Substituent effects on the amination of racemic allyl carbonates using commercially available chiral rhodium catalysts

Article abstract of DOI:10.1016/j.tetlet.2013.08.032

In the presence of commercially available chiral rhodium catalysts, a competitive benzy lamination of racemic allyl carbonates, substituted with p-X-Ph groups, shows that the reaction proceeds faster with substituents (X) that are more electron-withdrawing. Mechanistic implications of these results are discussed.

Full text of DOI:10.1016/j.tetlet.2013.08.032

Tetrahedron Letters 54 (2013) 5795–5798
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Substituent effects on the amination of racemic allyl carbonates
using commercially available chiral rhodium catalysts
a
a
b
Timothy Atallah a, Ronald L. Blankespoor a, , Philip Homan , Chase Hulderman , Brian M. Samas ,
⇑
Kurt Van Allsburg a, Derek C. Vrieze c
a Department of Chemistry and Biochemistry, Calvin College, 3201 Burton St. SE, Grand Rapids, MI 49546, USA
b Pfizer Global R.&D., Eastern Point Road, Groton, CT 06340, USA
c Vertex Pharmaceuticals Inc., 130 Waverly St., Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of commercially available chiral rhodium catalysts, a competitive benzylamination of
racemic allyl carbonates, substituted with p-X-Ph groups, shows that the reaction proceeds faster with
substituents (X) that are more electron-withdrawing. Mechanistic implications of these results are
discussed.
Received 10 June 2013
Revised 9 August 2013
Accepted 10 August 2013
Available online 24 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium-catalyzed
Allylic benzylamination
Hammett plot
Competitive substitution
Transition-metal-catalyzed asymmetric allylic substitution
reactions continue to receive considerable attention with com-
plexes of palladium,1a–c iridium,1d and rhodium2 serving as impor-
tant tools in synthesis. Madrahimov and Hartwig recently
conducted mechanistic studies of iridium-catalyzed allylic substi-
tution reactions that give products with overall retention of config-
uration as a result of two steps that occur with inversion of
configuration.1d They concluded that factors controlling the enanti-
oselectivity of these reactions are not the same as those of other
metal ions such as palladium.
In the presence of Rh(I) catalysts, allylic substitution reactions
often proceed with high regioselectivity.3 Thus, substrates with
secondary allylic leaving groups yield mostly branched substitu-
tion products whereas those with primary allylic leaving groups
generate linear substitution products in high yields. A variety of
compounds containing secondary allylic carbonates have been
alkylated,4 aminated,5 and etherified4h,6a,b in excellent yields and
high regioselectivities using rhodium catalysts. Allylic acetates
have also been substituted with malonates using chiral6c and achi-
ral6d rhodium catalysts.
branched products 2 with retention of stereochemical configura-
tion in high yields
LG
Nu
Nu
Nu
Rh(I)
Nu
ð1Þ
+
+
R
R
R
R
ent-2
linear
1
2
relative to enantiomer ent-2 and linear structural isomers
4g–i,5a–d,6b,7
(Eq. 1).
Interestingly, when Vrieze et al.5d reacted one
equivalent of the racemic substrate rac-1 (R = CH2Ph; LG = OCO2CH3)
with one-half equivalent of PhCH2NH2 in the presence of the com-
mercially available chiral rhodium catalyst, (S,S,R,R)-Tangphos-Rh
(A in Fig. 1), they obtained a 36% yield (50% is theoretical) of unre-
acted ent-1 in 99% ee and a 50% yield of 2 (R = CH2Ph; Nu = NHCH2
Ph) in 99% ee. These results demonstrate a kinetic resolution of
rac-1 in which ent-1 reacts slower than 1 due to a ‘mismatch’ with
H
H
H
P
P
+
P
P
P
P
The stereochemistry of rhodium-catalyzed allylic substitution
reactions has also been examined. Chiral substrates 1 generally re-
act with nucleophiles in the presence of an achiral catalyst to give
H
H
Rh
H
(H3C)3C
(H3C)3C
C(CH3)3
(H3C)3C
C(CH3)3
Rh +
C(CH3)3
Rh
+
(S,S,R,R)-Tangphos-Rh
(A)
(R,R,S,S)-Duanphos-Rh
(B)
(S,S,R,R)-Duanphos-Rh
⇑
(ent-B)
Corresponding author. Tel.: +1 616 526 6174.
