Diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones

Article abstract of DOI:10.1039/b511411j

A wide variety of tertiary carbinamines are synthesized in high yields via diastereoselective allylation and crotylation of in situ generated N-unsubstituted ketimines. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b511411j

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Diastereoselective allylation and crotylation of N-unsubstituted imines
derived from ketones{
Bhartesh Dhudshia, Jorge Tiburcio and Avinash N. Thadani*
Received (in Bloomington, IN, USA) 10th August 2005, Accepted 15th September 2005
First published as an Advance Article on the web 6th October 2005
DOI: 10.1039/b511411j
choice (Table 1). As anticipated, the more reactive allylboron
reagents, 5d and 5e,11 displayed the highest efficacy in terms
of isolated yields of homollylic amine 6a (entries 4 and 5). A
major issue of concern in all these reactions—chemoselectivity
of imine versus ketone addition—was addressed by analyzing
the organic extracts from the acid–base workup of 6a
(entries 4,5). It was determined that the corresponding homoallylic
alcohol of 6a was formed in minor amounts (¡5%). We
decided to continue our studies with allylboronic acid (5e) due
to its ease of preparation and the simple purification of the
resulting products.12
A wide variety of tertiary carbinamines are synthesized in high
yields via diastereoselective allylation and crotylation of in situ
generated N-unsubstituted ketimines.
Research into the addition of allyl organometallics to carbonyl
compounds and their derivatives continues to proceed unabated—
a consequence of the fact that the resulting homoallylic products
have proven to be valuable synthons.1 The majority of the
research, however, has focused on the addition of these organo-
metallics to aldehydes and, to a lesser extent, ketones.2 Until
recently, the expansion of the substrate scope to include imines and
their derivatives had received limited attention.3,4
A series of ketones were then reacted with reagent 5e in
methanolic ammonia (Table 2).{ Aliphatic (entries 1–4), electron
rich aromatic (entry 5), electron deficient aromatic (entries 6 and 7),
a,b-unsaturated (entry 8), cyclic (entries 9 and 10) and heterocyclic-
substituted (entries 11 and 12) ketones were successfully allylated
under the standard conditions. The resulting homoallylic amines
(6) were easily isolated in high yields through simple acid–base
extraction, and in all cases but one, did not require any further
purification. A variety of functional groups are tolerated in the
reaction sequence including the nitro (entry 7), cyano (entry 6),
As part of an alkaloid synthesis program, we required a tertiary
carbinamine (4) that we anticipated could be synthesized through
crotylation of an N-unsubstituted ketimine (2)—a previously
unknown reaction. Inspired by the elegant report of aminoallyla-
tion of aldehydes by Kobayashi and coworkers,5 we sought to
develop a robust methodology for the diastereoselective allylation
and crotylation of 2 (Scheme 1).
We surveyed a number of methods to synthesize and isolate the
requisite substrate (2),6 but concluded that a three-component
reaction of the ketone, excess ammonia and the allylorganometallic
(3) was the most efficient and effective protocol to generate the
desired homoallylic amines. We suggest that N-unsubstituted
ketimine (2) is formed in situ prior to its reaction with the
allylorganometallic,5,7–9 but our hypothesis needs further detailed
validation. Next, we investigated the addition of a series of
allyl organometallics to the in situ generated ketimine 2 (R1 5
4-BrC6H4, R2 5 Me). The allylboron class of reagents were
demonstrably superior in terms of reactivity and chemoselec-
tivity.10 A more detailed investigation of a range of allylboron
compounds was undertaken in order to ascertain the reagent of
Table 1 Addition of allyl boron reagents (5) to N-unsubstituted
ketimine derived from 1a
Entry
1
5
Yield of 6a (%)a
35
2
29
3
4
43
70b,c
Scheme 1 Diastereoselective allylation and crotylation of in situ
generated ketimines.
5
79b
Isolated yield after acid–base extraction. Analysis (1H NMR,
2.4,6-trimethylbenzene standard) of the organic phase from the acid–
base work-up revealed ¡5% of the corresponding homoallylic
a
b
Department of Chemistry and Biochemistry, University of Windsor,
Windsor, Ontario, Canada N9B 3P4. E-mail: athadani@uwindsor.ca;
Fax: 1 519 973 7098; Tel: 1 519 253 3000 ext. 3556
{ Electronic supplementary information (ESI) available: Experimental
details and full characterization data (1H, 13C NMR, IR, HRMS) for all
new compounds. See DOI: 10.1039/b511411j
c
alcohol. Isolated yield after acid–base extraction and preparative
TLC.
