-6 with this substrate.
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
(1) Syntex Student Intern, 1993.
(2) Roche Bioscience Student Intern, 1994.
(3) (a) Flippin, L. A.; Muchowski, J . M.; Carter, D. S. J . Org. Chem.
1993, 58, 2463. (b) Cushman, M.; Choong, T.-C.; Valko, J . T.; Koleck,
M. P. J . Org. Chem. 1980, 45, 5067. (c) Ziegler, F. E.; Fowler, K. W. J .
Org. Chem., 1976, 41, 1564.
(4) (a) Flippin, L. A.; Muchowski, J . M. J . Org. Chem. 1993, 58, 2631.
(b) Forth, M. A.; Mitchell, M. B.; Smith, S. A. C.; Gombatz, K.; Snyder,
L. J . Org. Chem. 1994, 59, 2616.
(5) (a) Flippin, L. A.; Carter, D. S.; Dubree, N. J . P. Tetrahedron
Lett. 1993, 34, 3255. (b) Reuter, D. C.; Flippin, L. A.; McIntosh, J .;
Caroon, J . M.; Hammaker, J . Tetrahedron Lett. 1994, 35, 4899.
(6) Parnes, J . S.; Carter, D. S.; Kurz, L. J .; Flippin, L. A. J . Org.
Chem. 1994, 59, 3497.
Simple araldimines containing a C-2 methoxy group
generally reacted with n-BuLi exclusively via a nucleo-
philic aromatic substitution pathway (Table 1).
However, imine 17, which in common with imines 1
and 3 contains methoxy groups at both the C-2 and C-5
S0022-3263(96)00217-4 CCC: $12.00 © 1996 American Chemical Society

Notes
Ta ble 2. Dir ected Or th o-Meta la tion of Ar a ld im in es
J . Org. Chem., Vol. 61, No. 14, 1996 4813
electron donation from the C-5 methoxy should attenuate
the rate of SNAr attack at C-2 in imine 17; the relatively
minor amount of SNAr product 21 seems to confirm this
effect.9
The general utility of the 2,4-dimethylpent-3-ylimino
group for directed metalation reactions is limited by
occasional side reactions, low selectivity or reactivity in
some examples, and unpredictability.3a For example,
benzaldehyde 2,4-dimethylpent-3-ylimine 29 suffers nu-
cleophilic addition of n-BuLi to the CdN bond under
typical metalation conditions (eq 3).
yieldb
(%)
entry imine R3
R4 reactiona product R2 R3
R4
1
2
22
22
MeO
H
A
B
no reaction
MeO Me 44
24
MeO 56
Me MeO MeO 73
23
24
26
28
H
Me MeO
Me H
H
3
4
25
27
H
MeO
B
A
MeO MeO
a
A: (1) n-BuLi, (2) CH3I (3) H3O+. B: (1) s-BuLi/TMEDA, (2)
CH3I, (3) H3O+. Yield of isolated product.
b
positions, gave a complex mixture upon treatment with
n-BuLi followed by quenching with excess methyl iodide
to assure efficient capture of any metalated intermedi-
ates. The crude imine products were hydrolyzed with
aqueous acid and the initial distribution of aldehyde
products was determined by 1H NMR analysis of the
crude reaction mixture before chromatographic separa-
tion. The distribution of aldehydes in the crude hydroly-
sis mixture was 18:19:20:21 ) 7:8:1:4, nearly identical
to the distribution of isolated aldehydes (eq 2).
In unexpected contrast to the results with imine 22,
imine 25 was easily metalated at C-2 using n-BuLi. A
methyl iodide quench of the metalation reaction mixture
and acid hydrolysis gave aldehyde 26 in modest isolated
yield; however, 1H NMR analysis of the crude hydrolysis
mixture showed that 26 was the exclusive new reaction
product (entry 3, Table 2). Similarly, imine 27 was
metalated at the C-2 position using n-BuLi (entry 4,
Table 2). Isomeric imines 31 and 33, both of which
contain potentially acidic aromatic ring positions and C-2
methyl groups, showed contrasting behavior under meta-
lation conditions (eqs 4 and 5). Imine 31 was unreactive
The reactions of simpler comparators 7 and 22 are not
readily predictive of the complex behavior of imine 17.
