Rapid Ti(Oi-Pr)4 facilitated synthesis of α,α,α-trisubstituted primary amines by the addition of Grignard reagents to nitriles under microwave heating conditions

Article abstract of DOI:10.1016/j.tetlet.2009.09.178

A series of carbinamines (α,α,α-trisubstituted amines) have been prepared in a simple and efficient one-pot procedure by the addition of Grignard reagents to a series of aliphatic, aromatic and heteroaromatic nitriles. The resulting magnesium imines are subsequently converted to the desired amine after treatment with Ti(Oi-Pr)₄ and additional microwave heating. Key to this procedure is the use of microwave heating for both steps of the reaction protocol, which significantly improves both reaction yields and reduces reaction times. In general, the Grignard addition reaction is complete within 5-10 min at 100 °C followed by conversion with Ti(Oi-Pr)₄ and additional microwave heating to give the target amines in good yields.

Full text of DOI:10.1016/j.tetlet.2009.09.178

Tetrahedron Letters 50 (2009) 7070–7073
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid Ti(Oi-Pr)4 facilitated synthesis of a,a,a-trisubstituted primary amines
by the addition of Grignard reagents to nitriles under microwave
heating conditions
*
Ruifang Wang, Brian T. Gregg , Wei Zhang, Kathryn C. Golden, John F. Quinn, Peng Cui,
Dmytro O. Tymoshenko
AMRI, Medicinal Chemistry Department, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of carbinamines (a,a,a-trisubstituted amines) have been prepared in a simple and efficient one-
Received 3 September 2009
Revised 29 September 2009
Accepted 30 September 2009
Available online 4 October 2009
pot procedure by the addition of Grignard reagents to a series of aliphatic, aromatic and heteroaromatic
nitriles. The resulting magnesium imines are subsequently converted to the desired amine after treat-
ment with Ti(Oi-Pr)4 and additional microwave heating. Key to this procedure is the use of microwave
heating for both steps of the reaction protocol, which significantly improves both reaction yields and
reduces reaction times. In general, the Grignard addition reaction is complete within 5–10 min at
100 °C followed by conversion with Ti(Oi-Pr)4 and additional microwave heating to give the target
amines in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Considerable attention has been focused on the identification,
preparation and use of ‘privileged structures’ in chemical library
design. The use of novel and medicinally relevant fragments, which
impart diversify on the core motif, are equally important for the
reagents to cerium(III) chloride) to nitriles and ketamines. An alter-
nate approach reported by Sokolov, de Meijere7 and co-workers
uses Grignard reagents and Ti(Oi-Pr)4 to prepare carbinamines
from nitriles. While both of these procedures reportedly worked
well for some substrates, they also suffer from a number of draw-
backs, including inconveniently long reaction times, low tempera-
ture conditions, poor to modest yields of product and/or limited
substrate scope. We therefore set out to apply our recently re-
success of the drug discovery effort. The use of
a,a-disubstituted
and -trisubstituted amines (carbinamines) and amides there-
a,a,a
of are excellent examples of compounds that have found much
utility in pharmaceutical applications.1 We have recently reported
a rapid, one-pot synthesis of
a
,a-disubstituted primary amines by
ported optimized conditions for the formation of
a
,a-disubstituted
the addition of Grignard reagents to nitriles under microwave
heating conditions followed by sodium borohydride reduction
(Scheme 1).2 Herein, we expand the scope of our work to the for-
Ti(Oi-Pr)
4
R MgX
R
1
mation of
a,a,a-trisubstituted amines. Both reactions rely upon
2
R
NH
NH
the addition of a Grignard reagent to a nitrile, yielding a magne-
sium–imine intermediate. A key observation from our previous
work was that microwave heating3 significantly accelerated the
formation of this magnesium–imine complex.
The classical method for the synthesis of this class of amines is
the Ritter reaction of tertiary alcohols (Scheme 2).4 This approach
suffers from a number of drawbacks, including strongly acidic con-
ditions for the carbocation addition to the nitrile as well as the
harsh reaction conditions required to hydrolyze the intermediate
amide to the amine. There are several alternate methods available
for the synthesis of carbinamines, generally based on modification
the procedure reported by Ciganek,5,6 involving the addition of
organocerium reagents (prepared by the addition of alkyllithium
2
50 °C,MW
R
2
1
MgX
R MgX
N
RCN
100 °C,MW
R
R
1
R
NaBH
4
1
R
rt, MeOH
2
Scheme 1.