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Chem. Commun., 2005, 5551–5553 | 5551

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Table 2 Reaction of N-unsubstituted imines derived from ketones
with allylboronic acid (5d)a
Table 3 Reaction of N-unsubstituted ketimines with (E)- and
(Z)-crotylboronic acid (7a/b)a
Entry
Ketone
Yield/%b
Yield/%b d.r.
1
2
Et2CLO
(1b)
(1c)
73 (6b)
80 (6c)
Entry Crotyl reagent Product
1
7a
80 (4a)
97 : 3
3
4
(1d)
(1e)
78 (6d)
85 (6e)
2
7b
73 (4b)c 96 : 4
5
6
7
8
4–MeOC6H4C(O)CH2CH3
4–NCC6H4C(O)CH3
4–O2NC6H4C(O)CH3
(1f)
(1g)
(1h)
(1i)
72 (6f)
80 (6g)
87 (6h)
70 (6i)c
3
4
5
7a
7b
7a
7a
95 (4c)d 97 : 3
92 (4d)d 96 : 4
9
(1j)
78 (6j)
50 (4e)
97 : 3
10
(1k)
92 (6k)
6
88 (4f)e 60 : 40
11
12
(1l)
75 (6l)
a
Standard reaction conditions: ketone (0.5 mmol), ammonia (ca. 7N
in MeOH, 0.75 mL, ca. 10 equiv.) and crotylboronic acid (7a/b) (2M
b
in MeOH, 0.50 mL, 1.00 mmol) were stirred for 24 h at rt. Isolated
(1m)
80 (6m)
c
yield after acid–base extraction. Isolated yield after acid–base
d
extraction, and preparative TLC. Methyl benzoylformate was
employed as the starting ketone, and aminolysis of the ester was
observed. Methylpyruvate was employed as the starting ketone,
and aminolysis of the ester was observed.
e
a
Standard reaction conditions: A solution of the ketone (0.5 mmol),
ammonia (ca. 7N in MeOH, 0.75 mL, ca. 10 equiv.) and allylboronic
acid (5e) (2M in MeOH, 0.40 mL, 0.80 mmol) was stirred for 16 h
b
c
at rt. Isolated yield after acid–base extraction. Isolated yield after
acid–base extraction, and preparative TLC.
ð1Þ
unprotected hydroxy (entry 2) and amino groups (entry 12). We
were, however, unable to extend the substrate scope to include
ketones that are either sterically hindered (e.g. pinacolone) or
contain active methylene groups (e.g. ethyl acetoacetate) under the
current conditions.
ð2Þ
ð3Þ
We next sought to investigate the allylation of ketones
containing a pre-existing stereocenter. The substrates (1n–q) were
subject to the standard set of reaction and work-up conditions, the
results of which are shown in eqns (1)–(4). Good to excellent yields
of tertiary carbinamines 6n–q were obtained in all cases, while the
observed diastereoselectivities, as determined by 1H NMR, varied
from modest for the reaction of 4-tert-butylcyclohexanone,
norchamphor, and benzoin13 (eqns (1), (2) and (3), respectively)
to excellent for verbenone (eqn (4)).
13
5552 | Chem. Commun., 2005, 5551–5553
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Tetrahedron Lett., 2001, 42, 7525; (e) J. G. Kim, K. M. Waltz,
I. F. Garcia, D. Kwiatkowski and P. J. Walsh, J. Am. Chem. Soc., 2004,
126, 12580; (f) T. R. Wu, L. Shen and J. M. Chong, Org. Lett., 2004, 6,
2701; (g) Y.-C. Teo, J.-D. Goh and T.-P. Loh, Org. Lett., 2005, 7, 2743.