Thus, imine 7 undergoes facile SNAr replacement of the
C-2 methoxy group with n-BuLi with no evidence of
competitive ring metalation (entry 1, Table 1). Imine 22,
having no viable SNAr pathway available, is also quite
resistant toward ring metalation with n-BuLi (entry 1,
Table 2), although more forcing conditions (s-BuLi-
TMEDA),7 led to poorly selective metalation at C-4 and
C-2 (entry 2, Table 2). In contrast, metalation at C-6 is
the predominant reaction course for imine 17, accounting
for almost 70% of the new products (19 + 20/19 + 20 +
21 × 100%). It is likely that electron donation from the
C-2 methoxy group increases the Lewis basicity and
ortho-directing ability of the C-5 methoxy.8 Concomitant
with n-BuLi alone; however, n-BuLi-TMEDA gave selec-
tive lateral metalation to afford, after methyl iodide
quench and hydrolysis, aldehyde 32 in fair yield (eq 4).
In contrast, imine 33 underwent highly selective ortho-
metalation at C-6 with n-BuLi (eq 5).
1
In the latter instance, H NMR analysis of the crude
hydrolysis mixture showed the presence of three trace
aldehydic products (total ) ca. 10 mol %) which were not
isolated.
(7) For a discussion of the sometimes dramatic TMEDA effect on
regioselectivity of directed ortho-metalation, see: Khaldi, M; Chretien,
F.; Chapleur, Y. Tetrahedron Lett. 1994, 35, 401.
(8) For a discussion of the effect of Lewis basicity (coordinative
potential) of substitutents on directed ortho-metalation, see: (a)
Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Gschwend, H. W.; Rodriguez,
H. R. Org. React. 1979, 26, 1.
(9) The rate-lowering effect of electron-donating substitutents situ-
ated para to the nucleofuge in SNAr reactions is well known. See:
March, J . Advanced Organic Chemistry, 4th ed.; Wiley Interscience:
New York, 1992; Chapter 13 and references therein.

4814 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
156.3, 139.2, 135.7, 112.5, 60.4, 55.7, 20.9, 11.9. Anal. Calcd
for C11H14O3: C, 68.02; H, 7.26. Found: C, 68.21; H, 7.38.
Dir ected -Meta la tion of Im in e 22. A stirred solution of 610
mg (2.6 mmol) of imine 3 and 470 mg (3.1 mmol) of TMEDA in
25 mL of ether was cooled to -72 °C, and 2.4 mL (3.1 mmol) of
a 1.3 M solution of s-BuLi in cyclohexane was added dropwise
to give a yellow solution. The reaction mixture was kept at -72
°C for 1 h, and 250 mg (3.9 mmol) of CH3I was added in one
portion. The reaction mixture was warmed to room temperature
and quenched with water. The crude reaction products were
extracted with ether, dried over K2CO3, and concentrated with
a rotary evaporator to give 670 mg of a yellow oil. The oily
product was hydrolyzed in a refluxing solution of 3:1 THF-10%
aqueous HCl (2 h), and the aldehyde products were isolated by
flash chromatography to give 174 mg (44%) of 23 and 94 mg
(24%) of 24.3a
Exp er im en ta l Section
Reactions were performed under a nitrogen atmosphere using
oven-dried glassware. Solvents were dried with standard drying
agents10 and distilled before use. Melting points are uncorrected.
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded at
room temperature on CDCl3 solutions. Imines 1, 3, 7, 9, 11,
13, 15, 17, 22, 25, 27, 31, and 33 were prepared from the
corresponding aldehyde and 3-amino-2,4-dimethylpentane (Acros
Organics, NJ ) as described elsewhere.3a,5a Flash column chro-
matography11 purification of aldehydes was performed on silica
gel 60 (230-400 mesh).