O
R
R
R
R
1
1
RCN
1
3
R
+
H
R
2
OH
R
NH
2
R
NH
2
2
+
Δ
H
R
R
3
3
* Corresponding author. Tel.: +1 518 512 2000; fax: +1 518 512 2079.
E-mail address: Brian.Gregg@amriglobal.com (B.T. Gregg).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.178

R. Wang et al. / Tetrahedron Letters 50 (2009) 7070–7073
7071
amines to the Ti(Oi-Pr)4 mediated synthesis of
amines.
a
,
a
,
a
-trisubstituted
critical to achieving improved yields. Conventional heating at re-
flux for 3 h (step 1) followed by the addition of Ti(Oi-Pr)4 and fur-
ther conventional heating for 12 h at 50 °C (step 2) afforded a 63%
yield of 2 (Table 1, entry 3). Repeating the same reaction with
microwave heating at 100 °C for 10 min (step 1), followed by heat-
ing at 50 °C for 1 h after Ti(Oi-Pr)4 addition (step 2), showed a sig-
nificant yield improvement (77%, Table 1, entry 5).
Microwave heating is less crucial for the second step. Use of
either microwave or traditional oil-bath heating at 50 °C gave com-
parable results (Table 1, entries 5 and 6). As expected, if no heating
was applied during the Ti(Oi-Pr)4 step, a diminished yield was ob-
tained (<70%, Table 1, entries 4 and 7). While the reaction of Grig-
nard reagents with nitriles generally proceeds without incident, we
chose to conduct all of our reactions under microwave heating for
reasons of convenience and safety.8
We have previously disclosed the experiments used to optimize
the synthesis of
a,a
-disubstituted amines.2 In that manuscript, we
concluded that the yield of the desired amine was dependent upon
the extent of formation of the key magnesium–imine complex
resulting from the addition of a Grignard reagent to a nitrile. Spe-
cifically, maximum yields were obtained with microwave heating
at 100 °C for 5–10 min after addition of the Grignard reagent. Addi-
tionally, we reported that THF was necessary due to its increased
solvating ability and being able to safely achieve higher reaction
temperatures when using microwave heating. We reasoned that
our improved procedures would be applicable to this transforma-
tion as well. The overall transformation involves a two-step, one-
pot synthesis. The first step is the Grignard addition to the nitrile
substrate to yield a magnesium–imine complex. The following
step is the Ti(Oi-Pr)4-mediated addition of a second equivalent of
Grignard reagent to give the desired amine. In cases where excess
Grignard reagent is used in the first step (R1MgX), the resulting
Significant advantages with our reported procedures over previ-
ous reports6b are that not only increased isolated yield is obtained,
but also a significant reduction in overall process time (from in ex-
cess of 12 h to less than 1.5 h) is achieved allowing for a more rapid
a
,
a
,
a
-trisubstituted amines bear the same R1 groups on the ter-
tiary alpha-carbon (R1 = R2). Amines differentially substituted at
the a
-carbon (R – R1 – R2) are achieved by the addition of R1MgBr
Table 2
Amine formation from double Grignard addition to nitriles under microwave heating
(1.2 equiv) and followed by R2MgBr (2.0 equiv) after the initial
magnesium–imine complex formation.
1
1) R MgBr, 100 °C, MW
NH
2
Optimization of the reaction conditions was conducted using 2-
naphthonitrile (1) and methyl magnesium bromide in THF. It was
previously reported7 that diethyl ether was the solvent of choice
for the Ti(Oi-Pr)4-mediated addition of Grignards to nitriles and
that with THF products ‘formed in very low yield, if at all.’ Indeed
in some instances diethyl ether is an acceptable solvent for this
transformation; however the utility of Et2O is limited to the sim-
plest of organic molecules due to its poor solvating capability
and inability to achieve high reaction temperatures that are re-
quired. Fortunately, we have demonstrated the THF is an accept-
able reaction solvent substitute.