3 For selected recent examples of addition of allylorganometallics to
aldimine derivatives, see: (a) C. Bellucci, P. G. Cozzi and A. Umani-
Ronchi, Tetrahedron Lett., 1995, 36, 7289; (b) H. Nakamura,
K. Nakamura and Y. Yamamoto, J. Am. Chem. Soc., 1998, 120,
4242; (c) F. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell
and K. A. Jørgensen, J. Org. Chem., 1999, 64, 4844; (d) T. Gastner,
H. Ishitani, R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed.,
2001, 40, 1896; (e) H. C. Aspinall, J. S. Bissett, N. Greeves and
D. Levin, Tetrahedron Lett., 2002, 43, 323; (f) M. Sugiura, F. Robvieux
and S. Kobayashi, Synlett., 2003, 1749; (g) R. A. Fernandes and
Y. Yamamoto, J. Org. Chem., 2004, 69, 735; (h) S.-W. Li and
R. A. Batey, Chem. Commun., 2004, 1382; (i) I. Shibata, K. Nose,
K. Sakamoto, M. Yasuda and A. Baba, J. Org. Chem., 2004, 69, 2185;
(j) C. Ogawa, M. Sugiura and S. Kobayashi, Angew. Chem., Int. Ed.,
2004, 43, 6491.
4 For selected recent examples of addition of allylorganometallics to
ketimine derivatives, see: (a) C. Ogawa, M. Sugiura and S. Kobayashi,
J. Org. Chem., 2002, 67, 5359; (b) S. Yamasaki, K. Fujii, R. Wada,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536; (c)
R. Berger, K. Duff and J. L. Leighton, J. Am. Chem. Soc., 2004, 126,
5686; (d) H. Ding and G. K. Friestad, Synthesis, 2004, 2216.
5 (a) M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004,
126, 7182; (b) S. Kobayashi, K. Hirano and M. Sugiura, Chem.
Commun., 2005, 104.
ð4Þ
Finally, crotylation of a select number of ketones was examined
under a slightly modified set of conditions (2.0 equiv. of 5e,
10 equiv. of NH3, rt, 24 h) (Table 3). Excellent diastereoselectivities
were obtained with acetophenone derivatives (entries 1–5). The
anti diastereomer (4a/c) was formed when (E)-crotylboronic acid
(7a) was employed as the reagent, while (Z)-crotylboronic acid (7b)
afforded the syn diastereomer (4b/d). The stereochemistry of the
crotylated products 4 were assigned based upon the reaction of 7a
with acetophenone (entry 5) which afforded the previously known
anti diastereomer 4e in moderate yield and excellent diastereo-
selectivity (d.r. 5 97:3).4a Crotylation of methylpyruvate (entry 6),
on the other hand, was not diastereoselective likely due to the
similar steric sizes of the methyl and methylformate groups. The
results from entries 3, 4 and 6 also constitute a convenient route to
a-allylated amino acid derivatives.14
6 (a) P. L. Pickard and T. L. Tolbert, J. Org. Chem., 1961, 26, 4886; (b)
D. R. Boyd, K. M. McCombe and N. D. Sharma, Tetrahedron Lett.,
1982, 23, 2907; (c) A. J. Bailey and B. R. James, Chem. Commun., 1996,
2343; (d) Y. Bergman, P. Perlmutter and N. Thienthong, Green Chem.,
2004, 6, 539; (e) R. W. Layer, Chem. Rev., 1963, 63, 489.
7 (a) B. Davis, J. Labelled Compd. Radiopharm., 1987, 24, 1221; (b)
N. Haider, G. Heinisch, I. Kurzmann-Rauscher and M. Wolf, Liebigs
Ann. Chem., 1985, 167.
8 For example, when ketone 1n is dissolved in ammonia-saturated
CD3OD, the 13C NMR signal changes from d 215.37 (the ketone
chemical shift) to d 187.25 (what we presume to be the chemical shift of
the N-unsubstituted imine 2). We are currently examining the
mechanism of the three-component reaction in greater detail.
9 It has been previously established through theoretical studies that
compound 2 (R1 5 Ph, R2 5 Me) preferentially exists in the ketimine
form as opposed to the enamine tautomer: G. Erker, M. Riedel,
S. Koch, T. Jo¨dicke and E.-U. Wu¨rthwein, J. Org. Chem., 1995, 60,
5284.