Dir ected Meta la tion of Im in es. 2-Meth yl-3,4,6-tr im eth -
oxyben za ld eh yd e (2). To a -78 °C solution of 554 mg (1.9
mmol) of imine 1 in 15 mL of ether was added 1.3 mL of a 1.6
M solution of n-BuLi in hexane over 5 min. After addition was
complete the reaction mixture was allowed to warm to room
temperature for 1 h. The solution was recooled to -78 °C,
methyl iodide (0.4 mL; 6.4 mmol) was added in one portion, and
the reaction mixture was allowed to warm to room temperature
over 30 min. The reaction mixture was quenched with saturated
NH4Cl and extracted with ether to give crude imine 3. Recrys-
tallization of the crude product from hexane gave 538 mg (92%)
3-Meth oxy-4-m eth ylben za ld eh yd e (23):16 mp 40.4-40.8 °C
1
(lit.16a mp 40-41 °C); H NMR δ 9.93 (s, 1H), 7.4-7.3 (m, 3H),
3.90 (s, 3H), 2.30 (s, 3H).
Rea ction of Im in e 17 w ith n -Bu Li-CH3I. To a -70 °C
solution of 501 mg (1.9 mmol) of imine 17 in 25 mL of ether was
added 1.4 mL of a 1.6 M solution of n-BuLi in hexane over 5
min. The reaction mixture was warmed to room temperature
for 1 h, recooled to -65 °C, and quenched rapidly with 0.6 mL
(9.5 mmol) of methyl iodide. The mixture was allowed to stand
at room temperature for 1 h and diluted with water, and the
layers were separated. The ether layer was washed with brine,
dried (Na2SO4), and concentrated to give 622 mg of a yellow oil.
The crude oil was dissolved in 25 mL of 4:1 THF-water
containing 3.6 mL of 1 M aqueous HCl, and the mixture was
refluxed for 1.5 h. The reaction mixture was extracted with
ether to give 399 mg of a viscous yellow syrup. Flash chroma-
tography (100:1 hexane-EtOAc) gave 51 mg (16%) of 2,5-
dimethoxybenzaldehyde 18 and three additional product alde-
hydes:
1
of pure imine 3: mp 74.5-75 °C; H NMR δ 8.40 (s, 1H), 6.37
(s, 1H), 3.88 (s, 3H), 3.80 (s, 3H) 3.72 (s, 3H), 2.48 (s, 3H), 2.43
(t, J ) 6 Hz, 1H), 2.03 (octet, J ) 6 Hz, 2H), 0.88 (d, J ) 6 Hz,
12H); 13C NMR δ 157.3, 156.2, 153.7, 141.6, 132.9, 117.8, 94.6,
85.0, 60.4, 56.3, 55.8, 29.3, 20.4, 18.4, 13.7. Anal. Calcd for
C
18H29NO3: C, 70.32; H, 9.51; N, 4.56. Found: C, 70.60; H, 9.54;
N, 4.55.
Imine 3 (369 mg; 1.2 mmol) was dissolved in 10 mL of THF.
Aqueous 4 M HCl (1.5 mL) was added, and the mixture was
refluxed for 1 h. The crude product was isolated by ether
extraction and recrystallized from hexane to give 228 mg (83%
yield from imine 1) of aldehyde 2: mp 99-100 °C (lit.12 mp 103-
104.5 °C); 1H NMR δ 10.49 (s, 1H), 6.37 (br s, 1H), 3.95 (s, 3H),
3.90 (s, 3H), 3.71 (s, 3H), 2.59 (s, 3H). 2,4-DNP d er iva tive:
mp 223-224 °C. Anal. Calcd for C17H18N4O7: C, 52.31; H, 4.65;
N, 14.35. Found: C, 52.45; H, 4.58; N, 14.56.
3,6-Dim eth oxy-2-eth ylben za ld eh yd e (19): 59 mg (16%);
1H NMR δ 10.58 (s, 1H), 7.01 (d, J ) 9 Hz, 1H), 6.77 (d, J ) 9
Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.98 (q, J ) 7.4 Hz, 2H), 1.13
(t, J ) 7.4 Hz, 3H); MS (m/ z) 194 (M+, 98), 193 (16), 179 (36),
164 (18).