10 min
2) Ti(Oi-Pr) , 50 °C, MW
1 h
1
CN
R
1
R
R
4
R
Entry Substrate (1 equiv)
R1MgBr
Product Isolated yielda
(3.5 equiv)
1
2
2-Naphthonitrile
1
Benzonitrile
Me
Me
2
4
77%
65% (44%)b
3
3
3
3
4
Ph
Et
5
6
57% (55%)b (36%)c
30% (60%)b (35%)c
The effect of time and temperature (using both traditional and
microwave heating) on the extent of conversion of 2-naphthonitri-
le (1) to a,a-dimethylnaphthylamine (2) are summarized in Table
1. At room temperature conditions, a modest 40% yield of 1 to 2
was observed (Table 1, entry 1). Yields steadily increased up to
77%, (Table 1, entry 5) when microwave heating was utilized. It
is especially important to note that conducting the first step at a
higher temperature available only with microwave heating was
H3CS
CN
5
6
Me
Me
8
78%
7
2-Furonitrile 9
10
80% 76%d
CN
H3C
7
Me
Me
12
79%
F
11
Table 1
8
9
2-Fluorobenzonitrile
13
2-Thiophenecarbonitrile Me
14
16
69%
Effect of time and temperature (both thermal and microwave irradiation) on the
extent of conversion of 2-naphthonitrile (1) to
a
,a
-dimethylnaphthyl amine (2)
82% (25%)b
15
NH2
CH3
CH3
1) CH3MgBr (3.5 equiv)
CN
THF
N
CN
11
Me
18
35%
61%
2) Ti(Oi-Pr)4
17
1
2
Entry
Time, temp (°C)
Time, temp (°C)
% Yieldb
Step 1a
Step 2a
F3C
CN
12
Me
20
1
2
3
4
5
6
7
3 h, rt
12 h, rt
40
46
63
68
77
75
60
19
3 h, rt
1 h, MWc 50 °C
12 h, bath 50 °Cd
12 h, rt
13
14
15
4-Cyanopyridine
Me
Me
Me
22
24
26
72%
3 h, bath refluxd
21
10 min, MWc 100 °C
10 min, MWc 100 °C
10 min, MWc 100 °C
10 min, MWc 100 °C
Isopropylnitrile
59% (27%)b
75%
1 h, MWc 50 °C
1 h, bath 50 °Cd
1 h, rt
23
Cyclohexylnitrile
25
a
Time and temperature for each step of the synthesis are reported. Step 1 refers
a
Unless otherwise noted, all reactions performed in tetrahydrofuran (5 mL),
1 mmol substrate, product was isolated as hydrochloride.
to the CH3MgBr (3.5 equiv) addition to 1, Step 2 refers to the subsequent addition of
Ti(Oi-Pr)4.
b
Reported yield in reference.
Observed yield using reference procedure.
5 mmol substrate scale.
b
Isolated yields reported.
Reaction heated using microwave irradiation.
c
c
d
d
Reaction heated by oil bath.

7072
R. Wang et al. / Tetrahedron Letters 50 (2009) 7070–7073
synthesis of multiple analogues. Rigorous air and moisture sensi-
tive handling techniques are not necessary due to the rapid reac-
tion times and sealed atmosphere achieved when using
microwave vials as the reaction apparatus. Table 2 summarizes
the scope of substrates and Grignards that can be used within
the scope of this reaction protocol.9 The substrates include a wide
range of aromatic and heteroaromatic nitriles and nitriles with
electron-withdrawing as well as electron-donating groups. Like-
wise, for all symmetrical amines (R1 = R2) our set of Grignard re-
agents gave acceptable yields and purity.10 When compared to
previously reported literature results, our procedure showed sig-
nificant improvements in yield; conversion of 3 to 4 was achieved
in 65% compared to 44%7b yield in the literature. Similarly, im-
proved yields were achieved for 15 to 16 (82% vs 25%11) and 23
to 24 (59% vs 27%12) (Table 2, entries 2, 9 and 14). Disappointingly,
benzylmagnesium bromide failed to generate any desired product
upon reaction with 1. Additionally, we observed a 30% isolated
yield of 6 from the addition of ethylmagnesium bromide to benzo-
nitrile (Table 2, entry 4); the reported literature yield for this trans-
formation (utilizing diethylether, not THF) is 60%.7a Even using
diethyl ether as a solvent we were unable to reproduce this result;
obtaining a modest 35% yield of product. Both Szymoniak13 and de
Meijere reported that ethylmagnesium Grignard reagents in the
presence of Ti(Oi-Pr)4 may form cyclopropyl species under certain
conditions which may account for our observations.