In summary, an easily executable three component methodology
for allylation of N-unsubstituted imines derived from a diverse
range of ketones has been presented. The resulting homoallylic
amines were isolated in good to excellent yields through simple
acid–base extraction. More importantly, the crotylation of
N-unsubstituted ketimines was also shown to be highly diastereo-
selective. We are currently striving to ameliorate the described
methodology by expanding the substrate scope and developing
enantioselective variants.
This work was supported by NSERC of Canada, ORDCF and
the University of Windsor.
References
{ General experimental procedure for allylation of N-unsubstituted ketimines:
To solution of the ketone (0.5 mmol) in ammonia (ca. 7N in MeOH,
0.75 mmol, ca. 10 equiv.), previously stirred for 15 min at rt, was added a
freshly prepared solution of allylboronic acid (5e) (2M in MeOH, 0.4 mL,
0.80 mmol) dropwise over 5 min. The reaction mixture was subsequently
stirred for 16 h at rt. The volatiles were removed in vacuo and the residue
redissolved in Et2O (15 mL). Aqueous HCl (1N, 15 mL) was next added
dropwise. The biphasic mixture was vigorously shaken, and the layers
separated. The acidic aqueous layer was washed with Et2O (3 6 15 mL),
and made basic by the addition of solid NaOH (ca. 5 g). The aqueous layer
was then extracted with CH2Cl2 (3 6 15 mL). The combined organic
extracts were dried (NaSO4), filtered and concentrated in vacuo to afford
the desired tertiary carbamine 6.
10 For reviews on allyl/crotyl boron reagents, see: (a) W. R. Roush,
in Houben-Weyl, Stereoselective Synthesis, ed. G. Helmchen,
R. W. Hoffmann, J. Mulzer and E. Schaumann, Georg Thieme
Verlag, Stuttgart, 1995, vol. E21b, pp. 1410–1486; (b) D. S. Matteson in
Stereodirected Synthesis with Organoboranes, Springer-Verlag, Berlin,
1995.
11 H. C. Brown, U. S. Racherla and P. J. Pellechia, J. Org. Chem., 1990,
55, 1868.
12 Pending further mechanistic studies, the possibility remains that
the active allylating species is in situ generated B-allyldimethoxyborane
and/or B-allyldiaminoborane.
13 The structure of 6p was confirmed by X-ray crystallography. Crystal
data, 6p: C17H19NO, M 5 253.33, monoclinic, space group P21/n,
˚
˚
˚
a 5 12.143(2) A, b 5 6.261(1) A, c 5 18.975(4) A, b 5 97.148(2)u, V 5
1431.4(5) A , Z 5 4, T 5 173(2) K, m(Mo Ka) 5 0.073 mm21, 2519
3
˚
1 For reviews, see: (a) S. E. Denmark and N. G. Almstead in Modern
Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10;
(b) Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; (c)
W. R. Roush in Comprehensive Organic Synthesis, ed. B. M. Trost,
I. Fleming and C. H. Heathcock, Pergamon, Oxford, 2nd edn, 1991,
vol. 2, pp. 1–53.
2 For selected recent examples of allylation of ketones, see: (a) L. F. Tietze,
K. Schiemann, C. Wegner and C. Wulff, Chem.–Eur. J., 1998, 4, 1862;
(b) S. Casolari, D. D’Addario and E. Tagliavini, Org. Lett., 1999, 1,
1061; (c) R. Hamasaki, Y. Chounan, H. Horino and Y. Yamamoto,
Tetrahedron Lett., 2000, 41, 9883; (d) R. M. Kamble and V. K. Singh,
independent reflections (Rint 5 0.0424), R1 5 0.0433, wR1 5 0.0931,
(1853 reflections, I . 2sI), R2 5 0.0661, wR2 5 0.1031, (all data).
Goodness-of-fit (F2) 5 1.011. Data were collected on a Bruker APEX
CCD instrument and solutions performed using the SHELXTL 5.03
Program Library, Siemens Analytical Instrument Division, Madison,
WI, USA, 1997. CCDC 283664. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b511411j.
14 Aminolysis of the ester functionality present in the starting ketones
[methyl benzoylformate (Table 3, entries 3,4); methylpyruvate (Table 3,
entry 6)] was observed in the final products (4c–4e respectively).
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Chem. Commun., 2005, 5551–5553 | 5553