E-mail addresses: blan@calvin.edu (R.L. Blankespoor), Brian.Samas@pfizer.com
ꢀ
(B.M. Samas), derek_vrieze@vrtx.com (D.C. Vrieze).
Figure 1. Rh(I) catalysts commercially available as BF4 salts.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.032

5796
T. Atallah et al. / Tetrahedron Letters 54 (2013) 5795–5798
chiral catalyst A. On the other hand, 1 is ‘matched’ with A and re-
acts faster with PhCH2NH2 giving 2 almost quantitatively with
retention of configuration.5d
identical as shown in Figure 2a inset for an equimolar solution of
the five carbonates before reaction. The NMR spectrum of the same
vinyl carbon after reaction of an equimolar mixture of rac-3 with
one-half equivalent of benzylamine (Fig. 2b) shows the presence
of both unreacted carbonates and product amines 4. As expected,
the peaks for 4 are at lower chemical shifts. It is clear from the inte-
grations of these signals that the allylic substitution reaction goes
faster as the substituents become more electron-withdrawing. Not
surprising, the Hammett type plot in Figure 3 shows a good corre-
lation between the negative logarithms of the unreacted carbonate
Evans and co-workers have proposed a
or distorted -allyl intermediate to account for the high regioselec-
r,p
-coordinated (enyl)8
p
tivity and stereospecificity of rhodium-catalyzed allylic substitu-
tion reactions (Scheme 1).4b,h This mechanism explains the high
yields of 2, provided that the enyl intermediate undergoes a rela-
tively slow
p–r–p rearrangement or metal–metal displacement.
In this study, we aim to better understand this mechanism by
determining substituent effects on the benzylamination of allyl
carbonates using Rh(I) chiral catalysts.
integrals in Figure 2b and
r with q = +0.36. If the reaction rate de-
pends upon the concentration of carbonate, which is likely, these
integrals underestimate the relative reactivities of the carbonates
because the more reactive a carbonate, the faster its concentration
would decrease with time.
Carbonates rac-3 with electron-donating and electron-with-
drawing substituents9 were reacted competitively with benzyl-
11
amine10 in the presence of catalyst A (Eq. 2).
To a mixture
containing 0.200 mmol of each of the five carbonates rac-3a–e
(i.e., 1.00 mmol total) were added 0.500 mmol of benzylamine
and a THF solution of A (Eq. 2). Given the 2:1 mole ratio of rac-3
to benzylamine, the carbonates are forced to compete for benzyl-
amine, the limiting reagent. The
We next investigated the stereochemistry of the reaction of the
five carbonates of rac-3 separately with one-half equivalent of
benzylamine in the presence of rhodium catalysts. In Table 1 are
the % ee’s of the recovered carbonates when catalyst A is used,
which range in value from 42 to 49% and have the R absolute con-
figuration based upon their optical rotations. Stereochemical data
are also given in Table 1 for amines 4 formed in this reaction using
a; R = Ph
b; R = p-CH3Ph
OCO2CH3
NHCH2Ph
Catalyst A
+
PhCH2NH2
limiting
R
c
: R = p-ClPh
ð2Þ
R
(0.6 mol %)
rac-3
(1.00 mmol total)
4
d
: R = p-CF3Ph
(0.50 mmol)
e
: R = p-NO2Ph
extent of reaction was then determined from the crude reaction
mixture using C-13 NMR. Although the integrals of carbon peaks
are normally unreliable for making quantitative comparisons, the
integrals of one of the vinyl carbons in carbonates rac-3 are almost
LG
Rh
LG
Rh
Nu
LG
Nu
Nu
Rh(I)
Rh(I)
R
R
R
or
π−σ−π
R
R
R
R
2
distorted π-allyl
1
enyl
LG
Rh
LG
Rh
Nu
LG
or
R
distorted π-allyl
ent-2
enyl
ent-1
Figure 3. A Hammett type plot using the integrals of one of the vinyl carbons in the
Scheme 1. Proposed mechanism for the transformation of 1 to 2 (and ent-1 to ent-
2) regioselectively and with retention of configuration.4j
carbonate NMR spectra in Figure 2b. [ꢀlog (integral) = (0.36 0.03)
r ꢀ (0.30
0.01); R2 = 0.98].