The developments of procedures that are not only reproducible,
but also scalable were paramount to our reaction protocol develop-
ment. It was successfully demonstrated that the scale of the reac-
tion was limited only by the constraints of the microwave reactor.
Specifically, the reaction of 2-furonitrile 9 to 10 was increased from
1 mmol to 5 mmol scale under identical reaction conditions, giving
comparable yield and purity results (Table 2, entry 6).
Access to differentially substituted a,a,a-trisubstituted amines
(R – R1 – R2) is also possible by careful control of Grignard addi-
tion and stoichiometry (Table 3). Specifically, R1MgBr (1.2 equiv)
is first added to the nitrile substrate. After microwave heating for
10 min at 100 °C, both Ti(O-iPr)4 and R2MgBr (2.0 equiv) are added
and the reaction mixture was heated for an additional 1 h at
50 °C.14 Using this procedure, a wide array of carbinamines are
accessible (Table 3) in moderate to high yield (25–71%).
To further expand the scope of accessible
a,a,a-trisubstituted
amines beyond those obtained when using commercially available
Grignard reagents we successfully employed the methodology de-
scribed by Prim15 to prepare in situ generated Grignard reagents.
Specifically, 2-bromothiophene (44) was pre-treated with iso-pro-
pylmagnesium chloride in THF for 30 min at 0 °C. After allowing
the metal-halogen exchange to occur, the in situ generated reagent
was added to benzonitrile and subjected to our standard micro-
wave irradiation reaction protocol16 1-(naphthalen-2-yl)-1-(thio-
phen-2-yl)ethanamine (47) was cleanly isolated in moderate
yield (42%, Table 4, entry 1).
Table 3
Amine formation from admixed Grignard addition to nitriles under microwave
heating
1) R1MgX (1.2 eq)
100 °C, MW, 10 min
NH2
R1
CH3
CN
R
R
2) Ti(Oi-Pr)4, MeMgBr (2.0 eq)
50 °C, MW, 1 h
Entry
Substrate
R1MgBr
Product
Isolated yielda
(%)
1
2
3
4
5
6
2-Naphthonitrile 1
1
1
1
Ph
Et
i-Pr
Benzyl
Cyclopropyl
Ph
27
28
29
30
31
32
70
36
39
25
43
62
Table 4
Amine formation from the in situ generated Grignard addition to nitriles under
microwave heating
1
1) iPrMgCl, THF, 30 min, 0 °C
2) R-CN, MW, 100 °C, 5 min
NH2
H3C
Benzonitrile
3
3
Br
R
7
Et
33
40
S
S
3) Ti(Oi-Pr) , MeMgBr, MW,
4
50 °C, 1 h
45a-d
44
H3CS
CN
8
Ph
34
42
Entry
1
Substrate
Product
Isolated yielda (%)
7
CN
H3C
9
10
7
Et
Ph
35
36
41
51%
NH2
S
2-Furonitrile
9
9
42
32
1
11
12
Et
37
38
48
45a
H3C
CN
F
H3C
NH2
S
Ph
38
H3CS
CN
2
11
7
H3CS
45b
13
14
2-Thiophenecarbonitrile
15
15
Ph
Et
39
40
71
47
O
H C NH2
O3
CN
S
3
4
61
44
9
F3C
CN
15
Ph
41
60
45c
19
S
H3C NH2
CN
16
17
Isopropylnitrile
23
Cyclohexylnitrile
25
Ph
Ph
42
43
64
58
S
S
15
45d
a
a
All reactions performed in tetrahydrofuran (5 mL), 1 mmol substrate, product
was isolated as hydrochloride.
All reactions performed in tetrahydrofuran (5 mL), 1 mmol substrate, product
was isolated as hydrochloride.