Using s-BuLi-TMEDA, the following compound was similarly
prepared from imine 25:
3,6-Dim eth oxy-2-m eth ylben za ld eh yd e17 (20): 7 mg (2%);
1H NMR δ 10.61 (s, 1H), 7.02 (d, J ) 9 Hz, 1H), 6.78 (d, J ) 9
Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 2.46 (s, 3H).
4-Meth oxy-2-m eth ylben za ld eh yd e13 (26): yield 56%; 1H
NMR δ 9.86 (s, 1H), 7.72 (dd, J ) 8.2, 2 Hz, 1H), 7.69 (m, 1H),
3.92 (s, 3H), 2.27 (s, 3H). 2,4-DNP d er iva tive: mp 227-228
°C. Anal. Calcd for C15H14N4O5: C, 54.55; H, 4.27; N, 16.96.
Found: C, 54.56; H, 4.32; N, 16.84.
1
2-n -Bu tyl-5-m eth oxyben za ld eh yd e (21): 29 mg (8%); H
NMR δ 10.30 (s, 1H), 7.35 (d, J ) 3 Hz, 1H), 7.17 (d, J ) 8.4 Hz,
1H), 7.06 (dd, J ) 8.4, 3 Hz, 1H), 3.84 (s, 3H), 2.95 (m, 2H), 1.58
(m, 2H), 1.40 (m, 2H), 0.93 (t, J ) 7.2 Hz, 3H); MS (m/ z) 192
(M+, 76), 177(10), 163 (30), 159 (40), 149 (100), 135 (40), 121
(96).
Using n-BuLi, the following compound was similarly prepared
from imine 27:
3,4-Dim eth oxy-2-m eth ylben za ld eh yd e (28):14 yield 73%;
mp 49.9-50.6 °C (lit.14a mp 47-49 °C); 1H NMR δ 10.11 (s, 1H),
7.59 (d, J ) 8.6 Hz, 1H), 6.89 (d, J ) 8.6 Hz, 1H), 3.94 (s, 3H),
3.80 (s, 3H), 2.56 (s, 3H). Anal. Calcd for C10H12O3: C, 66.65;
H, 6.71. Found: C, 66.99; H, 6.80.
SNAr R ea ct ion s of Im in es. 2-n -Bu t yl-4-m et h oxyb en z-
a ld eh yd e (12). Imine 11 (500 mg; 1.9 mmol) was dissolved in
10 mL of ether, and the stirred solution was cooled to -60 °C.
n-BuLi (1.4 mL of a 1.6 M solution in hexane; 2.3 mmol) was
added dropwise to the imine solution, and the reaction mixture
was allowed to warm to 20 °C over 1 h. The reaction mixture
was again cooled to -60 °C, and 0.6 mL (9.5 mmol) of methyl
iodide was added in one portion. (Note: The methyl iodide
quench step in this example served as a probe for metalation
processes; accordingly, this step can be eliminated from reaction
sequences where no metalation is observed or there is no
preparative value in capturing metalated intermediates). The
reaction mixture was warmed to 20 °C, quenched with water,
Using n-BuLi-TMEDA, the following compound was similarly
prepared from imine 31:
2-Eth yl-3,4-d im eth oxyben za ld eh yd e15 (32): yield 68%; 1H
NMR δ 10.11 (s, 1H), 7.63 (d, J ) 8.6 Hz, 1H), 6.90 (d, J ) 8.6
Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.10 (q, J ) 7.5 Hz, 2H), 1.22
(t, J ) 3 Hz, 3H). 2,4-DNP d er iva tive: mp 193-194 °C. Anal.
Calcd for C17H18N4O6: C, 54.54; H, 4.85; N, 14.97. Found: C,
54.67; H, 4.89; N, 14.91.