(a)
(b)
Figure 2. (a) C-13 NMR spectrum of an equimolar mixture of rac-3a–e with an inset of the region where one of the vinyl carbons in the five carbonates gives peaks. (b) Partial
C-13 NMR spectrum of products from the reaction in Eq. 2 which is an expansion of the inset in (a) along with the peaks from the same carbon in amines 4 at slightly lower
chemical shifts.

T. Atallah et al. / Tetrahedron Letters 54 (2013) 5795–5798
5797
Table 1
Recovered carbonates and amines from the reaction of rac-3 with one-half equivalent of PhCH2NH2 using rhodium catalystsa
Rac-3
Catalyst
% ee of Recovered carbonateb
Amine
% Yield of aminec
% ee of Amined
89e
[a]
a
b
c
d
e
a
b
c
A
A
A
A
A
B
B
B
49
48
44
48
42
4a
4b
4c
4d
4e
4a
4b
4c
39
43
40
32
41
f
—
96
95g
f
—
+11.4
+8.4
+7.0
d
e
a
b
c
B
B
4d
4e
+8.8
+16.8
ꢀ11.9
ꢀ8.9
ꢀ7.8
ꢀ9.8
ꢀ17.7
ent-B
ent-B
ent-B
ent-B
ent-B
ent-4a
ent-4b
ent-4c
ent-4d
ent-4e
d
e
a
ent-A is not available commercially. Work in our laboratory and the Pfizer laboratory5d has shown that the two catalysts in Figure 1 give the same results within
experimental error.
b
From GC analysis of corresponding alcohols using a chiral column; major enantiomer has the R absolute configuration.
c
Isolated yield of 50% is theoretical.
d
Amines 4 have the S absolute configuration,12 which was confirmed by X-ray analysis of the (S)-(+)-mandelic acid salts of 4b and 4c.
e
Ref.5d
f
Poorly resolved on chiral HPLC columns.
From HPLC analysis of the Marfey derivatives of 4d and ent-4d.
g
NHCH2Ph
OCO2CH3
of configuration is the result of two inversions as has been previ-
ously shown for rhodium4b- and iridium-catalyzed allylic substitu-
tion reactions.1d A more detailed mechanism consistent with these
observations is shown in Scheme 3.
NHCH2Ph
B
ent-B
Ph
Ph
+
Ph
4a
[α] = +11.4o
ent-4a
PhCH2NH2
[α] = -11.9o
The pathway for the conversion of carbonates 3 to amines 4
proceeds through a matched enyl complex with catalyst A or B,
which makes this pathway faster than the one for the ent-3 to
ent-4 conversion in which a mismatched complex forms. The high
yield of 4 from the reaction of rac-3 with one-half equivalent of
benzylamine is the result then of a kinetic resolution which re-
quires that the reaction of the matched enyl complex with benzyl-
amine be faster than the rate of isomerization of the two enyl
Scheme 2. Reaction of rac-3a with one-half equivalent of PhCH2NH2 using catalyst
B and its enantiomer, ent-B.12
catalyst A. High % ee’s are obtained from several of these amines,
and crystal structures of 4a,5d 4b, and 4c establish the S absolute
configuration. Reaction of the five carbonates of rac-3 separately
with one-half equivalent of benzylamine was also carried out using
catalyst B and its enantiomer, (S,S,R,R)-Duanphos-Rh (catalyst ent-
B),12 as shown in Scheme 2 for rac-3a. As expected, the specific
rotation of +11.4° for 4a13 is almost identical to the +11.2° rotation
that is obtained when this amine is made using catalyst A. The spe-
cific rotations of 4a–e and ent-4a–e in Table 1 show that carbon-
ates rac-3a–e react with one-half equivalent of benzylamine in
the presence of these catalysts to generate amines with retention
of configuration. The data in Table 1, along with the linear Ham-
mett plot in Figure 3, are strong evidence that a common mecha-
nism is operative in the competitive reaction in Eq. 2.