R. Wang et al. / Tetrahedron Letters 50 (2009) 7070–7073
7073
8. Microwave reactors are designed to work at high pressures and
In summary, we report herein the feasible and scalable proce-
dure for the formation of -trisubstituted amines and the first
temperatures and are engineered to contain debris in the event of
reaction vessel failure.
a
a,a,a
application of microwave irradiation heating to facilitate the prod-
uct formation. Our procedure utilizes both commercially available
Grignard reagents as well as those generated in situ from heteroar-
omatic halides. Reactions are highly reproducible, afford moderate
to high yields of the desired products, typically better than previ-
ously reported for a number of different substrates. Additionally,
overall reaction times have been dramatically decreased from in
excess of 12 h to less than 2 h for even the most difficult of sub-
strates. Key factors to the success of this protocol are the use of
THF as a reaction solvent, using microwave heating conditions to
rapidly generate the key magnesium–imine intermediate complex,
and the observation that all steps of the reaction can be conducted
in a one-pot two-step synthetic procedure.
9.
A representative procedure is as follows: 2-(4-(Methylthio)phenyl)propan-2-
amine hydrochloride (8): A 20 mL Biotage microwave process tube with stir bar
was charged with 4-(methylthio)benzonitrile (0.149 g, 1.0 mmol) and
tetrahydrofuran (5 mL) to which was added 3 M methylmagnesium bromide
in diethyl ether (1.17 mL, 3.5 mmol). The resulting mixture was heated under
microwave conditions at 100 °C for 10 min after which time Ti(Oi-Pr)4
(0.293 mL, 1.0 mmol) was carefully added. After heating under microwave
irradiation at 50 °C for 1 h, brine (10 mL) was added. The mixture was extracted
with CH2Cl2 (50 mL), the organic layer was washed with brine (20 mL Â 2),
separated, dried over Na2SO4 and filtered. 1 N HCl in diethyl ether (1 mL) was
added to the filtrate and the filtrate was concentrated to dryness under reduced
pressure. The crude product was triturated with diethyl ether to give the
desired product (0.170 g, 78%) as off white solid: 1H NMR (300 MHz, DMSO-d6)
d 8.52 (3H, br s), 7.48 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.7 Hz), 2.48 (3H, s), 1.61
(s, 6H); 13C NMR (75 MHz, DMSO-d6) d 139.3, 137.8, 125.8, 125.7, 55.1, 27.4,
14.6; APCI MS m/z 165 [M+1ÀNH3]+; HPLC 95.3% (AUC).
10. All compounds were fully characterized by 1H and 13C NMR and HPLC/APCI-MS
anaylses and compared to the literature results for known compounds.
11. Kong, X.; Wu, X.; Bouzide, A.; Valade, I.; Migneault, D.; Gervais, F.; Delorme, D.;
Bachand, B.; Atfani, M.; Levesque, S.; Samim, B. WO 2006085149, 2006.
12. Gomtsyan, A.; Bayburt, E. K.; Keddy, R.; Turner, S. C.; Jinkerson, T. K.;
Didomenico, S.; Perner, R. J.; Koenig, J. R.; Drizin, I.; McDonald, H. A.;
Surowy, C. S.; Honore, P.; Mikusa, J.; Marsh, K. C.; Wetter, J. M.; Faltynek, C.
R.; Lee, C.-H. Bioorg. Med. Chem. Lett. 2007, 17, 3894–3899.
Acknowledgements
The authors wish to thank Drs. Bruce F. Molino and Paul Zhich-
kin for their helpful discussions and suggestions.
13. Szymoniak, J.; Bertus, P. J. Org. Chem. 2002, 67, 3965–3968.
14. A representative procedure is as follows: 1-Phenyl-1-(thiophen-2-yl)ethanamine
hydrochloride (39): A 20 mL Biotage microwave process tube with stir bar was
References and notes
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Ballentine, S. K.; Shen, Z.; Fleener, C. A.; Rouleau, K. A.; Obermeier, M.; Yang, Z.;
McIntyre, K. W.; Shuster, D. J.; Witmer, M.; Dembach, D.; Chao, S.; Mathur, A.;
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Pesquera, A.; Adams, M.; Gruninger, R. H.; Seraj, J.; Middleton, S. A.; Davis, J. M.;
Moffat, D. F. C. Bioorg. Med. Chem. Lett. 2007, 17, 2179–2183; (c) Oelssner, W.