Using n-BuLi, the following compound was similarly prepared
from imine 33:
3,4-Dim eth oxy-2,6-dim eth ylben zaldeh yde (34): yield 40%;
mp 54.8-55.5 °C; 1H NMR δ 10.47 (s, 1H), 6.61 (s, 1H), 3.92 (s,
3H), 3.89 (s, 3H), 2.60 (s, 3H), 2.54 (s, 3H); 13C NMR δ 192.1,
and extracted with ether to give 560 mg of a crude imine.
A
mixture of 462 mg (1.7 mmol) of the crude imine and and 25
mmol of HCl in 1:1 THF-water was refluxed for 2 h. The acidic
reaction mixture was diluted with 50 mL of water and extracted
with ether. The combined ether extracts were washed with
saturated NaHCO3, dried (Na2SO4), and concentrated to give
320 mg of a yellow oil. Column chromatography afforded 281
mg (88%) of colorless 12: oil; 1H NMR δ 10.14 (s, 1H), 7.8 (d, J
) 8.6 Hz, 1H), 6.84 (dd, J ) 8.6, 2.5 Hz, 1H), 6.74 (d, J ) 2.5
Hz, 1H), 3.87 (s, 3H), 3.00 (m, 2H), 1.60 (m, 2H), 1.41 (sextet, J
) 7.3 Hz, 2H), 0.94 (t, J ) 7.3 Hz, 3H); 13C NMR δ 190.6, 163.7,
(10) Perrin, D. D.; Armarego, W. L. Purification of Laboratory
Chemicals; Pergamon: New York, 1988.
(11) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(12) (a) Burger, A.; Foggio, R. D. J . Am. Chem. Soc. 1956, 78, 4419.
(b) Cromartie, R. I. T.; Harley-Mason, J . J . Chem. Soc. 1952, 1052.
(13) (a) Akgun, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J . Org.
Chem. 1981, 46, 2730. (b) Shishido, K.; Yamashita, A.; Hiroya, K.;
Fukumoto, K. Tetrahedron 1989, 45, 5791.
(14) Azadi-Ardakani, M.; Wallace, T. W. Tetrahedron 1988, 44, 5939.
(15) Borchardt, R. T.; Reid, J . R.; Thakker, D. R.; Liang, Y. O.;
Wightman, R. W.; Adams, R. N. J . Med. Chem. 1976, 19, 1201.
(16) Kaiser, C.; Burger, A. J . Am. Chem. Soc. 1957, 79, 4365.
(17) (a) Ho, B. T.; McIsaac, W. M; An, R.; Tansey, L. W.; Walker, K.
E.; Englert, L. F.; Noel, M. B. J . Med. Chem. 1970, 13, 26. (b) Comins,
D. L.; Brown, J . D. J . Org. Chem. 1984, 49, 1078.

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4815
148.4, 134.1, 127.3, 116.0, 111.5, 55.3, 34.2, 32.4, 22.5, 13.8; MS
(m/ z) 192 (M+, 52), 191 (35), 163 (100), 150 (20), 149 (30), 121
(28, 91 (40). 2,4-DNP d er iva tive: mp ) 159-160 °C. Anal.
Calcd for C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C,
58.00; H, 5.39; N, 15.11.
3,4-Dim eth oxy-2-m eth yl-6-p h en ylben za ld eh yd e (5): yield
74%; mp 103.4-103.6 °C; 1H NMR δ 9.83 (s, 1H), 7.44 (m, 3H),
7.34 (m, 2H), 6.75 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 2.61 (s, 3H);
13C NMR δ 193.4, 155.6, 146.9, 145.3, 139.0, 134.5, 129.9, 128.2,
127.8, 126.4, 111.5, 60.4, 55.8, 12.9; MS (m/ z) 256 (M+, 100),
241 (25), 225 (18). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Found: C, 75.15; H, 6.17.
2-n -Bu tyl-3,4-d im eth oxyben za ld eh yd e (16). Imine 15
(344 mg; 1.2 mmol) was dissolved in 10 mL of ether. The stirred
solution was cooled to -78 °C, and 0.8 mL (1.3 mmol) of a 1.6 M
solution of n-BuLi in hexane was added dropwise over 3 min.