complexes via a
pꢀ
r p
process or metal–metal displacement.4c
ꢀ
The matched enyl complex is presumably formed in two steps
from 3. Which step occurs first is open to speculation, but it seems
unlikely that they would occur simultaneously. Given the small,
positive
q value of +0.36, either of the two inversion steps in the
pathway from 3 to 4 could be rate-determining. Backside displace-
ment at the benzylic carbon in 3 via an electron pair on Rh or N
would be expected to increase the electron density in the transi-
tion step resulting in a positive
q value. Theoretical work by Stre-
itwieser et al., led them to conclude that electron-withdrawing
groups lower the barriers of ionic SN2 reactions.14
The observation that the reaction in Eq. 2 goes faster as the sub-
stituents become more electron-withdrawing gives more clarity to
the mechanism in Scheme 1. The small, positive slope of +0.36 for
The mechanism in Scheme 3 also accounts for the relatively low
ee’s for the recovered carbonates in Table 1. If the reaction of the
mismatched enyl complex with benzylamine is slow enough to
q
in the Hammett plot is consistent with a rate-determining step
make the
p
ꢀ
r
ꢀ
p rearrangement competitive, some ent-3 would
(RDS) which has a transition state that is electron rich relative to
its reactant(s). It is reasonable to assume that the overall retention
be converted to 3 resulting in a low ee for the carbonates in the
PhH2C
+NH2
PhH2C
NH
Rh(I)
+
LG
Rh
NHCH2Ph
LGRh(I)
Rh(I)
PhCH2NH2
inv.
Rh(I)
-Rh(I)
-Rh(I)
R
R
R
R
R
R
R
+
inv.
+
+
LG-
3
LG-
4
CO2/CH3OH
"matched" enyl complex
LG = OCO2CH3
π−σ−π
Rh(I) = catalyst A or B
PhH2C
PhH2C
+
LG
Rh
NHCH2Ph
+NH
NH
+
2 Rh(I)
Rh(I)
Rh(I)
LG
PhCH2NH2
inv.
Rh(I)
R
R
R
R
+
R
+
inv.
LG-
LG-
ent-3
ent-4
CO2/CH3OH
"mismatched" enyl complex
Scheme 3. Proposed mechanism for the reaction of rac-3 with benzylamine using A or B as the Rh(I) catalyst.

5798
T. Atallah et al. / Tetrahedron Letters 54 (2013) 5795–5798
Okada, A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003, 5, 1713–1715; (d)
Takeuchi, R.; Kitamura, N. New J. Chem. 1998, 659–660.
7. (a) Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158–7159; (b) Evans,
P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D. Angew. Chem., Int. Ed. 2004, 46,
4788–4791; (c) Schmidt, B.; Staude, L. J. Org. Chem. 2011, 76, 2220–2226.
reaction mixture. In fact, rearrangement of ent-3c to 3c does occur
under the conditions of the reaction in Eq. 2. When rac-3c was
combined with catalyst B in the absence of benzylamine, the per-
centage of carbonate 3c, the enantiomer with the S configuration,
increased from 50 to 95. As expected, doing the same experiment
with catalyst ent-B, resulted in a carbonate mixture with a high
percentage of ent-3c, the carbonate enantiomer with the R config-
8. (a) Enyl complexes are by definition those which contain discreet
r– and p–
metal carbon interactions within (b) Sharp, P. R. In
a
single ligand.6b
;
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon Press: New York, 1995; p 272. Chapter 2.
9. General procedure for preparing carbonates 3:19 To p-X-PhCH(CH@CH2)OH
containing 5–10% p-X-PhCH2OH1 (20.0 mmol) and pyridine (30.0 mmol) in
20 mL CH2Cl2 at ca. ꢀ10° was added methyl chloroformate (22.0 mmol)
dropwise over 30–40 min. The mixture was allowed to warm slowly to room
uration. Additional evidence of competition between the
p
ꢀ
r p
ꢀ
rearrangement of the mismatched enyl complex and its reaction
with benzylamine comes from the reaction of one equivalent of
3a with one equivalent of benzylamine using catalyst A, which
gives 4 in 88% yield with an ee of 89%.5d
temperature. After ca. 24 h, the reaction mixture was transferred to
a
separatory funnel containing 50 mL ether and 20 mL sat NaCl. The aqueous
layer was separated and washed with 25 mL ether. The ether layers were
combined and dried over CaCl2. The bulk of the ether was removed under
In conclusion, we have shown that the reaction of aryl-substi-
tuted allylic carbonates with benzylamine in the presence Rh(I)
catalysts goes faster as the substituent in the aryl group becomes
more electron-withdrawing. A mechanism in which a matched
metal substrate complex (i.e., enyl complex) reacts with PhCH2NH2
is consistent with these results.