Acta Biol. Med. Germanica 1968, 20, 625; (d) Kukovetz, W. R.; Poech, G.;
Holtzman, S.; Paietta, E. Arzneim.-Forsch. 1976, 26, 1321; (e) Kessler, A.; Faure,
H.; Petrel, C.; Rognan, D.; Cesario, M.; Ruat, M.; Dauban, P.; Dod, R. J. Med. Chem.
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US 20060025453, 2006.; (g) Bettati, M.; Chambers, M. S.; Hunt, P. A.; Jones, P.;
MacLeod, A. M.; Szekeres, H. J.; Teall, M. R. WO 2004089911, 2004.
2. Gregg, B. T.; Golden, K. C.; Quinn, J. F.; Wang, H.-J.; Zhang, W.; Wang, R.;
Wekesa, F.; Tymoshenko, D. O. Tetrahedron Lett. 2009, 50, 3978–3981.
3. (a) For additional reports on microwave methods: Microwave Methods in
Organic Synthesis; Larhead, M. O. K., Ed.; Springer: Berlin, 2006; Quinn, J. F.;
Razzano, D. A.; Golden, K. C.; Gregg, B. T. Tetrahedron Lett. 2008, 49, 6137–6140;
(b) Pabba, C.; Wang, H.-J.; Mulligan, S. R.; Chen, Z.-J.; Stark, T. M.; Gregg, B. T.
Tetrahedron Lett. 2005, 46, 7553–7557; (c) Sauer, D. R.; Kalvin, D.; Phelan, K. M.
Org. Lett. 2003, 5, 4721–4724; (d) Wang, Y.; Sauer, D. R. Org. Lett. 2004, 6, 2793–
2796; (e) Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org. Lett. 2005, 7,
925–928; (f) Gregg, B. T.; Tymoshenko, D. O.; Razzano, D. A.; Johnson, M. R. J.
Comb. Chem. 2007, 9, 507–512; (g) Wang, H.-J.; Keilman, J.; Pabba, C.; Chen,
Z.-J.; Gregg, B. T. Tetrahedron Lett. 2005, 46, 2631–2634; (h) Tymoshenko, D. O.;
Gregg, B. T.; Hirsch, M. J.; Butcher, J. L. Lett. Drug Des. Discovery 2008, 5, 43–47;
(i) Gregg, B. T.; Golden, K. C.; Quinn, J. F.; Tymoshenko, D. O.; Earley, W. G.;
Maynard, D. A.; Razzano, D. A.; Rennells, W. M.; Butcher, J. J. Comb. Chem. 2007,
9, 1036–1040; (j) Yoon, D. S.; Han, Y.; Stark, T. M.; Haber, J. C.; Gregg, B. T.;
Stankovich, S. B. Org. Lett. 2004, 6, 4775–4778; (k) Gregg, B. T.; Golden, K. C.;
Quinn, J. F.; Tymoshenko, D. O.; Earley, W. G.; Maynard, D. A.; Razzano, D. A.;
Rennells, W. M.; Butcher, J. J. Comb. Chem. 2007, 9, 1036–1040.
charged
with
thiophene-2-carbonitrile
(109 mg,
1.0 mmol)
and
tetrahydrofuran (5 mL) to which was added 1 M phenylmagnesium bromide
in tetrahydrofuran (1.2 mL, 1.2 mmol). The resulting mixture was heated under
microwave irradiation at 100 °C for 10 min after which time Ti(Oi-Pr)4
(0.293 mL, 1.0 mmol) and 3 M methylmagnesium bromide in diethyl ether
(0.667 mL, 2.0 mmol) were carefully added. After heating under microwave
irradiation at 50 °C for 1 h, brine (10 mL) was added. The mixture was
extracted with CH2Cl2 (50 mL), the organic layer was washed with brine
(20 mL Â 2), separated, dried over Na2SO4 and concentrated to dryness under
reduced pressure. The crude product was purified by flash chromatography
(12 g silica gel, methylene chloride to 95:5 methylene chloride/methanol), 1 N
HCl/diethyl ether (1 mL) was added to the combined fractions and then
concentrated to dryness under reduced pressure to give the desired product
(0.170 g, 71%) as off white solid: 1H NMR (500 MHz, DMSO-d6) d 9.22 (3H, br s),
7.60 (1H, d, J = 5.0 Hz), 7.50–7.39 (5H, m), 7.25 (1H, d, J = 4.0 Hz), 7.10 (1H, dd,
J = 5.0, 4.0 Hz), 2.09 (3H, s);
13C NMR (75 MHz, DMSO-d6) d 146.6, 142.1, 128.5,
128.3, 127.1, 126.7, 126.6, 125.8, 58.5, 28.3; APCI MS m/z 187 [M+1ÀNH3]+;
HPLC 95.5% (AUC).