The reaction mixture was allowed to warm to 20 °C over 1 h
and quenched with saturated NH4Cl. The organic product was
extracted with ether, dried (Na2SO4), and concentrated with a
rotary evaporator to give a crude imine. The imine was
hydrolyzed with 3 mL of 1 M HCl in 10 mL of THF (reflux, 1 h),
and the crude aldehyde was extracted with ether. Purification
of the crude aldehyde by column chromatography gave 180 mg
6-n -Bu tyl-2-eth yl-3,4-d im eth oxyben za ld eh yd e (6). To a
-70 °C solution of 1.00 g (3.25 mmol) of imine 3 in 40 mL of
ether was added 5.1 mL of 1.6 M n-BuLi in hexane over 10 min.
The magenta reaction mixture was warmed to room temperature
for 2 h and recooled to -70 °C, and 1.0 mL (16 mmol) of methyl
iodide was added in one portion. The light yellow reaction
mixture was allowed to stand at room temperature for 30 min
and quenched with water. The mixture was extracted with
additional ether, and the combined organic layers were washed
with brine, dried (Na2SO4), and concentrated to give 1.209 g of
a yellow oil. The crude product was dissolved in 50 mL of 4:1
THF-water, and 5.2 mL of aqueous 1 M HCl was added. The
mixture was refluxed for 45 min and diluted with 100 mL of
ether, and the aqueous layer was discarded. The organic layer
was washed with water, dried (Na2SO4), and concentrated to
give a yellow oil. Flash chromatography of the crude material
gave 765 mg (94%) of aldehyde 5: oil; 1H NMR δ 10.40 (s, 1H),
6.61 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.03 (q, J ) 7.5 Hz, 2H),
2.91 (t, J ) 7.7 Hz, 2H), 1.56 (m, 2H), 1.43 (sextet, J ) 7.3 Hz,
2H), 1.20 (t, J ) 7.5 Hz, 3H), 0.95 (t, J ) 7.3 Hz, 3H); 13C NMR
δ 191.8, 156.1, 145.0, 144.4, 141.9, 124.9, 111.9, 60.8, 55.6, 34.7,
33.7, 22.7, 18.9, 16.1, 13.9; MS (m/ z) 250 (M+, 100), 221 (87),
207 (80), 193 (55), 179 (45), 91 (45). Anal. Calcd for C15H22O3:
C, 71.97; H, 8.86. Found: C, 72.20; H, 8.71.
1
(69%) of colorless 16: oil; H NMR δ 10.11 (s, 1H), 7.64 (d, J )
8.6 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H),
3.05 (m, 2H), 1.6-1.4 (m, 4H), 0.95 (t, J ) 7.2 Hz, 3H); 13C NMR
δ 191.0, 157.4, 147.1, 140.1, 129.1, 127.9, 109.4, 60.9, 55.8, 34.3,
24.6, 23.0, 13.9. 2,4-DNP d er iva tive: mp 142-143 °C. Anal.
Calcd for C19H22N4O6: C, 56.71; H, 5.51; N, 13.92. Found: C,
56.75; H, 5.42; N, 14.08.
The following compound was similarly prepared from imine
3:
6-n -Bu tyl-3,4-d im eth oxy-2-m eth ylben za ld eh yd e (4): yield
97%; 1H NMR δ 10.43 (s, 1H), 6.60 (s, 1H), 3.92 (s, 3H), 3.76 (s,
3H), 2.92 (t, J ) 7.7 Hz, 2H), 2.53 (s, 3H), 1.58 (m, 2H), 1.41
(sextet, J ) 7.4 Hz, 2H), 0.94 (t, J ) 7.2 Hz, 3H); 13C NMR δ
191.8, 156.2, 145.5, 144.5, 135.3, 125.6, 111.6, 60.2, 55.6, 34.8,
33.4, 22.6, 13.8, 12.2; MS (m/ z) 236 (M+, 100), 207 (52), 193 (54),
179 (28), 165 (33). Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.23; H, 8.80. 2,4-DNP d er iva tive: mp 163.6-
163.7 °C.
Using phenyllithium, the following compound was similarly
prepared from imine 3:
J O9602175