reduced pressure in
a rotary evaporator leaving a liquid that was
chromatographed on silica gel and eluted with 4–5% ethyl acetate in hexanes
(3a–d) or with 45:55 CH2Cl2–hexanes (3e). The desired carbonate was eluted
first closely followed by the carbonate of the corresponding benzyl alcohol.
Overall yields of p-X-PhCH(CH@CH2)OCO2CH3 from p-X-PhCHO were in the
range of 28–35%.
10. General procedure for preparing amines 4:5d In a glove box under nitrogen was
combined 1.00 mmol 3, 5 mol % of the catalyst, [Rh(1S,1S0,2R,2R0-
tangphos)(COD)]BF4, and 2 mL of deoxygenated THF. After stirring for several
minutes, 54 mg of benzylamine (0.52 mmol) was added and the mixture was
stirred for at least 16 h in the glove box. The reaction mixture was removed
from the glove box and dissolved in 25 mL ether. The amine product 4 was
extracted using 2.0 M HCl (3 ꢁ 20 mL). The aqueous extracts of the amine salt
were combined, washed with ether (2 ꢁ 5 mL), and made basic with the
addition of 7.0 mL of 2.5 M NaOH. The cloudy mixture containing 4 was
extracted with ether (3 ꢁ 5 mL). The ether extracts were combined, washed,
with sat. NaCl, and dried over CaCl2. Removal of the ether under reduced
pressure in a rotary evaporator left a viscous residue of 4 which could be
purified by chromatography on silica gel and elution with 4–10% ethyl acetate
in hexanes for 4a–d and 2:3 CH2Cl2–hexanes for 4e.
Acknowledgments
R.L.B. acknowledges the support of the Brummel Chair at Calvin
College and a grant from Pfizer Global Research and Development.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
032.
11. Procedure for the competitive benzylamination of carbonates 3: To a mixture of
0.20 mmol each of 3a, 3b, 3c, 3d, and 3e in a glove box under nitrogen was
added 2 mL of deoxygenated THF, 5 mol % of the catalyst, [Rh(1S,1S0,2R,2R0-
tangphos)(COD)]BF4, and 0.50 mmol of PhCH2NH2. After stirring overnight, the
reaction mixture was removed from the glove box and the bulk of the THF was
removed by evaporation. The residue was combined with 1 mL CDCl3 and
filtered to remove a small amount of solid, presumably, metal salts. The NMR
spectrum in Figure 3 was recorded.
12. The enantiomer of catalyst A was not available commercially.
13. The directions of rotation for 4a and ent-4a (i.e., positive and negative,
respectively) are known in the literature: Ohmura, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 15164–15165.
14. Streitwieser, A.; Jayasree, E. G.; Leung, S. S.-H.; Choy, G. S.-C. J. Org. Chem. 2005,
70, 8486–8491.
15. (a) Fisher, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126,
1628–1629; (b) Shekhar, S.; Tranto, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 8642–8643; (c) Miyabe, H.; Yoshida, K.; Yamauchi, M.;
Takemoto, Y. J. Org. Chem. 2005, 70, 2148–2153.
References and notes
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17. Procedure for derivatizing amine 4d with Marfey’s reagent (FDAA):19 A solution of
2.7 mg
(CH3CH2CH2)3 N, and 3.0 mg of rac-4d (or 4d) in 100 mg DMSO was heated
at 70° for 48 h. To the reaction mixture was added 40 L of 2.0 M HCl followed
FDAA
(1-fluoro-2-4-dinitrophenyl-5-
L-alanine
amide),
10 lL
l
by 8 mL ether. The water layer was separated and washed with 8 mL ether. The
ether extracts were combined, washed with 6 mL water and 6 mL sat. NaCl,
and dried over CaCl2. After the ether was evaporated, the residue was dissolved
in 45:55 heptane–IPA for HPLC analysis.
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