15. Terrasson, V.; Marque, S.; Scarpacci, A.; Prim, D. Synthesis 2006, 1858–1862.
16.
A
representative procedure is as follows: 1-(Furan-2-yl)-1-(thiophen-2-
yl)ethanamine hydrochloride (45c): 20 mL Biotage microwave process
A
tube with stir bar was charged with 2-bromothiophene (0.245 g, 1.5 mmol)
and tetrahydrofuran (5 mL) to which was added 2 M iso-propylmagnesium
chloride in tetrahydrofuran (0.75 mL, 1.5 mmol). The resulting mixture was
stirred at 0 °C for 30 min after which time furan-2-carbonitrile (93 mg,
1.0 mmol) was added. The resulting mixture was heated under microwave
conditions at 100 °C for 10 min after which time Ti(Oi-Pr)4 (0.293 mL,
1.0 mmol) and 3 M methylmagnesium bromide in diethyl ether (0.667 mL,
2.0 mmol) were carefully added. After heating under microwave irradiation
conditions at 50 °C for 1 h, brine (10 mL) was added. The mixture was
extracted with CH2Cl2 (50 mL), the organic layer was washed with brine
(20 mL Â 2), separated, dried over Na2SO4 and concentrated to dryness
under reduced pressure. The crude product was purified by flash
chromatography (12 g silica gel, methylene chloride to 95:5 methylene
chloride/methanol), 1 N HCl/diethyl ether (1 mL) was added to the
combined fractions and then concentrated to dryness under reduced
pressure to give the desired product (0.140 g, 61%) as light brown solid:
4. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045; (b) Ritter, J. J.;
Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048.
5. Ciganek, E. J. Org. Chem. 1992, 57, 4521–4527.
6. (a) Fedij, V.; Lenoir, E. A.; Suto, M. J.; Zeller, J. R.; Wemple, J. Tetrahedron:
Asymmetry 1994, 5, 1131–1134; (b) Neuvonen, K.; Pihlaja, K. J. Chem. Soc.,
Perkin Trans. 2 1988, 4, 461–467; (c) Calerwood, D. J.; Davies, R. V.; Rafferty, P.;
Twigger, H. L.; Whelan, H. M. Tetrahedron Lett. 1997, 38, 1241–1244.
7. (a) Tomashenko, O.; Sokolov, V.; Tomashevskiy, A.; de Meijere, A. Synlett 2007,
652–654; (b) Tomashenko, O. A.; Sokolov, V. V.; Tomashevskii, A. A.; Potekhin,
A. A.; de Meijere, A. Russ. J. Org. Chem. 2007, 43, 1421–1426.
1H NMR (500 MHz, DMSO-d6)
d 9.28 (br, s, 3H), 7.80 (1H, d, J = 1.5 Hz),
7.60 (1H, dd, J = 5.0, 1.0 Hz), 7.28 (1H, dd, J = 3.5, 1.0 Hz), 7.09 (1H, dd,
J = 5.0, 3.5 Hz), 6.60 (1H, d, J = 3.5 Hz), 6.56 (1H, dd, J = 3.5, 1.5 Hz), 2.05 (s,
3H); 13C NMR (75 MHz, DMSO-d6)
d 153.0, 143.8, 143.6, 127.1, 126.7,
126.4, 110.8, 107.9, 54.4, 25.9; APCI MS m/z 177 [M+1ÀNH3]+; HPLC 95.9%
(AUC).